Transcript Hypothyroidism

Hypothyroidism
DR LALEH GHANEI
ASSISTANT PROFESSOR OF
ENDOCRINOLOGY
Causes of hypothyroidism
Primary
• Chronic autoimmune thyroiditisgoitrous & atrophic forms
• Radiation
• Surgery
• Infiltrative
disease(amyloidosis,sclerodermia)
• Iodine deficiency
• Biosynthetic defect
• Drugs (lithium,iodine,contrast
agents)
Secondary
• Pituitary disease
• Hypothalamic disease
Chronic Autoimmune Thyroiditis
Hashimoto's thyroiditis (chronic autoimmune thyroiditis) is
the most common cause of hypothyroidism in iodinesufficient areas of the world.
gradual thyroid failure, goiter, or both, due to autoimmunemediated destruction of the thyroid gland.
Nearly all patients have high serum concentrations of
antibodies against
one or more thyroid antigens, lymphocytic infiltration of the
thyroid, which includes thyroid-specific B and T cells, and
apoptosis of thyroid follicular cells.
Incidence of hypothyroidism*
Female 40/10,000
Male
6/10,000
Prevalence of Hypothyroidism*
Female %9.3
Male
%1.3
*2779 people in UK with a medium age of 58 years
Whickham survey 1995
Spectrum of thyroid autoimmunity
Grave’s Disease
Hashimoto Disease
Postpartum thyroiditis
Silent thyroiditis
Drug induced thyroiditis
Possible precipitating factors
• Genetic
• Infection
• Stress
• Humoral factors (sex steroids , pregnancy)
Pathogenesis
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Thyroid auotantigenes
Role of B cells
The primary role of T cells
Potential mechanism of thyroid injury
Molecular mimicry
Bystander activation
Thyroid cell expression of HLA Ag
Thyroid cell apoptosis
PATHOLOGY
The characteristic histopathological
abnormalities are profuse lymphocytic
infiltration, lymphoid germinal centers, and
destruction of thyroid follicular cells .
fibrosis and areas of follicular-cell
hyperplasia, presumably induced by TSH,
are also seen in patients with severe
disease. The intrathyroidal lymphocytes are
both T and B lymphocytes.
Effects of Thyroid Hormone
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Fetal brain and skeletal maturation
Increase in basal metabolic rate
Inotropic and chronotropic effects on heart
Increases sensitivity to catecholamines
Stimulates gut motility
Increase bone turnover
Increase in serum glucose, decrease in serum
cholesterol
Table 330-5. Signs and Symptoms of Hypothyroidism (Descending
Order of Frequency)
Symptoms
Tiredness, weakness
Dry skin
Feeling cold
Hair loss
Difficulty concentrating and poor memory
Constipation
Weight gain with poor appetite
Dyspnea
Hoarse voice
Menorrhagia (later oligomenorrhea or amenorrhea)
Paresthesias
Impaired hearing
Signs
Dry coarse skin; cool peripheral extremities
Puffy face, hands and feet (myxedema)
Diffuse alopecia
Bradycardia
Peripheral edema
Delayed tendon reflex relaxation
Carpal tunnel syndrome
Serous cavity effusions
Figure 9-3. (A) The classic torpid facies of severe myxedema in a man. The face appears puffy, and the eyelids
are edematous. The skin is thickened and dry. (B) The facies in pituitary myxedema is often characterized by skin
of normal thickness, covered by fine wrinkles. Puffiness is usually less than in primary myxedema. The eyelids are
often edematous. The palpebral fissure may be narrwowed because of blepharoptosis, due to diminished tone of
the sympathetic nervous fibers to Müller's levator palpebral superious muscle and is the opposite of the lid
retraction seen in thyrotoxicosis. The modest measurable exophthalmos seen in some patients with myxedema is
presumably related to accumulation of the same mucous edema in the orbit as is seen elsewhere. It is not
progressive and carries no threat to vision, as in the ophthalmopathy of Graves' disease. The tongue is usually
large, occasionally to the point of clumsiness. Sometimes a patient will complain of this problem. Sometimes it is
smooth, as in pernicious anemia (of course, pernicious anemia may coexist). Patients do not usually complain of
soreness of the tongue, as they may in pernicious anemia. When anemia is marked, the tongue may be pale, but
more often it is red, in contrast to the pallid face
TSH and Free T4
TSH
TSH
TSH
TSH
Free T4
Free T4
Free T4
Free T4
Primary
hypothyroidism
Mild or
Subclinical
hypothyroidism
Central hypo.
