Acromegaly

A 45-year-old man presents to his GP with a 2-year history of increasing hand and shoe size, excessive sweating, and headaches. He also reports that his facial features have become coarser and that gaps have appeared between his teeth. On examination, he has a prominent supraorbital ridge, macroglossia, and a large fleshy nose. What is the likely diagnosis?

Pathophysiology

Acromegaly results from excess growth hormone (GH) secretion, usually caused by a benign pituitary GH-secreting adenoma. In children with excess GH production, the clinical presentation is gigantism.

• GH stimulates the liver to produce insulin-like growth factor 1 (IGF-1).
• IGF-1 mediates many of the effects of GH, including:
  • Bone and soft tissue growth: Leading to the characteristic features of acromegaly, such as enlarged hands, feet, and facial features.
  • Metabolic effects: glucose intolerance and insulin resistance, which can lead to the development of type 2 diabetes.

Aetiology

• Pituitary adenomas cause the vast majority of acromegaly cases (99%).
  • Macroadenomas (pituitary lesions larger than 10mm) account for 75% of cases at presentation.
  • Mutations in the alpha subunit of the stimulatory guanosine triphosphate (GTP) binding protein can lead to persistent elevation of cyclic adenosine monophosphate (cAMP). High cAMP levels stimulate the production of excess growth hormone.
• Ectopic GH or GHRH (growth hormone-releasing hormone) secretion is a rare cause of acromegaly.
  • Examples include GHRH-secreting tumours of the hypothalamus and GHRH secretion by neuroendocrine tumours like carcinoid tumours or small cell lung cancers.

Epidemiology & Risk Factors

• Age of onset: Typically presents in the 3rd decade of life, with the mean age at diagnosis being 40-45 years.
• Sex: Affects men and women equally.
• Prevalence: 40–86 cases per million population.
• Annual incidence: 4 new cases per million population in the UK.
• Acromegaly can also be associated with:
  • Multiple endocrine neoplasia type 1 (MEN1): Approximately 6% of acromegaly patients have MEN1, a genetic syndrome characterized by tumours in multiple endocrine glands (parathyroid and endocrine pancreas)
  • Carney complex: An autosomal dominant disorder characterised by spotty cutaneous pigmentation, cardiac and other myxomas, and endocrine overactivity, including Cushing’s syndrome and GH-secreting pituitary tumours.
  • McCune–Albright syndrome: A rare disorder caused by somatic mosaicism for the gsp mutation, characterised by fibrous dysplasia of bone, café-au-lait spots, and endocrine abnormalities, including acromegaly.
  • Familial isolated pituitary adenomas (FIPA): Acromegaly may run in families without features of other syndromes like MEN1 or Carney complex. This is an autosomal dominant condition, with most affected individuals presenting with acromegaly. About 30–50% of FIPA cases have a mutation in the AIP gene (a tumour suppressor gene).

Clinical Features

The clinical features of acromegaly result from the effects of excess GH and IGF-1 and the local effects of the pituitary tumour. The onset of symptoms is often insidious, with a considerable delay before diagnosis.

• Extremity enlargement: Increased hand and shoe size, spade-like hands with increased ring size, heel pad thickening. (Acromegaly literally means "extremity enlargement"!). Patients may notice that their rings or shoes no longer fit.
• Facial changes: This can include coarsening of facial features, enlargement of the nose, and protrusion of the jaw (prognathism).
• Headache: This may be due to the pituitary tumour itself or the effects of excess GH.
• Increased sweating: This is a very common symptom, affecting more than 80% of patients.
• Carpal tunnel syndrome: Compression of the median nerve in the wrist can cause pain, numbness, and tingling in the hand.
• Arthralgia and back pain: Excess GH can lead to joint pain and stiffness, particularly in the spine.
• Changes in voice: The vocal cords can become thickened, leading to a deeper, more hoarse voice.
• Sleep apnea: Enlargement of the tongue and soft tissues in the throat can obstruct breathing during sleep.
• Visual disturbances: The pituitary tumour may compress the optic chiasm, leading to bitemporal hemianopsia.
• Galactorrhoea (usually in women): due to concurrent raised prolactin.
• Erectile dysfunction/menstrual irregularities

On physical examination, patients may present with:

• Coarsened facial features: This can include prominent supraorbital ridges, enlarged nose, thickened lips, and widely spaced teeth.
• Macroglossia
• 'Spade-like' hands and feet: The hands and feet may appear broadened and thickened.
• Goiter: Enlargement of the thyroid gland.
• Skin changes: Acromegaly can cause oily skin, skin tags, and acanthosis nigricans (dark, velvety patches of skin).

Investigations

• Serum IGF-1:  The most important initial test to confirm GH excess. IGF-1 is released by the liver in response to GH secretion but, unlike GH, does not show diurnal variation.
• Oral glucose tolerance test (OGTT): In acromegaly, GH levels fail to suppress to <1 mcg/L in response to a 75g oral glucose load. Usually, GH is suppressed to undetectable levels. The OGTT may also demonstrate impaired glucose tolerance. This test is considered the gold standard for diagnosing acromegaly.
• Pituitary MRI: imaging modality of choice to visualise the pituitary gland, identify pituitary adenomas and assess their size and location.
  • If a pituitary adenoma is not found, CT scan of the chest and abdomen can help rule out ectopic sources of GH/GHRH.
• Other investigations: 
  • Perimetry: formal assessment of visual fields.
  • Assessment of other pituitary hormones: Since pituitary adenomas can affect the secretion of other hormones, it's important to assess TSH, FSH, LH, ACTH and PRL.
  • Evaluation for complications: Including blood pressure monitoring, echocardiography, and colonoscopy.

Management

The goals of acromegaly management are to:

• Control GH and IGF-1 levels.
• Reduce tumour size and mass effects.
• Manage associated complications.

Treatment Options:

• Surgery: Transsphenoidal resection is the first-line treatment for most patients with acromegaly.
• Medical therapy: Used when surgery is not feasible or as an adjunct to surgery. Medical therapies include:
  • Somatostatin analogues (e.g. octreotide, lanreotide) are the most commonly used medical therapy. They reduce GH and IGF-1 secretion by binding to somatostatin receptors on the pituitary tumour.
  • Dopamine agonists: (e.g. cabergoline, bromocriptine) can be effective in a subset of patients, particularly those with co-secretion of prolactin. They act by stimulating dopamine receptors, which inhibit GH release.
  • GH receptor antagonists (e.g. pegvisomant) block the action of GH at its receptor, reducing IGF-1 levels. They are particularly useful in patients who do not respond adequately to other medical therapies.
• Radiotherapy: Can be used as an adjunct to surgery or medical therapy, particularly in cases of residual tumour or when other treatments have failed. It can take years for radiation therapy to have its full effect on GH levels.

Complications & Prognosis

Untreated acromegaly is associated with significant morbidity and mortality, primarily due to cardiovascular disease, respiratory disease, and malignancies.

• Cardiovascular: Hypertension, left ventricular hypertrophy and cardiomyopathy, arrhythmias, increased risk of ischemic heart disease and stroke
• Respiratory: Sleep apnea, upper airway obstruction
• Metabolic: T2DM, hypertriglyceridemia, hypopituitism
• Musculoskeletal: arthropathy, carpal tunnel syndrome, proximal myopathy
• Neoplasia: Increased risk of colonic polyps and colorectal cancer

Prognosis:

• With appropriate treatment, life expectancy can approach normal.
• Long-term monitoring is essential to manage complications and ensure optimal control of GH and IGF-1 levels.