Acromegaly

What is Acromegaly?

Acromegaly is a severe, chronic neuroendocrine disease resulting from the overproduction of growth hormone by the pituitary adenoma (somatotropinoma).

The prevalence of acromegaly is about 40-60 cases per million population, the incidence of new cases is 3-4 per million people per year. It occurs with the same frequency in men and women, usually at the age of 40-60 years.

Causes of Acromegaly

In acromegaly, pituitary adenomas secreting growth hormone are detected in 99% of cases. Immunohistochemically, in addition to pure somatotropic adenomas (about 45%), mixed prolactosomatropins (about 30%) are isolated. The remaining 25% of adenomas, in addition, produce other adenohypophysial hormones: TSH, a-subunit, LH, FSH.

By their origin, somatotropinomas are monoclonal tumors that develop as a result of somatic mutation of somatotrophs. In 40% somatotropin, a mutation of the Gsp protein can be detected, which provides for the dimerization of the a and ß subunits of G proteins. Somatotropinoma can be an integral part of the 1st type multiple endocrine neoplasia syndrome (MEN-1).

Pathogenesis During Acromegaly

In adults, since after ossification of the epiphyseal cartilages, further growth is impossible, acromegaly develops (from akros – extreme, megas – large). With this pathology, accelerated growth of the body is also noted, but not in length, but in width due to soft tissues, which is manifested by disproportionate periosteal growth of the bones of the skeleton, an increase in the mass of internal organs and a characteristic metabolic disorder.

Changes in the organs of acromegaly are reduced to their true hypertrophy and hyperplasia, which is associated with the predominant growth of mesenchymal tissues. The parenchyma and stroma of all internal organs grows: lungs, heart, liver, pancreas, intestine, spleen. With the progression of the disease in connection with the proliferation of connective tissue in all organs, sclerotic changes occur, accompanied by the progressive development of their failure. In parallel, there is an increase in the risk of benign and malignant neoplasms in all tissues and organs, including endocrine ones.

Symptoms of Acromegaly

Acromegaly, as a rule, is characterized by a gradual onset with a slow increase in symptoms and a change in appearance. Acromegaly is diagnosed on average about 7 years after the actual onset of the disease. The main symptoms are:

• Changes in appearance are very characteristic and in the overwhelming majority of cases they are the ones that make acromegaly suspect. Characteristic coarsening of facial features associated with an increase in superciliary arches, cheek bones, lower jaw. Marked hypertrophy of the soft tissues of the face: nose, lips, ears. An increase in the mandible leads to a change in the bite due to the divergence of the interdental spaces. The tongue is enlarged (macroglossia), teeth are often visible on it. The change in appearance develops rather slowly, so that the patient himself does not notice him. In addition, there is an increase in the size of the hands and feet (patients often indicate an increase in shoe size, sometimes significant). When gigantism, unlike acromegaly, there is an increase in linear growth.

Severe articular cartilage hypertrophy causes arthralgia. An increase in the number and increase in the functional activity of the sweat glands leads to significant sweating (on examination, sweat streams can sometimes be seen flowing down the patient’s body). Activation and hypertrophy of the sebaceous glands, thickening of the skin lead to its characteristic appearance (dense, thickened, with deep folds, more pronounced on the scalp).

