Hyperparathyroidism recommendations. Modern ideas about the etiology, pathogenesis, clinical picture, diagnosis and treatment of primary hyperparathyroidism

RCHR (Republican Center for Health Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical protocols of the Ministry of Health of the Republic of Kazakhstan - 2018

Primary hyperparathyroidism (E21.0)

Endocrinology

General information

Brief description

Approved
Joint Commission on Healthcare Quality
Ministry of Health of the Republic of Kazakhstan
from April 18, 2019
Protocol No. 62

Primary hyperparathyroidism- primary disease of the parathyroid glands, manifested by hyperproduction of PTH and damage to the skeletal system and/or internal organs (primarily the kidneys and gastrointestinal tract).

INTRODUCTORY PART

ICD-10 code(s):
Date of protocol development/revision: 2013 (2018 revision)

Abbreviations used in the protocol:
Protocol users: endocrinologists, general practitioners, therapists.

Level of evidence scale:

Table 1. Relationship between strength of evidence and type of research

A	A high-quality meta-analysis, systematic review of RCTs, or large RCTs with a very low probability (++) of bias, the results of which can be generalized to an appropriate population.
IN	High-quality (++) systematic review of cohort or case-control studies or High-quality (++) cohort or case-control studies with very low risk of bias or RCTs with low (+) risk of bias, the results of which can be generalized to an appropriate population .
WITH	Cohort or case-control study or controlled trial without randomization with low risk of bias (+), the results of which can be generalized to the relevant population or RCT with very low or low risk of bias (++ or +), the results of which cannot be directly distributed to the relevant population.
D	Case series or uncontrolled study or expert opinion.
GPP	Best clinical practice. Recommended good clinical practice is based on the clinical experience of the members of the CP working group

Classification

Classification

Table 2. Clinical classification of primary hyperparathyroidism:

Diagnostics

METHODS, APPROACHES AND PROCEDURES FOR DIAGNOSIS AND TREATMENT

Complaints: for bone pain, weakness, decreased appetite, decreased growth.

Anamnesis: the presence of frequent, inadequate load-bearing and poorly consolidating fractures, urolithiasis, depressive states, polyuria, polydipsia

Physical examination:
Inspection: skeletal deformations, bone growths in the area of ​​the facial bones, large joints, long bones, lethargy, pallor, dry skin.

Main clinical manifestations :
- Musculoskeletal system: bone pain, bone deformities, pathological fractures, gout, pseudogout, muscle atrophy, soft tissue calcifications.
- Recurrent nephrolithiasis, nephrocalcinosis,
- Chronic pancreatitis, peptic ulcer of the stomach and duodenum
- Dyspeptic disorders, weight loss.
- Mental changes - depression, asthenic syndrome
- Insipid syndrome
- Heart rhythm disturbances, arterial hypertension

Laboratory research:
Table 3. Biochemical parameters in blood and urine during PHPT

Total blood Ca	>2.6 mmol/l (normal 2.2-2.6)
Ionized blood Ca	>1.3 mmol/l (normal 1.1-1.3)
Parathyroid hormone	Increased by 1.5-3 times
Total blood phosphorus	< 0,7 ммоль/л (норма 0,87-1,45)
Bone alkaline phosphatase activity	increase by 1.5 - 5 times
Calciuria	An increase of more than 10 mmol/day, or 250 mg/day - in women about 300 mg/day - in men
Markers of bone remodeling in the blood: osteocalcin and CTx	Increase from 1.5 to 20 times
Albuminemia	Hypoalbuminemia and decreased albumin/globulin ratio
25-OH-vitamin D	Decrease in level less than 30 ng/ml

Instrumental studies:
Table 4 Instrumental studies and changes in PHPT

Type of study	Characteristics of changes
Ultrasound of the thyroid glands and pancreas (informativeness 50 - 90%)
CT scan of the neck area with contrast (informativeness 34 - 87%)	Allows you to assess the size and localization of the PTC both in the case of their normal number and location, and in the presence of additional PTC and their ectopia, including in the mediastinum.
MRI of the neck area with contrast (informativeness 50 - 70%)	Detection of a mass in the neck and mediastinum. Widespread use of MRI is not recommended: it is expensive, less sensitive, and difficult to interpret the data obtained.
Scintigraphy with technetium, selenium-methionine, (MIBI, technetril), sensitivity of methods up to 90%	Detection of a mass in the neck area
Scintigraphy in combination with single photon emission computed tomography (SPECT).	SPECT images provide good topography and three-dimensional reconstruction, which significantly improves localization of radiotracer uptake.
Multislice computed tomography (MSCT) with contrast.	Used in controversial cases, when there is a discrepancy between the results of the above methods or when the presence of multiple or ectopic space-occupying formations is suspected
Positron emission tomography (PET)	recommended in selected cases in patients with persistent disease or recurrent PHPT in the absence of visualization of the PTG using other methods
Puncture biopsy of PTG formation under ultrasound control with determination of PTH in the flush from the needle	is a method of topical diagnosis and is recommended only if a diagnosis of PHPT is established. Indications for the use of the method are differential diagnosis between parathyroid tissue and other formations (lymph nodes, metastases of thyroid cancer), as well as to confirm or exclude intrathyroid parathyroidomas.
X-ray of bones	Signs of subperiosteal resorption, especially in the terminal phalanges of the hands (“lysis of the nail phalanges”), in the pelvic bones, long bone cysts, diffuse osteopenia and thinning of the cortical bone
X-ray densitometry	Decrease in bone mineral density of the thoracic and lumbar spine, radius and femur
Kidney ultrasound	Nephrolithiasis, nephrocalcinosis, detection of coral stones
EFGDS	Recurrent peptic ulcer of the stomach or duodenum, erosions and ulcers of the mucous membrane, calcifications

Indications for consultation with specialists:
Table 6. Indications for specialist consultations for PHPT

Specialist	Indications for consultation
Nephrologist consultation	With kidney damage, urolithiasis
Consultation with a gastroenterologist	If you suspect a peptic ulcer, pancreatitis
Psychiatrist consultation	For depression
Surgeon consultation	To resolve the issue of surgical treatment - removal of the formation of the pancreas
Genetic consultation	When diagnosing familial forms of PHPT to exclude MEN1 and MEN2 syndromes.

MEN syndrome 1 is a rare autosomal dominant disorder. The reason is a mutation in the MEN1 gene, located on the long arm of chromosome 11 (11q13).
MEN 1 is the most common cause of hereditary PHPT (2-4% of all cases of PHPT). It is PGPT that is often happens first manifestation of MEN 1 syndrome (85%). Other components of MEN1:
1) enteropancreatic tumors (60-70%): gastrinomas (Zollinger-Ellison syndrome), insulinomas, hormonally inactive tumors; tumors secreting voactive intestinal polypeptide (VIPomas), pancreatic polypeptide;
2) pituitary adenomas (prolactinomas, somatotropinomas, somatoprolactinomas, corticotropinomas and hormonally inactive adenomas);
3) tumors in more than 20 other endocrine and non-endocrine tissues (tumors of the adrenal cortex, facial angiofibromas, collagenomas, neuroendocrine tumors (NET) of the gastrointestinal tract, bronchopulmonary, thymus, etc.).

MEN 2A syndrome- a rare autosomal dominant disease. Caused by a mutation in the RET gene, located at the centromere of chromosome 10 and encoding the RET tyrosine kinase. PHPT occurs in 20-30% of MEN-2A cases.
Other components of the syndrome:
1) medullary thyroid cancer (MTC), 97-100%;
2) pheochromocytoma (50%).
The average age of manifestation is 38 years. PHPT never doesn't happen the first manifestation of the syndrome, and is diagnosed much later than the diagnosis and treatment of MTC, extremely rarely - during thyroidectomy. In the case of MEN 2 syndrome, the priority is surgical treatment of MTC

Diagnosis PHPT can be considered confirmed in the presence of hypercalcemia in combination with a persistent increase in PTH levels (excluding tertiary hyperparathyroidism). In addition, a PTH level at the upper limit of the reference interval, but not beyond it, in the presence of hypercalcemia, also corresponds to the diagnosis of PHPT.

