Spectrum of PRSS1, SPINK1, CTRC, CFTR, and CPA1 Gene Variants in Chronic Pancreatitis Patients in Russia.

The aim of the study was to define the spectrum of genetic risk factors of chronic pancreatitis (CP) development in patients living in the European part of the Russian Federation. Materials and Methods: The study group included 105 patients with CP, with the age of the disease onset under 40 years old (the average age of onset was 26.9 years). The control group consisted of 76 persons without clinical signs of pancreatitis. The diagnosis of chronic pancreatitis in patients was made on the basis of clinical manifestations and the results of laboratory and instrumental investigations. Genetic examination of patients was conducted using the next-generation sequencing (NGS) technology and included targeted sequencing of all exons and exon-intron boundaries of the PRSS1, SPINK1, CTRC, CFTR, and CPA1 genes. The genotyping of the rs61734659 locus of the PRSS2 gene was also conducted. Results: Genetic risk factors of the CP development were found in 61% of patients. Pathogenic and likely-pathogenic variants associated with the risk of CP development were identified in the following genes: CTRC (37.1% of patients), CFTR (18.1%), SPINK1 (8.6%), PRSS1 (8.6%), and CPA1 (6.7%). The frequent gene variants in Russian patients with CP were as follows: CTRC gene - c.180C>T (rs497078), c.760C>T (rs121909293), c.738_761del24 (rs746224507); cumulative odds ratio (OR) for all risk alleles was 1.848 (95% CI: 1.054-3.243); CFTR gene - c.3485G>T (rs1800120), c.1521_1523delCTT (p.Phe508del, rs113993960), and c.650A>G (rs121909046); OR=2.432 (95% CI: 1.066-5.553). In the SPINK1, PRSS1, and CPA1 genes, pathogenic variants were found only in the group of patients with CP. The frequent variants of the SPINK1 gene include c.101A>G (p.Asn34Ser, rs17107315) and c.194+2T>C (rs148954387); of the PRSS1 gene - c.86A>T (p.Asn29Ile, rs111033566); of the CPA1 gene - c.586-30C>T (rs782335525) and c.696+23_696+24delGG. The OR for the CP development for the c.180TT genotype (rs497078) CTRC according to the recessive model (TT vs. CT+CC) was 7.05 (95% CI: 0.86-263, p=0.011). In the CTRC gene, the variant c.493+49G>C (rs6679763) appeared to be benign, the c.493+51C>A (rs10803384) variant was frequently detected among both the diseased and healthy persons and did not demonstrate a protective effect. The protective factor c.571G>A (p.Gly191Arg, rs61734659) of the PRSS2 gene was detected only in the group of healthy individuals and confirmed its protective role. 12.4% of the patients with CP had risk factors in 2 or 3 genes. Conclusion: Sequencing of the coding regions of the PRSS1, SPINK1, CTRC, CFTR, and CPA1 genes allowed to identify genetic risk factors of the CP development in 61% of cases. Determining the genetic cause of CP helps to predict the disease course, perform preventive measures in the proband's relatives, and facilitate a personalized treatment of the patient in future.

[Assessment of exo- and endocrine function of pancreas following distal pancreatectomy].

AIM: The assessment of pancreatic resection volume influence on exo- and endocrine pancreatic functions. MATERIALS AND METHODS: The resected pancreatic volume influence was assessed in 47 patients: 31 (66%) patients after resections of pancreatic body and tail, and 16 (34%) patients after distal resections. The exocrine pancreatic function was assessed by pancreatic fecal elastase 1 as well as endocrine pancreatic function was assessed by C-peptide level measurement. Computed tomography with intravenous contrast enhancement and postprocessing was used for pre- and postoperative pancreatic volume assessment. All tests were performed before and 1, 3, and 6 months after surgery. RESULTS: Type of surgery had no influence on C-peptide and pancreatic fecal elastase 1 levels (p>0.05). Exo- and endocrine pancreatic functions markers tended to decrease in 1st month after surgery with consequent functions restoration towards 6 months after surgery. There were 15 (35.7%) patients from 42 patients with normal exocrine pancreatic function with a fecal elastase 1 level decrease to 114.7±61.8 µg/g; exocrine insuficiency remained only in 2 (4.8%) patients after 6 months after surgery. C-peptide concentration decrease before surgery to less than 1.1 ng/ml was noticed only in 8 (17%) patients. C-peptide concentration decreased in 30 (63.8%) patients in 1st month after surgery, but after 6 months after surgery, C-peptide level decrease was only in 7 (14.9%) patients. CONCLUSION: The exo- and endocrine function of the pancreas is restored in more than 80% of patients after DR. Probably it could be associated with the activation of the pancreatic compensatory abilities.

