Acromegaly


Article Author:
Oluwaseun Adigun


Article Editor:
Fassil Mesfin


Editors In Chief:
Temekis Hampton


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
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John Shell
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Heba Mahdy
Ahmad Malik
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Sarosh Vaqar
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James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
8/3/2019 7:11:18 PM

Introduction

Acromegaly is a disorder caused by excessive production of growth hormone from the anterior pituitary gland, resulting in excessive growth of body tissues and other metabolic dysfunctions. Adult patients with acromegaly have the characteristic facial features of a large lower jaw, prominent forehead, and large hands and feet. This takes place after the growth plates are fused, distinguishing acromegaly from gigantism which occurs before fusion of growth plates.[1][2][3]

Despite the slow growth, acromegaly is a life-threatening condition for which there is no cure, but with present-day treatment, most patients can have a good quality of life.

Etiology

Pituitary Tumor: In more than 95% of cases, the excessive growth hormone is caused by a pituitary tumor, usually a benign microadenoma of the pituitary gland.

Non-Pituitary Tumor: Tumors of the adrenals, lungs, and pancreas are implicated in a few cases. These tumors secrete growth hormone or growth hormone releasing Hormone (GH-RH).

Elevated levels of growth hormone stimulate the liver to produce Insulin-like growth factor-1 (IGF-1). Elevated levels of Insulin-like growth factor-1 stimulate the excessive growth of body tissues.

Epidemiology

Acromegaly has a worldwide prevalence of about 4,600 per million population, with about 116.9 new cases per million per year. Mean age at diagnosis 40 for men and 45 for women.[4][5] Acromegaly usually presents in the 3rd decade of life.

Pathophysiology

In about 95% of cases, acromegaly is associated with a pituitary microadenoma, while the remaining 5% are from non-pituitary ectopic sources of growth hormone or GH-RH. The common effect of the abnormal rise in growth hormone is the production of Insulin-like growth factor-1 (IGF-1) from the liver. The effect of IGF-1 on body tissues results in the multisystemic manifestation of acromegaly. IGF-1 also known as Somatomedin C is encoded by the IGF-1 gene on chromosome 12q23.2.[6][7]

The pathologic effect of IGF-1 after fusion of the growth plates resulting in the acral growth spurts manifested as large hands and feet and a prominent jaw and forehead. It is clearly different from the linear size increase that occurs in gigantism in which the effect of elevated IGF-1 occurs before the closure of the growth plate.

Acromegaly leads to elevated IGF-1 that affects the following pathways of metabolism:

  • Competes with insulin for the insulin receptor, resulting in relative insulin resistance which may be responsible for the co-existing diabetes mellitus in 10% to 20% of patients with acromegaly.
  • Results in general somatic hypertrophy seen as enlarged body organs, for example, macroglossia, acromegalic heart, large kidneys, and bulky skeletal muscles.
  • Somatic growth by binding insulin-like growth factor-1 Receptor (IGF-1R) which is relatively ubiquitous. IGF-1R is a receptor tyrosine kinase which brings about phosphorylation and activation of several intracellular signaling pathways, one of which is the AKT pathway activation that results in somatic cell growth and proliferation.

Toxicokinetics

IGF-1 is an insulin-like protein produced majorly in the liver. It is a single chain of 70 amino acids and three disulfide bridges with a molecular weight of approximately eight kilodaltons. IGF-1 level peaks around puberty, with low levels at extreme ages.

Synthetic IGF-1 analog is used in the treatment of growth disorders, for example, dwarfism.

IGF-1 almost always exists in the bound form. It is bound by the IGF-binding proteins (IGF-BPs), and the most abundant of them is IGFBP-3.

Nutrition also plays some role, as high protein intake tends to increase growth hormone and IGF-1 levels.

