ENDOCRINE SYSTEM

Dr. ARINDAM KARMAKAR

After this class you should be able to …
• Thyroid swelling –
oName major causes of thyroid swelling
oRelationship of thyroid swellings with Iodine metabolism
After this class you should be able to …
• Thyrotoxicosis –
• Major causes of thyrotoxicosis
• Graves disease –
oPathogenesis
oClinical feature
oHistological features
oSerological and biochemical findings
 After this class you should be able to …
• Hypothyroidism –
• Major causes of hypothyroidism
• What is autoimmune thyroid disease
• What are the major forms of autoimmune thyroid disease
• Hashimoto thyroiditis/ Lymphocytic thyroiditis –
• Etiology
• Pathogenesis
• Clinical feature
• Histological features
• Serological and biochemical features
After this class you should be able to …
• Name the major benign neoplasms of thyroid gland
• Name the major malignant neoplasms of thyroid
gland
• Name the commonest malignant neoplasm of thyroid
gland
• Papillary thyroid carcinoma
• Epidemiology
• Risk/ predisposing factors
• Histologic features
• Routes of spread
After this class you should know a little about …
• Hyperparathyoidism
• Pancreatic cancer
• Adrenal insufficiency
• Cushing syndrome
• Adrenal neoplasm
 THYROID GLAND
Secretion of thyroid hormones (T3 and T4) is
controlled by trophic factors secreted by both the
hypothalamus and the anterior pituitary.
Decreased levels of T3 and T4 stimulate the release
of thyrotropin-releasing hormone (TRH) from the
hypothalamus and thyroid-stimulating hormone
(TSH) from the anterior pituitary, causing T3 and T4
levels to rise. Elevated T3 and T4 levels, in turn,
feed back to suppress the secretion of both TRH
and TSH. TSH binds to the TSH receptor on the
thyroid follicular epithelium, which causes
activation of G-proteins, and cAMP-mediated
synthesis and release of thyroid hormones (T3 and
T4). In the periphery, T3 and T4 interact with the
thyroid hormone receptor to form a hormone-
receptor complex that translocates to the nucleus
and binds to so-called thyroid response elements
on target genes to initiate transcription.
HYPERTHYROIDISM/ THYROTOXICOSIS
Thyrotoxicosis is a hypermetabolic The most common causes of
state caused by elevated circulating
levels of free T3 and T4. thyrotoxicosis are associated
with hyperfunction of the gland and
Because it is caused most commonly
by hyperfunction of the thyroid gland, include the following:
it is often referred to as • Diffuse hyperplasia of the thyroid
hyperthyroidism. associated with Graves disease
Primary hyperthyroidism – intrinsic (approximately 85% of cases)
abnormality of thyroid gland
• Hyperfunctional multinodular goiter
• Hyperfunctional thyroid adenoma
Secondary hyperthyroidism – cause is
outside thyroid e.g. TSH-secreting
tumor of Pituitary.
 CLINICAL FEATURES OF HYPERTHYROIDISM
Dictated by hypermetabolic state due to excess thyroid hormone and
overactivity of sympathetic nervous system.
• Increase in basal metabolic rate – Heat intolerance, warm skin with increased
sweating, increased appetite and weight loss.
• Cardiac – tachycardia, palpitation, cardiomegaly and arrythmia, congestive
heart failure
• Tremor, anxiety, hyperactivity, emotional lability, inability to concentrate and
insomnia.
• Thyroid myopathy – Proximal muscle weakness, decreased muscle mass
• GIT – hypermobility and hyperdefecation
CLINICAL FEATURES OF HYPERTHYROIDISM
• Ocular changes – wide staring gaze and lid lag;
• Proptosis – only in Graves disease
• Bones – osteoporosis
• In Graves disease only -
• Atrophy of skeletal muscle
• Fatty liver
• Generalized lymphadenopathy and lymphoid hyperplasia
CLINICAL FEATURES OF HYPERTHYROIDISM
• Thyroid storm – abrupt onset of severe hyperthyroidism – common in
Graves disease – due to catecholamines – due to stress ( infection,
trauma, emotional hyperactivity, surgery, cessation of antithyroid
drug etc. ) – medical emergency – cause of death: cardiac arrythmia

