Acromegaly

Acromegaly is a rare chronic endocrine disorder resulting from hypersecretion of growth hormone (GH), typically by a pituitary adenoma, which results in abnormal musculoskeletal growth that is most often noted in the face and distal extremities. Diagnosis is made on the basis of GH and insulin-like growth factor testing.

Diagnosis

Indications for Testing

Adults
- Enlarged facial or acral features, abnormal musculoskeletal growth
- Combination of several of the following – chronic headaches, sleep apnea, bony arthritis, carpal tunnel syndrome, diabetes mellitus type 2, and hyperhidrosis (Katznelson, Endocrine Society, 2014)
Children
- Accelerated linear growth (gigantism)

Laboratory Testing

Screening
- Insulin-like growth factor 1 (IGF-1)
  - Most relevant test due to steady secretion
  - Highly specific if elevated
- Growth hormone (GH)
  - Secretion is pulsatile; even morning levels may not be elevated
  - Should not be used alone to diagnose acromegaly (Katznelson, Endocrine Society, 2014)

Confirmation

Perform glucose tolerance test (GTT) and measure GH

Administer 75 g glucose and perform GH measurements over 120 minutes
- Failure to suppress GH during hyperglycemia is diagnostic
- GH <1 ng/mL excludes acromegaly

Clinical scenarios resulting in high GH levels and nonsuppression of GH with GTT

High GH + Low IGF-1	High GH + Normal/High IGF-1
Anorexia/fasting	Pregnancy
Exogenous estrogen	Puberty
Liver disease	Uncontrolled hyperthyroidism
Renal insufficiency
Uncontrolled diabetes mellitus
GH, growth hormone; GTT, glucose tolerance test; IGF-1, insulin-like growth factor 1

Histology

Biopsy and pathologist examination may aid in diagnosis
Useful immunohistochemical stains include GH by immunohistochemistry
For detailed descriptions, including recommended use, refer to ARUP Laboratories’ Immunohistochemistry Stain Offerings

Imaging Studies and Procedures

Magnetic resonance imaging (MRI) – preferred modality to evaluate tumor presence and size
Computed tomography (CT) – if MRI unavailable
Visual field testing
- Recommended in pregnant patients with macroadenomas (Katznelson, Endocrine Society, 2014)
- Use if optic chiasm compression is suspected

Differential Diagnosis

Headache, visual field defects
- Other pituitary tumors
- Primary central nervous system (CNS) tumor
Glucose intolerance
- Diabetes mellitus type 2
- Metabolic syndrome
- Cushing syndrome
Malignancy with ectopic GH secretion
Clinical features of acromegaly
- Pachydermoperiostosis
- Untreated primary hypothyroidism
- Familial acromegaloid facial appearance

Monitoring

Monitor growth hormone (GH) and/or insulin-like growth factor 1 (IGF-1) levels for effectiveness of therapy
- Use the same test type for consistency, if possible
- Target concentrations
  - GH <1 ng/mL or
  - Normal IGF-1 levels
GH and/or IGF-1 monitoring not recommended during pregnancy (Katznelson, Endocrine Society, 2014)

Background

Epidemiology

Incidence – 3-4/million (Kannan, 2013)
Age – mean onset 40 years
Sex – M:F, equal

Etiology

Pituitary adenomas – most common cause
Tumors
- Carcinoid
- Small cell lung cancer
Familial disorders
- Multiple endocrine neoplasia type 1 (MEN1) (MEN1 gene)
- McCune-Albright syndrome (GNAS gene)
- Carney complex (PRKAR1A gene)
- Familial isolated pituitary adenoma (AIP gene in 20%)
Extrapituitary causes
- Growth hormone-releasing hormone (GHRH)-secreting hypothalamic tumor
- Ectopic secretion of GHRH

Pathophysiology

Most acromegaly is caused by sporadic GH-secreting pituitary adenomas
GH is synthesized in somatotroph cells of the anterior lobe of pituitary gland
- Pulsatile secretion
GH secretion is regulated by the hypothalamus
- Stimulated by GHRH
- Inhibited by somatostatin
Circulating GH stimulates synthesis and secretion of insulin-like growth factor 1 (IGF-1) from the liver
IGF-1 inhibits GH secretion at the pituitary and hypothalamus level, creating a negative feedback loop
Pituitary tumors mimic stimulation of adenylyl cyclase by GHRH receptor activation
- Causes autonomous GH secretion
- Symptoms are related to excess GH and IGF-1 secretion and to expansion of the pituitary mass

Clinical Presentation

Indolent course – delay in diagnosis of 4-10 years
Symptoms of pituitary mass expansion
- Headaches
- Visual field defects
- Cranial nerve palsies
- Symptoms consistent with hypopituitarism due to compression of remaining pituitary gland by expanding mass
Symptoms of GH excess
- Musculoskeletal
  - Hypertrophic arthropathy – both axial and peripheral skeleton
  - Carpal tunnel syndrome
  - Bony overgrowth
    - Coarse facial features, macrognathia, frontal bossing
    - Spade-shaped hands
    - Enlarged feet
    - Mandibular overgrowth – prognathia
    - Open epiphyses in children – linear bone growth causes gigantism
  - Obstructive sleep apnea – due to soft tissue overgrowth (eg, macroglossia)
- Cardiovascular
  - Hypertension
  - Cardiomyopathy – biventricular hypertrophy
  - Arrhythmias
- Dermatologic
  - Acanthosis nigricans
  - Hyperhydrosis
- Metabolic
  - Diabetes mellitus – insulin resistance
  - Dyslipidemia
  - Hypercalcuria (hypercalcemia rare)
  - Hyperphosphatemia
- Neoplastic
  - Premalignant colon polyps
    - Increased risk of colorectal cancer
Familial acromegaly
- MEN1
  - Autosomal dominant inheritance
  - ~10% incidence of GH-producing tumors
- McCune-Albright syndrome
  - Rare
  - Triad of peripheral precocious puberty, café-au-lait spots, fibrous dysplasia of the bone
  - Thyrotoxicosis
- Carney complex
  - Rare
  - Pigmented skin, myxoma, cardiac myxoma, thyroid nodules or carcinoma, primary pigmented nodular adrenocortical disease
  - ~10% incidence of GH-producing tumors
- Familial isolated pituitary adenoma
  - More common for childhood onset – frequent presentation is gigantism
  - Higher growth rate than with sporadic tumors