Primary hyperparathyroidism: clinical guidelines

List of Abbreviations

25(OH)D – 25-hydroxyvitamin D, calcifediol

1,25(OH)2D – 1,25-dihydroxyvitamin D, calcitriol

SHPT – secondary hyperparathyroidism

GI – gastrointestinal tract

CT – computed tomography

MIP – minimally invasive parathyroidectomy

ICD-10 – International Classification of Diseases, 10th Revision

BMD – bone mineral density

MRI – magnetic resonance imaging

MSCT – multislice computed tomography

MEN – multiple endocrine neoplasia syndrome

nPHPT – normocalcemic variant of primary hyperparathyroidism

PG – parathyroid gland

SPECT - single-photon emission computed tomography

SPECT/CT - single-photon emission computed tomography combined with (X-ray) computed tomography.

PHPT – primary hyperparathyroidism

ROD – renal osteodystrophy

PTH – parathyroid hormone

iPTH – intact parathyroid hormone

PTX – parathyroidectomy

PET – positron emission tomography

RP – radiopharmaceutical, diagnostic radiopharmaceuticals

GFR – glomerular filtration rate

tHPT – tertiary hyperparathyroidism

US – ultrasound examination

CKD – chronic kidney disease

TG – thyroid gland

Ca⁺⁺ - ionized calcium

CaSR – calcium-sensing receptor

FHH – familial hypocalciuric hypercalcemia

UCCR - urine calcium-to-creatinine clearance ratio

Terms and Definitions

Hyperparathyroidism is an endocrine disorder caused by excessive production of parathyroid hormone (PTH) by the parathyroid glands (PTG).

Primary hyperparathyroidism is an endocrine disorder characterized by excessive PTH secretion in the presence of upper-normal or elevated blood calcium levels due to primary pathology of the parathyroid glands.

Secondary hyperparathyroidism is a condition characterized by increased functional activity of the parathyroid glands due to various diseases or certain medications that impair calcium-phosphate homeostasis (chronic hypocalcemia, hyperphosphatemia, hypomagnesemia, 25(OH)D deficiency, or impaired synthesis of 1,25(OH)₂D), leading to compensatory hyperplasia in the absence of adequate treatment.

Tertiary hyperparathyroidism is an endocrine disorder developing as a result of long-standing secondary hyperparathyroidism and characterized by autonomous PTH secretion due to persistent hyperfunction of one or more parathyroid glands, despite the elimination of its causes, including successful renal transplantation.

Hypercalcemia is an elevated level of total and/or ionized calcium in the blood.

Hypercalcemic crisis is a severe, life-threatening condition that develops acutely in patients against the background of a rapid and sharp increase in blood calcium levels (the risk of a hypercalcemic crisis increases significantly when blood calcium exceeds 3.5 mmol/L).

Hypercalciuria is an increased urinary calcium excretion.

Insipidus syndrome is a condition characterized by polydipsia, polyuria, and low urine specific gravity (less than 1010 g/L).

Nephrocalcinosis is the diffuse deposition of calcium salts within renal epithelial cells, accompanied by inflammatory and sclerotic changes.

Nephrolithiasis is the presence of calculi in the renal pelvicalyceal system.

Osteoporosis is a chronic systemic metabolic skeletal disease characterized by reduced bone mass, microarchitectural deterioration of bone tissue, and consequently, fractures from minimal trauma.

Osteitis fibrosa cystica (osteitis fibrosis cystica, von Recklinghausen's disease, parathyroid osteodystrophy) is a skeletal disorder caused by hyperfunction of the parathyroid glands and excessive PTH secretion, manifested by excessive osteoclastic resorption, fibrous degeneration of the bone marrow, and generalized osteoporosis, leading to pathological fractures, skeletal deformity with cyst formation ("brown tumors").

Renal osteodystrophy (ROD) is a broad spectrum of bone disorders resulting from chronic kidney disease, including ROD with high bone turnover (fibrous osteitis and mixed osteodystrophy), ROD with normal bone turnover, ROD with low bone turnover (adynamic bone disease and osteomalacia); a component of the mineral and bone disorder syndrome in chronic kidney disease.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Primary hyperparathyroidism (PHPT) is an endocrine disorder characterized by excessive PTH secretion with upper-normal or elevated blood calcium levels due to primary pathology of the parathyroid glands. PHPT manifests with multiorgan disorders of varying severity and, as a result, can lead to a significant decrease in quality of life, patient disability, and an increased risk of premature death [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

PHPT is caused by a solitary parathyroid adenoma in 85–90% of cases, multiple adenomas or hyperplasia of several/all parathyroid glands in 5–10% of cases, and parathyroid carcinoma in 1%. In 90–95% of cases, PHPT is sporadic, while about 5–10% are hereditary forms that manifest as isolated parathyroid pathology or occur in combination with other components of genetically determined syndromes [2].

The pathogenesis of parathyroid tumors is insufficiently studied; the literature discusses the influence of certain proto-oncogenes and tumor suppressor genes on the development of parathyroid lesions. Chronic vitamin D deficiency and enhanced its inactivation in the liver are considered as putative mechanisms triggering hyperplasia with subsequent transformation into a parathyroid adenoma {Artemova, 2010 #627} [3]. The constant demand for PTH hypersecretion presumably induces the conversion of proto-oncogenes into oncogenes or the inactivation of proliferation suppressor genes. Tumor formation is often a multistep process during which cells acquire mutations/deletions in one or more genes; the involvement of epigenetic factors cannot be excluded. Most neoplasms are monoclonal, implying their origin from a single abnormal cell. In some cases of sporadic PHPT, key somatic oncogenic events may occur—somatic mutations in the MEN1, CDC73, CASR genes or cyclin-dependent kinase inhibitors CDKIs, leading to tumor transformation of the tissue. High-throughput sequencing (NGS) studies have shown that somatic MEN1 mutations underlie the formation of sporadic parathyroid adenomas in 35% of cases, and somatic mutations in other genes, e.g., EZH2, POT1, are identified in only 10% [4].

PHPT accompanied by parathyroid hyperplasia or multiple adenomas is typically associated with hereditary syndromes and can be caused by mutations in various genes. Multiple endocrine neoplasia type 1 (MEN-1) syndrome is associated with mutations in the tumor suppressor gene MEN1; MEN-2 syndrome is associated with mutations in the RET proto-oncogene; MEN-4 syndrome develops due to a mutation in the cyclin-dependent kinase inhibitor CDKN1B [5]. Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is associated with mutations in the CDC73 gene encoding the parafibromin protein [6]. Familial isolated hyperparathyroidism (FIHP) is a rare autosomal dominant disorder characterized by the development of tumors in one or more parathyroid glands and the absence of other endocrine and non-endocrine neoplasms, and sometimes it may represent an incomplete variant of other syndromes (MEN-1, HPT-JT). FIHP can be associated with mutations in the MEN1, CASR, and CDC73 genes [7]. Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous disorder caused by mutations in the CASR, Gα11, AP2S1 genes, requiring differential diagnosis with PHPT. [5]. For parathyroid carcinomas, mutations in the CDC73 gene (about 50% of cases) and PRUNE2 mutations (18%) have been described [8].

1.3 Epidemiology of the Disease or Condition

Until the mid-1970s, PHPT was considered a rare disorder of calcium-phosphate metabolism manifesting with severe clinical symptoms involving the kidneys (recurrent nephrolithiasis), the skeletal system (pathological fractures, skeletal deformity, osteitis fibrosa cystica), and the gastrointestinal tract (GIT, recurrent gastric and duodenal ulcers). According to a major epidemiological study conducted in 1965–1974 at the Mayo Clinic in Rochester, USA, the incidence of PHPT averaged 7.8±1.2 cases per 100,000 population [9].

Over the past decades, there have been significant changes in the understanding of the epidemiology of the disease. A sharp increase in PHPT detection rates has been noted, partly due to asymptomatic forms not accompanied by severe hypercalcemia. These changes are primarily driven by the advent of automated biochemical analyzers and the widespread implementation of routine blood calcium testing in North America, Western Europe, and China. In the general population, the prevalence of PHPT averages 0.86–1% [10]. It should be noted that the results of epidemiological studies remain variable due to differences in PHPT diagnostic criteria and the methodology of calcium biochemical screening. PHPT can occur in all age groups, including children and adolescents. However, cumulative evidence indicates that the incidence of PHPT increases with age, and the mean age at diagnosis is 54–59 years [11]. The majority of patients with sporadic PHPT are postmenopausal women, with the onset of the disease occurring within the first decade after menopause. The male-to-female ratio averages 1:3 [11].

The most objective data on the prevalence of primary hyperparathyroidism (PHPT) are provided by large-scale epidemiological studies conducted in Sweden between 1976 and 2002, and a 10-year prospective population-based study in a Scottish county among all residents over 20 years of age [12-15]. According to Swedish studies, the prevalence of PHPT among adults of both sexes over 18 years of age was approximately 1% of the entire adult population, increasing to 2.1% in postmenopausal women (aged 55-75 years). The 10-year Scottish population study registered 2,709 new cases of PHPT: 1,918 women (71%) and 791 men (29%). The vast majority of cases were diagnosed in individuals over 40 years of age. The peak incidence occurred between 60 and 70 years, confirming an increased risk of the disease with age. The female-to-male ratio increased from 2 (at age 40-49) to 4 (at age 80 and older). Consequently, the incidence of PHPT ranged from 4.13 to 11.3 cases per 10,000 person-years across different years [14]. In a recent epidemiological study of PHPT in California analyzing data from 15,234 patients with chronic hypercalcemia, PHPT was found to be the cause of elevated serum calcium in 87% of observations. The prevalence of PHPT averaged 34-120 cases per 10,000 among women and 13-36 cases among men. A significant increase in overall incidence and a female predominance were observed with age; furthermore, the authors identified a statistically significant difference in disease frequency depending on ethnicity (highest prevalence noted in African Americans, p<0.0001) [16]. Thus, primary parathyroid pathology remains the primary etiological factor of hypercalcemia. It should be noted that malignant neoplasms are the second leading cause of hypercalcemia. In more than 50% of cases, paraneoplastic hypercalcemia is caused by breast cancer with distant bone metastases. Hypercalcemia is also observed in lung and kidney cancers, as well as hemoblastomas (multiple myeloma, lymphomas, Hodgkin's lymphoma, leukemias). Elevated serum calcium develops as a result of metastatic skeletal involvement, as well as local activation of bone resorption due to metastasis-derived cytokines such as tumor necrosis factor and interleukin-1, or humoral osteoclast activators, particularly PTH-related peptide.

In the Russian Federation, hypercalcemia is diagnosed with a delay in the majority of patients because calcium testing is not included in routine general clinical blood chemistry panels. This creates conditions for late detection of hyperparathyroidism. According to Order No. 1006n of the Russian Ministry of Health dated December 3, 2012, "On Approval of the Procedure for Preventive Medical Examination of Certain Groups of the Adult Population," the general clinical biochemical blood test includes only the determination of total protein, albumin, creatinine, total bilirubin, aspartate aminotransferase, alanine aminotransferase, glucose, cholesterol, sodium, and potassium.

No large-scale epidemiological studies have been conducted in the Russian Federation. Pilot blood calcium screening studies were carried out between 2005 and 2017 in independent samples of adult residents from four Russian regions differing in ecological and social conditions (Surgut n=191 [Group 1], Irkutsk n=243 [Group 2], Moscow n=499 [Group 3], Moscow Region n=675 [Group 4]). The frequency of hypercalcemia across the groups was 9%, 5%, 3%, and 1% of cases, respectively, averaging approximately 3% (51/1608). These results are consistent with American epidemiological data, where elevated serum calcium was detected in 2.7% of cases.

According to the Russian National Register of Patients with PHPT as of December 2017, the detection rate of the disease in the Russian Federation was 1.3 cases per 100,000 population. Patients from Moscow and the Moscow Region accounted for 2/3 of the database. In Moscow, the detection rate of PHPT increased to 7.6 cases per 100,000 population (compared to 5.6 cases in 2016 and 4 cases per 100,000 population in 2010). In the Moscow Region, the detection rate of PHPT also increased, reaching 6.1 cases per 100,000 population by December 2017 (compared to 0.25 cases in 2014). Despite the increased prevalence, these data do not correspond to the frequency of hypercalcemia found in adult population calcium screening pilots. Manifest forms of PHPT predominated, accounting for 67% of cases, whereas asymptomatic disease was observed in 33%, whereas in countries of Europe and North America by 2004 the frequency of manifest forms did not exceed 20% [448].

1.4 Features of Coding the Disease or Condition

Hyperparathyroidism and other parathyroid disorders (E21):

• E21.0 Primary hyperparathyroidism

• E21.2 Other forms of hyperparathyroidism

• E21.3 Hyperparathyroidism, unspecified

• E21.4 Other specified parathyroid disorders

• E21.5 Disorder of parathyroid gland, unspecified

• D35.1 Benign neoplasm of parathyroid gland

• C75.0 Malignant neoplasm of parathyroid gland

1.5 Classification of the disease or condition

Forms of hyperparathyroidism are presented in Table 1.

Table 1. Forms of hyperparathyroidism

Symptomatic (manifest) PHPT is characterized by the presence of "classic" manifestations of the disease, which include bone disorders (osteoporosis, low-trauma fractures, and osteitis fibrosa cystica) and visceral disorders (nephrolithiasis, peptic ulcer disease of the upper gastrointestinal (GI) tract). The definition of the asymptomatic form of the disease is currently under development, as the issue of "non-classic" manifestations of PHPT, particularly regarding the neurocognitive and cardiovascular systems, remains open. This is primarily because the results of available randomized trials evaluating the effect of parathyroidectomy (PTX) on these pathological changes do not allow for a definitive conclusion regarding the contribution of PTH to cardiovascular remodeling and cognitive function impairments [2, 10]. Furthermore, studies have shown that upon careful questioning, "asymptomatic" patients report non-specific complaints in more than 90% of cases (general weakness, fatigue, decreased performance and mood, tendency to constipation, etc.). Given the non-specific nature of these changes, they are difficult to classify and can be attributed either to age-associated conditions or symptoms of other diseases, or to manifestations of PHPT.

Currently, patients with asymptomatic PHPT (previously classified as the mild form) are defined as individuals lacking specific disease manifestations, in whom diagnosis typically occurs during routine calcium screening. In European and North American countries, asymptomatic PHPT is the most common form of the disease, accounting for up to 80% of all cases. To date, it has not been definitively established whether asymptomatic PHPT represents the early stage of the disease or a distinct clinical form. A number of studies indicate the possibility of a prolonged benign course of asymptomatic PHPT in the majority of patients. However, some patients experience disease progression over time with the development of specific symptoms [11].

The most frequently diagnosed is the hypercalcemic variant of PHPT, characterized by elevated serum calcium levels combined with elevated (rarely high-normal) PTH levels. However, PHPT is not always accompanied by blood calcium levels exceeding the upper limit of the reference range. Normocalcemia can be transient in the hypercalcemic variant and persistent in the normocalcemic variant of the disease. The normocalcemic variant of PHPT (nPHPT) is characterized by consistently upper-normal total and ionized serum calcium levels combined with a persistently elevated PTH level, in the absence of obvious causes of secondary hyperparathyroidism (vitamin D deficiency, liver and kidney pathology, malabsorption syndrome, hypercalciuria, etc.) [11, 17]. The classification of PHPT is presented in Fig. 1.

Fig. 1 Classification of PHPT

1.6 Clinical presentation of the disease or condition

The development of the clinical presentation of PHPT is primarily due to the pathological effects of elevated PTH and blood calcium levels. In most cases, symptomatic PHPT is accompanied by "classic" manifestations, which include musculoskeletal disorders (osteoporosis, osteitis fibrosa cystica, bone deformations, fractures, gait disorders), renal pathology (nephrolithiasis/nephrocalcinosis, decreased renal filtration and concentration functions), and less commonly gastrointestinal disorders (recurrent defects of the duodenal and gastric mucosa, pancreatitis, pancreatic calcifications - pancreolithiasis). In addition, cardiovascular changes are detected (arterial hypertension, left ventricular myocardial hypertrophy and left ventricular diastolic dysfunction, cardiac rhythm and conduction disorders), which are directly dependent on intact PTH (iPTH) levels, calcium-phosphorus metabolism disorders, and renal filtration function, as well as neurocognitive disorders [18–22]. Nevertheless, there is still insufficient data to consider neurocognitive and cardiovascular disorders as characteristic clinical manifestations of PHPT, although a number of studies have shown improvement in these symptoms after parathyroidectomy.

According to the literature, PHPT may be an additional risk factor for obesity, lead to an increased risk of insulin resistance and type 2 diabetes mellitus, proatherogenic blood lipid profile disorders, and secondary hyperuricemia [23–25].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for diagnosing the hypercalcemic form of PHPT based on laboratory test results: hypercalcemia combined with a persistent elevation of PTH (excluding familial benign hypocalciuric hypercalcemia), hypercalcemia combined with a high-normal PTH level (at the upper limit of the reference interval, but not exceeding it).

• It is recommended to establish the diagnosis of the hypercalcemic form of PHPT in patients with hypercalcemia combined with a persistent elevation of PTH or a high-normal PTH level (at the upper limit of the reference interval, but not exceeding it), after excluding familial benign hypocalciuric hypercalcemia, in order to make a decision on additional examination and choose the optimal treatment tactics [26–28].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Criteria for diagnosing the normocalcemic form of PHPT based on laboratory test results, provided that they are determined at least twice within an interval of 3–6 months: persistent normocalcemia (retention of albumin-corrected and ionized calcium values within the reference range), elevated iPTH level after excluding possible secondary causes of hyperparathyroidism, normocalciuria.

• It is recommended to establish the diagnosis of the normocalcemic form of PHPT in patients meeting the following criteria [29–42] in order to decide on additional examination and choose optimal treatment tactics:

• persistent retention of albumin-corrected and ionized calcium values within the reference range over the entire observation period with an elevated iPTH level (determined at least twice at an interval of 3–6 months);

• exclusion of possible secondary causes of hyperparathyroidism (primarily vitamin D deficiency/insufficiency (25(OH)D ≥ 30 ng/mL) and CKD (GFR ≤ 60 mL/min));

• absence of hypercalciuria.

