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| Acromegaly | |
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Facial aspect of a patient with acromegaly. The cheekbones are pronounced, the forehead bulges, the jaw is enlarged and facial lines prominent.
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| Classification and external resources | |
| ICD-10 | E22.0 |
| ICD-9 | 253.0 |
| OMIM | 102200 |
| DiseasesDB | 114 |
| MedlinePlus | 000321 |
| eMedicine | med/27 derm/593 |
| Patient UK | Acromegaly |
| MeSH | D000172 |
Acromegaly (/ˌækrɵˈmɛɡəli/; from Ancient Greek άκρος akros "extreme" or "extremities" and μεγάλος megalos "large") is a syndrome that results when the anterior pituitary gland produces excess growth hormone (GH) after epiphyseal plate closure at puberty. If GH is produced in excess prior to epiphyseal plate closure, the result is gigantism (or giantism). A number of disorders may increase the pituitary's GH output, although most commonly it involves a tumor called pituitary adenoma, derived from a distinct type of cell (somatotrophs).
Acromegaly most commonly affects adults in middle age,[1] and can result in severe disfigurement, complicating conditions, and premature death if unchecked. Because of its pathogenesis and slow progression, the disease is hard to diagnose in the early stages and is frequently missed for years until changes in external features, especially of the face, become noticeable.
Gigantism is also caused by an excessive production of GH, but in contrast to acromegaly, it begins prior to epiphyseal plate closure.
Features that result from high level of GH or expanding tumor include:
Compared with the hand of a typical person (left), the hand of a patient with acromegaly (right) is enlarged, with fingers that are widened, thickened and stubby, and with thicker soft tissue
Mandibular overgrowth leads to prognathism, maxillary widening, teeth spacing and malocclusion.
Brow ridge and forehead protrusion remaining after tumor removal and tissue swelling eliminated
Lower jaw showing the classic spacing of teeth due to acromegaly
In over 90 percent of acromegaly patients, the overproduction of growth hormones is caused by a benign tumor of the pituitary gland, called an adenoma. These tumors produce excess growth hormones and, as they expand, compress surrounding brain tissues, such as the optic nerves. This expansion causes the headaches and visual disturbances that often accompany acromegaly. In addition, compression of the surrounding normal pituitary tissue can alter production of other hormones, leading to changes in menstruation and breast discharge in women and impotence in men because of reduced testosterone production.
There is a marked variation in rates of GH production and the aggressiveness of the tumor. Some adenomas grow slowly and symptoms of growth hormone excess are often not noticed for many years. Other adenomas grow rapidly and invade surrounding brain areas or the sinuses, which are located near the pituitary. In general, younger patients tend to have more aggressive tumors.
Most pituitary tumors arise spontaneously and are not genetically inherited. Many pituitary tumors arise from a genetic alteration in a single pituitary cell which leads to increased cell division and tumor formation. This genetic change, or mutation, is not present at birth, but is acquired during life. The mutation occurs in a gene that regulates the transmission of chemical signals within pituitary cells; it permanently switches on the signal that tells the cell to divide and secrete growth hormones. The events within the cell that cause disordered pituitary cell growth and growth hormone oversecretion currently are the subject of intensive research.
In a few patients, acromegaly is caused not by pituitary tumors but by tumors of the pancreas, lungs, and adrenal glands. These tumors also lead to an excess of GH, either because they produce GH themselves or, more frequently, because they produce GHRH (Growth Hormone Releasing Hormone), the hormone that stimulates the pituitary to make GH. In these patients, the excess GHRH can be measured in the blood and establishes that the cause of the acromegaly is not due to a pituitary defect. When these non-pituitary tumors are surgically removed, GH levels fall and the symptoms of acromegaly improve.
In patients with GHRH-producing, non-pituitary tumors, the pituitary still may be enlarged and may be mistaken for a tumor. Therefore, it is important that physicians carefully analyze all "pituitary tumors" removed from patients with acromegaly in order not to overlook the possibility that a tumor elsewhere in the hypoglycoma is causing the disorder.
If acromegaly is suspected, medical imaging and medical laboratory investigations are generally used together to confirm or rule out the presence of this condition.
IGF1 provides the most sensitive lab test for the diagnosis of acromegaly, and a GH suppression test following an oral glucose load, which is a very specific lab test, will confirm the diagnosis following a positive screening test for IGF1. A single value of the growth hormone (GH) is not useful in view of its pulsatality (levels in the blood vary greatly even in healthy individuals).
GH levels taken 2 hours after a 75 or 100 gram glucose tolerance test are helpful in the diagnosis: GH levels are suppressed below 1 μg/L in normal people, and levels higher than this cutoff are confirmatory of acromegaly.
