CHAPTER 24: THE ENDOCRINE SYSTEM

I. PITUITARY GLAND

MEN-1 (WERMER SYNDROME)

Genetics:

 Germline mutations in MEN1 tumor suppressor gene (encodes

menin protein).

Clinical Features: Triad of P's

Parathyroid: Primary hyperparathyroidism (most common manifestation, 80-95% of

patients).

Pancreas: Endocrine tumors (often aggressive, may present with metastatic

disease).

Pituitary: Prolactinomas (most frequent anterior pituitary tumor), somatotropin-

secreting tumors (leading to acromegaly).

Other Features:

 Duodenal gastrinomas (most common site).

 Carcinoid tumors, thyroid and adrenocortical adenomas,

lipomas.

Pathophysiology:

 Menin is involved in several transcription factor complexes that

regulate tumorigenesis.

 Loss-of-function mutations in MEN1 lead to constitutive

activation of JunD and upregulated expression of HOX genes.

MEN-2

Genetics:

 Germline gain-of-function mutations in RET proto-oncogene.

Subtypes:

MEN-2A (Sipple Syndrome)

Clinical Features:

 Medullary carcinoma of the thyroid (almost 100% of patients,

often multifocal).

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Pheochromocytomas (40-50% of patients, often bilateral).

Parathyroid hyperplasia (10-20% of patients).

Pathophysiology:

RET encodes a receptor tyrosine kinase that transmits growth and differentiation
signals.

Gain-of-function mutations lead to constitutive activation of RET.

MEN-2B

Clinical Features:

Medullary thyroid carcinomas (more aggressive than in MEN-2A).

Pheochromocytomas.

Neuromas or ganglioneuromas (involving skin, oral mucosa, eyes, respiratory tract,

and gastrointestinal tract).

Marfanoid habitus.

Pathophysiology:

Germline missense mutation affecting the tyrosine kinase domain of RET.

Constitutive activation of RET in the absence of ligand.

OTHER PITUITARY DISORDERS

DIABETES INSIPIDUS:

Genetics:

 Mutations in genes involved in vasopressin synthesis, secretion, or

action.

Clinical Features:

 Polyuria, polydipsia, hypernatremia.

PROLACTINOMAS:

Clinical Features:

 Galactorrhea, amenorrhea, infertility, hypogonadism.

ACROMEGALY:

Clinical Features:

 Enlargement of hands, feet, and facial bones, headaches, joint pain,

sleep apnea, diabetes, hypertension.

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CUSHING SYNDROME:

Clinical Features:

 Weight gain, moon facies, buffalo hump, hypertension,

hyperglycemia, striae, muscle weakness, osteoporosis, hirsutism,
menstrual irregularities.

II. THYROID GLAND

HYPERTHYROIDISM

Etiology:

 Graves Disease: Autoimmune disorder characterized by

autoantibodies against TSH receptor.

o Pathophysiology:
 Autoantibodies stimulate TSH receptor leading to increased thyroid
hormone production.

 Toxic Multinodular Goiter: Hyperplasia of thyroid follicular cells

leading to increased thyroid hormone production.

o Pathophysiology:
 Hyperplasia of thyroid follicular cells leads to increased thyroid
hormone production.

 Toxic Adenoma: Solitary hyperfunctioning thyroid adenoma.

o Pathophysiology:
 Autonomous thyroid hormone production by the adenoma.

Clinical Features:

 Increased metabolic rate, heat intolerance, weight loss, palpitations,

tachycardia, anxiety, tremors, insomnia, diarrhea, goiter,
exophthalmos (Graves Disease).

HYPOTHYROIDISM

Etiology:

 Hashimoto Thyroiditis: Autoimmune disorder leading to

destruction of thyroid follicular cells.

o Pathophysiology:

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  Autoantibodies attack thyroid follicular cells leading to decreased
thyroid hormone production.

 Iodine Deficiency: Decreased thyroid hormone production due to

lack of iodine.

o Pathophysiology:
 Iodine is essential for thyroid hormone synthesis.

 Surgical Removal or Radiation Therapy: Decreased thyroid

hormone production due to reduction of thyroid tissue.

o Pathophysiology:
 Reduced thyroid tissue leads to decreased thyroid hormone
production.

Clinical Features:

 Decreased metabolic rate, cold intolerance, weight gain, fatigue,

lethargy, constipation, dry skin, hair loss, bradycardia, goiter,
myxedema (severe hypothyroidism).

