)
Table of contents :
)),
pallor, depression,
and many other manifestations may occur. When cachexia is a prominent feature,
it is called hypophysial or pituitary cachexia.
or surgery
> LH
> FSH
> TSH
> ACTH
> PRL),
or excessive (PRL).
Sometimes there is downward herniation of the optic chiasm, which leads
to defects in the visual field.
=> hemorrhagic
shock
during delivery, and leading to variable patterns of hypopituitarism-producing)
(60-90% of circulating growth hormone is in the form of tetramers and dimers
(normal, 14-39% in plasma) and the patients' GH polymers are abnormally
resistant to conversion into monomers by urea)
due to increased LDL-Ch and decreased HDL-Ch => premature atherosclerosis
=> bone fracturs (RR = 3)]plasma
after challenge < 3 ng/mL]plasma
: a single low value is useless; lack of nocturnal peak]plasma
and [IGFBP3]plasma
reduced or normal (depending on sex and age)]plasma
(i.v. injection 1 mg/kg) + L-Arg
(30 g (adults) or 0.5 g/kg (babies)) => sampling at 0, 15', 30', 45', 60',
120' => normal if [GH]plasma
> 20 ng/mL
(i.v. injection of 0.05-0.15 IU/ kg) => sampling at -30', 0, 30', 60',
120' (insulin-tolerance test (ITT)) => glycemia < 40 mg/dL, [GH]plasma
> 3 ng/mL (or > 140 pmol/l) (> 10 ng/ml or > 465 pmol/l in babies) (sensitivity
= 85-100%)
(i.v. injection 1 mg/kg) => sampling at 0, 15',
30', 45', 60', 120' => normal if [GH]plasma
> 3 ng/mL]plasma
> 3 ng/mL (> 10 ng/ml in babies)
(4 ng/kg) => sampling at 60-120' => normal if [GH]plasma
> 3 ng/mL (sensitivity = 80%)
(p.o. 500 mg (adults) or 10 mg/kg (babies)) => sampling at 0, 30', 60',
120' => normal if [GH]plasma
> 3 ng/mL (sensitivity = 56-81%)-
and FSH-producing),
lack of sexual hairs)
=> [LH]plasma
increased by 10 IU/L and [FSH]plasma
increased by 2 IU/L
agonists
-producing)
=> [TSH]plasma
increased by 5 mU/L if thyroid hormones are not increased
(0.075-0.15 mg/die)
-producing)
(i.v. injection ovine at 8 a.m.) => sampling at 0, 15', 30', 60', 90',
and 120' => normal if [ACTH]plasma
increased by 2-4-folds, peak at 20-100 pg/mL]plasma
> 21 mg/dL; [aldosterone]plasma
4 ng/dL above normal level
every 8 hrs => [cortisol]plasma
> 21 mg/dL
tolerance test (ITT) (i.v. injection of 0.05-0.15 IU / kg) => glycemia
< 40 mg/dL => sampling at -30', 0, 30', 60, and 90' => normal if [cortisol]plasma
increase by 7 mg/dL or > 20 mg/dL
(inhibitor of conversion of 11-DOC into cortisol => removal of negative
feedbak on ACTH incretion) (30 mg/kg at 12 p.m.) => normal if at
8 a.m. [cortisol]plasma
< 4 mg/dL, [11-deoxycortisol (11-DOC)]plasma
> 7.5 mg/dL or > 0.22 mmol/L,
[ACTH]plasma
> 75 pg/mL-producing)]plasma
: as its value increases with stress (also venipuncture), basal values
are taken 15 minutes after cannulation
(bolus injection to prevent peripheral proteolysis before crossing the
BBB) => [PRL]plasma,
basal > 2 mg/dL with increase by 200%
(side effects : skin rash and incontinence)
(200 mg i.v.) => [PRL]plasma,
basal < ?,
1 mg/kg CRH,
100 mg GnRH
/ LHRH,
and 200 mg TRH)
or receptor agonist therapy
and one or more of the glycoprotein types
and GH
and is presumed to be a stem cell for both lactotrophs and somatotrophs.
and PRL-producing)-increting
tumors
incretion (< 1%)-increting
tumors (98%)ref1,
ref2,
ref3,
ref4
and breast cancerrefrefref.
It is a severe autosomal recessive dwarfism characterized by complete GH
insensitivity. Genetic and mutation analyses have attested to the high
molecular heterogeneity of this syndrome, and, to date, more than 30 different
GHR mutations including deletion, frameshift, nonsense, missense and splicing
defects have been described. However, among them, missense mutations are
of particular interest in potentially providing critical information on
the structure-function relationship of the GHR and related molecules. The
study of the recently described forms of atypical LS is now very promising.
These patients display detectable plasma GH binding activity associated
with complete or partial GH insensitivity. Molecular analysis of such a
phenotype with positive GHBP and complete GH insensitivity has revealed
the existence of a missense mutation abolishing receptor homodimerization,
thereby providing in vivo evidence for the critical role of the dimerization
process in the growth-promoting action of GH. Similarly, mutations in the
cytoplasmic region, which are expected to be associated with normal GH
binding activity, should contribute to the identification of other functionally
important domains. Partial GH insensitivity syndromes may theorically encompass
a wide range of distinct phenotypes with variable degrees of GH resistance.
Missense GHR mutations and a quantitative GHR mRNA defect have been identified
in some cases belonging to this heterogeneous group. Interestingly, exclusion
of linkage between the Laron phenotype and the GHR locus was demonstrated
in one affected family. This latter situation may indicate the existence
of other genes controlling GHR expression or required at different steps
of the signal transduction pathway. In this regard, the availability of
a possible animal model for LS should offer new prospects in the identification
of GH-inducible genesref.
Associated anormalities include spinal stenosis, os odontoideum, degenerative
changes of the atlanto-odontoid joint, and small oropharynxref.,
snoring, obstructive
sleep apnea syndrome (OSAS)
and thyroid stimulation by GH
and IGF-1)
(40%)
(acromegalic heart disease) => tachyarrhythmias
=> toothprint on tongue
(due to increased PRL and decreased DA)]plasma
(4.6%)]plasma
basal (3-4 dosages separated by 20-30' : doubtful result if 5 < x <
10 ng/mL) and circadian rhythm]night
urine]plasma
(more important than GH in follow-up)]plasma
:,
MRI
to look for SST2
and SST5
expression
agonists, SST2
agonists, SST3
agonists, SST4
agonists, SST5
agonists, D2
agonists, GH-R
antagonists. Even cases negative at 111In-DTPA-octreotide
scintigraphy
may respond, so a trial may be attempted for 5-8 months]plasma
basal > 2 ng/ml, the patient can be considered cured if after 2 hrs from
OGTT [GH]plasma
< 1 ng/ml)-producing)]plasma
> 200 ng/mL (directly relates with diameter)
(30% of patiens and 80% of patients in hemodialysis)
excess : hypothyroidismand
oligomenorrhea-hypomenorrhea-mild menorrhage (50%) => primary or secondary
amenorrhoea,
none after menopause ; hypoestrogenism (hot flushes, colpoxerosis, mastodynia,
decreased libido and depression)
test
agonists (bromocriptine, dihydroergocristine, lisuride, metergoline,
cabergoline) : only 33% of patients are cured-producing)
cells : hypertrophied thyrotrophs found in the adenohypophysis after
thyroidectomy and in severe thyroid hormone deficiency
-
and FSH-producing)-producing)
for Cushing's syndrome; it is
characterized by aggressive growth of the tumor and diffuse
hyperpigmentation of the skin
(10-20 mg at morning, 10 mg at evening)
(25 mg at morning, 12.5 mg at evening)
(5 mg at morning; 2.5 mg at evening)
appearance :
and nasal obstruction due to stirring of dura mater over diaphragma sellae
(rarely hydrocephalus)
(better assessment of posterior fossa and skull base). Improvements in
diagnostic imaging techniques over the last several years have led to an
increasing recognition of asymptomatic lesions in the pituitaryref1,
ref2.
The management of such pituitary incidentalomas is controversialref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8.
Some lesions may increase in size, owing to impaired pituitary hormone
production or compressed optic chiasm, whereas others will remain unchanged
in size and will never produce tumoral or hormonal symptoms. The type of
initial endocrinological assessment and the required frequency and length
of follow-up for pituitary incidentaloma need to be carefully determined,
taking cost effectiveness into account. In this setting, it is crucial
to obtain precise information about the natural history of each type of
pituitary lesion. Besides pituitary masses, physiological enlargement of
the pituitary gland is a frequent cause of incidentaloma and of referrals
to endocrinologists for hormonal evaluation and therapeutic advice. Sex-
and age-dependent variations in size and shape of the pituitary have been
reported. In neuroradiological series, 25–50% of healthy women, 18–35 yr
old, had a convex superior pituitary contour, but pituitary height exceeds
9 mm in less than 0.5% of casesref1,
ref2,
ref3,
ref4.
No thorough clinical and hormonal data or long-term endocrinological and
imaging follow-up data are available on these subjects. The present study
was thus designed to obtain more information, at the time of initial referral
and during follow-up, on the clinical, hormonal, and neuroradiological
characteristics of young women with incidentally diagnosed pituitary gland
enlargement (height 9 mm) and a suspected pituitary tumor, with the
aim of proposing practical guidelines. 7 eugonadal nulliparous women, 15-27
yr old, referred between 1989 and 1998 with incidentally diagnosed pituitary
gland enlargement (height > 9 mm) and a suspected pituitary tumor, were
studied. At presentation and at yearly intervals, PRL plasma levels and
corticotropic, somatotropic, and thyrotropic pituitary function were measured;
and pituitary dimensions and signal on magnetic resonance imaging (MRI),
before and after iv gadolinium-diethylene-triamine-pentaacetic acid injection,
were assessed. PRL plasma levels were normal; and corticotropic, somatotropic,
and thyrotropic pituitary function was considered normal in all cases.
In all the women, the upper boundary of the pituitary was convex, on MRI,
and touched the optic chiasm in 4 cases. The width and anteroposterior
diameter of the gland were normal. The pituitary itself seemed normal,
with a homogeneous signal, on plain and dynamic studies with iv contrast
injection. Despite normal initial hormone values, two women underwent surgery,
by the transsphenoidal approach, in another center. During surgery, the
pituitary seemed normal in both cases, with no evidence of tumoral or inflammatory
processes. Biopsy specimens showed the morphologic characteristics of a
normal, nonhyperplastic pituitary gland. All seven women were seen at yearly
intervals for 2-8 yr (median, 4 yr). Clinical and hormonal status remained
stable, as did the structure and size of pituitary, on serial MRI. No tumor
formation occurred, supporting the diagnosis of physiologic hypertrophy
of the pituitary gland. In conclusion, these observations suggest that
careful examination of MRI results may help to distinguish physiologic
pituitary hypertrophy from pituitary tumors and infiltrating lesions. The
former diagnosis is confirmed by normal baseline pituitary function in
extensive hormonal tests. Correct identification of such patients is important
to avoid unnecessary pituitary surgery and costly MRI surveillanceref.
,
L-T4,
and cortisol acetate
))-producing
cells : central or pituitary
diabetes insipidus (CDI)
,
desmopressin
i.n. 5-20 mg b.i.d. or p.o. 300-600
mg/die-producing
cells
(closed and penetrating)
=> nausea and vomiting,
confusion, mild headache,
seizures, coma
=> hypouricemia)),
60% at age 70. 14-40% of infant nodules are malignant (expecially when
male, single nodule, exposure to ionizing radiations, dysphonia, rapid
growth, adhesion to contigue tissues, cervical adenopathies)
or pink-yellow colour of FNAB) : they are more commonly degeneration of
solid nodules rather than epithelial cysts, so that 0.5-3% can degenerate
into carcinomas. They should be excised when larger than 4 cm, containing
bloody fluid, or undergo constant refilling after drainage.
detects cysts > 2 mm and solid nodules > 3-4 mm,
calcified amyloid in MTC), signs of extrathyroid extension
for cold or undeterminated nodules : sensitivity = 65-98%; specificity
= 72-100%; accuracy = 95%; false positives = 2.9%; false negatives = 0.5%;
useful also for cervical lymph nodes, associated with [thyroglobulin]washing
fluid in the needle. In general, FNAB results are classified as:)
: poor sensitivity and specificity, useless in babies unless thyrotoxicosis,
uncertain cytology (differential diagnosis with functional adenoma), thyroid
agenesis, neonatal hypothyroidism, ectopic thyroid tissue, follow-up of
differentiated carcinoma
for babies (evaluation of extension and accurate presurgical topographical
planning)
due to increased [TSH]plasma
or thyroid-stimulating immunoglobulin (TSI)
,
which inhibits iodide oxidation and incorporation into thyroglobulin (Wolff-Chaikoff
effect).
content, leading to hypoiodemia;
seen in mountainous areas,
autoimmunity, genetics (tRNA lysine
1 (TRK1)
rearrangements), ? leading to increased local secretion of cytokines and
growth factors => polyclonal or monoclonal (selective growth advantage)
hyperplasia
=> inspiratory stridor; respiratory failure if obstruct > 70% of tracheal
lumen), recurrent nerve, esophagus (expecially from retrosternal goitre),
or sympathetic trunk (miosis,
enophathalmos).
Complications : intragoiter hemorrhage leading to sudden swelling of the
neckref
(monitoring of decreased vascularization after presurgical treatment with
Lugol's
solution)
and hashitoxicosis
: dyshomogenous thyroid (cold and hot (hyperthyroid) areas)
and cytology (< 1% of nodules are malignant)+
FT4]plasma,
including type
1 amiodarone-induced
thyrotoxicosis (AIT) due to increased thyroid hormone synthesis and
secretion in patients with underlying preclinical Graves' disease or autonomous
nodular goitre (increased vascularization, mild increase in IL-6)ref
acts on TSHR
at high doses (rare; accompanied by low [TSH]plasma)
acts on TSHR
at high doses)
=> hyperemesis
gravidarum-induced
thyrotoxicosis (AIT)ref
administration, with little changes in serum T4 levelsref.
However, long-term treatment with OCAs may result in a high rate of recurrence
of hyperthyroidsm due to the escape phenomenonref1,
ref2.
The use of OCAs for a mixed form of AIT was previously reported in a case
report in association with thionamides, KClO4 and glucocorticoidsref.
OCAs have been used in combination with thionamides in the treatment of
type II AIT: this therapy was associated with normalization of both serum
free T4 (FT4) and free T3 (FT3)
levels or the occurrence of hypothyroidism after 15–31 wk of treatmentref.
Albeit iopanoic acid
and prednisone are effective, glucocorticoids are probably the drug of
choice for more rapidly curing type II AITref.
