Hypoparathyroidism in Adults: Clinical Guidelines

List of Abbreviations

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

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

APS – autoimmune polyglandular syndrome

ADH – autosomal dominant hypocalcemia

VLEL – vital and essential drugs

IFN – interferon

CT – computed tomography

LH – luteinizing hormone

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

BMD – bone mineral density

PT – parathyroid glands

preproPTH – pre-pro-parathyroid hormone

PTH – parathyroid hormone

PTHrP – parathyroid hormone-related peptide

PseudoPHP – pseudohypoparathyroidism

Pseudo-pseudoPHP – pseudo-pseudohypoparathyroidism

GFR – glomerular filtration rate

TSH – thyroid-stimulating hormone

US – ultrasound examination

FGF23 – fibroblast growth factor 23

FSH – follicle-stimulating hormone

CKD – chronic kidney disease

CNS – central nervous system

TG – thyroid gland

AIRE – autoimmune regulator gene

APECED – autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy

AR – autosomal recessive inheritance

AD – autosomal dominant inheritance

CaSR – calcium-sensing receptor

CHARGE – coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities, and ear abnormalities

DXA – dual-energy X-ray absorptiometry

FHHNC – familial hypomagnesemia with hypercalciuria and nephrocalcinosis

GATA3 – GATA-binding protein 3

HRD – hypoparathyroidism, retardation, dysmorphism syndrome

MELAS – mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes

MTP – mitochondrial trifunctional protein

NA – not available

PTH1R – parathyroid hormone 1 receptor

VDR – vitamin D receptor

Terms and Definitions

Hypoparathyroidism is a condition characterized by reduced production of parathyroid hormone (PTH) by the parathyroid glands (PTG) or tissue resistance to its action, leading to various disorders, primarily of calcium and phosphorus metabolism.

Transient postoperative hypoparathyroidism is hypocalcemia that develops within the first 24 hours after neck surgery and resolves within 4–6 weeks after the surgical intervention.

Chronic (permanent) postoperative hypoparathyroidism is hypocalcemia combined with an inappropriately low PTH level 6 months or more after neck surgery.

Congenital hypoparathyroidism is a group of diseases of the parathyroid glands with heterogeneous etiology, manifesting immediately after birth and characterized by partial or complete loss of their functions.

Pseudohypoparathyroidism is a rare hereditary disease characterized by clinical and laboratory signs of hypoparathyroidism against the background of an elevated blood PTH level.

Nephrocalcinosis is diffuse deposition of calcium salts in renal tissue, accompanied by inflammatory-sclerotic changes and renal failure.

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

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hypoparathyroidism is a condition characterized by reduced production of parathyroid hormone (PTH) by the parathyroid glands (PTG) or tissue resistance to its action, leading to various disorders, primarily of calcium and phosphorus metabolism.

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

1.2.1. Physiology of calcium and phosphorus metabolism

The parathyroid glands control extracellular calcium homeostasis through the secretion of PTH. Parathyrocytes initially synthesize a precursor peptide consisting of 115 amino acid residues (preproPTH (1–115)). As a result of specific proteolysis of the N-terminus of the precursor, it is transformed into the active full-length PTH molecule comprising 84 amino acid residues (1–84). PTH is packaged and stored in secretory granules and released from parathyrocytes in response to a decrease in the concentration of ionized blood calcium. A calcium-sensing receptor (CaSR) is expressed on the surface of parathyroid cells, the main function of which is considered to be the modulation of PTH synthesis and secretion, as well as the control of the parathyroid cell life cycle. PTH secretion is maximal at low ionized calcium levels; conversely, an increase in calcium levels decreases its secretion. PTH circulates in the bloodstream and subsequently binds to the transmembrane G protein-coupled receptor PTH1R. Activation of this receptor in bone tissue and kidneys leads to an increase in calcaemia and subsequent suppression of PTH production by the parathyroid glands via a negative feedback mechanism [1].

PTH is also involved in the regulation of phosphorus metabolism. An increase in the level of circulating blood phosphorus leads to the stimulation of PTH secretion, which in turn acts on the kidneys to reduce tubular reabsorption of phosphates. Phosphorus homeostasis is additionally regulated by fibroblast growth factor 23 (FGF23), which is a biologically active osteocyte-secreted polypeptide that inhibits renal tubular reabsorption of phosphates and the synthesis of calcitriol (1,25(OH)₂D) in the kidneys.

Magnesium is a trace element also closely related to calcium-phosphorus metabolism. It is capable of regulating PTH secretion similarly to calcium, acting as a CaSR agonist [2–4]. Hypermagnesemia activates CaSR in the parathyroid glands, suppressing PTH secretion. However, hypomagnesemia also leads to the development of hypocalcemia, the mechanism of which is not fully understood. Most likely, prolonged severe hypomagnesemia leads to the depletion of intracellular magnesium stores, resulting in CaSR hyperactivation, blockade of PTH secretion, and the development of tissue resistance to its effects [5]. PTH itself, in turn, influences the maintenance of magnesium homeostasis by increasing its reabsorption in the distal tubule and in the cells of the medullary portion of the distal convoluted tubule.

Another crucial regulator of calcium and phosphorus metabolism is calcitriol. Like steroid hormones, it binds to an intracellular receptor in the target cell. A hormone-receptor complex is formed, which interacts with chromatin and induces the transcription of structural genes, resulting in the synthesis of proteins that mediate the action of calcitriol. In enterocytes, calcitriol induces the synthesis of calcium-transporting proteins that ensure adequate absorption of calcium and phosphate ions from the intestinal lumen. Subsequently, calcitriol controls the transport of calcium ions from epithelial cells into the blood, thereby maintaining their concentration in extracellular fluid at a level necessary for the mineralization of the organic bone matrix. In the kidneys, calcitriol stimulates the reabsorption of calcium and phosphate ions.

Along with PTH and calcitriol, calcitonin, synthesized by parafollicular C-cells of the thyroid gland (TG), participates in the regulation of calcium metabolism. Its secretion increases with a rise in serum calcium concentration and, conversely, decreases with its reduction. Acting as a PTH antagonist, calcitonin affects the skeleton, where it inhibits bone resorption and, consequently, inhibits calcium release. In addition, it suppresses tubular reabsorption of calcium ions in the kidneys, thereby stimulating their renal excretion in urine. The main physiological role of calcitonin is to maintain skeletal structure during growth, pregnancy, and lactation, when tissue demand for calcium increases sharply [6].

1.2.2. State of calcium and phosphorus metabolism in hypoparathyroidism

In hypoparathyroidism, the absence or insufficiency of PTH is inevitably accompanied by the development of hypocalcemia. The main pathogenetic mechanisms include: decreased osteoclast activity with reduced release of calcium from bones; increased urinary calcium excretion; suppression of calcitriol synthesis in the kidneys; and reduced intestinal calcium absorption. PTH deficiency leads to hyperphosphatemia both directly through increased renal tubular reabsorption of phosphates and indirectly due to hypocalcemia. Chronic hyperphosphatemia in patients with hypoparathyroidism has been shown to be associated with elevated blood levels of FGF23. The main causes of hypoparathyroidism are presented in Table 1.

Table 1. Etiology of hypoparathyroidism [7].

1.2.3. Postoperative hypoparathyroidism

Neck surgery is the most common cause of hypoparathyroidism, accounting for about 75% of all cases of this condition. Surgeries associated with the development of hypoparathyroidism include thyroidectomy for malignant disease of the head and neck (with/without central and/or lateral neck lymph node dissection), diffuse toxic goiter, and multinodular goiter. Postoperative hypoparathyroidism can be caused by direct removal, intraoperative trauma, or impaired blood supply to the parathyroid glands. Postoperative hypoparathyroidism may also occur following surgical treatment for primary hyperparathyroidism, when, after the removal of the dominant parathyroid tissue, the remaining parathyroid glands are unable to restore sufficient PTH production.

Additional risk factors for the development of postoperative hypoparathyroidism include [8]:

• female sex;

• vitamin D deficiency;

• pregnancy and lactation;

• autoimmune thyroid diseases;

• prior gastric bypass surgery (bariatric surgery).

Transient postoperative hypoparathyroidism is defined as a decrease in PTH levels combined with hypocalcemia for no more than 6 months after surgery and is registered in 25–30% of patients undergoing total thyroidectomy. Persistent hypocalcemia combined with PTH levels below the reference range 6 months or more after surgical treatment indicates the development of chronic hypoparathyroidism, accounting for about 3% of cases [1,9]. Low calcium levels and preoperative vitamin D insufficiency/deficiency (25(OH)D), low intraoperative PTH levels, parathyroid autotransplantation (reimplantation of parathyroid tissue into the neck or forearm during surgery), and longer operative time have been identified as independent predictors of transient hypoparathyroidism following thyroidectomy. Risk factors for chronic hypoparathyroidism also include: insufficient surgeon experience, failure to visualize more than two parathyroid glands during surgery, a blood calcium level of less than 1.88 mmol/L (7.5 mg/dL) with a normal range of 2.12–2.62 mmol/L (8.5–10.5 mg/dL) at 24 hours postoperatively, and the need for reoperation due to hemorrhage. The risk of chronic hypoparathyroidism is closely correlated with the number of functioning parathyroid glands left in situ during surgery: 16% with 1–2 glands preserved, 6% with 3 glands, and 2.5% with 4 [10,11]. In rare cases, postoperative hypoparathyroidism may develop years after surgery. The mechanism underlying this phenomenon is not fully understood, but it is likely related to age-related changes in the vascular walls of the arteries supplying the residual parathyroid tissue.

1.2.4. Genetic causes of hypoparathyroidism

Genetic etiology of hypoparathyroidism accounts for less than 10% of cases [12]. Chromosomal microdeletions and monogenic abnormalities represent the primary cause of genetic hypoparathyroidism [13].

1.2.4.1. Autoimmune hypoparathyroidism

Autoimmune hypoparathyroidism is the second most common form of hypoparathyroidism, caused by immune-mediated destruction of parathyroid cells [14]. It can be an isolated condition, but is much more frequently part of hereditary autoimmune polyglandular syndrome (APS) type 1, also known as autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) [15]. APS type 1 is a monogenic autosomal recessive disorder caused by a mutation in the autoimmune regulator (AIRE) gene. The key mechanism of pathogenesis is autoimmune destruction of various endocrine glands, including the parathyroid glands. APS type 1 is characterized by the classic triad: mucocutaneous candidiasis, hypoparathyroidism, and chronic primary adrenal insufficiency. The disease typically manifests in childhood. In the vast majority of cases, the initial manifestation is mucocutaneous candidiasis, which develops within the first 10 years of life, most commonly around the age of 2 years. Against the background of mucocutaneous candidiasis, 84% of patients develop hypoparathyroidism, which debuts before the age of 10 in 88% of cases. Other components of the syndrome include type 1 diabetes mellitus, hypothyroidism, malabsorption, celiac disease, vitiligo, autoimmune hepatitis, hypogonadism, and others [16]. Detailed information is provided in the Additional Information section.

1.2.4.2. Genetic variants of isolated hypoparathyroidism

Depending on the pathogenesis of the disease, genetic variants of isolated hypoparathyroidism can be broadly divided into three main groups. The first group includes disorders characterized by normal parathyroid gland development but impaired PTH secretion. This group includes autosomal dominant hypocalcemia caused by activating point mutations in the CASR gene. To date, about 40 activating mutations have been described [17]. Activation of the receptor protein leads to impaired feedback regulation of PTH secretion, where normal or low calcium levels are accompanied by decreased hormone production. The disease is characterized by moderate hypocalcemia combined with low PTH levels, and the majority of patients present with hypomagnesemia. The clinical presentation is variable, ranging from asymptomatic hypocalcemia to hypocalcemic crises. Patients with this condition are prone to hypercalciuria with a high risk of nephrolithiasis/nephrocalcinosis and impaired renal function.

Parathyroid developmental anomalies belong to the second group of disorders resulting from transcription factor mutations. Defects in the GCM2 (glial cell missing 2) gene underlie impaired parathyroid gland formation and are inherited in an autosomal recessive manner. The X-linked recessive variant is associated with deletions and insertions in the Xq27.1 region. These mutations are presumed to affect the function of the SOX9 protein, a transcription factor important for parathyroid gland development [18].

The third group includes mutations in the PTH gene that lead to impaired processing and secretion of PTH, accompanied by isolated hypoparathyroidism. These mutations are relatively rare and follow autosomal recessive and autosomal dominant inheritance patterns. Post-translational processing of the preproparathyroid hormone molecule and/or messenger RNA translation is disrupted [19]. Homozygous mutations in the prepro-PTH gene lead to a significant decrease in PTH levels (down to undetectable values) combined with symptomatic hypocalcemia and hyperphosphatemia. Detailed information is provided in the Additional Information section.

