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Endocrine Diseases - Complete Guide from Endocrine Physiology

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TYPES OF ENDOCRINE DISORDERS (Overview)

1. Hormone Deficiency - Destruction of glandular tissue (often autoimmune), inherited mutations in hormone synthesis, or lack of precursors (e.g., iodine deficiency causing hypothyroidism)
2. Hormone Excess - Overproduction from tumors, ectopic secretion, or hyperplasia
3. Hormone Resistance - Adequate hormone levels but target tissues fail to respond (e.g., Type 2 diabetes); often driven by receptor mutations or signaling pathway failure

Ganong's Review of Medical Physiology, p. 303

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I. PANCREATIC / GLUCOSE DISORDERS

1. Type 1 Diabetes Mellitus (Insulin-Dependent)

• Cause: Autoimmune destruction of pancreatic beta cells, leading to complete or near-complete absence of insulin secretion. Viral infections and hereditary susceptibility also contribute. Often presents before age 14 ("juvenile diabetes").
• Pathophysiology: Without insulin, glucose cannot enter most peripheral cells. Blood glucose rises to 300-1200 mg/100 mL. Cells switch to fat and protein catabolism.
• Key Effects:
  • Glucosuria - blood glucose exceeds the renal threshold (~200 mg/dL), spilling into urine
  • Osmotic diuresis and dehydration - glucose in tubules pulls water out osmotically; severe cell dehydration occurs
  • Ketoacidosis - fat mobilization leads to excess acetoacetic acid, beta-hydroxybutyric acid, and acetone. Blood pH may fall to 7.0 or below (life-threatening)
  • Protein depletion - muscle and tissue proteins are broken down for gluconeogenesis
  • Atherosclerosis - excessive fat metabolism increases cholesterol and LDL; worsens vascular disease
• Chronic Complications: Retinopathy, nephropathy, neuropathy (from chronic hyperglycemia damaging capillary basement membranes)
• Treatment: Insulin replacement (multiple daily injections or continuous pump)

Guyton and Hall Textbook of Medical Physiology, p. 973

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2. Type 2 Diabetes Mellitus (Non-Insulin-Dependent)

• Cause: Insulin resistance in target tissues (muscle, liver, adipose), with a relative deficiency of insulin secretion. Strongly linked to obesity. Most common endocrine disorder of the 21st century.
• Mechanism: Reduced activation of phosphatidylinositol 3-kinase and other intracellular effector pathways that mediate insulin's actions. Feedback loops that suppress insulin secretion are similarly desensitized, leading to compensatory hyperinsulinemia initially.
• Effects: Similar to Type 1 but slower onset. Hyperglycemia, dyslipidemia, hypertension (metabolic syndrome). High maternal insulin levels in gestational Type 2 DM stimulate fetal overgrowth (macrosomia).
• Treatment: Lifestyle modification, oral hypoglycemic agents (metformin, etc.), insulin in advanced cases

Ganong's Review of Medical Physiology, p. 303; Guyton & Hall, p. 973

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3. Hypoglycemia

• Cause: Excessive insulin secretion (insulinoma), administration of excess exogenous insulin, or starvation.
• Types:
  • Neurogenic (adrenergic) symptoms - sweating, tremor, palpitations (from catecholamine release)
  • Neuroglycopenic symptoms - confusion, seizures, loss of consciousness (from brain glucose deprivation)
• Insulinoma: Tumor of pancreatic beta cells secreting insulin autonomously; causes episodic severe hypoglycemia
• Neonatal hypoglycemia: Infants of diabetic mothers have beta cell hyperplasia from intrauterine hyperinsulinism; blood glucose may fall to <20 mg/dL after birth

