gigantism and acromegaly
Introduction
Introduction to giant disease and acromegaly Excessive secretion of growth hormone in the body causes soft tissue, hypertrophy of bones and internal organs, and endocrine and metabolic disorders. It occurs before puberty, and the unincorporated sacral part is gigantism; after puberty, the crotch has been merged. For acromegaly. Giant disease patients often continue to develop acromegaly. This disease is not uncommon, and the ratio of men to women is about 1.5:1. The age of onset was the highest in the group of 31 to 40 years old, 21 to 30 years old, followed by the 41 to 50 years old group. Foreign literature reports that adult males are more than 2.0m tall and females greater than 1.85m are called giant human syndrome. However, it should be noted that in some areas, some familial bodies are taller than ordinary people, and their height is 1.9 to 2.0 m. Such people are not giant diseases. Giant disease has very little family genetic predisposition, and its parents and siblings are generally normal. basic knowledge The proportion of illness: 0.0006% Susceptible population: the most group from 31 to 40 years old Mode of infection: non-infectious Complications: carpal tunnel syndrome edema osteoporosis coronary heart disease myocardial infarction heart failure diabetes hyperprolactinemia
Cause
Giant disease and the cause of acromegaly
(1) Causes of the disease
In the endocrine system, thyroid, adrenal gland, and parathyroid glands can be seen early in hyperplasia and adenoma, early hyperplasia of the gonads, followed by atrophy, advanced thyroid, adrenal gland also atrophy, thymus showing persistent increase, visceral center, liver, pancreas, stomach, lung The spleen is huge, the intestine grows, and the lymphoid tissue proliferates.
Skeletal system lesions are obvious, with the following characteristics: long bone growth and thickening of giant disease, long bone epiphysis widening of acromegaly, exogenous osteophytes, skull, sinus both increase, and patients with giant disease are comprehensively enlarged Increased skull thickness in the acromegaly, thickening of the humerus and occipital bulge, obvious extension of the mandible to the front and lower, osteochondral hyperplasia of the spine, periosteal ossification, osteoporosis, wedge-shaped deformity of the vertebrae, lumbar vertebrae Sudden and thoracic vertebrae occur after the sputum, the finger (toe) end thickening hypertrophy.
(two) pathogenesis
Acromegaly and giant disease are almost secondary to pituitary adenomas, but the pathogenesis is not completely clear. GH tumors are primary changes in the pituitary itself, or secondary to hypothalamic dysregulation, which is secreted by GHRH. The increase is not fully conclusive, but most of the evidence supports that most of the acromegaly and giant disease are primary pituitary lesions, because the pituitary tissue outside the adenoma has no pathological hyperplasia; the GHRH in the blood of GH tumor patients is reduced. The GH secretion peak and GH level without sleep were not inhibited by glucose load; there was no GH secretion reaction to stress stimulation; pituitary GH tumor showed different degrees of functional autonomy, and guanosine was recently found in 40% GH tumor. Regulatory proteins have hereditary point mutations, which will lead to autonomic secretion and cell growth of GH. After successful resection of GH tumors, GH kinetics return to normal. It is suspected that hypothalamic abnormalities cause GH tumors based on: under normal circumstances, Dopamine and its potentiators (such as bromocriptine, apomorphine) stimulate GH secretion, but in 70% to 80% of patients with GH tumors, these drugs inhibit GH secretion, suggesting central defects, but still not sure Is originally from A pivotal defect, or due to the spontaneous secretion of GH, acromegaly or giant disease caused by increased GHRH secretion is rare, and there are few reports of excessive secretion of heterologous GH, which can be seen in bronchial or thymic carcinoid, islet cell tumor. Lung oat cell carcinoma, medullary thyroid carcinoma, hypothalamic ganglioneuroma, etc., they are most likely to secrete GHRH, and some may also secrete GH.
Pituitary growth hormone adenomas vary widely in individuals. In different patients, the volume of tumors and the pathological features of cells may be significantly different. Some adenomas may secrete other pituitary hormones in addition to secreting growth hormone. In cases, pituitary adenomas are mostly monoclonal in origin, but in very few patients, there may be growth hormone adenomas that are independent of each other.
Patients with acromegaly have a longer course of disease. Most pituitary adenomas have a diameter greater than 10 mm when diagnosed. About one-third of tumor patients may have an upward and/or lateral expansion of the sella. About 1/3 are microadenomas, and 30% to 40% of pituitary tumors are locally or diffusely infiltrated into the surrounding tissues, especially to the dura mater and bone. About 60% of the growth hormone cell adenomas are Eosinophilic adenomas, others are chromoblastomas. Electron microscopy shows that adenoma cells can have different numbers of secretory granules, and their number reflects the dynamic balance between hormone synthesis and release. The secretory granules of these adenomas can be dense or sparse. However, it is difficult to distinguish these two types of tumors from clinical manifestations. In cases of acromegaly caused by ectopic hormone releasing hormone tumors, pituitary growth hormone cell proliferation is often found, and adenoma formation is also reported.
Pituitary adenomas in patients with acromegaly are mainly secreted by growth hormone, but may also secrete other pituitary hormones at the same time, resulting in high secretion of two or more pituitary hormones, in patients with acromegaly, near Two-thirds of patients with pituitary adenoma secrete only growth hormone, and the growth hormone secreting granules in the cytoplasm of these adenoma cells can be expressed as dense or sparse.