1.2.4.3. Hypoparathyroidism as part of complex genetic syndromes

Hypoparathyroidism may be a component of complex genetic syndromes. DiGeorge syndrome is caused by a 22q11 deletion, leading to congenital parathyroid dysgenesis and consequently hypoparathyroidism. This disorder is also characterized by dysmorphic features, congenital heart defects, and severe immunodeficiency. Patients usually die in childhood [20]. Barakat syndrome, or HDR syndrome (hypoparathyroidism, deafness, and renal dysplasia syndrome), is an autosomal dominant disorder caused by a defect in the GATA3 gene located on the short arm of chromosome 10 (10p15). The gene encodes a protein responsible for the development of the parathyroid glands, inner ear, and kidneys. PTH levels range from the lower limit of normal to undetectable [21]. Kenny–Caffey syndrome includes short stature, eye anomalies, and osteosclerosis. Sanjad–Sakati syndrome, or HRD syndrome (hypoparathyroidism-retardation-dysmorphism), is often considered a variant of Kenny–Caffey syndrome and manifests as hypoparathyroidism, severe physical and psychomotor retardation, microcephaly, and distinct facial features. Patients with Kenny–Caffey syndrome type 1 (autosomal recessive inheritance) and Sanjad–Sakati syndrome carry mutations in the TBCE (tubulin-specific chaperone E) gene [22].

Hypoparathyroidism is a component of certain mitochondrial DNA disorders and is particularly characteristic of Kearns–Sayre syndrome in combination with external ophthalmoplegia, pigmentary retinopathy, myopathy, and cardiomyopathy. In MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), hypoparathyroidism is combined with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. Although hypoparathyroidism is generally not the primary symptom in these disorders, hypocalcemic seizures occasionally present as the initial manifestation, prompting further investigation. Detailed information is provided in the Additional Information section.

1.2.5. Hypoparathyroidism and hypomagnesemia

When serum magnesium levels decrease, similar to hypocalcemia, PTH secretion should increase; however, magnesium deficiency leads to a pathological reduction in PTH levels and the development of bone and renal resistance to its effects [17,23]. The pathogenetic mechanism of hypoparathyroidism in hypomagnesemia remains incompletely understood.

Magnesium deficiency is caused by:

• insufficient dietary intake;

• decreased intestinal absorption (malabsorption, short bowel syndrome, severe and prolonged vomiting, diarrhea, steatorrhea);

• familial hypomagnesemia with secondary hypocalcemia (TRPM6 mutation) [24,25];

• autosomal dominant hypocalcemia (activating mutation in the CASR gene) [26];

• familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) [26–28];

• medication use:

  • thiazides, furosemide**;

  • proton pump inhibitors;

  • systemic antibacterial drugs;

  • systemic antifungal drugs;

  • antineoplastic drugs;

  • immunosuppressants;

  • monoclonal antibodies and antibody conjugates.

Hypermagnesemia may also lead to impaired parathyroid gland function by suppressing PTH secretion, resulting in hypocalcemia. Hypermagnesemia can develop in the following conditions: chronic kidney disease (CKD); familial hypocalciuric hypercalcemia; excessive intake (parenteral administration of magnesium preparations, etc.); tocolytic therapy for eclampsia.

1.2.6. Other causes of hypoparathyroidism

Some cases of isolated hypoparathyroidism with an unidentified cause may also result from autoimmune damage to the parathyroid gland tissue. However, this is rather a diagnosis of exclusion for which specific diagnostic criteria have not been developed. In rare cases, the cause of hypoparathyroidism can be infiltrative diseases such as sarcoidosis, amyloidosis, Riedel's thyroiditis, and metastatic involvement of the parathyroid glands [29–32]. Parathyroid tissue is relatively resistant to radiation damage; nevertheless, very rare cases of radiation-induced hypoparathyroidism have been described in the literature [33–36]. Mineral deposits in parathyroid tissue—such as copper in Wilson's disease and iron in hemochromatosis—are rare causes of hypoparathyroidism. Cases of hypoparathyroidism resulting from massive repeated transfusions in patients with thalassemia have been described [37–41].

1.3 Epidemiology of the Disease or Condition

Available data on the prevalence of hypoparathyroidism are based on major epidemiological studies conducted in the USA, Denmark, Norway, Italy, and several other countries. The results obtained are relatively similar and indicate a prevalence of hypoparathyroidism ranging from 23 to 37 per 100,000 population [12,14,42–44].

Postoperative hypoparathyroidism is more common among women, which is associated with a higher incidence of thyroid pathology and, consequently, thyroidectomy [45,46]. The prevalence of hereditary forms of hypoparathyroidism does not differ between men and women [43]. In the Russian population, no large epidemiological studies have been conducted to assess the prevalence of hypoparathyroidism.

Data on mortality in patients with chronic hypoparathyroidism are limited [45,47]; however, a 2-fold increase in the risk of death has been noted among patients who developed postoperative hypoparathyroidism compared to the group without this surgical complication after thyroid surgery. The increased risk of death in patients with chronic hypoparathyroidism is associated with hyperphosphatemia, long disease duration, and the frequency of hypercalcemia episodes [47].

1.4 Features of Coding the Disease or Condition

E20.0 Idiopathic hypoparathyroidism

E20.8 Other forms of hypoparathyroidism

E20.9 Hypoparathyroidism, unspecified

E89.2 Postprocedural hypoparathyroidism

1.5 Classification of the disease or condition

1. Postoperative hypoparathyroidism: [48]

   • Transient hypoparathyroidism;

   • Chronic (permanent) hypoparathyroidism.

2. Autoimmune hypoparathyroidism*:

   • Autoimmune polyglandular syndrome type 1 (APS type 1);

   • Autoimmune polyglandular syndrome type 3 (APS type 3);

   • Autoimmune polyglandular syndrome type 4 (APS type 4).

3. Genetic isolated hypoparathyroidism:

   • Autosomal dominant hypocalcemia with hypercalciuria type 1 (HYPOC1-ADH1) / Bartter syndrome type 5;

   • Autosomal dominant hypocalcemia with hypercalciuria type 2 (HYPOC1-ADH2);

   • Familial isolated hypoparathyroidism (autosomal, X-linked).

4. Hypoparathyroidism as part of multi-component genetic syndromes:

   • DiGeorge syndrome type 1 (DGS1);

   • DiGeorge syndrome type 2 (DGS2);

   • CHARGE syndrome;

   • HDR syndrome;

   • Kenny-Caffey syndrome type 1 (KCS1);

   • Kenny-Caffey syndrome type 2 (KCS2);

   • Gracile bone dysplasia (GCLEB);

   • Mitochondrial diseases.

5. Other forms of hypoparathyroidism:

   • Magnesium metabolism disorders;

   • Infiltrative diseases (granulomatosis, hemochromatosis, metastasis);

   • Hypoparathyroidism resulting from radiation damage to parathyroid tissue.

6. Idiopathic hypoparathyroidism.

* – cases of hypoparathyroidism developing as part of autoimmune polyglandular syndrome type 2 (APS type 2) have not been described.

1.6 Clinical presentation of the disease or condition

The main clinical manifestations of hypoparathyroidism are due to hypocalcemia. Calcium deficiency in the body leads to partial depolarization of the resting membrane potential of neurons, thereby increasing the probability of action potential generation [49]. As a result, neuromuscular excitability and general autonomic reactivity increase. Enhanced sensitivity of sensory neurons manifests as paresthesias in the extremities and perioral region; of motor neurons, as muscle spasms up to tetany, ranging from classic carpopedal spasm to life-threatening laryngospasm [50]. Severe hypocalcemia is associated with both local and generalized tonic-clonic seizures.

The severity of symptoms depends on the serum calcium level and the rate of progression of hypocalcemia. A chronic course of the disease is characterized by adaptation to low serum calcium levels with the absence of prominent clinical symptoms even in severe hypocalcemia. Precipitating factors for clinical deterioration in such cases can include increased physical activity, medical procedures, pregnancy, and lactation [1,33].

1.6.1. Acute hypocalcemia (hypocalcemic crisis)

Acute hypocalcemia (hypocalcemic crisis) is a life-threatening condition that requires emergency medical interventions.

Clinically, it manifests as attacks of tetany, which may be preceded by paresthesias of the face, hands, and feet, a sense of fear, anxiety, and fibrillary twitching of individual muscles. Most commonly, spasms occur in the muscles of the upper extremities, less often in the lower ones. Due to spasms of the facial muscles, a sardonic smile appears, and the lips take on the shape of a "fish mouth." Spasm of the masticatory muscles causes spasmodic jaw clenching (trismus). Spasms in the muscles of the upper extremities lead to a characteristic hand posture known as the "obstetrician's hand": the fingers are adducted and slightly flexed at the metacarpophalangeal joints, the thumb is adducted, and the wrist is flexed. With spasms of the lower extremity muscles, the thighs and legs are extended, the feet are turned inward, and the trunk is arched backward (opisthotonos). As a result of spasmodic contractions of the intercostal muscles, abdominal muscles, and diaphragm, respiration is severely impaired. Changes in organs and systems during tetany depend on the predominance of sympathetic or parasympathetic tone. Activation of the sympathetic nervous system leads to tachycardia, elevated blood pressure, and pallor of the skin due to peripheral vasoconstriction, while parasympathetic activation leads to bradycardia, hypotension, vomiting, diarrhea, and polyuria. Spasms of the smooth muscles of internal organs and blood vessels can mimic various diseases, including cardiovascular pathology (attacks of angina pectoris, endarteritis, migraine, etc.), respiratory organs (e.g., bronchial asthma), the gastrointestinal tract (cholecystitis, pancreatitis, appendicitis, gastric ulcer), and the urogenital system (cystitis, nephritis, etc.) [51].

1.6.2. Clinical manifestations of chronic hypoparathyroidism

Clinical manifestations of chronic hypoparathyroidism are diverse and affect almost all body systems (Table 2). They can be associated with episodes of both hypo- and hypercalcemia, as well as hyperphosphatemia [33].

Table 2. Clinical symptoms of hypoparathyroidism.

The following risk factors for complications were identified in patients with chronic hypoparathyroidism [47]: hypoparathyroidism duration of more than 20 years, severe hypocalcemia, episodes of hypercalcemia (more than 4) as risk factors for cardiovascular complications; episodes of hypercalcemia (more than 4) were also associated with the development of renal pathology.

Central nervous system

Brain structure calcification in patients with hypoparathyroidism can be detected in 52–74% of cases [52,53]. Most commonly, calcifications are visualized in the basal ganglia; other localizations include the cerebral white matter, thalamus, and dentate nucleus. Although the exact cause leading to extraskeletal calcification has not been established, the progression of calcification is closely related to alterations in phosphorus metabolism (hyperphosphatemia). The clinical significance of central nervous system calcification in patients with a long-standing history of hypoparathyroidism is unknown. No direct correlation has been found with symptoms of parkinsonism (neurological movement disorders characterized by tremor, bradykinesia, rigidity, and postural instability) and dystonia (neurological movement disorders associated with "twisting" or abnormal fixed postures), and these disorders are noted much less frequently than, for example, isolated basal ganglia calcification on brain computed tomography (CT) scans [52–54]. The presence of a relationship between the volume and location of calcifications and neurological symptoms remains controversial [55]. Hypoparathyroidism is also associated with an increased risk of neuropsychiatric disorders, such as depression or bipolar affective disorder [45].

Cardiovascular system

Hypocalcemia contributes to cardiac rhythm disturbances. Patients with chronic hypocalcemia may exhibit QT interval prolongation on the electrocardiogram, along with U and T wave changes [56]. Patients with chronic hypoparathyroidism have an increased risk of atrial fibrillation, tachyarrhythmias, myocardial infarction, coronary artery disease, heart failure, stroke, cerebrovascular disease, and peripheral vascular disease [57].

Most of these symptoms resolve against the background of disease compensation and the achievement of sustained normocalcemia. Congestive heart failure refractory to standard medical therapy (especially in individuals with prior heart disease) develops rarely and is partially or completely reversible after calcium normalization. Hypocalcemic dilated cardiomyopathy developing in the course of long-term severe hypoparathyroidism is also generally reversible with disease compensation [58].

Kidneys

Conventional treatment with calcium and vitamin D preparations and their analogues promotes increased urinary calcium excretion due to the absence of PTH-mediated calcium reabsorption in the distal nephron. Hypercalciuria is a risk factor for nephrocalcinosis and nephrolithiasis associated with the development of chronic kidney disease (CKD), up to end-stage renal disease [59]. According to recent data, the incidence of nephrolithiasis/nephrocalcinosis in this patient cohort ranges from 12% to 57%, with the risk of manifestation being 5 times higher than the general population rates [52,59]. In addition, there is evidence of a significant increase in the risk of renal failure [60].

Musculoskeletal system and teeth

The absence of adequate PTH secretion contributes to a decrease in the rate of bone turnover, resulting in suboptimal bone tissue renewal after each remodeling cycle. At the same time, dual-energy X-ray absorptiometry (DXA) frequently reveals an increase in bone mineral density (BMD) parameters, particularly in areas with a predominance of the trabecular component [61,62].