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comments: in a number of patients with PHPT, the total blood calcium level may remain within the reference range while the level of its ionized fraction is elevated, which is also considered hypercalcemia and does not meet the criteria for diagnosing nPHPT [29]. Thus, determining Ca⁺⁺ will help avoid diagnostic errors, but not all clinical laboratories have the necessary equipment. In such cases, it is necessary to focus on albumin-corrected calcium indices. To verify nPHPT, normocalcemia and elevated PTH levels must be detected in at least two subsequent measurements over 3–6 months [30, 31].

In addition to vitamin D deficiency/insufficiency [32, 33] and CKD (GFR ≤ 60 mL/min) [34, 35], other secondary causes of hyperparathyroidism must also be excluded: medications affecting calcium/PTH levels (bisphosphonates (M05BA), #denosumab**, lithium preparations) [39–42]; hypercalciuria [36]; gastrointestinal diseases causing malabsorption [37, 38].

2.1 Complaints and Anamnesis

• The determination of total blood calcium is recommended for patients who have one or more of the following clinical conditions and/or signs, in order to make a decision on further examination to exclude or verify PHPT:

• clinical symptoms of hypercalcemia, including diabetes insipidus-like syndrome (polyuria/nicturia/polydipsia not caused by diabetes mellitus or diabetes insipidus); nausea, vomiting, decreased appetite, dehydration [43, 44];

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• osteoporosis or a history of prior low-energy fractures (especially femoral neck fractures, distal forearm fractures), clinical manifestations of osteitis fibrosa cystica, including skeletal deformations, rib pain [45–49];

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

• nephrolithiasis (especially recurrent), nephrocalcinosis [49–55];

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

• recurrent gastric or duodenal ulcer disease, calculous pancreatitis [56–58].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: clinical manifestations of PHPT in most cases are due to hypercalcemia. Mild hypercalcemia (total serum calcium <3 mmol/L (12 mg/dL)) can remain asymptomatic for a long time or manifest as nonspecific complaints, such as general and muscular weakness, fatigue, and depressed mood. Moderate hypercalcemia (total serum calcium >3–3.5 mmol/L (12–14 mg/dL)) in a chronic course may occur with minimal symptoms. Rapidly progressing hypercalcemia may be accompanied by clinical deterioration in the form of symptoms such as polyuria, polydipsia, dehydration, decreased appetite, nausea, and muscular weakness. Patients with severe hypercalcemia (total serum calcium >3.5 mmol/L (14 mg/dL)) have a high risk of hypercalcemic crisis [59, 60]. When taking a medical history, it is necessary to consider the intake of medications affecting calcium-phosphorus metabolism (see Section 7.4).

Nephrolithiasis is one of the main complications of PHPT, so it is necessary to consider a history of spasmodic lumbar pain attacks (renal colic) with nausea, vomiting, changes in urinary sediment, leukocyturia, and hematuria. In 10% of cases, symptomatic nephrolithiasis in PHPT may be characterized by a recurrent course with frequent attacks of renal colic [55, 61]. According to recent studies, the frequency of symptomatic nephrolithiasis in the cohort of patients with PHPT has significantly decreased, but with the use of imaging methods (ultrasound, computed tomography (CT) of the kidneys and adrenal glands), "silent" forms of the disease (asymptomatic nephrolithiasis/nephrocalcinosis) are diagnosed more often [62]. An analysis of the examination results of a cohort of patients with nephrolithiasis (5 large studies, n=5927) demonstrated that the prevalence of PHPT in this population can significantly exceed general population values and reach 3.2–5% [50–54].

Fibrostitis cystica belongs to severe bone disorders characteristic of symptomatic (manifest) PHPT and is accompanied by pronounced bone pain, skeletal deformations, and pathological fractures. Currently, osteitis fibrosa cystica is diagnosed significantly less frequently, nevertheless, patients may report prior low-energy fractures. In asymptomatic PHPT, skeletal pathological changes are verified, as a rule, upon a decrease in bone mineral density (BMD) according to X-ray densitometry [2, 63]. Available data indicate that PHPT is more frequently detected among older patients with a hip fracture compared to individuals with osteoporosis (diagnosed by X-ray densitometry) but without a fracture (n=888, 4.7% vs. 1.13%) [45]. When examining postmenopausal women (n=119), PHPT is detected in 6.7% of cases in the presence of a history of distal forearm fracture [46].

A thorough medical history regarding other symptoms associated with PHPT is required, including gastric and duodenal ulcer, gastroesophageal reflux disease, and acute pancreatitis, which are more frequently associated with moderate and severe hypercalcemia [64]. Recurrent upper GI peptic ulcers were previously considered frequent complications of PHPT. Currently, they are encountered significantly less frequently and are more characteristic of young patients with multiple endocrine neoplasia syndromes and concomitant gastrin-producing tumors. The results of studies on the pathogenetic relationship between PTH-mediated hypercalcemia and increased gastrin and gastric acid secretion remain controversial [65-67].

Musculoskeletal manifestations, including proximal muscle weakness and atrophy, are currently rare, but many patients with PHPT report subjective complaints of increased fatigue and generalized weakness [68-70]. Previously, severe cognitive and consciousness impairment and acute psychosis were considered classic psychiatric manifestations of PHPT. Currently, moderate psychiatric disorders such as fatigue, depression, emotional lability, sleep disturbances, memory impairment, and inability to concentrate are increasingly reported. Many patients assess the changes in their condition only retrospectively, after successful surgical treatment, noting an improvement in overall quality of life, memory, and mood [70-73].

A thorough personal and family history taking is required when syndromic forms of endocrinopathies are suspected (see the chapter "Hereditary Forms of PHPT") [5].

An appointment (examination, consultation) with an endocrinologist involves the assessment of general physical condition, height, and body weight. Upon examination, patients with a severe course of PHPT may exhibit muscle atrophy and a "waddling gait". Attention should be paid to skeletal deformations and the presence of bone overgrowths in the facial skull, large joints, and tubular bones.

2.2 Physical Examination

• For patients with suspected PHPT, it is recommended to assess general physical condition, measure height (detecting a height loss of 2 cm or more over 1-3 years or 4 cm or more over a lifetime), gait disturbances, visual examination of muscles and skeleton (deformations, fractures), and the presence of bone overgrowths in the facial skull, large joints, and tubular bones in order to identify characteristic skeletal manifestations of the disease [10, 74].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

2.3 Laboratory Diagnostics

The diagnosis of PHPT is based solely on laboratory test data.

• For patients with newly detected hypercalcemia, it is recommended to re-evaluate the levels of total calcium, albumin (with calculation of albumin-corrected calcium), and/or ionized calcium in the blood to exclude false-positive laboratory results [27, 75, 76].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: about 99% of calcium is deposited in bone tissue, and only 1% circulates in intracellular fluid and blood plasma. In plasma, calcium is present in ionized form (about 50%), protein-bound state (45%, mainly to albumins), and complexed with anions (phosphate, citrate — about 5%). The free (ionized) form of calcium is considered metabolically active.

The hypercalcemic variant of PHPT accounts for the majority of cases; therefore, when PHPT is suspected, initial determination of the blood albumin-corrected calcium level is indicated, and hypercalcemia must be confirmed in more than one measurement before the patient is scheduled for an expanded workup. Correcting calcium for blood albumin levels is necessary to exclude falsely elevated or falsely lowered calcaemia indicators when plasma protein concentrations change [76].

Formulas for calculating albumin-corrected calcium:

• blood albumin-corrected calcium (mmol/L) = measured blood total calcium level (mmol/L) + 0.02 x (40 - measured blood albumin level (g/L));

• blood albumin-corrected calcium (mg/dL) = measured blood total calcium level (mg/dL) + 0.8 x (4 - measured blood albumin level (g/dL));

• conversion factor: [calcium] mg/dL x 0.25 = [calcium] mmol/L.

False results can also be avoided by directly determining ionized calcium (Ca⁺⁺) [27]. This parameter is less variable, however, its determination requires special equipment—an analyzer using ion-selective electrodes, the availability of which in clinical laboratories may be limited. The correctness of Ca⁺⁺ determination depends on the technical condition and calibration of the apparatus, as well as accounting for the effect of blood pH on its concentration. Acid-base balance affects the blood Ca⁺⁺ content by influencing the process of calcium binding to proteins. Acidosis decreases its binding to blood proteins and leads to an increase in Ca⁺⁺ levels, whereas alkalosis enhances calcium binding to proteins and decreases its level. This correction is built into the software of modern analyzers, but was not used in earlier models [75]. Thus, in routine practice, determining albumin-corrected calcium is indicated rather than its ionized fraction.

• To verify the diagnosis in patients with suspected PHPT, it is recommended to test the levels of total calcium, albumin (with calculation of albumin-corrected calcium) and/or ionized calcium, and parathyroid hormone in the blood (iPTH) [27, 28, 76-81].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments:

Parathyroid hormone

In patients with PHPT, PTH levels are typically elevated or at the upper limit of the reference range [27, 28]. If medications capable of affecting calcium and/or PTH levels are taken (see section 7.4), performing laboratory tests is indicated after discontinuing the drugs. PTH levels in the lower range of normal values (<25-30 pg/mL) are more characteristic of other conditions associated with the development of hypercalcemia. First of all, paraneoplastic processes must be ruled out as the second most common cause of elevated blood calcium levels.

Currently, second- and third-generation assays exist for determining iPTH levels. Second-generation assays use immunoradiometric (IRMA) and immunochemiluminometric (ICMA) methods and detect both the intact PTH 1-84 molecule and large hormone-inactive C-terminal fragments (PTH 4-84, PTH 7-84, PTH 10-84, and PTH 15-84), and thus may overestimate the concentration of the biologically active hormone in serum [77]. These fragments account for up to 20% of immunoreactive PTH in serum in individuals with preserved renal function and up to 50% in individuals with renal failure. Third-generation assays are specific for intact PTH 1-84 because the capture antibody recognizes the PTH 39-84 fragment, and the detection antibody recognizes a small N-terminal region of PTH 1-4. Consequently, third-generation assays have higher diagnostic sensitivity. Compared to second-generation assays, the iPTH concentration measured using third-generation assays is 20% and 50% lower in healthy individuals and individuals with renal failure, respectively. The disadvantage of these assays is that they also recognize the PTH 1-84 molecule that has undergone post-translational modifications (serine phosphorylation) at region 15-20 (N-PTH), which is therefore a hormone-inactive form. However, the contribution of this molecule to the final PTH level measured using third-generation assays is less than 10% in healthy individuals and less than 15% in individuals with renal failure. N-PTH can be overproduced in parathyroid carcinoma and severe hyperparathyroidism [82].

When assessing the sensitivity of second- and third-generation assays in the diagnosis of PHPT, no clinically significant differences were found (91.3% vs. 89.1%, respectively); thus, the sensitivity of second- and third-generation assays for detecting elevated iPTH levels is identical [78].

In 1/3 of patients, hypophosphatemia is detected due to the reciprocal relationship between calcium and phosphorus. With normal renal function, an inverse relationship may be observed between elevated iPTH and decreased blood phosphorus. When renal function is impaired, phosphorus remains within the normal range or is elevated. PHPT is also characterized by elevated or high-normal levels of total alkaline phosphatase and more specific markers of bone metabolism when the skeleton is actively involved in the pathological process: bone resorption markers in blood—C-terminal telopeptide of type 1 collagen (CTX, β-crossLaps), N-terminal telopeptide of type 1 collagen (NTX); in urine—deoxypyridinoline and NTX; bone formation markers in blood—osteocalcin and N-terminal propeptide of type 1 procollagen (P1NP). Determination of these parameters can be useful in monitoring the effectiveness of antiresorptive therapy in the conservative management of PHPT [10].

• To assess renal filtration function and determine indications for surgical treatment, as well as to exclude secondary causes of elevated iPTH levels in patients with suspected PHPT, it is recommended to test blood creatinine levels with GFR calculation [79, 83-85]

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Serum creatinine is considered an important diagnostic tool in the cohort of patients with PHPT, since the kidneys are one of the main organs regulating calcium and phosphorus metabolism in the body. KDOQI (Kidney Disease Outcomes Quality Initiative) experts recommend assessing the glomerular filtration rate (GFR) based on age, sex, race parameters, and serum levels of creatinine, albumin, urea, and nitrogen. A decrease in renal filtration function is characteristic of patients with PHPT; evidence has been obtained regarding the role of CKD stages G3–G5 development in increasing the risk of sudden death in PHPT. Furthermore, a progressive decrease in GFR is associated with an increase in PTH levels and enhanced resorption processes in bone tissue [34, 35, 85]. Clearance radioisotope methods are the "gold standard" for determining GFR, but their cost and technical complexity severely limit their widespread use. In clinical practice, simple methods for calculating creatinine clearance that avoid 24-hour urine collection can be used to calculate GFR (Cockcroft-Gault, MDRD, CKD-EPI formulas). The CKD-EPI formula provides more accurate results, including in preserved renal function, which allows it to be used in outpatient practice [86]. The parameter can be calculated automatically using specialized online calculators.

• Patients with PHPT are recommended to have their blood 25-OH vitamin D level tested in order to diagnose its insufficiency/deficiency [87-90].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: reciprocal regulatory relationships exist between the levels of PTH, Ca⁺⁺, and the active form of vitamin D (calcitriol). An increase in the synthesis and secretion of PTH raises blood Ca⁺⁺ content and accelerates the hydroxylation of vitamin D in the kidneys; via negative feedback, elevated concentrations of Ca⁺⁺ and calcitriol suppress PTH production. Under normal physiological conditions, vitamin D deficiency and hypocalcemia contribute to increased PTH synthesis. A low 25(OH)D level in PHPT is associated with a higher PTH level, lower cortical bone BMD, higher bone turnover marker rates, more frequent development of osteitis fibrosa, and greater parathyroid adenoma weight [87-89]. Assessment of vitamin D status is carried out by testing blood 25-OH vitamin D levels, which is the most accessible and reliable method of laboratory diagnosis [75]. If 25(OH)D insufficiency/deficiency is detected, its replenishment is indicated, preferably at the preoperative stage or in the early postoperative period (see Section 3.2 Conservative treatment) [90].

• To verify the diagnosis in patients with PHPT and satisfactory renal filtration function (GFR >60 mL/min/1.73 m²), it is recommended to test calcium and creatinine levels in urine (24-hour urine collection) with calculation of the renal calcium-to-creatinine clearance ratio [26].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: testing the calcium level in 24-hour urine relative to creatinine excretion is necessary for the differential diagnosis of PHPT and FHH. FHH is a rare hereditary disease with an autosomal dominant inheritance pattern caused by a defect in calcium-sensing receptors (CaSR) in the kidneys and parathyroid glands. The diagnosis of FHH can be suspected when hypercalcemia, normal or slightly elevated PTH levels, and relative hypocalciuria are combined. Since urinary calcium excretion over a fixed time interval depends significantly on GFR and the duration of urine collection, total calcium excretion is not a valuable parameter for differentiating cases of FHH from typical PHPT. Therefore, the renal calcium-to-creatinine clearance ratio (UCCR) is calculated, which is usually less than 0.01 in FHH (formula for calculation: CaCl/CrCl = [Cau x Crs]/[Cru x Cas], where CaCl is calcium clearance, CrCl is creatinine clearance, Cau is urinary calcium concentration (mmol/L), Crs is serum creatinine concentration (µmol/L), Cru is urinary creatinine concentration (µmol/L), and Cas is serum calcium concentration (mmol/L)). For PHPT, the UCCR index is usually greater than 0.02; however, Christensen S.E. et al. demonstrated that a UCCR cutoff point of less than 0.01 without CASR gene testing will identify only 65% of FHH patients and incorrectly classify 4% of PHPT patients as having FHH. A UCCR within 0.01–0.02 is found in 33% of PHPT patients, while 35% of FHH patients have a UCCR ≥ 0.01 [26].

Genetic testing is indicated for all patients with suspected FHH (UCCR <0.01 on repeat testing), as the identification of a pathogenic mutation or likely pathogenic variants will confirm the diagnosis. Mutations in the CASR gene are most characteristic (about 65%), although rarer causes of the disease associated with the GNA11 and AP2S1 genes may also occur. Currently, sequencing of only the CASR gene is available in the Russian Federation, but it must be taken into account that this gene has a wide spectrum of missense variants with uncertain pathogenicity [91]. Moreover, the absence of mutations in all indicated genes does not allow the diagnosis of FHH to be definitively ruled out. Genetic testing has limited sensitivity, as >25% of patients with a clinical diagnosis of FHH do not have germline mutations in CASR/GNA11/AP2S1. Regular monitoring of patients with negative genetic test results and dynamic UCCR calculation are required. Family screening for FHH (determining calcemia followed by UCCR calculation if necessary) can serve as an important criterion in making the diagnosis, since the penetrance of this disease is >90% [92]. Thus, family screening, regardless of genetic testing results, is a key tool, and determining calcium levels in first-degree relatives helps in the timely diagnosis of FHH.

An additional value of determining 24-hour calciuria is the assessment of the risk of nephrolithiasis occurrence or progression. If 24-hour calcium excretion is found to be above 10 mmol/day, surgical treatment of PHPT is indicated (see Section "Surgical Treatment"). It should be noted that urinary calcium testing is uninformative when renal function is impaired (GFR <60 mL/min/1.73 m²).

• To perform differential diagnosis between primary normocalcemic PHPT (nPHPT) and secondary hyperparathyroidism (SHPT), patients with a combination of elevated iPTH levels and normocalcemia are recommended to undergo functional tests [74, 93-96].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: the combination of an elevated blood iPTH parameter with a normal serum calcium level remains an urgent clinical problem. For the purpose of differential diagnosis between the normocalcemic variant of PHPT and SHPT resulting from vitamin D deficiency or other conditions [98, 99], functional tests must be performed (Table 2) [30, 31]. In patients with PHPT, the intake of vitamin D preparations and their analogues (#cholecalciferol**, #alfacalcidol**, #calcitriol**) and/or #hydrochlorothiazide** typically provokes the development of hypercalcemia while maintaining an elevated iPTH level, whereas in patients with SHPT, it leads to normalization of the iPTH level with persistent normocalcemia [98, 100].

