Q1 - Diabetes Insipidus

1. Most Likely Diagnosis

2. Definition and Causes

Definition

• Goldman-Cecil Medicine, p. 2177

• Absent or inadequate secretion of antidiuretic hormone (ADH/vasopressin) from the hypothalamus-posterior pituitary, OR
• Lack of end-organ (renal tubule) responsiveness to ADH

Causes

• Tumors: craniopharyngiomas, ependymomas (suprasellar germinoma), pinealomas, pituitary adenomas with suprasellar extension, metastases (lung, breast, melanoma)
• Head injury / neurosurgical trauma (especially after pituitary surgery)
• Hemorrhage (subarachnoid, intracranial)
• Infections: tuberculous meningitis, encephalitis
• Infiltrative/granulomatous disease: histiocytosis, neurosarcoidosis, multiple sclerosis
• Idiopathic (a substantial proportion)
• Genetic/hereditary: autosomal dominant mutations in the signal peptide or neurophysin portion of the pre-prohormone; typically presents later in childhood despite normal infancy

• Genetic: X-linked mutations of AVPR2 gene (vasopressin V2 receptor) - accounts for >90% of congenital cases; AQP2 (aquaporin-2) gene mutations (autosomal dominant or recessive) account for <10%
• Drugs: lithium (most common acquired cause), demeclocycline, tetracyclines, furosemide
• Metabolic: hypokalemia, hypercalcemia
• Chronic kidney disease (medullary damage)
• Ureteric obstruction (post-obstructive diuresis)

• Guyton and Hall Textbook of Medical Physiology; Tietz Textbook of Laboratory Medicine 7th Ed.

3. Clinical Features

• Polyuria: the hallmark. Large volumes of dilute urine (urine osmolality as low as 100-150 mOsm/kg). Can exceed 15-20 L/day in severe central DI
• Polydipsia: extreme, constant thirst; patients drink large volumes compulsively to compensate
• Nocturia: waking multiple times at night to urinate (as in this patient, 4-5 times/night)
• Preference for cold water (a characteristic feature)
• Dehydration signs: if fluid intake fails to keep up - dry mouth, skin tenting, weakness
• Hypernatremia and hyperosmolality: if the thirst mechanism is also impaired (as in osmoreceptor dysfunction), this can progress rapidly to severe hypernatremia, neurological deterioration, and irreversible brain damage
• In children: if present from childhood, can cause massive dilatation of the renal pelvis, ureters, and bladder (hydronephrosis/megacystis)
• Neurological features from the underlying cause: visual field defects if a pituitary/hypothalamic tumor is present
• Low urine osmolality with normal/elevated plasma osmolality (this distinguishes DI from primary polydipsia, where plasma osmolality is low)
• Goldman-Cecil Medicine, p. 2166

4. Types

5. Treatment

Central DI

• Desmopressin (DDAVP) - synthetic ADH analogue, acts selectively on V2 receptors to increase aquaporin-2 insertion into collecting duct cells. Can be given:
  • Intranasally (10-40 mcg/day in 1-2 divided doses)
  • Orally (0.1-0.8 mg/day)
  • By injection (1-4 mcg/day subcutaneously or IV)
• Dose is titrated to normalize urine output and plasma sodium. In pregnancy, enough desmopressin to maintain plasma osmolality at the (physiologically lower) pregnant set-point
• Treat the underlying cause (surgery/radiotherapy for tumors, etc.)

Nephrogenic DI

• Correct the underlying cause if possible (stop lithium, correct hypercalcemia/hypokalemia)
• Low-sodium diet (reduces osmotic load and urine volume)
• Thiazide diuretics (e.g., hydrochlorothiazide): paradoxically reduce urine output by inducing mild volume depletion, increasing proximal tubule reabsorption and reducing distal delivery
• NSAIDs (e.g., indomethacin): inhibit prostaglandin synthesis, potentiating the effect of residual ADH
• Amiloride: specifically useful in lithium-induced nephrogenic DI as it blocks lithium entry into principal cells
• Desmopressin is ineffective in nephrogenic DI (the kidney cannot respond)

Primary Polydipsia

• Behavioral/psychiatric treatment (fluid restriction, CBT)
• Treat underlying psychiatric condition
• Guyton and Hall Textbook of Medical Physiology; Goldman-Cecil Medicine

Q2 - Hyperthyroidism (Thyrotoxicosis)

1. Most Likely Diagnosis and Definition

Definition

2. Causes

• TSH-secreting pituitary adenoma (central hyperthyroidism): rare; 75% are macroadenomas; TSH inappropriately normal or elevated with elevated T3/T4
• Thyroiditis (subacute, autoimmune, postpartum): release of preformed hormone - NOT true hyperthyroidism; radioactive iodine uptake is very low
• Tietz Textbook of Laboratory Medicine 7th Ed.; Goldman-Cecil Medicine

