Primary hyperparathyroidism

Primary hyperparathyroidism can occur at any age, but children rarely get sick. Hereditary forms of the disease usually appear in childhood, adolescence and young adulthood.

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Epidemiology

The concept of the prevalence of the disease changed dramatically in the early 1970s, when automatic biochemical blood analyzers were introduced into general medical practice in the United States and then in Western Europe, and the level of total blood calcium was included in the mandatory components of regular laboratory testing of all outpatients and hospitalized patients by the health care system of these countries. This innovative laboratory and diagnostic approach led to the unexpected detection of a huge number of seemingly "asymptomatic" patients with primary hyperparathyroidism, who would hardly have been diagnosed in the usual clinical way. The incidence rate increased 5 times over several years, and the concept of the disease, traditionally accompanied by severe destructive changes in bones, kidney stones, mental and gastrointestinal complications, changed dramatically. It became clear that the disease has a long period of latent low-symptom course, and the structure of the pathology is dominated by erased subclinical forms.

Every year in developed countries of the world, tens of thousands (in the USA - 100,000) of new patients with hyperparathyroidism are identified, most of whom undergo surgical treatment.

Such a high incidence rate was explained by the effect of "capture" of previously accumulating low-symptom cases of the disease in the population. By the 1990s, the incidence rates began to decrease, but in countries where the blood calcium screening system was introduced later, the situation with an epidemically increasing incidence rate was repeated (for example, in Beijing, China). The current incidence rate, estimated by a large-scale epidemiological study in Rochester (Minnesota, USA), shows a decrease in incidence from 75 to 21 cases per 100,000 population, explained by the "washout" of previously accumulated cases of the disease.

However, a recent detailed study of the incidence of primary hyperparathyroidism in women aged 55-75 years in Europe found a still high incidence rate of 21 per 1000, which translates into 3 cases per 1000 in the general population.

No less interesting are the data from autopsy studies of parathyroid glands in people who died from various causes. The frequency of morphological changes corresponding to various forms of hyperparathyroidism is 5-10% of all autopsies.

Several factors are discussed that may influence the changing incidence of primary hyperparathyroidism. Among them is the unexpectedly high incidence of vitamin D deficiency in people, especially the elderly (even in southern European countries), which mitigates hypercalcemia (increases the number of so-called normocalcemic cases of primary hyperparathyroidism) but leads to more severe clinical manifestations of the disease.

Other causes include the possible influence of ionizing radiation, which can cause a surge in morbidity after a 30-40 year latent period (for example, due to man-made accidents, including the consequences of the Chernobyl disaster, nuclear weapons testing, and therapeutic radiation in childhood).

Social factors include an underdeveloped system of laboratory screening for hypercalcemia in countries with inefficient economies and backward health care systems, as well as a reduction in health care costs in developed countries. Thus, in Western Europe, there is a gradual move away from total biochemical screening of calcium in the blood, and it is examined when metabolic disorders are suspected. On the other hand, increasing attention is paid to screening for osteoporosis in older people, which inevitably leads to the identification of a large number of new patients in this common risk group.

An interesting confirmation that the true incidence rate changes little over time is the recent work of South Korean scientists who identified parathyroid adenoma as an incidental finding (parathyroid incidentaloma) in 0.4% of 6469 patients examined by sonography and needle biopsy due to the presence of thyroid nodules.

Thus, Ukraine, where the detection rate of primary hyperparathyroidism still does not exceed 150-200 cases per year per 46 million population, is faced with the need to radically change the attitude towards the problem, introduce large-scale screening of hypercalcemia cases, and increase the level of knowledge of doctors in all branches of medicine about primary hyperparathyroidism.

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Causes primary hyperparathyroidism

The source of increased synthesis and secretion of parathyroid hormone in primary hyperparathyroidism is one or more pathologically altered parathyroid glands. In 80% of cases, such pathology is a single sporadically occurring benign tumor - adenoma of the parathyroid gland. Hyperplasia of the parathyroid glands, which usually affects all glands (however, not always simultaneously), occurs in 15-20% of cases. In 3-10% of cases (according to data from various clinical series), the cause of primary hyperparathyroidism can be multiple adenomas (in 99% - double), which, along with hyperplasia of the parathyroid glands, form a group of the so-called multiglandular form of the disease. Many authors currently question such a high frequency or even the very probability of the occurrence of multiple adenomas of the parathyroid glands, arguing that it is practically impossible to reliably distinguish adenoma from hyperplasia.

Even the use of genetic markers, the principle of monoclonality of adenomas, a complex of differential macroscopic and histological criteria does not allow distinguishing between adenoma and hyperplasia if a section of normal, unchanged parathyroid gland is not simultaneously present in the preparation. In most cases, multiglandular parathyroid gland lesions are hereditary family pathology that fits into one of the known genetic syndromes or does not have a clear syndromic basis.

Rarely (<1% or 2-5% in clinically diagnosed cases, as is predominantly the case in countries where hypercalcemia screening is not available), hyperparathyroidism is caused by parathyroid cancer.

The pathomorphological classification of tumors and tumor-like formations of the parathyroid glands is based on the International Histological Classification of Endocrine Tumors recommended by the World Health Organization and identifies the following pathological variants of these glands:

1. Adenoma:
   • chief cell adenoma (chief cell adenoma);
   • oncocytoma;
   • adenoma with vacuolated cells;
   • lipoadenoma.
2. Atypical adenoma.
3. Carcinoma (cancer) of the parathyroid gland.
4. Tumor-like lesions:
   • primary chief cell hyperplasia;
   • primary hyperplasia of vacuolated cells;
   • hyperplasia associated with tertiary hyperparathyroidism.
5. Cysts.
6. Parathyroidism.
7. Secondary tumors.
8. Unclassifiable tumors.

Typical variants of the pathomorphological picture of lesions of the parathyroid glands in primary hyperparathyroidism are presented in Figures 6.1-6.6 with a brief description of the histological structure.

A rare cause of primary hyperparathyroidism is a parathyroid cyst. As a rule, clinically and laboratory, such pathology corresponds to asymptomatic or mild hyperparathyroidism; sonography reveals an anechoic formation adjacent to the thyroid gland. When performing a differential diagnostic puncture biopsy, the doctor should be alerted by absolutely transparent (crystal-water - clear water) aspiration fluid, which does not happen during a puncture of the thyroid nodes, where the cystic fluid has a yellowish-brown, bloody or colloidal character. An analysis of the aspirate for parathyroid hormone content can help in making a diagnosis; in the case of parathyroid cysts, it will be sharply elevated even compared to the patient's blood.

Excessive, inadequate to the level of extracellular calcium, secretion of parathyroid hormone by the parathyroid glands, which underlies primary hyperparathyroidism, is caused either by a violation (decrease) in the sensitivity of parathyroid cells to the normal level of calcium in the blood, or by an absolute increase in the mass and number of secreting cells. The second mechanism is more characteristic of hyperplasia of the parathyroid glands, the first is much more universal and explains the hyperproduction of parathyroid hormone by both adenomas and some cases of gland hyperplasia. This discovery was made a little over ten years ago, when Kifor et al. in 1996 showed that the specific G-protein of the parathyroid cell membrane, associated with the calcium-sensitive receptor, is expressed 2 times less in adenoma cells compared to the normal parathyroid gland. This in turn leads to a much higher concentration of extracellular Ca++, necessary for the inhibition of parathyroid hormone production. The causes of this anomaly are predominantly genetic.

However, despite the obvious successes of medical genetics, the etiology of most cases of primary hyperparathyroidism remains unknown. Several groups of genetic disorders leading to primary hyperparathyroidism or closely associated with its development have been discovered.

The most studied genetic bases are those of hereditary syndromic variants of primary hyperparathyroidism: multiple endocrine neoplasia syndromes - MEN 1 or MEN 2a, hyperparathyroidism-jaw tumor syndrome (HPT-JT).

Familial isolated hyperparathyroidism (FIHPT) and a special form of isolated familial hyperparathyroidism, autosomal dominant mild hyperparathyroidism or familial hypercalcemia with hypercalciuria (ADMH), have a genetic basis.

Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are also hereditary syndromes associated with a mutation in the gene encoding the calcium sensing receptor (CASR) on chromosome 3. Homozygous patients develop severe neonatal hyperparathyroidism, leading to death from hypercalcemia in the first weeks of life unless emergency total parathyroidectomy is performed. Heterozygous patients develop familial benign hypocalciuric hypercalcemia, which must be differentiated from primary hyperparathyroidism. It is usually not life-threatening and has little impact on the well-being of patients. Surgery is not indicated for this variant of hereditary disease.

MEN 1 syndrome, also known as Wermer syndrome, is a genetically mediated hereditary tumor lesion of several endocrine organs (primarily the parathyroid glands, pituitary gland, endocrine pancreatic cells), the cause of which is an inactivating mutation of the MEN 1 gene. This gene is localized in chromosome llql3, contains 10 exons and codes for the menin protein, which is a tumor suppressor of neuroectodermal origin. At the same time, a major role of a similar mutation in somatic cells has been proven in the occurrence of sporadic (non-hereditary) cases of endocrine neoplasia (21% of parathyroid adenomas, 33% of gastrinomas, 17% of insulinomas, 36% of bronchial carcinoids), which may indicate a fairly high universality of this genetic mechanism.