Ganong's, p. 303; Guyton & Hall (neonatal), p. 1056

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II. THYROID DISORDERS

4. Hyperthyroidism (Thyrotoxicosis)

• Cause:
  • Graves Disease (most common): Autoimmune - antibodies called Thyroid-Stimulating Immunoglobulins (TSIs) bind TSH receptors and activate them continuously (for up to 12 hours vs. 1 hour for TSH). This suppresses TSH to near zero.
  • Toxic adenoma: A secreting thyroid tumor (autonomous); suppresses rest of gland via feedback. Not associated with autoimmune markers.
  • Multinodular toxic goiter
• Clinical Features (from excess thyroid hormone):
  • High excitability, nervousness, insomnia with extreme fatigue
  • Intolerance to heat, increased sweating
  • Weight loss (sometimes extreme)
  • Diarrhea, muscle weakness, tremor of hands
  • Exophthalmos (in Graves): Retro-orbital edematous swelling pushes eyeballs forward; affects ~1/3 of patients. Can cause corneal ulceration, optic nerve stretch, and visual loss.
• Diagnosis: Low/absent TSH, elevated T3/T4
• Treatment: Antithyroid drugs (propylthiouracil, methimazole), radioactive iodine, or thyroidectomy

Guyton and Hall, p. 939

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5. Hypothyroidism

• Types:
  • Hashimoto Disease: Most common form; autoimmune thyroiditis destroys the gland progressively, leading to fibrosis and absent hormone secretion
  • Endemic (Iodine-Deficiency) Goiter: Insufficient dietary iodine prevents T3/T4 synthesis; TSH rises dramatically (negative feedback lost), causing massive thyroid enlargement (10-20x normal). Classic in Swiss Alps, Andes, Great Lakes regions
  • Idiopathic Nontoxic Colloid Goiter: Enlarged thyroid without clear iodine deficiency; often due to subtle enzyme defects
  • Enzymatic defects: Deficient iodide trapping, peroxidase deficiency, defective tyrosine coupling, or deiodinase deficiency
• Clinical Features: Decreased metabolism, weight gain, cold intolerance, constipation, dry skin, bradycardia, myxedema (accumulation of mucopolysaccharides in subcutaneous tissues)
• Myxedema coma: End-stage severe hypothyroidism - extreme bradycardia, hypothermia, respiratory failure, death

Guyton and Hall, p. 940; Medical Physiology (BOX 49-3)

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6. Cretinism (Congenital Hypothyroidism)

• Cause: Absent thyroid hormone secretion in fetal life or early infancy. May be due to thyroid agenesis, enzyme defects, or severe iodine deficiency in the mother.
• Features: Severe intellectual disability, stunted bone growth (skeletal dysplasia), failure of sexual maturation. Bones grow poorly and the brain fails to develop normally.
• Treatment: Must be started early in life; thyroid hormone replacement

Guyton and Hall, p. 1056 (fetal/neonatal)

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III. ADRENAL CORTEX DISORDERS

7. Addison Disease (Primary Adrenocortical Insufficiency)

• Cause: ~80% autoimmune destruction of all zones of adrenal cortex; also tuberculosis, metastatic cancer, or adrenal agenesis. Loss of all three cortical products: cortisol, aldosterone, and adrenal androgens.
• Key Features (from Costanzo's table):

• Adrenal Crisis: A stress event (infection, surgery, trauma) that a normal person handles by increasing cortisol output; an Addison patient cannot mount this response and may die rapidly
• Treatment: Lifelong glucocorticoid and mineralocorticoid replacement (cortisol + fludrocortisone)

Costanzo Physiology, p. 440; Guyton & Hall, p. 957

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8. Cushing Syndrome (Hyperadrenalism / Glucocorticoid Excess)