Studies have found that densely secreted granules grow slowly, clinical symptoms are often inconspicuous, and tumors with sparsely secreted granules develop rapidly and are often invasive. A considerable number of adenomas in patients with acromegaly are caused by growth hormone secreting cells and prolactin. The secretory cells are mixed, and the growth hormone and prolactin can be synthesized and secreted simultaneously. Immunohistochemical methods can be used to find cells containing prolactin secreting cells between growth hormone adenoma cells, and some adenoma tumor cells have a single shape. It consists of the same kind of cells, but it can secrete both growth hormone and prolactin. Other adenomas are derived from eosinophils, which are developed from common precursor cells of cells that secrete growth hormone and cells that secrete prolactin. The adenomas have a low degree of cell differentiation, and the tumors grow rapidly, mostly invasive, but the clinical manifestations of acromegaly are often not obvious.
Under normal conditions, growth hormone is secreted by the pituitary gland in adults, and its hormone release is pulsed and regulated by various neuroendocrine factors. Age, sex, sleep, nutrition, etc. can also affect its secretion, and the release of fasting growth hormone is high. After ingesting food, the release of growth hormone during sleep also increases, growth hormone secretion is regulated twice, hypothalamic growth hormone releasing hormone can stimulate growth hormone secretion, while hypothalamic somatostatin inhibits growth hormone secretion, in nutritional status In good cases, normal human IGF-I synthesis is mainly dependent on the secretion of growth hormone, while growth hormone and IGF-I inhibit the secretion of growth hormone through negative feedback on the level of hypothalamus and pituitary.
Pituitary growth hormone adenoma also changes in the rhythm of secreted growth hormone, which is characterized by loss of circadian rhythm. The level of growth hormone in the blood can be measured at any time in one day. The peak of growth hormone in most patients is at 4 o'clock in the morning, the valley value. At 16 o'clock in the afternoon, some patients even had multiple secretion peaks within one day. After treatment, the secretion rhythm of growth hormone could be restored.
Insulin-like growth factor II (IGF-II) has been reported to be involved in cell proliferation in a variety of tumors. Koyoyama et al. used in situ hybridization to find a large amount of IGF-II mRNA in pituitary adenomas, indicating that IGF-II is in the pituitary gland. High expression in adenoma suggests that it may be involved in the formation of adenomas.
Prevention
Giant disease and acromegaly prevention
There is no effective preventive measure for this disease. Early detection and early diagnosis are the key to the prevention and treatment of this disease.
Complication
Giant disease and acromegaly complications Complications carpal tunnel syndrome edema osteoporosis coronary heart disease myocardial infarction heart failure diabetes hyperprolactinemia
1. Some patients may be due to soft tissue hyperplasia, oppression of the median nerve, leading to carpal tunnel syndrome, manifested as the median nerve in the carpal tunnel is compressed, there is a regional sensory disturbance in the distribution of the median nerve, finger edema, skin tension, shiny and inter-animal contraction And other symptoms.
2. Patients with acromegaly are often accompanied by osteoporosis, which further aggravates the bone lesions. Under the action of excess growth hormone and IGF-I, although the intestinal absorption of calcium increases, the loss of calcium in the urine also increases. The patient is still in the negative calcium balance, the activity of osteoblasts and osteoclasts is increased, the level of bone turnover is increased, the serum collagen cross-linking which reflects collagen turnover and the serum osteocalcin level which reflects the activity of osteoblasts rises, lumbar vertebrae The trabecular bone density decreased, serum parathyroid hormone, vitamin D and blood calcium concentrations were generally at normal levels, but there were also reports of elevated vitamin D concentrations.
3. Patients are also prone to coronary heart disease, the cause is unknown, may be related to insulin resistance, dyslipidemia, and growth hormone and IGF-I stimulation of arterial smooth muscle cell proliferation, therefore, patients with acromegaly grow with the age The risk of functional failure is also increasing.
Due to the special effects of growth hormone on blood sugar and blood lipids, atherosclerosis often occurs prematurely in patients with acromegaly. Arrhythmia may occur in patients with longer course of disease, and may even have serious cardiovascular complications such as myocardial infarction or heart failure. .
4. Sleep apnea is a common symptom in patients with acromegaly. It is reported that about 20% can be caused by central causes, or it may be prolapsed with hypertrophic tongue into the airway. Throat soft tissue hyperplasia makes the throat Related to stenosis, apnea during sleep can aggravate hypoxia at night, and can lead to myocardial hypoxia over time, and even severe arrhythmia can occur.
5. The literature reports that about 40% of patients with acromegaly can develop impaired glucose tolerance. Some patients can develop diabetes. After resection of the tumor, diabetes can be controlled quickly. The abnormal glucose tolerance can be alleviated or corrected. Hypertrophy is a serious condition, and older patients with longer duration are more likely to develop diabetes.