History and Physical

Acromegaly is usually a slow progressing disorder, with onset usually in the third or fourth decade of life. The presenting complaints include the following:

  • joint pain due to hypertrophic arthropathy
  • wrist pain and numbness from carpal tunnel syndrome
  • snoring and sleep disorders, like sleep apnea, due to macroglossia
  • headaches and visual disturbances (bitemporal hemianopia) and pressure effects of pituitary adenoma on adjoining structures in the brain, for example, compression of the optic chiasma
  • erectile dysfunction or low sex drive
  • abnormal menses in women
  • sweaty palms and soles (hyperhidrosis)

Signs upon physical examination include the following:

General Examination

  • coarse facial features, prominent forehead, prominent brow, and prognathism (mandibular enlargement)
  • prominent forehead crease and nasolabial folds
  • large tongue and widely spaced dentition
  • thick eyelids, large nose, and lower lip

Visual field examination

  • bitemporal hemianopsia

Neck

  • feel for a thyroid mass
  • observe for raised JVP (in acromegalic cardiomyopathy)

Integuments

  • skin is thick and rough
  • skin tags
  • oily skin
  • abnormal or excess hair distribution, e.g., hirsutism(in women), hypertrichosis
  • hyperpigmentation
  • acanthosis nigricans especially in the axilla

Breast Exam

  • galactorrhea
  • dry atrophied skin

Cardiovascular

  • problems of  acromegalic cardiomyopathy
  • elevated blood pressure
  • cardiac murmur (a pansystolic murmur may indicate mitral valve regurgitation)

Chest

  • bibasal crepitation may indicate a congestive heart failure in a patient with acromegalic cardiomyopathy

Limbs

  • acral enlargement: large hands (with stubby fingers) and feet
  • proximal myopathy
  • genu varum
  • rolling gait

Evaluation

Laboratory investigations

GH suppression test:

  • administer 100 g glucose to the patient orally
  • one hour later measure serum growth hormone levels
  • result: normal GH levels which are less than five ng/ml excludes acromegaly, while elevated levels of greater than ten ng/ml are suggestive of acromegaly

IGF-1 Levels

  • a direct dose-response relationship with growth hormone levels
  • levels measured for age and sex
  • useful for diagnosis and treatment monitoring
  • pregnancy can cause elevated IGF-1 levels

Growth Hormone Releasing Hormone (GHRH) Levels

  • elevated levels usually > 300ng/mL is suggestive of extra-pituitary sources

Prolactin

  • Elevated prolactin levels due to pituitary stalk compression by an adenoma or by a co-prolactin producing pituitary adenoma.

Imaging Studies

Brain Scan

  • MRI is more sensitive in visualizing the Sella turcica and adjacent structures, but a CT scan can be done if this is not available

X-rays

Skull x-ray: thickened calvaria, enlarged sella, long and thick mandibles, exaggerated ridges, dilated sinuses

Chest x-ray: barrel rib cage with long ribs

Hand x-ray: cortical thickening, ungal tufting, wide distal phalangeal bases, osteophytes, and soft tissue hypertrophy

Treatment / Management

Treatment Guidelines

  • Removal of the pituitary gland should be the primary treatment in most patients
  • An imaging study should be done after 12-16 weeks post surgery to determine if there is any residual tumor left
  • Follow up required to ensure the patient does not have signs and symptoms of hypopituitarism
  • For patients with residual disease, medical therapy is offered

Surgical Treatment

  • Endonasal Transsphenoidal Surgery:  A minimally invasive surgery using an endoscope through a small incision in the nose or at the upper lip to remove the pituitary adenoma will promptly relief the pressure symptoms as well as lower elevated growth hormone (GH) levels. Recovery time is shorter compared to traditional transsphenoidal surgery.
  • Transnasal Transsphenoidal Microscopic Surgery:  This is a traditional pituitary surgery that utilizes direct visualization of the tumor using a microscope. Recent retrospective studies showed gross total resection with a resolution of IGF-1 endonasal approach which is comparable to transnasal transsphenoidal microscopic surgery.

