This study aims to investigate the etiological relationship among hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol as risk factors in a cohort of hepatocellular carcinoma (HCC) patients from India. The clinical and biochemical profiles and tumor characteristics in the HCC cases were also evaluated.A total of 357 consecutive cases of HCC fulfilling the diagnostic criteria from the Barcelona-2000 EASL conference were included in the study. The blood samples were evaluated for serological evidence of HBV and HCV infection, viral load, and genotypes using serological tests, reverse transcription-polymerase chain reaction, and restriction fragment length polymorphism.The male/female ratio for the HCC cases was 5.87:1. Majority of the HCC patients (33.9%) were 50 to 59 years of age, with a mean age of 4±13.23 years. More than half the cases (60.8%) had underlying cirrhosis at presentation. Among the HCC patients, 68.9% were HBV related, 21.3% were HCV related, 18.8% were alcoholic, and 18.2% were of cryptogenic origin. The presence of any marker positive for HBV increased the risk for developing HCC by almost 27 times [OR: 27.33; (12.87-60.0)]. An increased risk of 10.6 times was observed for HCC development for cases positive for any HCV marker [OR: 10.55; (3.13-42.73)]. Heavy alcohol consumption along with HCV RNA positivity in cirrhotic patients was found to be a risk for developing HCC by 3 folds [OR: 3.17; (0.37-70.71)].Patients of chronic HBV infection followed by chronic HCV infection were at higher risk of developing HCC in India. Chronic alcohol consumption was found to be a risk factor in cirrhotic cases only when it was associated with HCV RNA positivity. Most of the patients had a large tumor size (>5 cm) with multiple liver nodules, indicating an advanced stage of the disease thus making curative therapies difficult.

AIMS:

Prevalence of chronic hepatitis C virus (HCV) infection among alcoholics is thought to be higher than in the general population, although prevalence rates reported are quite variable. Our study is aimed to analyze HCV prevalence in a cohort of alcoholics and to perform a systematic review on this topic.

PATIENTS AND METHODS:

A total of 396 alcoholic patients consecutively referred to our Alcoholism Unit were included. HCV infection status and other clinical variables were recorded for each patient. Variables associated with HCV infection were analyzed by means of logistic regression. Additionally, we performed a systematic review focused on previous studies on this topic.

RESULTS:

Among our alcoholic patients, 14 of them (3.53%) had chronic HCV infection. Variables independently associated with HCV infection were female gender, injection drug use (IDU) and the presence of alcoholic liver disease (ALD). Twenty-four studies analyzing HCV prevalence in alcoholic patients were included in our systematic review, showing prevalence rates of HCV infection ranging from 2.1 to 51% and an average weighted prevalence of 16.32%.

CONCLUSION:

In our series, the prevalence rate of chronic HCV infection among alcoholic patients is lower than previously reported, which is probably explained by the relatively low number of patients with ALD or IDU in our sample. Prevalence rates previously published are quite different and the presence of ALD and/or IDU can act as confounding factors for HCV prevalence among alcoholics.

Interleukin-6 (IL-6) is a pleiotropic cytokine which is expressed in many inflammatory cells in response to different types of stimuli, regulating a number of biological processes. The IL-6 gene is polymorphic in both the 5' and 3' flanking regions and more than 150 single nucleotide polymorphisms have been identified so far. Genetic polymorphisms of IL-6 may affect the outcomes of several diseases, where the presence of high levels of circulating IL-6 have been correlated to the stage and/or the progression of the disease itself. The -174 G/C polymorphism is a frequent polymorphism, that is located in the upstream regulatory region of the IL-6 gene and affects IL-6 production. However, the data in the literature on the genetic association between the -174 G/C polymorphism and some specific liver diseases characterized by different etiologies are still controversial. In particular, most of the studies are quite unanimous in describing a correlation between the presence of the high-producer genotype and a worse evolution of the chronic liver disease. This is valid for patients with hepatitis C virus (HCV)-related chronic hepatitis and liver cirrhosis and hepatocellular carcinoma (HCC) whatever the etiology. Studies in hepatitis B virus-related chronic liver diseases are not conclusive, while specific populations like non alcoholic fatty liver disease/non-alcoholic steatohepatitis, autoimmune and human immunodeficiency virus/HCV co-infected patients show a higher prevalence of the low-producer genotype, probably due to the complexity of these clinical pictures. In this direction, a systematic revision of these data should shed more light on the role of this polymorphism in chronic liver diseases and HCC.