• Apathetic hyperthyroidism – Hyperthyroidism in older people –

clinical features not prominent – may be only weight loss and
worsening of cardiac disease.
 LABORATORY FINDINGS OF HYPERTHYROIDISM
• Primary hyperthyroidism - Low TSH, high T4
• Secondary hyperthyroidism – High TSH, high T4 → TRH
stimulation test
• Radioiodine scan of thyroid –
• Diffuse increased uptake – Graves disease
• Hot nodule – Toxic adenoma (rare)
• Diffuse low uptake – Thyroiditis
• Cold nodule - Tumor
HYPOTHYROIDISM
Hypothyroidism is a condition caused by a structural or
functional derangement that interferes with the production
of thyroid hormone.
Causes of hypothyroidism
Primary
• Genetic defects in thyroid development (PAX8, FOXE1, TSH receptor mutations;
rare)
• Thyroid hormone resistance syndrome (THRB mutations; rare)
• Postablative - Surgery, radioiodine therapy, or external irradiation
• Autoimmune hypothyroidism
• Hashimoto thyroiditis
• Iodine deficiency
• Drugs (lithium, iodides, p-aminosalicylic acid)
• Congenital biosynthetic defect (dyshormonogenetic goiter; rare)
Secondary (“Central Hypothyroidism”)
• Pituitary failure (rare)
• Hypothalamic failure (rare)
Primary hypothyroidism
• Congenital hypothyroidism –
• Iodine deficiency – ENDEMIC IODINE DEFICIENCY
• Dyshormonogenetic goitre –
• Thyroid agenesis/ hypoplasia –
• Iatrogenic hypothyroidism – Surgery, Radiation, Excess antithyroid drug,
Other drugs (lithium, p-ASA)
• Autoimmune hypothyroidism - most common cause of hypothyroidism
in iodine sufficient areas – mostly due to Hashimoto thyroiditis
Secondary (or central) hypothyroidism
• caused by deficiencies of TSH or, far more uncommonly, TRH.
• Any of the causes of hypopituitarism (e.g., pituitary tumor,
postpartum pituitary necrosis, trauma, and nonpituitary
tumors) or
• hypothalamic damage (e.g., tumors, trauma, radiation
therapy, or infiltrative diseases) can cause central
hypothyroidism.
Cretinism
• Cretinism refers to hypothyroidism that develops in infancy or early
childhood.
• Cause – endemic iodine deficiency (e.g. mountainous areas) &
Dyshormonogenetic goitre
• Iodine deficiency in early pregnancy (before the development of
fetal thyroid gland) hinders brain development of fetus. Iodine
deficiency in later part of pregnancy does not cause mental
disability.
• Clinical feature - severe intellectual disability, short stature, coarse
facial features, a protruding tongue, and umbilical hernia. The
severity of the mental impairment seems to be related to the time at
which thyroid deficiency occurs in utero.
Myxedema
• The term myxedema is applied to hypothyroidism developing in the older
child or adult.
• Weakness, lethargy, sluggish mental and physical activity, increased sleep
• Weight gain
• Cold intolerance
• Decreased exercise tolerance – due to reduced cardiac output
• Skin – Cool, Pale, Non- pitting edema
• Deposition of matrix e.g. HA, GAG in skin, subcutaneous, visceral sites –
nonpitting edema, broadening and coarsening of facial features,
enlargement of tongue, deepening of voice
• Increase in total cholesterol and LDL → Pro-atherogenic
• Biochemical features – low T4, high TSH (Primary) [low TSH
(Secondary)]
HASHIMOTO THYROIDITIS
• Hashimoto thyroiditis is an autoimmune disease that results in
destruction of the thyroid gland and gradual and progressive thyroid
failure.
• Most prevalent between 45 and 65 years of age and is more common in
women than in men (10 : 1 to 20 : 1)
• Can also occur in children → major cause of nonendemic goiter in the
pediatric population.
HASHIMOTO THYROIDITIS - pathogenesis
Hashimoto thyroiditis is caused by a breakdown in self-tolerance to
thyroid autoantigens.
• Genetic susceptibility – CTLA4, PTPN22
• Abnormality in Treg , exposure to sequestered antigens
• Association with Type 1 DM
• Thyroid autoimmunity → progressive depletion of thyroid epithelial
cells and replacement of the thyroid parenchyma by lymphocytic
infiltrates and fibrosis.
Morphology of Hashimoto thyroiditis
• Gross: The thyroid is usually diffusely enlarged. The capsule is intact,
and the gland is well demarcated from adjacent structures. The cut
surface is pale, yellow-tan, firm, and somewhat nodular
Microscopic feature of HT

