Effect of lifetime alcohol consumption on the histological severity of non‐alcoholic fatty liver disease

Background & Aims Non‐alcoholic fatty liver disease ( NAFLD ) is defined based on recent alcohol consumption; however, remote or lifetime alcohol consumption is not taken into account. It is not known whether lifetime alcohol consumption contributes to the severity of disease in patients with NAFLD . To determine the effect of lifetime alcohol consumption on the histological severity in patients with NAFLD . Patients & Methods Adults >18 years of age with presumed NAFLD and alcohol consumption <40 g/week were enrolled. Lifetime alcohol consumption was determined using a questionnaire. Patients with a history of long‐term alcohol abuse or dependence were excluded. A liver biopsy was reviewed by a single pathologist in a blinded fashion. Demographic, clinical and histological findings were compared in those who had regular alcohol consumption and those who did not. Results A total of 77 patients had fatty liver on biopsy. Fifty‐two patients had a history of regular alcohol consumption. The median lifetime cumulative alcohol intake was 24 gram‐years. On multivariable analysis, increasing age ( OR 1.07, 95% CI 1.01–1.14) was associated with severe liver disease, whereas alcohol consumption of ≥24 gram‐years was associated with less severe disease ( OR 0.26, 95% CI 0.07–0.97, P  = 0.04). Patients who continued to consume alcohol or had been abstinent for ≤1 year had less severe disease. Conclusion Some degree of regular alcohol consumption over the course of a lifetime compared to minimal intake appears to have a protective effect on the histological severity of liver disease among patients with strictly defined NAFLD .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102218/1/liv12230.pd

Ethanol and Acetaminophen Synergistically Induce Hepatic Aggregation and TCH346-Insensitive Nuclear Translocation of GAPDH

The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) signals during cellular stress via several post-translational modifications that change its folding properties, protein-protein interactions and sub-cellular localization. We examined GAPDH properties in acute mouse liver injury due to ethanol and/or acetaminophen (APAP) treatment. Synergistic robust and time-dependent nuclear accumulation and aggregation of GAPDH were observed only in combined, but not individual, ethanol/APAP treatments. The small molecule GAPDH-targeting compound TCH346 partially attenuated liver damage possibly via mitochondrial mechanisms, and independent of nuclear accumulation and aggregation of GAPDH. These findings provide a novel potential mechanism for hepatotoxicity caused by combined alcohol and acetaminophen exposure

Risk of colorectal cancer in self-reported inflammatory bowel disease and modification of risk by statin and NSAID use

BACKGROUND: Statins and nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with reduced risk of colorectal cancer (CRC) in some studies. The objective of this study was to quantify the relative risk of inflammatory bowel disease (IBD) as a risk factor for CRC and to estimate whether this risk may be modified by long-term use of NSAIDs or statins. METHODS: The Molecular Epidemiology of Colorectal Cancer study is a population-based, case-control study of incident colorectal cancer in northern Israel and controls matched by age, sex, clinic, and ethnicity. Personal histories of IBD and medication use were measured by structured, in-person interview. The relative risk of IBD and effect modification by statins and NSAIDs were quantified by conditional and unconditional logistic regression. RESULTS: Among 1921 matched pairs of CRC cases and controls, a self-reported history of IBD was associated with a 1.9-fold increased risk of CRC (95% confidence interval [CI], 1.12-3.26). Long-term statin use was associated with a reduced risk of both IBD-associated CRC (odds ratio [OR] = 0.07; 95% CI, 0.01-0.78) and non-IBD CRC (OR = 0.49; 95% CI, 0.39-0.62). Stratified analysis suggested that statins may be more protective among those with IBD (ratio of OR = 0.14; 95% CI, 0.01-1.31; P = .51), although not statistically significant. NSAID use in patients with a history of IBD was suggestive of reduced risk of CRC but did not reach statistical significance (OR = 0.47; 95% CI, 0.12-1.86). CONCLUSIONS: The risk of CRC was elevated 1.9-fold in patients with IBD. Long-term statin use was associated with reduced risk of CRC in patients with IBD. Cancer 2011. © 2010 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/84387/1/25731_ftp.pd