Diagnostic algorithm for PHPT for incidentally detected hypercalcemia:

Differential diagnosis

Differential diagnosisand rationale for additional research:

Table 7. Differential diagnosis of PHPT

Pathology	Differential diagnostic criteria
Paraneoplastic hypercalcemia	There is a primary tumor (lung, ovarian, lymphoid cancer, etc.), PTH is reduced
Metastatic process	May be accompanied by the development of pathological and compression fractures of the vertebrae, increased levels of calcium, phosphorus and alkaline phosphatase in the blood. X-rays reveal clearly defined foci of clearing against the background of an unchanged bone tissue structure.
Rustitsky-Kahler myeloma (plasmocytoma)	It differs from PHPT in the severity of the process, an increase in ESR, the presence of Bence Jones protein in the urine, paraproteinemia, plasmacytic infiltration of the bone marrow, the rapid development of amyloidosis, and the absence of subperiosteal regeneration. sorption of skeletal bones
Granulomatosis (tuberculosis, sarcoidosis)	Cough, fever, shortness of breath, radiological signs, decreased PTH, increased ESR, blood lymphocytosis.
Hypervitaminosis D	The patient has a history of taking large doses of vitamin D. The level of 25-hydroxyvitamin D is increased, PTH is decreased.
Thyrotoxicosis	Clinic of hyperthyroidism (tachycardia, sweating, goiter), increased free T4 and T3, decreased TSH, normal PTH.
Hypothyroidism	Clinic of hypothyroidism (dry skin, weight gain, slow speech, pastosity and swelling, drowsiness, menstrual and sexual dysfunction), increased TSH, decreased PTH, fT 4
Acromegaly	Acromegaloid features (changes in appearance: enlargement of limbs, coarsening of facial features, macroglossia, diastema; menstrual irregularities), headaches, possibly bitemporal hemianopsia, narrowing of visual fields - with large tumor sizes, increased size of the sella turcica on a skull radiograph, signs of pituitary adenoma on MRI, increase in somatotropic hormone (STH), IGF-1, decrease in PTH
Adrenal insufficiency	Hyperpigmentation of the skin and mucous membranes, vitiligo, significant weight loss, arterial hypotension, hypoglycemic attacks, hyperkalemia, hyponatremia, decreased plasma cortisol levels and urinary excretion of free cortisol, decreased PTH
Pheochromocytoma	Sympatho-adrenal crises, headaches, elevated plasma levels of catecholamines and their metabolites (metanephrines and normetanephrines), topical diagnosis of adrenal tumors using CT and MRI methods
Application thiazide diuretics	History: taking thiazide diuretics, moderate increase in Ca and decrease in PTH in plasma, normalization of parameters after discontinuation of drugs
Paget's disease	The disease develops in old and senile age, is not accompanied by systemic osteoporosis, renal function is not impaired, the content of calcium and phosphorus in the blood is not changed, and the level of alkaline phosphatase is increased. The x-ray shows multiple areas of compaction with a characteristic “cotton-wool” pattern. The brain part of the skull increases while the facial size is normal, the spine and tubular bones are deformed.
Osteogenesis imperfecta (“blue sclera syndrome”)	A genetic disease that is detected in childhood. It is characterized by short stature, increased joint mobility, pathological fragility of bones with the development of lush bone calluses at the site of fractures.

Table 8. Differential diagnostic signs of various forms of hyperaparathyroidism

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Treatment

Drugs (active ingredients) used in treatment

Treatment (outpatient clinic)

OUTPATIENT TREATMENT TACTICS

Goal of treatment PGPT:
- Elimination of the source of PTH hyperproduction
- Normalization or reduction of Ca and PTH levels in the blood
- Elimination and/or prevention of progression of osteovisceral disorders
Conservative management in patients with PHPT is used when there is a medical contraindication for parathyroidectomy; the patient's refusal to undergo surgical treatment; in patients with asymptomatic forms of the disease without sufficient indications for parathyroidectomy.

Non-drug treatment:
Diet therapy: table No. 9, adequate rehydration.
Physical activity: Limiting physical activity, preventing fractures.

Drug treatment
Indicated for:
- the presence of mild bone abnormalities and mild hypercalcemia or
normocalcemia
- absence of remission after surgical treatment
- manifest hyperparathyroidism and the presence of contraindications to surgical treatment or if the patient refuses surgery.

Table 9. Drug treatment for PHPT

Drugs	Mechanism of action	Doses	Level of evidence
Alendronic acid	Bisphosphonate, suppresses osteoclastic bone resorption, increases bone mineral density, promotes the formation of bone tissue with normal histological structure, reduces Ca	Orally on an empty stomach 70 mg once a week	IN
Ibandronic acid		Intravenously 3 mg once every 3 months	IN
Zoledronic acid		IV, drip, 5 mg once every 12 months.	IN
Denosumab	A human monoclonal antibody (IgG2) with affinity and specificity for receptor activator of nuclear factor κB (RANKL) ligand inhibits bone resorption and increases the mass and strength of cortical and trabecular bone.	Subcutaneously 60 mg once every 6 months	IN
Calcimimetic (cinacalcet)	Stimulate calcium receptors, increase calcium sensitivity, reduce PTH and calcium	Orally 30-50 mg 2 times a day. Maximum dose - 90 mg 4 times a day	IN

Surgical intervention: No.

- Normalization of PTH, Ca, phosphorus, alkaline phosphatase levels, no relapses.

Treatment (inpatient)

TREATMENT TACTICS AT THE INPATIENT LEVEL

Patient observation card, patient routing: No.

Non-drug treatment: see Outpatient level

Drug treatment: see Outpatient level

Surgical intervention: parathyroidectomy, effectiveness 95-98%.
The gold standard for surgical treatment of PHPT is considered to be parathyroidectomy using local anesthesia. Depending on the extent of damage to the parathyroid gland, partial, subtotal or total parathyroidectomy is performed.

Absolute indications for surgical treatment:
- Age less than 50 years
- Impossibility of long-term observation under medical supervision
- Excess of total calcium in the blood by more than 0.25 mmol/l above the upper limit of normal
- Urinary calcium excretion of more than 400 mg per day with a normal diet
- Decrease in GFR less than 60 mg/min
- Presence of nephrocalcinosis
- Bone mineral density - T-score less than -2.5 in any area and/or history of fracture
- Parathyroid cancer

Complications after surgical treatment
- Damage to the recurrent laryngeal nerve
- Transient or persistent hypocalcemia, hypomagnesemia, “hungry bone syndrome.”

Treatment of hypocalcemic crisis:
1. 1500-2000 mg Ca and alfacalcidol 1-3 mg/day;
2. For seizures - calcium gluconate 80 ml with 0.9% NaCl solution daily.

Further management: In the postoperative period, restoration of calcium metabolism does not occur immediately, and patients require additional intake of calcium and vitamin D3.
Upon reaching remission:
- Clinical observation by an endocrinologist, treatment of osteoporosis.
- Monitoring the activity of alkaline phosphatase in the blood serum once every 3-6 months.
- X-ray control once every 3 years
In case of relapse, repeat courses of treatment.
Relapse rate:
Sporadic hyperparathyroidism - 5-10%
For hyperparathyroidism as part of MEN syndromes - 15-25%
For parathyroid cancer - 32%

Indicators of treatment effectiveness:
- Normalization of PTH, Ca and blood phosphorus levels, alkaline phosphatase, absence of relapses.

Hospitalization

INDICATIONS FOR HOSPITALIZATION WITH INDICATION OF THE TYPE OF HOSPITALIZATION

Indications for planned hospitalization:
1. In case of severe hypercalcemia and in cases of refusal of surgical treatment, hospitalize the patient for rehydration and treatment of cardiovascular and neurological complications of PHPT. Rehydration is carried out by introducing a 0.9% sodium chloride solution to reduce the toxic effect of hypercalcemia on target organs and increase calcium excretion in the urine.
2. Carrying out a planned operation to remove adenoma or carcinoma of the parathyroid gland

Indications for emergency hospitalization: hypercalcemic crisis.
Hypercalcemic crisis- an acute complication of PHPT, is severe, life-threatening calcium intoxication. Develops when plasma calcium levels exceed 3.5 mmol/l.
Provoked:
- rough palpation of the thyroid gland and parathyroid gland
- pregnancy
- taking thiazide diuretics, calcium and vitamin D supplements
- fractures
- infections
- long bed rest
The clinical picture develops very quickly, with increasing symptoms of dehydration, damage to the central nervous system (psychosis, stupor, coma) and gastrointestinal tract (nausea, uncontrollable vomiting, thirst, epigastric pain, often imitating the picture of an “acute abdomen”). Hyperthermia up to 40 °C, thrombosis of various localizations, disseminated intravascular coagulation syndrome, acute renal, respiratory and cardiovascular failure are noted. Symptoms increase like an avalanche, anuria develops, and coma develops.
Treatmenthypercalcemic crisis:
- restoration of bcc (infusion therapy with a 0.9% NaCl solution in a volume of 3000-4000 ml/day while maintaining plasma osmolality at 280-290 mOsm/kg in combination with diuretics).
- At the same time, the level of calcium is normalized (bisphosphonates are used).
- After normalization of the patient’s condition, parathyroidectomy of pathologically altered parathyroid glands is recommended.

Information

Sources and literature

1. Minutes of meetings of the Joint Commission on the quality of medical services of the Ministry of Health of the Republic of Kazakhstan, 2018
   1. 1. Dedov I.I., Melnichenko G.A., Endocrinology national guide, Moscow, “GEOTAR - Media”, 2018, pp. 817-832. 2. Primary hyperparathyroidism: clinical picture, diagnosis, differential diagnosis, treatment methods. Clinical protocol. FSBI "Endocrinological Research Center" of the Ministry of Health of Russia, Moscow. Problems of endocrinology, No. 6, 2016, pp. 40-77 3. Primary hyperparathyroidism: Modern approaches to diagnosis and treatment. Educational and methodological manual, Minsk BSMU 2016, 21 p. 4. Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus. Osteoporos Int., 2017; 28(1): P.1–19. 5. The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surg. 2016;151(10): P.959-968. 6. Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism: Summary Statement from the Fourth International Workshop. The Journal of Clinical Endocrinology & Metabolism, V, 99, Issue 10, 1 October 2014, P.3561–3569.