NTI
Drug effect
Normal
SCREANING
• goiter
• women older than 60 years (AACE&ATA
consensus)
• history of autoimmune disease(EX DMI)
• previous radioactive iodine therapy
• History of head and neck irradiation
• family history of thyroid disease
• use of medications that may impair thyroid
function
SCREANING
• symptoms of hypothyroidism
• laboratory or radiologic abnormalities that
could be caused by hypothyroidism
• patients taking drugs that may impair
thyroid function
SCREANING
• We also suggest universal screening for
thyroid dysfunction in pregnant women or
those hoping to become pregnant
As examples, thyroid function should be
measured in patients with the following:
• Substantial hyperlipidemia
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Hyponatremia,
High serum muscle enzyme concentrations.
Macrocytic anemia
Pericardial or pleural effusions
Pituitary or hypothalamic disorders
History of autoimmune diseases
three settings in which measurement of serum TSH
may not be a useful tool for the diagnosis of
hypothyroidism
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pituitary or hypothalamic disease is known or
suspected.
• In hospitalized patients
• In patients receiving drugs or with underlying diseases
which affect TSH secretion . Drugs that can decrease
TSH secretion include dopamine, high doses of
glucocorticoids, phenytoin, and somatostatin analogues
(such as octreotide). Drugs that increase TSH secretion
include dopamine antagonists
(metoclopramide or domperidone), amiodarone, and oral
cholecystographic dyes (sodium ipodate).
Hypothroidism in adulscent
• Hypothyroidism is the most common disturbance of
thyroid function in children, and is most often
caused by chronic autoimmune thyroiditis
• Euthyroid goiter is more common than
hypothyroidism
• Hypothyroidism in children can have deleterious
effects on growth, pubertal development and school
performance.
Hypothroidism in adulscent
• The most common physical finding at
presentation is a goiter.
• The most common manifestation of
hypothyroidism in children is declining
growth velocity, often resulting in short
stature.
Hypothroidism in adulscent
• Pubertal development is delayed in most ,
some children have sexual precocity.
• A few patients have hyperprolactinemia
and rarely galactorrhea. Growth hormone
normal or decreased, and serum insulin-like
growth factor I (IGF-I) levels are usually
decreased
Hypothroidism in adulscent
primary hypothyroidism must
be excluded in any child with
an enlarged sella turcica.
it rarely causes symptoms or signs,
unlike a pituitary tumor or
craniopharyngioma, and is
reversible with T4 therapy.
Hypothroidism in adulscent
• Atrophic thyroiditis is primarily the result of
cell-mediated cytotoxicity leading to follicular
cell apoptosis;
• complement-dependent antibody-mediated
cytotoxicity may contribute to thyroid damage.
• TSH receptor blocking antibodies result in loss
of thyroid morphological integrity, which may
be reversible.
Hypothroidism in adulscent
• Goitrous thyroiditis may be induced by
one of three mechanisms: lymphocytic and
plasma cell infiltration (and lymphoid
germinal centers),
• the production of antibodies that stimulate
thyroid growth,
• or excess TSH secretion.
