Risk Of Chronic Liver Disease Research Articles

A randomised controlled trial of a Mediterranean Dietary Intervention for Adults with Non Alcoholic Fatty Liver Disease (MEDINA): study protocol.

BackgroundNon-alcoholic fatty liver disease, the most prevalent liver disease in developed countries, remains difficult to manage with no proven safe and effective pharmacotherapy available. While weight reduction is the most commonly practiced treatment strategy, this is difficult to both achieve and/or maintain in the majority. Furthermore evidence-based dietary recommendations to guide the nutritional management of these patients are lacking. Using a randomised controlled trial design, this study compares the effectiveness of the Mediterranean diet to a standard low fat diet in terms of differences in insulin sensitivity, hepatic steatosis and metabolic outcomes in participants with non-alcoholic fatty liver disease.MethodsNinety four eligible patients who have non-alcoholic fatty liver disease and who are insulin resistant, will be randomised into either a Mediterranean or low fat diet group for a 3 month intervention period. Insulin sensitivity will be measured on peripheral blood using Homeostatic Model Assessment and liver fat content quantified using Magnetic Resonance Spectroscopy. Both arms will consist of three face to face and three telephone call follow up consultations delivered by an Accredited Practicing Dietitian. The intervention arm focuses on recommendations from the traditional Mediterranean diet which have been tailored for use in the Australian population The standard arm uses the Australian Guide to Healthy Eating and the Australian National Heart Foundation dietary guidelines. Study recruitment will take place at four major metropolitan hospitals in Melbourne, Australia. Data collection will occur at all face to face reviews including baseline, 6, and 12 weeks. A follow up assessment to measure sustainability will take place at 6 and 12 months. The primary end point is improved insulin sensitivity scores at the 12 week time point.DiscussionThis trial aims to demonstrate in a large cohort of participants with NALFD that a Mediterranean diet independent of weight loss can result in significant benefits in liver fat and insulin sensitivity and that these changes are sustained at 12 months. These metabolic changes would potentially lead to reductions in the risk of chronic liver disease, heart disease, type 2 diabetes and liver cancer.Trial registrationAustralia and New Zealand Clinical Trials Register ACTRN: ACTRN12615001010583.

Genetically obese (ob/ob) mice are resistant to the lethal effects of thioacetamide hepatotoxicity

Obesity increases the risk of chronic liver diseases, including viral hepatitis, alcohol-induced liver disease, and non-alcoholic steatohepatitis. In this study, we investigated the effects of obesity in acute hepatic failure using a murine model of thioacetamide (TA)-induced liver injury. Genetically obese ob/ob mice, together with non-obese ob/+ littermates, were subjected to a single intraperitoneal injection of TA, and examined for signs of hepatic injury. ob/ob mice showed a significantly higher survival rate, lower levels of serum alanine aminotransferase and aspartate aminotransferase, and less hepatic necrosis and apoptosis, compared with ob/+ mice. In addition, ob/ob mice exhibited significantly lower levels of malondialdehyde and significantly higher levels of glutathione and antioxidant enzyme activities compared with their ob/+ counterparts. Bioactivation analyses revealed reduced plasma clearance of TA and covalent binding of [14C]TA to liver macromolecules in ob/ob mice. Together, these data demonstrate that genetically obese mice are resistant to TA-induced acute liver injury through diminished bioactivation of TA and antioxidant effects.

Influence of ethnicity on the distribution of genetic polymorphisms associated with risk of chronic liver disease in South American populations.

