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.

[Clinical case of IgG4-related disease in a patient with Burkitt lymphoma].

The article provides a case of primary diagnosis of IgG4-related disease in a patient with Burkitt lymphoma.

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.

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.

[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.

[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.

[The specific features of pancreatic incretory dysfunction in chronic pancreatitis].

AIM: To reveal the specific features of pancreatogenic diabetes mellitus (DM) and to discuss the principles of its medical therapy. SUBJECTS AND METHODS: Sixty-six patients (55 men and 11 women) aged 30 to 65 years with chronic pancreatitis (CP) were examined. The disease was accompanied with pancreatic calcification and cyst formation in 22 and 13 patients, respectively; 5 patients were found to have a pseudotumorous form of CP and 10 had clinically and laboratorily verified DM. 14 resections and 11 drainages for complicated CP were performed. Its diagnosis was established on the basis of clinical, instrumental, and laboratory findings. Pancreatic exocrine function was evaluated from the results of the 13C-trioctanain breath test (BT) that is designed for its in vivo diagnosis. The level of C-peptide was studied by an enzyme immunoassay. RESULTS: The findings suggest that pancreatic exocrine function is diminished in CP patients both with and without complications as compared with the normal value in 44% (24.3 +/- 1.7 and 26.6 +/- 1.3%, respectively), as shown by BT. According to the results of BT, a substantial decrease in the total proportion of a released label was noted in patients with CP and pancreatic calcification, diabetes mellitus, after resection operations for complications of CP and there were also significant differences, as compared to a group of CP patients without complications. In these patient groups, the level of C-peptide fell to a larger extent than that in CP patients without complications and in patients with CP and DM it was decreased to 0.11 +/- 0.02 ng/ml, the normal level being 0.7-1.9 ng/ml. There was a direct correlation between C-peptide levels and BT results in the patients with CP after resection operations. Insulin antibodies were absent in all the examined patients with CP, which proves the specific type of DM in CP. These are detectable only in type 1 DM. Seven patients with CP and DM were found to have calcification, 5 underwent resection operations, 3 had calcification and underwent pancreatic resection operations. CONCLUSION: The development of DM may be predicted in CP patients with formation of pancreatic calcification and resections. In these patients, pancreatic exocrine dysfunction achieves a severe degree.

[Peculiarities of diabetes mellitus course in chronic pancreatitis].

In order to identify features of the course pancreatic diabetes and discussion of the principles of conservative therapy were examined 66 patients with CP in age of 30 to 65 years (55 men, 11 women). Among them in 22 cases disease was followed with formation of calcification of pancreas, 13 - pancreatic cysts, and 5 revealed pseudo tumor form of CP, 10 patients had clinical and laboratory evidence of diabetes. Concerning CP complicated course were performed 14 resection and 11 draining operations on the pancreas. Based on clinical, instrumental and laboratory data was made the diagnosis of CP. Exocrine pancreatic function was assessed on the results of the breath test, using 13C-trioktanaine, which is applied for exocrine pancreatic function in vivo test. The content of C-peptide was investigated by enzyme-linked immunosorbent assay (ELISA). The data indicate pancreatic exocrine function decrease in patients with CP with complications and without complications in compare with the norm of 44% (24,3 +/- 1,7, 26,6 +/- 1,3%, respectively) according to the breath test. Significant decrease of the cumulative output tags based on the test data of patients with CP and pancreatic calcification, diabetes mellitus, after resection surgery with CP complications, and there were significant differences in compare with a group of patients with CP without complications (p = 0.5). The level of C-peptide in these groups of patients decreased significantly in compare with a group of patients with CP without complications, and patients with CP and Diabetes was reduced to 0,11 +/- 0,02 ng/ml, at a rate range of 0.7-1.9 ng/ml, ie below the minimum values of norm. Obtained a direct correlation between the level of C-peptide and indicators breath test in patients after resection HP (r = 0,84, p = 0,03). Antibodies to insulin in the whole group of studied patients CPs were negative, which proves the specific type of Diabetes at HP. Antibodies to insulin can be detected only at diabetes type 1. In 7 patients with CP and CD detected calcification, 5 patients performed resection surgery, 3 patients had calcification and conducted the pancreas resection. Thus, we can conclude that in patients with CP and formation of pancreas calcification, pancreas resections may predict the development of diabetes.

[Painless course of chronic calcificated pancreatitis manifesting as hyperglycemia].

The clinical case of chronic calcifying pancreas (CCP) was described. It was reveal that obligate sign CCP as a painful syndrome can disappeared in some circumstances, in particular when the patient refused of smoking and alcohol intake.

[Autoimmune reaction component in chronic pancreatitis: clinical and experimental study].

UNLABELLED: The study was undertaken to identify the relationship between inflammatory and autoimmune processes in chronic pancreatitis and to determine the prognostic significance of autoantibodies to antigens of acinar cells and hepatocytes, immunoglobulin G1-4. MATERIALS AND METHODS: In 85 patients with CP (43 men, 42 women) were studied autoantibodies to antigens of acinar and liver cells, IgG1-4. Of these, 43 patients HP was characterized by complications (cysts, calcification, pseudotumoral form), 40 patients--HP without complications, 2 patients were diagnosed chronic autoimmune pancreatitis (CAP), confirmed histologically. 20 people-- the control group. Experimental studies on animals, reproduction of acute and chronic pancreatitis. RESULTS: Maximize the level of autoantibodies--32.4 +/- 5.6 U / ml (control--10.5 +/- 2.5 U / ml) (p < or = 0.01), as well as IgG4--24 mg/ml in normal (0.8 +/- 0.08 mg/ml)--was recorded in patients with autoimmune pancreatitis. The average value of autoantibodies--in patients with CP complications: 24.2 +/- 3.8 U/ml (p < or = 0.01). The minimum value of autoantibodies--in patients with CP without complications: 18.6 +/- 2.6 U/ml (p < or = 0.05). CONCLUSION: The course of autoimmune pancreatitis accompanied by an increase of autoantibodies to antigens of acinar and liver cells, as well as serum IgG1-4, especially IgG4, which reflects the intensity of the autoimmune responses in this disease. In addition, the exacerbation of chronic pancreatitis with complications is clearly defined autoimmune component of disease. Experimental studies with preimmunization of animals allogeneic tissues have convincingly demonstrated that the formation of antibodies is not only to the antigens, reflecting the specific characteristics of these tissues, but also to general cell structures of other tissues.

