Hypothyroidism
Hypothyroidism results from deficient
production of thyroid hormone or a defect in
thyroid hormone receptor activity .
The disorder may be manifested from birth
or acquired.
When symptoms appear after a period of
apparently normal thyroid function, the
disorder may be truly “acquired” or may only
appear so as a result of one of a variety of
congenital defects in which the manifestation
of the deficiency is delayed.
Thyroid Regulation
HYPOTHALAMUS - TRH
ANT. PITUITARY - TSH
TSH -R
THYROID T4 and T3
PLASMA T4 + FT4
PLASMA T3 + FT3
TISSUES FT4 to FT3, rT3
2 [Link]
Etiology
PRIMARY HYPOTHYROIDISM
• Hoshimoto’s thyroiditis-most common
• Idiopathic hypothyroidism-probably old Hoshimoto’s
• Irradiation of thyroid
• Surgical removal
• Late stage invasive fibrous thyroiditis
• Iodine deficiency
• Drug therapy (Lithium, Interferon)
• Infiltrative Diseases:
Sarcoidosis, Amyloidosis
Scleroderma, Hemochromatosis
SECONDARY HYPOTHYROIDISM
• 5% of cases.
• Pituitary or hypothalmic neoplasm.
• Congenital hypopituitarism.
• Pituitary necrosis (Sheehan’s syndrome)
Congenital Hypothyroidism
5
Etiologic Classification of Congenital
Hypothyroidism
CENTRAL (HYPOPITUITARY) HYPOTHYROIDISM PIT-
1 mutations .
Deficiency of thyrotropin (TSH), growth hormone,
and prolactin
Multiple hypothalamic deficiencies (e.g., septo-
optic dysplasia)
Mutations in TRH receptor TSH deficiency
Mutations in β-chain Multiple pituitary deficiencies
(e.g., craniopharyngioma)
PRIMARY HYPOTHYROIDISM Defect of
fetal thyroid development .
Aplasia, hypoplasia, ectopia (dysgenesis)
Defect in thyroid hormone synthesis (e.g.,
goitrous hypothyroidism)
Iodide transport defect
Thyroglobulin synthesis
defect . Deiodination defect Defect in
thyroid hormone transport Iodine
deficiency (endemic goiter)
Maternal medications Radioiodine,
iodides Propylthiouracil,
methimazole Amiodarone
CONGENITAL HYPOTHYROIDISM
Most cases of congenital hypothyroidism are
not hereditary and result from thyroid
dysgenesis. Some cases may be familial,
usually caused by one of the inborn errors of
thyroid hormone synthesis, and may be
associated with a goiter. In many cases, the
deficiency of thyroid hormone is severe, and
symptoms develop in the early weeks of life. In
others, lesser degrees of deficiency occur, and
manifestations may be delayed for months.
EPIDEMIOLOGY.
The prevalence of congenital
hypothyroidism based on nationwide
programs for neonatal screening is 1/4,000
infants worldwide; prevalence is lower in
black Americans (1/32,000) and higher in
Hispanics and Native Americans (1/2,000).
Twice as many girls as boys are affected.
Thyroid Dysgenesis.
Some form of thyroid dysgenesis (aplasia,
hypoplasia, or an ectopic gland) is the most
common cause of congenital hypothyroidism,
accounting for 85% of cases; 10% are caused by
an inborn error of thyroxine synthesis, and 5%
are the result of transplacental maternal
thyrotropin-receptor blocking antibody (TRBAb).
In about ⅓ of cases of dysgenesis, even sensitive
radionuclide scans can find no remnants of
thyroid tissue (aplasia).
In the other ⅔ of infants, rudiments of thyroid
tissue are found in an ectopic location, anywhere
from the base of the tongue (lingual thyroid) to
the normal position in the neck (hypoplasia).
The exact cause of thyroid dysgenesis is unknown
in most cases. Thyroid dysgenesis occurs
sporadically, but familial cases occasionally have
been reported. The finding that thyroid
developmental anomalies, such as thyroglossal
duct cysts and hemiagenesis, are present in 8–
10% of 1st-degree relatives of infants with thyroid
dysgenesis supports an underlying genetic
component.
CLINICAL MANIFESTATIONS.
Most infants with congenital
hypothyroidism are asymptomatic at birth,
even if there is complete agenesis of the
thyroid gland. This situation is attributed to
the transplacental passage of moderate
amounts of maternal T4, which provides
fetal levels that are approximately 33% of
normal at birth. These low serum levels of
T4 and concomitantly elevated levels of TSH
make it possible to screen and detect
hypothyroid neonates.
The clinician is dependent on neonatal
screening tests for the diagnosis of
congenital hypothyroidism. Laboratory
errors occur, however, and awareness of
early symptoms and signs must be
maintained. Congenital hypothyroidism is
twice as common in girls as in boys
Respiratory difficulties, due in part to the
large tongue, include apneic episodes, noisy
respirations, and nasal obstruction.
Typical respiratory distress syndrome may
also occur. Affected infants cry little, sleep
much, have poor appetites, and are generally
sluggish.
LABORATORY FINDINGS.
Most newborn screening programs in North
America measure levels of T4, followed by
measurement of TSH when T4 is low. This
approach identifies infants with primary
hypothyroidism, some with hypothalamic or
pituitary hypothyroidism, and infants with a
delayed increase in TSH levels.