MEN 2a syndrome, also called Sipple syndrome, involves the thyroid gland (medullary C-cell carcinoma), adrenal medulla (pheochromocytoma), and parathyroid glands (mostly hyperplasia or adenoma of 1-2 glands). The syndrome is caused by an activating germline mutation of the Ret proto-oncogene on chromosome 10.

Germline mutation of the HRPT2 gene, localized on chromosome arm lq, is responsible for HPT-JT syndrome, while familial isolated hyperparathyroidism (FIHPT) is a genetically heterogeneous disease.

For a number of parathyroid gland adenomas, the cause of their development is excessive synthesis of the cell division regulator - cyclin D1. The pathology is based on clonal chromosomal inversion, in which the 6'-regulatory region of the parathyroid hormone gene (normally it is located in the chromosomal position lip 15) is transferred to the place of the coding region of the parathyroid adenoma 1 oncogene (PRADl/cyclin D1), located in the position llql3. Such rearrangement causes overexpression of the gene and cyclin D1, responsible for disruption of the cell cycle and the development of parathyroid adenomas, as well as some other tumors. Excessive expression of the PRAD1 oncogene is detected in 18-39% of parathyroid adenomas.

For more than a quarter of all parathyroid adenomas, the characteristic cause is considered to be the loss of some tumor suppressor genes associated with loss of heterozygosity on chromosome arms lp, 6q, lip, llq and 15q, but involvement of the well-known tumor suppressor gene p53 has been noted in only a few parathyroid carcinomas.

For parathyroid cancer, a characteristic, but not 100% genetic feature is the deletion or inactivation of the retinoblastoma gene (RB gene), now recognized as an important differential and prognostic diagnostic criterion. Also, a high risk of developing parathyroid carcinoma - 15% - is noted in the syndrome "hyperparathyroidism-mandibular tumor" (HPT-JT).

The hypothesis that the main cause of parathyroid adenomas is a mutation in the calcium receptor gene (CASR gene) remains controversial, as it is confirmed by less than 10% of tumors. At the same time, mutations affecting mainly the tail, cytoplasmic part of this receptor protein are responsible for ADMH, FHH and NSHPT syndromes, the last of which is the most severe and becomes lethal for newborns.

Polymorphism or mutations of the vitamin D receptor gene (VDR gene) appear to be of significant importance in the etiology of primary hyperparathyroidism. Abnormalities in vitamin D receptor concentrations have been found in adenomas compared with normal parathyroid tissue. In 60% of postmenopausal women with primary hyperparathyroidism, gene expression is weakened compared with controls.

None of the genetic markers of hyperparathyroidism can help distinguish adenoma from hyperplasia of the parathyroid gland, since similar genetic changes are found in both the first and second variants of the disease.

Furthermore, no clear correlation was found between adenoma mass and the severity of hyperparathyroidism.

Ionizing radiation plays a certain role in the etiology of primary hyperparathyroidism. This was first noted in a study of radiation-induced thyroid cancer in individuals who received therapeutic irradiation in childhood. The latent period is longer than that of thyroid cancer and is 20-45 years. At least 15-20% of patients with primary hyperparathyroidism have a history of previous irradiation. An analysis of a large number of such patients (2555 people) with a long-term follow-up period (36 years) made it possible to establish a dose-dependent relationship with irradiation, with a significant increase in the relative risk of the disease (starting from 0.11 cGy) and no effect of gender or age at the time of the disease.

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Symptoms primary hyperparathyroidism

During the first decade of conscious study of clinical cases of primary hyperparathyroidism, fibrocystic osteitis was observed in almost all patients, which was considered the main and, perhaps, the only specific manifestation of the disease. As already indicated in the historical essay on primary hyperparathyroidism, at the beginning of the 20th century, researchers believed that bone destruction was primary and only then led to secondary compensatory hyperplasia of the parathyroid glands. Only in 1934, F. Albright noted that 80% of patients with fibrocystic osteitis have kidney damage in the form of urolithiasis or nephrocalcinosis. With the help of this authoritative scientist, in the next 20-30 years, urolithiasis became the defining symptom of primary hyperparathyroidism. Later, in 1946, the relationship between primary hyperparathyroidism and peptic ulcers of the stomach and duodenum was traced. A frequent combination of the disease with gout (due to an increase in the concentration of uric acid in the blood) and pseudogout (due to the deposition of calcium phosphate crystals) was also established.

In 1957, summarizing the known clinical symptoms of primary hyperparathyroidism, WS Goer was the first to propose a succinct mnemonic description of the manifestations of the disease in the form of the triad “stones, bones, and abdominal groans”, later supplemented by another component - mental disorders, which in the original received a rhyming sound: “stones, bones, abdominal groans and psychical moans”.

Symptoms of primary hyperparathyroidism today rarely fit into such a scheme. Blurred clinical forms become predominant, although urolithiasis continues to occur in approximately 30-50% of patients. Gallstone disease is quite often present as a concomitant disease (about 5-10% of cases). Thus, according to American authors, in 1981, out of 197 examined patients with primary hyperparathyroidism, urolithiasis was present in 51% of cases and radiological signs of bone damage in 24%. At the end of the 90s of the last century, only 20% had nephrolithiasis, bone involvement became very rare.

Even in countries where screening for hypercalcemia and primary hyperparathyroidism is low (including Ukraine), patients increasingly rarely demonstrate pronounced symptoms with severe skeletal bone damage, urolithiasis, gastrointestinal manifestations, neuromuscular and mental disorders.

A sharp increase in the frequency of detection of the disease with the beginning of widespread use in developed countries of biochemical blood testing on automatic analyzers led to the "washing out" of clinically expressed cases of primary hyperparathyroidism, which, in turn, changed the structure of the clinic of new patients towards a huge predominance of asymptomatic or low-symptom forms (from 10-20% before the introduction of hypercalcemia screening to 80-95% of such patients in the last two decades). In this regard, interest in the description of the clinical picture of the disease in modern literature has significantly weakened. Large-scale monographs devoted to primary hyperparathyroidism only briefly touch on the issue of clinical symptoms. The emphasis in them is on the need for not selective (if the disease is suspected), but a continuous examination of the population by periodically determining the level of calcium in the blood.

At the same time, it can be assumed that in the conditions of limited funding of medical projects in developing countries, clinically oriented approaches to the diagnosis of primary hyperparathyroidism will be relevant for a long time. Therefore, knowledge of possible manifestations of the disease will bring undoubted benefit both from the point of view of diagnostics and differential diagnostics, and from the point of view of predicting the development of certain pathological conditions associated with primary hyperparathyroidism.

Only changes in the skeletal system have a direct relation to the pathological action of excess parathyroid hormone - systemic osteoporosis and subperiosteal resorption of long bones, which are accompanied by a decrease in skeletal strength, an increased tendency to fractures, and bone pain. The action of parathyroid hormone on the renal tubules can lead to a decrease in renal function even in the absence of urolithiasis. The possibility of a direct action of parathyroid hormone on the heart muscle, causing hypertension, left ventricular hypertrophy and failure, is also discussed. Both of the latter syndromes (renal and cardiac) are currently being closely studied in the context of the reversibility of these changes after curing hyperparathyroidism, but controlled randomized studies have not yet been conducted.

The remaining symptoms are predominantly of indirect (through hypercalcemia) origin. These include the processes of formation of calcium deposits (calcification of parenchymatous organs, vessels, cornea, soft tissues) and stones in the kidneys, bile and pancreatic ducts, the effect of increased concentrations of extracellular calcium on neuromuscular conduction, muscle contractility, secretion of digestive glands and many other physiological processes (see sections "Physiology of calcium metabolism", "Etiology and pathogenesis of primary hyperparathyroidism").

Symptoms and complaints that may occur in patients with primary hyperparathyroidism

Urinary

• Polyuria, low back pain, renal colic, hematuria

Musculoskeletal

• Pain in the bones, especially in the long tubular bones, pain in the joints, their swelling, tendency to fractures, pathological fractures of the bones (radius, femoral neck, clavicle, humerus, etc.

Digestive

• Anorexia, nausea (in severe cases - vomiting), dyspepsia, constipation, abdominal pain

Psychoneurological

• Depression, weakness, fatigue, apathy, lethargy, confusion of varying degrees of severity, psychosis

Cardiovascular

• Arterial hypertension, bradycardia, arrhythmia

Many patients may not present specific complaints now, even when questioned. Some patients assess their condition only retrospectively, after successful surgical treatment of primary hyperparathyroidism, noting that they have acquired a "new, better quality of life" consisting of many components: greater vital activity, higher physical performance, a positive attitude to life, improved memory, disappearance of joint stiffness and muscle weakness, etc. Indicative are the works based on the principles of evidence-based medicine, which used subtle tools for assessing the psychological and emotional state of patients (the most popular questionnaire of psychosocial well-being - SF-36 and a detailed scale for assessing psychosomatic symptoms - SCL-90R).

They convincingly demonstrated that after surgical treatment of primary hyperparathyroidism, significant positive changes in the quality of life, a decrease in pain, an increase in vitality and other positive changes occur over a certain period of time (from 6 months to 2 years), which the patient can rarely describe on his own. In the control groups of patients under observation, such changes did not occur.