6. A considerable proportion of patients with acromegaly are accompanied by hyperprolactinemia, which may be due to the simultaneous secretion of growth hormone and prolactin from pituitary tumor cells, or may be due to the large volume of growth hormone adenoma, which is compressed to the pituitary gland. The stalk affects the normal regulation of prolactin secretion by the hypothalamus and causes high secretion of prolactin. In short, the cause of sexual dysfunction in patients with acromegaly may be related to some patients with hyperprolactinemia. The aspect may also be due to pituitary tumors compressing the gonadotropin-secreting cells of the normal pituitary gland.
7. Foot weakness caused by muscle weakness and neuropathy is also the most common complication of patients with giant disease.
Symptom
Giant symptoms and acromegaly symptoms Common symptoms Osteoporosis Head enlargement Urine phosphorus amenorrhea Whole body Skin thickening Hypertension Drinking weak libido Decompression Vision defect
Acromegaly has a longer course and is more insidious. Many patients initially have fatigue, sweating, headache, rough face, large hands and feet, thick skin and other appearance changes, usually not noticed. The average time from the appearance of these symptoms to the diagnosis can be as long as 6 to 7 years. Patients often have excessive growth hormone secretion or pituitary lesions due to carpal tunnel syndrome or visual field defects. With the development of imaging technology, the discovery rate of pituitary tumors has increased. Patients often have accidental findings of pituitary tumors during head imaging because of headaches, car accidents, or other diseases that are not related to pituitary tumors. The literature also refers to the pituitary tumors thus discovered as Incidentalomas. For acromegaly, early diagnosis can greatly improve the efficacy. Therefore, it is very important to maintain a high degree of vigilance against the initial symptoms of acromegaly. Acromegaly can affect patients of all ages, 20 to 50 years of age is the most common period of acromegaly, if growing Excessive secretion of hormones begins in childhood and often manifests as giant pituitary tumors at the time of diagnosis. Moreover, these children are generally complicated by gonadotropin deficiency, leading to delayed puberty, excessive growth hormone secretion and hypogonadism caused by hypogonadism. Eventually it can lead to giant disease.
Growth hormone is a hormone with many physiological functions. Excessive growth hormone secretion and elevated IGF-I can affect almost all organs in the body, but growth hormone has different effects in adolescents and adults. Patients of different ages The clinical symptoms appear different. In adults, the bones of all parts of the body (especially the long bones) are closed. When the acromegaly occurs, the height is no longer high, and in the adolescent or prepubertal patients, the epiphysis Not yet closed, mainly manifested in height and height, often significantly higher than their peers.
Acromegaly (adult)
(1) Appearance changes: patients with terminal hypertrophy have a typical face, thick skin, especially on the face, wrinkles on the scalp, hypertrophy of the sebaceous glands, increased secretion, making the patient's skin greasy, sweat glands also hypertrophy, sweating Increased, skull deformation, head lengthening, mandibular protrusion, lower incisors are often located in front of the upper incisors, bite dislocation, increased tooth gap, forehead and mastoid protrusion, thickening of the forehead skin and eyelids, scalp sagging, big nose, The lips are hypertrophy. In addition, the tongue is hypertrophy, the vocal cords are thickened and grown, the pronunciation is thick, and the throat tissue is hyperplasia, which may make the patient's breathing unobstructed, causing snoring, apnea during sleep, and declining sleep quality, which makes it easy to sleep during the day. Symptoms gradually increase with the prolongation of the lesion time, and the patient's hands and feet become larger. Some patients find that the original shoes are too small to be diagnosed as this disease. (See Figure 1) Some patients may have soft tissue hyperplasia and oppress the median nerve. Carpal tunnel syndrome, when the median nerve is compressed in the carpal tunnel, there is a sensory disturbance in the distribution of the median nerve, finger edema, skin Zhang, shiny and thenar shrinkage and other symptoms, some women may occur in patients with hairy armpits and neck acanthosis nigricans may occur.
(2) Osteoarticular system: Adult patients, because the growth plate of the epiphysis has been closed, the position and direction of bone growth are different from those of children, mainly characterized by thickening of cortical bone, and excessive bone hyperplasia is the main feature of acromegaly: patient skull Increase, the surface is uneven, the frontal bone hypertrophy, frontal sinus enlargement, eyebrow arch, humeral protrusion, occipital nodules are obvious, the lower jaw is also enlarged, protruding forward and downward, fingers and toes end are scorpion-like changes, The latter is characteristic on the X-ray film, the vertebral body is widened, thickened, the neck and lumbar intervertebral disc are also thickened, and the front end of the thoracic intervertebral disc is thinned, resulting in a patient's hunch-like body type, the intervertebral ligament is often hypertrophied, slack, and the enlarged intervertebral disc Compressible nerve-induced low back pain, with the aggravation of acromegaly, skeletal abnormal hyperplasia will continue to increase, cartilage and epiphyseal hyperplasia, leading to osteoarthrosis and osteoarthritis, joint disease is a prominent manifestation of acromegaly In one of the cases, the joint lesions of most patients with acromegaly are degenerative diseases. The mechanism of formation may be that excessive growth hormone not only increases the level of IGF-I in the circulation, but also makes the joints Increased production of IGF-I, active hyperplasia of articular chondrocytes, strong synthesis and secretion, eventually leading to excessive matrix synthesis, so the joint surface becomes thicker, the joint cavity becomes wider, and eventually the joint deforms, and growth hormone stimulates the tissue around the joint. Hyperplasia, resulting in thickening and relaxation of the joint ligament, synovial hypertrophy, the joint cartilage wear and tear, the joint surface can appear cracks, on this basis can form new fibrocartilage, the latter can appear ossification, resulting in osteophyte formation, serious Case fissures can be deep to the subchondral bone, which is widened, resulting in ulceration on the surface of articular cartilage. The articular cartilage is thickened in the long course of disease, and the joint cavity can be increased by 2 to 3 times than normal. The knee joint is most susceptible, followed by the hip. Deformation of joints, shoulder joints, bones and joints sometimes requires surgery or joint replacement. Changes in ribs can cause thoracic movement limitation and are prone to lung disease.
