Acromegaly

Definition

Etiology

• Harrison's Principles of Internal Medicine 22E, p. 3051
• Goldman-Cecil Medicine, p. 1471

Pathophysiology

• Continuous soft tissue and bony overgrowth
• Metabolic effects (insulin resistance, lipolysis)
• Organomegaly (viscera, heart, thyroid, salivary glands)

Clinical Features

Skeletal/Craniofacial

• Coarsening of facial features (frontal bossing, prognathism, macroglossia, splayed teeth, malocclusion)
• Enlargement of hands and feet (patients notice increasing ring, shoe, and hat size)
• Acromegalic arthropathy - initially cartilage hypertrophy widens joints (especially MCP joints visible on hand X-ray), then premature osteoarthritis develops as cartilage weakens; spinal involvement can cause cord compression
• Generalized osteoporosis (from hypogonadism and direct GH effects)

Skin

• Thickened, oily skin with exaggerated skin folds (nasolabial grooves, forehead wrinkling)
• Hyperhidrosis (excessive sweating at rest - very common and persistent even after treatment)
• Skin tags (acrochordon) - often associated with premalignant colonic polyps and colon cancer
• Hypertrichosis, hyperpigmentation
• Cutis verticis gyrata (~30% of patients)
• Thick lips and tongue

Mass Effects (Pituitary Tumor)

• Headaches (up to 60% at presentation)
• Bitemporal hemianopsia (~10%) from optic chiasm compression
• Cranial nerve palsies (in invasive tumors)

Systemic/Metabolic Complications

• Cardiovascular: Cardiomegaly (myocardial hypertrophy), hypertension, increased risk of ischemic heart disease and heart failure - the leading cause of death in untreated acromegaly
• Respiratory: Sleep apnea (obstructive, due to macroglossia and pharyngeal soft tissue enlargement; also central)
• Metabolic: Glucose intolerance/diabetes mellitus (GH is counter-regulatory, causing insulin resistance)
• Neurological: Carpal tunnel syndrome (median nerve entrapment), peripheral neuropathy
• Renal: GH and IGF-1 enhance phosphate reabsorption in proximal tubules (via increased Npt2a expression), leading to hyperphosphatemia; also associated with hypercalciuria and nephrolithiasis
• ENT: Voice deepening (resonant, rough voice), prognathism causing dental problems, enlarged sinuses

Co-secretion

• Mixed GH+PRL tumors produce features of hyperprolactinemia (hypogonadism, galactorrhea, infertility) on top of acromegaly
• Acidophilic stem cell adenomas often have hyperprolactinemia features predominating

Diagnosis

Step 1 - Screening: Serum IGF-1

• Age- and gender-matched serum IGF-1 is the single best screening test
• Elevated in virtually all cases; correlates well with 24-hour GH secretion
• Random GH is unreliable due to pulsatile secretion (normal peaks can exceed 50 ng/mL)

Step 2 - Confirmation: Oral Glucose Tolerance Test (OGTT)

• 75 g oral glucose load; measure GH at 0, 30, 60, 90, 120 minutes
• Normal: GH suppressed to <0.3 μg/L (nadir)
• Acromegaly: GH fails to suppress below 0.3 μg/L (or paradoxical rise)
• Combination of failure to suppress GH + elevated IGF-1 = diagnostic of acromegaly
• Normal IGF-1 + GH suppression to <0.3 μg/L excludes acromegaly

Step 3 - Imaging: Pituitary MRI

• MRI with contrast to identify and characterize the adenoma (size, extension, cavernous sinus invasion)
• Used to plan surgery and assess completeness of resection

Additional workup

• Assess for co-secretion (prolactin, ACTH, TSH, α-subunit)
• Screen for associated conditions: colonoscopy (colon polyps/cancer), echocardiogram (cardiomyopathy), sleep study (sleep apnea)
• If no pituitary adenoma found on MRI: measure plasma GHRH to look for ectopic source; CT chest/abdomen to look for carcinoid tumor
• Henry's Clinical Diagnosis and Management by Laboratory Methods
• Harrison's Principles of Internal Medicine 22E, p. 3051

Treatment

1. Surgery (First-line for most patients)

• Curative in ~85% of microadenomas (GH normalized postoperatively)
• Only ~50% of macroadenomas are cured by surgery alone (due to cavernous sinus invasion or large size)
• Rapid relief of mass effects (headache, visual field defects improve within days)

2. Somatostatin Receptor Ligands (SRLs) - Primary Medical Therapy

• Normalize IGF-1 in ~50-70% of patients
• Reduce tumor size in many patients
• Can be used as primary therapy when surgery is not feasible (e.g., medically unfit patient, patient preference) or as adjuvant therapy after incomplete surgery

• Transient nausea, abdominal discomfort, diarrhea, fat malabsorption (resolves within 2 weeks)
• Gallstones/biliary sludge (up to 30% with long-term use, usually asymptomatic)
• Mild glucose intolerance (transient insulin suppression)
• Asymptomatic bradycardia, mild hypothyroxinemia

3. GH Receptor Antagonist: Pegvisomant

• Blocks peripheral GH binding to its receptor → suppresses IGF-1 production
• Daily subcutaneous injection (10-30 mg/day)
• Normalizes IGF-1 in ~70% of patients even in SRL-resistant cases
• Note: GH levels remain elevated (does not act on the adenoma) - monitor tumor size with MRI
• Side effects: reversible liver enzyme elevation, lipodystrophy, injection site pain

4. Dopamine Agonists

• Cabergoline at very high doses (up to 0.5 mg/day) achieves modest GH suppression
• Combined octreotide + cabergoline may have additive biochemical control
• Used as adjuvant in patients with co-secreting GH+PRL tumors or mild residual disease

5. Radiation Therapy

• External beam radiotherapy or stereotactic radiosurgery (Gamma Knife, CyberKnife)
• Reserved for patients with residual/recurrent disease not controlled by surgery or medical therapy
• Advantage: does not require patient compliance with ongoing treatment
• Disadvantage: slow effect - 50% of patients need ≥8 years to achieve GH <5 μg/L; 90% achieve this after 18 years
• Major concern: hypopituitarism develops in most patients (gonadotropin, ACTH, TSH deficiency) within 10 years of radiotherapy

Management Algorithm

Prognosis

Differential Diagnosis

• Pseudoacromegaly: Acquired in severe insulin-resistant diabetes (fibroblast defect) or with long-term minoxidil use - no GH/IGF-1 abnormality
• Acromegaloid facial appearance syndrome: Inherited condition with only facial changes, normal GH
• Pachydermoperiostosis, Paget disease, myxedema - can mimic facial/acral changes
• Leonine facies of leprosy (Hansen disease)

Recent Evidence