One of the most frequent causes of elevated iPTH in patients with persistent normocalcemia is vitamin D insufficiency/deficiency, which is asymptomatic in the majority of cases. Chronic 25(OH)D deficiency is accompanied by the development of relative (less frequently absolute) hypocalcemia, in response to which PTH synthesis increases compensatorily. Suppression of compensatory excessive iPTH secretion in most individuals is observed at serum 25(OH)D concentrations above 30 ng/mL [38, 101].

Achieving the target 25(OH)D level does not always provide a clear understanding of the genesis of hyperparathyroidism, as a single patient may have a combination of several factors leading to PTH hypersecretion. The target 25(OH)D level and normal estimated GFR (eGFR) do not exclude the presence of active vitamin D metabolite deficiency. In 13% of patients with eGFR ≥ 80 mL/min, a decreased concentration of 1,25(OH)₂D₃ may be observed, and among patients with eGFR less than 30 mL/min, low calcitriol levels can be recorded in more than 60% of patients [102]. Therefore, for the differential diagnosis of normocalcemic primary hyperparathyroidism (nPHPT) and secondary hyperparathyroidism (SHPT), particularly in the patient population with various stages of CKD, a functional test with vitamin D and its analogues appears relevant.

In the presence of hypercalciuria, it is advisable to perform a test with thiazide diuretics (thiazides). This test has a number of significant limitations. Mandatory monitoring of electrolytes is required during the test, and in some cases, prior to its initiation. The test with thiazide diuretics should not be performed in patients with eGFR < 60 mL/min/1.73 m², since, on the one hand, stage 3-5 chronic kidney disease is itself a cause of elevated iPTH levels, which complicates the interpretation of the results obtained, and on the other hand, a creatinine clearance of less than 30 mL/min is an absolute contraindication to the use of these drugs. In addition, the drug should be used with caution in patients with cardiac arrhythmias receiving cardiac glycosides or glucocorticosteroids due to the high risk of hypokalemia and cardiac arrhythmias [97].

It must be taken into account that prolonged vitamin D deficiency can lead to hyperplasia of one or all parathyroid glands due to a decrease in the inhibitory effect of vitamin D on parathyroid cell division, as well as due to the stimulating effect of low blood calcium levels on the same process. Therefore, imaging techniques are not used for the differential diagnosis of hyperparathyroidism.

Table 2. Functional tests for the differential diagnosis between the normocalcemic form of primary hyperparathyroidism and secondary hyperparathyroidism.

¹ A longer test duration is possible: if a downward trend in PTH and normocalcemia is detected, continue the test until the development of hypercalcemia under medical supervision

• For the purpose of differential diagnosis between nPHPT and SHPT in an inpatient setting, patients presenting with a combination of elevated iPTH levels and normocalcemia are recommended to undergo modified functional tests with #alfacalcidol**/#calcitriol** or #hydrochlorothiazide** (Table 3) [105, 106]

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: The differential diagnosis of various forms of hyperparathyroidism is particularly relevant for patients undergoing examination in an inpatient setting, when a definitive diagnosis and further management tactics must be established within a limited timeframe. Stable normocalcemia and normalization of iPTH based on the results of modified tests confirm SHPT, avoiding prolonged differential diagnosis and thereby reducing financial costs for additional examinations. Achieving hypercalcemia combined with elevated or upper-normal iPTH levels based on the results of modified tests confirms PHPT, avoiding prolonged differential diagnosis and thereby allowing the patient to be referred for radical treatment in a shorter timeframe when indications are present.

Table 3. Modified short functional tests for the differential diagnosis between normocalcemic and secondary forms of hyperparathyroidism

2.4 Instrumental Diagnostics

1. The diagnosis of PHPT is established exclusively on the basis of laboratory test results; data from imaging studies should not be considered in the context of verifying or excluding the disease.

2. The use of imaging studies is mandatory when preparing patients for planned surgical treatment (parathyroidectomy).

3. The goal of preoperative topical diagnosis of a parathyroid lesion in PHPT is preparation for selective parathyroidectomy (PTX). Planning effective surgical treatment requires information on the exact location of the parathyroid lesion. First-line instrumental diagnostic methods in PHPT are ultrasound and radionuclide studies (planar scintigraphy (parathyroid scintigraphy), single-photon emission computed tomography (SPECT) of the parathyroid glands, SPECT-CT). The second-line diagnostic method is contrast-enhanced MSCT. Additional research methods include PET-CT and MRI.

• Patients with PHPT as the first stage of topical diagnosis in PHPT are recommended to undergo ultrasound examination of the parathyroid glands [107-113].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: the sensitivity of ultrasound in the case of a solitary parathyroid lesion ranges from 76% to 91% according to various data and largely depends on the specialist's qualifications [107-110]. The specificity of the method can reach 96% [111-113]. A high positive predictive value and diagnostic accuracy of parathyroid ultrasound have been established (93.2% and 88%, respectively) [107].

A parathyroid adenoma typically presents as a round or oval formation with a hypoechoic structure, outlined by an isoechoic line and contrasting with the overlying hyperechoic thyroid tissue. In some cases, calcifications may be visualized and cystic degeneration determined. Ultrasound is most effective when the parathyroid adenoma is located close to the thyroid gland and the cervical part of the thymus. The capabilities of the method are sharply limited for parathyroid lesions located retrotracheally, retroesophageally, or in cases of their ectopia into the mediastinum [109, 110]. Clear ultrasound signs of malignant parathyroid lesions are absent. However, suspicious features for parathyroid carcinoma include an inhomogeneous structure, irregular shape, size greater than 3 cm, indistinct margins, and decreased echogenicity [114].

Recently, contrast-enhanced ultrasound (CEUS) has been used for topographic diagnosis in primary hyperparathyroidism (PHPT). The method provides a quantitative and qualitative assessment of the microvascular bed vascularization of the glands, which helps identify parathyroid tumors. Contrast-enhanced ultrasound has particular advantages in the presence of concomitant goiter, cervical lymphadenopathy, and polyglandular parathyroid disease, even after previous neck surgeries [115].

Advantages of the method:

- absence of radiation exposure;

- relatively low cost and high availability of the study;

- ability to detect concomitant thyroid pathology.

Disadvantages of the method:

- significant variability in diagnostic accuracy depending on the operator's qualifications and technical equipment;

- false-positive results due to thyroid nodules or lymph nodes;

- significant limitations in performing the study with atypical localization of parathyroid glands (e.g., retrosternal, in the retroesophageal space).

• For patients with PHPT, for the purpose of topographic diagnosis of parathyroid lesions after ultrasound as a first-line method, it is recommended to perform parathyroid scintigraphy (parathyroid gland scintigraphy) with technetium [99mTc] sestamibi at an activity of 400–900 MBq, preferably combined with SPECT (single-photon emission computed tomography of the parathyroid glands) or SPECT/CT [114, 116–118].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: to detect parathyroid lesions, the radiopharmaceutical (diagnostic radiopharmaceutical agent) based on the technetium [99mTc] isotope and 2-methoxyisobutylisonitrile (sestamibi, MIBI) lyophilizate—technetium [99mTc] sestamibi—is most frequently used. It is a lipophilic cation that distributes in the body in proportion to blood flow and penetrates cell cytoplasm via simple diffusion based on the thermodynamic driving force caused by the transmembrane potential gradient of the cell membrane. The radiopharmaceutical is fixed on the inner surface of mitochondrial membranes, generating a high negative potential. The factor of prolonged retention of technetium [99mTc] sestamibi in numerous mitochondria of pathologically altered parathyroid glands is the main diagnostic sign in radionuclide topographic diagnosis of PHPT.

Physiological uptake of technetium [99mTc] sestamibi is observed in many tissues, including the thyroid gland, and in its normal functional status, it is characterized by rapid washout of the radiopharmaceutical from the thyroid tissue, which allows visualization of altered parathyroid glands on delayed scans [119]. However, one of the main challenges in visualizing parathyroid lesions is the ability of technetium [99mTc] sestamibi to actively accumulate and be retained for a long time in thyroid tissue in autoimmune disease and/or nodular goiter. Also, in some cases, the washout of the radiopharmaceutical from the parathyroid glands can occur much faster than from the thyroid gland due to high expression of membrane P-glycoprotein, causing rapid ATP-dependent elimination of the radiopharmaceutical from the cell cytoplasm into the extracellular space. For this reason, some adenomas and, to a greater extent, hyperplastic parathyroid glands (in particular, those closely adjacent to the thyroid), lacking typical signs of prolonged radiopharmaceutical retention, remain undetected [120].

Radionuclide imaging methods include planar scintigraphy, SPECT, and SPECT/CT.

The most common standard examination technique is dual-phase single-isotope planar scintigraphy after intravenous administration of technetium [99mTc] sestamibi at an activity of 400–900 MBq. It is based on the different washout rates of the radiopharmaceutical between the early phase (10–15 minutes after administration) and the late phase (90–150 minutes after administration): persistent retention of the radiotracer in the parathyroid lesion against the background of progressively decreasing activity in the normal thyroid gland [447].

Another, less common type of planar scintigraphy is the dual-isotope (subtraction) method, which uses two radiopharmaceuticals. The essence of the technique is as follows: one radiopharmaceutical (technetium [99mTc] sestamibi) is captured by both thyroid and parathyroid cells, while other radiopharmaceuticals (sodium pertechnetate [99mTc] or sodium iodide [123I]) accumulate only in the functioning thyroid parenchyma. Using radiological workstation software, one image is "subtracted" from the other, which makes it possible to identify the location of parathyroid lesions [121].

It is important to note that recent administration of contrast agents (<1 month), intake of antithyroid drugs, sodium levothyroxine**, or iodine preparations makes the interpretation of studies with sodium iodide [123I] or sodium pertechnetate [99mTc] impossible [122, 123].

Currently, single-photon emission computed tomography (SPECT) or hybrid SPECT/CT technology is used in most medical centers. Unlike planar scintigraphy, during which an image of radiopharmaceutical accumulation in a single plane is obtained, the SPECT technique involves obtaining dozens of such tomographic slices performed by a rotating gamma camera, followed by reconstruction into a 3D image of radiopharmaceutical accumulation in the body. With the advent of SPECT, it became possible to detect parathyroid lesions not visualized on planar scintigraphy, as well as to reduce the number of false-positive results caused by thyroid nodules.

Unlike SPECT, the hybrid SPECT/CT system provides the radiologist with important additional structural (anatomical) information that increases the diagnostic value of the study. SPECT/CT clearly localizes the anatomical position of altered parathyroid glands and also allows differentiation of abnormal radiopharmaceutical uptake from physiological uptake. Many studies demonstrate the superior sensitivity of SPECT/CT (86%) compared to SPECT (74%) and planar scintigraphy (70%) [124]. It should be noted that sensitivity and specificity rates vary depending on the study design and the center where they were evaluated. For so-called centers of competence, sensitivity and specificity can reach 90% (with high positive and negative predictive values, 83–96% and 83–88%, respectively) when performing planar scintigraphy in combination with SPECT/CT [125, 126]. The spatial resolution of SPECT/CT makes it possible to detect virtually all enlarged parathyroid glands measuring ≥ 7–8 mm [127].

A positive result for planar scintigraphy and SPECT is considered to be the visualization of pathological focus/foci of radiopharmaceutical accumulation distinct from physiological uptake. Physiological active accumulation of technetium [99mTc] sestamibi implies radiopharmaceutical accumulation in the thyroid gland, salivary glands, and myocardium. In the case of SPECT/CT, a positive case is the visualization of a soft-tissue lesion accumulating the radiopharmaceutical in typical locations of the parathyroid glands and areas of possible ectopia.

Advantages of the method:

- determination of the localization of both typically located and ectopic parathyroid lesions, including in the mediastinum.

Disadvantages of the method:

- significant variability in the diagnostic accuracy of the study depending on the center (specialist experience, technical equipment – planar scintigraphy, SPECT, SPECT/CT) where the study is performed;

- possible false-positive and false-negative results in the presence of concomitant thyroid diseases (autoimmune thyroiditis, multinodular goiter, diffuse/nodular toxic goiter, thyroid cancer, intrathyroid parathyroid glands);

- radiation exposure.

The combination of parathyroid ultrasound and expert-class SPECT/CT with technetium [99mTc] sestamibi, with mandatory evaluation of the thyroid structure at the preoperative stage of PHPT diagnosis, increases the overall accuracy of detecting altered parathyroid lesions up to 99% [128]. The main operating characteristic of imaging methods in controversial diagnostic cases is the negative predictive value, which is highest for SPECT/CT or the combination of ultrasound and SPECT/CT [128, 129].

Multiple parathyroid gland involvement is associated with a significant decrease in the diagnostic efficacy of all imaging modalities [109, 130]. To minimize false-negative and false-positive results of topographical diagnosis during the preparation for minimally invasive parathyroidectomy (MIP), all patients should undergo a comprehensive evaluation combining the results of both ultrasound and radionuclide imaging (preferably SPECT/CT). If the results of the two diagnostic tests are concordant, proceed with MIP; if results are equivocal, perform additional tests [128].

• In patients with PHPT when parathyroid lesions are not clearly visualized by first-line imaging modalities (ultrasound and radionuclide imaging), it is recommended to perform additional diagnostic tests:

- multispiral computed tomography (MSCT) of the neck and mediastinum with contrast enhancement (computed tomography of the neck with intravenous bolus contrast enhancement, computed tomography of the mediastinum with intravenous bolus contrast enhancement) [118], whole-body positron emission tomography (PET) with tumorotropic radiopharmaceuticals [132];

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

• magnetic resonance imaging (MRI) of the neck [131, 133].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: Non-contrast neck computed tomography currently has limited utility in diagnosing parathyroid lesions due to its low sensitivity. Meanwhile, contrast-enhanced MSCT (computed tomography of the neck with intravenous bolus contrast enhancement, computed tomography of the mediastinum with intravenous bolus contrast enhancement) allows for a fairly accurate assessment of the size and localization of parathyroid lesions, both in their typical locations and in the presence of altered ectopic parathyroid glands, including within the mediastinum. This is because parathyroid lesions are hypervascular and show strong contrast enhancement. A positive result on contrast-enhanced MSCT is the visualization of parathyroid lesions, which typically exhibit lower initial density on native CT and a greater increase in density during the arterial phase, followed by rapid washout of the contrast agent into the venous and delayed phases compared to thyroid tissue. According to the literature, the method has high diagnostic efficacy, with an average sensitivity exceeding 88% and a positive predictive value reaching 93.5% [134]. At the same time, contrast-enhanced MSCT has one of the highest rates of false-positive results among all topographical diagnostic methods.

In some cases, in patients with significant comorbid thyroid pathology, it is advisable to use contrast-enhanced MSCT as a first-line method, provided that the images are interpreted by a highly experienced radiologist [128].

In patients with autoimmune thyroid diseases (hypertrophic form of autoimmune thyroiditis, diffuse/nodular toxic goiter, with characteristic ultrasound features), there is an increased rate of false-negative results in radionuclide imaging (especially planar scintigraphy and SPECT) due to the "shielding" of small parathyroid lesions by persistent active radiopharmaceutical uptake in the thyroid tissue. These pathological changes in the thyroid gland have a much lesser impact on the results of contrast-enhanced CT. Therefore, when choosing a topographical diagnostic method for this group of patients, contrast-enhanced CT should be performed primarily, while SPECT/CT should be used as a second-line method.

The disadvantages of the method include the potential nephrotoxicity of the contrast agent and, consequently, limited use in patients with CKD, as well as radiation exposure. However, when using state-of-the-art dual-source CT scanners with iterative reconstruction, the radiation exposure even in a 4-phase protocol can be as low as 4–5 mSv.

A relatively high sensitivity of the method is maintained in multiple parathyroid involvement as well — 62.5–85.7% [135–137].

It should be noted that the isolated diagnostic efficacy of planar scintigraphy and non-contrast MSCT is extremely low; therefore, these tests should not be performed for preoperative localization in patients with PHPT when planning MIP.

The use of positron emission tomography (PET, whole-body positron emission tomography with tumorotropic radiopharmaceuticals) is indicated in certain cases when altered parathyroid glands cannot be localized using routine diagnostic methods, or in the case of recurrent/persistent PHPT. According to the literature, PET/CT is the most effective method for preoperative topographical diagnosis of parathyroid lesions in PHPT and can be considered as a first-line method, but its routine use is limited due to low availability and high cost [138].

PET/CT in patients with PHPT can currently be performed when other imaging modalities yield negative results. There are several radiopharmaceuticals potentially applicable for PET imaging of hyperfunctioning parathyroid glands [116]; the most well-known to date is fludeoxyglucose [18F], and other radioisotopes may also be used [139].

Magnetic resonance imaging (MRI) is another diagnostic imaging method used to search for parathyroid lesions; it shares the same limitations as CT (presence of altered cervical lymph nodes, thyroid nodules, and tortuous vessels) and offers no advantages other than the absence of radiation exposure. In addition to high cost and long image acquisition time, MRI is characterized by low sensitivity (64–84% using a 1.5T MR scanner), which is why this method has not found widespread application [131, 133]. On MRI, compared to the thyroid gland, an altered parathyroid gland typically appears as an iso- to hypointense structure on T1-weighted images and iso- to hyperintense on T2-weighted images.

• If differential diagnosis between parathyroid lesions and other pathological formations in the neck region (thyroid nodules, lymph nodes, cysts) is necessary in patients with PHPT, it is recommended to perform fine-needle aspiration biopsy (FNAB) of the parathyroid gland followed by measurement of PTH levels in the washout fluid [140–143].

