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					Thyroid Diseases

Embryology and anatomy

The thyroid gland develops from the floor of the
at 4 weeks gestation in the form of a diverticulum which
travels inferiorly leaving the thyroglossal tract in the

                          Ganong's Review of Medical Physiology , 23 edition (July 24, 2009)
The main function of the thyroid gland is to
thyroxine (T4) and triiodothyronine (T3).

Control of thyroid metabolism

The hypothalamus secretes thyrotrophin-
releasing hormone (TRH) which stimulates
the anterior pituitary to secrete thyroid-
stimulating hormone (TSH).
TSH acts on the thyroid cell by binding to a
specific receptor (TSH-R).
Thyroxine synthesis
The thyroid is composed of follicles that secrete thyroid hormone.
They contain two types of cells that surround a central core of colloid.
The major constituent of colloid is thyroglobulin (Tg), a large
iodinated, glycoprotein that functions as a thyroid hormone precursor
and permits storage of iodine and of iodinated tyrosyl residues.
Iodine is actively taken up by the thyroid follicular cells
and oxidized to iodide.
Tyrosyl residues on the thyroglobulin molecule are then iodinated to
form monoiodotyrosine (MIT) and diiodotyrosine (DIT).
These iodinated tyrosine molecules are coupled to form the
iodothyronines, T3 and T4 followed by cleavage of the residues from the
thyroglobulin molecule to release MIT, DIT, T3 and T4.
The thyroid gland is the, sole producer of T4 and produces 20% of T3.
 Most T3 is produced by deiodination in the peripheral tissues. T3 is 3–4
times more potent than T4 and is responsible for most thyroid activity.
Thyroxine metabolism
After T4 is secreted by the thyroid gland, it is metabolized
by the tissue enzymes deiodinase type I, II and III.

Type II deiodinase catalyses T4 to T3 conversion by outer ring
deiodination (ORD) .
Type III deiodinase converts T4 to the inactive reverse T3
(rT3) by inner ring deiodination (IRD) while type I
deiodinase catalyses both ORD and IRD.
Seventy per cent of circulating T4 and 50% of circulating T3 is
bound to thyroxine-binding globulin (TBG), the remainder
to other proteins, primarily albumin.
Only 0.03% of circulating T4 and 0.3% of T3 is unbound.
Action of the thyroid hormones

The thyroid hormones have profound effects on
growth, neurological development, metabolism, and
cardiovascular function.

T4 and T3 bind to receptors in the target tissues, e.g.
pituitary and hypothalamus liver, heart ,and brain.

This results in an increase in oxygen consumption,
altered protein, carbohydrate and lipid metabolism
and potentiation of the action of catecholamines.
Fetal thyroid metabolism

During the first trimester the fetus is largely
dependent on small amounts of maternal T4 and T3
that cross the placenta.

Levels of TSH start to rise from the second trimester

Total T4 rises in response to this and also to
increasing TBG levels.
Thyroid function in term neonates

At birth there is an acute release of TSH so TSH is high
during the first days of life and this associated with
increased T4 and T3 levels .

These levels start falling thereafter so that by 14 days of
age concentrations are similar to those foundin infancy
and childhood.
Thyroid function in preterm neonates

The preterm infant, especially below 34 weeks gestation,
shows the fetal pattern of low plasma T3 and T4 with high

Factors contributing to this pattern include immaturity
of the hypothalamic–pituitary axis, premature cessation
of the small but significant maternal contribution to
circulating thyroid hormone levels, and persistence of the
fetal tendency towards inactivation of T4 and T3.
Congenital hypothyroidism
Primary hypothyroidism, between 1 in 2500 to one in 4000 births.
Secondary hypothyroidism, 1 in 50.000 to 1 in 100.000

Thyroid dysgenesis accounts for approximately 85% of
congenital hypothyroidism.
Capillary blood is collected from the baby’s heel.
Screening options include

 TSH measurement only (which will miss secondary and
 tertiary hypothyroidism),
 T4 measurement only (which will miss compensated
 measurement of both T4 and TSH.
Causes of Congenital Hypothyroidism.
 Thyroid dysgenesis (85%)
  Thyroid agenesis
  Hypoplastic gland
  Ectopic (usually sublingual) gland
 Synthetic defects (10%)
  TRH and TSH deficiency
  TSH receptor defect
  G-protein defect (as part of Albright’s hereditary
Defects in T4 synthesis
  1. iodide transport defect
  2. organification defect
  3. peroxidase deficiency
  4. thyroglobulin defect
  5. deiodinase deficiency
  6. Pendred’s syndrome
Maternal disease (5%)
 Thyroid disease with transplacental transfer of
peroxidase antibody or thyrotropin receptor
blocking antibody
Maternal drugs, e.g. carbimazole
Down’s syndrome
Clinical features
Most cases are clinically normal at birth.
Congenital hypothyroidism is twice as common in girls as in
Symptoms and signs

