Important problems in the diagnosis and treatment of primary sclerosing cholangitis (based on the Russian consensus on diagnosis and treatment autoimmune hepatitis. Moscow, 2018).

The article is published based on the results of the Russian Consensus on the diagnosis and treatment of primary sclerosing cholangitis (PSC), discussed at the 44th annual Scientific Session of the CNIIG "Personalized Medicine in the Era of Standards" (March 1, 2018). The aim of the review is to highlight the current issues of classification of diagnosis and treatment of patients with PSC, which causes the greatest interest of specialists. The urgency of the problem is determined by the multivariate nature of the clinical manifestations, by often asymptomatic flow, severe prognosis, complexity of diagnosis and insufficient study of PSC, the natural course of which in some cases can be considered as a function with many variables in terms of the nature and speed of progression with numerous possible clinical outcomes. In addition to progression to portal hypertension, cirrhosis and its complications, PSC can be accompanied by clinical manifestations of obstructive jaundice, bacterial cholangitis, cholangiocarcinoma and colorectal cancer. Magnetic resonance cholangiography is the main method of radial diagnostics of PSC, which allows to obtain an image of bile ducts in an un-invasive way. The use of liver biopsy is best justified when there is a suspicion of small-diameter PSC, autoimmune cross-syndrome PSC-AIG, IgG4-sclerosing cholangitis. Currently, a drug registered to treat primary sclerosing cholangitis which can significantly change the course and prognosis of the disease does not exist. There is no unified view on the effectiveness and usefulness of ursodeoxycholic acid and its dosage in PSC. Early diagnosis and determination of the phenotype of PSC is of clinical importance. It allows to determine the tactics of treatment, detection and prevention of complications.

Important problems in the diagnosis and treatment of autoimmune hepatitis (based on the Russian consensus 2017).

The analysis of publications devoted to the Russian Consensus on the Diagnostic and Treatment of Autoimmune Hepatitis (AIH), which was considered at the 43rd annual Scientific Session of the CNIIG From Traditions to Innovation (March 4, 2017) is carried out. The presence of clear algorithms and recommendations for the diagnosis and treatment of AIH significantly help the doctor in real clinical practice, but do not exclude a personified approach to the patient.

[Myocardial injury associated with chronic hepatitis C: Clinical types and pathogenetic components]. / Porazhenie miokarda, assotsiirovannoe s khronicheskim gepatitom S: klinicheskie varianty i patogeneticheskie zven'ia.

Heart injury is one of the extrahepatic manifestations of chronic hepatitis C (CHC). The paper gives Russian and foreign authors' data on a relationship between CHC and myocardial injury. It discusses different pathogenetic components (the direct effect of the virus, immunological components), through which hepatitis C virus can induce myocarditis and cardiomyopathies in patients with CHC.

[THE INFLUENCE OF CHRONIC HEPATITIS C ON ATHEROSCLEROSIS PROGRESSION].

We analysed the data of domestic andforeign authors on the relationship between hepatitis C and atherosclerosis. The possible role of the former condition as a risk factor of atherosclerosis even in very young patients is due to the properties of hepatitis C virus, mediators of inflammation, and metabolic disorders.

[Endothelial dysfunction gene polymorphisms and the rate of liver fibrosis in chronic hepatitis C].

AIM: To assess the association of the CYBA, NOS3, and MTHFR gene polymorphisms and a rate of fibrosis progression in chronic hepatitis C (CHC). SUBJECTS AND METHODS: One hundred and nine CHC patients with the verified stage of liver fibrosis and cirrhosis at its onset were examined. The disease duration was determined in all the patients and additional risk factors of liver lesion were absent. A group of rapidly progressive fibrosis comprised 55 patients with a calculated fibrosis progression rate of 0.130 fibrosis units/year or higher and 54 patients with a progression rate of less than 0.130 fibrosis units/year were assigned to a slow fibrosis group. A compression group consisted of 299 healthy blood donors. The polymorphism of the genes under study was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The mutant TT genotype of the CYBA gene was significantly more common in the CHC patients with rapidly progressive fibrosis than in those with slowly progressive fibrosis (odds ratio for TT 9.09 at 95% confidence interval, 1.09 to 74.83; p = 0.0161). No significant differences were found in the distribution of the alleles and genotypes of the NOS3 and MTHFR genes between the groups of patients with slowly and rapidly progressive fibrosis. CONCLUSION: The findings make it possible to regard the TT genotype of the CYBA gene from the C242T locus as profibrogenic and as one of the markers of the poor course of CHC.

