13.2 Acromegaly, Diabetes Insipidus & SIADH
Key Takeaways
- Acromegaly is confirmed when growth hormone fails to suppress below 1 microgram/L during a 75 g oral glucose tolerance test.
- In the water deprivation test, concentration of urine after desmopressin indicates cranial diabetes insipidus, while failure to concentrate indicates nephrogenic disease.
- Lithium is the classic drug cause of nephrogenic diabetes insipidus, and demeclocycline is used to treat resistant SIADH.
3. Acromegaly
Etiology & Pathophysiology
Acromegaly is caused by autonomous, chronic hypersecretion of growth hormone (GH), which stimulates hepatic synthesis and systemic secretion of Insulin-like Growth Factor 1 (IGF-1). More than $99%$ of cases arise from a benign pituitary somatotroph adenoma (macroadenoma in $> 75%$). Rare ectopic sources ($< 1%$) include neuroendocrine tumors (bronchial or pancreatic carcinoids) hypersecreting GHRH.
Clinical Manifestations
The insidious onset results in an average diagnostic delay of 5 to 10 years:
- Somatic & Acral Overgrowth: Enlargement of hands and feet (increasing shoe, ring, and glove sizes), characteristic spade-like fleshy hands with blunt digits, coarse facial features, frontal bossing, prominent supraorbital ridges, prognathism (protruding mandible leading to dental malocclusion and widened teeth spacing), and macroglossia.
- Soft Tissue & Metabolic: Severe hyperhidrosis (excessive, pungent greasy sweating due to sweat gland hypertrophy), oily skin, multiple skin tags (acrochordons), obstructive sleep apnoea (OSA in up to $70%$), bilateral carpal tunnel syndrome (due to perineural oedema and soft tissue hypertrophy within the carpal tunnel), proximal myopathy, and arthralgia/severe premature osteoarthritis.
- Cardiovascular & Endocrine: Systemic hypertension, concentric left ventricular hypertrophy, biventricular diastolic dysfunction, and secondary dilated cardiomyopathy. GH promotes hepatic gluconeogenesis and peripheral insulin resistance, causing impaired glucose tolerance ($45%$) or overt diabetes mellitus ($25%$).
- Colorectal Neoplasia: High circulating GH and IGF-1 promote mucosal cellular proliferation; patients have an increased prevalence of adenomatous colonic polyps and colorectal cancer. NICE guidelines mandate baseline screening colonoscopy at age 40, with ongoing surveillance intervals tailored to polyp findings.
Diagnostic Protocol
- First-Line Screening: Serum IGF-1: Unlike pituitary GH (which is pulsatile with a half-life of 20 minutes and easily provoked by stress, sleep, or exercise), serum IGF-1 has a stable circulating half-life and reflects integrated 24-hour GH activity. A normal age- and sex-matched serum IGF-1 robustly excludes acromegaly.
- Confirmatory Test: Oral Glucose Tolerance Test (OGTT) with GH Measurement: In healthy individuals, oral glucose ($75\text{ g}$) induces hyperglycaemia that suppresses pituitary GH secretion to $< 1.0\text{ mcg/L}$ ($< 0.4\text{ mcg/L}$ on modern ultrasensitive chemiluminescent assays). In acromegaly, there is failure of GH suppression to $< 1.0\text{ mcg/L}$ (or a paradoxical rise in GH).
- Anatomical Imaging: Pituitary MRI with gadolinium enhancement to define adenoma dimensions and optic chiasm compression; formal Humphrey visual field perimetry.
Therapeutic Strategy
- Transsphenoidal Hypophysectomy: First-line definitive treatment of choice. Cures $> 80%$ of microadenomas and approximately $40\text{–}50%$ of macroadenomas.
- Medical Therapy (Second-Line / Adjuvant):
- Somatostatin Receptor Ligands (SRLs): First-line medical therapy for persistent postoperative disease or poor surgical candidates. Long-acting depot injections administered monthly: Octreotide LAR or Lanreotide Autogel. Bind preferentially to somatostatin receptor subtype 2 (SSTR2), inhibiting GH release and shrinking tumor mass in $50%$. Adverse effects: Biliary sludge and cholesterol cholelithiasis ($> 25%$), abdominal cramping, and steatorrhoea. Pasireotide (multi-receptor SRL binding SSTR1, 2, 3, 5) is used for resistant cases but causes profound hyperglycaemia via insulin suppression.
- Dopamine Agonists (Cabergoline): Modestly effective; useful in mild disease or mixed GH/prolactin-secreting tumors.
- GH Receptor Antagonist (Pegvisomant): Genetically modified analogue of human GH that competitively blocks peripheral GH receptors, preventing hepatic IGF-1 generation. Highly effective at normalizing serum IGF-1 ($> 90%$), but does not act on the pituitary adenoma (pituitary MRI must be monitored for tumor enlargement, and circulating GH levels rise paradoxical to IGF-1 reduction). Requires regular liver function monitoring due to hepatotoxicity risk.
- Stereotactic Radiotherapy (Gamma Knife): Third-line adjuvant therapy for residual or refractory invasive tumors.