GCR ALEL 2Grade of Recommendation A (Level of Evidence – 2

Comments: Ultrasound-guided FNAB with needle washout for PTH is indicated as an additional test when verification of candidate parathyroid lesions is necessary and cannot be used as a standalone preoperative diagnostic method. The method is useful when differential diagnosis between parathyroid lesions and thyroid nodules is required in the absence of clear confirmation of the intrathyroidal location of a parathyroid adenoma based on imaging modalities. PTH levels are determined using standard assay kits. This technique is relatively safe and accessible, and is characterized by high sensitivity, specificity, and predictive value. It should be noted that cytological examination of parathyroid aspirates is not performed due to the difficulty of differential diagnosis with follicular thyroid neoplasms. Furthermore, cytological examination cannot differentiate between benign and malignant parathyroid lesions [140–142].

Procedure: under linear ultrasound guidance, puncture of the lesion is performed using a 5.0 or 10.0 ml syringe with a 21–23G needle. The needle is withdrawn. Then, a lavage with 2.0 ml of sodium chloride** is performed through the puncture needle (several times). The PTH level is measured in the obtained washout fluid. It should be emphasized that the results of parathyroid FNAB with PTH measurement in the aspirate indicate whether the punctured tissue is parathyroid tissue or another type of tissue. However, the PTH level in the aspirate does not allow for differentiation between parathyroid adenoma and hyperplasia. A washout PTH level >100 pg/ml corresponds to parathyroid tissue. A PTH level >500 pg/ml typically corresponds to a pathologically altered parathyroid gland. If the PTH level is <100 pg/ml, the aspirate is most likely from the thyroid gland, in which case thyroglobulin (Tg) is measured in the same washout fluid as a second step. A high Tg level combined with a low PTH level confirms that thyroid tissue was sampled [143].

2.5 Other Procedures

• To determine the spectrum and severity of bone involvement in patients with PHPT, it is recommended to undergo an evaluation that includes quantitative assessment of bone mineral density in 3 skeletal sites using dual-energy X-ray absorptiometry (DXA), and radiological assessment of skeletal integrity when fractures are suspected, including lateral radiography of the thoracic and lumbar spine in case of a height loss of 4 cm since youth or a height loss of 2 cm over the last year [63, 144–148].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: The development of bone disorders in PHPT is a result of the direct action of high PTH levels, characterized by accelerated bone remodeling with a predominance of resorptive processes. Previously, osteitis fibrosa cystica was considered one of the most frequent skeletal manifestations of PHPT, diagnosed in more than 50% of patients [145, 149]. In recent years, due to earlier diagnosis of the disease, these bone lesions are detected less frequently. Nevertheless, X-ray examination of the skeleton remains valuable in PHPT as it allows for the verification of bone disorders in patients with severe symptomatic forms of the disease. The radiological picture of bone lesions due to PHPT includes subperiosteal resorption, cyst formation, periosteal hypertrophy, and demineralization of the cranial bones. A rare but specific radiological sign is the formation of "brown" tumors, which most commonly develop in various parts of the skeleton (femur, pelvis, clavicles, ribs, jaw, skull) [47, 150]. Bone loss in the peripheral skeleton is first detected in the terminal parts of tubular bones due to the predominance of trabecular bone there. Lateral X-ray imaging of the lumbar and thoracic spine is necessary to exclude or verify compression fractures of the vertebral bodies, especially in patients with a clinically significant decrease in height [145].

In cases of asymptomatic PHPT, pathological skeletal changes are typically detected by a decrease in BMD based on X-ray densitometry (dual-energy X-ray absorptiometry, DEXA), which is the gold standard for bone density testing and early preclinical diagnosis of osteoporosis. The World Health Organization (WHO) defines osteopenia as a BMD reduction ranging from 1 to 2.5 standard deviations below the young adult peak bone mass (T-score between -1.0 and -2.5 SD), and osteoporosis as a BMD reduction equal to or greater than 2.5 standard deviations (T-score <-2.5 SD; for BMD assessment in men under 50 and premenopausal women, the Z-score is used, with a value <-2.0 SD corresponding to BMD reduction relative to age-matched norms). In PHPT, in addition to standard evaluation of the axial skeleton (lumbar spine and proximal femur), it is necessary to assess BMD in peripheral bones (distal third of the forearm), which have predominantly cortical structure and are exposed to the maximum bone-resorptive effect of PTH [63].

Relatively recent studies using high-resolution peripheral quantitative computed tomography (HRpQCT) have demonstrated that both cortical and trabecular bone tissue are affected in patients with PHPT [151, 152]. Pathological changes in the trabecular bone are confirmed by a decrease in the trabecular bone score (TBS) of the lumbar spine [153, 154], as well as a twofold increase in the risk of vertebral and non-vertebral fractures according to epidemiological studies [155, 156]. TBS, determined using additional software during standard lumbar spine densitometry, allows for the indirect assessment of qualitative characteristics of bone structure from densitometric images and thus complements traditional densitometry. TBS evaluation helps predict fracture risk independently of BMD. Evidence suggests that the deterioration of bone microarchitecture in PHPT manifests as lower TBS values compared to sex- and age-matched controls [153]. Following parathyroidectomy, a significant increase in BMD is observed both in patients with the asymptomatic form of the disease with minimal bone damage and in those with severe involvement characterized by osteitis fibrosa cystica [157, 158]. Furthermore, radically performed surgical treatment also leads to an increase in TBS [159].

• To determine the spectrum and severity of renal impairment in patients with PHPT, it is recommended to perform a comprehensive evaluation, including blood creatinine levels with GFR calculation, 24-hour urinary calcium levels, and ultrasound and/or CT of the retroperitoneal space/kidneys and adrenal glands [62, 86, 160-163].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Renal manifestations of PHPT include nephrolithiasis, nephrocalcinosis, and impairment of filtration and concentration functions [2, 83, 164]. Sometimes kidney involvement may be the only manifestation of the disease and present as recurrent nephrolithiasis. Both single and multiple calculi in one or both kidneys can be detected. Renal calculi in PHPT consist predominantly of calcium oxalates or phosphates [83, 164].

Currently, the frequency of symptomatic nephrolithiasis generally does not exceed 7-20% of cases [160, 163, 165], while the prevalence of "silent" stones and nephrocalcinosis based on renal imaging techniques can reach 25-55% [62]. The presence of structural renal changes is an absolute indication for parathyroidectomy; therefore, all patients with PHPT should undergo renal and adrenal ultrasound and/or CT. CT is considered the most informative method for diagnosing renal parenchymal calcification [160].

GFR calculation is required for all patients with PHPT. Renal failure is one of the most severe and poorly reversible complications and is associated with more pronounced clinical manifestations, an increased risk of death, and a higher prevalence of arterial hypertension [34, 83]. A decrease in GFR corresponding to stage 3 CKD is diagnosed in 17–20% of patients with PHPT, and some patients may have an asymptomatic form of the disease [86].

The diagnostic value of measuring urinary calcium levels in PHPT has long been questioned, as the pathogenetic contribution of hypercalciuria to the development of nephrolithiasis/nephrocalcinosis in PHPT patients remains a subject of debate. According to most studies, the risk of nephrolithiasis in PHPT patients is significantly associated with young age and male sex [163]. Hypercalciuria likely contributes to an increased risk of nephrolithiasis, but it is not the sole triggering factor [86, 163]. Daily hypercalciuria is more characteristic of PHPT complicated by nephrolithiasis [161, 162]. Nevertheless, successfully performed parathyroidectomy reduces the risk of progression or recurrence of nephrolithiasis; therefore, pronounced hypercalciuria exceeding 10 mmol/day (greater than 400 mg/day) has come to be considered an indication for surgical treatment of PHPT [163].

• Esophagogastroduodenoscopy to assess the state of the upper gastrointestinal tract in patients with PHPT is recommended in the presence of relevant clinical symptoms and/or as part of the preoperative workup [65–67, 166].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: peptic ulcer disease of the stomach and duodenum in PHPT is currently rare, occurring significantly more often in young patients with MEN-1 or MEN-4 syndromes and concomitant gastrin-producing tumors. The results of studies on the pathogenetic relationship between PTH-mediated hypercalcemia and increased secretion of gastrin and gastric juice remain contradictory [65–67]. The only prospective study did not confirm this association [66]. Pathogenetically, inflammatory and structural changes in the pancreas are more associated with hypercalcemia than directly with PHPT. It has been shown that hypercalcemia of any etiology can lead to the development of acute or chronic pancreatitis [166].

• To enable timely detection of metabolic disorders and assess cardiovascular risks, it is recommended that all patients with PHPT undergo blood tests for glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and uric acid [167–169].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• For the diagnosis of cardiovascular pathology and preparation for surgical treatment, it is recommended that all patients with PHPT undergo blood pressure measurement in peripheral arteries and electrocardiography, followed by an appointment (examination, consultation) with a cardiologist [168, 170].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Domestic and foreign studies demonstrate an increased prevalence of carbohydrate metabolism disorders (impaired fasting glucose/impaired glucose tolerance – up to 25%, diabetes mellitus – 8-18% of PHPT cases), lipid metabolism disorders (various types of dyslipidemia – 31.1-68.3%), and hyperuricemia (47-54.1%) in patients with PHPT compared to general population rates, which determines the mortality rate of this disease [167-169]. Metabolic disorders are mainly associated with age and the symptomatic form of the disease [25, 171, 172]. According to a meta-analysis of 34 studies, after radical surgical treatment, there is a statistically significant decrease in glycemic levels and serum insulin concentration with no significant change in lipid profile parameters [173].

PHPT is associated with the development of cardiovascular diseases (CVD) [174-176]. According to the Russian Federation register of patients with PHPT, CVD was recorded in 45.4% of patients with PHPT, with the cumulative incidence of cardiovascular pathology expectedly increasing with age. In the 18–49 age group, CVD was detected in 3.9%, 50–64 years — in 38.1%, 65 years and older — in 58.1%. The high prevalence of CVD was more characteristic of the symptomatic form of PHPT, most commonly presenting as arterial hypertension (AH) — in 41.6% [170]. Based on the analysis of the database of the National Medical Research Center for Endocrinology of the Russian Ministry of Health, the prevalence of AH ranged from 29.7% in individuals under 50 years to 94% in patients older than 65 years. Persistent uncompensated elevation of blood pressure also increased the likelihood of developing left ventricular myocardial hypertrophy [177]. A history of CHD was reported by 2.6 to 21.9% of patients with PHPT depending on age, which also exceeds general population figures [168]. A relatively high incidence of cardiac arrhythmias was noted (8-21.7% depending on age), while the QT interval duration inversely correlates with serum calcium concentration [168]. Following the achievement of PHPT remission, the course of CVD may improve, although a consensus on this issue has not been reached [178].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Surgical Treatment

Surgical treatment is the only radical and effective method for managing PHPT.

• Surgical treatment for PHPT (parathyroidectomy) is recommended:

• for all patients with symptomatic (manifest) PHPT [19, 22, 155, 163, 179-181];

(Recommendation grade B (level of evidence – 3);

• for patients under 50 years of age [182-186];

(Recommendation grade B (level of evidence – 3);

• for patients with an increase in serum albumin-corrected calcium levels by 0.25 mmol/L (1 mg/dL) above the upper limit of the reference range established by the local laboratory, regardless of the presence or absence of clinical symptoms [22, 187-189].

(Recommendation grade C (level of evidence – 2);

• for patients with osteoporosis: a history of low-energy fractures and/or radiologically verified vertebral body fractures; or a decrease in bone mineral density (BMD) at the radius, proximal femur, or lumbar spine of less than -2.5 SD by T-score in postmenopausal women and men over 50 years of age according to X-ray densitometry [22, 48, 159, 187, 189-195]

(level of recommendation A (level of evidence – 2);

• for patients with functional and/or structural renal pathology: decreased glomerular filtration rate less than 60 mL/min/1.73 m², nephrocalcinosis, nephrolithiasis [83, 85, 181, 196-200];

(level of recommendation C (level of evidence – 4)

• for patients with a 24-hour urinary calcium excretion of more than 10 mmol (400 mg) per day; [74]

(level of recommendation C (level of evidence – 5)

Comments: removal of the pathologically altered parathyroid gland(s) is the only radical treatment method for PHPT. Medical therapy addresses only individual manifestations of the disease, but no drug can affect the disease as a whole. Active surveillance and medical therapy are less cost-effective even in asymptomatic PHPT [201-203]. Surgical treatment is indicated for all patients with classical manifestations of the disease [19, 22, 179, 204]. The benefits of radical treatment include normalization of calcium levels and elimination of hypercalcemia-associated symptoms, with significant improvement in the status of major target organs: bone tissue [22, 155, 180] and kidneys [163, 181]. Additional benefits include improvements in the cardiovascular and neuropsychiatric systems, as well as gastrointestinal diseases, though this requires confirmation in large randomized controlled trials [22, 205]. Surgical treatment may also be performed in asymptomatic PHPT without indications for parathyroidectomy if the patient so desires, provided that the benefit-to-risk ratio of the surgery is assessed. Results of randomized trials indicate an improvement in the quality of life of patients with asymptomatic PHPT after surgical treatment [18, 70, 191, 206].

Parathyroidectomy is indicated for all individuals under 50 years of age, including children. If surgical treatment is refused, patients under 50 will require a longer period of follow-up, which is associated with increased financial costs. In addition, the risk of developing specific disease-related complications increases. Young patients are characterized by a more rapid progression of PHPT; among individuals ≤50 years of age at diagnosis, disease progression can be observed in more than 65% of cases over a 10-year follow-up period, whereas in the ≥50 years group it is less than 25% [182-186]. Parathyroidectomy in children and adolescents is characterized by high efficacy rates, similar to the adult population [207, 208].

Chronic hypercalcemia (exceeding the upper limit of the laboratory reference range by more than 0.25 mmol/L [1 mg/dL]) is associated with the development and progression of PHPT complications, including increased bone resorption, nephrolithiasis/nephrocalcinosis, decreased renal filtration function, and increased vascular stiffness [22, 188, 189, 209-212].

Parathyroidectomy promotes an increase in BMD, a decrease in trabecular bone porosity, and an increase in cortical thickness in both symptomatic (manifest) and asymptomatic PHPT [18, 19, 191, 192, 212]. The average BMD increase in the proximal femur over 10 years can reach +14% [19]. By comparison, at a 15-year follow-up, the decrease in BMD in the femur and distal forearm in untreated patients is 10% and 35%, respectively [18]. Results of shorter randomized controlled trials (24 months) also show a significant increase in BMD in all skeletal sites, confirming the efficacy of surgical management regarding bone disorders compared to active surveillance [159, 191, 193]. Data on fracture rates after surgery are limited, but results from several controlled studies indicate a reduction after parathyroidectomy [22, 187, 195]. In a retrospective cohort study, the risk of fracture after surgical treatment was significantly reduced both in patients with verified osteoporosis and in individuals with normal BMD or osteopenia [187].

Following successful parathyroidectomy, the likelihood of developing new kidney stones is significantly reduced, but the risk of recurrence remains [198-200]. Surgical treatment does not reverse pre-existing nephrocalcinosis and chronic renal failure, but it can prevent the progression of structural renal changes and further decline in GFR [83, 85, 181, 196, 197].

Surgical treatment efficacy rates reach 95–98% with a postoperative complication rate of 1–2%, provided the surgery is performed by experienced surgeons. Mortality rates for PHPT surgery are low. The most serious postoperative complications include recurrent laryngeal nerve palsy, persistent hypocalcemia, hemorrhage, and lack of disease remission [205, 213]. The absence of remission after surgical intervention is usually observed in cases of multiple parathyroid gland involvement, undiagnosed multiple endocrine neoplasia syndrome, atypical location of a parathyroid lesion, advanced parathyroid carcinoma, or lack of surgeon experience.

• Patients with confirmed PHPT are recommended an initial consultation (examination, evaluation) with a surgeon regardless of the topographic imaging results in order to resolve the issue of surgical treatment (parathyroidectomy) [74].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• In the presence of a solitary parathyroid lesion confirmed by concordant structural (ultrasound or CT) and functional (scintigraphy, SPECT-CT) topographic diagnostic methods, and in the absence of risk factors for multiple or malignant parathyroid disease, patients with primary hyperparathyroidism (PHPT) are recommended to undergo parathyroidectomy (PTE) in the scope of removing the solitary lesion (selective parathyroidectomy) [214-219].

  Level of recommendation evidence C (reliability level of evidence – 4)

Comments: not so long ago, the most common surgical interventions for PHPT were "revision" operations—unilateral and bilateral neck explorations. The choice of such surgical volumes was due to the low efficacy of preoperative topographic diagnostics and the lack of intraoperative monitoring methods. The purpose of such operations is not only to remove the affected parathyroid gland, but also to prevent possible recurrences of PHPT by visualizing the parathyroid glands on one or both sides. However, any "revision" operations entailed greater invasiveness and a risk of intraoperative complications [168–171]. In addition, "revision" operations led to a higher incidence of postoperative hypoparathyroidism (up to 50%). With the advent of more advanced topographic diagnostic methods that significantly improved the localization results of affected parathyroid glands, selective PTE (parathyroidectomy) became the main operation for PHPT and solitary disease. During this operation, the surgeon removes only the affected parathyroid gland based on preoperative examination data [205]. The remaining glands are not inspected or traumatized. Selective PTE (parathyroidectomy) is characterized by high efficacy (95–98%) and a low risk of postoperative complications (1–3%) [214-217, 220].

The ability to remove only the affected parathyroid gland has significantly reduced the incision size. Such operations have become the preferred approach, referred to in foreign literature as "minimally invasive parathyroidectomy" (MIP) [205]. Today, MIP is the global standard of surgical treatment for PHPT with a solitary lesion. An even less invasive operation is "minimally invasive video-assisted parathyroidectomy" (MIVAP), developed and first performed by the Italian surgeon P. Miccoli [221]. The main advantages of this technique, in addition to less invasiveness and a better cosmetic outcome, include good visualization of the surgical field and the possibility of performing a full bilateral exploration if necessary [218, 222]. Additional advantages of MIP include reduced operation time and hospital stay, as well as economic efficiency [214].

