Main Cause Of Liver Disease Research Articles

Characterization of Circulating HCV Genotypes: A Cohort Study in Uttar Pradesh, India

Hepatitis C virus infection is one of the main causes of liver disease that can lead to liver cirrhosis and finally to the chronic development of Hepatocellular Carcinoma (HCC). With 8 different HCV genotypes circulating, it becomes necessary to characterize the pathogenesis caused by each one of the HCV genotypes infecting population of a particular setting. Present study aims to identify the circulating Hepatitis C virus (HCV) genotypes in the different areas of State of Uttar Pradesh, India and understand their clinical etiology and related co-morbidities. The patients reporting to Sharda Hospital, Uttar Pradesh, India who were diagnosed positive for HCV were included in the study. The informed consent was obtained and then blood was drawn. In-house primers, for all the 8 genotypes were prepared and RT-PCR was performed. The amplified product was subjected to Agarose gel electrophoresis to identify the genotypes present in individual samples. Total 30 serum samples were taken. Of these, 21 (70%) showed presence of multiple genotypes, while 7 (23.33%) showed positivity for single genotype and two did not show any bands. Presence of multiple genotypes in individual patient has been reported for the first time. The pathological consequences of multiple genotypes within one host need to be studied further in terms of increased risk of developing a chronic liver disease. Further studies are being undertaken to study association of specific HCV genotype and multiple genotypes, Core, NS3 and NS5 viral proteins with the disease progression to develop predictors of liver cirrhosis and HCC.

A new approach to prevent, diagnose, and treat hepatitis B in Africa.

There are 82 million people living with hepatitis B (PLWHB) in the World Health Organization Africa region, where it is the main cause of liver disease. Effective vaccines have been available for over 40years, yet there are 990,000 new infections annually, due to limited implementation of hepatitis B birth dose vaccination and antenatal tenofovir prophylaxis for highly viraemic women, which could eliminate mother-to-child transmission. Despite effective and cheap antiviral treatment which can suppress hepatitis B virus replication and reduce the risk of hepatocellular carcinoma (HCC), < 2% of PLWHB are diagnosed, and only 0.1% are treated. As a result, PLWHB are frequently diagnosed only when they have already developed decompensated cirrhosis and late-stage HCC, and consequently 80,000 hepatitis B-associated deaths occur each year. Major barriers include complex treatment guidelines which were derived from high-income settings, lack of affordable diagnostics, lack or insufficient domestic funding for hepatitis care, and limited healthcare infrastructure. Current treatment criteria may overlook patients at risk of cirrhosis and HCC. Therefore, expanded and simplified treatment criteria are needed. We advocate for decentralized community treatment programmes, adapted for low-resource and rural settings with limited laboratory infrastructure. We propose a strategy of treat-all except patients fulfilling criteria that suggest low risk of disease progression. Expanded treatment represents a financial challenge requiring concerted action from policy makers, industry, and international donor agencies. It is crucial to accelerate hepatitis B elimination plans, integrate hepatitis B care into existing healthcare programmes, and prioritize longitudinal and implementation research to improve care for PLWHB.

MicroRNA-574–5p targeting HOXC6 expression inhibits the hepatocyte lipid uptake to alleviate non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of liver disease that has reached its last stage. Over the past few years, evidence for miRNAs' centrality in NAFLD pathogenesis has accumulated. According to some studies, miR-574–5p plays a role in lipid metabolism. However, research on the relationship between miR-574–5p and NAFLD is lacking. For in vivo experiments, we induced the NAFLD mice model with a high-fat diet (HFD). AgomiR-574–5p was injected intravenously into HFD-fed mice for eight weeks, and qPCR was used to identify the expression of miR-574–5p in the serum. In in vitro experiments, The treatment of L-O2 cells with a miR-574–5p mimic resulted in a significant reduction in lipid deposition, suggesting that miR-574–5p can inhibit lipid accumulation and lipid formation induced by OA. The dual-luciferase reporter gene assay revealed that miR-574–5p targets the 3′ UTR region of HOXC6 directly. We discovered that OA-induced lipid accumulation in hepatocytes might be mediated through the miR-574-5p-HOXC6 signaling axis. Additional research is required in order to determine the specific mechanism by which HOXC6 downstream pathways are involved in the miR-574–5p induced lipid uptake.