[A variety of extrahepatic manifestations of chronic viral hepatitis B and C: basic treatment principles].

Chronic viral hepatitides B and C are systemic diseases with a great number of extrahepatic manifestations caused by different immune abnormalities due to viral replication in and outside the liver and to the direct pathological effects of viral particles. Many of them can be the only manifestation of the infection and come to the foreground in its clinical picture, by determining the prognosis of the disease.

[Variant form of hepatic lesion: autoimmune hepatitis--primary biliary cirrhosis in patients with Sjögren's syndrome].

Two clinical observations of the variant form of hepatic lesion: autoimmune hepatitis--primary biliary cirrhosis with systemic manifestations are presented in patients with long-standing Sjogren's syndrome, one at the stage of lever cirrhosis, the other at stage F2 of fibrosis. Difficulties encountered in diagnostics and the necessity of changing the entire spectrum of autoimmune markers characteristic of Sjogren's syndrome, autoimmune hepatitis and primary biliary cirrhosis are discussed. The possibility of different forms of hepatic lesions in autoimmune hepatitis--primary biliary cirrhosis is emphasized.

[Possibilities provided by personalized therapy of chronic hepatitis C (case conference at E.M.Tareev Clinic of Nephrology, Internal and Occupational Diseases)].

The presented clinical case gave rise to discussion of the main mechanisms and factors behind the progress of chronic hepatitis C. Special emphasis is laid on the currently available possibilities of antiviral therapy and its future prospects. The efficacy of personalized treatment and approaches to its improvement are considered based on the proper preventive measures and correction of factors responsible for poor responsiveness to the treatment, in the first place metabolic disorders (obesity, hepatic steatosis).

[Hepatitis virus genotype structure in patients with chronic hepatitis C].

AIM: Studies of hepatitis C virus (HCV) genotype and subtype structure in patients with chronic hepatitis C in 3 regions of the Central federal district of Russia. MATERIALS AND METHODS: Hepatitis C virus genotype and subtype structure was determined in patients with chronic HCV infection in Moscow (1993 - 1995 and 2005), Moscow region (2008) and Vladimir region (1993 -1995, 2005-2007). HCV genotype was determined by using A. Widell et al. (1994) technique, PCR (AmpliSens diagnostic kits), Genotype C test system. RESULTS: In all studied regions and during all the time periods the first position in rating belonged to HCV 1b subtype. In 1993 - 1995 and 2005 - 2007 period changes in HCV genotype and subtype structure were registered that consisted of relative weight of 1b subtype decrease and 3a subtype increase. Subtype 1b in females with chronic hepatitis C was registered more often than in males. In Vladimir region 3a subtype in males was detected more often than in females. In males older than 30 years the first rating position belongs to 1b subtype and in males younger than 30 years--subtype 3a. In females older than 30 years in Moscow region and Vladimir region, as well as in females younger than 30 years in Vladimir region subtype 1b was detected more often, while in Moscow region HCV subtypes 1b and 3a were detected with the same rate of 47.6%. CONCLUSION: Currently there is an urgent need to include mandatory monitoring of hepatitis C virus genetic variants into the system of hepatitis C epidemiologic control in Russia. This approach will allow for a significant increase in quality of hepatitis C serological diagnostics, and can be used in the prognosis of evolution of the epidemic process of this disease.

[System manifestations of primary biliary cirrhosis].

Primary biliary cirrhosis (PBC) is characterized by high frequency of systemic extrahepatic manifestations (EHM), which often precede the development of full clinical picture of PBC and play the leading part in the clinical course of the disease, sometimes determining its prognosis. The examination of 145 PBC patients (including two men) found a frequency of EHM of 72. 4%. The majority of EHM were caused by delayed-type hypersensitivity reactions, such as Sjogren syndrome, fibrosing alveolitis, autoimmune thyroiditis, tubulointerstitial nephritis, pulmonary granulomatosis/sarcoidosis, systemic scleroderma, rheumatoid arthritis, and ulcerative colitis; immunocomplex pathology including vasculites involving blood vessels of different caliber and localization and polyneuropathy was rarer. In 24.1% of PBC patients, system EHM manifestations were the first clinical signs of the disease. In 62.8% of patients with EHM their different combinations were registered. The most frequent one was a combination of Sjogren syndrome, fibrosing alveolitis, and tubulointerstitial nephritis, which was found in 16.2% of the patients. 6 7% of the patients had a combination of four EHM - Sjogren syndrome, fibrosing alveolitis, tubulointerstitial nephritis, and autoimmune thyroiditis. A long duration of PBC (more than five years from the debut), stage IV of the disease, and the presence of the rheumatoid factor in blood serum, were risk factors of the development of system PBC manifestations. In 20% of EHM patients their symptoms prevailed in the clinical picture, thus determining the severity of the condition. Three patients died of system EHM of PBC (systemic scleroderma, pulmonary granulomatosis). Thus, PBC diagnostics must be performed with taking into account system EHM found in this category of patients.