Hypothroidism in adulscent
• Children at increased risk for chronic autoimmune
thyroiditis and, to a lesser extent, hypothyroidism. :
• Down syndrome (trisomy 21),
• Turner syndrome,
• type 1 (autoimmune) diabetes mellitus, ( 20 percent have
high serum antithyroid antibody concentrations, and 5
percent have abnormalities in thyroid function, usually
subclinical hypothyroidism)
• celiac disease, and
• possibly Klinefelter syndrome
Hypothroidism in adulscent
• children with Down, Turner, or Klinefelter
syndrome, type 1 diabetes, or celiac disease
should be screened annually for
hypothyroidism by measuring serum TSH.
DIAGNOSIS
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TSH levels have diurnal variation, and one series
suggests that TSH values measured at 8 AM are more
sensitive for the diagnosis of mild primary
hypothyroidism as compared with measurements at
4 PM
• Mild elevations of serum TSH (up to 7.5 mU/L), TSH
levels are normal in up to 70 percent of patients when
the test is repeated .
• Thus,Treatment decisions in such patients should be
made only after repeat testing.
Pharmacokinetics of oral thyroid hormones
T4
T3
Absorption
~ 80%
~90%
Time to peak level
2-4 h
1-2h
Increase in serum concentration 20-40%
Half-life
6-7days
250-600%
~1days
TREATMENT
• In most patients, hypothyroidism is a permanent
condition requiring lifelong treatment.
• Therapy consists of thyroid hormone replacement
unless the hypothyroidism is transient (as after
painless thyroiditis or subacute thyroiditis) or
reversible (due to a drug that can be discontinued).
TREATMENT
• The treatment of choice for correction of
hypothyroidism is synthetic thyroxine (T4).
• Approximately 80 percent of a dose of T4 is
absorbed and, because the plasma half-life of T4 is
long (seven days), once-daily treatment results in
nearly constant serum T4 and triiodothyronine
(T3) concentrations when a steady state is reached
TREATMENT
• Because there may be subtle differences in
bioavailability between T4 formulations, we feel
that it is preferable to stay with one formulation
when possible.
• If the preparation must be changed, follow-up
biochemical monitoring should be done to
determine if retitration of the dose is necessary.
We typically measure a serum TSH six weeks
after changing preparations
TREATMENT
• Adverse effects of T4 replacement are rare as long
as the correct dose is given.
• Rare patients have an allergy to the dye or filler in
the tablets. For dye sensitivities, multiples of the
white 50 mcg tablets can be given.
Dose and monitoring
• The average replacement dose of T4 in adults is
approximately 1.6 mcg/kg body weight per day
(112 mcg/day in a 70-kg adult)
• T4 requirements correlate better with lean body
mass than total body weightT4 requirements
correlate better with lean body mass than total
body weight
Average Replacement Dose of T4
• I.6 to 1.8µ/kg ideal body wight/day
• 75-125μg/day in women and 125200μg/day in men
• Older patients(>60years) require 20% to
30% less T4 per kg ideal body weight than
do younger patients
Timing of dose
• T4 should be taken on an empty stomach, ideally an hour
before breakfast
• T4 should not be taken with other medications that interfere with
its absorption, such as bile acid resins, proton pump
inhibitors, calcium carbonate, and ferrous sulfate.
• ( should be taken several hours after the T4 dose. )
• after initiation of T4 therapy, the patient should be reevaluated
and serum TSH measured in six weeks. TSH above the normal
reference range, the dose of T4 can be increased by 12 to 25
mcg/day.
Goals of therapy
• amelioration of symptoms
• normalization of TSH secretion
• reduction in the size of the goiter
• keep TSH within the normal reference range
(approximately 0.5 to 5.0 mU/L).
• hypothyroid symptoms, and the TSH at the upper limit,
increase the dose and to aim for a serum TSH value in the
lower half of the normal range.
It is prudent to keep TSH values in
the lower normal range(0.4-2.0 mU/l),
and to avoid TSH levels of <0.1 mU/l
Hypothroidism in adulscent
• There is some controversy about the need to
treat children with mild subclinical
hypothyroidism, characterized by TSH
elevations between 6 and 10 mU/L.
