Development Of Severe Liver Disease Research Articles

Autophagy and Senescence: The Molecular Mechanisms and Implications in Liver Diseases

The liver is the primary organ accountable for complex physiological functions, including lipid metabolism, toxic chemical degradation, bile acid synthesis, and glucose metabolism. Liver function homeostasis is essential for the stability of bodily functions and is involved in the complex regulation of the balance between cell proliferation and cell death. Cell proliferation-halting mechanisms, including autophagy and senescence, are implicated in the development of several liver diseases, such as cholestasis, viral hepatitis, nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Among various cell death mechanisms, autophagy is a highly conserved and self-degradative cellular process that recycles damaged organelles, cellular debris, and proteins. This process also provides the substrate for further metabolism. A defect in the autophagy machinery can lead to premature diseases, accelerated aging, inflammatory state, tumorigenesis, and cellular senescence. Senescence, another cell death type, is an active player in eliminating premalignant cells. At the same time, senescent cells can affect the function of neighboring cells by secreting the senescence-associated secretory phenotype and induce paracrine senescence. Autophagy can promote and delay cellular senescence under different contexts. This review decodes the roles of autophagy and senescence in multiple liver diseases to achieve a better understanding of the regulatory mechanisms and implications of autophagy and senescence in various liver diseases.

Phenotype and fate of liver-resident CD8 T cells during acute and chronic hepacivirus infection.

Immune correlates of hepatitis C virus (HCV) clearance and control remain poorly defined due to the lack of an informative animal model. We recently described acute and chronic rodent HCV-like virus (RHV) infections in lab mice. Here, we developed MHC class I and class II tetramers to characterize the serial changes in RHV-specific CD8 and CD4 T cells during acute and chronic infection in C57BL/6J mice. RHV infection induced rapid expansion of T cells targeting viral structural and nonstructural proteins. After virus clearance, the virus-specific T cells transitioned from effectors to long-lived liver-resident memory T cells (TRM). The effector and memory CD8 and CD4 T cells primarily produced Th1 cytokines, IFN-γ, TNF-α, and IL-2, upon ex vivo antigen stimulation, and their phenotype and transcriptome differed significantly between the liver and spleen. Rapid clearance of RHV reinfection coincided with the proliferation of virus-specific CD8 TRM cells in the liver. Chronic RHV infection was associated with the exhaustion of CD8 T cells (Tex) and the development of severe liver diseases. Interestingly, the virus-specific CD8 Tex cells continued proliferation in the liver despite the persistent high-titer viremia and retained partial antiviral functions, as evident from their ability to degranulate and produce IFN-γ upon ex vivo antigen stimulation. Thus, RHV infection in mice provides a unique model to study the function and fate of liver-resident T cells during acute and chronic hepatotropic infection.

Lippia javanica (Burm. F.) Herbal Tea: Modulation of Hepatoprotective Effects in Chang Liver Cells via Mitigation of Redox Imbalance and Modulation of Perturbed Metabolic Activities.

Introduction: Hepatic oxidative injury is one of the pathological mechanisms that significantly contributes to the development of several liver diseases. In the present study, the hepatoprotective effect of Lippia javanica herbal tea was investigated in Fe2+- mediated hepatic oxidative injury. Methods: Using an in vitro experimental approach, hepatic oxidative injury was induced by co-incubating 7mM FeSO4 with Chang liver cells that have been pre-incubated with or without different concentrations (15-240μg/mL) of L. javanica infusion. Gallic acid and ascorbic acid served as the standard antioxidants. Results: The infusion displayed a reducing antioxidant activity in ferric-reducing antioxidant power (FRAP) assay and a potent scavenging activity on 2,2-diphenyl-2- picrylhydrazyl (DPPH) radical. Pretreatment with L. javanica infusion significantly elevated the levels of reduced glutathione and non-protein thiol, and the activities of superoxide dismutase (SOD) and catalase, with concomitant decrease in hepatic malondialdehyde levels, acetylcholinesterase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glycogen phosphorylase and lipase activities. The infusion showed the presence of phytoconstituents such as phenolic compounds, tannins, phenolic glycosides and terpenoids when subjected to liquid chromatography-mass spectrometry analysis. Molecular docking revealed a strong binding affinity of dihydroroseoside and obacunone with both SOD and catalase compared to other phytoconstituents. Conclusion: These results portray a potent antioxidant and hepatoprotective effect of L. javanica, which may support the local usage of the herbal tea as a prospective therapeutic agent for oxidative stress-related liver diseases.