Studies that examined the dynamics of the condition of untreated patients note a gradual progression of complaints or their appearance over 10 years of observation. One study recorded clear indications for surgical treatment in 26% of patients and death from various causes in 24%. Another long-term prospective study of the course of mild forms of hyperparathyroidism found disease progression in 24%, the appearance of new stones in the urinary tract, hypercalcemic crises, and the need for emergency parathyroidectomy. A large number of studies demonstrate a steady progression of bone mineral density reduction with increasing disease duration, regardless of the initial condition, gender, and age.

The accumulation of such data has led to an understanding of the need to develop a consensus on the indications for surgical treatment of asymptomatic clinical forms of primary hyperparathyroidism. Such consensuses under the auspices of the US National Institutes of Health (NIH) have been adopted and amended three times since 1991 (the last revision was in 2009). The essence of these recommendations boils down to attempts to objectify the indications for surgery in latent forms of the disease, based on such criteria as the severity of hypercalcemia, the severity of osteoporosis, renal dysfunction, the presence of urolithiasis, the age of patients (less than or more than 50 years) and their commitment to careful medical supervision. This will be discussed in the section on surgical treatment of primary hyperparathyroidism. In addition, a thorough study of the psychoneurological state of patients shows the presence of such "minor" symptoms in almost all patients, which makes the concept of an asymptomatic variant of the disease not entirely valid.

Renal manifestations of the disease remain among the most recurring clinical symptoms, although their severity and frequency are decreasing. It remains unexplained why renal calculi do not form in some patients with a long history of hyperparathyroidism, as well as the lack of correlation between the severity of hyperparathyroidism, the severity of hypercalciuria and the presence of urolithiasis. The formation of kidney stones is facilitated by tubular acidosis, which occurs due to increased excretion of bicarbonate under the influence of parathyroid hormone. In addition to anatomical changes in the kidneys (stone formation, nephrocalcinosis, secondary shrunken kidney due to chronic pyelonephritis against the background of long-standing urolithiasis), primary hyperparathyroidism is also characterized by functional changes that develop as hyperparathyroidism progresses, resulting in chronic renal failure and associated mainly with damage to the proximal renal tubules. Typical manifestations of functional renal disorders are proximal tubular acidosis type 2, amino- and glucosuria, and polyuria.

The action of parathyroid hormone on bones, previously considered the only manifestation of primary hyperparathyroidism, can demonstrate destructive consequences in patients with very severe and long-term primary hyperparathyroidism, although it is increasingly rare in the form of the classic form of fibrocystic osteitis. According to foreign authors, if in the 30s of the XIX century the frequency of this syndrome exceeded 80%, then by the 50s it decreased to 50%, by the 70s to 9%, and in the era of calcium screening - almost to zero. It is extremely rare now to see a detailed radiographic picture of bone lesions - subperiosteal resorption, cyst formation, hypertrophy of the periosteum, pathological fractures, diffuse demineralization ("transparent" bones), uneven resorption and reorganization of bone substance in the bones of the skull, manifested by the radiographic symptom of "salt and pepper").

The action of parathyroid hormone is dual, as was established in the 90s of the last century, and depends not only on the absolute amount of the secreted hormone, but also on the nature of secretion - constant or pulsating. The maximum osteoresorptive effect is observed in bones with a pronounced cortical structure (long tubular bones), while bones of trabecular structure (vertebrae, iliac crest) can maintain their density or even increase it. This effect has a certain differential diagnostic value when X-ray absorption densitometry of patients with primary hyperparathyroidism records a decrease in bone density in the radius area, less in the femur and often absent in the vertebrae. In a typical case of postmenopausal hypoestrogenic osteoporosis in women over 50 years of age, a decrease in density is observed primarily in the vertebrae.

At the same time, the fact of an increase in mineral density primarily of spongy bones (vertebral bodies and proximal femur) and, to a lesser extent, of the radius after surgical treatment of patients with primary hyperparathyroidism remains not fully explained. This fact was confirmed by independent studies of different years that assessed the comparative dynamics of bone density in groups of patients with moderate hyperparathyroidism who underwent surgery or received conservative treatment (bisphosphonates, calcium mimetics) or were under observation. It is believed that restoration of the normal (pulsating) type of parathyroid hormone secretion is a more powerful stimulus for restoration of spongy bone density than an absolute decrease in hormone concentration. Damage to the compact substance of tubular bones remains almost irreversible even after hyperparathyroidism is eliminated.

During observation and even treatment with calcium mimetics (cinacalcet), it was not possible to achieve a significant increase in bone mineral density. Although cinacalcet led to a decrease in the calcium level in the blood, it had virtually no effect on the parathyroid hormone level.

Thus, long-term primary hyperparathyroidism is fraught with catastrophic consequences for the skeleton, regardless of the type of bone structure. In addition to the risk of pathological fractures of long bones, flattening of the vertebral bodies, kyphoscoliosis, and a sharp decrease in human height are observed.

A rare but very specific radiological symptom is the formation of "brown" or "brown" tumors (in foreign literature - brown tumors), more often in spongy bones - jaws, collarbones. These pseudo-tumor formations of granulomatous structure simulate a bone neoplastic process, become the cause of tragic diagnostic and therapeutic errors. Thus, due to a false diagnosis of bone sarcoma, amputations are performed, mutilating operations on the jaws are performed, while similar changes in hyperparathyroidism are reversible and require only the elimination of the cause of primary hyperparathyroidism.

It is important to remember the possible combination of such a jaw tumor and primary hyperparathyroidism within the framework of the hereditary syndrome of the same name (JT-PHPT syndrome), in which there is a high probability of a malignant tumor of the parathyroid gland (up to 20%), which requires correction of treatment tactics.

Joints are also a weak link in the body of patients with primary hyperparathyroidism. The load on them increases due to erosive changes in the epiphyses, and disturbances in bone geometry. Another pathogenetic factor of arthropathy is the deposition of calcium salts in the synovial membranes, cartilage, and periarticularly, which leads to chronic trauma and severe pain syndrome.

Neuromuscular changes in primary hyperparathyroidism manifest themselves in weakness and fatigue, mainly affecting the proximal muscles of the lower extremities. This is a reversible syndrome that quickly disappears after surgery, characterized in severe cases by a typical complaint - difficulty getting up from a chair without assistance.

Psychoneurological disorders are sometimes very difficult to assess due to the personal or age characteristics of patients. In general, they correspond to the symptoms of depressive states, personality changes, memory impairment. Sometimes, especially with significant hypercalcemia, obvious psychotic states or confusion, inhibition, lethargy up to coma can be observed. Communication with relatives or people close to the patient helps to recognize personality changes. Some patients, due to the lack of timely diagnosis of hyperparathyroidism, become dependent on antidepressants, painkillers, neuroleptics and other psychotropic substances.

Gastrointestinal symptoms may include clinical features of peptic ulcer of the stomach or duodenum, hyperacid gastritis, cholelithiasis, chronic and sometimes acute pancreatitis. Disorders of the digestive system may be both true manifestations of hyperparathyroidism and hypercalcemia, and consequences of concomitant hypergastrinemia within the framework of MEN-1 syndrome or Zollinger-Ellison syndrome.

The cause-and-effect relationship between hyperparathyroidism and pancreatitis, which is observed in 10-25% of patients, is not entirely clear. Probable causes include hyperacidity of gastric juice and campe formation in the ducts. Not only hypercalcemia, but also normocalcemia in acute pancreatitis should alert clinicians, since free fatty acids due to excessive lipolysis bind calcium, leading to a decrease in its concentration in the blood.

Arterial hypertension is much more common in patients with primary hyperparathyroidism than in the general population, although the exact mechanisms of this disease effect remain poorly understood. Possible causes include the direct action of parathyroid hormone on the heart muscle, left ventricular hypertrophy, calcification of the heart valves, myocardium, and aorta (in more than half of patients). Parathyroidectomy itself does not always significantly affect the further course of hypertension, although left ventricular hypertrophy is reversible in most patients.

Bradycardia, discomfort in the heart region, and interruptions in its work are often encountered in primary hyperparathyroidism and correlate with the severity of hypercalcemia.

Primary hyperparathyroidism, in addition to gradually developing pathological changes in many organs and tissues, can also cause urgent life-threatening conditions, the main one of which is a hypercalcemic crisis. The severity of clinical manifestations generally correlates well with the severity of hypercalcemia, but there are cases with a relatively mild course of the disease with calcemia over 4 mmol / l and cases with a pronounced clinical picture of severe hypercalcemia with a calcium level of 3.2-3.5 mmol / l. This depends on the rate of increase in the concentration of calcium in the blood and the presence of intercurrent diseases.

Severe hypercalcemia (usually more than 3.5 mmol/l) leads to anorexia, nausea, vomiting, which further aggravates the growth of calcium concentration. Weakness and lethargy associated with the central and neuromuscular effects of abnormally high calcium levels lead to immobilization of the patient, which enhances osteoresorptive processes. Gradually, pathological brain disorders worsen, confusion of consciousness occurs, and then coma (the calcium level usually exceeds 4.3-4.4 mmol/l). If the patient in this condition is not provided with assistance, oliguric renal failure, cardiac arrhythmia and death develop.

In general, even moderate primary hyperparathyroidism significantly increases the risk of premature death, mainly from cardiovascular and circulatory complications, consequences of bone fractures, peptic ulcers and, according to some data, more frequent oncological diseases. Recent population studies by Scottish scientists on a huge data set (more than 3000 cases of the disease) showed a twofold increase in the risk of developing malignant tumors and a threefold increase in the risk of death for patients with primary hyperparathyroidism compared to corresponding cohorts of people without hyperparathyroidism.

