Table of contents : 

General toxicology Chemical elements hydrogen metabolic acidosis respiratory acidosis metabolic alkalosis respiratory alkalosis oxygen sodium hyponatremia  hypernatremia magnesium phosphorus chlorine potassium hypokalemia hyperkalemia calcium hypocalcemia hypercalcemia iron cuprum zinc arsenic iodine mercury Endogenous metabolites ketones lactic acid creatinine uric acid urea homocysteine catecholamines dyslipidemias triglycerides cholesterol glucose bilirubin

Naturally occurring toxins (taxonomic classification)  Bacteria (bacterial toxins) Eukarya (eukaryal toxins) Fungi (fungal toxins / mycotoxins) Viridiplantae (vegetal or botanical toxins / phytotoxins) Metazoa toxins Alveolata toxins Annelida toxins Bryozoa toxins Cnidaria toxins Porifera toxins Mollusca toxins Arthropoda toxins Chordata toxins Amphibia toxins Archosauria toxins Lepidosauria toxins Mammalia toxins Synthetic chemicals (classification according to use) synthetic polluttants air polluttants liquid solvents and vapors synthetic pesticides algaecides fungicides herbicides molluscicides insecticides ectoparasiticides piscicides rodenticides synthetic drugs of abuse (classification according to chemical structure) chemical weapons  Classification according to induced damage : carcinogens  endocrine disrupters Occupational toxicology Web resources

Chemical elements (below are listed alterations of plasma concentrations; see also alterations of urinary concentrations). When perfusion pressure falls, the homeostatic mechanisms of the human body tend to preserve euvolemia rather than concentration of solutes

• hydrogen (₁H)
• H⁺ ion

Algorithm : acidemia or alkalemia ? respiratory (acute or chonic ?) or metabolic disorder ? if metabolic acidosis, increased or normal anion gap ? if metabolic acidosis with increased anion gap, other acidoses ? if metabolic disorder, is respiratory apparatus adequately compensating it ?

• simple alterations
• alkalosis : pH > 7.45 in the blood (alkalemia) and most body tissues

Pathogenesis : decreased cerebral blood flow (CBF), less pronounced effect on other organs
Symptoms & signs : mental confusion, obtundation, delirium, seizures, muscular hyperexcitability and tetanus, decreased cardiovascular electrical stability, VF, increased sensitivity to digitalis glucosides, secondary systemic arterial hypertension, depression of inotropism, hypoventilation and decreased strength of respiratory muscles
Laboratory examinations : hypokalemia, hypocalcemia, hypophosphatemia, increased glycolysis, right shift in hemoglobin dissociation curve
• respiratory alkalosis : P_CO2 < 36 mmHg in the blood (hypocapnia / hypocarbia) and most body tissues

Aetiology : hyperventilation
• hypoxemia => stimulation of carotid and aortic chemoreceptors => stimulation of respiratory centres
• lung diseases (APE, PTE, fibrosis, pneumonia, etc.)
• CHF
• hypotension, severe anemia
• low atmospheric P_O2
• lung diseases => stimulation of juxtacapillary and paraepithelial receptors => vagus nerve => stimulation of respiratory centres
• direct stimulation of respiratory centres : high environmental P_CO2, hepatic failure, surgery, Gram negative sepsis, salicylate intoxication, hepatic encephalopathy, pulmonary embolism, fever, mechanical ventilation, anxiety, panic attack, less commonly in tetanus due to hypocalcemia or hypophosphatemia due to intracellular shift, post-acidemic alkalosis, progesterone in pregnancy and luteal stage of menstrual cycle
• compensated respiratory alkalosis : the pH of the blood has been returned toward normal through retention of acid or excretion of base by renal mechanisms
Predicted compensatory variations :
• acute : decrease of [HCO₃^-] (mmol/L) = - 0.2 ^. decrease of P_{CO2, art} (mmHg)
• chronic : decrease [HCO₃^-] (mmol/L) = - 0.4 ^. decrease of P_{CO2, art} (mmHg)
Laboratory examinations : hyponatremia, mild hypokalemia, hypophosphatemia, decreased free calcium (increased protein-bound calcium), hyperchloremia
Symptoms & signs : decreased cerebral blood flow => vertigo, mental confusion and convulsions; in anaesthetised or mechanically ventilated patients, cardiac output and arterial blood pressure fall due to effects of anaesthesia or positive pressure ventilation on heart rate, peripheral resistances and venous return. Bohr effect impairs O₂ cession from hemoglobin => cardiac arrhythmia in patients with myocardium ischemias; paraesthesias, perioral unsensitivity, chest constriction or pain, respiratory failure, tetany (rare); hyperventilation syndrome : a complex of symptoms that accompany hypocapnia caused by hyperventilation, including palpitations, shortness of breath, lightheadedness, profuse perspiration, and tingling sensations in the fingertips, face, or toes; prolonged overbreathing may result in vasomotor collapse and loss of consciousness. Hyperventilation unrecognized by the patient is a common cause of the subjective somatic symptoms associated with chronic anxiety or panic attacks.
Therapy :
• aetiological
• correction of hypophosphatemia
• psychological support or mild sedation
• breathe in an air bag (CO₂ rebreathing)
• b-AR blockers to treat hyperadrenergic symptoms
• metabolic alkalosis : [HCO₃^-] > 27 mEq/L in the blood (hyperbicarbonatemia) and most body tissues

Aetiology :
• exogenous HCO₃^- loads
• antiacids associated with ion exchange resins (aluminum hydroxide and sulfonated sodium polystirene)
• acute p.o. or i.v. HCO₃^-
• acetate (solutions for parenteral hyperfeeding)
• citrate (transfusions)
• milk-alkali syndrome
• hypovolemia, normotension, and hyperreninemic hyperaldosteronism
• loss of noncarbonic, or fixed (nonvolatile) acids :
• loss of Na⁺Cl^- and H⁺Cl^- due to prolonged gastric vomiting (also hypochloremia, hyponatremia, and hypokalemia)
• gastric aspiration
• congenital chloridorrhea
• villous adenoma
• administration of polystirene sodium sulfonate together with aluminum hydroxide
• retention of base
• diuretics inducing chloruresis without bicarbonaturia
• thiazide diuretics
• loop diuretics
• edema
• rebound after acute therapy of acidoses (worsened by acidosis-induced hypokalemia, renal new HCO₃^- production, and alkali therapy)
• post-hypercapnia
• post-lactic acidosis or ketoacidosis (lactate and ketones are metabolized to equivalent quantities of HCO₃^-)
• hypercalcemia or hypoparathyroidism
• nonreabsorbable anions (penicillin, carbenicillin) increase transepithelial voltage in distal renal tubule => increased potassium secretion
• hypokalemia
• juxtaglomerular cell hyperplasia / Bartter's syndrome
• hyperaldosteronism (hypervolemia, secondary systemic arterial hypertension)
• Liddle syndrome (hypervolemia, secondary systemic arterial hypertension, hyporeninemic hypoaldosteronism)
• compensated respiratory alkalosis : the pH of the blood has been returned toward normal through retention of acid or excretion of base by renal mechanisms
Pathogenesis : renal HCO₃^- retention
Predicted compensatory variation : increase in P_{CO2, art} (mmHg) =
• + 0.75 ^. increase [HCO₃^-]_plasma (mmol/L)
• + 0.6 ^. increase [HCO₃^-]_plasma (mmol/L)
... or P_{CO2, art} (mmHg) = [HCO₃^-]_plasma (mmol/L) + 15
Symptoms & signs : similar to hypocalcemia
Laboratory examinations : hypochloremia, hypophosphatemia and hypokalemia
Therapy :
• if renal function is preserved, pH < 7.5 and [HCO₃^-]_plasma < 39 mmol/L => hydratation and potassium correct alteration within 48 hrs
• if pH > 7.5 and [HCO₃^-]_plasma > 39 mmol/L => CAI (acetazolamide 200-400 mg i.v. every 4-6 hrs blocks renal HCO₃^- production)
• if renal failure : hemodialysis vs.dialyzed with low [HCO₃^-] and high [Cl^-]
• in neurological emergencies, central venous infusion of diluted HCl
Compensation : proximal renal tubule reabsorbs the standard quote of HCO₃^- (=> basic urine with pH = 8), while the distal tubule secretes H⁺ into plasma and HCO₃^- into tubule by "inverting" membrane domains (creating a pancreas-like arrangements but with Na⁺ channels replaced by K⁺ channels), without involving Na⁺ as the position of Na⁺/K⁺ ATPase is not inverted. Hypokalemia is a side effect.
• acidosis : pH < 7.35 in the blood (acidemia) and most body tissues
• compensated acidosis : pH = 7.38-7.40
• uncompensated acidosis : pH < 7.38
Pathogenesis :
• cellular effects : protein change, shape and function, increased protein breakdown, decreased energy metabolism (glycolysis and oxidative phosphorylation), decreased Ca²⁺ binding, change in dissociation rate of the weak acids and bases; decreased receptor number and function (insulin and catecholamines resistance)
• functional effects : vagal hypertone, reduced myocardial contractility, arteriolar dilatation, venoconstriction and centralization of blood volume, increased pulmonary vascular resistance; sensitization to reentrant arrhythmias and decreased threshold of VF (pH < 7.1 = cardiac arrest); decreased strength of respiratory muscle and promotion of muscle fatigue; inhibition of cerebral metabolism and cell volume regulation
• systemic effects : decreased cardiac output => decreased renal and hepatic flow, ventilatory failure, obtundation and coma despite hyperperfusion
• hypercapnic or respiratory acidosis : P_CO2 > 44 mmHg in the blood (hypercapnia / hypercarbia) and most body tissues. CO₂ is usually transported in blood ...
• dissolved (10%).
• PaCO₂ = 0.863 ^. (V^._CO2 / V^._A) = 36-44 mmHg = 4.7-6.0 kPa (low SD) (3-5% free CO₂, 5% HbCO₂, 90% HCO₃^-). It doesn't depend on patient's age.
• PvCO₂ = 41-49 mmHg
• bicarbonate (60%)
• bound to proteins (30%)
Aetiology :
• hypoventilation
• acute :
• inhibition of respiratory centre : drugs, trauma, O₂-therapy in COPD, cardiac arrest, shock central sleep apnea
• respiratory muscle diseases : myasthenia gravis, periodic palsy, GBS, aminoglycoside toxicity, hypophosphatemia, hypokalemia
• aspiration of foreign body or gastrointestinal content (regurgitation or vomiting), obstructive sleep apnea, laryngospasm
• impaired respiration : reacutizationof COPD, ARDS, APE, asthma, pneumonia, pneumothorax
• chronic :
• inhibition of respiratory centre : severe obesity, CNS injuries, respiratory alkalosis
• respiratory muscle disease : spinal injuries, poliomyelitis
• thoracic cage diseases : kyphoscoliosos, severe obesity
• impaired respiration : COPD, severe obesity
• mechanical ventilation

• high PEEP increases alveolar dead volume
• mechanical ventilation unappropiately regulated to face
• increased CO₂ production (fever, agitation, sepsis, excessive feeding)
• decreased alveolar ventilation (worsened pulmonary function)
• permissive hypercapnia : artificially induced hypercapnia in patients with acute respiratory distress syndrome or respiratory failure, done to lower the inspiratory pressure and tidal volume and thus the possibility of lung injury
• compensated respiratory acidosis : the pH of the blood has been returned toward normal by renal compensatory mechanisms.
Predicted compensatory variations : [HCO₃^-]_plasma < 38 mmol/L (> 38 mmHg in metabolic alkalosis)
• acute : increase of [HCO₃^-]_plasma (mmol/L) = - 0.1 ^. increase of P_{CO2, art} (mmHg)
• chronic : increase [HCO₃^-]_plasma (mmol/L) = - 0.35-0.4 ^. increase of P_{CO2, art} (mmHg)
Symptoms & signs :
• acute : anxiety, dyspnea, confusion, psychosis, hallucinations, coma
• chronic : sleep disturbances, amnesia, daysleeping, personality disorders, coordination and motory disturbances (tremors, myoclonus, asterixis, headache, pseudotumor cerebri)
Laboratory examinations : changing levels of CO₂ in the breath show that a patient is running into respiratory trouble and may need emergency intervention. In hospitals, doctors have sophisticated machinery to measure this vital sign, but emergency workers need smaller, portable equipment to use on the spot. To tackle this problem, Alexander Star of the technology company Nanomix in Emeryville, California, and his colleagues turned to carbon nanotubes. These are tiny, hollow tubes of carbon that conduct electricity and can be used as transistors. The team fused carbon nanotubes with custom-made polymers that detect CO₂. When the polymers react with CO₂, their electrical charge is altered and this in turn creates a measurable voltage change in the attached nanotubes. This is detected with an electronic sensor. A 10% rise in CO₂ levels altered the electrical conductance of the carbon nanotubes by 20%. The transistor's conductivity changed in parallel with the levels of CO₂.
Therapy : aetiological and mechanical ventilation
• nonrespiratory or metabolic acidosis : [HCO₃^-] < 23 mEq/L in the blood (hypobicarbonatemia) and most body tissues and anion gap > 30 mEq/L

Aetiology :
• metabolic acidosis with normal anion gap / hyperchloremic acidosis due to reciprocal variations of [Cl^-] and [HCO₃^-]
• gastrointestinal loss of HCO₃^-
• duodenal vomiting
• diarrhea
• external drainage of pancreas or small bowel
• ureterosigmoidostomy, jejunal loop, ileal loop
• calcium chloride (acidifier)
Symptoms & signs : metabolic acidosis and hypokalemia increase renal NH₄⁺ synthesis and excretion => urinary pH = 5-6
Laboratory examinations : negative urinary anion gap, no bicarbonaturia (EL_HCO3- < 10% FL, variable daily HCO₃^- requirement), hypokalemia
Therapy : aetiological
• renal tubular acidosis (RTA)
• with hypokalemia
• proximal RTA / type 2 RTA : caused by malfunction of the proximal tubules.

Aetiology :
• autosomal dominant
• autosomal recessive
• X-linked
• Fanconi's syndrome
• CAI
Pathogenesis : impaired  reabsorption => bicarbonaturia (EL_HCO3- > 15% FL, HCO₃^- requirement > 4 mmol/kg/die).
Laboratory examinations : urinary pH < 5.5, hypophosphatemia, hypercalciuria (=> hypocalcemia), normal or increased citraturia (reduced reabsorption in proximal tubule), hypovitaminosis 1a,25-(OH)₂-vitamin D₃, NaHCO₃ therapy increases renal K⁺ loss => worsened hypokalemia; after administration of 0.1 g (1.9 mmol) NH₄Cl/kg_{body weight}, pH urinary falls regularly
Therapy : thiazide diuretics, sodium-poor diet
• distal RTA / type 1 RTA : loss of the usual lowering of the pH of urine in the distal tubules
• type 3 RTA : self-limiting type 1 RTA with bicarbonaturia in babies (currently the term is no longer used)
Aetiology :
• autosomal dominant : mutations in SLC4A1
• autosomal recessive
• acquired
• Sjogren's syndrome
• hypergammaglobulinemia
• chronic active hepatitis
• systemic lupus erythematosus
Pathogenesis : excessive H⁺ retrodiffusion from collecting duct or inadequate H⁺ transport.
Laboratory examinations : urinary pH > 5.5 despite acidosis (low ammoniuria), no bicarbonaturia (EL_HCO3- < 10% FL, HCO₃^- requirement < 4 mmol/kg/die), hypercalciuria (=> hypocalcemia => mild secondary hyperparathyroidism) and hypocitraturia => nephrocalcinosis and phosphate calcium oxalate urolithiasis, polyuria; after administration of 0.1 g (1.9 mmol) NH₄Cl/kg_{body weight}, pH urinary doesn't fall below 5.5 despite worsening of acidemia (false positives during infections by urease⁺ bacteria)
Therapy : potassium.
• with hyperkalemia : generalized distal RTA / type 4 RTA

Aetiology : hypoaldosteronism
Laboratory examinations : urinary pH < 5.5 (despite impaired H⁺ excretion, as NH₃ excretion in proximal tubule is far more impaired by hyperkalemiaand cannot buffer the few protons in distal tubule), no bicarbonaturia (EL_HCO3- < 10% FL, HCO₃^- requirement < 4 mmol/kg/die)
Therapy : that for hyperkalemia
Laboratory examinations : mildly positive urinary anion gap,
• hyperkalemia associated to renal failure with 20 < GFR < 50 mL/min
• other causes
• exogenous acid intake
• lysine or arginine chloride
• hyperproteic diet
• ammonium chloride
• potential  loss : ketosis with ketone excretion
• expansion acidosis (rapid infusion of physiological solution)
• hippurate
• ion exchange resins
Therapy : HCO₃^- buffering to maintain HCO₃^- > 10 mmol/L and pH > 7.2. Dose to infuse = [body weight ^. 0.5 ^. (15 - [HCO₃^-]_{plasma, current}] / 2
• metabolic acidosis with increased anion gap / normochloremic acidosis : retention of acids other than HCO₃^- (fixed or nonvolatile acids)
• organic acids
• hyperuricemia
• azotemia
• advanced acute renal failure (GFR < 20 mL/min). Poor tolerance to pH fall.
• advanced chronic renal failure (GFR < 20 mL/min) (uremic acidosis) : the condition in uremic syndrome in which the ability to excrete acid is decreased). pH down to 7.3 are quite well tolerated.
Symptoms & signs : osteopenia, hypercalciuria
Therapy :
• p.o. Shohl solution or NaHCO₃. As citrate increases gastrointestinal aluminum absorption, it shouldn't be associated with antacids.
• hemodialysis
• hyperketonemia
• diabetic ketoacidosis (DKA) in patients with type 1 DM / IDDM

Pathogenesis => signs : hypoinsulinemia (expecially when insulin requests are increased as during concomitant disease), excess of contrainsular hormones (hyperglucagonemia, hypercatecholaminemia, hypercortisolemia, and hyper-GH) =>
• => increased protein catabolism => asthenia & azotemia
• =>
• diminished peripheral glucose uptake & increased gluconeogenesis => hyperglycemia => osmotic polyuria => loss of salts and water => dehydrated skin
• increased lipolysis in adipocytes => increased liver ketogenesis => ketosis => exhaustion of bicarbonate buffering increases ketoacidemia => metabolic acidosis => hyperkalemia, nausea and vomiting
=> ileus, gastric retention, anorexia
=> dehydratation => hypovolemia => heart failure => systemic arterial hypotension => hypovolemic shock => ketoacidotic coma
Laboratory examinations^ref :

	mild	moderate	severe
plasma glucose (mg/dl)	> 250; 400-1,000 mg/dL or > 17 mmol/L (increased)	> 250	> 250
arterial pH	7.25–7.30	7.00–7.24	<7.00 (>6.75)
serum bicarbonate (mEq/l)	15–18	10 to <15	< 10
urine ketones (nitroprusside reaction method)	positive	positive	positive
serum ketones (nitroprusside reaction method)	positive (3-27 mM/L (increased))	positive	positive
effective serum osmolality (mOsm/kg) = 2[measured Na (mEq/l)] + glucose (mg/dl)/18	variable = 310-380 mOsm/kg (normal or decreased)	variable	variable
anion gap = (Na+) - (Cl- + HCO3-) (mEq/l)	> 10	> 12	> 12
alteration in sensoria or mental obtundation	alert	alert/drowsy	stupor/coma
kalemia	3.5-7 mEq/L (normal or increased) (potassium deficit = 3-5 mEq/kg
natremia	125-140 mEq/L (normal) (sodium deficit = 7-10 mEq/kg)
bicarbonatemia	< 20 mEq/L
uremia	15-40 mg/dL
water deficit	6 (3-7) L = 100 ml/kg
chloride deficit	3-5 mEq/l
phosphate deficit	5-7 mmol/kg
magnesium deficit	1-2 mEq/kg
calcium deficit	1-2 mEq/kg

Therapy (chronological order):
• pediatric patients (< 20 years) : complete initial evaluation. Start i.v. fluids: 1.0 L of 0.9% NaCl per hour initially =>
• IV fluids => determine hydration status =>
• hypovolemic shock => administer 0.9% NaCl (20 ml/kg/h) and/or plasma expanders until shock resolved
• mild hypotension => administer 0.9% NaCl (10 ml/kg/h) for initial hour =>
• replace fluid deficit evenly over 48 h with 0.45-0.9% NaCl => when serum glucose reaches 250 mg/dl => change to 5% dextrose with 0.45-0.75% NaCl, at a rate to complete rehydration in 48 h and to maintain glucose between 150-250 mg/dl (10% dextrose with electrolytes may be required) => check glucose and electrolytes every 2-4 h until stable. Look for precipitating causes. After resolution of DKA, initiate SC insulin (0.5-1.0 U/kg/d given as 2/3 in the a.m. [1/3 short-acting, 2/3 intermediate-acting], 1/3 in p.m. [1/2 short-acting, 1/2 intermediate-acting]) or as 0.1-0.25 U/kg regular every 6-8 hours during the first 24 hours for new patients to determine insulin requirements
• rehydratation (total : 5.5 L)
• 0-30' : 1 L
• 30'-1 hr : 0.5 L
• 1-2 hr : 1 L
• 2-4 hr : 1 L
• 4-8 hr : 1 L
• 8-12 hr : 1 L
• insulin :
• IV route => IV insulin infusion : regular insulin 0.1 U/kg/h => continue until acidosis clears (pH > 7.3, HCO₃ > 15) => decrease to 0.05 U/kg/h until SC insulin replacement intiated
• IM (if no IV access) : regular insulin 0.1 U/Kg IV bolus followed by 0.1 U/kg/hr SC or IM
• potassium infusion :
• K⁺ < 2.5 mEq/l => administer 1 mEq/kg of KCL in IV over 1 h. Withhold insulin until K⁺> 2.5
• K⁺ 2.5-3.5 mEq/l => administer K⁺ 40-60 mEq/l in IV solution until K⁺ > 3.5. Monitor K⁺ hourly => check results of hourly K⁺ monitoring =>
• K⁺ < 2.5 mEq/l => see above
• K⁺ = 2.5-3.5 mEq/l => continue as above
• K⁺ > 3.5 mEq/l => see below
• K⁺ 3.5-5.5 mEq/l => administer K⁺ 30-50 mEq/l in IV solution to maintain serum K⁺ at 3.5-5.5 mEq/l
• K⁺ > 5.0 mEq/l => do not give IV K⁺. Monitor K⁺ hourly until K+ < 5.0 mEq/l => see above
• glucose infusion
• assess need for bicarbonate => administer slowly to prevent severe hypokalemia with reduced oxygen cession from hemoglobin to tissues and paradoxical reduction in pH_CSF
• pH < 7.0 => repeat pH after initial hydration bolus =>
• pH < 7.0 => over 1 h, administer NaHCO₃ (2 mEq/kg) added to NaCl to produce a solution that does not exceed 155 mEq/l of Na over 1 hr
• pH > 7.0 => see below
• pH > 7.0 => no HCO₃ indicated
• adult patients : complete initial evaluation. Start i.v. fluids: 1.0 L of 0.9% NaCl per hour initially (15-20 ml/kg/hr) =>
• IV fluids => determine hydration status =>
• hypovolemic shock => administer 0.9% NaCl (1 L/h) and/or plasma expanders
• mild hypotension => evaluate corrected natremia
• hypernatremia or normonatremia => 0.45% NaCl (4-14 ml/kg/hr depending on state of hydration => when serum glucose reaches 300 mg/dl => change to 5% dextrose with 0.45% NaCl at 150-250 ml/h with adequate insulin (0.05-0.1 units/kg/hr IV infusion or 5-10 units SC every 2 hr) to keep the serum glucose between 150-200 mg/dl until metabolic control is achieved => check electrolytes, BUN, creatinine, and glucose every 2-4 h until stable. After resolution of DKA, if the patient is NPO, continue IV insulin and supplement with SC regular insulin as needed. When the patient can eat, initiate a multidose insulin regimen and adjust as needed. Continue IV insulin infusion for 1-2 hr after SC insulin is begun to ensure adequate plasma insulin levels. Continue to look for precipitating cause(s)
• hyponatremia => 0.9% NaCl (4-14 ml/kg/hr) depending on state of hydration => when serum glucose reaches 300 mg/dl => change to 5% dextrose with 0.45% NaCl at 150-250 ml/h with adequate insulin (0.05-0.1 units/kg/hr IV infusion or 5-10 units SC every 2 hr) to keep the serum glucose between 150-200 mg/dl until metabolic control is achieved => check electrolytes, BUN, creatinine, and glucose every 2-4 h until stable. After resolution of DKA, if the patient is NPO, continue IV insulin and supplement with SC regular insulin as needed. When the patient can eat, initiate a multidose insulin regimen and adjust as needed. Continue IV insulin infusion for 1-2 hr after SC insulin is begun to ensure adequate plasma insulin levels. Continue to look for precipitating cause(s)
• cardiogenic shock => hemodynamic monitoring
• insulin
• IV route => regular insulin 0.15 U/kg as IV bolus => 0.1 U/kg/h IV insulin infusion
• SC/IM route => regular insulin 0.4 U/kg 1/2 IV bolus, 1/2 IM or SC => 0.1 U/kg/h regular insulin SC or IM
=> if serum glucose does not fall by 50-70 mg/dl in first hour =>
• double insulin infusion hourly
• give hourly IV insulin bolus (10 U)
... until glucose falls by 50-70 mg/dl. When serum glucose reaches 300 mg/dl => change to 5% dextrose with 0.45% NaCl at 150-250 ml/h with adequate insulin (0.05-0.1 units/kg/hr IV infusion or 5-10 units SC every 2 hr) to keep the serum glucose between 150-200 mg/dl until metabolic control is achieved => check electrolytes, BUN, creatinine, and glucose every 2-4 h until stable. After resolution of DKA, if the patient is NPO, continue IV insulin and supplement with SC regular insulin as needed. When the patient can eat, initiate a multidose insulin regimen and adjust as needed. Continue IV insulin infusion for 1-2 hr after SC insulin is begun to ensure adequate plasma insulin levels. Continue to look for precipitating cause(s)
• potassium => if initial serum
• K⁺ < 3.3 mEq/l => hold insulin and give 40 mEq K⁺ per h (2/3 KCL and 1/3 KPO₄) until K > 3.3 mEq/l
• K⁺ 3.3-5 mEq/l => give 20-30 mEq K⁺ in each liter of IV fluid (2/3 KCL and 1/3 KPO₄) to keep serum K⁺ at 4-5 mEq/l
• K⁺ > 5.0 mEq/l => do not give K⁺, but check K⁺ every 2 h
• assess need for bicarbonate =>
• pH < 6.9 => NaHCO₃ (100 mmol) dilute in 400 ml H₂O, infuse at 200 ml/h
• pH = 6.9-7.0 => NaHCO₃ (50 mmol) dilute in 200 ml H₂O, infuse at 200 ml/h
• repeat HCO₃ administration every 2 h until pH > 7.0. Monitor serum K⁺
• pH > 7.0 => no HCO₃ indicated :
• if kalemia < 3 mEq/L => administer 40 mEq/hr
• if 3 < kalemia < 4 mEq/L => administer 26 mEq/hr
• if 4 < kalemia < 5 mEq/L => administer 20 mEq/hr
• if 5 < kalemia < 6 mEq/L => administer 13 mEq/hr
• if kalemia > 6 mEq/L => interrupt infusion =>
Complications : edemas
• acute pulmonary edema due to excess of liquids
• cerebral edema due to excessive rapidity in normalization of hyperglycemia
Summary of major recommendations :
• initiate insulin therapy according to recommendations in position statement (level of evidence A)
• unless the episode of DKA is mild, regular insulin by continuous intravenous infusion is preferred (level of evidence B)
• assess need for bicarbonate therapy and, if necessary, follow treatment recommendations in position statement: bicarbonate may be beneficial in patients with a pH <6.9; not necessary if pH is >7.0°C
• studies have failed to show any beneficial effect of phosphate replacement on the clinical outcome in DKA. However, to avoid cardiac and skeletal muscle weakness and respiratory depression due to hypophosphatemia, careful phosphate replacement may sometimes be indicated in patients with cardiac dysfunction, anemia, or respiratory depression and in those with serum phosphate concentration <1.0 mg/dl (level of evidence A)
• studies of cerebral edema in DKA are limited in number. Therefore, to avoid the occurrence of cerebral edema, follow the recommendations in the position statement regarding a gradual correction of glucose and osmolality as well as the judicious use of isotonic or hypotonic saline, depending on serum sodium and the hemodynamic status of the patient (level of evidence C)
• initiate fluid replacement therapy based on recommendations in position statement (level of evidence A)
• starvation acidosis or ketoacidosis : a type of metabolic acidosis produced by accumulation of ketone bodies which may accompany a marasmus. This is the only case of metabolic acidosis in which excess protons are endogenous in origin.
• ethanol craving ketoacidosis

Symptoms & signs : abdominal pain, denutrition, hypovolemia
Laboratory examinations : low insulinemia, high triglycerids, cortisol, glucagon, and GH. Acetest may detect acetoacetate but not b-hydroxybutyrate leading to underevaluation of ketonemia and ketonuria
Therapy : i.v. 5% Glc in NaCl 0.9%; correct hypophosphatemia, hypokalemia, and hypomagnesemia
• hyperlactacidemia (lactic acidosis)
• type A (hypoxia)
• type B (aerobic disturbances)
• neoplasms
• diabetes mellitus
• renal failure
• liver failure (massive liver metastases)
• severe infections (cholera, malaria, HIV-1)
• convulsions
• drugs / toxins (biguanides, ethanol, methanol, isoniazid, AZT analogues, fructose)
• D-lactate acidosis : produced by intestinal bacteria in patients with
• jejunoileal bypass
• intestinal occlusion
Therapy :
• treatment of hypoperfusion or sepsis
• NaHCO₃ stimulates PFK and may depress cardiac functionality increasing lactacidemia. Fluid administration is poorly tolerated due to central venoconstriction. After removal of cause, blood lactate is converted to HCO₃^- and may cause rebound metabolic alkalosis
• toxins generating organic acids
• PEG (metabolytes : glycolic acid => glyoxylic acid => oxalic acid, other organic acids)
• methanol (metabolytes : formic and lactic acids)
• toluene (metabolytes : hippuric acid)
• salicylates (metabolytes : lactic acid and ketones)

Therapy : gastric washing with isotonic solution (without NaHCO₃) => active charcoal, i.v. NaHCO₃ (dangerous if respiratory alkalosis occurred) or CAI + HCO₃^- (to prevent systemic metabolic acidosis) until urinary pH > 7.5
Therapy : hemodialysis
Therapy :
• administration of physiological solution (Na:Cl 1:1)
• chlorinated acidifying salts (HCl)
• HCO₃^- and Na⁺ losses : H + Tr Na:Cl 1:1
• increase in organic acid and Na⁺ : H + Tr Na:Cl 1:1
• mucosal exchange : HCO₃^-/Cl^- + NH₄Cl
• glomerular-tubular disequilibrium : Tr Na:Cl 1:1
• compensated metabolic acidosis : the pH of the blood has been returned toward normal by respiratory compensatory mechanisms
Predicted compensatory variation : decrease in P_{CO2, art} (mmHg) = - 1.25 ^. decrease [HCO₃^-]_plasma (mmol/L)
... or :
• P_{CO2, art} (mmHg) = [HCO₃^-]_plasma (mmol/L) + 15
• P_{CO2, art} (mmHg) = (1.5 ^. [HCO₃^-]_plasma (mmol/L)) + 8
Classification according to H⁺ input rate
• 30-70 mmol/min (very fast acid) : hypoxia/ischemic lactic acidosis
• < 1 mmol/min (fast acid) : D-lactate acidosis, biguanides, toxics, DKA, AKA, intoxication (methanol, PEG, toluene, salicylates)
• 0.05 mmol/min (slow acid) : renal acidosis, renal or gastrointestinal HCO₃^- loss
Symptoms & signs : Kussmaul breathing, negative inotropic effect (normalized by incretion of catecholamines), peripheral arterial vasodilatation and central venoconstriction, reduction of central and pulmonary vascular compliance => acute pulmonary edema, headache, lethargy, stupor, impaired glucose tolarance
Therapy : [potential HCO₃^-]_plasma = D(anion gap) = (anion gap)_patient - 10. NaHCO₃ or Shohl solution p.o. or i.v.; check [K⁺]_plasma
Comparison among acidoses with normal anion gap :

	type 1 RTA	type 2 RTA	type 4 RTA	diarrhea
minimal urinary pH	> 5.5	< 5.5	< 5.5	5-6
% excretion of filtered HCO3-	< 10	> 15	< 10	< 10
potassiemia	hypokalemia	hypokalemia	hyperkalemia	hypokalemia
Fanconi's syndrome	no	yes	no	no
nephrolithiasis / nephrocalcinosis	yes	no	no	no
acid excretion in 24 hrs	low	normal	low	high
urinary anion gap (UAG)	positive urinary anion gap			negative
HCO3- requirement (mmol/kg/24 hrs)	< 4	> 4	< 4	variable

Compensation : proximal renal tubule reabsorbs all HCO₃^- filtered (kinetics limited by number of transporters) and distal tubule produces more : it keeps more CO₂ from plasma and produces both HCO₃^- (which outflows in interstitium) and H⁺ (which outflows into the tubule via Na⁺/H⁺ antiporter and eventually H⁺ ATPase and K⁺/H⁺ antiporter : in the latter case K⁺ is secreted back into the plasma by K⁺Cl^- symporter generating hyperkalemia. ATPases can create a tubular pH = 4.5 (DpH = 3), but H⁺ are buffered by HPO₄^2-, H₂PO₄^-, and NH₃, that have pK_a ~ pH_{distal tubule}. NH₃ (and 2 HCO₃^-) come from Gln and diffuse into the tubule : once accepted H⁺, NH₄⁺ can no longer come back into type A intercalated cell and acidic urine (pH 4.5) is generated. By titrating [NaH₂PO₄ + H₃PO₄ + NH₄⁺]_urine one can deduct pH_plasma coming from nonvolatile acids.
Therapy :
• HCO₃^- = ([HCO₃^-]_normal - [HCO₃^-]_observed) ^. volume of distribution_CO2 = base excess ^. body weight ^. 0.3 until pH = 7.2 or = 8-10 mEq/L (check effectiveness of ventilation)

Side effects : hypernatremia, overload, metabolic alkalosis, hypokalemia
• NaHCO₃ + Na₂CO₃ (Carbicarb) improves heart function and consumes CO₂, increasing [HCO₃^-]_extracelluar
• mixed alteration
• double alterations
• diabetic ketoacidosis (metabolic acidosis) causes sensory blur => hyperventilation (respiratory alkalosis) => compensated metabolic acidosis
• sepsis : hypoperfusion (metabolic acidosis) causes fever and hyperventilation (respiratory alkalosis) => compensated metabolic acidosis
• triple alterations
• alcoholic ketoacidosis (metabolic acidosis) => vomiting (=> metabolic alkalosis) and liver dysfunction or alcohol craving => hyperventilation (=> respiratory alkalosis)
The actual values are different from the predicted values for simple alterations, but the compensatory mechanism never overwhelms the primary alteration !
COPD patients always have high P_{CO2, art} (respiratory acidosis), so urgence should be evaluated only from pH and level of consciousness, verifying eventual metabolic acidosis. In chronic diseases, even if ABG shows respiratory acidosis, calculations should be done starting from the previous situation (considered as normal).
When pH is normal, an high anion gap may show metabolic acidosis compensated by metabolic alkalosis
• daily acid production
• 20,000 mmol/day of volatile acid (HCO₃^-)
• 70-100 mmol/day of fixed or nonvolatile acids (phosphates, urates, and H₂SO₃ from -SH groups of animal proteins => vegetarians have mild metabolic alkalosis)
• buffering
• chemical buffers (instantaneous control : they don't change mass but only partial pressures)
• extracellular fluid chemical buffers
• plasma chemical buffers : CO₂ + H₂O <=> H₂CO₃ <=> HCO₃^- + H⁺ => K_a = ([HCO₃^-] ^. [H⁺]) / ([CO₂] ^. [H₂O]) (pK_a = 6.1, distant from 7.4, low absolute concentrations, but relative concentrations can be precisely regulated !)
• urinary chemical buffers :
• NH₃ (pK_a = 9.2; absolute concentration >> P_i, but can be increased by Gln)
• HPO₄^2- and H₂PO₄^- (pK_a = 6.8, near to that of urine, where general urine concentration increases its absolute concentration)
• intracellular fluid chemical buffers
• inorganic phosphate (P_i : pK_a = 6.8, similar to that of cytosol, where it is more represented than in ECF)
• His in proteins, expecially HGB (it requires hours, but includes 70% of buffering activity)
• change in production of organic acids (OAs)
• lungs (require 3-12' to regulate pH after stimulation via peripheral => central chemoreceptors, but have a buffering power double than that of chemical buffers)
• kidneys (long-term buffering)
• H⁺ secretion into tubule
• to eliminate nonvolatile acids (other than H₂CO₃, mainly H₂SO₃)
• to reabsorb filtered HCO₃^-
• ex novo HCO₃^- production by excreting H⁺ into urine (then buffered by urinary chemical buffers)
Acid-base nomograms show 95% confidence interval for any simple acid-base alteration : anyway laboratory values falling within these areas can arise even from mixed alterations.
Web resources :
• GASNet
• The Virtual Anaesthesia Textbook
• Critical Patient.org
• Acid-Base Physiology
• lithium (₃Li)
• hyperlithemia : > 1.5 mEq/L

Sources : drug for treatment of mania (optimal plasma level = 0.5-0.8 mEq/L)
Symptoms & signs :
• acute renal failure
• reduced tubular resporption => polyuria
• primary polydipsia
• medullary hypoplasia
• hypothyroidism (interfers with synthesis and relase of thyroid hormones)
• EKG and EEG alterations
• sedation
• high-frequency hand tremors (> 1  mEq / L)
• ataxia
• psychomotory retardation
• hidradenitis
• primary hyperparathyroidism
• diarrhea and other gastrointestinal disorders
• dermatitis
• epilepsy
• sometimes disturbances of equilibrium
• it accelerates vasculopathies, CHF, and edemas
Overdose therapy : urea, sodium chloride, diuretics (< 2 mEq / L; mild symptoms; acetazolamide) => hemodialysis
• beryllium (₄Be)
• berylliosis / beryllium poisoning : a hypersensitivity response to beryllium, usually involving the lungs and less often the skin, subcutaneous tissues, lymph nodes, liver, or other structures. Beryllium fumes, its oxide and salts, and finely divided dust all may cause a tissue reaction when inhaled or implanted in the skin. 2 varieties are distinguished :
• acute berylliosis : an often fulminating reaction to inhalation of beryllium, characterized by a toxic or allergic pneumonitis, sometimes with rhinitis, pharyngitis, and tracheobronchitis. Symptoms may last for weeks, and serious cases can be fatal.
• chronic berylliosis : the usual form of berylliosis, characterized by beryllium granulomas and Schaumann's (conchoid) bodies, a diffuse inflammatory reaction that may be indistinguishable from sarcoidosis, and sometimes dyspnea and hypertrophic pulmonary osteoarthropathy. In time the granulomas may combine to form pulmonary nodules with fibrosis. Radiographically it is characterized by the development of either small rounded or occasionally irregular linear opacities usually confined to the bases.
• boron (₅B) : poisoning of humans or other animals by boron, boric acid, or a borate salt such as sodium borate (borax).