Metabolic Syndrome Is Associated with Greater Histologic Severity, Higher Carbohydrate, and Lower Fat Diet in Patients with NAFLD

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73077/1/j.1572-0241.2006.00719.x.pd

Microsatellite instability and loss of heterozygosity at DNA mismatch repair gene loci occurs during hepatic carcinogenesis

DNA mismatch repair is an important mechanism involved in maintaining the fidelity of genomic DNA. Defective DNA mismatch repair is implicated in a variety of gastrointestinal and other tumors; however, its role in hepatocellular carcinoma (HCC) has not been assessed. Formalin-fixed, paraffin-embedded archival pathology tissues from 46 primary liver tumors were studied by microdissection and microsatellite analysis of extracted DNA to assess the degree of microsatellite instability, a marker of defective mismatch repair, and to determine the extent and timing of allelic loss of two DNA mismatch repair genes, human Mut S homologue-2 (hMSH2) and human Mut L homologue-1 (hMLH1), and the tumor suppressor genes adenomatous polyposis coli gene (APC), p53, and DPC4. Microsatellite instability was detected in 16 of the tumors (34.8%). Loss of heterozygosity at microsatellites linked to the DNA mismatch repair genes, hMSH2 and/or hMLH1, was found in 9 cases (19.6%), usually in association with microsatellite instability. Importantly, the pattern of allelic loss was uniform in 8 of these 9 tumors, suggesting that clonal loss had occurred. Moreover, loss at these loci also occurred in nonmalignant tissue adjacent to 4 of these tumors, where it was associated with marked allelic heterogeneity. There was relatively infrequent loss of APC, p53, or DPC4 loci that appeared unrelated to loss of hMSH2 or hMLH1 gene loci. Loss of heterozygosity at hMSH2 and/or hMLH1 gene loci, and the associated microsatellite instability in premalignant hepatic tissues suggests a possible causal role in hepatic carcinogenesis in a subset of hepatomas.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34772/1/510280114_ftp.pd

Human papillomavirus is not associated with colorectal cancer in a large international study

Recent publications have reported an association between colon cancer and human papillomaviruses (HPV), suggesting that HPV infection of the colonic mucosa may contribute to the development of colorectal cancer. The GP5+/GP6+ PCR reverse line blot method was used for detection of 37 types of human papillomavirus (HPV) in DNA from paraffin-embedded or frozen tissues from patients with colorectal cancer (n = 279) and normal adjacent tissue (n = 30) in three different study populations, including samples from the United States (n = 73), Israel (n = 106) and Spain (n = 100). Additionally, SPF10 PCR was run on all samples (n = 279) and the Innogenetics INNO-LiPA assay was performed on a subset of samples (n = 15). All samples were negative for all types of HPV using both the GP5+/GP6+ PCR reverse line blot method and the SPF10 INNO-LiPA method. We conclude that HPV types associated with malignant transformation do not meaningfully contribute to adenocarcinoma of the colon

Identification of a Specific Vimentin Isoform That Induces an Antibody Response in Pancreatic Cancer