THYROID NEOPLASMS

Types:

 Papillary Thyroid Carcinoma: Most common type, slow-growing,

usually confined to thyroid gland.

o Clinical Features:
 Usually asymptomatic, may present with goiter, nodules, or
dysphagia.
o Pathophysiology:
 Mutations in genes involved in thyroid hormone synthesis or cell
growth.

 Follicular Thyroid Carcinoma: Second most common type, may

metastasize to other organs.

o Clinical Features:
 Usually asymptomatic, may present with goiter, nodules, or
dysphagia.
o Pathophysiology:
 Mutations in genes involved in thyroid hormone synthesis or cell
growth.

 Medullary Thyroid Carcinoma: Arises from C-cells, may produce

calcitonin.

o Clinical Features:
 May present with goiter, nodules, or symptoms of calcitonin
excess.

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 o Pathophysiology:
 Mutations in the RET proto-oncogene.

 Anaplastic Thyroid Carcinoma: Highly aggressive, often

metastasize to other organs.

o Clinical Features:
 Rapidly growing, may present with dysphagia, hoarseness, or
respiratory distress.

III. PARATHYROID GLAND

HYPERPARATHYROIDISM

Etiology:

 Primary Hyperparathyroidism: Excess PTH production due to

parathyroid adenoma, hyperplasia, or carcinoma.

o Pathophysiology:
 Increased PTH leads to increased bone resorption and increased
calcium reabsorption in the kidneys.

 Secondary Hyperparathyroidism: Increased PTH production in

response to hypocalcemia (e.g., vitamin D deficiency, chronic
kidney disease).

o Pathophysiology:

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  Increased PTH is a compensatory mechanism to maintain calcium
levels in the face of hypocalcemia.

 Tertiary Hyperparathyroidism: Autonomous hypersecretion of

PTH by hyperplastic parathyroid glands (seen in long-standing
secondary hyperparathyroidism).

o Pathophysiology:
 Autonomous hypersecretion of PTH leads to persistent
hypercalcemia.

Clinical Features:

 Hypercalcemia, hypophosphatemia, increased bone resorption,

nephrolithiasis, pancreatitis, fatigue, muscle weakness, bone pain,
constipation, depression, anxiety, cognitive impairment.

HYPOPARATHYROIDISM

Etiology:

 Autoimmune Hypoparathyroidism: Destruction of parathyroid

glands by autoimmune process.

 Surgical Removal or Radiation Therapy: Decreased PTH

production due to reduction of parathyroid tissue.

 Congenital Hypoparathyroidism: Defective development of

parathyroid glands.

Clinical Features:

 Hypocalcemia, hyperphosphatemia, increased neuromuscular

excitability (e.g., tetany, seizures, muscle cramps), fatigue,
lethargy, dry skin, hair loss, brittle nails, cataracts, dental enamel
defects.

Pathophysiology:

 Decreased PTH leads to decreased calcium reabsorption in the

kidneys and decreased bone resorption.

IV. ADRENAL CORTEX

CUSHING SYNDROME

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Etiology:

 ACTH-dependent Cushing Syndrome:

o Pituitary Adenoma: Most common cause, excess ACTH

production.

o Ectopic ACTH Production: Non-pituitary tumors (e.g., small

cell lung cancer) producing ACTH.

o ACTH-independent Cushing Syndrome: Adrenal adenoma

or carcinoma producing cortisol.

Clinical Features:

 Weight gain, moon facies, buffalo hump, hypertension,

hyperglycemia, striae, muscle weakness, osteoporosis, hirsutism,
menstrual irregularities.

Pathophysiology:

 Increased cortisol production leads to hyperglycemia, hypertension,

and other metabolic abnormalities.

ADRENAL INSUFFICIENCY (ADDISON DISEASE)

Etiology:

 Primary Adrenal Insufficiency: Destruction of adrenal cortex

(e.g., autoimmune disease, tuberculosis, fungal infections).

 Secondary Adrenal Insufficiency: Decreased ACTH production

(e.g., pituitary tumor, pituitary surgery, pituitary radiation) leading
to decreased cortisol production.

Clinical Features:

 Fatigue, weakness, anorexia, weight loss, hypotension,

hypoglycemia, hyperpigmentation (primary adrenal insufficiency),
hyponatremia, hyperkalemia, salt craving, nausea, vomiting,
abdominal pain, diarrhea, menstrual irregularities.

Pathophysiology:

 Decreased cortisol production leads to hypoglycemia, hypotension,

and other metabolic abnormalities.

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CONGENITAL ADRENAL HYPERPLASIA

Genetics:

 Autosomal recessive disorders involving defects in enzymes

involved in cortisol synthesis.

Clinical Features:

 Variable depending on the specific enzyme deficiency, may present

with salt wasting, ambiguous genitalia, or precocious puberty.

