Acromegaly: who is the patient going to present to and how to recognize the disease.

We all have a definite picture of a patient with excess of growth hormone secretion. They will be huge, complain of changed facial features and enlarging hands and feet, will have a protruding lower jaw and will be generally easily recognizable. As a matter of fact it may be 7-10 years before a patient notices any of these features which are often put down to normal aging and some obesity. The idea is  to pick up the features early so the damage can be prevented. So what are the subtle signs we should be on the lookout for? The subtle signs are; acral overgrowth (most patients miss the enlargement of their hands and feet specially in the tropics where open sandals or slippers are worn, gloves are rarely worn and finger rings are a rarity specially for men), soft-tissue swelling like sausage like fingers (the patient specially if he/she work with their hands may complain of clumsiness holding a knife or needle or other fine instruments), arthralgias, jaw prognathism, fasting hyperglycemia, and hyperhidrosis to florid osteoarthritis, frontal bone bossing, diabetes mellitus, hypertension, and respiratory and cardiac failure. So if your patient with florid diabetes and uncontrolled hypertension also has frontal bossing and a large protruding jaw bingo!

So which doctor are they going to see?About 40% of cases initially go to and are diagnosed by an internist, and the rest are diagnosed when patients are seen by ophthalmologists for visual disturbances, by dental surgeons for bite disorders, by gynecologists for menstrual dysfunction and infertility, by rheumatologists for osteoarthritis, or by sleep-disorder specialists for obstructive sleep apnea. They are usually going to their internist for uncontrolled diabetes, hypertension and symptoms of heart failure. Be on the lookout for frontal bossing, large hands and feet and a protruding jaw. Ask for an old photograph if you have to. In rural areas in the third world people, especially men rarely have the need to look in a mirror.

Why does acromegaly present in the 50s? The pituitary tumours are slow growing and so take time to produce symptoms and signs. In young patients the the tumour may grow faster so the signs occur earlier. Be on guard for local signs such as visual field defects in these patients.

Important factors determining the coexisting illnesses in a given patient include levels of growth hormone before and after treatment, IGF-I levels, the patient’s age, the size of the tumor, the degree of tumor invasion, and the duration of symptoms before diagnosis. Carcinoma of the pituitary is very rare and diagnosed because of symptoms produced by brain metastasis.

Skeletal disorders account for the most significant, functional disability and compromised quality of life in patients with acromegaly. Up to 70% of such patients have large-joint and axial arthropathy that includes thickened articular cartilage, periarticular calcifications, osteophyte overgrowth, and synovitis. Degenerative osteoarthritis, scoliosis, kyphosis, and vertebral fractures develop in patients whose disease is not brought under control quickly hence the physician must be aware of all these and take appropriate preventive measures.

Acromegaly develops when somatotrophs (cells in the anterior pituitary gland that produce growth hormone) proliferate and oversecrete the hormone. A cascade of interacting transcription factors and genetic elements normally determines the ability of somatotroph cells to synthesize and secrete gro

An activating mutation of the alpha subunit of the guanine nucleotide stimulatory protein (Gs-alpha) gene is found in approximately 40 percent of somatotroph adenomas. These mutations result in constitutive activation of adenylyl cyclase, which may play a role in both cell division in and excessive GH secretion by these adenomas. The development and proliferation of somatotrophs are largely determined by a gene called the Prophet of Pit-1 (PROP1), which controls the embryonic development of cells of the Pit-1 (POU1F1) transcription factor lineage, as well as gonadotroph hormone–secreting cells.

What is growth hormone? Growth hormone is secreted as a long sequence, 191-amino-acid, 4-helix bundle protein and a less abundant shorter 176-amino-acid form. It enters the circulation in a pulsatile fashion under dual hypothalamic control through hypothalamic-releasing and hypothalamic-inhibiting hormones that traverse the hypophysial portal system and impinge directly on specific somatotroph surface receptors. Remember that the liver alone does not have a portal system, so does the pituitary gland! There are approximately 10 intermittent pulses of growth hormone per 24 hours, most often at night, when the level can be as high as 30 μg per liter. These peaks may overlap with the range of elevated levels of growth hormone observed in patients with acromegaly. Fasting increases the secretion of growth hormone, whereas aging and obesity are associated with suppressed secretory bursts of the hormone.

What factors regulate the growth hormone?