Information

ORGANIZATIONAL ASPECTS OF THE PROTOCOL

List of protocol developers with qualification information:

1. Nurbekova Akmaral Asylovna - Doctor of Medical Sciences, Professor of the Department of Endocrinology of JSC National Medical University;
2. Rimma Bazarbekovna Bazarbekova - Doctor of Medical Sciences, Professor, Head of the Department of Endocrinology of JSC “Kazakh Medical University of Continuing Education”, Chairman of the RPO “Association of Endocrinologists of Kazakhstan”.
3. Taubaldieva Zhannat Satybaevna - Candidate of Medical Sciences, Head of the Department of Endocrinology, JSC National Scientific Medical Center.
4. Kalieva Sholpan Sabataevna - Candidate of Medical Sciences, Associate Professor, Head of the Department of Evidence-Based Medicine and Pharmacology of Karaganda Medical University JSC.

Disclosure of no conflict of interest: No.

Reviewer:
Dosanova Ainur Kasimbekovna - Candidate of Medical Sciences, Associate Professor of the Department of Endocrinology of the Kazakh Medical University of Continuing Education JSC, Secretary of the Regional Educational Institution AVEC.

Indication of the conditions for reviewing the protocol: review of the protocol 5 years after its publication and effective date or if new methods with a level of evidence are available.

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Hyperparathyroidism is a disease caused by endocrinological disorders that provoke an increase in the secretion of parathyroid hormones. It is characterized by a significant disruption of the metabolic processes of calcium and phosphorus. As a result of this disorder, the bones become fragile, increasing the risk of damage and fractures.

There are primary, secondary, and tertiary forms of the disease. Nutritional hyperparathyroidism occurs only in veterinary practice.

Let's talk on the www.site about how hyperparathyroidism manifests itself, what is its treatment, what are its causes, what are the recommendations of specialists on the disease - our conversation today will focus on all this:

Causes, symptoms of the disease

Primary hyperparathyroidism (Recklinghausen's disease):

Reasons

The most common cause of this form is the presence of a solitary adenoma of the parathyroid gland or, in other words, parathyroma. Less commonly, the cause of the primary form is called multiple adenomas. Even less common is parathyroid cancer. This form of the disease is most often diagnosed in adults, but can sometimes occur in children and the elderly.

It should be noted that primary hyperparathyroidism is observed in multiple endocrine neoplasia syndromes.

How primary hyperparathyroidism manifests itself (symptoms)

The disease may not manifest itself for a long time, as it develops asymptomatically. This is typical for the initial stage, when calcium levels are slightly elevated. As the disease progresses, characteristic symptoms appear. Severe complications, such as hypercalcemic crisis, may develop.

However, most often this form manifests itself with the following symptoms:

Changes in bone tissue: bone fragility increases, frequent fractures occur. Sometimes there may be a decrease in the patient's height;

Urolithiasis, nephrolithiasis;

Increased level of ionized calcium, severe calciuria, manifestations of severe hypercalcemia;

Visceral complications of the primary form of hyperparathyroidism: fibrous periostitis, nephrocalcinosis;

Secondary and tertiary hyperparathyroidism

Secondary hyperfunction and hyperplasia of the parathyroid glands, occurring against the background of prolonged hypocalcemia, hyperphosphatemia, is called secondary hyperparathyroidism.

Tertiary is characterized by the development of adenoma of the parathyroid glands, which occurs against the background of secondary hyperparathyroidism lasting a long time.

Causes of secondary hyperparathyroidism

The main causes of the secondary form of the pathology are chronic renal failure, as well as some diseases of the digestive system.

How do tertiary and secondary hyperparathyroidism manifest (symptoms)?

Clinical signs of the secondary and tertiary forms are similar to those of the underlying disease. The most common diagnosis is chronic renal failure (CRF).

Specific signs include:

Bone soreness;

Muscle weakness, arthralgia;

Frequent injuries, fractures, bone deformations;

Calcification of the arteries may also be a characteristic symptom. This condition provokes ischemic changes. Manifested by the formation of periarticular calcifications on the arms and legs.

It is also possible to develop calcification of the conjunctiva. When this pathology is combined with recurrent conjunctivitis, a condition occurs that experts refer to as red eye syndrome.

How is tertiary and secondary hyperparathyroidism corrected (treatment)?

Treatment of secondary and tertiary forms of hyperparathyroidism is quite complex. In severe cases, hemodialysis is prescribed and kidney transplantation is performed, which prolongs the patient's life by about 10-15 years.

When prescribing drug treatment, the drug Rocaltrol is used. At the same time, careful monitoring of calcium excreted in the urine is carried out. Vitamin D metabolites are prescribed, for example, Calcitriol, and aluminum phosphate binders are used.

If the level of calcium is very high, as well as in the presence of severe symptoms, the patient must be hospitalized, after which treatment is carried out in a hospital setting. If there is high fragility of bone tissue, strict bed rest and therapeutic nutrition are indicated.

If the calcium level is slightly elevated, characteristic symptoms are absent or mild, emergency medical intervention is not required. The patient can lead a normal life without limitations in performance. On the recommendation of a doctor, the patient may be prescribed therapeutic nutrition. Its principles are always developed individually.

In order to prevent hyperparathyroidism, chronic diseases of the kidneys and digestive system should be treated in a timely manner. Visit more, play sports, practice with sun and air baths. It is very important to avoid stressful conditions. Be healthy!

Primary hyperparathyroidism (PHPT) is a disease whose development is associated with excessive secretion of parathyroid hormone (PTH) and, as a result, an increase in calcium levels in the blood serum. PHPT is one of the causes of hypercalcemia, a metabolic disorder manifested by an increase in the level of calcium in the blood serum and accompanied by varying degrees of severity of the clinical picture. In addition to PHPT, hypercalcemia is accompanied by malignant neoplasms (osteolytic metastases of malignant tumors in the bone); pseudohyperparathyroidism; familial isolated hyperparathyroidism; tertiary hyperparathyroidism; thyrotoxicosis; chronic adrenal insufficiency; pheochromocytoma; VIPoma; diseases of the blood system (leukemia, lymphoma, myeloma, lymphogranulomatosis); drug-induced hypercalcemia; bone fractures; prolonged immobility; acute renal failure and familial hypocalciuric hypercalcemia.

Epidemiology of PHPT

PHPT is the most common cause of hypercalcemia. The incidence of PHPT is approximately 25-28 cases per 100,000 population. The prevalence of PHPT is 0.05-0.1%, and it occurs 4 times more often in women than in men. Approximately half of all cases of the disease occur in the age group from 40 to 60 years, the peak incidence is at 60-70 years. Thus, in the group of women over 50 years of age, the prevalence of hyperparathyroidism is 1-2%. Over the past 50 years, the clinical picture of this disease has undergone significant changes. In the countries of Western Europe and North America by 1965, manifest forms of PHPT predominated: 60% - renal pathology, 25% - skeletal system and only 2% - asymptomatic form of PHPT. By 1975, about 50% of the renal forms were identified, 15% of the bone forms and 20% of asymptomatic or low-symptomatic forms; by 1990, 18% were renal pathologies, bone manifestations decreased to 2%, and the proportion of asymptomatic and mild forms of PHPT increased to 80%. In Russia, until 2000, asymptomatic and mild forms of PHPT were practically not identified and treated, while manifest, often severe forms of PHPT were diagnosed in 85-90% of cases. According to preliminary data obtained in the Department of Neuroendocrinology and Osteopathy of the Federal State Institution Scientific Center of Russian Medical Technologies, among 340 patients observed for PHPT, the proportion of manifest forms is comparable to the proportion of low-symptomatic ones. Thus, there is a trend toward an increase in the proportion of mild and asymptomatic forms of PHPT in Russia.

Etiology and pathogenesis of PHPT

PHPT is caused by adenoma or hyperplasia and, less commonly, parathyroid carcinoma (PTC). In most cases, solitary parathyroma (80-89%) is detected, less often - multiple adenomas (2-3%), hyperplasia (2-6%) and parathyroid cancer (0.5-3%). Hyperparathyroidism, accompanied by parathyroid hyperplasia or multiple adenomas, is usually combined with hereditary syndromes: multiple endocrine neoplasia type 1 (MEN-1), hyperparathyroidism syndrome with a tumor of the lower jaw, familial isolated hyperparathyroidism syndrome and familial hypercalciuria. As for sporadic forms, in addition to age and gender, a significant risk factor is irradiation of the neck area for diagnostic or therapeutic purposes.

Parathyroid adenomas are usually benign. According to modern data, the development of parathyroid adenoma is associated with two types of mutations: type I - a mutation in mitotic control and type II - a mutation in the mechanism of final control of PTH secretion by calcium. Monoclonal tumors of the parathyroid gland also include adenomas observed in MEN-1, sporadic (non-familial) hyperplasia and secondary or tertiary hyperplasia of the parathyroid gland in chronic renal failure (CRF) and uremia.