Symptoms & signs : weakness, ataxia, tremors, convulsions, and often death.
• carbon (₆C)
• charcoal : carbon prepared by charring wood or other organic material.
• activated charcoal / carbo activatus : the residue from the destructive distillation of various organic materials, treated to increase its adsorptive powers; used as a general purpose antidote
• animal charcoal / animal, ivory, or Paris black / bone-black : charcoal prepared from bone
• purified animal charcoal : charcoal prepared from bone and purified by removal of materials dissolved by hot hydrochloric acid and water; adsorbent and decolorizer.
Symptoms & signs : coal workers' pneumoconiosis (CWP) / black or coal miner's lung : a form caused by deposition of large amounts of coal dust in the lungs, and typically characterized by centrilobular emphysema. Different varieties of coal have different risks; those with certain types of contaminants may cause other types of pneumoconiosis.
• anthracosis : anthracite coal
• bituminosis : bituminous coal
Complications : progressive massive fibrosis (PMF)
Laboratory examinations : black induration (hardening and pigmentation of lung tissue)
• nitrogen (₇N)
• hypernitremia : excessive nitrogen in the blood
• hyponitremia : a low level of nitrogen in the blood, sometimes associated with protein malnutrition or overhydration
Total body nitrogen = 28,8 x lean body mass (LBM) (kg) + 2,28
Total daily nitrogen losses =
• ([urea]_{urine, 24 hrs} (mmol/day) x 0,06)/2,14 + 2
• Lee formula : [urea]_{urine, 24 hrs}  (g) x 0,58
• for patients with hyperazotemia : [urea]_{urine, 24 hrs} (g) x 0,58 + [increase in [urea]_plasma (g/l) x weight(kg) x 0,28]
• oxygen (₈O) :
• oxygen partial pressure :
• in inspirated air P_O2 = P_ATM ^.inhaled fraction O₂ (FiO₂) = 760 mmHg ^. 21 = 160 mmHg
• in alveolar (humidified) air P_O2 = 120 mmHg
• in arterial blood Pa_O2 = 100 mmHg, due to physiological dead volume and shunting of venous blood (bronchial arteries and veins). It depends on :
• age
• P_{O2, artery, expected} = 109 - (0.43 ^. age (yy)) [mmHg]
• 96 mmHg at age 30
• 77 mmHg at age 75
• P_{O2, artery, expected} = 103.5 - (0.42 ^. age (yy)) [mmHg]
• body temperature
• atmospheric P_O2 (if breathing 100% O₂, P_{O2, artery} may be > 500 mmHg)
• P_{O2, artery, standard (if patient wouldn't hyperventilate)} = [(P_{CO2, artery, measured} ^. 1.66) + P_{O2, artery, measured}] - 66.4 = 75-110 mmHg = 10.0-13.3 kPa
• P_{O2, artery, standard/expected}
• P_{O2, alveoli} - P_{O2, artery} = 5÷6 mmHg (low SD)
• in tissues P_O2 = 5-20 mmHg
• in venous blood Pv_O2 =

• hemoglobin O₂ saturation :
• in arterial blood (SaO₂) : 95-99%
• SaO_{2, aorta} = 98%
• in mixed venous blood (SvO₂) : 65-80%
• SvO_{2, inferior vena cava} = 80%
• SvO_{2, superior vena cava} = 65-75%
• total oxygen concentration or content :
• in arterial blood (CaO₂) = HGB^. SaO₂ ^. 1.39 + 0.0031 ^. Pa_O2 = 5 mL/ 100 mL blood
• O₂ content = [Hb (98%)] + [free plasma O₂ (2%)] = 19.8 mL / dL blood
• in mixed venous blood (CvO₂) : HGB^. SvO₂ ^. 1.39 + 0.0031 ^. Pv_O2 =
As 98% of oxygen is carried in blood as HbO₂ and only 2% is free in plasma, changes in SaO₂ have a greater impact on CaO₂ than changes in PaO₂ : e.g. a 50% decrease in SaO2 (from 15 mg/dL to 7.5 mg/dL) causes a 50% fall in CaO₂, while a 50% decrease in PaO₂ (from 90 to 45 mmHg) cause a 20% fall in CaO₂.
• oxygen availability (DO₂) = CO ^. CaO₂ = 13.4 ^. CI ^. HGB^. SaO₂ = 13.4 ^. (LVEDV - LVESV) ^. HR ^.HGB^. SaO₂ / BSA
• oxygen consumption (VO₂) = CO ^. (CaO₂ - CvO₂) = 13.4 ^. CI ^. HGB^. (SaO₂ - SvO₂) = 250 mL/min
• extraction rate (O₂ER) = 100 ^. VO₂/DO₂ = (CaO₂ - CvO₂)/CaO₂
• hyperoxia : an excess of O₂ in the system

Aetiology : exposure to high O₂ concentrations, especially to hyperbaric pressures of O₂
Symptoms & signs : oxygen poisoning or toxicity : the effects of hyperoxia due to the breathing of high partial pressures of oxygen for prolonged periods; they include serious, sometimes irreversible, damage to the pulmonary capillary endothelium, followed by cerebral edema and convulsions that can be fatal
• hypoxia : reduction of oxygen supply to tissue below physiological levels
• anoxia : a total lack of oxygen; often used interchangeably with hypoxia to mean a reduced supply of oxygen to the tissues.
Aetiology :
• hypoxic hypoxia : that due to insufficient oxygen reaching the blood
• anoxic anoxia : anoxia resulting from interference with the source of oxygen
• asphyxia [Gr. “a stopping of the pulse”] : pathological changes caused by lack of oxygen in respired air, resulting in hypoxia and hypercapnia
• acute respiratory failure
• alveolar hypoventilation
• asphyxiation / suffocation : the causing of or state of asphyxia
• traumatic asphyxia : asphyxia occurring as a result of sudden or severe mechanical injuries causing traumatic asphyxia of the thorax or upper abdomen, or both

Laboratory examinations :
• ecchymotic mask : cyanotic discoloration of the head and neck
• Tardieu's spots : spots of ecchymosis under the pleura following death by suffocation
Occurrence :
• fetal asphyxia : asphyxia in utero

Aetiology : fetal hypoxia : hypoxia in utero, caused by
• inadequate placental function (often abruptio placentae)
• preeclamptic toxicity
• prolapse of the umbilical cord
• complications from anesthetic administration
• anoxia neonatorum : anoxia of the newborn.
• birth or perinatal asphyxia : asphyxia in the infant

Aetiology :
• during labor (antepartum asphyxia)
• gestational diabetes mellitus
• chronic hypertension
• anemia
• isoimmunization
• previous fetal or neontal death
• during delivery (intrapartum asphyxia) (> 90%)
• during the immediate postnatal period (< 10%)
• CNS : IVH, drugs, seizures, hypoxic-ischemic encephalopathy, hernias, neuromuscular disorders, Leigh syndrome, cerebral infarction or anomalise (olivopontocerebellar atrophy)
• respiratory apparatus : pneumonia, obstructive airway lesions, atelectasis, extreme prematurity (< 1,000 g), laryngeal reflex, phrenic nerve paralysis, severe HMD, pneumothorax, hypoxia
• infections : sepsis, NEC, meningitis (bacterial, viral or mycotic), RSV, gastrointestinal infections, oral feeding, intestinal peristalsis, GERD, esophagitis, intestinal perforation
• metabolic causes : hypoglycemia, hypocalcemia, hypophosphoremia, hyponatremia or hypernatremia, hyperammoniemia, organic acidosis, increased room temperature, hypothermia
• cardiovascular causes : hypotension or hypertension, cardiac failure, anemia, hypovolemia, vagal hypertone
• idiopathic : immaturity of respiratory centres, sleep
Symptoms & signs : apnea neonatorum
Laboratory examinations : Apgar score (named in honor of one of the first pediatricians to specialise in newborn (neonatal) care, Dr. Virginia Apgar)

	0 points	1 point	2 points
Activity (muscle tone)	no movement, "floppy" tone	arms and legs flexed with little movement	active, spontaneous movement
Pulse	absent	< 100 bpm	> 100 bpm
Grimace (responsiveness or reflex irritability)	no response	facial movement only (grimace)	sneeze, cough, pulls away
Appearance (skin color)	normal color all over (hands and feet are pink)	normal color (but hands and feet are bluish)	bluish-gray or pale all over
Respiration (rate and effort)	absent	slow or irregular breathing	normal rate and effort or crying

A score is given for each sign the end of the first minute of extrauterine life and after 5'. If there are problems with the baby an additional score is given at 10 minutes. A score of 7-10 is considered normal, while 4-7 might require some resuscitative measures, and a baby with APGAR < 3 requires immediate resuscitation.
Limitation : poorly predictive for preterm newborns (skin is almost cyanotic, bradypnea, poor reactivity, flebile crying). Commonly only 3 parameters are used to establish if therapy is required (heart rate < 100 bpm; breath rate, cyanotic skin) independently of primary or secondary apnea.
Complications : postasphyxial hypoxic-ischemic encephalopathy (HIE) : Sarnat HB & Sarnat MS classification^ref :
• 1 (mild) : lasting < 24 hours, hyperalertness, uninhibited Moro and stretch reflexes, sympathetic effects, and a normal EEG; mild hypotonia (floppy infant syndrome), poor suction reflex, hypersympathicotonia (tachycardia, mydriasis). Prognosis : good
• 2 (moderate) : obtundation, hypotonia, strong distal flexion, multifocal seizures, lack of suction reflex.. The EEG showed a periodic pattern sometimes preceded by continuous delta activity. Prognosis : good in 50%, cerebral palsy in 25%, lesser handicap (dyslalia, dysgraphia) in 25%. Infants who do not enter stage 3 and who have signs of stage 2 for < 5 days appear normal in later infancy. Persistence of stage 2 for > 7 days or failure of the EEG to revert to normal is associated with later neurologic impairment or death.
• 3 (severe) : stuporous, severe hypotonia, and brain stem and autonomic functions were suppressed (coma, sustained convulsions, depression of respiratory centre). The EEG was isopotential or had infrequent periodic discharges. Prognosis : usually death, otherwise severe complications
Therapy :
• neonatal resuscitation
• mechanical ventilation
• cardiac massage
• cerebral hypothermia (lowered by 3-4°C for 72 hours after birth using a water-filled cap) can improve outcome of experimental perinatal hypoxia-ischaemia. Although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe amplitude integrated electroencephalography (aEEG) changes^ref.
• in the following 2-3 days :
• decrease fluid intake by 20-30%
• ABPM
• normalization of P_CO2 (30-50 mmHg)
• euglycemia
• mannitol 1 g/kg 20' infusion every 4-6 hrs if intracranial hypertension
• AEDs
• neuroprotectors : useless when apoptosis has already occurred (i.e. after 8-24 hrs)
• NMDAR antagonists (ketamine, D-methorphan, PQQ)
• inhibitors of EAA secretion (lamotrigine, riluzole)
• K_ATP inhibitors (diazoxide, galanine)
• antiedemagenic (GR agonists, diuretics)
• CCBs (nifedipine, nicardipine, nimodipine) => Side effect : severe systemic arterial hypotension when the fetus is already hypotensive
• MgSO₄ (membrane hyperpolarization) => transient hypotonia and lethargy. Side effect : cerebral hemorrahges
• antioxidants (SOD, catalase, vitamin E, allopurinol, indomethacin) in reperfusion
• phenobarbital (antioxidant, CCBs and hyperpolarizer) : doubtful effectiveness in prevention
• asphyxia neonatorum : perinatal asphyxia in the newborn.
• asphyxia cyanotica or livida / blue asphyxia : perinatal asphyxia in which the skin is cyanotic from the lack of oxygen in the blood
• asphyxia pallida / white asphyxia : perinatal asphyxia attended with paleness of the skin
• secondary asphyxia : asphyxia recurring after apparent recovery from suffocation.
• high altitude anoxia or sickness : the condition resulting from difficulty in adjusting to diminished oxygen pressure at high altitudes. It may take the form of :
• high-altitude pulmonary edema (HAPE)
• high-altitude cerebral edema (HACE)
• mountain disease or sickness : a type of high altitude sickness caused by exposure to altitude high enough to cause hypoxia, occurring as a result of decreased atmospheric pressure with consequent lowering of arterial oxygen content. It occurs as :
• acute mountain sickness (AMS) / Acosta's disease : a type that appears a few hours after exposure to high altitude, characterized by fatigue, dizziness, breathlessness, headache, nausea and vomiting, insomnia, impairment of mental capacity, and prostration, ending with high-altitude cerebral edema (HACE)
• subacute mountain sickness (a.k.a. "Montezuma maledition") : a type milder than the chronic form and similar clinically to the acute form except for being persistent and amenable to cure by a descent in altitude.
• chronic mountain sickness / Andes disease / Monge's disease : a type characterized by loss of tolerance to hypoxia in a previously acclimatized person, with secondary polycythemia. It occurs in 2 types:
• emphysematous type in which dyspnea is the dominant symptom and bronchitis, laryngitis, and cyanosis are often present
• erythremic type in which there is an erythremic color that becomes cyanotic on mild exertion, with fatigue, headache, episodic stupor, paresthesias, anorexia, nausea and vomiting, and decreased visual acuity
SNPs in mtDNA of inhabitants that routinely dwell at altitudes of > 4,000 metres have been reported :
• indigens of the Tibetan plateau (colonized 23,000 years ago) have relatively low haemoglobin levels but breathe faster to take in more oxygen. Tibetans who live approximately 2-3 miles above sea level have significantly higher levels of glutathione-S-transferase and enoyl coenzyme A hydratase, and possess fewer mitochondria. Once non-genetic factors such as age, illness, or smoking were removed, a subset of Tibetan women has a blood-oxygen concentration that is 10% higher than normal. This trait is inherited in a way that suggests the difference is due to a single gene. The children of women with this putative gene are much more likely to survive to the age of 15, when they are old enough to have children of their own. In the low-oxygen group, each woman has on average 2.5 children that died during childhood. In the high-oxygen group, that average is just 0.4^ref. Maybe the trait allows the children to reach a higher birth weight or, if inherited, it might help children to survive bouts of respiratory illness that would otherwise prove fatal.
• indigens of the Ethiopian plateau (colonized about 50,000 years ago)
• indigens of the Andean Altiplano in Peru and Bolivia (10,000 years ago - after humans arrived in the New World) pump out more haemoglobin
Given enough time, they might all evolve the same adaptations to the high life. But it's perhaps more likely that they are all on their own genetic paths towards different adaptations
The subacute and chronic forms can be cured by descent to a lower altitude.
Climbers on Mount Everest could die because of sudden drops in air pressure triggered by high winds. The top of Mount Everest sits in the upper troposphere, a part of the atmosphere where winds travelling at 110 km an hour can pummel climbers. This region is also affected by jet streaks, extra fast bursts of wind within the jet streams that race around the Earth from west to east. Jet streaks can drag a huge draught of air up the side of the mountain, lowering the air pressure. This typically reduces the partial pressure of oxygen in the air by about 6%, which translates to a 14% reduction in oxygen uptake for the climbers. Air at that altitude already contains only 33% as much oxygen as sea-level air. At these altitudes climbers are already at the limits of endurance. The sudden drop in pressure could have driven some of these climbers into severe physiological distress. Intrepid mountaineers usually start their ascent of the world's highest mountain from a base camp at about 5000 m, trekking to the South Col at a height of around 8000 m. From there it is a full day's climb to the summit at 8850 m. On 8 May 1978, Reinhold Messner and Peter Habeler achieved the first ascent of Mount Everest without an oxygen supply. Since then, more and more climbers have opted to go to the highest place in the world without the support of oxygen cylinders.
Web resources :
• Everest Panorama
• Physiology on Everest
• National Geographic: Everest
• Jet Streaks
• MIT Weather Probe
• myocardial anoxia : failure of coronary blood flow to keep up with myocardial needs.
• anemic hypoxia => anoxia : hypoxia => anoxia due to severe anemia or defective hemoglobin
• stagnant hypoxia : that due to failure to transport sufficient oxygen because of inadequate blood flow, as in heart failure and shock
• stagnant anoxia : particularly severe stagnant hypoxia
• histotoxic hypoxia => anoxia : that due to impaired utilization of oxygen by tissues, as in CO or CN^- poisoning
• hypoxia-ischemia : the changes occurring in tissues when the blood supply is cut off, particularly in a fetus or infant with asphyxia
• hypoxemia : P_{O2, artery} < 80 mmHg or < [109 - 0.43 ^. age (yy)] [mmHg] or anyway P_{O2, artery} < 60 mmHg when measured outdoor at sea level.
• orthodeoxia : accentuation of arterial hypoxemia in the erect position, improved by assumption of a recumbent position

Aetiology : platypnea-orthodeoxia syndrome (POS)
• platydeoxia :

Aetiology : ascending aortic aneurysm compressing the right main pulmonary artery => right-to-left shunting, increased by supine position ^ref
Therapy : a pillow to maintain the lateral decubitus position during sleep prevent nighttime oxygen desaturation.
Pathogenesis : hypoxidosis (impaired cell function due to reduced supply of oxygen) => adaptation mechanisms => decrease in DO₂ causes a compensatory increase in O₂ER, so that VO₂ remains unchanged => when DO₂ < DO_2crit, also VO₂ decreases in a directly related manner => metabolic (lactic) or mixed acidosis => depletion of ATP => alterations in membrane pumps => circulation redistribution => loss of autoregulation in brain => cerebral vascular pressures relates to systemic arterial blood pressure => risk for cerebral hemorrhages in early stages and cerebral ischemia in later stages (hyperlactacidemia => neuronal membrane depolarization => IRI => increased excitatory amino acids => excitotoxicity) => decreased cardiac output, astrocyte and neuronal swelling, neuronal apoptosis (hippocampus, diencephalon, brainstem, cerebellum => cerebral palsy, intellectual deficiencies, epilepsy) => multiple organ failure (MOF). Hypoxic pulmonary vasoconstriction (HPV) (a reflex activated by hypoxia, acidosis or hypercapnia) shifts blood from unventilated to ventilated lobules. Anemia-, metahemoglobinemia- and carboxyhemoglobin-associated anemia doesn't cause hyperventilation because PO₂ remains normal in peripheral blood
Symptoms & signs :
• inspiratory dyspnea or irritative period (30"-1')
• expiratory dyspnea or convulsions period (1'-2') : expiration caused by hypercapnia => expiratory cramp, mydriasis, orthosympathetic secondary systemic arterial hypertension
• apneic period (2'-3') : cessation of respiratory movements, absolute loss of consciousness, deep coma, complete muscular relaxation and lack of reflexes while heartbeat persists (apparent death)
• gasping period (3'-5/6') : reappearance of irregular respiratory acts due to residual excitability of bulbar nervous centres, accompanied by intermittent movements of mouth and alae nasi
• death
Necroptic findings :
• external findings :
• delayed cadaver cooling (convulsions => hyperthermia)
• early rigor mortis due to muscular hyperactivity before death (convulsions)
• early, abundant and diffuse cadaveric ecchymoses due to blood hypoviscosity
• accelerated putrefaction due to blood hypoviscosity
• internal findings :
• dark blood due to hypoxemia
• persistent blood hypoviscosity
• pointed subpleural and subepicardial ecchymoses
• organ hyperemia (oligoemia in spleen due to orthosympathetic contraction of the capsule)
• acute pulmonary emphysema due to inspiratory and expiratory efforts
• in newborns : cerebral edema, status marmoratus of basal ganglia, thalamus (and eventually cortex), watershed infarction (parasagittal cerebral lesion : the commonest ischemic injury, between anterior, middle and posterior cerebral artery areas => spastic tetraplegia), focal or multifocal infarction => porencephalia (when multiple : multicystic encephalomalacia => hydranencephaly => spastic tetraparesis, epilepsy), periventricular leukomalacia (PVL) in trigoni (expecially in preterm newborns => spastic diplegia)
• fluoride (₉F)
• hypofluoremia
• hyperfluoremia

Epidemiology : historically, most cases of fluoride toxicity have followed accidental ingestion of insecticides or rodenticides. A power plant on the upper reaches of the Yuexi River in Sichuan province was to blame for the pollution, which prompted environmental officials to suspend water supplies to 20 000 people in Guanyin Town^ref since Wed 15 Feb 2006^ref. Water was being trucked in to residents, but it was insufficient to meet demand : the river had been polluted with chemicals, including fluoride and nitrogen. Earlier in Feb 2006, 3 tanks at a chemical company in the northwestern province of Shaanxi collapsed, discharging about 2000 tons of alkaline waste into a river which flows into the Yellow River, China's 2nd-longest. In one of the worst incidents, water supplies to millions of people in northeastern China were suspended after a blast at a chemical plant in November 2005 caused cancer-causing benzene compounds to leak into a major river. The chief of China's environment watchdog was forced to resign following that spill, which became an international incident, as the river flows into Russia. The Chinese government has promised to improve environmental safeguards and has spent billions of yuan on cleaning up the country's rivers, though experts warn some of it is misspent and ineffective.
Sources : exposure to excessive amounts of fluorine or its compounds, resulting from
• accidental or intentional ingestion of many common household products, including toothpaste (e.g., sodium monofluorophosphate), dietary supplements (e.g., sodium fluoride), glass-etching or chrome-cleaning agents (e.g., ammonium bifluoride), and certain insecticides and rodenticides (e.g., sodium fluoride)
• chronic inhalation of industrial dusts or gases
• prolonged ingestion of water containing large amounts of fluorides (used in fluoroprophylaxis) : fluoridation in Israel was first mooted in 1973 and finally incorporated into law in November 2002 obligating the Ministry of Health to add fluoride to the nation's water supply. Epidemiology studies in the USA have shown that the addition of 1 ppm of fluoride to the drinking water reduced the caries rate of children's teeth by 50-60% with no side effects. Both the WHO in 1994 and the American Surgeon General's report of 2000 declared that fluoridation of drinking water was the safest and most efficient way of preventing dental caries in all age groups and populations. Opposition to fluoridation has arisen from "antifluoridation" groups who object to the "pollution" of drinking water by the addition of chemicals and mass medication in violation of the "Patient's Rights" law and the Basic Law of Human Dignity and Liberty. However, none of the many independent professional committees reviewing the negative aspects of fluoridation have found any scientific evidence associating fluoridation with any ill-effects or health problems. In Israel, where dental treatment is not included in the basket of Health Services, fluoridation is the most efficient and cheapest way of reducing dental disease, especially for the poorer members of the population^ref. Sodium fluoride is a white, crystalline, water-soluble powder used in municipal water fluoridation systems, in various dental products, and in a variety of industrial applications. Toxicology and carcinogenesis studies were conducted with F344/N rats and B6C3F1 mice of each sex by incorporating sodium fluoride into the drinking water in studies lasting 14 days, 6 months, and 2 years. In addition, genetic toxicology studies were performed with Salmonella typhimurium, with mouse L5178Y cells, and with Chinese hamster ovary cells. 14-Day Studies: Rats and mice received sodium fluoride in drinking water at concentrations as high as 800 ppm. (Concentrations are expressed as sodium fluoride; fluoride ion is 45% of the sodium salt by weight.) In the high-dose groups, 5/5 male and 5/5 female rats and 2/5 male mice died; one female rat was given 400 ppm in the drinking water also died before the end of the studies. No gross lesions were attributed to sodium fluoride administration. 6-Month Studies: Rats received concentrations of sodium fluoride in drinking water as high as 300 ppm, and mice as high as 600 ppm. No rats died during the studies; however, among the mice, 4/9 high-dose males, 9/11 high-dose females, and 1/8 males in the 300 ppm group died before the end of the studies. Weight gains were less than those of controls for rats receiving 300 ppm and mice receiving 200 to 600 ppm. The teeth of rats and mice receiving the higher doses of sodium fluoride were chalky white and chipped or showed unusual wear patterns. Mice and male rats given the higher concentrations had microscopic focal degeneration of the enamel organ. Rats receiving 100 or 300 ppm sodium fluoride had minimal hyperplasia of the gastric mucosa of the stomach, and one high-dose rat of each sex had an ulcer. Acute nephrosis and/or lesions in the liver and myocardium were observed in mice that died early, and minimal alterations in bone growth/remodeling were observed in the long bones of mice receiving sodium fluoride at concentrations of 50 to 600 ppm. The sodium fluoride concentrations selected for the 2-year studies in both rats and mice were 0, 25, 100, and 175 ppm in the drinking water. These concentrations were selected based on the decreased weight gain of rats at 300 ppm and of mice at 200 ppm and above, on the incidence of gastric lesions in rats at 300 ppm in the 6-month studies, and on the absence of significant toxic effects at sodium fluoride concentrations as high as 100 ppm in an earlier 2-year study. Body Weights and Survival in the 2-Year Studies: Mean body weights of dosed and control groups of rats and mice were similar throughout the 2-year studies. Survival of rats and mice was not affected by sodium fluoride administration. Survival rates after 2 years were: male rats-control, 42/80; 25 ppm, 25/51; 100 ppm, 23/50; 175 ppm, 42/80; female rats-59/80; 31/50; 34/50; 54/81; male mice-58/79; 39/50; 37/51; 65/80; female mice-53/80; 38/52; 34/50; 52/80. Neoplastic and Nonneoplastic Effects in the 2-Year Studies: The teeth of rats and mice has a dose-dependent whitish discoloration, and male rats had an increased incidence of tooth deformities and attrition leading on occasion to malocclusion. The teeth of male and, to a lesser degree, female rats had areas of microscopic dentine dysplasia and degeneration of ameloblasts. Dentine dysplasia occurred in both dosed and control groups of male and female mice; the incidence of this lesion was significantly greater in high-dose than in control male mice. Osteosclerosis of long bones was increased in female rats given drinking water containing 175 ppm sodium fluoride. No other significant nonneoplastic lesions in rats or mice appeared related to sodium fluoride administration. Osteosarcomas of bone were observed in 1/50 male rats in the 100 ppm group and in 3/80 male rats in the 175 ppm group. None were seen in the control or 25 ppm dose groups. One other 175 ppm male rat had an extraskeletal osteosarcoma arising in the subcutaneous tissue. Osteosarcomas occur in historical control male rats at an incian incidence of 0.5%; (range 0-6%). The historical incidence is not directly comparable with the incidences observed in this study because examination of bone was more comprehensive in the sodium fluoride studies than in previous NTP studies of other chemicals, and the diet used in previous studies was not controlled for fluoride content. In the current study, although the pairwise comparison of the incidence in the 175 ppm group versus that in the controls was not statistically significant, osteosarcomas occurred with a statistically significant dose-response trend, leading to the conclusion that a weak association may exist between the occurrence of these neoplasms and the administration of sodium fluoride. No other neoplastic lesions in rats or mice were considered possibly related to chemical administration. Genetic Toxicology: Sodium fluoride was negative for gene mutation induction in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 with and without S9. In two laboratories, sodium fluoride was tested for induction of trifluorothymidine resistance in mouse L5178Y lymphoma cells; results were positive both with and without S9. Sodium fluoride was tested for cytogenetic effects in Chinese hamster ovary (CHO) cells in two laboratories. In the first laboratory, the sister chromatid exchange (SCE) test was negative with and without S9, and the chromosomal aberration (Abs) test was positive in the absence of S9; in the second laboratory, the SCE test was positive with and without S9, but no induction of Abs was observed. The laboratory that reported a negative result for Abs tested at doses below that shown to be positive at the other laboratory. Similarly, the positive SCE result was obtained at a higher dose and longer harvest time than used by the laboratory reporting the negative SCE response. Conclusions: Under the conditions of these 2-year dosed water studies, there was equivocal evidence of carcinogenic activity of sodium fluoride in male F344/N rats, based on the occurrence of a small number of osteosarcomas in dosed animals. "Equivocal evidence" is a category for uncertain findings defined as studies that are interpreted as showing a marginal increase of neoplasms that may be related to chemical administration. There was no evidence of carcinogenic activity in female F344/N rats receiving sodium fluoride at concentrations of 25, 100, or 175 ppm (11, 45, or 79 ppm fluoride) in drinking water for 2 years. There was no evidence of carcinogenic activity of sodium fluoride in male or female mice receiving sodium fluoride at concentrations of 25, 100, or 175 ppm in drinking water for 2 years. Dosed rats had lesions typical of fluorosis of the teeth and female rats receiving drinking water containing 175 ppm sodium fluoride had increased osteosclerosis of long bones^ref. Early geographical studies of cancer in areas that have naturally-occurring fluoride at different levels gave no indication of an effect on cancer rates associated with higher intakes of fluoride. Following widespread fluoridation to improve dental health in the United States and Britain, non-epidemiologists presented analyses of cancer data which they claimed demonstrated such an effect. However, subsequent large-scale comparisons of cancer rates in fluoridated and non-fluoridated areas for successive periods following fluoridation have not indicated any increase, either for all cancer or for malignancies across the range of individual sites. Studies undertaken specifically to examine the claims of the non-epidemiologists have, time-and-again, shown that, with the use of accurate data and correct statistical methods, the purported effects cease to be apparent. Details of the earlier evidence and claims are given in the 'Report of a Working Party on the Fluoridation of Water and Cancer' by Professor George Knox (1985) and of more recent analyses in Hoover et al. (1991a; 1991b; unpublished internal US PHS Memo, 1993^{ref1, ref2, ref3}). The present paper gives a brief overview of the evidence that fluoride in drinking water has not been shown to cause an increase in the risk of developing cancer and of the errors in the analyses that purport to show such an increase^ref. Initial claims that fluoride offers protection against atherosclerosis remain viable, but here too, much more directed research is needed. Early studies suggested that a water fluoride content greater than 1 ppm resulted in a lower prevalence of osteoporotic fractures. Recent epidemiologic data seriously question this conclusion and raise the possibility that even this relatively low level may increase the prevalence of osteoporotic hip fractures. Other elements, including calcium and magnesium, also vary in amount as water fluoride content varies, and it has proved difficult to distinguish the independent effects of the various nutrients in water from each other^ref. Although a recent bioassay showed increased frequency of bone cancer in rats with high oral intake of fluoride, the data are reported as equivocal evidence of carcinogenicity. In humans, occupational fluoride exposure may cause skeletal fluorosis, and our earlier follow-up of fluoride-exposed workers showed increased incidence of respiratory cancers. To further evaluate occupational fluoride exposure as a carcinogenic risk factor, we extended by approximately one decade the follow-up of a cohort of 425 men and 97 women employed for at least 6 months in the period 1924-1961 at the Copenhagen cryolite processing plant. Cryolite ore contains about 50% fluoride. METHODS: Cancer mortality was determined for the period 1941-1989, and incidence for 1943-1987. For comparison, we used national mortality rates and cancer incidence rates for the Copenhagen area. Among the men, 300 deaths occurred; 223 were expected. Respiratory (lung and laryngeal) cancers and violent death were responsible for most of this excess; rates for mortality from cardiovascular disease were close to the rates expected. Of the 423 male workers, 119 developed cancers; 103.6 were expected. There was excess incidence of cancers of the lungs (35 men; standard incidence ratio [SIR] = 1.35), larynx (5 men; SIR = 2.29), and urinary bladder (17 men; SIR = 1.84). Maximum incidence occurred after 10-19 years of employment, but otherwise, no stable relationship between cancer incidence and duration of employment was observed. The incidence of respiratory and urinary cancers was particularly high in men less than 35 years old at first employment. Cancers in female workers were too few to allow detailed evaluation. The increased incidence of respiratory cancers suggests that cigarette smoking was frequent in this cohort, despite the unremarkable cardiovascular mortality, but the disproportionate increase in the incidence of bladder cancer is difficult to explain by smoking habits alone. Because this industrial cohort was exposed to high concentrations of fluoride dust, heavy respiratory exposure to fluoride may have contributed to the increased cancer risk. If these workers inhaled a carcinogenic substance partly excreted in the urine, an increased incidence of respiratory and bladder cancers would not be inconceivable. The potential role of fluoride as a cause of bladder cancer needs to be explored^ref.
Symptoms & signs :
• acute toxicity : usually occurs within minutes of exposure. Ingested fluoride initially acts locally on the intestinal mucosa. It can form hydrofluoric acid in the stomach, which leads to GI irritation or corrosive effects. Following ingestion, the GI tract is the earliest and most commonly affected organ system. Once absorbed, fluoride binds calcium ions and may lead to hypocalcemia. Fluoride has direct cytotoxic effects and interferes with a number of enzyme systems; it disrupts oxidative phosphorylation, glycolysis, coagulation, and neurotransmission (by binding calcium). Fluoride inhibits Na⁺/K⁺-ATPase, which may lead to hyperkalemia by extracellular release of potassium. Fluoride inhibits acetylcholinesterase, which may be partly responsible for hypersalivation, vomiting, and diarrhea (cholinergic signs). Seizures may result from both hypomagnesemia and hypocalcemia. Severe fluoride toxicity will result in multiorgan failure. Central vasomotor depression as well as direct cardiotoxicity also may occur. Death usually results from respiratory paralysis, dysrhythmia, or cardiac failure^ref
• chronic toxicity (fluorosis) :
• osteofluorosis => hip fractures
• mottled enamel / dental fluorosis when exposure occurs during enamel formation
• neoplasms (osteosarcoma in teenagers)
• toxicity on reproductive apparatus
• neurobehavioural toxicity
• neon (₁₀Ne)
• sodium (₁₁Na)
• hypernatremia / hypernatronemia : >145 mEq/L