[Spectrum, incidence and prognostic value of systemic manifestations in chronic hepatitis C of low activity].

AIM: To study the incidence and prognostic significance of extrahepatic manifestations of chronic HCV-infection with low activity of hepatic process and to specify treatment policy. MATERIAL AND METHODS: Sixty-two patients with low-active chronic hepatitis C (CHC) entered the study. Blood samples from all the patients were studied clinically, biochemically, immunologically and virusologically. In 58 patients the diagnosis was confirmed morphologically (liver tissue). RESULTS: Systemic manifestations of CHC were observed in 23 (37.1%) patients, in 12 of them they were associated with cryoglobulinemia. Most frequent was cryoglobulinemic vasculitis with skin (12.9%) and joint (9.7%) involvement, cryoglobulinemic glomerulonephritis (11.3%), arthralgia without association with cryoglobulinemia (11.3%). Independent risk factors for development of systemic disorders in CHC of low activity comprised female gender, age over 45, the disease duration and presence of cryoglobulinemia. CONCLUSION: CHC of low activity is characterized by high occurrence of systemic manifestations primarily associated with cryoglobulinemia. Renal affection with development of cryoglobulinemic glomerulonephritis is most prognostically significant.

[The rate of HCV-RNA detection in the serum, saliva, and tissue of the minor salivary glands in chronic hepatitis C with Sjogren's syndrome]. / Izuchenie chastoty vyiavleniia HCV-RNK v syvorotke, sliune i tkani malykh sliunnykh zhelez pri khronicheskom gepatite s sindromom Sjogrena.

The trial enrolled 38 patients with chronic HCV-infection and Sjogren's syndrome (mean age 44.3 +/- 13.7 years). Biopsy of the minor salivary glands (MSG) was made in 20 patients. Polymerase chain reaction was used to study 20 MSG biopsies, 38 samples of native saliva for HCV-RNA. Saliva samples were also studied for Herpes virus DNA (EBV, CMV, HHV-VI type). All the patients with VHC appeared to have signs of xerostomia, 24 (63.2%) patients had xerophthalmia. MSG pathohistological changes were found in 19 (95%) patients. In the majority of cases (86.9%) they were characterized by mild infiltration and advanced fibrosis. HCV-RNA was found in the saliva of 23 (57.5%) patients, in MSG tissue--in 9 (39.1%) patients. HCV-RNA detection in the saliva did not depend on the degree of viremia, viral RNA in MSG correlated with viral load. EBV and HHV-VI, HHV-VI only and EBV were detected only in 7 (18.4%), 10 (26.3%) and 6 (15.8%) patients, respectively. Xerostomia occurred with the same rate (26.1 and 31.3%) in patients with and without herpes viruses in the saliva. Detection rate for HCV-RNA in the saliva was not related with viremia degree. Sjogren's disease symptoms in CHC patients did not depend on the presence or absence of DNA of herpes viruses in the saliva.

[Efficacy of lamivudine in HBeAg-negative chronic hepatitis B]. / Effektivnost' lamibudina pri HBeAg-hegativnom khronocheskom gepatite B.

The necessity of the search for new drugs to treat chronic hepatitis B (CHB) is explained by the necessity to prevent hepatic cirrhosis (HC) and hepatocellular carcinoma. Treatment of HBeAg-negative CHB rests on the same principles as of HBeAg-positive one. Efficacy of nucleoside analogue lamivudin is well studied in HBeAg-positive CHB. The aim of this study was to evaluate lamivudine efficacy in therapy of HBeAg-negative CHB. Lamivudine (epivir--150 mg/day or zeffix--100 mg/day) was given for 1 year to 10 patients (5 males, 5 females, mean age 49.5 +/- 13.5). Their blood serum contained no HBeAg but contained HBeAb and HBVDNA. Chronic hepatitis was verified morphologically in 9 patients of whom 2 had HC and 2 developing HC. Moderate activity of the disease was in 4 patients, low--in 5. All the patients had a high ALT level (150 +/- 140 U/l, 60-528 U/l, high normal value 40 U/l). ALT and HBV DNA in the serum were examined by polymerase chain reaction in the course of treatment and for 6 months after its end. To the end of the treatment a complete response (absence of HBVDNA and normalization of ALT) was achieved in 8 (80%) patients. 5 (63%) of them 2-4 months after the end of the treatment had the exacerbation with appearance of HBVDNA in the serum and elevation of ALT level. A persistent response (6 months after lamivudin treatment) was in 3 (30%) patients, in 2 of them HBsAg was not detected. Lamivudin therapy is effective in HBeAg-negative CHB. In this study a high baseline level of ALT was the factor predisposing to a lasting response to treatment.