Preventive Effect of Gamma-Oryzanol on Physiopathological Process Related to Nonalcoholic Fatty Liver Disease in Animals Submitted to High Sugar/Fat Diet

Nonalcoholic fatty liver disease (NAFLD) is the main cause of liver disease. The physiopathological processes involved in the disease are metabolic syndrome (MetS) components (central obesity, dyslipidemia, insulin resistance/type 2 diabetes, hypertension), genetic, and dietary factors, including unsaturated fats and sweetened beverages, which are able to lead to inflammation and oxidative stress, conditions associated with progression and severity of NAFLD. Gamma-oryzanol (γOz) is a nutraceutical obtained from rice brain oil with many benefits to health, from immunological to metabolic. The aim of this study is to test the preventive effect of γOz on the physiopathological process related to nonalcoholic fatty liver disease in animals submitted to high sugar/fat diet. Male Wistar rats (±187 g) were randomly divided into four experimental groups to receive: control diet (C, n = 6), control diet plus γOz (C + γOz, n = 6), high sugar/fat diet (HSF, n = 6), or high sugar/fat diet plus γOz (HSF + γOz, n = 6) during 30 weeks. HSF groups also received water plus sucrose (25%). γOz was added to diets to reach 0.5% of final concentration. The HSF group presented MetS, liver inflammation and oxidative stress, and micro and macrovesicular steatosis. HSF plus γOz was protected against these changes. It is possible to conclude that gamma-oryzanol was effective in modulating the physiopathological process related to nonalcoholic fatty liver disease in animals submitted to a high sugar/fat diet.

Signaling Induced by Chronic Viral Hepatitis: Dependence and Consequences.

Chronic viral hepatitis is a main cause of liver disease and hepatocellular carcinoma. There are striking similarities in the pathological impact of hepatitis B, C, and D, although these diseases are caused by very different viruses. Paired with the conventional study of protein–host interactions, the rapid technological development of -omics and bioinformatics has allowed highlighting the important role of signaling networks in viral pathogenesis. In this review, we provide an integrated look on the three major viruses associated with chronic viral hepatitis in patients, summarizing similarities and differences in virus-induced cellular signaling relevant to the viral life cycles and liver disease progression.

Preoperative prediction score of hepatocellular carcinoma recurrence in living donor liver transplantation: Validation of SNAPP score developed at Asan Medical Center

Preoperative prediction score of hepatocellular carcinoma recurrence in living donor liver transplantation: Validation of SNAPP score developed at Asan Medical Center

Validation of a new prognostic model to predict short and medium-term survival in patients with liver cirrhosis