• Extensive infiltration of the

parenchyma by a mononuclear
inflammatory infiltrate containing
small lymphocytes, plasma cells, and
well-developed germinal centers.
• The thyroid follicles are atrophic and
are lined in many areas by epithelial
cells with abundant eosinophilic,
granular cytoplasm, termed Hürthle
cells, which represent a metaplastic
response of the normally low
cuboidal follicular epithelium to
chronic injury.
CLINICAL FEATURES OF HASHIMOTO
THYROIDITIS
• MIDDLE AGED WOMEN
• DIFFUSE PAINLESS ENLARGEMENT OF THYROID GLAND
• GRADUAL ONSET OF HYPOTHYROIDISM
• LABORATORY FEATURE – High TSH, low T4
• HASHITOXICOSIS – Thyrotoxicosis in the beginning due to destruction of thyroid
follicles and release of thyroid hormone
• LABORATORY FEATURE – low TSH, high T4, T3
• SEROLOGY – Anti-TPO antibody and Anti- Thyroglobulin antibody
• OTHER INVESTIGATIONS – FNAC, HPE
RISK OF – PAPILLARY CARCINOMA OF THYROID, OTHER AUTOIMMUNE DISEASES
Other forms of thyroiditis

• Subacute lymphocytic thyroiditis

• Granulomatous thyroiditis (De Quervain thyroiditis)
• Riedel thyroiditis
 GRAVES DISEASE
The disease is characterized by a triad of clinical findings:
• Hyperthyroidism associated with diffuse enlargement of the gland
• Infiltrative ophthalmopathy and resultant exophthalmos
• Localized, infiltrative dermopathy, sometimes called pretibial myxedema, which
is present in a minority of patients.

❑Graves disease has a peak incidence between 20 and 40 years of age.