     Birthweight and length are
    Feeding difficulties
    Respiratory difficulties
    Prolonged jaundice.
    Hoarse cry.
    Coarse facies.
    Large abdomen
    Umbilical hernia.
    Dry, cold and mottled skin
     Wide posterior and anterior
Peripheral cyanosis.
Oedema of the genitals and extremities .
Retardation of physical and mental
Slow pulse, heart murmurs and
Macrocytic anemia
The mouth is open, and the thick, broad
tongue protrudes
The neck is short and thick
The hands are broad and the fingers are
The muscles are usually hypotonic
 The hairline reaches far down on the
Sexual maturation may be delayed
Lab findings

  Serum TSH level is high
  Serum levels of T4 or free T4 are low
  Retardation of osseous development
  Scintigraphy can help to pinpoint the
 underlying cause in infants with congenital
  Thyroid ultrasound
  All infants with congenital hypothyroidism
should have their hearing tested
Focal activity of Tc-99m in the base of the tongue consistent with Lingual thyroid tissue
In a well term baby with unequivocal
TSH elevation (>30 mU/L) the likelihood of true
congenital hypothyroidism is such that
treatment should be started immediately. If the
TSH<30mU/L and there are no clinical features
of hypothyroidism then treatment can be
deferred until the results of the venous sample
are known (transient neonatal

 Starting dose in newborn 10–15 mcg/kg/day.

  Soy milk formulas and iron medication
administered in close time proximity to thyroxine can
interfere with thyroxine absorption.
 T4, TSH and clinical evaluation
   •2 wk after initial treatment is
   •Every 1 mo in the first 6 mo.
   •Every 2 mo between 6 mo and 1 y
   of age.
   •Every 2-4 mo from 1 y of age 3

Goal of therapy
Maintain TSH at lower half of of
normal range and or T4 and FT4 in
upper half of reference range.
A period off treatment for 3 weeks with
measurement of FT4 (or T4) and TSH before
and after stopping treatment is indicated in
selected cases at about 3 years of age to exclude
transient hypothyroidism.
             Acquired hypothyroidism

    Autoimmune (Hashimoto’s) thyroiditis.
    Thyroid surgery.
    Iodine deficiency.
     Irradiation of the thyroid
     Radioactive iodine
     External irradiation of non-thyroid tumors
      Drugs: Antithyroid drugs (carbimazole,
      Goitrogens ( cabbage, sweet potatoes, cauliflower,
      broccoli, soybeans)
Secondary and tertiary
    Craniopharyngioma and other
    infection (meningitis)
    Cranial irradiation.
Iodine deficiency
     Is the most common cause of hypothyroidism in
    some parts of the world.
     It more more commonely causes euthroid goiter.
    It is diagnosed by urinary iodine measurements
    treated with iodine.
     Autoimmune (Hashimoto’s) thyroiditis

The most common cause of acquired hypothyroidism.
 more common in girls.
 The most common age at presentation is adolescence
  but the disease may occur at any age, even infancy.
 Goiter, which is present in approximately two thirds
  of children
 may be associated with hypothyroidism ,
  euthyroidism or hyperthyroidism
Autoantibodies are present in 95% of
 Autoimmune thyroiditis may be
  associated with other
  autoimmune diseases, such as
   diabetes mellitus
   Addison’s disease,
   skin disorders, such as alopecia
  and vitiligo.
 The incidence is increased in patients
  with Turner, Down and Klinefelter
Clinical features
    • Weight gain.
    • Tiredness.
    • Constipation.
    • Cold intolerance.
    • Slowing of linear growth ± short stature.
    • Poor school performance.
    • Delayed puberty (occasionally precocious puberty).
    • Menstrual irregularity.
    • Presence of other autoimmune disorders.
    • History of slipped femoral epiphysis.
     • Family history of thyroid or other autoimmune
    • Myxoedematous facies.
    • Short stature.
    • Goitre.
    • Obesity.
    • Dry skin.
    • Increase in body hair.
    • Pallor.
    • Vitiligo

   FT4 and TSH measurement
  thyroid peroxidase (TPO) antibodies
  bone age will show delay.
  If there is no goitre and the autoantibody
screen is negative then an isotope scan should
be performed to exclude a late presentation of
thyroid dysgenesis.
 most children who are hypothyroid remain
  spontaneous recovery may occur