(3) Cardiovascular system: vascular disease is one of the main causes of death from acromegaly. In patients with acromegaly, the heart is obviously hypertrophied, and the proportion can exceed the extent of other visceral enlargement. Long-term acromegaly Can lead to cardiac hypertrophy and heart enlargement, 80% of patients may have left ventricular muscle hypertrophy, cardiac hypertrophy and growth hormone or IGF-I concentration is not well correlated, accompanied by decreased cardiac function, diastolic function decline The decline of systolic function is more common, and changes in right ventricular function have also been reported. Myocardial hyperplasia is reversible. When the growth hormone level is controlled and decreased, cardiac hypertrophy can also gradually subside. Among some patients with left ventricular hypertrophy, there is no Hypertension, coronary angiography also did not show coronary heart disease, these patients after treatment to reduce growth hormone, left ventricular lesions can be improved rapidly; in other patients after the growth hormone decreased to normal left ventricular lesions still no significant improvement, suggesting these Left ventricular lesions may be secondary to hypertension, coronary heart disease, acromegaly, electrocardiogram often shows left axis deviation, bundle branch block, arrhythmia Pathological studies have found that myocardial interstitial fibrosis and lymphocyte mononuclear cell infiltration are also common. Therefore, some researchers suggest that there may be a lesion caused by growth hormone directly acting on the heart, called "acromegaly. Cardiomyopathy, these changes can at least partially recover after a decrease in growth hormone levels.
There may also be a slight increase in blood pressure in patients with acromegaly, which may be due to the anti-neotrophic effect of growth hormone and the activation of the renin angiotensin system, resulting in an increase in total circulating capacity, according to Nabarro's 1987 statistics. The incidence of hypertension accounts for 30% to 40% of patients with acromegaly.
(4) Respiratory system: Respiratory diseases are also one of the important causes of death in patients with acromegaly. People who die of respiratory diseases can be 2 to 3 times higher than normal people, and are related to functional abnormalities caused by structural changes in the upper respiratory tract, such as mucous membranes. Thickening and thickening, narrowing of the oropharynx and vocal cord, airway is not easy to cause upper airway obstruction, in addition, there is a certain relationship with the posterior process of the spine and the joint lesions of the lumbar ribs, patients with acromegaly Increased bronchial mucosal hyperplasia, alveolar enlargement, narrowing of airway, decreased lung elasticity, decreased lung capacity, further impaired lung compliance, rib lengthening and thickening, chest tilting restricted thoracic activity, pulmonary venous pressure increased, lung Insufficiency may also be an important factor. The enlargement of the tongue and the proliferation of lymphoid tissue in the throat make the airflow in the upper airway poor, which is particularly prone to nighttime hypoxia. In addition, the effects of excess growth hormone and IGF-I on the skeletal system, Osteoarticular lesions can often occur, and rib involvement may lead to limited thoracic movement, decreased respiratory function, and easily induce and aggravate respiratory diseases.
(5) Effects on energy metabolism: Growth hormone has a wide influence on energy metabolism, which affects growth and affects the metabolism of sugar, protein and fat. In terms of protein, it mainly promotes its synthesis. For fat, it mainly promotes the decomposition of peripheral fat. And mobilize to the liver for oxidation, resulting in decreased body fat, altered blood lipids, decreased HDL, increased LDL and cholesterol, which promote the formation of atherosclerosis, fatty acid mobilized to the liver, after degradation, and finally form a ketone body, in Under the action of a large amount of growth hormone, since the ketone body produced by the liver exceeds the ability of the peripheral tissue to utilize the ketone body, in general, the body has a tendency to accumulate ketone, but in the presence of insulin, the ketone accumulation phenomenon does not occur. It will occur that in the early stage of the effect of growth hormone on glucose metabolism, insulin-like action occurs, which causes blood sugar to decrease. Under the long-term action of growth hormone, different degrees of insulin resistance can be induced, the utilization of sugar by surrounding tissues is reduced, and sugar finally occurs. Impaired tolerance, and even diabetes, which is prone to impaired glucose tolerance in patients with acromegaly The reason is that in patients with acromegaly, the blood glucose is still in the normal glucose tolerance stage, insulin-dependent tissue insulin receptor affinity is compensatory, so the resistance to insulin is relatively light at this time; but after diabetes, insulin-dependent The number of insulin receptors on the surface of peripheral tissue cells is reduced, and defects in receptors and receptors are further developed. At the same time, growth hormone induces gluconeogenesis and increased glycogenolysis, which are important causes of diabetes. In general, the condition of diabetes mellitus complicated by growth hormone tumors is mostly not very serious, and chronic complications of diabetes are generally rare.