It is typical that for patients operated in the pre-screening era (i.e. mainly with a long history and a vivid clinical picture), the risk of premature death remains elevated for 15 or more years after the operation. At the same time, patients diagnosed at early stages of the disease, with a short history, gradually equalize the risk of premature death with population control groups. Danish scientists confirmed similar data, establishing increased risks of diseases and death from cardiovascular diseases, bone diseases and peptic ulcers of the stomach, and these risks decreased after surgical treatment, although they did not reach the level of control groups. It was even possible to calculate the mathematical dependence of the expected risk of death on gender, age and weight of the parathyroid gland tumor.

Thus, primary hyperparathyroidism is a chronic disease with a multifaceted clinical picture (currently far from the classical descriptions of the disease), involving many organs and systems in the pathological process, leading to a significant deficit in the quality of life, an increased risk of premature death and the risk of malignant tumors. Early diagnosis and timely surgical treatment can significantly reduce or eliminate the above risks, significantly improving the quality of life of patients.

Diagnostics primary hyperparathyroidism

Laboratory diagnostics of primary hyperparathyroidism is the basis for timely recognition of primary hyperparathyroidism and the widest possible detection of the disease in the population.

The key criteria for laboratory diagnosis of primary hyperparathyroidism are two indicators: elevated parathyroid hormone levels and elevated calcium levels in the blood plasma. The simultaneous detection of these two laboratory signs in a patient leaves virtually no doubt about the diagnosis of primary hyperparathyroidism. Thus, in the classic bright variants of the disease, its laboratory diagnosis cannot but amaze with its simplicity. Why then are errors in diagnosis so common? Why does an undetected disease continue to develop for decades, leaving destructive traces in the body?..

Next, we will try to analyze possible pitfalls in laboratory diagnostics of primary hyperparathyroidism, the causes of errors, ways of verifying the diagnosis, as well as pathological conditions that mask or simulate the biochemical picture of the disease.

Let's start with the main indicators: calcium and parathyroid hormone in the blood.

They learned to determine calcium in the blood in a clinic a little over a hundred years ago - in 1907. In the blood, calcium is found in three main forms: the ionized fraction of the element - 50%, the fraction associated with proteins - 40-45%, the fraction consisting of complex phosphate and citrate compounds - 5%. The main clinical laboratory parameters for studying this element in the body are the concentration of total calcium and the concentration of ionized (or free) calcium in the blood.

The normal range of total calcium values is 2.1-2.55 mmol/l; ionized calcium - 1.05-1.30 mmol/l.

It should be noted that the upper limit of normal values for total calcium has been revised several times over the past 30 years, each time with downward adjustments and has decreased from 2.75 to 2.65 and 2.55 mmol/L in the latest guidelines. Total calcium is the most widely used indicator, which is used as one of the main components of complex biochemical blood tests using modern automatic analyzers. It was the introduction of an automatic study of total calcium that helped to discover the true frequency of primary hyperparathyroidism in the population.

With this research method, this parameter is quite reliable, since it depends little on the human factor when standard requirements for collection and determination are met. However, in the real practice of domestic medicine, one can often encounter a manual biochemical blood test for total calcium, in which rather gross deviations are possible both in the direction of decrease (long-term presence of blood in a test tube at room temperature, calibration errors, etc.) and in the direction of increase (glassware, not plastic vacutainers for collecting and centrifuging blood, impurities of other reagents, etc.).

In addition, even a correctly performed analysis to determine the total calcium in the blood requires adjustment for the level of proteins in the blood, primarily albumin. The lower the albumin concentration compared to the norm (40 g/l), the higher the true calcium concentration should be when compared to the registered one and, conversely, with an increase in the albumin concentration, the correction should be made towards a decrease in the calcium level in the blood. The method is quite approximate and requires an adjustment of 0.2 mmol/l for every 10 g/l deviation from the average normal albumin value.

For example, if the laboratory indicator of total blood calcium concentration is 2.5 mmol/L and the albumin level is 20 g/L, then the corrected calcium concentration will be 2.9 mmol/L, i.e. 2.5 + (40-20): 10 HOW

Another method of correcting the total calcium value based on the blood protein level involves adjusting the total calcium value based on the total protein concentration in the blood.

Thus, it is quite possible not to miss true hypercalcemia with a reduced level of albumin or total blood protein. The opposite picture can be observed with an increase in the concentration of plasma proteins, which happens, for example, in myeloma. A sharp increase in the protein-bound calcium fraction will lead to an increased indicator of total blood calcium. Such errors can be avoided by directly determining ionized blood calcium. This indicator is less variable, but special equipment is needed to determine it - an analyzer using ion-selective electrodes.

The correctness of the determination and interpretation of the ionized calcium level depends on the technical condition and careful calibration of the equipment, as well as on taking into account the effect of the blood pH on the calcium concentration. The acid-base state affects the content of ionized calcium in the blood by influencing the process of calcium binding to proteins. Acidosis reduces the binding of calcium to blood proteins and leads to an increase in the level of ionized calcium, while alkalosis increases the process of calcium binding to proteins and reduces the level of ionized calcium. This correction is built into the automatic program of modern ionized calcium analyzers, but was not used in earlier models, which can lead to an incorrect assessment of the indicator and be one of the reasons for the delay in establishing the correct diagnosis of primary hyperparathyroidism.

The main external factors influencing the blood calcium level are the intake of vitamin D and thiazide diuretics (both factors contribute to its increase). More details on the regulation of calcium metabolism and the causes of hypercalcemia are mentioned in the relevant sections of the monograph.

The second of the main components of laboratory diagnostics of primary hyperparathyroidism - the level of parathyroid hormone in the blood - also requires a competent assessment and consideration of objective and subjective factors that can distort its true value.

We will not consider the features of previously used laboratory tests for fragments of the parathyroid hormone molecule (C- and N-terminal parts of the molecule). They had a number of limitations and errors, so they are now practically not used, giving way to immunoradiometric or immunoenzyme determination of the whole (intact) parathyroid hormone molecule, consisting of 84 amino acid residues.

The normal range of parathyroid hormone concentrations in healthy subjects is 10-65 μg/L (pg/mL) or 12-60 pmol/dL.

Having undoubted advantages over the terminal fragments of the parathyroid hormone molecule in terms of the adequacy of the parameter to the studied purposes, the determination of intact parathyroid hormone is associated with a number of difficulties. First of all, this is a very short half-life of the molecule in the body (several minutes) and the sensitivity of the analysis to the time of blood and serum at room temperature. This is why sometimes the analyses done on the same day in different laboratories differ so much. After all, it is enough to collect blood not in a vacutainer, but in an open test tube, leave the test tube at room temperature for 10-15 minutes or use an uncooled centrifuge - and the analysis result can change significantly towards underestimation of the concentration. As a rule, in practice, it is precisely a false underestimation of the study results that occurs, which is why out of several serial studies in a short time, you should trust the highest result. Therefore, not only the standardization of the hormonal study itself is critically important, but also the stage of blood collection and preparation of serum for analysis. This should be done with the shortest possible time of blood being uncooled. In short, the more standardized and automated the process of blood collection and analysis, the more reliable the results.

In the last decade, 2nd and 3rd generation reagents have appeared, as well as automatic devices for instant blood testing for parathyroid hormone, used mainly intraoperatively to assess the radicality of the operation. The latest development of the Dutch company Phillips, announced at the congress of the European Society of Endocrine Surgeons (ESES-2010, Vienna) promises to simplify the procedure to a minimum, automate all processes (not plasma, but whole blood is loaded into the device!) and reduce the time of the study to 3-5 minutes.

When evaluating the results of a blood parathyroid hormone study, it is necessary to take into account the daily rhythm of hormone secretion (with a peak concentration at 2 a.m. and a minimum at 2 p.m.), and the possibility of interference during night operation.

Some medications can alter the natural concentration of parathyroid hormone. For example, phosphates, anticonvulsants, steroids, isoniazid, lithium, rifampicin increase the concentration, and cimetidine and propranolol decrease the level of parathyroid hormone in the blood.

Apparently, the most significant impact on the correct assessment of the main laboratory pair of criteria - calcium/parathyroid hormone - is exerted by a decrease in kidney function and vitamin D deficiency, the frequency of which is significantly underestimated by doctors.

Impaired renal function has a multifaceted impact on both the initial diagnosis and clinical evaluation of the course of primary hyperparathyroidism. Thus, a 30% decrease in creatinine clearance, and in the latest edition of the guidelines for asymptomatic primary hyperparathyroidism, a decrease in glomerular filtration below 60 ml/min are recognized as indications for surgical treatment of low-symptom variants of the disease. However, long-term renal dysfunction, which could be caused by the direct action of parathyroid hormone or secondary pyelonephritis due to urolithiasis, is itself accompanied by increased loss of calcium in the urine (primarily in response to reduced phosphate excretion due to the loss of its excretion by the affected kidneys). The early appearance of deficiency of active 1,25(OH)2-vitamin D3 in renal failure (due to decreased activity of renal la-hydroxylase) also contributes to some decrease in serum calcium concentration due to decreased intestinal absorption. These factors can largely explain the frequent cases of normocalcemic primary hyperparathyroidism or the absence of persistent hypercalcemia, which complicates diagnosis.