   • Graves’ disease. More than 95% of cases.
   • Autoimmune (Hashimoto’s) thyroiditis.
   • Autonomous nodules.
   • TSH-dependent hyperthyroidism.
   • Activating mutations of the TSH receptor.
Graves’ disease
     Graves’ disease is rare, with an incidence of
    0.8 per 100 000
      children per year.
     It usually occurs in the second decade,
     Is 6-8 times more common in girls
      In up to 60% of cases there is a family history of
     thyroid disease.
  Graves’ disease has been described
in children with other autoimmune
   • diabetes mellitus
   • Addison’s disease
   • vitiligo, systemic lupus
    erythematosis, rheumatoid arthritis,
    myasthenia gravis, periodic
    paralysis, idiopathic
    thrombocytopenia purpura and
    pernicious anemia.
It is caused by stimulation of the TSH receptor by
Clinical features
usually insidious, over several months, but may be acute.
• Anxiety.
• Irritability and hyperactivity.
• Tiredness.
• Deteriorating school performance and handwriting.
• Weight loss in spite of increased appetite.
• Palpitations.
• Heat intolerance.
• Sleep disturbance.
• Diarrhoea.
• Menstrual irregularities or amenorrhoea.
   • Goitre (usually diffuse).
   • Exophthalmos
   • Tachycardia.
   • Hypertension.
   • Facial flushing.
   • Tremor.
   • Sweatiness.
   • Relative tall stature
   • Thyroid bruit.
   • Heart murmur.
Thyroid crisis or storm
a form of thyrotoxicosis characterized by an acute
onset which may be precipitated by surgery,
infections, drug withdrawal/non-compliance and
radioiodine treatment.
The patient develops hyperthermia, severe
tachycardia and restlessness and may become
delirious, comatose or die.
elevated FT4 (or T4) and T3 concentrations, with TSH
Rarely, FT4 (or T4) levels are normal but T3 levels are
 elevated, so called ‘T3 toxicosis’.
 TSH receptor antibodies (TRAb) are elevated and in
  most cases thyroid peroxidase (TPO) antibodies are
  also positive.
 Bone age is usually advanced.
 Thyroid isotope scan
The three modalities of treatment in Graves’ disease are
medical, radioactive iodine and surgery.

1. Medical treatment
     carbimazole or methimazole
       Their antithyroid effect by inhibiting the organifi cation
       of iodine and the coupling of iodotyrosine residues on
       the Tg molecule to generate T3 and T4.

2. Radioactive iodine
     Radioiodine is administered orally and is given with
     the aim of ablating the thyroid gland and inducing

3. Thyroid surgery
Neonatal thyrotoxicosis

This rare condition is caused by the transplacental transfer of
maternal TSH receptor antibodies which stimulate the fetal
and neonatal thyroid.

These usually develop at 24–48 hours of age, but may be
delayed for up to 10 days in babies whose mothers are on
antithyroid drugs which can cross
the placenta.

 Most infants have biochemical thyrotoxicosis with no or few
symptoms but a minority will be severely affected with goitre,
tachycardia, arrhythmias,
hypertension, cardiac failure, increased appetite, weight
loss, diarrhoea, irritability and exophthalmos.
     carbimazole or methimazole
     Chloral hydrate
     In severe cases prednisolone
     The antithyroid drugs may be needed for 6
       to 3 months
Colloid (simple) goitre
  During adolescence the thyroid gland may become
       diffusely enlarged.
  Thyroid function tests and an autoantibody screen
       are normal.
   The goitre usually resolves spontaneously.
  A therapeutic trial may be tried when the goiter is
  large. In some cases, surgery may be required for
Parathyroid Glands
Circulating levels of calcium and phosphate ions are controlled by cells
that sense the levels of these electrolytes in the blood and release
hormones, and effects of these hormones are evident in mobilization of the
minerals from the bones, intestinal absorption, and/or renal wasting.
The majority of the calcium in the body is stored in the bones but it is the
free, ionized calcium in the cells and extracellular fluids that fulfills
physiological roles in cell signaling, nerve function, muscle contraction, and
blood coagulation, among others.
Phosphate is likewise predominantly stored in the bones and regulated by
many of the same factors that influence calcium levels.
The two major hormones regulating calcium and phosphate homeostasis
are 1,25-dihydroxycholecalciferol (a derivative of vitamin D) and parathyroid
hormone; calcitonin is also capable of regulating levels of these ions, but its
full physiologic contribution is unclear.

