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.

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 beenunknown 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.

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.

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.

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.

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 on the pathogenesis and treatment of primary biliarycirrhosis

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 intrahepatic 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.

Maintaining the metabolic homeostasis of Helicobacter pylori through chronic hyperglycemia in diabetes mellitus:A hypothesis

Helicobacter pylori(H.pylori)infection occurs in almost half of the world's population,most of whom are merely carriers of this microorganism.H.pylori is shown to be detected more frequently in patients with diabetes mellitus(DM)than in the general population,which is accompanied by a significantly increased risk of developing H.pylori-associated diseases.In addition,eradication therapy shows a low efficiency for H.pylori infection in patients with DM.There is a relationship between the level of chronic hyperglycemia and a higher detection rate of H.pylori as well as a lower efficiency of eradication therapy in patients with DM.The exact mechanisms of these phenomena are unknown.The authors make a hypothesis that explains the relationship between chronic hyperglycemia and the increased detection rate of H.pylori,as well as the mechanisms contributing to the improved survival of this bacterium in patients with DM during eradication therapy.

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 rain. Global critical intestinal ischemia was made by atraumatic occlusion of the cranial mesenteric artery （CMA） for 90 rain 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 rain of ischemic period. Mean systemic arterial blood pressure （BPM） registration, intravital microscopy and morphological examination of ischemic intestine and its mesentery were performed in both groups. RESULTS： During 90 min of reperfusion, BPM 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 μm 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 90th 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.

Mechanism for development of malnutrition in primary biliary cholangitis

Primary biliary cholangitis(PBC)is a chronic cholestatic liver disease that is associated with impaired biliary excretion processes.Along with the development of cholestasis,there is a deficient flow of bile acids into the intestinal lumen causing malnutrition(MN)that is manifested in deficiencies of both macro-and micronutrients.The mechanism for development of trophological insufficiency is multifactorial.However,the trigger of MN in PBC is impaired enterohepatic circulation of bile acids.The ingress of bile acids with a detergent effect into the general bloodstream,followed by elimination via the kidneys and skin,triggers a cascade of metabolic disturbances,which leads to the gradual development and progression of calorie MN.The latter gradually transforms into protein-calorie MN(PСM)(as marasmus)due to the insufficient entry of bile acids into the duodenum,which is accompanied by a decrease in the emulsification,hydrolysis,and absorption of fats and fat-soluble vitamins,as well as disturbance of intestinal motility and bacterial overgrowth.Fat-soluble vitamin deficiencies complement PСM with vitamin and mineral MN.The development of hepatocellular failure enhances the progression of PСM due to the impaired protein synthetic function of hepatocytes in the advanced stage of PBC,which results in deficiency of not only the somatic but also the visceral pool of proteins.A mixed PСM form of marasmus and kwashiorkor develops.Early recognition of energy,protein,micronutrient,and macronutrient deficiencies is of great importance because timely nutritional support can improve liver function and quality of life in patients with PBC.In this case,it is important to know what type(energy,proteincalorie,vitamin,and vitamin-mineral)and form(marasmus,marasmuskwashiorkor)of MN is present in the patient and how it is associated with the stage of the disease.Therefore,it is recommended to screen all patients with PBC for MN,from the early asymptomatic stage of the disease in order to identify and avoid preventable complications,such as fatigue,malaise,performance decrement,sarcopenia,osteoporosis,and hepatic encephalopathy,which will be able to provide appropriate nutritional support for correction of the trophological status.