Table of Contents
Definition and Overview of Acromegaly
Acromegaly – also known as gigantism
In 1886, French physician Pierre Marie first presented the term acromegaly. The disease is the result of an autonomously triggered production of GH (growth hormone). Main symptoms and complications arise from the enlarging organs and extremities as well as changes in the metabolism. Body changes in afflicted patients include hypertension, pathologic glucose tolerance, visual disturbances and visceromegaly.
Description and synonyms: acromegaly (ancient Greek for “extreme” and “large”), gigantism, Pierre Marie’s disease.
Epidemiology of Acromegaly
In the United States, there are approximately 1,000 – 2,000 newly diagnosed cases of acromegaly per year. It has a prevalence of approximately 20,000 in the United States.
The median age of diagnosis of this disease is about 40 years. Since this disease is marked by a stealthy beginning and course, a lag of 9 – 10 years between the start of the disease and its diagnosis is common, even with advanced medicine.
No significant differences have been proven regarding the incidence of disease between men and women. Life expectancy is shortened by about 10 years in patients with acromegaly since malignant tumors are common.
Etiology and Pathogenesis of Acromegaly
Growth hormone (GH) in acromegaly
GH is a peptide hormone which is produced in the adenohypophysis. GH is secreted predominantly during sleep and in puberty. It has an insulin-antagonistic, growth-stimulating and anabolic (intracellular integration of amino acids ↑, protein synthesis ↑) effect. GH has no direct effect, but commutes via the IGF-1 synthesis in the liver. Nutrition also affects GH production. It increases with the following:
- Physical strain
2. GH increases gluconeogenesis in the liver and stimulates glucagon secretion.
- The hypothalamus forms GH-releasing hormone somatoliberin GHRH ⇒ stimulation of GH-formation.
- The hypothalamus forms GH-Inhibiting hormone somatostatin GHIH ⇒ inhibition of GH-formation.
- GH acts in the periphery through the liver-formed insulin-like growth hormone IGF-1. The negative feedback mechanism does not function in acromegaly. For more information, read the Hypothalamus Pituitary Adrenal Axis article.
GH-producing hypophyseal adenoma
In most cases, the overproduction during acromegaly is caused by a monoclonal pituitary adenoma. GH-producing tumors make up 20% of hypophyseal adenomas. In rare cases, acromegaly is caused by a decrease in somatotropin production or an excess of GHRH. An undue secretion of growth hormone leads to an enlargement of organs and extremities which gives the impression of crude facial aspects.
When an overproduction of GH occurs in childhood, where growth plates have not yet fused, it results in gigantism. The afflicted are commonly over 6’6” tall. Due to malocclusion and enlargement of the temporomandibular joint, orthodontists and dentists are the primarily consulted specialists.
Symptoms and Clinical Presentation of Acromegaly
Clinical symptoms of acromegaly are the result of elevated stimulation of endochondral and appositional bone growth, elevated stimulation of skin and skin appendages as well as organ growth.
|Children (before growth plate fusion)||Adults (post growth plate fusion)|
|Hypophyseal gigantism > 6’6”||Acromegaly, visceromegaly|
Typical characteristics of acromegaly
- Visceromegaly (visible organ enlargement, e.g., goiter formation);
- Enlargement of osseous extremities;
- Thickening of the dermis (pachydermia): hypesthesia, paresthesia;
- Macroglossia: enlargement of the tongue with dysphonia;
- Enlarged nose;
- Formation of supraorbital bulges;
- Separation of the teeth and broadened interdental grooves;
- Headache, fatigue, bone pain, perspiration.
Acromegaly – possible complications
- Cessation of functioning of remaining adenohypophysis – symptoms through encroaching growth.
- Disturbances of the visual field (bitemporal hemianopsia due to compression of the chasma opticum).
- Carpal tunnel syndrome due to connective tissue hyperplasia.
Secondary complications in acromegaly
- Sleep apnea (> 90 % of patients are affected);
- Diabetes mellitus;
- Secondary hypogonadism (women: secondary amenorrhea and menstrual cycle disturbances, men: loss of libido and potency), hyperprolactinemia, erectile dysfunction;
- Hypertension (30 % of patients);
- Spinal column and joint complaints;
- Increased incidence of colon and breast cancers.
An acromegaly case report
The following could be a case report for acromegaly in a board exam:
A 45-year-old male was noted to display the typical changes of acromegaly (enlargement of nose, ears, lips, tongue, fingers and toes). Endocrinologic diagnostic procedures showed pathologically elevated growth hormone levels. A diagnosis of acromegaly was concluded. Following MRI showed a small pituitary tumor with little contrast agent uptake, which hinted at a growth hormone releasing adenoma.
The tumor was surgically removed by gaining access via the right nasal cavity and sphenoidal sinus using a surgical microscope and endoscope. Post-operative growth hormone levels returned to normal levels. A post-surgical MRI showed a complete removal of the adenoma with proper visualization of the normal pituitary gland. Post-operative hormone tests supported normal functioning of the remaining pituitary gland such that the patient did not require hormone substitutes. The acromegaly was cured with surgical intervention alone.