In other cases, under the influence of various factors (low calcium or calcitriol levels), a population of rapidly proliferating PTG cells arises, which can cause hyperplasia or hyperplastic adenoma. In such cases, polyclonal adenoma develops.

A specific role in the mutation of the gene encoding PTH belongs to the specific PRAD1 gene, which belongs to proto-oncogenes and is localized on the arm of chromosome 11q13, on which the gene encoding PTH, 11p15, is also localized. Subsequently, it was proven that the PRAD1 oncogene belongs to cyclins—cell cycle regulators. Cyclin A is involved in the regulation of the S-phase, and cyclin B is involved in the regulation of the C2-M phase of the cell cycle. The PRAD1 protein gene, or cyclin D1, is overexpressed in parathyroid adenomas.

In recent years, it has been established that, in addition to the above factors in the formation of parathyroid tumors, microsatellite instability contributes to this. Microsatellites are short tandem repeats in polymorphic regions of DNA (usually CA repeats). Variations in the number of tandemly repeated nucleotides in tumors but not in normal tissue are called microsatellite instability. Microsatellite instability was identified by L. A. Loeb as a marker of the mutagenic phenotype in cancer. This concept is confirmed by a study conducted by M. Sarquis et al., in which it was first shown that a sporadic large parathyroid adenoma, removed from a girl at the age of 8.5 years, contained instability of 4 dinucleotide markers in three different loci 1, 10 1st and 11th chromosomes.

It has been suggested that disruption of the physiological effect of vitamin D is one of the factors predisposing to the development of parathyroid adenoma. This assumption was confirmed by a study by T. Carling et al., who believe that the level of vitamin D receptor mRNA was significantly reduced in adenomas or hyperplasia of the parathyroid gland (42 ± 2.8 and 44.0 ± 4.0%, respectively) compared with its content in normal parathyroid gland. Reduced expression of the vitamin D receptor gene probably impairs 1,25(OH)2D3-mediated control of parathyroid functions, and this is important in the pathogenesis of not only secondary hyperparathyroidism in chronic renal failure, but also PHPT.

Clinical picture of PHPT

Clinically, PHPT can manifest as an asymptomatic form, a mild form, a clinically manifested form without complications, and a clinically manifested form with the development of complications.

The development of clinical manifestations of PHPT is caused by hypercalcemia, which is a consequence of hypersecretion of PTH. In the asymptomatic form, hypercalcemia is usually moderate, and clinical manifestations are nonspecific.

Hypercalcemia is manifested by numerous symptoms and signs of the disease, which can be represented in the following groups:

1) manifestations of a systemic nature (general weakness, dehydration, calcification of the cornea, soft and other tissues);
2) disturbances in the activity of the central nervous system (decreased concentration, depression, psychosis, changes in consciousness - from twilight consciousness to coma);
3) pathology of the musculoskeletal system (osteoporosis, hyperparathyroid osteodystrophy, fractures, proximal myopathy);
4) disorders of the gastrointestinal tract (nausea, vomiting, anorexia, constipation, abdominal pain with pancreatitis and peptic ulcer);
5) renal dysfunction (polyuria, polydipsia, isosthenuria, decreased glomerular filtration rate, nephrolithiasis, nephrocalcinosis);
6) dysfunction of the cardiovascular system (hypertension, shortening of the QT interval, increased sensitivity to digitalis drugs).

There are several clinical (manifest) forms of PHPT:

• bone - osteoporotic, fibrocystic osteitis, subjetoid;
• visceropathic - with primary damage to the kidneys, gastrointestinal tract, and cardiovascular system;
• mixed.

Damage to the skeletal system is one of the constant symptoms of hyperparathyroidism. Bone losses in the peripheral skeleton are first detected in the end sections of long bones due to the predominance of cancellous bone there. Endosteal resorption plays a dominant role in PHPT. The result of this process is a widening of the medullary canal with thinning of the cortex. Previously, it was believed that one of the most common lesions of the skeletal system in hyperparathyroidism is generalized osteitis fibrocystis, which was observed in more than 50% of patients. In recent years, due to earlier diagnosis of the disease, these bone tissue lesions are detected less frequently (10-15%). Cysts and giant cell tumors are usually located in long bones and are detected by radiography. Cysts are also found in the wrist bones, ribs, and pelvic bones. On radiographs, giant cell tumors have a mesh-like structure and a characteristic honeycomb appearance. Histological examination of bone tissue lesions reveals a decrease in the number of trabeculae, an increase in multinucleated osteoclasts and replacement of cellular and bone marrow elements with fibrovascular tissue. The osteoporotic variant is characterized by a progressive decrease in bone mass per unit of bone volume in relation to the normal value in individuals of the corresponding sex and age, a violation of the microarchitecture of bone tissue, leading to increased fragility of bones and an increased risk of fractures from minimal trauma and even without it. PHPT often results in a diffuse decrease in bone mineral density (BMD), which can be difficult to distinguish from age-related or postmenopausal osteoporosis. It is believed that the more frequent detection of osteoporosis is associated with an earlier diagnosis of hyperparathyroidism, when the processes characteristic of osteitis fibrocystis are not yet fully formed. These data reflect the effect of low concentrations of PTH causing diffuse osteolysis rather than localized osteoclastic proliferation. Along with this, in some patients characteristic subperiosteal resorption of bone tissue is detected, most often localized in the phalanges of the fingers. In this case, resorption prevails over osteoformation, which is reflected in changes in the levels of bone resorption markers.

In most cases, patients with PHPT experience changes in the bones of the spine, characterized by varying degrees of osteoporosis from slight deformation of the vertebrae to a characteristic “fish vertebra”, sometimes with fractures of the vertebral bodies. In these cases, patients indicate a decrease in growth during the disease. Many patients have complaints of back pain, which worsens after physical activity, with prolonged stay in one position (standing or sitting). Often with PHPT, joint damage is observed - chondrocalcinosis (deposition of calcium phosphate hydrate crystals).

The visceral form with predominant kidney damage occurs in more than 60% of cases of primary manifest hyperparathyroidism; sometimes kidney damage may be its only manifestation and more often occurs in the form of urolithiasis. In 13-15% of cases, single stones are detected, in 25-30% - multiple and in 30-32% of cases - stones in both kidneys. In cases of visceral manifestations of hyperparathyroidism, for example, in the form of urolithiasis, surgical removal of the stone does not lead to recovery; stones can form in another kidney, and often in the operated one. However, the prognosis for urolithiasis after removal of a parathyroid adenoma is favorable if chronic renal failure does not develop. Kidney stones in hyperparathyroidism are composed of calcium oxalate or calcium phosphate.

In the visceral form with predominant damage to the cardiovascular system, PHPT is accompanied by hypertension, calcification of the coronary arteries and heart valves, left ventricular hypertrophy and deposition of calcium salts into the heart muscle, etc. The deposition of calcium salts into the heart muscle can cause myocardial necrosis with the clinical picture of acute myocardial infarction. In a prospective study by T. Stefanelli et al. found that PTH per se plays an important role in maintaining myocardial hypertrophy. After parathyroidectomy and normalization of serum calcium levels over 41 months, the authors observed regression of septal, posterior wall and left ventricular hypertrophy by 6-21%.

Gastrointestinal symptoms are detected in half of patients with PHPT. Patients complain of anorexia, constipation, nausea, flatulence, and weight loss. Peptic ulcers of the stomach and/or duodenum occur in 10-15% of cases, pancreatitis in 7-12%, less commonly pancreacalculosis and pancreacalcinosis. The development of gastric ulcers with hypercalcemia is associated with an increase in the secretion of gastrin and hydrochloric acid under the influence of hyperparathyroidism, which returns to normal after removal of the parathyroid adenoma. The course of gastric ulcers with PHPT is characterized by a more pronounced clinical picture (frequent exacerbations with severe pain, possible perforations) than with gastric ulcers caused by other factors.

In addition to the symptoms described above, PHPT occurs, in rare cases, skin necrosis due to the deposition of calcium salts, calcification of the auricles, rim keratitis (linear keratopathy), which develops due to the deposition of calcium salts in the capsule of the cornea of ​​the eye.

One of the serious complications of PHPT is hypercalcemic crisis. An increase in calcium content above 3.49-3.99 mmol/l (14-16 mg/100 ml) leads to the development of signs of intoxication characteristic of hypercalcemia.

Hypercalcemic crisis is a severe complication of PHPT that occurs against the background of fractures, infectious diseases, pregnancy, immobilization, and intake of absorbable antacids (calcium carbonate). It develops suddenly, causing nausea, uncontrollable vomiting, thirst, acute abdominal pain, muscle and joint pain, high fever, convulsions, confusion, stupor, coma. Mortality during hypercalcemic crisis reaches 60%. Against the background of anuria, cardiovascular failure appears. If hypercalcemia increases to 4.99 mmol/l (20 mg/100 ml), then the activity of the central nervous system is inhibited with inhibition of the function of the respiratory and vasomotor centers and irreversible shock develops.