Normocalcemic primary hyperparathyroidism, according to authoritative modern scientists, is a real diagnostic problem and a challenge to modern laboratory diagnostics; it must be differentiated from cases of idiopathic hypercalciuria associated with increased intestinal calcium absorption, decreased tubular calcium reabsorption or primary hyperphosphaturia in order to avoid unnecessary operations. On the other hand, untimely diagnosis of primary normocalcemic hyperparathyroidism will lead to an increase in renal failure, the formation of new urinary stones.

A test with thiazide diuretics can help differentiate between these two conditions, which are similar in laboratory signs. The latter will correct hypercalciuria associated with the "dumping" of excess calcium and normalize the parathyroid hormone level. In normocalcemic primary hyperparathyroidism, thiazide diuretics will promote hypercalcemia and will not reduce the parathyroid hormone level.

In connection with the above circumstances, it is necessary to mention another very important criterion of laboratory diagnostics - the level of daily calciuria. This indicator has more differential than diagnostic value. It allows to differentiate a disease similar in its main criteria (simultaneous increase in the level of calcium and parathyroid hormone in the blood) - familial benign hypocalciuric hypercalcemia. This pathology has now become more understandable and is rather not one, but a whole group of conditions associated with a violation of the regulation of calcium metabolism, which are based on mutations of the calcium receptor gene (more than 30 of them are already known). The fundamental difference of this condition, in which stable hypercalcemia and a slight increase in the level of parathyroid hormone will be observed, is a decrease in the level of calciuria (usually less than 2 mmol / day), whereas in primary hyperparathyroidism the level of calciuria remains normal or increases (more than 6-8 mmol / l), depending on the severity of the process and the state of kidney function.

The most accurate method for assessing calciuria is to calculate the ratio of calcium clearance to creatinine clearance, since calcium excretion is directly dependent on the glomerular filtration rate. The calculation formula is as follows:

Clearance Ca / Clearance Cr = Cau X Crs / Cru x Cas

Where Cau is urine calcium, Cr is serum creatinine, Cru is urine creatinine, Cas is serum calcium.

It is important that all indicators are converted into the same units of measurement (e.g., mmol/l). The ratio of 1:100 (or 0.01) is differentiating (in favor of familial hypocalciuric hypercalcemia), while in primary hyperparathyroidism it is usually 3:100 - 4:100. A study of blood relatives (first-line siblings) will also help in diagnosis, since the disease is autosomal dominant and probably affects half of the descendants (with the development of laboratory manifestations already in early childhood). Due to the low-symptom course of the disease, treatment is usually not required, and surgery does not have a significant clinical effect.

The influence of vitamin D deficiency on the clinical manifestations and laboratory diagnostics of primary hyperparathyroidism appears to be no less complex.

Vitamin D generally acts synergistically with parathyroid hormone, exerting a hypercalcemic effect. However, there is also a direct negative interaction of vitamin D with parathyrocytes, inhibiting the synthesis of parathyroid hormone (with an excess of the vitamin) and stimulating its production (with a deficiency) through molecular mechanisms of gene transcription and, possibly, by direct action on certain receptors.

Vitamin D deficiency, previously associated exclusively with pediatric problems, has proven to be extremely common in all age groups, even in prosperous developed countries. Thus, among hospitalized patients in the United States, vitamin D deficiency was detected with a frequency of 57%. The problem is now so urgent that the issue of revising the normal limits of parathyroid hormone concentrations in the blood (with the establishment of an optimal minimum and a safe upper limit) is being discussed, taking into account the degree of vitamin D deficiency. Consensus guidelines for the diagnosis and treatment of asymptomatic primary hyperparathyroidism call for determining the level of 25(OH) vitamin D in all patients suspected of having primary hyperparathyroidism.

In case of detection of decreased (less than 20 ng/ml) or lower-normal level of 25(OH) vitamin D, careful correction should be carried out with subsequent repeated examination to decide on treatment tactics. At the same time, many authors focus on the change in the clinical course of primary hyperparathyroidism in conditions of vitamin D deficiency (mainly towards aggravation), despite less pronounced biochemical shifts. Unfortunately, determination of vitamin D concentration in Ukraine remains inaccessible due to the high cost of the study and its implementation only in commercial laboratories.

The primary additional criteria for diagnosing and differentiating primary hyperparathyroidism from some other conditions with similar clinical and laboratory parameters include the blood phosphorus level. The normal value of phosphatemia for adults is within 0.85-1.45 mmol/l. Primary hyperparathyroidism is characterized by a decrease in this indicator to the lower limit of the norm or below it in severe hypercalcemia, which occurs in approximately 30% of patients. This parameter is especially indicative when detecting a simultaneous increase in renal excretion of phosphorus associated with the inhibition of phosphate reabsorption by parathyroid hormone. Hypophosphatemia may occur in some patients with cholestatic liver disease.

Let us recall that the levels of calcium and phosphorus in the blood are extremely closely related in an inversely proportional relationship; the product of serum concentrations of total calcium and phosphorus (Ca x P) is a very important and stable parameter of human homeostasis, controlled by many systems. Exceeding this product to values greater than 4.5 (mmol/l)2 or 70 (mg/l)2 leads to massive formation of insoluble calcium phosphate compounds in the blood, which can cause all sorts of ischemic and necrotic lesions. In addition to its diagnostic value (to confirm the diagnosis of primary hyperparathyroidism), the level of phosphorus in the blood serves as a differentiating criterion for distinguishing between primary and secondary hyperparathyroidism caused by chronic renal failure.

In this case, the phosphorus level tends to increase depending on the severity of the renal dysfunction, which is associated with the loss of the ability to actively excrete phosphates. Severe hyperphosphatemia in the terminal stages of chronic renal failure can only be corrected by hemodialysis, so the indicator should be assessed before dialysis. In addition to hyperphosphatemia, a distinctive feature of secondary hyperparathyroidism will always be a normal or reduced level of calcium in the blood until the disease moves to the next phase - tertiary hyperparathyroidism (development of adenomas against the background of long-term hyperplasia of the parathyroid glands with autonomization of their function).

Moderate hyperchloremia is also an additional laboratory diagnostic criterion. It is related to inconstant symptoms. A more accurate indicator is the ratio of chlorine to phosphorus concentration in the blood - in primary hyperparathyroidism it exceeds 100 when measured in mmol/l, and normally it is less than 100.

Indicators of increased bone remodeling and osteoresorption under the influence of prolonged excessive secretion of parathyroid hormone into the blood are useful for diagnosis and determination of the severity of the disease. Markers of osteoresorption include elevated levels of alkaline phosphatase (its bone fraction), blood osteocalcin, and urinary excretion of hydroxyproline and cyclic adenosine monophosphate. However, these indicators are nonspecific and can be found in any form of hyperparathyroidism and other conditions associated with active bone remodeling (for example, in Paget's disease). Their values are more informative as indicators of the severity of bone damage.

Thus, summarizing the principles of laboratory diagnostics of primary hyperparathyroidism, the following key points can be formulated.

Screening for hypercalcemia is the most rational method for identifying primary hyperparathyroidism in the population.

The most important diagnostic indicators are the simultaneous increase in calcium and parathyroid hormone in the blood. In this case, certain proportions of this increase should be taken into account: calcium in primary hyperparathyroidism rarely exceeds 3 mmol/l; severe hypercalcemia is usually accompanied by a very high level of parathyroid hormone (at least 5-10-fold).

Marked hypercalcemia and a slight increase in parathyroid hormone (or its upper normal values) are more characteristic of familial hypocalciuric hypercalcemia. It can be confirmed by studying daily calciuria (should be reduced), preferably in relation to creatinine clearance, as well as by examining blood relatives.

A moderate increase (or upper normal values) in blood calcium and a slight increase in parathyroid hormone levels are more indicative of primary hyperparathyroidism (its latent forms) due to the unsuppressed level of parathyroid hormone, which normally decreases rapidly due to a memontal reactive decrease in its secretion by the parathyroid glands in response to a slight increase in blood calcium levels.

All cases of hypercalcemia of endogenous (malignant tumors, myeloma, granulomatosis, thyrotoxicosis, etc.) or exogenous (hypervitaminosis D, thiazide diuretics, milk-alkali syndrome, etc.) origin are accompanied by a suppressed or even zero level of parathyroid hormone in the blood.

Secondary hyperparathyroidism is a diagnostic problem more often in primary vitamin D deficiency, when there is a moderate increase in parathyroid hormone levels and normal blood calcium levels. Secondary hyperparathyroidism of renal genesis is easier to diagnose due to the presence of hyperphosphatemia and decreased or below normal blood calcium levels, as well as signs of impaired renal function.

In any of the clinical variants of the disease, a balanced decision on the final diagnosis, serial examination of parameters, and study of additional diagnostic factors are very important due to fundamental differences in treatment tactics for primary hyperparathyroidism and other conditions.

The necessary laboratory tests for primary hyperparathyroidism should also include genetic testing for possible mutations that determine the development of hereditary forms of hyperparathyroidism (MEN-1, MEN-2a, PHT-JT syndrome) and variants of the pathology of the gene encoding the calcium receptor. However, for now we have to admit the practical inaccessibility of genetic methods for wide clinical use in Ukraine.

How is primary hyperparathyroidism diagnosed?