BackgroundThe global burden of chronic liver disease is rising. Besides environmental, behavioral, viral and metabolic factors, genetic polymorphisms in patatin-like phospholipase-3 (PNPLA3) and vitamin D receptor (VDR) genes have been related to the development of chronic liver disease and progression towards liver cancer. Although their prevalence differs remarkably among ethnic groups, the frequency of these polymorphisms in South American populations -whose genetic background is highly admixed- has been poorly studied. Hence, the aim of this study was to characterize polymorphisms related to chronic liver disease and their association with the genetic ancestry of South American populations.ResultsDNA samples from 258 healthy unrelated male volunteers were analyzed. The frequencies of G and C alleles of rs738409 polymorphism (PNPLA3 gene) were 74 % and 26 %, respectively; whereas the bAt (CCA) haplotype (VDR gene) was observed in 32.5 % of the samples. The GG genotype of PNPLA3 rs738409 and the bAt (CCA) haplotype -associated with an increased risk of chronic liver disease and progression towards liver cancer- were significantly more frequent among samples exhibiting maternal and paternal Native American haplogroups (63.7 % and 64.6 %), intermediate among admixed samples (45.1 % and 44.9 %; p = 0.03) and the lowest for Non-native American ancestry (30.1 % and 29.6 %; p = 0.001 and p = 0.0008).ConclusionsThese results suggest that individuals with Native American ancestry might have a high risk of chronic liver disorders and cancer. Furthermore, these data not only support the molecular evaluation of ancestry in multi-ethnic population studies, but also suggest that the characterization of these variants in South American populations may be useful for establishing public health policies aimed at high risk ethnic communities.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0255-3) contains supplementary material, which is available to authorized users.

Relieving hepatic steatosis: Another benefit of dipeptidyl peptidase-4 (DPP4) inhibitors

Hepatic steatosis is strongly associated with type 2 diabetes (T2DM), both of which are common disorders resulting from obesity [1]. Compared to the general population, there is a higher risk for chronic liver disease and cirrhosis, arising from hepatic steatosis, in diabetic persons [2.3-fold increase of mortality in older onset (diagnosed after age 30) and 4.8-fold increase of mortality in younger onset (diagnosed before age 30)] [2]. Therefore, hepatic steatosis is a key issue in the treatment of T2DM. Furthermore in recent studies, dipeptidyl peptidase-4 (DPP4) inhibition has been suggested to ameliorate hepatic steatosis [3-5]. Oral delivery of glucose induces a greater insulin response than intravenous delivery, a phenomenon called ＂incretin effect＂. This effect is mediated by so called ＂incretin hormones＂, including glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), two small peptides produced by enteroendocrine L cells and K cells, respectively [6]. One primary role of incretins is to promote postprandial insulin secretion. They increase insulin biosynthesis through a PDX-1- dependent pathway [7]. These incretins can be rapidly inactivated by DPP4 [8]. DPP4 inhibitors are a novel class of oral anti-diabetic drugs with several available in the market for the treatment of diabetes: sitagliptin (Januvia, marketed by Merck & Co., FDA approved 2006), vildagliptin (Galvus, marketed by Novartis, European Medicines Agency approved 2007), Saxagliptin (Onglyza, marketed by Bristol-Myers Squibb and AstraZeneca, FDA approved 2009), linagliptin (Tradjenta, marketed by Eli Lily Co and Boehringer Ingelheim), and alogliptin (Nesina, marketed by Takeda Pharmaceutical Co., FDA approved 2013).There are also two DPP4 inhibitors that were approved in Japan in 2012: anagliptin (trade name Suiny) and teneligliptin (trade name Tenelia). DPP4 inhibitors have shown mild effect on glycemia lowering, with a 0.4- 0.8% lowering of HbA1c [9-11]. However, they are weight neutral, easy to use (oral delivery), and well-tolerated (especially with regards to hypoglycemia) and thus widely utilized in clinic. Both clinical trials and experimental evidence indicate DPP4 inhibitors are safe from a cardiovascular standpoint [12- 15]. In a recent paper published in the June 2015 issue of Diabetes, DPP4 inhibition by MK0626, an analog of des-fluoro-sitagliptin (Merck Research Laboratories, West Point, PA), prevented western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function [3]. We showed that DPP4 inhibition improved liver insulin sensitivity and ameliorated hepatic diacylglycerol accumulation, independent of changes in body weight or adiposity. Triglyceride accumulation in the liver is a major cause of hepatic steatosis and hepatic triglyceride export, via very low density lipoprotein (VLDL), is an important mechanism utilized by the liver to eliminate excessive triglycerides [16]. Western diet resulted in a dramatic reduction in liver triglyceride secretion and MK0626 was shown to partially reverse this effect. VLDL export of triglyceride requires microsomal triglyceride transfer protein (MTTP) and Apolipoprotein B (apoB), both of which increased in MK0626-treated western diet-fed mice. We showed that DPP4 inhibition also reduced hepatic diacylglycerol and triglyceride accumulation by enhancing mitochondrial carbohydrate utilization. Hepatic mitochondrial function was significantly improved in MK0626-treated mice as evidenced by increased pyruvate dehydrogenase (PDH) activity and tricarboxylic acid (TCA) cycle flux. Western diet-induced reduction of sirtuin-1 (Sirt1), an important regulator of mitochondrial function [17], was completely prevented by DPP4 inhibition. Consistent with this, Sirt1-regulated genes (including PGC-1α, CPT-1, TFAM and PPAR-α) increased in MK0626-treated mice. DPP4 inhibition also decreased incomplete palmitate oxidation, a marker of hepatic insulin resistance and mitochondrial dysfunction [18], in western diet-fed mice. In summary, there are several recent studies suggesting a role of DPP4 inhibitors in improving diabetes-associated fatty liver disease. Both hepatic lipid remodeling and mitochondrial function modulation may perhaps be involved in this process. However, further studies are required to confirm the relieving effect of DPP4 on fatty liver disease. Effect of other DPP4 inhibitors need to be further examined. Although the improving effect of vildagliptin on hepatic steatosis has been observed in a human study with a total of 44 T2DM patients, this effect in humans needs to be confirmed in future studies with a larger sample size.