Pancreatic cancer has a poor prognosis, in part due to lack of early detection. The identification of circulating tumor antigens or their related autoantibodies provides a means for early cancer diagnosis. We have used a proteomic approach to identify proteins that commonly induce a humoral response in pancreatic cancer. Proteins from a pancreatic adenocarcinoma cell line (Panc-1) were subjected to two-dimensional PAGE, followed by Western blot analysis in which individual sera were tested for autoantibodies. Sera from 36 newly diagnosed patients with pancreatic cancer, 18 patients with chronic pancreatitis and 15 healthy subjects were analyzed. Autoantibodies were detected against a protein identified by mass spectrometry as vimentin, in sera from 16/36 patients with pancreatic cancer (44.4%). Only one of 18 chronic pancreatitis patients and none of the healthy controls exhibited reactivity against this vimentin isoform. Interestingly, none of several other isoforms of vimentin detectable in 2-D gels exhibited reactivity with patient sera. Vimentin protein expression levels were investigated by comparing the integrated intensity of spots visualized in 2-D PAGE gels of various cancers. Pancreatic tumor tissues showed greater than a 3-fold higher expression of total vimentin protein than did the lung, colon, and ovarian tumors that were analyzed. The specific antigenic isoform was found at 5–10 fold higher levels. The detection of autoantibodies to this specific isoform of vimentin may have utility for the early diagnosis of pancreatic cancer

A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C

Information on the stage of liver fibrosis is essential in managing chronic hepatitis C (CHC) patients. However, most models for predicting liver fibrosis are complicated and separate formulas are needed to predict significant fibrosis and cirrhosis. The aim of our study was to construct one simple model consisting of routine laboratory data to predict both significant fibrosis and cirrhosis among patients with CHC. Consecutive treatment-naive CHC patients who underwent liver biopsy over a 25-month period were divided into 2 sequential cohorts: training set (n = 192) and validation set (n = 78). The best model for predicting both significant fibrosis (Ishak score ≥ 3) and cirrhosis in the training set included platelets, aspartate aminotransferase (AST), and alkaline phosphatase with an area under ROC curves (AUC) of 0.82 and 0.92, respectively. A novel index, AST to platelet ratio index (APRI), was developed to amplify the opposing effects of liver fibrosis on AST and platelet count. The AUC of APRI for predicting significant fibrosis and cirrhosis were 0.80 and 0.89, respectively, in the training set. Using optimized cut-off values, significant fibrosis could be predicted accurately in 51% and cirrhosis in 81% of patients. The AUC of APRI for predicting significant fibrosis and cirrhosis in the validation set were 0.88 and 0.94, respectively. In conclusion, our study showed that a simple index using readily available laboratory results can identify CHC patients with significant fibrosis and cirrhosis with a high degree of accuracy. Application of this index may decrease the need for staging liver biopsy specimens among CHC patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34794/1/510380230_ftp.pd

Evolution of hepatic steatosis in patients with advanced hepatitis C: Results from the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial

Hepatic steatosis is a common histologic feature in patients with chronic hepatitis C (CHC) but there are no large longitudinal studies describing the progression of steatosis in CHC. We examined changes in steatosis on serial biopsies among CHC patients participating in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. All 1050 patients in the trial had advanced fibrosis at baseline biopsy and were documented not to have had a sustained virological response to peginterferon and ribavirin. Most (94%) patients had genotype 1 infection. At least one protocol follow-up biopsy was read on 892 patients, and 699 had the last biopsy performed 3.5 years after randomization. At enrollment, 39% had cirrhosis and 61% had bridging fibrosis; 18%, 41%, 31%, and 10% had steatosis scores of 0, 1, 2, and 3 or 4, respectively. The mean steatosis score decreased in the follow-up biopsies in both the interferon-treated patients and controls with no effect of treatment assignment ( P = 0.66). A decrease in steatosis score by ≥1 point was observed in 30% of patients and was associated with both progression to cirrhosis and continued presence of cirrhosis ( P = 0.02). Compared to patients without a decrease in steatosis, those with a decrease in steatosis had worse metabolic parameters at enrollment, and were more likely to have a decrease in alcohol intake, improvement in metabolic parameters, and worsening liver disease (cirrhosis, esophageal varices, and deterioration in liver function). Conclusion: Serial biopsies demonstrated that in patients with CHC, steatosis recedes during progression from advanced fibrosis to cirrhosis. Decreased alcohol intake and improved metabolic parameters are associated with a decline in steatosis and may modulate hepatitis C progression. (H EPATOLOGY 2009.)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63058/1/22865_ftp.pd