Instrumental research methods for primary hyperparathyroidism are aimed at:

1. confirmation of diagnosis;
2. determining the severity of the disease and damage to other organs and systems (bones, kidneys);
3. topical diagnostics and visualization of pathologically altered and hyperfunctioning parathyroid glands.

The true diagnostic role of instrumental methods of examination of patients with suspected primary hyperparathyroidism is small. Detection of certain indirect symptoms will still be of an auxiliary nature and will not be valid in making a diagnosis without the main laboratory criteria of the disease. At the same time, it should not be forgotten that for a significant part of patients, the impetus for targeted diagnostics is still the accidental detection of certain clinical, radiological, sonographic or densitometric signs of the disease. Therefore, in the totality of data that allow one to think about the diagnosis, it is certainly worth considering the data of ultrasound examination of the abdominal cavity and retroperitoneal space: echo-positive stones in the kidneys and urinary tract, stones in the bile ducts and gall bladder, nephrocalcinosis. Recurrent kidney stones and coral stones should be especially alarming. The frequency of primary hyperparathyroidism among their owners reaches 17%.

Although ultrasound examination of the kidneys is not considered a mandatory examination for primary hyperparathyroidism, the presence of urolithiasis, even with minor biochemical changes, will indicate a clinically expressed disease requiring surgical treatment.

Radiological examination methods for primary hyperparathyroidism include plain radiography of the chest, abdominal cavity (allow for incidental detection of consolidated rib fractures, calcification of the heart valves, pericardium and aorta, radio-positive kidney stones, so-called "brown" tumors or granulomatous growths in spongy bones - the iliac crest, ribs, vertebrae, to establish kyphoscoliotic curvature of the spine, to detect foci of metastatic calcification of soft tissues, calcification of tendons, synovial bags, joints), as well as targeted X-ray examination of skeletal bones.

The greatest experience of X-ray semiotics of primary hyperparathyroidism was accumulated during the times of the enormous prevalence of bone forms of primary hyperparathyroidism, in the pre-screening era of the first half of the 20th century. Now, when the disease is recognized mainly by laboratory methods at early stages of pathology development, the frequency of X-ray signs of hyperparathyroidism has significantly decreased. Even more unacceptable are the mistakes of radiologists who do not notice or incorrectly interpret pronounced osteodystrophic changes in the skeleton, characteristic of primary hyperparathyroidism.

In order of decreasing frequency of occurrence of radiographic changes in bones in primary hyperparathyroidism, the following are distinguished:

1. diffuse thinning of the bone cortex;
2. osteosclerosis (mainly of the pelvic bones and skull);
3. osteolysis of the nail phalanges of the hands and feet;
4. subperiosteal resorption (primarily of the radial surfaces of the middle phalanges of the fingers, the distal part of the ulna);
5. formation of bone cysts in long tubular bones and the upper and lower jaws, ribs, collarbone;
6. pathological fractures and traces of their delayed consolidation.

Radiographic signs of skeletal damage in primary hyperparathyroidism (uneven focal resorption and remodeling of the bone substance of the skull - "salt and pepper").

One of the characteristic features of severe secondary hyperparathyroidism is massive diffuse and focal deposits of insoluble calcium-phosphate compounds in soft tissues of various localizations, which can be clearly seen both on conventional planar radiography and on computed tomography. In primary hyperparathyroidism and preserved renal function, metastatic deposits of calcifications are rare due to the simultaneous decrease in the level of phosphorus in the blood with hypercalcemia.

Electrocardiographic changes characteristic of primary hyperparathyroidism and reflecting predominantly the hypercalcemic state of patients, as well as myocardial hypertrophy, also have a certain diagnostic value. Such changes in the ECG curve include shortening of the QT interval, prolongation of the PR interval, widening of the QRS complex, shortening of the ST interval, flattening or inversion of the T wave, and its widening.

The results of bone densitometric studies are of great diagnostic and prognostic importance. Tumor-like accumulation of calcium phosphates (metastatic extravascular calcification) in the hip joint of a patient with severe secondary hyperparathyroidism has acquired particular importance in the last two decades, when classical radiographic signs of bone damage have lost their relevance for most patients. Accurate noninvasive methods for assessing the osteoresorptive effect of chronic parathyroid hormone excess in such conditions help prevent serious skeletal complications, predict unfavorable development of the disease, and prevent prolongation with surgical treatment.

A method for studying bone mineral density using dual X-ray absorptiometry (DXA) has become widespread in the world. The device is a computerized complex containing two sources of X-ray radiation of different energy levels directed at areas of the patient's skeleton. After subtracting the radiation absorbed by soft tissues, the absorption of energy from each emitter by bone tissue is calculated and the final indicator of bone mineral density is calculated. This method is not only the most accurate, standardized, but also does not carry the risk of radiation due to minimal dose loads (about 1 μSv). Typically, the study is aimed at studying the mineral density of skeletal areas most susceptible to fractures due to osteoporosis (hip, vertebrae, radius), but can also measure the density of bone matter in the entire body. It is important not only to record a decrease in bone mineral density, but also to accurately assess this decrease, as well as the response of the skeletal system to treatment and the dynamics of changes when monitoring patients.

Other methods for determining bone mass and density are also known and used in practice. These include peripheral DXA (pDXA), which performs densitometry of peripheral bone fragments (fingers, wrist, heel); peripheral quantitative computed tomography (pQCT), which requires special equipment and is used mainly for research purposes to study the cortical and spongy bone substance; quantitative computed tomography on conventional equipment, but with special volumetric programs (although it involves more radiation, it can serve as an alternative to DXA); ultrasound quantitative densitometry aimed at studying distal bone fragments (calcaneus, elbow, wrist), using an approximate estimate of bone mineral density based on changes in the speed of ultrasound waves (used as a screening and evaluation method, provides a calculated indicator equivalent to the T-criterion); Radiographic absorptiometry (or photodensitometry), which uses conventional X-rays to take pictures of the bones of the fingers and then analyzes the pictures using software; Single X-ray absorptiometry (with one X-ray emitter), which is used to study the density of peripheral bone segments (calcaneus, wrist) immersed in water.

For the diagnosis and treatment of osteoporosis, only dual X-ray absorptiometry is recommended by WHO experts for clinical use.

It is important to understand the basic indicators of bone densitometry. These are the T-score and the Z-score. The T-score shows the mineral density of the bone substance of an individual when it is compared with the average indicators of a group of healthy young adult volunteers who are considered to have reached peak bone mass (usually women 30-40 years old).

The deviation from the mean, measured by the number of standard deviations in the simple distribution diagram, will determine the numerical characteristic of the T-criterion.

In 1994, a WHO working group developed a classification of osteoporosis based on the bone mineral density index obtained by dual X-ray absorptiometry. The four classification categories proposed reflect overall fracture risk over a lifetime:

• norm: bone mineral density in the proximal femur is within 1 standard deviation below the mean reference value for young adult women - T-score greater than -1;
• low bone mass (osteopenia) - T-criterion in the range of -1...-2.5;
• osteoporosis - femur T-score lower than -2.5 compared to young adult women;
• severe osteoporosis (or clinically manifested osteoporosis) - T-score less than -2.5 and one or more fragility fractures are present.

Another key indicator used in studying bone mineral density is the Z-score, which compares the state of an individual's bone matter with a relative norm selected for age, gender, and ethnic group. Thus, the Z-score allows one to evaluate how individual bone mineral density compares with the expected value for a given age and body weight.

Both T- and Z-scores are used in guidelines for the treatment of primary hyperparathyroidism. However, while the first NIH consensus (1991) suggested assessing indications for surgery based only on the T-score (less than -2), subsequent guidelines indicate the importance of also studying the Z-score for premenopausal women and men under 50 years of age.

Since the osteoresorptive effect of parathyroid hormone is most pronounced in compact bone tissue, namely in the distal part of the radius, less so in the femur, which contains an equal amount of compact and spongy tissue, and even less so in the vertebrae, it is recommended to use all three of these points for densitometry in patients with hyperparathyroidism.

The latest National Institutes of Health guidelines use a T-score of -2.5 or less for post- and perimenopausal women and men over 50 years of age when examining the lumbar spine, femoral neck, entire femur, or distal radius as criteria for determining the indication for surgery in asymptomatic primary hyperparathyroidism. For premenopausal women and men under 50 years of age, a Z-score of -2.5 or less is considered more appropriate.

[ 23 ], [ 24 ], [ 25 ], [ 26 ], [ 27 ], [ 28 ]

Imaging techniques for hyperfunctioning parathyroid glands

The last two decades have been marked by revolutionary changes in the clinical application of modern methods of imaging of the parathyroid glands. Classical parathyroidology is skeptical about the value of imaging methods for the diagnosis and improvement of the treatment of primary hyperparathyroidism. The consensus guideline for the treatment of asymptomatic hyperparathyroidism in 2002 reaffirmed the well-known postulate that the best technology for detecting the parathyroid glands is the presence of an experienced surgeon undertaking a traditional operation with revision of all four parathyroid glands.

An example of the effectiveness of such an approach can be the experience of one of the luminaries of modern endocrine surgery, J. A. Van Heerden, who cites unsurpassed results (99.5%) of surgical treatment of patients with primary hyperparathyroidism in a series of 384 consecutive operations using a traditional method over a two-year period, achieved without the use of any technical means of preoperative visualization of parathyroid adenomas.