Significant reduction in end-stage liver diseases burden through the national viral hepatitis therapy program in Taiwan

A national viral hepatitis therapy program was launched in Taiwan in October 2003. This study aimed to assess the impact of the program on reduction of end-stage liver disease (ESLD) burden. Profiles of national registries of households, cancers, and death certificates were used to derive incidence and mortality of ESLDs from 2000 to 2011. Age-gender-adjusted incidence and mortality rates of hepatocellular carcinoma (HCC) and chronic liver diseases (CLDs) and cirrhosis of adults ages 30-69 years were compared before and after launching the program using Poisson's regression models. A total of 157,570 and 61,823 patients (15%-25% of those eligible for reimbursed treatment) received therapy for chronic hepatitis B and C, respectively, by 2011. There were 42,526 CLDs and cirrhosis deaths, 47,392 HCC deaths, and 74,832 incident HCC cases occurred in 140,814,448 person-years from 2000 to 2011. Male gender and elder age were associated with a significantly increased risk of CLDs and cirrhosis and HCC. Mortality and incidence rates of ESLDs decreased continuously from 2000 to 2003 (before therapy program) through 2004-2007 to 2008-2011 in all age and gender groups. The age-gender-adjusted rate ratio (95% confidence interval; P value) in 2008-2011 was 0.78 (0.76-0.80; P < 0.001) for CLDs and cirrhosis mortality, 0.76 (0.75-0.78; P < 0.005) for HCC mortality, and 0.86 (0.85-0.88; P < 0.005) for HCC incidence using 2000-2003 as the reference period (rate ratio = 1.0). The national viral hepatitis therapy program has significantly reduced the mortality of CLDs and cirrhosis and incidence and mortality of HCC.

