Block A - Medicine - Endocrine teaching clinic - Polyuria

Question 1

Physiology of ADH secretion

Answer 1

Supraoptic and paraventricular nuclei receive signals from:
 Baroreceptors – carotid sinus body
 Osmoreceptors – in hypothalamus/ great veins

Stimulate production of vasopressin (ADH) → travels down axon along
neurohypophysis (= posterior pituitary) and released into capillaries

Question 2

Physiological function of ADH

Answer 2

ADH on kidney tubules: increase trafficking + expression of aquaporin-2 (= water channel) in collecting duct
water in collecting tubules moves out along osmotic gradient to interstitium

Aquaporin -2:
 Detectable in urine (level increases with AVP)
 Mutations → nephrogenic diabetes insipidus

Question 3

Diabetes insipidus

Presentation

Answer 3

○ Polyuria (copious amount of dilute urine)
○ Polydipsia
○ ± hypernatraemia

Question 4

Diabetes insipidus

Clinical test for diagnosis

Answer 4

1. Water deprivation test: No fluid for 8 h (8:30 am – 4:30 pm)
   ● Measure Hourly body weight (lose 3% = excessive dehydration), urine output
   Normal response:
   ● Serum osmolarity should increase due to dehydration - increase ADH
   ● Urinary volume should decrease
   ● Urinary osmolarity should increase (U/P >=2)

Diabetes insipidus: when P > 300***, U/P ≤1.9

2. Central/cranial DI: responds to parenteral DDAVP test
   ○ Reduced urine output (collect for 2 h)
   ○ Increased urine osmolality
   o Decreased serum osmolality

Question 5

Causes of cranial DI

Answer 5

Acquired – lesions of hypothalamus/ pituitary stalk/ posterior pituitary:

• Trauma: accidental, blunt force trauma, transphenoidal/ transfrontal pituitary surgery
• Neoplasm: craniopharyngioma, dysgerminoma, meningioma, metastatic tumor
• Granuloma: TB, Sarcoidosis, Histocytosis, Toxoplasmosis
• Infection: Meningitis, encephalitis
• Vascular: Aneurysm compression, Sheehan’s syndrome

Familial:
- Vasopressin prohormone mutation

Question 6

Treatment for central DI

Answer 6

DDAVP (1-deamino-8-D-arginine vasopressin: intranasal / oral / parenteral / buccal)

Question 7

Nephrogenic diabetes insipidus

Causes

Answer 7

Acquired:

• Renal: Chronic pyelonephritis, interstitial nephritis, obstructive uropathy
• Metabolic: HypoK, HyperCa
• Drugs: Lithium carbonate** (bipolar disorder or psychosis drug) causing hypercalcemia and hypothyroidism
• Nephrotoxic drugs e.g. cisplatin, amphotericin

Familial:
X-linked recessive – vasopressin receptor gene mutation (V2 receptor defect)
Autosomal recessive – aquaporin-2 gene mutation

Question 8

Explain how lithium carbonate causes nephrogenic DI

Answer 8

Lithium carbonate causes endocrine dysfunction at higher dose

1. Hypercalcemia: impair calcium-sensing of PTH-producing cells (CaSR), increase serum PTH; drug also causes Tubular CaSR defects, decreases calcium excretion
2. Hypothyroidism: lithium impairs thyroid hormone synthesis and secretion

Question 9

F/50:
 History of CA breast: L mastectomy 1996
 Local radiotherapy & Tamoxifen for 5 years
 R lung metastasis Feb 2004&raquo_space; chemotherapy (alkylating agent)
 Polyuria and polydipsia since Dec 2003

Ddx possible causes?

Answer 9

Hypercalcemia (nephrogenic DI) due to:
 Paraneoplastic PRP (PTHrP: breast, lung, kidney cancer)
 Secondary bone metastasis
 Drug: cisplatin

Pituitary metastasis (central DI)

Psychogenic – overdrinking of water due to depression

Renal problem involving tubules:
 Tubulointerstitial nephritis
 Chronic pyelonephritis

Question 10

Difference in presentation between primary polydipsia with DI

Answer 10

Primary polydipsia: polyuria in daytime, hyponatremia (serum osmolality low or normal)

DI: increased urinary volume in both daytime and nighttime, +/- hypernatremia

To differentiate between polyuria and excessive drinking: chart the input, output

Question 11

First-line investigations for DI

Answer 11

Urine input/ output charts

U:S osmolality

Serum Na/K/Ca: Hypercalcemia, hypokalemia can cause nephrogenic DI; DI causes hypernatremia

Random glucose 4.6 mmol/L - r/o DM causing osmotic diuresis

Urea and creatinine - dehydration, renal causes of polyuria

Question 12

Interpret Chart

Next investigation?

Answer 12

Responsive to DDAVP - results compatible with cranial DI

Further investigations:

• MRI brain : loss of bright spot in posterior pituitary which normally represents storage granule of pituitary hormone
• Other pituitary functions: TSH and fT4, FSH and LH, ACTH, Cortisol…

Question 13

Treatment of cranial DI due to secondary pituitary tumor

Answer 13

 Radiotherapy for secondary pituitary
 Maintenance treatment if low cortisol level
 Steroid cover and antibiotics cover to prevent adrenal crisis in case of infections

Question 14

Risks of hypokalemia

Answer 14

 Arrhythmia (ventricular fibrillation, ventricular tachycardia, ectopic atrial fibrillation)
 Muscle weakness – generalized, may progress to respiratory failure

Must assess HCO3 for possible renal tubular acidosis (Low compensation with bicarbonate)

Question 15

Investigations for cause of nephrogenic DI

Answer 15

Renal tubular causes:

1. Ultrasound: presence and size of kidneys, any Chronic nephritis, obstructive uropathy…
2. Clotting profile and platelet: risk of bleeding for renal biopsy
3. Renal biopsy
4. Non-contrast CT of kidneys

Serum electrolytes: HypoK, HyperCa (metabolic causes)

Drug cause: Lithium carbonate, nephrotoxic drugs…etc

Thyroid function test

Autoimmune markers: anti-thyroid antibodies, Rheumatoid factors, Anti-Ro**

Serum and urine osmolality

DDAVP test