The pathological significance of altered bone microarchitecture is not fully understood, although data exist regarding an increased frequency of skeletal fractures in this pathology [45,61]. Chronic hypoparathyroidism may also be associated with spondyloarthropathy characterized by ligamentous ossification and syndesmophyte formation [63]. Skeletal muscle myopathy detected in patients with chronic hypoparathyroidism is characterized by elevated serum creatine phosphokinase levels and histological changes in biopsy material, and appears to be a manifestation of long-standing uncompensated severe hypocalcemia [64]. Dental pathology in chronic hypoparathyroidism includes dental enamel hypoplasia, root shortening, tooth hypoplasia, or absence [65,66].

Organs of vision

Hypoparathyroidism is characterized by an increased risk of developing subcapsular cataract; the prevalence of this complication is variable, ranging from 27% to 55%. It is hypothesized that additional risk factors for this complication are age at manifestation and/or disease duration [67–69].

Rare cases of papilledema (optic disc edema caused by increased intracranial pressure) have been described in patients with chronic hypoparathyroidism. Symptom reversibility was noted following the correction of hypocalcemia [70].

Skin and Its Appendages

Hypoparathyroidism leads to disorders of the skin and its appendages, manifested primarily by skin dryness, nail fragility, and an increased susceptibility to onycholysis (detachment of the nail plate from the soft tissue of the nail bed). Severe pustular psoriasis rarely develops as a complication of chronic hypoparathyroidism, possibly due to the involvement of intracellular calcium in the regulation of keratinocyte proliferation and differentiation [71,72].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria for hypoparathyroidism based on laboratory findings: hypocalcemia (low level of albumin-corrected or ionized blood calcium) combined with a decreased PTH level (or detection of an inappropriately low PTH level).

Comments: the most common test for diagnosing hypocalcemia is the serum total calcium assay. Calcium correction for serum albumin levels is necessary to exclude false-negative or false-positive results of calcemia when plasma protein concentrations change.

Formulas for calculating albumin-corrected calcium:

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

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

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

It is also possible to assay ionized calcium in the blood, which normally lies within the reference range of 1.03–1.29 mmol/L. To confirm the presence of hypocalcemia in doubtful results (low-normal or slightly below the lower limit of the reference range blood calcium level), a twofold calcium determination is recommended (assay of ionized calcium in the blood and/or total calcium in the blood, and blood albumin with calculation of albumin-corrected blood calcium).

Measurement of blood PTH content provides essential information, but at the same time, its results must be interpreted correctly, as hypocalcemia can lead to a compensatory relative increase in PTH secretion and mask true hypoparathyroidism. Thus, hypocalcemia against the background of a normal PTH concentration can be a reason for dynamic monitoring and further patient evaluation.

2.1 Complaints and Anamnesis

The most frequent complaint of patients with hypoparathyroidism is the presence of cramps and/or paresthesias in the muscles of the upper and lower extremities and the perioral region. Patients with a long-standing history of hypoparathyroidism complain of "brain fog", decreased memory, and poor concentration. The main complaints of patients with hypoparathyroidism are presented in Table 3.

Table 3. Physical, cognitive, and emotional symptoms of hypoparathyroidism [83].

• Patients with suspected hypoparathyroidism are recommended to undergo anamnestic data collection (history taking and evaluation of complaints in endocrinology) regarding previous surgical interventions on the neck organs, as well as comorbidities associated with phosphorus-calcium metabolism [1,7,75,84].

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

Comments: the following factors allow suspecting the presence of hypocalcemia and hypoparathyroidism in a patient:

• history of neck surgery;

• presence of paresthesia in the face, upper and lower extremities;

• presence of fibrillary muscle twitches, cramps in proximal muscles;

• detection of brain calcification;

• in case of cardiac arrhythmias.

2.2 Physical Examination

• Patients with suspected hypoparathyroidism are recommended to undergo an examination of the anterior neck surface to assess whether neck surgery has been performed [84].

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

• In patients with suspected hypoparathyroidism, assessment of Chvostek's and Trousseau's signs is recommended to identify clinical manifestations of hypocalcemia [1,85].

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

Comments: a positive Trousseau's sign is the appearance of carpal spasm (" obstetrician's hand ") 1–3 minutes after arm compression with a blood pressure cuff. This sign is a highly sensitive and specific indicator of hypocalcemia, detected in 94% of patients with hypocalcemia and in 1% of individuals with normocalcemia. Chvostek's sign, which is facial muscle contraction when tapping over the facial nerve exit site, is a less sensitive and specific sign. A negative Chvostek's sign is observed in 30% of patients with hypocalcemia, and a positive sign in 10% of individuals without this pathology.

2.3 Laboratory Diagnostics

• In patients with suspected hypoparathyroidism, to rule out secondary causes of hypocalcemia, it is recommended to test blood inorganic phosphorus, serum total magnesium, blood 25-OH vitamin D, and blood creatinine with GFR calculation [73–75,86–89].

GCR CLEL 5Level of Evidence C (Level of Data Reliability – 5)

Comments:

• in severe hypomagnesemia, PTH secretion decreases, and bone and renal resistance to PTH increases;

• severe vitamin D deficiency may be associated with hypocalcemia. Vitamin D status is assessed by determining 25(OH)D, which is the most accessible and reliable laboratory diagnostic method. It is recommended to verify the reliability of the 25(OH)D assay method used against generally accepted international standards (DEQAS, NIST). Determination of the active metabolite 1,25(OH)₂D is not indicated, as this metabolite has a short half-life and does not reflect the body's vitamin D status;

• in acute hyperphosphatemia, phosphorus actively binds calcium, leading to its deposition mainly in bones and other tissues, causing hypocalcemia;

• hypocalcemia is frequently observed with a decrease in glomerular filtration rate (GFR) and the development of CKD, especially in CKD stages 4 and 5. Hypocalcemia in CKD is a consequence of decreased synthesis of 1,25(OH)₂D and is accompanied by hyperphosphatemia, which in turn leads to the deposition of calcium phosphates in soft tissues, thereby further contributing to hypocalcemia.

• GFR calculation according to CKD-EPI is performed using the formula: GFR = a × (blood creatinine (mg/dL)/b)^c × (0.993)^age. The variable "a" has the following values depending on race and gender: Black: women = 166; men = 164; White/other races: women = 144; men = 141. The variable "b" has the following values depending on race and gender: women = 0.7; men = 0.9. The variable "c" has the following values depending on race and creatinine measurement: women: blood creatinine <= 0.7 mg/dL = -0.329; blood creatinine > 0.7 mg/dL = -1.209; men: blood creatinine <= 0.7 mg/dL = -0.411; blood creatinine > 0.7 mg/dL = -1.209. [https://www.kidney.org/content/ckd-epi-creatinine-equation-2009]

• Patients with postoperative hypoparathyroidism are recommended to be diagnosed with the chronic form of the disease if hypocalcemia persists in combination with low or low-normal PTH levels 6 months or more after neck surgery [1,33,74–79,82,85,90].

LoR BLoE 4Level of Recommendation B (Level of Evidence – 4)

Comments: about 60–70% of postoperative hypocalcemia cases are transient and resolve within 4–6 weeks after surgery (transient hypoparathyroidism). Persistent hypocalcemia (ongoing need for vitamin D and its analogs (alphacalcidol**, calcitriol**) and calcium preparations) combined with PTH levels below reference values 6 months or more after surgical treatment indicates the development of chronic hypoparathyroidism.

• Patients with hypoparathyroidism are recommended to undergo dynamic monitoring of blood and urine parameters (blood total calcium, blood albumin, blood ionized calcium, blood inorganic phosphorus, blood creatinine, and 24-hour urine calcium) to assess therapy adequacy [74,75,84].

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

Comments: dynamic assessment of blood total calcium, blood albumin (with albumin-corrected calcium calculation), blood phosphorus, and blood creatinine with GFR calculation in compensated disease is recommended every 3–6 months. In the absence of hypoparathyroidism compensation and/or adjustment of standard therapy doses, more frequent evaluation of calcium-phosphorus metabolism parameters (up to several times a week) is recommended to assess the adequacy of the selected therapy.

Dynamic monitoring of daily urinary calcium excretion (urinary calcium testing) is recommended every 6–12 months. In case of hypercalciuria and/or prescription of thiazide or thiazide-like diuretics, a follow-up 24-hour urinary calcium test is recommended after 1.5–2 months to assess treatment adequacy.

2.4 Instrumental Diagnostics

• Patients with hypoparathyroidism are recommended to undergo renal ultrasound and/or renal and adrenal computed tomography to assess structural changes due to the increased risk of nephrolithiasis/nephrocalcinosis [74,75,91–100,174-177].

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

Comments: in patients with chronic hypoparathyroidism receiving therapy with vitamin D and its analogs, and calcium preparations, the risk of developing nephrolithiasis/nephrocalcinosis is significantly increased. Regular imaging facilitates early detection of these complications. Ultrasound is preferable for diagnosing medullary nephrocalcinosis in hypoparathyroidism patients. The frequency of examination is determined individually depending on existing changes, but most experts suggest performing renal ultrasound and/or renal and adrenal computed tomography once a year.

• Patients with chronic hypoparathyroidism with a disease duration of more than 10 years are recommended to undergo periodic comprehensive ophthalmological examination (initial ophthalmologist consultation, follow-up ophthalmologist consultation) to detect cataract [101,102, 178].

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

Comments: patients with chronic hypoparathyroidism have an increased risk of developing cataract. Disease duration and lack of hypoparathyroidism compensation are considered predisposing factors, although the pathogenesis of cataract development in hypoparathyroidism is currently not fully understood. Patients with a long history of hypoparathyroidism are indicated for ophthalmological follow-up (initial ophthalmologist consultation, follow-up ophthalmologist consultation) for timely diagnosis of cataract development and determination of the need for specialized treatment.

• In the presence of neurological symptoms, patients with chronic hypoparathyroidism are recommended to undergo brain computed tomography and a neurologist consultation [43,45,53,55,74,75,103,104].

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

Comments: The clinical manifestations of calcification in various parts of the central nervous system in patients with a long history of hypoparathyroidism are nonspecific. The most common include movement disorders: muscle rigidity, parkinsonism, movement disorders (chorea, tremor, dystonia, athetosis, orofacial dyskinesia); cognitive impairment; cerebellar symptoms; and speech disorders. In some cases, epileptic seizures and dementia are observed. A combination of various clinical symptoms is frequently noted. The question of whether there is a pathogenetic relationship between neurological symptoms and the extent or localization of calcifications remains controversial. If these symptoms occur and/or brain CT reveals basal ganglia calcification, an appointment (examination, consultation) with a neurologist is indicated.

• Patients with chronic hypoparathyroidism are not recommended to undergo regular DXA to assess bone tissue status [45,74,75,105–108].

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

Comments: in hypoparathyroidism, bone turnover is slowed down; therefore, there are no prerequisites for a decrease in BMD over time in the absence of concomitant risk factors, such as glucocorticoid therapy. To assess bone status in patients with chronic hypoparathyroidism, it is advisable to perform a comprehensive examination, including the determination of bone turnover markers (serum C-terminal telopeptide, serum osteocalcin, serum alkaline phosphatase activity) and bone radiography (thoracic spine radiography (1 projection), lumbar spine radiography (1 projection), radiography of the affected skeletal part).

2.5 Other Procedures

• Patients with hypoparathyroidism of undetermined etiology are recommended to undergo genetic counseling (appointment (examination, consultation) with a geneticist) if a hereditary nature of the pathology is suspected [1,15,16,74,75,109–113].

LE RLoE 4Level of Evidence / Recommendation Grade: C (Level of Evidence – 4)

Comments:

• patients with isolated hypoparathyroidism of unclear etiology that manifested after the first year of life are recommended to undergo a detailed history taking and symptom assessment, as well as AIRE gene testing to rule out APS type 1 (initially evaluating for the R257X mutation as the most frequent in the Russian population, followed by gene sequencing in case of a negative result). The diagnosis of APS type 1 can be established clinically if the patient has at least two of the three "major" components of the disease ("classic dyad or triad"), or one of them if a first-degree relative has the disease. To verify the syndrome, testing for antibodies to type 1 interferons, especially IFN-ω and IFN-α2, which have been proposed as diagnostic criteria for the disease, can also be used. Testing for 21-hydroxylase antibodies is useful for predicting the development of adrenal insufficiency. The examination algorithm for suspected autoimmune hypoparathyroidism is presented in the Additional Information section (Subsection 7.4).

