Acromegaly

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