Aetiology :
• primary sodium excess
• excessive administration of hypertonic NaCl or NaHCO3 solutions
• replacement of sugars with salts in pediatric infusions
• primary water deficiency
• increased water loss
• renal loss => sodium-independent polyuria
• hyperaldosteronism
• Liddle syndrome
• diuretics
• hyperglycemia
• loss of sodium chloride and hydrochloric acid due to prolonged vomiting (also metabolic alkalosis, hypochloremia, and hypokalemia)
• extrarenal loss
• increased perspiratio insensibilis
• fever
• physical exercise (hyperventilation)
• heat exposure
• severe burns
• mechanical ventilation
• profuse sweat (low sodium content)
• osmotic diarrhea
• adipsic or hypodipsic hypernatremia : an uncommon syndrome of chronic or recurrent episodes of severe hypernatremia with dehydration and lack of thirst, seen in persons with various congenital or acquired diseases of hypothalamic osmoceptors
• babies
• handicap
• patients with psychic disorders
• postoperatory period
• patients ventilated in ICUs
• genetic : Schenzel-Giedion midface-retraction syndrome (autosomal recessive)
• congenital :
• malformation of median line (septum and corpus callosum)
• microcephaly
• acquired
• vascular : occlusion of anterior communicating artery
• tumors
• primitive
• craniopharyngioma
• pinealoma
• dysgerminomas
• glioma
• metastases
• lung carcinoma
• breast carcinoma
• granulomatous
• neurosarcoidosis
• histiocytosis
• trauma
• closed
• penetrating (hypothalamo-hypophysary surgery)
• psychogenous (psychotic depression)
• hydrocephalus
• neurodegenerative diseases
• HIV-1
• HHV-5 / CMV encephalitis
• essential hypernatremia : osmoceptors are sensitive to volemia but not to plasma osmolality. Water intake induces secretion of AVP and causes further water loss
Symptoms & signs : when [Na⁺]_plasma > 160 mEq/L : neuron shrinkage => hypernatremic encephalopathy, parenchymatousor subarachnoid hemorrhage, astheny, neuromuscular irritability, focal neurological deficiency, coma and convulsions, polyuria, thirst (cold water in patients with central diabetes insipidus)
Laboratory examinations : plasma hyperosmolarity, loop diuretics, oliguria, urine osmolality > 800 mosmol/kg, natriuria > 100 mmol/L if caused by primary sodium exces
Therapy :
• hypovolemia with perfusion
• compromised : isotonic saline solution until adequate perfusion is restablished
• normal : saline solution or D5W
• renal failure : monitoring electrolyte loss and rehydration with p.o. or i.v. H₂O = [([Na⁺]_{plasma, current} - [Na⁺]_{plasma, desired}) ^. TBW]/[Na⁺]_{plasma, desired} = [([Na⁺]_plasma - 140) ^. body weight ^. (0.5 in men or 0.4 in women)] / 140 (approximatively 1 l of water every 3 mEq of increased natremia)
• seizures : free water
• diabetes  : ADH
• . -0.5 mmol/L/hr and < 12mmol/L/24 hrs
Side effect from too fast therapy : neuron swelling
• hyponatremia : < 135 mEq/L

Epidemiology : up to 4% of hospitalized patients in the USA each year^ref
Aetiology :
• according to plasma osmolality
• pseudohyponatremia
• isotonic hyponatremia (normal plasma osmolality)
• hyperlipidemia increases the serum non-water volume
• hyperproteinemia increases the serum non-sodium solute
• massive assorption of isoosmotic (mannitol) or hypoosmotic (sorbitol and glycine, metabolized to CO₂ and H₂O) solutions used for vesical irrigation after transurethral resection of prostate or bladder cancer
• hypertonic hyponatremia (increased plasma osmolality : they actually cause hypernatremia)
• hyperglycemia (- 1.4 mmol/L for every + 100 mg/dL of Glc; associated with relative hyperkalemia and hyponatremia due to osmotic polyuria)
• i.v. mannitol
• urea
• ethanol
• hypoosmolar hyponatremia
• primary sodium loss (secondary water increase)
• skin loss : sweat, burns
• gastrointestinal losses : vomiting, draining, fistulae, occlusion, secretory diarrhea
• renal losses : => hypernatriuria
• primary water increase / water intoxication and normal ECF volume : the condition induced by the undue retention of water with decrease in sodium concentration; it is marked by lethargy, nausea and vomiting, and mild mental aberrations, and in severe cases by convulsions and coma (secondary sodium loss)
• primary polydipsia (> 12 L/die)
• excessive infusion of glucosated solutions : in nondiabetic patients glucose is metabolized and has no osmotic effect, so diluting plasma
• reduced solute intake (e.g. beer potomania associated with low protein and electrolyte diet)
• ADH incretion induced by ...
• pain
• nausea and vomiting
• drugs : e.g. morphine, tricyclic antidepressants (TCA), clofibrate, antineoplastic agents, chlorpropamide, aminophylline, indomethacin
• SIADH
• hypoadrenalism : glucocorticoid deficiency induces ADH hyperincretion (directly due to cosecretion with ACTH and indirectly by inducing hypovolemia) and is more important than mineralocorticoid deficiency; euvolemia and decreased circulating effective arterial volume
• hypothyroidism : decreased CO => decreased GFR, increased ADH incretion, euvolemia and decreased circulating effective arterial volume
• chronic renal failure (CRF)
• hypovolemia and expanded ECF volume => primary sodium increase (overwhelmed by a secondary water increase and diuretics use)
• heart failure
• liver cirrhosis
• nephrotic syndrome
• acute renal failure or chronic renal failure (CRF) with oliguria when hydric intake overwhelms capability to eliminate equivalent volumes.
• according to plasma volume
• type I (hypervolemic or dilutional) hyponatremia : that in which there is a low plasma concentration of sodium resulting from loss of sodium from the body with nonosmotic retention of water
• edema
• type II (hypovolemic or depletional) hyponatremia : that in which there is a low plasma concentration of sodium associated with low total body sodium and hypovolemia
• hypoaldosteronism
• severe gastroenteritis
• abuse of loop diuretics
• type III (euvolemic) hyponatremia : SIADH
Symptoms & signs : neuron swelling (compensated by osmotic adaptation if chronic) => intracranial hypertension => neurological symptoms according to rapidity of onset and entity : nausea and vomiting, malaise, headache, sleepiness, confusion, obnubilation of sensation, stupor, convulsions, coma
Laboratory examinations : natriuria < 20 mmol/L (> 20 mmol/L in renal losses)
Therapy^ref :
• if hypovolemia : ripristinate euvolemia to eliminate stimuli for AVP incretion
• if hypervolemia : restriction of dietary water and sodium, correction of hypokalemia, loop diuretics, aquaresis with selective dual V_1a/V₂ antagonists (conivaptan). Vaprisol therapy will begin with a loading dose of 20 mg IV administration followed by 20 mg administered as a continuous infusion over 24 hours. Following the initial day of treatment, Vaprisol is to be administered for an additional 1 to 3 days as a continuous infusion of 20 mg/day. If serum sodium does not rise at the desired rate, Vaprisol may be titrated upward to a daily dose of 40 mg, again administered in a continuous infusion. Vaprisol is indicated for the treatment of euvolemic hyponatremia (e.g., the syndrome of inappropriate secretion of antidiuretic hormone, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorders, etc.) in hospitalized patients. Vaprisol is contraindicated in patients who have hypovolemic hyponatremia and in those who have hypersensitivity to any of its components. The co-administration of Vaprisol with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated. The common adverse reactions reported with Vaprisol administration include infusion site reactions, hypokalemia, headache, thirst and vomiting. The majority of the reactions were mild and did not lead to discontinuation of the drug. The use of Vaprisol in patients with hepatic impairment (including ascites, cirrhosis or portal hypertension) has not been systematically evaluated. Vaprisol is not indicated for the treatment of patients with congestive heart failure.
• if normovolemia : selective dual V_1a/V₂ antagonists (conivaptan)
• asymptomatic or moderately symptomatic patient : rise plasma concentration by < 0.5-1 mmol/L/hr (< 1-2 mmol/L/hr if natremia < 100-115 mmol/L) for 3-4 hrs; < 12 mmol/L in 24 hrs
• patient in coma or with convulsions : fast 3% NaCl infusion until symptoms remit or plasma concentration is 5 mEq/L
Side effects from excessively fast correction of natremia :
• central pontine myelinolysis
• osmotic demyelination syndrome (ODS), expecially in patients with chronic hyponatremia who have undergone osmotic adaptation => neuron shrinkage => flaccid paralysis, dysarthria and dysphagia
• magnesium (₁₂Mg)
• hypermagnesemia / magnesemia : > 2 mEq/L or > 1.3 mOsm

Aetiology :
• renal failure treated with
• magnesium-containing antacids
• magnesium-containing laxatives
• acute renal failure (ARF) due to rhabdomyolysis
• untreated ketoacidosis
• familial hypocalciuric hypercalcemia (FHH)
• hypovolemia
• hyperlithemia
• Epsom salt (magnesium sulfate) accidental ingestion
Symptoms & signs  : => hypoparathyroidism => hypocalcemia (see for symptoms & signs); loss of deep tendon reflexes, paralysis of respiratory muscles => respiratory depression and apnea; enlengthnment of PR tract, QRS complex and QT tract; complete AV block, cardiac arrest
Therapy : interruption of assumption; calcium replacement therapy
• hypomagnesemia : < 1.5 mEq/L or < 0.8 mOsm

Aetiology :
• increased renal excretion
• hypervolemia (as magnesium excretion is tightly related to that of sodium and calcium)
• hypercalcemia and hypercalciuria reduce tubular reabsorption
• osmotic diuresis in diabetes mellitus
• nephropathies with loss of magnesium
• metabolic acidosis
• Bartter syndrome
• drugs
• loop diuretics
• aminoglycosides
• cisplatin
• cyclosporine
• amphotericin B
• pentamidine
• increased intestinal losses
• vomiting (up to 0.5 mmol/L = 1 mEq/L = 1.2 mg/dL)
• nasogastric probe
• malabsorption
• ileitis
• colitis
• intestinal and biliary fistulae
• acute and chronic diarrhea (up to 7.4 mmol/L = 18 mEq/L = 15 mg/dL)
• ethanol (associated with hypophosphatemia and hypokalemia)
• intestinal resection or bypass
• endocrinopathies
• primary hyperparathyroidism
• hypoparathyroidism
• hyperthyroidism
• hypophosphatemia
• ketoacidosis
Symptoms & signs : => hypoparathyroidism => hypocalcemia (see for symptoms & signs) and hypokalemia
Therapy : replacement therapy by oral administration (side effect : diarrhea), i.v. infusion or intramuscular injection (painful). Monitor with magnesiuria.
• aluminum (₁₃Al)

Sources :
• enteral :
• use of aluminum pot for cooking
• antacids
• parenteral :
• hemodialysis including dialysate derived from aluminum-treated water^ref
• contaminated intravenous-feeding solutions^ref
• intravenous drug use^ref : concentrating an oral methadone solution by heating it and redissolving the residue allows the drug user to avoid injecting large volumes of fluid intravenously. The citric acid in the methadone preparation reacted with the aluminum oxide of the uncoated pot, resulting in water-soluble aluminum species^ref
Symptoms & signs :
• in the gastrointestinal tract aluminum inhibits absorption of :
• calcium and phosphates => osteomalacia
• fluorides
• iron => sideropenic microcytic anemia
• aluminosis (a pneumoconiosis from inhalation of bauxite fumes)
• progressive dialysis encephalopathy : neurological symptoms that can be fatal
• alopecia
• adynamic bone disease
Therapy : continuous intravenous infusion of desferrioxamine at a rate of 50 mg per hour
• silicon (₁₄Si)
• silica / silicon dioxide / silicic anhydride (SiO₂)

Aetiology : inhalation of SiO₂ tetrahedrons in ...
• crystals
• quartz / rock crystal (a crystalline form of silica) dust (> 100 particles/L air)
• dust of stone (marble, ...) in stone quarries and mines
• mason's lung : pneumoconiosis (usually silicosis) in stone masons due to the inhalation of stone dusts
• sand (small, gritty particles, usually of some mineral such as silica) (sand-sprayers, glass-factories; mountain desert silicosis in high landers of the Himalayas)
• thermorefractory iron furnace in foundries : only crystalline silica is toxic but amorphous silica may transform into crystalline silica after heating
• flint
• agate
• amethyst
• chalcedony
• cristobalite : a translucent crystalline form of silica used in casting investments because it has a high capacity for thermal expansion and is resistant to being broken down by heat
• tridymite
• non-crystalline
• pyrophillite (pyrophillitosis) : tiny irregular branching structures (TIB) have a centrilobular distribution and are characteristic of pyrophillitosis; small round opacities (SRO) have both centrilobular and perilobular distributions and are considered to be changes modified by the aspiration of silica. Large opacities (LO) of pyrophillitosis are classified into 3 types, that is, spherical type (seen in patients exposed to both pyrophillite and silica), flat type (seen in patients exposed to only pyrophillite) parallel to the bronchus and flat type parallel to the thoracic wall
• major constituent of dental porcelain
• pumice stone dust (liparosis from Lipari Islands in Italy)
• common filler in resin composites
• in granular form it serves as a dental abrasive and polishing agent
• graphite dust, which often contains up to 10% silica (graphite fibrosis or pneumoconiosis / graphitosis)
• dust of diatomite (hard, dry infusorial earth) (diatomite fibrosis)
• volcanic ash
• taconite is a low-grade iron ore consisting of iron, quartz, and numerous silicates. Taconite from the eastern tip of the Mesabi Iron Range contains the amphibole silicate cummingtonite-grunerite, which is a mineral relative of amosite asbestos.
Symptoms & signs : silicosis / pneumosilicosis / grinders' disease (pneumoconiosis with formation of generalized nodular fibrotic changes in both lungs. Alveolar macrophages secrete fibronectin, a fibroblast chemokine and growth factor => in early stages of experimental silicosis an excessive amount of collagen accumulates in the lung. Later, some of the deposited collagen is resorbed. Since many common minerals contain silica, there are numerous different types of silicosis). "onion-shaped" nodules are continuously growing multiple layers of connective tissue separating alternating layers of fibroblasts and alveolar macrophages => there is no correlation between dose and latency of disease (even after 40 years). Nodules are placed in upper and middle lobes and parahilar regions (near bronchovascular foci of pulmonary veins and pleural surfaces). Lymphadenomegaly (lack of intranodal calcifications allows differential diagnosis with pulmonary tuberculosis). Classical radiographic features are the presence of small rounded opacities or nodules in the lung parenchyma : peripheral eggshell calcification may occur in hilar and peritracheo-bronchial  lymph nodes (uniformly calcified and hyperdense LNs are common in silicosis but eggshell LN calcification is rare : they are also seen in patients with coal-worker's pneumoconiosis, sarcoidosis, postirradiation Hodgkin disease, blastomycosis, scleroderma, amyloidosis and histoplasmosis), and eventually the diseases may be complicated by the development of large massive areas of fibrosis in the upper lung zones and paracicatricial emphysema. Confluent radioopacities are termed silicomas. There are associations between LN attenuation and lung function impairment, and CT grades of nodular profusion and progressive massive fibrosis.
• micronodular silicosis
• reticulomicronodular silicosis
• nodular silicosis
• reticular silicosis (massive but not diffuse)
Complications :
• progressive massive fibrosis (PMF)
• silicoproteinosis : a rapidly fatal pneumoconiosis occurring several weeks to months after massive exposure to silica dust, characterized by the presence of proteinaceous fluid in the air spaces.
• silicotuberculosis / infective silicosis / tuberculosilicosis : silicosis followed by pulmonary tuberculosis (due to exhaustion of alveolar macrophages)
• Caplan's syndrome / rheumatoid pneumoconiosis : silicosis + rheumatoid arthritis
• lung carcinomas (IARC group 1 carcinogen)
Necroptic findings :
• early stages : normal  lung, chronic bronchitis, emphysema and fibrosis
• late stages : hard, palpable sclero-anthracotic (black) nodules at hilus entrapped within cicatricial lesions that tend to confluence (look as vulcanized gum). Polarizing light microscopy detect silica crystals (starred sky look). Subpleural nodules may cause lateral pleural symphysis. When caseous necrosis is present it is termed pseudotuberculosis.
• phosphorus (₁₅P)
• hyperphosphoremia : an excessive amount of phosphorus compounds in the blood
• hyperphosphatemia (> 5 mg/dL or > 1.6 mmol/L in adults; higher in babies); it is usually asymptomatic.
Aetiology :
• decreased renal clearance
• acute renal failure (ARF)
• chronic renal failure (CRF)
• hypoparathyroidism
• hypothyroidism
• tumoral calcinosis
• bisphosphonates
• acromegalic disease
• others
• ingestion or inhalation  of phosphorus
• hypervitaminosis 1a,25-(OH)₂-vitamin D₃
• acidosis
• rhabdomyolysis => crush syndrome
• tumour lysis syndrome (TLS)
• fulminant hepatitis
• movement of phosphates from intracellular into extracellular compartment
• menopause
• babies within age 1
• laboratory artefacts due to hemolysis
• thrombocytolysis in thrombocytosis and multiple myeloma : in pseudohyperphosphatemia PO₄^2- binds to the abnormal immunoglobulin, so that total phosphate is increased, but ionized phosphate is normal and no treatment is required^ref
Symptoms & signs :
• acute : due to hypocalcemia (hypercalcemia in hypervitaminosis 1a,25-(OH)₂-vitamin D₃) and hypovitaminosis 1a,25-(OH)₂-vitamin D₃ => secondary hyperparathyroidism
• white phosphorus (a.k.a. "Willy Pete" in military slang) burns when exposed to air. If tissue is exposed to it, it produces a painful burning sensation. The white phosphorus can be removed underwater, which would also prevent the spontaneous fires. Treating patients who have ingested the substance is much more difficult and may prove unrewarding^ref
• chronic
• calcinosis if associated with normocalcemia
• phosphorus necrosis / phosphonecrosis / phossy jaw : necrosis of the jaw, sometimes associated with deposition of new subperiosteal bone, occurring in workers exposed to yellow phosphorus fumes
• toothache
• anorexia
• weakness
• anemia
Therapy :
• aetiological
• symptomatic : the inability to exclude phosphorus from the diet
• hemodialysis (incomplete removal of phosphorus)
• oral phosphorus binders
• aluminium-containing binders (side effect : aluminosis)
• aluminum hydroxide (Al(OH)₃)
• calcium-containing binders (side effects : vascular calcification)
• calcium carbonate (CaCO₃)
• calcium acetate (CaAc₂)
• magnesium hydroxide (Mg(OH)₂)
• sevelamer hydrochloride / PAA-B (a cross-linked polymeric amine : RenaGel^®). It also exhibits bile acid-binding properties resulting in LDL cholesterol lowering but does not interfere with digoxin or warfarin pharmacokinetics.


• lanthanum (III) carbonate hexahydrate (Fosrenol^® : La₂(CO₃)₃ ^. 6H₂O) has very low tissue uptake, and is a good example of low bioavailability being exploited to good effect. Its high stability and insolubility allows safe removal of phosphate from the circulation of patients with kidney failure
• mixed metal hydroxy-carbonate compounds (MMHCs)
• MgFe hydroxy-carbonate
• hypophosphoremia
• hypophosphatemia (< 2.81 mg/dL or < 0.87 mmol/L)
Aetiology :
• dietary deficiency
• defective intestinal phosphate absorption
• malabsorption
• phosphate-chelating antacids
• hyperinsulinism (insulin secretion after carbohydrate-rich meals or insulin HRT) => movement from extracellular into intracellular compartment (0.3-0.5 mmol/dL = 1-1.5 mg/dL)
• increased renal phosphate excretion => hyperphosphaturia
• mixed disorders
• hypovitaminosis 1a,25-(OH)₂-vitamin D₃ (decreased intestinal absorption, secondary hyperparathyroidism)
• hypophosphatemic bone disease (HBD)
• alkalosis
• rapid correction of chronic respiratory acidosis => myasthenia of diaphragm => worsen respiratory failure
• ketoacidosis => degradation of intracellular and organic phosphorus => hyperphosphatemia => hyperphosphaturia
• corrected ketosis
• blastic crises during leukemia (phosphorus enters cells with high mitotic index)
• malnutrition
• insulin HRT
• hungry bone syndrome after parotidectomy
• recovery after hypothermy^{ref1, ref2}
• sepsis
• PDGFR inhibitors (imatinib)
• ethanol addiction and abstinence (dietary deficiency, aluminum or calcium-containing antacids; hypocalcemia and hypovitaminosis 1a,25-(OH)₂-vitamin D₃ => secondary hyperparathyroidism; alcoholic ketoacidosis)
Symptoms & signs :
• acute
• hypercalcemia
• decreased ATP and creatine phosphate =>
• intravascular hemolysis^{ref1, ref2}, decreased 2,3 DPG => tissue hypoxia => hyperventilation
• decreased phagocytary function and opsonization => increased susceptibility to bacterial and fungal infections
• myopathy : myasthenia and myalgia => rhabdomyolysis and respiratory failure
• metabolic encephalopathy => irritability, apprehension, torpor, paraesthesia, epilepsy => coma => death
• upper gastrointestinal hemorrhages
• pancreatitis
• pneumonia
• cardiomyopathies : ventricular arrhythmia
• systemic arterial hypotension
• chronic : rickets in babies, osteomalacia in adults, expecially associated to phenobarbital use
• sulfur (₁₆S)
• chlorine (₁₇Cl)
• hyperchloremia (> 111 mEq/L)

Aetiology : sources of exposure to chlorine include
• chlorination is used in water disinfection.
• swimming pools
• sewer systems
• industrial bleaching
• chemical warfare : chlorine gas (a greenish-yellow gas with pungent odor) was 1st used by the Germans in 1915 in World War 1 as a chemical weapon
This is not intended to be a comprehensive list. Although chlorine gas has a detectable odor, our sense of smell does not tell us when it is above a dangerous level.
Pathogenesis : chlorine gas is moderately soluble in water. It reacts with the moisture in the respiratory system to result in irritation of the respiratory system, the eyes, the nose, and almost any other mucus membrane. The irritation is prolonged in moist conditions. Chlorine may combine with the water to form hypochlorous and hydrochloric acid, which are intensely irritating. Chlorine gas is greenish-yellow and generally heavier than air, so it stays near the ground; without a wind, or in damp conditions, it is not immediately dissipated
Symptoms & signs : chlorine gas toxicity produces acute effects including inflammation of the
• conjunctivae
• nose
• pharynx
• larynx
• trachea
• bronchi.
Irritation of the airway mucosa causes local edema or swelling and may be secondary to active arterial and capillary hyperemia. Plasma exudation causes alveolar edema, resulting in pulmonary congestion, which may lead to death, particularly in individuals with compromised respiratory systems. The eyes may burn and tear and corneal ulcers may occur. Generally the eyes will heal without many long-lasting sequelae. Generally the affected individuals have a cough, chest pain, eye pain, nausea or vomiting, tearing, pain and tightness in the throat, choking and headache. These must be differentiated from the symptoms of asthma, chronic obstructive pulmonary disease, intoxication with phosgene, cyanide, hydrogen sulfide and ammonia
Laboratory examinations : hyperchloruria
• hypochloremia / hypochloridemia (< 95 mEq/L)

Aetiology : loss of sodium chloride and hydrochloric acid due to prolonged gastric vomiting (also metabolic alkalosis, hyponatremia, and hypokalemia)
Symptoms & signs : hypochloruria
• potassium (₁₉K)
• hyperkalemia / hyperkaliemia / hyperpotassiemia (> 5.3 mEq/L)

Aetiology :
• excessive intake
• excessive parenteral K⁺ administration
• potassium-rich fruits (grapes, cherry, apricot)
• shift from intracellular to extracellular compartment
• b-blockers
• hypoinsulinism
• hyperkalemic periodic paralysis (HYPP) : mutations in SCN4A (precipitated by stimuli that normally cause mild hyperkaliemia, e.g. physical exercise)
• hyperosmolality (e.g. hyperglycemia)
• moderate or intense physical exercise => loss from skeletal muscle fibers => glycogenolysis and local vasodilatation; usually self-limiting and followed by a reboud hypokalemia
• intravascular hemolysis
• tumor lysis syndrome (TLS)
• rhabdomyolysis
• metabolic acidosis (+ 0.6 mmol/L for any decrease of 0.1 pH unit; due to intracellular H⁺ buffering; except acidoses due to organic acids, which are readily transported into cells)
• Na⁺/K⁺ ATPase inhibitors
• voltage-gated Na⁺ channel blockers
• defective renal excretion or oligoanuria => hypopotassiuria
• pseudohyperkalemia : a laboratory artifact in which serum potassium is elevated when plasma potassium is normal.
• thrombocytosis or leukocytosis, most commonly in myeloproliferative disorders, because blood clotting causes the release of potassium from platelets and leukocytes. Prevention : measure K⁺ concentration in plasma rather than in serum
• prolonged use of hemostatic lace
• prolonged movements of fingers before sampling
• hemolysis
Pathogenesis : partial membrane depolarization => hypoexcitability
Symptoms & signs (rare below 6 mM : many patients with chronic renal failure tolerate hyperkaliemia up to 6.5 mM withot symptoms) :
• myasthenia => flaccid paralysis (hypoventilation if respiratory muscles are involved)
• lingual paraesthesias
• inhibition of renal ammoniogenesis and NH₄⁺ reabsorption in thick ascending limb of Henle's loop => metabolic acidosis => further hyperkalemia
Laboratory examinations :
• EKG abnormalities (widened or raised T waves (tent-shaped T wave), depressed P waves; severe hyperkalemia : enlengthned PR tract, wide QRS complexes fusing with T wave (sinusoidal wave), delayed atrioventricular conduction and disappearance of P wave => ventricular fibrillation or atrial asystolia)
• hyperkaliuria > 200 mmol/die (except in defective renal excretion). TTKG > 10 suggests hypoaldosteronism (normalized by MR agonists) or aldosterone resistance. [Renin and aldosterone]_plasma are measured in clinostatic and orthostatic positions after 3 days with Na⁺_diet < 10 mmol/die and loop diuretics to induce mild loop diuretics
Therapy :
• K⁺ should not be added to maintenance therapy of postoperatory patients in the first 24 hrs
• when [K⁺]_plasma < 6 mM : decreased  intake with diet
• when [K⁺]_plasma > 6 mM acutely or with EKG alterations :
• i.v. calcium gluconate to reduce membrane excitability within seconds to minutes
• NaHCO₃ 134 mmol/L induces transcellular shifts within 30-60'
• b₂-AR agonists
• 10-20 IU insulin (to induce cellular captation) + 25-50 g Glc (to avoid hypoglycemia; except in patients with hyperglycemia) act within 30-60'
• diuretics
• p.o. (act after > 6 hours) or per rectum (act within 1-4 hrs) potassium-binding ion exchange resins bind and hasten excretion  of K⁺ secreted into colon (polystirene sodium sulfonate exchanges Na⁺ with K⁺ : 25-500 mg + 100 mL sorbitol to prevent constipation, except in postoperatory period when risk of necrotizing colitis is higher, expecially after kidney transplantation)
• hemodialysis or peritoneal dialysis induces K⁺ movement across a concentration gradient and is then excreted (immediate action)
Course : -0.5 -1.5 mmol/L in 15-30'
• hypokalemia / hypokaliemia / hypopotassemia (< 3.5 mEq/L)

Aetiology :
• decreased intake
• malnutrition
• decreased absorption (from 90% to 40-50%) in chronic renal failure (CRF)
• argilla ingestion in South-American Afro-Americans (it binds dietary potassium and iron)
• transcellular shifts
• metabolic alkalosis (less severe due to low intracellular buffering)
• hormonal causes
• insulin stimulates Na⁺/H⁺ antiporter and indirectly Na⁺/K⁺ ATPase
• VIPoma
• endogenous or exogenous b₂-AR agonists
• a-AR antagonists
• diuretics
• theophyllin
• amphotericin
• primary hyperaldosteronism
• renal artery stenosis
• anabolic state
• vitamin B₁₂ or folic acid (erythropoiesis)
• GM-CSF (leukopoiesis)
• total parenteral feeding (TPF)
• other causes
• pseudohypokalemia : in patients with leukocytosis, WBCs captate K⁺ at room temperature. Prevention : blood surgelation or early separation of plasma (or serum) from blood cells
• massive transfusions of congelated RBCs (they lose half their potassium content during preservation, so then they uptake it from recipient's plasma)
• hypothermy
• hypokaliemic periodic paralysis (HOKPP1) : mutations in CACNA1S, SCN4A, or KCNE3
• barium toxicity
• excessive potassium loss by
• renal route => hyperpotassiuria
• gastrointestinal route
• loss of sodium chloride and hydrochloric acid due to prolonged vomiting (not direct loss but indirect loss : metabolic alkalosis and hypovolemia => hyperaldosteronism => hyperpotassiuria ; also hyponatremia and hypochloremia)
• nasogastric tube suction
• secretory diarrhea
• massive burns (combined hypovolemia => hyperaldosteronism and tissue damage)
• profuse sweat
Pathogenesis : hypokaliuria (< 15 mmol/die; except in losses by renal route), increased proximal HCO₃^- reabsorption, increased renal ammoniogenesis and increased distal H⁺ secretion => hypobicarbonaturia and increased HCO₃^- neoproduction => metabolic alkalosis (metabolic acidosis in RTA or chronic diarrhea), nephrogenic diabetes insipidus, impaired glucose tolerance (due to both reduced insulin incretion and peripheral insulin resistance)
Symptoms & signs :
• when [K⁺]_plasma < 2.5 mM : neuromuscular disorders ranging from weakness, fatigue, and myalgia (causing hypoventilation if involving respiratory muscles) to paralysis, rhabdomyolysis, and ileus
Laboratory examinations :
• when [K⁺]_plasma < 3 mM : EKG abnormalities (poorly related with plasma concentration; exacerbated by metabolic alkalosis, digoxine and hypercalcemia) due to delayed ventricular repolarization : flattening or inversion of the T wave, elevation of the U wave, underleveling of the ST tract and enlengthnment of QT and QU tract (differential diagnosis with other causes of ST segment elevation); severe hypokalemia also leads to enlenghtnment of PR tract, decreased voltage and enlargement of QRS complex and risk of ventricular arrhythmia
• as few solutes are reabsorbed in the medullary collecting duct (MCD) and K⁺ isn't secreted or reabsorbed in the MCD, transtubular K⁺ concentration gradient (TTKG) = [K⁺]_{cortical collecting duct (CCD)} / [K⁺]_plasma = ([K⁺]_urine^. osmolality_plasma) / ([K⁺]_plasma^. osmolality_urine). If TTKG >4 => renal loss due to increased distal K⁺ secretion.
Therapy : p.o. (safer than i.v., but i.v. is recommended when [K⁺]_plasma < 3 mM) K⁺ up to 40 mM up to 20-40 mEq/hr (K⁺bicarbonate or citrate - metabolized to HCO₃^- - are used to treat hypokalemia associated with metabolic acidosis) under EKG monitoring. Too fast correction may led to hyperkalemia
• calcium (₂₀Ca)
• calcicosis (a pneumoconiosis)
• hypercalcemia / calcemia / hypercalcinemia (> 10.5 mg/dL or > 2.55 mM (ionized Ca²⁺ > 5.5 mg/dL) ; value inversely relates to
• volemia
• albuminemia (check protidemia and protidogram). In patients with hypoalbuminemia corrected calcemia => total measured calcemia + (4.0 - albuminemia [g/dL]) ^. 0.8  [mg/dL]
Aetiology :
• primary hyperparathyroidism
• paraneoplastic hypercalcemia (a systemic oncological emergency)
• leukemia
• multiple myeloma (20-40%) due to OAF : in pseudohypercalcemia Ca²⁺ binds to the abnormal immunoglobulin, so that total calcium is increased, but ionized calcium is normal and no treatment is required^{ref1, ref2, ref3}
• bone cancer
• breast canrcinoma (7-8%)
• head & neck and gastrointestinaltumors (6-9%)
• osteolytic bone metastases (average survival after diagnosis < 6 months)
• cancers secreting humoral mediators of hypercalcemia
• renal adenocarcinoma
• lung adenocarcinoma / NSCLC (27-35%)
• hypervitaminosis 1a,25-(OH)₂-vitamin D₃
• associated with high bone remodeling
• hyperthyroidism
• immobilization
• thiazide diuretics
• hypervitaminosis A
• associated with renal failure
• milk-alkali syndrome / Burnett's syndrome / hypercalcemia syndrome : a syndrome characterized by hypercalcemia without hypercalciuria or hypophosphatemia, with only mild alkalosis, normal serum phosphatase, severe renal insufficiency with hyperazotemia, and calcinosis, attributed to ingestion of milk and absorbable alkali for long periods of time to treat peptic disease
• hypophosphatasia : a genetic metabolic disorder resulting from serum and bone alkaline phosphatase deficiency leading to hypercalcemia, ethanolamine phosphatemia, and ethanolamine phosphaturia.