Attribution of diabetes to the development of severe liver disease in the general population.

Diabetes is associated with advanced liver disease and predicts mortality regardless of the primary aetiology of the liver disease. Even a family history of diabetes has been linked to advanced liver fibrosis in non-alcoholic fatty liver disease (NAFLD). However, the fraction of liver-related outcomes in the general population that are attributable to diabetes remains unclear. The population attributable fraction (PAF) of diabetes for liver disease as a time-dependent exposure was estimated in the Finnish FINRISK study (n=28 787) and the British Whitehall II study (n=7855). We also assessed the predictive ability of a family history of diabetes for liver-related outcomes. Incident diabetes data were from drug purchase/reimbursement and healthcare registries (FINRISK) or follow-up examinations (Whitehall II). Incident severe liver outcomes were identified through linkage with national healthcare registries. Diabetes was associated with a two-fold risk of liver-related outcomes in both the FINRISK (HR, 1.92; p< .001) and Whitehall II (HR, 2.37; p< .001) cohorts, and this remained significant after adjusting for multiple confounders. PAF analyses demonstrated that diabetes explained 12-14% of the risk for severe liver-related outcomes after 10 and 20 years of follow-up. Also, maternal diabetes increased the risk of liver-related outcomes in the FINRISK (HR, 1.43; p= .044) and Whitehall II (HR, 2.04; p= .051) cohorts. Approximately 12%-14% of severe liver-related outcomes are attributable to diabetes at the population level. The association between maternal diabetes and liver disease might suggest a mitochondrial genetic mechanism.

Inborn and acquired risk factors for severe liver disease in Europeans with type 2 diabetes from the UK Biobank

Background & AimsType 2 diabetes is a major driver of fatty liver disease and its long-term complications. The aim of this study was to investigate the individual contribution of inborn and acquired risk factors for severe liver disease in individuals with type 2 diabetes from the UK Biobank study.MethodsA total of 22,812 UK Biobank participants of European descent without clinical history of liver disease and liver cancer were prospectively followed for the development of severe liver disease, defined as a composite diagnosis of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation from the National Health Service records. The contribution of inborn and acquired risk factors to the risk of incident severe liver disease was assessed by Cox proportional hazards models.ResultsDuring a median follow-up of 8.9 years (IQR 8.1–9.6), there were 279 individuals with severe liver disease, including 255 with cirrhosis and/or decompensated liver disease, 47 with hepatocellular carcinoma, and 5 with liver transplantation; death from severe liver disease occurred in 83 individuals. Risk factors independently associated with increased risk of incident severe liver disease included abnormal aspartate aminotransferase (adjusted hazard ratio [aHR] 4.85, 95% CI 2.76–8.54), decrease in serum albumin (aHR 2.39, 95% CI 1.76–3.24) and platelet count (aHR 1.12, 95% CI 1.09–1.16), cardiovascular disease (aHR 1.86, 95% CI 1.23–2.79), microalbuminuria (aHR 1.55, 95% CI 1.04–2.30), PNPLA3 rs738409 (aHR 1.67, 95% CI 1.27–2.18) and TM6SF2 rs58542926 (aHR 1.63, 95% CI 1.12–2.39), while the net effect of male sex was protective (aHR 0.49, 95% CI 0.26–0.94).ConclusionsThese findings may help in clinical care to identify individuals with type 2 diabetes at risk of severe liver disease, in turn leading to personalised risk prediction and prevention strategies.Lay summaryType 2 diabetes is a key driver of severe liver disease, namely cirrhosis, hepatocellular carcinoma, and liver-related mortality. In Europeans with type 2 diabetes from the prospective UK Biobank study, abnormal liver function, cardiovascular disease, microalbuminuria, and genetic variants in PNPLA3 and TM6SF2 genes are the major independent risk factors for severe liver disease. These findings may contribute in clinical care to identify and closely monitor individuals with type 2 diabetes at risk of developing severe liver disease, requiring more intensive follow-up strategies.

