Q1 - Diabetes Insipidus

1. Most Likely Diagnosis

2. Definition and Causes

• Comprehensive Clinical Nephrology, 7th Ed.; Guyton and Hall Textbook of Medical Physiology

Central (Neurogenic) DI - failure of ADH secretion from the hypothalamus/posterior pituitary:

• Head trauma / neurosurgery (most common acquired causes)
• Tumors: craniopharyngioma, metastatic (especially breast), pinealoma
• Granulomatous disease: sarcoidosis, tuberculosis, histiocytosis (Langerhans cell histiocytosis)
• Vascular: aneurysm, hemorrhage
• Infections: encephalitis, meningitis
• Guillain-Barre syndrome
• Drugs

• Autosomal dominant: point mutations in vasopressin precursor gene causing misfolding of pro-vasopressin
• Wolfram syndrome (autosomal recessive): DI + diabetes mellitus + optic atrophy + deafness (DIDMOAD)
• Idiopathic

Nephrogenic DI - failure of renal tubules to respond to ADH:

• Mutations in AVPR2 gene (V2 vasopressin receptor) - X-linked, accounts for >90% of congenital nephrogenic DI; prevalence ~4 per million males
• Mutations in AQP2 gene (aquaporin-2 water channel) - autosomal dominant or recessive

• Drugs: Lithium (most common drug cause), demeclocycline, amphotericin B, furosemide (impairs loop of Henle), tetracyclines
• Metabolic: hypokalemia, hypercalcemia
• Chronic kidney disease (especially tubulointerstitial diseases)
• Ureteric/urinary tract obstruction (post-obstructive)

Other related conditions:

• Primary (psychogenic) polydipsia - compulsive water drinking from psychiatric illness (must be differentiated from true DI)
• Dipsogenic DI - reset thirst threshold below ADH secretion threshold
• Comprehensive Clinical Nephrology, 7th Ed.; Tietz Textbook of Laboratory Medicine, 7th Ed.; Henry's Clinical Diagnosis and Management

3. Clinical Features

• Polyuria - hallmark; characteristically massive (can reach 15-20 L/day). The patient often has a constant and irresistible need to urinate.
• Polydipsia - excessive thirst; patients typically have a predilection for cold water (distinguishing feature from psychogenic polydipsia)
• Nocturia - waking 4-5 times per night to void is typical; by contrast, compulsive water drinkers rarely have nocturia
• Dilute urine - urine appears very pale/colourless, with low specific gravity and low osmolality (can be as low as 50-100 mOsm/kg)
• Dehydration signs if thirst mechanism is impaired or fluid access is restricted: dry mucous membranes, sunken eyes, reduced skin turgor, hypotension
• Hypernatremia - if the patient cannot keep up with fluid losses (plasma osmolality >295 mOsm/kg H2O is suggestive of central DI)
• Neurological sequelae - repeated hyperosmolar episodes from unrecognized dehydration can cause irreversible brain damage
• Urological complications in childhood-onset cases: massive dilatation of the renal pelvis, ureters, and bladder (megacystis, hydronephrosis)
• Onset is usually abrupt in central DI; gradual in nephrogenic forms
• Goldman-Cecil Medicine; Comprehensive Clinical Nephrology, 7th Ed.

4. Types

• Complete vs. Partial DI - each type can be complete (no ADH effect) or partial (reduced ADH effect, some concentrating ability preserved)
• Henry's Clinical Diagnosis and Management; Tietz Textbook of Laboratory Medicine

1. Withhold all fluids; collect hourly urine osmolality, plasma osmolality, plasma sodium, urine volume, and body weight
2. Stop when urine osmolality plateaus (increase <30 mOsm/kg for 3 consecutive hours), or body weight drops 3-5%, or systolic BP falls >20 mmHg
3. Then administer desmopressin (1 mcg IV/IM or 5 mcg SC AVP) and measure urine osmolality at 30, 60, and 120 minutes

• Central DI: urine osmolality rises significantly after desmopressin
• Nephrogenic DI: little or no rise in urine osmolality after desmopressin

5. Treatment

Central DI:

• Desmopressin is safe in pregnancy, has long half-life, and lacks the vasopressor effects of native vasopressin
• In partial central DI, adjunctive agents that potentiate ADH release may be used: chlorpropamide (250-500 mg/day), clofibrate (500 mg every 6-8 h), carbamazepine
• Comprehensive Clinical Nephrology, 7th Ed.; Guyton and Hall Textbook of Medical Physiology; Katzung's Basic and Clinical Pharmacology

Nephrogenic DI:

• Treat the underlying cause first (e.g., stop offending drug like lithium, correct hypokalemia/hypercalcemia)
• Low-sodium diet - reduces urine volume by decreasing solute delivery to the nephron
• Thiazide diuretics - paradoxically reduce urine volume by inducing mild volume depletion, which enhances proximal tubule sodium and water reabsorption, reducing distal delivery
• Indomethacin (NSAIDs) - used especially in congenital nephrogenic DI in children
• Desmopressin is ineffective in nephrogenic DI (the receptor/channel itself is defective)

All types:

• Ensure adequate fluid intake to match urine output and prevent dehydration/hypernatremia
• Monitor plasma sodium and osmolality regularly

Q2 - Hyperthyroidism (Graves' Disease / Thyrotoxicosis)

1. Most Likely Diagnosis and Definition

• Ganong's Review of Medical Physiology, 26th Ed.