• Non-surgical hypoparathyroidism can be caused by a number of different factors. If the cause of hypoparathyroidism is not established, a detailed history taking and symptom assessment, genetic testing, and/or family screening are recommended. There is currently no standard testing protocol. This recommendation is especially important for young patients, as making a diagnosis is necessary for pregnancy planning and subsequent monitoring for the possible development of disease components associated with hypoparathyroidism (e.g., hearing and kidney pathology in GATA3 mutations). Genetic forms of hypoparathyroidism can present either as part of a syndromic disorder or as an isolated endocrinopathy, such as autosomal dominant hypocalcemia. Hereditary forms of the disease are presented in Table 4. The examination algorithm for suspected hypoparathyroidism within a hereditary syndrome is presented in the Additional Information section (Subsection 7.5).

Table 4. Hereditary forms of hypoparathyroidism [77].

AD – autosomal dominant, AR – autosomal recessive, NA – not available. Mitochondrial. – mitochondrial. MTP – mitochondrial trifunctional protein.

1 – the causal role of SOX3 in the development of X-linked hypoparathyroidism has not been determined.

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

3.1 Treatment goals and monitoring of hypoparathyroidism

The main goals of long-term therapy for hypoparathyroidism are presented in Table 5.

Table 5. Main goals of long-term therapy for hypoparathyroidism.

• In patients with hypoparathyroidism, it is recommended to maintain serum calcium levels (albumin-corrected or ionized calcium) at or slightly below the lower limit of the reference range, provided there are no symptoms and signs of hypocalcemia, in order to prevent the development of disease complications [74,75,78,114].

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

Comments: currently, there is no universal consensus regarding the optimal serum calcium level during hypoparathyroidism therapy. Maintaining serum calcium at the lower limit of the reference range or slightly below is driven by the desire to prevent hypercalciuria and renal complications. Therapeutic targets—serum albumin-corrected calcium levels within 2.1–2.3 mmol/L or ionized calcium within 1.05–1.15 mmol/L—are based on maintaining physiological processes in the body. However, some patients may require higher serum calcium levels to relieve symptoms of hypocalcemia.

• In patients with hypoparathyroidism, it is recommended to maintain 24-hour urinary calcium excretion within the sex-specific target range to prevent renal complications [52,74,75,93,114].

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

Comments: due to PTH deficiency and the lack of its effect on tubular calcium reabsorption in the kidneys, patients with hypoparathyroidism are characterized by hypercalciuria and, consequently, an increased risk of nephrolithiasis/nephrocalcinosis. There is currently insufficient data on the association between the degree of hypercalciuria and the risk of developing renal pathology. Assuming that the pathogenesis of kidney stone formation in patients with eu- and hypoparathyroidism and hypercalciuria is similar, maintaining 24-hour urinary calcium excretion within the sex-specific reference range will help prevent this complication. The target range for urinary calcium levels in 24-hour urine is up to 7.5 mmol/day (300 mg/day) for men, up to 6.25 mmol/day (250 mg/day) for women, or less than 0.1 mmol/kg/day (4 mg/kg/day) for both sexes. Urinary calcium determination in patients with chronic hypoparathyroidism is recommended every 6–12 months, as well as in the event of elevated creatinine and decreased GFR detected during follow-up monitoring.

• In patients with hypoparathyroidism, it is recommended to maintain serum inorganic phosphorus levels within the reference range to prevent extraskeletal calcification [1,33,52,74,75].

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

Comments: maintaining phosphorus levels within the reference range is necessary to prevent extraskeletal calcifications. Hyperphosphatemia in hypoparathyroidism is caused both by the lack of the phosphaturic action of PTH and by increased intestinal phosphate absorption under the influence of therapy with vitamin D and its analogs.

• In patients with hypoparathyroidism, it is recommended to maintain magnesium levels within the reference range [74,75,115,116].

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

Comments: in hypoparathyroidism, a decrease in serum magnesium levels is frequently observed. Hypomagnesemia itself can cause hypocalcemia and functional hypoparathyroidism, as well as prevent the achievement of disease compensation. Proton pump inhibitors or thiazide/thiazide-like diuretics can be causes of hypomagnesemia. Magnesium supplements are recommended to normalize serum magnesium levels. Magnesium preparations are not always well tolerated due to gastrointestinal side effects. The interval between calcium and magnesium administration should be at least 1.5–2 hours to avoid reducing the absorption of both micronutrients!

• In patients with hypoparathyroidism, it is recommended to maintain the 25-OH vitamin D level within the range recommended for the general population [1,74,75,82,117–121].

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

Comments:

• currently, due to the lack of comparative studies, data are limited regarding the benefits of combined therapy with vitamin D and its analogues (alfacalcidol**, calcitriol**) and native vitamin D (cholecalciferol**) over monotherapy with vitamin D and its analogues (alfacalcidol**, calcitriol**). However, the hospitalization rate for acute hypocalcemia is significantly higher with monotherapy using vitamin D and its analogues (alfacalcidol**, calcitriol**) compared to therapy with native vitamin D (cholecalciferol**) in supraphysiological doses. These findings can be explained by different half-lives of the drugs, where once an adequate 25(OH)D level is achieved, blood calcium fluctuations are less pronounced than when using short-acting vitamin D and its analogues (alfacalcidol**, calcitriol**).

• For patients with hypoparathyroidism, as for the general population, vitamin D insufficiency or deficiency is characteristic in most cases. Therefore, the use of native forms of vitamin D (cholecalciferol**) is advisable for its correction.

• For the Russian population, optimal 25(OH)D levels are established in the range of 30–60 ng/mL (75–150 nmol/L). 25(OH)D levels above 100 ng/mL (250 nmol/L) may cause toxic effects of vitamin D on the body and are not recommended.

• Vitamin D insufficiency is associated with impaired mineralization and bone remodeling processes. However, the functions of vitamin D are not limited to the control of phosphorus-calcium metabolism; it also affects many physiological processes in the body. Extraskeletal ("non-classical") effects of vitamin D are mediated by specific receptors (VDR) present in many cells; additionally, some tissues contain their own 1 alpha-hydroxylase for intracellular synthesis of the active hormone form.

• Therapy with vitamin D preparations and their derivatives (alfacalcidol**, calcitriol**) does not affect serum 25(OH)D levels.

• In patients with chronic hypoparathyroidism who have hyperphosphatemia and/or exceed target daily urinary calcium levels against the background of normocalcemia, it is recommended to perform a 24-hour calciemia profile (12-fold measurement of total blood calcium, blood albumin with calculation of albumin-adjusted blood calcium per day) to detect "hidden" episodes of hypo-/hypercalcemia and personalize therapy with indication of individual dosing frequency and administration time [101,122].

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

Comments: having a target serum calcium level in the early morning hours on standard therapy may be an insufficient criterion for determining disease compensation. Given the relatively short half-life of vitamin D preparations and their derivatives (alfacalcidol**, calcitriol**), administering them several times a day is recommended to stably maintain target blood calcium values. Assessing the 24-hour calciemia profile in patients with chronic hypoparathyroidism receiving standard therapy is a useful tool for evaluating the efficacy of drugs throughout the day. This allows recording blood calcium fluctuations that underlie the discrepancy between laboratory and clinical compensation of hypoparathyroidism, especially in patients with hyperphosphatemia and/or exceeding target daily urinary calcium levels.

• The methodology for performing a 24-hour calciemia profile in patients with chronic hypoparathyroidism involves measuring total blood calcium and blood albumin (with calculation of albumin-adjusted blood calcium) every 2 hours over 24 hours while receiving standard hypoparathyroidism therapy. During the day when blood calcium measurements are taken, the patient keeps a diary noting the time of administration and doses of calcium supplements and vitamin D preparations and their analogues (alfacalcidol**, calcitriol**). The results of the 24-hour calciemia profile are analyzed by an endocrinologist along with the patient's medication schedule. Based on this information, the endocrinologist draws conclusions regarding the need to adjust doses and/or frequency of calcium and vitamin D preparations and their analogues (alfacalcidol**, calcitriol**).

Comments: dynamic observation and regular monitoring of blood and urine biochemical parameters are recommended in patients with hypoparathyroidism; however, despite regular monitoring and adequate therapy, the risk of hypo- and hypercalcemic states persists. Thus, the patient's subjective assessment of their own condition, knowledge of symptoms and disease manifestations, comorbid conditions, and signs of drug overdose are an important aspect of treatment and achieving long-term disease control. Table 6 presents clinical symptoms that should be communicated to patients so they can independently suspect early-stage hypo- or hypercalcemia.

Table 6. Clinical symptoms that should be communicated to patients so they can independently suspect early-stage hypo- or hypercalcemia.

3.2 Conservative treatment

Medicines used for the treatment of hypoparathyroidism are presented in Table 7.

Table 7. Medicines for the treatment of hypoparathyroidism (replacing calcium and magnesium deficiencies).

¹ – sulfonamides acting on the cortical segment of the loop of Henle.

² – preventive dose of cholecalciferol**, indicated at 25(OH)D >30 ng/mL (75 nmol/L); in case of vitamin D deficiency or insufficiency, a higher dose may be required.

³ – including as part of the combined preparation "calcium carbonate + cholecalciferol**".

⁴ – calculated as elemental calcium

⁵ – calculated as elemental magnesium

^** – the drug is included in the list of vital and essential drugs (VED).

• Drug therapy is recommended for all patients with chronic hypoparathyroidism with symptoms of hypocalcemia and an albumin-adjusted calcium level of less than 2.0 mmol/L or serum ionized calcium of less than 1.0 mmol/L. In cases of asymptomatic chronic hypoparathyroidism and an albumin-adjusted calcium level between 2.0 mmol/L and the lower limit of the reference range, trial therapy with subsequent evaluation of general well-being is recommended [1,33,52,74,75,127].

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

Comments: drug therapy for hypoparathyroidism in patients with pronounced symptoms of hypocalcemia is unquestionable; however, the need for treatment in asymptomatic patients with laboratory-confirmed mild hypocalcemia remains an open question. The exact blood calcium level at which therapy should be initiated has not been established. A sharp decrease in serum calcium levels can provoke the development of hypocalcemia symptoms even while laboratory normocalcemia is maintained. On the other hand, slowly developing and prolonged severe hypocalcemia may occur without clinical symptoms, which is most likely due to the body's adaptation to chronic changes in calcium homeostasis. In patients with preserved parathyroid gland function, the calcium level is maintained within a very narrow reference range. Thus, patients with asymptomatic hypoparathyroidism may be recommended treatment for a potential improvement in their condition. If no improvement occurs after 6–12 months of therapy, the need for treatment may be reconsidered, especially in cases of mild hypocalcemia.

• To achieve disease compensation in patients with hypoparathyroidism, it is recommended to prescribe vitamin D preparations and their analogues (alphacalcidol**, calcitriol**) in combination with calcium preparations [1,33,74,75,84,85,121,128–132].

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

Comments:

• Standard therapy for hypoparathyroidism includes vitamin D preparations and their analogues (alphacalcidol**, calcitriol**) and calcium preparations. Average therapeutic doses of calcitriol** are 0.25–2.0 mcg/day, and alphacalcidol** – 1.0–4.0 mcg/day. The duration of the hypercalcemic effect of calcitriol** averages 2 to 6 hours, and that of alphacalcidol** – 6 to 8 hours. Therefore, ensuring a stable blood calcium level requires multiple daily doses, especially when doses exceeding 1.5–2.0 mcg per day are necessary.

• To maintain blood calcium within the target range, titration of the doses of vitamin D preparations and their analogues, along with dividing the total daily dose into 2–3 intakes, is recommended. Dose titration is usually performed in increments of 0.5 (or 0.25) mcg for alphacalcidol** and 0.25 mcg for calcitriol**. Larger dose adjustments may be required in cases of pronounced hypo- or hypercalcemia. The recommended time interval for adjusting the doses of vitamin D preparations and their analogues (alphacalcidol**, calcitriol**) is 2–3 days, which is due to their pharmacokinetics and allows an adequate assessment of the implemented changes. In cases of mild symptoms and moderate fluctuations in calcemia parameters, laboratory evaluation of the adequacy of the adjusted doses can be performed after 7–10 days. Assessing the clinical efficacy of the selected therapy and achieving stable calcemia values may take about 2–3 months, especially for patients with a high demand for vitamin D preparations and their analogues.

• Isolated administration of calcium preparations is pathogenetically unjustified and causes only a short-term increase in serum calcium levels.

• Dietary modification with a high intake of calcium-rich foods is recommended for patients with hypoparathyroidism.

• Various calcium preparations are used to treat hypoparathyroidism (to replenish calcium deficiency). As a rule, preparations containing calcium carbonate (40% elemental calcium) are used, including combination drugs such as "calcium carbonate + cholecalciferol" at average daily doses of 1–3 g (higher doses may also be used). Calcium citrate dietary supplements (21% elemental calcium) can also be used. When prescribing, the pharmacokinetic features of different preparations must be considered: calcium carbonate is better absorbed in an acidic gastric environment and is therefore preferred when taken with food; calcium citrate is recommended for patients with achlorhydria or those receiving proton pump inhibitor therapy.