• In cases of multiple parathyroid lesions, questionable, discordant, or negative topographic diagnostic data, the absence of an adequate decrease in intraoperative intact PTH (iPTH), or at the discretion of the surgeon, bilateral neck exploration with the removal of pathologically altered parathyroid glands (parathyroidectomy) is recommended [219, 223, 224].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: selective removal of a parathyroid lesion (parathyroidectomy) imposes special requirements on the quality of preoperative examination, since the choice of surgical access to the pathologically altered parathyroid gland is based on concordant results of structural and functional topographic diagnostic methods [130, 225-227]. An additional condition for performing selective PTE (parathyroidectomy) is the possibility of intraoperative rapid assay of blood iPTH levels [228-232]. If 10-15 minutes after adenoma removal the iPTH level does not decrease (see below), conversion of the surgical access is performed, followed by a full bilateral exploration [233, 234]. In case of negative, questionable, or discordant topographic diagnostic results, the presence of multiple parathyroid lesions, or the absence of an adequate decrease in intraoperative iPTH, as well as in patients with lithium-induced hyperparathyroidism, bilateral neck exploration with removal of the affected parathyroid glands (parathyroidectomy) is indicated [234-236].

The technique of bilateral neck exploration requires compliance with mandatory conditions, namely the search for and discovery of all parathyroid glands regardless of their typical location [223, 224]. Only pathologically altered parathyroid glands are removed. An exception is operations for MEN type 1 syndrome, which involve subtotal or total PTE with autotransplantation of a portion of the least altered parathyroid gland [237].

Parathyroid carcinoma is a rare pathology, frequently diagnosed years after initial surgical treatment. Nevertheless, it is generally accepted that parathyroid carcinoma is characterized by a more severe clinical course and prominent manifestations of PHPT. The presence of a malignant parathyroid lesion should be suspected in the case of a marked increase in iPTH (more than 3-fold), severe hypercalcemia (serum albumin-adjusted calcium level >3 mmol/L), and lesion dimensions greater than 3 cm [238-240]. Detailed information on the clinical features of PHPT and the scope of surgical intervention in genetic syndromes and parathyroid carcinoma is presented in the relevant sections.

• To assess the adequacy of surgical treatment in patients with PHPT, intraoperative assessment of blood iPTH levels before and 15 minutes after lesion removal is recommended [228-232, 241].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: given the relatively short half-life of iPTH in the bloodstream (3-5 min), a significant decrease in circulating hormone levels is observed after the removal of the source(s) of PTH hypersecretion. Intraoperative measurement of iPTH levels before and 15 minutes after lesion removal makes it possible to evaluate the radicalness of the intervention performed. A decrease in iPTH levels allows the surgeon to complete the operation without exploring other areas; conversely, persistence of initially high iPTH levels indicates that the source(s) of PTH hypersecretion remain and requires exploration to locate them [228-232].

Some uncertainty still exists regarding the degree of intraoperative decrease in iPTH levels that determines treatment radicalness. The most commonly used rule is a 50% decrease in iPTH from its baseline value 10 minutes after parathyroid tumor removal ("Miami criterion") [228-232]. Studies have shown that the minimum time required to evaluate results is 5 minutes, but the best sensitivity and specificity are observed 15-20 minutes after PTE, since the half-life of PTH depends on renal functional status [242]. A more stringent criterion is the reduction of iPTH levels to the normal range [243]. The overall accuracy of the method is about 80% [241]. As with preoperative topographic diagnostics, the best results are observed in solitary parathyroid lesions (83-97%). In multiple lesions, the accuracy of intraoperative iPTH determination decreases to 58% [241, 244].

• In the early postoperative period (the day after PTE), patients with PHPT are recommended to have their albumin-adjusted calcium levels monitored for the timely diagnosis of postoperative hypocalcemia [113, 213, 223, 245-251]

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

• All patients with symptomatic PHPT in the postoperative period are recommended vitamin D and its analogue therapy, and in case of clinical manifestations of hypocalcemia, in combination with calcium supplements [113, 445]

GCR ALEL 2Grade of Recommendation A (Level of Evidence – 2)

Comments: following PTE, the incidence of postoperative hypocalcemia can vary widely from 5% to 47%. A drop in calcium levels below the reference range may be due to prolonged suppression of normal parathyroid glands by an active parathyroid adenoma, postoperative edema of the remaining parathyroid glands, or "hungry bone" syndrome. Subsequently (within a period ranging from several days to six months), the calcium sensitivity of parathyroid cells in normal parathyroid glands recovers. Hypocalcemia develops more frequently in individuals with concurrent vitamin D deficiency or malabsorption syndromes of various etiologies (celiac disease or prior bariatric surgery). It is worth noting that cholecalciferol** intake for 2 weeks to 2 months prior to PTE reduces the risk of postoperative hypocalcemia in PHPT patients by a factor of 2 to 33 [452]. As a rule, the drop in calcium levels below the reference range is transient and can be managed on an outpatient basis [113, 213, 223, 245-247]. The incidence of chronic hypoparathyroidism after primary surgical treatment is extremely low: according to various studies, it ranges from 0 to 3.6% [213, 223, 252]. A lower blood calcium level and more pronounced symptoms are noted in patients who underwent bilateral neck exploration compared to those after minimally invasive PTE [223, 248, 249].

Hungry bone syndrome, leading to severe hypocalcemia, typically develops in the early postoperative period in patients with severe bone manifestations of primary hyperparathyroidism (PHPT). As a result of eliminating the stimulating effect of PTH overproduction on osteoclastic bone resorption, there is an active shift of minerals (calcium, phosphorus, magnesium) from the blood into the newly forming bone tissue. The main risk factors for the syndrome include advanced age and radiologically verified bone lesions (25–90% of cases vs. 0–6% without radiologically confirmed skeletal changes). According to most studies, hungry bone syndrome is associated with subperiosteal erosions, lytic bone lesions, brown tumors, and multiple fractures at the preoperative stage. Osteitis fibrosa cystica can be detected in 47–100% of patients with this syndrome. Other prognostically unfavorable factors are the weight and size of the parathyroid adenoma. The results of studies evaluating the relationship between the risk of hungry bone syndrome and a number of laboratory parameters (primarily PTH, calcium, alkaline phosphatase, osteocalcin, C-terminal telopeptide of type I collagen, and vitamin D levels) remain contradictory. There is insufficient data on the effective prevention of this condition [253].

Treatment with vitamin D preparations and its analogs after surgery is indicated for all patients with symptomatic PHPT, and in combination with calcium supplements for patients with symptoms of hypocalcemia and/or a decrease in albumin-corrected calcium below 2.1 mmol/L (ionized calcium below 1.0 mmol/L) [254-256] (see section 7.6). To correct hypocalcemia, which may persist for several months after successful parathyroidectomy, adequate correction of magnesium deficiency and normalization of bone turnover are required. Preoperative treatment with bisphosphonates (M05BA) may reduce the risks of postoperative hypocalcemia, but currently there are no prospective studies addressing this issue [113, 213, 253].

3.2. Conservative Treatment

Currently, there is no equivalent to surgical treatment for PHPT, as none of the drugs used can achieve an equal effect in normalizing laboratory parameters and improving bone mineral density compared to parathyroidectomy. Conservative treatment of PHPT using medications is primarily aimed at correcting hypercalcemia, preventing hypercalcemic crises, and preventing low-energy fractures.

• Patients with asymptomatic PHPT and no indications for surgery may be recommended a conservative management strategy with regular monitoring of the following parameters [18, 19, 30, 90, 189, 191, 193, 198, 257, 258]:

• serum total calcium and albumin testing (with calculation of albumin-corrected serum calcium) – once every 3–6 months;

• serum creatinine testing with GFR calculation (CKD-EPI) – once every 6 months;

• serum intact PTH testing – once every 6 months;

• urine calcium testing (24-hour urine collection) – once every 6 months;

• renal ultrasound once a year (retroperitoneal CT if necessary);

• dual-energy X-ray absorptiometry (DXA) of the lumbar spine, proximal femur, and forearm; lateral X-ray of the thoracic and lumbar spine if vertebral fractures are suspected (height loss, onset of back pain) once a year.

GCR ALoE 2Grade of Recommendation A (Level of Evidence – 2).

Comments: recommendations for the dynamic monitoring of patients with asymptomatic PHPT are based on the results of studies evaluating and comparing the natural course of the disease with surgical management [18, 19, 30, 90, 189, 191, 193, 257]. Currently, the maximum follow-up period for patients with PHPT without surgical treatment is 15 years [18]. According to the data obtained, during conservative therapy, biochemical parameters of phosphorus-calcium metabolism remained stable for 12 years, followed by a trend toward increasing serum calcium levels. BMD parameters remained without significant changes during the first 8-10 years of follow-up, followed by deterioration at the distal forearm and proximal femur. The emergence of one or more indications for surgical treatment over the entire follow-up period was recorded in 37% of patients [18]. Data on the natural progression of nPHPT remain limited. While some researchers reported high progression rates in the form of hypercalcemia, nephrolithiasis, hypercalciuria, fractures, and decreased BMD over a short follow-up period (22-41%) [30, 90], other authors obtained opposite results, indicating a low risk of PHPT-associated complications in this cohort of patients [17, 259].

All patients require a diet with moderate calcium intake and increased fluid intake up to 1.5–2.0 L per day [260]. Dietary recommendations regarding daily calcium intake in patients with PHPT remain controversial as data on this issue are limited. It is expected that restricting calcium intake will lead to a decrease in urinary calcium excretion and, consequently, a reduced risk of nephrolithiasis. On the other hand, a low-calcium diet may be accompanied by a greater increase in PTH levels and more pronounced bone demineralization, indirectly leading to a greater "calcium" burden on the kidneys. When comparing patient groups with a daily calcium intake of 300 mg, 300–800 mg, and more than 800 mg, no significant effect on serum calcium, PTH, 25(OH)D, 1,25(OH)₂D levels, or urinary calcium excretion was identified [261]. However, patients with higher 1,25(OH)₂D levels showed significantly higher PTH values and 24-hour calciuria [261]. In an open-label, one-year study as part of the large Tromsø epidemiological study (1994–1995), the hypothesis of the benefits of calcium supplementation in patients with asymptomatic PHPT and a low-calcium diet (<450 mg per day) was tested. Daily intake of 500 mg of calcium was associated with a decrease in PTH levels developed 4 weeks after the start of therapy and a significant increase in femoral neck bone mineral density after 52 weeks [262]. Studies confirming the benefits of drastic dietary calcium restriction in patients with PHPT are lacking in the literature.

There are data on the use of thiazide diuretics in patients with PHPT to correct hypercalciuria, prevent nephrolithiasis/nephrocalcinosis, and renal impairment. Recent studies have shown that a reduction in daily calcium excretion during treatment with minimum and average therapeutic doses of hydrochlorothiazide** in patients with PHPT did not lead to increased calcemia [263, 264]. Data on the effect of thiazides on PTH levels remain contradictory, necessitating large randomized clinical trials. The main limitations to the use of thiazides are a GFR below 30 mL/min/1.73 m², severe hypercalcemia, gout, and poorly controlled diabetes mellitus. When prescribing thiazides, regular monitoring of serum calcium, creatinine, magnesium, and potassium is required.

• Conservative treatment of patients with symptomatic PHPT or indications for parathyroidectomy may be recommended in the following cases [204, 265-268]:

• if the patient refuses surgical treatment;

• if there are contraindications to surgical treatment (severe comorbidities).

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: if parathyroid visualization fails using all available imaging modalities, conservative therapy helps stabilize disease progression, but the patient remains a candidate for surgery if a pathological parathyroid lesion is detected during follow-up.

• If surgery is not feasible, antiresorptive therapy (#alendronate sodium**, 10 mg daily or 70 mg once weekly, #denosumab** 60 mg subcutaneously every 6 months) and/or cinacalcet** therapy is recommended for patients with PHPT to correct hypercalcemia and reduce bone mass loss [269-273].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: antiresorptive therapy is indicated for patients with PHPT with a decrease in bone mineral density at the forearm, proximal femur, or lumbar spine of ≤-2.5 SD by T-score in postmenopausal women and men over 50 years of age based on DXA results, and/or in the presence of low-energy fractures when surgery cannot be performed [269].

Drugs of choice for the treatment of bone manifestations of PHPT are antiresorptive agents, which help reduce bone resorption activity to prevent the progression of bone loss. Bisphosphonates (M05BA) reduce osteoclast activity by enhancing their apoptosis and slow down bone resorption [274]. Based on the similarities in the pathogenetic mechanisms of postmenopausal osteoporosis and bone disorders in PHPT, several comparative studies have evaluated the efficacy and safety of oral bisphosphonates (M05BA) (#alendronic acid**) (Table 3). A meta-analysis of 25 observational studies and 8 randomized controlled trials evaluating the efficacy of surgical treatment versus bisphosphonate therapy (M05BA) demonstrated a comparable increase in BMD in the lumbar spine and proximal femur in both groups (at 1–2 years of follow-up) [270]. Data on the long-term efficacy of bisphosphonates (M05BA) regarding fracture risk are limited to individual studies [275-277].

Table 3. Clinical trial data on the efficacy of #alendronic acid**

* RCT – randomized controlled trial; ND – no data

Data on the effect of #denosumab** on BMD gains in patients with PHPT are limited [283-286]. However, according to the DENOCINA phase 3 randomized placebo-controlled double-blind study, the use of #denosumab** at a dose of 60 mg every 6 months is effective in improving BMD and reducing bone turnover rate in patients with PHPT regardless of concurrent cinacalcet** therapy [272]. #Denosumab** has a hypocalcemic effect and is therefore successfully used to manage severe hypercalcemia of oncogenic origin, including parathyroid carcinoma [287, 288]. Furthermore, #denosumab** has an advantage over bisphosphonates (M05BA) regarding BMD gains in cortical bone [289], as well as due to the absence of GFR restrictions.

Cinacalcet** reduces serum calcium and intact PTH levels by increasing the sensitivity of CaSR to extracellular calcium concentration. The use of cinacalcet** leads to sustained normalization of calcemia in 70-80% of patients with PHPT [290]. The effect may persist for up to 5 years, but serum calcium levels return to baseline immediately after discontinuation of therapy. This drug does not directly affect BMD parameters or bone resorption markers [290]. Convincing data on the drug's effect on hypercalcemia symptoms, nephrolithiasis, or quality of life are not presented in the literature. A retrospective evaluation of the efficacy of combination therapy with #alendronic acid** and cinacalcet** (for 12 months) showed a significant increase in BMD in the lumbar spine and proximal femur compared to cinacalcet** monotherapy, while a decrease in serum calcium levels was observed in both groups [291]. According to a phase 3 multicenter RCT evaluating cinacalcet** therapy in patients with PHPT and contraindications to surgery, normalization of calcemia was achieved in 76% compared to 0% in the placebo group. The drug was reported to be well tolerated, with side effects limited to mild nausea and occasional muscle cramps. Table 4 presents data from major studies on the use of cinacalcet** in PHPT.

Additional information on the conservative management of hypercalcemia is provided in Section 7.7.

Table 4. Data from studies on the efficacy of cinacalcet** in PHPT

* RCT – randomized controlled trial; ND – no data; PG – placebo; IG – intervention group.

• In patients with PHPT and a serum calcium level <3 mmol/L (<12 mg/dL), preoperative correction of concomitant vitamin D deficiency / insufficiency using cholecalciferol** is recommended to eliminate secondary elevation of iPTH, improve bone tissue status, and prevent the development of severe postoperative hypocalcemia [299]

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• In patients with PHPT and a calcium level >3 mmol/L (>12 mg/dL), correction of concomitant vitamin D deficiency / insufficiency prior to successful parathyroidectomy (PTX) is not recommended due to the lack of data on the safety of prescribing the drug [299]

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• In patients with PHPT after PTX with concomitant vitamin D deficiency/insufficiency, cholecalciferol** therapy is recommended to achieve the target 25(OH)-vitamin D level [184, 300].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments: Vitamin D deficiency in PHPT is associated with a more significant increase in iPTH levels and, consequently, more pronounced hypercalcemia, severe bone disorders, lower BMD values, and a higher risk of postoperative hypocalcemia, including hungry bone syndrome [87-89, 301], [452]. To eliminate secondary elevation of iPTH associated with vitamin D deficiency, it is necessary to maintain 25(OH)D levels at no less than 20 ng/mL (50 nmol/L); a level of >30 ng/mL (75 nmol/L) is considered optimal [32, 302, 303]. The issue of cholecalciferol** treatment regimens in patients with PHPT remains open. According to a meta-analysis of 10 observational studies (n=340), the use of this drug in loading doses (up to 100,000 IU per week) during the preoperative preparation stage was accompanied by a decrease in iPTH levels, a significant increase in 25(OH)D, and—in most cases—maintenance of baseline serum calcium and 24-hour urinary calcium levels. An increase in hypercalcemia resulting in drug discontinuation was registered in 2.2% of cases. This meta-analysis included studies with asymptomatic PHPT with a mean hypercalcemia level of 2.7-2.8 mmol/L [299]. A randomized double-blind study evaluating the efficacy and safety of cholecalciferol** at a dose of 2,800 IU daily for 6 months before and after surgery demonstrated a significant decrease in baseline iPTH levels with the achievement of optimal 25(OH)D values, while calcium levels and 24-hour urinary calcium remained unchanged [304].

Following successful PTX, a number of patients maintain an elevated iPTH level, which may be due to existing vitamin D deficiency/insufficiency [305-308]. Achieving an optimal vitamin D level after radical surgery helps normalize iPTH levels, ensure adequate calcium reabsorption, and improve BMD parameters [184, 300].

• In patients with PHPT who have undergone surgical treatment, monitoring of albumin-corrected and/or ionized calcium, creatinine, and iPTH levels is recommended 1 month after surgery; in the presence of concomitant 25(OH)D deficiency, extending the active follow-up period to 2-3 months with dynamic laboratory assessment is recommended to achieve the target vitamin D level [306, 308, 309].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

3.3 Other Treatment

• In patients with PHPT complicated by hypercalcemic crisis, urgent surgical treatment is recommended following intensive preoperative preparation aimed at correcting hypovolemia and reducing hypercalcemia [310-317].