[Sjogren's syndrome in chronic hepatitis C: clinical features and diagnosis]. / Sindroma Shegrena pri khronicheskom gepatite C: kliknicheskie osobennosti i diagnostika.

AIM: To examine clinical features of Sjogren's syndrome (SS) and morphological picture of the lesser salivary glands (LSG) in chronic hepatitis C (CHC). MATERIAL AND METHODS: The examination of 42 patients with SS and chronic HCV infection (mean age 44.3 +/- 13.7 years) has detected signs of chronic hepatitis and hepatic cirrhosis, respectively, in 31 (71.4%) and 11 (26.2%) patients. "Dry syndrome" was diagnosed by criteria of European SS Study Group. LSG biopsy of the lower lip was conducted in 23 (54.7%) of 42 patients. RESULTS: The "dry" syndrome in CHC ran subclinically in 73.8% patients. Apparent symptoms of SS were seen primarily in middle-aged and aged women with CHC history over 10 years. The first signs of SS occurred in 25 (59.5%) patients 2.9 +/- 3.1 years prior to diagnosis of hepatic disease. All the patients had xerostomy. Xerophthalmia was recorded 1.5 times less frequently. In 16 (47.1%) patients with CHC "dry eye" and in 6 (17.6%) patients dry keratoconjunctivitis were detected. Pathohistological changes of LSG were diagnosed in 21 (91.3%) of 23 patients with CHC. In the majority of cases (86.9%) the glands exhibited insignificant inflammatory infiltration and advanced fibrosis. LSG in CHC is characterized by fibrosis prevalence over cell infiltration. 83.3% CHC patients had SS and other extrahepatic lesions. SS was most evident in 28.6% CHC patients with cryoglobulinemia. CONCLUSION: Registration of SS symptoms in CHC patients depends on targeted examination of patients with chronic HCV infection. The severity of the symptoms correlates directly with the infection duration and age of the patient. LSG lesions in CHC patients with SS are characterized by fibrosis pre-domination over cell infiltration.

[Assessment of survival and risk of hepatocellular carcinoma in patients with cirrhosis of mixed (viral, alcoholic) etiology]. / Otsenka vyzhivaemosti i riska razvitiia gepatotselliuliarnoi kartsinomy u bol'nykh tsirrozom pecheni sochetannoi (virusnoi, alkogol'noi) étiologii.

AIM: To determine factors affecting overall survival and risk to develop hepatocellular carcinoma (HCC) in patients with hepatic cirrhosis (HC) of mixed (viral, alcoholic) etiology. MATERIAL AND METHODS: Mono- and multi-variance analysis of prognostic effects of such factors as age of the patients, mixed infection VHB/VHC, markers of HBV replication, antibodies to nuclear antigen of HBV (HBcAb) without HBs-system in the serum ("isolated" HBcAb), duration of viral infection, alcohol intake and abuse, dilatation of the esophageal veins, some laboratory parameters were studied in 55 HC patients having at least one marker of hepatitis B virus (HBV) and/or hepatitis C virus (HCV), long history of alcohol abuse. RESULTS: It was found that risk of HCC was associated with duration of alcohol abuse and infection, mixed HBV/HCV infection, age 60 and older. Of independent significance was only duration of alcohol abuse. Lethal outcomes in HC patients in the mixed infection were due to development of HCC (36%) and HC complications (64%). Survival of the patients was less in severe dilatation of the esophageal veins, high clinicolaboratory index, low level of serum albumin, presence of "isolated" BcAb and mixed viral infection. CONCLUSION: Of the greatest prognostic efficacy in respect of survival was the model combining "isolated" HBcAb, the degree of esophageal veins dilatation and hepatitis activity.