BackgroundMELD score and MELD score derivates are used to objectify and grade the risk of liver-related death in patients with liver cirrhosis. We recently proposed a new predictive model that combines serum creatinine levels and maximum liver function capacity (LiMAx®), namely the CreLiMAx risk score. In this validation study we have aimed to reproduce its diagnostic accuracy in patients with end-stage liver disease.MethodsLiver function of 113 patients with liver cirrhosis was prospectively investigated. Primary end-point of the study was liver-related death within 12 months of follow-up.ResultsAlcoholic liver disease was the main cause of liver disease (n = 51; 45%). Within 12 months of follow-up 11 patients (9.7%) underwent liver transplantation and 17 (15.1%) died (13 deaths were related to liver disease, two not). Measures of diagnostic accuracy were comparable for MELD, MELD-Na and the CreLiMAx risk score as to power in predicting short and medium-term mortality risk in the overall cohort: AUROCS for liver related risk of death were for MELD [6 months 0.89 (95% CI 0.80–0.98) p < 0.001; 12 months 0.89 (95% CI 0.81–0.96) p < 0.001]; MELD-Na [6 months 0.93 (95% CI 0.85–1.00) p < 0.001 and 12 months 0.89 (95% CI 0.80–0.98) p < 0.001]; CPS 6 months 0.91 (95% CI 0.85–0.97) p < 0.01 and 12 months 0.88 (95% CI 0.80–0.96) p < 0.001] and CreLiMAx score [6 months 0.80 (95% CI 0.67–0.96) p < 0.01 and 12 months 0.79 (95% CI 0.64–0.94) p = 0.001]. In a subgroup analysis of patients with Child-Pugh Class B cirrhosis, the CreLiMAx risk score remained the only parameter significantly differing in non-survivors and survivors. Furthermore, in these patients the proposed score had a good predictive performance.ConclusionThe CreLiMAx risk score appears to be a competitive and valid tool for estimating not only short- but also medium-term survival of patients with end-stage liver disease. Particularly in patients with Child-Pugh Class B cirrhosis the new score showed a good ability to identify patients not at risk of death.

Hepatic and circulating levels of PCSK9 in morbidly obese patients: Relation with severity of liver steatosis

Non-alcoholic fatty liver disease (NAFLD) is becoming the main cause of liver disease in Western countries, especially in morbidly obese patients (MOPs). The proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recently studied because of its possible involvement in the pathogenesis of NAFLD, but its role, at least in MOPs, is still controversial. The aim of this study was to clarify the correlation between the circulating levels of the PCSK9 protein (cPCSK9) and its hepatic expression with the severity of liver damage in a population of MOPs with NAFLD undergoing bariatric surgery. PCSK9 mRNA was positively correlated with FASN, PPARγ and PPARα mRNAs, while no significant differences were found in PCSK9 mRNA expression in relation to the severity of liver steatosis, lobular inflammation and hepatocellular ballooning. In addition, hepatic PCSK9 protein expression levels were not related to histological parameters of lobular inflammation and hepatocyte ballooning, decreased significantly only in relation to the severity of hepatic steatosis, and were inversely correlated with ALT and AST serum levels. cPCSK9 levels in the whole population were associated with the severity of hepatic steatosis and were positively correlated to total cholesterol levels. In multivariate analysis, cPCSK9 levels were associated with age, total cholesterol and HbA1c. In conclusion, in MOPs our findings support a role for PCSK9 in liver fat accumulation, but not in liver damage progression, and confirm its role in the increase of blood cholesterol, which ultimately may contribute to increased cardiovascular risk in this population.

Detoxification of bilirubin and bile acids with intermittent coupled plasmafiltration and adsorption in liver failure (HERCOLE study)

BackgroundCPFA is an extracorporeal treatment used in severe sepsis to remove circulating proinflammatory cytokines. Limited evidence exists on the effectiveness of bilirubin adsorption by the hydrophobic styrenic resin, the distinctive part of CPFA. The aim of this study is to validate CPFA effectiveness in liver detoxification.MethodsIn this prospective observational study, we enrolled patients with acute or acute-on-chronic liver failure (serum total bilirubin > 20 mg/dL or MELD Score > 20) hospitalized from June 2013 to November 2017. CPFA was performed using the Lynda (Bellco/MedTronic, Mirandola, Italy) or the Amplya (Bellco/MedTronic, Mirandola, Italy) machines. Anticoagulation was provided with unfractionated heparin or citrate. Bilirubin and bile acids reduction ratios per session (RRs) were the main parameters for hepatic detoxification.ResultsTwelve patients with acute (n = 3) or acute-on-chronic (n = 9) liver failure were enrolled. Alcohol was the main cause of liver disease. Thirty-one CPFA treatments of 6 h each were performed, 19 with heparin and 12 with citrate. RRs was 28.8% (range 2.2–40.5) for total bilirubin, 32.7% (range 8.3–48.9) for direct bilirubin, 29.5% (range 6.5–65.4) for indirect bilirubin and 28.9% (16.7- 59.7) for bile acids. One patient received liver transplantation and 8/9 were alive at 1 year of follow-up. Three patients (25%) died: 2 during hospitalization and 1 for a cardiac event at 4 months of follow up with restored liver function.ConclusionsCPFA resulted to be effective in liver detoxification. Thus, it may be considered as a “bridge technique” both to the liver transplant and to the recovery of the basal liver function.