Source: University of Greifswald
Diagnosis of Acromegaly
Acromegaly should be diagnosed as early as possible.
Secretion of GH varies by time of day. Therefore, single observations of GH are not useful for diagnosing acromegaly. The easiest diagnostic medium is the OGTT (oral glucose tolerance test) with a parallel observation of serum GH. In the presence of acromegaly, a missing suppression of GH < 1 μg/l is typical.
Furthermore, a hormone analysis of IGF-1 and GH can be useful, which would show pathologically high levels for both. Bound IGF-1 has a serum half-life of up to 18 hrs, which indicates that serum observation is sufficiently meaningful.
For purposes of ruling out further hormone producing adenomas of the adenohypophysis, testing for LH/FSH, TSH, prolactin and ACTH are called for. Often complete or partial hypopituitarism is observed in parallel.
Microscopically, one can differentiate sparsely-granulated (aggressive) and densely-granulated (less aggressive) tumors. In a third of the cases there is also an elevated secretion of prolactin (monomorphic, mono-cellular, mixed cell adenomas).
Radiologic proceduresPatients with acromegaly will show an enlarged sella turcica on x-ray, the nasal sinuses and the heart. MRI is well suited for tumor discovery.
Similar diseases such as acromegaly
|GH-disturbance without adenoma||Hereditary acromegaly||Further differential diagnoses|
|Pituitary hyperplasia||MEN-1 syndrome||Constitutional tallness|
|Ectopic/paraneoplastic GH-/GHRH-formation||McCune-Albright syndrome||Acromegaloid|
|Familial acromegaly||Hyperostosis generalisata (primary hypertrophic osteoarthropathy, pachydermoperiostosis)|
Treatment of Acromegaly
Trans-sphenoidal adenoidectomy via endo-nasal access is the current standard of care. This surgery is performed because of its curative potential. With complete removal of the tumor, the hormone level decreases immediately.
Final proof for successful tumor removal with cure of the acromegaly is declared several weeks after the surgery through renewed endocrinologic examination.
Inoperable tumors or an incomplete resection can call for stereotactic radiosurgery, proton therapy and conventional radiation therapy. The effect of the radiation, however, is often not immediate but can occur after several years under certain circumstances. Furthermore, one must consider the risk of anterior pituitary insufficiency.
In the case of inoperability and transient radiotherapy, pharmacologic treatment is called for. If the patient’s tumor is large, preoperative pharmacologic treatment can be useful to induce tumor shrinkage and improve the patient’s general constitution. All medication targets the inhibition of GH secretion:
|Dopamine-D2-agonists||Inhibition of GH-production by the pituitary adenoma||Bromocriptine, Cabergoline|
|GH-receptor-antagonists||Normalization of the elevated IGF-1 level||Pegvisomant|
|Somatostatin-analogs||Decreased size of the adenoma, normalized GH level||Octreotide, Lanreotide|
Prognosis of Acromegaly
Lowered life expectancy for acromegaly patients.
Life expectancy of people with acromegaly is significantly limited due to secondary complications. Lethality is twice as high and up to four times as high as healthy individuals. Main reasons for this are usually hypertension, cardiovascular disease and diabetes mellitus.
The answers are below the references.
1. Clubbed nails were observed during the routine exam of 48-year-old Mrs. F. Clubbed nails are typical in a host of diseases. Which of the following diseases is most indicated?
- Pituitary adenoma (e.g., prolactinoma, acromegaly)
- Mitochondrial diseases (e.g., chronic, progressive ophthalmoplegia)
- Chronic insufficiency of the adrenal gland cortex (e.g., Addison’s disease)
- Malignant lung disease (e.g., bronchial carcinoma)
- Chronic renal insufficiency (e.g., diabetic nephropathy, analgesic nephropathy)
2. A 65-year-old female patient complains during consultation about persistent and increasingly worsening pain in her legs and pelvis. She further notes, by-the-by, that her hats have been getting tight, such that some no longer fit. Lab work shows high levels of alkaline phosphatase (ALP) at 550 U/L. You order cranial x-rays and skeletal scintigraphy. Which diagnosis, however, do you suspect already?
- Metastatic breast cancer
- Renal osteopathy
- Ostitis deformans (Paget’s disease)
- Chronic arsenic toxicity
3. Over the past two years, the facial features of a 61-year-old male patient have become increasingly crude and his hands have enlarged. Blood work revealed increased GH levels. Magnetic resonance imaging showed a microadenoma of the pituitary gland. After surgical removal of the adenoma via trans-nasal, trans-sphenoidal access, the soft tissue swelling as well as the high hormone levels observed in the blood reversed completely. MRI showed a complete removal of the hormone-producing microadenoma. If the adenoma had been inoperable, which of the following drug groups could have been called on?