Diagnosis and differential PHPT

The diagnosis of hyperparathyroidism is based on medical history, patient complaints, clinical picture (peptic ulcer, urolithiasis, pancreatitis, chondrocalcinosis, bone changes - osteoporosis, bone cysts) and laboratory test results.

Laboratory research

During laboratory testing, the cardinal sign of suspected PHPT is an increase in PTH levels, which in most cases is accompanied by hypercalcemia. A constant sign of hyperparathyroidism is hypercalcemia; hypophosphatemia is less persistent than elevated serum calcium. The content of alkaline phosphatase in the blood serum is increased. Less common is hypomagnesemia. Along with this, the excretion of calcium and phosphorus in the urine is increased.

In some patients with elevated PTH levels, the serum total calcium concentration is normal. This condition is commonly called the normocalcemic variant of PHPT.

Causes of the normocalcemic variant of PHPT:

• renal failure (impaired tubular reabsorption of calcium);
• impaired absorption of calcium in the intestine;
• vitamin deficiency D.

To distinguish hyperparathyroidism with vitamin D deficiency from isolated vitamin D deficiency, a trial treatment with vitamin D is performed. During vitamin D replacement therapy, hypercalcemia occurs in patients with hyperparathyroidism, and normocalcemia is restored in patients with isolated vitamin D deficiency. Transient normocalcemia may occur early in the development of PHPT. To confirm the diagnosis of hyperparathyroidism in patients with recurrent urolithiasis and normocalcemia, a provocative test with thiazide diuretics is performed.

Bone and mixed forms of PHPT are characterized by a significant increase in bone metabolism with an increase in the frequency of activations and the predominance of resorption processes. In the manifest form of PHPT, the average level of osteocalcin exceeded the normative values ​​by 2.6-20 times, and a significant correlation was revealed between the activity of alkaline phosphatase and PTH (r = 0.53, p< 0,01), между уровнем остеокальцина и ПТГ (r = 0,68, p < 0,01). У больных ПГПТ отмечается повышение общей щелочной фосфатазы крови, остеокальцина крови и оксипролина мочи, а также дезоксипиридинолина мочи и тартратрезистентной кислой фосфатазы крови . В исследовании пациентов с ПГПТ были выявлены статистически значимые корреляции между дезоксипиридинолином мочи и сывороточной костной щелочной фосфатазой, а также остеокальцином сыворотки. Кроме того, отрицательные корреляции высокой степени были выявлены между дезоксипиридинолином мочи и минеральной плотностью костной ткани как в позвоночнике, так и в лучевой кости .

The effect of PTH on the production of osteoprotogerin (OPG) and NF-kappaB receptor activator ligand (RANKL) in humans has not been fully established. PTH has been demonstrated to reduce OPG production and increase RANKL production. It was noted that before surgical treatment of hyperparathyroidism, RANKL and osteoprotogerin were correlated with serum osteocalcin. The RANKL/osteoprotogerin ratio decreased after surgical treatment, indicating the possibility of their use as markers of bone tissue condition in PHPT.

Speaking about the role of the N-terminal telopeptide, it should be noted that, according to researchers, a high level of this marker is a factor indicating the greatest effectiveness of surgical treatment.

The diagnosis of hyperparathyroidism is confirmed by determining the level of PTH in the blood serum. Sensitive methods for determining PTH in blood have been developed: immunoradiometric (IRMA) and immunochemiluminometric (ICMA). Thus, the basis for the diagnosis of PHPT is persistent hypercalcemia and elevated serum PTH levels.

Instrumental studies

To identify bone changes, radiography of the tubular bones, pelvic bones, thoracic and lumbar spine, osteodensitometry of the lumbar vertebrae, proximal femur, and radius are performed.

Determining the nature of hypercalcemia and establishing a diagnosis of hyperparathyroidism should be carried out comprehensively, including studies to determine the localization of adenoma or hyperplasia of the parathyroid gland: ultrasound examination (ultrasound), arteriography, scintigraphy, selective catheterization of veins and determination of the content of PTH in the blood flowing from the gland, computed tomography (CT) , magnetic resonance imaging (MRI).

Ultrasound of the parathyroid gland. The sensitivity of the method ranges from 34% to 95%, specificity reaches up to 99%. The results of the study depend on the experience of the ultrasound diagnostic specialist and the mass of the parathyroid gland (with a mass of the gland less than 500 mg, the sensitivity is significantly reduced to 30%). The method is not informative for atypical localization of the parathyroid gland - behind the sternum, in the retroesophageal space.

Scintigraphy. As a rule, it is performed with thallium 201Tl, technetium pertechnate 99 mTc, which accumulate in the thyroid gland and in enlarged parathyroid glands. One of the latest methods is scintigraphy using Technetril-99Tc (99mTc-sestamibi-scintigraphy) - a complex of technetium 99m and methoxyisobutylnitrile. Compared to 201Tl, scintigraphy with Technetril-99Tc is characterized by significantly lower radiation exposure and greater accessibility; the sensitivity of the method reaches 91%. It should be noted that in the presence of giant cell tumors in the bones, which occur in severe forms of PHPT and are detected radiographically, the accumulation of 99mTc in the lesions of these bones can give a false positive result of topical diagnosis, which should be kept in mind when assessing PTG scintigraphy data, which should be compared with results of x-ray examination of the corresponding part of the skeleton.

CT can detect parathyroid adenomas measuring 0.2-0.3 cm. The sensitivity of the method ranges from 34% to 87%. The disadvantages of the method are the load in the form of ionizing radiation.

Some authors consider MRI to be one of the most effective methods for visualizing the parathyroid gland, but due to the high cost and length of time spent on image acquisition, it is not widely used. There is an opinion that PTGs located in the tissues of the thyroid gland are much more difficult to differentiate with MRI than with ultrasound, but, based on the latest data, we can assume that MRI is a fairly sensitive method (50-90%).

Invasive research methods include puncture of the parathyroid gland under ultrasound control, selective arteriography, catheterization of a vein and taking blood flowing from the gland to determine PTH in it. Invasive methods are used in case of relapse of PHPT or after unsuccessful revision of the parathyroid gland when signs of PHPT persist.

However, sometimes, despite the use of all research methods, it is not possible to confirm the presence of an adenoma, and the course of the disease does not allow continuing conservative therapy. In these cases, an operation is recommended, during which an audit of all parathyroid glands is performed. More often (60-75%) adenoma is located in the lower parathyroid glands, and detection of a tumor in one of them, as a rule, excludes adenomas in the remaining parathyroid glands. However, revision of the remaining glands is mandatory.

Treatment of primary hyperparathyroidism. Choice of therapy

The choice of treatment method depends on the presence or absence of parathyroid adenoma, the severity of hypercalcemia and the presence of complications, such as nephrocalcinosis, gastric ulcer, etc. In the presence of a confirmed tumor, hypercalcemia and complications, surgery is recommended. According to the consensus on the diagnosis and management of patients with PHPT, surgery is indicated in the following cases:

1) the concentration of total calcium in the blood serum is 0.25 mmol/l (1 mg%) higher than the norm established in this laboratory for this age group;
2) a decrease in glomerular filtration rate by more than 30% compared to the norm established in a given laboratory for a given age group;
3) visceral manifestations of PHPT;
4) daily calcium excretion more than 400 mg;
5) decrease in BMD of cortical bones by more than 2.5 SD according to the T-criterion;
6) age less than 50 years.

Surgical methods of treatment

As a rule, during operations on the parathyroid gland for PHPT, all four parathyroid glands are inspected, since preoperative topical diagnostics do not always reveal multiple adenomas and hyperplasias, adenomas of the accessory glands.

According to J. N. Attie, out of 1196 patients operated on for hyperparathyroidism, a single adenoma was discovered in 1079 patients during surgery (including one patient with MEN-2 syndrome); 41 patients had two adenomas; 4 had three adenomas; 23 had primary hyperplasia; 30 had secondary hyperplasia; 6 had tertiary hyperplasia; 12 had parathyroid cancer and 1 patient had parathyroid cancer in one and adenoma in the second. It is interesting that of the 1158 patients operated on by this author for PHPT, 274 (23.7%) were simultaneously diagnosed with thyroid diseases: in 236 patients, changes in the thyroid tissue were benign and in 38 papillary or follicular thyroid cancer was detected glands. Of the 38 patients with malignant tumors of the thyroid gland, in 26 the tumors were palpable before surgery; in 2 patients they were detected on ultrasound and in 10 they were discovered by chance during surgery to remove a parathyroid adenoma.

If PHPT is diagnosed during pregnancy, parathyroidectomy is acceptable in the second trimester of pregnancy.