• There is general agreement to treat
children with subclinical hypothyroidism
and TSH levels >10 mU/L.
Hypothroidism in adulscent
• central hypothyroidism in children is
characterized by a low ratio of the TSH
values taken at 8 AM and 4 PM (8AM:4PM
ratio <1.3 in central hypothyroidism;
normal 8AM:4PM ratio >1.5), when serum
free T4 is in the lower third of the normal
range.
Treatment in children
• The goals of treatment are to restore normal growth
and development, including pubertal development.
• Children clear T4 more rapidly than adults; as a
result, the daily replacement dose on a weight basis
is higher:
• Age 1 to 3 years — 4 to 6 mcg/kg body weight
• Age 3 to 10 years — 3 to 5 mcg/kg
• Age 10 to 16 years — 2 to 4 mcg/kg
• Alternatively, the replacement dose can be
calculated as a function of body surface
area, in which case the dose at any age is
approximately 100 mcg/m2/day. Body
surface area can be determined from height
and weight using a calculator
• BSA=sqr(height*weight/3600)
• In children with primary hypothyroidism, the
recommended target range for TSH is in the
lower half of the reference range (optimally 0.5
to 2.0 mU/L) and for T4 or free T4 is in the
upper half of the reference range
• The optimal T4 range is between 9 and 13 ug/dL
(116 to 167 nmol/L)
• if the normal free T4 reference range is 0.6 to 1.8
ng/dL (8 to 23 pmol/L), the corresponding optimal
free T4 range would be between 1.2 and 1.8 ng/dL
(15 to 23 pmol/L).
• For most children, therapy should be initiated with a
dose in the middle of the appropriate range for age.
• However, in those with long-standing
hypothyroidism, a somewhat lower dose should be
given to avoid overly rapid acceleration of skeletal
maturation and loss of adult height.
• In one study of children presenting prior to puberty
with severe hypothyroidism, the height deficit after
treatment ranged from 8 to 14 cm at the end of
puberty
• Patients with longstanding hypothyroidism
are at risk for developing pseudotumor
cerebri shortly after initiation
of levothyroxine treatment .
• Children with persistent headaches or
vision changes should contact their
physician.
Course
• Hypothyroidism caused by chronic autoimmune
thyroiditis is not invariably permanent; some children
treated for several years have persistently normal
thyroid function after T4 treatment is discontinued
• Once T4 therapy is started, it probably is best to
continue treatment until growth and pubertal
development are complete.
• At that time, the question of permanency of
hypothyroidism can be addressed by discontinuing
T4 and measuring serum TSH one month later
• Serum antithyroid antibodies need not be
measured routinely in patients with overt
primary hypothyroidism, because almost all have
chronic autoimmune thyroiditis.
• However, a test for antithyroid peroxidase
antibodies may be useful to predict the likelihood of
progression to permanent overt hypothyroidism in
patients with subclinical hypothyroidism or those
with painless (silent) thyroiditis or postpartum
thyroiditis.
Risk of a suppressed TSH
• Effects on Bone Mass
• Cardiac Effects
Increased L-T4 dose requirement
• Decreased intestinal absorption of T4
Malabsorption(e.g.celiac disease,short bowel syn.)
Dietary fiber supplements
Drugs:colestipol,colestyramine,sucralfate,aluminium
hydroxide,ferrus sulfate
• Increased need for T4
Weigt gain,pregnancy,estrogens
• Increased clearance for T4
Phenobarbital,phenytoin,carbamazepin,rifampin
• Precise mechanism unknown
sertraline,chloroquine,lovastatin
Decreased L-T4 dose requirement
• Decreased need for T4
weight loss
androgens
• Decreased clearance of T4
Old age
• pituitary-adrenal function should be
assessed, usually by an ACTH stimulation
test, before T4 therapy is begun in patients
with central hypothyroidism, and
glucocorticoid therapy should be given
with T4 if adrenal insufficiency is
present.