Reply

We thank Dr. Vinciguerra for his interest in our article,1 which examined associations between two dietary indices, the Healthy Eating Index-2010 (HEI-2010) and the alternate Mediterranean Diet Score (aMED), with risk of chronic liver disease (CLD) mortality and hepatocellular carcinoma (HCC) incidence in the NIH-AARP Diet and Health Study. He specifically asks about protein intake, pointing out a recently published study examining the association of protein intake with total mortality in NHANES III. In that study, the authors observed that high protein intake was associated with higher mortality among those 65 years or younger, but lower mortality among those aged 66 years or older.2 As discussed in our article, we examined overall dietary patterns because it is difficult to disentangle individual components of diet from each other. For example, individuals who like to eat red meat may be more likely to eat sweets and less likely to eat beans, fruits and vegetables, and whole grains. As we mentioned, both HEI-2010 and aMED have been associated with a variety of disease outcomes.1 Nevertheless, it is also important to examine distinct aspects of diet as well, which is why we included these data. As there may be some confusion about the terms used for each dietary component in our article, we wish to clarify here. The total protein foods component in HEI-2010 specifically refers to lean red meat and poultry, eggs, as well as beans and peas (which are included when the total protein foods standard is not met). It does not include dairy; or seafood and plant proteins (except beans and peas), which are separate components in HEI-2010. We would also like to clarify that the red and processed meat of aMED was actually associated with CLD and HCC in the opposite direction, as mentioned by Vinciguerra, with participants eating more red and processed meat having nonsignificantly higher risk of HCC incidence and CLD mortality than participants eating less. Looking across the sources of protein, we see some evidence for increased risks, with eating more red and processed meat and decreased relative risks with eating more eggs, beans, and peas. Associations for dairy were mixed for each endpoint. As is always the case, and particularly with regard to observational studies, public health recommendations should only be made based on the totality of the evidence, not on the results of individual studies. Unfortunately, relatively few studies of diet in CLD and HCC are available. Future studies of dietary patterns and individual dietary components, such as protein, are needed. Wen-Qing Li, Ph.D.1,2 Yikyung Park, Sc.D.3 Katherine A. McGlynn, Ph.D.4 Albert R. Hollenbeck, Ph.D.5 Philip R. Taylor, M.D., Sc.D.2 Alisa M. Goldstein, Ph.D.2 Neal D. Freedman, Ph.D.3 1Department of Dermatology Brown University Warren Alpert Medical School Providence, RI 2Genetic Epidemiology Branch Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Rockville, MD 3Nutritional Epidemiology Branch Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Rockville, MD 4Hormonal and Reproductive Epidemiology Branch Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Rockville, MD 5AARP (retired) Washington, DC

Association of Coffee Intake With Reduced Incidence of Liver Cancer and Death From Chronic Liver Disease in the US Multiethnic Cohort

Coffee consumption has been proposed to reduce risk for hepatocellular carcinoma (HCC) and chronic liver disease (CLD), but few data are available from prospective, US multiethnic populations. We evaluated the association of coffee intake with HCC and CLD in 162,022 African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites in the US Multiethnic Cohort (MEC). We collected data from the MEC, a population-based prospective cohort study of >215,000 men and women from Hawaii and California, assembled in 1993-1996. Participants reported coffee consumption and other dietary and lifestyle factors when they joined the study. During an 18-year follow-up period, there were 451 incident cases of HCC and 654 deaths from CLD. Hazard rate ratios (RRs) and 95% confidence intervals (CIs) were calculated using Cox regression, adjusting for known HCC risk factors. High levels of coffee consumption were associated with reduced risk of incident HCC and CLD mortality (Ptrend ≤ .0002). Compared with non-coffee drinkers, those who drank 2-3 cups per day had a 38% reduction in risk for HCC (RR = 0.62; 95% CI: 0.46-0.84); those who drank ≥4 cups per day had a 41% reduction in HCC risk (RR = 0.59; 95% CI: 0.35-0.99). Compared with non-coffee drinkers, participants who consumed 2-3 cups coffee per day had a 46% reduction in risk of death from CLD (RR = 0.54; 95% CI: 0.42-0.69) and those who drank ≥4 cups per day had a 71% reduction (RR = 0.29; 95% CI: 0.17-0.50). The inverse associations were similar regardless of the participants' ethnicity, sex, body mass index, smoking status, alcohol intake, or diabetes status. Increased coffee consumption reduces the risk of HCC and CLD in multiethnic US populations.

Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study.

