Q1 - DIABETES INSIPIDUS

1. Most Likely Diagnosis

2. Definition and Causes

Definition

• Prevalence: rare, approximately 1 in 25,000 people
• Goldman-Cecil Medicine

Causes

• Idiopathic (autoimmune lymphocytic infundibuloneurohypophysis - most common in adults)
• Tumors: craniopharyngioma, germinoma, pinealoma, pituitary adenoma with suprasellar extension, metastases (lung, breast, melanoma)
• Head trauma / deceleration injuries / basilar skull fractures
• Neurosurgical resection of pituitary adenomas
• Granulomatous diseases: Langerhans cell histiocytosis, sarcoidosis, tuberculosis
• Infiltrative: lymphoma, leukemia
• Vascular: hemorrhage, infarction
• Autosomal dominant hereditary DI (mutations in signal peptide or neurophysin of pre-prohormone)
• Multiple sclerosis, tuberculous meningitis
• Postpartum (lymphocytic infundibuloneurohypophysis)

• Congenital:
  • Mutations in AVPR2 gene (arginine vasopressin receptor 2) - X-linked, >90% of congenital cases, prevalence 4-8 per million males
  • Mutations in AQP2 gene (aquaporin-2 water channel) - autosomal dominant or recessive
• Acquired:
  • Drugs: lithium (most common), demeclocycline, amphotericin B
  • Electrolyte disorders: hypokalemia, hypercalcemia
  • Chronic kidney disease
  • Ureteral obstruction
  • Downregulation of AQP2 in any of the above

3. Clinical Features

• Polyuria - hallmark; large volumes of dilute urine (>3 L/day, can exceed 20 L/day in severe cases)
• Polydipsia - constant, intense thirst; patients crave cold water
• Nocturia - frequent nocturnal urination (as in this patient - 4-5 times/night)
• Dehydration signs if fluid intake cannot keep pace: dry mucous membranes, reduced skin turgor, weakness
• Hypernatremia/hyperosmolality - if thirst mechanism is also impaired (dangerous)
• Neurological complications - repeated hyperosmolar episodes can cause irreversible brain damage
• Urological complications - if present from childhood: massive dilatation of renal pelvis, ureters, and bladder (hydroureteronephrosis)
• Growth retardation and developmental delay in children with congenital forms
• Fatigue, irritability, cognitive impairment from chronic dehydration

• Urine osmolality < 300 mOsm/kg (often 50-200 mOsm/kg)
• Serum osmolality > 295 mOsm/kg
• Serum sodium elevated or high-normal
• No glycosuria, no hyperglycemia (differentiates from DM)
• Urine specific gravity < 1.005

4. Types of Diabetes Insipidus

• Urine osmolality <800 mOsm/kg confirms hypotonic polyuria
• Plasma copeptin level ≥21.4 pmol/L = nephrogenic DI
• Plasma copeptin <2.6 pmol/L = complete central DI
• Water deprivation test or hypertonic saline infusion test may be needed for intermediate results
• MRI of hypothalamus/pituitary for central DI: look for absent T1 "bright spot" and stalk thickening

5. Treatment

Central DI

• Desmopressin (DDAVP) - synthetic vasopressin analogue; first-line treatment
  • Intranasal: 10-40 mcg at bedtime or twice daily
  • Oral: 0.1-0.8 mg/day
  • Subcutaneous/IV: 1-4 mcg/day
  • Relieves polyuria and polydipsia by acting on V2 renal receptors to increase water reabsorption
• Treat underlying cause (e.g., surgery/radiation for tumor)
• Chlorpropamide, carbamazepine, clofibrate - potentiate residual vasopressin (for partial central DI)
• Low-sodium, low-protein diet - reduces osmotic load

Nephrogenic DI

• Remove/treat the cause (e.g., stop lithium, correct hypokalemia/hypercalcemia)
• Thiazide diuretics (e.g., hydrochlorothiazide) - paradoxically reduce urine output by causing mild volume depletion, increasing proximal reabsorption (reduces distal delivery of water)
• Amiloride - particularly useful in lithium-induced nephrogenic DI; blocks Li+ entry into collecting duct cells
• NSAIDs (indomethacin) - reduce prostaglandin synthesis, enhancing ADH action
• Low-sodium, low-protein diet - reduces solute load
• DDAVP is generally ineffective in complete nephrogenic DI

Dipsogenic / Primary Polydipsia

• Behavioral modification, psychiatric treatment if compulsive
• Fluid restriction (carefully supervised)
• DDAVP is dangerous (can cause severe hyponatremia)

General Supportive Measures

• Ensure free access to water at all times to prevent severe dehydration
• Monitor serum sodium and osmolality closely
• In unconscious patients: IV hypotonic solutions with careful rate adjustment to avoid rapid osmolality shifts
• Goldman-Cecil Medicine, Chapter 206
• Tietz Textbook of Laboratory Medicine, 7th Edition

Q2 - HYPERTHYROIDISM (GRAVES' DISEASE)

1. Most Likely Diagnosis and Definition

Definition

• Tietz Textbook of Laboratory Medicine, 7th Edition

2. Causes

Primary Hyperthyroidism (low TSH, high T3/T4)