• High doses of calcium preparations can reduce the need for vitamin D and its analogues and improve the control of target serum phosphorus levels by binding phosphates in the intestine.

• For patients with chronic hypoparathyroidism and hypercalciuria, it is recommended to reduce the doses of calcium preparations and follow a low-salt diet to achieve the target level of calcium excretion [1,33,52,74,75,84,85,93,121,123,124,126,133–138].

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

• For patients with chronic hypoparathyroidism and hypercalciuria, therapy with thiazides (#hydrochlorothiazide**)/thiazide-like diuretics (#chlorthalidone**) is recommended to achieve the target level of calcium excretion, provided that overdosage with calcium preparations and vitamin D preparations and their analogues (alphacalcidol**, calcitriol**) has been ruled out [1,33,52,74,75,84,85,93,121,123,124,126,133–138].

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

Comments:

• Hypercalciuria is a risk factor for renal complications in chronic hypoparathyroidism; therefore, daily urinary calcium excretion should be maintained within the target range.

• Hypercalciuria in the presence of normocalcemia, either alone or combined with hyperphosphatemia, may indicate overdosage with calcium preparations and vitamin D preparations and their analogues (alphacalcidol**, calcitriol**). In such patients, it is recommended first to divide the daily doses into 2–4 intakes and to reduce the doses of calcium preparations and/or vitamin D preparations and their analogues (alphacalcidol**, calcitriol**).

• If dietary recommendations and dose adjustments fail to produce an effect, the use of thiazide therapy (e.g., #hydrochlorothiazide**) is recommended. By reducing urinary calcium excretion, thiazides help increase serum calcium levels and decrease the requirement for calcium preparations and vitamin D and its analogues.

• The recommendation to use #hydrochlorothiazide** and #chlorthalidone in patients with hypoparathyroidism is based on studies demonstrating a reduction in calcium excretion during their use. The efficacy of thiazides (#hydrochlorothiazide**) in reducing daily urinary calcium excretion and the risk of nephrocalcinosis has been proven in several randomized clinical trials, which served as the basis for a meta-analysis (n=571) (P < 0.0001) [123]. In a study by Santos F. et al., the use of #hydrochlorothiazide** at a dose of 1–2 mg/kg/day in patients with chronic hypoparathyroidism resulted in a decrease in daily calcium excretion and the calcium/creatinine ratio from 3.2±0.8 mg/kg/day and 0.19±0.04 to 1.3±0.6 mg/kg/day and 0.05±0.02, respectively. Thus, the use of #hydrochlorothiazide** helps reduce urinary calcium excretion in this patient cohort [138]. It has been shown that the use of #chlorthalidone in patients with hypoparathyroidism also leads to decreased calcium excretion. A study by Porter R.H. et al. found that #chlorthalidone intake reduced daily calcium excretion from 179 to 88 mg/day (P < 0.001), while the mean blood calcium level reached the reference range (from 8.2 mg/dL to 9.3, P < 0.05) (n=7, study duration – 25 months) [126].

• The efficacy of thiazides is dose-dependent, and their administration must be combined with a low-salt diet. Thiazides are recommended to be taken orally twice daily; the starting dose of #hydrochlorothiazide** can be 25–50 mg per day [52,123–125]. Sulfonamides (#chlorthalidone) can be used orally once daily at a dose of 25–200 mg [125,126]. The duration of treatment is individual and depends on achieving disease compensation and the development of side effects.

• The risk of side effects increases with higher drug doses; potential adverse effects should be carefully monitored during treatment, primarily by assessing blood electrolyte panels (blood potassium, blood sodium, and blood magnesium levels) and blood pressure.

• For patients with chronic hypoparathyroidism and hyperphosphatemia, a low-phosphate diet and dose adjustment of standard therapy are recommended to achieve normophosphatemia and prevent extraskeletal calcification [47,74,75,121,139].

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

Comments: high serum phosphorus levels increase the risk of extraskeletal calcification, although the mechanism of these changes is unknown.

• To correct hyperphosphatemia, adherence to dietary recommendations limiting the intake of phosphorus-rich foods is recommended. It is also recommended to increase the dose of calcium preparations and decrease the dose of vitamin D preparations and their analogues (alphacalcidol**, calcitriol**) to reduce intestinal phosphorus absorption.

• Hyperphosphatemia with normocalcemia may indicate an overdose of vitamin D and its analogues (alfacalcidol**, calcitriol**).

• In turn, hyperphosphatemia against the background of hypocalcemia is secondary to a decrease in serum calcium levels and is not an indication for reducing the doses of vitamin D and its analogues (alfacalcidol**, calcitriol**), but rather for increasing them until normocalcemia is achieved.

• In patients with hypoparathyroidism, if concomitant vitamin D deficiency/insufficiency is detected, it is recommended to prescribe native vitamin D preparations (cholecalciferol**) in standard doses as for the general population, despite treatment with vitamin D and its analogues (alfacalcidol**, calcitriol**) [74,75,84,140,141].

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

Comments: in patients with hypoparathyroidism receiving therapy with vitamin D and its analogues and calcium preparations, maintaining the target 25(OH)D level allows for the realization of extra-skeletal "non-classical" effects of vitamin D, as well as more stable calcemia indices. Therapy with vitamin D and its analogues (alfacalcidol**, calcitriol**) does not affect serum 25(OH)D levels. Prescribing the native form of vitamin D (cholecalciferol**) is necessary to correct vitamin D deficiency/insufficiency. The doses of cholecalciferol** used to correct vitamin D deficiency/insufficiency, as well as maintenance doses, do not differ from those recommended for the general population. Patients with hypoparathyroidism are recommended to monitor calcium-phosphorus metabolism during the administration of loading doses of cholecalciferol** to timely detect a tendency towards hypercalcemia and adjust therapy.

Comments: normocalcemia in patients with hypoparathyroidism can be achieved using therapy with parathyroid hormones and their analogues (ATX code: H05AA). In the Russian Federation, the registered drug of this group is #Teriparatide**, used for the treatment of osteoporosis. In several studies on the use of the drug in the treatment of chronic hypoparathyroidism, the average dose was 37±2.6 mcg/day [142–145]. #Teriparatide** therapy is accompanied by a decrease in the doses of calcium preparations and vitamin D and its analogues (alfacalcidol**, calcitriol**) and helps maintain serum calcium levels within the target range. #Teriparatide** therapy can improve 24-hour urinary calcium excretion and patients' quality of life, as well as reduce the risks of renal complications. However, to date, insufficient knowledge has been accumulated regarding the long-term outcomes of using this drug. In the Russian Federation, drugs from the group "Parathyroid hormone and analogues (ATX code: H05AA)" are not registered for the indication of treating patients with hypoparathyroidism. #Teriparatide** therapy at a regimen of 20 mcg 1–2 times a day subcutaneously may be considered for individual patients with chronic hypoparathyroidism in the absence of disease compensation on high doses of calcium and vitamin D preparations, solely by the decision of a medical commission. The duration of therapy is determined individually [142-145].

The efficacy and safety of #Teriparatide** therapy for the treatment of hypoparathyroidism were demonstrated in a 3-year open-label randomized trial (n=27, age 18-70 years). Patients with chronic hypoparathyroidism were randomized into 2 groups: those receiving standard therapy (mean calcitriol** dose 0.91±0.2 mcg/day) and #Teriparatide** therapy 2 times a day (mean dose 37±2.6 mcg/day (0.5 mcg/kg)). After the 3-year study period, compensation of hypoparathyroidism was achieved in both groups, and a decrease in the severity of hypercalciuria was also noted during #Teriparatide** treatment. Thus, #Teriparatide** therapy has proven its efficacy and safety in the treatment of hypoparathyroidism [142].

The advantage of using #Teriparatide** therapy in a twice-daily injection regimen compared to a single daily injection was demonstrated in another randomized trial (n=30, age 48.6±18.4 years). This study showed that teriparatide at a regimen of 20 mcg once daily was insufficient to discontinue calcium and calcitriol** preparations to maintain normal serum calcium concentrations. Conversely, for more than half of the patients receiving teriparatide 20 mcg twice daily, standard therapy was discontinued [143].

Another randomized study also demonstrated the superiority of twice-daily #Teriparatide** injections compared to single-daily injections in patients with hypoparathyroidism (n=14, age 4-17 years). The study duration was 28 weeks. The findings established that twice-daily #Teriparatide** injections successfully achieve and maintain target calcium levels throughout the day, as well as reduce the variability of the 24-hour calcemia profile, using a lower daily dose of the drug compared to the once-daily #Teriparatide** injection regimen (drug dose in the twice-daily regimen was 25±15 mcg/day; in the once-daily injection regimen – 58 ± 28 mcg/day; P < 0.001) [144].

Currently, the maximum duration of #Teriparatide** therapy in children with non-surgical forms of hypoparathyroidism is 6.9±3.1 years (1.5; 10), at a mean dose of 0.75±0.15 mcg/kg/day. Treatment is accompanied by a significant decrease in the requirement for calcium and vitamin D preparations and their analogues, along with positive dynamics in bone resorption markers [145].

Comments: dihydrotachysterol – a synthetic analogue of vitamin D, formerly widely used in the complex therapy of hypoparathyroidism. According to modern concepts, this drug should not be used in the treatment of chronic hypoparathyroidism. The specific metabolism of dihydrotachysterol (long half-life, absence of feedback regulation in the synthesis of active dihydrotachysterol metabolites, high biological activity) and, consequently, a narrow therapeutic range lead to the frequent development of hypercalcemia and associated disorders. Dihydrotachysterol is deposited in the liver, adipose tissue, skin, muscles, and bones, meaning its action can continue for another 1-2 months after cessation of intake. This causes prolonged drug toxicity. Dihydrotachysterol overdose leads to hypercalcemia; and if it persists for a long time – to impaired renal function, cardiosclerosis, pneumosclerosis, and nephrosclerosis. Hypercalcemia caused by dihydrotachysterol intoxication requires prolonged management and the selection of a more active treatment strategy.

3.3 Surgical Treatment

Surgical treatments for this condition have not been developed.

3.4 Other treatment

No other treatments are used.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific rehabilitation has not been developed.

5. Prevention and Dispensary Observation

• Patients scheduled for neck surgery are recommended to have their blood 25-OH vitamin D levels tested and deficiency/insufficiency corrected to prevent postoperative transient hypoparathyroidism [80,139,150–157].

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

Comments: the development of postoperative transient hypoparathyroidism is associated with preoperative 25(OH)D deficiency/insufficiency.

• To avoid injury and/or devascularization of the parathyroid glands, routine exploration during neck surgery is not recommended [158–160].

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

Comments: performing parathyroid visualization during surgery carries risks of damaging the glands' blood supply and can significantly increase operative time, which is an independent risk factor for hypoparathyroidism. To identify the parathyroid glands and assess their viability during surgery, fluorescence angiography with #indocyanine green is preferred [179]. #Indocyanine green powder (25 mg) is dissolved in 20 ml of sterile water for injections, after which 5 ml of the solution is administered intravenously (concentration 8.3 mg per 1 procedure).

• During the first 24 hours after neck surgery, it is recommended to measure blood parathyroid hormone levels, total blood calcium levels, blood albumin levels with calculation of albumin-corrected serum calcium, or ionized calcium levels in the blood to diagnose hypoparathyroidism and determine the need for calcium and vitamin D preparations and their derivatives [80].

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

Comments: although there are currently no well-defined time criteria for blood sampling to assess PTH and calcium levels in the postoperative period, studies demonstrate the value of measuring these parameters within the first 24 hours after neck surgery. A PTH level of less than 10–15 pg/mL on the first postoperative day is considered a predictor of postoperative hypoparathyroidism (sensitivity 97.7%, specificity 82.6%). Postoperative evaluation of laboratory parameters of calcium-phosphorus metabolism is a prerequisite for the timely administration of vitamin D preparations and their analogues, as well as calcium preparations.

• In patients who have undergone total thyroidectomy, it is recommended to routinely use oral calcium preparations during the first 2 weeks after surgery to prevent acute hypocalcemia [161,162].

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

• During neck surgery, if devascularization of the parathyroid glands occurs, it is recommended to perform their autotransplantation to prevent postoperative hypoparathyroidism [164,165].

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

Comments: autotransplantation of parathyroid glands devascularized during neck surgery is an effective method for preventing postoperative hypoparathyroidism. Normally functioning parathyroid glands are typically transplanted into the sternocleidomastoid muscle, whereas altered, hyperplastic glands are preferably transplanted into the brachioradialis muscle of the non-dominant forearm.

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) instrumental examination: renal ultrasound (renal CT as indicated), brain CT as indicated;

3) consultations with related specialists: ophthalmologist, urologist (as indicated), nephrologist (as indicated), cardiologist (as indicated), neurologist (as indicated);

4) adjustment of standard therapy for hypoparathyroidism to achieve target parameters of calcium-phosphorus metabolism.