Functional insufficiency of the pancreas and the metabolic activity of the microbiota in cystic fibrosis adults patients.

AIM: In order to optimize the therapy, the functional state of the pancreas (P) and the peculiarities of metabolic activity of intestinal microbiota in adults with cystic fibrosis (CF) were assessed. MATERIALS AND METHODS: 14 CF patients (20-34 years, 7 men, 7 women) were enrolled. In 8 patients, the diagnosis was confirmed in the first year of life on the basis of clinical data, positive sweat test, 5 had genetic confirmation. In 4 patients, the diagnosis was confirmed at the age of 8-13 years and 2 patients aged 18, 27 years. In this group, genetic confirmation was in 4 subjects. In addition to general clinical studies, the level of C-peptide in blood, elastase and the concentration of short chain fatty acids in feces was determined. RESULTS: Of elastase feces in 9 patients was 5.5±4.7 icg/g, that is revealed severe exocrine insufficiency of the pancreas and in 5 patients the elastase level was normal and amounted to 402±124 icg/g. Deployed the clinical picture of diabetes mellitus was observed in 3 patients. Metabolic activity of the colon microflora as a whole was reduced, the sum of the concentration of short-chain fatty acids (ΣCn) was 6.03±4.11 mg/g at a rate of 10.61±5.11 (p<0.05). At the same time, in some patients (group 1, n=9), who were at the time of the study on antibiotic therapy, the value of ΣCn was 3.32±0.33 mg/g, and in patients receiving probiotic drugs (group 2, n=5), the activity of microflora did not differ from the norm ((ΣCn=11.03±2.01 mg/g). The correlation dependence of the ratio of the total iso-acids fraction in patients with MV to the normal values and the level of fecal elastase (r= -0.46, p=0.049) was revealed. CONCLUSION: Most patients with CF (64%) diagnosed with exocrine pancreatic insufficiency severe according elastase stool. The activity of faecal elastase correlated with parameters of microbiocenosis, which indicates the necessity of correction is not only functional insufficiency of the pancreas, but also the state of the microbiota.

Russian consensus on exo- and endocrine pancreatic insufficiency after surgical treatment.

The Russian consensus on exo- and endocrine pancreatic insufficiency after surgical treatment was prepared on the initiative of the Russian "Pancreatic Club" on the Delphi method. His goal was to clarify and consolidate the opinions of specialists on the most relevant issues of diagnosis and treatment of exo- and endocrine insufficiency after surgical interventions on the pancreas. An interdisciplinary approach is provided by the participation of leading gastroenterologists and surgeons.

[The Russian consensus on the diagnosis and treatment of chronic pancreatitis: Enzyme replacement therapy]. / Rossiiskii konsensus po diagnostike i lecheniiu khronicheskogo pankreatita: zamestitel'naia fermentnaia terapiia.

Pancreatology Club Professional Medical Community, 1A.S. Loginov Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow; 2A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia, Moscow; 3Kazan State Medical University, Ministry of Health of Russia, Kazan; 4Kazan (Volga) Federal University, Kazan; 5Far Eastern State Medical University, Ministry of Health of Russia, Khabarovsk; 6Morozov City Children's Clinical Hospital, Moscow Healthcare Department, Moscow; 7I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia, Saint Petersburg; 8Siberian State Medical University, Ministry of Health of Russia, Tomsk; 9M.F. Vladimirsky Moscow Regional Research Clinical Institute, Moscow; 10Maimonides State Classical Academy, Moscow; 11V.I. Razumovsky State Medical University, Ministry of Health of Russia, Saratov; 12I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow; 13S.M. Kirov Military Medical Academy, Ministry of Defense of Russia, Saint Petersburg; 14Surgut State Medical University, Ministry of Health of Russia, Surgut; 15City Clinical Hospital Five, Moscow Healthcare Department, Moscow; 16Nizhny Novgorod Medical Academy, Ministry of Health of Russia, Nizhny Novgorod; 17Territorial Clinical Hospital Two, Ministry of Health of the Krasnodar Territory, Krasnodar; 18Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia, Saint Petersburg; 19Rostov State Medical University, Ministry of Health of Russia, Rostov-on-Don; 20Omsk Medical University, Ministry of Health of Russia, Omsk; 21Russian Medical Academy of Postgraduate Education, Ministry of Health of Russia, Moscow; 22Novosibirsk State Medical University, Ministry of Health of Russia, Novosibirsk; 23Stavropol State Medical University, Ministry of Health of Russia, Stavropol; 24Kemerovo State Medical University, Ministry of Health of Russia, Kemerovo; 25N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow; 26A.M. Nikiforov All-Russian Center of Emergency and Radiation Medicine, Russian Ministry for Civil Defense, Emergencies and Elimination of Consequences of Natural Disasters, Saint Petersburg; 27Research Institute for Medical Problems of the North, Siberian Branch, Russian Academy of Sciences, Krasnoyarsk; 28S.P. Botkin City Clinical Hospital, Moscow Healthcare Department, Moscow; 29Tver State Medical University, Ministry of Health of Russia, Tver The Russian consensus on the diagnosis and treatment of chronic pancreatitis has been prepared on the initiative of the Russian Pancreatology Club to clarify and consolidate the opinions of Russian specialists (gastroenterologists, surgeons, and pediatricians) on the most significant problems of diagnosis and treatment of chronic pancreatitis. This article continues a series of publications explaining the most significant interdisciplinary consensus statements and deals with enzyme replacement therapy.