In addition, under the action of growth hormone, the body's intake of important elements such as sodium, potassium, calcium, phosphorus and sulfur is enhanced. The growth hormone of strontium phosphorus is directly achieved by increasing the reabsorption of phosphorus by the renal tubules, rather than by thyroid. The role of parathyroid hormone is similar to the distribution of potassium and phosphorus in tissues. The ratio of potassium or phosphorus to nitrogen in interstitial tissues is higher than that in muscle tissue. The retention of potassium indicates the growth of new tissues, and growth hormone also causes retention of chlorine and sodium. This also correspondingly allows the water to be retained, thereby increasing the volume of the extra-tissue fluid, which provides conditions for the formation of hypertension.
(6) Gastrointestinal system: Acromegaly can cause generalized hypertrophy of the internal organs, the mechanism is unknown, and the incidence of gastrointestinal polyps and cancer in patients with acromegaly increases, which may be related to cell proliferation by growth hormone and IGF-I. It has been reported that colon cancer can be used to confirm the adenomatous polyps in patients with this disease up to 30%. It is also reported that the risk of colon cancer or polyp cancer in patients with acromegaly is 4 to 5 times higher than that of the general population, including colon. The incidence of malignant tumors such as stomach, esophagus and melanoma can reach about 10%. Patients with skin sputum should be highly alert to the possibility of colon polyps. Patients with multiple skin fistulas should be more Therefore, male patients over the age of 50, such as those with a disease duration of more than 10 years, and multiple skin sputum, should be alert to the possibility of colon polyps or adenocarcinoma. In vitro experiments have shown that growth hormone can stimulate c-myc. IGF-I can stimulate the proliferation of cells by the expression of proto-oncogenes and the growth of tumors. It has been reported that some tumors in the human body have IGF-I receptors and can express IGF-I. In addition, growth hormone can promote the growth of hormones. Mitosis of somatic cells may be associated with an increased risk of developing tumors in patients with acromegaly. During the treatment with octreotide in patients with acromegaly, researchers have observed cholelithiasis, an increased incidence of gastritis, and vitamins. B12 patients with malabsorption have also increased, but further studies by Anderson et al in 1992 found that the incidence of gastritis in untreated acromegaly did not appear to increase, Catnach et al reported in 1993, gallbladder patients with acromegaly The emptying function is reduced, but the incidence of cholelithiasis is not much different from the general population.
(7) genitourinary system: excessive secretion of growth hormone, can cause kidney hypertrophy, glomerular and tubular volume increase, followed by high renal filtration, accompanied by glomerular glomerular vasodilation, with Growth hormone stimulates the increase of phosphate reabsorption in the renal tubule. About half of the patients may have mild hyperphosphatemia. Growth hormone stimulates the activity of 1a-hydroxylase and makes the blood 1,25-dihydroxyvitamin D3 level. Increased, intestinal calcium absorption increased, but patients generally do not have hypercalcemia, the reason is that the urinary system increased calcium excretion, increased urinary calcium, resulting in urinary calculi, female hypogonadism easily lead to bone Loose, urinary albumin excretion rate can be slightly increased, but few patients have persistent microalbuminuria, after the excessive secretion of growth hormone is corrected, the performance of high filtration and increased albumin excretion can be restored. The male and female genital organs are enlarged, and the testosterone secretion of males is increased, so that sexual desire can be enhanced in the early stage of the disease. As the course of the disease increases, sexual desire gradually decreases, spermatogenesis decreases, and reproductive ability Female sexual desire also decreased, menstrual disorders, amenorrhea, infertility, galactorrhea, male and female sexual dysfunction were 46% and 70%, respectively, in short, the cause of sexual dysfunction in patients with acromegaly may be accompanied by some patients It is associated with hyperprolactinemia, and on the other hand, it may be due to the pituitary tumors compressing the gonadotropin-secreting cells of the normal pituitary gland.
(8) Skin: soft tissue hypertrophy in patients with acromegaly, hyaluronic acid increases the water in the tissue, leading to thickening and roughening of the skin, due to the presence of growth hormone receptors in the hair follicles, sweat glands and other tissues, acromegaly Patients may have increased hair follicles, thickened hair, increased sweating, oily skin, hemorrhoids, and frequent small fibroids, wrinkles on the face and skull. Some researchers believe that if there is more than one acromegaly The appearance of skin sputum, suggesting a corresponding increase in the risk of colon polyps and colon cancer, Kolawale et al reported the performance and incidence of scalp sag (CVG) in patients with acromegaly in CT, Among the 17 patients surveyed, 5 patients had CVG. These patients had thickened scalp, curly, brain-like or gear-like changes, CVG and patient's age, gender, disease duration, and hormone level. Irrelevant, Kolawale suggested that if CVG findings were found during CT examination, the possibility of pituitary growth hormone adenoma should be considered.