There is no licensed treatment for non-alcoholic fatty liver disease (NAFLD), a condition that increases risk of chronic liver disease, type 2 diabetes and cardiovascular disease. We tested whether 15-18 months treatment with docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA) (Omacor/Lovaza) (4 g/day) decreased liver fat and improved two histologically-validated liver fibrosis biomarker scores (primary outcomes). Patients with NAFLD were randomised in a double blind placebo-controlled trial [DHA+EPA(n=51), placebo(n=52)]. We quantified liver fat percentage (%) by magnetic resonance spectroscopy in three liver zones. We measured liver fibrosis using two validated scores. We tested adherence to the intervention (Omacor group) and contamination (with DHA and EPA) (placebo group) by measuring erythrocyte percentage DHA and EPA enrichment (gas chromatography). We undertook multivariable linear regression to test effects of: a) DHA+EPA treatment (ITT analyses) and b) erythrocyte DHA and EPA enrichment (secondary analysis). Median (IQR) baseline and end of study liver fat% were 21.7 (19.3) and 19.7 (18.0) (placebo), and 23.0 (36.2) and 16.3 (22.0), (DHA+EPA). In the fully adjusted regression model there was a trend towards improvement in liver fat% with DHA+EPA treatment (β=-3.64 (95%CI -8.0,0.8); p=0.1) but there was evidence of contamination in the placebo group and variable adherence to the intervention in the Omacor group. Further regression analysis showed that DHA enrichment was independently associated with a decrease in liver fat% (for each 1% enrichment, β=-1.70 (95%CI -2.9,-0.5); p=0.007). No improvement in the fibrosis scores occurred. Conclusion. Erythrocyte DHA enrichment with DHA+EPA treatment is linearly associated with decreased liver fat%. Substantial decreases in liver fat% can be achieved with high percentage erythrocyte DHA enrichment in NAFLD. (Hepatology 2014;).

Pharmacokinetics in patients with chronic liver disease and hepatic safety of incretin-based therapies for the management of type2 diabetes mellitus.

Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients.

Incomplete hepatitis B immunization, maternal carrier status, and increased risk of liver diseases: A 20-year cohort study of 3.8 million vaccinees

Hepatitis B immunization has been documented to prevent fulminant hepatic failure (FHF) and hepatocellular carcinoma (HCC) by historical comparison studies in Taiwan. This study aimed to assess long-term risks and predictors of various liver diseases associated with incomplete immunization in 3.8 million vaccinees. Profiles of the National Hepatitis B Immunization Registry, National Cancer Registry, and National Death Certification Registry were linked to ascertain newly diagnosed cases of HCC and deaths from FHF and chronic liver diseases (CLDs) from infancy to early adulthood of 3,836,988 newborn vaccinees. Cox's proportional hazards models were used to estimate hazard ratios (HRs) for various risk predictors. There were 49 newly developed cases of HCC, 73 deaths from FHF, and 74 deaths from CLDs during the follow-up of 41,854,715 person-years. There were striking differences between unvaccinated and vaccinated newborns after the launch of a national immunization program for HCC incidence (0.293 vs. 0.117 per 100,000 person-years), FHF mortality (0.733 vs. 0.174 per 100,000 person-years), and CLD mortality (2.206 vs. 0.177 per 100,000 person-years). Among vaccinees, incomplete immunization was the most important risk predictor of HCC, FHF, and CLDs, showing an HR (95% confidence interval, P value) of 2.52 (1.25-5.05; P = 0.0094), 4.97 (3.05-8.11; P < 0.0001), and 6.27 (3.62-10.84; P < 0.0001), respectively, after adjustment for maternal hepatitis B serostatus. Hepatitis B immunization can significantly prevent the long-term risk of HCC, FHF, and CLDs from infancy to early adulthood. Incomplete immunization with hepatitis B immunoglobulin or vaccines was the most important risk predictor of the liver disease among vaccinees.

Alpha‐1‐antitrypsin deficiency: from genoma to liver disease. PiZ mouse as model for the development of liver pathology in human