P841 Evaluation of gut microbiota composition in NAFLD with UC pancolitis in clinical remission: a pilot study

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver disease in Western countries and is a frequently reported comorbidity in inflammatory bowel disease (IBD). A complex interaction among polygenic predisposition, IBD-specific risk factors, microbiome, multiple environmental and patients’ factors could explain the development of NAFLD in IBD. Gut dysbiosis is increasingly recognised as an important player in NAFLD, as well as in IBD pathogenesis. So far, no study has examined the gut microbiota composition in IBD patients with NAFLD. We aimed to characterise faecal microbiota according to NAFLD status in a pilot cohort of ulcerative colitis (UC) pancolitis in clinical remission. Methods This was a cross-sectional pilot study using transient elastography (TE) with controlled attenuation parameter (CAP) to diagnose NAFLD in UC pancolitis patients in clinical remission, defined as partial Mayo score ≤1. NAFLD was diagnosed non-invasively as CAP ≥248 dB/m. Exclusion criteria included: use of corticosteroids in the last year and antibiotics or probiotics/prebiotics in the last 2 months prior to inclusion; significant alcohol intake (AUDIT-C &amp;lt;5); hepatitis B or C infection. Stool samples were collected within 12 h from TE with CAP evaluation. Gut microbiota composition was analysed by 16S rRNA gene sequencing with Illumina technique. Statistical analysis by NAFLD status was performed using Fisher’s exact or Mann–Whitney’s test as appropriate. Results A total of 11 UC pancolitis patients in clinical remission were included (mean age 53 years, 36.4% male, time since IBD diagnosis 16 years). NAFLD was diagnosed in 7 cases (63.6%, mean CAP 291 dB/m). Patients with pancolitis and NAFLD had higher BMI (mean 31 vs. 22 kg/m2, p = 0.006) as well as waist circumference (mean 100 vs. 81 cm, p = 0.006) compared with those without NAFLD, but no other differences in demographic, clinical or pharmacological parameters were found between pancolitis with or without NAFLD. Patients with pancolitis and NAFLD clustered separately from those without NAFLD, when computing Bray Curtis dissimilarities (tested with Adonis, p = 0.006). In addition, patients with pancolitis and NAFLD presented with decreased bacterial richness (p = 0.017) but not diversity. This was accompanied by a significant increase of Bacteroides spp. relative abundance in faecal samples of patients with pancolitis and NAFLD (q = 0.017). Conclusion This pilot study demonstrates, for the first time, that, in UC pancolitis patients, NAFLD associates with altered gut microbiota composition. Further studies are needed to understand the exact role of gut microbiota in UC pancolitis with NAFLD and to evaluate the use of microbiota-directed approaches for the treatment of NAFLD in these patients.

Prevalence of hepatitis B markers and vaccination status of healthcare personnel: Experience of the Tunis Military Hospital