(9) Peripheral nerve and neuromuscular tissue: In patients with growth hormone deficiency, if exogenous biosynthesis of growth hormone replacement therapy is given, muscle tissue and muscle strength can be increased, but growth hormone levels are too high, and cannot The normal muscle strength is further increased, but it shows obvious muscle weakness and paresthesia, which may be caused by myopathy caused by acromegaly, or caused by peripheral nerve dysfunction, electromyography and muscle biopsy Can indicate the presence of myopathy and muscle atrophy, but the concentration of creatine kinase can be normal, excessive secretion of growth hormone can cause thickening inside or outside the nerve tissue, and lead to ganglion damage, including demyelination or hypertrophy, affecting The function of the Schwann cell system ultimately leads to sequelae such as muscle atrophy or other peripheral neuropathy. In addition, about 30% of patients may also swell soft tissue due to excessive growth hormone secretion, compressing the median nerve and causing carpal tunnel syndrome.
(10) Central nervous system: The effects of acromegaly on the brain are currently unknown. There is evidence that in normal individuals, there is a certain intrinsic relationship between growth hormone and central nervous system function, nighttime growth hormone secretion and sleep. Start-up and slow-wave sleep (SWS) are associated. In addition, growth hormone-releasing hormone may induce slow-wave sleep. However, in patients with acromegaly, the cause of hypothalamic growth hormone-releasing hormone levels Elevation and further lead to excessive secretion of growth hormone, or elevated levels of growth hormone in the pituitary gland, and feedback to reduce the level of growth hormone releasing hormone, it is still unclear, it has been found that patients with acromegaly have increased sleep during the day, rapid eye movement Rapid-eye-movement sleep (REM) and slow-wave sleep time are shortened. These manifestations are not related to the occurrence of apnea during sleep, and the symptoms can disappear when the patient is well treated, suggesting that these changes are likely to originate from the central nervous system. System changes.
Some studies have suggested that in patients with acromegaly, the connection between the brain and the pituitary gland is confusing. These findings include growth hormones that exhibit abnormal responses to TRH, LHRH glucose, and galanin (Galanin). The exact mechanism of the response has not yet been elucidated. It may be due to hypothalamic dysfunction affecting the pituitary gland, causing abnormal secretion of growth hormone in the pituitary gland, but it may also be a special receptor on adenoma cells.
Another important effect of acromegaly on the central nervous system is to cause changes in mental behavior and mood, manifested as depression, apathy, reduced initiative, etc., but almost all symptoms of emotional disorders appear later than the changes in body morphology and From the psychosocial abnormalities caused by illness, it is found in animal experiments (including primates other than humans) that the limbic system is an important factor in the growth hormone regulation system, and electrical stimulation of different parts of the limbic system can be changed. Growth hormone secretion, and growth hormone receptors exist in all parts of the limbic system, but the relationship between the limbic system and the occurrence of acromegaly remains to be further studied.
(11) Endocrine organs: Almost all endocrine organs are affected when excessive growth hormone is secreted. Usually, endocrine glands are enlarged. Only a few patients show increased hormone secretion and hyperfunction, such as elevated free thyroxine. Increased iodine absorption, but simple goiter is more common, and the TSH level or thyroid function of these patients is usually normal. The enlargement of thyroid or the formation of adenoma may be caused by elevated IGF-I levels in patients with acromegaly. The basal metabolic rate of patients with acromegaly may increase slightly, which may be related to the direct action of growth hormone. The parathyroid gland is also often enlarged, but the PTH level is generally within the normal range, and the islets of the pancreas are also Can increase, patients can have hyperinsulinemia, but this is generally not the result of beta cell proliferation, but a compensatory response to peripheral tissue insulin resistance, large pituitary tumors can damage the function of the pituitary gland, leading to the periphery The secondary function of the target organ is insufficient. In addition, the patient may have menstrual disorders, loss of libido and impotence, and patients with acromegaly. Adrenal cortex often increases, and the medulla is generally normal. The enlarged cortex sometimes contains adenomas, but it is rare in patients with typical cortisol. Secondary hypothyroidism is rare. Patients may also have galactorrhea symptoms. The reason may be accompanied by the prolactin secretion and/or the high concentration of growth hormone.
(12) Immune system: There is increasing evidence that growth hormone and IGF-I are a member of the neuroendocrine-immune system axis, and growth hormone can act on lymphocytes to stimulate their proliferation and produce a series of special functions. Some of the functions are mediated by local production of IGF-I, and lymphocytes also have the function of synthesizing and secreting growth hormone, which may play a paracrine role. Both growth hormone and IGF-I can stimulate the original red blood cells. Proliferation and erythropoiesis, on the contrary, the immune system can also act on the brain and/or pituitary gland, affecting the secretion of growth hormone. Therefore, growth hormone and IGF-I may pass systemic, endocrine or local, paracrine, respectively. To regulate the immune system, studies on growth hormone-deficient animals and humans support these findings, but in patients with acromegaly, the physiological significance of this neuroendocrine-immune system and its possible mechanisms of disorder have not yet Illuminated.