Symptoms & signs : severe skeletal defects resembling vitamin D–resistant rickets, failure of the calvarium to calcify, dyspnea, cyanosis, nausea and vomiting, constipation, nephrocalcinosis, failure to thrive, disorders of movement, beading of the costochondral junction, and rachitic bone changes (bowing). 3 clinical types based upon age of onset and the severity of the symptoms
• autosomal recessive
• infantile, the severest, lethal in over 50% of the cases
• childhood, whose first symptom is usually the spontaneous loss of the deciduous teeth
• autosomal dominant : adult, mildest form
• pseudohypophosphatasia : a condition resembling hypophosphatasia, characterized by osteopathy of the skull and long bones, muscular hypotonia, hypercalcemia, and increased urinary excretion of phosphoethanolamine. It is distinguished by normal alkaline phosphatase activity
• calciphylaxis / calcific uremic arteriopathy (CUA) / uremic small artery disease with medial calcification and intimal hyperproliferation : the formation of calcified tissue in response to administration of a challenging agent subsequent to induction of a hypersensitive state.
• systemic calciphylaxis : the generalized appearance of calcifications in internal organs or tissues, occurring in response to intravenous or intraperitoneal injection of the challenging agent.
• topical calciphylaxis : the formation of a circumscribed area of calcification in response to subcutaneous injection of the challenging agent
Risk factors : CAD, PAD, ESRD, hyperhomocysteinemia, secondary hyperparathyroidism
Symptoms & signs : ischemic ulcers in lower limbs
Laboratory examinations : Rx to detect calcifications, biopsy
Therapy :
• local : EMLA anaesthetic, antisepticals, debridment, amputation
• systemic : Duragesic, nitroglycerin, antibiotics, 1,25-(OH)₂-vitamin D₃, parotidectomy, phosphate-poor diet
Prognosis : 50% undergo exitus
Symptoms & signs :
• myasthenia
• depression
• anorexia
• nausea and vomiting
• constipation => ileus
• lethargy => coma
• calcinosis : a condition marked by the deposition of calcium salts in various tissues of the body.
• calcinosis cutis
• calcinosis circumscripta : localized deposition of calcium in small nodules in subcutaneous tissues or muscle, usually in systemic scleroderma or dermatomyositis.
• calcinosis universalis : widespread deposition of calcium salts in the dermis, panniculus, and muscles, in the form of nodules or plaques, most often in juvenile dermatomyositis
• soft tissues calcinosis
• bilateral nephrocalcinosis => nephrolithiasis => relapsing renal colics
• calcinosis intervertebralis / chondritis intervertebralis calcanea / Verse's disease : deposit of calcium in one or more intervertebral disks
• gastic mucosal calcinosis
• blood vessel walls calcinosis
• chondrocalcinosis
• pancreas calcinosis
• calcifications in anterior chamber of eye
• tumoral calcinosis : development of large periarticular masses about the shoulder, elbow, and hip, marked by symptoms such as sciatica due to pressure on adjacent nerves. It is of unknown etiology, with onset usually in the first or second decade of life.
• hypophoshoremia
• hypercreatininemia
Laboratory examinations : EKG : ST segment elevation (differential diagnosis with other causes)
Therapy :
• removal of tumour
• hydratation
• asymptomatic hypercalcemia < 12.5 mg/dL => oral hydratation (+2-4 L/die)
• hypercalcemia > 12.5 mg/dL or symptomatic => 150-200 mL/hr physiological solution up to 250-300 mL with monitoring of heart and renal function
• loop diuretics (furosemide 20-80 mg i.v. every 4-6 hours)
• r-calcitonin
• bisphosphonates
• hypocalcemia (< 8.5 mg/dL or < 2.10 mmol/L)

Aetiology :
• hypoparathyroidism (parathyroid tetany / parathyroprival tetany)
• uneffective PTH
• pseudohypoparathyroidism
• hypovitaminosis 1a,25-(OH)₂-vitamin D₃
Pathogenesis : metabolic acidosis is a compensation to hypocalcemia and its sudden correction with bicorbanates may cause tetany
Symptoms & signs :
• acute
• tetany : hyperexcitability of nerves and muscles causing carpopedal spasm, muscular twitching and cramps, bronchospasm, laryngospasm with inspiratory stridor, hyperreflexia, peripheral and perioral paraesthesia, anxiety, choreiform movements, Chvostek-Weiss-Schultze or facial sign (spasm of the facial muscles elicited by tapping the facial nerve in the region of the parotid gland; seen in tetany), Trousseau phenomenon or sign (spasmodic contractions of muscles provoked by pressure upon the nerves which go to them), Hochsinger's phenomenon (pressure on the inner side of the biceps muscle produces closure of the fist), Pool's phenomenon (the arm muscles contract when the arm is raised above the head with the forearm extended, so as to cause stretching of the brachial plexus), Escherich's reflex or sign (percussion of the inner surface of the lips or tongue produces contraction of the lips, tongue, and masseter muscles), Pool's or Schlesinger's sign or phenomenon (if the patient's leg is held at the knee joint and flexed strongly at the hip joint, there will follow within a short time an extensor spasm at the knee joint, with extreme supination of the foot), Erb sign (), QT tract enlengthnment; only irritability and lethargy in babies. Threshold is lowered by hypomagnesemia and alkalosis, lifted by hypokalemia and acidosis
• duration tetany (Dt) : a continuous tetanic contraction in response to a very strong continuous current; it occurs especially in degenerated muscles
• gastric tetany : a severe form due to disease of the stomach, attended by difficult respiration and painful tonic spasms of the extremities.
• hyperventilation tetany : tetany produced by forced inspiration and expiration continued for a considerable time.
• latent tetany : tetany elicited by the application of electrical and mechanical stimulation.
• neonatal tetany / tetany of newborn : hypocalcemic tetany occurring in the first few days of life, often marked by irritability, muscular twitchings, jitteriness, tremors, and convulsions, and less frequently by laryngospasm and carpopedal spasm.
• chronic : hypocalcemic cataract, rickets in babies, osteomalacia in adults, expecially associated to phenobarbital use
• hyperphosphoremia
Therapy : i.v. calcium gluconate
• titanium (₂₂Ti)
• titanium carbide

Symptoms & signs : hard metal diseases (a pneumoconiosis)
• titanium dioxide (TiO₂)

Symptoms & signs : titanium dioxide pneumoconiosis (a pneumoconiosis)
• vanadium (₂₃V) : a rare, gray, metallic element; atomic weight, 50.942. Its salts have been used in treating various diseases. Vanadium compounds representative of 3 different physiologically compatible oxidation states of vanadium, V(V), V(IV), and V(III), are currently being explored as orally available insulin-enhancing therapeutics for diabetes mellitus. Vanadium works in ways yet to be completely elucidated by regulating several enzymes, including specific kinases and phosphatases, possibly bypassing nonfunctional components of the insulin signaling pathway. In diabetic animals, vanadium normalizes blood glucose and lipids, and human clinical trials have indicated modest restoration of insulin sensitivity. V(IV) compounds tend to be relatively more effective as glucose-lowering agents than their V(III) and V(V) analogs. High bioavailability of any vanadium candidate glucose-lowering drug is desirable to minimize dose over long periods and reduce tissue accumulation, as vanadium has a particularly low toxicity profile and may increase oxidative stress, even in nutraceutical formulations. Several V(IV) complexes have been designed for treatmnt of type II diabetes : for example, a series of biguanides, including metformin, have been complexed to vanadium to produce vandayl metformin (wherein the ligand is a clinically approved type 2 agent) and analogs. Similarly, thiazolidinedione-type compounds (also containing a drug) have been used as ligands for V(IV) insulin-enhancing compounds. Both systems are orally active in animal models of diabetes.

Sources : vanadium pentoxide : a yellow to brown oxide of vanadium, used to add color and ultraviolet blocking to glass and as a component of photographic developers; its fumes can cause vanadiumism and vanadium bronchitis.
Symptoms & signs : vanadiumism : a chronic intoxication caused by absorption of vanadium compounds, usually via the lungs; symptoms include irritation of the respiratory tract (vanadium bronchitis), pneumonitis, nasal septal perforation, conjunctivitis, and anemia.
• chromium (₂₄C)

Sources :
• chromite (chromium iron oxide)
• metallic
• chromated compounds
• bivalent compounds : unstable, easily oxidized
• trivalent compounds
• hexavalent compounds
Applications :
• welding of stainless steel (high-efficiency electrodes)
• varnishing
• skin tanning
• chromates/bichromates
• galvanic baths
• diet
• dietary supplementation
Pathogenesis : toxicity relates to valence, solubility and route of intoxication
• Cr⁰ has no toxic effects
• Cr(III) compounds sensitize but are far less toxic than Cr⁶⁺. Cr³⁺ picolinate can be reduced to compounds of Cr²⁺ in the cells which can then produce free hydroxyl radical in the so called Fenton reaction : cell culture and in vivo rat studies have indicated that it probably generates oxidative damage of DNA and lipids and is mutagenic.
• Cr(VI) compounds are highly toxic (sensitize and oxidate) and carcinogenic
Routes of intoxications :
• skin : Cr⁶⁺ penetrates skin >> Cr³⁺
• GI-tract : 0.1-4.5% is absorbed (Cr⁶⁺ > Cr³⁺); gastric pH reduces Cr⁶⁺ to Cr³⁺ (reduction is impaired by starvation and achlorhydria)
• respiratory route : alveolar macrophages keep 97% of Cr³⁺ particles < 0.5 mm for as long as yers, while 80% of particles sized 0.5-2 mm are expired with air
=> intercellular transport (also intracellular for Cr⁶⁺) => in blood Cr³⁺ binds to siderophilin, while Cr⁶⁺ enters RBCs and is partly reduced to Cr³⁺. Blood half-life = 15-41 hours => renal and biliary clearance. Distribution relates to valence : Cr⁶⁺ enters epithelial cells.
Symptoms & signs :
• acute toxicity : DL₅₀ for adults : 50-70 mg/kg p.o. : vomiting, diarrhea, gastrointestinal hemorrhages => cardiovascular shock, acute tubular necrosis (ATN)
• chronic toxicity :
• dermatitis
• irritant contact dermatitis (ICD) : Cr⁶⁺ > Cr³⁺ binds -COOH groups => protein denaturation => orthoergic ulcerative dermatitis => chrome or tanner's ulcer (a 5-10 mm, "pigeon eye"-shaped ulcer produced by chromium or its salts that evolute to eschar and heals in 3 weeks leaving a scar with no increased risk of cancer; seen in tanners and others working in chromium). KCrO₄(a 0.5% soution is used for patch tests) is reduced by -SH groups in proteins to Cr³⁺, expecially in alkaline environments such as those of building workers (KCrO₄ concentration in cement : cement eczema)
• allergic contact dermatitis (ACD) (30% only in hands; 70% also in other locations)
• lung carcinomas (Cr⁶⁺; after as long as 15-20 years; cases up to 47 years after exposure have been described)
• atrophic rhinitis (pus and crusts) => painless ulceration => nasal septal perforation; olfaction is preserved (if only chromium is present)
• bronchopulmonary :
• irritative : obstructive and restrictive LRT and URT disease
• bronchial asthma
• nephropathies : increased [b-glucuronidase]_urine after ingestion > inhalation
• gastrointestinal tract : gastroduodenitis => ulcer; chromium enteropathy (mimicking IBDs)
• teratogen
Laboratory examinations : TLV (ACGIH) for 8 hour-exposure
• chromate : 0.05 mg/m²
• zinc chromate : 0.05 mg/m²
• chromite : 0.05 mg/m²
• metallic chromium : 0.5 mg/m²
• chromose and chromic salts : 0.5 mg/m²
• soluble and insoluble chromates : 0.05 mg/m²
• Cr²⁺ : 0.5 mg/m²
• Cr³⁺ : 0.05 mg/m²
• Cr⁶⁺ (insoluble and soluble) : 0.05 mg/m²
• chromyl chloride : 0.05 mg/m²
• exposure markers
• [Cr]_RBC (Cr⁶⁺)
• [Cr]_serum (Cr³⁺ > Cr⁶⁺)
• [Cr]_urine
• occasional sampling > 15 mg/g creatinine
• differential between monday morning and friday evening (after a week working) > 5 mg/g creatinine
• effect marker : [b₂m]urine if exposure was 2-20 mg/m³
Surveillance :
• chest X-rays
• spirometry
• [Cr]_urine
• liver and kidney function tests
• [b₂m and NAG-AAP]_urine  once a year
• manganese (₂₅Mn)
• hypomanganesemia

Symptoms & signs : heart and bone problems and in children, stunted growth
• hypermanganesemia :

Sources : the liver removes extra dietary manganese (mainly from leafy vegetables and tea) from the circulation, so ingested manganese is not a major concern. A series of active macrocycle compounds that are mimetics of MnSOD (Mn(II)) and catalase (Mn(III)) have proven active in rodent models as synthetic catalytic scavengers of ROS, and 2 are in clincal trials. The air is suffused with low levels of the metal stirred up from soil : when manganese is inhaled ...
• blood ferries it from lungs to the brain, where it can readily cross the blood-brain barrier
• head from the olfactor bulb straight to the striatum through the olfactory nerve. Anyway because rat nasal passages are proportionally much larger than people's and the animals breathe only though their noses, they should absorb 40 times more manganese by that route than people do.
Further manganese particles spewed from tailpipes are smaller than those from natural sources and therefore more likely to lodge deep in the lungs.
Pathogenesis : enter cells via SLC11A2
Symptoms & signs (manganism):
• low doses : exposure from methyl cyclopentadienyl manganese tricarbonyl (MMT), a substitute for tetraethyl lead as an additive to increase octane levels (which boosts engine performance and enables fuel to be burned more evenly) manufactured by Ethyl since 1950s and approved in Canada since 1976, is low : Canada, for example, allows < 18 mg MMT/L gasoline, and only a fraction of this amount is thought to reach the air as manganese particles. In the USA, the main additive is methyl tertiary butyl ether (MTBE), but the ease with which this potential human carcinogen can infiltrate groundwater at levels that can be smelled and tested has alarmed the public. The main selling points are that MMT is cheaper and reduces tailpipe emissions of nitrogen oxides, which include precursors to smog. Health Canada's latests assessment, in 1994, assumed a safe threshold of 110 ng/m³ for inhaled manganese. In USA, however in 1993  the EPA had set a lower threshold for inhaled manganese of 50 ng/m³, and in 1998 the RTI Toronto Exposure Study recommended a theshold of 20 ng/m³. MMT combusting-derived manganese includes highly soluble forms (manganese sulfate the most soluble form) that more readily cross from lung alveoli into the bloodstream than other forms in crustal dust. Vulnerable groups could be those with genetic prediposition, simultanous intake of other chemicals that induce pre-Parkinson's condition, or hyposideremia (that's important because MMT isnow being added to gas in some developing nations where many people are malnourished)
• high doses (in workers in manganese mines with airborne concentrations > 100 mg/m³ (known since 1837) ; in inhabitants around a manganese alloy plant in Beauharnois, near Montreal, Quebec; in 1% of welders after age 60 : they fix joints together with molten flux from metal bars that sometimes contain manganese, but iron in welding bars could compete with manganese for binding sites on proteins that transport it aacross the BBB, potentially counteracting any toxic effect) : manganese pneumonitis => manganism (a dreaded illness marked by parkinsonism, violent outbursts, and hallucinations).There is an elevated rate of Parkinson's disturbances in people living near a ferroalloy plant.
• iron (₂₆Fe). The measurement of serum iron concentration is subject to many variables, which may introduce substantial error into results. Such variables include inadequately processed glassware, contamination of reagents with very small amounts of iron, turbidity, and entrapment of iron in plasma proteins during their precipitation. The reagents used in some techniques may not be entirely specific for iron. The presence of free hemoglobin in concentrations too small to be detected visually may give erroneously high results by the atomic absorption methods unless protein-free extract of serum is routinely used.
• hyposideremia / hypoferremia / hypoferrism / iron deficiency / sideropenia (< 75 mg/dL or < 13 mmol/L for males; < 65 mg/dL or < 11 mmol/L for males)

Aetiology :
• deficitary intake
• physiologically diurnal rhythm; it decreases in late afternoon and evening, reaching a nadir near 9 p.m.
• serum iron concentration decreases at about the time of menstrual bleeding either when menses are under normal hormonal control or when bleeding occurs after withdrawal of contraceptive agents
• acute or chronic inflammatory processes or malignancy and following acute myocardial infaction. The serum iron concentration under these circumstances may be decreased sufficiently to suggest iron deficiency.
Symptoms & signs :
• sideropenic anemia
• Plummer-Vinson esophagitis
• pica
Laboratory examinations : ferritinemia  = 0-12 ng/mL = 0-4.8 nmol/L (suspect if 13-20 ng/mL = 5.2-8 nmol/L)
Therapy : replacement therapy. Although being equal in short-term efficacy and overall tolerability our results suggest a better gastrointestinal tolerability for iron sucrose. Larger trials are mandatory to prove a possible advantage of iron sucrose in short- and long-term efficacy as well as in tolerability over iron sulfate in the management of sideropenic anemia in inflammatory bowel disease^ref
• hypersideremia / hyperferremia / hyperferricemia / siderosis / iron overload (> 175 mg/dL or > 31 mmol/L for males; > 165 mg/dL or > 29 mmol/L for males)

Iron is essential for cell metabolism but also cytotoxic due to the ability to promote formation of highly ROSs, e.g. by Fenton's reaction at pH 3-5 (if the pH is too high, the iron precipitates as Fe(OH)₃ and catalytically decomposes the H₂O₂ to O₂):
• Fe²⁺ + H₂O₂ ----> Fe³⁺ + OH ^- + ^. OH
• Fe³⁺ + H₂O₂ ----> Fe²⁺ + ^. OOH + H⁺
Presumably for this reason and to limit its availability to siderophores of Bacteria Fe acquisition, transport, and storage are tightly regulated
Aetiology :
• physiologically diurnal rhythm; it increases to its maximum between 7 and 10 a.m..
• nutritional siderosis : excessive iron in the blood due to a diet very high in iron and low in protein and calories, such as in children who eat iron supplement tablets like candy
• Bantu siderosis : a form of siderosis observed among the Bantu people of southern Africa; it was formerly thought to be always caused by use of cast iron vessels for cooking and food storage, but in some families a hereditary susceptibility has been found.
• hereditary or idiopathic hemochromatosis
• chronic blood transfusions
• chemotherapy of malignancy : from the third to the seventh day after inception of chemotherapy of a variety of tumors
• iron deficiency anemia if such patients receive iron medication before blood is drawn for these measurement
• multiple vitamin preparation, which commonly contain about 18 mg of elemental iron per tablet : oral iron medication must be withheld for 24 h
• parenteral injection of iron dextran may result in a very high serum iron concentration (e.g., 500-1,000 mg/dl) for several weeks.
Pathogenesis : during iron overloads, hepatocytes secrete hepcidin
Symptoms & signs :
• acute toxicity : mild poisoning occurs at 20 mg iron /kg body weight and lethal toxicites are reached at 60 mg/kg body weight. Children are more susceptible than adults. Within 1-2 hours after the ingestion of doses of 10 to 20 mg/kg of the equivalent of elemental iron
• ulceration of the gastrointestinal tract => nausea and vomiting (hematemesis), diarrhea, and abdominal pain
• vasodilation with shock => metabolic acidosis
• if the toxicity is profound, subsequent systemic effects include secondary systemic arterial hypertension and shock as well as hepatoxicity => liver failure (hypocoagulation)
• chronic toxicity :
• siderosis : the deposit of iron in tissues
• siderosis bulbi : the deposit of an iron pigment within the eyeball.
• siderosis conjunctivae : a rust brown or yellowish discoloration of the conjunctiva due to the presence of an iron foreign body; the condition may also be seen in hemochromatosis.
• hepatic siderosis : the deposit of an abnormal quantity of iron in the liver
• pulmonary siderosis : a benign type of pneumoconiosis caused by the inhalation of iron particles; it usually becomes serious only when combined with silicosis (siderosilicosis)
• urinary siderosis : presence of hemosiderin granules in the urine.
• hemosiderosis : a focal or general increase in tissue iron stores due to deposit of an abnormal quantity of hemosiderin in RES cells, without associated tissue damage
• hepatic hemosiderosis : the deposit of an abnormal quantity of hemosiderin in the liver, usually in Kupffer cells, which is not associated with cirrhosis, as is hemochromatosis.
• pulmonary hemosiderosis : the deposition of abnormal amounts of hemosiderin in the lungs, due to bleeding into the lung. The hemosiderin is found mainly in alveolar macrophages, but also in the interstitium. It is seen in any condition, such as severe congestive heart failure, in which repeated hemorrhages into the lungs occur.
• hemochromatosis : a disorder due to deposition of hemosiderin in the parenchymal cells (mainly hepatocytes), causing tissue damage
• hereditary or idiopathic hemochromatosis
• neonatal or perinatal hemochromatosis : a rare fulminant disease of the liver, of unknown cause, characterized by massive deposition of iron in the liver, pancreas, heart, and endocrine glands; symptoms are those of neonatal hepatitis and appear in utero or within the first week of life, with death usually occurring by 4 months of age.
• secondary or acquired hemochromatosis
• siderochromatosis
• blood transfusions
• excessive dietary iron
• thalassemias
• sideroblastic anemias
• congenital atransferrinemia
• porphyria cutanea tarda
• alcoholic cirrhosis
Symptoms & signs : dysfunction of the :
• liver : liver cirrhosis, hepatosplenomegaly
• pancreas : diabetes mellitus
• heart :
• pituitary : hypogonadotropic hypogonadism
• bronze pigmentation of skin
• arthropathy
• alopecia.
Full development of the disease among women is restricted by menstruation and pregnancy.
Web resources :
• Hemochromatosis
• Hemochromatosis at CDC
• infections from :
• Listeria monocytogenes
• Yersinia enterocolitica
• Aeromonas hydrophila
• Escherichia coli
• Vibrio vulnificus
• Cunninghamella bertholletiae
• Rhizopus arrhizus
• parkinsonism
Laboratory examinations : ferritinemia > 400 ng/mL or > 160 nmol/L; hepcidin deficiency (either absolute or relative to iron overload) is the hallmark of hemochromatosis,2 and hepcidin homozygous mutations cause the most severe, juvenile form of the disease^ref.3
Therapy : specific management can include limiting iron absorption by using activated charcoal and/or by administering chelation therapy, ie. compounds that complex with iron in the gut (phosphates or bicarbonates) to produce insoluble salts. Gastric evacuation and cleansing of the colon may help reduce additional iron absorption. Iron intoxication may be treated with intravenous deferoxamine. CCBs (as Fe²⁺ enters cardiomyocytes and pituitary gland cells via L-type calcium channels).
Web resources : Iron overload at CDC
• iron oxide

Symptoms & signs : welder's lung (a pneumoconiosis)
HEMOCHROMATOSIS
Ernest Beutler, MD*
 

Definition
Hemochromatosis is generally considered to be a disease in which increased iron storage causes pathologic changes. However, the definition of hemochromatosis has undergone considerable evolution since the disorder was recognized as a distinct clinical syndrome in the late 19th century. Until the performance of plasma iron and ferritin determinations became commonplace, the designation was reserved for patients who had, as a result of iron deposition, frank cirrhosis of the liver and usually diabetes, bronzing of the skin, and cardiac disease. The disease was sometimes called "bronzed diabetes." But in the 1970s the definition of the disease gradually changed. Instead of being applied only to patients who had severe clinical manifestations of iron storage, patients who had elevated serum transferrin saturation and ferritin levels were also designated as having hemochromatosis, especially if they had the HLA type A4 B14 that was commonly associated with the disease. Even larger numbers of patients were considered to have hemochromatosis after the HLA-linked gene that was associated with the disease, HFE, was discovered.

But who, then, should be considered to have hemochromatosis? Only those with disease? Or those who merely have the genotype? No consensus exists concerning what definition is to be used. Classification :

• hereditary hemochromatosis
• classical hemochromatosis (hereditary hemochromatosis; HFE hemochromatosis) (Type 1)
• juvenile hemochromatosis (Type 2)
• chromosome 1q-linked
• abnormality of hepcidin
• transferrin receptor-2 deficiency (Type 3)
• ferroportin deficiency (includes some cases of African iron overload1,2) (Type 4)
• African iron overload
• secondary hemochromatosis
Primary (hereditary) hemochromatosis : the hereditary form can be divided into several subgroups. A numerical classification has been proposed (http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?235200), but such a system does not add to our understanding, since most of the forms of hemochromatosis can simply be designated by the mutation that is their cause, and some forms of iron storage disease (e.g., African iron overload) are not included.
Secondary hemochromatosis can arise in many disorders, inborn or acquired. These disorders have in common the fact that the patient is anemic. Transfusions of erythrocytes add, nearly stoichiometrically, to the body iron burden: each milliliter of red cells contains one milligram of iron. When anemia is accompanied by ineffective erythropoiesis, inappropriate absorption of iron from the gastrointestinal tract seems to be activated. Patients with anemias in which ineffective erythropoiesis does not play a role seem much less prone to hyperabsorb iron. Thus, it is patients with ineffective erythropoiesis who develop the largest iron burdens. Among the hereditary forms, the most common are the thalassemias; among the acquired forms, the acquired sideroblastic anemias predominate. Some causes of secondary hemochromatosis :
• hereditary disorders
• thalassemia3,4
• pyruvate kinase deficiency5,6
• dyserythropoietic anemia7–11
• glucose-6-phosphate dehydrogenase (G6PD) deficiency12
• hereditary spherocytosis13,14
• sideroblastic anemia (ALA-S deficiency)
• acquired disorders
• sideroblastic and other dyserythropoietic anemias15
• any anemia, except for that due to blood loss, in which multiple transfusions are required.
Penetrance of a mutation may be defined as the extent to which a phenotypic effect is exerted in individuals carrying the mutation. But which phenotypic effect? Clearly, the penetrance is a function of which endpoint is selected.
Penetrance of the homozygous HFE mutation : the C282Y mutation of the HFE gene is a very common one. About 15% of the northern European population is heterozygous; accordingly, one would expect over 5 per 1000 in the population to be homozygous, and this is, indeed, the case.
Biochemical penetrance: Relatively few studies have been conducted in which an unbiased population was screened for the C282Y mutation and the transferrin saturation and ferritin levels of the homozygotes were determined. Deugnier et al16 screened over 9000 individuals (3367 men and 6029 women) in France and found 10 homozygous men and 44 homozygous women. Although the population was relatively young, 80% of the men had transferrin saturations over 55%, and 44% of the women had transferrin saturations over 50%. In our study of patients in the health appraisal clinic of Kaiser Permanente in San Diego we found that among 152 homozygotes, 75% of men and 40% of women had a transferrin saturation higher than 50%.17–19 Serum ferritin levels were increased in 76% of the men and 54% of the women. In another small study all 5 homozygotes detected have transferrin saturations greater than 55%.20 Thus, there is agreement that homozygotes for the HFE C282Y mutation usually have increased serum transferrin saturation levels and increased serum ferritin levels. Clearly, there is a subset of homozygotes who do not show these biochemical stigmata. A few of these prove to be frequent blood donors, but most of them are not. It is simply that even on a biochemical level the homozygous state is not always expressed.
Clinical penetrance: Clinicians do not encounter many cases of full-blown hemochromatosis. Our attempts to obtain samples from patients with iron overload who manifested diabetes, cirrhosis, cardiomyopathy, and darkening of the skin from our own clinic and from major centers in which many patients with hemochromatosis are treated have met with very little success. Most of the many patients that have been diagnosed as having hemochromatosis have been diagnosed on the basis of biochemical changes and non-specific symptoms, such as fatigue and arthropathy. Neither common clinical experience21,22 nor autopsy series21,23–25 suggest that hemochromatosis is a common cause of death. However, it has been a common belief that milder symptoms are, in contrast, very common in patients homozygous for the C282Y mutation, and it has been suggested that most of the homozygous males will develop symptoms by the time they are 40 years of age.26 This impression that a mild phenotype exists (and the accompanying assumption that this leads to the more severe phenotype if not treated) has been based largely on uncontrolled observations in which the patients being assessed and the physician performing the assessment knew the diagnosis and could well have been influenced by it. Between 1998 and 2001 we had the opportunity for the first time to study a large population, genotyping all participants for the HFE mutations and comparing symptoms, laboratory findings, and survival in homozygotes for the HFE C282Y mutation, C282Y/H63D compound heterozygotes, and homozygous wildtype individuals. When we first presented our results at the ASH meeting in 2000, having analyzed data from 26,000 genotyped subjects,27 they were surprising. Although many homozygotes manifested the non-specific symptoms that are associated with hemochromatosis—fatigue, arrhythmias, impotence, and arthralgias—the prevalence of such symptoms proved to be no higher than those in homozygous wildtype controls (Figure 1). There was no demonstrable effect on lifespan. The only significant difference found between homozygotes for the C282Y mutation and controls was a higher prevalence of abnormal liver function tests. Upon completion of the study,17–19 the preliminary findings were confirmed. Only one of 152 homozygotes had the typical clinical syndrome of hemochromatosis and we estimated the clinical penetrance of the homozygous state to be of the order of 1% (Figure 1).
Symptoms and laboratory findings in white homozygotes for the C282Y mutation (light bars) and in wildtype controls (heavy bars). Adapted from the data of the Kaiser/Scripps study19

No one had expected the penetrance to be so low, and predictably, the results were greeted with considerable skepticism. In attempting to reconcile our data with the concept that the homozygous state had a much higher penetrance, it was suggested that the data were "flawed" in a number of respects. It was proposed that we were dealing with an unusually healthy population28 or a population with an extraordinarily healthy life style. Alternatively, it was proposed that our population was unusually "sickly" and that the manifestations of hemochromatosis had been obscured by the poor health of the controls.29 Obviously it is impossible to reconcile these two objections: the population cannot be too well and too sickly at the same time. But, in fact, neither criticism applies. The most cogent objection was that our study was biased by selecting a healthy population. If, indeed, patients with symptoms had been excluded because they did not attend a health appraisal clinic, having died or being taken care of in a more intense medical setting, we might have erroneously concluded that the penetrance of the homozygous state is very low. But there is a straightforward way to address this problem. If homozygotes were systematically excluded then the number found in the population should fall short of the number predicted by the Hardy-Weinberg equilibrium based on the gene frequency in the population. But in fact, the number of homozygotes actually exceeds the predicted number.17–19,30–32 Another way to examine the possible lethal effect of the hemochromatosis mutation is to examine the age distribution of homozygotes. Since hemochromatosis is a late-onset disease, one would expect underrepresentation of the homozygous genotype in the elderly if the disease caused an appreciable number of early deaths. No significant shift in age distribution has been observed. In fact, extensive meta-analysis of 161 publications giving gene frequency data and the number of homozygotes in each population confirms these results (J Waalen et al, unpublished). In the past two years numerous studies from different parts of the world have all confirmed these findings: The homozygous state is only rarely associated with illness17,22,33–36 (Figure 2). The percentage of homozygotes for the C282Y mutation (genotypic homozygotes) and of subjects with persistently elevated transferrin saturation and ferritin (phenotypic homozygotes) who consider themselves to be in less than good or excellent health. Based on the data from Åsberg et al34) :

Figure reprinted with permission from Beutler E. Response to Ajioka and Kushner. Blood. 2003;101:3354–3357.[Free Full Text]
Why, then, is there a controversy about the penetrance of hemochromatosis? One issue that seems to have muddied the waters is the interpretation of non-specific symptoms such as fatigue, joint pains or impotence. Suggestions that symptoms are common come from uncontrolled studies in which the subjects knew their diagnosis.37,38 But to be meaningful the history must be elicited before the patient has been informed of the diagnosis and must be compared with age, sex and ethnically matched wildtype controls. Studies that have been carried out in this manner show that no symptoms are statistically significantly more common in homozygotes than controls in any study.17,34 The only possible exception is a small French study in which 7 of 10 male homozygotes complained a fatigue, a number that was statistically significant, but had not been corrected for multiple comparisons.16 The other issue is the significance of the abnormality in liver function tests and biopsy interpretations in homozygotes. The reading of liver biopsies is subject to observer bias and, unfortunately, there are never control biopsies with which to compare the patient cohort. Nonetheless, there is considerable consistency in the data. Olynyk38 reported that of 16 homozygotes (of whom two refused biopsy) 3 had fibrosis, and one alcoholic subject had cirrhosis (25%). Bulaj37 found 16 patients with cirrhosis and 17 with fibrosis out of 210 homozyotes (15%), and Åsberg et al39 found 12 of an estimated 400 homozygotes had fibrosis or cirrhosis (3%). For ethical reasons we could not perform liver biopsies on our patients, but found that 8.2% had elevated SGOT levels compared to 3.2% of controls. Serum collagen IV levels, considered a surrogate for hepatic fibrosis, were elevated in 25.8% of the homozygotes in our study compared with only 11.1% of matched controls. Notably, the elevated liver function tests were not age-related. Thus, all of the data, including our own (except for a small French study that found 3/54 [5.5%] homozygotes had elevated ALT levels, compared to 5% in controls16), indicate that there is a subset of patients, considerably larger than 1% who have abnormal liver function tests. Those who hold that the penetrance of hemochromatosis is higher than the approximately 1% estimate can point to the presence of hepatic fibrosis as an indication that iron overload is clinically important. We, however, take the point of view that since the fibrosis did not produce any clinical symptoms in the vast majority of subjects, and that it does not appear progressive, it is not important for the person to whom it should matter the most, the patient. Thus, to some degree the disagreement about penetrance comes down to the single issue of whether hepatic fibrosis seen on liver biopsy by pathologists or abnormal liver function is important if it is not associated with measurable morbidity or mortality.
Penetrance of the compound heterozygous C282Y/H63D HFE mutation
On the average, compound heterozygotes manifest significantly higher transferrin saturations and serum ferritin levels than do individuals with the wildtype genotype. Because the H63D mutation is very prevalent in the population, this compound heterozygous genotype is very common in the population. Among patients who had been classified as having "hemochromatosis" on the basis of increased biochemical parameters there is an increased number of compound heterozygotes, and it has been calculated that the biochemical penetrance of this genotype is only about 1% of that of the homozygous genotype.40 Accordingly, patients with this genotype who develop severe cirrhosis and other clinical manifestations of hemochromatosis are very rare.

