Transcript T 4 -binding globulin

THYROID
PHYSIOLOGY AND
DEVELOPMENT
• Thyrotropin-releasing hormone (TRH), a
tripeptide synthesized in the hypothalamus,
stimulates the release of pituitary thyroidstimulating hormone (TSH). Pituitary TSH is a
glycoprotein that stimulates the synthesis and
release of thyroid hormones by the thyroid
gland.
•Thyroid function
develops in three stages:
• Embryogenesis begins on the floor of the primitive oral
cavity, and the gland descends to its definitive position in
the anterior lower neck by the end of the first trimester.
Thyroid glands that do not reach the normal location are
ectopic but may retain function; however, the glands most
often become insufficient by early to mid childhood to
support full thyroid secretion (a lingual or sublingual site or
even tissue found in a thyroglossal duct cyst may be the
only functioning thyroid gland).
• The hypothalamic-pituitary-thyroid axis becomes functional
in the second trimester.
• Peripheral metabolism of thyroid hormones matures in the
third trimester.
• T4, triiodothyronine (T3), and TSH do not cross the
placenta in significant amounts, so
concentrations in fetal serum reflect primarily
fetal secretion and metabolism. Antithyroid
antibodies, thyroid-stimulating immunoglobulins
(TSIs), iodides (including radioactive iodides), and
medications given to mothers to treat
hyperthyroidism (e.g., propylthiouracil and
methimazole) do cross the placenta, however,
and affect fetal thyroid function.
• An infant born prematurely or with
intrauterine growth retardation may have an
interruption of the normal maturational
process and appear to have hypothyroidism by
standard tests. It is controversial as to
whether treatment is indicated in such
situations.
• The thyroid gland (1) concentrates iodine and
(2) attaches it (organifies it) to tyrosine
molecules to produce either
monoiodotyrosine or diiodotyrosine, with
subsequent (3) coupling of two tyrosines, T4 or
T3. The major fraction of circulating T3
(approximately two thirds) is derived from
peripheral deiodination of T4 to T3, but some
is produced by the thyroid gland itself
• In Graves disease, a larger fraction originates in
the thyroid gland. The conversion of T4 to T3
requires the removal of one iodine from the
outer ring of tyrosine; removing an iodine from
the inner ring results in reverse T3, which has
little biologic effect. Preferential conversion of T4
to reverse T3 rather than T3 occurs in utero and in
all forms of severe illness, including respiratory
distress syndrome, fevers, anorexia, cachexia, and
starvation. Conversion from T4 to T3 increases
immediately after birth and throughout life.
• T4 and T3 are noncovalently bound to a
specific serum carrier protein, T4-binding
globulin, and, to a lesser extent, albumin.
Only small (<0.02%) fractions of T4 and T3 are
not bound; free T4 (as it is converted to free
T3) and free T3 are biologically active. Free T3
exerts metabolic effects and negative
feedback on TSH release
• Although a thyroid scan rarely is indicated in
the evaluation of pediatric thyroid disease, the
presence of thyroid agenesis or of ectopic
thyroid tissue and the diagnoses of
hyperfunctioning "hot" nodules or of
nonfunctioning "cold" nodules may be
detected by this test.
• Ultrasound may determine whether it is cystic
or solid. If the nodule is solid, a 123I scan
indicates its functional status. Excisional
biopsies usually are performed on solitary
nodules. Scans are rarely indicated in the
diagnosis of Hashimoto thyroiditis or
thyrotoxicosis.
•Hypothyroidism
• Hypothyroidism is diagnosed by a decreased
serum free T4. Hypothyroidism might be the
result of disease of the thyroid gland (primary
hypothyroidism) or of abnormalities of the
pituitary gland (secondary) or the result of
abnormality of the hypothalamus (tertiary).
Hypothyroidism is congenital or acquired and
may be associated with a goiter .
• Congenital hypothyroidism occurs in
approximately 1 in 4000 live births and usually
is caused by dysgenesis: disorders of
embryogenesis (agenesis, aplasia, ectopia).
Thyroid tissue usually is not palpable in these
sporadic nongoitrous conditions.