Surgical tactics for PTG cancer are characterized by certain features. PTG cancer usually grows slowly and rarely metastasizes. With complete removal of the gland without damage to the capsule, the prognosis is favorable. In some cases, parathyroid cancer is more aggressive, and already at the first operation metastases are detected in the lungs, liver and bones. It is not always possible to immediately determine that the primary tumor is cancer; Histological examination of a non-invasive tumor can reveal an increase in the number of mitotic figures and fibrosis of the gland stroma. PTG cancer is often diagnosed retrospectively. Hyperparathyroidism due to parathyroid cancer often cannot be distinguished from other forms of PHPT. At the same time, it is known that parathyroid cancer is often accompanied by severe hypercalcemia. Therefore, when the level of calcium in the blood is more than 3.5-3.7 mmol/l, the surgeon must be especially careful to prevent damage to the capsule when removing the affected gland.

The incidence of complications and mortality in surgical treatment of PHPT is not high, and recovery occurs in more than 90% of cases. With successful intervention, the postoperative period proceeds, as a rule, without complications. It is necessary to determine the calcium level in the blood 2 times a day; if it decreases quickly, it is recommended to take calcium supplements. ECG is constantly monitored.

The most common postoperative complications include: damage to the recurrent laryngeal nerve, transient or persistent hypocalcemia, very rarely hypomagnesemia; in patients who suffered from severe hypercalcemia before surgery, “hungry bone syndrome” may develop.

Treatment of postoperative hypocalcemia (“hungry bone syndrome”)

Most clinical symptoms of PHPT reverse after successful surgery. After surgical treatment of PHPT, i.e. after elimination of PTH hyperproduction, a fairly rapid reverse development of clinical symptoms and biochemical parameters is observed. After adequate surgical treatment, in some cases hypocalcemia occurs, requiring the use of vitamin D or its active metabolites and calcium supplements. To eliminate the “hungry bone” syndrome in the bone form of hyperparathyroidism in the postoperative period, calcium supplements are prescribed in a dose of 1500-3000 mg (calcium element) in combination with alfacalcidol (Etalfa, Alpha D3-Teva) 1.5-3.0 mcg per day and/or dihydrotachysterol (Dihydrotachysterol, A.T. 10) 20-60 drops per day. With persistent normocalcemia, doses are gradually reduced to maintenance: 1000 mg of calcium and 1-1.5 mcg of alfacalcidol for 0.5-2 years. In our practice, Calcium-D3 Nycomed Forte is most often prescribed (1 chewable tablet contains 500 mg of calcium and 400 IU of vitamin D3) in combination with alfacalcidol. These drugs are well tolerated, easy to use and safe.

Treatment of patients with mild forms of PHPT

Patients over 50 years of age with mild hypercalcemia, normal or slightly reduced bone mass, and normal or slightly impaired renal function can be treated conservatively. In these cases it is recommended:

• increase fluid intake;
• limit sodium, protein and calcium intake;
• take diuretics;
• take medications that reduce the rate of bone resorption.

Based on a 10-year prospective study of 120 patients with PHPT, with or without surgical treatment, the authors concluded that there were no significant differences in biochemical parameters and bone mineral density in non-surgical patients with oligosymptomatic and asymptomatic hyperparathyroidism. However, a number of patients were identified who, during the observation process, had indications for surgical treatment (the onset or progression of urolithiasis, negative dynamics of bone mineral density, low-traumatic fractures). However, if patients with PHPT do not experience worsening signs of the disease, surgical treatment can be avoided.

In mild forms of PHPT with a moderate decrease in BMD in women during menopause, it is recommended to prescribe estrogen or bisphosphonates to prevent the progression of osteoporosis. In recent years, bisphosphonates have been prescribed more frequently. The goal of long-term bisphosphonates is to correct osteoporosis rather than lower PTH levels, but it may reduce hypercalcemia. When treating with bisphosphonates, pamidronic acid (Pamidronate medac), risedronate, and alendronate are used. S. A. Reasner et al. used to treat patients with osteoporosis and PHPT, risedronate, which within 7 days normalized the level of calcium in the blood serum while simultaneously reducing not only the content of alkaline phosphatase in the blood, but also the excretion of hydroxyproline, as well as increasing the renal tubular reabsorption of calcium. Good results were also noted with the use of alendronate.

It should be emphasized that the effectiveness of the listed treatment methods varies greatly depending on the pathogenetic type of hypercalcemia and the individual sensitivity of the patient to one or another drug. Treatment tactics must necessarily take into account the dynamics of laboratory parameters and the possibility of reducing hypercalcemia.

Conclusion

Thus, the above review of the literature on the etiology, pathogenesis, diagnosis and treatment of PHPT indicates both significant achievements and a number of unresolved problems in this area. Due to the difficulties in the early diagnosis of PHPT, normocalcemic variants of PHPT due to vitamin D deficiency, and the lack of widespread determination of calcium in the blood and urine in routine clinical practice, patients with mild or asymptomatic forms are poorly identified. The issue of indications for surgical treatment and conservative treatment of patients with mild forms of PHPT continues to be discussed. All this necessitates further study of the clinical manifestations of the disease and improvement of methods for differential diagnosis and optimization of treatment for patients with PHPT.

For questions regarding literature, please contact the editor.

L. Ya. Rozhinskaya, Doctor of Medical Sciences
ENC Rosmedtekhnologii, Moscow

For quotation: Antsiferov M.B., Markina N.V. Modern approaches to the diagnosis and treatment of primary hyperparathyroidism // Breast Cancer. 2014. No. 13. P. 974

Introduction

Until recently, primary hyperparathyroidism (PHPT) was considered to be one of the rare endocrine diseases, which is accompanied by a violation of phosphorus-calcium metabolism with the development of urolithiasis (KD), damage to the skeletal system and pathological (low-traumatic) fractures.

Until recently, primary hyperparathyroidism (PHPT) was spoken of as one of the rare endocrine diseases, which is accompanied by disturbances in phosphorus-calcium metabolism with the development of urolithiasis (UCD), damage to the skeletal system with pathological (low-traumatic) fractures.

Changes in the understanding of the true prevalence of this disease occurred after the widespread introduction of determination of total and ionized calcium into standard biochemical blood tests. This allowed us to talk about PHPT as a more common endocrine disease. According to epidemiological studies, the prevalence of PHPT ranges from 3.2 cases per 100 thousand inhabitants in Switzerland to 7.8 cases per 100 thousand inhabitants in the USA. The prevalence of PHPT among young men and women is almost the same, while with age, women's susceptibility to this disease becomes 3 times higher than men. According to the Endocrinological Dispensary (ED) of the Moscow Department of Health, PHPT is common in all groups of the population, but its predominance is noted in the older age group. PHPT is most often diagnosed in women over 55 years of age. Among the 302 patients who applied to the ED with newly diagnosed PHPT, there were 290 women and 12 men.

Diagnosis of primary hyperparathyroidism

The development of PHPT in 80-85% of cases is caused by an adenoma of one of the four parathyroid glands (PTG), in 10-15% of cases there is hyperplasia of one or more PTG or multiple adenomas. Topical diagnosis of parathyroid adenoma is carried out using ultrasound examination (ultrasound). The information content of this method reaches 95%, but when the mass of the gland is less than 0.5 g it decreases to 30%. As a rule, parathyroid adenomas are visualized during scintigraphy using technetril. The sensitivity of this method for PTG adenoma reaches 100%, and for PTG hyperplasia - 75%. Ectopic parathyroid adenoma can be observed in 20% of cases and is not always detected on scintigraphy. In this case, an additional multislice computed tomography of the head and neck organs is performed to identify adenomas in the anterior mediastinum, pericardium, and retroesophageal space.

Laboratory methods for diagnosing PHPT are based on the determination of parathyroid hormone (PTH), free and ionized calcium, phosphorus, alkaline phosphatase, creatinine, vitamin D in the blood, calcium and phosphorus in daily urine.

Pathogenesis and clinical manifestations of osteovisceral complications of primary hyperparathyroidism

The main target organs that are affected in PHPT due to excessive secretion of PTH and hypercalcemia are the musculoskeletal, urinary systems, and the gastrointestinal tract (GIT). A direct relationship has been identified between PTH and calcium levels and increased morbidity and mortality from cardiovascular pathology.

Damage to the musculoskeletal system in PHPT is manifested by a decrease in bone mineral density (BMD) and the formation of secondary osteoporosis. The development of osteoporosis is directly related to the effect of PTH on bone tissue. PTH is involved in the processes of differentiation and proliferation of osteoclasts. Under the influence of lysosomal enzymes and hydrogen ions produced by mature osteoclasts, the bone matrix dissolves and degrades. In conditions of PHPT, the processes of bone tissue resorption prevail over the processes of formation of new bone tissue and are the cause of the development of low-traumatic fractures.

The indirect effect of PTH on bone tissue is associated with its effect on the renal tubules. PTH, by reducing the reabsorption of phosphate in the renal tubules, increases phosphaturia, which leads to a decrease in the level of phosphate in the blood plasma and the mobilization of calcium from the bones.

Osteoporotic changes in the bones of the spine range from minor bone deformities to compression fractures. The greatest changes are found in bones with a cortical structure. As a rule, patients complain of muscle weakness, bone pain, frequent fractures, and decreased height during the course of the disease. The risk of developing fractures with PHPT is 2 times higher in bones that have both a cortical and trabecular structure.