(13) Occupation performance: The onset of acromegaly is relatively concealed, and the course of disease is long. The volume of pituitary growth hormone adenoma is generally larger when diagnosed. Some patients have typical manifestations of acromegaly, such as tumor compression of normal pituitary tissue. Symptoms of other pituitary dysfunction may occur, especially the gonads are most susceptible. In adolescent patients, there may be puberty not developed. Adult women may have amenorrhea, males may have impotence, sexual dysfunction and other symptoms, thyroid and adrenal cortex. Less functional decline, headache symptoms can appear earlier in the early stage of the tumor, headache is one of the common symptoms, but its severity is not necessarily proportional to the size of the tumor, such as the growth of the saddle tumor, due to the swelling of the saddle Can cause headaches, tumor invasion to the saddle or even the outside of the saddle, headache can also occur when the meninges and vascular membranes are compressed, and then with the further increase of tumor volume, such as the development of the upper and lower, oppressed to the optic chiasm, patients Can be manifested as vision loss or even blindness, visual field defects, more common is the temporal side hemianopia, can involve unilateral or bilateral, such as the tumor to the saddle Development, can produce cavernous sinus syndrome, such as tumor affecting the outer side of the cavernous sinus can make the third, IV, VI damage to the cranial nerve, clinically there may be diplopia, strabismus, ptosis and other symptoms, a small number of patients with tumor down Growth, cerebrospinal fluid rhinorrhea may occur, and even meningitis may occur. When the tumor compresses the hypothalamus, a series of hypothalamic groups such as obesity, lethargy, anorexia or bulimia, and unexplained hypothermia may also occur. , mental decline, diabetes insipidus and so on.
2. Giants patients with pituitary growth hormone adenomas before the onset of puberty, because the long bones are not closed at this time, under the effect of excessive secretion of growth hormone, the growth of the epiphyseal growth plate is delayed, and the height of the bones grows rapidly, making the patient tall and burly. Muscle, arm strength, leading to giant disease, therefore, in children, if the growth rate suddenly accelerates, sexual organs develop in advance, sexual desire is stronger than normal people, and can not be explained by puberty, should be suspected of this disease, these diseases Before being diagnosed, children can often find that their height is significantly higher than other children of the same age. The trunk and visceral growth rate is the main feature of giant disease. There was a case of giant disease. The height of a 7-year-old boy has reached 168 cm. In general, patients with giant disease can reach a height of 2 to 2.5 m. Some patients can maintain a normal proportion of growth in various parts of the body. However, most patients develop from long bones, so the limbs are particularly long, and the lower body is longer than the upper body. Giant disease In the advanced stage, there is often a secondary hypogonadism, which may be due to the huge pituitary tumor compression. Insufficient gonadotropin secretion caused by somatic gonadotropes, therefore, these adolescent patients can continue to grow up to the age of 30 after normal puberty, with slender fingers, similar to testosterone-free, if not as early as possible to remove their growth Hormone adenomas will gradually develop the clinical manifestations of acromegaly on the basis of giant disease. In a small number of patients, precocious puberty and weight gain may occur.
Examine
Giant disease and acromegaly examination
1. Laboratory basic inspection
(1) Serum GH: Human GH is pulsed and secreted with circadian rhythm secretion. However, due to exercise, stress and metabolic changes, human GH secretion has 5 to 10 secretion peaks per day, with a peak value of up to 40 g/ L, the peak value between the peaks is less than 0.2g / L, normal people in the exercise, stress state, or GH secretion peak blood, its blood GH value is high (female obvious), GH secretion in patients with acromegaly Loss of circadian rhythm, but still maintains intermittent pulse secretion, the individual difference of blood concentration is large, but most of the pituitary GH tumors are GH autocrine secretion, the frequency of GH pulse secretion is increased, and the blood GH basic value and fasting result Increased (in mild and elderly patients taking blood as the peak of the secretion peak, the increase may not be obvious), it is reported that for every 10 years of age increase, the blood GH value decreased by 7g / L, and the GH value detected by different radioimmunoassay The difference is large, so only one blood GH measurement can not be used as a basis for diagnosis.
The lowest value of serum GH measured by radioimmunoassay is only 1.5-2.0g/L, although the sensitivity can reach 0.5g/L, but the basic value of 50%-80% of normal people is lower than this value, the latest The sensitivity of immunofluorescence or immunoluminescence assay is 0.005~0.01g/L, which can accurately measure the basic level of blood GH in normal people. The radioimmunoassay technique is to detect the immunoreactivity level of GH, not the biological activity, GH should play Its biological effects must be combined with its specific receptors, and the results measured by immunoradiometric receptors can better reflect the biological effects of GH.
The GH component in serum is very heterogeneous, containing 20kD, 22kD GH polymer and other forms. The blood GH spectrum is a better method for confirming the excessive secretion of GH, because it can understand the components and proportion of blood GH increase. The half-life of GH in blood is 20 to 25 minutes. Therefore, when blood GH spectrum is measured, blood is taken every 5 to 20 minutes, and continuous measurement is performed for 1 night or 24 hours. The basic value of blood GH in patients with acromegaly is higher than that of normal people. Up to tens of times, more than 1g / L, GH pulse secretion peak frequency increased by 2 to 3 times, on the other hand, GH spectrum may also be related to the concentration of GH secreted into the blood, Ng and other data suggest that after oral glucose The serum was mainly composed of 20kD GH, and after stimulation with TRH/GnRH, the blood was dominated by 22kD GH.