Hepatitis B is the main cause of liver disease in the world. Chronic hepatitis B may lead to cirrhosis, liver insufficiency or liver cancer. Tunisia is considered as a country with intermediate endemicity, where hepatitis B presents a real public health problem. The aims of this study were to evaluate the prevalence of viral biomarkers of hepatitis B in healthcare personnel; to look for potential risk factors associated with HbS antigen carriage and to evaluate the prevalence of vaccination in this particular population. Sero-epidemiological, prospective and descriptive study, among 2411healthcare personnel in the Military Hospital of Tunis, during a 5-month period from September 2013to January 2014. Blood samples were collected from 1497 volunteers among the hospital staff. Two hundred and seventy-one individuals had a positive HbC antibody titer (prevalence 18.1%), including 229 who were positive for HbC and HbS antibodies (prevalence 15.3%), 12 positive for only HbC antibody (prevalence 0.8%), and 30 positive for HBsAg (prevalence 2%). Among HbS Ag carriers, 56.6% reported needle stick and sharp object injuries during their professional careers. Among HbS Ag carriers, there were three patients with a history of acute viral hepatitis with jaundice, and 27 patients (90%) who were asymptomatic and were diagnosed during our study. Among healthcare workers in the hospital, 56.1% were immunized through vaccination (positive HbS antibodies without HbC antibodies), of whom 66% had durable protective immunity (HbS antibodies>100mU/mL). Lastly, 25.8% of the hospital workers remained without any protection against hepatitis B (serology entirely negative) and were then offered a complete vaccination. Hepatitis B vaccine is the mainstay of hepatitis B prevention. Safe injection practices, blood safety and promoting wider access to monitoring and screening, care and treatment services for hepatitis B are the best guarantees to prevent and control this disease.

Upper gastrointestinal bleeding in Egyptian patients with cirrhosis: Post-therapeutic outcome and prognostic indicators.

Upper gastrointestinal bleeding (UGIB) is a serious complication of portal hypertension in cirrhotic patients. The objective of this study is to identify the risk factors for morbidity and mortality occurring after an UGIB attack. A total of 1097 UGIB attacks in 690 patients with liver cirrhosis were studied. Their clinical, laboratory, and endoscopic data were reviewed. Mean age 53.2±10.6 (20-90) years, 78% men and the main cause of liver disease was hepatitis C (94.9%). Complications occurred after 467 attacks (42.6%): hepatic encephalopathy 31.4%, spontaneous bacterial peritonitis 18%, renal impairment 13.2%, and re-bleeding in 7.8%, while 199 patients (18.1%) died. Complications followed 78.4% of bleeding from gastric varices, 75% of post-interventional ulcers, 10.8% of peptic ulcers, and 5.9% of telangiectasias. By univariate analysis: packed red blood cells units transfused, transaminases, Child-Pugh (CP), model of end-stage liver disease (MELD), and albumin-bilirubin (ALBI) scores, beside the presence of hepatocellular carcinoma (HCC), previous hemorrhage in the previous 6months, and the source of bleeding, were associated with occurrence of complications. By multivariate analysis, independent predictors of complications were CP, MELD, and ALBI scores (odds ratio, 95% confidence interval: 5.63, 3.55-8.93; 1.15, 1.11-1.19; and 2.11, 1.4-3.19, respectively) beside the presence of HCC (4.89, 2.48-9.64). Mortality predictors were packed red blood cells units transfused (1.11, 1.01-1.24), CP (5.1, 1.42-18.25) MELD (1.27, 1.21-1.32) scores, and presence of HCC (6.62, 2.93-14.95). High CP, MELD, and ALBI scores beside the presence of HCC could predict poor outcome of UGIB. In the absence of these risk factors, early discharge could be considered if the source of bleeding is peptic ulcer or telangiectasia.

Chronic Liver Disease Questionnaire as a Tool to Evaluate the Quality of Life in Liver Transplant Candidates.

The advanced stage of liver disease causes impairments in the quality of life due to the physiological symptoms, besides the social and emotional stress. The aim of this study was to evaluate the quality of life of candidates for liver transplantation in specialized center in the interior of the state of São Paulo, Brazil. An observational study was carried out, with a quantitative approach. The sample was of convenience with the participation of 50 candidates for liver transplantation. Demographic characterization data, clinical data, and the Chronic Liver Disease Questionnaire were used to evaluate the quality of life. The majority of the participants were male (68%), married (76%), with an average age of 55.7 years and average income of 2 to 3 minimum wages (42%). The main cause of liver disease was alcoholism (34%), mean time on the waiting list was 247.8 days, and mean model for end-stage liver disease was 20.5 points. The mean quality of life score was 2.9 points (standard deviation = 1.0) and the analysis of the 6 domains showed greater impairment of fatigue (2.2), activity (2.7), and concern (2.9) and better evaluation of systemic symptoms (3.4) and emotion (3.3). Quality of life is impaired in most of the participants, indicating the need for greater attention and evaluation in the physical, mental, and social scope of this clientele.