Growth hormone–releasing hormone induces the synthesis and secretion of growth hormone, and somatostatin suppresses the secretion of growth hormone.

Growth hormone is also regulated by ghrelin, a growth hormone secretagogue–receptor ligand that is synthesized mainly in the gastrointestinal tract in response to the availability of nutrients. Studies to date suggest that ghrelin acts as a growth hormone–releasing hormone predominantly through hypothalamic mechanisms.

How else does GH work?

The action of growth hormone is mediated by a growth hormone receptor, which is expressed mainly in the liver and in cartilage and is composed of preformed dimers that undergo conformational change when occupied by a growth hormone ligand, promoting signaling. Cleavage of the growth hormone receptor also yields a circulating growth hormone–binding protein, which prolongs the half-life and mediates the cellular transport of growth hormone.

Growth hormone induces the synthesis of peripheral insulin-like growth factor I (IGF-I), and both circulating (endocrine) and local (autocrine and paracrine) IGF-I induces cell proliferation and inhibits apoptosis. The production of IGF-I is suppressed in malnourished patients, as well as in patients with liver disease, hypothyroidism, or poorly controlled diabetes. Although IGF-I levels usually reflect the integrated secretory activity of growth hormone, subtly elevated growth hormone levels may not uniformly induce high IGF-I levels. Hence IGF-I cannot be used as a surrogate measurement for GH.

What happens in the somatotropin producing adenoma?

Genetic changes in somatotroph adenoma cells develop on a background of chromosomal instability, epigenetic alterations, and mutations. Hypothalamic and paracrine growth hormone–releasing hormone and somatostatin, as well as growth factors, facilitate the expansion of the population of somatotroph tumor cells.

More than 90% of patients with acromegaly have a benign monoclonal growth hormone–secreting pituitary adenoma surrounded by nonhyperplastic pituitary tissue. Densely granulated somatotroph adenomas grow slowly, and patients presenting with these adenomas are usually older than 50 years of age. Younger patients usually present with more rapidly growing, sparsely granulated adenomas composed of growth hormone cells. About 25% of growth hormone adenomas cosecrete prolactin; these include dimorphous adenomas composed of growth hormone and prolactin cells, monomorphous mammosomatotroph adenomas (which produce both prolactin and growth hormone), and more primitive acidophil stem-cell adenomas. The third type are more commonly encountered in teenagers, often causing gigantism.

So densly granulated adenomas grow slowly and produce acromegaly in older people 45-50 years of age, sparsely granulated adenomas occur in younger patients and acidophilic primitive cell adenomas occur in adolescents and cause gigantism. Plurihormonal hypersecretion is rarely clinically apparent. Silent somatotroph adenomas have been described in patients with elevated levels of prolactin and IGF-I. Extrapituitary ectopic hypersecretion of growth hormone has been reported in isolated cases of pancreatic islet-cell tumors or lymphoma. Familial acromegaly syndromes are rare.

What does the GH do to the heart?

Excessive levels of growth hormone and IGF-I can cause major structural and functional cardiac changes. By the time of diagnosis, arrhythmias, hypertension, and valvular heart disease are present in up to 60% of patients. With untreated, prolonged disease, concentric myocardial hypertrophy develops, and diastolic heart failure occurs. Unlike heart failure, aortic and mitral valve regurgitation and hypertension are not reversible with octreotide treatment. Soft-tissue edema and impaired exercise capacity are reversed once the hypersecretion of growth hormone is controlled.

Do people with acromegaly have a higher incidence of cancer. Most studies show that this is not so except that prospective, controlled studies of colonoscopic screening indicate that the risk of colon cancer in patients with acromegaly is about twice that in the general population, which probably reflects a trophic IGF-I effect on the proliferation of epithelial cells.

Patients with acromegaly have a higher mortality than the general population but what causes this? Factors contributing to increased mortality among persons with acromegaly include the higher prevalence of hypertension, hyperglycemia or overt diabetes, cardiomyopathy, and sleep apnea in this population. Multivariate analysis of determinants of survival in long-term studies indicates that growth hormone levels of less than 2.5 μg per liter, a younger age, a shorter duration of disease, and the absence of hypertension independently predict longer survival. Increased IGF-I levels are associated with higher mortality. 

How do we confirm a diagnosis of acromegaly?

