New insights into the pathogenesis of primary biliary cholangitis asymptomatic stage.

Primary biliary cholangitis (PBC) is a chronic cholestatic progressive liver disease and one of the most important progressive cholangiopathies in adults. Damage to cholangiocytes triggers the development of intrahepatic cholestasis, which progresses to cirrhosis in the terminal stage of the disease. Accumulating data indicate that damage to biliary epithelial cells [(BECs), cholangiocytes] is most likely associated with the intracellular accumulation of bile acids, which have potent detergent properties and damaging effects on cell membranes. The mechanisms underlying uncontrolled bile acid intake into BECs in PBC are associated with pH change in the bile duct lumen, which is controlled by the bicarbonate (HCO3-) buffer system "biliary HCO3- umbrella". The impaired production and entry of HCO3- from BECs into the bile duct lumen is due to epigenetic changes in expression of the X-linked microRNA 506. Based on the growing body of knowledge on the molecular mechanisms of cholangiocyte damage in patients with PBC, we propose a hypothesis explaining the pathogenesis of the first morphologic (ductulopenia), immunologic (antimitochondrial autoantibodies) and clinical (weakness, malaise, rapid fatigue) signs of the disease in the asymptomatic stage. This review focuses on the consideration of these mechanisms.

Helicobacter pylori: Commensal, symbiont or pathogen?

This review considers the data on Helicobacter pylori (H. pylori), which have been accumulated over 40 years since its description as an etiological factor in gastrointestinal diseases. The majority of modern publications are devoted to the study of the pathogenic properties of the microorganism in the development of chronic gastritis, peptic ulcer disease, and gastric cancer, as well as methods for its eradication. However, in recent years, there have been more and more studies which have suggested that H. pylori has a beneficial, or potentially positive, effect on the human body. The authors have attempted to objectively analyze the information accumulated in the literature on H. pylori. Some studies consider it as one of the recently identified human bacterial pathogens, and special attention is paid to the evidence suggesting that it is probably part of the composition of the human microbiome as a commensal (commensal from French to English is a table companion) or even a symbiont. The presented data discussing the presence or absence of the effect of H. pylori on human health suggest that there is an apparent ambiguity of the problem. The re-assessment of the data available on H. pylori infection is important in order to answer the question of whether it is necessary to create a program of mass H. pylori eradication or to apply a more personalized approach to treating patients with H. pylori-associated gastrointestinal diseases and to perform eradication therapy.

Significance of dormant forms of Helicobacter pylori in ulcerogenesis.

Nearly half of the global population are carriers of Helicobacter pylori (H. pylori), a Gram-negative bacterium that persists in the healthy human stomach. H. pylori can be a pathogen and causes development of peptic ulcer disease in a certain state of the macroorganism. It is well established that H. pylori infection is the main cause of chronic gastritis and peptic ulcer disease (PUD). Decontamination of the gastric mucosa with various antibiotics leads to H. pylori elimination and longer remission in this disease. However, the reasons for repeated detection of H. pylori in recurrent PUD after its successful eradication remain unclear. The reason for the redetection of H. pylori in recurrent PUD can be either reinfection or ineffective anti-Helicobacter therapy. The administration of antibacterial drugs can lead not only to the emergence of resistant strains of microorganisms, but also contribute to the conversion of H. pylori into the resting (dormant) state. The dormant forms of H. pylori have been shown to play a potential role in the development of relapses of PUD. The paper discusses morphological H. pylori forms, such as S-shaped, C-shaped, U-shaped, and coccoid ones. The authors proposes the classification of H. pylori according to its morphological forms and viability.

Primary biliary cirrhosis: Clinical and laboratory criteria for its diagnosis.

Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic granulomatous, and destructive inflammatory lesion of small intralobular and septal bile ducts, which is likely to be caused by an autoimmune mechanism with a the presence of serum antimitochondrial antibodies and a potential tendency to progress to cirrhosis. Despite the fact that the etiology of this disease has been unknown so far, there has been a considerable body of scientific evidence that can reveal the clinical and laboratory signs of PBC and the individual components of its pathogenesis and elaborate diagnostic criteria for the disease and its symptomatic therapy. Deficiencies in autoimmune tolerance are critical factors for the initiation and perpetuation of the disease. The purpose of this review is to summarize the data available in the literature and the author's findings on clinical and laboratory criteria for the diagnosis of PBC. This review describes the major clinical manifestations of the disease and the mechanisms of its development. It presents the immunological, biochemical, and morphological signs of PBC and their significance for its diagnosis. A great deal of novel scientific evidence for the problem of PBC has been accumulated. However, the inadequate efficiency of therapy for the disease lends impetus to the quest for its etiological factors and to further investigations of its pathogenetic mechanisms and, on this basis, to searches for new methods for its early diagnosis.

Physiological and molecular biochemical mechanisms of bile formation.

This review considers the physiological and molecular biochemical mechanisms of bile formation. The composition of bile and structure of a bile canaliculus, biosynthesis and conjugation of bile acids, bile phospholipids, formation of bile micellar structures, and enterohepatic circulation of bile acids are described. In general, the review focuses on the molecular physiology of the transporting systems of the hepatocyte sinusoidal and apical membranes. Knowledge of physiological and biochemical basis of bile formation has implications for understanding the mechanisms of development of pathological processes, associated with diseases of the liver and biliary tract.

Concept of the pathogenesis and treatment of cholelithiasis.