To identify bone complications of PHPT, dual-energy X-ray absorptiometry of the distal radius, lumbar spine, and proximal femurs is performed. The need to include the distal radius in the study is due to the most significant decrease in BMD in this area in PHPT.

In severe manifest course of PHPT, X-ray examination reveals severe bone disorders: cystic fibrous osteodystrophy, subperiosteal bone resorption. The main cause of the development of visceral disorders against the background of PHPT is hypercalcemia. Increased urinary calcium excretion leads to a decrease in the sensitivity of the renal tubules to antidiuretic hormone, which is manifested in a decrease in renal water reabsorption and the concentrating ability of the kidneys. Long-term hypercalcemia leads to the development of nephrocalcinosis and, as a consequence, to a decrease in glomerular filtration rate and the development of chronic renal failure. A decrease in GFR of less than 60 ml/min is an indication for surgical treatment of PHPT. Recurrent urolithiasis in patients with PHPT occurs in more than 60% of cases. Detection of nephrolithiasis is also an absolute indication for surgical removal of the parathyroid adenoma. Despite radical treatment, the risk of developing nephrolithiasis remains over the next 10 years.

All patients with PHPT undergo renal ultrasound and glomerular filtration rate (GFR) is determined to identify visceral disorders.

Structural changes in the coronary vessels in the absence of symptoms of damage to the cardiovascular system are present in patients with a mild form of PHPT. Arterial hypertension (AH) is detected with PHPT in 15-50% of cases. In more severe cases of PHPT, damage to the cardiovascular system is accompanied by calcification of the coronary arteries and heart valves, and left ventricular hypertrophy. Along with hypercalcemia, the mechanism of development of hypertension also involves an increase in intracellular calcium content, an increase in plasma renin activity, hypomagnesemia and a decrease in glomerular filtration rate with the development of chronic renal failure. Several population-based studies have confirmed a direct relationship between increased morbidity and mortality from cardiovascular disease and blood levels of PTH and calcium.

Gastrointestinal diseases are also directly related to hypercalcemia, which leads to increased secretion of gastrin and hydrochloric acid. 50% of patients with PHPT develop peptic ulcers of the stomach and duodenum. The course of peptic ulcer disease in patients with PHPT is accompanied by nausea, vomiting, anorexia, and pain in the epigastric region. To identify visceral gastrointestinal complications of PHPT, esophagogastroduodenoscopy (EGDS) is performed.

Management and treatment of patients with various forms of primary hyperparathyroidism

Depending on the level of calcium, the presence of bone, visceral or osteovisceral complications, manifest and mild forms of PHPT are distinguished. The mild form of PHPT, in turn, is divided into oligosymptomatic and asymptomatic forms.

The mild form of PHPT can be diagnosed:

• with normocalcemia or serum calcium levels exceeding the upper limit of normal by no more than 0.25 mmol/l;
• in the absence of visceral manifestations of PHPT;
• according to the results of densitometry, BMD is reduced according to the T-criterion by no more than 2.5 SD;
• There is no indication in the anamnesis of low-traumatic fractures.

Recently, the detection rate of patients with mild forms of PHPT has increased to 80%.

In 40% of patients with the normocalcemic form of PHPT, during the 3-year observation period, severe hypercalciuria with the development of nephrolithiasis was detected, and there was a decrease in BMD with the development of low-traumatic fractures. At the same time, the majority of patients observed for 8 years did not develop bone and visceral complications of PHPT. Thus, the decision to surgically treat a patient must be made on a case-by-case basis. With the progression of urolithiasis, a decrease in GFR less than 60 ml/min, the development of osteoporosis or low-traumatic fractures, as well as negative dynamics of laboratory parameters (increased levels of calcium and PTH in the blood serum), surgical treatment is recommended.

Management of patients with a mild, asymptomatic form of PHPT with osteopenia without a history of fractures is usually conservative. All patients are recommended to follow a diet limiting calcium intake to 800-1000 mg/day and increasing fluid intake to 1.5-2.0 l. If during dynamic observation there is a decrease in BMD with the development of osteoporosis, patients are prescribed drugs from the group of bisphosphonates. Bisphosphonates (BPs) are analogues of inorganic pyrophosphates. The phosphate groups of BF have two main functions: binding to cellular minerals and cell-mediated antiresorptive activity. The main target cell for the action of BP is the osteoclast. When they enter the osteoclast by endocytosis, BPs affect the mevalonate pathway - they block the enzyme farnesyl pyrophosphate synthase, which leads to inhibition of the modification of signaling proteins necessary for the normal function of the osteoclast and a decrease in its resorptive activity. The tactics of active monitoring of patients must necessarily include monitoring of indicators such as PTH, total and ionized calcium, creatinine, daily calcium excretion in urine (once every 3 months, then once every 6 months). Every 12 months Kidney ultrasound and densitometry must be performed.

Recently, it has become possible to treat secondary osteoporosis in patients with PHPT using monoclonal human antibodies to RANKL (denosumab). Unlike other antiresorptive drugs (bisphosphonates), denosumab reduces the formation of osteoclasts without impairing the function of mature cells. Denosumab (60 mg x 6 months) demonstrated better results in terms of increasing cortical and trabecular bone mineral density compared to alendronate (70 mg x 1 week). The administration of denosumab after therapy with bisphosphonates (alendronate) leads to a further increase in BMD.

The manifest form of PHPT is diagnosed if:

• the level of total calcium in the blood is more than 0.25 mmol/l above the upper limit of normal;
• there are bone, visceral or osteovisceral complications of PHPT.

When calcium levels are above 3.0 mmol/l, patients may develop psychosis. Calcium levels in the range of 3.5-4.0 mmol/l can cause the development of a hypercalcemic crisis, in which mortality reaches 50-60%.

If a manifest form of PHPT with a specified localization of the parathyroid adenoma is detected, surgical treatment is recommended. If the results of ultrasound and scintigraphy of the parathyroid gland, MSCT of the mediastinal and neck organs are negative in patients with high levels of calcium and PTH and in the presence of bone and visceral complications, surgical intervention with revision of all areas of the possible location of the parathyroid gland is possible. To confirm successful removal of PTG adenoma, intraoperative determination of PTH level is recommended.

Removal of the parathyroid adenoma is the most radical method of treating PHPT. A postoperative complication of PHPT is persistent or transient hypocalcemia. In this regard, patients need to take active metabolites of vitamin D (alfacalcidol, calcitriol) and calcium supplements for a long time. In the postoperative period, the average dose of alfacalcidol can be 1.75 mcg/day, the average dose of calcium can be up to 2000 mg/day. With persistent normocalcemia, the dose of drugs is gradually reduced to maintenance - 1.0-1.5 mcg of active metabolites of vitamin D and 1000 mg of calcium per day. Surgical treatment and postoperative administration of active vitamin D metabolites and calcium supplements lead to a significant increase in BMD over 12 months. Menopausal women with symptoms of severe osteoporosis after taking calcium and alfacalcidol for a year need to be prescribed drugs from the group of bisphosphonates.

Conservative management of patients with manifest form of PHPT is carried out:

• with recurrent hyperparathyroidism;
• after a non-radical operation;
• if there are contraindications to surgical treatment (severe concomitant diseases);
• with an atypically located parathyroid adenoma;
• if it is impossible to visualize the adenoma on scintigraphy of the parathyroid gland, MSCT of the mediastinal and neck organs.

Patients are under dynamic observation; imaging studies of the adenoma are carried out once every 12 months.

In the manifest form of PHPT, there is a high level of calcium in the blood. In this regard, patients are prescribed an allosteric modulator of the calcium-sensing receptor (CaSR) - cinacalcet. The initial dose of the drug is 30 mg/day, followed by titration every 2-4 weeks. until the target calcium level is reached. The maximum dose of the drug is 90 mg x 4 times / day. The drug is taken orally during or immediately after meals. The dose of the drug is titrated under the control of the levels of total and ionized calcium, calcium and phosphorus excretion in the urine.

Against the background of 3 years of use of cinacalcet (30-90 mg/day) in 65 patients with a manifest form of PHPT, not only a decrease in the level of calcium in the blood was noted during the first 2 months, but also retention of the obtained result throughout the entire observation period. The average level of total calcium in the blood before treatment was 2.91 mmol/l, after 3 years during treatment - 2.33 mmol/l (p<0,001; норма — 2,15-2,57 ммоль/л). Также отмечалось уменьшение уровня ионизированного кальция с 1,50 ммоль/л до 1,22 ммоль/л (р<0,001; норма — 1,02-1,30 ммоль/л).

Patients with manifest PHPT with severe bone complications are prescribed antiresorptive therapy with drugs from the bisphosphonate group to prevent further bone loss and reduce the risk of fractures.

Primary hyperparathyroidism as part of multiple endocrine neoplasia syndrome (MEN syndrome)

It must be taken into account that hyperparathyroidism caused by adenoma or hyperplasia of the parathyroid gland can be part of the syndrome of multiple endocrine neoplasia (MEN syndrome) in 1-2% of cases.