Penetrance of the simple heterozygous genotype
It is clear from large studies that simple heterozygotes for the C282Y or H63D mutations have, on the average, very slightly higher transferrin saturations and ferritin levels than do homozygotes for the wildtype. Numerous claims have been made that these minor changes translate into increased prevalence of a variety disorders including diabetes,41,42 heart disease,43,44 and cancer.45,46 None of these claims has been widely substantiated,18,36,47,48 and it seems unlikely that the heterozygote for these common mutations suffers ill health because of them with one notable, rather uncommon exception. Carrying either the C282Y or H63D does appear to be a risk factor for porphyria cutanea tarda.49,50 In general, however, it is much more likely that mutations that have gained a high prevalence in the genome have a beneficial effect, i.e., that they constitute a balanced polymorphism. Their beneficial effect is probably that of preventing iron deficiency in women.51,52

Diagnosis
It is a tragedy when a patient dies of a treatable disease such as hemochromatosis without receiving the benefits of therapy. However, the enthusiasm for general population screening for hereditary hemochromatosis has abated with the realization that the penetrance is very low.53 The burden for making the diagnosis of hemochromatosis therefore falls squarely upon the physician. The diagnosis of hemochromatosis should be considered in patients with cirrhosis of the liver, particularly those with diabetes. Alcoholism is no bar to consideration of hemochromatosis in a cirrhotic patient; indeed, a high proportion of patients with clinical hemochromatosis ingest excessive amounts of alcohol54,55 and cirrhosis is much more common in patients with the hemochromatosis genotype who have heavy alcohol intake.56

The most efficient approach to diagnosis of patients who are suspected to have the disease is to measure the serum transferrin saturation and ferritin levels. Increased transferrin saturation is an important hallmark of the disease. If the transferrin saturation is < 40% it is very unlikely that the patient has hemochromatosis. About 90% of patients with genotypic hemochromatosis will have a transferrin saturation at least this high, and the few who do not are unlikely to have clinical manifestations of the disorder. While transferrin saturation is considered to be an indicator of the underlying genetic defect, serum ferritin concentrations more closely mirror the total body iron content. It is sometimes assumed that there is a linear relationship between body iron burden and serum ferritin levels. In reality, the ferritin values only provide a rough approximation of the body iron burden.57 Figure 3 presents the results of a recent study in which ferritin levels are compared with the actual amount of iron in the body as measured by phlebotomy. Serum ferritin levels are of considerable value in predicting the likelihood that a given patient has cirrhosis: patients with serum ferritin levels of under 1,000 ng/mL are extremely unlikely to have cirrhosis.58,59 The relationship between serum ferritin levels and storage iron as determined by serial phlebotomy :

The dots represent patients homozygous for the C282Y mutation. Squares represent patients with a diagnosis of hemochromatosis who are not homozygous for the C282Y mutation. The plus signs represent those whose phlebotomy program had not yet been completed. Figure reprinted with permission from Beutler E, Felitti V, Ho N, Gelbart T. Relationship of body iron stores to levels of serum ferritin, serum iron, unsaturated iron binding capacity and transferrin saturation in patients with iron storage disease. Acta Haematol (Basel). 2002;107:145–149.[CrossRef]
Genotyping patients for the C282Y and H63D mutations is useful to confirm the diagnosis and for family studies, but it must be borne in mind that in the US some 20% of patients who have been diagnosed as having hereditary hemochromatosis do not have mutations of HFE.60 In southern Europe, the proportion of hemochromatosis patients who do not carry this mutation is even larger.61 The presence of excessive iron stores in a patient with putative hemochromatosis can be confirmed by carrying out serial phlebotomies (see "Treatment"). Some physicians consider liver biopsy as an essential part of the workup of a patient with possible hemochromatosis. Liver biopsy will show whether the iron is deposited chiefly in liver parenchymal cells, which is characteristic of the disease, it will allow quantitation of liver iron, and it will establish whether the patient has cirrhosis. However, serial phlebotomy will quantitate the iron. Therefore, the major benefit to the patient of undergoing liver biopsy is to establish whether cirrhosis is present. Hepatic cirrhosis affects prognosis, but not treatment, and many or most patients may not be eager to know what their estimated lifespan will be. Cirrhosis also increases greatly the risk of hepatocellular carcinoma, an important complication in patients with hemochromatosis and cirrhosis. Patients with cirrhosis may therefore be better candidates for periodic screening for this disease. As treatment for hepatocellular carcinoma becomes more effective, establishing whether or not cirrhosis is present may be important for optimal management and may therefore be a reason for performing a biopsy.
Treatment : the aim of treatment of iron storage disease is to remove from the body the excess iron that has accumulated. In the case of patients without primary disorders of hematopoiesis (i.e., patients with one of the forms of primary hemochromatosis), this is best achieved by phlebotomy, since regeneration of erythrocytes by the marrow utilizes iron, which is therefore withdrawn from various body pools. Phlebotomy is only occasionally feasible in patients who have augmented iron stores because of ineffective erythropoiesis and is generally precluded in those in whom the iron overload is the result of multiple transfusions. Such patients require treatment with an iron chelating agent, as discussed in Section II. One ml of erythrocytes contains 1 mg of iron. Hence, removing one unit (~450 mL) of blood with a hematocrit of 45% removes approximately 200 mg of iron from the body. Iron absorption is increased in patients with hemochromatosis who are undergoing phlebotomy, and may be more than 5 mg per day.62 But with even this level of iron absorption, it is relatively simple to achieve a negative iron balance by instituting a phlebotomy program. Initially, some patients feel enervated by phlebotomies, and I find that compliance is improved by initially phlebotomizing every two weeks. But after this has been done for a month or two, weekly phlebotomies are almost always well tolerated. The aim of phlebotomy is to deplete the body iron stores, and the most easily appreciated endpoint is mild iron deficiency anemia. One of the easiest guides to incipient iron depletion is a falling MCV.63 The other useful parameter is the serum ferritin level, which should be brought to under 10 ng per ml. Some clinicians prefer a higher cutoff, but there is usually appreciable residual, difficult-to-mobilize tissue iron even when the erythron is iron depleted, and the mobilization of this iron and enhanced gastrointestinal iron absorption that is present in iron-depleted patients with hemochromatosis will quickly correct any deficiency that may have been induced. Maintenance phlebotomy is initiated when the ferritin level rises to 80 or 100 ng/ml, and the rate of maintenance phlebotomy required varies widely between patients. Some physicians prescribe an iron-poor diet, but this seems to me to represent more interference with the patient’s lifestyle than is justified by the slight decrease in intervals between phlebotomies that may be achieved by restricting iron intake. One of the manifestations of hereditary hemochromatosis is increased susceptibility to infection. Death due to overwhelming sepsis is not uncommon in severely affected patients. Because of the risk of infection with organisms such as Yersinia enterocolitica or Vibrio vulnificus, patients are usually advised to avoid the ingestion of raw shellfish. Because of the fulminating nature of some infections in patients with hemochromatosis, vigorous early treatment of febrile diseases is recommended. The prevalence of hepatomas is increased in patients with hemochromatosis, particularly those with cirrhosis; a relative risk of 1.8 (CI 1.1–2.9) has been reported.64 Some cases have been documented in non-cirrhotic patients,65,66 but these are only case reports, and it is unclear whether the relative risk is increased. It is probably prudent to monitor the liver by ultrasound every 6 to 12 months, although the value of this procedure is in some doubt since the treatment results for hepatoma are so unsatisfactory. It is universally stated that phlebotomy improves the health and increases the lifespan of patients with hemochromatosis. This assumption is based upon a study in which it was shown that phlebotomized patients with "hemochromatosis" had a normal lifespan.67 We now recognize that unphlebotomized patients with hemochromatosis also have a normal lifespan when the selection criterion is based on either genotype or chemical phenotype. The fact is that there are no data that allow us to show definitively that phlebotomy improves survival. No such data can be obtained because of ethical issues. Nonetheless, the concept that removing iron from a patient whose disease is due to an excess of iron will be helpful is compelling, and therefore treating patients with hemochromatosis who have clinical disease is mandatory. The recognition that most patients with the genetic and biochemical stigmata of hemochromatosis will have a normal lifespan without intervention raises the question of whether all patients with hemochromatosis should be phlebotomized. Fortunately, the treatment is almost entirely risk free and potentially beneficial to society. Moreover, our current state of knowledge is such that we cannot predict which of the patients with hemochromatosis will be the rare ones who develop serious clinical consequences. Thus, it seems prudent to phlebotomize all patients with hemochromatosis who have elevated body iron stores as estimated by serum ferritin levels. It is useful in this regard to consider the fact that cirrhosis is very largely limited to patients with the serum ferritin levels higher than 1000 ng/mL.59,68 There is no harm, however, in phlebotomizing patients with less elevated ferritin levels. Family studies are also potentially useful, since homozygous relatives of non-expressing homozygotes are potentially more seriously affected. The management of patients with the juvenile hemochromatosis is similar to that of patients with HFE hemochromatosis, but knowing that this is an aggressive form of disease, a vigorous phlebotomy program should be initiated early.
Summary
There are many forms of iron storage disease, primary (or hereditary) and secondary to various hematologic disorders. The most common of the primary forms are associated with mutations of an HLA-linked gene designated HFE. Five per thousand northern Europeans are homozygous for the common C282Y mutation of HFE. Very few of these develop any clinical symptoms, but uncommonly cirrhosis, diabetes, arthropathies, and bronzing of the skin may result, and approximately 25% will have elevated serum collagen IV levels, a surrogate marker for hepatic fibrosis, compared with 11% of controls. Hereditary hemochromatosis is characterized by an increased serum transferrin saturation. It is treated by serial phlebotomy to remove the accumulated iron. Secondary hemochromatosis has clinical manifestations similar to those of primary hemochromatosis, but by necessity treatment usually consists of the administration of iron chelating agents.

II. IRON CHELATION THERAPY

A. Victor Hoffbrand, DM, FRCP*
These are exciting times for patients with thalassemia major (TM) and other transfusion-dependent patients with refractory anemias who need chelation therapy. Although at present deferoxamine (DFO) remains the standard of care recent data suggest that deferiprone, orally active and in clinical trials for 16 years, may for many patients be a safe and effective alternative to the more cumbersome drug DFO. There is the new possibility of combination chelation therapy with DFO and deferiprone, and a second orally active iron chelator, ICL 670, is now in early clinical trials. Figure 4 shows the chemical structures of these three compounds. The structural formulae of deferoxamine, ICL 670, and deferiprone :

Approximately 72,000 patients with TM or thalassemia/hemoglobin E disease receive regular blood transfusions worldwide. Because DFO is expensive and cumbersome to administer, about 42,000 receive no chelation therapy; about 25,000 are prescribed DFO and 5000 (mainly in India) receive deferiprone (C.B. Modell). Some 2000–4000 thalassemia patients die each year from iron overload. The lack of an inexpensive orally active iron chelator has been a major reason why iron chelation therapy is not considered for these patients in poor countries. In many of these countries, regular blood transfusions, which in the absence of iron chelation will inevitably lead to death from iron overload, are not even contemplated. Indeed, only about 3500 of the 27,000 transfusion-dependent children born each year are transfused at all.
There are two other large groups of patients requiring iron chelation therapy: (1) patients with non-transfusion-dependent but nevertheless severe genetic diseases of hemoglobin synthesis (thalassemia intermedia) who become iron overloaded because of increased iron absorption but are too anemic to undergo phlebotomy to reduce iron overload; and (2) regularly transfused patients with, for instance, sickle cell anemia, myelodysplasia, myelofibrosis, red cell aplasia, aplastic anemia, congenital dyserythropoietic anemia, and congenital sideroblastic anemia.
Requirements of Iron Chelation Therapy : the chelator must result in excretion of sufficient iron to prevent damage to the endocrine organs, liver, and most importantly heart. In TM, about 100–200 mL of pure red cells/kg/y are transfused, equivalent to 0.32–0.64 mg/kg/d of iron.1 In thalassemia intermedia, iron absorption is about 5–10 times the normal amount, around 0.1 mg/kg/d. Excretion levels of these rates must be achieved to maintain a "safe" level of body iron. Monitoring of iron chelation therapy requires: (1) estimation of the iron content of different organs, and (2) assessment of the function of the heart, liver, and endocrine glands, the organs particularly damaged by iron overload. These aspects have recently been extensively reviewed and are only briefly discussed here.2,3
Estimation of Tissue Iron

• serum ferritin : this is a useful technique for assessing changes in body iron, although the absolute level is an imprecise measure of body iron. This is partly because inflammation—for example, hepatitis C—raises the level, while vitamin C deficiency lowers it, both frequent complications of TM. Most studies have found a wide range in liver iron at any given serum ferritin level. The Thalassemia International Federation guidelines1 recommend maintaining serum ferritin levels around 1000 µg/L; nevertheless, levels below this may in some individuals be associated with cardiac complications. One study in TM patients receiving DFO found that those with at least two-thirds of serial serum ferritin estimations less than 2500 µg/L had significantly less cardiac disease than those with higher levels.4 More recently, a level consistently below 1500 µg/L was found to be associated with few complications in 32 patients with TM followed for approximately 15 years.5 When effective chelation therapy is initiated, the serum ferritin falls more rapidly than body iron. This may happen partly because of improvement in liver function and partly because serum ferritin may reflect predominantly reticular endothelial iron rather than parenchymal iron in the liver and other organs.6
• liver iron has been described as the "gold standard" for determining body iron and has been recently shown to correlate with total body iron stores.7 It can be measured chemically after liver biopsy (which can be inaccurate because of fibrosis, cirrhosis, or uneven distribution of iron) or noninvasively by the superconducting quantum interface device (SQUID) (available in only a few centers) or by magnetic resonance imaging (MRI). Brittenham et al8 studied 59 TM patients who were more than 7 years old. All patients who died had liver iron concentrations > 15 mg/g dry weight, and this level has been subsequently regarded as an index of high risk of death from cardiac disease. More recently, Angelucci et al7 have shown that this level is also associated with liver fibrosis and cirrhosis. The level of 7 mg/g is the upper limit found in carriers of genetic hemochromatosis. For levels between 7 and 15 mg/g, Angelucci et al found no evidence of liver damage except in patients who had hepatitis C and were messenger RNA positive; the combination of iron overload and hepatitis C infection is particularly damaging to the liver.
• The value of liver iron, whether > 15 mg/g or in the range of 7 to 15 mg/g, as a predictor of cardiac iron has recently been questioned. MRI data using the T2* technique (Figure 5)9 and spin-echo10 have shown no correlation between cardiac and liver iron, although other MRI techniques, possibly less sensitive and accurate, have shown such a correlation. Possible explanations for these discrepant observations have been discussed.3,9
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•    Figure 5. Magnetic resonance scans in patients with thalassemia major.Left scans are horizontal long axis, the right ones mid-short axis. (A) Low myocardial iron deposition. The left ventricular volumes are normal, and myocardial signal intensity (long arrow) is similar to that arising from skeletal muscle (short arrow). Left ventricular ejection fraction was 70%. In this case, the liver is very dark (dotted arrow), indicating heavy hepatic iron deposition despite the normal myocardial appearances. (B) Severe myocardial iron overload. The myocardial signal intensity is dark (long arrow) compared with skeletal muscle (short arrow). The ventricle is dilated and thickened. Cine imaging showed greatly reduced systolic function (left ventricular ejection fraction 39%) with a restrictive filling pattern. Liver signal in this case is well preserved (dotted arrow).
• Reproduced with permission from Anderson LJ, Wonke N, Prescott E, et al. Improved myocardial iron levels and ventricular function with oral deferiprone compared with subcutaneous desferrioxamine in thalassaemia. Lancet. 2002;360:516–520..9[CrossRef][Medline]
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• Cardiac iron
• Direct measurement of cardiac iron by endomyocardial biopsy of the right atrium is inappropriate since iron locates mainly to the myocardium of the ventricles. The recent development of a reproducible, sensitive, and accurate indirect measure of cardiac iron using the MRI T2* technique11 has provided substantial important new data. A T2* value less than 20 ms has been found to correlate with the presence of cardiac dysfunction, detected by echocardiography, 24-hour monitoring, or the need for cardiac therapy. It is also valuable for monitoring changes in cardiac iron during intensive chelation therapy.12
• Non-transferrin-bound iron
• In severely iron-loaded patients, non-transferrin-bound iron (NTBI) is present in plasma. It occurs in 80% of patients with TM and represents a highly toxic species causing tissue iron loading. NTBI is also found in patients receiving chemotherapy or undergoing heart bypass operations and those having other conditions in which large amounts of iron from hemoglobin breakdown are released into the circulation.13 NTBI is removed by administration of DFO or DFP but reappears rapidly (i.e., usually within 1 hour of discontinuing intravenous DFO therapy) unless body iron burden is substantially reduced.
• Urine iron excretion
• Iron excreted in response to a single dose of DFO or deferiprone has been taken as an index of body iron burden. It will vary, however, with the dose of chelator used and, for DFO, whether vitamin C is also given and with the hemoglobin level. There is also considerable day-to-day variation, even with apparently the same conditions.2 Nevertheless, in one recent study it has been found to correlate closely with cardiac iron measured by MRI.10
• Estimation of Iron-Induced Tissue Damage
In addition to measuring iron status, it is important to assess the function of the heart, liver, and endocrine glands, the organs particularly damaged by iron overload. Early detection of cardiac dysfunction is especially important so that increased chelation therapy can be instituted before cardiac damage is irreversible. Once the patient has started chelation therapy, it will also be necessary to monitor for potential side effects of the iron chelator being used (Table 3).
Pharmacokinetic and clinical characteristics of three iron chelators.

Chelation Therapy
Deferoxamine
The management of iron overload using subcutaneous DFO has been extensively reviewed.2 DFO is hexadentate, 1 molecule binding 1 atom of iron (Table 3). Standard therapy is with 40 mg/kg infused subcutaneously over a period of 8–12 hours on 5–7 nights each week using a battery-operated infusion pump. Therapy is usually begun in children after 10–20 transfusions have been given or when serum ferritin levels reach 1000 µg/L. Vitamin C, 200 mg, given orally when the infusion is started, enhances urine iron excretion. Alternative routes of administration that have been tried include twice-daily bolus subcutaneous injections,14 continuous infusions over 24 or 48 hours using disposable prefilled balloons,15 and continuous intravenous infusion using an indwelling central line or Portacath.16
First introduced in 1976 as subcutaneous treatment for TM, DFO has substantially improved the life expectancy in the disease.4,8,17 Deaths continue to occur from cardiac failure due to iron overload, but these are mainly caused by lack of compliance.17,18 Defining compliance as more than 250 infusions a year, Gabutti and Piga17 found that 95% of compliant patients are alive at 30 years of age, compared with only 12% of noncompliant patients. Modell et al18 reported that only 50% of TM patients in the UK reach 35 years, the poor result again being attributable to cardiac failure due to poor compliance.

DFO can reverse iron-induced cardiomyopathy in some but not all patients.16,19 Continuous intravenous DFO results in comparatively rapid improvement in ventricular function compared with the slow clearance of cardiac iron, which can remain high even after 1 year.12 Recent studies show that liver iron clears more rapidly and, despite severe iron overload initially, may be normal at 6 months.12

Although cost and lack of compliance are the main obstacles to DFO therapy, complications may also exclude some patients. High-frequency hearing loss, deafness, and retinal damage with impaired vision (e.g., night blindness) can occur when large doses of the drug are given to less severely iron-loaded patients, especially children, in whom growth retardation and skeletal damage have also been reported. Generalized hypersensitivity is rare, but painful local reactions at the injection site are common and often lead to lack of compliance. Infection with Yersinia is increased, and on rare occasions other infections (e.g. Klebsiella) are precipitated.

Deferiprone : the orally active bidentate iron chelator deferiprone (1,2 dimethyl-3-hydroxy-pyrid-4-one, also known as L1, CP20, Ferriprox, or Kelfer) was designed in R.C. Hider’s laboratories (Figure 4).20 First tested clinically in 1987, this drug is now licensed in 25 countries for patients with TM unable to be effectively treated with DFO. Reviews of its chemistry, pharmacology, and clinical results have recently been or are being published.20–22
Pharmacokinetics : deferiprone is rapidly absorbed, appearing in plasma within 15 minutes of ingestion, with a peak plasma level within 45–60 minutes (Table 3). It forms a 3:1 chelator:iron complex that is excreted with the free drug in urine. Only 4% of a single oral dose of the drug is excreted bound to iron, even in heavily iron-loaded patients. Its iron chelation site is inactivated by glucuronidation, the speed of which varies from patient to patient. This explains much of the individual variation in response, the area under the curve of the concentration of free drug in plasma being related to the amount of iron excreted.23 Deferiprone mobilizes iron from parenchymal and reticuloendothelial pools and from transferrin, ferritin, and hemosiderin. Unlike DFO, it is also capable of chelating iron from intact red cells in vitro and in vivo, shown in patients with sickle cell anemia24 and thalassemia intermedia.25 The enhanced ability of DFP to cross cell membranes may underlie what is emerging as its superior ability, compared with DFO, to protect the heart from iron and also the "shuttle effect" for iron when the 2 drugs are given simultaneously (Figure 6).
The concept of combination therapy.

Abbreviations: DFO, deferoxamine; DFP, deferiprone; NTBI, non-transferrin-bound iron.
Modified from Liu et al.20
Clinical studies : short-term studies showed that iron excretion occurs in the urine with negligible amounts in feces, although some subsequent studies have suggested excretion up to 33%. Iron excretion increases with the dose of the drug and the transfusional iron load of the patients. Although initial studies showed that 100 mg/kg/d was more effective,26,27 the dose used in most trials has been 75 mg/kg/day fractionated into 3 doses. This dose was reported in early studies to be as effective as standard-dose DFO at increasing urine iron excretion.28,29 In most patients urine iron excretion around 0.5 mg/kg/day was achieved with no indication of a diminishing response with time. There were early concerns that doses higher than 75 mg/kg might produce more side effects, e.g., arthropathy.27 Balance studies suggest that total iron excretion with 75 mg/kg deferiprone is somewhat less than that with 40 mg/kg DFO given over 8 hours subcutaneously, but only small numbers of patients have been studied and there is wide patient-to-patient variability.30
Final mean serum ferritin concentrations in 9 published trials in patients (mainly DFO ‘failures’ with TM) treated from 1 to 56 months with deferiprone have ranged from 1779 to 3273 µg/L.22 In 7 of the trials, there was a significant fall in serum ferritin, and in 2 there was no significant change. Serum ferritin levels fell mainly in the patients starting with the highest levels. In 6 studies in which serial liver iron determinations were made, hepatic iron fell significantly in 1, rose significantly in 1, and did not change significantly in the other 4.22 When SQUID technique was used in 54 thalassemia patients (aged 7–22 years), median liver iron concentration rose from 1456 mg/g liver to 2029 mg at 2 years and 2449 mg at 3.2 years.6 These patients were well chelated before starting deferiprone, but their iron intake from transfusions rose substantially during the study. Recent MRI data retrospectively comparing 15 patients treated long term with deferiprone with 30 matched patients treated with DFO, in which liver MRI T2* was converted to estimated dry-weight liver iron, showed significantly higher liver iron: 5.1 versus 3.5 mg/g in the deferiprone compared with the DFO group.9 In a short-term study, raising the dose of deferiprone to around 100 mg/kg led to reduction of serum ferritin levels in patients inadequately chelated at 75 mg/kg.31 Prospective trials are needed to assess whether doses of deferiprone (around 100 mg/kg daily) can safely be given long term and will result in more effective iron chelation in patients inadequately chelated on 75 mg/kg daily. There is also a need for further (> 3 years) long-term studies to determine liver iron levels in large numbers of patients receiving deferiprone to determine more accurately the proportion of patients in whom liver iron is adequately controlled. The most important aspect of iron chelation therapy is protection of the heart. Two recent studies, albeit retrospective, show significant benefit for the patients receiving deferiprone compared with DFO. In a London study, 15 TM patients who had received deferiprone 75 mg/kg/d for 3 years showed a lower incidence of cardiac disease (assessed by echocardiography and need for cardiac drug therapy) and lower cardiac iron estimated indirectly by MRI T2* than 30 age- and sex-matched patients who had received DFO 40 mg/kg/d subcutaneously on 5–7 days each week (median myocardial T2* 34.0 vs 11.4 ms, P = .02).9 Excess myocardial iron (T2* < 20 ms) was significantly less common in the deferiprone group (27%) than in the DFO group (67%), P = .025. In a Turin study, 54 patients who had received deferiprone were compared retrospectively with 75 patients who had received DFO; the drugs were given at standard doses over an average of 6 years.32 No patient in the deferiprone group compared with 3 in the DFO group died of cardiac failure. Deterioration of preexisting cardiac dysfunction or new cardiac disease occurred in 2 (4%) of the deferiprone-treated patients compared with 15 (20%) of the DFO group (P = .007).32 Formal prospective studies are needed to confirm the apparent greater cardioprotective effect against iron toxicity of deferiprone compared with subcutaneous DFO suggested by these two retrospective studies. In a short-term (12 months) prospective randomized study, Maggio et al33 found no difference in any of the parameters used to detect cardiac abnormalities between patients receiving DFO and patients receiving deferiprone.
Complications : the incidence of the now well-established complications of deferiprone therapy—agranulocytosis, neutropenia, arthralgia, gastrointestinal symptoms, transient changes in liver enzymes, and zinc deficiency—has been established in recent prospective trials34–36 and reviewed.22 Hepatic fibrosis has also been suggested in one small retrospective study to be a consequence of deferiprone therapy.37 However, recent evidence based on 56 repeat biopsies in patients treated for a mean of 3.1 years shows no evidence for this.38 No other study has reported significant increase in hepatic fibrosis ascribed to deferiprone. Transient changes in alanine aminotransferase (ALT) levels, especially in the first few months of therapy and in hepatitis C antibody–positive patients, have been observed. The mean ALT levels did not increase among 151 patients treated for 3 years.36 Occasional patients have, however, been withdrawn from therapy in some trials because of concerns about raised ALT levels.34 Agranulocytosis, the most serious complication of deferiprone, occurs in about 1% of patients and appears to be idiosyncratic; it is probably more frequent in females. Patients with agranulocytosis should be permanently withdrawn from therapy, although a proportion of patients with less severe degrees of neutropenia have successfully been re-exposed to the drug. Most patients with the other side effects can usually continue with the drug, often after a period of withdrawal and retreatment initially at a lower dose.
Combination therapy with DFO and deferiprone commenced in 1998, when it was reported that DFO and deferiprone could be safely given simultaneously and that the urine iron excretion achieved is at least equivalent to the iron excretion resulting when the 2 drugs are given on separate days.31 Six clinical studies of combination therapy have now been reported (Table 4). All show decreasing serum ferritin levels and, where measured, decreasing liver iron. Mourad et al,40 for instance, report that deferiprone 75 mg/kg 7 days a week and DFO 40 mg/kg subcutaneously over 8–12 hours 2 days a week gives approximately equivalent iron chelation, based on serum ferritin levels, to 5 days a week of DFO. Compliance is likely to be improved longer term for a patient needing 2 rather than 5 days of subcutaneous infusions. Combined therapy with deferiprone and deferoxamine (from Liu20) :

		Iron Dextran	SFG
Maximum dose (mg iron)		500–1000	125
Test dose required		yes	no
Administration time		2–4 hours	10 min
Utilization time		weeks	days
Anaphylactic		uncommon (0.61%)	common (2.5%)
Delayed		common (2.5%)	uncommon (0.4%)

The basis for this additive or synergistic effect is given by the studies of Grady et al30 and Breuer et al.45 These suggest that deferiprone enters cells and chelates iron, which it brings into plasma. The iron is then transferred to DFO for excretion in urine and feces (Figure 6). If combination therapy in longer-term studies does not show any unexpected toxicity, it is an exciting therapeutic advance for improving compliance and avoiding large, potentially toxic doses of either drug. Alternating (sequential) therapy with DFO and deferiprone has also been studied in 7 children noncompliant to DFO.46 Compliance was improved when deferiprone was given for 4 days and then DFO for 2 days each week. Over 6 months, liver iron fell significantly and there was a nonsignificant fall in mean serum ferritin from 5536 to 3778 µg/L. More prolonged studies are needed to determine the place of this approach.
Thalassemia intermedia : oral iron chelation therapy is a potentially attractive option for patients with iron overload who are too anemic for phlebotomy. Olivieri et al47 first reported a patient with thalassemia intermedia in whom deferiprone was effective in reducing both liver iron and serum ferritin to normal within 12 months of therapy. Pootrakul et al25 have recently extended these observations. They found in 8 thalassemia intermedia patients in Thailand (mainly suffering from thalassemia/hemoglobin E) that deferiprone at the low dose of 50 mg/kg/d not only significantly reduced serum ferritin and red cell membrane liver iron over 12 months but also resulted in an increase in hemoglobin and serum erythropoietin levels and improvement in weight and appetite. No side effects requiring drug withdrawal were encountered.
Other transfusion-dependent anemias : similar results to those in TM have been obtained with deferiprone in patients with myelodysplasia, myelofibrosis, and other acquired marrow diseases. Although there has been theoretical concern that agranulocytosis may be more frequent in these acquired bone marrow disorders than in TM, there are no data to suggest this.
ICL 670 (4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-y1] benzoic acid) (Figure 4) was developed by Novartis Pharma AG after many hundreds of potential orally active iron chelators were screened. Preclinical studies show that it forms a 2:1 chelator:iron complex and produces an increase predominantly in fecal iron excretion after a single oral dose, only 6% of iron excretion accruing in the urine (Table 3). It is highly selective for iron, is rapidly absorbed, and circulates for several hours. In the non-iron-loaded marmoset and rat, its main toxic effect was on the renal tubular epithelial cells, but this effect was abrogated in iron-loaded marmosets and substantially reduced in iron-loaded rats.48 Short-term clinical trials have recently been reported.49 Single daily doses of 10, 20, and 40 mg/kg body weight were studied. Peak plasma concentration after a single oral dose occurred at about 2 hours, and the drug was still detectable in plasma in almost all patients at 24 hours; the mean elimination half-life was between 11–16 hours after multiple dose administration. Net iron excretion after 6 days of exposure was linearly related to the dose of the drug. Iron excretion at 12 days was related to the area under the curve of the concentration of free drug in plasma. Five of 6 patients receiving 20 mg/kg were calculated to excrete iron equivalent to the amount received in blood transfusions. The main side effect was skin rashes that required withdrawal of 4 patients given the highest dose of 40 mg/kg over 8–10 days. Sporadic transaminase rises occurred in 1 of these patients and in 4 other patients. Mild nausea, diarrhea, and abdominal pain—none requiring discontinuation of the drug—occurred in other patients. Longer-term studies of the drug at the dose of 20 mg/kg have been carried out.50 These showed that total body iron excretion ranged from 7.7–28.5 mg iron/d. These did not show any additional toxic effects and showed that liver iron decreased in 12 (57.1%), was unchanged in 8 (38.1%), and rose in 1 (4.8%) of 21 patients studied using the SQUID technique.
Conclusions : the prospect for transfusion-dependent patients to receive effective iron chelation therapy has substantially improved in the last few years. Subcutaneous DFO 40 mg/kg over 8–12 hours on at least 5 days a week protects most compliant patients against cardiac disease and other serious complications and remains the first choice. Its cost, frequent lack of compliance, and complications means that alternative approaches are needed. After many years of short-term clinical trials of the orally active agent deferiprone and much controversy about its efficacy and toxicity, recent published data have been favorable on both aspects. These suggest that the drug at a dose of 75 mg/kg/d may be at least as effective as DFO in protecting patients from iron-induced cardiomyopathy. Hepatic fibrosis does not appear to be a problem, and the established side effects do not lead to the need for discontinuation of the drug in the majority of patients. Combination therapy with DFO and deferiprone is an exciting new possibility for those patients inadequately chelated on either drug alone. ICL 670, a new oral iron chelator in early clinical trial, promises to expand further the range of possibilities for effective and safe iron chelation therapy for patients with TM and other iron-loaded transfusion-dependent or -independent patients with severe refractory anemias. Whichever chelation regimen is chosen, patients must be closely monitored both for effectiveness of therapy, with particular attention to cardiac iron and function, and for toxic side effects of the chelating drug.
III. NEWER ASPECTS OF THE DIAGNOSIS AND TREATMENT OF IRON DEFICIENCY

James D. Cook, MD*
 

Iron deficiency is by far the most common hematological disorder encountered in general practice. The basic approach to its diagnosis and management is well established and outlined in most medicine and hematology texts. My emphasis in this selective review is on soluble transferrin receptor (sTfR) measurements, iron deficiency induced by recombinant erythropoietin (rHuEPO) therapy, and parenteral iron therapy with sodium ferric gluconate.

Diagnosis of Iron Deficiency
There are two main categories of laboratory methods for identifying iron deficiency: screening measurements that detect iron deficient erythropoiesis (IDE) and definitive measurements that evaluate tissue iron status (Table 5). Newer tests include the percentage of hypochromic erythrocytes, reticulocyte hemoglobin content (CHr), and sTfR. It should be added that a therapeutic trial iron has been proposed as a convenient method to diagnose iron deficiency. This is a reasonable approach in otherwise healthy populations, such as teenage girls and pregnant women, at high risk of deficiency. However, in most clinical settings, it is preferable to make a definitive diagnosis at the outset.
 
 
 

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   Table 5. Laboratory measurements for the diagnosis of iron deficiency.

• screening :
• hemoglobin
• transferrin saturation
• mean corpuscular volume
• percentage hypochromic erythrocytes
• reticulocyte hemoglobin content (CHr)
• zinc protoporphyrin (ZPP)
• definitive
• storage iron
• serum ferritin
• bone marrow hemosiderin
• tissue iron
• serum transferrin receptor (sTfR)
Screening measurements
The initial screening method for iron deficiency in clinical practice is invariably the hemoglobin or hematocrit but additional laboratory evidence is needed, except perhaps in patients with obvious blood loss. Screening measurements to detect IDE narrow the diagnostic possibilities but are not specific. The traditional measurement is the transferrin saturation, which has the advantages of low cost and wide availability. However, marked diurnal variation and the numerous clinical disorders that affect the transferrin saturation limit its clinical utility. A normal or elevated value is as useful for excluding iron deficiency anemia as a low value is for diagnosing it.
Other screening methods are based on signs of restricted iron supply in circulating red cells. Examination of the peripheral smear is reliable in experienced hands but not cost-effective in routine clinical practice. The traditional measurement is the mean corpuscular volume (MCV) but it is one of the last parameters to change with the onset of IDE. The latter can be detected earlier by an increased percentage of hypochromic erythrocytes measured by selected hematology analyzers, but it is also a relatively late indicator of IDE.1 On the other hand, the reticulocyte hemoglobin content (CHr) declines within a few days of the onset of IDE because of the short 1–2 day lifespan of circulating reticulocytes.1–3 Falsely normal values of the CHr can be observed with an elevated MCV or thalassemia4 but the main limitation to its wider use is that it can be measured by only one model of analyzer (Bayer Advia). The low specificity of the percent hypochromic erythrocytes and the CHr is reflected in a recent study reporting that 62% of predominantly anemic patients had abnormal values on admission to hospital.1

The measurement of erythrocyte zinc protoporphyrin (ZPP), a product of abnormal heme synthesis, is a simple and precise measure of IDE but still not widely used for clinical purposes.5 One important advantage is the ability to measure the ratio of ZPP/heme directly on a drop of whole blood using a dedicated portable instrument called a hematofluorimeter. The ZPP is ideally suited for field surveys of iron status or pediatric and obstetrical clinics where uncomplicated iron deficiency is relatively common. The ZPP is redundant in laboratories equipped for percentage hypochromic red cell measurements because the two tests provide similar information. ZPP increases with lead toxicity and falsely elevated values and can occur in patients with elevated serum bilirubin or on regular hemodialysis, although the interference can be eliminated with prior washing of the red cells.6

Storage iron and serum ferritin
The serum ferritin is a universally available and well-standardized measurement that has been the single most important laboratory measure of iron status during the past quarter century. Phlebotomy studies in normal subjects have demonstrated that 1 µg/L serum ferritin corresponds to 8–10 mg or 120 µg storage iron/kg body weight,7 although a log transformation gives a more accurate estimate.8 Numerous studies have demonstrated its superiority over other iron-related measurements in identifying iron deficiency anemia. In 55 studies culled from 1179 relevant citations, receiver-operator characteristic curves in 2579 subjects gave a mean area for the serum ferritin of 0.95 ± 0.1 (95% confidence limits) as compared with 0.77 for the ZPP, 0.76 for the MCV, and 0.74 for the transferrin saturation.9 The well-known limitation of the serum ferritin is the elevation in values independent of iron status that occur with acute or chronic inflammation, malignancy, liver disease, and alcoholism.

Many hematologists still rely on the assessment of stainable iron on aspirated marrow smears or biopsy for the definitive diagnosis of iron deficiency anemia. Although still widely regarded as the gold standard for the diagnosis of iron deficiency, the reliability of the marrow iron stain is often suboptimal when used for routine clinical purposes. In a recent study, 108 consecutive bone marrow specimens from unselected hematology patients reported to have absent iron were reviewed.10 One-third of the reports were incorrect due either to an inadequate specimen or detectable iron stores, and less than half of the patients with absent marrow iron had clinical evidence that supported the diagnosis of iron deficiency anemia. In another recent review of iron stains, high intra-observer variability in pathological diagnosis led the authors to conclude that the bone marrow is not a perfect gold standard.4 It should also be noted that the bone marrow is no longer reliable in diagnosing iron deficiency anemia after parenteral iron therapy. While marrow iron staining continues to play a critical role in validating newer laboratory measurements of iron status when performed and reviewed under standardized conditions in prospective studies by experienced investigators, bone marrow examinations should seldom be performed solely to diagnose iron deficiency because of the expense, discomfort, and technical pitfalls with this approach.

Tissue iron and serum transferrin receptor
Transferrin receptors are membrane glycoproteins that serve as the gateway for circulating transferrin iron to the interior of all body cells. In addition to erythroid precursors that contain 80% of the total body receptor mass, rapidly dividing cells and the placenta contain a high density of receptors. The synthesis of ferritin and transferrin receptors is precisely regulated by a common mechanism involving the iron response protein and a nucleotide sequence termed the iron response element.

The sTfR is a soluble form of the cellular receptor lacking the first 100 amino acids and composed of the extracellular domain. Countless articles have been published on the clinical utility of the sTfR since it was first discovered in 1986 by Kohgo and coworkers.11 Ferrokinetic studies have demonstrated that the sTfR is directly correlated with the total mass of erythroid precursors over the complete spectrum of hematological disorders ranging from marrow aplasia to thalassemia major.12 Its use for assessing erythropoiesis has been reviewed recently.13 The only determinant of the sTfR other than the erythroid precursor mass is tissue iron deficiency, which increases the sTfR in proportion to the severity of iron deficit.14 Several commercial assays are now available, but wider application of sTfR measurements is limited by the divergent values reported with different assays,15 differences that could probably be eliminated by the development of an international standard.