• Causes:
  1. Cushing Disease (pituitary adenoma secreting excess ACTH - most common cause)
  2. Hypothalamic dysfunction with excess CRH
  3. Ectopic ACTH secretion (e.g., small cell lung carcinoma)
  4. Adrenal adenoma/carcinoma (primary, ACTH-independent)
  5. Iatrogenic - prolonged glucocorticoid therapy (e.g., for rheumatoid arthritis)
• Dexamethasone Suppression Test: Low-dose dexamethasone does NOT suppress ACTH in pituitary adenoma (unlike normal); high-dose CAN suppress it. Ectopic ACTH tumors do not suppress at any dose.
• Clinical Features:
  • Central obesity with "buffalo hump" (fat over upper back/thorax)
  • Moon face (edematous, rounded appearance)
  • Supraclavicular fat pads
  • Purple abdominal striae
  • Muscle wasting and weakness
  • Hyperglycemia (gluconeogenesis)
  • Osteoporosis (bone resorption)
  • Hypertension
  • Virilization and menstrual disorders in women (from excess androgens)
• Treatment: Surgical removal of causative tumor; ketoconazole or metyrapone for medical management

Guyton and Hall, p. 958; Costanzo Physiology, p. 440

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9. Conn Syndrome (Primary Hyperaldosteronism)

• Cause: Aldosterone-secreting adrenal adenoma (or bilateral adrenal hyperplasia)
• Features:
  • Hypertension (from Na+ and water retention)
  • Hypokalemia (from excessive K+ secretion)
  • Metabolic alkalosis
  • Decreased renin levels (aldosterone suppresses renin via volume expansion)
• Treatment: Aldosterone antagonist (spironolactone) or surgical excision

Costanzo Physiology (Table 9.12)

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10. Congenital Adrenal Hyperplasia (21β-Hydroxylase Deficiency - most common)

• Cause: Enzyme defect blocks cortisol and aldosterone synthesis; ACTH rises (feedback), driving adrenal hyperplasia and accumulation of androgenic precursors (androgens synthesized instead)
• Features:
  • Virilization of female infants (ambiguous genitalia)
  • Early acceleration of linear growth (then premature fusion)
  • Early pubic/axillary hair
  • Glucocorticoid and mineralocorticoid deficiency symptoms
• 17α-Hydroxylase Deficiency (rarer):
  • No sex hormones or cortisol; excess mineralocorticoids
  • Lack of pubic/axillary hair in females; hypertension from mineralocorticoid excess

Costanzo Physiology (Table 9.12)

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11. Pheochromocytoma

• Cause: Tumor (benign or malignant) of adrenal medullary or extra-adrenal chromaffin tissue; secretes catecholamines (epinephrine + norepinephrine) in an unregulated, autonomous fashion
• Clinical Features:
  • Paroxysmal (episodic) hypertension - sudden severe spikes
  • Tachycardia, palpitations
  • Severe headache
  • Diaphoresis (sweating)
  • Anxiety, tremor
  • Glucose intolerance (catecholamines are counter-regulatory)
• Diagnosis: Elevated serum and urinary catecholamines and their metabolites (metanephrines, VMA)
• Treatment: Surgical resection; if bilateral adrenalectomy required, lifelong hormone replacement needed

Medical Physiology (BOX 50-5), p. 1518

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IV. PITUITARY DISORDERS

12. Gigantism

• Cause: GH-secreting pituitary adenoma (somatotrope adenoma) developing before puberty (while epiphyses are open)
• Features: Extraordinary height; abnormal linear growth. Internal organs also enlarge.
• Treatment: Somatostatin analogues (octreotide), surgical removal of adenoma, GH receptor antagonist (pegvisomant)

Ganong's Review of Medical Physiology, p. 332

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13. Acromegaly

• Cause: Same GH-secreting pituitary adenoma but developing after puberty (epiphyses closed; linear growth not possible)
• Features:
  • Enlarged hands, feet, jaw (prognathism), brow protrusion
  • Vertebral changes (osteoarthritis)
  • Soft tissue swelling and hirsutism
  • Co-secretion of prolactin in 20-40% of cases
  • Abnormal glucose tolerance in ~25%; frank diabetes in 4%
  • Can be fatal if untreated (cardiac failure, airway obstruction)
• Rare causes: Extra-pituitary GH-secreting tumors, hypothalamic GHRH-secreting tumors
• Treatment: Somatostatin analogues, surgery, GH receptor antagonist

Ganong's Review of Medical Physiology, p. 332

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14. Dwarfism (Short Stature - GH-related)