Indications for scheduled hospitalization in a medical organization:

1) the need to adjust standard therapy for hypoparathyroidism to achieve target parameters of calcium-phosphorus metabolism;

2) the inability to achieve target parameters of calcium-phosphorus metabolism using standard hypoparathyroidism therapy.

Indications for emergency hospitalization in a medical organization:

1) acute hypocalcemia;

2) development of life-threatening complications associated with acute hypocalcemia (laryngospasm/bronchospasm, cardiac arrhythmias, generalized seizures);

Indications for discharging a patient from a medical organization:

1) steady improvement in condition, allowing the patient to continue treatment in an outpatient clinic or at home without prejudice to health;

2) when it is necessary to transfer the patient to another healthcare 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 Treatment of acute hypocalcemia

To relieve acute hypocalcemia, placement of a central venous catheter is recommended to prevent sclerosis of peripheral veins resulting from calcium infusion. Calcium gluconate** is preferred, as calcium chloride carries a severe risk of soft tissue necrosis if the solution extravasates.

To relieve acute hypocalcemia, intravenous administration of calcium preparations is performed in 2 stages: 1–2 ampoules of 10% calcium gluconate** solution, containing 90–180 mg of elemental calcium respectively, in 50 mL of 0.9% sodium chloride** solution (or 5% dextrose** solution) over 10–20 minutes; followed by slow intravenous infusion of 100 mL of calcium gluconate** (10 ampoules) at a rate of 0.5–1.5 mg/kg/h in 1000 mL of 0.9% sodium chloride** solution (or 5% dextrose solution) over an average of 8–10 hours.

Depending on the clinical situation, the following options for parenteral administration of calcium preparations may be used:

1. Intravenous bolus administration of calcium gluconate** in a volume of 20–60 mL rapidly without dilution with 0.9% sodium chloride** solution (or 5% dextrose solution). This method is used for severe symptoms of hypocalcemia (patients presenting with a clinical picture of "fear of death" or in an unconscious state). The administered calcium dose is determined by the disappearance of dyspeptic complaints.

2. Administration of half the dose of calcium gluconate** as an IV bolus without dilution (40–50 mL of 10% calcium gluconate** solution), with the remaining calcium dose (50–60 mL of 10% calcium gluconate** solution) administered slowly IV in a diluted state (with 0.9% sodium chloride** solution or 5% dextrose**) using an infusion pump at a rate of 0.5–1.5 mcg/kg/h. This route of administration is the most common for arresting acute hypocalcemia, allowing rapid normalization of the patient's clinical condition.

3. Administration of the total dose of parenteral calcium preparations (80–100 mL of 10% calcium gluconate** solution) diluted in solution (0.9% sodium chloride** or 5% dextrose**). This method is used primarily to maintain an adequate calcium level to prevent the development of acute hypocalcemia.

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

Intravenous calcium administration requires caution in patients with hypokalemia and in those taking digoxin** due to an increased risk of arrhythmias.

Simultaneous administration of oral calcium preparations and vitamin D preparations and their analogues (alphacalcidol**, calcitriol**) is prescribed. The goal of therapy is to relieve symptoms of acute hypocalcemia due to hypoparathyroidism and to normalize total and ionized calcium levels at or slightly below the lower limit of the reference range in the absence of clinical symptoms of hypocalcemia. Frequent monitoring of blood calcium levels is necessary to adjust therapy (every 6–12 hours at the start of treatment, and every 24 hours after the patient's condition stabilizes).

It is worth noting that if the patient has pronounced hypomagnesemia, its correction is indicated using both oral preparations (combination magnesium preparations 300–400 mg/day) and intravenous forms: 2 grams of magnesium sulfate** IV push over 10–20 minutes, or 2–4 grams of 25% magnesium sulfate** solution in 150–200 mL of normal saline (sodium chloride**) as an IV drip.

Algorithm for managing acute hypocalcemia due to hypoparathyroidism:

1) Calcium gluconate** 20–60 mL IV bolus, and/or 1–2 ampoules of 10% calcium gluconate** solution (90–180 mg of elemental calcium respectively) in 50–100 mL of 0.9% sodium chloride** solution (or 5% aqueous dextrose** solution) IV over 10–20 minutes, with simultaneous prescription of oral calcium preparations and vitamin D preparations and their analogues (alphacalcidol**, calcitriol**). If necessary, calcium gluconate infusion therapy can be continued according to the following regimen: 10 ampoules of 10% calcium gluconate** solution (900 mg of elemental calcium) in 1000 mL of 0.9% NaCl** solution (or 5% dextrose solution) at a rate of 50 mL/h (on average for 8–10 hours).

2) Vitamin D preparations and their analogues (alphacalcidol** on average 3–3.5 mcg/day and/or calcitriol** 1.5–2 mcg/day orally) combined with calcium preparations averaging 3000 mg of elemental calcium orally divided into 3–6 doses per day during or immediately after meals. If hypocalcemia persists, higher doses may be used under the control of blood calcium and phosphorus.

7.2 Management of pregnancy in hypoparathyroidism

Physiological aspects of mineral metabolism regulation during pregnancy

One of the main compensatory mechanisms providing the fetus with a sufficient amount of calcium during pregnancy is enhanced maternal intestinal calcium absorption. During lactation, adequate calcium concentration in breast milk is achieved mainly by enhancing bone resorption processes. These changes are associated with increased production of key hormones such as calcitriol and parathyroid hormone-related peptide (PTHrP).

An increase in calcitriol synthesis is observed starting from the 1st trimester, and by the end of pregnancy its level reaches up to 2–3 times the normal value. The regulation of vitamin D metabolism in pregnant women largely depends on the activity of renal 1α-hydroxylase, which is controlled by estrogens, prolactin, and human placental lactogen. Meanwhile, the 25(OH)D level remains stable despite the increased conversion into its active form. In many body tissues, including the mammary glands, decidua, placenta, etc., PTHrP synthesis increases. The PTHrP level rises from week 3 to week 13 of gestation, exceeding the pre-pregnancy level by more than three times. It is during these periods that PTHrP acts as an endocrine factor regulating mineral and bone homeostasis independently of PTH. Similar to PTH, PTHrP is capable of stimulating bone resorption and renal calcium reabsorption, which together ensure that breast milk is supplied with the amount of calcium necessary for the newborn.

Parathyroid hormone (PTH) production by the parathyroid glands decreases upon the onset of pregnancy, and its blood level remains in the low-normal range or even below population reference values in the 1st trimester, which is associated with the gestational increase in PTHrP and calcitriol production starting from the 3rd week of pregnancy. Thus, PTH, as a regulator of calcium-phosphorus metabolism, loses its dominant role during this period and its production recovers only by the end of the 3rd trimester.

Calcitonin is a PTH-antagonist hormone produced by thyroid C-cells, and during pregnancy and lactation, by the mammary glands and placenta. An increase in calcitonin levels during pregnancy and lactation has also been noted in patients with a history of total thyroidectomy. The increase in the synthesis of this hormone during pregnancy is driven by the effects of estrogens (estradiol, estrone, and estriol) and aims to suppress active demineralization of the maternal skeleton.

During pregnancy and lactation, due to an increase in circulating blood volume and hemodilution, the serum total calcium level decreases, while the albumin-corrected and ionized calcium levels remain unchanged. The fetal blood calcium level is generally somewhat higher than maternal calcemia values.

Studies on the management of pregnancy in chronic hypoparathyroidism are limited by small sample sizes (mostly case series reports). Nevertheless, the expert community highlights key principles for the management and treatment of this condition during gestation.

Key principles for managing pregnancy in a patient with chronic hypoparathyroidism:

• maintaining blood ionized and albumin-corrected calcium levels within the lower-normal range (for albumin-corrected calcium within 2.1–2.3 mmol/l, for ionized calcium within 1.05–1.15 mmol/l) is considered optimal to avoid adverse effects on the development of the fetal parathyroid glands. To calculate the albumin-corrected calcium level, the formula is used: plasma albumin-corrected calcium (adjusted) (mmol/l) = measured total plasma calcium level (mmol/l) + 0.02 × (40 - measured plasma albumin level (g/l));

• during gestation, monitoring of calcium-phosphorus metabolism parameters (testing blood total calcium, blood albumin, blood ionized calcium, and blood phosphorus levels) should be performed at least once every 4–6 weeks to prevent hypo- and hypercalcemia;

• if therapy is altered, more frequent monitoring may be required, on average once every 7–14 days until target calcemia levels are achieved;

• phosphorus, magnesium, and 25(OH)D levels should be maintained within the reference range;

• treatment with thiazide/thiazide-like diuretics should be discontinued during pregnancy and lactation;

• treatment with parathyroid hormone preparations and their analogs should be discontinued during pregnancy and lactation;

• patients with chronic hypoparathyroidism require education aimed at increasing awareness of the symptoms of hypo- and hypercalcemia.

In available studies on the treatment of chronic hypoparathyroidism during pregnancy, women experienced significant changes in their requirement for calcium preparations, vitamin D preparations, and their analogs (most commonly calcitriol**, less commonly #alphacalcidol) depending on the gestational age and lactation period. Mean doses of calcium preparations reached 2000–3000 mg per day, calcitriol** doses 1–2 mcg per day, and #alphacalcidol doses an average of 2 mcg per day. Laboratory monitoring was performed every 4–6 weeks throughout pregnancy to ensure adequate condition management and dosage adjustment when necessary. It is important to note that although pregnancy and lactation are listed as contraindications for calcitriol**/#alphacalcidol**, no alternatives exist for treating chronic hypoparathyroidism during gestation. Available studies have demonstrated the safety of using these medications in the specified doses [180–182].

7.3. Autoimmune hypoparathyroidism

Autoimmune hypoparathyroidism is the second most common form of hypoparathyroidism, caused by immune-mediated destruction of parathyroid cells. It can be an isolated condition, but it is much more frequently encountered as part of hereditary autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) type 1 [14]. The prevalence of this disease is estimated at 1:100,000 population in most countries, with a higher prevalence noted in countries such as Finland (1:25,000) and Sardinia (1:14,000), and among Persian Jews in Israel (1:9,000) [166].

APECED type 1 is a monogenic autosomal recessive disorder caused by a structural defect in the autoimmune regulator (AIRE) gene. The AIRE gene is located on the long arm of chromosome 21, encodes a nuclear transcription factor, and plays a key role in the formation of immune tolerance. The pathogenesis is based on autoimmune destruction of various endocrine glands [167]. APECED type 1 is characterized by the classical triad: mucocutaneous candidiasis, hypoparathyroidism, and chronic primary adrenal insufficiency. The disease typically debuts in childhood. In more than 80% of patients with APECED type 1, hypoparathyroidism is the sole endocrine manifestation of the disease [167].

In the vast majority of cases, the first manifestation is mucocutaneous candidiasis, developing within the first 10 years of life, most often around the age of 2 years. Against the background of mucocutaneous candidiasis, 84% of patients develop hypoparathyroidism, with 88% of cases debuting before the age of 10. Other components of the syndrome include type 1 diabetes mellitus, Hashimoto's thyroiditis, celiac disease, vitiligo, autoimmune hepatitis, hypogonadism, and others [16].

Components of APECED type 1:

• Major components:

  • mucocutaneous candidiasis;

  • hypoparathyroidism;

  • primary adrenal insufficiency.

• Other possible manifestations:

  • keratitis;

  • autoimmune hepatitis;

  • primary ovarian dysfunction;

  • dental enamel hypoplasia;

  • enteropathy with chronic diarrhea or constipation;

  • photophobia;

  • periodic fever with rash;

  • pneumonitis;

  • nephritis;

  • pancreatitis;

  • type 1 diabetes mellitus;

  • functional asplenia;

  • celiac disease;

  • thyroiditis;

  • retinitis;

  • bone marrow red cell aplasia;

  • polyarthritis.

Currently, the target for autoimmune damage to parathyroid cells remains unknown. Several antigens, the autoantibodies against which may be responsible for the development of hypoparathyroidism, have been discussed in the literature. In 1996, Y. Li et al. first identified activating antibodies against CaSR. The study included 25 patients, among whom 17 had hypoparathyroidism caused by APECED type 1, and 8 had a combination of hypoparathyroidism and autoimmune thyroiditis. As a result, high titers of anti-CaSR antibodies were detected in 56% of patients with hypoparathyroidism, whereas these antibodies were not found in any individuals in the control group [168]. However, several other studies found no correlation between activating anti-CaSR antibodies and hypoparathyroidism in patients with APECED type 1 [169]. Anti-CaSR antibodies possessing blocking properties have also been detected in autoimmune hypocalciuric hypercalcemia [170].