GPP CLE 4Grade of Recommendation C (Level of Evidence 4)

Comments: severe hypercalcemia in patients with PHPT is currently rare. A sharp increase in serum calcium levels can lead to a hypercalcemic crisis and is triggered by severe intercurrent conditions such as infectious diseases, fractures, prolonged immobilization, or the use of antacids [310, 311]. A hypercalcemic crisis typically occurs when the albumin-corrected calcium level exceeds 3.5 mmol/L (ionized calcium above 1.8 mmol/L)* and is characterized by symptoms of multiorgan dysfunction, including gastrointestinal involvement (anorexia, nausea, intractable vomiting with dehydration, acute abdominal pain, acute pancreatitis), renal involvement (oliguria, acute renal failure, renal colic), cardiovascular involvement (conduction and heart rhythm disorders, QT interval shortening), and neurological involvement (myalgia, muscle weakness, confusion, stupor, coma in up to 40% of cases) [310-316].

Timely treatment of patients with a hypercalcemic crisis is critical, as this condition is associated with a high mortality rate [310, 312]. A hypercalcemic crisis in PHPT is an indication for emergency surgery. The patient's severe general condition, caused by pronounced hypercalcemia and concomitant multiorgan disorders, often precludes immediate parathyroidectomy (PTX). To reduce the risk of general anesthesia, conservative methods are used to correct hypovolemia, stimulate renal calcium excretion, and inhibit accelerated bone resorption. It is also necessary to eliminate the causes contributing to the progression of hypercalcemia and to compensate for intercurrent conditions (see Section 7.7).

Conservative treatment of patients with severe hypercalcemia should be regarded as "preparation" for surgical treatment and, whenever possible, carried out in an intensive care unit [310-316]. The optimal timing of PTX in patients with a hypercalcemic crisis remains debatable. Based on the results of topographical diagnostic methods, selective PTX can be considered the optimal strategy for the majority of patients. Nevertheless, severe hypercalcemia / hypercalcemic crisis may be due to parathyroid carcinoma in 4.5–12% of cases, which requires a more extensive surgical approach [313-315] (see Section 7.2).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• Patients with PHPT and associated bone complications following surgical treatment are recommended to undergo a comprehensive rehabilitation program to improve BMD recovery, reduce the incidence of falls, and prevent low-trauma fractures [97].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

5. Prevention and Dispensary Observation

• Follow-up dual-energy X-ray absorptiometry to assess BMD gains is recommended for patients with PHPT one year after surgical treatment and subsequently once a year for 3 years [18, 19, 149, 187, 191, 192, 318, 319].

GCR CLOE 4Grade of Recommendation C (Level of Evidence – 4

Comments:

As a rule, active restoration of bone metabolism and a significant increase in BMD (on average 5-10% per year), depending on the severity of bone loss and the patient's age, occur within the first 2 years after successfully performed PTX. During this period, no additional treatment is required, except for maintaining adequate levels of 25(OH)vitamin D and calcium [18, 19, 149, 187, 191, 192, 318].

• For patients with PHPT, treatment of disease complications (nephrolithiasis / nephrocalcinosis, gastric and duodenal ulcers, rhythm disturbances, and other disorders) after successful PTX should be recommended under the supervision of appropriate specialists, if necessary [10, 74].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

6. Organization of Medical Care

Outpatient stage of medical care:

1) laboratory testing with determination of biochemical parameters of calcium-phosphorus metabolism in blood and urine;

2) consultations with related specialists as indicated: initial/follow-up consultation (examination) by a urologist, initial/follow-up consultation (examination) by a nephrologist, initial/follow-up consultation (examination) by a cardiologist, initial/follow-up consultation (examination) by a neurologist;

3) adjustment of standard therapy under a conservative management strategy.

Indications for elective hospitalization:

1) the need for a comprehensive examination assessing the main parameters of calcium-phosphorus metabolism and bone-visceral manifestations of PHPT to determine further management tactics (conservative management vs. surgical treatment); the need for instrumental examination for topographical diagnostics of parathyroid lesions if indications for surgical treatment are present;

2) the need for a comprehensive examination assessing the main parameters of calcium-phosphorus metabolism and bone-visceral manifestations of PHPT under a conservative management strategy;

3) the need for planned surgical treatment in a specialized hospital;

4) the need for a comprehensive laboratory and instrumental examination to assess the efficacy of surgical treatment.

Indications for emergency hospitalization:

1) severe hypercalcemia with the risk of a hypercalcemic crisis.

Indications for discharging the patient from the hospital:

1) persistent clinical improvement, when the patient can continue treatment in an outpatient clinic or at home without detriment to health, or a stable condition of the patient followed by planned hospitalization in a surgical department for surgical treatment;

2) if necessary, transfer of the patient to another medical organization;

3) gross violation of the hospital regime;

4) upon the written request of the patient or their legal representative, provided that discharge does not threaten the patient's life and is not dangerous to others. In this case, discharge may only be carried out with the permission of the hospital's chief physician or their deputy for medical work.

7. Additional Information

7.1 Hereditary forms of primary hyperparathyroidism

Up to 10% of PHPT cases are hereditary in nature (Table 5). Hereditary forms of PHPT are characterized by manifestation at a young age and the absence of gender differences [5]. Molecular genetic testing allows for a timely diagnosis and the initiation of screening for syndrome components and their treatment, which is particularly important for the asymptomatic course of diseases.

Table 5. Hereditary syndromes associated with the development of PHPT

Abbreviations: AD — autosomal dominant. MEN1 — gene encoding the menin protein; RET — proto-oncogene encoding a receptor tyrosine kinase, CDKN1B — gene encoding the cyclin-dependent kinase inhibitor p27(Kip1), HRPT2/CDC73 — gene encoding the parafibromin protein, CaSR — gene encoding the calcium-sensing receptor. ¹ MEN-2A syndrome does not occur as a cause of FIHP. ² In some families with FIHP, mutations in the MEN1, CaSR or CDC73/HRPT2 genes have been detected.

• Diagnostic evaluation for multiple endocrine neoplasia type 1 syndrome, including molecular genetic testing, is recommended for patients presenting with one or more of the following features [320]:

- manifestation of PHPT in patients under 40 years of age;

- multiglandular parathyroid involvement at any age;

- persistent/recurrent PHPT;

- presence of 2 or more MEN-associated lesions (parathyroid tumors, pancreatic neuroendocrine tumors (NETs), pituitary adenoma);

- first-degree relative who is a carrier of a MEN1 gene mutation (even in the absence of symptoms);

- gastrinoma or pancreatic NET at any age in the presence of 2 or more MEN-associated tumors not belonging to the classic MEN-1 triad.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: MEN-1 syndrome is an autosomal dominant disorder caused by germline mutations in the MEN1 gene. MEN1 is a tumor suppressor gene encoding the menin protein, which regulates various functions of cellular and genomic homeostasis. No genotype-phenotype correlations have been identified for the disease [5]. The prevalence of the syndrome is 2–3 cases per 100,000 population. To identify potential carriers of MEN1 gene mutations, a thorough history of both the patient and their immediate family members is required.

MEN-1 syndrome is characterized by the concurrent development of parathyroid tumors (in 95% of cases), anterior pituitary adenomas (15–55%), and pancreatic islet cell tumors (30–80%), which constitute the "classic triad" of the disease. Tumors of the adrenal glands, thymic NETs, lung and gastrointestinal NETs, angiofibromas, collagenomas, lipomas, leiomyomas, meningiomas, and others are diagnosed less frequently [321-327]. Most neoplasms associated with the syndrome are benign, and the clinical presentation is generally driven by hormonal hypersecretion or "mass effect," though a high risk of malignant progression persists. The life expectancy of patients with MEN-1 syndrome is lower than that of the general population, averaging about 55 years [325, 328]. The most frequent causes of death are duodenopancreatic neuroendocrine tumors as well as thymic and bronchial carcinoids [325].

Primary hyperparathyroidism (PHPT) is typically the earliest manifestation of the syndrome (up to 75%) [321, 329, 330], with the prevalence of MEN-1 among PHPT patients ranging from 1% to 18% [329]. The onset of PHPT in MEN-1 usually occurs between the ages of 20 and 25 [324, 329, 331], and the penetrance of the disease in MEN-1 reaches 90–100% with age [332]. Parathyroid involvement is frequently multiple and usually does not occur simultaneously (multiple hyperplasias or adenomas). In 20% of cases, supernumerary and ectopic parathyroid glands are involved, potentially localizing in the thymus, thyroid gland, anterior mediastinum, and occasionally the pericardium [329, 333, 334]. The clinical presentation includes both asymptomatic (asymptomatic hypercalcemia) and symptomatic forms of PHPT (nephrolithiasis, osteitis fibrosa cystica, polydipsia-polyuria syndrome, gastrointestinal mucosal ulcerations). MEN-1–associated PHPT is characterized by a higher recurrence rate compared to sporadic forms [321, 329, 335].

Pituitary adenomas are predominantly prolactinomas (65%) and somatotropinomas (25%), while corticotropinomas and non-functioning pituitary adenomas are less common (approximately 5%) [326]. The mean age at manifestation is 38 years; in 25% of sporadic and 10% of familial MEN-1 cases, pituitary adenomas may be the initial manifestation of the syndrome [322, 334]. The mean age at diagnosis of GI NETs is approximately 40 years, and by age 80, roughly 80% of MEN-1 patients develop a duodenopancreatic NET [336-338]. Non-functioning pancreatic NETs are among the most common enteropancreatic lesions (50–80% in individuals under 50 years of age) and carry a worse prognosis compared to functioning lesions [325]. Functioning lesions are diagnosed less frequently: gastrinomas (~20–30%), insulinomas (~10%), VIPomas, and glucagonomas (<5%) [325, 339].

According to studies, the probability of a genetic etiology for PHPT increases as the age of disease onset decreases [321]; however, recommendations for genetic screening under the age of 30, 35, or 40 have not been established [332, 340-343]. A separate group includes patients with PHPT under 40 years of age presenting with concurrent multiglandular parathyroid involvement, as this group has the highest suspicion for MEN-1 syndrome despite the absence of a significant family history [340, 344]. Findings from pilot studies in the Russian population indicate a shift in the age of disease manifestation to the 3rd decade of life; therefore, genetic testing is warranted in cases of PHPT onset under the age of 40 [334, 345].

• Patients with symptomatic PHPT in the context of MEN-1 syndrome are recommended to undergo surgical treatment in the form of subtotal or total parathyroidectomy with autotransplantation to prevent disease recurrence [237, 346-351].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: The goals of PHPT treatment in MEN-1 include: achieving and maintaining sustained normocalcemia, and reducing the risk of persistent postoperative hypocalcemia. Due to the multiglandular parathyroid involvement in MEN-1 syndrome, the primary treatment modality for PHPT remains bilateral neck exploration with subtotal (≥ 3.5 glands) or total parathyroidectomy and autotransplantation of a piece of the least altered tissue into the brachioradialis muscle, which carries the lowest risk of disease recurrence [346-350]. The incidence of chronic hypoparathyroidism, including severe cases, is significantly higher in the total parathyroidectomy group compared to the subtotal parathyroidectomy group [346-348]. When choosing the extent of surgery, factors such as the severity of parathyroid changes, the surgeon's experience, and the feasibility of long-term calcium monitoring must be taken into account. A unified consensus regarding the optimal timing of surgical treatment has not been reached. Early parathyroidectomy can significantly reduce the frequency and severity of long-term hyperparathyroidism complications, but is associated with earlier PHPT recurrence and the development of chronic hypoparathyroidism [351]. Patients with asymptomatic forms of the disease should be managed with active surveillance, including regular evaluation of calcium and phosphorus metabolism parameters, and undergo parathyroidectomy if the disease progresses [352].

The option of concurrent transcervical thymectomy is being discussed, given the risk of parathyroid ectopy in the thymus and the risk of thymic NET development [349, 350, 353, 354], although the efficacy of this approach remains controversial [353, 355].

• Patients with verified MEN-1 are recommended to undergo regular comprehensive laboratory and instrumental evaluations aimed at the timely diagnosis of the syndrome's components [322-324, 335, 356].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Patients with verified MEN-1 require regular lifelong follow-up due to the risk of developing new components of the syndrome. The required investigations and their frequency are presented in Table 6.

Table 6. Biochemical and radiological screening in patients with MEN-1 syndrome

Note: PP – pancreatic polypeptide; VIP – vasoactive intestinal polypeptide; IGF-1 – insulin-like growth factor 1.

• Diagnostic evaluation for multiple endocrine neoplasia type 2A (MEN-2A) syndrome, including molecular genetic testing, is recommended for patients with one or more of the following features [320, 333, 357-361]:

- a history of medullary thyroid carcinoma or at the time of PHPT diagnosis;

- a history of pheochromocytoma or at the time of PHPT diagnosis;

- data indicating the presence of medullary thyroid carcinoma and/or pheochromocytoma and/or MEN-2A syndrome in first-degree relatives.

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: MEN-2A syndrome manifests with the development of medullary thyroid carcinoma (90-100%), pheochromocytoma (50%), PHPT (20-30%), and is caused by germline mutations in the RET proto-oncogene leading to its gain of function [357-359]. RET is a tyrosine kinase-linked receptor involved in the regulation of cell growth, differentiation, and survival. Mutation of the RET gene in embryonic cells leads to the expression of a pathologically altered, hyperactive RET protein in neuroendocrine tissues, resulting in uncontrolled cellular proliferation. The RET mutation at codon 634 is associated with the development of PHPT [5]. In MEN-2A, PHPT precedes the development of other components in only 5% of cases; in the overwhelming majority, the disease is detected during surgery for medullary thyroid carcinoma or years after it. PHPT has a milder course compared to MEN-1 syndrome and is asymptomatic in 42-84% of cases [333, 360, 361]. The mean age at diagnosis is 35-39 years [357]. A single clinical case has been described of a 5-year-old girl from a MEN-2A family who was diagnosed with PHPT prior to prophylactic thyroidectomy (in the absence of thyroid pathology) [362]. More frequently than in MEN type 1 (27-48%), only a single parathyroid gland is affected, and paired adenomas or hyperplasia are detected in only 8% of cases [363, 364].

• In patients with verified MEN-2A syndrome, surgical treatment of PHPT is recommended in the scope of removal of the altered parathyroid glands (parathyroidectomy) [205, 361, 365, 366].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: there is currently no consensus regarding the scope of surgical treatment for PHPT in the context of MEN-2A. An ongoing clinical challenge is the high risk of severe chronic hypoparathyroidism, primarily caused by extended thyroidectomy performed for medullary thyroid carcinoma. In patients with MEN-2A who have undergone prophylactic thyroidectomy, serum calcium levels must be assessed during the preoperative evaluation stage. In addition, prior to surgeries for either medullary thyroid carcinoma or PHPT, the diagnosis of pheochromocytoma must be ruled out [359].

Surgical treatment options for PHPT include: removal of visually altered parathyroid glands; subtotal parathyroidectomy (PTX); total PTX with heterotopic autotransplantation [205, 365, 366]. Most experts lean toward removing only the pathologically altered parathyroid glands. This approach in MEN-2A syndrome reliably avoids chronic hypoparathyroidism, and the probability of recurrence from the remaining unaffected parathyroid glands after initial surgery is extremely low [361]. Subtotal and total PTX with heterotopic autotransplantation are justified in cases of multiglandular parathyroid involvement [361].

• Diagnostic evaluation for hyperparathyroidism-jaw tumor (HPT-JT) syndrome, including molecular genetic testing, is recommended for patients with one or more of the following features [367-371]:

- presence of a first-degree relative with HPT-JT syndrome;

- parathyroid carcinoma;

- presence of ossifying fibromas of the mandible/maxilla;

- presence of polycystic kidney disease, renal tumors, uterine tumors.

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: HPT-JT syndrome is a rare autosomal dominant disorder. The cause is a mutation in the CDC73 (HRPT2) gene encoding parafibromin. It is characterized by the development of PHPT, ossifying fibromas of the mandible and/or maxilla in 30-40% of cases, uterine tumors (leiomyomas, endometrial hyperplasia, adenosarcomas, adenofibromas, multiple adenomatous polyps) in 57.3% of female patients, and less frequently renal involvement (hamartomas, polycystic kidney disease, Wilms tumors, adenocarcinomas) in 13.3% of cases. The true prevalence of HPT-JT syndrome remains unknown. By 2015, fewer than 300 cases of the disease from approximately 100 families had been described [367-371].

PHPT is the primary manifestation of HPT-JT and is detected in approximately 95% of cases of this disease [367, 370]. The frequency of PHPT increases with age, although the disease manifests at an early age; the youngest reported age for parathyroid carcinoma is 20 years [372]. PHPT in the context of HPT-JT is usually caused by a single benign parathyroid adenoma, cystic or with atypical histological features. Unlike other hereditary variants of PHPT, the prevalence of parathyroid carcinomas in HPT-JT is higher, reaching 10-21.6% [367]. Multiglandular disease is rarely diagnosed at initial surgery (20% of cases); a second parathyroid adenoma may appear metachronously years or decades after the primary tumor (23.9% of cases). The disease may be asymptomatic, and parathyroid carcinomas frequently present with hypercalcemic crises [367].

The optimal surgical approach for PHPT in the context of HPT-JT has not yet been established. Previously, some authors recommended bilateral neck exploration and subtotal PTX or total PTX with or without autotransplantation due to the risk of multiglandular disease and malignancy. However, autotransplantation may potentially be associated with the dissemination of cancer cells. Recently, selective PTX has been more frequently proposed when a single parathyroid gland is affected and there is no suspicion of malignancy. This strategy provides a lower risk of developing hypoparathyroidism. In cases of suspected parathyroid carcinoma (large parathyroid lesions with infiltrative growth, extremely high calcium and intact PTH levels), en bloc resection is preferred, removing the parathyroid tumor, the ipsilateral hemithyroid, surrounding adipose tissue, and any tissue adherent to the tumor to prevent tumor disruption and dissemination [367, 368].

Other hereditary syndromes in which PHPT may occur are extremely rare, which precludes the formation of clinical guidelines for their diagnosis and treatment. However, they should be suspected in the presence of the following features characteristic of each syndrome.