Evaluation of Hepatic Complications for High Dose Methotrexate in Children: 10 Years after Treatment of Malignancy

Background Methotrexate is a chemotherapy drug used in high doses to treat malignancies that can lead to serious liver damage, especially cirrhosis in a dose-dependent manner. We aimed to evaluate the hepatic complications, 10 years after treating children with hematologic malignancies by high-dose Methotrexate regimen. Materials and Methods: In a descriptive-analytical study, all children with hematologic malignancies who received high-dose methotrexate for treating cancer and who were hospitalized in Tabriz Children’s Hospital, Tabriz, Iran, from 2008 to 2009 were included. Demographic data were extracted from medical records. Liver enzyme tests, ultrasonography, as well as a Doppler ultrasound of the portal vein were performed for all participants in the Tabriz Children’s Hospital. Data were analyzed using descriptive statistics. The Chi-Square test was used to examine the relationship between variables using SPSS software version 22.0. Results: Out of 30 patients, 18 cases (60%) were boys and 23 (76.67%) of patients had Acute Lymphoblastic Leukemia. ALT, Total BILL, and Direct BILL levels were increased by 13.33%, 13.33%, and 10% of cases, respectively. AST, PT, and PTT levels were normal in all patients. The liver and spleen spans were larger than normal in 26.67% and 40% of cases, respectively and 5 patients (16.67%) had grade 1 fatty liver. Port vein diameter was normal in all patients. Conclusion Based on the results of the study, it is possible to consider the long-term safety of high dose Methotrexate in terms of the development of severe liver disease following treating malignancies in children. However, patient follow-up is recommended to identify complications for years after discontinuing treatment.

Effects of Gut Metabolites and Microbiota in Healthy and Marginal Livers Submitted to Surgery.

Microbiota is defined as the collection of microorganisms within the gastrointestinal ecosystem. These microbes are strongly implicated in the stimulation of immune responses. An unbalanced microbiota, termed dysbiosis, is related to the development of several liver diseases. The bidirectional relationship between the gut, its microbiota and the liver is referred to as the gut–liver axis. The translocation of bacterial products from the intestine to the liver induces inflammation in different cell types such as Kupffer cells, and a fibrotic response in hepatic stellate cells, resulting in deleterious effects on hepatocytes. Moreover, ischemia-reperfusion injury, a consequence of liver surgery, alters the microbiota profile, affecting inflammation, the immune response and even liver regeneration. Microbiota also seems to play an important role in post-operative outcomes (i.e., liver transplantation or liver resection). Nonetheless, studies to determine changes in the gut microbial populations produced during and after surgery, and affecting liver function and regeneration are scarce. In the present review we analyze and discuss the preclinical and clinical studies reported in the literature focused on the evaluation of alterations in microbiota and its products as well as their effects on post-operative outcomes in hepatic surgery.

Pathogenesis and pathways: nonalcoholic fatty liver disease &amp; alcoholic liver disease

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) account for the majority of hepatic morbidity and deaths due to cirrhosis in the United States. ALD is an umbrella term for a number of conditions linked to excessive alcohol consumption including simple steatosis, cirrhosis, acute alcoholic hepatitis (AH) with or without cirrhosis, and hepatocellular carcinoma (HCC) as a complication of cirrhosis. Although it presents with histological features resembling alcohol-induced liver injury, NAFLD occurs in patients with little or no history of alcohol consumption. NAFLD is a broad-spectrum term used to describe anything from fat accumulation in hepatocytes without inflammation or fibrosis (simple hepatic steatosis) to hepatic steatosis with a necroinflammatory component (steatohepatitis) with or without associated fibrosis. The pathogenesis is not fully understood for either disease. Development of severe liver disease is highly variable amongst chronic abusers of alcohol. Sex, age, genetics, host microbiome, and behavior are all factors linked to the development of ALD. These factors also contribute to NAFLD, but by contrast, insulin resistance is widely believed to be the main driver of nonalcoholic hepatic steatosis. The mechanism behind the transition from nonalcoholic steatosis to steatohepatitis remains a matter of debate with insulin resistance, oxidative injury, hepatic iron, gut hormones, antioxidant deficiency, and host microbiome all suspected to play part of the role.