Medical Therapy: Either as an adjunct to surgery or when surgery is not desirable.[8][9][10]

  • Somatostatin analogs (octreotide, Lanreotide): These act on the somatostatin receptor to bring about inhibition of growth hormone secretion. It is usually administered as once-monthly intramuscular injections. It also can be used to shrink large pituitary adenomas before surgery.
  • Dopamine receptor agonists (cabergoline, bromocriptine): These act on D2 receptors and are not as effective as the Somatostatin analogs. They are often used as adjuncts. Cabergoline is more potent than bromocriptine in lowering GH levels.
  • GH- Receptor antagonist (Pegvisomant): This novel drug blocks growth hormone at the receptors, lowering IGF-1 levels while GH levels remain unaffected.

Radiotherapy

  • Conventional radiotherapy: Often administered as an adjunct to surgery to either prevent relapse or when surgery is not able to bring about the acceptable lowering of GH levels. It is associated with the risk of irradiating adjacent brain tissues.
  • Stereotactic radiosurgery: This is precision radiotherapy, directing high dose radiation to the tumor, and minimizing risk to nearby healthy brain tissues.

Differential Diagnosis

  • Carney complex
  • McCune Albright syndrome
  • Pseudoacromegaly

Prognosis

  • Because of the rarity of the condition, the exact statistics on mortality are unknown. However, acromegaly is associated with high mortality rates, chiefly due to malignancies, cardiovascular and respiratory disorders.
  • The effects of IGF-1 results in an enlarged heart, increased muscle mass and kidney size, hypertrophy of the joints, thickened skin, macroglossia, nerve entrapment syndromes, cerebral aneurysms, and hyperhidrosis.
  • Individuals with acromegaly have 2-3 times the mortality rate compared to the general population.

Complications

  • Diabetes mellitus, hyperinsulinemia, and hypertriglyceridemia
  • Airway narrowing, dyspnea, stridor and sleep apnea
  • Hypertension, acromegalic heart, left ventricular hypertrophy
  • Urolithiasis, hypercalciuria
  • Muscle weakness, radiculopathies, nerve root compression, spinal stenosis, and carpal tunnel syndrome
  • Increased risk of cancer, breast and prostate cancer

Postoperative and Rehabilitation Care

  1. Long term monitoring is vital because the risk of hypopituitarism is high after surgery
  2. GH levels post-surgery should be less than 1.0 ng/ml
  3. Cardiac evaluation is necessary as patients may develop cardiomyopathy, mitral regurgitation, hypertension, arrhythmias, and coronary artery disease
  4. Perform colonoscopy screening to rule out colon cancer
  5. Assess lung function, joints, and presence of sleep apnea

Pearls and Other Issues

Minoxidil use has been associated with a condition characterized by facial features of acromegaly, but with normal growth hormone and IGF-1 blood levels. This condition is known as pseudoacromegaly.

Enhancing Healthcare Team Outcomes

Acromegaly is not a common disorder in North America, but when it presents, it is associated with very high morbidity and mortality rates. Because the presentation of acromegaly is systemic, an interprofessional team approach is necessary. There is no cure for acromegaly and the current treatments only manage the symptoms. 

In particular, a cardiologist, oncologist, neurologist, and a pulmonologist should be involved as the disorder is associated with malignancies, adverse cardiac, CNS and pulmonary events.

The nurse practitioner should ensure that the patients are not showing signs of hypopituitarism after treatment and during followup appointments and report to the clinician as concerns arise. Levels of GH and IGF need to be monitored for life. Because of the risk of cancer, these patients should be referred to the appropriate specialist on a timely basis. Patients need to be educated about the importance of follow up because the morbidity from cardiac and respiratory complications are very high. Because of joint dysfunction, early physical therapy is recommended. Many of these individuals are not gainfully employed and thus social work should be involved in helping to manage their financial status. Due to the challenges of managing medical therapy, a pharmacist should be involved in assisting in drug reconciliation and evaluating for toxicity. Any concerns should be reported to the clinical team. [Level V]

The mortality rates of patients with acromegaly are 3 times the general population, with most dying from respiratory and cardiac complications. These patients also develop several types of tumors including prostatic hypertrophy, uterine myomas, and skin tags. The overall outcome depends on whether the cause of acromegaly can be treated. even after surgical removal of a pituitary tumor, some patients may need treatment as a result of residual disease. The quality of life in these patients is poor.[11][12][13] Thus, it is also important not to subject these patients to unnecessary procedures, when medical treatment will suffice. The goal is not to harm the patient.