❑Women are affected as much as 10 times more frequently than men.
Pathogenesis
• Autoantibody to TSH receptor (most commonly Thyroid stimulating
immunoglobulin) → increased release of Thyroid hormones
• Genetic susceptibility – CTLA4, PTPN22, IL2RA
• Association with other autoimmune diseases
• Infiltrative ophthalmopathy: CD4+ T cells secrete cytokines →
fibroblasts proliferate & secrete matrix material (GAG) + INFILTRATION
by mononuclear cell + EDEMA + SWELLING OF EXTRAOCULAR
MUSCLES + FATTY INFILTRATION → EXOPTHALMOS
MORPHOLOGY OF GD
• GROSS: The thyroid gland is usually symmetrically enlarged due to diffuse
hypertrophy and hyperplasia of thyroid follicular epithelial cells. Increases in
weight to over 80 g are not uncommon. On cut section, the parenchyma has
a soft, meaty appearance resembling muscle.
• HISTOLOGY: Follicle epithelial cells in untreated cases are tall and more
crowded than usual. This crowding often results in the formation of small
papillae that project into the follicle lumen and encroach on the colloid,
sometimes filling the follicles. Such papillae lack fibrovascular cores, in
contrast to those of papillary carcinoma. The colloid within the follicle
lumen is pale, with scalloped margins. Lymphoid infiltrates, consisting
predominantly of T cells, along with scattered B cells and mature plasma
cells, are present throughout the interstitium. Germinal centers are
common.
DIFFUSE AND MULTINODULAR
GOITER
• Diffuse Nontoxic (Simple) Goiter
• Multinodular Goiter
THYROID TUMOURS
• Solitary nodules, nodules in younger patients, and nodules in males are
more likely to be neoplastic.
• A history of radiation treatment to the head and neck region is
associated with an increased incidence of thyroid malignancy.
• Functional nodules that take up radioactive iodine in imaging studies (hot
nodules) are much more likely to be benign.
THYROID ADENOMAS
• Adenomas of the thyroid are typically discrete, solitary masses, derived
from follicle epithelium, and hence they are also known as follicular
adenomas.
• Clinically, follicular adenomas can be difficult to distinguish from
dominant nodules of follicular hyperplasia or from the less common
follicular carcinomas.
• In general, follicular adenomas are not forerunners to carcinomas.
• Although the vast majority of adenomas are nonfunctional, a small
minority produces thyroid hormones and causes clinically apparent
thyrotoxicosis.
• Hormone production in functional adenomas (called toxic adenomas) is
independent of TSH stimulation.
FOLLICULAR ADENOMA
ONCOCYTOMA/ HURTHLE CELL ADENOMA
 Thyroid Carcinomas
Major subtypes of thyroid carcinoma:
• Papillary thyroid carcinoma (PTC) - This category includes the newly
described lesion known as “noninvasive follicular thyroid neoplasm with
papillary-like nuclear features,” or NIFTP - a low-grade neoplasm with
such a minimal risk of recurrence that “carcinoma” has been removed
from its name.
• Follicular carcinoma (10% to 15% of cases)
• Poorly differentiated and anaplastic (undifferentiated) carcinoma
(<5% of cases)
• Medullary carcinoma (5% of cases)
 DRIVER MUTATIONS
• PAPILLARY CARCINOMA – RET/PTC & BRAF
• FOLLICULAR CARCINOMA – RAS
• ANAPLASTIC CARCINOMA – P53 & TERT
• MEDULLARY CARCINOMA – RET; Familial tumor in MEN -2 SYNDROME
(not RET/PTC of papillary carcinoma)

• Ionizing radiation is a risk factor

PAPILLARY
CARCINOMA
FOLLICULAR
CARCINOMA
MEDULLARY
CARCINOMA
PARATHYROID ADENOMA
Most common cause of
primary
hyperparathyroidism