Homozygous individuals with alpha-1-antitrypsin deficiency (AATD) type PiZ have an increased risk of chronic liver disease and hepatocellular carcinoma (HCC). It is noteworthy that HCCs are composed by hepatocytes without accumulation of AAT, but the reason for this remains unclear. The aim of this study was to determine liver pathology in PiZ mice, focusing the attention on the distribution of AAT globules in normal liver, regenerative foci and neoplastic nodules. Liver of 79 PiZ mice and 18 wild type (Wt) was histologically analysed for steatosis, clear cell foci, hyperplasia and neoplasia. The expression of human-AAT transgene and murine AAT, in non-neoplastic liver and in hyperplastic/neoplastic nodules was tested by qPCR and qRT-PCR. RT-PCR was used to study expression of hepatic markers: albumin, α-foetoprotein, transthyretin, AAT, glucose-6-phospate, tyrosine aminotransferase. Liver pathology was seen more frequently in PiZ (47/79) than in Wt (5/18) and its development was age related. In older PiZ mice (18-24 m), livers showed malignant tumours (HCC and angiosarcoma) (17/50), hyperplastic nodules (28/50), non-specific changes (33/50), whereas only 9/50 were normal. Both human-AATZ DNA and mRNA showed no differences between tumours/nodules and normal liver, while murine-AAT mRNA was reduced in tumours/nodules. Accumulation of AAT is associated with an increased risk of liver nodules. The presence of globule-devoid hepatocytes and the reduced expression of murine-AAT mRNA in hyperplastic and neoplastic nodules suggest that these hepatic lesions in AATD could originate from proliferating dedifferentiated cells, lacking AAT storage and becoming capable of AFP re-expression.

Chronic hepatitis C in Swedish subjects receiving opiate substitution therapy—Factors associated with advanced fibrosis

Opiate substitution therapy (OST) reduces the risk of death from directly drug-related causes in heroin users, allowing other chronic health problems to emerge. People who inject drugs (PWID) are exposed to hepatitis C virus (HCV), with an associated risk of chronic liver disease. We investigated HCV prevalence and liver-related morbidity in a cohort of OST recipients, and analyzed factors associated with significant hepatic fibrosis. All patients registered on 1 April 2008 in 4 clinics providing OST in the 3 largest cities in Sweden were eligible for inclusion. HCV viremic subjects were evaluated for fibrosis stage by liver biopsy, transient elastometry (TE), and/or a biochemical fibrosis index (Göteborg University Cirrhosis Index; GUCI). Factors associated with severity of fibrosis were determined by logistic regression analysis. Out of 524 eligible patients, 277 consented to enrolment. Two hundred and thirty-six subjects (88%) were anti-HCV-positive, and 162 of these were viremic (69%). Significant liver fibrosis (defined as Ishak stages F3-F6, TE value ≥ 8.85 kPa, or GUCI > 0.33) was found in 69 out of 103 (67%) tested viremic patients, and was associated with alcohol intake (p = 0.03), higher body mass index (BMI; p = 0.04), and the presence of anti-HBc antibodies (indicating exposure to hepatitis B virus (HBV); p = 0.02). Significant liver fibrosis was detected in two-thirds of HCV viremic OST recipients in this cohort, and was associated with alcohol use, high BMI, and exposure to HBV. These findings indicate that the management of HCV and associated risk factors should be emphasized in Swedish OST programs.

The PNPLA3 I148M variant and chronic liver disease: When a genetic mutation meets nutrients

The isoleucine to methionine substitution at position 148 in the patatin-like phospholipase domain containing 3 protein (PNPLA3; I148M variant, rs738409) is associated with liver fat accumulation and an increased risk of chronic liver disease ranging from hepatitis to hepatocellular carcinoma. This review discusses the interaction between the PNPLA3 I148M variant and obesity/intake of specific nutrients in determining the susceptibility to liver disease. We present the results of several studies showing that obesity or alcohol abuse enhances the effect of the PNPLA3 I148M variant on the liver. We also show that specific nutrients interact with the PNPLA3 I148M variant in modulating liver disease susceptibility.