(80-95%)
with mild steatorrhea (8-33%)
(65-80%)
and hyperreflexia
(39-80%)
(rare),
urticaria (10-25%)
(40%)
(50-90%) => hot intolerance,
conjunctival irritation, diplopia)
(50-60%)
(10-40%; more common in patients above age 50, due to underlying disease)
(28-77%) => systolic
systemic arterial hypertension
(66%) and vascular murmurs on thyroid (also due to hypervascularization)
and reduced sexual function in tertiary hyperthyroidism (TRH also stimulates
PRL incretion)
=> hypercalcemia
and hypercalciuria
challenge
(diabetes mellitus)
(nodules and cysts > 3 mm)
detects hypervascularization ("thyroid hell")
challenge test : no increase in serum TSH
to control adrenergic symptoms before other therapies work
(propylthiouracil 300-1000 mg/day; methimazole 30-100 mg/day) before surgery
or if surgery is refused (e.g. in newborns, youngs, pregnants). Prolonged
remission in 30% after 8-months course : 15% become hypothyroid. Side effects
from PTU : skin erythema and fever (3-4%) and agranulocytosis (0.1-0.4%)
=> fibrosis and atrophy (only in patients with age > 18 yy, not pregnant,
with small goiter and drug intolerance)
increase sialylization and decrease clearance)
deficiency,
reduced thyroid hormone metabolic response
]plasma
and
increased [FT4]plasma : high [FT4]plasma,
high [FT3]plasma, normal or decreased [TSH]plasma;,
nephrotic
syndrome
deficiency (autosomal recessive, only 35 cases reported)
deficiency (autosomal recessive : 1 every 40,000)
deficiency (autosomal recessive)
=> loss of iodine recirculation
(< 5%)]plasma
and
decreased [T4]plasma
(Wolff-Chaikoff effect)
to treat ...
(3-4 months, due to reversible damages rather than cell destruction)
(rare only if accompanied to natural goitrogenous or hyposeleniemia; 2-3%
of pregnants due to increased thyroid hormone requirements)
in vegetables or milk from cattle who ate such vegetables
and amiodarone-induced
thyroiditis) or referred as pharyngodynia or otodynia, dysphagy, erythema
over thyroid, regional lymphadenitis. Complications : tracheal obstruction,
septicemia, retropharyngeal abscess, mediastinitis,
jugular vein thrombosis.
(ASA 2-3 g/day + antacids) => GR
agonists
as analgesics (prednisone 20-40 mg/day; gradually reduced in 6-8 weeks
until ESR normalized)
-induced
thyroiditis
(type II amiodarone-induced
thyrotoxicosis (AIT) due to lysosomal activation and histiocyte infiltration
=> cytotoxic damage, decreased vascularization, high IL-6)
|
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|
|
||
| macroscopic | consistence |
|
|
|
| lymph node involvement | diffuse | diffuse | asymmetric | |
| adhesion to surrounding structures | no or mild | no or mild | strong | |
| microscopic | microabscesses | present | absent | absent |
| lymphatic infiltration | minimal | diffuse with presence of germinal centres | minima | |
| giant cells | frequent | rare | absent | |
| fibrous tissue | increased | mildly increased | strongly increased | |
]plasma
and decreased [T4]plasma. Upon TRH
challenge test, [TSH]plasma
increases within 1 hour but [T4]plasma doesn't
increase.
]plasma
and
decreased [T4]plasma. Upon TRH challenge test,
[TSH]plasma
increases a little (the negative feedback doesn't works) and hence [T4]plasma
increases a little, too.
(autosomal recessive nongoitrous
hypothyroidism).
deficiency; it is marked by slowing and cessation of growth, thickening
and yellowing of the skin, coarse facies, delayed puberty, and short stature
at maturity]plasma
and
decreased [T4]plasma. Upon TRH challenge test,
[TSH]plasma
doesn't increase and hence [T4]plasma doesn't
increase, too.
=> weight gain (despite anorexia)
and rarefaction of hairs on outer thirds of eyebrowns
and hypertriglyceridemia
or myasthenia of respiratory muscles)
(30%),
dementia,
psychosis
=> mixedematous coma
associated with hypothyroidism occurs due to reduced cardiac output and
subsequent renal hypoperfusionref,
and, in severe cases, acute renal failure secondary to rhabdomyolysisref.
In most cases, clinical features of hypothyroidism are apparent and there
are associated biochemical abnormalities such as raised serum creatine
kinase concentrationref.
Improvement in renal function following treatment of hypothyroidism in
patients with chronic renal failure has been previously reported, and it
has been suggested that investigation of unexplained deterioration in renal
function in these patients should include thyroid function testingref.
Reduced T3 and T4 concentrations can occur in chronic
renal failure in the absence of hypothyroidism, but these are not associated
with increased TSH concentrationref.
CRF may also lead to normochromic
normocytic anemiaref
(nodules and cysts > 3 mm)
(longer half-life than L-T3); 33% of patients
experience increased [TSH]plasma
even
after [T4]plasma and [T3]plasma
are normalized. Doses cannot be increased as at high concentrations it
has toxic effects.
or Gas
in > 90%
,
K-Ras,
N-Ras
.
Aggressive as tall cell variant
(not in 131I radiometabolic therapy). Higher incidence in natives
of the Marshall Islands and 62-fold higher incidence in the children of
Belaru, Ukraine and Bryansk, following the accident at Chernobyl Nuclear
Power Plant on April 26, 1986 : 70% have mutation in c-Ret
vs. 2.5% in Saudi Arabia and 35% in Italy,
Gas,
and PTEN
(in Cowden syndrome); RET/PTC1:(inv(10q11.2q21),
RET/PTC2:(t(10;17)(q11.2;q23)), RET/PTC3:ELE1/TK (20-40%), H-Ras,
K-Ras,
N-Ras,
CDKN2A
deletion, c-Myc
overexpression, and LOH; multifocal (30-50%; 70-80% if radioinduced). Individual
tumor foci in patients with multifocal papillary thyroid cancer often arise
as independent tumorsref
|
|
|
|
| stage I | any T, any N, M0 | T1, N0, M0 |
| stage II (80%) | any T, any N, M1 | T2 or T3, N0, M0 |
| stage III | - | T4, N0, M0
any T, N1, M0 |
| stage IV (1%) | - | any T, any N, M1 |
and pulmonary
metastases
(except 131I radiometabolic therapy)
rearrangements, point mutations in TSHR,
Gas,
H-Ras,
K-Ras,
N-Ras,
CDKN2A
deletion, c-Met
and c-Myc
overexpression, PAX8-PPARg1
translocation, and LOH; 5 years of latency, multicentricity and lymph node
involvement (10-20%)
|
|
|
|
| stage I | any T, any N, M0 | T1, N0, M0 |
| stage II | any T, any N, M1 | T2 or T3, N0, M0 |
| stage III | - | T4, N0, M0
any T, N1, M0 |
| stage IV | - | any T, any N, M1 |
,
brain
metastases,
and bone metastases
to inhibit TSH incretion
followed by 131I radiometabolic surgery of thyroid remnants
(this allow evaluation of 121I total body scintigraphy (TBS)
and [TG]plasma to assess relapses and metastases), but is associated
in age < 16 years with recurrent nerve injury (0.3-30%), hypocalcemia
(8-24%), and acute respiratory failure (5%), expecially when there is extrathyroid
invasion, lymph node metastases, previous surgery, anatomical variants
of recurrent nerve or parathyroids, poor training of the surgeon. Minimally
invasive video-assisted thyroidectomy has lower mortality
reduces relapses, but there is risk for inferior laryngeal nerve injury
for vertebral metastases.
(differential diagnosis with primary lymphomas
(MALTomas)),
point mutations in APC,
p21/WAF
overexpression, and LOH.
are marginally beneficial
: as the conventional techniques that are used cannot distinguish between
benign follicular thyroid adenoma and
invasive
follicular carcinoma, all patients with follicular lesions undergo
thyroidectomy.
SAGE analysis identified a combination of 4 genes (DDIT3,
ARG2,
ITM1,
and C1orf24)
that can be used to identify carcinomas with 83% accuracy, so this approach
might spare patients from unnecessary surgeryref.
to make differential diagnosis with hemorrhagic cyst
to assess bone metastases
(10% : risk of injury of recurrent nerve)
for bone metastases,
it could be due to metastases or uncomplete thryoidectomy (also ectopic
embryological remnants; struma ovarii are usually nonfunctioning)
,
pulmonary
metastases,
bone
metastases
,
histaminase, DOPA decarboxylase,
NSE,
CGRP,
SST,
TG, TSH,
ACTH,
GRP,
5-HT,
chromogranin A, and substance
P.
,
secondary
Cushing syndrome
]plasma
agonists (pentagastrin) > Ca2+ gluconate assessed at time 0,
2', 5', 15', and 30' (not recommended in individuals with peptic ulcer)
> TRH
> histamine (through H1-receptors, through nonspecific vascular
dilation "washing out" preformed calcitonin) > PPI
(omeprazole increases endogenous gastrin)
with complete emptying of central lymph nodal compartment
of CCK2-expressing
medullary thyroid cancers with radiolabeled minigastrin
and chemotherapy are palliative
(1-2%)
(pulmonary metastases
are usually asymptomatic)
< multiple endocrine neoplasia
(MEN) IIB / III / Wagenmann-Froboese syndrome / ganglioneuromatosis of
the alimentary tract
< anaplastic thyroid carcinoma)
gene
or PTH
gene,
MTND6,
or tRNA glutamine (MTTQ)
during pregnancy
hypoparathyroidism : accidental ablation of parathyroid tissue
gene inherited from the mother and predicted to interfere with the parent-specific
methylation of this gene
activity/protein leading to the same physical appearance as patients with
PHP IA but no endocrine abnormalities,
obesity,
short metacarpals, and ectopic calcification.
following thyroid surgery is usually transient : if becomes chronic if
persists > 2-3 weeks
gene or PTH
gene (autosomal dominant or recessive)
gene
gene may be more sensitive to extracellular Ca2+ changes
(renal hyperparathyroidism) => phosphate retention; inahibility
to hydroxylate vitamin D3 => reduced intestinal calcium absorption
=> hypocalcemia
=> parathyroid hyperplasia and increased serum PTH => bone resistance =>
increased serum calcitonin
+ calcium)
(MIP) + forearm muscle parathyroid
autograftin
patients refractory to medical therapyref.
It is important to remove all parathyroid glands, including supernumerary
glands, at the initial operation and to choose appropriate and adequate
parathyroid tissue for the autograft to prevent persistent or recurrent
2HPTref.
There is a significant rate of recurrent secondary hyperparathyroidism
(rSHPT), mainly due to the parathyroid autografts (30% at 7 years after
the initial operationref),
but in some cases there are previously undetected residual or ectopic parathyroid
glands that can be identified with an echo-guided approach and treated
with echo-guided percutaneous
ethanol injection therapy (PEIT)
or percutaneous calcitriol injection therapy (PCIT); however, there
is a risk of iatrogenic primary hypoparathyroidism
in patients with non-functioning parathyroid autografts. As parathyroid
autografts consist of multiple nodules, echo-guided injection of ethanol
or calcitriol to each nodule is almost impossible and therefore resection
of the autograft is indicated for autograft-dependent recurrent renal hyperparathyroidismref.
A modified Casanova testref
can discriminate between the graft-bearing arm and the neck as the site
of the recurrence : the test measures intact PTH in blood obtained from
the non-graft-bearing arm before an ischemic period and from the arm bearing
the parathyroid graft during an ischemic period caused by an Esmarch
bandage (application of turniquet to the upper arm). Graft-dependent
recurrence (GDR) is suggested when PTH levels dropp by > 50% and neck-dominated
recurrence (NDR) whenever the PTH levels dropp to < 20%. Patients are
operated on accordingly. This abbreviated form of the Casanova test is
less time-consuming, satisfactory in an ambulatory setting, equally effective,
and less invasive than the original Casanova procedureref.
agonists (calcimimeticsref);
they possess lowering effects not only on serum PTH levels but also on
serum calcium x phosphorus product levels, a hallmark of an increased risk
for cardiovascular death in dialysis patients with end-stage renal disease
(ESRD)
:,
nausea
and vomiting,
peptic
ulcer,
constipation and abdominal
pain
and polydipsia,
psychosis
(15-20%)
=> chronic
pancreatitis
(25%, expecially in premenopausal females or nonhypogonadic males; it affects
mainly bones with high content of compact bone, eg radius and external
third of clavicle, skull and dental alveoli) => osteolysis => pain and
tenderness of bones and spontaneous fractures or osteitis
fibrosa cystica generalisata / von Recklinghausen's disease / osteitis
fibrosa osteoplastica / parathyroid osteitis
=> brown tumor (a giant-cell granuloma produced in and replacing
bone in jaw or third finger)
=> hypercalciuria
> 300 mg/24 hr (40%)
=> hypophosphatemia
(40%, due to PTH-induced reduced bicarbonate resorption in the proximal
renal tubule)
of lumbar vertebrae, hips and radium
and echocolordoppler (ECD)
or fine-needle
aspiration biopsy (FNAB)
(=> PTH dosage) : accuracy depends on diameter, location, thyroid status
(parathyroids may be confused with enlarged lymph nodes during thyroiditis),
devices and experience-SPECT
fusion to assess relationships with surrounding organs-PETfusion
within the same gantry is an aspecific test to be practiced after a definite
diagnosis or for early post-therapeutical follow-up
+ MRI
1 mg/dL over normal value, hypercalciuria > 400 mg/die, creatinine clearance
decreased by 30%) and age < 50 years => surgical ablation of hyperactive
parothydeal gland(s) (minimally invasive parathyroidectomy
(MIP)) after marking parathyroids with methylene blue or intraoperative
MIBI g-probe (IMGP) technique at the time
point at which the target-to-background ratio is maximal in the performance
of minimally invasive radio-guided surgery (MIRS) => evaluation
of decreased [PTH]blood within 20' (normal parathyroid glands
are still inhibited by hypercalcemia) with
quick PTH assay (QPTH).
False positivity may occur if parothydeal ischemia prevents PTH from being
released in bloodstream. When all 4 parathyroids are hyperplastic, 3 are
removed, while the fourth is sectioed to let about 100 mg of parathyroid
tissue, assessing good vascularization and marking it with nonreabsorbable
suture or metallic clip for future surgical explorations. If all 4 parathyroids
are normal, the patient should be reevaluated. If the fourth parathyroid
is not found, a hemithyroidectomy should be performed assuming an intraparenchymal
parathyroid. Complications : hemorrhage, recurrent
nerve injury, involvement of superior laryngeal nerve, thyroid storm, hypoparathyroidism
(more comon in patients with severe bone calcium depletion (hungry bones)).