MEN type 1 syndrome has an autosomal dominant pattern of inheritance and is associated with a mutation in the tumor suppressor gene in the long arm of chromosome 11. In 90% of cases, PHPT is the first manifestation of the disease, which remains asymptomatic for a long time. As a rule, with MEN type 1 syndrome, an ectopic location of the parathyroid adenoma or hyperplasia of all glands is detected. In type 1 MEN syndrome, PHPT is combined with multiple formations of other endocrine glands: in 70% - with tumors of the anterior pituitary gland (prolactinoma, somatostatinoma, corticotropinoma), in 40% of cases - with islet cell tumors (insulinoma, glucagonoma, gastrinoma) .

MEN type 2 syndrome is an autosomal dominant RET syndrome associated with a gene mutation. The disease is characterized by parathyroid hyperplasia, the development of medullary thyroid cancer and pheochromocytoma. In 50% of cases it is inherited.

Conclusion

Thus, PHPT is a severely disabling disease. Detection of PHPT in the early stages and surgical removal of the parathyroid adenoma can prevent the development of osteovisceral complications. At the same time, there is a group of patients who cannot be operated on for a number of reasons. Conservative management of these patients includes therapy with cinacalcet. In the presence of bone complications, drugs from the bisphosphonate group are prescribed for a long time. Careful attention should be paid to young patients with newly diagnosed PHPT, since it may be part of the MEN type 1 or 2 syndrome. Algorithms for differential diagnosis and management of patients with PHPT are presented in Schemes 1 and 2.

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Hyperparathyroidism is a disease that affects women more than men, and it occurs 2-3 times more often. This disease is a disorder of the endocrine system and is caused by excessive production of parathyroid hormone (PTH) by the parathyroid glands. This hormone leads to the accumulation of calcium in the blood, which causes bone tissue and kidney damage. When diagnosed with hyperparathyroidism, symptoms and treatment in women - information that is necessary for everyone who has problems with the thyroid gland, especially if the girl is at risk - between the ages of 25 and 50 years.

Reasons

A healthy thyroid gland produces a normal amount of parathyroid hormone, but when problems occur in it, the amount can either decrease or increase significantly. The functioning of the gland is affected by:

1. Tumors, appearing in the tissues of the thyroid gland or lymph nodes of the neck. In this case, disturbances are caused by both malignant and benign neoplasms.
2. Kidney failure which has passed into the chronic stage.
3. Hereditary autosomal dominant syndrome, which provokes tumors in one or more endocrine glands. Sometimes diseases cause hyperplasia instead of a tumor.
4. Diseases associated with gastrointestinal tract.
5. Secondary hyperparathyroidism against the background of vitamin D deficiency - one of the rare cases of the disease, usually has a chronic form, which leads to changes in the tissues of internal organs. Most often, a disorder in the thyroid gland is not its only symptom.
6. Nutritional hyperparathyroidism- a disease caused by poor nutrition. It can be present even with a varied and balanced diet, if the body does not absorb some of the nutrients.

Depending on the reasons that caused the disease, there are:

1. Primary hyperparathyroidism - the disorder is caused by diseases of the thyroid gland. Most often these are hereditary disorders that are diagnosed at an early age.
2. Secondary - appears as the body's response to a long-term lack of calcium caused by poor diet or lack of vitamin D. Another cause of secondary hyperparathyroidism is diseases of the bone tissue or digestive organs, and also when the kidneys remove calcium from the body too quickly.
3. Tertiary - appears only with a long course of secondary hyperparathyroidism, which, without proper treatment, provokes the appearance of adenomas in the parathyroid glands.

In addition to this disease caused by disorders in the thyroid gland, there is pseudohyperparathyroidism, caused by the production of a substance similar in function to parathyroid hormone. This disease occurs due to malignant tumors that produce this substance. In this case, neoplasms affect other glands in the body and do not directly affect the secretion of parathyroid hormone.

Symptoms

Hyperparathyroidism, the symptoms of which are not specific in the early stages, and in some cases the disease resolves without significant manifestations. Therefore, the disorder is rarely diagnosed in a mild form, unless there are significant changes in the thyroid tissue.

In the early stages appear:

• Headache and cognitive decline.
• Increased fatigue.
• Decreased muscle tone, which leads to difficulties with movement; it is especially difficult for the patient to climb stairs, even to a small height.
• Deterioration in the emotional sphere, the appearance of signs of neurasthenia, and sometimes depression. People with reduced immunity, as well as children and the elderly, may develop mental disorders that cannot be explained by genetic predisposition or external influences.
• Changes in skin color to pale, and with prolonged disturbance, it acquires an earthy tint.
• A change in gait, which becomes a “duck-like” waddle, due to decreased tone of the pelvic muscles or changes in the bone structure of the hips.

At a later stage, disorders occur in bone tissue:

1. Osteoporotic- developing decrease in bone mass, as well as disturbances in its structure.
2. Osteitis fibrocystis- inflammation in the bones, leading to the appearance of cystic tumors.

Due to a violation of the bone structure, patients often experience fractures during normal movements, which are not traumatic. So, a person can break an arm or leg while in bed. At this stage of the disease, pain occurs without a clear localization, and most often it is characterized as “bone aches.” Fractures that appear at this stage cause less pain than in a healthy person, but they heal less well and are more often accompanied by complications. Broken bones often heal incorrectly, causing limb deformities.

Problems with the bone structure cause not only fractures, but also changes in the spine, which can cause a person to become shorter or have a sharp deterioration in their posture. A common case is a violation of the integrity of the teeth, in which they begin to become loose due to disturbances in the alveolar bone and gum tissue. Often in such cases, even healthy molars begin to fall out.

Hyperparathyroidism, the symptoms of which are nonspecific, is called visceropathic. It is very rare. This case of the disease develops gradually, which makes diagnosis difficult. Initially, a person develops signs of intoxication, frequently recurring vomiting or diarrhea, increased flatulence, as well as decreased appetite and rapid weight loss.

Ulcers may appear in the gastrointestinal tract, which are accompanied by bleeding, while treatment of the mucous membrane is ineffective, which is why frequent exacerbations and relapses occur. Possible damage to the pancreas, liver or gallbladder. They also often record an increase in the amount of urine excreted above the daily norm, which is why patients develop a constant thirst that cannot be quenched. As the disease develops, calcium salts are deposited in the kidney tissues, which causes changes in them and, over time, kidney failure.

Diagnostics

Initially, the disease has no specific symptoms, which makes it difficult to diagnose. But there are a number of general tests that can show an increase in calcium levels in the body:

1. General urine analysis - the liquid becomes more alkaline, while calcium salts are found in it, and the amount of phosphorus also increases. Sometimes protein is found in the urine, which indicates inflammation in the kidneys. At the same time, the density of the secretions decreases, but their quantity increases.
2. Biochemical blood test - allows you to find out the composition of the blood and accurately determine the imbalance of proportions. With hyperparathyroidism, the amount of total and ionized calcium in the blood is increased, and phosphorus is decreased.

Specific tests:

1. Chemiluminescent immunoassay- collection of venous blood to determine the amount of parathyroid hormone.
2. Ultrasound of the thyroid gland- allows you to determine changes in tissues, as well as detect abnormalities in the lymph nodes.
3. X-ray, CT or MRI- carried out both in the neck and limbs if the patient complains of pain, unexpected fractures, or changes in mobility.
4. Scintigraphy of the gland— makes it possible to determine how normally the parathyroid glands are located, as well as what tissues are part of them, whether there are pathological changes, and how the organ functions.

In addition to general and specific tests, the doctor may prescribe additional tests to identify the cause of the disease. This is especially important if the disease is secondary.

Treatment

If hyperparathyroidism is detected, treatment should be comprehensive; it will depend on the root cause of the disease. Because tumors or other abnormalities of the thyroid gland are often present, a combination of surgery and drug therapy is considered optimal.

When hyperparathyroidism is initially diagnosed, doctors’ clinical recommendations most often include removal of the tumor or dysplasia of the parathyroid glands. If the size of the altered tissue is small, then special endoscopic equipment is used, which reduces interference in the body, which has a beneficial effect on the speed of recovery.

In addition, doctors prescribe various measures to help reduce calcium in the blood. To do this, a sodium chloride solution can be administered intravenously, and furosemide, potassium chloride and a 5% glucose solution can also be prescribed. But such measures are only necessary if the calcium content is too high, which can provoke a crisis. This increases the load on the kidneys, so all medications should be taken only under the supervision of a doctor to reduce the likelihood of pathological changes.

If the disease is caused by malignant tumors, then after their removal a course of radiation or chemotherapy is administered, selected individually, depending on the course of the disease.

If the disease is diagnosed in the early stages and there are no serious chronic diseases in the body, then the prognosis for treatment is quite favorable. When the disease begins to affect bone tissue, but has not gone too far, therapy takes from 4 to 24 months. A more severe case is kidney damage due to pathological changes in the organs.

The disease hyperparathyroidism, symptoms and treatment in women do not differ from those typical for men, but due to unstable hormonal levels, the endocrine glands are more susceptible to changes. Therefore, it is important for sexually mature women to monitor the health of the thyroid gland and regularly check the amount of calcium in the blood.