Predictors of chronic liver disease in individuals with human immunodeficiency virus infection

Introduction. Chronic liver disease (CLD) is becoming a major cause of mortality in patients who are positive with human immunodeficiency virus (HIV). Our aim was to assess the prevalence of CLD in HIV+ individuals.Material and methods. We utilized the National Health and Nutrition Examination Survey (1999-2008) to assess the association of CLD with HIV infection. In eligible participants (18-49 years), HIV infection was defined as positive anti-HIV by enzyme immunoassay further confirmed by Western blot. The diagnosis of CLD included chronic hepatitis C (CH-C), alcohol-related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Clinic-demographic and laboratory parameters were used to assess differences between those with and without HIV infection.Results. 14,685 adults were included. Of those, 0.43 ± 0.08% were HIV-positive and 13.8% had evidence of CLD, including 26.3% in HIV-positive individuals and 13.7% in HIV-negative controls (p = 0.0341). In the U.S. population, independent predictors of CLD included HIV positivity [OR = 1.96 (1.02-3.77), p = 0.04], older age [OR = 1.03 (1.02-1.03), p < 0.0001], male gender [OR = 2.15 (1.89-2.44), p < 0.0001] and obesity [OR = 2.10 (1.82-2.43), p < 0.0001], while African American race/ethnicity was associated with lower risk for CLD [OR = 0.68 (0.58-0.80), p < 0.0001].Conclusions. CLD is common in HIV positive individuals. With successful long term treatment of HIV, management of CLD will continue to remain very important in these patients.

Increased Risk of Chronic Liver Disease in Patients with Schizophrenia: A Population-Based Cohort Study

To investigate the prevalence and incidence of chronic liver disease in patients with schizophrenia in Taiwan. We used a random sample of 661,266 subjects aged ≥ 18 from the National Health Research Institute database in the year 2000. Subjects with at least one primary diagnosis of schizophrenia (The International Classification of Diseases, Ninth Revision, Clinical Modification: 295) in 2000 were selected. Patients with a primary or secondary diagnosis of chronic liver disease (The International Classification of Diseases, Ninth Revision, Clinical Modification: 571) were also defined. We compared the prevalence and associated factors of chronic liver disease between patients with schizophrenia and the general population in 2000. We also compared the incidence of chronic liver disease in patients with schizophrenia and the general population from 2001 through 2010. The prevalence of chronic liver disease in patients with schizophrenia (7.0%) was 1.27 times as high as that of the general population (6.1%) in 2000. The average annual incidence of chronic liver disease in patients with schizophrenia from 2001-2010 was also higher than that of the general population (2.9% vs 2.5%, risk ratio, 1.15; 95% confidence interval, 1.07-1.24). Younger patients with schizophrenia were found to have a much higher prevalence and incidence than those in the general population, and diabetes was a risk factor for patients with schizophrenia in developing chronic liver disease. Patients with schizophrenia exhibited a significantly higher prevalence and incidence of chronic liver disease than those in the general population, and younger patients with schizophrenia have a much higher prevalence and incidence than those in the general population. Co-morbidity with diabetes was the primary risk factor for patients with schizophrenia to develop chronic liver disease.

115 INFLUENCE OF BMI AND ALCOHOL ON LIVER-RELATED MORBIDITY AND MORTALITY IN A COHORT OF 108,000 WOMEN FROM THE GENERAL POPULATION FROM UKCTOCS

Introduction Alcohol and fat are major causes of chronic liver disease (CLD), however their relative influences are not well understood. We aimed to determine liver-related morbidity and mortality attributable to fat and alcohol by stratifying a cohort of 202,638 women according to BMI and alcohol intake. Methods 107,742 women participating in the UK Collaborative Trial of Ovarian Cancer Screening where self-reported height, weight and alcohol intake were available were included. First episode related to cirrhosis (ICD-10 codes K70, K73, K74) either from inpatient Hospital Episode Statistics or death certificate was recorded following trial entry. Participants were stratified by low or high BMI ( Results Median age at recruitment was 60 years (50–75). Mean BMI was 26.4 kg/m2. There were 90 events (54 inpatient episodes and 36 deaths). There was no difference in risk of event between the BMI groups, however there was a significant increase in risk in the high alcohol group (Log-Rank Conclusion These data indicate that the combination of high BMI and alcohol intake is associated with a synergistically increased risk of CLD. Alcohol may be the more significant contributing factor. Further work will define thresholds for each risk factor that independently and in combination increase CLD risk. Disclosure of Interest None Declared

Biochemical Evaluation of Some Liver Enzymes in Type 2 Diabetes Mellitus Iraqi Patients

