Thyroid Disorders

Endocrine and Metabolic Disorders

Unit-II
Pathophysiology-II

By M. Iqbal
 Objectives
• Review the Anatomy and Physiology of thyroid
gland, hypothalamic pituitary thyroid feedback
system.
• Discuss hyperthyroidism and the following:
• Goiter (non-toxic)
• Cretinism
• Myxedema
• Discuss hyperthyroidism and the following:
• Grave’s disease
• Goiter (toxic)
 Thyroid Anatomy Review
• The thyroid lies over the trachea below larynx.
• The thyroid gland consists of two lobes of
endocrine tissue joined in the middle by a
narrow portion of the gland called isthmus.
• The major Hormone secretory Cells: are
Follicular cells organized into
colloid.
 HORMONES OF THYROID GLAND

Thyroid gland secretes three hormones:

• 1. Tetraiodothyronine or T4 (thyroxine)
• 2. Tri-iodothyronine or T3
• 3. Calcitonin
Both T4 and T3 are iodine-containing derivatives of
amino acid tyrosine.
 Thyroid Hormone

• Half-life
• Thyroid hormones have long half-life. T4 has a
long half life of 7 days. Half-life of T3 is varying
between 10 and 24 hours.
• Rate of Secretion
• T4 = 80 to 90 μg/day
• T3 = 4 to 5 μg/day
• Plasma Level
• Total T3 = 0.12 μg/dL
• Total T4 = 8 μg/dL.
 FUNCTIONS OF THYROID HORMONES

• Thyroid hormones have two major effects on

the body:
• I. To increase basal metabolic rate
• II. To stimulate growth in children.
 Thyroid Disorders
• Hypothyroidism
• Hyperthyroidism
 Hypothyroidism
• Hypothyroidism is caused by any structural or
functional derangement that interferes with
the production of adequate levels of thyroid
hormone.
 Causes of Hypothyroidism
• Primary
• Post ablative: surgery, radioiodine therapy, or external
radiation.
• Hashimoto thyroiditis
• Iodine deficiency.
• Congenital biosynthetic defect
• Drugs (lithium, p-aminosalicylic acid)
• Rare developmental abnormalities of the thyroid (thyroid
dysgenesis)
• Secondary
• Pituitary or hypothalamic failure (uncommon)
 Hypothyroidism

• The clinical manifestations of hypothyroidism

include cretinism and myxedema.
• Cretinism refers to hypothyroidism developing in
infancy or early childhood.
• This disorder was formerly fairly common in
areas of the world where dietary iodine
deficiency is endemic.(continent or country wise)
 Hypothyroidism
• On rare occasions cretinism may also result from
inborn errors in metabolism (e.g., enzyme
deficiencies) that interfere with the biosynthesis of
normal levels of thyroid hormone (sporadic
cretinism).
• Clinical features of cretinism include impaired
development of the skeletal system and central
nervous system, with severe mental retardation,
short stature, coarse facial features, a protruding
tongue, and umbilical hernia, and decreased heart
rate and contraction.
 Hypothyroidism

• Normally, maternal hormones that are critical to

fetal brain development, including T3 and T4,
cross the placenta. If there is maternal thyroid
deficiency before the development of the fetal
thyroid gland, mental retardation is severe.
• In contrast, reduction in maternal thyroid
hormones later in pregnancy, after the fetal
thyroid has developed, allows normal brain
development.
 Hypothyroidism
• Hypothyroidism developing in older children and adults results
in a condition known as myxedema.
• Myxedema, or Gull disease, named after Sir William Gull in
1873. Manifestations of myxedema include apathy and mental
sluggishness that in the early stages of disease may mimic
depression. Individuals with myxedema are listless, cold
intolerant, and often obese.
• Mucopolysaccharide-rich edema accumulates in skin,
subcutaneous tissue, and a number of visceral sites, with
resultant broadening and coarsening of facial features,
enlargement of the tongue, and deepening of the voice. Bowel
motility is decreased, resulting in constipation. Pericardial
effusions are common; in later stages the heart is enlarged,
and heart failure may occur.
 Hypothyroidism