However, the development of new imaging methods, primarily parathyroid gland scintigraphy using the radiopharmaceutical 99mTc-MIBI, provides a unique opportunity to verify the ectopic location of parathyroid adenoma before surgery, which in itself cannot fail to attract surgeons.

The following methods are used to visualize the parathyroid glands:

• Real-time ultrasonography with Doppler examination;
• scintigraphy of the parathyroid glands with various radiopharmaceuticals and isotopes;
• spiral computed tomography;
• magnetic resonance imaging;
• angiography of the vessels of the parathyroid glands;
• positron emission tomography.

The most accessible and attractive method due to the possibility of volumetric and structural examination of the pathological parathyroid gland is ultrasound examination, which is capable of detecting hyperplastic parathyroid glands larger than 5-7 mm in their cervical localization. The disadvantages of the method include its uselessness in the case of retrosternal (intrathymic or mediastinal) location of adenomas, as well as the direct proportional dependence of the success of localization on the size of the gland and the experience of the doctor. The sensitivity of the sonography method for visualizing hyperfunctioning parathyroid glands is on average 75-80% (from 40% to 86% according to various data). The specificity of the method is much lower (35-50%), due to many objective and subjective factors (the presence of an enlarged thyroid gland and nodule formation in it, autoimmune thyroiditis, cervical lymphadenitis, cicatricial changes associated with previous operations, individual features of the anatomical structure of the neck, experience and intuition of the sonographer).

The latter factor currently plays a decisive role in Ukraine. With the widespread use of ultrasound machines in large and small cities, in specialized and non-specialized institutions, the widespread "passion" of sonographers for thyroid problems with an almost complete lack of experience in diagnosing primary hyperparathyroidism and enlarged parathyroid glands remains. After all, even with the accidental detection of a suspicious parathyroid adenoma formation on the neck, thousands of new patients would be diagnosed in the country every year, given the huge number of thyroid examinations (often unfounded and useless) that are carried out in clinics, diagnostic centers and hospitals. In reality, we have to deal with long-term (sometimes for 5-10 years) ultrasound monitoring of thyroid nodules, often even with a puncture biopsy of the latter (!), which are in fact parathyroid adenomas.

The presence of constant feedback between sonographers, endocrinologists and surgeons within one specialized institution, in conditions when it is possible to follow the process of verification of the diagnosis of primary hyperparathyroidism from suspicion (according to sonography data) to laboratory and intraoperative confirmation, allows to significantly increase the competence of doctors and the efficiency of ultrasound diagnostics of enlarged parathyroid glands. It is necessary to maximally encourage the practice of intra- and inter-institutional advanced training of doctors, to refer ultrasound diagnostic doctors examining neck organs to advanced training courses in specialized endocrinology medical centers.

Ultrasound examination of the parathyroid glands is performed with the patient lying on his back with his head slightly thrown back and a small cushion under the shoulders (the latter is especially important with a short neck). A linear transducer (similar to the sensor for the thyroid gland) with a frequency of 5-7.5 MHz is used, which ensures an optimal examination depth of 3-5 cm. Scanning is performed systematically, bilaterally and comparatively for both sides. First, transverse scanning is performed, then longitudinal. Initially, the area of the typical location of the parathyroid glands is examined - from the long muscles of the neck at the back to the thyroid gland at the front and from the trachea medially to the carotid arteries laterally.

The examination then continues in broader boundaries, covering the submandibular areas, vascular bundles of the neck and the anterior-superior mediastinum (for this, the sensor is maximally immersed in the jugular notch). On the left, it is necessary to examine the paraesophageal space, for which the patient's head is turned in the opposite direction. Both the linear dimensions of the parathyroid glands and their shape, echogenicity, homogeneity and location are studied. At the end, the study is supplemented with color Doppler mapping to assess vascularization, interposition with large vessels. In addition, the structure of the thyroid gland, the presence of focal formations in it, and possible intrathyroid location of the parathyroid glands are studied.

In typical cases, the ultrasound picture of a single parathyroid gland adenoma is quite characteristic and has a number of specific signs. An experienced researcher can not only detect a parathyroid adenoma (or significant hyperplasia) and differentiate it from thyroid gland nodes and lymph nodes of the neck, but also determine its probable belonging to the upper or lower parathyroid glands. Moreover, the latter issue is resolved not so much by the height of the pathological substrate along the longitudinal axis of the thyroid gland as by spatial relationships with the posterior surface of the thyroid gland, trachea and esophagus.

Adenomas originating from the upper parathyroid glands are usually located at the level of the upper two-thirds of the thyroid lobe, adjacent to its posterior surface, often occupying the space between the lateral surface of the trachea and the posteromedial surface of the thyroid gland. In this case, the parathyroid adenoma is formed by the pressure of these neighboring organs and, being much softer and more delicate than them in consistency, acquires polygonal-irregular outlines (usually triangular, sometimes rounded with constrictions from nearby vessels or the recurrent laryngeal nerve, usually located along the ventral surface of such an adenoma).

A typical sonographic picture of a parathyroid adenoma is a small (1-2 cm), clearly defined hypoechoic formation of irregular ovoid shape with increased intraglandular blood flow, located behind the thyroid gland, separated from it by a fascial layer. Adenoma (hyperplasia) of the parathyroid gland is characterized by very low echogenicity, which is always lower than the echogenicity of the thyroid gland, sometimes almost indistinguishable from the echogenicity of a cystic fluid formation. The echo structure of parathyroid tissue is very delicate, fine-grained, often absolutely homogeneous.

Exceptions are long-standing adenomas with secondary changes (sclerosis, hemorrhages, calcifications) or malignant tumors, which are usually large (over 3-4 cm) and accompanied by clinical features of severe hypercalcemia. Difficulties may arise in differentiating intrathyroid adenoma of the parathyroid gland and thyroid nodes.

It should also be remembered that the natural migration of adenomas of the upper parathyroid glands occurs in the direction of the upper posterior mediastinum, on the left - along the tracheoesophageal groove, on the right - retrotracheally in front of the spine. Lower adenomas migrate to the anterior superior mediastinum, located in a more superficial plane in relation to the anterior chest wall.

Pathologically enlarged inferior parathyroid glands are usually located near the lower poles of the thyroid gland, sometimes along the posterior, sometimes along the anterolateral surface.

In 40-50% of cases, they are located in the thyrothymic tract or upper poles of the thymus. In general, the more superficial the adenoma, the more likely it is to originate from the lower parathyroid glands.

Puncture biopsy of parathyroid gland adenomas is an undesirable element of patient examination due to possible parathyroidism (semination of tumor cells) of the surrounding tissue. However, if such a study was conducted (differentiation with thyroid nodules), then the probable similarity of the cytological picture with colloid or atypical (suspicious for cancer) thyroid nodules should be taken into account. The differentiating criterion in such cases would be staining for thyroglobulin or parathyroid hormone, but the real possibilities of such studies are very limited and require at least an initial suspicion of hyperparathyroidism.

The second most frequently used and first in diagnostic imaging capabilities is radioisotope scintigraphic examination of the parathyroid glands using the radiopharmaceutical 99mTc-MIBI.

Previously, in the 80-90s of the 20th century, the study of parathyroid glands with the isotope thallium (201T1) was used independently or in the image subtraction method together with scintigraphy with 99mTc with a sensitivity of about 40-70%. With the discovery in the early 1990s of the selectivity of absorption by parathyroid tissue of the radiopharmaceutical 91raTc-M1B1 - an isotope of technetium combined with methoxy-isobutyl-isonitrile (a cationic lipophilic derivative of isonitrile), other isotopic preparations lost their significance. Scintigraphy with 99rаTc-MGB1 has a certain functional character, although it is not absolutely specific for parathyroid tissue, since the organically bound isotope has tropism for other tissues with high mitochondrial activity (in the neck area - these are the thyroid and parathyroid glands, salivary glands). The images obtained during scanning can be a static planar picture or be combined with computed tomography (the so-called single-photon emission computed tomography - SPECT), which gives a three-dimensional image.

To obtain an image of the parathyroid glands, either a two-phase protocol or a dual-isotope (subtraction, based on image subtraction) protocol is used. The two-phase protocol is based on different rates of isotope washout from the thyroid and parathyroid glands. Static images are taken at 10-15, 60 and 120 minutes of the study after intravenous administration of 740 MBq 99gaTc-M1B1. A positive result is considered to be the retention of the isotope in the zone of possible localization of parathyroid adenoma on delayed images. It is important to take images at both the 60th and 120th minutes (in Ukraine, only the 120-minute interval is mainly used), since the isotope washout rate can vary significantly (Fig. 10.14).

The subtraction protocol of scintigraphy is based on "subtraction" from the image obtained using 99mTc-MIBI (accumulates both by the thyroid and parathyroid glands) of the thyroid gland image obtained using a triple isotope only to it - it is preferable to use iodine-123 (in Ukraine, due to the high cost of the latter, technetium-99m-sodium pertechnetate is used). For this purpose, 12 MBq of iodine-123 is initially prescribed 2 hours before the examination. Two hours later, the first scan is performed, then 740 MBq of 99mTc-MIBI is administered and the scan is repeated. The image is assessed after "subtraction" of the images normalized by the patient's position. The accumulation focus obtained after "subtraction" is considered positive.

