)
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) (hypomagnesemic
hypoparathyroidismref)
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) syndromeTherapy :oral hypoglycemizing
drugs are contraindicated in chronic
renal
failure
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
inhibitors
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 ref,
corticosteroids,
liposuction
with compression, and surgical excision of especially
painful lipomasref1,
ref2.
IFN-a2b
was used to treat chronic hepatitis C in 2 patients with
adiposis dolorosa, and it induced long-term relief of painref.
Several case reports during the past 30 years have described
the use of systemically administered lidocaine (Dercum FX. A
subcutaneous connective tissue dystrophy of the arms and
back, associated with symptoms resembling myxoedema. Univ
Med Mag Phila 1888;1: 140-50)ref1,
ref2,
ref3,
ref4,
but long-term intravenous administration of lidocaine is
impractical and is associated with neurotoxicity. Several
voltage-gated sodium-channel blockers are clinically
available, including the anticonvulsant agents
carbamazepine, oxcarbazepine, phenytoin, lamotrigine,
topiramate, and zonisamide; the antiarrhythmic agent
mexiletine; and the tricyclic antidepressant agent
amitriptyline. Some of these drugs exhibit multiple
mechanisms of action, but even the relatively selective
sodium-channel blockers lack the pharmacologic specificity
that is required to avoid also targeting normal physiologic
activity of the central nervous system and so may be
associated with dose-related adverse effects. The narrow
therapeutic ratio of this class of drugs may account in part
for the inability to show analgesic efficacy consistently in
clinical trials of peripheral neuropathic pain (with the
exception of trigeminal neuralgia)
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)
) :
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