Acromegaly is a rare, insidious disease that until recently had a mortality rate twice that of the general population.1 With greater awareness, better therapeutics, and more precise imaging and biochemical assays, patients with acromegaly can be treated, and oftentimes cured, so that the mortality rate is now comparable to that for those without the disease.2
Previously, most deaths from acromegaly were attributable to cardiovascular disease, but now cancer has taken the lead.3 Fifty years ago, 50% of patients with acromegaly would die before age 50 years, with 89% facing death before their 60th birthday.3
Why Late Diagnosis Is Common
Although the mean age of acromegaly onset is 32 years, the disease is not usually diagnosed until years later, between ages 40 and 45 years.1 Acromegaly is a very rare disease with an estimated annual incidence of 3 to 4 cases/million people, making it difficult for clinicians to recognize and diagnose.3
In most cases of acromegaly, a slow-growing pituitary benign tumor or adenoma causes excess growth hormone (GH) secretion, causing an elevated insulin-like growth factor-1 (IGF-1) level in the body.1 The tumor generally remains undetected until patients present with enlarged hands, feet, or soft tissues. Because the pituitary tumors are imperceptible, some may not be detected until later stages. Joint pain, diabetes, hypertension, and heart or respiratory failure are presentations that prompt clinical attention.1
“Early-stage diagnosis of the condition is most challenging, as the disease is insidious in nature,” according to Salma AlDallal, PhD, from the Hematology and Blood Bank Department in the Kuwait Ministry of Health, Amiri Hospital in Sharq. “The patients, their families, or the doctors are not able to identify the condition at a very early stage. This condition involves normal GH concentration and dynamics, mild or absent clinical conditions, and a miniscule pituitary tumor, which is too small to be detected by [magnetic resonance imaging] at an early stage.”
Excessive secretion of GH affects multiple organs and systems, including the pituitary gland, liver, kidney, muscles, and gastrointestinal tract. Typical presentations of acromegaly are thickened skin and uneven growth of cartilage, bone, and epithelial tissue. Patients may also have goiter, hepatomegaly, splenomegaly, and an enlarged tongue.1
Acromegaly diagnosis is suspected when the GH level is >0.4 μg/L and IGF-1 is elevated. During an oral glucose tolerance test, a GH level of >0.4 μg/L suggests acromegaly, which is later confirmed by magnetic resonance imaging of the pituitary gland.1
Common comorbidities, which may confound an acromegaly diagnosis, include cardiovascular disease, hypertension, sleep apnea, colon carcinoma, thyroid cancer, vertebral fractures, joint disease, and glucose dysregulation. Women with acromegaly may have menstrual irregularities and infertility, and hyperprolactinemia develops in 30% of patients.1
Treatment Options to Eradicate or Stabilize Disease
Transsphenoidal surgery, in which the pituitary tumor is debulked or excised, is the first-line therapy for acromegaly.1-3 For patients in whom surgery is contraindicated, medications such as the somatostatin analogs octreotide, lanreotide, and pasireotide; the dopamine agonist cabergoline; or the growth hormone antagonist pegvisomant may be used in combination or sequentially.2 When medications fail to stabilize the disease, radiotherapy may be necessary.2
To determine risk factors that predicted disease severity in patients with acromegaly, researchers analyzed data from the Swiss Pituitary Registry of 21 patients with acromegaly (mean age, 48.9 years; 52% women).4 Of the 19 patients who were treated with transsphenoidal surgery, 42% (n = 8) had complete remission. The remainder were treated with medication to control the disease.4
The researchers found that small adenoma size and low levels of IGF-1 were the primary factors that predicted full remission.4 Large adenoma size at initial presentation (odds ratio [OR], 12.0; 95% CI, 1.02-141.0; P =.048) and high postoperative levels of IGF-1 (OR, 4.53; 95% CI, 1.07-19.2; P =.040) predicted whether patients would not have a complete remission and uncontrolled disease, respectively.4 Patients whose surgery and medication failed to control the disease had subsequent trials of different agents, as well as radiotherapy.4
“It is important to understand the prognosis of patients with acromegaly, which, based on our paper, is dependent on adenoma size and postoperative IGF-1 levels,” explained coauthor and internist Philipp Schuetz, MD, MPH, from the University Department of Medicine, Kantonsspital Aarau, Switzerland. “Based on these factors, physicians may choose to monitor patients more closely after surgery to start medical treatment early if the tumor removal does not cure.”
Cost-Effectiveness: Surgery Bests Medication
A team of investigators conducted a systematic review of 16 studies to determine the most efficient means to treat, and in some cases eradicate, acromegaly.5 Although surgery is the first-line therapy to cure the disease, it is not always possible for patients to undergo the procedure or for surgery to completely ameliorate complications, so many patients undergo combination therapies.5 In addition to surgery, somatostatin analogs, cabergoline, pegvisomant, and radiotherapy may stabilize acromegaly.5
For operable tumors, surgery is the recommended treatment, calculated at an average lifetime cost of $430,648, or $11,333/year. Initial treatment with somatostatin analogs was the most expensive treatment, at a lifetime cost of $899,789, or $23,678/year. Of the 4 studies that examined the cost-effectiveness of medical treatment, 3 studies found octreotide to be more effective than lanreotide.5
“We attempted to show that the comparative economic studies that we have on acromegaly are not transparent enough to apprise everything a decision maker may need to know to determine the best approach to treat acromegaly patients,” said coauthor and pharmacy professor Roberto Pontarolo, PhD, from the Universidade Federal do Paraná in Curitiba, Brazil. “It is still lacking a model that can be fully trustworthy and reproducible. We hope effort is applied to improving this matter, so we can select the best, cost-effective alternative to treat acromegaly, applicable to the reality of each health center scenario.”
Summary & Clinical Applicability
Acromegaly is a rare, insidious disease with a high mortality rate if not treated. Surgical removal of the adenoma is the primary cure, and for patients unable to withstand surgery, pharmacotherapy and radiotherapy can mitigate the symptoms of the disease.
Limitations & Disclosures
1. AlDallal S. Acromegaly: a challenging condition to diagnose. Int J Gen Med. 2018;11:337-343.
2. Melmed S, Bronstein MD, Chanson P, et al. A consensus statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. 2018;14(9):552-561.
3. Gadelha MR, Kasuki L, Lim DS, Fleseriu M. Systemic complications of acromegaly and the impact of the current treatment landscape: an update [published online August 31, 2018]. Endocr Rev. doi:10.1210/er.2018-00115
4. Kempf J, Schmitz A, Meier A, et al. Adenoma size and postoperative IGF-1 levels predict surgical outcomes in acromegaly patients: results of the Swiss Pituitary Registry (SwissPit). Swiss Med Wkly. 2018;148:w14653.
5. Leonart LP, Borba HHL, Ferreira VL, Riveros BS, Pontarolo R. Cost-effectiveness of acromegaly treatments: a systematic review [published online August 30, 2018]. Pituitary. doi:10.1007/s11102-018-0908-0