Myxedema Cretinism
• Full blown expression of
• Hypothyroidism
hypothyroidism is called
during fetal
myxedema. Water
development can/
accumulates in the skin,
lead to cretinism.
leading to a condition
called myxedema ( in
adults), in which the skin
has a thickened, puffy
appearance.
 Hypothyroidism
• Pathophysiology of Myxedema
• Myxedema results from the accumulation of
increased amounts of hyaluronic acid and chondroitin
sulfate in the dermis in both lesional and normal skin.
• The mechanism that causes myxedema is still not yet
understood, although animal model studies suggest
that thyroid hormones affect the synthesis and
catabolism of mucopolysaccharides and collagen by
dermal fibroblasts.
 Goiter
• Goiter is a pathological enlarged of thyroid gland.
A goiter occurs whenever either TSH or TSI
excessively stimulates the thyroid gland.
• Goiter may accompany hypothyroidism or
hyperthyroidism, but it needs not be present in
either condition. Knowing the hypothalamus
pituitary thyroid axis and feedback control, we
can predict which types of thyroid dysfunction
will produce a goiter.
 Goiter

• Endemic goiter is due to dietary iodine deficiency.

• Without iodine, the gland cannot synthesize TH.
• Without TH, the pituitary gland receives no
feedback and acts as if the thyroid were
understimulated.
• It produces extra TSH, which stimulates
hypertrophy of the thyroid gland.
• The goiter may be toxic or non-toxic
 Hyperthyroidism

• Hyperthyroidism or thyrotoxicosis is excessive

secretion of thyroid hormone.
• The most common cause of hypersecretion is
Grave’s disease.
 GRAVES DISEASE
• In 1835 Robert Graves reported on his
observations of a disease characterized by
"violent and long continued palpitations in
females" associated with enlargement of the
thyroid gland.
 Graves disease cont...

• Graves disease, the most common cause of endogenous

hyperthyroidism, is characterized by the triad of
thyrotoxicosis, ophthalmopathy, and dermopathy.
• Graves disease is an autoimmune disorder caused by
activation of thyroid epithelial cells by autoantibodies to the
TSH receptor that mimic TSH action.
• The thyroid in Graves disease is characterized by diffuse
hypertrophy and hyperplasia of follicles and lymphoid
infiltrates; glycosaminoglycan deposition and lymphoid
infiltrates characterize the ophthalmopathy and dermopathy.
• Laboratory features include elevations in serum free T3 and
T4, and decreased serum TSH.
 Grave’s Disease cont....

• Pathophysiology:
• Graves disease is an autoimmune disorder caused
by TSI.
• Thyroid-stimulating immunoglobulin (TSI): An IgG
antibody that binds to the TSH receptor and mimics
the action of TSH, stimulating adenyl cyclase, with
resultant increased release of thyroid hormones.
Almost all persons with Graves disease have
detectable amounts of this autoantibody to the
TSH receptor. This antibody is relatively specific for
Graves disease.
Grave’s Disease
 Clinical Features

• The clinical manifestations of Graves disease include those common

to all forms of thyrotoxicosis, as well as those associated uniquely
with Graves disease: diffuse hyperplasia of the thyroid---
thyrotoxicosis, ophthalmopathy, and dermopathy.
• Sympathetic overactivity produces a characteristic wide, staring gaze
and lid lag.
• The ophthalmopathy of Graves disease results in abnormal
protrusion of the eyeball (exophthalmos). The extra-ocular muscles
are often weak. The exophthalmos may persist or progress despite
successful treatment of the thyrotoxicosis, sometimes resulting in
corneal injury.
• The infiltrative dermopathy, or tibial myxedema, is most common in
the skin overlying the shins, where it presents as scaly thickening of
the skin.
 Toxic Goiter (Graves Disease) Thyroid hypersectretion

• toxic goiter (Graves disease), in which auto-antibodies

mimic the effect of TSH on the thyroid, causing thyroid
hypersecretion.
• Toxic goiter (Graves disease) Thyroid hypertrophy and
hypersecretion, occurring when autoantibodies mimic
the effect of TSH and overstimulate the thyroid.
• Results in elevated metabolic rate and heart rate,
nervousness, sleeplessness, weight loss, abnormal heat
sensitivity and sweating, and bulging of the eyes
(exophthalmos) resulting from eyelid retraction and
edema of the orbital tissues.
Grave’s Disease
 Types of Thyroid Dysfunction
Thyroid Cause Plasma Concentrations Goiter
Dysfunction

