Primary hyperparathyroidism occurs with a frequency of about 25 new cases per 100,000 population per year. About 35% of cases of hypercalcemia syndrome are associated with primary hyperparathyroidism. After diabetes mellitus and thyrotoxicosis, primary hyperparathyroidism is the third most common endocrine disease. The peak in incidence is 40-50 years, with primary hyperparathyroidism 2 times more common among women (occurring in 3% of women in the postmenopausal period). Hypercalcemia is registered in adults in 0.5-1.1% of cases, more often in women older than 50 years.
Etiology
The most common cause of hyperparathyroidism is solitary parathyroid adenoma (parathyroma), much less often – multiple adenomas (5%), even less often (<5%) – parathyroid cancer. Primary hyperplasia of all parathyroid glands occurs in approximately 15% of patients.
Of fundamental clinical importance is the fact that primary hyperparathyroidism occurs in both types of syndromes of multiple endocrine neoplasias. Thus, upon detection of primary hyperparathyroidism, a screening survey is needed to identify other components (pheochromocytoma, medullary cancer of the glandular cancer, islet cell tumors).
Pathogenesis
Hyperproduction of parathyroid hormone leads to excessive excretion of phosphate through the kidneys. A decrease in the plasma level of the latter stimulates the synthesis of calcitriol, which promotes the absorption of excess Ca2 + in the intestine. In advanced stages of the process, hypercalcemia is enhanced by activation of osteoclast parathyroid hormone in excess. Excess parathyroid hormone accelerates bone metabolism, accelerates bone resorption and bone formation, but the formation of new bone lags behind its resorption, which leads to generalized osteoporosis and osteodystrophy, leaching of calcium from bone depot and hypercalcemia, as well as hypercalciuria, contributing damage to the epithelium of the renal tubules and the formation of kidney stones. Nephrocalcinosis, in turn, leads to a decrease in renal function. Hypercalcemia with arteriolosclerosis and vascular calcification play an important role in the occurrence of ulcerative lesions of the stomach and duodenum. Along with an increase in arterial pressure, hypercalcemia creates prerequisites for the formation of left ventricular hypertrophy, whose function is also worsened by valvular, coronary and myocardial calcinates typical of hyperparathyroidism.
In the case of anatomopathological study in case of severe, advanced primary hyperparathyroidism, the bones are soft; flat bones can easily be cut with a knife, diffuse osteoporosis is detected, which is often combined with the formation of cysts. Calcium deposits are detected in the kidneys, muscles, myocardium, and walls of large arteries.
Clinic
The clinical manifestations of hyperparathyroidism are diverse. Currently, in more than 50% of cases, the diagnosis of primary hyperparathyroidism is established with the occasional discovery of hypercalcemia. Symptoms of primary hyperparathyroidism consist of renal, bone, neuromuscular and gastrointestinal syndromes. In accordance with this, bone marrow, visceropathic, neuropsychic, and mixed forms of hyperparathyroidism are distinguished. A severe complication of primary hyperparathyroidism is hypercalcemic crisis.
Renal symptomatology is clinically expressed in 40–50% of cases. Thirst and polyuria with a decrease in the specific gravity of urine are among the earliest symptoms of hyperpatyroidism and can be mistakenly regarded by doctors as manifestations of diabetes insipidus.
Refractory to ADH insipidarny syndrome (polyuria, polydipsia, hypoisostenuria) is caused by impaired renal water reabsorption due to the insensitivity of the renal canals to ADH due to massive hypercalciuria. Nephrolithiasis, often accompanied by pyelonephritis, occurs in 25% of patients with hyperparathyroidism. It is much less common, but nephrocalcinosis is difficult, leading to progressive renal failure. Primary hyperparathyroidism occurs in about 2–5% of all patients with urolithiasis.
Bone changes are detected in 50% of cases, and the osteoporotic variant, fibrous cystic osteitis, is distinguished. Diffuse osteoporosis is most often radiologically detected: in the study of the hands in 40% of cases, the spine – in 20%. In severe cases of primary hyperparathyroidism, pathognomonic subperiosteal resorption and acrosteolysis of the end phalanges of the hands and feet can be detected. In severe cases, skeletal deformity, gait disturbance (“duck”), and pathological bone fractures develop.
Cysts, giant cell tumors and epulides are currently extremely rarely detected. Epulides are cystic formations, often mistaken for a malignant tumor, which is the reason for the lack of new operations. Often develops damage to the joints in the form of chondrocalcinosis.