Isolated iron deficiency
Isolated or uncomplicated iron deficiency in the absence of other diseases that influence measurements of iron status is seen most often with rapid growth or during gestation, and in patients with excessive uterine or gastrointestinal blood loss. The key laboratory measurement for its identification is the serum ferritin. A low hemoglobin concentration in a patient with a serum ferritin < 30 µg/L is diagnostic of iron deficiency anemia.

One drawback of relying solely on a low hemoglobin and serum ferritin is that milder iron deficiency without anemia goes undetected. Individuals with baseline hemoglobin values in the upper normal range must lose 20%–30% of their body iron before iron deficiency can be detected by anemia. A method for measuring body iron quantitatively using the log(sTfR/serum ferritin) ratio that permits detection of mild tissue iron deficiency has been described recently.16 The method estimates in mg/kg the surplus of storage iron in replete individuals or the tissue deficit in those with iron deficiency. Serial measurements in an individual remain constant over several months allowing those at risk of recurrent iron deficiency to be monitored prospectively. The relevance of iron deficiency without anemia that can be assessed with this approach has been unclear largely because of the difficulty in identifying it. Greater improvement in exercise performance was observed in iron-depleted nonanemic females given iron supplements as compared with unsupplemented controls despite no effect on hemoglobin values.17 Mild iron deficiency without anemia could explain chronic fatigue in some individuals.18,19 It is also preferable to detect declining tissue iron levels in individuals with recurrent iron deficiency before overt anemia develops.

Iron deficiency and chronic disease
The diagnosis of iron deficiency would be simple if it were not for the many clinical disorders that influence the internal iron cycle. The anemia of chronic disease is a common hematological disorder that is easier to recognize than it is to define. Because it alters screening tests for iron status in the same manner as true iron deficiency, the distinction between the anemia of chronic disease and iron deficiency anemia requires tissue-related iron measurements. To avoid the need for bone marrow examinations in patients in whom iron deficiency anemia is suspected, reliance is often placed on the serum ferritin concentration despite the well-known elevation with acute or chronic inflammation. The optimal cut-off values of the serum ferritin to distinguish iron deficiency anemia from the anemia of chronic disease was examined in a landmark study in 259 anemic patients over 65 years of age.20 In 36% of patients with iron deficiency anemia based on bone marrow examination, the serum ferritin was the only test of several that added useful diagnostic information. Only 2 of 49 patients with serum ferritin < 18 µg/L did not have iron deficiency anemia and only 8 of 116 with a serum ferritin > 100 µg/L had iron deficiency anemia. Between 18 and 100 µg/L, 40% had iron deficiency anemia although only 1 such patient had a serum ferritin > 45 µg/L. The authors later proposed serum ferritin values < 40 and < 70 µg/L to diagnose iron deficiency anemia in anemic patients without and with inflammation respectively.9 A serum ferritin < 50 µg/L has been proposed as the best cutoff to identify iron deficiency anemia in patients with liver disease.21

Because the sTfR concentration remains normal in patients with the anemia of chronic disease,22 it is an invaluable addition to the serum ferritin measurement. The sTfR cannot only distinguish iron deficiency anemia from the anemia of chronic disease but it can also identify iron deficiency anemia when it occurs in patients with the anemia of chronic disease. In 129 consecutive anemic patients receiving a bone marrow for stainable iron, iron deficiency anemia was identified in 48, the anemia of chronic disease in 64 and both disorders in 17.23 The sTfR was normal in all patients with the anemia of chronic disease, elevated in 41 of 48 patients with iron deficiency anemia and in 13 of 17 patients with both the anemia of chronic disease and iron deficiency. The separation between the 3 groups was further improved using the sTfR/log(serum ferritin) ratio; no patients with iron deficiency anemia overlapped those with anemia of chronic disease and all but 1 patient with both the anemia of chronic disease and iron deficiency anemia had higher values than patients with the anemia of chronic disease only. A recent study has indicated that even better discrimination can be obtained with the log(sTfR/serum ferritin)24 as described above for quantifying body iron. Use of the receptor/ferritin ratio can eliminate the need for bone marrow examination to detect iron deficiency in patients with chronic inflammatory joint or bowel disease who are usually reluctant to undergo this unpleasant procedure.

Iron deficiency and rHuEPO therapy
Iron status in patients with chronic renal failure has varied widely over the past half century. Transfusional iron overload was invariable until the introduction of hemodialysis when iron deficiency emerged due to dialyzer blood loss. Vigorous parenteral iron therapy led to reports of significant iron overload but with the introduction of rHuEPO therapy, iron deficiency again became widespread. Vigorous parenteral iron therapy has again raised concern about iatrogenic iron overload.25

The term functional iron deficiency has arisen mainly in the nephrology literature in reference to the IDE induced by rHuEPO therapy in dialysis patients with residual iron stores.26 The diagnosis is usually based on one or more screening measurements (Table 5). Aggressive parenteral iron therapy is commonly advised for its treatment on the assumption that functional iron deficiency is the major cause of resistance to rHuEPO therapy. While this is undoubtedly true in many patients, the laboratory features are also typical of the anemia of chronic disease and there is sparse information about the role of inflammation in so-called functional iron deficiency. The sTfR is not an optimal guide to the need for additional parenteral iron because of the enhancing effect of rHuEPO on erythropoiesis and consequently on the sTfR. More data is needed on the extent to which inflammation contributes to functional iron deficiency and whether a rise in sTfR concentration in patients on stable doses of rHuEPO can be used as a guide to parenteral iron therapy.

In a dialysis patient without laboratory evidence of inflammation, the amount of iron that should be given during the first 2–3 weeks of initiating rHuEPO therapy can be calculated from the anticipated increase in circulating hemoglobin (roughly 4 mg iron/kg body weight for each 10 g/L hemoglobin rise) minus iron stores based on 8 mg available iron per µg/L serum ferritin or 3–4 mg/µg/L serum ferritin if the CRP is elevated. After achieving a hematological response, parenteral iron should be continued to maintain a serum ferritin > 100 µg/L if the CRP is normal and > 200–300 µg/L if elevated. There is evidence that serum ferritin values above 500–800 µg/L increase the risk of infections in hemodialysis patients26 and this risk could be even greater in pancytopenic patients given rHuEPO therapy who are already at increased risk of infection.

Treatment of Iron Deficiency
Oral iron therapy
It is preferable to treat iron deficiency with oral rather than parenteral iron. One iron tablet taken daily without food is as effective as 3 tablets with meals, and the disparity is even greater in patients with atrophic gastritis, chronic suppression of gastric acid secretion, and gastric stapling or bypass surgery. The major obstacle to successful oral therapy is the nausea and epigastric discomfort that occurs 30–60 minutes after taking iron, symptoms that are dose-related but often subside after 2–3 days with continued treatment. Reducing the dose or taking a tablet at bedtime is usually helpful in reducing side effects. Diarrhea or constipation are not dose-related and should be managed symptomatically. Commercial iron preparations promoted on the basis of fewer side effects are invariably less well absorbed. A brief follow-up clinic visit 2–3 weeks after initiating oral therapy can be helpful in tailoring an oral iron regimen in patients having troublesome side effects. Parenteral iron should not be used simply as a convenience for the patient or physician.

Parenteral iron therapy
The main indications for parenteral iron are uncontrolled blood loss, intolerance to oral iron, intestinal malabsorption, and poor adherence to an oral regimen. Iron malabsorption can be detected by observing an increase in serum iron of less than 100 µg% over baseline in a fasting patient 1 or 2 hours after taking 60 mg iron as ferrous sulfate.

Until recently, iron dextran has been the only parenteral iron preparation available in the United States. It is a low molecular weight dextran complexed with ferric oxide and supplied as a dark brown solution containing 50 mg iron per mL. Although intramuscular administration is still recommended by current manufacturers, intravenous (IV) administration is preferred by most physicians because of the ability to administer larger doses. In hemodialysis patients in whom multiple treatments can be given conveniently, 6–10 injections of 100 mg iron can be administered on consecutive dialysis days.27 In other patients, a major advantage of iron dextran is the ability to administer relatively large doses of 500–2000 mg iron on a single occasion.28,29 After diluting the dose in 500 mL normal saline, and premedicating with diphenylhydramine with or without steroids, the first 20–30 mL is given slowly over 5 minutes as a test dose. If no allergic reaction occurs within the first 15–30 minutes, the remainder of the dose is given over the next 3–4 hours.

The major drawback of iron dextran is a severe anaphylactic reaction that occurs within a few minutes of initiating the infusion and is sometimes fatal. At least 30 deaths have been attributed to iron dextran use in the US since 197630 and because anaphylaxis can occur in those who have not reacted to iron dextran in the past, a test dose is always required. Another drawback of iron dextran is a less serious delayed reaction occurring 24–48 hours after the infusion. Characterized by myalgia, arthralgia, headache, and malaise, delayed reactions occured in over 10% of patients given total dose infusions.31 These symptoms usually respond promptly to nonsteroidal anti-inflammatory drugs but the reaction can be severe and prolonged in patients with inflammatory joint disease.

Sodium ferric gluconate (SFG)
This form of parenteral iron was approved in the US in 1999 under the Food and Drug Administration’s priority drug review, although it has been used in Europe for many years. SFG in sucrose is a stable macromolecular complex supplied as a deep red solution in 5 mL ampoules containing 62.5 mg elemental iron. The current product label advises administration of 5–10 mL as a direct IV push at a rate of 12.5 mg per min for 10 minutes for a recommended dose of 125 mg iron. No test dose is required. Unlike iron dextran, which can require several weeks for complete processing by macrophages, roughly 80% of SFG is delivered to transferrin within 24 hours. One report suggested that saturation of circulating transferrin can be exceeded following the infusion of SFG32 but this was later explained by the release iron from the ferric gluconate during the serum iron determination.33

The appeal of SFG administration is avoidance of the risk of the serious anaphylactic reactions associated with iron dextran. In a review of data from the World Health Organization and pharmaceutical manufacturers, no deaths were reported with 25 million infusions of SFG as compared with 31 deaths from about half the number of administratons of iron dextran.30 Adverse reactions with SFG in a multicenter, randomized, crossover, double-blind, placebo-controlled prospective study in 2534 hemodialysis patients was recently reported.34 Adverse events were similar between SFG and placebo groups, 12.3% versus 9.8%. Life-threatening events (immediate reactions requiring resuscitation measures) and drug intolerance rates (any event that precluded further SFG infusions) were compared to historical adverse events in 3768 patient exposures to iron dextran. A life-threatening event was observed in a single patient given SFG as compared with 23 patients given iron dextran while drug intolerance occurred in 11 patients receiving SFG as compared with 64 patients given iron dextran (Table 6). These results are a compelling reason for using SFG rather iron dextran in hemodialysis patients and in most patients requiring parenteral iron. The feasibility of large single doses with iron dextran provides a useful alternative in noncompliant patients or those who are seriously inconvenienced by multiple iron infusions.
 
 
 

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   Table 6. Comparison of iron dextran and sodium ferric gluconate (SFG).
 
 

Iron sucrose
Iron sucrose (saccharate) was approved for use in the US in late 2000, providing a third option for intravenous iron therapy. Iron sucrose has also been used for several decades outside of the US although recently published experience is more limited than with SFG. Iron sucrose is supplied as an aqueous brown solution in 5 mL vials containing 100 mg of elemental iron. No test dose is required. It is recommended that 5 ml iron sucrose (100 mg iron) either be infused directly or first diluted in 100 mL normal saline and infused over 15 min to reduce the risk of hypotensive episodes. The safety profiles of iron sucrose and SFG are similar although most studies have evaluated efficacy rather than adverse reactions.
Summary and Conclusions
In otherwise healthy individuals at higher risk of iron deficiency due to rapid growth, pregnancy, or excessive blood loss, a low hemoglobin and serum ferritin < 30 µg/L is diagnostic of iron deficiency anemia. In hospitalized or elderly patients who have a higher prevalence of chronic disease, a CRP and sTfR should be added to the initial laboratory evaluation. If the CRP is normal, anemia and a serum ferritin < 30 µg/L establish iron deficiency anemia. If anemia is present and the CRP is elevated, iron deficiency anemia can be diagnosed in patients with anemia of chronic disease by an elevated sTfR. Prospective trials are needed to determine the optimal laboratory approach for monitoring initial and maintenance parenteral iron therapy in patients receiving rHuEPO therapy. When parenteral iron is indicated because of iron malabsorption, heavy iron losses or intolerance to oral iron, sodium ferric gluconate or iron sucrose is preferable to iron dextran because of reduced acute and delayed drug reactions.
 
 

• cobalt (₂₇Co)

Symptoms & signs : poisoning from long-term excessive exposure to cobalt, seen in those who work with cobalt and formerly in beer drinkers because for years cobalt was added to beer as a foam stabilizer
• nausea and vomiting
• tinnitus
• nerve deafness
• beer-drinkers' cardiomyopathy
• cobaltosis (a pneumoconiosis)
• nickel (₂₈Ni) : a silver-white metallic element: symbol, Ni; specific gravity, 8.9; atomic number, 28; atomic weight, 58.71
• nickel carbonyl : a combination of nickel and carbonyl ions, produced in the refining of nickel; it is extremely toxic, causing acute pulmonary edema and dyspnea, and carcinogenic, causing lung and nasal cancers.
Pathogenesis :
• voltage-sensitive calcium channel blocker
Symptoms & signs :
• long-term excessive exposure to metallic nickel, such as on jewelry, can cause type I hypersensitivity (contact dermatitis : nickel dermatitis)
• excessive exposure to nickel fumes can cause nasal cancer, paranasal sinuses cancers, and lung carcinomas
• copper (₂₉Cu)
• hypercupremia (> 200 mg/dL or > 31 mmol/L)

Aetiology :
• Menkes disease
• Wilson's disease / hepatolenticular degeneration
• excessive intake of medicinal cupric sulfate
• ingestion of a liquid that had been kept in a metallic container
• copper in drinking water
• non-Wilsonian hepatic copper toxicosis
Pathogenesis : up-regulation of metallothioneins
Symptoms & signs : nausea and blue or green vomiting, which may be bluegreen, systemic arterial hypotension, jaundice, and coma that may end in death. Chronic buildup of liver copper stores resulting in release of copper into the bloodstream may cause symptoms similar to those of acute poisoning, sunflower cataract and may be fatal.
Chelation therapy
• hypocupremia (< 100 mg/dL or < 16 mmol/L)

Aetiology : hyperzinchemia due to an indirect interaction between the 2 metals in the intestine. When exposed to excess dietary zinc, the absorptive duodenal cells upregulate metallothionein, an intracellular metal-binding ligand. Metallothionein binds both zinc and copper ions but has a much greater affinity for copper. Dietary copper that is bound to metallothionein becomes sequestered within the duodenal enterocytes, which are sloughed into the intestinal lumen. Increased oral copper intake is ineffective in restoring the zinc–copper balance in the presence of excess dietary zinc, as the induced metallothionein continues to intercept the copper and reduce its absorption. Since ceruloplasmin, the main copper metalloprotein in the blood, is produced by the incorporation of cupric ions into a protein moiety, copper deficiency also results in reduced production and therefore a reduced serum concentration of ceruloplasmin. Copper-deficiency anemia secondary to zinc excess was first reported in 1977, and 18 cases have subsequently been reported. Most of these cases involved self-medication with OTC dietary supplements; the daily amount of zinc ranged from 29 mg for 7 months to 2000 mg for 3 months. The daily zinc intake of our patient was 100 to 120 mg for 5 years. Instructions on a bottle of OTC zinc lozenges recommend 5 to 20 mg every 2 hours during the onset of a cold, to a maximum of 50 mg daily.
Symptoms & signs : reversible bicytopenia (macrocytic anemia, neutropenia, normal platelet count, and elevated serum ferritin and EPO levels)^ref
• zinc (₃₀Zn) : a blue-white metal, many of whose salts are used in medicine; atomic weight, 65.37. Zinc is necessary in trace amounts in the body, and hence in the diet; it forms an essential part of many enzymes (e.g., carbonic anhydrase, important in carbon dioxide metabolism) and plays an important role in protein synthesis and in cell division
• zinc acetate : a salt produced by the reaction of zinc oxide with acetic acid, used as a pharmaceutic necessity for zinc-eugenol cement and as an astringent, styptic, and formerly as an emetic.
• zinc carbonate : a zinc salt used as a topical antiseptic and astringent. It may be used in the preparation of calamine (calamine contains zinc oxide).
• zinc chloride : a compound, ZnCl₂, with a variety of industrial uses; if its fumes are inhaled they can cause zinc poisoning. Also a preparation used as a nutritional supplement in total parenteral nutrition. Zinc chloride is also used topically as an astringent and desensitizer for dentin.
• zinc gluconate : a zinc salt used as a dietary supplement; administered orally.
• zinc hydroxide : a white powder, Zn(OH)₂, an ingredient of medicinal zinc peroxide.
• zinc oxide / white zinc : a compound, ZnO, used in welding; inhalation of its fumes can cause zinc poisoning. Also a powdered form of this compound, used topically as an astringent and protectant in various cutaneous conditions and as an ingredient in calamine. It is also found in several dental cements
• zinc peroxide : a white to yellowish white odorless powder used in pharmaceuticals.
• medicinal zinc peroxide : a mixture of zinc peroxide, zinc carbonate, and zinc hydroxide, used topically in a 40% solution as a local anti-infective and oxidant. It is also used as an astringent and deodorant.
• zinc phosphide : the phosphide salt of zinc, a rodenticide that is toxic to most mammalian species, including humans; it causes vomiting, convulsions, and dyspnea from acute pulmonary edema.
• zinc pyrithione : a compound used as an antibacterial, topical antifungal, and antiseborrheic.
• zinc salicylate : a salt which has been used as an antiseptic and astringent.
• zinc stearate : a compound of zinc with variable proportions of stearic acid and palmitic acid, used as a dusting powder.
• zinc sulfate : the heptahydrate zinc salt of sulfuric acid, used as an astringent for the mucous membranes, especially for those of the eye, being considered specific for conjunctivitis due to Haemophilus duplex. It has also been used in various dermatological preparations and internally as an antiemetic, especially in the treatment of poisoning.
• hypozincemia (< 60 mg/dL or < 9 mmol/L)

Aetiology : malbsorption
Symptoms & signs : anemia, short stature, hypogonadism, impaired wound healing, acrodermatitis enteropathica, and geophagia (pica)
• hyperzincemia (> 150 mg/dL or > 23 mmol/L)

Aetiology :
• a common supplement and widely available as a standard component of many over-the-counter products
• inhalation of zinc or zinc oxide fumes, most commonly in metal workers
• ingestion of a liquid that had been kept in a metallic container
Pathogenesis : up-regulation of metallothioneins
Symptoms & signs (zincalism or zinc poisoning) : after a longer incubation period (several hours) than other heavy metal poisonings : fever, chills, myalgia, diarrhea, nausea and vomiting after several hours of incubation, parageusia, and pneumonitis
Zinc interferes with pigment synthesis somewhere in the earthworm Lumbricus rubellus turning it from a dingy greenish-brown not bright enough to be visible into a nearly transparent colour.
• gallium (₃₁Ga) : ⁶⁷Ga-citrate is also used in SPECT
• arsenic (₃₃As)

Sources :
• despite its low crustal abundance (0.0001%), arsenic is widely distributed in nature and is commonly associated with the ores of metals like copper, lead, and gold. Arsenic can exist in 4 oxidation states: As(-III), As(0), As(III), and As(V). Native(elemental) arsenic occurs rarely, whereas traces of toxic aresines can be deteced in gases emanating from anoxic environments. The predominant form of inorganic arsenic in aqueous, aerobic environments is arsenate [As(V) as H₂AsO₄^- and HAsO₄^2-], whereas arsenite [As(III) as H₃AsO₃⁰ and H₂AsO^3-] is more prevalent in anoxic environments. Arsenate is strongly absorbed to the surface of several common minerals, such as ferrihydrite and alumina, a property that constrains its hydrologic mobility. Arsenite adsorbs less strongly to fewer minerals, which makes it the more reliable oxyanion. A number of methylated organoarsenicals (e.g. methylarsonic, methylarsonus, and dimethylarsenic acids) are found in natural waters as breakdown or excretory products from aquatic biota or as urinary excretions of animals, including humans.
• anthropogenic point sources contribute to arsenic found in the environment :
• smelter slag
• coal combustion
• runoff from mine tailings
• hide tanning waste
• pigment production for paints and dyes
• processing of pressure-treated woods (e.g. copper chromated arsenate (CCA))
• arsenic-based pesticides : for nearly 5 decades (1930 to 1980), their application alone amounted to 10,000 metric tons per year
• Kaiserstuhl disease : a form of chronic arsenic poisoning that occurred prior to World War II among German workers in vineyards, due to arsenic-containing insecticides used on the grapes
• the production and storage of chemical weapons (e.g. arsenic-based vesicants, arsine, and arsenic-based emetics) has resulted in the gross contamination (> 900 mg/kg) of several former military bases in Eastern Europe.
• arsenic has been replaced inmost applications by synthetic dyes and pesticides, but it is still used in agricultue. Organic arsenicals like roxarsone (4-hydroxy-3-nitrophenyl arsonic acid) act as an intestinal palliative for swine and prevent coccidiosis, improve pigmentation, and increase growth in feddlot-raised poultry. It has been estimated that the poultry industry on the east coast of the USA uses 20 to 50 metric tons of roxarsone annually. The arsenic does not accumulate in the flesh, meat, or eggs but is excreted, resulting in excess of 20 mg/kg in manure.
• therapeutics
• melarsoprol
• although it is carcinogenic and known since antiquity as a homicidal agent (once referred as "inheritance powder"), As₂O₃ (Fowler's solution) is used in acute promyelocytic leukemia (APL) therapy as it restores proper localization of PML (PML oncogenic domains (PODs) were disrupted by the heterodimerization of PML-RARa with PML) resulting in apoptosis of APL cells.
• rice grown in the USA contains an average of 1.4 to 5 times more arsenic than rice from Europe, India and Banglades. This means that people eating a 'subsistence' diet of 500 grams of dry American rice a day are probably consuming more than the maximum intake of arsenic provisionally recommended by the WHO. Low doses of arsenic such as these do not cause acute illness. It's more about long term intake that can elevate levels of cancer. Research in Taiwan has linked arsenic-contaminated rice to an increase in bladder cancer, for example^ref. The survey team thinks that the contamination is a legacy of cotton farming, which relies on arsenic-based chemicals to kill boll weevils and to remove plants' leaves before harvest. Quite a lot of land in Mississippi and Arkansas that previously grew cotton is now used for rice cultivation. When rice was first grown in these soils, the crop often failed owing to an arsenic-induced disease known as straighthead. So new, straighthead-resistant rice varieties were bred that could withstand the arsenic. However, this means that they are more likely to accumulate arsenic in apparently healthy grainsI don't think they should be growing rice on old cotton fields. Of the rice eaten in the United States, the vast majority is home-grown. About half of all US-grown rice is exported. Meharg tested rice bought from markets in Aberdeen that had been grown in America, Europe, India, and Bangladesh. He found an average of 0.26 micrograms of arsenic in each gram of US rice. Indian rice hit a low of 0.05 micrograms per gram, whereas Bangladesh, which has had recurring problems with arsenic contamination owing to naturally high levels of the poison in groundwater, and Europe had about 0.15 mg/g^ref. There are still many gaps to fill in before we will know whether an overdose of US rice might be bad for you. The work is fine as far as it goes, but you can't draw broad conclusions from such a limited survey. Others point out that there is no epidemiological evidence that anyone with a high rice diet, such as those of Asian descent, for example, is experiencing ill effects. There simply are no known negative health issues with US rice. The rice may not be particularly toxic, because of the form that the arsenic takes in the plants. Health effects are diminished if the arsenic atoms are bound up with carbon-based molecules. Inorganic arsenic (the form found in drinking water) is estimated by Duxbury to be five to ten times more toxic. Just 42% of arsenic in US rice was inorganic, compared with 81% of arsenic in Indian rice. But Meharg points out that organic arsenic can still cause problems^ref, and could convert into the inorganic form in the body^ref. The health effects of arsenic in food are hard to verify because the increase in cancer risk is small. If 10,000 people were exposed to the WHO limit over their lifetime, this would result in an extra 92 cases of bladder cancer. Given the uncertainties, regulations are few. Even the WHO has not ratified its provisional guidelines. Australia is the only country that has a safety limit for arsenic in food. There are a few different types of arsenic pesticides and herbicides licensed for use in the USA. All are undergoing safety reviews at the moment and decisions are planned for next year. Duxbury cautions that arsenic in US rice might come from natural, geological sources. It may be that the arsenic in pesticides is in a form that is harder for the plants to take up, he adds, which could lower concerns about the chemicals themselves. The work serves as a good base from which to work out how crops can be contaminated. This could help to breed plants that tend not to store arsenic in an inorganic form. There's potential for a lot of follow up from this.

Web resources :
• Venomous Earth
• in contrast to localized sources of anthropogenic arsenic pollution, naturally occurring arsenic is very broadly distributed in many subsurface drinking water aquifers around the globe. Ironically, it is these "natural" sources that are of the most concern to human health on a global basis. To prevent Vibrio cholerae epidemics, the government decided to use high depth wells. In response, the Bangladeshi government and the children's charity UNICEF sunk > 1 million wells in the 1970s and 1980s. In 1992, the British Geological Survey (BGS) was called in to survey the toxicity of the well water. The study looked for chemical contaminants such as iron and phosphorous, but did not look for arsenic. The BGS declared the water safe to drink. Only in 1995, when villagers began to display symptoms of poisoning such as major skin lesions, did experts realize that the water was heavily polluted : it emerged that As (from geological sources) has contaminated well water in parts of the Bengal Delta, India and Bangladesh, Vietnam and Chile. This is the coastal floodplain of numerous rivers, including the Ganges and is shared by Bangladesh and the Indian state of West Bengal. The problem has been described as the worst mass poisoning in history - health experts estimate that 100,000 people living on the Bengal delta have suffered debilitating skin lesions. The latest surveys estimate that around 36 million people in the Bengal Delta are drinking contaminated water, and 150 million are at risk. In the village of Semria Ojha Patti in the Indian state of Bihar, 50% of wells contain 5 times the accepted safe limit of arsenic; 1 in 5 wells have 30 times the safe level. Villagers could obtain safer water by collecting some of Bangladesh's huge annual rainfall, but they would need to store it cleanly. BGS defends itself saying at the time of the study, there was no reason to expect arsenic to be there but a similar problem in neighbouring West Bengal was documented in a World Health Organization bulletin as long ago as 1988
Toxicity : the mode of toxicity depends on the chemical form of arsenic.
• organic arsenicals (arsphenamine, sodium arsanilate)

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• As⁵⁺ (arsenate, eg. lead arsenate : PbHAsO₄) is a molecular analog of phosphate and inhibits oxidative phosphorylation, short-circuiting life's main energy-generation system. It usual mode of entry is through phosphate transporters (SLC17A1, SLC17A3, SLC20A1, SLC20A2, SLC25A3, SLC34A1, SLC34A2).

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• As³⁺ (arsenites : KAsO₂ ; salts of arsenious acid) binds to sulfhydril groups, imparing the function of many proteins. It also affects respiration by binding to the vicinal thiols in pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase. More recently, it has been shown to interact with the glucocorticoid receptor (GR). Arsenite is uncharged at pH values < 9.2 and enters the cell via aquaporins.

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• arsine (SA) (AsH₃) : any member of a peculiar group of volatile arsenical bases, formed when arsenous acid is brought in contact with albuminous substances. The typical arsine is AsH₃, arsenous hydride or arseniuretted hydrogen, a very poisonous gas. It has been described as having a slight garlic odor