Most patients present with florid disease features and are readily spotted. Biochemical diagnosis is made by assessing autonomous secretion of growth hormone. This is done by measuring growth hormone levels during a 2-hour period after a standard 75-g oral glucose load (glucose-tolerance test), as well as by assessing the peripheral biologic effect of hypersecretion of growth hormone, as reflected by changes in IGF-I levels.

In addition, clinical changes engendered by elevated levels of growth hormone and IGF-I should be assessed. Several factors may make the biochemical diagnosis challenging, including the pulsatile nature of growth hormone secretion, the sensitivity of secretion of the hormone to sleep, and changes in the hormone according to the age and nutritional status of the patient. Measurements of growth hormone are also confounded by the lack of uniformity in reference standards and technical differences among assays, which contribute to poor reproducibility and wide interassay variation. Ideally, levels of growth hormone should be based on commonly accepted reference calibrations for recombinant human growth hormone and expressed in mass units, which would permit an accurate diagnosis of acromegaly, even in the context of subtle clinical features.

Look for local effects such as headaches, visual field defects i.e bitemporal hemianopia as the tumour presses on the optic chiasma affecting the colour fibres first, enlargement of the pituitary fossa which can be seen as double outline of the pituitary fossa in an X ray of the skull lateral view and its enlargement as the posterior wall is eroded. A number of cranial nerves are located in fibrous sheaths along the lateral wall of each cavernous sinus: the oculomotor nerve (cranial nerve III), the trochlear nerve (cranial nerve IV), and the ophthalmic (V1) and maxillary branches (V2) of the trigeminal nerve. The abducens nerve (cranial nerve VI) is located more medially. If the adenoma invades the cavernous sinus these cranial nerves can be affected.

As the soft tissue of the hands develop carpal tunnel syndrome may also develop, as well as acroparathesias and arthritis. Similar changes occur in the feet. The jaw enlarges, prognathism and the lower jaw bite overides the upper jaw. There is proximal myopathy with the patient complaining about climbing stairs and getting up from a squatting position and from low seats or sofa chairs. There may be gigantism in a youngster.

In the pulmonary system there may be sleep disturbances, sleep apnoea and daytime sleepiness. The heart shows evidence of asymmetric septal hypertrophy, left ventricular hypertrophy, cardiomyopathy and diastolic heart failure. The skin may be oily and there is excessive sweating. The tongue enlarges as do the liver and kidneys and a goiter may develop. There is hypertension, hyper-triglycidemia, hyperglycemia with a high degree of insulin resistance, hypercalciuria, a low rennin level and a high aldosterone level, low thyroxine binding globulin and hydroxyproline in the urine. Most of these biochemical changes are not diagnostic of but support the diagnosis. There may be associated hyperparathyroidism and pancreatic islet cell tumours.

How are you going to treat acromegaly?

All the approaches to therapy — surgery, radiotherapy, and medications — have specific advantages and disadvantages. The goals of therapy in patients with acromegaly are to lower the serum insulin-like growth factor-1 (IGF-1) concentration to within the normal range for the patient’s age and gender, control adenoma size and reduce mass effects, improve symptoms, and reverse metabolic abnormalities such as diabetes mellitus. In addition to lowering IGF-1, another biochemical goal is to lower the serum growth hormone (GH) concentration to <1 mcg/L. The goal of a cure should ideally be achieved while minimizing side effects.

Surgery is indicated for growth hormone–secreting microadenomas, as well as for decompressing mass effects on vital structures, particularly the optic tracts. Patients with small tumors (less than 10 mm in diameter) and growth hormone levels of less than 40 μg per liter should do well with transsphenoidal surgery, provided the neurosurgeon is experienced. Tumors that have invaded the cavernous sinus cannot be completely resected, and the hypersecretion of growth hormone invariably persists postoperatively in such patients. Surgery may not be indicated as first-line therapy if it appears that the tumor mass is unlikely to be resectable and it does not endanger vital structures or if the patient declines surgery. If the entire adenoma is not resected further medical treatment is indicated and becomes more effective after surgical debulking.

Take care of problems such as airway obstruction, severe glucose intolerance, hypertension, and heart failure  with appropriate medical management before surgery. Recent surgical advances that involve the use of imaging guidance, navigation and endoscopic approaches and perioperative pharmacotherapy of the tumor have contributed to improved outcomes.