NALP5 is a multiprotein complex that activates intracellular kinases and the synthesis of pro-inflammatory cytokines, including NACНT (neuronal apoptosis inhibitor protein), C2TA (MHC class 2 transcription activator), HET-E (incompatibility locus protein from Podospora anserina), and TP1 (telomerase-associated protein); it was first discovered by M. Alimohammadi et al. as a specific parathyroid gland antigen. A total of 87 patients with APS type 1 were examined, 73 of whom had hypoparathyroidism. Among patients with hypoparathyroidism, anti-NALP5 antibodies were identified in 49% of cases, whereas in patients with APS type 1 without decreased parathyroid function, these antibodies were not detected in any patient [171]. Similar results were obtained by A. Meloni et al., in whose study anti-NALP5 antibodies were detected in 64.3% of patients with hypoparathyroidism and were not detected in patients without hypoparathyroidism [172]. Various forms of autoimmune hypoparathyroidism are presented in Table 8.

Table 8. Autoimmune forms of hypoparathyroidism.

Characteristics of the main syndromes associated with autoimmune hypoparathyroidism are presented in Table 9.

Table 9. Classification and characteristics of APS.

IPEX – immune dysregulation polyendocrinopathy enteropathy X-linked, MHC – major histocompatibility complex, GAD65 – glutamic acid decarboxylase 65; IA-2 – islet antigen 2; TPO – thyroid peroxidase.

Interferons (IFNs) were first discovered in 1957 as agents protecting cells against viral infection. There are two groups of IFNs: type 1 IFNs include IFN-α, IFN-β, IFN-ε, IFN-κ, IFN-ω, IFN-δ, and IFN-τ, while type 2 IFNs include only IFN-γ [173]. When examining patients with a genetically confirmed diagnosis of APS type 1, as well as APS type 2 and isolated autoimmune target organ damage, it was found that patients with APS type 1 had high titers of antibodies against most IFN-α subtypes, especially IFN-α2 and IFN-ω (in 100% of patients). None of the patients with APS type 2 or isolated autoimmune diseases had these antibodies detected. Thus, anti-IFN-ω antibodies proved to be highly specific for APS type 1 regardless of the spectrum of manifested components [110].

The presence of anti-IFN-ω antibodies is a diagnostic criterion for APS type 1. Sequencing of the AIRE gene remains an important step in the diagnosis of this syndrome, as it enables genetic counseling and family planning. The diagnostic algorithm for various forms of autoimmune hypoparathyroidism is shown in Flowchart 1.

Flowchart 1. Diagnostic algorithm for various forms of autoimmune hypoparathyroidism.

7.4. Hypoparathyroidism as part of hereditary syndromes

DiGeorge syndrome

DiGeorge syndrome is a consequence of abnormal development of organs derived from the third and fourth pharyngeal pouches. It occurs in 1 out of 4,000–5,000 newborns and in the majority of cases (70–80%) is a result of a heterozygous microdeletion in the 22q11.21-q11.23 regions. Although most cases are sporadic, nuclear families with an autosomal dominant inheritance pattern of the syndrome have also been described. Clinically, DiGeorge syndrome manifests as developmental delay, cleft palate, parathyroid and thymic aplasia or hypoplasia, congenital heart defects, and characteristic facial appearance (broad nasal root). DiGeorge syndrome is the leading cause of persistent hypocalcemia in newborns, and hypoparathyroidism in such patients can manifest either in the neonatal period or later in life. Among all individuals with this condition, hypoparathyroidism occurs in 60% of patients.

HDR syndrome (Hypoparathyroidism, Sensorineural Deafness, and Renal Dysplasia Syndrome)

HDR syndrome is a consequence of a mutation in the GATA3 gene located on the short arm of chromosome 10 (10p14–15). GATA3 itself is a transcription factor expressed in vertebrates in the kidneys, parathyroid glands, thymus, inner ear, and central nervous system. Cases of both autosomal dominant and autosomal recessive inheritance of the syndrome have been described. The main manifestations of the disease are renal dysplasia, sensorineural deafness, and hypoparathyroidism. Furthermore, patients with HDR syndrome are most often short in stature, which may be associated with growth hormone deficiency.

Sanjad-Sakati syndrome and Kenny-Caffey syndrome type 1

Sanjad-Sakati syndrome and Kenny-Caffey syndrome type 1 are characterized by similar clinical manifestations: congenital hypoparathyroidism, marked growth retardation, intellectual disability, microcephaly, and facial dysmorphism. Sanjad-Sakati syndrome is most commonly found in individuals of Arabic descent. In patients with Kenny-Caffey syndrome, in addition to the described abnormalities, osteosclerosis and immunodeficiency are also observed. Both disorders result from a mutation in the tubulin-specific chaperone E gene (TBCE) in the locus encoding the protein responsible for tubulin binding.

Kenny–Caffey syndrome type 2

Kenny-Caffey syndrome type 2 is a genetic disorder primarily affecting the skeleton and eyes, and various head and neck malformations also occur. One of the frequent components of the disease (diagnosed in 30–79% of patients) is hypoparathyroidism. The disease manifests with frequent episodes of hypocalcemia, and its direct cause is various mutations in the FAM111A gene (family with sequence similarity 111 member A). The inheritance of the syndrome is autosomal dominant.

Isolated hypoparathyroidism

Hypoparathyroidism may occur in isolation and be inherited in either an autosomal or X-linked manner.

Autosomal recessive isolated hypoparathyroidism. To date, the literature contains descriptions of several families with autosomal recessive hypoparathyroidism. The main cause of this disorder is loss of function of the GCM2 (glial cells missing) gene, also known as GCMB at the 6p23–24 locus. GCM2 is expressed primarily in developing parathyroid glands. Hypoparathyroidism manifests clinically in newborn infants due to parathyroid agenesis. The most frequent GCM2 mutation variants are dominant negative or recessive inactivating. At the same time, heterozygous mutations in GCM2 do not lead to any abnormalities in the formation and function of the parathyroid glands.

X-linked isolated hypoparathyroidism. Deletions/insertions at the Xq27.1 and 2p25.3 loci and the resulting X-linked hypoparathyroidism have been described in two related families. Males with this syndrome develop hypocalcemic seizures from childhood due to an isolated developmental defect of the parathyroid glands.

Decreased synthesis or secretion of PTH

Autosomal dominant hypocalcemia (ADH)

Type 1 ADH is characterized by an activating mutation in the CASR gene. CaSR becomes hypersensitive to serum calcium concentrations, while PTH synthesis and secretion are suppressed despite normocalcemia. Thus, functional hypoparathyroidism develops. Type 2 ADH occurs in the presence of an activating mutation in the GNA11 gene (guanine nucleotide-binding protein alpha 11). GNA11 encodes the alpha subunit of the G11 G-protein, which is a key mediator of the CaSR-mediated signaling pathway. The GNA11 mutation leads to excessive suppression of PTH secretion even in the presence of hypocalcemia. Patients with ADH develop mild hypocalcemia; severe hypocalcemia may occur under stress conditions. Renal calcium reabsorption in type 1 ADH is decreased due to the CaSR mutation in the kidneys; these patients develop hypercalciuria. Renal calcium reabsorption in type 2 ADH is unaffected.

One of the rare manifestation variants of ADH is Bartter syndrome with hypocalcemia. It is characterized by hypocalcemia, hypomagnesemia, and hypoparathyroidism, as well as signs of loop of Henle dysfunction (polyuria, hypokalemic alkalosis, elevated plasma renin and aldosterone concentrations, low blood pressure, and vascular resistance to angiotensin II). The cause of the syndrome is a mutation at the 3q21.1 locus responsible for CaSR.

Mutations in the PTH gene

Several rare mutations in the PTH gene disrupting its synthesis and PTH secretion have been described in the literature. For example, an autosomal dominant mutation in the preproPTH signal sequence disrupts normal molecule processing and, consequently, PTH formation. Families with isolated hypoparathyroidism due to an autosomal recessive mutation in the PTH gene have also been described.

Anti-CaSR antibodies

In late-onset hypoparathyroidism, a possible cause may be circulating activating antibodies against CaSR. These antibodies do not lead to irreversible destruction of the parathyroid glands, so there is a possibility of spontaneous remission. The literature describes both isolated forms of hypoparathyroidism caused by anti-CaSR antibodies and cases associated with other autoimmune diseases (Hashimoto's thyroiditis, Addison's disease).

PTH resistance syndromes

Target organ resistance to PTH, also known as pseudohypoparathyroidism (PHP), is a collective term for several heterogeneous disorders characterized by peripheral tissue insensitivity to PTH. Laboratory studies in such patients show hypocalcemia, hyperphosphatemia, and elevated PTH levels. Below is a description of the main forms of PHP.

Type 1 PHP

Type 1 PHP is a consequence of a mutation in the GNAS1 gene encoding the alpha subunit of the stimulatory G-protein associated with the PTH receptor. These mutations result in the inability of the G-protein to activate adenylate cyclase following PTH binding to its receptor, ultimately leading to a failure of signal transduction in target organs. In humans, the maternal allele of this gene is predominantly expressed in the pituitary gland, gonads, and thyroid gland. Therefore, the clinical manifestations of the disease depend on whether the mutation is located in the maternal or paternal allele. Based on these differences, several subtypes of type 1 PHP are distinguished.

Pseudohypoparathyroidism type 1a. This type of PHP is an autosomal dominant disorder caused by a loss-of-function mutation in GNAS1. Type 1a PHP is inherited maternally. With this mutation, activation of adenylate cyclase and signal transduction do not occur after PTH binds to the receptor. Clinically, type 1a PHP most often manifests as a complex of symptoms known as Albright hereditary osteodystrophy: short stature, obesity, short neck, round facies, subcutaneous calcifications, shortened fourth and fifth metacarpal and metatarsal bones, and developmental delay. In addition, patients with type 1a PHP may exhibit resistance to other hormones whose action is mediated via G-proteins: gonadotropin-releasing hormone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). A biochemical blood test reveals hypocalcemia with hyperphosphatemia, developing as a result of renal resistance to PTH action, and secondary hyperparathyroidism. In addition, patients may develop osteitis fibrosa, since skeletal resistance to PTH does not occur.

Pseudopseudohypoparathyroidism. Inheritance of an inactivating mutation in the GNAS1 gene paternally also leads to the Albright hereditary osteodystrophy phenotype. However, provided a normal maternal GNAS1 allele is present, renal insensitivity to PTH does not occur. Serum calcium, phosphorus, and PTH levels in such patients remain within the normal range. This condition is termed pseudopseudohypoparathyroidism.

Progressive osseous heteroplasia. Paternally inherited GNAS1 inactivation can also cause progressive osseous heteroplasia. This disorder debuts in early childhood and is characterized by ectopic bone formation in the dermis, muscles, and connective tissue. The clinical presentation may include features characteristic of Albright hereditary osteodystrophy, unaccompanied by changes in serum calcium or PTH concentrations.

Pseudohypoparathyroidism type 1b. Type 1b PHP is a rare autosomal dominant disorder inherited maternally. It is caused by a mutation affecting regulatory elements of the GNAS1 gene rather than the gene itself. In this case, PTH resistance presumably develops only in renal tissue, so these patients present with hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism without any features of Albright hereditary osteodystrophy.

Pseudohypoparathyroidism type 1c. This disorder is the result of a mutation disrupting the binding of the G-protein to the PTH receptor. Thus, the G-protein is able to activate adenylate cyclase, but this process is uncoupled from PTH receptor activation. Phenotypically, these patients are similar to those with type 1a PHP and exhibit all features characteristic of Albright osteodystrophy.

Type 2 PHP

Patients with type 2 PHP do not have clinical features characteristic of Albright hereditary osteodystrophy. They are characterized by elevated urinary cyclic adenosine monophosphate (cAMP) concentrations not accompanied by hyperphosphaturia in response to exogenous PTH administration.

Other forms of PTH resistance

PTH resistance can also be caused by a recessive missense mutation in the sequence encoding PTH (1-84), which results in the inability of the hormone to bind to its receptor.

Other causes of hypoparathyroidism

Mitochondrial diseases

Hypoparathyroidism is a component of many mitochondrial diseases resulting from mitochondrial DNA deletions. Below is a brief description of certain mitochondrial disorders accompanied by hypoparathyroidism.

Kearns-Sayre syndrome is a mitochondrial cytopathy characterized by encephalopathy, ophthalmoplegia, pigmentary retinopathy, and cardiomyopathy.

MELAS syndrome is a combination of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. It arises from a point mutation in mitochondrial transfer ribonucleic acid (tRNA) and is maternally inherited. It most commonly manifests in childhood, following a relatively uneventful early development period.

Mitochondrial trifunctional protein deficiency (MTPDS) is a fatty acid oxidation disorder manifesting as non-ketotic hypoglycemia and accompanied by cardiomyopathy, liver dysfunction, skeletal myopathy, and developmental delay. In some cases, mothers of children with MTPDS experienced an episode of acute liver injury during pregnancy [48,77].

Data on the main causes of hereditary hypoparathyroidism, key clinical manifestations, and laboratory abnormalities are presented in Table 10.

Table 10. Main causes of hereditary hypoparathyroidism [75].