Gallstone disease (GD) is a chronic recurrent hepatobiliary disease, the basis for which is the impaired metabolism of cholesterol, bilirubin and bile acids, which is characterized by the formation of gallstones in the hepatic bile duct, common bile duct, or gallbladder. GD is one of the most prevalent gastrointestinal diseases with a substantial burden to health care systems. GD can result in serious outcomes, such as acute gallstone pancreatitis and gallbladder cancer. The epidemiology, pathogenesis and treatment of GD are discussed in this review. The prevalence of GD varies widely by region. The prevalence of gallstone disease has increased in recent years. This is connected with a change in lifestyle: reduction of motor activity, reduction of the physical load and changes to diets. One of the important benefits of early screening for gallstone disease is that ultrasonography can detect asymptomatic cases, which results in early treatment and the prevention of serious outcomes. The pathogenesis of GD is suggested to be multifactorial and probably develops from complex interactions between many genetic and environmental factors. It suggests that corticosteroids and oral contraceptives, which contain hormones related to steroid hormones, may be regarded as a model system of cholelithiasis development in man. The achievement in the study of the physiology of bile formation and the pathogenesis of GD has allowed expanding indications for therapeutic treatment of GD.

Hepatitis G virus.

A number of new hepatitis viruses (G, TT, SEN) were discovered late in the past century. We review the data available in the literature and our own findings suggesting that the new hepatitis G virus (HGV), disclosed in the late 1990s, has been rather well studied. Analysis of many studies dealing with HGV mainly suggests the lymphotropicity of this virus. HGV or GBV-C has been ascertained to influence course and prognosis in the HIV-infected patient. Until now, the frequent presence of GBV-C in coinfections, hematological diseases, and biliary pathology gives no grounds to determine it as an "accidental tourist" that is of no significance. The similarity in properties of GBV-C and hepatitis C virus (HCV) offers the possibility of using HGV, and its induced experimental infection, as a model to study hepatitis C and to develop a hepatitis C vaccine.

Concept on the pathogenesis and treatment of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease that predominantly affects women and is characterized by chronic, progressive destruction of small intrahepatic bile ducts with portal inflammation and ultimately fibrosis, leading to liver failure in the absence of treatment. Little is known about the etiology of PBC. PBC is characterized by anti-mitochondrial antibodies and destruction of intra-hepatic bile ducts. The serologic hallmark of PBC is the presence of auto-antibodies to mitochondria, especially to the E2 component of the pyruvate dehydrogenase complex (PDC). Current theories on the pathogenesis of PBC favor the hypothesis that the disease develops as a result of an inappropriate immune response following stimulation by an environmental or infectious agent. Some reports suggest that xenobiotics and viral infections may induce PBC. The pathogenetic mechanism is believed to be caused by a defect in immunologic tolerance, resulting in the activation and expansion of self-antigen specific T and B lymphocyte clones and the production of circulating autoantibodies in addition to a myriad of cytokines and other inflammatory mediators. This leads to ductulopenia and persistent cholestasis, by developing end-stage hepatic-cell failure. In this review are given our own and literary data about mechanisms of development of intrahepatic cholestasis and possible ways of its correction.

Reperfusion injury after critical intestinal ischemia and its correction with perfluorochemical emulsion "perftoran".

AIM: To investigate the anti-ischemic properties of perfluorochemical emulsion "perftoran" in mesenteric region. METHODS: Experiments were conducted on 146 nonlinear white male rats weighing 200-350 g. Partial critical intestinal ischemia was induced by thorough atraumatic strangulation of 5-6 cm jejunal loop with its mesentery for 90 min. Global critical intestinal ischemia was made by atraumatic occlusion of the cranial mesenteric artery (CMA) for 90 min also. Perftoran (PF, 0.8-1.0 mL per 100 g) in experimental groups or 0.9% sodium chloride in control groups was injected at 75 min of ischemic period. Mean systemic arterial blood pressure (BP(M)) registration, intravital microscopy and morphological examination of ischemic intestine and its mesentery were performed in both groups. RESULTS: During 90 min of reperfusion, BP(M) progressively decreased to 27.3+/-7.4% after PF administration vs 38.6+/-8.0% in the control group of rats with partial intestinal ischemia (NS) and to 50.3+/-6.9% vs 53.1+/-5.8% in rats after global ischemia (NS). During the reperfusion period, full restoration of microcirculation was never registered; parts with restored blood flow had leukocyte and erythrocyte stasis and intra-vascular clotting, a typical "non-reflow" phenomenon. The reduction of mesenteric 50-400 mum feeding artery diameter was significantly less in the PF group than in the control group (24+/-5.5% vs 45.2+/-3.6%, P<0.05) 5 min after partial intestinal ischemia. This decrease progressed but differences between groups minimized at the 90(th) min of reperfusion (41.5+/-4.2% and 50.3+/-2.8%, respectively). In reperfusion of rat's intestine, a significant mucosal alteration was registered. Villous height decreased 2.5-3 times and the quantity of crypts decreased more than twice. In the group of rats administered PF, intestinal mucosal layer was protected from irreversible post-ischemic derangement during reperfusion. Saved cryptal epithelial cells were the source of regeneration of the epithelium, which began to cover renewing intestinal villi after 24 h of blood flow restoration. View of morphological alterations was more heterogeneous in CMA groups. CONCLUSION: Systemic administration of perftoran promotes earlier and more complete structural regeneration during reperfusion in rats after partial and global critical intestinal ischemia.