)
> 140/90 mmHg
> 130/85 or receiving current medication for hypertension
> 150 mg/dL (or > 1.69 mmol/L)|
|
|
|
| Europids : in the USA, the ATP III
values (102 cm male; 88 cm female) are likely to continue to be used for clinical purposes |
male | >= 94 cm |
| female | >= 80 cm | |
| South Asians : based on a Chinese, Malay and Asian-Indian population | male | >= 90 cm |
| female | >= 80 cm | |
| Chinese | male | >= 90 cm |
| female | >= 80 cm | |
| Japanese | male | >= 90 cm |
| female | >= 80 cm | |
| Ethnic South and Central Americans | use South Asian recommendations until more specific data are available | |
| Sub-Saharan Africans | use European data until more specific data are available | |
| Eastern Mediterranean and Middle East (Arab) populations | use European data until more specific data are available | |
within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. Homozygous
Clock
mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic
and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia,
hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts
encoding selected hypothalamic peptides associated with energy balance
was attenuated in the Clock mutant mice. These results suggest that the
circadian clock gene network plays an important role in mammalian energy
balanceref.
|
|
|
|
|
| high |
< 130
|
< 40
|
> 400
|
| borderline |
100-129
|
40-60
|
150-400
|
| low |
< 100 (therapeutic goal)
|
> 60
|
< 150
|
(RR = 4 for fatal ACS, and 2 for total and cardiovascular mortality)
is significantly elevated in those with metabolic syndrome (2.36 mg/L vs.1.56
mg/L) and measurement enhanced the prediction of both CHD and diabetes.
gene mutations
leads to apoptosis of > 80% b-cells in pancreas.
(usually accompanied by kidney
transplantation),
affects young women, obesity, hyperandrogenism, severe hyperinsulinemia,
GLUT4,
MAPK8IP1,
mitochondrial
glycerol-3-phosphate dehydrogenase 2 (GPD2), ABCC8
/ sulfonylurea receptor 1 (SUR1)...)
do not increase the risk of developing DM : siblings of children who have
DM -- and are therefore more likely to develop the condition themselves
-- are not more likely to become diabetics if they are vaccinatedref
levels are increased in the TNF-a- and dexamethasone-induced
modelsref
=> relative insulin resistance in skeletal muscles and liver (prevalence
= 20%; aetiology : IRS-1 polymorphism => down-regulation of peripheral
InsR
expression and catalytic activity; obesity => lipotoxicity,
including increased [FFA]serum=Randall cycle=> decreased
[Glc]serum) => lack of peripheral glucose usage after meals
(=> induction of ketogenesis => increased synthesis of VLDL (liver
steatosis) => inhibition of hepatic lipase => decreased HDL-Ch, hyperglycosylated
LDL => increased risk of CVD)
=> hyperglycemia=>
compensatory hyperinsulinemia (inversely related to impairment of
first phase of secretion)
amyloid fibrils in Langerhans' islets
or IL-18R, and in mice transgenic for expression of IL-18BPref.
:
gene, with severe insulin resistance and acanthosis
nigricans
as well as thick hair, abnormalities of teeth and nails, and hyperplasia
of the pineal gland.
marked by slow physical and mental development, the elfin facies suggested
by the name (wide-set eyes, low-set ears, and hirsutism), and severe endocrine
disorders such as enlargement of the clitoris and breasts in females and
of the phallus in males
=> deleterious effects of oxidative phosphorylation inhibition on
pancreatic islet cell function,
middle-age women, hyperandrogenism, autoimmune disorders
(HAIR-AN) syndrome
and liver failure
(=> shift to insulin replacement
therapy)
activators
agonists
inhibitors
agonists (side effect : 70% increased risk of heart
failure,
8.8% vs. 5.5%)
agonists
for initial stages
has an anti-diabetic effect on obese patients but also on non-obese diabetic
(NOD) mice)
and characterized by b-cell failure, insulinopenia,
insulin resistance, and moderate to severe hyperglycemia, but without ketosis
(anyway most patients also markers of autoimmune b-cell
destruction)
(thiazide diabetes : they inhibit insulin secretion, possibly through
thiazide-induced hypokalemia)
(steroid diabetes / steroidogenic diabetes : target tissue insulin
resistance; it is characterized by a relatively low incidence of microvascular
sequelae)
(gestational diabetes mellitus (GDM))
: with onset or first recognition during pregnancy; this category does
not include diabetics who become pregnant or women who become lactosuric
have a 48% lower rate of GDM, as it probably acts as a surrogate for general
nutritional deficiency,
estrogens,
progesterone,
and cortisol)
and an increased insulin degradation by placental insulinase => physiological
insulin-resistance
(aimed to shift nutrients to the developing fetus) is deficiently compensated
by maternal hyperinsulinism (expecially in diabetic pregnants) to obtain
a normal glucose tolerance => maternal hyperglycemia (there is a risk for
ketoacidotic coma if more insulin is not administered : the lack of increased
insulin requirements in a diabetic pregnant marks placental insufficiency
and fetal risks, expecially when associated with nephropathy or pre-eclampsia)
=> fetal hyperglycemia (maternal insulin doesn't cross blood-placenta barrier)
=> fetal hyperinsulinism. Maternal diabetic complications are increased
by pregnant's predisposition to develop urinary tract infections, neuropathies,
nephropathy, and retinopathy. During last weeks of pregnancy and labor
there is instability in glycemia, with a tendency to develop acidosis.
After delivery instability persists but carbohydrate tolerance increases
abruptly reducing insulin requirements : during puerperium there is a gradual
increase of carbohydrate tolerance (due to loss of calories with lactation
and loss of placental hormones), which returns to pre-pregnancy levels
within 6 months.
(> 4 kg or > 95th percentile at delivery; normally sized head, larger than
normal trunk) may complicate delivery due to cephalopelvic disproportion
or preeclampsia
/ gestosis / pregnancy induced hyperension (PIH)
;
women who develop GDM had SHBG
levels that were much lower than those of women who remain diabetes-free
throughout pregnancy
,
genetics, oxidative stress, and VEGF SNPs) : hyperglycemia
=> glucotoxicity
=>
DHAP => methylglyoxal (MG) (an a-oxoaldehyde)
=> methyl glyoxal-derived advanced glycation end products (MG-AGE)
(including hydroimidazolone) => RAGE
=> inhibition of InsR
translocation
& UTIs
: excess of nonreabsorbed glucose => H2O is recalled into tubule
=> D[Na+]tubule < 0
=> increased gradient allows Na+ leakage into tubule => further
H2O recalling into tubule and so on (positive feedback)
due to dehydratation
(in type 1 diabetes mellitus)
(in type 2 diabetes mellitus)
due to iatrogenic insulin-induced
hypoglycemiadue
to impaired aerobic glycolysis
due to nephropathy
=> inhibition of GAPDH activityref
to
stimulate natriuresis => glomerular hypertension => GFR increases by 20-40%,
PRF increases by 10-15%, and hence filtration fraction increases, too =>
microalbuminuria
(5-15 years after diagnosis of IDDM or 2-3 years after diagnosis of NIDDM
: incipient or silent diabetic nephropathy) and renal hypertrophy
=> macroalbuminuria
(overt diabetic nephropathy : 40% of patients with IDDM and 15%
of patients with NIDDM develop manifest diabetic nephropathy within 10-25
years; relates with periodontitis
in patients with NIDDM) and glomerulosclerosis =>
GFR decreases by 1 mL/min/month, leading to ESRD
within 4-10 years.,
ABCC8
/ sulfonylurea receptor 1 (SUR1) activators
and metformin
=> decreased requirements.
due to diabetic autonomic neuropathy and loss of reflex tachycardia,
more difficult vascular access, rapid progression of retinopathy)
(+ non-DHP CCBs))
: overt nephropathy < 125/75 mmHg and/or as lower as you can
(+ non-DHP CCBs))
:
,
but the cause-effect relationship may be bidirectional.
or abdominal painis
the most debilitating complication
alternated to constipation
(differential diagnosis with celiac
disease
in type 1 diabetes mellitus)
and retrograde ejaculation. Impaired eNOS function is associated with erectile
dysfunction in DM, but the exact molecular basis for the eNOS defect in
the diabetic penis remains unclear. Hyperglycemia increases O-GlcNAc
modification of eNOS in the penis, preventing phosphorylation at the primary
positive regulatory site on the enzyme and hampering mechanisms of the
erectile response. T1DM was induced in male rats by alloxan (140 mg/kg,
i.p.). After 5 wk, the diabetic rat penis exhibited increased O-GlcNAc
modification of eNOS and decreased eNOS phosphorylation at Ser1177
at baseline compared with the control rat penis; eNOS phosphorylation at
Thr495, Ser615, and Ser633 was not affected.
In addition, eNOS phosphorylation at Ser1177 was impaired in
the diabetic rat penis in response to penile blood flow (shear stress)
elicited by electrical stimulation (ES) of the cavernous nerve and to recombinant
human VEGF165. Phosphorylation of Akt, a mediator of shear stress-induced
eNOS phosphorylation at Ser1177, was decreased in the diabetic
penis at baseline, but it was restored by ES. Erectile response to shear
stress elicited by ES and to VEGF was decreased in diabetic compared with
control rats. eNOS inactivation occurs in the diabetic penis by a glycosylation
mechanism specifically at Ser1177, by which the enzyme is rendered
incapable of activation by fluid shear stress stimuli and VEGF signaling.
In
vivo penile erection paradigm supports the physiologic relevance of
O-GlcNAc
modification in vascular disorders associated with diabetesref.
with sluggish reaction to light
(> 50% of newly diagnosed NIDDM cases have CAD; 10-year AMI risk is the
same for non-AMI diabetics and nondiabetic AMI patients; mortality of patients
with new hyperglycemia in both non-ICU and ICU is far higher than mortality
of known diabetes patients; it relates with periodontitis
in patients with NIDDM; the Hp2 allele of the haptoglobin
gene is highly predictive of adverse cardiac events in diabetic patients
after they undergo PTCA). DM is considered a CHD
risk equivalent
(3-fold increase of strokes) : due to myocardial ischemia (due to atherosclerosis
and systemic
arterial hypertension)
and dysfunction of cardiomyocytes secondary to chronic hyperglycemia.
(no claudicatio)|
|
|
|
|
|
| A (no infection or ischemia) | ||||
| B (+ infection) | ||||
| C (+ ischemia) | ||||
| D (+ infection and ischemia) |
results from a combination of neuropathy and obliterating arteriopathy
of lower limbs.
=> opportunistic infections
and spongiositis
complicated by emphysematous
pyelonephritis
and renal
papillary necrosis / necrotizing renal papillitis
colonization in skin folds and narices
and pruritus
(RR up to 3) : people with diabetes have a 30-40% increased chance of developing
CRC and tend to have a higher death rate after being diagnosed. People
who received > 3 years of insulin therapy had 3 times the risk of developing
that cancer compared with patients who received no insulin. The risk for
people on > 5 years of insulin therapy is 4 times higher than the no-insulin
group
risk due to placental insufficiency associated with IUGR
is higher in F, R, and FR classes
in most patients, severe in 10% vs. < 1% in non-diabetic pregnants
(20% vs. 3-10% in non-diabetic pregnants)
(favorable in both pregnant and fetus)]blood
> 6.1% (relates to FPG + postprandial glucose (PPG) : monitored at
home with A1cNow®). Measurements reflect time-averaged glycemia
in
the past 2–3 monthsref1,
ref2,
ref3,
ref4,
ref5.
Correlations between HbA1c concentration and average plasma
glucose :ref1,
ref2,
ref3
and liver
cirrhosisref,
so you should correct as follows : corrected HbA1c (%) = measured
HbA1c (%) + [0.224 x measured erythrocyte creatine (mmol/g
Hb)] - 0.05
.
| HbA1c (%) |
|
|
|
|
| 4.0–5.9 |
|
|||
| 6.0–6.5 | target | |||
| 6.6–6.9 | action | Target Aa | Target | Target |
| 7.0–7.9 | Target Bb | Action | Action | |
| 8.0–8.9 | Target Cc | |||
| > 9.0 | Action | |||
inhibitors to prevent postprandial hyperglycemia
to prevent glycation
therapies to prevent methylglyoxal formation
antagonists
inhibitors| Diabetes news
|
,
mental confusion, and disturbances of vision.,
CT,
intraoperatory echography
or KATP activators
;
most are islet cell tumors of non-b cells in
the pancreas, but some are found at sites such as the antrum of the stomach,
duodenum, the hilus of the spleen, or regional lymph nodes. This is the
usual cause of Zollinger-Ellison
syndrome;
most are islet cell tumors, but some are found in the duodenum,
hypokalemia,
and achlorhydria
,
deep
vein thrombosis (DVT),
diabetes
mellitus or IGT, and
hypoaminoacidemia)
/ CT
/ MRI,
5-fluorouracil,
platin compounds,
(if Octreoscan scintigraphy was positive)
during arterial phase, with slow wash-out)
(acute tuberculous adrenitis)
(histoplasmosis)
(size, contrast attenuation values)/MRI
(intravascular extension, chemical shift) => adrenal
scintigraphy
(functional evaluation and discordant pattern; sensitive also for non-secreting
pheochromocytomas)|
|
|
P value | |
| maximal diameter > 4 cm | 78% :
> 5 cm : adrenal carcinoma) |
22% | 0.0001 |
| irregular margin | 63% | 53.8% | NS |
| inhomogeneity | 80% | 100% | NS |
| calcifications | 13% | 31% | NS |
| hypodensity | 100% | 100% | NS |
| no cortical uptake at 131I-norcholesterol scintigraphy | 27.7% | 100% | 0.001 |
| cortical uptake at 131I-MIBG scintigraphy | 84.4% | 100% | 0.001 |
)
is at present restricted to patients with
for all patients with frank or subclinical hormonal incretion, suspect
malignancy based on radiological or scintigraphic studies
every year for the first 2 years.
deficiency, with normal production of all other adrenocortical steroids.
activity (PRA).
Some affected infants outgrow the need for dietary salt supplements in
early childhood.
and hyperkalemia
but without salt wasting, due to abnormally increased absorption of chloride
by the renal tubules
and 11b-hydroxysteroid
dehydrogenase 2 (HSD11B2) inhibitors,
hypernatriuria
=> dehydration and hyponatremia
=> systemic
arterial hypotension
(normonatremia and hypertension in Gordon's syndrome !)