In the presence of clinical features of MEN-1 syndrome and in the absence of a MEN1 gene mutation, multiple endocrine neoplasia type 4 (MEN-4) syndrome should be suspected, which is caused by a mutation in the CDKN1B gene. The most frequent components of the syndrome are PHPT and pituitary adenomas. Other manifestations include bronchial and gastric neuroendocrine tumors (NETs), gastrinomas, papillary thyroid carcinoma, and mass lesions of the pancreas and adrenal glands. It is extremely rare, with only isolated cases described worldwide. Treatment consists of surgical removal of a single parathyroid adenoma or subtotal PTX [373].

If a family has several members with PHPT and no other endocrine or non-endocrine tumors, familial isolated hyperparathyroidism (FIHP) should be suspected. It is a rare autosomal dominant disorder characterized by single or multiple parathyroid gland involvement in the absence of specific manifestations of other syndromes (MEN1, HPT-JT, FHH). More than 100 families with FIHP have been described to date, but the genetic basis remains unknown in most cases [7, 374, 375]. In 20–23% of cases, the disease is caused by a germline MEN1 mutation, in 14–18% by CaSR, less frequently by CDC73, and extremely rarely by CDKN1A, CDKN2B, and CDKN2C [374]. PHPT as part of FIHP may manifest with hypercalcemia, osteoporosis, and nephrolithiasis, or be asymptomatic. The optimal surgical approach for PHPT in FIHP has not been established. Selective parathyroidectomy (PTX) may be performed for single parathyroid gland involvement, while subtotal resection is recommended for multiglandular disease. In the presence of MEN1 and CDC73 mutations, management follows MEN1 and HPT-JT protocols [7].

7.2. Parathyroid Cancer

Parathyroid cancer (carcinoma) is a rare pathology characterized by a severe clinical course and high mortality due to marked hypercalcemia. Often, the diagnosis of parathyroid carcinoma is established years after disease onset when a recurrence develops.

Parathyroid cancer accounts for less than 1% of PHPT cases [376]. According to a retrospective analysis of a US database, the proportion of parathyroid cancer among all malignant neoplasms is approximately 0.005% (0.015 per 100,000 general population) [240, 377]. According to the US SEER (Surveillance, Epidemiology, and End Results) registry, an incidence increase of 60% in parathyroid cancer was recorded in the USA from 1988 to 2003 (3.58 per 10 million population from 1988 to 1991; 5.73 per 10 million population from 2000 to 2003) [376]. The increased incidence in some countries is most likely associated with growing interest in this issue, attempts to systematize diagnostic approaches, and improved quality of morphological examinations [378]. According to a retrospective analysis of postoperative material from 358 PHPT patients conducted at the National Medical Research Center for Endocrinology of the Russian Ministry of Health, parathyroid cancer was diagnosed in 5% of cases [379].

The capabilities of preoperative differential diagnosis between malignant and benign parathyroid tumors are sharply limited. The clinical picture is nonspecific and, as a rule, caused by symptoms of hypercalcemia [378]. Given the absence of specific markers for parathyroid cancer, physicians currently have to rely solely on a combination of certain clinical and laboratory features.

• Patients with a verified diagnosis of PHPT are recommended to be classified into the high-risk group for malignant parathyroid tumors in the presence of the following signs:

- a combination of albumin-corrected calcium elevation > 3 mmol/L and one of the longitudinal dimensions of the parathyroid lesion > 3 cm [380];

- blood ionized calcium levels > 1.6–1.7 mmol/L [114, 378, 379];

- mass-effect symptoms in the absence of other space-occupying lesions and prior neck surgery in the history [114, 381–383].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: it is generally accepted that parathyroid cancer is characterized by a more severe course and a prominent clinical presentation; nevertheless, asymptomatic cases of carcinoma have been described in the literature (about 5% of all parathyroid cancer cases), where the clinical picture is limited solely to mechanical pressure on surrounding tissues, i.e., a "mass effect" [384]. The "mass effect" may manifest as a foreign body sensation in the neck, hoarseness, and dysphagia, which do not typically trouble patients with benign parathyroid tumors. A lump-in-the-throat sensation occurs in approximately 40% of patients with parathyroid carcinoma, which can be mistakenly attributed to a thyroid or thymus mass.

The main clinical, laboratory, and instrumental characteristics of parathyroid cancer are summarized in Table 7. Preoperative topographical diagnostics for malignant parathyroid tumors correspond to the general principles of topographical diagnostics in PHPT [329].

Table 7. Comparative table of clinical and biochemical manifestations of malignant and benign parathyroid tumors [240, 380, 382, 385]

2(N)* - 2-fold increase in ipTH relative to the upper limit of the reference range

• In the presence of intraoperative signs of malignant parathyroid involvement, PHPT patients are recommended to undergo en bloc tumor resection together with adjacent tissues to prevent disease recurrence [240, 380, 386, 387].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: en bloc surgical removal of the tumor along with adjacent tissues remains the treatment of choice for parathyroid cancer. The main goal is to avoid rupture of the carcinoma capsule during surgery, which is an adverse prognostic factor. The minimum extent of surgery when parathyroid cancer is suspected should include, in addition to removing the parathyroid gland itself, resection of the adjacent thyroid lobe and surrounding adipose tissue, as well as any tissue fused with the tumor [380, 386, 387]. According to recent retrospective studies, prophylactic lymphadenectomy does not affect survival rates while carrying risks of numerous complications [388].

Preoperative diagnosis of malignant parathyroid tumors is difficult; the surgeon's experience is of great importance in helping to suspect carcinoma during surgery and perform the necessary volume of surgical intervention. Parathyroid cancer is typically characterized by a dense tumor consistency, adhesion to surrounding tissues, and the presence of altered lymph nodes [380, 386, 387].

In cases of retrospective diagnosis and when disease remission is achieved after selective parathyroidectomy (PTX), the question of reoperation should be decided on an individual basis.

• A definitive diagnosis of parathyroid cancer in PHPT patients is recommended to be established based on morphological examination results meeting criteria for malignant tumor growth: invasive growth and/or presence of metastases [383].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: the updated 2022 World Health Organization (WHO) classification of endocrine organ tumors states that parathyroid carcinomas should include tumors with at least one of the following features: 1) vascular invasion; 2) lymphatic invasion; 3) peri- or intraneural invasion; 4) invasion into adjacent anatomical structures (such as the thyroid gland and soft tissues); 5) histologically or cytologically confirmed metastases [389].

Atypical parathyroid adenoma is a rare pathology. This group of tumors is characterized by features associated with malignant potential (broad fibrous bands, mitoses, adherence to neighboring structures [without invasion into them], presence of tumor cell complexes within the capsule surrounding the adenoma, solid or trabecular growth pattern, nuclear atypia, prominent nucleoli), but lacks definitive signs of invasive growth [389], [390]. Atypical adenomas can be considered tumors with uncertain malignant potential, while the majority of patients have a favorable prognosis; however, cases of disease recurrence (most commonly metachronous involvement) and metastasis have been described, necessitating dynamic patient monitoring [391].

The TNM classification of parathyroid cancer was first proposed and published in 2017 (8th edition of the American Joint Committee on Cancer staging manual). Nevertheless, a unified staging system for these tumors has not yet been developed [391, 392].

• Patients with verified parathyroid cancer are recommended to undergo molecular genetic testing to rule out germline mutations in the CDC73 gene [6, 378, 393–395].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: currently, the key role in the development of parathyroid cancer is assigned to mutations in the CDC73 (HRPT2) gene [396]. The detection of loss of heterozygosity at the 1q31.2 locus in parathyroid tumors from patients with germline CDC73 mutations indicates biallelic gene inactivation in the tumor and is consistent with the putative function of parafibromin as a tumor suppressor. To date, over 110 mutations (2/3 of which are germline; 1/3 are somatic) in the CDC73 gene are known. Mutations can be inherited or arise de novo. Germline CDC73 mutations can lead to HPT-JT syndrome (see the chapter "Hereditary Syndromes") [397]. Studies on parathyroid cancer in the Russian population are limited. According to one study, nonsense mutations were identified in three out of four female patients with parathyroid cancer [393].

• Patients with verified parathyroid cancer are recommended lifelong dynamic follow-up (dispensary appointments (examinations, consultations) by an oncologist and an endocrinologist) for the timely diagnosis and treatment of disease recurrence [383].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: parathyroid carcinoma is characterized by slow tumor growth and late metastases to the lungs, cervical lymph nodes, liver, and bones. Metastases to the pleura, pancreas, and pericardium are less common [107]. The absence of remission, as well as PHPT recurrence, is established by a combination of hypercalcemia and elevated intact PTH (iPTH) levels. An increase in iPTH with normocalcemia or hypocalcemia should be differentiated from secondary hyperparathyroidism.

In the case of proven parathyroid cancer metastasis, its surgical removal is recommended when feasible. Resection of distant metastases increases patient survival by achieving normocalcemia (hypercalcemia is the main cause of death in patients with parathyroid cancer) [123]. In the absence of remission or in case of PHPT recurrence after surgical treatment in a patient with parathyroid cancer, standard instrumental diagnostic methods are advisable to search for metastatic lesions.

The search for secondary lesions (metastases), most frequently localized in the bones, is complicated by the presence of osteitis fibrosa cystica, characteristic of the majority of parathyroid cancer cases, while their differential diagnosis using bone scintigraphy is currently not feasible. Osteitis fibrosa cystica with the formation of brown tumors in severe PHPT is often the cause of false-positive conclusions regarding metastatic bone involvement [398-400].

• Routine chemotherapy is not recommended for patients with disseminated parathyroid cancer [401, 402].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• Radiation therapy for patients with disseminated parathyroid cancer is recommended by decision of a multidisciplinary team in a specialized inpatient setting [383, 403, 404].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: parathyroid cancer is insensitive to chemo- and radiotherapy. In most patients, radiation therapy does not lead to tumor growth deceleration or a reduction in its hormonal activity [383]. Results of the successful use of radiation therapy as adjuvant treatment after surgery are ambiguous and have been demonstrated in a small sample [403].

• If radical treatment for parathyroid cancer is impossible (in cases of its disseminated form), conservative therapy is recommended for patients [287, 405-409].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: severe hypercalcemia, which often accompanies parathyroid cancer, is a life-threatening condition requiring conservative correction when radical surgical treatment is not feasible. Under these conditions, the risk of developing a hypercalcemic crisis increases; general principles of hypercalcemia correction are used for its prevention (see section 7.7)

Cinacalcet is the first-line drug for patients with disseminated parathyroid carcinoma** [408, 409]; however, more effective management of hypercalcemia often requires its combination with bisphosphonates (M05BA) or #denosumab** [287, 410]. The dose of cinacalcet** can be increased up to 360 mg per day if necessary. To correct hypercalcemia in parathyroid carcinoma, higher doses and more frequent administration of drugs may be required: the #denosumab** administration regimen is 120 mg subcutaneously every 28 days. #Denosumab** has demonstrated superior efficacy compared to zoledronic acid** in patients with bone metastases [411–413]. Compared to intravenous bisphosphonates (M05BA) #denosumab** appears to be the preferred drug in patients with CKD due to the absence of nephrotoxicity. The evaluation of treatment efficacy and the decision on dose adjustment should be based primarily on the assessment of calcemia rather than the intact PTH level.

The first positive results of targeted therapy with protein kinase inhibitors have been obtained in patients with disseminated forms of parathyroid carcinoma [414, 415]. The possibility of prescribing such treatment should be discussed and decided at federal-level medical institutions based on the results of a multidisciplinary board review.

• If the morphological examination of the postoperative specimen diagnoses an atypical parathyroid tumor, it is recommended to perform an immunohistochemical study with staining for endothelial markers and PTH (pathological examination of biopsy (surgical) material of the parathyroid gland using immunohistochemical methods) to rule out parathyroid carcinoma [451].

GCR BLeL 3 Grade of Recommendation B (Level of Evidence – 3

Comments: Based on the results of the immunohistochemical study, in 18.5% of cases the initial morphological diagnosis of an atypical tumor is revised to parathyroid carcinoma; among them, vascular invasion identified by vascular endothelial staining is detected in 82% [451]. Differential diagnosis of various parathyroid lesions is critically important in determining the further prognosis and management tactics for patients.

7.3. Hyperparathyroidism and Pregnancy

The detection rate of primary hyperparathyroidism among women of childbearing age is about 8 per 100,000 population/year, and among pregnant women, from 0.15% to 1.4%. In 67% of cases, primary hyperparathyroidism during pregnancy leads to maternal complications and in 80% to fetal pathology. The rate of antenatal fetal death or neonatal death can reach 20–30% [416].

• The diagnosis of primary hyperparathyroidism during pregnancy is recommended to be established based on an elevated level of albumin-corrected and/or ionized calcium (measured twice) combined with an elevated intact PTH level [417–420].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: hypercalcemia is one of the main biochemical markers of primary hyperparathyroidism. During pregnancy, as a result of active calcium transport from mother to fetus, increased urinary calcium excretion, and hypoalbuminemia, total calcium levels may decrease, which significantly complicates timely diagnosis. Therefore, the initial diagnosis of primary hyperparathyroidism during pregnancy should be based on the assessment of calcemia with the determination of ionized and/or albumin-corrected calcium (study of total calcium levels in blood, study of blood albumin levels, study of ionized calcium levels in blood), which are the most informative indicators. The diagnosis of primary hyperparathyroidism should be suspected if elevated albumin-corrected or ionized calcium, or hypophosphatemia is detected in combination with an increased intact PTH level [417, 418]. In addition, screening for hyperparathyroidism should be performed in case of any metabolic bone disorders, non-traumatic fractures, recurrent urolithiasis, persistent pancreatitis, recurrent gastric or duodenal ulcers, or diabetes insipidus syndrome [417].

• Parathyroid ultrasound (ultrasonography of the parathyroid glands) in pregnant patients with primary hyperparathyroidism is recommended as the primary topographic diagnostic method [421, 422].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: the primary method of topographic diagnosis of primary hyperparathyroidism during pregnancy is parathyroid ultrasound (ultrasonography of the parathyroid glands). Computed tomography (computed tomography of the neck with intravenous bolus contrast enhancement, computed tomography of the mediastinum with intravenous bolus contrast enhancement) and parathyroid scintigraphy are generally not used due to potential risk to the fetus [421, 422]. Radiation risks depend on gestational age and absorbed dose. They are maximal during organogenesis and the early embryonic period, decrease somewhat in the second trimester, and are minimal in the third trimester. In utero irradiation is associated with an increased risk of fetal developmental anomalies, mental retardation, growth restriction, pregnancy loss, or cancer due to ionizing radiation [423].

In a quarter of cases, primary hyperparathyroidism (PHPT) during pregnancy can be asymptomatic and manifest only as laboratory-confirmed mild hypercalcemia [418]. However, the development of clinical manifestations correlates with the severity of hypercalcemia and is characterized by both bone and visceral disorders. Nephrolithiasis is the most frequent manifestation of PHPT during pregnancy (26–36%). Other disorders include depression, constipation, low-energy fractures, maternal cardiac arrhythmias, pancreatitis, hypercalcemic crisis, or hyperemesis gravidarum. In some cases, the lack of timely diagnosis and treatment leads to acute renal and cardiovascular failure. Central nervous system involvement occurs only in extremely severe hypercalcemia and presents as psychosis, altered consciousness ranging from clouding to coma. Arterial hypertension and preeclampsia are observed in 25% of pregnant women with the manifest form of PHPT [418, 424].

Hypercalcemic crisis is the most dangerous complication of PHPT during pregnancy, most frequently developing in the early postpartum period after the cessation of maternal calcium outflow through the placenta to the fetus. In these cases, blood calcium levels usually exceed 3.5 mmol/L, accompanied by nausea, vomiting, extreme weakness, and psychiatric disorders. Maternal hypercalcemic crisis can lead to perinatal death in 25% of cases and neonatal tetany in 50%. In some cases, uremia develops, leading to a fatal outcome [425].

Fetal complications are noted in 80% of PHPT cases in pregnant women who did not receive timely pathogenetic treatment [426]. The most frequent and severe complication of maternal hypercalcemia is neonatal hypocalcemia, which develops due to the suppression of fetal parathyroid gland development and manifests as both tetany and stillbirth [427]. Perinatal complications can develop in 46% of cases, and neonatal complications in 45%. Tetany is the main cause of mortality. Other fetal complications include preterm birth (13%), intrauterine growth restriction, neonatal tetany (25%), stillbirth, and—rarely—persistent hypoparathyroidism [427].

• In the presence of absolute indications for surgical treatment in pregnant patients with PHPT, it is recommended to perform parathyroidectomy (PTX) in the second trimester [421, 428–432].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: surgical treatment is the only effective method when the albumin-corrected calcium level increases by more than 0.25 mmol/L above the upper limit of the reference range established by the given laboratory. Parathyroidectomy effectively eliminates persistent maternal hypercalcemia and, consequently, reduces the risk of fetal complications. Conservative therapy for PHPT during pregnancy may lead to an increased incidence of neonatal complications (53%) compared to surgical removal of the parathyroid gland tumor (12.5%) [418].

Surgical treatment is optimally performed in the second trimester of pregnancy, when organogenesis is complete and the risk of preterm birth is significantly lower compared to the third trimester [421, 428–430]. Nevertheless, if PHPT is diagnosed in the third trimester of pregnancy, the feasibility of surgical treatment remains controversial and must be decided on an individual basis [433]. If surgery can be delayed (in cases of mildly pronounced hypercalcemia), surgical removal of the parathyroid tumor should be performed as early as possible after delivery to prevent a hypercalcemic crisis. In some cases, simultaneous cesarean section and PTX are required, which reduces risks for both the fetus and the mother [434]. The efficacy of PTX in a specialized center reaches 95%, while the risk of postoperative complications (recurrent laryngeal nerve palsy, hypocalcemia) is only 1–3%. Intraoperative PTH assay is necessary to assess the radicalness of the surgery [416].