About 10% of patients will have relapse of the disease after surgery, and 30-70% will have deficiency of some or all of the pituitary hormones. This is permanent and will have to be looked out for.

Radiotherapy is generally reserved for tumors that have recurred or persisted after surgery in patients with resistance to or intolerance of medical treatment. Conventional external-beam radiotherapy is administered over a period of several weeks. Several centers now perform stereotactic radiosurgery with the use of the gamma knife, which delivers a single radiation fraction to a small tumor target. This technique requires precise delineation of the target mass and is limited by the vulnerability of adjacent soft-tissue structures, including the optic tracts. Advanced computerized imaging has permitted accurate targeting of the tumor mass, minimized radiation scatter to normal surrounding tissues, and reduced treatment times. Initial reports suggest the effectiveness of gamma-knife radiosurgery, with similar complication rates.

IGF-I levels attenuate very slowly after radiation therapy, and maximal control of the release of growth hormone may require more than 15 years. Within 10 years after radiation therapy, about 50% of patients have hypopituitarism involving one or more trophic axes.

Medical treatment involves the use of somatostatin receptor ligands, such as octreotide and lanreotide.  These compounds bind to somatostatin receptors, which, once stimulated, signal the pituitary to suppress the secretion of growth hormone and the proliferation of somatotroph cells and also act on the liver to block the synthesis of IGF-I78. Panselective, monoselective, and chimeric somatostatin receptor ligands are currently under investigation . In addition, a growth hormone–receptor antagonist acts peripherally to block growth hormone signaling. Although somatotroph adenomas express dopamine D2 receptors, D2-receptor agonists are not as effective as other agents.

Octreotide and lanreotide are selective for SST2 and SST5 and are generally safe for treating patients with growth hormone–secreting adenomas, given the long half-lives and absence of insulin-suppressing effects of both drugs. Depot preparations — long-acting-release octreotide and a long-acting aqueous-gel preparation of lanreotide — allow for injections every 14 to 28 days yet maintain highly effective drug levels. Reports suggest that 80% of patients who were followed for up to 9 years during treatment with somatostatin receptor ligands had growth hormone levels of less than 2.5 μg per liter and normal IGF-I levels. Shrinkage of tumor mass occurs in approximately 50% of patients but generally reverses when treatment is discontinued.

Pasireotide — The somatostatin analog pasireotide is also effective in some patients with acromegaly and is approved for its treatment, but it frequently causes or worsens hyperglycemia.

Dopamine Receptor Agonists
Despite the poor efficacy of the first dopamine receptor agonists, agents such as cabergoline appear to be promising. In an uncontrolled study, high doses of cabergoline offered a partial benefit, especially in combination with somatostatin receptor ligands and in patients with tumors that also secreted prolactin. The addition of high doses of cabergoline to treatment with somatostatin receptor ligands may improve the responsiveness of growth hormone in patients who otherwise have resistance to maximal doses of somatostatin receptor ligands. A trial of cabergoline, rather than somatostatin analogs or pegvisomant, may be used in patients with modest biochemical abnormalities, eg, GH concentrations >1 mcg/L but <1.3 mcg/L and only mild symptoms of GH excess

Pegvisomant, a Growth Hormone–Receptor Antagonist
Pegvisomant is a pegylated growth hormone analogue with eight amino acid substitutions in growth hormone–binding site 1 and the substitution of glycine for alanine at position 120, resulting in both enhanced affinity for the growth hormone receptor and prevention of functional growth hormone–receptor signaling. Pegvisomant is used in patients with resistance to or intolerance of somatostatin analogues. The drug should be used in patients who do not have central compressive symptoms and in those with resistant diabetes. Daily injection of 40 mg of pegvisomant blocks the growth hormone–mediated generation of IGF-I in approximately 90% of patients, which improves peripheral soft-tissue features. Combined administration of a somatostatin receptor ligand and a growth hormone–receptor antagonist has been reported as an additional treatment to suppress the production of IGF-I, improving glucose tolerance, and to permit the administration of lower doses of growth hormone–receptor antagonist.

Information for this post has been taken from:

Review article: Acromegaly. Author: Shlomo Melmed, M.B., Ch.B.

December 14, 2006
N Engl J Med 2006; 355:2558-2573
DOI: 10.1056/NEJMra062453

Uptodate: articles on Diagnosis of Acromegaly, Treatment of Acromegaly

 

 

 

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shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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