Fatty liver disease, an emerging etiology of hepatocellular carcinoma in Argentina.

AIMTo investigate any changing trends in the etiologies of hepatocellular carcinoma (HCC) in Argentina during the last years.METHODSA longitudinal cohort study was conducted by 14 regional hospitals starting in 2009 through 2016. All adult patients with newly diagnosed HCC either with pathology or imaging criteria were included. Patients were classified as presenting non-alcoholic fatty liver disease (NAFLD) either by histology or clinically, provided that all other etiologies of liver disease were ruled out, fatty liver was present on abdominal ultrasound and alcohol consumption was excluded. Complete follow-up was assessed in all included subjects since the date of HCC diagnosis until death or last medical visit.RESULTSA total of 708 consecutive adults with HCC were included. Six out of 14 hospitals were liver transplant centers (n = 484). The prevalence of diabetes mellitus was 27.7%. Overall, HCV was the main cause of liver disease related with HCC (37%) including cirrhotic and non-cirrhotic patients, followed by alcoholic liver disease 20.8%, NAFLD 11.4%, cryptogenic 9.6%, HBV 5.4% infection, cholestatic disease and autoimmune hepatitis 2.2%, and other causes 9.9%. A 6-fold increase in the percentage corresponding to NAFLD-HCC was detected when the starting year, i.e., 2009 was compared to the last one, i.e., 2015 (4.3% vs 25.6%; P < 0.0001). Accordingly, a higher prevalence of diabetes mellitus was present in NAFLD-HCC group 61.7% when compared to other than NAFLD-HCC 23.3% (P < 0.0001). Lower median AFP values at HCC diagnosis were observed between NAFLD-HCC and non-NAFLD groups (6.6 ng/mL vs 26 ng/mL; P = 0.02). Neither NAFLD nor other HCC etiologies were associated with higher mortality.CONCLUSIONThe growing incidence of NAFLD-HCC documented in the United States and Europe is also observed in Argentina, a confirmation with important Public Health implications.

Multiple effects of toxins isolated from Crotalus durissus terrificus on the hepatitis C virus life cycle.

Hepatitis C virus (HCV) is one of the main causes of liver disease and transplantation worldwide. Current therapy is expensive, presents additional side effects and viral resistance has been described. Therefore, studies for developing more efficient antivirals against HCV are needed. Compounds isolated from animal venoms have shown antiviral activity against some viruses such as Dengue virus, Yellow fever virus and Measles virus. In this study, we evaluated the effect of the complex crotoxin (CX) and its subunits crotapotin (CP) and phospholipase A2 (PLA2-CB) isolated from the venom of Crotalus durissus terrificus on HCV life cycle. Huh 7.5 cells were infected with HCVcc JFH-1 strain in the presence or absence of these toxins and virus was titrated by focus formation units assay or by qPCR. Toxins were added to the cells at different time points depending on the stage of virus life cycle to be evaluated. The results showed that treatment with PLA2-CB inhibited HCV entry and replication but no effect on HCV release was observed. CX reduced virus entry and release but not replication. By treating cells with CP, an antiviral effect was observed on HCV release, the only stage inhibited by this compound. Our data demonstrated the multiple antiviral effects of toxins from animal venoms on HCV life cycle.