3. Signs and Symptoms

Symptoms (what the patient reports):

• Constitutional: weight loss (despite normal or increased appetite), fatigue, heat intolerance, excessive sweating
• Cardiovascular: palpitations, exercise intolerance, exertional dyspnea, angina/chest pain
• Neuropsychiatric: anxiety, irritability, emotional lability, difficulty concentrating, insomnia
• GI: increased bowel frequency (hyperdefecation), nausea; weight loss from elevated basal metabolic rate
• Reproductive: irregular menstrual periods (oligomenorrhea), reduced fertility
• Musculoskeletal: proximal muscle weakness (thyrotoxic myopathy), fatigue on exertion

Signs (clinician finds on exam):

• Vital signs: tachycardia (resting heart rate often >100 bpm), systolic hypertension, widened pulse pressure, elevated temperature
• Thyroid: goiter (diffuse in Graves', nodular in toxic MNG)
• Eyes (Graves' specific): exophthalmos (proptosis), lid lag, lid retraction, periorbital edema, diplopia (Graves' orbitopathy)
• Skin: warm, moist, smooth skin; pretibial myxedema (Graves'); onycholysis (Plummer's nails)
• Neurological: fine tremor (especially hands), hyperreflexia, proximal myopathy
• Cardiovascular: atrial fibrillation (especially in older patients), systolic flow murmur, cardiac hypertrophy, peripheral edema, signs of heart failure in severe cases
• Hair: fine, thin hair; hair loss

• Tietz Textbook of Laboratory Medicine 7th Ed., pp. 2319-2322

4. Investigations

First-line (Essential):

Second-line / Confirmatory:

Associated laboratory changes:

• Liver enzymes (ALT, AST, ALP) mildly elevated
• Serum calcium mildly elevated (due to bone resorption by excess T4); may cause hypercalciuria/nephrolithiasis
• Alkaline phosphatase elevated (bone + liver origin)
• Neutropenia + lymphocytosis (in Graves' disease)
• CBC baseline before starting antithyroid drugs (both can cause neutropenia)
• Goldman-Cecil Medicine, pp. 2987-2989

5. Treatment and Management

A. Symptomatic Control (all causes)

• Beta-blockers (propranolol 40-80 mg every 6-8 hours, or atenolol): rapidly relieve palpitations, tremor, anxiety, heat intolerance; block T4→T3 peripheral conversion (propranolol); do NOT reduce thyroid hormone levels
• Start immediately once diagnosis is made

B. Antithyroid Drugs (Thionamides)

• Methimazole (MMI) - preferred; given once or twice daily (e.g., 10-30 mg/day initially); inhibits thyroid peroxidase, blocking organification of iodine
• Propylthiouracil (PTU) - given three times daily; also blocks peripheral T4→T3 conversion; preferred in first trimester of pregnancy and thyroid storm
• Mainstay of treatment in Graves' disease (typically 12-18 months course; ~50% remission rate)
• Side effects: agranulocytosis (rare but serious - monitor WBC if fever/sore throat), hepatotoxicity, rash

C. Radioactive Iodine (RAI, ¹³¹I)

• Effective for Graves', toxic MNG, and toxic adenoma
• Destroys thyroid tissue; most patients become hypothyroid afterward and require lifelong levothyroxine
• Absolutely contraindicated in pregnancy or possible pregnancy
• May worsen Graves' ophthalmopathy - use with caution; cover with steroids if orbitopathy is present

D. Surgery (Thyroidectomy)

• Total or near-total thyroidectomy indicated for:
  • Large goiter with compressive symptoms
  • Patient preference
  • Coexisting suspicious thyroid nodule
  • Severe or uncontrolled hyperthyroidism
  • Pregnancy where antithyroid drugs are not tolerated
• Requires pre-operative euthyroid state (antithyroid drugs + iodine solution - Lugol's iodine)
• Risks: hypothyroidism (expected), hypoparathyroidism, recurrent laryngeal nerve damage

E. Special Situations

• High-dose beta-blockade: propranolol 60-80 mg orally every 4-6 hours (or IV esmolol 50-100 mcg/kg/min)
• High-dose PTU (200-400 mg every 4-6 hours) - preferred over methimazole as it also blocks T4→T3
• Iodine solution (Lugol's or potassium iodide) - given 1 hour AFTER PTU to block hormone release (Wolff-Chaikoff effect)
• Corticosteroids (hydrocortisone 100 mg IV every 8 hours) - reduce T4→T3 conversion and treat relative adrenal insufficiency
• Treat precipitating cause (infection, surgery, trauma)

• Goldman-Cecil Medicine; Tietz Textbook of Laboratory Medicine 7th Ed.; Guyton and Hall Medical Physiology