Sources : some of its compounds have been used as chemical weapons. A major industrial use is in the production of microelectronic components.
Symptoms & signs : possible cherry red skin; frostbite may occur from skin contact with liquid arsine; it is carcinogenic and also can produce delayed (up to 24 hours) hemolysis, jaundice, gastroenteritis, and nephritis
Arsenic does not directly damage DNA, but may act as a carcinogen through inhibition of DNA repair mechanism, leading indirectly to increased mutations from other DNA damaging agents : individuals exposed to high levels of arsenic (i.e., drinking water arsenic levels of 10 µg/L or more and arsenic levels in toenail clippings of 0.2 µg/g) had significantly diminished expression of the NER genes ERCC1 (p < 0.0001), ERCC3 / XPB (p < 0.0001), and ERCC4 / XPF (p < 0.002) compared with those with low levels of arsenic exposure.
Several different mechanisms have evolved to rid cells of arsenic. These include methylation, and expulsion involving an As(III)-specific transporter. In higher eukaryotes, glutathione reduces As(V) to As(III), which then accepts a methyl group from S-adenosylmethionine, producing monomethylarsonic acid (MMA) or dimethylarsonic acid (DMA). Fungi produce trimethylarsine, whereas bacteria may produce MMA and DMA. Such diverse microbes as anaerobic methanogenic Archaea and aerobic Eubacteria can also form methylated arsines. Arsenic may also be converted to arsenobetaine and arsenic-containing sugars, benign compounds that are found in high abundance in some marine animals and algae as well as terrestrial plants and animals. The most well studied mechanism of detoxification and resistance, however, is the ArsC system. At least 3 different but structurally related arsenate reductases have convergently evolved in bacteria and yeast. ArsC, a small-molecular mass protein (13 to 16 kDa), mediates the reduction of As(V) to As(III) in the cytoplasm. Although As(III) is more toxic, it can be excreted via an As(III)-specific transporter, ArsB. The ars operon in Escherichia coli has both plasmid and chromosomal loci. The plasmid R733 has 4 genes - arsA, arsB, arsC, arsD, and arsR - whereas the chromosomal locus has only arsB, arsC, and arsR. A cysteine residue near the N-terminal of ArsC binds the As(V), which is then reduced with electrons donated by the reduced glutathione. The As(III) is then expelled from the cytoplasm through an adenosine 5'-triphosphate (ATP)-dependent arsenite transporter formed by ArsAB. The ars operon in plasmid pI258 of Staphylococcus aureus contains only arsB, arsC, and arsD. Reduced thioredoxin provides the electrons to reduce As(V), and As(III) is expelled from the cell via an ATP-independent ArsB. Although this process has been studied in detail in E.coli and S.aureus, it is found in many other bacteria and occurs in strrict anaerobes like Clostridium and Desulfovibrio. Arsenate reduction to As(III) has ben noted in several aerobic bacteria isolated from As-contaminated soils and mine tailings, suggesting that As(V) resistance plays an important role in the biogeochemical cycling of this element in nature. Considering the toxicity of arsenic to both prokaryotes and eukaryotes, the discovery that As(V) serves as a "nutrient" to certain anareobes by functioning as their respiratory oxidant came as a surprise. The reaction is energetically favorable when coupled with the oxidation of organic matter because the As(V)/(As(III) oxidation/reduction potential is +135 mV. 2 closely related representatives of the e-Proteobacteria, Sulfurospirillum arsenophilum and Sulfospirillum barnesii, were the first microbes reported that could achieve this feat. Both conserve energy by linking the oxidation of lactate to the reduction of As(V) to As(III) [DG° = -295 kJ/mol lactate]. At present there are at least 16 species in pure culture, and include representatives from the g-, d-, and e-Proteobacteria, low GC-Gram positive bacteria, thermophilic Eubacteria, and Crenoarchaea. We collectively refer to these microbes as dissimilatory arsenate-reducing prokaryotes (DARPs). They have been isolated from freshwater sediments, estuaries, soda lakes, hot springs, and gold mines; the gastrointestinal tract of animals; and subsurface of aquifer materials from Bangladesh. They include several extremophiles adapted to high temperature, pH, and/or salinity. These organisms can use a variety of electron donors including hydrogen, acetate, formate, pyruvate, butyrate, citrate, succinate, fumarate, malate and glucose. Recently, some strains have been found to degrade more complex aromatic molecules like benzoate and even toluene. Certain species are more sensitive to arsenic than others. Whereas the haloalkalophile Bacillus selenitireducens grows well at 10 mM As(V), possibly because the product As(III) is charged at high pH and cannot enter the cell, Sulfurospirillum species grow best at 5 mM. To date, no "obligate" DARPs have been found, because all the strains examined can use other electron acceptors for growth. For example, Desulfotomaculum auripigmentum and Desulfomicrobium strain Ben-RB also respire sulfate. S.barnesii is the most versatile, because it also respires selenate, nitrate, nitrite, fumarate, Fe(III), thiosulfate, elemental sulfur, dimethylsulfoxide (DMSO), and trimethylamine oxide. This metabolic diversity may be an important ecological factor, because sulfur, iron, and nitrate chemical species [e.g., S(-II), FeOOH, NO₃^-] interact with arsenic in the environment. Although the biochemistry of respiratory As(V) reductases remains to be fully elucidated, it is clear that they differ both functionally and structurally from ArsC. The respiratory arsenate reductase from Chrysiogenes arsenatis is a heterodimer consisting of subunits of 87 and 29 kDa and is located in periplasm. N-terminal sequence data suggest that both subunits contain an iron-sulfur cluster, placing this protein in the dimethylsulfoxide (DMSO) reductase family of mononuclear molybdenum enzymes. Initial investigations of the As(V) reductase from the Gram-positive bacterium B.selenitireducens revealed similar characteristics. N-terminal sequence analyses indicate a 50% sequence identity and 85% similarity of both ArrA and ArrB subunits of C.arsenatis. The putative arsenate reductase from S.barnesii is also believed to be oriented in the periplasm, but it consists of a single subunit (48 kDa) and has no metal associated with it. Enzymological and immunological analyses further indicate that notable differences in the enzyme from S.barnesii and related Sulfospirillum species (S.arsenophilum, S.deleyianum). The ability to respire arsenate does not preclude the presence of a separate, arsenate-resistance system as well. Recently, Shewanella strain ANA-3 was found to have both respiratory and detoxifying arsenate reductases. The environmental impact of DARPs has only recently been realized. Their activity can be readily discerned using incubations of anoxic sediment slurries amended with millimolar (1 to 5) arsenate. Most-probable-number determinations of sediments from arsenate-contaminated lakes indicate resident populations of between 10⁴ and 10⁵ cells per gram. The process of dissimilatory As(V) reduction occurring in near.surface hyporheic zones greatly affects the transport and speciation of arsenic in freshwater streams. DARPs can also attack As(V) adsorbed to solid phases like ferrihydrite and alumina and reduce the As(V) contained in oxidized minerals like scorodite. This latter point contrasts with finding from studies done with nonrespiratory arsenic-reducing bacteria that showed release of adsorbed As(V) as a result of iron reduction or negligible release of As(V) and no dissolution of the mineral substrate. Although considered negligible in most environments, the role of DARPs in the oxidation of autochthonous organic matter can be appreciable in specific cases. In situ measurements of arsenate respiration in Mono Lake, California (a particularly arsenic-rich environment; dissolved inorganic arsenic = 200 mM), made with the radiotracer ⁷³As(V), revealed that as much as 14% of annual primary productivity was mineralized to CO₂ in the anoxic water column by the activity of DARPs. In the anoxic water column of Mono Lake, DARPs number between 10² and 10³/mL. These numbers appear to be low, probably because the method requres that they achieve growth in the medium provided. Culture-independent PCR techniques to enumerate DARPs have not yet emerged, in part because their diverse phylogeny negates the utility of commonly used 16S ribosomal DNA probes and because DARPs isolated thus far are opportunists capable of respiring electron acceptors other than arsenate. Denatured gradient gel electrophoresis (DGGE) of DNA extracted from anoxic Mono Lake water incubate with 1 mM As(V) resolved bands suggesting that members of the e- (Thiomicrospira) and d-Proteobacteria (Desulfovibrio) might be contributing to arsenate respiration in these waters. In contrast, DGGE resolution of in situ DNA from bottom water indicated that the Bacillus and Clostridium genera were the dominant population. Because the arsenate-respiring Bacillus arsenicoselenatis and Bacillus selenitireducens species were originally isolated from Mono Lake's bottom sediments, they may typify most of the DARPs present in the water column. The microbiological oxidation of As(III) to As(V) can also impact the mobility and speciation of arsenic in the environment. The process has been known for many years, and more thann 30 strains representing at least 9 genera have been reported to be involved, including a-, b-, and g-Proteobacteria; Deinocci (i.e., Thermus); and Crenarchaeota. Physiologically diverse, they include both heterotrophic arsenite oxidizers (HAOs) and the more recently described chemolithoautotrophic arsenite oxidizers (CAOs). Heterotrophic oxidation of As(III) encountered on the cell's outer membrane into the less toxic form, As(V), perhaps making it less likely to enter the cell. CAOs couple the oxidation of arsenite (e.g., electron donor) to the reduction of either oxygen or nitrate and use the energy derived to fix CO₂ into organic cellular material and achieve growth. In HAOs the oxidation of As(II) is catalyxed by a periplasmic enzyme that is distinct from the dissimilatory arsenate reductase. This mononuclear molybdenum enzyme, belonging to the DMSO reductase family, is structurally related to the periplasmic nityrate reductase (NapA) from Desulfovibrio desulfuricans. It is a heterodimer with a catalytic subunit (85 kDa) that contains molybdenum bound to 2 pterin cofactors and a [3Fe-4S] cluster. The associated subunit (14 kDa) presumably functions as an alectron shuttle and has a Rieske-type [2F-2S] cluster, a feature that is unique among molybdenum enzymes. The arsenite oxidases of CAOs, however, remain to be fully characterized. Arsenite oxidation is being studied as the basis for bioremediation of systems where As(III) is a polluttant, because the As(V) can be immobilized onto strong adsorbents. Interest in this ubject has resulted in nthe recent isolation of several novel spexies of both heteroitrophic and autotrophic aerobic As(II) oxidizers from arsenic-rich environments. Strain NT-26, a fast-growing CAO, is a member of the Rhizobium clade of the a-Proteobacteria and grows either by chemoautotrophic As(III) ocidation or as a conventional heterotroph by using organic compounds in lieu of As(III). A curious thermophilic species of Thermus (strain HR 13) has been isolated from an As-rich hot spring. Under aerobic conditions it will oxidize As(III) for detoxification purposes without conserving the energy produced by the reaction. However, udner anaerobic conditions, strain HR 13 can grow on lactate using As(V) as its electron acceptor. Field studies have demonstrated that microbial oxidation of As(III) occurs along reaches of arsenic-rich geothermal streams, and molecular techniques have been used to identify arsenite-oxidizing populations (HAOs) of thermophilic prokaryotes present in various hot springs of Yellowstone National Park. Recently, a novel species of the Ectothiorhodospira clade of Eubacteria was isolated from Mono Lake that gre under anaerobic conditions using As(III) as its electron donor and nitrate as its electron acceptor: H₂AsO₃^- + NO₃^- => HAsO₄^2- + NO₂^- + H⁺ [DG° = -56.6 kJ/mol]. This nonphotosynthetic bacterium, strain MLHE-1, also grew as an autotroph with sulfide or hydrogen gas in lieu of As(III), and additionally grew as heterotroph on acetate with oxygen  or nitrate as the electron acceptor. Curiously, it was unable to grow on or oxidize As(III) under aerobic conditions. The occurence of anaerobic arsenite oxidation suggested that there might be a tight coupling between respiratory reduction of As(V) at the expense of electron donors like organic compounds and H2, and its resupply as carried out by microbial As(II) oxidation at the expense of commonly occurring strong oxidants like nitrate, nitrite, or perhaps Fe(III). Mono Lake is an "extreme" environment in terms of its high pH (9.8), high salinity (90 g/L), and high content of other toxic eminerals. Recently, nitrate-linked microbial oxidation of arsenite was shown to occur in an arsenic contaminated freshwater lake, and injection of nitrate into a subsurface aquifer resulted in the immobilization of arsenic. Thus, this phenomenon appears to be widespread in nature. It remains to be determined what types of microorganisms crry out this reaction in freshwater or marine systems, as compared with those found in soda lakes. The contribution made by microorganisms to the biogeochemistry of arsenic in the environment is extensive and detailed as it involves  various oxidation, reduction, methylation, and demethylation reactions of its dominant chemical species. Unlike sulfur, where volatile organic species can play a crucial role in its biogeochemical cycle, it is apparaent that natural organoarsenicals do not contribute substantially in this regard. However, from an ecological perspective, we can limit this scope to consider only the flow of energy linked to arsenic metabolism that translates into a capacity to do biological work (i.e., cell growth). We therefore consider the ecology of arsenic to be simple in the sense that it is predominantly confined to microbial transformations between its +3 abd +5 oxidation states, constrained further by considering only those prokaryotes that conserve the energy associated with these redox reactions to achieve growth. Although energy-yielding biochemical reactions mediating the oxidation or reduction of the 0 or -3 oxidation states of arsenic may be possible, they have not been observed. Regardless of the simplicity of the cycle, understanding the role or microorganisms in the hydrologic mobility of arsenic in drinking water aquifers is a highly complex but unresolved environmental question that is of critical importanceto the health of millions of people worldwide. Factored into such complexity are the competing chemical reactions that affect both the speciation and the partitioning of arsenic between the aqueous phase and the solid mineral phase of the aquifer matrix. In Bangladesh alone, perhaps 30 million people drink well waters that contain elevated arsenic concentration, and thousands of new cases of severe arseniasis (arsenicosis) occur annuall in that country. Several theories have been proposed to explain the subsurface mobilization of arsenic. These include the oxidation of As-copntaining pyrites, the release of As(V) from reduction of iron oxides by autochthonous organic matter (e.g., peat), the reduction of iron oxides by allochthonous organic matter (from dissolved organics in recharging waters), and the exchange of adsorbed As(V) with fertilizer phosphates. In light of our above discussion of microbes that metabolize arsenic, we suggest that these are not necessarily mutually exclusive processes, but that over time microorganisms probably play an essential role in both the direct reduction and oxidation of the arsenic species, as well as the iron minerals contained in these aquifers. On the basis of what we know is possible with regard to the microbial metabolism of arsenic in nature, we can begin to formulate a conceptual model for what might be occurring in the aquifer of Bangladesh. Perhaps the initial process is the oxidation of the original As(III)-containing minerals (e.g. arsenopyrite) during transport and semimentation by pioneering CAOs and HAOs taking place ver recent geologic time periods. This would result in the accumulation of As(V) onto surfaces of oxidized minerals like ferrihydrite. Subsequent human activity in the form of intensive irrigated agriculture, digging of wells, and lowering of groundwater tables would provide oxidants (e.g., oxygen, nitrate) that would further stimulate As(III) oxidation. This would cause a buildup of microbial biomass (and its associated organic matter) and the creation of anoxic conditions. This organic matter, in conjunction with other sources either from decomposing buried peat deposits or from that dissolved in seasonal recharge from agricultural surface waters, would in turn promote the dissimilatory reduction of adsorbed As(V) by DARPs and the eventual dissolution of adsorbent minerals like ferrihydrite. The end result of these processes acting in concert over time and accelerated by human activities would be the release of arsenic into the aqueous phase. Indeed, preliminary evidence suggests the presence of an anaerobic, microbial arsenic cycle in the subsurface of aquifers of Bangladesh. Injection of nitrate into the aquifer promoted the rapid removal of As(III), which indicates the presence of a community of microorganisms similar in physiology to MLHE-1. In addition, DARPs have been cultured from As-contaminated Bangladesh aquifer sediments. Although there is an immediate research need for a fuller understanding of the role(s) of subsurface microbes in mobilizing arsenic in aquifers, on a more speculative level, it is tempting to contemplate a microbial "biome" supported by arsenic cycling. Indeed, it can be argued that because arsenic is a "chalcophilic" (sulfur-loving) element, it should be more abundant in the Earth's interior than in its crust, and possibly more abundant on the surface of less differentiated, volcanically active planetary bodies like Mars and Europa. Provided that liquid water was present, and that there were also oxidants available that were stronger than As(V) to recycle As(III) (e.g. nitrate), Mars or Europa could conceivably have evolved primitive microbial ecosystems based in part upon use of arsenic as an energy source. Although such speculation on our part certainly borders on the fanciful, it also poses the more relevant question, how did prokaryotes on Earth evolve  enzyme systems that are capable of exploiting the energy to be gained by reducing or oxidizing inorganic arsenic? Are these ancient systems dfating back to the anoxic Archaean era of some 3.5 billion years pastr, when noxious substances were abundant on this planet's surface and the ability to exploit them for energy gain may have conferred some selective advantage? Conversely, are they more recent in origin and reflective of the need for an oxidizing atmosphere and strong oxidants to recycle As(III)? Does the wide phylogenetic distribution of DARPs among the prokaryotes indicate a long vertical evolution from one original gene, a convergent evolution of several independent genes, or merely a high degree of lateral gene transfer of a useful trait?
Symptoms & signs (arseniasis / arsenicosis) :
• acute arsenic poisoning, which may result in shock and death, is marked by erythematous skin eruptions, nausea and vomiting, diarrhea, abdominal pain, muscular cramps, and swelling of the eyelids, feet, and hands
• chronic arsenic poisoning (arsenicalism / arsenism), due to the ingestion of small amounts over a long period of time, is marked by pigmentation of the skin accompanied by scaling, hyperkeratosis of the palms and soles, Mees' lines, headache, peripheral neuropathy, and confusion, brain purpura,arsenic neuropathy => arsenic tremor, tinnitus, lung carcinomas, nasal septal perforation, stomatitis arsenicalis, exfoliative keratitis, skin lesions => skin carcinomas, alopecia, high rates of miscarriage and premature delivery.
Laboratory examinations :
• the new EPA limit for arsenic concentrations in drinking water is 10 mg/L
• existing chemical tests are unreliable, especially at low, but still dangerous, concentrations: field assays can wrongly label up to 44% of polluted wells as arsenic-free. A better approach is to exploit bacteria's natural sensitivity to arsenic by inserting genes for colour-producing proteins into the DNA regions that control arsenic resistance in Escherichia coli : dried onto paper strips they can detectg both arsenites and arsenates. Drawbacks are that bacteria are also sensitive to many other chemicals found in water (highly toxic copper, for example, is common near arsenic deposits) and the tests contain genetically modified bacteria, so are not allowed outside the laboratory. Arsenic interferes with pigment synthesis somewhere in the earthworm Lumbricus rubellus turning it from a dingy greenish-brown not bright enough to be visible into a mustard yellow.
Tolerance to arsenic levels as high as 70 mg (fatal to most people) can be developed by regular assumption of progressive doses, which allows up-regulation of methylase expression in hepatocytes (however, 1 mg of arsenic a day does significantly increase the risk of cancer and causes other serious health problems, eg hair whitening).
Phytofiltration
Web resources :
• Arsenic Health Effects Research Programme
• EPA Arsenic Standards
• WHO Arsenic Factsheet
• WHO: Arsenic in Drinking Water
• selenium (₃₄Se)
• hyperseleniemia

Aetiology : poisoning of livestock from grazing on plants that have absorbed excessive selenium from the soil. Areas of selenium-rich soil have been found in the northern Great Plains of North America, Ireland, Israel, China, Russia, and elsewhere. Plants that can cause selenium poisoning are Acacia cana, Aster spp., Astragalus (certain species only)*, Andrachne, Atriplex spp., Castilleja spp., Comandra pallida, Greyia spp., Grindelia spp., Gutierrezia spp., Machaeranthera spp., Morinda reticulata, Neptunia amplexicaulis, Oonopsis spp.*, Penstemon spp., Sideranthus spp., Stanleya spp., Xylorrhiza spp.* (* = plants that grow preferentially in selenium-rich soils = selenium indicators).
Symptoms & signs (selenosis) :
• chronic selenium poisoning / alkali disease : cirrhosis of the liver, anemia, loss of hair, erosions of long bones, and emaciation
• acute selenium poisoning / blind staggers : impaired vision, an unsteady gait, and increasing incoordination with respiratory failure and often death within 24 hours
• hyposeleniemia

Symptoms & signs : primary hypothyroidism
• bromine (₃₅Br)

Sources : also in pyridostigmine bromide, rapacuronium bromide, pancuronium bromide, vecuronium bromide, rocuronium bromide, totropium broimide, ipratropium bromide; NaBr is used against iodine toxicity; calcium bromo-galactogluconate (Calcibronat^®))
Symptoms & signs (bromism / brominism) : chronic bromide intoxication, once a common problem, now rare, caused by chronic ingestion of proprietary bromide preparations; it is characterized by
• mental dullness, short-time deficient memory, slurred speech, drowsiness, tremors, and ataxia
• mental disorder, which may be a delirium, an auditory and visual hallucinosis, or a transitory psychotic state resembling paranoid schizophrenia
• skin eruptions of various forms are common, e.g. induced acne (bromoderma)
• a block in spermatogenesis => male sterility
• zirconium (₄₀Zr) : a rather rare metallic element; atomic weight, 91.22; chiefly obtained from a mineral called zircon

Symptoms & signs (zirconium pneumoconiosis)
• molybdenum (₄₂Mo)

Symptoms & signs (molybdenosis) :  due to ingestion of large amounts of molybdenum, characterized by weakness, diarrhea, and loss of hair pigmentation; seen primarily in livestock that graze in certain kinds of pastures (teart)
• technetium (₄₃Tc) : ^99mTc-citrate is also used in SPECT
• silver (₄₇Ag)
• argyremia : the presence of silver or silver salts in the blood.

Symptoms & signs :
• argyria / argyrosis / argyriasis / argyrism : a permanent, irreversible ashen-gray discoloration of the skin, conjunctiva, and internal organs that results from subepithelial silver deposits due to long-continued use of silver salts
• argyria nasalis (argyric discoloration of the nasal mucosa) => anosmia
• toxic cataract
• cadmium (₄₈Cd) : a bivalent metal, similar to tin in appearance and properties; atomic weight = 112.40

Sources :
• occupational : it does not corrode or oxide easily; acid-soluble
• metal coatings : galvanization (the application of one metal cover placed one above the other by galvanic current) and galvanoplasty (it is the art of overlaping at one solid corps a metallic cover by galvanic current. Chemical behavior by which it is obtained the copper's copies of engraves pages, etc.)
• pigments for paints (expecially yellow-colored ones), plastics, textiles, soaps, inks, papers, ...
• alkaline batteries (Ni-Cd)
• metallic alloys
• ceramics, glasses, mirrors
• resistances for screens, lamps, ...
• cadmium bromide (CdBr₂) : a compound used in photography, process engraving, and lithography
• non-occupational
• all soils and rocks (as cadmium sulfate or chloride), including coal and fertilizers
• breathing air contaminated by cigarette smoke (doubles the average daily intake) or atmospheric emissions
• drinking water contaminated by stratum or released from plumbing
• eating contaminated foods : meat, fish, fruit (1-50 mg/kg), cereals (10-150 mg/kg), crustaceans (100-1,000 mg/kg), fungi (in single fruiting-bodies the lowest cadmium content is found in the stem, whereas the highest content is found in the gills and tubes. Cadmium content of the gills is at most 5 times the amount present in the cup. In cadmium-rich mushrooms a marked concentration as compared with the cadmium content of the soil occurs)
• until 1997, cadmium carbonate and cadmium chloride were used as fungicides for golf courses and home lawns
Foundry Cove on the Hudson River was one of the most heavily metal-polluted areas in the world. Between 1953 and 1979, a battery factory released approximately 53 tons of cadmium and nickel hydride waste into the cove, resulting in sediment Cd concentrations as high as 10,000 ppm. The cove's commonest invertebrate, Limnodrilus hoffmeisteri, an oligochaete worm, evolved resistance to the Cd, and its central position in the food web is thought to promote the transfer of the metal through the ecosystem : it has subsequently lost its resistance following a $100 million Superfund cleanup of the site, which immediately brought sediment Cd concentrations < 10 ppm. Resistant worms grew more slowly than nonresistant worms, probably because of a diversion of resources into the production of large quantities of a metal-binding metallothionein-like protein. Such selection against Cd resistance in the absence of the metal resulted in the worm reverting to its nonresistant state in an estimated 9 to 18 generations and demonstrated the potential for ecological restoration to rapidly reduce the potential for the transfer of pollutants through ecosystems.
In the south, cadmium levels had been found to be 10 times normal in the Shaoguan city section of the North River cutting across Guangdong province north to south, after the smelter's discharge of waste during equipment maintenance last week. Several villages and factories near Yingde, a city 90 km (54 miles) downstream from Shaoguan, had been without running water for days. At a suburban Yingde cement plant, fire engines had been dispensing drinking water to thousands of workers and their families. Taps are only on for showers in the evening for a couple of hours. Workers have been collecting drinking water with plastic buckets from fire engines since Sun Dec 18. The city has begun drawing drinking water for its 100 000 residents from a nearby reservoir. The most polluted slick of water reached Shakou township, 30 km upstream from Yingde, and dam gates at the nearby Baishiyao hydropower plant had been lowered to stall it. They want to dilute the toxins there by reservoirs further upstream increasing discharges and then flushing them quickly past Yingde. The diluted pollutants should not affect Foshan and the provincial capital, Guangzhou, cities of 800 000 and 9 million respectively in the booming Pearl River Delta manufacturing hub. Nevertheless, the 2 cities have been asked to start emergency plans to ensure safe drinking water. Qingyuan city, between Guangzhou and Yingde and with a population of half a million, has also taken emergency  measures. In Shaoguan, authorities had halted operations at the zinc smelter -- China's 3rd largest -- and shut down another 14 small smelters. In China's northeast, the Songhua River toxic slick was expected to reach the Russian border city of Khabarovsk on Thursday but workers temporarily dammed a waterway to divert the pollution away from Khabarovsk's water supplies.
The normal level for cadmium in the human diet appears to between 1 and 3 mg/day, without harm.
Routes of intoxication :
• respiratory route : 20-50% (higher for cadmium oxide and chloride)
• gastrointestinal route : 2-10% (higher if calcium and protein intake is low)
• transcutaneous route : mild absorption for hydrosoluble compounds such as cadmium nitrate
Distribution : 95% is found in RBCs bound to hemoglobin or metallothionein
Excretion : urinary, faecal (0.1%), and skin
Pathogenesis : enter cells via SLC11A2 and acts as ...
• voltage-sensitive calcium channel blocker
• endocrine disrupter as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor, acting as an agonist^{ref1, ref2}. Exposure to cadmium increases uterine wet weight, promotes growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight is accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promotes an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicks the effects of estrogens. Female offspring experience an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.
• concentrations that may well be environmentally relevant (especially to cadmium-related industry workers and smokers) block post-replication MMR of natural errors and thus increase the mutations dramatically – as much as 2,000 fold
Symptoms & signs :
• acute toxicity :
• respiratory symptoms following inhalation of 1 mg/m³ of fumes and 3 mg/m³ of dusts)
• after 4-6 hrs : chemical pneumonia (cadmium lung) with fever and chills, nausea and vomiting, headache, dyspnea, and feeling of chest constriction (similar to foundryman's or metal fume fever : an occupational disorder occurring in those engaged in welding and other metallic operations and due to inhalation of volatilized metals; it is characterized by sudden onset of thirst and a metallic taste in the mouth, followed by high fever, muscular aches and pains, shaking chills, headache, weakness, diaphoresis, and leukocytosis. The symptoms usually subside within 24 to 48 hours, but repeated attacks are common. The disorder includes :
• brassfounder's fever or ague / brass or brazier's chill : metal fume fever caused by fumes of any of several metals, most commonly zinc, copper, or magnesium
• spelter's fever or chill / zinc chill or fume fever : metal fume fever caused by fumes in zinc smelters
A related condition is polymer fume fever / Teflon shakes
• after 1-2 days : partial or total remission of symptoms, acute pulmonary edema
• after 5-7 days : recovery or onset of interstitial pneumonia
• gastrointestinal symptoms : stomach irritation => nausea and vomiting, salivation, diarrhea, abdominal pain, and occasionally cardiovascular collapse
• chronic toxicity :
• nephropathy after exposure to 50 mg/m³ for > 10 years or daily intake of 140-260 mg of cadmium with food for 50 years : tubular microproteinuria (100-200 mg/24 hrs) => 1-3 g/day, eventually regressing after cessation of exposure
• pulmonary emphysema : onset after nephropathy and after 20 years of exposure, with progressive fibrosis and alveolar damage persisting even after cessation of exposure
• osteoporosis/osteomalacia due to direct action on bone metabolism (decreased protein and calcium concentrations), reduced vitamin D and phosphate concentration due to renal insufficiency and exocrine pancreas insufficiency
• pneumoconiosis (a cadmiosis) => lung carcinomas
• cancer : IARC group 1 carcinogen
• prostate carcinoma
• anemia
• secondary systemic arterial hypertension
• yellow pigmentation in teeth
• itai-itai ("couch-couch") disease (acute tubular necrosis (ATN), pulmonary emphysema, pulmonary fibrosis, osteomalacia, testicular necrosis, cancer)
Its half-life in the human body can be as long as 20 years.
Laboratory examinations :
• urinary protein electrophoresis
• complete urine examination
• calcium and phosphate balance
• chest X-rays and bone mineral density
• functional respiratory tests
• dose markers :
• [Cd]_plasma > 5 mg/L
• [Cd]_urine > 5 mg/g creatinine
• effect markers :
• [b₂-microglobulin]_urine > 200 mg/g creatinine
• [N-acetylglucosaminidase and retinol-binding protein (RBP)]_urine
• transparent zebrafish have been genetically modified to sense the presence of cadmium in water as sentinel species : the fish carry a gene that makes a fluorescent protein under a certain stress, beginning from the nose
Chelation therapy
Prognosis : poor in patients with pulmonary emphysema due to develoment of chronic cor pulmonale. Tubular proteinuria doesn't mark severe renal disease, while glomerulopathy may lead to severe chronic renal failure
Prevention :
• technical and environmental prevention :
• monitoring dust and fume concentration in workplaces
• closed-circuit technological cycles for aspiration of dusts ad fumes
• individual protection
• hygienical and sanitary measurs
• diligent personal hygiene
• change of working clothes
• do not smoke, eat or drink at workplace
Phytoremediation : Arabidopsis thaliana plants overexpressing the yeast protein YCF1, which detoxifies cadmium by transporting it into vacuoles, have enhanced tolerance of Pb(II) and Cd(II) and accumulated greater amounts of these metals.
• indium (₄₉In) : ¹¹¹In-DTPA is also used in SPECT
• tin (₅₀Sn)

Aetiology : ingestion of a liquid that had been kept in a metallic container, tin coating of utensils^ref
Symptoms & signs : vomiting and diarrhea within 1 hour
• tin oxide

Symptoms & signs : stannosis (a pneumoconiosis)
• antimony (₅₁Sb) : antimonial compounds are also used in therapy of parasitic diseases

Aetiology : ingestion of a liquid that had been kept in a metallic container
Symptoms & signs (stibialism) :
• similar to those of acute arsenic poisoning, with vomiting a prominent symptom
• antimony pneumoconiosis
• iodine (₅₃I)
• hyperiodemia (> 1 mg / dL) => iodism

Aetiology :
• excessive intake (ingestion) of various forms of iodine
• iodine-rich additives or food (crustaceans, algae)
• amiodarone
• iodinated radiology contrast agents
• tincture of iodine
• Lugol's solution
• Pima syrup
• subcutaneous^ref or mediastinal^ref irrigation with povidone-iodine is used commonly for treating severe postoperative deep infections. However, concurrent iodine toxicity has been reported, particularly in patients with renal dysfunction (likely because absorbed iodine is renally excreted)
• potassium iodide (SSKI) used during nuclear accidents from radioactive isotopes

Epidemiology : A minor incident at the Balakovskaya nuclear power plant created widespread panic in Saratov and nearby regions, with people clearing iodine off drugstore shelves and several being rushed to the hospital with symptoms of iodine poisoning. Reactor No. 2 at the Balakovskaya nuclear power plant, located outside the city of Balakov in the Saratov region, some 900 km southeast of Moscow, shut down on Thu 11 Nov 2004 after a pipe burst, but, there was no radiation leak. However, the incident, which was 1st reported on Fri 12 Nov morning, sparked a panic, after Saratov radio stations reported the news, along with advice to residents about how to protect themselves from radiation. Greenpeace activists then hit the streets in regional cities and towns to distribute leaflets explaining how to protect oneself from a radiation leak. Some local residents said they saw a white cloud above the plant and did not believe the authorities' assurances, suspecting a cover-up like the one that followed the 1986 explosion at the Chernobyl nuclear power plant. Rumors spread quickly throughout the day that authorities were trying to hush up the danger and were informally advising schools to let children go home early. Some kindergartens rushed to seal their windows. Adding to the speculation was the unusual appearance of several generals, and about a dozen government vehicles with black military license plates : the officials were there as part of a regularly planned Emergency Situations Ministry exercise. Worried Saratov residents cleared drugstore shelves of iodine, and more expensive iodine-based medicines such as sea kale and vitamins. Some vendors at outdoor markets started selling iodine to panicked customers at 10 rubles [USD 0.35] a drop. At least 7 people checked into Saratov hospitals with symptoms of iodine poisoning. People were telling each other to drink vodka, take iodine, and -- no matter what -- not to use public drinking water. Reports of panic also poured in from the neighboring Tambov, Penza, Ulyanovsk, and Nizhny Novgorod regions, as well as Astrakhan and Rostov, even though the 2 regions do not border Saratov. The nuclear power plant's reactor was restarted early Sat 13 Nov and was running normally. Russia has 10 nuclear power plants with a total of 30 nuclear reactors, which are regularly shut down for repairs or due to minor accidents
• iodinated glycerol (organidin)
• deiodinase 1 (D₁) deficiency
Pathogenesis : the pathologic consequences of iodine excess will ensue only when thyroid autoregulation is defective, in that escape from the Wolff-Chaikoff effect cannot occur, or when autoregulation is absent. Defective autoregulation characterizes the fetal and neonatal thyroid, Hashimoto's thyroiditis, radioiodine or surgically treated Graves' diseases, the thyroid of patients with cystic fibrosis, and the thyroid that has been exposed to weak inhibitors of the organic binding of iodine. In these circumstances, the provision of excess iodine may lead to iodide goiter with or without hypothyroidism. Absent autoregulation may be a feature of longstanding multinodular goiter, and the provision of excess iodine in this circumstance may induce primary hyperthyroidism (jod-Basedow phenomenon)
Symptoms & signs : pain in the mouth and throat, a metallic taste in the mouth, fever, thirst, shock, acute renal failure, vomiting, diarrhea, and abdominal pain. Additionally, there may be delirium, stupor, and seizures.
Laboratory examinations : hyperioduria, thyroid dysfunctions, hypocalcemia, lactic acidosis, cardiac arrhythmia
Therapy :
• acute intoxication : gastric lavage with activated charcoal and supportive care
• subacute/chronic intoxication : renal replacement therapy (RRT)^ref
Prognosis : survival depends upon the amount ingested and time to treatment. Death is possible, and esophageal stricture is a possible complication. Others are Graves' diseases, primary hypothyroidism (Wolff-Chaikoff effect) and  multiple endocrine neoplasia (MEN) IIB / III / Wagenmann-Froboese syndrome / ganglioneuromatosis of the alimentary tract, induced acne
• hypoiodemia (< 1 mg / dL) => hypoiodidism

Aetiology :
• deficitary intake (high prevalence in mountain regions, Central Africa, central areas of South America, and Northern Asia). The number of nations where iodine deficiency is a public health problem fell to 54 in 2003 from 110 a decade earlier
• excessive renal losses => hyperioduria
Symptoms & signs : hypoioduria (except in excessive renal losses), primary hypothyroidism, endemic goiter
Web resources : Iodine deficiency at WHO
Laboratory examinations
• xenon (₅₄Xe)
• barium (₅₆Ba) : BaSO₄ / barite / baryta / baryte is a metal salt with low bioavailability used as gastrointestinal X-ray contrast enhancement agent

Symptoms & signs :
• gastrointestinal symptoms such as stomach pain, nausea and vomiting, and diarrhea, followed by severe, sometimes fatal hypokalemia with paralysis.
• baritosis / barytosis (a a benign pneumoconiosis due to inhalation of the dust of barium or barite)
• lanthanum (₅₇La)

Pathogenesis : voltage-sensitive calcium channel blocker
• gadolinium (₆₄Gd) : Gd³⁺ is also used as contrast agent for MRI
• tantalum (₇₃Ta)
• tantalum carbide

Symptoms & signs : hard metal diseases (a pneumoconiosis)
• tungsten (₇₄W)
• tungsten carbide

Symptoms & signs : hard metal diseases (a pneumoconiosis; deficits in short-term verbal memory, allocation of central processing resources, and remote verbal memory)
Symptoms & signs : leukemia & lymphomas
• platinum (₇₈Pt) : platinum coordination complexes are also used for antineoplastic therapy

=> platinosis : a morbid condition caused by exposure to soluble platinum salts, with involvement of the upper respiratory tract and allergic skin manifestations.
• gold (₇₉Au) is also used for chrysotherapy

Symptoms & signs : chrysiasis / auriasis deposition of gold particles in the tissues as a result of prolonged or excessive parenteral chrysotherapy, which commonly causes adverse reactions consisting primarily of dermatitis (60% : chrysoderma), pemphigus, stomatitis, or transient mild proteinuria; more serious toxicity involves the hematopoietic system, hepatitis, kidney, eye (cornea, lens), encephalopathy, peripheral neuropathy, or other vital organ
• mercury (₈₀Hg) is an element occurring naturally and abundantly, and people are regularly exposed to it at low levels. Some mercury exists in the air as a result of natural processes, such as erosion and soil decomposition. Human activities, such as burning fuel and garbage, add to the amount of atmospheric mercury. Mercury is also returned to soil and water through precipitation

Sources : coal-fire power stations and chlorine-production plants, as well as gold and silver mines
• elemental, liquid or metallic mercury / liquid silver / quicksilver is the purest form : it is is an extremely heavy, odorless, silver-colored liquid. Mercury exists as a natural element in the earth's crust. It is liquid at room temperature, but can be dangerous to breathe if it evaporates. Many of the reports of toxicity are in association with gold mining where mercury is used to leach out the gold in a process that involves a vaporization of the mercury. There are several sources of elemental mercury in the home, including broken mercury thermometers and batteries, broken fluorescent light bulbs, dental amalgam fillings, mercury-containing latex paints, extraction of gold from ore using mercury, and contaminated clothing from workers in thermometer-making plants. Elemental mercury is also used as a Indian or Mexican folk medicine to treat "empacho," a chronic stomach disorder.
• elemental mercury is the most commonly swallowed form of mercury, usually from a broken thermometer. Fortunately, elemental mercury is not absorbed from the stomach and will not cause any poisoning in a healthy person. The swallowed mercury is slippery, and will roll into the stomach, out into the bowels, and will be quickly eliminated without causing any symptoms.
• however, if the person has severe inflammatory bowel disease or a fistula (hole or opening) in their intestine, problems may result if the mercury is not all cleared out, resulting in prolonged exposure.
• the ingestion of elemental mercury is widely regarded as harmless because it is poorly absorbed. However, prolonged exposure caused by continuous oral intake of large quantities may result in systemic toxicity because the elemental mercury is volatized into a highly absorbable vapor or converted to a toxic divalent form^ref
• handling liquid mercury for a very short period of time usually does not result in any problems. An allergic rash is possible. Mercury is not well-absorbed through the skin, so skin contact is not likely to cause mercury poisoning, especially with a brief one-time exposure. Even if a person has cuts in the skin, mercury is too heavy to be contained by a cut. Merely washing the wound well will remove the mercury.
• inhalation of elemental mercury vapors is the main cause of toxicity, as mercury is well-absorbed through the lungs. Problems from inhalation result either from a large one-time exposure or a long-term exposure. A small, one-time exposure is not likely to cause problems. The lungs are the primary target organ following a large, one-time inhalation exposure of mercury vapor. Other signs and symptoms may develop as well. Clinical signs develop within a few hours and include chills, metallic taste, mouth sores, swollen gums, nausea, vomiting, abdominal pain, diarrhea, headache, weakness, confusion, shortness of breath, cough, chest tightness, bronchitis, pneumonia and kidney damage. Long-term exposure of inhaled vapors is generally more dangerous, with the nervous system being the primary target organ of toxicity. Symptoms may occur within weeks but usually develop insidiously over a period of years. Neurologic symptoms include tremors, headache, short-term memory loss, incoordination, weakness, loss of appetite, altered sense of taste and smell, numbness and tingling in the hands and feet, insomnia, and excessive sweating. Psychiatric effects are also seen after long-term exposure. Acrodynia can result from repeated exposures to mercury-containing latex paint fumes. Acrodynia is usually seen in younger children. The symptoms include chills, sweating, body rash, irritability, sleeplessness, leg cramps, swelling of the cheeks, nose, hands and feet, light sensitivity in the eyes, and peeling skin layers on the palms of the hands and soles of the feet. Mercury vapor is very dangerous. Symptoms of mercury poisoning are progressive. The 1st stage is paresthesia, distinguished by a tingling or numb sensation in the fingers, toes, and face. Paresthesia may be followed by difficulty walking and speaking, impaired vision and hearing, fatigue and weakness, headache and trouble concentrating, and tremors
• inorganic mercury is part of a compound with another element (often chlorine, oxygen, or sulfur). It is used in antiseptics and in thimerosal, a component of some medications (e.g. Rhogam) and vaccines (e.g. MMR). It usually is found in powdered form. At 12.5-25 mg mercury per vaccine dose, an infant can take up to 100 mg mercury in the first 6 months of life. Soon after vaccination with thimerosal-containing vaccines, blood concentrations up to 20.55 nM can be detected. Anyway plasma half-life is about 7 days and much mercury is rapidly excreted in faeces.
• HgCl₂
• stupp : a poisonous kind of soot which accumulates in the condensers of mercury smelters; it contains metallic mercury in a finely divided condition
• mercury in drug and biologic products^ref
• thimerosal (TM)
• phenylmercuric acetate (PMA)
• phenylmercuric nitrate (PMN)
• mercuric acetate (MA)
• mercuric nitrate (MN)
• merbromin (MB)
• mercuric oxide yellow (MOY)
• organic mercury forms a compound with carbon. Organic mercury compounds are often produced by microorganisms in the soil or in water.
• methylmercury is often found in fish. Pregnant women, nursing mothers and even those thinking of getting pregnant are warned to limit their consumption of tuna, shark, swordfish, king mackerel and tilefish and other fish and shellfish to 12 ounces a week. Among seafood, tuna ranks second only to shrimp in popularity in the USA : tuna steaks and canned albacore tuna (known as white tuna) generally contain almost 3 times as much mercury as canned light tuna