 


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Acromegaly - Questions

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What is the most common cause of acromegaly?



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A female with signs and symptoms of acromegaly has been noticing visual problems for the past five months. Which of the following vision defects are most common in such a patient?



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A 40-year-old woman reports going through menopause beginning about a year ago with irregular menses. For the past 6 months, she has had no flow. She is married, but repeated pregnancy tests have been negative. The patient also reports fatigue, weakness, hip and knee pain, hand swelling, and an increase in body hair. The exam shows normal vital signs, a large jaw, and large hands. Her hair is coarse with hirsutism. The thyroid is 2+/4 enlarged without nodules or tenderness. Her heart exam is regular without extra heart sounds, but the point of maximal impulse is displaced laterally. Which of the following would be appropriate for the management of this patient?



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A 39-year-old male was found down, resuscitated, and presented to the University Hospital after he had cardiac arrhythmia while he was playing basketball. The emergency room provider recognized that the patient had classic signs and symptoms of acromegaly. Which is not a possible sign and symptom?



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A middle-aged man is noted over 20 years to have protrusion of his brows, increasing foot size, and coarsening of his facial features. Which pair of hormones regulates the responsible hormone in normal situations?



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Which of the following conditions can be associated with a barrel chest?



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A 55-year-old man develops protrusion of the brows, increasing foot size, and coarse facial features over the last 14 years. Which pair of hormones may be responsible for his clinical features?



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A 55-year-old male complains of a several year history of enlargement of his tongue and shoe size. Acromegaly is the working diagnosis. Which of the following tests should be ordered?



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A 52-year-old male complains of generalized headaches every day for a year. Prior to this time, he reports he had frequent headaches but they have become much more frequent. He denies an exacerbating factors or triggers. His past medical history is unremarkable. Exam shows normal vital signs and normal funduscopic and neurologic exams. He has prominent cheekbones and a large nose. His wife complains that he snores. The patient reports that he had to buy a larger pair of gloves this year. What is the appropriate next step in management?



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What causes acromegaly's musculoskeletal manifestations?



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What is the drug of choice for acromegaly?



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Which of the following is responsible for the musculoskeletal manifestations of acromegaly?



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Which of the following is a first-line treatment of acromegaly?



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A 45-year-old female presented with classic signs and symptoms of acromegaly. What is the initial diagnostic test to order to aid the diagnosis of acromegaly?



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A 45-year-old complains of occasional headaches and increasing fatigue. The patient is quite distressed that shoes and gloves no longer fit. Exam shows frontal bossing, an enlarged tongue, a prominent lower jaw, and large feet and hands. Random blood glucose is elevated. What is the most probable diagnosis?



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What heel pad size measurement is seen in acromegaly?



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What is the likely location of a tumor that causes the mandible to become heavier and the calvaria to markedly thicken?



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A 45-year-old man presents to the clinic complaining from heat intolerance, decreased energy with increased sleep requirement, and weight gain. He also is diabetic. He has coarse facial features and protrusion of the brows. Upon questioning, the patient reports having to wear larger shoes than he did when he was younger man. Which of the following hormones normally regulates the hormone responsible for his condition?



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A 40-year-old male presented with progressive wrinkling of the facial skin, a prominent jaw, and large hands. He had a normal childhood and early adulthood. What is the most likely diagnosis?