Other pituitary hormones have to be assessed to address the secretory effects of the tumor as well as the mass effect of the tumor on the normal pituitary gland. They include TSH (thyroid stimulating hormone), gonadotropic hormones (FSH, LH), ACTH (adrenocorticotropic hormone), prolactin.
An MRI of the brain focusing on the sella turcica after gadolinium administration allows for clear delineation of the pituitary and the hypothalamus and the location of the tumor.
The goals of treatment are to reduce GH production to normal levels, to relieve the pressure that the growing pituitary tumor exerts on the surrounding brain areas, to preserve normal pituitary function, and to reverse or ameliorate the symptoms of acromegaly. Currently, treatment options include surgical removal of the tumor, drug therapy, and radiation therapy of the pituitary.
The primary current medical treatment of acromegaly is to use somatostatin analogues – octreotide (Sandostatin) or lanreotide (Somatuline). These somatostatin analogues are synthetic forms of a brain hormone, somatostatin, which stops GH production. The long-acting forms of these drugs must be injected every 2 to 4 weeks for effective treatment. Most patients with acromegaly respond to this medication. In many patients, GH levels fall within one hour and headaches improve within minutes after the injection. Octreotide and lanreotide are effective for long-term treatment. Octreotide and lanreotide have also been used successfully to treat patients with acromegaly caused by non-pituitary tumors.
Somatostatin analogues are also sometimes used to shrink large tumors before surgery.
Because octreotide inhibits gastrointestinal and pancreatic function, long-term use causes digestive problems such as loose stools, nausea, and gas in one third of patients. In addition, approximately 25 percent of patients develop gallstones, which are usually asymptomatic. In some cases, octreotide treatment can cause diabetes due to the fact that somatostatin and its analogues can inhibit the release of insulin. On the other hand, scientists have found that in some acromegaly patients who already have diabetes, octreotide can reduce the need for insulin and improve blood sugar control.
For those who are unresponsive to somatostatin analogues, or for whom they are otherwise contraindicated, it is possible to treat using one of the dopamine agonists, Bromocriptine (Parlodel) or Cabergoline. These have the advantage of being tablets rather than injections, and cost considerably less. These drugs can also be used as an adjunct to somatostatin analogue therapy. They are most effective in those whose pituitary tumours cosecrete prolactin. Side effects of these dopamine agonists include gastrointestinal upset, nausea, vomiting, light-headedness when standing, and nasal congestion. These side effects can be reduced or eliminated if medication is started at a very low dose at bedtime, taken with food, and gradually increased to the full therapeutic dose. However, bromocriptine lowers GH and IGF-1 levels and reduces tumor size in fewer than half of patients with acromegaly. Some patients report improvement in their symptoms although their GH and IGF-1 levels still are elevated.
The latest development in the medical treatment of acromegaly is the use of growth hormone receptor antagonists. The only available member of this family is pegvisomant (Somavert). By blocking the action of the endogenous growth hormone molecules, this compound is able to control disease activity of acromegaly in virtually all patients. Pegvisomant has to be administered subcutaneously by daily injections. Combinations of long-acting somatostatin analogues and weekly injections of pegvisomant seem to be equally effective as daily injections of pegvisomant.
Surgery is a rapid and effective treatment, of which there are two alternative methods. The first method, a procedure known as Endonasal Transphenoidal surgery, involves the surgeon reaching the pituitary through an incision in the nasal cavity wall. The wall is reached by passing through the nostrils with microsurgical instruments. The second method is Transsphenoidal surgery during which an incision is made into the gum beneath the upper lip. Further incisions are made to cut through the septum to reach the nasal cavity, where the pituitary is located. Endonasal Transphenoidal surgery is a less invasive procedure with a shorter recovery time than the older method of Transphenoidal surgery, and the likelihood of removing the entire tumor is greater with reduced side-effects. Consequently, Endonasal Transphenoidal surgery is often used as a first option, with Transphenoidal and other treatments, such as medicinal therapy or stereotactic radiosurgery, being used to reduce the remaining adverse effects of the remaining tumor.
These procedures normally relieve the pressure on the surrounding brain regions and lead to a lowering of GH levels. Surgery is most successful in patients with blood GH levels below 40 ng/ml before the operation and with pituitary tumors no larger than 10 mm in diameter. Success depends on the skill and experience of the surgeon. The success rate also depends on what level of GH is defined as a cure. The best measure of surgical success is normalization of GH and IGF-1 levels. Ideally, GH should be less than 2 ng/ml after an oral glucose load. A review of GH levels in 1,360 patients worldwide immediately after surgery revealed that 60 percent had random GH levels below 5 ng/ml. Complications of surgery may include cerebrospinal fluid leaks, meningitis, or damage to the surrounding normal pituitary tissue, requiring lifelong pituitary hormone replacement.