Adjustment of maintenance dose
• serum TSH measured once yearly
• more often if there is an abnormal result or a change in the
patient's status.
• Increases in dosage may be required during pregnancyThe
increase in T4 requirements occurs as early as the fifth
week of gestation and plateaus by week 16 to 20.
Adjustment of maintenance dose
• Estrogen therapy
In women receiving T4 therapy, estrogens increase
serum TBG concentrations, as they do in normal
women, and may increase the need for T4.
• data suggest that serum TSH should be measured
approximately 12 weeks after starting estrogen
therapy in women receiving T4 therapy to
determine if an increase in T4 dose is needed.
Adjustment of maintenance dose
• Small increases:
whom thyroid hormone
absorption is diminished (patients with impaired
acid secretion or other gastrointestinal disorders),
excretion is increased (nephrotic syndrome), rate
of metabolism is increased (therapy
with rifampin,carbamazepine, phenytoin,
or phenobarbital)
Adjustment of maintenance dose
Small decreases:
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patients age
after parturition
loses weight
during androgen therapy
Adjustment of maintenance dose
• A high-fiber diet is another factor that can
interfere with the absorption of T4
• Coffee, in comparison to water, reduces the
absorption of levothyroxine by 27 to 36
percent
• Patients with autoimmune gastritis have
higher T4 requirements.
Adjustment of maintenance
dose
• . Several patients who appeared to be
resistant to levothyroxine administration did
not absorb levothyroxine tablets well but
absorbed levothyroxine tablets after they
were pulverized
Complication of hypo in
Surgical patients
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perioperative and postoperative ileus,
hypotension,
hyponatremia, and
central nervous system dysfunction
less fever during serious infections and
increased sensitivity to anesthesia and
opiate pain medications.
Surgical patients
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urgent surgery should not be postponed in hypothyroid
patients, but the patient should be managed expectantly for
the complications described above.
postpone surgery until the euthyroid state is restored
when hypothyroidism is discovered in a patient being
evaluated for elective surgery.
• Patients receiving chronic T4 therapy who undergo
surgery : If oral intake cannot be resumed in five to seven
days, then T4 should be given intravenously. dose should
be approximately 70-80 percent of the patient's usual oral
dose
Surgical patients
• Patients receiving chronic T4 therapy who
undergo surgery : If oral intake cannot be
resumed in five to seven days, then T4
should be given intravenously.
• dose should be approximately 70-80
percent of the patient's usual oral dose
Poorly compliant patients
• These patients may be given their total
weekly dose of T4 once per week
• Weekly dosing should probably not be used
in patients with coronary heart disease.
When the diagnosis of hypothyroidism is
uncertain
• a high serum TSH concentration suggests that the patient is
hypothyroid, and the T4 dose should be increased
accordingly.
• If, however, the serum TSH values are normal or low, the
dose of thyroid hormone can be reduced by one-half and
serum TSH measured again in four to six weeks. If the
value is normal, the dose can be reduced further or
stopped.
When the diagnosis of hypothyroidism
is uncertain
• reluctant to discontinue their thyroid
hormone:, In this case, the goal (a normal
serum TSH concentration) to avoid the
potential adverse cardiac and skeletal
effects of overtreatment.
Overreplacement
• atrial fibrillation, which occurs three times more
often in older patients with serum TSH
concentrations <0.1mU/L than in normal
subjects
• postmenopausal women, may also have
accelerated bone loss.
• more severe iatrogenic hyperthyroidism (TSH
<0.03 mU/L) had a significantly increased risk
of arrhythmia (HR 1.6) and fractures (HR 2.0)
Subacute Thyroiditis
(DeQuervain’s, Granulomatous)
Tenderness
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Subacute thyroiditis
Hemorrhagic nodule
Acute bacterial thyroiditis
Infected thyroglossal duct cyst
Goitrous autoimmune thyroiditis
Rapidly enlarging thyroid carcinoma
Radioactive thyroidiyis
Trauma induced thyroiditis
Cellulitis of the anterior neck
Transient hypothyroidism
Postpartum thyroiditis
Subacute thyroiditis
After withdrawal of thyroid hormone
Therapy in euthyroid patients
Following I131 treatment for Graves’disease
Removal of toxic adenoma or subtotal thyroidectomy
for Graves’disease
Subclinical hypothyroidism
• Unlike patients with overt hypothyroidism,
these patients have normal serum levels of T3
and T4 and only mildly elevated serum TSH
levels.