Glucagon like Peptide-1(GLP-1) a Novel Therapeutic Strategy in Non-Alcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is a main cause of liver disease and its global prevalence is estimated to be 24%. At present no approved medicines are available for NAFLD treatment. Glucagon-like peptide-1 (GLP-1) is a significant regulator of energy balance, show potential efficacy in the management of NAFLD. GLP-1 and GLP-1 receptor agonist (GLP-1RAs) are attractive options for the treatment of type 2 diabetes (T2D) since they efficiently reduce weight, HbA1C and blood glucose without having a risk of hypoglycaemia. This incretin hormone by normalizing of insulin resistance (IR), oxidative stress, lipid accumulation, lipotoxicity, and liver cell apoptosis is proposed for the management of NAFLD and nonalcoholic steatohepatitis (NASH) patient. Hence, the aim of this review was to discuss the useful effects of GLP-1, GLP-1 receptor agonist (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) on NAFLD. In this paper we provided a new finding which highlighted the role of GLP-1 and GLP-1RAs in the treatment of NAFLD.

ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency.

BackgroundThe most common and severe disease causing allele of Alpha 1-Antitrypsin Deficiency (1ATD) is Z-1AT. This protein aggregates in the endoplasmic reticulum, which is the main cause of liver disease in childhood. Based on recent evidences and on the frequency of liver disease occurrence in Z-1AT patients, it seems that liver disease progression is linked to still unknown genetic factors.MethodsWe used an innovative approach combining yeast genetic screens with next generation exome sequencing to identify and functionally characterize the genes involved in 1ATD associated liver disease.ResultsUsing yeast genetic screens, we identified HRD1, an Endoplasmic Reticulum Associated Degradation (ERAD) associated protein, as an inducer of Z-mediated toxicity. Whole exome sequencing of 1ATD patients resulted in the identification of two variants associated with liver damages in Z-1AT homozygous cases: HFE H63D and HERPUD1 R50H. Functional characterization in Z-1AT model cell lines demonstrated that impairment of the ERAD machinery combined with the HFE H63D variant expression decreased both cell proliferation and cell viability, while Unfolded Protein Response (UPR)-mediated cell death was hyperstimulated.ConclusionThis powerful experimental pipeline allowed us to identify and functionally validate two genes involved in Z-1AT-mediated severe liver toxicity. This pilot study moves forward our understanding on genetic modifiers involved in 1ATD and highlights the UPR pathway as a target for the treatment of liver diseases associated with 1ATD. Finally, these findings support a larger scale screening for HERPUD1 R50H and HFE H63D variants in the sub-group of 1ATD patients developing significant chronic hepatic injuries (hepatomegaly, chronic cholestasis, elevated liver enzymes) and at risk developing liver cirrhosis.

Diagnosis of Liver Involvement in Primary Sjögren Syndrome.

Liver involvement was one of the first extraglandular manifestations to be reported in patients with primary Sjögren syndrome (SS). In the 1990s, a study of liver involvement in patients with primary SS integrated the evaluation of clinical signs of liver disease, liver function and a complete panel of autoantibodies. Recent developments in the field of hepatic and viral diseases have significantly changed the diagnostic approach to liver involvement in SS. The most recent studies have shown that, after eliminating hepatotoxic drugs and fatty liver disease, the two main causes of liver disease in primary SS are chronic viral infections and autoimmune liver diseases. The differential diagnosis of liver disease in primary SS (viral vs autoimmune) is clinically important, since the two processes require different therapeutic approaches and have different prognoses. With respect to viral infections, chronic HCV infection is the main cause of liver involvement in SS patients from the Mediterranean area, while chronic HBV infection may be the main cause of liver involvement in SS patients from Asian countries. After eliminating viral hepatitis, primary biliary cirrhosis (PBC) should be considered the main cause of liver disease in primary SS. PBC-related SS patients may have a broad spectrum of abnormalities of the liver, including having no clinical or analytical data suggestive of liver disease. Autoimmune hepatitis (AIH) is the second most frequently found autoimmune liver disease to be associated with SS (all reported cases are type I), and nearly 10% of these patients have an AIH-PBC overlap. Finally, IgG4-related disease must be investigated in patients with SS presenting with sclerosing cholangitis, especially when autoimmune pancreatitis or retroperitoneal fibrosis are also present.