Even when surgery is successful and hormone levels return to normal, patients must be carefully monitored for years for possible recurrence. More commonly, hormone levels may improve, but not return completely to normal. These patients may then require additional treatment, usually with medications.
Radiation therapy has been used both as a primary treatment and combined with surgery or drugs. It is usually reserved for patients who have tumor remaining after surgery. These patients often also receive medication to lower GH levels. Radiation therapy is given in divided doses over four to six weeks. This treatment lowers GH levels by about 50 percent over 2 to 5 years. Patients monitored for more than 5 years show significant further improvement. Radiation therapy causes a gradual loss of production of other pituitary hormones with time. Loss of vision and brain injury, which have been reported, are very rare complications of radiation treatments.
No single treatment is effective for all patients. Treatment should be individualized depending on patient characteristics, such as age and tumor size. If the tumor has not yet invaded surrounding brain tissues, removal of the pituitary adenoma by an experienced neurosurgeon is usually the first choice. After surgery, a patient must be monitored for a long time for increasing GH levels. If surgery does not normalize hormone levels or a relapse occurs, a doctor will usually begin additional drug therapy. The current first choice is generally octreotide or lanreotide. However, bromocriptine or cabergoline are much cheaper and easier to administer. With both types of medication, long-term therapy is necessary because their withdrawal can lead to rising GH levels and tumor re-expansion. Radiation therapy is generally used for patients whose tumors are not completely removed by surgery; for patients who are not good candidates for surgery because of other health problems; and for patients who do not respond adequately to surgery and medication.
Upon successful treatment, symptoms and complications generally improve substantially or disappear, including headaches, visual disturbances, excess sweating and diabetes.[4] Soft tissue swellings generally decrease and acromegaly-associated facial features gradually return towards normal although this may take some time.[4] Life expectancy after the successful treatment of early acromegaly is equal to that of the normal population.[4]
Pseudoacromegaly is a condition with the usual acromegaloid features but without an increase in growth hormone and IGF-1. It is frequently associated with insulin resistance.[5] Cases have been reported due to minoxidil at an unusually high dose.[6] It can also be caused by a selective post-receptor defect of insulin signalling, leading to the impairment of metabolic but preservation of mitogenic signalling.[7]
In order to confirm this disease, a doctor first performs some physical tests. A doctor observes the behavior and the body organs of the patients. A test is performed to measure the level of growth hormone in the body. Some other tests that are conducted for diagnosing this disease include: • Blood Test A blood test is performed to measure the levels of GH and IGF-I in the body. Increased levels of these growth hormones indicate that a patient is suffering from this disease. You should have fasted overnight if your doctor performs this test. • Growth Hormone Suppression Test. This is the most accurate test for verifying Acromegaly. The patient is asked to drink glucose. And the doctor measures the level of blood vessels of growth hormones before and after taking the glucose. People suffering from Acromegaly have higher levels of GH. • Magnetic Resonance Imaging This test is also recommended sometimes by the doctors. This imaging is performed to find the level and the position of pituitary tumor of pituitary gland. In this way, non pituitary tumors are also looked that also become a cause of high levels of the growth hormones. Prognosis A good prognosis of Acromegaly requires an early diagnosis. Patients receiving prompt treatment have good prognosis. Surgery is the best for treatment according to size of the tumor as the size of pituitary adenoma affects the remission rates and the level of growth hormones mainly. If the size of tumor is less than 10mm (microadenoma), you can have better prognosis. With macroadenomas disease become long lasting after the surgery. GH concentration post treatment is the best survival predictor.
There are several drugs that are used for the prevention of this disease. These drugs work for blocking the function of growth hormones. These drugs include: • Somatostatin Analogues Drugs octreotide and lanreotide are Somatostatin analogues. Somatostatin is the brain hormone. These drugs interfere with the excessive production of GH. Thus, the level of GH is decreased. • Dopamine Agonists. Drugs cabergoline and Parlodel can lower the level of GH and IGF-I. These drugs are taken in the form of pills and can also reduce the size of the tumor. • Growth hormone antagonist The medication Somavert eliminates the effects of GH on the body tissues. This is the best preventive treatment. This medication also normalizes the level of IGF-I Complications There are some complications that are originated from the Acromegaly disease. Some of these are: • Loss of Vision • High Blood Pressure • Enlargement of Heart • Suppression of Spinal Cord • Sleep Apnea • Diabetes Mellitus • Uterine Fibroid • High Risks of Cancer • Increased Death Rate • Fatigue • Weakness • Psychological Changes • Depression
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| リンク元 | 「成長ホルモン産生下垂体腺腫」「somatotroph adenoma」 |
| 関連記事 | 「grow」「pituitary」「adeno」「growth」 |