Endocrine System Pathophysiology

Major Endocrine Glands

• Pituitary: anterior (GH, TSH, ACTH, FSH, LH, prolactin), posterior (ADH, oxytocin)
• Thyroid: T4, T3, calcitonin
• Parathyroid: parathyroid hormone (PTH)
• Adrenal cortex: cortisol, aldosterone, androgens
• Adrenal medulla: epinephrine, norepinephrine
• Pancreas: insulin, glucagon, somatostatin
• Gonads: testosterone, estrogen, progesterone

Hormone Types & Action

• Steroid/Lipid-soluble: penetrate cell membrane, bind intracellular receptors (cortisol, testosterone, estrogen)
• Thyroid hormones: lipid-soluble, bind intracellular receptors (T3, T4)
• Protein/Peptide: water-soluble, bind surface receptors, activate cascades (insulin, GH, TSH)
• Catecholamines: derived from tyrosine, act like protein hormones (epinephrine, norepinephrine)

Feedback Mechanisms

• Negative feedback: end product inhibits further secretion (maintains homeostasis, most common)
• Positive feedback: end product stimulates further secretion (ovulation surge)
• Circadian rhythm: cortisol peaks morning, lowest evening
• Permissive: one hormone needed for another to exert effects

Hyperthyroidism (Thyrotoxicosis)

• Causes: Graves' disease (autoimmune, IgG antibodies), toxic nodule, thyroiditis, excess iodine
• Pathophysiology: ↑ T3/T4 → ↑ metabolic rate, ↑ thermogenesis, ↑ sympathetic tone
• Symptoms: weight loss (despite ↑ appetite), heat intolerance, tremor, palpitations, anxiety
• Thyroid Storm: life-threatening, fever, tachycardia >140, altered mental status
• Management: antithyroid drugs (PTU, methimazole), beta-blockers, radioactive iodine, surgery

Hypothyroidism

• Causes: Hashimoto's thyroiditis (autoimmune, most common), iodine deficiency, post-surgery/radiation, medications
• Pathophysiology: ↓ T3/T4 → ↓ metabolic rate, ↓ thermogenesis, ↓ sympathetic tone
• Symptoms: weight gain (despite ↓ appetite), cold intolerance, bradycardia, fatigue, depression, myxedema
• Myxedema Coma: life-threatening, hypothermia, profound bradycardia, altered consciousness
• Management: levothyroxine replacement, monitor TSH

Thyroid Axis

Hypothalamus → TRH → Anterior pituitary → TSH → Thyroid gland → T4/T3

• T4 → T3 conversion: occurs in tissues, T3 is the active form
• Negative feedback: ↑ T3/T4 → ↓ TRH → ↓ TSH
• TSH: best screening test for thyroid dysfunction

Normal Glucose Regulation

• Insulin: anabolic hormone (fed state), ↑ glucose uptake, ↑ protein synthesis, ↑ fat storage
• Glucagon: catabolic hormone (fasting state), ↑ glucose production, ↑ lipolysis, ↑ ketogenesis
• Normal fasting: 70-100 mg/dL
• Normal 2-hour post-meal: <140 mg/dL

Type 1 Diabetes

• Pathophysiology: autoimmune destruction of beta cells → absolute insulin deficiency
• Onset: usually childhood/young adults, sometimes any age
• Hyperglycemia: glucose can't enter cells, accumulated in blood and urine
• Consequence: lipolysis for energy → ketone production → DKA risk
• Management: insulin replacement (basal + bolus), carbohydrate counting, tight control

Type 2 Diabetes

• Pathophysiology: insulin resistance + inadequate compensatory insulin production
• Onset: usually adults, increasing in children, often asymptomatic initially
• Associated: obesity, sedentary lifestyle, metabolic syndrome
• Often undiagnosed: found on screening
• Management: lifestyle (weight loss, exercise), metformin, sulfonylureas, insulin if needed

Diabetic Ketoacidosis (DKA)

• Occurs in: Type 1 diabetes (insufficient insulin)
• Pathophysiology: ↓ glucose uptake → ↑ lipolysis → ketone production → metabolic acidosis
• Severity: pH <7.25, HCO3- <15, positive serum/urine ketones
• Respiratory compensation: Kussmaul respirations (deep, rapid)
• Management: IV fluids, insulin, potassium monitoring (severe hypokalemia risk)

Chronic Complications

• Nephropathy: glomerular basement membrane thickening → proteinuria → kidney failure
• Neuropathy: peripheral (tingling, pain), autonomic (blood pressure, GI, sexual dysfunction)
• Retinopathy: microvascular damage → vision loss, blindness
• Cardiovascular: accelerated atherosclerosis, MI, stroke

Cushing's Syndrome (Excess Cortisol)

• Causes: pituitary adenoma (70%), ectopic ACTH (15%), adrenal tumor (15%)
• Pathophysiology: ↑ cortisol → ↑ glucose, ↑ central obesity, ↓ immunity, ↓ bone formation, Na+ retention
• Signs: central obesity/buffalo hump, purple striae, easy bruising, proximal weakness, hypertension
• Testing: 24-hour urine cortisol, late-night salivary cortisol, dexamethasone suppression
• Management: address underlying cause (surgery, medications for refractory)

Addison's Disease (Cortisol Deficiency)

• Causes: autoimmune destruction (90%), TB, metastatic cancer
• Pathophysiology: ↓ cortisol + ↓ aldosterone
• Effects: ↓ cortisol: hypotension, hypoglycemia; ↓ aldosterone: Na+ loss
• Signs: hyperpigmentation (melanin stimulation), fatigue, weakness, hypotension
• Addisonian Crisis: severe hypotension, shock (medical emergency)
• Management: cortisol + mineralocorticoid replacement, stress dosing

Hyperparathyroidism (Excess PTH)

• Primary: autonomous PTH production (adenoma 80%)
• Pathophysiology: ↑ bone resorption, ↑ kidney calcium reabsorption, ↑ vitamin D
• Results: hypercalcemia, nephrogenic DI, kidney stones, bone loss
• Management: parathyroidectomy (definitive), medications for refractory

Hypoparathyroidism (PTH Deficiency)

• Causes: surgical removal, autoimmune, pseudohypoparathyroidism (PTH resistance)
• Results: hypocalcemia, hyperphosphatemia, low PTH
• Symptoms: Chvostek's sign, Trousseau's sign, tetany, seizures
• Management: calcium + vitamin D replacement

1. Explain the pathophysiology of Graves' disease, including why exophthalmos develops despite removing the thyroid.

2. A patient with type 1 diabetes presents with DKA. Explain the metabolic derangement from insufficient insulin to metabolic acidosis and hyperosmolality.

3. Compare and contrast primary, secondary, and tertiary hyperparathyroidism in terms of PTH and calcium levels.

4. Explain why hypercalcemia causes nephrogenic diabetes insipidus and how this worsens the clinical condition.

5. Compare Cushing's disease (pituitary) versus ectopic ACTP secretion in terms of ACTH/cortisol levels and treatment approach.