• Splanchnomegaly with the subsequent development of organ failure. The influence of growth hormone on the muscles and internal organs in the initial stages of the disease is hardly noticeable, and sometimes, especially among athletes and physical workers, is perceived positively, since working capacity and physical activity increase, but as the disease progresses, muscle fibers degenerate, causing increasing weakness, progressive reduction in performance . Uncompensated long-term hyperproduction of growth hormone leads to the development of concentric myocardial hypertrophy, which is replaced by hypertrophic myocardiodystrophy, and in advanced cases of the disease, it becomes dilated, leading to progressive heart failure, which is the cause of death of patients. Arterial hypertension is detected in 30% of patients with acromegaly.
• Headaches associated with the destruction of the Turkish saddle, its diaphragm and intracranial hypertension.
• Sleep apnea syndrome develops in 90% of patients with acromegaly. This is due to the proliferation of soft tissues of the upper respiratory tract and damage to the respiratory centers.
• Pituitary failure is associated with the destruction and compression of the pituitary by the tumor. Reproductive disorders (menstrual disorders, erectile dysfunction), in addition to impaired gonadotropin production, are often associated with hyperprolactinemia, which in turn may be associated with concomitant hyperproduction of prolactin, or compression of the pituitary stem.
• Chiasmatic syndrome.
• Symptomatic diabetes mellitus (up to 50% of patients).
• The development of benign and malignant tumors of different localization due to chronic overproduction of growth factors (IGF-1, etc.). Acromegaly often reveals a nodular or diffuse goiter, adenomatous hyperplasia of the adrenal glands, fibrocystic mastopathy, uterine myoma, polycystic ovary, intestinal polyposis. Intestinal polyps occur in 20-50% of cases, intestinal adenocarcinomas – in 7% of all cases of acromegaly.

Diagnosis of Acromegaly

1. An increase in the basal level of growth hormone is detected in the majority of patients with a developed clinical picture of acromegaly.
2. The oral glucose tolerance test involves examining the level of growth hormone initially, as well as in blood samples 30, 60, 90 and 120 minutes after ingesting 75 g of glucose. Normally, with a glucose load, the level of growth hormone decreases. In the active phase of acromegaly, the level of growth hormone does not decrease below 2 ng / ml, or a paradoxical increase in the level of growth hormone is detected. The glucose tolerance test is indicated in a situation where a patient with clinical manifestations of acromegaly determines only a moderate increase in the basal level of growth hormone, or he is normal. In addition, the test is used to assess the effectiveness of treatment.
3. A very informative study is the determination of the level of IGF-1 (somatomedin C). In adults, acromegaly is the only reason for increasing the level of IGF-1, and detection of a normal IGF-1 level virtually excludes this diagnosis. IGF-1, in contrast to growth hormone, has a longer plasma half-life and reflects growth hormone levels over a long time.
4. MRI of the pituitary gland for visualization of adenoma.
5. Examination for possible complications (polyposis of the intestine, diabetes mellitus, multinodular goiter, etc.).

Differential diagnostics

Acromegaly is differentiated from severe hypothyroidism, Paget’s disease, individual features of appearance.

Acromegaly Treatment

The goal of the treatment of acromegaly is the elimination of autonomous hyperproduction of growth hormone, normalization of the level of IGF-1 in the blood and the absence of an increase in plasma level of growth hormone in the glucose tolerance test (75 g glucose) above 1 ng / ml. These criteria correspond to the remission of the disease.

• The method of choice in the treatment of patients with acromegaly is the removal of pituitary adenoma. With microadenomas in 85% of cases, the level of growth hormone after surgery returns to normal. In the case of small encapsulated adenomas, surgical treatment usually leads to stable remission of the disease. In macroadenomas, full recovery after the first operation is achieved in 30% of cases. Tumors with extracellular growth have the worst prognosis.
• Somatostatin analogs (octreotide, long-acting octreotide, lanreotide) can normalize growth hormone levels and IGF-1 in 50-70% of patients. The size of pituitary adenoma decreases less often, only in 30-50% of cases and usually not much.
• Growth hormone receptor blockers (pegvisomant) reduce the synthesis of IGF-1 by competing with endogenous growth hormone for binding to its receptor. According to preliminary data during pegvisomant therapy, the level of IGF-1 is reduced in 90% of patients. Due to the lack of data on the long-term results of treatment, it is still used when other methods fail.
• Radiation therapy is low effective and can be used as an auxiliary treatment method. A more promising method is the directional irradiation of the residual tumor with b-particles (gamma knife).

Forecast

Mortality with acromegaly is 2-4 times higher than among the population. In general, primarily due to cardiovascular diseases. With the normalization of the level of IGF-1 and the elimination of hypersecretion of GH, mortality is reduced to the average.