Gastrointestinal symptoms are also detected in half of the patients. Most often it is anorexia, nausea, obstipa tion, flatulence, weight loss. In 10% of cases, peptic ulcers of the stomach and / or duodenum develop, in 10% of cases – pancreatitis, less frequently pancreatic ulcers. Gallstone disease occurs 2 times more often than in the population.
The clinical picture of the initial period of primary hyperparathyroidism is diverse and nonspecific, which makes it difficult to establish a diagnosis. Patients are concerned about general and muscular weakness, lethargy, weakness, and increased fatigue. Depending on the form, early manifestations may be predominantly gastro-enterologic (acute epigastric pain, decreased appetite, nausea, sometimes the clinical picture of acute stomach develops, pancreatitis, pancreatocalcinosis may develop); urological (polyuria, nephrolithiasis). The most pronounced symptoms occur with lesions of the skeletal system: tooth decay and loss due to osteoporosis of the jaws, pain in the bones when walking, chest deformities, multiple pathological fractures.
Cardiovascular manifestations of hyperparathyroidism include arterial hypertension and arrhythmias. Left ventricular hypertrophy, detected even in the group of persons with minimal manifestations of hyperparathyroidism, is one of the factors of increased mortality in this disease.
Neuropsychiatric disorders may for a long time be the only manifestations of the disease; their range ranges from depression to dementia. Spinal injuries and resulting radicular disorders lead to the appearance of tension symptoms, paralysis of the muscles of the pelvic girdle, lower extremities, and paresthesias. Mental arousal is typical of a hyperparathyroid (hypercalcemic) crisis.
Hypercalcemic crisis is currently rarely seen in less than 5% of patients with primary hyperparathyroidism. The crisis develops at a plasma calcium level of about 4 mmol / l and is provoked by prolonged bed rest, the administration of thiazide diuretics, calcium and vitamin D drugs. The prescription of the latter is based on an erroneous medical hypothesis of osteoporosis without specifying its specific genesis.
Clinically, a hypercalcemic crisis is characterized by the adherence of central nervous system lesions (drowsiness, stupor, coma, psychosis) following the growing symptoms of gastrointestinal lesions (anorexia, nausea, vomiting, constipation, epigastric pain, thirst). Acute weakness, dehydration, anuria, a coma, which is difficult to differentiate with a coma of another origin, develop rapidly. The most severe neurological complication is a myopathy involving not only the proximal parts of the body, but also the intercostal muscles and the diaphragm, which requires the patient to be transferred to artificial respiration. Fever is typical to 38–39 ° C.
Diagnosis of primary hyperparathyroidism is based on data from clinical, laboratory and instrumental studies. In a laboratory study, hypercalcemia is determined in 90% of cases of primary hyperparathyroidism. In most cases, it is combined with hypophosphatemia. In addition, hypercalciuria and hyperphosphaturia, elevated plasma alkaline phosphatase, and urinary excretion of hydroxyproline and cAMP are determined. Primary hyperparathyroidism is characterized not only by increased bone resorption, but also by increased bone formation, namely, a high level of bone metabolism, which corresponds to a high content of osteo-calcine, which is a marker of osteoblastic function.
The diagnosis of primary hyperparathyroidism is confirmed by a high level of intact parathyroid hormone in plasma, which can be detected in 90% of cases of primary hyperparathyroidism.
X-ray marker of primary hyperparathyroidism is the detection of osteoporosis, with a sharp thinning of the cortical layer of bones, the appearance of deformities, cysts, swellings, protrusions. The phenomena of subperiostal resorption are characteristic: subperiosteal resorption of the bone, especially noticeable in the hands.
Radiological changes can be divided into 3 types:
1) osteoporotic (generalized osteoporosis);
2) classical, in which cyst, deformities, subperiosteal resorption, fibrocystic osteitis are detected on the background of osteoporosis;
3) a pedzhetoid layer, in which the compact layer is not thinned, but, on the contrary, is unevenly thickened, and a “wadded pattern” is revealed in the bones of the skull.
X-ray and ultrasound examinations
Nephrocalcinosis and nephrolithiasis can be detected. Classic
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short ECG signs of hypercalcemia are shortening of the Q — T interval, S — T depression, atrioventricular block. Echocardiography reveals left ventricular hypertrophy, calcinata in myocardium.
When diagnosing primary hyperparathyroidism, ultrasound is quite informative. Invasive studies are carried out only with the established diagnosis of primary hyperparathyroidism for the purpose of topical diagnosis of non-informative non-invasive methods and include non-selective arteriography with contrast agents and catheterization of veins with selective determination of parathyroid hormone.
