Medical Experts
Straseski
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)
- Insulin-like growth factor 1 (IGF-1)
- 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
- Administer 75 g glucose and perform GH measurements over 120 minutes
- Perform glucose tolerance test (GTT) and measure GH
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
- Premalignant colon polyps
- Musculoskeletal
- 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
- MEN1
ARUP Laboratory Tests
Quantitative Chemiluminescent Immunoassay
Quantitative Enzymatic Assay
Quantitative Chemiluminescent Immunoassay
Immunohistochemistry
Quantitative Chemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay
References
17429592
Bidlingmaier M, Strasburger CJ. Growth hormone assays: current methodologies and their limitations. Pituitary. 2007;10(2):115-119.
26136383
Capatina C, Wass JAH. 60 years of neuroendocrinology: acromegaly. J Endocrinol. 2015;226(2):T141-T160.
19345931
Chanson P, Bertherat J, Beckers A , et al. French consensus on the management of acromegaly. Ann Endocrinol (Paris). 2009;70(2):92-106.
18578866
Chanson P, Salenave S. Acromegaly. Orphanet J Rare Dis. 2008;3:17.
19945023
Chanson P, Salenave S, Kamenicky P, et al. Pituitary tumours: acromegaly. Best Pract Res Clin Endocrinol Metab. 2009;23(5):555-574.
18236162
Cordero RA, Barkan AL. Current diagnosis of acromegaly. Rev Endocr Metab Disord. 2008;9(1):13-19.
20410227
Giustina A, Chanson P, Bronstein MD, et al. A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab. 2010;95(7):3141-3148.
23971897
Kannan S, Kennedy L. Diagnosis of acromegaly: state of the art. Expert Opin Med Diagn. 2013;7(5):443-453.
25356808
Katznelson L, Laws ER, Melmed S , et al. Acromegaly: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933-3951.
19208732
Melmed S, Colao A, Barkan A , et al. Guidelines for acromegaly management: an update. J Clin Endocrinol Metab. 2009;94(5):1509-1517.
17047383
Tzanela M. Dynamic tests and basal values for defining active acromegaly. Neuroendocrinology. 2006;83(3-4):200-204.