(70-90%)
(adrenal calcifications are detectable with Rx in 50% of cases),
sore throat, chills, rigors, weakness, malaise, restlessness, apprehension,
myalgias, arthralgias, and fever. These symptoms are usually abrupt in
their onset. Petechiae
are present in approximately 50-60% of patients (purpura fulminans).
and subsequent adrenal hyperplasia as well as hyperandrogenism (in
type III and type IV) or hypoandrogenism (in type I, II, and V)|
|
|
|
|
|
|
|
|
|
|
steroidogenic acute regulatory (StAR) protein : death during childhood |
|
|
|
|
none | all |
|
|
HSD3B2 |
|
|||||
| salt wasting |
|
|
|
DHEA, 17-OH -pregnenolone | aldo, T, cort, estradiol | ||
|
|
|
|
|
DHEA, 17-OH- pregnenolone | aldo, T, cort, estradiol | ||
|
|
|
|
|
DHEA, 17-OH- pregnenolone | - | ||
|
|
CYP21A2 / 21 hydroxylase
(95% : homozygous deficiency causes fetal death due to lack of cortisol
synthesis)
|
|
|||||
|
|
|
|
,
vomiting, hypovolemia
and cardiovascular shock within first weeks of life |
progesterone, 17-OH- progesterone, D4- androstenedione | aldo, cort | ||
|
|
|
|
|
17-OH- progesterone, D4-A | cort | ||
|
|
|
|
|
17-OH- progesterone, D4-A | - | ||
|
|
CYP11B1 / 11b
hydroxylase |
|
|
|
|
11-DOC, 11- deoxycortisol | cort, aldo |
|
|
|
|
|
11-deoxycortisol ± 11-DOC | - | ||
|
|
CYP17A1
steroid 17a-hydroxylase activity |
|
|
|
|
11-DOC, corticosterone | aldo, andro, cort, estro |
| CYP17A1
17,20 lyase activity |
|
|
|
|
- | DHEA, T, D4-A | |
| multiple deficiency |
incretion
progressing to shock and, if untreated, death,
anorexia,
abdominal pain)
=> hypoglycemic
coma,
anorexia,
abdominal
pain(34%),
diarrhea
(20%), constipation
(19%) => weight loss (97%)
=> systemic
arterial hypotension
< 110/70 (87%; orthostatic in 12%) => syncope
(16%)
(98% : "black Adddison" vs. "white Addison") on sun-exposed areas,
palmar skin folds, gingivae, and anal mucosa (82%) (cortisol
deficiency removes negative feedback on a-MSH
secretion)
(9%), alopecia areata]urineand
[cortisol,
DHEA, DHEA-S, aldosterone]plasma,
plasma
renin
activity (PRA)]plasma
and hypernatriuria
and hypokaliuria
challenge test : reduced response (cortisol peak < 16-18 mg/dL
or < 150% basal value) in primary panhypoadrenocorticism; normal response
in central panhypoadrenocorticism
tolerance test (ITT) : weak ACTH and cortisol response to insulin-induced
hypoglycemia cannot distinguish central from peripheral Addison disease
as hypophysary ACTH pool is limited; normal ACTH and reduced cortisol response
indicates primary panhypoadrenocorticism
challenge test : in secondary panhypoadrenocorticism ACTH response
< 20 pg/ml (4.4 pmol/l) and cortisol response < 7 mg/dl (200 nmol/l)
(hydrocortisone, cortisol) and MR
agonists
(9a-fludrocortisone acetate)
.
Suppression of aldosterone with cyproheptadine suggests a serotonin-mediated
aldosterone-stimulating system. Hyperactivity of this system may be the
cause of IHA associated with adrenal hyperplasiaref,
but actually cyproheptadine is a partial MR agonist/predominant antagonistref.
and CYP11B1
genes that leads to ACTH-sensitive mineralocorticoid incretion by zona
fasciculata. (The various hemoglobins Lepore have a fusion b-type
subunit that is delta globin at the NH2 end and b
globin at the COOH end. This chimeric structure results from nonhomologous
pairing and unequal crossing-over between the contiguous d
and b globin genes. The hemoglobins Lepore result
from d-b fusion because
the d globin gene is located upstream from the
b
globin gene. The hemoglobins anti-Lepore, e.g., Hb Miyada and Hb P(Nilotic),
are the reciprocal product of nonhomologous pairing and unequal crossing-over
between the HBD and HBB genes; they are
b-d
fusion globins. In GRA, the 5' portion of the downstream gene is the 5'
portion of the fusion gene; hence, it is an anti-Lepore fusion). The genes
for CYP11B2 and CYP11B1 are located in close proximity on 8q and have identical
intron-exon structures. The 2 genes share 95% sequence homology but are
usually only expressed in their respective adrenal zones under separate
regulation by angiotensin II and ACTH, respectively. Subjects with GRA
have 2 normal copies of genes encoding CYP11B2 and CYP11B1, but they also
have an abnormal gene duplication. This hybrid, or chimeric, gene combines
the ACTH-responsive promoter sequence of the CYP11B1 gene fused to the
more distal CYP11B2 coding sequence. This chimeric gene results from variable,
and unequal, crossing-over between the 2 genesref.
The variability of the crossover site suggests that these mutations arose
independently in each pedigree, and did not originate from a single ancestral
mutation. As a result, aldosterone synthase is ectopically expressed in
the cortisol-producing zone of the adrenal cortex under the regulation
of ACTH. The chimerism also results in the production of the hybrid steroids
18-oxocortisol and 18-hydroxycortisol that can be used as diagnostic aidesref.
Genetic analysis of GRA kindreds has revealed that the disorder is inherited
as an autosomal dominant traitref.
Celtic ancestry is frequent among the reported pedigrees, and no cases
have been reported among blacksref.
0.5 mg x 4 times/day (every 6 hours) x 2-3 days => aldosterone < 4 ng/dl
on day 3 at 8 a.m.ref.
On the other hand, in one study, 10% of 60 patients with elevated aldosterone
levels and a positive dexamethasone suppression study had negative genetic
testingref.
is effective by providing feedback suppression of pituitary ACTH release,
which suppresses the abnormal regulation of aldosterone secretion (dexamethazone
0.125-0.25 mg/day or prednisolone 2.5-5 mg/day), usually administered at
bedtime. However, iatrogenic Cushing’s syndrome and impaired linear growth
in children have resulted from glucocorticoid overdosingref.
The therapeutic goal should be normotension, and not normalization of biochemical
markers, such as urinary 18-oxosteroid or serum aldosterone levels, since
these remain elevated in the majority of patients who normalize blood pressureref.
In fact, therapy to normalize laboratory values may unnecessarily increase
the risk of cushingoid side effectsref.
They normalize aldosterone, ABP, and kalemia
have also been used successfully
and ACEIs
are less likely to be efficacious in the setting of a suppressed RAAS.
DHP CCBs can be useful adjunctive treatment to the above diuretic agents
activation of MR
=> myasthenia (80%), polyuria (72%), hyposthenuria (72%), polydipsia (46%,
nycturia (30%), paraesthesia (24%), intermittent paralysis (21%), tetania
(20%), asymptomatic (21%), volume-dependent and vasoconstriction-induced
secondary
systemic arterial hypertension
(1% of all hypertension cases, 5% in referring centres, 20% in drug-resistent
patients), orthostatic
systemic arterial hypotension
without tachycardia, reduced Valsalva's maneuver, headaches, no edemas.
activity (PRA) < 1 ng/ml/hr => autonomy tests :
(1.25 L in 2 hrs or 2 L in 4 hrs): positive if aldolsteronemia > 6 mg/dl
p.o. test, which in normal patients reduce aldosteronemia (< 15 ng/dl)
after 1 and 2 hrs and increases PRA]
0.5 mg x 4 times/day (every 6 hours) x 2-3 days : test is positive for
GRH if aldosteronuria becomes normal|
|
|
|
| BP | +++ | + |
| [aldosterone]plasma |
> 25 ng/dl | < 25 ng/dl |
| [aldosterone]urine |
> 30 ng/day | < 30 ng/day |
| age | < 50 years | > 50 years |
and
MRI
have good sensitivity (up to 80%) only for nodules > 1 cm
after suppression of the healthy adrenal gland with dexamethasone
shows early (in the first 24 hours) and persisting (up to day 5-7) uptake
of the tracer in autonomically functioning tissue
in lateral decubitus (side effect : acute pulmonary edema) after pretreatment
with phenoxybenzamine (7 days), propanolol (3 days), and hydroelectrolyte
repletion to precompensate shock after tumorectomy. Aldosteronemia, PRA,
and kaliemia normalize in 100%, hypertension in 60-70%, type 2 DM in 100%
(100-400 mg/day for aldosterone and 100-200 mg/day for catabolites; side
effects : gynecomastia and sexual deficits in the male and amenorrhea in
females) and epithelial sodium
channel (ENaC)
inhibitors
and hypovolemia
(CHF; cirrhosis, diuretics, vomiting, salt-wasting nephropathy),
hypocalciuria
,
no edema, insensitivity to the pressor effects of angiotensin
:-secreting
neoplasms (reninomas)
activity (PRA)]plasma
/ plasma mineralocorticoid activity (PMA) > 15 ng/dl in clinostatism
and orthostatism]urine
> 10 ng/day (IC95 = 5-20) in clinostatism and orthostatism]plasma/
PRA ratio (ARR) > 20 h. b-blockers,
ACEI and diuretics
should be suspended > 3-4 weeks before testing PRA ! The antihypertensive
treatment can be replaced by a long-acting non-DHP CCBs.
The salt intake should be 60-80 mEq/day (51 g/day) and potassium intake
40-60 mEq/day
when diet is normosodic (6 g/day for > 1 week in hospital settings) =>
muscular weakness, type 2 DM due to b-cell
dysfunction (50%), arrhythmias
and metabolic alkalosis
> 20-25 mEq/day (> 30 mEq/l) => osmotic polyuria and nycturia due to deficiency
of renal concentration => secondary polydypsia
: U wave, cardiac hypertrophy
: ventricular septal hypertrophy
: metabolic alkalosis
and adult-onset diabetes mellitus in postmenopausal
women resulting from overproduction of adrenocortical androgens.
(1%)
excess (tertiary Cushing's
syndrome) :
excess (secondary Cushing's
syndrome) :
excess (ectopic ACTH syndrome);
depending on its duration, it may be subtle, resembling true Cushing's
disease, but hypokalemic alkalosis and weakness are often prominent.
if severe symptoms
(iatrogenic Cushing's syndrome / Cushing's syndrome medicamentosus)
(side effect : Nelson's syndrome))
(50-87%)
of the spine (40%) => kyphosis and rachialgias (58%), ischemic necrosis
of femur head
which are located only on abdomen.
with slow healing (45-65%)
(16%)
=> IGT (55%) => polyuria
and polydipsia (23%), diabetes mellitus (15%)
(75%)
=> infections,
hypokalemia,
and metabolic alkalosis
=> systemic
arterial hypertension
> 150/90 (75-82%) => benign endocranial hypertension and edema
(30-62%)
=> arrhythmias
in 65-80%; acne in 45%; amenorrhoea in
60-77%, clitoris hypertrophy in 19%)
(in secondary or tertiary Cushing's syndrome) : diffuse
hyperpigmentation
(20%)
(14%, expecially from hypophysary causes)
incretion precedes hypercortisolemia (> 7-8 mg/dL
at 12 p.m.; difference < 50% between morning and bedtime values)]pl]pl
(FUC) + 17-OH-cortisol]urine
:
challenge test (1 mg/kg i.v.; samples since
-30 to +120 minutes every 30 minutes) : paraneoplastic secondary and tertiary
Cushing's syndromes don't respond with an ACTH peak
challenge test (10 mg i.v.; samples for ACTH
and cortisol since -30 to +90 minutes, every 15 minutes) is positive only
in Cushing disease
test (inhibitor of the enzyme steroid 11b-hydroxylase)
: plasma 11-deoxycortisol or urinary 17-hydroxycorticosteroids are measured
after the administration of metyrapone; levels are increased in patients
with Cushing's disease but not in patients with ectopic ACTH syndrome.
(onset before age 20; multifocal in 20%; not associated with other endocrinopathies,
clinically malignant in > 50%)
(> 20%; 100% in extraadrenal pheochromocytomas) and adrenalin
(< 80%; 100% in MEN) =>
(15-20% are normotensive; severe and occasionally malignant (5-10%); 1%
of all hypertension in pediatric age and 0.05-0.1% in adulthood) => vertigo
and hypertensive retinopathy, cardiac or noncardiac acute
pulmonary edema,
saralasine, glucagon)
(imipramine, desimipramine)
due to down-regulation of vascular a-AR and
vasoconstriction-induced hypovolemia. 71% occur in previously hypertensive
patients, while 29% occur in normotensive patients.
and mild weight loss
=> acute renal
failure (ARF)
(57%,
supraventricular arrhythmias, and ventricular extrasystoles
(palpitations : 64%), angina
pectoris
and AMI(myocytolysis)
due to increased O2 consumption and coronary spasm, aspecific
alterations of ST tract and T wave, raised U waves, left ventricular overcharge,
left or right bundle branch block => congestive or hypertrophic (eccentric
or concentric) myocardiopathy (30%)
(80%)
(15-20%) => abdominal
pain
and nausea and vomiting
=> unexplained orthostatic
systemic arterial hypotension
or shock during surgery or trauma (also due to hypovolemia)
=> hypercalcemia
(20%)
=> true
erythrocytosis
(sometimes just relative erythrocytosis due to hypovolemia)
=> secondary Cushing's syndrome
=> fever and increased ESR.
| sensitivity | specificity | |
[total catecholamines]urine, 24h, beginning
collection during hypertensive crisis > 250 mg/die or > 1480 nmol/die
|
85-100% | 72-99% |
[metanephrine]urine, 24h, beginning collection
during hypertensive crisis > 1.3 mg/die or > 7 mmol/die
|
97-100% | 84-100% |
| [vanilmandelic
acid (VMA)]urine,
24h, beginning collection during hypertensive crisis > 7 mg/die or
> 35 mmol/die or = 500 - 3,500 mg/hr (normally
240 +/- 120 mg/hr) |
50-75% | 83-88% |
hypercatecholaminemia (66%) : increased [catecholamines]plasma,
during hypertensive crisis (t1/2 = 2-3' !)
|
75-85% | 75-98% |
| [metanephrine]plasma | 88-100 | 75-88 |
| chromogranine A | 65-85% | 89-98% |
i.v.
=> if after 2' [noradrenaline + adrenaline]plasma > 1,500 pg/mL
or > 3-folds basal values. Sensitivity = 81; Specificity = 100% => if negative
you can exclude pheochromocytoma.,
flush, and a brief fall in blood pressure, but those with pheochromocytoma,
after a fall in blood pressure, experience a marked rise in blood pressure,
fear, excitability, etc.
p.o. => sampling after 2 and 3 hours => positive if [noradrenaline + adrenaline]plasma<
500 pg/mL or < 50% basal values. Sensitivity = 97%; specificity = 67%|
|
|
|
| CT |
|
|
| MRI
(hyperintensity in T2wi) |
|
|
| 131I-metaiodobenzylguanidine (MIBG) adrenal
scintigraphy
(only when CT gives doubtful results or multiple localization is suspected) |
|
|
| octreotide scintigraphy |
|
|
| 6-18F-dopamine or 11C-hydroxyephedrine PET |
,
lymph node metastases, liver
metastases,
brain
metastases,
and pulmonary
metastases.