2. Causes

Primary Hyperthyroidism (TSH suppressed):

Secondary Hyperthyroidism (TSH elevated or normal):

• TSH-secreting pituitary adenoma
• Thyroid hormone resistance syndrome (THRB mutations)
• Chorionic gonadotropin-secreting tumors
• Gestational thyrotoxicosis (hCG stimulates TSH receptor)
• Harrison's Principles of Internal Medicine, 22nd Ed. (2025)

• Lymphocytes in thyroid, bone marrow, and lymph nodes produce thyroid-stimulating immunoglobulins (TSIs) - IgG autoantibodies that bind and activate the TSH receptor, causing unregulated T3/T4 production and thyroid gland enlargement
• TSH receptor antibodies (TRAb) can be detected by immunoassay
• Associated antibodies: anti-thyroid peroxidase (TPO) and anti-thyroglobulin (Tg) antibodies occur in up to 80% of Graves' cases
• Cytokines (IFN-γ, TNF, IL-1) drive orbital fibroblast activation causing ophthalmopathy
• Risk factors: female sex, family history of autoimmune disease, post-partum state, after HAART therapy, after immune checkpoint inhibitors

3. Signs and Symptoms

Symptoms (in order of frequency):

• Weight loss despite normal or increased appetite (hyperphagia)
• Heat intolerance, feeling hot in cool environments
• Excessive sweating
• Fatigue and weakness

• Palpitations (most prominent symptom in young patients)
• Exertional dyspnoea
• Chest pain/angina (if pre-existing cardiac disease)
• Tachycardia (even at rest)

• Nervousness, anxiety, irritability
• Insomnia
• Fine tremor of outstretched hands
• Hyperactivity, restlessness
• Emotional lability

• Hyperdefecation (increased bowel motility; shortened small bowel transit time)
• Weight loss; increased appetite
• Nausea/vomiting (can precede thyroid storm)

• Proximal muscle weakness (thyrotoxic myopathy)
• Osteoporosis risk (chronic cases)

• Menstrual irregularities (oligomenorrhea, amenorrhea)
• Reduced fertility

Signs:

• Tachycardia (heart rate >100 bpm even at rest)
• Systolic hypertension with widened pulse pressure
• Atrial fibrillation (especially in older patients)
• Cardiac hypertrophy, hyperdynamic apex beat

• Goiter - diffuse smooth enlargement in Graves' disease; nodular in toxic MNG
• Thyroid bruit (due to increased vascularity)

• Warm, moist, smooth skin
• Palmar erythema
• Onycholysis (separation of nail from bed - Plummer's nails)
• Hair thinning/alopecia

• Exophthalmos/Proptosis - forward protrusion of eyeballs (occurs in ~50% of Graves' patients, often precedes overt hyperthyroidism)
• Lid lag and lid retraction (Dalrymple's sign)
• Chemosis (conjunctival oedema)
• Diplopia from extraocular muscle involvement
• Corneal involvement, visual loss (severe cases)

• Pretibial myxedema - non-pitting, indurated plaques over anterior shins; pink/purple "orange peel" appearance (in <5% of Graves' patients)
• Thyroid acropachy - soft tissue swelling of digits and clubbing (<1% of patients)

• Fine tremor
• Hyperreflexia
• Proximal myopathy
• Tietz Textbook of Laboratory Medicine, 7th Ed.; Harrison's Principles of Internal Medicine, 22nd Ed.; Ganong's Review of Medical Physiology

4. Investigations

Biochemical (First-line):

• In TSH-secreting pituitary adenoma: TSH is normal or elevated (non-suppressed) with high fT4/fT3
• In secondary hyperthyroidism: TSH is not suppressed

Autoimmune markers (Second-line):

• TSH receptor antibody (TRAb) - elevated; confirms Graves' disease, used to monitor in pregnancy
• Thyroid stimulating immunoglobulins (TSI) - positive in Graves'
• Anti-TPO and anti-thyroglobulin antibodies - positive in up to 80% of Graves' cases

Additional blood tests:

• FBC: microcytic anaemia, thrombocytopenia may occur
• LFTs: elevated bilirubin, aminotransferases, alkaline phosphatase (mixed bone + liver origin)
• Ferritin: may be elevated
• Blood glucose: may be mildly elevated

Imaging:

• Radionuclide thyroid scan (99mTc, 123I, or 131I):
  • Graves': diffuse, high, uniform uptake
  • Toxic adenoma: focal hot nodule with suppression of rest
  • Toxic MNG: patchy, multiple hot areas
  • Destructive thyroiditis: low/no uptake
  • Distinguishes Graves' from all other causes
• Thyroid ultrasound with color-flow Doppler:
  • Hyperthyroid states: increased blood flow
  • Destructive thyroiditis: decreased blood flow
  • Avoids radioactivity; particularly useful in pregnancy
• CT or MRI of orbits - in moderate-severe Graves' ophthalmopathy to assess intraorbital pressure, extraocular muscles
• CT or MRI of pituitary - if TSH-secreting adenoma suspected (non-suppressed TSH)
• Harrison's Principles of Internal Medicine, 22nd Ed.; Tietz Textbook of Laboratory Medicine, 7th Ed.

5. Treatment and Management

A. Antithyroid Drugs (Thioureylenes) - First-line Medical Therapy

• Drug of choice for Graves' disease
• Starting dose: 15-40 mg/day (single daily dose - better adherence)
• Mechanism: inhibits thyroid peroxidase, blocking iodination of tyrosine residues and coupling reaction
• Advantages over PTU: longer half-life (4-6 h vs. 75 min), can be given once daily, less hepatotoxic
• Euthyroid state typically achieved within 12 weeks; then dose reduced to maintenance

• Starting dose: 100 mg every 8 hours (up to every 4-6 h if >300 mg/day needed)
• Additionally blocks peripheral conversion of T4 to T3 (via D2 deiodinase inhibition)
• Preferred in first trimester of pregnancy (methimazole teratogenic in T1)
• Side effects: rare but severe fulminant hepatic necrosis (~1/10,000 adults); agranulocytosis (0.1-0.5%)

• Check thyroid function tests (fT4, T3) every 2-4 months after starting treatment
• Once euthyroid: follow up every 4-6 months
• Watch for goiter size reduction and TSH normalization (guide dose reduction)

B. Beta-blockers (Symptomatic Relief)

• Propranolol 40-80 mg every 6-8 hours (non-selective, also reduces peripheral T4-to-T3 conversion)
• Atenolol or metoprolol (cardioselective alternatives)
• Indication: rapid control of tachycardia, palpitations, tremor, anxiety, heat intolerance
• Mechanism: blocks sympathetic adrenergic effects of thyroid hormone excess
• Used as adjunct to antithyroid drugs; not a standalone cure

C. Radioactive Iodine (131I) - Definitive Therapy

• Indication: Graves' disease, toxic MNG, toxic adenoma
• Mechanism: absorbed by thyroid tissue, emits beta-radiation destroying thyroid follicular cells
• Can be given as primary treatment or after initial antithyroid drug therapy to control thyrotoxicosis before RAI
• Contraindicated in: pregnancy, breastfeeding, active/severe ophthalmopathy
• Major consequence: hypothyroidism (expected long-term; thyroid replacement therapy required)
• Antithyroid drugs should ideally be stopped 5-7 days before RAI to allow iodine uptake

D. Surgery (Thyroidectomy)

• Indications:
  • Very large goiter causing obstructive symptoms (dysphagia, stridor)
  • Suspected malignancy
  • Failure of medical therapy or patient preference
  • Contraindications to RAI (pregnancy)
  • Severe or relapsing disease
• Total or near-total thyroidectomy for Graves'; leads to euthyroid state or hypothyroidism requiring lifelong levothyroxine
• Preoperative preparation: achieve euthyroid state with antithyroid drugs, then give Lugol's iodine (potassium iodide) 7-10 days before surgery to reduce vascularity of the gland and decrease intraoperative bleeding

E. Graves' Ophthalmopathy Management

• Selenium supplementation (200 mcg/day) for mild active disease
• High-dose IV glucocorticoids for moderate-severe active disease
• Teprotumumab - monoclonal antibody targeting IGF-1R; new therapy that reduces TSH-R/IGF-1R complexes and orbital tissue expansion
• Orbital radiotherapy or orbital decompression surgery for severe/sight-threatening cases
• Ophthalmology referral mandatory for moderate-severe eye disease

F. Thyroid Storm (Thyrotoxic Crisis)

• Life-threatening emergency: treat with PTU, IV beta-blockers, IV iodine (after PTU given), glucocorticoids, cooling, IV fluids, and ICU admission

• Harrison's Principles of Internal Medicine, 22nd Ed. (2025), Block 43
• Tietz Textbook of Laboratory Medicine, 7th Ed., Blocks 21 and 25
• Guyton and Hall Textbook of Medical Physiology, Blocks 4 and 9
• Comprehensive Clinical Nephrology, 7th Ed., Block 2
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Block 13
• Ganong's Review of Medical Physiology, 26th Ed., Block 3
• Goldman-Cecil Medicine International Edition, Block 14