[Duodenal dystrophy: An interdisciplinary problem].

Duodenal dystrophy (DD) is the pathological change in the wall of the duodenum, which is caused by chronic inflammation in its ectopic pancreatic tissue. The most common complications of DD are acute or chronic pancreatitis and impaired duodenal patency, which along with severe pain are an indication for surgical treatment. Pancreaticoduodenal resection is recognized as the operation of choice. The paper describes a clinical case demonstrating the efficiency and safety of minimally invasive (laparoscopic) surgical technologies in this category of patients. Resectional interventions of this volume are also shown to be accompanied by the development of pancreatic insufficiency that necessitates continuous enzyme replacement therapy.

[Seronegative celiac disease: A case report].

The paper describes a rare case of celiac disease in the absence of serum anti-tissue transglutaminase (anti-tTG) antibodies. A 51-year-old patient has been suffering from diarrheas for 20 years. He has lost 15 kg gradually; weakness progressed; muscle cramps, leg edemas, and signs of dynamic pseudoobstruction appeared. Morphological examination revealed small intestinal mucosal (SIM) villous atrophy (Marsh IIIC stage). IgA anti-tTG and IgG anti-tTG antibodies were 0.086 and 0.178, respectively. The patient was prescribed a gluten-free diet, water electrolyte solutions to correct metabolic disturbances, and prednisolone. During a control examination after 6 months, the patient had no complaints and gained 22 kg, and the SIM villus height was increased. The specific feature of the case is specific negative serological tests for celiac disease.

COMPARATIVE RESEARCH OF EFFICACY OF MONOTHERAPY WITH UDCA AND THE COMBINATION OF UDCA GIMEKROMONOM C IN PATIENTS WITH BILIARY SLUDGE2 STAGES.

Aim of research: Evaluate clinical advantages of combined therapy using Ursodeoxycholic acid (UDCA) with spasmolytic of patients with second stage biliary sludge (BS) - in a form of echo-heterogeneous bile containing clots. MATERIALS AND METHODS: 42 patients with 2nd stage BS were examined. 1st group (21 patients) was treated by UDCA monotherapy, 2,d group (21 patients) received combined therapy: UDCA with Hymecromone for 4 weeks. 4 week later, clinical and echographical assessment of the therapy provided was conducted. RESULTS: patients who received the combined therapy had more expressed decrease of pain syndrome in the right hypochondrium than those who received the monotherapy. During the study of gallbladder contraction function (GCF) any reliable evidence of its change wasn't found in both groups, thus the combined therapy (UDCA + Hymecromone) does not increase GCF. According to ultrasonography, an improvement of gallbladder content (transition from the 2nd stage BS to the 1st and reduction of an amount and size of clots and suspension) was observed in 81% patients from the Ist group (UDCA), and in 95% patients from the 2nd group (UDCA + Hymecromone). CONCLUSION: research data show increased effectiveness of treatment of patients with 2nd stage BS while using the combi- nation of UDCA and Hymecromone.

[Shwachman-Diamond syndrome].