(phenoxybenzamine 10 mg bid (increase by 10 mg/day up to 40-80 mg/day),
doxazosin or prazosin (1 mg q8h up to 8-12 mgday) and i.v. phentolamine
for 1-2 weeks before surgery to treat crises =>
(not before a-AR block as they could cause skeletal
muscular ischemia; atenolol 50-100 mg/day or propanolol 0.01-0.1 mg/kg/day)
to treat shunt and reflexed
tachycardia
(survival after 5 years > 95% and relapses < 10%)
(survival after 5 years < 50%).
(normally-sized adrenals are seen only in thin patients) => CT
(accuracy = 89%; if < 15 HU, 90% are benign, while when > 15 HU benign
or malignant) => MRI
or adrenal scintigraphy)
that is a pinealoma in which the pineal cells are not well differentiated,
compression of the optic chiasm, and hypopituitarism.)
and FSH)
and FSH)
or mixed gonadal dysgenesis)
or gonadoblastoma
=> masculinization)
or mixed gonadal dysgenesis))
in males, diffuse renal mesangial sclerosis
(congenital adrenal hypoplasia and hypogonadotropic hypogonadism)
or LH
deficiencyor
gonadoblastoma)
,
gynecomastia,
normal penis, male psychosexuality, decreased [testosterone]plasma,
increased [estradiol]plasma,
increased [FSH
and LH]plasma,
urine, short height, hypospadia
| Symptoms & signs \ Aetiology |
|
|
| hyalinization of seminiferous tubules |
|
|
| microorchidism
(hard testes) |
|
|
| azoospermia |
|
|
| decreased [testosterone]plasma |
|
|
| decreased face hairs |
|
|
| increased [FSH
and LH]plasma,
urine |
|
|
| decreased sexual function |
|
|
| gynecomastia |
|
|
| decreased axillary hairs |
|
|
| micropenis |
|
|
| increased [estradiol]plasma
due to increased extragonadal aromatization |
is 20-60-folds higher than in normal males. There is an association with
germ cell tumorsref
and childhood leukemia
may worsen gynecomastia
by increasing substrate for extragonadal aromatization; fertility via IVF
defects
mutations, causing it to be misrouted so that it can never perform its
binding function
or FSH
or both may be deficient
,
a secreted protein that suppresses male sexual differentiation, is thought
to repress the biosynthesis of gonadal androgen in female mammals : WNT4
appears to be important in the development and maintenance of the female
phenotype in women, by means of the regulation of müllerian-duct formation
and control of ovarian steroidogenesisref.
=> no conversion of testosterone
into DHT
in peripheral androgen-sensitive tissues => Wolffian ducts develop but
urogenital sinus and external genitalia do not. Severe pseudovaginal
hypospadia,
closed-end pseudovagina opening in urogenital sinus or urethra, and collecting
drainage of ejaculatory ducts. Female look with normal pubic and axillary
hairs, but without female breast development (as testosterone inhibits
LH,
no gynecomastia
occurs !). Lack of uterus and fallopian tubes. Variable masculinization
at puberty.]plasma
= 3.4-31 mIU / mL]plasma
= 6-34 mIU / mL]plasma
= 288-1556 ng / dL]plasma
= 8-20 ng / dL
not requiring 5a reduction
incretion => increased [LH]plasma => increased testicular testosterone
and estrogen incretion (only estrogens can exerct a partial negative feedback
on LH
incretion)
=> Wolffian ducts don't develop => external genitalia are females (normally
developed breast)occurs
in abdomen, along inguinal canal (simulating inguinal hernia) or in labia
majora. No spermatogenesis and feminizing puberty with primary
amenorrhea. Patients tend to be tall with female psychosexual development
,
male psychosexual development
and bilateral uterine tubes, a uterus, and an upper vagina. When a testis
descends the homolateral fallopian tube and tube maybe located in inguinal
canal (hernia uteri inguinalis) or scrotum. Vasa deferentes are
located in the uterine wall and this increased risk for sterility during
surgery to remove uterus or vagina
to prevent abortion
deficiency,
single kidney in pelvis), skeletal anomalies involving rachis, limbs or
ribs, wedge vertebrae, synostosis, Klippel-Feil
syndrome
(dexamethasone crosses placenta and is used to treat diagnosed fetuses)
suppress adrenal DOC syhnthesis (preventing hypertension and hypokaliemia)
and androgen synthesis (allowing normal gonadotropin incretion, testes
development and spermatogenesis). MR
agonists
are used in type III CAH with salt wasting or increased RPA.)
]plasma
< 10 ng/mL
5,000-10,000 IU 7 days at day 14)
50-250 mg/day for 5 days (repeated even for 6 months) works better in MAP-test+
females and suppress the negative estrogen feedback on hypothalamus. Effective
in 70-80% (40% undergo pregnancy, mostly in the first 3 cycles). Side effects
: hot flushes (10%), gastrointestinal disorders (6%), mastodynia
(2%), visual disorders (1.5%), OHSS if > 100 mg/day, multiple pregnancy
= 3-7%
and rLH
in hypogonadotropic hypogonadism.
infusion pump in hypothalamic hypogonadism (low risk of complications)
is administered when [estradiol]plasma > 1500 pg/mL and ovarian
echography shows 3-4 developed follicles) : ovarian
hyperstimulation syndrome (OHSS),
multiple pregnancy
/ endometriotic cysts,
diarrhea,
headache,
vertigo and fatigue; dyspareunia; molimen ([L. “effort”] a laborious
effort made for the performance of any normal body function, especially
that manifested by a variety of mild but unpleasant symptoms preceding
or accompanying the menstrual period)
;
side effects : dry throat)
(33%))refincretion)
(15-30%; accompanied to galactorrhoea
in 30-50%)
(deficiency of GH,
FSH,
...)
or climacterium praecox / early or premature menopause / premature ovarian
failure (POF) : premature failure of ovulation before age 40
and/or LH
(estroprogestins to prevent hypoestrogenism); GR
agonists
for autoimmune
oophoritis
,
SHBG,
CYP11A1,
insulin,
InsR,
Met196Arg polymorphism in exon 6 of TNFRSF1B,
enhanced peripheral 5a-reductase
activity, lower expression of TIMP-1
in follicular fluid, increased plasma PAI-1
levels, decreased HOXA10
mRNA in endometrial cells
(reduction of type I of skeletal muscle fibres which are sensitive to insulin,
and the increase of type II fibres which are resistant to insulin) except
than in techal and hilar ovarian cells => increased ghrelin
on steroidogenesis by granulosa cells via InsR and IGF-1R and downregulates
synthesis of SHBG, but this interaction may compromise further growth of
medium-sized antral follicles by generation of 'preovulatory' concentrations
of cAMP within the granulosa cell and thereby leading, prematurely, to
terminal differentiation of granulosa cells => hyperandrogenism
=>
levels
(with anticortisol effect) support the development of abdominal obesity
=> enhanced LH
secretion (approximately one LH pulse per hour), while FSH is typically
in the lower follicular range (reversed LH-to-FSH ratio > 2.5) even during
the luteal-follicular transition is critical for follicular development
=> absence of follicular dominance => arrested growth of antral follicles
(granulosa cells from anovulatory women with PCOS hypersecrete oestradiol
due to advanced maturation of medium-sized antral follicles) => anovulation,
the regulatory IIb-component of PKA, and hormone-sensitive
lipase (HSL)
and acanthosis
nigricans
(40%)
(association with valproate
?)
or PPARgagonists
(troglitazone), octretotide, a-glucosidase
inhibitors, chromium (III)
with ethinyl estradiol (EE)
as the estrogen component and as the progestin component
can decrease facial hair and acne and regulate the menstrual cycle
(flutamide 125-500 mg/day, associated with oral contraceptive as during
pregnancy could cause feminization of external genitalia in a male fetus)
(finasteride 5 mg/day, associated with oral contraceptive as during pregnancy
could cause feminization of external genitalia in a male fetus)
preparations, and possibly, GnRH antagonists
to prevent LH surges,
chemotherapy. Hematomas (12.5% in females, 33% in males). 0.01% (13% are
immigrated people who experience catch-up growth, 11.5% myelomeningocele,
10.5% hydrocephalus, 5% dysmorphic syndromes, 4.3% encephalopathies, 3.7%
neurofibromatosis)
and maturation of the gonads
in males
in Leydig cells, and patients usually have normal fertility as adults
in females
(< 10%)
=> menarche 1.2 +/- 0.8 years after discontinuation
|
|
|
|
| biological | taller than peers but may end up short | short stature but later should achieve normal height; osteoporosis |
| psychological | psychological effects positive in boys (higher self esteem), negative in girls (low self esteem) | low self esteem in boys; no major problems in girls |
| social | different from peers; treated as adolescent while still a child | treated by adults and peers as less mature than real age; difficulty in separating from parents and in getting work |
).
Lines were drawn largely based on mortality statistics from European and
American populations. Some research suggests that the cut-offs should be
higher for elderly populations and Asian populations don't fit into the
existing scale. There are mounting evidence that Asian populations have
a particularly high risk of type 2 diabetes, cardiovascular disease and
mortality from other causes at relatively low BMIs. That is thought to
be largely due to their higher proportion of body fat, often hoarded around
the waist, relative to other ethnic groups. For these populations, they
found that a BMI of 26-31 was high risk. The panel recommends that intermediate
'public health action points' be inserted at BMI values of 23.0, 27.5,
32.5 and 37.5. This would allow countries to use disease data on their
own population to decide on BMI targets. The combination of underweight
in children and overweight in adults, frequently coexisting in the same
family, is a relatively new phenomenon in developing countries undergoing
the nutrition transitionref
deficiency
deficiency (5% of severe obesity cases)
deficiciency
deficiency
deficiency (rare)
deficiency (rare)
: chromosomal abnormalities underlying the disease cause the highest ghrelin
levels ever measured in any humans
excess
under the control of the adipocyte-specific promoter FABP4
eat unlimited amounts of high-fat mouse chow, but consume slightly less
oxygen and have about 50% less body fat than normal mice on a low-fat diet.
And despite they produce half the normal amount of leptin, the insulin
sensitivity and glucose tolerance of transgenic mice on a high-fat diet
was better than that of normal mice on a low-fat diet : they show no signs
of diabetes or other metabolic disorders, which are common in animals with
too little fat. The mice have underdeveloped mammary glands, an inability
to generate body heat and skin that's twice as thick as normal.-/-
mice exhibit a profound increase in whole-body energy expenditure as determined
by 10°C increased core temperature and 30% increased whole-body oxygen
consumption. As a consequence, these mice displayed a 50% decrease in adiposity,
primarily due to a reduction in cell size despite a 30% increase in food
intake. These changes were accompanied by a significant increase in activity
(2- to 3-fold). In addition, c-Cbl-/- mice displayed a marked
improvement in whole-body insulin action, primarily due to changes in muscle
metabolism, making it more resistant to type II diabetes. They also have
increased protein levels of the insulin receptor (4-fold) and uncoupling
protein-3 (UCP-3)
(2-fold) in skeletal muscle and a significant increase in the phosphorylation
of AMPK and acetyl-CoA carboxylaseref.
and elevated ghrelin.
These differences in leptin and ghrelin are likely to increase appetite,
possibly explaining the increased BMI observed with short sleep duration.
In Western societies, where chronic sleep restriction is common and food
is widely available, changes in appetite regulatory hormones with sleep
curtailment may contribute to obesityref.
Habitual sleep duration below 7.7 h was associated with increased BMI,
similar to findings in other studies including childrenref1,
ref2,
adolescentsref,
and adultsref1,
ref2.
A significant association of sleep duration with leptin and ghrelin that
is independent of BMI, age, sex, sleep-disordered
breathing (SDB)
(a pathology associated with increased BMI), and other possible confounding
factors (analysis not shown for SDB and other confounders) has also been
reported. Short sleep duration was associated with decreased leptin and
increased ghrelin, changes that have also been observed in reaction to
food restriction and weight loss and are typically associated with increased
appetite. These hormone alterations may contribute to the BMI increase
that occurs with sleep curtailment. Previous studies have shown that both
acute sleep deprivationref
and chronic partial sleep deprivation (sleep restriction)ref
can cause a decrease in serum leptin concentrations. These studies, however,
were performed under highly controlled laboratory circumstances and results
validate the association of decreased leptin with decreased sleep time
in a large sample of adults under real-life conditions and, now, indicate
a role for ghrelin. Leptin deficiency increases appetite and produces obesityref1,
ref2.
Leptin administration suppresses food intake and reduces energy expenditureref1,
ref2.
Importantly, low leptin as observed with sleep loss has a greater impact
on appetite than high leptin levels, which are associated with leptin resistance,
as occurs with obesityref.
Levels of ghrelin, a potent stimulator of appetiteref1,
ref2,
ref3,
were higher in those with shorter sleep. Ghrelin levels are also positively
associated with hunger ratingsref,
but decrease with increased BMI. In one study, after 3 mo of dietary supervision,
a reduction in BMI of approximately 5% was associated with a 12% increase
in ghrelin and a 15% decrease in leptinref.
These changes, in participants of similar BMI to our sample and presumably
producing increased appetite, are comparable to those observed with sleep
loss of 2–3 h/night. With sleep loss, however, relatively high ghrelin
and low leptin levels are associated with increased BMI. These changes
can be hypothesized to play a contributory, rather than compensatory, role
in the development of overweight and obesity with sleep restriction. Hormone
measurements were all performed on a single fasted, morning sample and
may not reflect the 24-h profile. It is possible that participants with
shorter sleep woke up earlier and that hormone differences may be partially
related to circadian time. Leptin and ghrelin levels rise slightly during
the nightref,
and this could result in higher hormone levels in short sleepers. This
may be an issue for ghrelin, as levels increased with acute sleep restriction.
It is, however, unlikely to play a role in the leptin finding, since lower
levels were found with chronic but not acute sleep restriction. Additionally,
studies have shown a high correlation between morning, fasting leptin and
ghrelin levels and 24-h mean profileref1,
ref2.
Ghrelin and leptin changes were unaffected by morningness tendencies. The
fact that studies investigating the diurnal profile of these hormones found
similar hormonal changes over the entire 24-h period after experimental
sleep restriction also corroborates our resultsref.
The robustness of these findings and similar observations from smaller
controlled studiesref
also suggest that our statistically significant results are unlikely to
be a reflection of the number of analyses carried out. Animal studies have
suggested a link between sleep and metabolismref.
In rats, prolonged, complete sleep deprivation increased both food intake
and energy expenditure. The net effect was weight loss and, ultimately,
deathref.