• Such patients are often identified through
routine screening or in the course of an
evaluation of common nonspecific symptoms or
hypercholesterolemia.
Subclinical hypothyroidism
• The worldwide prevalence of subclinical
hypothyroidism ranges from 1 to 10 percent;
the highest age- and sex-specific rates are in
women older than 60 years of age, approaching
20 percent in some reports
• Up to 75 percent of patients have only mildly
elevated serum thyrotropin values (5 to 10 mU
per liter), and 50 to 80 percent of patients have
positive tests for antibodies against
thyroperoxidase, depending on the age, sex, and
serum thyrotropin levels.
Volume 345:260-265
July 26, 2001
Subclinical Hypothyroidism
David S. Cooper, M.D.
Number 4
Subclinical hypothyroidism
• Unlike patients with overt hypothyroidism, these
patients have normal serum levels of T3 and T4 and
only mildly elevated serum TSH levels.
• Such patients are often identified through routine
screening or in the course of an evaluation of common
nonspecific symptoms or hypercholesterolemia.
• Patients with treated hyperthyroidism, a history of
neck irradiation, postpartum thyroiditis, and certain
autoimmune disorders, especially type 1 diabetes, are at
increased risk for subclinical hypothyroidism.
Subclinical hypothyroidism
• Subclinical hypothyroidism may also develop in
patients who are being treated with the iodinecontaining antiarrhythmic agent amiodarone, lithium,
or immune-response modulators, such as interferon
alfa, but most patients have no obvious risk factors.
• Other causes of elevated levels of serum TSH and
normal levels of serum free T4 include intermittent
noncompliance with thyroxine therapy, recovery from
severe nonthyroidal illness, chronic renal failure,
primary adrenal failure, high thyrotropin levels as an
artifact due to circulating heterophilic antibodies
against thyrotropin.
Conclusions and Recommendations
Thyroxine Therapy
• An initial dose of thyroxine of 0.05 to 0.075 mg per day is
usually sufficient to normalize the serum thyrotropin level.
• Patients with coronary artery disease should receive lower
initial doses (e.g., 0.0125 to 0.025 mg daily).
• Serum TSH levels should be measured four to six weeks
after therapy is begun, after any change in the dose, and
then annually once the levels become stable.
• Thyroxine requirements may increase over time if there is
progressive thyroid failure.
Hypothyroidism in pregnancy
• The thyroxine dose often needs to be incremented by 4–6 wk
gestation and may require a 30–50% increment in dosage.
• Levothyroxine requirements may increase as early as the fifth
week of gestation.
• Greater increases in thyroxine are generally required for women
without residual functioning thyroid tissue such as following
radioiodine ablation or thyroidectomy
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TSH < 2.5 mU/l in the first trimester and < 3 mU/l in later
pregnancy should be aims of treatment.
Hypothyroidism in pregnancy
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The prevalence of overt and subclinical hypothyroidism in pregnancy is estimated at 0.3 – 0.5
and 2 – 3% respectively
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The main cause of hypothyroidism in iodine-replete populations is chronic autoimmune
thyroiditis
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Observational data suggest that SCH may be associated with poor obstetrical outcomes.
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At present, with the exception of studies on iodide supplementation, only two prospective,
randomized intervention trials have been published in this area.
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The clinical data certainly suggest that pediatric neurodevelopment is affected by maternal
thyroid status, but there has not been a clinical trial that specifically addresses isolated
subclinical hypothyroidism and neurodevelopmental outcomes