Hypothyroidism Primary failure of the thyroid gland T3 and T4, TSH Yes

T3 and T4, TSH Yes

Lack of dietary iodine

Secondary to hypothalamic or anterior No

T3 and T4, TRH and/or TSH
pituitary failure

Hyperthyroidism Abnormal presence of thyroid-stimulating T3 and T4, TSH Yes

immunoglobulin (TSI) (Graves’ disease)

Secondary to excess hypothalamic or anterior T3 and T4, TRH and/or TSH Yes
pituitary secretion

Hypersecreting thyroid tumor T3 and T4, TSH No

 Calcitonin
• Calcitonin is secreted by the parafollicular cells
or clear cells (C cells), situated amongst the
follicles in thyroid gland.
• Calcitonin is a polypeptide chain with 32 amino
acids. Its mole cular weight is about 3,400. It is
synthesized from procalcitonin.
• Plasma Level and Half-life
• Plasma level of calcitonin is 1 to 2 ng/dL. It has
a half life of 5 to 10 minutes.
 Calcium Homeostasis

• The homeostasis of calcium, phosphate and

magnesium is influenced by parathyroid
hormone(PTH), and calcitonin (CT), as well as a
sterol hormone, 1,25 dihydroxy cholecalciferol
(1,25 (OH)2D3
 ACTIONS OF CALCITONIN

• 1. On Blood Calcium Level

• Calcitonin plays an important role in controlling the blood calcium
level. It decreases the blood calcium level and thereby counteracts
parathormone. Calcitonin reduces the blood calcium level by acting on
bones, kidneys and intestine.
• i. On bones
• Calcitonin stimulates osteoblastic activity and facilitates the
deposition of calcium on bones. At the same time, it suppresses the
activity of osteoclasts and inhibits the resorption of calcium from
bones. It inhibits even the development of new osteoclasts in bones.
• ii. On kidney
• Calcitonin increases excretion of calcium through urine, by inhibiting
the reabsorption from the renal tubules.
• iii. On intestine
• Calcitonin prevents the absorption of calcium from intestine into the
blood.
Parathyroid Gland Disorder
 Parathyroid Gland

• Human beings have four parathyroid glands, which are

situated on the posterior surface of upper and lower poles of
thyroid gland.
• Parathyroid glands are very small in size, measuring about 6
mm long, 3 mm wide and 2 mm thick, with dark brown color.
• Parathormone (PTH) is secreted by the chief cells of the
parathyroid glands.
• Chemistry
• Parathormone is protein in nature, having 84 amino acids. Its
molecular weight is 9,500.
• Half-life and Plasma Level
• Parathormone has a half-life of 10 minutes. Normal
• plasma level of PTH is about 1.5 to 5.5 ng/dL.
 Functions of PTH
• PTH maintains blood calcium level by acting on:
• 1. Bones
• 2. Kidney
• 3. Gastrointestinal tract.
 HYPOPARATHYROIDISM
• Hyposecretion of PTH is called hypoparathyroidism.
• It leads to hypocalcemia.
• Causes for Hypoparathyroidism
1. Parathyroidectomy
2. Removal of parathyroid glands during surgical removal of
thyroid gland (thyroidectomy)
3. Autoimmune disease
4. Deficiency of receptors for PTH in the target cells.
In this, the PTH secretion is normal or increased
but the hormone cannot act on the target cells. This
condition is called pseudohypoparathyroidism.
 Hypoparathyroidism

• Hypocalcemia and Tetany

• Hypoparathyroidism leads to hypocalcemia, by
decreasing the resorption of calcium from bones.
Hypocalcemia causes neuromuscular
hyperexcitability, resulting in hypocalcemic
tetany.
• Normally, tetany occurs when plasma calcium
level falls below 6 mg/dL from its normal value of
9.4 mg/dL.
 Hypoparathyroidism