Other causes –
• Parathyroid hyperplasia
• Parathyroid carcinoma
Hypoparathyroidism –
• Surgical
• Autoimmune
• Autosomal dominant
• Familial isolated hypoparathyroidism
• Congenital absence
PITUITARY GLAND
Posterior Pituitary:
ADH
OXYTOCIN
Gigantism
• When GH excess occurs prior to epiphyseal closure, gigantism is
produced.
• Gigantism, therefore, occurs in prepubertal boys and girls and is much
less frequent than acromegaly.
• The main clinical feature in gigantism is the excessive and
proportionate growth of the child.
• There is enlargement as well as thickening of the bones resulting in
considerable increase in height and enlarged thoracic cage.
 Acromegaly
• Acromegaly results when there is overproduction of GH in adults following
cessation of bone growth and is more common than gigantism.
• The term ‘acromegaly’ means increased growth of extremities (acro=extremity).
• There is enlargement of hands and feet, coarseness of facial features with increase
in soft tissues, prominent supraorbital ridges and a more prominent lower jaw
which when clenched results in protrusion of the lower teeth in front of upper teeth
(prognathism).
• Other features include enlargement of the tongue and lips, thickening of the skin
and kyphosis.
• Sometimes, a few associated features such as TSH excess resulting in thyrotoxicosis,
and gonadotropin insufficiency causing amenorrhoea in the females and impotence
in the male, are found.
PITUITARY DWARFISM
• Severe deficiency of GH in children before growth is completed results in retarded
growth and pituitary dwarfism.
• Most commonly, isolated GH deficiency is the result of an inherited autosomal
recessive disorder.
• Less often, it may be due to a pituitary adenoma or craniopharyngioma,
infarction and trauma to the pituitary.
• Clinical features of inherited cases of pituitary dwarfism appear after one year of
age.
• Proportionate retardation in growth of bones,
• normal mental state for age,
• poorly-developed genitalia, delayed puberty and
• episodes of hypoglycaemia.
• Pituitary dwarf must be distinguished from hypothyroid dwarf (cretinism) in
which there is achondroplasia and mental retardation.
Adrenal gland
• Adrenal cortex

• Adrenal medulla
Cushing Syndrome – Elevated glucocorticoid
levels
• Exogenous – iatrogenic
• Endogenous
• ACTH dependent
• ACTH independent
Causes of endogenous Cushing syndrome
Clinical features of Cushing syndrome
• Gradual onset
• Weight gain
• Hypertension
• Central obesity, buffalo hump,
moon facies
• Proximal muscle weakness
• Osteoporosis
• Poor wound healing, striae
• Secondary diabetes
Adrenocortial insufficiency
Adrenal tumors
Adrenal cortex Adrenal medulla
• Adrenocortical adenoma • Pheochromocytoma
• Adrenocortical carcinoma
Multiple Endocrine Neoplasia Syndromes
The MEN syndromes are a group of inherited diseases resulting in proliferative
lesions (hyperplasia, adenomas, and carcinomas) of multiple endocrine organs.
• Tumors occur at a younger age than sporadic tumors.
• Involve multiple endocrine organs, either synchronously or metachronously.
Even in one organ, the tumors are often multifocal.
• The tumors are usually preceded by an asymptomatic stage of hyperplasia
involving the cell of origin. For example, individuals with MEN-2 almost
universally demonstrate C-cell hyperplasia in the thyroid parenchyma adjacent
to medullary thyroid carcinomas.
• These tumors are usually more aggressive and recur in a higher proportion of
cases than do similar sporadic endocrine tumors.
MULTIPLE ENDOCRINE NEOPLASIA, TYPE 1/ Wermer
Syndrome
3 ‘p’ s –
• Parathyroid – hyperplasia and adenoma
• Pancreas – Zollinger-Ellison Syndrome (Gastrinoma – commonly in
duodenum) and Hypoglycemia & neurologic manifestation (Insulinoma)
• Pituitary – Prolactinoma and GH secreting tumors.

MEN-1 syndrome is caused by germline mutations in the MEN1 tumor

suppressor gene, which encodes a protein called menin.
MULTIPLE ENDOCRINE NEOPLASIA, TYPE 2
MEN- 2A / Sipple syndrome MEN- 2B
• Pheochromocytoma • Pheochromocytoma
• Medullary carcinoma of thyroid • Medullary carcinoma of thyroid –
multifocal and more aggressive
• Parathyroid hyperplasia • neuromas or ganglioneuromas involving the
skin, oral mucosa, eyes, respiratory tract,
and gastrointestinal tract,
• Marfanoid habitus, with long axial skeletal
• Germline gain-of-function features and hyperextensible joints
mutations in the RET
protooncogene. • Germline missense mutation leading to a
single amino acid change in RET, distinct
from the mutations that are seen in
MEN-2A
MEN -4
• Like MEN-1 but with germline CDKN1B mutation → reduced p27
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