Distribution of hepatitis B virus genotypes in the general population of Myanmar via nationwide study

BackgroundHepatitis B virus (HBV) infections are a severe health concern worldwide. HBV is a DNA virus with a rapid rate of mutation. Based on heterogeneity of the nucleotide sequence, the HBV strains are divided into nine genotypes, each with a characteristic geographical distribution. Identifying and tracking alterations of HBV genotypes is important in epidemiological and transmission studies, and contributes to predicting the risk for development of severe liver disease and response to antiviral treatment. The present study was undertaken to detect HBV genotypes and sub-genotypes in the general population of different states and regions in Myanmar.MethodsIn 2015, a total of 5547 adults of the general population, residing in seven states, seven regions and the Nay Pyi Taw Union Territory, were screened for Hepatitis B Surface antigen (HBsAg) by the immunochromatographic test (ICT). Of the 353 HBsAg positive samples, the HBVDNA was identified using polymerase chain reactions (PCR) targeting the DNA sequences encoding the Pre-S region. A total of 153 PCR positive samples were subsequently subjected to genotyping by partial genome sequencing in both directions. The resulting sequences were then edited, aligned, and compared with reference sequences using the National Centre for Biotechnology Information (NCBI) web-based genotyping tool.ResultsThree HBV genotypes (HBV genotype B, genotype C and genotype D) were detected in Myanmar, of which genotype HBV genotype C (66.7%) was the most prevalent, followed by HBV genotype D (32%) and HBV genotype B (1.3%). Sub-genotyping revealed a total of 7 variants within the B, C and D genotypes: 2 (B4 and B5) in HBV genotype B, 3 (C1, C5 and C7) in HBV genotype C, and 2 (D3 and D6) in HBV genotype D.ConclusionHBV genotype C, sub-genotype C1 was predominantly distributed in all states and regions of Myanmar. This study is the first report on the nationwide distribution of HBV genotypes and sub-genotypes in Myanmar. We believe our findings will enable huge support for the hepatitis disease surveillance program, since HBV infection is one of the National Priority Diseases in Myanmar.

Adlay Seed (Coix lacryma-jobi L.) Extracts Exhibit a Prophylactic Effect on Diet-Induced Metabolic Dysfunction and Nonalcoholic Fatty Liver Disease in Mice.

Nonalcoholic fatty liver disease (NAFLD) is common worldwide and closely associated with metabolic dysfunction. NAFLD leads to a higher risk of development of severe liver diseases, such as nonalcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma (HCC). To date, no pharmacotherapy targeting NAFLD has received general approval. Adlay is a plant that has been used as traditional herbal medicine in Asia and is a promising candidate to solve this global issue. We have established a mouse model of NAFLD by feeding a high-fat diet (HFD) for 10 weeks. Here, ethanolic or water extracts of adlay seed (ASE and ASW, respectively), mixed with HFD, were fed to the mice for 10 weeks. The ASE and ASW treatment ameliorated hyperglycemia and improved the glucose tolerance and insulin resistance in the HFD mice. Hyperlipidemia in HFD mice was prevented by the ASE and ASW diet. In addition, the ASE and ASW supplementation attenuated hepatic steatosis and inflammation, improved liver function, and caused no harm to the kidneys. Moreover, the mechanism of the effect of ASE and ASW on inhibiting hepatic lipogenesis and inducing fatty acid β-oxidation was certified by the simulated human fatty liver cell model. Our study showed the regulatory potential of the extracts of adlay seeds for alleviating NAFLD, as well as related liver and metabolic diseases.

Genetic and lifestyle risk factors for advanced liver disease among men and women.