• Types:
  • GHRH deficiency - growth hormone response to exogenous GHRH is normal
  • GH deficiency - from pituitary somatotrope abnormalities
  • Laron Dwarfism (GH Insensitivity): Normal/elevated GH but loss-of-function mutations in GH receptors; markedly reduced IGF-1
  • IGF-1 deficiency
  • Hypothyroid dwarfism (cretinism): From childhood hypothyroidism
  • Gonadal dysgenesis (Turner Syndrome, XO): Short stature with ovarian failure
  • Achondroplasia: Most common dwarfism overall; autosomal dominant mutation in FGFR3; short limbs with normal trunk
  • Psychosocial dwarfism (Kaspar Hauser Syndrome): Abuse/neglect causes dwarfism independent of nutrition
• Treatment: Recombinant GH or IGF-1 if started early in childhood; underlying cause-specific treatment

Ganong's Review of Medical Physiology, p. 332

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15. Hyperprolactinemia

• Causes:
  • Prolactinoma (prolactin-secreting pituitary adenoma; chromophobe adenomas are most common)
  • Pituitary stalk damage (removes dopamine inhibition of prolactin)
  • Drug-induced: dopamine antagonists (haloperidol, phenothiazines, antipsychotics, cisapride) - most common cause in clinical practice
• Features:
  • Galactorrhea (milk production outside pregnancy)
  • Secondary amenorrhea (15-20% of cases; due to gonadotropin blockade)
  • Osteoporosis (from estrogen deficiency from gonadal suppression)
  • In men: erectile dysfunction and hypogonadism
• Treatment: Dopamine agonists (cabergoline, bromocriptine); withdraw offending drug if possible

Ganong's Review of Medical Physiology, p. 520

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16. Panhypopituitarism

• Cause: Destruction or loss of all anterior pituitary cells (tumor, radiation, surgery, infarction - e.g., Sheehan's syndrome postpartum)
• Features: Deficiency of all pituitary-dependent hormones - secondary hypothyroidism, secondary adrenal insufficiency (but no hyperpigmentation since ACTH is low), secondary hypogonadism, GH deficiency, dwarfing, delayed puberty (eunuchoidism in males, primary amenorrhea in females)
• Key distinction from Addison: No hyperpigmentation (ACTH is low or absent)

Ganong's Review of Medical Physiology, p. 332

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V. POSTERIOR PITUITARY / ADH DISORDERS

17. Diabetes Insipidus (DI)

• Central DI: Posterior pituitary fails to secrete ADH (from trauma, tumors, infections, or idiopathic). Without ADH, collecting ducts are impermeable to water, producing massive dilute urine (polyuria) and severe thirst/polydipsia. Plasma osmolarity rises sharply.
• Nephrogenic DI: ADH is secreted normally or in excess (stimulated by high plasma osmolarity), but kidneys do NOT respond to it (receptor/signaling mutations). Same clinical picture of dilute polyuria but ADH levels are high.

• Treatment: Central DI - desmopressin (synthetic ADH); Nephrogenic DI - thiazide diuretics, low-solute diet

Costanzo Physiology, p. 311

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18. SIADH (Syndrome of Inappropriate ADH Secretion)

• Cause: ADH secreted autonomously without osmotic stimulus - from posterior pituitary (after head injury, meningitis) or ectopically from tumors (small cell lung cancer, pancreatic carcinoma)
• Pathophysiology: High ADH → excess water reabsorption by collecting ducts → dilute plasma (hyponatremia) → hypoosmolar state. Urine is paradoxically concentrated (hyperosmotic) despite low plasma osmolarity.
• Features: Hyponatremia (low serum Na+), low plasma osmolarity, hyperosmotic urine (>100 mOsm/kg), no edema, euvolemia
• Treatment: Fluid restriction; demeclocycline (blocks ADH action on renal tubules); vasopressin receptor antagonists (vaptans) for severe cases