SPECT (or OREST) examination can be performed with both scintigraphy protocol options 45 minutes after the 99mTc-MIBI injection. Scanning covers not only the neck area, but also the mediastinum and chest area. A huge advantage of the method is the ability to assess the relative position of the thyroid and parathyroid glands, as well as foci of ectopic accumulation of the isotope with their precise reference to anatomical structures.

“Posterior” location of the isotope accumulation focus relative to the frontal plane of the thyroid gland on the scintigram, corresponding to the superior parathyroid gland

The foci of local accumulation of the isotope are classified as posterior and anterior (in relation to the posterior surface of the thyroid gland), which is more informative. The frontal plane passing through the apex of the lower pole of the thyroid gland separates the posterior (almost always correspond to the upper parathyroid glands) foci of isotope uptake from the anterior (more often correspond to the lower parathyroid glands.

Serial images in the EFECT study are significantly more accurate than planar scintigraphy.

The use of parathyroid scintigraphy becomes especially important in cases of repeated neck surgery, after one or more unsuccessful attempts at surgical treatment of primary hyperparathyroidism, in cases of relapse of the latter, or in cases of suspected metastasis of parathyroid carcinoma.

The efficiency of the method reaches 80-95%, but it decreases significantly with low hormonal activity and adenoma size, with hyperplasia of the parathyroid glands or damage to several glands. Thus, the sensitivity for detecting single parathyroid adenomas reaches 95-100%, with hyperplasia of the gland it decreases to 50-62%, and with multiple adenomas - to 37%. It is necessary to remember the possibility of false-negative data with a double adenoma, when a large and more active tumor dominates the image and imitates a single lesion, although the correct detection of double adenomas is not uncommon.

Currently, studies are being conducted on other radiopharmaceuticals that promise greater diagnostic efficiency compared to 99mTc-MIBI - these are compounds of technetium-99m with tetrofosmin and furifosmin, but they have not yet been introduced into clinical practice.

Other imaging methods have significantly lower sensitivity, significantly lower specificity and are used mainly when the above methods are ineffective.

Thus, spiral multidetector computed tomography using 3 mm slices and intravenous contrast enhancement (it is necessary to remember the difficulty of subsequent radioisotope examination of the thyroid gland).

Magnetic resonance imaging has no significant advantages over computed tomography and is used less frequently. Its disadvantages, as with computed tomography, include the appearance of artifacts associated with swallowing, breathing, and other patient movements, as well as low specificity of the results. Typically, parathyroid adenomas demonstrate increased signal intensity with T2-weighting and isointensity with T1-weighted signal. Signal enhancement is possible with gadolinium contrast.

Angiography of the vessels that feed the parathyroid glands is used casuistically rarely and mainly in cases of unsuccessful localization of a recurrent or persistent tumor (sometimes together with blood sampling to determine the comparative concentration of parathyroid hormone from the right and left jugular veins to localize the side of the lesion).

The positron emission tomography (PET) method has demonstrated extraordinary popularity and promise in recent years. Already in the first comparative studies with 11T-fluorodeoxyglucose (FDG), it showed higher sensitivity compared to scintigraphy, as well as with the use of n-O-methionine. The high cost of the study remains an obstacle to the widespread introduction of the PET method.

In the last few years, there have been reports about the possibility of combining (computer fusion) images obtained using several visualization methods - scintigraphy, computed tomography, PET, angiography, sonography. Such a "virtual" image, according to a number of authors, has made it possible to significantly increase the effectiveness of treating relapses of primary hyperparathyroidism.

In addition to the previously mentioned advantages of correct preoperative localization of pathologically altered parathyroid glands, it should be mentioned that positive and coinciding (ultrasound + scintigraphy) results of visualization studies are an indispensable condition for performing minimally invasive surgical interventions for primary hyperparathyroidism, which have become so popular in the last decade (in specialized clinics, these operations account for 45-80% of all interventions).

Treatment primary hyperparathyroidism

The lack of an effective alternative to surgical treatment of primary hyperparathyroidism, as well as the destructive effect of the disease on many body systems during its long course, make surgery the only correct tactical option for managing patients after diagnosis. This is also facilitated by advances in improving the technique of surgical treatment of primary hyperparathyroidism, a high level of cure (up to 99%) and a low risk of complications.

The surgeon's experience in operations on the parathyroid glands, as 80 years ago (during the establishment of parathyroid surgery), remains the main factor determining the success of surgical intervention. This is clearly illustrated by the following statements by the leading figures in the study of primary hyperparathyroidism.

"The success of parathyroid surgery must depend on the surgeon's ability to recognize the parathyroid gland when he sees it, to know the likely sites of hidden glands, and to have a delicate operating technique that will enable him to apply this knowledge."

"Detection of parathyroid adenoma by an experienced parathyroid surgeon is more effective than the use of preoperative imaging tests; parathyroidectomy should be performed only by the most experienced surgeons who are experts in the field, and they have the responsibility of training the next generation of experts in parathyroid surgery."

"Parathyroid surgery requires the participation of only a highly experienced specialist in this field, otherwise the frequency of unsuccessful operations and the level of complications will be unacceptably high."

The goal of surgical intervention is the removal of one or more pathologically enlarged parathyroid glands, ensuring the restoration of constant normocalcemia. The operation should be accompanied by the minimum possible trauma to the surrounding tissues and normal parathyroid glands.

Despite the obvious advantages of rapid and effective surgical treatment of primary hyperparathyroidism, the issue of a balanced determination of indications for surgery remains relevant for a number of patients. The reason for this is a number of circumstances: an increasing number of low-symptom or asymptomatic cases of the disease, its very slow progression in 2/3 of patients with an asymptomatic variant of the disease, potential (albeit low) risks of surgical intervention and anesthesia, which may increase in intercurrent pathological conditions. The significance of this aspect of the problem is confirmed by three international consensus guidelines for the management of patients with asymptomatic primary hyperparathyroidism, prepared under the auspices of the US National Institute of Health (NIH) and published in 1991, 2002 and 2009. Of course, for Ukraine this issue is not so acute today, because mainly still quite pronounced cases of the disease are detected, often in an advanced state, when there are no alternatives to surgical treatment. However, with the widespread introduction of screening for primary hyperparathyroidism, we will inevitably be faced with the fact that there are a large number of patients with “mild” forms of the disease, for whom the risk of surgery, due to age-related or other health problems, may be higher than the potential benefits of surgical treatment.

Indications for surgery

The operation is indicated for all clinical symptomatic forms of primary hyperparathyroidism, that is, for laboratory-confirmed disease with typical clinical manifestations or consequences of long-term hypercalcemia or elevated parathyroid hormone levels.

We have already discussed clinical manifestations in the relevant section. It should only be recalled that with a thorough questioning and examination of the patient, registration of subtle disturbances of the psychoneurological state, there will be very few cases of true asymptomatic variants of the disease.

Pregnancy is not a contraindication to surgical treatment. It is preferable to operate in the second trimester, but in case of severe hypercalcemia, the gestational age does not matter due to the transplacental negative effect of high calcium levels and the risk of complications for the fetus (80%), the threat of miscarriage, labor weakness and other complications for the mother (67%). Surgery in the last weeks of pregnancy is indicated in case of critical hypercalcemia with simultaneous consideration of the issue of delivery by cesarean section.

The higher the blood calcium level, the more urgent the surgery should be, since predicting the development of a hypercalcemic crisis, a potentially fatal complication, is very difficult.

Patients with severe renal impairment should be operated on in conditions where hemodialysis is possible due to the risk of temporary deterioration of renal filtration.

In choosing treatment strategies for patients with truly asymptomatic primary hyperparathyroidism, one should rely on the recommendations of an international working group first convened under the auspices of the US National Institutes of Health in 1990. A third revision of these guidelines, held at a meeting in 2008, was published in 2009. It will be interesting to follow trends in the treatment of asymptomatic hyperparathyroidism over the past 20 years by comparing previous and current guidelines.

The authors repeatedly emphasize in these recommendations that only surgical treatment is exhaustive and final, therefore, when choosing observational treatment tactics, it is important not only to strictly adhere to the proposed criteria, but also to take into account the need for regular monitoring of the main indicators (calcium level, parathyroid hormone, glomerular filtration rate or creatinine clearance, as well as the dynamics of bone mineral density), at least once a year.

In addition, it should be emphasized that for patients younger than 50 years, surgery is always preferable, since a steady decrease in bone mineral density with an increasing risk of fractures and a lifelong risk of developing other irreversible systemic changes is more relevant for patients of this age. Another serious criterion is the degree of hypercalcemia. A calcium level exceeding the upper limit of normal by more than 0.25 mmol / l (i.e. > 2.8 mmol / l) is incompatible with the concept of asymptomatic primary hyperparathyroidism and the choice of a treatment strategy other than surgery.

Particular attention is paid to the characteristics of renal function. In accordance with the K/DOQI recommendations, it was decided to regard the value of the estimated glomerular filtration rate less than 60 ml/min (i.e. stage 3 chronic kidney disease) as a serious argument in favor of surgery, despite the fact that the causes affecting renal function may be associated not only with hyperparathyroidism.

The most substantiated provisions seem to be those concerning the necessity of surgery in case of osteoporosis progression in primary hyperparathyroidism. They are based on several randomized controlled studies confirming the opinion that progressive decrease in bone mineral density is observed also in mild asymptomatic primary hyperparathyroidism, and on the other hand, that only surgery can stop the development and lead to regression of osteoporosis in such a disease as primary hyperparathyroidism.