Rats fed a high protein-to-calorie diet had accelerated weight loss, compared
to sleep-deprived rats fed calorie-augmented (fatty) diets. Food consumption
remained normal in sleep-deprived rats fed protein-rich diets, but increased
250% in rats fed calorie-rich diets. Preference for fatty foods has also
been reported anecdotally in sleep-deprived humans. Sleep deprivation may
thus increase not only appetite but also preference for lipid-rich, high-calorie
foods. Animal experiments that have found weight loss after prolonged sleep
deprivation have to be interpreted in the context of a stressful procedure
producing intense sleep debtref1,
ref2,
which may interfere with adequate food intake. From our study, we hypothesize
that the moderate chronic sleep debt associated with habitual short sleep
is associated with increased appetite and energy expenditure. In societies
where high-calorie food is freely available and consumption uncontrolled,
after milder chronic sleep restriction, the equation may be tipped towards
food intake for high-calorie food rather than expenditure, culminating
in obesity. Short sleepers may also have more time to overeat. Sleep loss
from a baseline of 7.7 h was associated with a dose-dependent increase
in BMI. This was the predominant effect in a population increasingly curtailing
sleepref.
Sleep > 7.7 h, however, was also associated with increased BMI. Patients
with SDB may spend a longer time in bed to compensate for fragmented sleep;
however, controlling for AHI did not change the curvilinear BMI–sleep association.
Another possibility is that in long sleepers, reduced energy expenditure
due to increased time in bed has a greater impact than reduced food intake.
In favor of this hypothesis, long sleepers exercise lessref.
The odds ratio of high levels of self-reported exercise (>7 h/wk), based
on a single survey question, decreased with increased sleep time, but controlling
for this variable also did not change our findings. Insulin resistance
with sleep deprivation has been reported in a laboratory study of young,
healthy volunteersref.
When controlling for BMI, we found no significant correlation between insulin,
glucose, or adiponectin levels and various measures of sleep duration.
Also, there was no significant correlation between QUICKI (or the homeostatic
model assessment HOMAref)
and sleep duration. This may be due to difficulties in detecting small
effects on glucose tolerance under less-controlled conditions of large
population studies.-resistance
and leptin-resistance
.
In vitro, human CRP directly inhibits the binding of leptin to its
receptors and blocks its ability to signal in cultured cells. In vivo,
infusion of human CRP into ob/ob mice blocked the effects of leptin upon
satiety and weight reduction. In mice that express a transgene encoding
human CRP, the actions of human leptin were completely blunted. Physiological
concentrations of leptin can stimulate expression of CRP in human primary
hepatocytes. Recently, human CRP has been correlated with increased adiposity
and plasma leptin. Thus, our results suggest a potential mechanism contributing
to leptin resistance, by which circulating CRP binds to leptin and attenuates
its physiological functionsref.
secretion => down-regulation of InsR,
inhibition of NO production by endothelial cells
=> insulin-resistance in skeletal muscle
=> increased hepatic synthesis of haptoglobin
and hexokinase, inhibition of NO production by endothelial cells
levels than people of normal weight, but production increases in people
who have lost weight through dieting. Many think that leptin's main role
is protecting against weight loss in times of deprivation rather than against
weight gain in times of plenty : when a person's fat stores shrink, so
does leptin incretion (in response, appetite increases while metabolism
decreases), but the converse does not happen (beyond a certain point, increased
leptin production does little to inhibit appetite or increase metabolism).
.
Previous research, however, had only found CRP to be produced in liver
tissue, although Drs. Yeh, Willerson and Paolo Calabro, MD, discovered
in 2003 that the protein also is manufactured in the walls of blood vessels.
But that didn't explain obesity's connection to high levels of CRP and
it also was not clear why CRP is higher in patients who have metabolic
disorders. So the research team decided to see whether fat cells themselves
could be stimulated by inflammatory cytokines or resistin
to produce CRP. To help find out, plastic surgery patients at M.D. Anderson
donated adipose tissue that would have been discarded, and the research
team then isolated fat cells, cultured them and stimulated them under a
number of different conditions. The cells produced cytokines that resulted
in inflammation and that this process triggered production of high levels
of CRP. Resistin, produced itself by fat cells, could stimulate production
of CRP. Patients with metabolic syndromes have higher levels of CRPs, as
well as a higher risk of developing heart disease and stroke, but no one
understands why that is. Aspirin, statins and troglitazone can reduce CRP
levels in cultured fat cells that were producing high levels of CRPsref
,
particularly among participants older than age 50 years, for use > 90 days,
or for diets < 20 g/d of carbohydrates. Among the published studies,
participant weight loss while using low-carbohydrate diets was principally
associated with decreased caloric intake and increased diet duration but
not with reduced carbohydrate contentref.
Indeed, a low carbohydrate diet appears to help patients lose more weight
than other diets up until the 6-month mark. But by 1 year, the difference
between low-carbohydrate and low fat diets disappears. Doctors should help
patients choose a diet that helps them reduce portion size and that includes
a healthy eating lifestyle they can stick to. Preliminary research on new
internet-based weight loss programs suggests the technology may be a useful
tool for some patients. Overweight patients who have access to online weight
loss resources lost on average 1.6 kg over 6 months. Subjects who also
submitted calorie and exercise information to an online bulletin board
and received weekly e-mail counseling and feedback lost considerably more,
or 4.1 kg over the same time periodref1,
ref2.
(atorvastatin 10 mg daily is safe and efficacious in reducing the risk
of first cardiovascular disease events (acute coronary heart disease events,
coronary revascularisation, or stroke) by 33% (48% for stroke) and death
rate by 27% in patients with type 2 diabetes without high LDL-cholesterol
(orlistat) interfere with fatty acid hydrolysis and uptake by the gut,
but produces only modest weight loss and may have unwelcome side effects
allows the body to establish a new, svelter set point
(rimonabant : these receptors support "the munchies", the food-craving
effects of marijuana)ref1,
ref2,
ref3,
ref4.
Recently reported phase III clinical trails show that 2-year treatment
with rimonabant reduced weight, reduced abdominal fat, and improved cardiovascular
risk factorsref1,
ref2.
The first in a new class of pharmaceutical agents, rimonabant is promising
as an anti-obesity therapy, but its clinical value compared with that of
existing therapies must await results of future investigations..
Exendin-4 is a 39–amino acid peptide originally isolated from the saliva
of the Gila Monster that resists degradation by DPP-IV while retaining
GLP-1–like effects on glucose metabolism and food intakeref.
Activity of GLP-1 is prolonged by conjugation to albumin (liraglutide)
or inhibition of DPP-IV
causes weight loss in diabetic cohorts, but its efficacy in the general
population is uncertain
or alternatively activation of PPAR,
as suggested by studies of OEA action, will await the results of clinical
trials.
=> lipolysis
replacement is effective in the rare cases of human leptin deficiencyref,
but leptin resistance limits its utility in ordinary obesity. Increasing
leptin action by promoting its transport into the brain or by antagonizing
inhibitors of leptin signaling pathways might be effective, but the relevant
pharmaceutical targets have proven challenging
acts through leptin-like pathways in the hypothalamus. Although effective
in animal models, human obesity trials were limited by neutralizing antibodiesref.
blocking antibody not only reduces angiogenesis and tissue growth but also
inhibits preadipocyte differentiation : part of this inhibition stems from
the paracrine interaction between endothelial cells and preadipocytes and
that VEGF-VEGFR2 signaling in endothelial cells, but not preadipocytes,
mediates this process.
(sibutramine) produce only modest weight loss and may have unwelcome side
effects
patients).
,
hypothalamic center manipulation, liposuction,
balloon
insertion, unbanded
gastric
partitioning,
vagotomy,
gastrogastrostomy,
horizontal gastroplasty,
gastric wrap, gastroclip, and any variety of gastroplasty without a reinforced
stoma, intestinal bypass, duodenal bypass and biliointestinal bypassref.
All bariatric surgical procedures have been performed as open and laparoscopic
procedures.
(fig.A)
(fig.B)
(70% in USA) (fig.D)
(fig.C),
impaired immunocompetence, vitamin deficiency, expecially thiamine with
neuropathy/encephalopathy, hair loss, gallstone formation; anemia, iron
and vitamin B12 deficiency, dumping for gastric bypass
|
|
|
|
| gastric banding (lap-band) |
|
|
| vertical banded gastroplasty
/ silastic ring gastroplasty |
|
|
| gastric bypass (Roux-en-Y
anastomosis) |
|
|
| partial pancreaticobiliary
bypass / biliopancreatic diversion (with/without duodenal switch) |
|
|
and
25% by pulmonary
embolism.
Laparoscopic gastric bypass is associated with fewer wound complications,
less postoperative pain, less blood loss, and shorter hospital stays and
convalescence periods than does the open procedure; however, late anastomotic
strictures occur more frequently after the laparoscopic than after the
open procedure.
in premenopausal women
in postmenopausal women-resistance
=> hyperinsulinemia => type II diabetes mellitus
=>.
Overweight children (age 5-23) are also at risk of heart attacks : the
greater the BMI, the greater the incidence and severity of left ventricular
mass or thickness.
=> gout
=> asthma
& hypercapnia => Pickwick
disease / pickwickian or obesity-hypoventilation syndrome [from the
description of Joe, the fat boy in Charles Dickens' Pickwick Papers]
: a complex of obesity, somnolence, snoring, hypoventilation, and erythrocytosis
incretion
(the issue is whether the tumor booster is insulin resistance or hyperinsulinemia)
in postmenopausal women
=> endometrial
carcinoma
(controversial association; increases the risk for higher grade prostate
cancer and higher recurrence rates after radical prostatectomy)
(demented women in their 80's are more likely to have an average BMI of
28 at 70 years of age : each additional point raises the risk of AD by
36%). Patients with diabetes can experience anything from short-term memory
loss to Alzheimer's-like symptoms and leptin is the key. An increasing
number of reports show that abnormal levels of leptin can significantly
alter brain cell function : intrahippocampal injection of leptin increases
long-term
potentiation,
which provides a cellular basis for memory and learningref.
From studies of individual neurons isolated in a dish, the amount of leptin
produced by normal food intake in rats boosts long-term potentiation by
3 times. But increasing the dose 100-fold abolishes this effect. So could
abnormally high leptin levels in children with weight problems be hindering
their ability to perform in school? Given the increasing incidence of obesity
in the young, researchers should investigate the potential link. Understanding
the role of leptin secretion in metabolic disorders will help explain why
these illnesses increase the risk of impaired cognitive function. It may
tell us about what goes wrong in these diseases, which could serve as targets
for treatments.TABLE 3. Behavioral Strategies to Improve Weight Management
Strategy Description
Self-monitoring Record “what, where, and when” of eating and physical
activity to increase patients’ awareness of their own behavior.
Goal setting Set specific short-term targets in eating and exercise
habits to achieve incremental improvements.
Stimulus control Identify triggers associated with poor eating and
physical activity behaviors, and design strategies to break link.
Cognitive restructuring Change perceptions, thoughts, or beliefs undermining
weight control efforts, and help patients develop realistic expectations
about weight loss.
Problem solving Analyze situations preventing maintenance of a healthier
lifestyle and identify possible solutions to problems; maintain philosophy
that planning, not willpower, is key to weight management.
Relapse prevention Develop skills based on premise that lapses in weight
control behavior can be anticipated in certain situations (eg, travel,
celebrations, bad mood).
Stress management
Decrease psychological stress to prevent dysfunctional eating.
Contingency management Use rewards (tangible or verbal) to increase
performance of specific behaviors or when specified goals reached.
Social support Use assistance from family members and friends in modifying
lifestyle behaviors.
Ongoing contact Maintain visits, telephone calls, or Internet communication
with physician and office staff or other healthcare professionals to promote
adherence with recommended lifestyle changes.
taken, and (3) weight scales on which to measure changes in body weight.
Self-monitoring increases patients’ awareness of their behaviors, generates
records that can be reviewed by healthcare professionals, and provides
targets for intervention. In clinical practice, formal behavior therapy
can be provided through group sessions or individual meetings with a healthcare
professional who is skilled in the delivery of behavioral techniques used
to modify lifestyle habits.155,157 If possible, contact should be regular,
preferably once every 1 to 2 weeks, during the initial 6-month phase of
a treatment program.155 Comprehensive group behavior therapy, in conjunction
with diet and physical activity, usually results in an 9% body weight
loss within 26 weeks of treatment (0.5kg/week).157 Patients usually regain
33% of their lost weight in the year after ending behavior therapy, but
most still maintain a weight loss of 5% at the end of 1 year.Providing
ongoing contact by scheduled visits, telephone calls, food evaluation and
exercise diaries, and Internet communication can enhance long-term adherence
and helps prevent weight regain.158,159 In addition, Internet-based treatment
programs for weight loss160,161 and structured commercial programs such
as Weight Watchers162 can augment the professional guidance provided by
the physician.
Pharmacotherapy
Pharmacotherapy can help selected patients lose weight. The approved
indications for drug therapy for obesity are a BMI 30 kg/m2 or a BMI between
27 and 29.9 kg/m2 in conjunctionwith an obesity-related medical complication
in patients with no contraindications for therapy. Effective pharmacotherapy
for obesity is likely to require long-term, if not lifelong, treatment
because patients who respond to drug therapy usually regain weight when
the therapy is stopped. The expected length of drug treatment of obese
patients who respond to therapy makes it important to carefully consider
the long-term risks of being obese, the beneficial effects of pharmacotherapy
on body weight and obesity-associated diseases, and the side effects and
costs of treatment before beginning therapy. In addition, pharmacotherapy
alone is not as effective as pharmacotherapy given in conjunction with
a
comprehensive weight-management program.163 Therefore, patients given
drug treatment without the other standard approaches to weight management,
including behavior modification, diet education, and activity counseling,
are exposed to all of the risks of drug treatment without all of the medical
benefits. Drug therapy adds a level of complexity to the treatment of obesity.
The patient with medication prescribed for obesity may have comorbidities
that already require pharmacotherapy, thereby increasing the likelihood
of nonadherence.164 Strategies to enhance medication compliance include
regularly assessing adherence and response to therapy, counseling about
and reinforcing the importance of adherence, simplifying
the treatment regimen, assisting the patient in reducing barriers to
adherence, providing reminders and cues to facilitate improved adherence,
and enlisting support when needed.159,164 –166 In addition, weight loss
drugs usually are not covered by health insurance or health care plans,
so a
considerable economic incentive exists for the obese patient to discontinue
taking these medications. Medications for the treatment of obesity available
in the United States are listed in Table 4. Effective therapy for obesity
usually requires chronic intervention; however, only 2 drugs, sibutramine
and orlistat, are approved for long-term use.
Sibutramine
Pharmacology : sibutramine is a -phenethylamine derivative that blocksthe
reuptake of norepinephrine, sibutramine, and, to a lesser degree, dopamine.
Sibutramine decreases food intake by producing early satiety during feeding
and by delaying initiation of the next meal. Although sibutramine has no
potential for abuse, it is classified as a Schedule IV drug. Sibutramine
is available in 5-, 10-, and 15-mg doses; 10 mg/d as a single daily dose
is the recommended starting level, with titration up or down based on response.
Doses 15 mg/d are not recommended.