Web resources : FDA: Seafood Information
• ethylmercury
• phenylmercury
• p-chloromercuribenzoate : a univalent organic mercury compound that reacts with sulfhydryl groups on proteins, or other molecules, thereby often inhibiting their activities
TLV-TWA : 0.05 mg/m³
TLV-STEL : 0.15 mg/m³
People are regularly exposed to all 3 types of mercury, although the organic kind is the most likely to cause adverse health effects because of its tendency to build up in the body. Some forms of mercury will form a vapor and may be inhaled; it is especially dangerous in this form^{ref1, ref2, ref3, ref4, ref5, ref6, ref7}.
Symptoms & signs (hydrargyrism) :
• acute form,
• ingestion : severe abdominalgia, parageusia (metallic taste in the mouth), nausea and vomiting, bloody diarrhea with watery stools, oliguria or anuria (usually at onset), and corrosion and ulceration of the entire digestive tract
• heavy inhalation of aerosol after vaporization of elemental mercury : chills, fever, cough, chest pain, diffuse organized pneumonia, hemoptysis, disseminated intravascular coagulopathy and infarcts in the brain and kidneys (renal cortical necrosis). The oxidized elemental mercury is readily absorbed from the alveoli and can subsequently enter the brain. The wider range of clinical findings after elemental mercury exposure appears to relate to the rate of oxidation of mercury to its salts and the rate of excretion^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8}
• chronic form, due to absorption by the skin and mucous membranes, inhalation of vapors, or ingestion of mercury salts, is marked by
• mercurial stomatitis
• parageusia (metallic taste in the mouth)
• blue line along the border of the gum, sore hypertrophied gums that bleed easily, loosening of the teeth
• erethism
• sialorrhea
• alopecia
• nasal septal perforation
• Minamata disease : a severe neurologic disorder usually characterized by peripheral and circumoral paresthesia (tingling or numb sensation in the fingers, toes, and face), ataxia, dysarthria, loss of peripheral vision and hearing, fatigue and weakness, headache and trouble concentrating, and tremor mercurialis, leading to severe permanent neurologic (dermatopolyneuritis, tinnitus, anosmia) and mental disabilities (toxic dementia) or death; it is caused by methyl mercury poisoning and was prevalent between 1953 and 1958 among those who ate seafood from a bay in Japan that was polluted with alkyl mercury compounds. Minamata Disease first raised its dreadful head in early 1956 when a 5-year old girl was admitted to the Chisso Company Hospital in Minamata with a strange, unfathomable illness afflicting the central nervous system. Several other cases of this "Strange Disease", so labeled by the populace followed. Numerous other cases appeared in all age groups, and the bizarre symptoms so stigmatized sufferers that they were avoided by neighbors and the public in general and treated like lepers of biblical times. The cause was eventually traced to the Chisso Company, originally a producer of carbides and fertilizers (whence the name: Chisso means 'nitrogen' in Japanese). Cats, too, were afflicted, showing strange behavior, whirling in circles; those falling off a sea wall and drowning were labeled "suicides"! Dogs and pigs were also affected. When Chisso became a manufacturer of petrochemicals, one of its products was acetaldehyde, used to make a variety of plastics and drugs. To produce acetaldehyde, a catalyst is needed and mercury, as organic mercury (methyl mercury), met the need; the effluent was dumped into Minamata Bay. By some accounts, around 200,000 tons of methyl mercury were dumped into the Bay, producing a sludge on the bottom. Victims chronically exposed to the environmental mercury showed high levels of mercury in their hair (up 200 ppm). Fish, the dietary staple, were similarly poisoned. Steven Rose, writing in the New Scientist states in  "Notes from Minamata" (1978, 80: 628-629 Nov. 23) that there were more than 8,100 persons on the register of victims, with 10 or  more being added each month. A comprehensive account of this episode, with numerous photographs, is given in the book by W. Eugene Smith and his wife, Aileen M.Smith  MINAMATA. The story of the poisoning of a city and of the people who chose to carry the burden of courage. 1975. Holt, Rinehart and Winston. New York. The book also carries Minamata Disease: A Medical Report by Masazumi Harada, an authority on the disease
• barometer-maker's disease : chronic mercurial poisoning in makers of barometers, due to the inhalation of the fumes of mercury.
• mercury pneumonitis
• toxic cataract
• autism
• some researchers think these compounds are toxic only to babies as they develop in the womb, and that older children recover and are unlikely to suffer developmental problems from the poison. But a study of the health of 1,000 children on the Faroe Islands in the North Atlantic, where inhabitants eat lots of seafood and whale meat and so are exposed to relatively high levels of mercury, indicates that any harm done by mercury before birth or in early childhood was not repaired as the children grew up and continued mercury exposure may continue to affect the brains of teenagers. The group previously found that the children, when 7 years of age, had delayed brainstem auditory evoked potential (BAEP) latencies. Now that the children are 14 years old, after a continued diet of fish and whale meat, the researchers find that this disruption is even worse^ref. They also found evidence that mercury exposure is linked to subtle difficulties in cardiac autonomic activity controlling blood pressure^ref. A second large study on long-term effectrs of dietary methylmercury being carried out in the Seychelles has found little evidence that it causes harm. At the moment, the US Food and Drug Administration (FDA) advises pregnant women, nursing mothers and young children to avoid eating shark, swordfish, king mackerel and tilefish, in order to keep mercury intakes low, but safety messages about mercury should highlight the toxin's potential impact on older children as well. Others are not convinced that a wider warning is needed as the Faroe Islanders are virtually unique in their whale-rich diet, so it doesn't make sense to extend the study's results to other populations : in addition there may be other toxins in whale meat such as PCBs and dioxins that might explain some of the detrimental effects
Laboratory examinations
Chelation therapy.
Prevention : at the beginning of the UN Environment Programme (UNEP)'s Governing Council  meeting, which was held in Nairobi, Kenya, from 21 to 25 February 2005, representatives from European countries promoted the idea of a treaty to ban the export of mercury completely. But the USA championed the development of voluntary partnerships to help countries improve their mercury management, believing that an aggressive global strategy such as the one they have proposed will be faster at achieving real reductions than negotiating an international binding agreement on mercury. Scientists have estimated that 8% of American women have mercury levels above those considered safe by the US Environmental Protection Agency^ref. Some countries have already begun phasing out the use of mercury in industrial processes. The European Union's executive arm has proposed banning mercury exports from the European bloc by 2011 : this will probably receive final approval by early summer. But mercury can travel easily from one corner of the globe to another through natural cycling, and this underlines the importance of an international approach. February's agreement asks UNEP, to prepare a report detailing the supply of, trade in and demand for mercury. It also requests that governments and the private sector work with non-governmental organizations to reduce mercury pollution and associated risks for human health. That formalizes the partnerships suggested by the USA. The governments at the meeting will review the success of these partnerships in two years, at which point they may reconsider the idea of a legally-binding agreement. But the non-binding nature of the agreement makes its impact uncertain. While it is difficult to predict progress, it is clear from past experience that partnerships, especially in developing countries, generally have not worked
Web resources : Mercury Policy Project, based in Montpelier, Vermont
• thallium (₈₁Tl) (see also radiotoxicity of ²⁰¹Tl)

Sources :
• natural processes can mobilize thallium, which may enter the food chain as a "hidden health killer" with severe health impacts on local human population. Natural processes may be exacerbated by human activities such as mining and farming, and may cause enrichment of Tl in the environment. In geochemically anomalous areas with concentrated levels of Tl in the surface environment (bedrocks, waters, soils, and crops), such as the Lanmuchang area in southwestern Guizhou Province, China, it is essential to establish base-level values and to pay heed to the geological context of "natural contamination," as high concentrations of Tl in bedrocks/ores (6-35,000 mg/kg) can lead to enrichment of Tl in the aquatic system (0.005-1100 mg/l in groundwaters and 0.07-31 mg/l in surface waters) and soil layers (1.5-124 mg/kg). In sensitive areas such as the Yanshang area of southwestern Guizhou, elevated natural levels of Tl from bedrocks may also cause higher concentrations of Tl in the surface environment, and thus more attention must be paid to geoenvironmental management of human activities if socio-economic catastrophes are to be avoided. Due to high uptake of Tl by crops, Tl can be transferred from soils to crops and remarkably concentrated in food crops. Concentrations of 1-500 mg/kg Tl based on dry weight (DW) were determined in many food crops growing on Tl-contaminated arable soils from the Lanmuchang area. The daily intake of 1.9 mg of Tl from consumed food crops was estimated for the local adult inhabitant of Lanmuchang. Thus, Tl is regarded as a latent health hazard with potential risk of toxicity in humans within areas of "natural" contamination by Tl^ref
• thallium sulfate was used until the late sixties as a rodenticide. Accidental posonings of children, dogs and cats have occurred
Symptoms & signs (thallitoxicosis / thallotoxicosis) : described in order of frequency are: vomiting, cutaneous alterations (erythematous lesions around the mouth, the nares and the anus which were later covered by a crusty material => alopecia), depression, anorexia, neurologic and psychic signs including ataxia, restlessness, delirium, hallucinations, delusions, semicoma, toxic cataract, blindness, diarrhea, respiratory distress, conjunctivitis, liver and kidney damage, dehydration and esophageal paralysis
Laboratory examinations : lymphopenia, neutrophilia, eosinopenia, left shift of neutrophils, hemoconcentration and circulating immature red blood cells; also elevated BUN, glutamic pyruvic transaminase and serum glutamic oxaloacetic transaminase; also proteinuria and bilirubinuria
Therapy : chelation, hemodialysis and diuretics
• lead (₈₂Pb) > 20 mg/dL (> 1.0 mmol/l)

Sources :
• lead fusion and recovery
• battery manufacturers
• pewter manufacture (lead-tin alloy)
• covering of containers
• cutting of minium (red lead)-varnished plates during demolition of battleships
• preparation of glazes (lead concentration = 6-15%) => dusts and smokes (low fusion temperature)
• bullet and lead-shot manufacture : lead-shot accumulation in the cecal appendix of an Alaskan native, which was probably caused by the ingestion of shotgun-culled waterfowl, has been reported^ref. Blood lead levels almost twice those of controls may be found after sequestration of just one or two shot pellets in the appendix^ref; a toxic level of lead (67.4 µg/dl) was reported after the retention of 29 pellets^ref. In 1991, the USA instituted a nationwide ban on lead shot for waterfowl hunting, owing in part to the concern regarding lead toxicity from this practice. Unfortunately, the ban does not extend to all hunting; thus, there is a risk to hunters and others who inadvertently eat lead from their catch^ref. Countries such as Denmark and the Netherlands have a complete ban on lead for hunting; alternatives to lead shot include bismuth, steel, tin, and tungsten. Therefore, a solution to lead ingestion and potential toxicity problems is present. It is reasonable to screen for lead when shot is found in the appendix during radiography. If an elevated lead level is found, appropriate action should be taken^ref.
• production of lead arsenate
• oil additives => vegetables and grapes grown along roads
• file-cutters' disease : lead poisoning from inhaling lead particles rising from the bed of lead used in file cutting
• surma : a lead sulfide traditionally applied to the eyelids in India for cosmetic and medical purposes; it can cause lead poisoning
Absorption routes :
• respiratory route => liver and kidney
• enteral route => CNS, bones (lead phosphate), and muscles
Pathogenesis :
• interference with heme synthesis via inhibition of ... :
• d-ALA dehydratase
• coproporphyrogenase
• ferrochelatase / heme synthetase
• spasms in smooth muscles
• neurotoxic
• nephrotoxic
• early prenatal exposure to lead caused kids to have a retinal deficit up to 10 years later : it causes the proapoptotic protein Bax to translocate from the cell's cytosol to the mitochondria. Lead also increases calcium ions in rod cells, resulting in increased contact sites in the mitochondrial membrane and decreased mitochondrial membrane potential. The mitochondrial effects trigger a release of cytochrome c, setting in motion cellular apoptosis.
Symptoms & signs : saturnism / plumbism
• loss of appetite, weight loss, lead colic (spasm of smooth muscle prevents transit of gases and stools causing painful, opiate-resistant abdomen distention for tens of days), constipation
• insomnia, headache, dizziness, irritability, lead encephalopathy (especially in children) (=> toxic dementia and organic epilepsy) with or without peripheral lead neuropathy (=> lead palsy (radial nerve palsy = dropping hand is the most easily observed clinical sign) , tinnitus, anosmia or parosmia)
• moderate secondary systemic arterial hypertension
• lead stomatitis, blue-black line at the interface of the teeth and gums (Burton's lead line) due to precipitation of PbS (after reaction of Pb with bacterial H₂S), absent at edentulous locations
• Balkan endemic nephropathy (BEN), nephrosclerosis => albuminuria, spasm of glomerular arteriolae, JGC hyperplasia => hyperreninemia (arteriologlomerulosclerosis) => saturnine end-stage kidney
• hemolytic anemia, basophilia punctata, sideroblastic anemia
• alopecia
Classes of exposure according to lab exams :

	analytes	I	II	III	IV
exposure markers	[Pb]plasma [mg%]	< 40	40-60	60-70	> 70
	[Ala]urine [mg/g creatinine]	< 5	5-8	8-15	> 15
	[zincoprotoporphyrine (ZPP)]RBC [mg/dL]	< 40	40-110	110-170	> 170
effect marker	activity ALA dehydrataseplasma [U]	> 50	50-40	40-80	< 30

• class III (mild intoxication) is associated with clinical signs and requires only removal from workplace.
• class IV requires therapy
Laboratory examinations :
• exposure markers : VLP_air 0.15 mg/m³
• effect markers : BLV
• [Pb]_blood : 60 mg/dL
• [Pb]_urine : 100 mg/24 hrs
• Ala-dehydrogenase : 30 UB
• [coproporphyrine]_urine : 300 mg/24 hrs
• Ala-U : 10 mg/L
• [zincoprotoporphyrine (ZPP)]_RBC : 110 mg/dL
Increased [Pb]_urine after administration of EDTA is suggestive of saturnism.
Prevention : lead interferes with pigment synthesis somewhere in the earthworm Lumbricus rubellus turning it from a dingy greenish-brown not bright enough to be visible into a very dark colour.
Therapy : chelation
Web resources : Lead poisoning at CDC
• bismuth (₈₃Bi) (bismuth subsalicylate (Pepto-Bismol^®) is also used for stomach ulcer treatment : its antimicrobial action is complemented by fortification of the gastric mucus and stimulation of cytoprotective processes)

Biological effects (bismuthism / bismuthosis) :
• anuria
• dermatitis
• diarrhea
• bismuth gingivitis or stomatitis
• alopecia
• radon (₈₆Rn) is a naturally occurring radioactive gas which is colourless, odourless and tasteless and can only be measured using specialised equipment. It is formed in the ground. One of the highest levels ever recorded in Europe was identified at a house in Castleisland in Co Kerry, Ireland, in 2003

Symptoms & signs : lung carcinoma
• thorium (₉₀Th) (thorium dioxide is used as contrast agent)

Symptoms & signs : malignant liver tumours (hepatocellular carcinoma (HCC) and cholangiocarcinoma)

• ketones
• hyperketonemia / ketonemia
• ketotic hypoglycemia
• alcoholic hyperketonemia
• starvation hyperketonemia
Laboratory examinations
• ketoacidosis : acidosis accompanied by the accumulation of ketone bodies (ketosis) in the body tissues and fluids
• diabetic ketoacidosis
• starvation ketoacidosis
• low-carbohydrate diet^ref
• lactic acid
• hypolactacidemia
• hyperlactacidemia : [lactic acid ]_plasma > 2 mEq/L

Aetiology : acute hypoxia causing impaired cellular respiration. It occurs most commonly in disorders in which O₂ is inadequately delivered to tissues, e.g.,
• shock
• ischemia
• phenformin
• salicylic acid
• septicemia
• extreme hypoxemia
• exogenous or endogenous metabolic defects
Laboratory examinations
• creatinine
• hypocreatininemia

Aetiology :
• muscular dystrophies (including elderlies)
• hypercreatininemia :

Aetiology :
• renal failure with GFR < 40 mL/min
• hypercalcemia
Laboratory examinations
• disorders of purine metabolism
• uric acid is the end-product of purine catabolism (no uricase exists in humans). Only 2-3% of plasma uric acid is bound to a₂-globulin : its solubility directly relates to temperature and pH. 700 mg of the 1200 mg stored in our body are renewed each day : 66% of uric acid is filtered, reabsorbed and secreted in nephrons and excreted with urine, while the remaining 33% is removed via bowels, skin, sweat, tears, saliva, ... Mammals that degrade uric acid are not affected by gout or urate kidney stones.


• hyperuricemia ([urates] > 7 mg/dL or > 420 mmol/L)

Epidemiology : prevalence = 1.36-3.7% in males (expecially after age 50), 0.64% in females (expecially after age 60).
Aetiology : familial in 12%; chronic in 25%
• excessive endogenous synthesis and/or exogenous intake (metabolic gout) (10%)
• primitive
• idiopathic
• hypoxanthine phosphoribosyltransferase (HPRT1) deficiency => decreased PRPP levels => increased IMP and GMP => defective purine de novo pathway
• complete deficiency / Lesch-Nyhan syndrome
• incomplete deficiency / Kelley-Seegmiller syndrome : no neurological manifestations
• PRPP synthetase 1 or 2 hyperactivity => increased PPP levels => decreased IMP and GMP => decreased negative feedback on amido-PRT => favourited purine de novo pathway
• secondary
• increased dietary purine intake (offals (liver, pancreas, thymus, kidney ..), anchovy, raw meat)
• accelerated nucleic acid turnover
• accelerated ATP degradation
• type III, type V, and type VII glycogenoses
• strenuous physical exercise with heat stress
• epilepsy
• smokers
• acute myocardial infaction
• acute respiratory failure
• hemolysis
• rhabdomyolysis
• blastic crises in lymphoproliferative diseases
• myeloproliferative diseases
• polycythemia vera
• cytotoxic drugs
• tumor lysis syndrome (TLS)
• obesity
• psoriasis
• Paget disease of bone
• defective excretion => hypouricuria (nephrogenic gout) (90%)
• both (combined gout)
• ethanol => accelerated liver degradation of ATP; alcohol intake is strongly associated with an increased risk of gout. This risk varies substantially according to type of alcoholic beverage: beer confers a larger risk than spirits, whereas moderate wine drinking does not increase the risk^ref
• shock
• G6PD deficiency : accelerated ATP degradation during fasting hypoglycemia => reduced IMP and GMP => decreased negative feedback on amido-PRT => hyperlactacidemia => decreased tubular secretion of urates
• hereditary fructose intolerance : nausea and vomiting and reactive hypoglycemia => liver failure and proximal renal tubule dysfunction => type 2 renal tubular acidosis and accumulation of fructose 1-phosphate => ATP deficiency => accelerated catabolism of purine nucleotides, lactic acidosis
Pathogenesis : at T = 37°C and pH = 7.4, plasma is saturated at [monosodium urate] = 6.8 mg/dL = 415 mmol/L (anyway sometimes the presence of solubilizing agents may prevent precipitation up to 80 mg/dL = 4800 mmol/L) => precipitation of urate crystals : monosodium urate (MSU) crystals are a danger signal for the immune system.
Symptoms & signs : gout (prevalence : 1.3-3.7%)
• urate nephropathy / uric acid nephropathy
• urolithiasis
• gouty arthritis spontaneously regress within 7-10 days
• gouty pearl : a sodium urate concretion on the cartilage of the ear in gouty persons
Laboratory examinations :
• during purine-free diet :
• uricuria < 3.6 mmol/die (= 600 mg/die) => hypouricuria
• uricuria > 3.6 mmol/die (= 600 mg/die) => excessive endogenous production
• during normal diet :
• uricuria < 4.2 mmol/die (= 800 mg/die) => hypouricuria
• uricuria > 4.2 mmol/die (= 800 mg/die) => excessive endogenous production
• pyrazinamide and SLC22A6 blockers may be used to assess tubular secretion and post-secretory reabsorption, respectively
Therapy :
• total water intake > 2 L/die
• CSI (unless chronic renal failure)
• xanthine oxidase inhibitors (allopurinol 100-300 mg/day; side effects : it may worsen symptoms in acute phase (so add colchicine for the first week (1-mg grains until pain disappears or diarrhea occurs; effects occur within 12 hours, so should be initiated soon; side effects : nausea, vomiting and diarrhea; aplastic anemia, agranulocytosis)), skin rash, erythrodermia, exfoliative dermatitis, leukopenia, medullary aplasia, hepatitis, vasculitis, increased half-life of bronchodilators and oral anticoagulants) =>
• urate oxidase
• GR agonists
• urine alkalinization with i.v. NaHCO₃ or CAI
• hypouricemia

Epidemiology : prevalence = 0.2%
Aetiology :
• increased renal excretion => hyperuricuria
• reduced endogenous production
• xanthine oxidase deficiency
• congenital
• type I xanthinuria
• associated with deficiency of sulfate oxidase
• acquired
• xanthine oxidase inhibitors
Symptoms & signs : xanthinuria, hypoxanthinuria, xanthic urolithiasis, myopathy or relapsing polyarthritis
• purine nucleoside phosphorylase (PNP) deficiency

Symptoms & signs : CMI immunodeficiency
Laboratory examinations : increased urinary excretion of guanosine, deoxyguanosine, inosine, and deoxyinosine
Symptoms & signs : none
Laboratory examinations
• myoadenylate deaminase / adenosine monophosphate deaminase 1 (AMPD1), isoform Mdeficiency

Symptoms & signs : none or myopathy with untolerance to physical exercise
• adenosine deaminase (ADA) deficiency

Symptoms & signs : ADA-SCID
• adenylosuccinate lyase / adenylosuccinase (ADSL) deficiency

Symptoms & signs : autism, psychomotory retardation, motility disorders
• 2,8-dihydroxyadenine urolithiasis due to deficiency of adenine phosphoribosyltransferase (APRT)
• type I (complete deficiency) in Whites
• type II (partial deficiency) in Japanese
Pathogenesis : in the absence of APRT, adenine is converted by xanthine oxidase into 2,8-dihydroxyadenine
Symptoms & signs : 2,8-dihydroxyadenine urolithiasis
Therapy : xanthine oxidase inhibitors
• disorders of pyrimidine metabolism
• oroticaciduria
• type I oroticaciduria : loss-of-function mutations in uridin-5'-monophosphate synthetase (UMPS) (orotidine-5'-phosphate (OMP) decarboxylase + orotidine-5'-pyrophosphorylase / orotate phosphoribosyl-transferase (OPRT))
• type II oroticaciduria :
• loss-of-function mutations in orotidine-5'-phosphate (OMP) decarboxylase but gain-of-function in orotidine-5'-pyrophosphorylase / orotate phosphoribosyl-transferase (OPRT)
• inhibitors : allopurinol
• hemolytic anemia due to pyrimidine 5'-nucleotidase (P5N) / uridine 5'-monophosphate hydrolase (UMPH1) deficiency : accumulation of cytidine diphosphate cholein (CDPC) => basophilic spotting in RBCs => hemolysis
• hereditary thymine-uraciluria due to dihydropyrimidine dehydrogenase (DPYD) deficiency. Also 5-FU neurotoxicity due to lack of catabolism.
• dihydroorotate dehydrogenase (DHODH) inhibitors : leflunomide
• disorders of amino acids :
• glycine :
• hyperglycinemia :
• nonketotic hyperglycinemia (NKH)
• classical NKH
• atypical NKH :
• neonatal form is similar to the classical one but the subsequent outcome is significantly better. Mental retardation and behavioral abnormalities are prevalent in both infantile and late onset forms although the phenotype in late onset atypical NKH is more heterogeneous
• infantile
• late onset
Patients with the atypical NKH tend to have a lower CSF/plasma glycine ratio when compared with the classical form, but overlap occurs. Hyperglycinemia in the neonatal and infantile atypical NKH, similar to the classical form, is caused by a deficient glycine cleavage system, whereas the cause of hyperglycinemia in late onset atypical NKH is unknown. A mutation of the T-protein AMT gene and several mutations of P-protein GLDC gene have been identified in homozygous or compound heterozygous state. Some of the GLDC mutations are associated with residual glycine decarboxylase activity when expressed in COS7 cells and early therapeutic intervention may be crucial to improve the outcome in patients harboring such mutations. Identification of more mutations causing atypical NKH and information about the mutations' effect on enzyme activity may help to predict patients with a milder phenotype as well as those who may respond to early therapeutic intervention^ref
• phenylalanine :
• tyrosine
• homocysteine
• hyperhomocysteinemia (> 16 mmol/L)

Aetiology :
• severe hyperhomocysteinemia is found in a number of inborn errors of metabolism
• homocystinuria, a disorder most commonly due to cystathione b-synthase deficiency producing increased urinary homocystine and methionine. Major clinical manifestations involve the eyes and the central nervous, skeletal, and vascular systems.
• vitamin B₁₂ metabolic defect (277400, 277410) : combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR). Different forms of the disorder have been classified according to complementation groups of cells in vitro:
• cobalamin C type (cblC) (cobalamin C disease) is an inborn metabolic disorder consisting of an impaired intracellular synthesis of the 2 active forms of vitamin B₁₂, namely, adenosylcobalamin and methylcobalamin, that results in increased levels of methylmalonic acid and homocysteine in the blood and urine. Most patients present in the first year of life with systemic, hematological, and neurological abnormalities. Left untreated, this treatable condition can lead to death or irreversible damage to the nervous system.
• cblD
• cblF
Isolated methymalonic acidurias have also been classified by complementation groups: MMA 'mut', caused by mutation in the MUT gene on chromosome 6p21; MMA cblA, caused by mutation in the MMAA gene on 4q31; and MMA cblB, caused by mutation in the MMAB gene on 12q24.
• selective intestinal malabsorption of vitamin B₁₂
• N^5,10-methylenetetrahydrofolate reductase deficiency
• methylcobalamin deficiency, cbl G type
• transcobalamin II deficiency
• vitamin B₁₂-responsive homocystinuria, cbl G type
• mild hyperhomocysteinemia is
• estrogen-based oral contraceptives and ERT decrease concentrations of folic acid, with secondary hyperhomocysteinemia
• fasting homocysteine plasma levels largely depend on GFR, impaired in renal failure
Disulfide forms of homocysteine account for >98% of total homocysteine in plasma from healthy individuals. Hcy reacts with albumin-Cys(34)-S-S-cysteine to form homocysteine-cysteine mixed disulfide and albumin-Cys(34) thiolate anion : the latter then reacts with homocystine or homocysteine-cysteine mixed disulfide to form albumin-bound homocysteine. Human albumin, but not ceruloplasmin, mediates the conversion of homocysteine to its low molecular weight disulfide forms (homocystine and homocysteine-cysteine mixed disulfide) by thiol/disulfide exchange reactions : only a small fraction of homocystine is formed by an oxidative process in which copper bound to albumin, but not ceruloplasmin, mediates the reaction (when copper is removed from albumin by chelation, the overall conversion of homocysteine to its disulfide forms is reduced by only 20%). In contrast, ceruloplasmin is a highly efficient catalyst for the oxidation of cysteine and cysteinylglycine to cystine and bis(-S-cysteinylglycine), respectively, by copper-dependent autooxidation.
Pathogenesis : Hcy induces NO inactivation (=> renal dysfunction), generates ROS (=> oxidant injury to the endothelium) and may undergo autooxidation. Indirect pathways allow N-homocysteinylation of proteins, including transthyretin and LDLs :
• S-nitroso-homocysteine (synthesized in human vascular endothelial cells) : reversible S-nitrosylation of Hcy with NO produced by eNOS => aminoacylation of tRNAMet with S-nitroso-Hcy catalyzed by MetRS => translational transfer of S-nitroso-Hcy from S-nitroso-Hcy-tRNAMet into growing polypeptide chains at positions normally occupied by methionine => transnitrosylation leaves Hcy in the protein chain. Hcy-N-hemoglobin and Hcy-N-albumin constitute a major pool of Hcy in human blood.
• homocysteine thiolactone (HTL), synthesized by methionyl-tRNA synthetase in all organisms investigated, including human, modifies proteins post-translationally by forming adducts in which Hcy is linked by amide bonds to e-amino group of protein lysine residues (protein-bound homocystamide) as well as with the N-terminal amino group or C-terminal carboxy group^ref. HTL is present in human plasma and is hydrolized to Hcy by Hcy-thiolactonase/paraoxonase (PON1, 2, and 3) present in a subset of HDL particles in humans.
Irreversible N-homocysteinylation of long-lived proteins should lead to cumulative damage and progressive clinical manifestations. Fibrillin 1 is seen as the paradigm of extracellular connective tissue proteins that are specially susceptible to attack. The prominent presence of EGF-like domains in fibrillin and in many other extracellular proteins of the coagulation, anticoagulation, and lipoprotein transport pathways, all of which malfunction in hyperhomocysteinemia, suggests that EGF-like domains may be preferential sites of homocysteinylation.
Symptoms & signs : risk factor for cancer (while Hcy inhibits key steps of angiogenesis and tumor invasion, HTL behaves as a pro-angiogenic compound^ref), atherosclerosis, coronary artery diseases, stroke, cognitive decline, senile osteoporosis and presbyopia. The elevated levels of homocysteine in human NTDpregnancies may reflect a disturbance in folate-related metabolism rather than a direct cause of NTD
Laboratory examinations : homocysteinemia > 100 mmol/l in homozygotes; methionine challenge test (0.1 g/kg p.o.) unmasks hyperhomocysteinemia after 4-8 hours in heterozygotes
Therapy : vitamin B₆ + folic acid, betaine
• catecholamines
• hypercatecholaminemia

Aetiology :
• psychophysical stress
• caffeine
• nicotine
• pheochromocytoma
• exogenous catecholamines
• methyldopa (?)
• L-DOPA (?)
• labetalol
• posterior fossa tumors or subarachnoid hemorrhage => intracranial hypertension
• diencephalic or autonomic epilepsy
• brain cancer
• neuroblastoma
• intrahepatic cholelithiasis
• Guillain-Barré syndrome
• carcinoids
• porphyrias
• drugs that inhibit degradation of catecholamines : MAOI
• drugs that inhibit catecholamine reuptake : TCA, reserpine, guanethidine
• drugs that displace catecholamines from cytoplasmic vesicles or have sympathomimetic action : tyramine, amphetamines, bronchodilators, central antitussives, anorexiants
• drugs that increase release of catecholamines : rapid discontinuation of clonidine, vasodilators (e.g. nitroderivates, short-acting CCBs, sodium nitroprusside), opiate antagonists (nalozone), antidopaminergic drugs (sulpiride, metochlopramide, domperidone)
• hypocatecholaminemia

Aetiology :
• a-methyltyrosine
• a₂-agonists : clonidine
• dopaminergic : bromocriptine, L-DOPA, a-methyldopa
Dosing of metanephrine is reduced by methylglucamine (contained in some radiological contrast agents)
Dosing of VMA is reduced by clofibrate and increased by nalidixic acid, tetracyclines, foods such as vanilla and bananas
Laboratory examinations
• glutamine
• hypoglutaminemia
• glutamine synthetase deficiency : brain seizures and malformations, cutaneous manifestations^ref. Low-to-deficient glutamate concentrations in cerebrospinal fluid indicate a chronic depletion of neuronal glutamate stores, since astrocytic glutamine synthase is crucial for their replenishment. After the bioenergetic coupling of and metabolite trafficking between astrocytes and neurons occur^ref, a complete deficiency of this enzyme should result in a severe depletion of neuronal glutamate stores in the long run and, subsequently, a drain of intermediates of the tricarboxylic acid cycle due to increased new synthesis of glutamate and insufficient anaplerosis through pyruvate carboxylation in neurons. Neurotransmission of glutamate is important for the developing brain, for modulating neuronal migration, for growth spurts of the brain, and for apoptosis^ref. Dysfunction of these mechanisms probably induces brain damage and malformations^{ref1, ref2}, => low glutamate concentrations
• hyperglutaminemia
• glutamate
• Chinese restaurant syndrome : a transient syndrome associated with arterial dilatation, due to ingestion of monosodium glutamate, which is sometimes used liberally in seasoning Chinese food; it is characterized by throbbing of the head, lightheadedness, tightness of the jaw, neck, and shoulders, and backache
• carotene
• hypercarotenemia / carotenemia : an elevated level of carotene in the blood

Aetiology :
• excessive ingestion of carotenoids
• decreased ability to convert carotenoids to vitamin A
• hypothyroidism
Symptoms & signs : yellowing of the skin (carotenosis)
• oxalate
• hyperoxalemia : an excess in the blood of oxalic acid

Aetiology :
• enteric hyperoxaluria : a form occurring after extensive resection or disease of the ileum and resulting from excessive absorption of oxalate from the colon
• lack of Oxalobacter formigenes
• primary hyperoxaluria : a genetic disorder characterized by urinary excretion of large amounts of oxalate, with nephrolithiasis, nephrocalcinosis, early onset of renal failure, and often a generalized deposit of calcium oxalate (oxalosis), resulting from a defect in glyoxylate metabolism
• type I : an autosomal recessive disorder characterized by urinary excretion of oxalic, glyoxylic, and glycolic acids and is due to deficiency of alanine–glyoxylate transaminase
• type II : excretion of oxalic and L-glyceric acids and is due to a defect in the metabolism of hydroxypyruvate to D-glycerate, causing increased production of L-glycerate, probably an autosomal recessive defect in glycerate dehydrogenase
• PEG poisoning
• methoxyfluorane
• oxalate poisoning / oxalism : poisoning of humans or other animals by oxalic acid or oxalates, usually by ingesting large quantities of oxalate-containing plants (Amaranthus retroflexus, Atriplex spp., Beta spp., Calandrinia spp., Emex australis, Enchylaena tomentosa, Halogeton glomeratus, Oxalis spp., Panicum antidotale, Portulaca oleracea, Rheum rhaponticum, Rumex spp, Salsola kali, Sarcobatus vermiculatus, Setaria sphacelata, Threlkeldia proceriflora, Trianthema spp.)
Symptoms & signs : gastroenteritis, systemic arterial hypotension, hypocalcemia, muscle weakness and twitching, nephrosis
Laboratory examinations : hyperoxaluria
• hypooxalemia
• azotemia : an excess in the blood of
• uremia : urea > 50 mg/dL

Aetiology :
• renal azotemia : azotemia due to reduced GFR resulting from intrarenal renal failure
• extrarenal azotemia : that due to a condition or process outside the kidney
• hyperproteic diet
• tissue destruction
• fasting
• hemolysis
• gastrointestinal hemorrhages
• healing
• GR agonists
• tetracyclines
• prerenal acute renal failure (prerenal azotemia)
• postrenal acute renal failure (postrenal azotemia)
Symptoms & signs : uremic syndrome
• accumulation of urea crystals in subcutaneous tissue => uremids (urea frost on the skin), erythema, papulae, pruritis => scraping injuries
• nausea and vomiting and anorexia
• symbiont oral bacteria ferment urea to ammonium => ageusia (metallic taste in the mouth), uremic stomatitis, urinoid breath smell
• uremic encephalopathy
• uremic pericarditis
Differential diagnosis : pseudouremia : uremia-like symptoms occurring in acute glomerulonephritis and in hypertensive vascular disease (hypertensive encephalopathy).

	CHF	CRF
urine osmolality	> 400 mOsm	< 350 mOsm
natriuria	< 15 mEq/l	> 40 mEq/l
sediment	negative	cylinders
[urea]urine/[urea]plasma	> 8	< 3
[creatinine]urine/[creatinine]plasma	> 40	< 20
[urea/creatinine]plasma	> 10:1	< 10:1

Laboratory examinations
Therapy :
• hemodialysis
• k opioid receptor agonists to treat uremic pruritus
• ammonium
• hyperammonaemia

Aetiology :
• urinary tract infection (UTI) with any urease-producing bacteria if there is urinary stasis
• prune-belly syndrome
Symptoms & signs : hyperammonaemic encephalopathy
• hyperlipidemia / hyperlipemia / lipidemia / lipemia : a general term for elevated concentrations of any or all of the lipids in the plasma
• alimentary lipemia : hyperlipidemia after eating, such as carbohydrate-induced, familial fat-induced, and combined fat- and carbohydrate-induced hyperlipemia
• hyperlipoproteinemia (HLP) : an excess of lipoproteins in the blood, due to a disorder of lipoprotein metabolism
In Westernized countries 50-100 g triglycerids and 0.5 g cholesterol/die are found in diet. Normolipemic patients eliminate them from bloodstream within 8 hours since meal, but patients with high VLDL levels require > 24 hrs.