The determination of GH level is also helpful in judging the therapeutic effect and prognosis. The condition is active for a long time, and the mortality of the tumor with a large amount of GH is high, and the quality of life is poor.
(2) Urinary GH: a new method for the development of recent years. The measurement of urinary GH can reflect the amount of GH secretion in a period of time, and is positively correlated with blood IGF-I. 24 h or 12 h urinary GH sputum in patients with limb hypertrophy The secretion is often 50 to 100 times higher than normal.
(3) Blood IGF-I:
1 It is generally believed that serum IGF-I levels are the best indicator of excessive secretion of chronic GH due to:
A. The clinical manifestations of acromegaly are mainly due to the enhanced effect of IGF-I.
B. The concentration of IGF-I in most patients with active acromegaly is increased. Some data show that patients with elevated serum IGF-I or previous tumors are particularly prone to colon, rectum, thyroid, stomach and other parts. Tumors, men are more dangerous than women.
C. The serum IGF-I concentration of patients is related to the activity of the disease and the blood GH value 24 h before the measurement, so it can reflect the biological effects of GH secreted 24 h before the measurement.
D. Blood IGF-I binds to IGF-I binding protein, has a long half-life, and its blood concentration changes little at 24h, and is not affected by blood sampling time, meal or not, testosterone and dexamethasone.
E. Those with milder disease, even if the blood GH is slightly increased, the blood IGF-I level is significantly increased.
F. Occasionally, patients with acromegaly can present with normal GH, GH is slow to respond to hypoglycemia, GH lacks pulsatile secretion, and blood IGF-I and PRL increase significantly, possibly with tissue versus GH It is particularly sensitive, so the diagnosis must rely on the IGF-I assay.
2 Note the following points when interpreting blood IGF-I results:
A. The blood GH and IGF-I levels are logarithmic rather than linear. When the blood GH level is higher than 20g/L, the blood IGF-I level reaches the peak platform level, that is, the GH level stimulates the liver to synthesize IGF- The highest effective level of I, which explains why patients with different GH levels can have similar disease activity.
B. Each laboratory must have its own normal gender and age. The blood IGF-I level is higher in adolescent children, and the blood IGF-I level in elderly patients with mild acromegaly can be within the normal range. .
C. Diabetes patients with poor disease control stimulate the liver to produce IGF-I, leading to elevated blood IGF-I levels.
D. Blood IGF-I levels are affected by nutritional status, with malnutrition, hunger and liver disease can reduce blood IGF-I levels.
E. Pregnant women, especially in the last 3 months of pregnancy, have elevated levels of blood IGF-I, which is 2 to 3 times higher than normal, because the placenta can secrete placenta GH, and women have acromegaly in pregnancy. IGF-333µg/LIGF-IGF-GHIGF-24hIGF-IGF-
(4)IGF-3(IGFBP-3)IGF-GHIGFBP-3150kd10µlIGFBP-3GHIGF-IGFBP-3IGFBP-3IGFBP-3IGF-IGFBP-3GHIGF-IGFBP-3IGFIBP-3IGFBP-324mg/L10mg/L
(5)(GHBP)GH22kdGHGHGHGHBPFPLCGHGHGHBP(octreotide)GHBPGHBP
GHBPGHGHNb2IgGsGHIGF-GH
(6)IGF-IGF-IGF-IGF-
2.
(1)75g30min306090120minGH120minGH2µg/L(<0.05µg/L)(<0.5µg/L)GHGHGH13µg/L2µg/LGH0.20.1µg/LGH
(2)GHRHGHRHGHSSGHGHRH 100µg15min0153045607590105120minGHGH2GHRHGHRHGHRHGHRHGsGHRHGH
(GHRPs)GHRHGHGHRHGTP(GHRP)GHGHGHRPGHTRHGHRHGH100µg GHRP-6GHTRH
(3)TRHTRH 200500µgGHGHTRHGH
GHGHRH
TRHTRH 200500µg15min0153045607590105120minGH(TSH)GH50%GH5µg/L75%GHTRHTRHGHTRHGHGHGHRH
(4)(GnRH)GnRHGH100µg GnRH15min01530607590105120minGH15min30minCH
(5)()GHGHGHGH5µg/kg015306090120minGHGH70%
(6)(SS)GH1L-0.5g/kg(250ml)30min0306090120minGH
(7)(L-dopa)1(L-dopa)500mg0306090120minGHL-dopa
IGF-IGF-IGF-24hIGF-IGF-IGF-IGF-IGF(Insulin-like growth factor binding proteinIGFBP)13
0.1250.25mmol/LMEN-1PTHMEN-lPRLPRLGHRHFT4
3.X(716mm7mm;714mm9.5mm)
4.CTMRI MRIMRI;;CT
5.CT
6.111In123I(PET)
Diagnosis
Diagnostic criteria
Clinical features
(1)
(2)l
(3)
(4)
2. Check
(1)GH5ng/ml5ng/ml5ng/ml1GH(GH)GH
(2)TRHGH;1Oµg/ml
(3)-l
(4)(ACTH)(TSH)PRL(FSH)(LH)
(5)
(6)
(7)CTX
Differential diagnosis
1.GH4XGH
2.Marfan30%()GH
3.XGH
4.GH