                                    Ganong's Review of Medical Physiology , 23 edition (July 24, 2009)
1,25-dihydroxycholecalciferol acts to elevate plasma calcium and
phosphate, whereas parathyroid hormone elevates calcium but decreases
phosphate by increasing the latter's renal excretion. Calcitonin lowers
both calcium and phosphate levels.

                                 Ganong's Review of Medical Physiology , 23 edition (July 24, 2009)
 PTH secretion changes in response to acute
 changes in plasma calcium and there is a
 continuous tonic secretion of PTH, which
 maintains plasma ionized calcium at whatever
 level is ‘set’ by the CaSR.

CaSRs present in the PT glands, renal tubule,
 bone, cartilage, and other tissues.

 The calcium concentration is detected by a CaSR
  located on the surface of the parathyroid glands.
PTH release is stimulated by hypocalcaemia and
 inhibited by hypercalcaemia.
Mutations within the CaSR gene result in either
  inactivation or activation of the receptor, which
 result in hyper- and hypocalcemia, respectively.
 Inactivating mutations cause insensitivity
  to calcium so PTH secretion is switched
  off at a higher concentration than normal
  and hypercalcemia results. The resulting
  condition is known as familial
  hypocalciuric hypercalcemia .

  Activating mutations of the receptor
  cause chronic hypocalcemia and
  hypercalciuria, a condition known as
  autosomal-dominant hypocalcemia
PTH stimulates activity of 1α-hydroxylase in
 the kidney, enhancing production of 1,25-
 dihydroxycholecalciferol .
This active form of vitamin D increases the
 intestinal absorption of calcium.

PTH also mobilizes calcium by directly
 enhancing bone resorption, an effect that
 requires 1,25[OH]2D3.
 Within minutes changes in PTH secretion
 affect renal tubular function, increasing
 calcium absorption and phosphate
 excretion, and osteoclastic bone

Isolated hypoparathyroidism
  •PTH deficiency is not associated with other
  endocrine disorders or developmental Defects.
  •Is usually sporadic but may occur on a familial
    (Hypoparathyroidism can be inherited by
    dominant, autosomal recessive, and X-linked
  •The age at onset 1 month to 30 years, but the
  hypoparathyroidism is most commonly diagnosed
  during childhood.

 The Kearns–Sayre syndrome (KSS)
  comprises hypoparathyroidism with
  progressive external ophthalmoplegia,
  pigmentary retinopathy, heart block or
  cardiomyopathy, and proximal myopathy
 DiGeorge syndrome (DGS) consists of PT gland
  hypoplasia, thymic immunodeficiency, congenital
  heart disease and facial anomalies, structures all
  derived from the third and fourth branchial pouches.

 The autosomal-recessive Kenny–Caffey and Sanjad–
  Sakati syndromes as well as that described by
  and Kirk are probably all variants of the same condition
  where hypoparathyroidism is associated with
  short stature and developmental delay.
polyglandular autoimmune type 1
 syndrome,association between
 mucocutaneous candidiasis and

Thyroid surgery

Isolated autoimmune hypoparathyroidism

Familia, often autosomal dominant disease caused
by peripheral resistance to PTH.
 Hypocalcemia occurs despite very elevated PTH
In Type Ia PHP or Albright hereditar osteodystrophy
The characteristic phenotype is
      short stature
      chubby appearance
      developmental delay
      round face
      short distal phalanx of the thumb
   brachymetatarsals and brachymetacarpals
   Dental hypoplasia
      subcutaneous calcifications.
Hypocalcemia is often not diagnosed
until the middle childhood years.
 Inactivating mutations in the α
subunit of the stimulatory protein Gs
are responsible for PTH resistance in
this condition
  Type Ib PHP resembles type Ia except that Gsα subunit is
normal, pointing to a defect in another step of the pathway
that stimulates cAMP.

  Type II PHP is another variant where the phenotypic
features are
absent and infusion of PTH induces the normal elevation of
urinary cAMP but without the expected phosphaturia,
suggesting a defect distal to cAMP production.

  Pseudopseudohypoparathyroidism is Albright
osteodystrophy phenotype without the biochemical
seizure, tetany, numbness, and carpopedal

Decreased serum Ca
Increased serum P
Markedly decreased PTH
Treatment of hypoparathyroidism

Treatment is aimed at maintaining plasma calcium
levels within the lower part of the normal range
without causing hypercalciuria.

The mainstay of treatmentis vitamin D either in its
active form, 1α,25(OH)2D (calcitriol), or the analog
1α-hydroxy-cholecalciferol (alfacalcidol).

Calcium supplements are usually required, which
may enable the dose of alfacalcidol to be reduced.

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