• Signs and symptoms of hypocalcemic tetany:

1. Hyper-reflexia and convulsions
• Increase in neural excitability results in hyper-
reflexia (overactive reflex actions) and
convulsive muscular contractions.
• 2. Carpopedal spasm
• i. Flexion at wrist joint
• ii. Flexion at
metacarpophalangeal joints
• iii. Extension at
interphalangeal joints
• iv. Adduction of thumb.
• 3. Laryngeal stridor
• Stridor means noisy breathing. Laryngeal
stridor means a loud crowing sound during
inspiration, which occurs mainly due to
laryngospasm (involuntary contraction of
laryngeal muscles).
• Laryngeal stridor is a common dangerous
feature of hypocalcemic tetany.
• 4. Cardiovascular changes
• i. Dilatation of the heart
• ii. Prolonged duration of ST segment and QT
• interval in ECG
• iii. Arrhythmias (irregular heartbeat)
• iv. Hypotension
• v. Heart failure.
• Latent Tetany
• Latent tetany, also known as subclinical tetany is the
neuromuscular hyperexcitability due to
hypocalcemia that develops before the onset of
tetany.
• It is characterized by general weakness and cramps
in feet and hand.
• Hyperexcitability in these patients is detected by
some signs, which do not appear in normal persons.
• 1. Trousseau sign
• Trousseau sign is the spasm of the hand that is
developed after 3 minutes of arresting the blood flow to
lower arm and hand. The blood flow to lower arm and
hand is arrested by inflating the blood pressure cuff 20
mm Hg above the patient’s systolic pressure.
• 2. Chvostek sign
• Chvostek sign is the twitch of the facial muscles, caused
by a gentle tap over the facial nerve in front of the ear. It
is due to the hyperirritability of facial nerve.
 Hyperparathyroidism – hypercalcemia

• Hypersecretion of PTH is called hyperparathyroidism. It results in

hypercalcemia. Hyperparathyroidism is of three types:
• 1. Primary hyperparathyroidism
• Primary hyperparathyroidism is due to the development of tumor
in one or more parathyroid glands. Sometimes, tumor may
develop in all the four glands.
• 2. Secondary hyperparathyroidism
• Secondary hyperparathyroidism is due to the physiological
compensatory hypertrophy of parathyroid glands, in response to
hypocalcemia which occurs due to other pathological conditions
such as:
• i. Chronic renal failure
• ii. Vitamin D deficiency
• iii. Rickets.
 Hyperparathyroidism Cont....

• 3. Tertiary hyperparathyroidism
• Tertiary hyperparathyroidism is due to
hyperplasia (abnormal increase in the number
of cells) of all the parathyroid glands that
develops due to chronic secondary
hyperparathyroidism.
 Hyperparathyroidism
• Hypercalcemia
• Hypercalcemia is the increase in plasma calcium level.
• It occurs in hyperparathyroidism because of increased resorption
of calcium from bones.
• Signs and symptoms of hypercalcemia
• i. Depression of the nervous system
• ii. Sluggishness of reflex activities
• iii. Reduced ST segment and QT interval in ECG
• iv. Lack of appetite
• v. Constipation.
• Depressive effects of hypercalcemia are noticed when the blood
calcium level increases to 12 mg/dL.
• The condition becomes severe with 15 mg/dL and it becomes
lethal when blood calcium level reaches 17 mg/dL.
 Hyperparathyroidism

• Other effects of hypercalcemia:

• i. Development of bone diseases such as osteitis fibrosa cystica
• Ii. Development of parathyroid poisoning. It is the condition
characterized by severe manifestations that occur when blood
calcium level rises above 15 mg/dL. In hyperparathyroidism, the
concentration of both calcium and phosphate increases leading
to formation of calcium phosphate crystals.
• Concentration of phosphate also increases because, kidney
cannot excrete the excess amount of phosphate resorbed from
the bone.
• iii. Deposition of calcium-phosphate crystals in renal tubules,
thyroid gland, alveoli of lungs, gastric mucosa and in the wall of
the arteries, resulting in dysfunction of these organs.
• Renal stones are formed when it is deposited in kidney.