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A 47-year-old man presents because he was told by the wife that his facial appearance has changed over the last 6 months. He also noticed that his wedding ring no longer fit. Which of the following test would be the best initial test to screen him for growth hormone excess?



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What condition results from hypersecretion of the pituitary gland causing in enlarged extremities?



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Hypersecretion of the pituitary gland resulting in enlarged extremities is known as which one of the following?



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Acromegaly - References

References

Drewes AM,Arlien-Søborg MC,Lunde Jørgensen JO,Jensen MP, [Acromegaly and symptoms of the motor apparatus]. Ugeskrift for laeger. 2018 Nov 12     [PubMed]
Pazarlı AC,Köseoğlu Hİ,Kutlutürk F,Gökçe E, Association of Acromegaly and Central Sleep Apnea Syndrome. Turkish thoracic journal. 2017 Nov 29     [PubMed]
Postma MR,Wolters TL,van den Berg G,van Herwaarden AE,Muller-Kobold A,Sluiter WJ,Wagenmakers MA,van den Bergh ACM,Wolffenbuttel BHR,Hermus A,Netea-Maier R,van Beek AP, Postoperative use of somatostatin analogs and mortality in patients with acromegaly. European journal of endocrinology. 2018 Oct 1     [PubMed]
Matyjaszek-Matuszek B,Obel E,Lewicki M,Kowalczyk-Bołtuć J,Smoleń A, Prevalence of neoplasms in patients with acromegaly - the need for a national registry. Annals of agricultural and environmental medicine : AAEM. 2018 Sep 25     [PubMed]
Sharma AN,Tan M,Amsterdam EA,Singh GD, Acromegalic cardiomyopathy: Epidemiology, diagnosis, and management. Clinical cardiology. 2018 Mar     [PubMed]
Pasupulati AK,Menon RK, Growth hormone and chronic kidney disease. Current opinion in nephrology and hypertension. 2018 Nov 1     [PubMed]
Buchman M,Bell S,Kopchick JJ, Growth Hormone Discovery and Structure. Pediatric endocrinology reviews : PER. 2018 Sep     [PubMed]
Granada ML, Biochemical following-up of treated acromegaly. Limitations of the current determinations of IGF-1 and perspective. Minerva endocrinologica. 2018 Oct 10     [PubMed]
Leonart LP,Borba HHL,Ferreira VL,Riveros BS,Pontarolo R, Cost-effectiveness of acromegaly treatments: a systematic review. Pituitary. 2018 Dec     [PubMed]
Ahmad MM,Buhary BM,Al Mousawi F,Alshahrani F,Brema I,Al Dahmani KM,Beshyah SA,AlMalki MH, Management of acromegaly: an exploratory survey of physicians from the Middle East and North Africa. Hormones (Athens, Greece). 2018 Sep     [PubMed]
Buchfelder M,van der Lely AJ,Biller BMK,Webb SM,Brue T,Strasburger CJ,Ghigo E,Camacho-Hubner C,Pan K,Lavenberg J,Jonsson P,Hey-Hadavi JH, Long-term treatment with pegvisomant: observations from 2090 acromegaly patients in ACROSTUDY European journal of endocrinology. 2018 Oct 1     [PubMed]
He W,Yan L,Wang M,Li Q,He M,Ma Z,Ye Z,Zhang Q,Zhang Y,Qiao N,Lu Y,Ye H,Lu B,Shou X,Zhao Y,Li Y,Li S,Zhang Z,Shen M,Wang Y, Surgical outcomes and predictors of glucose metabolism alterations for growth hormone-secreting pituitary adenomas: a hospital-based study of 151 cases. Endocrine. 2018 Sep 20     [PubMed]
Rick J,Jahangiri A,Flanigan PM,Chandra A,Kunwar S,Blevins L,Aghi MK, Growth hormone and prolactin-staining tumors causing acromegaly: a retrospective review of clinical presentations and surgical outcomes. Journal of neurosurgery. 2018 Sep 14     [PubMed]

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