Liver disease is traditionally categorized as alcoholic and non-alcoholic. We studied various risk factors predictive of advanced non-viral liver disease in general population and analyzed the interaction between these factors and alcohol consumption. Persons without underlying liver disease who participated in the Health2000 or FINRISK studies 1992-2012 comprised a cohort of 41260 individuals. Pattern of alcohol consumption and metabolic, lifestyle-related, and anthropometric parameters were analyzed with Cox regression analysis using severe liver disease hospitalization, cancer, or death as end-point. Viral liver diseases were excluded. A total of 355 liver events occurred during the mean 12.4-year follow-up (511789 person-years). In the multivariate model, age (hazard ratio [HR] 1.03, P=0.0083 for men; HR 1.04, P=0.0198 for women), waist-to-hip ratio (WHR) (HR 1.52, P=0.0006 for men; HR 1.58, P=0.0167 for women), patatin-like phospholipase-containing domain 3 mutations (HR 1.9, P=0.024 for men; HR 2.7, P=0.0109 for women), and weekly binge drinking (HR 2.4, P=0.0024 for men; HR 7.4, P<0.0001 for women) predicted development of severe liver disease. Among men, diabetes (HR 2.7, P=0.0002), average alcohol consumption (HR for 10g/day 1.1, P=0.0022), non-married status (HR 1.9, P=0.0397 for single; HR 2.4, P=0.0002 for widowed/separated), and serum high-density lipoprotein (HR 2.2, P=0.0022) and non-high-density lipoprotein cholesterol (HR 1.2, P=0.0237) were additional risk factors. Alcohol intake increased the risk especially among persons with high WHR (P for interaction 0.009). Age, patatin-like phospholipase-containing domain 3 haplotype, and WHR increase the risk for development of severe liver disease. We found strong synergism between alcohol and central obesity. Binge drinking is an additional risk factor.

Variable Outcome of Acute Viral Hepatitis in Diabetic and Nondiabetic Patients in Bangladesh.

ABSTRACTDiabetes mellitus (DM) are common in Bangladesh, and this country is also well-known for frequent outbreaks of acute viral hepatitis (AVH). The study presented here was designed for the clinical courses of acute hepatitis with and without DM. A total of 300 patients with AVH were enrolled into two groups; group A; patients of AVH with DM (N = 140) and group B; patients with AVH without DM (N = 160). There was no significant difference regarding age, sex, and levels of alanine aminotransferase (ALT) between the two groups. The main cause of AVH was hepatitis E virus (HEV) in 100 and 112 patients of groups A and B, respectively. Jaundice persisted for more than 6 months in 68 of 140 (49%) patients of group A, whereas, this was found in only 11 of 160 patients of group B. Forty-two patients of group A showed evidence of esophageal varices; however, the endoscopic assessment did not reveal any abnormality in patients with group B. Moderate to several hepatic fibrosis was seen in 19 of 140 patients with group A, however, these were not detected in any patient of group B (patient with AVH without DM). Even more important is the fact that four patients of group A died of liver failure, whereas there was no mortality in any patient of group B. The study presented here indicates that all patients with DM with superimposed AVH should be carefully followed up with the possibility of development of severe liver diseases and even mortality.How to cite this article: Harun-or-Rashid, Khan MR, et al. Variable Outcome of Acute Viral Hepatitis in Diabetic and Nondiabetic Patients in Bangladesh. Euroasian J Hepatogastroenterol 2019;9(1): 20-22.

SAT-485 - Risk factors for development of severe liver disease in more than 400 000 patients with type 2 diabetes: A population-based cohort study

SAT-485 - Risk factors for development of severe liver disease in more than 400 000 patients with type 2 diabetes: A population-based cohort study

From the Editor’s desk...: March 2018

Excessive alcohol consumption in young people is a major public health problem worldwide. Whether alcohol consumption early in life is associated with later development of severe liver disease is uncertain. In this issue of the Journal, Hagström et al. used data on alcohol consumption at conscription to military service from 43,296 men (18–20 years) in Sweden during the late 60s. During a mean follow-up of 38 years, 383 men developed severe liver disease. Alcohol consumption in people between 18 and 20 years old was associated with an increased risk of development of severe liver disease in a dose-response pattern. This important study highlights that alcohol consumption in young men is associated with an increased risk of severe liver disease. The risk was dose-dependent, with no sign of a threshold effect. Current guidelines for safe alcohol intake in men might have to be revised, and more effective campaigns aimed at preventing excessive alcohol consumption among young people should be launched.