[Effect of enzyme supportive therapy of the Ermital' on a quality of life of patients with chronic pancreatitis].

The purpose of the study was to evaluate the quality of life in patients with chronic pancreatitis with the presence of complications treated conservatively and surgical treatment. With the help of a questionnaire MOS SF-36 were asked 80 patients with CP, of whom 15 patients were after the operation, the PDR, 10 patients underwent draining operations, 15 patients had a history of pancreatic necrosis, in 20 patients with CP were characterized by complications (cyst calcification, kalkulez, pseudotumoral form of HP, diabetes) and surgical interventions were not performed in 20 CPs proceeded without complications. Were obtained significant differences on all scales of the questionnaire with the control group all CP patients. Assessment of coping with pain in long-terms after various operations was revealed significantly better results and got rid of persistent pain in patients with a complicated course, who underwent surgery. 23 CP patients with a complicated course, as enzyme replacement therapy received in ermital dose of 20,000 IU lipase 3-4 times a day for 3 weeks. The assessment of quality of life before and after therapy with ermital. The intensity of pain significant changes in the groups received. On the other hand the improvement in general health, physical and social functioning.

[Computer--tomographic resecability criteria at cancer head of the pancreas].

UNLABELLED: The aim of the study was to explore the possibilities of CT in evaluating resectability of pancreatic head adenocarcinoma, depending on the tumor. MATERIALS: The results of CT and intraoperative findings in 62 patients with cancer of the head of the pancreas. RESULTS: It was shown that the tumor localized in caudal glands, had higher resectability when compared with tumors of the cranial localization at tumor sizes of 3-4 cm in size tumor less than 3 cm, the probability that radical surgery was highest in patients with central localization of the tumor.

[A cytokine status in chronic alcoholic and biliary pancreatitis].

AIM: To determine characteristics of a cytokine status in chronic pancreatitis (CP) depending on etiological factor, stage of the disease, complications, therapy. Material and methods. 72 patients had chronic alcoholic pancreatitis (CAP), 38 patients--chronic biliary pancreatitis (CBP). Control group consisted of 20 healthy subjects. RESULTS: At early stages and height of CAP exacerbation, concentrations of IL-1beta, IL-6, IL-8, TNF-gamma and TNFalpha were elevated (951.1 +/- 104.2 pg/ml; 172.8 +/- 24.3 pg/ml; 432.6 +/- 68.5 pg/ml; 823.3 +/- 97.5 pg/ml; 158.7 +/- 19.6 pg/ml, respectively). Regenerative processes in CP were accompanied with IL-4 elevation to 614.9 +/- 64.6 pg/ml. In CAP without complications and with them the levels of cytokines differed significantly. The level of TGF-beta1 stimulating development of fibrosis was in CAP patients 627.8 +/- 92.2 pg/ml, in CAP patients with complications--796.8 +/- 102.5, in the controls--40.2 +/- 4.6 pg/ml (p < 0.05). In early stages of CBP exacerbation, IL-1beta rose to 527.2 +/- 62.7 pg/ml, IL-6--to 80.9 +/- 11.4 pg/ml, IL-8--to 290.4 +/- 46.8 pg/ml, INF-gamma to 853.3 +/- 91.6 pg/ml; TNF-alpha--to 79.7 +/- 8.3 pg/ml, TGF-beta1--534.1 +/- 78.4 pg/ml. With attenuation of acute syndromes and development ofregeneration, levels of IL-4 went up (226.7 +/- 32.4 pg/ml). CONCLUSION: CP is accompanied by increase in cytokine contents depending on the etiological factor, variants of course, stage, presence of complications.

[Change of the endocrine function of the pancreas in patients with chronic pancreatitis]. / Izmenenie éndokrinnoi funktsii podzheludochnoi zhelezy u bol'nykh khronicheskim pankreatitom.

There was a study of 19 chronic pancreatitis patients (10 male and 9 female), 11 chronic pancreatitis and pancreatogenic diabetes mellitus patients (8 male and 3 female) and 12 type 2 diabetes mellitus patients (4 male and 8 female) at the age of 30-60 as well as 15 control group subjects at the same age range. The content of the C-peptide and such peptides as INCINE, PAMG-cine and PAMG-tin in the blood serum was subjected to the immunoradiometric assay. It was discovered that there is a trend to the increased C-peptide level in CP patients while the C-peptide level in CP patients with diabetes mellitus was smaller than that in the control group; the C-peptide level in CP patients with type 2 diabetes mellitus was higher as compared to that in the control group. It was shown that erythrocytes of CP patients are less sensitive to insulin action and do not respond to the presence of insulinomimetic peptides under examination during the glucose uptake test. CP patients with diabetes mellitus and type 2 diabetes mellitus patients are more sensitive to the action of insulin and peptides applied. Synthetic insulinomimetic peptides can serve as a means for discovering the functional cell deficiency under the glucose uptake test.