GNA11 – G protein alpha subunit 11, GATA3 – GATA-binding protein 3, FAM111A – family with sequence similarity 111 member A, GCMB – glial cell missing gene, HRD – hypoparathyroidism retardation dismorfism, SOX3 – sry-related HMG box, TBCE – tubulin folding cofactor E, MTPDS – mitochondrial trifunctional protein deficiency

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Supervisors:

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, Doctor of Medical Sciences, Corresponding Member of the RAS, Member of the Russian Association of Endocrinologists, Scientific Head of the Department of Parathyroid Pathology and Mineral Metabolism Disorders.

Working Group:

Andreeva E.N.¹ – Doctor of Medical Sciences, Professor, Director of the Institute of Reproductive Medicine, Head of the Department of Endocrine Gynecology.

Beltsevich D.G.¹ – Doctor of Medical Sciences, Professor, Member of the Association of Endocrine Surgeons, Head of Surgical Department No. 1.

Bibik E.E.¹ – Candidate of Medical Sciences, Senior Researcher at the Department of Parathyroid Pathology and Mineral Metabolism Disorders.

Eremkina A.K.¹ – Candidate of Medical Sciences, Head of the Department of Parathyroid Pathology and Mineral Metabolism Disorders.

Karonova T.L.⁴ – Doctor of Medical Sciences, Professor of the Department of Internal Diseases, Head of the Research Laboratory of Clinical Endocrinology.

Kim I.V.¹ – Candidate of Medical Sciences, Member of the Association of Endocrine Surgeons, Head of Surgical Department No. 3.

Kovaleva E.V.¹ – Candidate of Medical Sciences, Researcher at the Department of Parathyroid Pathology and Mineral Metabolism Disorders.

Kryukova I.V.³ – Candidate of Medical Sciences, Associate Professor of the Department of Endocrinology, Advanced Training Faculty.

Kuznetsov N.S.¹ – Doctor of Medical Sciences, Member of the Association of Endocrine Surgeons, Professor, Head of the Endocrine Surgery Group.

Mirnaya S.S.⁵ – Candidate of Medical Sciences, Member of the Russian Association of Endocrinologists.

Mudunov A.M.² – Doctor of Medical Sciences, Professor of the RAS, President of the Russian Society of Head and Neck Oncology Specialists, Head of the Department of Head and Neck Tumors.

¹ – National Medical Research Center for Endocrinology of the Russian Ministry of Health

² – Lapino Clinical Hospital "Mother and Child"

³ – Moscow Regional Research Clinical Institute named after M.F. Vladimirsky (MONIKI)

⁴ – Almazov National Medical Research Centre of the Russian Ministry of Health

⁵ – Fomin Clinic Dolgorukovskaya LLC

Conflict of interest:

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

Methods used for evidence collection/selection: electronic database search using keywords related to hypoparathyroidism and corresponding sections of clinical guidelines. Assessment of the quality and relevance of found sources (AGREE).

Description of methods used for evidence collection/selection: the evidence base for the recommendations includes publications from the Cochrane Library, EMBASE, MEDLINE, and eLIBRARY databases. The search depth was over 15 years.

Methods used for assessing the quality and strength of evidence:

• Expert consensus.

• Significance assessment in accordance with levels of evidence and grades of recommendations (attached).

Target audience for these clinical guidelines:

1. endocrinologist;

2. surgeon;

3. general practitioner (family physician);

4. internist;

5. urologist;

6. nephrologist;

7. neurologist;

8. cardiologist;

9. obstetrician-gynecologist.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The update mechanism for clinical guidelines involves their systematic revision—at least once every 6 months, or upon the emergence of new information regarding the management of patients with this disease. The decision to update is made by the Russian Ministry of Health based on proposals submitted by professional medical non-profit organizations. The formulated proposals must take into account the results of comprehensive assessments of drugs and medical devices, as well as the results of clinical approbation.

Appendix A3. Reference Materials

Up-to-date instructions for medical product use can be found on the official website of the Ministry of Health of the Russian Federation 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.Ya., Belaya Zh.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).

Appendix B. Physician Action Algorithms

Algorithm for assessing the degree of compensation of chronic hypoparathyroidism and indications for 24-hour blood calcium profile monitoring

Appendix C. Patient Information

What are the parathyroid glands (PTGs) and how do they work?

The parathyroid glands (PTGs) are small (rice-grain sized) endocrine glands located in the neck near the thyroid gland, on its posterior surface. Humans typically have 4 PTGs—one upper and one lower on each side.

Parathyroid hormone (PTH) is the primary hormone regulating blood calcium and phosphorus levels. PTH is produced by the parathyroid glands.

If the PTGs are removed during surgery or produce insufficient PTH, a condition characterized by low blood calcium levels—hypoparathyroidism—develops.

What is Hypoparathyroidism?

This is a rare condition in which blood calcium levels decrease as a result of reduced PTH secretion.

What are the causes of Hypoparathyroidism?

Most commonly, hypoparathyroidism develops following neck surgery—removal of the thyroid gland or the PTGs. Since the PTGs are located adjacent to the thyroid gland, its removal can lead to their damage, impaired blood supply, or inadvertent removal.

The disease can also develop as a result of hereditary genetic disorders, specifically when PTG cells are damaged by specific proteins (antibodies). Such damage is referred to as an autoimmune disease. In this case, hypoparathyroidism may be either the sole manifestation or accompanied by the development of other conditions, such as adrenal pathology (primary adrenal insufficiency) and skin and mucosal lesions (mucocutaneous candidiasis). Rarely, hypoparathyroidism may be caused by other genetic alterations ("mutations" in genes).

Why is calcium so important?

Calcium is the most abundant mineral in the human body and is essential for various physiological processes. Calcium is necessary for bones and teeth, as well as for the function of the heart, muscles, nerves, and other organs.

What are the symptoms of Hypoparathyroidism?

The symptoms of hypoparathyroidism develop due to low blood calcium levels (hypocalcemia).

You need to know them if:

• you have previously undergone surgery to remove the thyroid gland or PTGs;

• there is a family history of conditions associated with low blood calcium levels.

Symptoms of hypocalcemia are very diverse and include:

• Tingling and numbness around the mouth, as well as in the hands and feet;

• Muscle cramps, twitches, or stiffness;

• A sensation of "internal trembling";

• Unexplained fatigue and weakness;

• Brain fog, confusion ("mental fog").

Long-standing hypoparathyroidism can cause the development of:

• depression;

• impairment of memory and concentration;

• kidney pathology (kidney stones);

• dental enamel pathology or vision problems (cataracts);

• cardiovascular pathology (cardiac arrhythmias, heart palpitations / irregular heartbeat).

If you are taking medications for the treatment of hypoparathyroidism—calcium supplements and vitamin D preparations and their analogues—overdose may lead to an excessive increase in blood calcium levels (hypercalcemia) and the appearance of the following symptoms:

• Dry mouth, thirst, and frequent urination;

• Headache;

• Fatigue;

• Loss of appetite, nausea, vomiting.

How is Hypoparathyroidism diagnosed?

If you have symptoms of hypocalcemia, your doctor will refer you for laboratory testing to determine blood levels of calcium, phosphorus, and PTH. If low calcium and PTH levels and high phosphorus levels are detected, you will be referred to an endocrinologist.

Symptoms of hypocalcemia developing within the first few days after neck surgery generally allow for a rapid diagnosis. For other forms of hypoparathyroidism, an expanded workup is often required for diagnosis.

What you need to know about the treatment of hypoparathyroidism?

Treatment is prescribed to maintain blood calcium levels within the lower limit of the normal range (2.1–2.3 mmol/L) to prevent or minimize symptoms of hypocalcemia. Regular follow-up examinations, including blood and urine tests, are necessary to prevent complications of the disease.

Vitamin D and its analogues, as well as calcium preparations, are prescribed as the main therapy for hypoparathyroidism.

Chronic (permanent) hypoparathyroidism requires lifelong treatment!

Parathyroid hormone preparations and its analogues for hormone replacement therapy of hypoparathyroidism are not registered in Russia.

What is the treatment for Hypoparathyroidism?

Treatment for chronic (permanent) hypoparathyroidism is lifelong. Standard therapy for hypoparathyroidism involves taking active vitamin D metabolites and their analogues (alfacalcidol**, calcitriol**), as well as calcium preparations. The active form of vitamin D is necessary for the absorption of calcium from the gastrointestinal tract—both from food (dairy products) and from calcium supplements. Doses and frequency of administration depend on the severity of hypocalcemia symptoms and blood calcium levels. Regular evaluation by an endocrinologist (consultation/examination by an endocrinologist) is necessary to adjust treatment and achieve compensation.

Pregnancy and lactation

Hypoparathyroidism is not a contraindication to pregnancy, provided the disease is compensated.

If you are planning a pregnancy or breastfeeding, it is important to carefully monitor blood calcium levels and maintain them within the target range to prevent deterioration of well-being and the development of complications.

During pregnancy, it is necessary to determine the blood ionized calcium level or use the calculated albumin-corrected serum calcium parameter, as they more accurately reflect blood calcium content than total calcium levels.

Measurements of ionized or albumin-corrected blood calcium levels should be performed once every 2–3 weeks, depending on individual needs and the treatment plan.

If you or your partner has a genetic or familial (hereditary) form of hypoparathyroidism, pregnancy planning should include genetic counseling to determine the risk of transmitting the disease and potential prevention options.

Calcium levels and the menstrual cycle

Calcium levels are closely linked to fluctuations in estrogen, the female sex hormone.

Estrogen levels vary throughout the menstrual cycle, and consequently, blood calcium levels change as well. If you notice symptoms of low blood calcium during your periods, take slightly higher doses of calcium supplements during this time.

It has also been noted that sugar cravings may increase during the premenstrual period. Excessive consumption of sweets can lead to enhanced urinary calcium excretion and the development of hypocalcemia symptoms. To keep calcium levels more stable, replace sweets with, for example, 70-85% dark chocolate.

What situations can trigger a drop in calcium?

✓ intense and/or prolonged physical exertion;

✓ stressful situations;

✓ stool disorders (diarrhea) or other gastrointestinal diseases that reduce drug absorption;

✓ changes in the doses of concomitant medications or the prescription of new ones;

✓ dietary changes, reduced dietary intake of calcium and vitamin D;

✓ other conditions accompanied by diarrhea, nausea, and/or loss of appetite;

✓ low levels of 25(OH)vitamin D;

✓ menstruation.

If symptoms of low blood calcium (hypocalcemia) develop:

✓ take your scheduled calcium, vitamin D, and analog medications earlier, as soon as you feel your condition worsening;

✓ you may take an additional calcium supplement tablet if necessary;

✓ if low calcium symptoms bother you for several days, this is a reason for an unscheduled total blood calcium test and a consultation with an endocrinologist to adjust therapy;

✓ ignoring symptoms can lead to a marked deterioration in well-being. Acute hypocalcemia is primarily dangerous due to cardiac arrhythmias!

✓ if your condition deteriorates rapidly despite additional intake of calcium, vitamin D, and their analogs, call an ambulance—paramedics can administer intravenous calcium preparations and rapidly raise blood calcium levels.

What situations can trigger an increase in calcium?

✓ medication overdose;

✓ a sharp increase in the doses of calcium, vitamin D, and their analogs, especially without monitoring blood test results;

✓ high blood calcium levels most commonly manifest as loss of appetite, nausea, potential vomiting, thirst, and dry mouth.

If symptoms of high blood calcium (hypercalcemia) develop:

✓ drink as much fluid as possible (at least 2–2.5 liters of drinking water per day);

✓ promptly perform a total blood calcium/ionized blood calcium test and visit an endocrinologist to adjust therapy;

✓ in case of high blood calcium, your attending physician may reduce the dose or completely discontinue calcium, vitamin D, and analog medications for a certain period;

✓ after this situation resolves, you need to resume vitamin D, its analogs, and calcium supplements under strict laboratory monitoring and the supervision of your attending physician.

Which specialists are needed?

You may need follow-up with several specialists depending on your symptoms and the presence of complications.

• Endocrinologist – the primary physician for treating hypoparathyroidism, who will adjust your therapy and order necessary examinations to monitor the disease;

• Nephrologist – required if kidney function is impaired;

• Urologist – if kidney stones are present;

• Ophthalmologist – for regular eye examinations and detection of cataracts (clouding of the eye lens);

• Cardiologist – if arrhythmia, tachycardia, or chest pain develops.

How often do you need to undergo examinations?

Most patients with long-standing hypoparathyroidism require laboratory testing every 3–6 months.

You may need more frequent laboratory monitoring, up to several times a week, at the start of treatment or when adjustments are necessary. If symptoms of either hypo- or hypercalcemia occur, unscheduled blood tests are required.

Hypoparathyroidism Patient Checklist*

* enter your test results and medication doses and show them to your attending physician to track the dynamics of key parameters.

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

Not applicable.