Costanzo Physiology, p. 311

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VI. PARATHYROID DISORDERS

19. Primary Hyperparathyroidism

• Cause: Parathyroid adenoma (non-cancerous tumor, 3-4x more common in women). Autonomous excess PTH secretion.
• Pathophysiology: Excess PTH drives osteoclastic bone resorption (releasing Ca²+ and phosphate), increases renal Ca²+ reabsorption, and increases 1,25-(OH)₂D₃ (vitamin D activation)
• Features:
  • Hypercalcemia (kidney stones - "stones"), bone pain and fractures
  • Osteitis fibrosa cystica - punched-out cystic bone lesions from extreme osteoclastic activity; giant cell "brown tumors"
  • Hypophosphatemia (phosphate excreted by kidney)
  • Nausea, constipation, confusion (hypercalcemia effects - "groans, moans, bones, and psychic overtones")
  • Pathological fractures from even slight trauma

Guyton and Hall, p. 993

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20. Hypoparathyroidism

• Cause: Surgical removal (inadvertent during thyroidectomy), autoimmune, congenital absence (DiGeorge Syndrome)
• Pathophysiology: Without PTH, osteoclast activity nearly stops, calcium is not released from bone, serum Ca²+ falls to 6-7 mg/dL (from normal ~9.4 mg/dL), phosphate doubles
• Features:
  • Hypocalcemia → Tetany (painful muscle spasms)
  • Laryngospasm (laryngeal muscle tetany → respiratory obstruction → death if untreated)
  • Chvostek's sign (facial muscle twitch on tapping facial nerve)
  • Trousseau's sign (carpal spasm with blood pressure cuff inflation)
• Treatment: Large doses of vitamin D (or 1,25-dihydroxycholecalciferol) + oral calcium supplementation; PTH injections rarely used (expensive, antibodies develop)

Guyton and Hall, p. 993

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VII. REPRODUCTIVE / GONADAL DISORDERS

21. Gonadal Dysgenesis (Turner Syndrome - 45,XO)

• Cause: Absent or streak gonads from 45,XO chromosomal pattern
• Features: Short stature (GH axis not involved but linear growth limited), sexual infantilism, primary amenorrhea, infertility, webbed neck, cardiovascular defects
• Pathophysiology: Gonads cannot respond to FSH/LH; high gonadotropins, no estrogen/testosterone

Ganong's Review of Medical Physiology, p. 332

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22. Precocious Puberty (Gonadotropin-Independent)

• Cause: Activating mutations in G-protein coupled to LH/FSH receptors → gonadotropin-independent sex hormone production
• Features: Early development of secondary sexual characteristics; early growth spurt followed by short final stature (from premature epiphyseal fusion)

Ganong's Review of Medical Physiology

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23. Delayed / Absent Puberty

• Causes: Panhypopituitarism, gonadal dysgenesis, or idiopathic hypogonadotropic hypogonadism (Kallmann Syndrome - GnRH deficiency with anosmia)
• Males: Eunuchoidism - small testes, no virilization, sparse body hair, high-pitched voice
• Females: Primary amenorrhea - no menarche by age 17

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VIII. NEONATAL / SPECIAL ENDOCRINE DISORDERS

24. Neonatal Hermaphroditism (Congenital Adrenal Hyperplasia in Females)

• Cause: Maternal androgen excess during pregnancy (exogenous androgens or virilizing tumor) masculinizes female fetus
• Features: Female infant born with masculinized external genitalia (pseudohermaphroditism)

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25. Neonatal Mastitis / Galactorrhea

• Placental/maternal sex hormones cause transient breast development or milk production in newborns; resolves spontaneously

Guyton and Hall, p. 1056

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SUMMARY TABLE

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• Guyton and Hall Textbook of Medical Physiology (Chapters 77, 78, 79, 85)
• Ganong's Review of Medical Physiology, 26th Ed. (Chapters 16, 18, 19, 20, 22, 23, 24)
• Costanzo Physiology, 7th Ed. (Chapters 6, 9)
• Medical Physiology (Chapters 49, 50, 51)