Pathophysiology:

 Defective cortisol synthesis leads to increased ACTH production and

adrenal hyperplasia.

V. ADRENAL MEDULLA

PHEOCHROMOCYTOMA

Genetics:

 Sporadic: Most common type, usually benign.

 Familial: Associated with germline mutations in genes involved in

growth factor receptor pathway signaling (e.g., RET, NF1) or HIF-
1α/HIF-2α stability (e.g., VHL, EPAS1)).

Clinical Features:

 Hypertension (often paroxysmal), palpitations, headaches,

sweating, tremor, anxiety, abdominal or chest pain, nausea,
vomiting, orthostatic hypotension, hyperglycemia,
hypermetabolism.

Pathophysiology:

 Excess catecholamine production (e.g., epinephrine,

norepinephrine) leads to hypertension, palpitations, and other
symptoms.

 May secrete other hormones (e.g., ACTH, somatostatin) leading to

additional clinical features.

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VI. OTHER ENDOCRINE DISORDERS

DIABETES MELLITUS

Types:

 Type 1 Diabetes: Autoimmune destruction of beta cells in the

pancreas leading to absolute insulin deficiency.

o Pathophysiology:
 Lack of insulin leads to hyperglycemia, ketoacidosis, and other
metabolic abnormalities.

 Type 2 Diabetes: Insulin resistance in peripheral tissues combined

with relative insulin deficiency.

o Pathophysiology:
 Insulin resistance prevents glucose uptake in peripheral tissues
leading to hyperglycemia.

 Gestational Diabetes: Insulin resistance developing during

pregnancy.

o Pathophysiology:
 Hormonal changes during pregnancy lead to insulin resistance.

Clinical Features:

 Hyperglycemia, polyuria, polydipsia, polyphagia, weight loss,

fatigue, blurred vision, frequent infections, slow-healing wounds,
ketoacidosis (Type 1 Diabetes).

HYPOGLYCEMIA

Etiology:

 Insulinoma: Tumor of beta cells in the pancreas producing insulin.

 Other Causes: Hypoglycemic agents, alcohol, prolonged fasting,

severe liver disease, adrenal insufficiency.

Clinical Features:

 Symptoms of hypoglycemia (e.g., sweating, tremor, palpitations,

anxiety, confusion, seizures, coma) may be triggered by exercise,
stress, or fasting.

Pathophysiology:

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  Excess insulin leads to hypoglycemia.

ACROMEGALY

Etiology:

 Usually due to pituitary adenoma producing growth hormone.

Clinical Features:

 Enlargement of hands, feet, and facial bones, headaches, joint pain,

sleep apnea, diabetes, hypertension, goiter, exophthalmos.

Pathophysiology:

 Excess growth hormone leads to overgrowth of tissues and other

clinical features.

CUSHING SYNDROME

Etiology:

 Usually due to pituitary adenoma producing ACTH.

Clinical Features:

 Weight gain, moon facies, buffalo hump, hypertension,

hyperglycemia, striae, muscle weakness, osteoporosis, hirsutism,
menstrual irregularities.

Pathophysiology:

 Increased cortisol production leads to hyperglycemia, hypertension,

and other metabolic abnormalities.

ADRENAL INSUFFICIENCY (ADDISON DISEASE)

Etiology:

 Usually due to autoimmune destruction of adrenal cortex.

Clinical Features:

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  Fatigue, weakness, anorexia, weight loss, hypotension,
hypoglycemia, hyperpigmentation, hyponatremia, hyperkalemia,
salt craving, nausea, vomiting, abdominal pain, diarrhea, menstrual
irregularities.

Pathophysiology:

 Decreased cortisol production leads to hypoglycemia, hypotension,

and other metabolic abnormalities.

CONGENITAL ADRENAL HYPERPLASIA

Genetics:

 Autosomal recessive disorders involving defects in enzymes

involved in cortisol synthesis.

Clinical Features:

 Variable depending on the specific enzyme deficiency, may present

with salt wasting, ambiguous genitalia, or precocious puberty.

Pathophysiology:

 Defective cortisol synthesis leads to increased ACTH production and

adrenal hyperplasia.

VII. KEY POINTS TO REMEMBER

Endocrine disorders are often chronic conditions requiring long-term

management.

Diagnosis is based on clinical history, physical examination, and

laboratory tests.

Treatment may involve medication, surgery, or lifestyle modifications.

Genetic testing is important for identifying individuals at risk for familial

endocrine disorders.

Early diagnosis and treatment are essential for preventing complications

and improving outcomes.

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