High resolution UPLC-MS/MS profiling of polyphenolics in the methanol extract of Syzygium samarangense leaves and its hepatoprotective activity in rats with CCl4-induced hepatic damage

Oxidative stress plays a crucial role in the development of several liver diseases. Many natural polyphenols can attenuate oxidative stress and liver injury. In this study, a phytochemical profiling of a methanol extract from leaves of Syzygium samarangense revealed 92 compounds belonging to flavonoids, phenolic acids, condensed tannins, and ellagitannins. The S. samarangense extract exhibited a noticeable antioxidant activity with an EC50 of 5.80 μg/mL measured by DPPH scavenging capacity assay, 2632 Trolox equivalents, 10 mM Fe2+ equivalents/mg of samples by TEAC and FRAP assays, respectively. The total phenolic content was 419 mg gallic acid equivalent GAE/g extract. In a cell-based model (HaCaT cells), the extract completely inhibited ROS production induced by UVA, and prevented GSH-depletion and p38 phosphorylation. In addition, the extract exhibited a substantial antioxidant and hepatoprotective activities in CCl4-treated rats, with an increase in GSH (reduced glutathione) and SOD (superoxide dismutase) activities by 84.75 and 26.27%, respectively, and a decrease of 19.08, 63.05, 52.21, 37.00, 13.26, and 15.15% in MDA, ALT, AST, TB (total bilirubin), TC (total cholesterol), and TG (total glycerides), respectively. These results were confirmed by histopathological analyses. We believe that Syzygium samarangense is a good candidate for further evaluation as an antioxidant and liver protecting drug.

Alcohol consumption in late adolescence is associated with an increased risk of severe liver disease later in life

High alcohol consumption is associated with an increased risk of severe liver disease. Current recommendations suggest it is safe for men to consume 30 grams of alcohol per day. We investigated the association between alcohol consumption early in life and later development of severe liver disease. We used data on alcohol consumption at conscription to military service from 43,296 men (18-20 years) in Sweden between 1969 and 1970. Outcomes were defined as incident diagnoses of severe liver disease from systematic national registration of clinical events until the end of 2009. A Cox regression model adjusted for body mass index, smoking, use of narcotics, cognitive ability and cardiovascular capacity was applied. During a mean follow-up of 37.8 years, 383 men developed severe liver disease. Alcohol consumption was associated with an increased risk of development of severe liver disease in a dose-response pattern (adjusted hazard ratio for every one gram/day increase 1.02; 95% CI 1.01-1.02). No evidence of a threshold effect was found. Importantly, a clear trend pointed towards an increased risk of severe liver disease in men who consumed less than 30 grams of alcohol per day. Alcohol consumption in young men is associated with an increased risk of severe liver disease, up to 39 years later in life. The risk was dose-dependent, with no sign of a threshold effect. Current guidelines for safe alcohol intake in men might have to be revised. We investigated more than 43,000 Swedish men in their late teens enlisted for conscription in 1969-1970. After almost 40 years of follow-up, we found that alcohol consumption was a significant risk factor for developing severe liver disease, independent of confounders. This risk was dose-dependent, and was most pronounced in men consuming two drinks per day or more.

Histologic Risk Factor for Mortality and Development of Severe Liver Disease in Biopsy-proven Non-alcoholic Fatty Liver Disease

Histologic Risk Factor for Mortality and Development of Severe Liver Disease in Biopsy-proven Non-alcoholic Fatty Liver Disease

Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD

Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but identifying patients with increased risk of mortality and liver-specific morbidity remains a challenge. Non-alcoholic steatohepatitis (NASH) is thought to enhance this risk; therefore, resolution of NASH is a major endpoint in current pharmacologic studies. Herein, we aim to investigate the long-term prognosis of a large cohort of NAFLD patients, and to study the specific effect of NASH and fibrosis stage on prognosis. We conducted a retrospective cohort study of 646 biopsy-proven NAFLD patients. Each case was matched for age, sex and municipality to ten controls. Outcomes on mortality and severe liver disease, defined as cirrhosis, liver decompensation/failure or hepatocellular carcinoma, were evaluated using population-based registers. Cox regression models adjusted for age, sex and type 2 diabetes were used to examine the long-term risk according to fibrosis stage. Likelihood ratio tests were used to assess whether adding NASH to these models increased the predictive capacity. Laplace regression was used to estimate the time to severe liver disease according to stage of fibrosis. During a follow-up of mean 20years (range 0-40) equivalent to 139,163 person-years, 12% of NAFLD patients and 2.2% of controls developed severe liver disease (p<0.001). Compared to controls, the risk of severe liver disease increased per stage of fibrosis (hazard ratio ranging from 1.9 in F0 to 104.9 in F4). Accounting for the presence of NASH did not change these estimates significantly (likelihood ratio test >0.05 for all stages of fibrosis). Similar results were seen for overall mortality. The lower end of the 95% confidence interval for the 10th percentile of time to development of severe liver disease was 22-26years in F0-1, 9.3years in F2, 2.3years in F3, and 0.9years to liver decompensation in F4. In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions. Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but reaching an accurate prognosis remains challenging. We investigate the long-term prognosis of a large cohort of NAFLD patients. In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions.

Waist/Hip Ratio Better Predicts Development of Severe Liver Disease Within 20 Years Than Body Mass Index: A Population-based Cohort Study.

Obesity, commonly assessed based on body mass index (BMI), is associated with an increased risk for severe liver disease. It is not known if other measures of body composition are better determinants of risk for severe liver disease, and/or if these differ between women and men. We investigated the body composition measures that best predict the development of severe liver disease. We collected data from the Malmö Diet and Cancer study in Sweden, comprising 16,784 women and 10,833 (mean age, 58.1 years at baseline), and followed patients for a median 19.8 years. We analyzed data on measures of body composition including BMI, waist/hip ratio, and others. We determined whether subjects were diagnosed with severe liver disease, or died from severe liver disease, until the end of 2014 using Swedish national registers. Associations between body composition measures and severe liver disease were assessed using Cox regression models, stratified by sex and adjusted for age, alcohol consumption, smoking, education, and physical activity. All studied measures of body composition were significantly associated with severe liver disease. Waist/hip ratio was the best predictor of severe liver disease in women (hazard ratio [HR] per standard deviation increment, 1.30; 95% confidence interval [CI], 1.16-1.46) and men (HR, 1.46; 95% CI, 1.31-1.63). BMI had the lowest HR in women (HR, 1.12; 95% CI, 1.00-1.27) and men (HR, 1.26; 95% CI, 1.12-1.42). The association between waist/hip ratio and development of liver disease was independent of BMI. In a Swedish population-based cohort study, we associated all measures of body composition with risk of severe liver disease. However, measures of abdominal obesity were best at predicting development of severe liver disease.

HBV COVALENTLY CLOSED CIRCULAR DNA AS A MARKER OF PREVALENCE OF OCCULT HEPATITIS В IN PATIENTS WITH HBV, HDV AND HCV INFECTION IN UZBEKISTAN

Aim. Evaluate significance of covalently closed circular DNA of hepatitis В virus as a marker for detection of occult viral hepatitis В in Uzbekistan population with hepatitis of various genesis. Materials and methods. Blood plasma and liver biopsy from 39 patients with different severity levels of liver fibrosis and cirrhosis served as study material. HBV covalently closed circular DNA detection was carried out according to Pollicino T. et al. (2004). Results. Covalently closed circular DNA of hepatitis В virus was detected in 82% of samples, including in 54.5% of patients with chronic viral hepatitis C (CVHC) and in 100% of patients with hepatitis of unknown etiology. Quantitative evaluation of content of covalently closed circular DNA of hepatitis В virus in liver tissue in patients with CVHB has shown an average of 2.5 copies of HBV genome as ccc DNA per cell, in patients with CVHB + D an average of 0.7 copies/cell, in patients with co-infection by HCV and HBV - 0.5 copies/cell, in patients with CVHC an average of 0.12 copies/cell, and in patients with cryptogenic hepatitis - 0.2 copies/cell. Conclusion. Detection of HBV DNA is a complex problem for effective laboratory diagnostics of hepatitis. Detection of H BV ccc DNA as a marker of occult hepatitis В in patients with CVHC and patients with hepatitis of unclear etiology is an important factor for diagnostics, selection of adequate therapy, prognosis of disease outcome and prevention of development of severe liver diseases.