4. Diabetes Insipidus (DI) vs SIADH
Pathophysiology & Classification of Diabetes Insipidus
Diabetes insipidus is characterized by excretion of large volumes ($> 3\text{ L/24h}$ or $> 40\text{–}50\text{ mL/kg/24h}$) of hypotonic, dilute urine:
- Central (Cranial) Diabetes Insipidus: Deficient synthesis or secretion of arginine vasopressin (AVP/ADH) from the posterior pituitary. Causes include idiopathic autoimmune infundibuloneurohypophysitis, pituitary or hypothalamic surgery (classically a triphasic response: initial transient DI [days 1–2], followed by SIADH due to dying axon peptide leakage [days 3–7], culminating in permanent DI [day 8+]), closed head trauma, craniopharyngioma, pinealoma, suprasellar germinoma, Langerhans cell histiocytosis, and sarcoidosis.
- Nephrogenic Diabetes Insipidus: Normal or elevated circulating AVP concentrations paired with renal collecting duct resistance to AVP. Causes include:
- Pharmacological: Lithium carbonate (downregulates aquaporin-2 water channel transcription via glycogen synthase kinase-3$\beta$ inhibition; develops in up to $20\text{–}40%$ of chronic users), demeclocycline, amphotericin B.
- Metabolic: Hypercalcaemia (activates calcium-sensing receptors in the thick ascending limb, impairing medullary countercurrent multiplication) and hypokalaemia (impairs collecting duct cAMP generation).
- Renal Disease: Chronic tubulointerstitial nephritis, medullary cystic kidney disease, post-obstructive uropathy.
- Congenital: X-linked recessive mutations in the vasopressin V2 receptor gene ($AVPR2$, $90%$), or autosomal mutations in the aquaporin-2 gene ($AQP2$, $10%$).
Water Deprivation (Fluid Deprivation) Test Protocol
The water deprivation test is the cornerstone investigation for polyuria-polydipsia syndromes. Patients must be closely supervised with hourly recordings of body weight, serum osmolality, and urine osmolality:
| Phase & Condition | Serum Osmolality (mOsm/kg) | Urine Osmolality (mOsm/kg) | Post-DDAVP Urine Osmolality (mOsm/kg) |
|---|---|---|---|
| Normal Physiology | Normal ($280\text{–}295$) | Concentrates $> 750$ | Minimal increase ($< 5%$) |
| Primary (Psychogenic) Polydipsia | Low-normal ($< 280\text{–}285$) | Concentrates $> 500\text{–}750$ (partial medullary washout) | Minimal increase ($< 10%$) |
| Central (Cranial) DI | High ($> 295\text{–}300$) | Fails to concentrate ($< 300$) | Marked rise $> 50%$ (typically $> 750$) |
| Nephrogenic DI | High ($> 295\text{–}300$) | Fails to concentrate ($< 300$) | Fails to respond ($< 50%$ rise, stays $< 300\text{–}400$) |
Therapeutic Regimens
- Central DI: Treated with the synthetic vasopressin analogue Desmopressin (DDAVP), administered orally, sublingually, or via nasal spray. Acts selectively on renal V2 receptors with minimal V1 vascular pressor activity.
- Nephrogenic DI: Treat underlying electrolyte abnormalities. If lithium-induced, review indication and consider switching; if lithium must be continued, co-administer Amiloride (selectively blocks the epithelial sodium channel [ENaC] in the luminal membrane of principal collecting duct cells, preventing intracellular entry and accumulation of lithium). Paradoxical treatment with thiazide diuretics (e.g. bendroflumethiazide) induces mild volume contraction, triggering compensatory sodium and water reabsorption in the proximal convoluted tubule and decreasing distal fluid delivery to uncollecting ducts. A low-salt, low-protein diet and NSAIDs (e.g. indomethacin, which inhibits renal prostaglandin synthesis that otherwise antagonizes AVP) provide further benefit.
A 48-year-old man presents to his general practitioner reporting that his wedding ring no longer fits and his shoe size has increased from 9 to 11 over the past 5 years. He describes excessive sweating, generalized joint aches, and daytime somnolence. Physical examination reveals broad, spade-like hands, a prominent jaw with widening interdental spaces, and bilateral Tinel's sign over the wrists. His blood pressure is 158/96 mmHg. Initial laboratory investigations demonstrate an elevated age- and sex-adjusted serum insulin-like growth factor 1 (IGF-1) concentration. Which investigation is the definitive confirmatory test required to establish the diagnosis?
A 42-year-old woman with a 12-year history of bipolar affective disorder managed with lithium carbonate presents with profound thirst, waking 4 to 5 times nightly to pass large volumes of urine. She drinks approximately 7 liters of ice-cold water daily. Baseline investigations reveal serum sodium 145 mmol/L, potassium 4.2 mmol/L, serum calcium 2.32 mmol/L, and serum osmolality 302 mOsm/kg. An 8-hour water deprivation test is performed: after 8 hours of fluid restriction, her serum osmolality is 314 mOsm/kg and urine osmolality is 205 mOsm/kg. She is then administered 2 mcg of intramuscular desmopressin (DDAVP); one hour later, her urine osmolality is 220 mOsm/kg. What is the diagnosis, and which medication can specifically reduce renal lithium uptake?