• Conservative management of PHPT during pregnancy may be recommended for patients with an asymptomatic course of the disease and a calcium level elevation of no more than 0.25 mmol/L (1 mg/dL) above the upper limit of the reference range [418, 421].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: in cases of asymptomatic PHPT with a moderate increase in calcium levels, conservative management of patients is permitted, maintaining adequate hydration and regular monitoring of phosphorus-calcium metabolism parameters. In case of vitamin D deficiency, cholecalciferol** is indicated, as this prevents further secondary increases in iPTH levels and is necessary to prevent neonatal hypocalcemia in the early postpartum period and hungry bone syndrome in the mother. However, rapid loading with vitamin D and its analogs can lead to a hypercalcemic crisis; therefore, small doses of cholecalciferol** (500–1000 IU/day) and frequent monitoring of phosphorus-calcium metabolism parameters must be used [418, 421].

• Pharmacotherapy of PHPT during pregnancy is not recommended due to potential harm to fetal development [435-439]

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: calcitonin** is a category C drug. Calcitonin** does not cross the placental barrier, which is considered its advantage. However, its low efficacy and the risk of tachyphylaxis limit its use during pregnancy [435].

Bisphosphonates (M05BA) belong to category C drugs. Currently, there are no controlled randomized clinical trials on the safety of #alendronic acid** during pregnancy and lactation. In animal studies, the use of high doses of these drugs (8 times exceeding the average therapeutic doses) in pregnant rats was characterized by a teratogenic effect: the appearance of bone malformations and impaired endochondral bone development in the fetus. The literature presents isolated cases of bisphosphonates (M05BA) use during pregnancy not accompanied by teratogenic effects; nevertheless, their use is possible on an individual basis solely by the decision of a medical commission [436].

Cinacalcet** belongs to category C drugs. To date, there are no reliable data on the effect of the drug on calcium metabolism in the fetus. Calcium-sensing receptors are present in the placenta; therefore, the use of cinacalcet** may disrupt transplacental calcium transport and cause suppression of fetal PTH secretion and subsequent neonatal hypocalcemia. On the other hand, the negative impact of cinacalcet** on the activity of fetal parathyroid glands, which are in a suppressed state due to maternal primary hyperparathyroidism, does not appear significant. Isolated cases of cinacalcet** use during pregnancy have been described in the literature [437-439].

7.4. Drugs Affecting Phosphorus-Calcium Metabolism Parameters

After confirming hypercalcemia, it is necessary to interview the patient regarding the intake of medications that potentially affect blood calcium and PTH levels, and discontinue them if possible.

Table 8. Drugs affecting phosphorus-calcium metabolism parameters

7.5 Differential diagnosis of hypercalcemia

The purpose of differential diagnosis of PHPT with other conditions accompanied by elevated calcium levels is to determine the cause of hypercalcemia, which would allow for prescribing appropriate treatment aimed at eliminating the primary disease. In some patients, the elevated serum calcium concentration itself poses a life-threatening risk and requires immediate correction. In this situation, it is necessary to determine the underlying cause of hypercalcemia as early as possible and initiate appropriate treatment.

The first step in the differential diagnosis is taking a complete and detailed medical history, paying special attention to known symptoms associated with hypercalcemia. The history should include detailed information about drug therapy prescribed by a physician or taken by the patient independently, as well as dietary habits, including the intake of vitamins from food products or dietary supplements.

The most frequent cause of hypercalcemia is PHPT, accounting for more than 80% of blood calcium elevation cases. Among hospitalized patients, malignant neoplasms of the lung and kidney, and hemoblastomas (multiple myeloma, lymphomas, Hodgkin's disease, leukemias) come in first place among the causes of hypercalcemia, accounting for 50–60%. Elevated calcium levels are less commonly noted in colon and prostate cancer. Ectopic neoplasms producing PTH outside the parathyroid gland tissue have been described, most frequently in breast cancer. Sarcoidosis is associated with hypercalcemia in 20% of cases and with hypercalciuria in approximately 40% of cases. Hypercalcemia may also develop as a result of chemotherapy for oncological diseases (20–30%), leading to increased bone resorption (the severity of the effect is dose-dependent). The main causes of hypercalcemia are presented in Table 9.

Table 9. Diseases associated with the development of hypercalcemia

7.6 Treatment of acute and chronic hypocalcemia

Clinical manifestations of hypocalcemia:

· paresthesias;

· positive Chvostek's and Trousseau's signs;

· tetany;

· laryngospasm;

· ECG changes (arrhythmia, QT interval prolongation).

As a rule, symptoms of hypocalcemia develop when total calcium drops below 1.9 mmol/L. However, these symptoms can also develop at other values, depending on the rate at which calcium levels decline.

Treatment of acute hypocalcemia

Intravenous administration of calcium preparations is necessary when the albumin-corrected calcium level drops below 1.9 mmol/L and/or when the patient has symptoms of hypocalcemia [246, 450]. Central venous catheter placement is preferred to prevent peripheral vein sclerosis resulting from calcium infusion. Calcium gluconate** infusion is preferred (1 ampoule (10 mL) = 1000 mg of calcium gluconate**, containing 90 mg of elemental calcium), since calcium chloride has a greater irritating effect on surrounding tissues. Intravenous calcium administration requires caution in patients with hypokalemia and in patients taking digoxin, as rapid IV calcium administration in these conditions can provoke cardiac arrhythmias.

Parenteral calcium administration should always be discontinued if dyspeptic symptoms (nausea, vomiting) appear.

Parenteral preparations may be used concurrently: alphacalcidol**/calcitriol** and calcium preparations.

1) Alphacalcidol** on average 3–3.5 mcg/day or #calcitriol** 2 mcg/day orally. If hypocalcemia persists, higher doses may be used under the control of blood and urine calcium.

2) Calcium carbonate + colecalciferol 3 g in terms of elemental calcium (on average), divided into 3 doses per day during or immediately after meals [246, 450].

Treatment of chronic hypocalcemia

1) Calcium carbonate + colecalciferol 500–1000 mg of elemental calcium 3 times/day, dose adjustment until total and ionized calcium levels reach the lower limit of normal and hypocalcemia symptoms are relieved. Dose increase up to 1–2 g of elemental calcium 3 times/day is possible.

2) Vitamin D and its analogues – alphacalcidol**/calcitriol** (monitoring calcium and creatinine levels):

alphacalcidol** 0.5–3 mcg/day, dose increase possible if necessary. Onset of action – 1–2 days, cessation of action in 5–7 days; administration several times a day is preferred.

calcitriol** 0.25–2 mcg/day, dose increase possible if necessary. Onset of action – within 1–2 days, cessation of action in 2–3 days; administration several times a day is preferred.

colecalciferol** in accordance with current clinical guidelines for vitamin D — monitoring blood 25(OH)D levels is necessary, as vitamin D deficiency can stimulate PTH synthesis. The optimal level for suppressing secondary PTH elevation is 25(OH)D above 30 ng/mL (75 nmol/L). Onset of action – in 10–14 days, cessation of action in 14–75 days.

7.7. Conservative treatment of severe hypercalcemia

Dehydration is one of the main pathophysiological links of hypercalcemia, so therapy begins with replenishing circulating blood volume. In the absence of severe cardiovascular pathology and renal failure, sodium chloride** administration is started at a rate of 300–500 mL per hour until fluid deficit is fully compensated and diuresis of at least 200–300 mL/h is restored. Rehydration therapy and restoration of renal perfusion lead to the normalization of urinary calcium excretion and a decrease in calcemia by an average of 0.6 mmol/L. The absence of adequate diuresis within several hours after starting infusion therapy is an indication for emergency hemodialysis.

After correction of hypovolemia, loop diuretics can be added to therapy to increase renal calcium excretion. Since increased natriuresis increases urinary calcium concentration, forced diuresis with #furosemide** is performed against the background of ongoing infusion therapy. Forced diuresis is associated with the development of hypokalemia and hypomagnesemia, therefore frequent monitoring of electrolyte parameters and electrolyte replenishment in case of deficiency are necessary. Under conditions of hyperhydration, pulmonary edema may develop, so it is advisable to monitor central venous pressure. A cautious approach in choosing #furosemide** doses is necessary to avoid repeated dehydration. Rehydration therapy combined with forced diuresis is indicated in almost all cases of severe hypercalcemia, but one must remember the increased risk of kidney stone formation against the background of enhanced calcium excretion. The advantages of infusion therapy are a rapid onset of action, calculated in hours, and pathophysiological rationale, since rehydration is indicated in all cases [284, 289].

One of the main pathophysiological mechanisms for the development of a hypercalcemic crisis is excessive mobilization of calcium from bone tissue. The use of intravenous bisphosphonates (M05BA) and #denosumab** can be effective in lowering serum calcium levels, but this effect develops with a delay. In addition, these drugs are not approved for the relief of hypercalcemia of non-oncogenic etiology [284, 289]. There is experience with the use of calcitonin** and glucocorticoids. However, the action of calcitonin** is relatively short and the greatest hypocalcemic effect is observed when combined with bisphosphonates (M05BA) [284], [289].

Data on the efficacy of cinacalcet** for the relief of hypercalcemic crisis are insufficient. High doses of the drug (up to 90 mg twice daily) may be required to significantly reduce serum calcium levels [291–293]. The main therapeutic measures for correcting severe hypercalcemia are summarized in Table 10.

Table 10. Conservative treatment of severe hypercalcemia

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Chairs:

Dedov I.I.¹ – President of the Center, Member of the Presidium of the Russian Academy of Sciences, Academician, President of the Russian Association of Endocrinologists, Chief Freelance Endocrinologist of the Russian Ministry of Health.

Melnichenko G.A.¹ – Academician of the Russian Academy of Sciences, Vice-President of the Russian Association of Endocrinologists, Deputy Director for Research.

Mokrysheva N.G.¹ – Director of the Center, Professor, Corresponding Member of the Russian Academy of Sciences, Member of the Russian Association of Endocrinologists.

Working Group:

1. Andreeva E.N.¹ - D.Sc. (Medicine), Professor, Director of the Institute of Reproductive Medicine, Head of the Department of Endocrine Gynecology

2. Antsiferov M.B.² - D.Sc. (Medicine), Professor, Chief Freelance Endocrinologist, Chief Medical Officer

3. Beltsevich D.G.¹ - D.Sc. (Medicine), Head of Surgical Department No. 1, Chief Researcher, Member of the Association of Endocrine Surgeons

4. Bibik E.E.¹ - Researcher, Department of Parathyroid Pathology and Mineral Metabolism Disorders

5. Gorbacheva A.M.¹ - Researcher, Department of Parathyroid Pathology and Mineral Metabolism Disorders

6. Degtyarev M.V.¹ – Radiologist, Head of the Department of Radionuclide Diagnostics

7. Eremkina A.K.¹ - Ph.D. (Medicine), Head of the Department of Parathyroid Pathology and Mineral Metabolism Disorders

8. Karonova T.L.⁵ - D.Sc. (Medicine), Head of the Research Laboratory of Clinical Endocrinology, Associate Professor, Department of Internal Diseases

9. Kim I.V.¹ - Ph.D. (Medicine), Head of Surgical Department No. 3, Leading Researcher, Member of the Association of Endocrine Surgeons

10. Kryukova I.V.⁴ - Ph.D. (Medicine), Associate Professor, Department of Endocrinology

11. Kuznetsov N.S.¹ - D.Sc. (Medicine), Professor, Head of the Endocrine Surgery Research Group, Member of the Association of Endocrine Surgeons

12. Lukyanov S.V.⁶ – Ph.D. (Medicine), Associate Professor, Department of Surgical Diseases No. 1

13. Mamedova E.O.¹ – Ph.D. (Medicine), Senior Researcher, Department of Osteoporosis and Osteopathies

14. Markina N.V.² – Ph.D. (Medicine), Staff Member, Specialized Endocrinology Department

15. Mirnaya S.S.³ - Ph.D. (Medicine), Endocrinologist, Member of the Russian Association of Endocrinologists

16. Pigarova E.A.¹ - D.Sc. (Medicine), Leading Researcher, Department of Neuroendocrinology

17. Rozhinskaya L.Ya.¹ - D.Sc. (Medicine), Professor, Chief Researcher, Department of Osteoporosis and Osteopathies

18. Slashchuk K.Yu.¹ – Ph.D. (Medicine), Senior Researcher, Department of Radionuclide Therapy

19. Sleptsov I.V.⁷ – D.Sc. (Medicine), Professor, Department of Faculty Surgery

20. Chagai N.B.⁸ – D.Sc. (Medicine), Professor, Department of Clinical Cardiology with a Course in Introscopy

1 - National Medical Research Center for Endocrinology of the Ministry of Health of Russia

2 - Endocrinology Dispensary of the Moscow Healthcare Department

3 - Family Medical Centers Network No. 1 LLC

4 - Moscow Regional Research Clinical Institute named after M.F. Vladimirsky (MONIKI)

5 - National Medical Research Center named after V.A. Almazov of the Ministry of Health of Russia

6 - Rostov State Medical University of the Ministry of Health of Russia

7 - Saint Petersburg State University, Saint Petersburg Multidisciplinary Center of the Russian Ministry of Health

8 - Stavropol State Medical University

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

The authors and experts declared no conflicts of interest regarding the development of the clinical guidelines.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. endocrinologist;

2. surgeon;

3. general practitioner (family physician);

4. general physician / internist;

5. urologist;

6. nephrologist;

7. gastroenterologist;

8. cardiologist;

9. obstetrician-gynecologist.

Appendix 1. Levels of Evidence (LoE) Grading Scale for Diagnostic Methods (Diagnostic Interventions)

Appendix 2. Levels of Evidence (LoE) Grading Scale for Preventive, Therapeutic, and Rehabilitation Methods (Preventive, Therapeutic, and Rehabilitation Interventions)

Appendix 3. Grades of Recommendation (GoR) Scale for Preventive, Diagnostic, Therapeutic, and Rehabilitation Methods (Preventive, Diagnostic, Therapeutic, and Rehabilitation Interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Current instructions for medical product use are available on the official website of the Russian Ministry of Health at http://grls.rosminzdrav.ru/Default.aspx (http://grls.rosminzdrav.ru/Default.aspx).

The principles of treatment and prevention of vitamin D deficiency/insufficiency in patients with hypoparathyroidism correspond to the principles outlined in the clinical guidelines "VITAMIN D DEFICIENCY IN ADULTS: DIAGNOSIS, TREATMENT, AND PREVENTION" (Authors: Pigarova E.A., Rozhinskaya L.Y., Belaya Z.E., Dzeranova L.K., Karonova T.L., Ilyin A.V., Melnichenko G.A., Dedov I.I.) doi: 10.1185/03007995.2013.766162, https://minzdrav.gov-murman.ru/documents/poryadki-okazaniya-meditsinskoy-pomoshchi/D%2019042014.pdf

Use of calcitriol** for the prevention of postoperative hypocalcemia

According to a meta-analysis (Alhefdhi A. et al., 2013) including 9 randomized controlled trials with a total of 2,285 patients, the use of calcium salt supplements at a minimum dose of 3 g/day combined with calcitriol** at a dose of 1 mcg/day in patients undergoing neck surgery who are at high risk of postoperative hypocalcemia is necessary for its prevention. This treatment is recommended in the early postoperative period for 2 weeks with mandatory assessment of calcium-phosphorus metabolism and evaluation of therapy adjustment upon completion of this period [444].

Use of #denosumab** in patients with PHPT when surgical treatment is not feasible, with the aim of reducing BMD loss and correcting hypercalcemia.

According to the results of the phase 3 randomized, double-blind, placebo-controlled DENOCINA trial, the use of #denosumab** at a dose of 60 mg every 6 months is effective in improving BMD and reducing bone turnover rate in patients with PHPT, regardless of concomitant cinacalcet** therapy [272].

#Denosumab** exhibits a hypocalcemic effect and has therefore been successfully used to manage severe hypercalcemia of oncogenic etiology, including parathyroid carcinoma [287, 288, 441].

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Calcium and phosphorus are the primary building blocks for skeletal bone formation; calcium is involved in muscle contraction, heart rhythm regulation, and many other processes. PTH is parathyroid hormone, which regulates calcium and phosphorus metabolism. It is produced in the parathyroid glands, which are located on the posterior surface of the thyroid gland.

Under pathological conditions, a persistent elevation in PTH levels is termed hyperparathyroidism, which can be primary (PHPT), secondary (SHPT), or tertiary (THPT).

Who needs a blood calcium test?

• All patients with urolithiasis;

• All women and men diagnosed with osteoporosis, regardless of age;

• Patients with a history of low-trauma fractures;

• Patients with bone deformities;

• Patients with suspected bone tumors;

• Patients with marked generalized and muscular weakness;

• Patients with multiple non-specific complaints of thirst, frequent urination, bone pain, depressed mood, generalized and muscular weakness;

• Patients with frequent dyspeptic complaints: vomiting, diarrhea;

• Patients with muscle cramps;

• Patients with chronic kidney disease;

• Patients receiving standard or peritoneal dialysis therapy;

• Patients after kidney transplantation;

• Patients with a restricted intake of foods containing calcium and phosphorus (dairy products, seafood).

Primary hyperparathyroidism can remain asymptomatic for a long time, manifesting only at the stage of complications (fractures, renal colic, gastric and duodenal ulcers). Today, diagnosis and treatment of this severe condition are possible at the stage of laboratory abnormalities alone, prior to the development of the aforementioned complications.

The primary treatment method for primary hyperparathyroidism is surgical removal of the parathyroid adenoma. Such surgery, parathyroidectomy, is indicated for all patients with the symptomatic (manifest) form of the disease and for patients with the asymptomatic form (patients under 50 years of age, as well as those with high blood calcium levels, osteoporosis, or impaired renal function). However, in the absence of symptoms, some patients older than 50 years may be offered observation and conservative management. This includes medical examination once every 6–12 months to monitor key disease parameters and the condition of organs most frequently affected by it. If any parameters worsen over time, surgical treatment may be offered. If osteoporosis and elevated bone turnover markers are detected in a patient with primary hyperparathyroidism, medications that improve bone tissue status may also be prescribed. All patients are advised to increase fluid intake to up to 2 liters per day to help prevent the adverse effects of hypercalcemia on the kidneys.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Specific questionnaires have not been developed and are not used.