Liver Diseases and Autoimmunity.

Based on the principal clinical and pathological features, autoimmune diseases can be broadly divided into localized (involving only a single organ or tissue) and systemic (involving multiple organs). The liver is a lymphoid organ that not only participates in the immune response, but also a target of autoimmune reactions. Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are three major types of autoimmune diseases localized in the liver or autoimmune liver diseases, whereas granulomatous diseases such as sarcoidosis and connective tissue diseases such as systemic lupus erythematosus, rheumatoid arthritis and primary Sjogren syndrome (PSS) are the major systemic autoimmune diseases with liver involvement. Over the past decade, advances have been achieved in the diagnosis and treatment of autoimmune liver diseases and liver involvement in systemic autoimmune diseases.1–5 Accordingly, in this issue of Journal of Clinical Translational Hepatology, the aim of the review articles is to update the knowledge and current management of autoimmune liver diseases and liver involvement in systemic autoimmune diseases. AIH is a chronic inflammatory liver disease of unknown cause, with an estimated prevalence of 0.5–1.0 per 100,000; it is more common in women than in men. There have been extensive studies on this important disease, and remission of the disease is now achievable by immunosuppression; however, the prognosis is very poor if the patients are left untreated. In this issue, Kapila et al. present the clinical manifestations of AIH, update pathogenesis of liver-directed immune injury and new concepts in the understanding of immune tolerance, and finally provide insight into the development of novel therapeutic approaches.6 Sarcoidosis is a systemic, granulomatous disease that usually affects multiple organs including the liver. The estimated prevalence of sarcoidosis is 2–60 per 100,000. So far, little is unknown about its etiology. Liver involvement in sarcoidosis is very common. In this issue, Tadros et al. introduce the epidemiology and clinical spectrum of hepatic sarcoidosis of the disease and explore the underlying mechanism for liver injury in hepatic sarcoidosis.7 Moreover, they provide state-of-the-art knowledge on the diagnosis, differential diagnosis (with PBC and PSC) and treatment of the disease. PSS is a systemic autoimmune disorder with secretory gland dysfunction. The estimated prevalence is 0.1–3.3%, with significant female preponderance, and it is reportedly associated with increased risk of cancers. Liver involvement is one of the commonly reported extraglandular manifestations of PSS, and two main causes of liver disease, namely chronic viral infections and autoimmune liver diseases contribute to liver involvement in PSS. Diagnosis of the causes of liver involvement in PSS is very important but challenging. In this issue, Briton-Zeron et al. 8 specifically describe the causes, and provide the diagnostic strategy accordingly. There is no doubt that the new data provided in this issue will enrich our understanding and improve clinical treatment of autoimmune liver diseases and liver involvement in systemic autoimmune diseases. This is consistent with the objective of Journal of Clinical Translational Hepatology to deliver recent advances in pathogenetic mechanisms, and developments in basic, translational and clinical studies.

Topological and functional analysis of nonalcoholic steatohepatitis through protein interaction mapping.

The corresponding proteins are important for network mapping since the interaction analysis can provide a new interpretation about disease underlying mechanisms as the aim of this study. Nonalcoholic steatohepatitis (NASH) is one of the main causes of liver disease in the world. It has been known with many susceptible proteins that play essential role in its pathogenesis. In this paper, protein-protein interaction (PPI) network analysis of fatty liver disease retrieved from STRING db by the application of Cytoscape Software. ClueGO analyzed the associated pathways for the selected top proteins. INS, PPARA, LEP, SREBF1, and ALB are the introduced biomarker panel for fatty liver disease. It seems that pathways related to insulin have a prominent role in fatty liver disease. Therefore, investigation in this case is required to confirm the possible linkage of introduced panel and involvement of insulin pathway in the disease.