In the differential diagnosis exclude conditions accompanied by hypercalcemia, as well as other metabolic osteopathies.
Malignant tumors are the most frequent (60%) cause of the development of hypercalcemia syndrome. As a rule, we are talking about lung cancer, breast cancer, multiple myeloma. Hypercalcemia can have osteolytic genesis in advanced bone metastasis and can be para-neoplastic due to tumor production of a peptide related to parathyroid hormone, the level of which is increased in 90% of cases of tumor hypercalcemia. In multiple myeloma, it is not defined. In the latter case, an increase in ESR, Bens-Jones protein in the urine, and the absence of an increase in the level of parathyroid hormone are found.
Paget’s disease (deforming osteitis) must be differentiated from the “pedzhetoidnoy” form of hyperparathyroidism, which allows you to achieve normal levels of calcium, phosphorus and parathyroid hormone in Paget’s disease.
The erased forms of primary hyperparathyroidism must be differentiated from benign familial hypocalcic hypercalcemia resulting from a mutation in the gene encoding the formation of calcium-sensitive receptors. In the latter case, the level of parathyroid hormone is normal, there are no changes in the structure of bones and somatic signs of hyperparathyroidism.
In recent years, subclinical (mild) forms of primary hyperparathyroidism have been increasingly registered, the only manifestation of which are unespecific symptoms such as depression, weakness, sleep and memory disorders. Sub Clinical primary hyperparathyroidism occurs more often, mainly in old age, and is extremely difficult for a timely diagnosis.
Treatment
With parathyroma, surgical treatment is indicated. The operation of paratiroma removal itself is relatively non-durable, and 90% of the time it takes to search for a tumor. With an obvious clinical picture (visceropathic, bone form), confirmed by convincing laboratory data (hypercalcemia, a high level of intact parathyroid hormone), it is recommended to perform an operative intervention even in the absence of convincing data of topical diagnosis.
The operation is absolutely indicated for saving the patient’s life in clinically obvious hyperparathyroidism and in primary hyperparathyroidism in young or somatically healthy patients. In case of accidentally detected asymptomatic primary hyperparathyroidism in patients over the age of 50, the intervention is performed:
1) in the presence of progression of osteoporosis;
2) when the level of ionized calcium is more than 3 x mmol / l (12 mg / dl), severe calciuria (more than 10 mmol / day or 400 mg / day), or if there are episodes of severe hypercalcemia; 3) in the presence of visceral complications of primary hyperparathyroidism (fibrous periostitis, nephrocalcinosis);
4) with creatinine clearance less than 30% of the age norm.
If a decision is made not to carry out an operative intervention In general, patients should receive a sufficient amount of liquid, avoid hypodynamia and dehydration. They are contraindicated thiazide diuretics and cardiac glycosides. It is necessary to control the level of blood pressure, patients in postmenopausal women should be prescribed estrogen therapy. Every 6 months, it is necessary to investigate the content of calcium, plasma creatinine, creatinine clearance, calcium excretion level. An ultrasound of the abdominal organs and bone densitometry are shown annually.
In case of hyperplasia of the parathyroid glands, total parathyroidectomy is shown with infusion of the removed glands into the cellular tissue forearm After the elimination of hyperparathyroidism, osteoporosis is treated for a long time.
Treatment of hypercalcemic crisis with established hyperparathyroidism is carried out simultaneously with preparation for surgery. The first stage of treatment is rehydration with the introduction of about 2–4 l of isotonic sodium chloride solution (injection rate of about 1 l / h), after which they begin to inject intravenously bisphosphonates (pamidronate or etidronate) for 4–24 hours. The previously recommended use of “looped” diuretics (furosemide) should not be carried out at the first stage of treatment, as this will aggravate extracellular fluid loss. Furosemide is administered intravenously after at least 30 minutes of rehydration with careful monitoring of the level of electrolytes. Calcitonin is one of the safest drugs. In a crisis, it is recommended to inject intramuscularly at 4–8 IU / kg every 6–12 hours. At the level of inorganic phosphorus in sy The crank is less than 1 mmol / l (the norm for adults is 1–1.5 mmol / l) using preparations containing phosphorus salts. If a hypercalcemic crisis develops in osteolytic metastases of malignant tumors, mitramycin cytostatic is prescribed. When hypercalcemic crisis, developed as a result of an overdose of vitamin D drugs, glucocorticoids are prescribed. If the crisis has developed against the background of renal failure, hemodialysis with calcium-free buffer is indicated.