• The goiter reflects an inborn error of
metabolism in the pathway of iodide
incorporation or thyroid hormone
biosynthesis or reflects the transplacental
passage of antithyroid drugs given to the
mother. The free T4 concentration is low, and
the TSH level is elevated, proving primary
hypothyroidism
• Isolated secondary or tertiary hypothyroidism
is rare, occurring in 1 in 100,000 live births;
the free T4 is normal to low. When tertiary or
secondary hypothyroidism is detected,
assessment of other pituitary hormones and
investigation of pituitary-hypothalamic
anatomy via MRI are indicated
• Although not a hypothyroid condition,
congenital T4-binding globulin deficiency
occurs in about 1 in 10,000 live births and is
associated with a low serum total T4
concentration, a normal TSH and serum free
T4, and a euthyroid status. This entity does not
require treatment with thyroid hormone
because it is merely a binding protein
abnormality and is commonly X-linked
dominant.
•Clinical manifestations
• Newborn screening is crucial to make an early
diagnosis and initiate thyroid replacement
therapy by younger than 1 month of age and
in the absence of definitive signs.
• Findings at various stages after birth include gestation
greater than 42 weeks, birth weight greater than 4 kg,
hypothermia, acrocyanosis, respiratory distress, large
posterior fontanel, abdominal distention, lethargy and
poor feeding, jaundice more than 3 days after birth,
edema, umbilical hernia, mottled skin, constipation,
large tongue, dry skin, and hoarse cry. Thyroid
hormones are crucial for maturation and
differentiation of tissues such as bone (the bone age is
often delayed at birth because of intrauterine
hypothyroidism) and brain (most thyroid-dependent
brain maturation occurs 2 to 3 years after birth
• When treatment is initiated within 1 month or
less after birth, the prognosis for normal
intellectual development is excellent; screening
programs usually offer therapy within 1 to 2
weeks of birth. If therapy is instituted after 6
months, when the signs of severe hypothyroidism
are present, the likelihood of normal intellectual
function is markedly decreased. Growth improves
after thyroid replacement even in late diagnosed
cases.
• The dose of T4 changes with age; 10 to 15
μg/kg of T4 is used for a newborn, but about 3
μg/kg is used later in childhood. In neonatal
hypothyroidism, the goal is to bring the serum
free T4 rapidly into the upper half of the range
of normal. Suppression of TSH is not seen in
all cases and is not necessary in all cases
because such suppression may lead to
excessive doses of T4.
• Acquired Hypothyroidism
• The most common cause of acquired
hypothyroidism in older children in the U.S. is
lymphocytic autoimmune thyroiditis
(Hashimoto thyroiditis). In many areas of the
world, iodine deficiency is the etiology of
endemic goiter (endemic cretinism
• Also known as autoimmune or lymphocytic
thyroiditis, Hashimoto thyroiditis is a common
cause of goiter and acquired thyroid disease in
older children and adolescents. A family history
of thyroid disease is present in 25% to 35% of
patients, suggesting a genetic predisposition. The
etiology is an autoimmune process targeted
against the thyroid gland with lymphocytic
infiltration and lymphoid follicle and germinal
center formation preceding fibrosis and atrophy.
•Clinical manifestations
• manifestations include a firm, nontender
euthyroid, hypothyroid, or, rarely, hyperthyroid
(hashitoxicosis) diffuse goiter with a pebble-like
feeling; an insidious onset after 6 years of age
(the incidence peaks in adolescence, with a
female predominance); and sometimes a peasized Delphian lymph node above the thyroid
isthmus. Associated autoimmune diseases
include DM1, adrenal insufficiency (Schmidt
syndrome), and hypoparathyroidism.
• Autoimmune polyglandular syndrome type I
consists of hypoparathyroidism, Addison
disease, mucocutaneous candidiasis, and
often hypothyroidism. Autoimmune
polyglandular syndrome type II consists of
Addison disease, DM1, and frequently
autoimmune hypothyroidism. Trisomy 21 and
Turner syndrome predispose to the
development of autoimmune thyroiditis.
• The diagnosis may be confirmed by serum
antithyroid peroxidase (previously
antimicrosomal) and antithyroglobulin
antibodies. Neither biopsy nor thyroid scan is
indicated in Hashimoto thyroiditis, although
the thyroid scan and uptake may differentiate
hashitoxicosis from Graves disease.
• Treatment with thyroid hormone sufficient to
suppress TSH to a normal level is indicated for
hypothyroidism in Hashimoto thyroiditis.
Patients without manifestation of
hypothyroidism require periodic thyroid
function testing (serum TSH and free T4) every
6 to 12 months to detect the later
development of hypothyroidism. Goiter with a
normal TSH usually is not an indication for
treatment.