• Autoimmune: TSH receptor antibodies (TRAb/TSI) activate the TSH receptor continuously, driving unregulated thyroid hormone synthesis
• Associated with other autoimmune diseases (type 1 DM, vitiligo, pernicious anemia)
• Triggered/worsened by: pregnancy, postpartum period, stress, HAART therapy, alemtuzumab, immune checkpoint inhibitors (nivolumab, pembrolizumab)
• Harrison's Principles of Internal Medicine 22E

• Autonomous thyroid nodules independently produce excess hormone
• Common in elderly and iodine-deficient areas

• Single autonomously functioning nodule

• Transient release of stored thyroid hormone from inflamed gland
• Subacute (de Quervain's): viral, painful; silent: autoimmune, painless

• Drugs: amiodarone (contains 37% iodine), iodine excess (Jod-Basedow phenomenon), cytokines (IFN-alpha), tyrosine kinase inhibitors, immune checkpoint inhibitors
• Ingestion of excess exogenous thyroid hormone (thyrotoxicosis factitia)
• Struma ovarii (ectopic thyroid tissue in ovarian teratoma)
• Metastatic follicular thyroid carcinoma

Secondary/Central Hyperthyroidism (normal or elevated TSH)

• TSH-secreting pituitary adenoma (thyrotropinoma)
• Thyroid hormone resistance syndrome (RTHβ - mutations in THRB gene)
• hCG-secreting tumors (choriocarcinoma, hydatidiform mole, embryonal carcinoma) - hCG cross-reacts with TSH receptors
• Gestational thyrotoxicosis (high hCG in normal pregnancy)

3. Signs and Symptoms

Symptoms (in descending order of frequency)

Signs

• Tietz Textbook of Laboratory Medicine, 7th Edition; Harrison's Principles of Internal Medicine 22E

4. Investigations

First-Line Tests

Second-Line / Cause-Specific Tests

Baseline Safety Tests (before starting antithyroid drugs)

• Full blood count (FBC/CBC) with differential - baseline WBC (monitor for agranulocytosis from thionamides)
• Liver function tests (LFTs) - bilirubin, transaminases (mild elevation common in hyperthyroidism itself; thionamides can cause hepatotoxicity)
• Bone profile - calcium, phosphate, ALP
• ECG - assess for AF, tachyarrhythmias
• Serum glucose - thyroid hormone affects insulin sensitivity

5. Treatment and Management

A. Beta-Blockers (Symptomatic Relief - Immediate)

• Propranolol 40-160 mg/day (non-selective) - first-line for rapid control of symptoms
• Mechanism: blocks beta-adrenergic effects; propranolol also inhibits peripheral T4 to T3 conversion
• Relieves: palpitations, tremor, anxiety, heat intolerance
• Used as bridge until euthyroid state is achieved
• Atenolol or metoprolol - alternatives (cardioselective, avoid in asthmatics)

B. Antithyroid Drugs (Thionamides) - Definitive Pharmacological Treatment

• Monitor: FBC and LFTs regularly
• Main side effects: agranulocytosis (0.1-0.5%), rash, arthralgia, hepatotoxicity (PTU >> MMI)
• Remission after 12-18 months in ~30-50% of Graves' patients

C. Radioactive Iodine Therapy (131I)

• Mechanism: concentrated in thyroid tissue, causes radiation-induced follicular cell destruction
• Indications: definitive treatment for Graves', toxic multinodular goiter, toxic adenoma; relapse after ATDs
• Advantages: simple (single oral dose), highly effective, curative
• Contraindications: pregnancy (absolutely), breastfeeding, active severe ophthalmopathy
• Outcome: hypothyroidism occurs in majority (expected outcome, managed with levothyroxine)
• Treatment of choice for toxic multinodular goiter and toxic adenoma

D. Thyroidectomy (Surgical Treatment)

• Types: total thyroidectomy (Graves') or subtotal/hemithyroidectomy (toxic adenoma)
• Indications:
  • Large goiter causing compressive symptoms
  • Suspected malignancy
  • Failed or intolerant to ATDs
  • Active severe Graves' ophthalmopathy (relative)
  • Pregnancy where ATDs cannot be used
  • Patient preference
• Preparation: patient must be euthyroid before surgery (using ATDs + beta-blockers); Lugol's iodine given 10 days pre-op to reduce vascularity
• Complications: hypoparathyroidism (hypocalcemia), recurrent laryngeal nerve injury (hoarseness), hypothyroidism, hemorrhage

E. Specific Treatment for Graves' Ophthalmopathy

• Selenium supplementation - mild active disease
• IV glucocorticoids - moderate-to-severe active ophthalmopathy
• Teprotumumab - new monoclonal antibody targeting IGF-1R/TSH-R complexes (reduces orbital tissue expansion); approved by FDA
• Orbital radiotherapy - adjunct
• Orbital decompression surgery - sight-threatening disease

F. Thyroid Storm (Thyrotoxic Crisis) - Emergency Management

• High-dose PTU + beta-blocker (propranolol IV) + hydrocortisone + iodine (Lugol's) + supportive care
• PTU preferred as it also blocks T4→T3 conversion

Monitoring

• TSH and fT4 every 4-6 weeks initially, then every 3-6 months
• Watch for hypothyroidism (especially post-RAI or post-surgery)
• Tietz Textbook of Laboratory Medicine, 7th Edition; Harrison's Principles of Internal Medicine 22E; Lippincott Pharmacology