Liver is the main organ of glucose storage as glycogen and metabolism.This key function of liver exposes it to many types of diseases with metabolic disorders, particularly diabetes.Many studies had showed that; diabetes is associated with high risk of chronic liver disease, primary liver cancers and liver cirrhosis. However, most of these studies were performed in Western countries, and there is a lack of information from Iraq.&#x0D; The aim of the study is to evaluate some hepatic enzymes in Iraqi patients with chronic type 2 diabetes mellitus (T2DM) compared with healthy volunteers.Sixty Iraqi subjects with type 2 DM, and sixty healthy volunteers as control group were included in this study. The levels of (Glucose, ALT, AST, GGT, and ALP) were measured.The mean values of concentration levels of ALT, AST and GGT were significantly higher in T2DM than the control group (P≤ 0.001 for ALT, GGT and P≤ 0.05 for AST). In contrast, there is no significant difference in ALP levels in the two study groups.The results of this study are in accordance with previously reported high prevalence rates of abnormal liver enzymes in patients with type 2 diabetes mellitus in other populations.

Occult hepatitis B virus and the risk for chronic liver disease: A meta-analysis

BackgroundThe role of occult hepatitis B virus infection as a cause of liver disease is still debated although many studies found a higher prevalence of this condition in subjects than those without liver disease compared. A recent meta-analysis showed an increased risk of hepatocellular carcinoma for occult hepatitis B virus infection. AimsWe carried out a meta-analysis of observational studies to summarize the existing evidence and assess quantitatively the association between occult hepatitis B virus infection and chronic liver disease. MethodsWe searched the available literature on this issue published up to May 2012 using PubMed and EMBASE. All articles that provided enough information to estimate the chronic liver disease risk associated with occult hepatitis B virus infection were selected. Fourteen studies were retrieved. ResultsA total of 1503 subjects with (cases) and 2052 without chronic liver disease (controls) were included. The summary odds ratio for chronic liver disease from all studies was 8.9 (95% confidence interval: 4.1–19.5). The meta-analysis restricted to 7 studies with more precise effect estimate (wt%>8%) provided a lower odds ratio estimate (odds ratio=3.9; 95% confidence interval: 1.7–9.0). ConclusionsThese findings suggest a relevant association between occult hepatitis B virus infection and chronic liver disease, confirming the hypothesis that hepatitis B virus may play a pathogenic role even in the “occult” status.

142 Prospective Multicenter Pediatric Cohort Study: Patients With Liver Enzyme Elevations in the First 3 Months After Diagnosis of Inflammatory Bowel Disease are at Increased Risk of Chronic Liver Disease

142 Prospective Multicenter Pediatric Cohort Study: Patients With Liver Enzyme Elevations in the First 3 Months After Diagnosis of Inflammatory Bowel Disease are at Increased Risk of Chronic Liver Disease

Upper normal threshold of serum alanine aminotransferase in identifying individuals at risk for chronic liver disease

Serum alanine aminotransferase (ALT) is an easily available, low-cost screening tool for detecting silent chronic liver disease. Recent studies have suggested that the currently accepted healthy ALT thresholds be lowered. In this retrospective cross-sectional study, we determined upper thresholds for ALT values in a nationally representative healthy cohort (n = 3337) from the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV). Sensitivity and specificity of the currently used ALT threshold (40 IU/L, regardless of gender) was compared against study-derived, gender-specific ALT thresholds for detecting individuals at risk for chronic liver disease in 27 913 health check-up participants. The 95th percentile levels for ALT in healthy weight, metabolically normal, liver disease-free KNHANES participants were 34 IU/L for men and 25 IU/L for women. The prevalence of ALT elevation among health check-up participants was 11.0% in currently used thresholds, and increased to 22.6% with study-derived, gender-specific thresholds. Of the population who were additionally defined to have elevated ALT levels under new ALT threshold, 65.7% were at risk for chronic liver disease. Sensitivity for detecting individuals at risk for chronic liver disease improved from 18 to 33% with new thresholds whereas a trade-off in specificity (from 96 to 88%) was observed. It is recommendable to lower the current ALT thresholds to better identify individuals at risk for chronic liver disease.