Shwachman-Diamond syndrome is an inherited autosomal recessive disease that appears as exocrine pancreatic insufficiency, neutropenia, impaired neutrophil chemotaxis, aplastic anemia, thrombocytopenia, metaphyseal dysplasia, and physical retardation. Its worldwide prevalence is 1:10,000 to 1:20,000 live births depending on the region. The SBDS gene and a few mutations, which lead to this syndrome, have been found in the past decade. The paper describes a case of this rare disease in a 28-year-old male patient who has all characteristic manifestations as lipomatosis and severe exocrine pancreatic insufficiency, neutropenia with bone marrow hypoplasia, physical retardation, glucose intolerance, secondary osteopenia, and minor cardiac anomalies. Its clinical diagnosis was verified by molecular genetic testing.

[Diagnostic difficulties and remission criteria of autoimmune pancreatitis].

The paper describes a clinical case in a 56-year-old female patient who has been suffering from chronic autoimmune pancreatitis, chronic recurrent cholangitis for 3 years. It demonstrates diagnostic difficulties at the early stage of the disease, the specific features of its course, the sequence of treatment in the patient, and problems in choosing a therapy option to achieve a remission.

[Correction of atherogenic dyslipidemia with honey, pollen and bee bread in patients with different body mass].

AIM: To assess efficacy of treatment of patients with atherogenic dyslipidemia (ADL) with beekeeping products (honey, pollen, bee bread). MATERIAL AND METHODS: ADL parameters were examined in 157 patients (64 males and 93 females) aged 39 to 72 (mean age 61,7 + 8,5 years) with ADL. Products of beekeeping were given in the absence of allergy and individual resistance to honey, pollen, bee bread. The patients were divided into four groups: patients on hypolipidemic diet only, on diet and honey or pollen, on bee bread, combined treatment - diet, honey, pollen. RESULTS: A significant hypolipidemic effect was registered in patients taking honey in combination with pollen (total cholesterol decreased by 18,3 %, LDLP cholesterol by 23,9 %) and bee bread (total cholesterol decreased by 15,7 %, LDLP cholesterol by 20,5 %). CONCLUSION: Improvement of blood lipid composition in taking honey and pollen in overweight (body mass index - BMI 25 - 30) and obese (BMI over 30) patients occurs only in loss of body mass.

[Biliary pancreatitis].

It is provided the basic information of the etiopathogenesis, diagnosis of biliary pancreatitis, drug treatment of patients with holetsistolitiaz, and the information of biliary pancreatitis's prevention.

[Structure, biological properties of honey, pollen and royal jelly and their possible use in nutrition therapy].

There is a description of chemical composition beekeeping's products: honey, pollen and royal jelly in this article. Biological effects of their separate ingredients have been analyzed and problems of their application in food for treatment have been considered on evidence derived from the scientific literature.

[Influence of honey, royal jelly and propolis on accelerating acetate healing of experimental gastric ulcers in rats].

This study examines gastric acetic ulcer healing in the rat after administration of honey, royal jelly and propolis into the stomach. Chronic gastric ulcers were induced in male Wistar rats by the application of 100% acetic acid to the serosal surface of the stomach on 60 sec. Bee-keeping products were administrated into the stomach from 2nd to 7th day after acetic ulcer induction. On 7th day animals were killed, and ulcer area was measured in mm2. In gastric juice pH and activity of pepsin were measured. The healing of acetic ulcers is accelerated with the administration of honey, royal jelly or propolis during six days. The largest healing effect was demonstrated with propolis and royal jelly, smaller one with the honey. It was revealed decrease of stomach acid secretion in the rats, which have received bee-keeping products versus the rats of control group.

[Products of bee-keeping and prophylaxis of premature aging].

Natural bee honey is one of compound natural products in which structure more than four hundred various components are revealed, including enzymes, organic acids, vitamins and microelements. One of the basic biological properties of honey is the ability to slow down processes of aging, because there are vitamins E, C, enzymes with antioxidative properties and a succinic acid in its structure. Examination of 193 beekeepers daily using honey in quantity of 57.2 +/- 8.6 gram with definition of their biological age was carried out. The received results have been compared to results of examination of 35 workers who are doing manual labour in the same degree, as the beekeepers, but do not use products of beekeeping. The research has shown that the biological age of 70% of beekeepers is lower than that of the average in population, 15% of beekeepers are of the same and 15% are of higher biological age than that of the average in population. The biological age of people in the group of comparison is lower than the average in population only in 28.6% of cases, corresponds in 31.4% and is higher than the average in population in 40.0% of cases. The biological age of beekeepers appeared not only less, than of the persons who are not using products of beekeeping, but it also is less than biological age of the population as a whole.