Clinical Efficacy
In a 1-year RCT, subjects treated with sibutramine lost 7% of their
initial body weight and those treated with placebo lost 2%. Of the subjects
treated with sibutramine or placebo, 57% and 20%, respectively, lost 5%
of their initial body weight;34% and 7%, respectively, lost 10% of their
initial body weight.167 Weight loss with intermittent sibutramine therapy
(15 mg/d given during weeks 1 through 12, 19 through 30, and 37 through
48, and placebo given during the two 6-week periods when sibutramine was
withdrawn) was equivalent to weight loss with continuous sibutramine therapy
(15 mg/d).168 Sibutramine therapy also has been shown to maintain weight
loss for 12 to 18 months in subjects who initially lost weight by eating
a VLCD163 or who successfully lost weight after 6 months of sibutramine
treatment.170 The use of sibutramine in obese patients with either medication-controlled
hypertension171 or type 2 diabetes mellitus172causes greater weight loss
than with placebo therapy, but the overall weight loss is less than that
observed in studies conducted in subjects who do not have comorbid disease.
Weight loss with sibutramine therapy is more effective
when combined with behavior and dietary therapies. In a 1-year RCT,
weight loss with sibutramine therapy alone was 5 kg, with sibutramine
therapy plus behavior modification was 10 kg, and with sibutramine therapy
plus behavior modification and a structured meal plan was 15 kg.173
Side Effects and Safety
The most common side effects of sibutramine are dry mouth, constipation,
and insomnia. Sibutramine increases
TABLE 4. Drugs Approved by FDA for Treating Obesity
Generic Name
DEA
Schedule
Orlistat None
Sibutramine hydrochloride IV
Phentermine IV
Diethylpropion hydrochloride IV
Benzphetamine hydrochloride III
Phendimetrazine tartrate III
DEA indicates Drug Enforcement Agency.
2958 Circulation November 2, 2004
heart rate (a dose of 10 to 15 mg/d causes an increase in heart rate
of 4 to 6 bpm) usually in the first few weeks of treatment and lasts as
long as the drug is taken. Sibutramine also causes a dose-related increase
in blood pressure (a dose of 10 to 15 mg/d causes an average increase in
systolic and diastolic blood pressure of 2 to 4 mm Hg) and can prevent
weight loss–induced decrease in blood pressure.155 Therefore, careful monitoring
is needed when combining sibutramine with other drugs that can increase
blood pressure. Sibutramine should not be used in patients who have uncontrolled
hypertension, a history of coronary artery disease, congestive heart failure,
cardiac arrhythmias, or stroke, or who are being treated with
monoamine oxidase inhibitors or selective serotonin reuptake inhibitors.
CVD Risk Factors
The composite data from RCTs demonstrate that sibutramine causes improvements
in serum triglyceride, total cholesterol, LDL-C, and HDL-C concentrations
that are directly related to the magnitude of the weight loss. However,
sibutramine therapy decreases or eliminates weight loss–
induced benefits on blood pressure.
Orlistat
Pharmacology
Orlistat blocks the digestion and absorption of dietary fat by binding
to intestinal lipases.174 The percentage of fat that is malabsorbed is
related to drug dose in a curvilinear fashion.175 Near-maximal fat malabsorption
occurs at a dose of 120 mg when given with a meal, which causes malabsorption
of 30% of fat ingested from a meal that contains 30of energy as fat.
Less than 1% of ingested orlistat is absorbed;
therefore, it has no effect on systemic lipases.176
Clinical Efficacy
The effects of orlistat on body weight and CHD risk factors have been
evaluated in a large number of RCTs. The data from most studies demonstrate
that at 1 year, subjects who were randomized to orlistat therapy (120 mg
tid) lost 8% to10% of their initial body weight and those randomized to
placebo therapy lost 4% to 6%.177–181 Approximately 33%more patients
treated with orlistat lost 5% of their bodyweight than did those treated
with placebo; 2 times as manypatients treated with orlistat lost 10%
of their body weightas did those treated with placebo. Ending orlistat
therapy
results in weight regain,177,180 and starting orlistat therapy after
successful diet-induced weight loss helps maintain body weight.182 In subjects
with obesity and type 2 diabetes mellitus who are treated with sulfonylureas,183
metformin,184 or insulin,185 the percentage who achieve a 5% or 10% reduction
in body weight is 2 to 3 times higher in those receiving orlistat plus
dietary therapy than it is in those receiving dietary therapy alone. The
overall weight loss effect of orlistat therapy in patients with diabetes
is less than that reported in previous studies of obese patients who did
not
have diabetes, however. Recently, the results of a 4-year RCT were
reported.28 The lowest body weight was achieved during the first year and
was greater in the orlistat-treated group (11% weight loss) than in
the placebo-treated group (6% weight loss). Subjects regained weight during
the remainder of the trial; orlistattreated subjects had lost 6.9% of their
initial body weight and placebo-treated subjects had lost 4.1% at the end
of 4 years. Orlistat therapy also decreased the cumulative 4-year incidence
of type 2 diabetes mellitus by 37%. Side Effects and Safety About 70% to
80% of subjects treated with orlistat experienced 1 gastrointestinal event
as compared with50% to 60% of those treated with placebo. Gastrointestinal
events usually occurred early (within the first 4 weeks), were of mild
or moderate intensity, were usually limited to 1 or 2 episodes, and resolved
despite continued orlistat treatment. Approximately 4% of subjects treated
with orlistat and 1% of subjects treated with placebo withdrew from the
studies because of gastrointestinal complaints. During treatment, small
decreases in plasma fat-soluble vitamins, particularly vitamins A, D, and
E, can
occur, although plasma concentrations almost always remain within the
reference range. A few patients, however, may experience decreases in plasma
vitamin concentrations to below the reference range. Because it is impossible
to determine a priori which patients will need vitamin supplements, it
is recommended that all patients who are treated with orlistat be given
a daily multivitamin supplement that is taken at a time when orlistat is
not being
ingested. Orlistat can have medically significant effects on the absorption
of lipophilic medications if both drugs are taken simultaneously. Subtherapeutic
plasma cyclosporin levels that occurred in organ transplant recipients
after they began orlistat therapy for obesity have been reported.186–189
Therefore, orlistat should not be taken for 2 hours before or afterthe
ingestion of lipophilic drugs, and plasma drug concentrations should be
followed to ensure appropriate dosing. Orlistat does not affect the absorption
of selected drugs with a narrow therapeutic index (warfarin, digoxin, phenytoin)
and selected drugs that are likely to be taken concomitantly with orlistat
(glyburide, oral contraceptives, furosemide, captopril, nifedipine, and
atenolol).189CVD Risk Factors Because of its weight loss effects, orlistat
therapy improves all major cardiovascular disease risk factors such
as blood pressure and insulin sensitivity. Moreover, data from several
RCTs suggest that orlistat has a beneficial effect on serum cholesterol
concentrations that is independent of weight loss alone. Subjects given
orlistat had a greater reduction in serum LDL-C concentrations than
those given placebo, even after adjusting for percentage of weight
loss.178,179 The mechanism responsible for this additional lipid-lowering
effect may be related to the effect of orlistat in blocking both dietary
cholesterol and triglyceride absorption.190 In contrast, orlistat is not
as effective in lowering serum triglyceride concentrations, presumably
because it increases the proportion of absorbed energy derived from carbohydrate,
which tends to increase serum triglycerides.191
Phentermine
Phentermine is a -phenethylamine derivative that stimulatesthe release
of norepinephrine and dopamine from nerve terminals. Although phentermine
is not approved by the Food and Drug Administration (FDA) for long-term
use, it is the most commonly prescribed anorexiant medication in the United
States,192 presumably because it is less expensive than sibutramine. Phentermine
was approved by the FDA 30 years ago, when the criteria needed for approval
were less rigorous than they are currently. Therefore, fewer studies have
evaluated the efficacy and safety Klein et al Clinical Implications of
Obesity 2959 of phentermine therapy than have evaluated sibutramine and
orlistat. Only one long-term (36 weeks) RCT evaluated the effect of phentermine
therapy on body weight.193 In that study, obese women were randomized to
dietary therapy and treatment with daily phentermine, daily phentermine
every other month alternating with daily placebo every other month, or
daily placebo. Of the 108 enrolled subjects, approximately two thirds completed
the study; among those who completed the study, the groups that received
either continuous or intermittent phentermine therapy lost 13% of their
initial weight as compared with a 5% weight loss in the placebo group.
Side Effects and Safety
The most common side effects of phentermine are dry mouth, insomnia,
and constipation. Although all sympathomimetic agents can increase blood
pressure and heart rate, these side effects are uncommon when weight loss
is adequate.
Herbal Products
Several different dietary supplements and herbal preparations have
been used to treat obesity, including chromium picolinate, garcinia cambogia
as a source of hydroxycitrate, chitosan that is claimed to reduce fat absorption,
phenylephrine from Citrus aurantium (bitter orange), and ma huang as a
source of ephedra alkaloids with or without guarana as a source of
caffeine. In general, few RCTs have evaluated the clinical efficacy of
these agents, and most of the RCTs that have been done were of substandard
quality194–196; however, data from several RCTs demonstrated greater weight
loss in subjects given herbal products that contain ephedra than in those
given placebo.197,198 Nonetheless, the sale of ephedra in over-the-counter
products was recently banned by the FDA because of concerns about serious
adverse cardiovascular effects.
Clinical Evaluation
The physician’s office should be an environment that is sensitive to
the needs of obese patients. The waiting room should contain chairs without
arms, large gowns and large blood pressure cuffs should be available, and
a scale that can weigh patients who weigh 300 lb should be available and
located in a private area. The initial assessment should include an
appropriate history, physical examination, and laboratory tests.
History
In addition to a standard medical interview, a patient’s history should
include an assessment of (1) weight history (highest and lowest adult body
weight, previous weight loss attempts, weight pattern, and potential triggers
and social and environmental factors that contributed to weight gain),
(2) dietary history, including an assessment of types and timing of meals
and snacks and an attempt to identify possible triggers that result in
excessive energy intake, (3) physical activity and function (daily and
exercise activities, physical limitations, effect of obesity on physical
ifestyle), (4) obesity-related health risk (age of onset and duration of
obesity, family history of obesity and obesity-related medical complications,
current obesity-related disease),
(5) possible psychiatric illnesses, such as binge eating disorder and
depression, that may require therapy before a weight loss program is initiated,
and (6) ability to lose weight (desire to lose weight, weight loss goals
and expectations, limitations for achieving weight loss, including medications
and illnesses, lifestyle and work patterns, financial resources, and special
needs).
Physical Examination
The patient’s BMI and waist circumference should be determined. BMI
is generally correlated with percentage of body fat in a curvilinear fashion.208
Some people with an “obese” BMI, who have a normal amount of body fat and
a large muscle mass, are not at increased risk for CHD, whereas people
with a “normal” BMI, who have excessive body fat and small muscle mass,
are at increased risk. Waist circumference, measured halfway between the
lastrib and the iliac crest, correlates with abdominal fat mass.5 Table
6 provides a classification of risk based on BMI. A waist circumference
of 88 cm (35 in) for women and102 cm (40 in) for men is associated with
an increasedrisk of metabolic diseases and CHD.1 Additional assessments
should include measuring blood pressure with a large cuff and searching
for physical signs of right or left ventricular dysfunction, congestive
heart failure, and pulmonary disease. An electronic stethoscope can increase
a physician’s ability to detect cardiac abnormalities in patients
who are extremely obese.
Laboratory Tests
An ECG is needed to check for evidence of CHD and to obtain a baseline
tracing for future comparisons. Standard blood tests should be performed
to search for CHD risk factors, including prediabetes (impaired fasting
blood glucose or impaired glucose tolerance), dyslipidemia (increased triglycerides,
low HDL-C, and increased LDL-C), and the metabolic syndrome. Additional
studies may be needed to further evaluate specific clinical suspicions
based on the history and physical examination, such as
TABLE 6. Weight Classification by BMI*
Obesity Class BMI, kg/m2 Disease Risk
Underweight 18.5 Increased
Normal 18.5–24.9 Normal
Overweight 25.0–29.9 Increased
Obesity I 30.0–34.9 High
II 35.0–39.9 Very high
Extreme Obesity III 40.0 Extremely high
*Data from Obes Res.1
Additional adiposity-related risk factors: waist circumference 40
(in men)
and 35 (in women); weight gain of 5 kg since age 18–20 y.
TABLE 7. Weight Loss Treatment Guidelines*
BMI Category, kg/m2
Treatment 25.0 –26.9 27.0 –29.9 30.0 –34.9 35.0 –39.9 40.0
Diet, physical activity, behavior therapy, or all 3 Yes Yes Yes Yes
Yes
Pharmacotherapy† With obesity-related disease Yes Yes Yes
Surgery‡ With obesity-related disease Yes
*Data from Obes Res.1
†Pharmacotherapy should be considered only in patients who are not
able to achieve adequate weight loss by available conventional lifestyle
modifications and
who have no absolute contraindications for drug therapy.
‡Bariatric surgery should be considered only in patients who are unable
to lose weight with available conventional therapy and who have no absolute
contraindications for surgery.
Klein et al Clinical Implications of Obesity 2961
sleep studies to diagnose OHS or OSA and an exercise treadmill test
or electron beam computerized tomography scanning or both to evaluate CHD
risk. The comparative value of exercise tolerance testing and electron
beam computerized tomography in obese subjects has not been determined.
Exercise treadmill testing is not recommended for patients without cardiac
symptoms, and neither exercise treadmill testing nor electron beam computerized
tomography scanning should be performed in patients who are at low risk
for CHD, based on clinical judgment or Framingham risk score.209 –211
Therapeutic Options
Appropriate management requires identifying patients whoneed treatment,
developing a realistic treatment plan, and implementing a defined treatment
strategy that can be modified as needed during long-term surveillance.
The Practical Guide to the Identification, Evaluation, and Treatment of
Overweight and Obesity in Adults was developed by the North American Association
for the Study of Obesity in conjunction with the National Heart,
Lung, and Blood Institute.212 Suggested guidelines from the guide for
selecting among different weight loss treatment options, based on disease
risk, are shown in Table 7. A typical clinical consultation involves a
physician’s giving advice without adequate consideration of the patient’s
priorities, motivation, or confidence in undertaking change.213 In contrast,
obesity therapy should involve “patient-centered counseling,” which encourages
patients to set goals and express their own ideas for therapy, with input
from the healthcare professional. The treatment plan also must take into
account the patient’s readiness for therapy and the patient’s ability to
comply with the proposed treatment plan. Realistic goals should be established
and frequent follow-up visits should be scheduled to monitor progress,
modify the treatment plan as needed, and provide encouragement. Effective
therapy requires a longterm structured approach with continued support
from the physician and other caregivers, particularly during periods of
patient recidivism and weight regain. Reducing energy intake is the cornerstone
of weight management therapy. Providing appropriate nutrition counseling
and the behavior modification therapy needed to implement dietary changes
within the setting of a busy outpatient practice is difficult if not impossible
for most physicians because they do not have the time or expertise to provide
this kind of care. Therefore, referral to a reputable weight loss program
or experienced dietitian should be considered, if these resources are available.