TREATMENT.
Levothyroxine given orally is the
treatment of choice. Because 80% of
circulating T3 is formed by
monodeiodination of T4, serum levels of T4
and T3 in treated infants return to normal.
This is also true in the brain, where 80% of
required T3 is produced locally from T4. In
neonates, the recommended initial
starting dose is 10–15 μg/kg (37.5 to 50
μg/24 h
Newborns with more severe hypothyroidism, as
judged by a serum T4 <3 μg/dL, should be started
at the higher end of the dosage range. Thyroxine
tablets should not be mixed with soy protein
formulas or iron, because these can bind T4 and
inhibit its absorption. Levels of T4or free T4 and TSH
should be monitored at recommended intervals
(approximately monthly in the first 6 mo of life,
and then every 2–3 mo between 6 mo and 2 yr)
and maintained in the normal range for age.
Children with hypothyroidism require about 4
μg/kg/24 hr, and adults require only 2 μg/kg/24 hr.
European and Japanese neonatal
screening programs are based on a
primary measurement of TSH; some
North American programs are switching
to primary TSH screening. This approach
detects infants with primary
hypothyroidism and may detect infants
with subclinical hypothyroidism (normal
T4, elevated TSH), but it misses infants
with delayed
TSH elevation and with hypothalamic or
pituitary hypothyroidism. With any of these
tests, special care should be given to the
normal range of values for age of the patient,
particularly in the 1st weeks of life ( Table 566-2
). Regardless of the approach used for
screening, some infants escape detection
because of technical or human errors; clinicians
must maintain their vigilance for clinical
manifestations of hypothyroidism
Serum levels of T4 or free T4 are low; serum
levels of T3 may be normal and are not helpful in
the diagnosis. If the defect is primarily in the
thyroid, levels of TSH are elevated, often to
greater than 100 mU/L. Serum levels of prolactin
are elevated, correlating with those of TSH.
Serum levels of thyroglobulin are usually low in
infants with thyroid agenesis or defects of
thyroglobulin synthesis or secretion, whereas
they may be elevated with ectopic glands and
other inborn errors of thyroxine synthesis
ACQUIRED HYPOTHYROIDISM
EPIDEMIOLOGY.
Studies of school-aged children report that
hypothyroidism occurs in approximately 0.3%
(1/333).
Acquired hypothyroidism is most commonly a
result of chronic lymphocytic thyroiditis; 6% of
children aged 12–19 yr have evidence of
autoimmune thyroid disease, which occurs with
a 2 : 1 female to male preponderance.
ETIOLOGY.
The most common cause of acquired
hypothyroidism is chronic lymphocytic
thyroiditis .
Etiologic Classification of Acquired
Hypothyroidism
AUTOIMMUNE (ACQUIRED
HYPOTHYROIDISM) Hashimoto
thyroiditis . Polyglandular autoimmune
syndrome, types I and II.
IATROGENIC Propylthiouracil, methimazole,
iodides, lithium, amiodarone
Irradiation Irradiation of the area of thyroid
that is incidental to the treatment of Hodgkin
disease or other head and neck malignancies
or that is administered before bone marrow
transplantation often results in thyroid
damage
Radioiodine . Thyroidectomy
SYSTEMIC DISEASE Cystinosis
( Children with nephropathic
cystinosis )
Langerhans cell
histiocytosis(Histicytic infiltration of
thyroid with a langerhansn cell
histiocytosis may result in
hypothyroisim)
CLINICAL MANIFESTATIONS.
Deceleration of growth is usually the first
clinical manifestation, but this sign often goes
unrecognized .
Goiter, which may be a presenting feature,
typically is non-tender and firm, with a rubbery
consistency and a pebbly surface.
Myxedematous changes of the skin,
constipation, cold intolerance, decreased
energy, and an increased need for sleep develop
insidiously.
Osseous maturation is delayed, often
strikingly, which is an indication of the
duration of the hypothyroidism.
Adolescents typically have delayed
puberty, whereas younger children may
present with galactorrhea or
pseudoprecocious puberty. Galactorrhea is
a result of increased TRH stimulating
prolactin secretion.
The precocious puberty, characterized by
breast development in girls and macro-
orchidism in boys, is thought to be the
result of abnormally high TSH
concentrations binding to the follicle-
stimulating hormone receptor with
subsequent stimulation
Some children have headaches and visual
problems; they usually have hyperplastic
enlargement of the pituitary gland, sometimes
with suprasellar extension, after long-standing
hypothyroidism; this condition, believed to be
the result of thyrotroph hyperplasia, may be
mistaken for a pituitary tumor
Additional features include nerve
entrapment, ataxia, muscle weakness or
cramps, menstrual disturbances,
bradycardia, weight gain, and abnormal
laboratory studies (hyponatremia,
macrocytic anemia,
hypercholesterolemia, elevated CPK,
hyperprolactinemia)
COMPLICATIONS
Heart failure
Hyponatremia
Bowel hypomotility (Ileus)
Medication sensitivity
Adrenal insufficiency
DIAGNOSTIC STUDIES AND TREATMENT.
Treatment and diagnostic studies are the
same as those described for congenital
hypothyroidism. Measurement of
antithyroglobulin and antiperoxidase
(formerly, antimicrosomal) antibodies may
pinpoint autoimmune thyroiditis as the cause.
Generally, there is no indication for thyroid
imaging.