Additional therapy with weight loss medications or bariatric surgery can
be useful in properly selected patientsref.
Prevention : in a typical US housing estate,
the only way to reach workplaces, shops and schools is by car. Many streets
lack pavements, and cycle paths are virtually unheard of. To really fight
the flab, US public-health officials are now realizing that they may have
to change the entire layout of towns. The suburban mansion and sport-utility
vehicle (SUV) may fulfil the American dream, they say, but it is taking
an unforeseen toll on health. One study from last year compared the health
of people living in foot-friendly city areas with that of those dwelling
in sprawling, car-dependent suburbs. People's average weight and level
of hypertension rose along with the degree of sprawl. And although purpose-built
recreation centres and parks are well intentioned, experts say that only
a fraction of people make the effort to use them. One seemingly obvious
way to eliminate people's dependence on cars is to design communities in
which shops, schools and workplaces are within walking distance of homes.
One community called Southern Village
in North Carolina, for example, is built to be more like a traditional
neighbourhood with pavements, trails and parks aplenty. Such solutions
may seem intuitive, but researchers point out that there is no evidence
that living in such communities actually stops people piling on the pounds.
Concerns about traffic, crime or other social factors can prevent people
from venturing outdoors. At present, for instance, many US local authorities
have zoning regulations that were originally designed to get people out
of polluted or unsafe cities into the countryside, and these prohibit the
construction of houses and businesses next door to one another. Some commentators
point out that the house-building, motor and road industries are not used
to considering public health in their plans, and are somewhat slow to change.
More studies showing the effectiveness of exercise-friendly communities
will help to convince policy-makers and industries of the importance of
health. The health institute has $3 million of funding for such research
next year and hopes to offer more in future years
Prognosis : yearly, around a quarter of
a million deaths in Europe and more than 2.5 million deaths worldwide are
weight-related, with cardiovascular disease as the leading cause
Web resources
injection sites caused by the lipogenic effect of insulin,
and membranoproliferative
glomerulonephritis
and diabetes mellitus
(90%) => activation of alternative pathway of complement cascade => cytolysis
of adipocytes expressing factor
D / adipsin
,
autoimmune diseases (systemic
lupus erythematosus,
autoimmune
gastritis,
juvenile
dermatomyositis,
rheumatoid
arthritis,
celiac
disease
with dermatitis
herpetiformis,
Sjogren's
syndrome,
giant
cell arteritis,
leukocytoclastic
vasculitis)
;
stavudine-based regimens have a higher cumulative prevalence of lipoatrophy
than regimens based on zidovudine, abacavir, or tenofovir. Regimens based
on nelfinavir are associated with more rapid fat loss than efavirenz. In
general, thymidine-based nucleoside analogues have been most associated
with lipoatrophy and protease inhibitor drugs most associated with the
metabolic syndrome.
and diabetes mellitus
has led to some success with managing the metabolic manifestations and
local fat accumulations
or lipectomy,
b3-AR,
fatty
acid binding protein 2 (FABP2), IGF-1R,
IRS-1,
HSL,
leptin,
PPARg,
and CGL1
/ granzyme B
,
umbilical hernia or raised umbilicus, liver steatosis, splenomegaly and
nephromegaly (abdominal protuberances), hypertrophic cardiomyopathy, acromegaloid
habitus, hyperhidrosis,
and hirsutism.
Fatty tissue still remains at hand palsm and foot soles, orbits, scalp,
perineum, iuxtaarticular and epidural regions. Pancreas amyloidosis
and extreme insulin resistance => diabetes mellitus,
hypertriglyceridemia
,
acute
pancreatitis,
diabetic
nephropathy,
measles
virus,
Bordetella
pertussis,
pneumonia,
osteomyelitis,
mumps
virus,
HHV-4
/ EBV,
hepatitis
,
juvenile
rheumatoid arthritis,
Hashimoto's
disease,
autoimmune
hemolytic anemia,
autoimmune
hepatitis,
vitiligo)
with anti-adipocyte antibodies
=> mild hirsutism,
acanthosis
nigricans
(33%), liver steatosis,
diabetes
mellitus. Superficial muscles and veins are accentuated.
increase subcutaneous fat mass, but rosiglitazone, at the maximum dose
of 8 mg a day, does not improve fat mass in HIV lipoatrophyref.
on adipose tissue mass are not reported. Both treatments improve metabolic
variables and reduce the size of the liver. Additionally, leptin reduces
hepatic and intramyocellular lipid content.
(also peripheral neuropathy,
myopathy,
cerebellar
ataxia,myoclonus
and hearing loss)
exposure (46%; excessively covered babies (53%), milk lactation without
chemoprophylaxis (51% : winter pregnancies are those at highest risk),
expecially in Muslim societies, adoptees or immigrated from orphanotrophy)
: sunlight radiation is reflexed by sand and sea, so seashore exposure
may help
(phenobarbital, diphenylidantoine, primidone and carbamazepine up-regulate
CYPs => more polar compounds excreted in faeces and urine, alterated bone
turnover, inhibition of intestinal absorption and bone resorption of Ca2+
: prophylactic supplementation with 25-OH-D3 is recommended)
(sodium valproate decrease tubular resorption of calcium and phosphate
=> calciuria and phosphaturia)
(tubulopathies)(renal
osteodystrophy)
(decreased 25-hydroxylation, decreased intestinal absorption of calcium
and vitamin D, impaired enterohepatic circulation of 25-OH-vitamin D3,
GR agonists decrease intestinal calcium absorption, decreased DBP, malnutrition,
decreased sunlight exposure)
(cystic fibrosis)
(celiac disease),
hypophosphatemia
exposure (uneffective feedback on CYP27A1
/ steroid 25-hydroxylase
leads to 25-OH-vitamin D3 concentrations as high as 1200 nmol/L
= 500 ng/mL, which allow biological activity on the VDR)
intoxication, and characterized by elevated serum calcium levels and increased
density of the skeleton, with mental deterioration progressing to severe
retardation, and nephrocalcinosis
causing chronic uremia.
(chromosome 19q13.1),
tachypnea, sweating, cyanosis, increased CO2 production, and
usually muscle rigidity
is associated with this syndrome, including phenothiazines, butyrophenones,
thioxanthenes, benzamides and miscellaneous novel antipsychotic agents
such as clozapineref
and risperidoneref1,
ref2,
zotepineref,
ziprasidoneref,
perospironeref,
olanzapineref1,
ref2,
aripiprazoleref1,
ref2,
quetiapineref
(+fluvoxamineref),
promethazineref,
SSRIs (clomipiramineref,
venlafaxineref)ref.
Other circumstances, such as abrupt discontinuation of neuroleptic or
antiparkinsonian agents, and the use of dopamine-depleting agents,
have also been reported to produce NMS. The onset of the syndrome is not
related to the duration of exposure to neuroleptics or to toxic
overdose. Cases have been reported in both psychiatric and medical
patients including after multiple trauma or preoperative use of neuroleptic
agents. Alcoholic patients are at greater risk of developing NMS during
treatment of delirium or its prevention by droperidol or tiaprideref.
Abnormalities of muscle metabolism in alcoholic patients are caused by
ethanol
toxicity and malnutritionref.
This may sensitize the muscle to the action of neuroleptics. In a psychiatric
population, several studiesref1,
ref2,
ref3
showed that patients with NMS displayed significantly greater psychomotor
agitation, received significantly higher doses of neuroleptics at greater
dose increments, and received more intramuscular injections than other
patients having similar medication without evidence of NMS. Many authors
have pointed out that most cases have occurred in patients receiving haloperidol
or, to a lesser extent, depot fluphenazineref.
These clinical observations do not necessarily mean that the 2 drugs carry
a higher risk of causing NMS. One must consider the frequency with which
the drug is prescribed: haloperidol is one of the most commonly used medications.
Furthermore, sicker patients are more likely to receive haloperidol or
fluphenazine than other neuroleptics. Sicker patients may also be at higher
risk of NMS because of greater likelihood of dehydration, exhaustion or
malnutritionref1,
ref2,
ref3.
Other suggested predisposing factors include infection, concurrent organic
brain disease or sympathoadrenal hyperactivityref.
In Lewy body
dementia
onset of NMS is often related to commencement of treatment, change of drug,
or increase dose, but may occur in the absence of such an event. Physical
stress has been suggested as a precipitating factorref.
and chronic psychosis who developed NMS when dopaminergic agonists were
withdrawn but haloperidol was continuedref.
NMS has also been observed in a patient with Huntington’s
chorea
taking methyltyrosine,
a cathecholamine synthesis inhibitor, and tetrabenazine, which depletes
CNS catecholaminesref.
This suggests that NMS is caused by dopamine depletion or blockade, leading
to abnormal central thermoregulation. The dopamine blockade theory is supported
by the report of a case in which NMS developed when L-dopa/carbidopa and
amantadine were abruptly discontinued in a patient with Parkinson’s disease
who had never taken neurolepticsref.
Some dopamine-function-enhancing drugs, such as bromocriptineref
or amantadineref,
have shown efficacy in treating NMS. The blockade of dopamine receptors
in the hypothalamus is thought to lead to impaired heat dissipation. In
addition, blockade of dopamine receptors in the corpus striatum is thought
to cause muscular rigidity, generating heat. The excess heat production,
in association with a decrease in heat dissipation, produces hyperthermia,
which is one of the main signs of the syndrome. The peripheral anticholinergic
effects of neuroleptics which reduce sweating probably do not play a major
role in hyperthermia associated with NMS since most NMS patients (70%)
are in a sweat. However, it is unlikely that blockade of dopamine receptors
in the hypothalamus and corpus striatum could completely explain all the
signs of NMS. Indeed, hypothalamic thermoregulation involves noradrenergic,
serotoninergic, cholinergic and central dopaminergic pathwaysref.
Many neuroleptics may have additional selective effects on peptides co-transmitting
with dopamine in the striatum and other parts of the brain.
and 5-HT2A
receptor genes do not determine susceptibility to NMSref.
Other studies do not support an association between NMS and the mutations
in the ryanodine receptor gene reported with malignant hyperthermiaref
,
rigidity, serum CPK
>1000 IU/l, reflecting myonecrosis secondary to intense muscle contracture
and often resulting in myoglobinuric acute
renal failure,
(unstable ?) systemic
arterial hypertension,
tachypnoea,
diaphoresis
are are common signs of autonomic dysfunction, altered consciousness
(ranges from agitation to stupor or coma), leucocytosis
(ranging from a slight elevation to 30,000/mm3)
should be done for the differential diagnosis but is usually normal in
NMS. Cerebral CT scan is normal; non-specific changes are usually observed
in muscle biopsy or post-mortem histopathological studies of the brain.
These criteria for guidance in the diagnosis of NMS are commonly used in
clinical research studiesref1,
ref2.
Similarly, Pope, Keck and McElroyref
have published ‘definite’ and ‘probable’ criteria for NMS. Others still
prefer to think in terms of a spectrum of neuroleptic-related neurotoxicity,
with varying combinations that enhance the potential for inappropriate
diagnosis or managementref.
is a strong predictor of mortality, representing a mortality risk of approximately
50%.
: agitation, delirium, hyperthermic reactions and death have been described
as adverse effects of monoamine oxidase inhibitors in combination with
narcotic drugs or tricyclic antidepressants. It has been suggested that
the amine reuptake inhibitory properties of tricyclic antidepressants could
interact dangerously with the sympathomimetic properties of monoamine oxidase
inhibitors. Similar signs may be seen with overdosage of monoamine oxidase
inhibitors. Patients taking neuroleptics may also be receiving treatment
with monoamide oxidase inhibitors.
The patient is usually confused and disorientated (anticholinergic delirium)
and the temperature is often elevated. Physostigmine may induce a resolution
of symptoms that is not observed in NMS.,
must be treated aggressively
seems to be indicated to prevent venous thrombosis in an immobilized patient
(14 patients), bromocriptine
(22 patients), benzodiazepine (1 patient) and combinations of the above
(9 patients). Efficacy was evaluated in each case by determining the delay
in the clinical response and time to complete recovery. Therapy with bromocriptine
(5 mg orally or nasogastrically four times daily) was effective after approximately
1 day. This was significantly more rapid than that achieved by supportive
therapy alone. Complete resolution was achieved more quickly with bromocriptine
(10 days) or dantrolene (9 days; 2–3 mg/kg/day–1 i.v. without exceeding
10 mg kg–1 day–1) than with supportive therapy (15 days). The place of
sodium dantrolene,
the drug of choice for malignant hyperthermia, is less well defined in
the treatment of NMS. Sodium dantrolene inhibits calcium release from RYR1
in sarcoplasmic reticulum, decreasing available calcium for ongoing muscle
contracture. The drug is a non-specific, directly acting muscle relaxant
and a decrease in body temperature coincides with muscle relaxation. Oxygen
consumption diminishes and heart rate and respiratory rate decrease correspondingly.
It has been suggested that the initial dosage should be 2 mg/day given
intravenouslyref.
This dose may be repeated every 10 min, up to a total dose of 10 mg/kg/day.
The oral dosage has ranged from 50 to 200 mg/day. Hepatic toxicity may
occur with doses of >10 mg/kg/day,
a dopamine agonist, is also used to treat NMSref.
Bromocriptine doses have ranged from 2.5 to 10 mg 4 times a day. Hypotension
is the most limiting side-effect. The drug seems to be well tolerated by
psychotic patients even though it is a strong central dopamine agonist.
Rigidity may begin to decrease during the first few hours followed by a
decrease in temperature, along with normalization of arterial pressure.
This effect on rigidity and tremor strengthens the hypothesis of a dopamine-receptor
blockade in NMS. Bromocriptine and dantrolene have been used together without
complicationsref,
has been used successfully in some casesref,
combined with the dopadecarboxylase inhibitor carbidopa,
has also been reported to be effective in reversing hyperthermiaref.
Treatment may have to be continued for several days,
usually do not reduce the rigidity of NMS and do not affect hyperthermia
derivatives, which enhance GABA-ergic function, have caused transient decreases
in symptoms. In every case, these drugs are recommended to control ‘agitated’
patients being treated for NMS. Carbamazepine has been used successfully
in two patients: NMS completely resolved within 8 href
has improved some of the syndrome’s components, notably fever, sweating
and level of consciousnessref.in
animals, but association between hypothermia and pancytopenia has rarely
been reported in humans and may be underdiagnosed especially in cases of
transient or milder presentations (patients with thermoregulatory dysfunction
subsequent to surgical resection of a craniopharyngioma). The pancytopenia
improves upon rewarming the patient to a temperature of 36°C
: J wave/Osborn wave (differential
diagnosis with other causes of ST segment elevation)
)
:
Copyright © 2001-2005 Daniele Focosi.
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