Silymarin, an extract of the seeds of milk thistle (Silybum marianum), is used as an herbal remedy, particularly for hepatoprotection. The main chemical constituents in silymarin are seven flavonolignans. Recent studies explored the non-selective methylation of one flavonolignan, silybin B, and then tested those analogues for cytotoxicity and inhibition of both cytochrome P450 (CYP) 2C9 activity in human liver microsomes and hepatitis C virus infection in a human hepatoma (Huh7.5.1) cell line. In general, enhanced bioactivity was observed with the analogues. To further probe the biological consequences of methylation of the seven major flavonolignans, a series of 7-O-methylflavonolignans were generated. Optimization of the reaction conditions permitted selective methylation at the phenol in the 7-position in the presence of each metabolite's 4-5 other phenolic and/or alcoholic positions without the use of protecting groups. These 7-O-methylated analogues, in parallel with the corresponding parent compounds, were evaluated for cytotoxicity against Huh7.5.1 cells; in all cases the monomethylated analogues were more cytotoxic than the parent compounds. Moreover, parent compounds that were relatively non-toxic and inactive or weak inhibitors of hepatitis C virus infection had enhanced cytotoxicity and anti-HCV activity upon 7-O-methylation. Also, the compounds were tested for inhibition of major drug metabolizing enzymes (CYP2C9, CYP3A4/5, UDP-glucuronsyltransferases) in pooled human liver or intestinal microsomes. Methylation of flavonolignans differentially modified inhibitory potency, with compounds demonstrating both increased and decreased potency depending upon the compound tested and the enzyme system investigated. In total, these data indicated that monomethylation modulates the cytotoxic, antiviral, and drug interaction potential of silymarin flavonolignans.

To survey gastroenterologists and hepatologists regarding their current views on treating hepatitis C virus (HCV) infected alcoholic hepatitis (AH) patients.A sixteen item questionnaire was electronically mailed to gastroenterologists and hepatologists. A reminder was sent after 2 mo to increase the response rate. Participation of respondents was confidential. Accessing secured web site to respond to the questionnaire was considered as informed consent. Responses received on the secured website were downloaded in an excel sheet for data analysis.Analyzing 416 responses to 1556 (27% response rate) emails, 57% respondents (56% gastroenterologists) reported HCV prevalence > 20% amongst AH patients. Sixty nine percent often treated AH and 46% preferred corticosteroids (CS). Proportion of respondents with consensus (75% or more respondents agreeing on question) on specific management of HCV infected AH were: routine HCV testing (94%), HCV not changing response to CS (80%) or pentoxifylline (91%), no change in approach to treating HCV infected AH (75%). None of respondent variables: age, specialty, annual number of patients seen, and HCV prevalence could predict respondent to be in consensus on any of or all 4 questions. Further, only 4% would choose CS for treating HCV infected AH as opposed to 47% while treating HCV negative AH.Gastroenterologists and hepatologists believe that AH patients be routinely checked for HCV. However, there is lack of consensus on choice of drug for treatment and outcome of HCV positive AH patients. Studies are needed to develop guidelines for management of HCV infected AH patients.

Liver progenitor cells, thought to reside in the terminal bile ductules (canals of Hering) at the interface between portal tracts and liver lobule, proliferate during severe hepatic injury. They may contribute to hepatocyte regeneration, or even take over this role if the liver injury is severe and associated with an impairment of hepatocyte proliferation. They represent promising targets in an attempt to stimulate liver regeneration in chronic diseases. Recent studies on liver progenitor cell recruitment in response to injury in chronic viral hepatitis B, hepatitis C, alcoholic and non-alcoholic liver diseases are presented in this review, as well as clinical trials in which stem cells are administered as a therapeutic intervention to promote liver regeneration. Liver progenitor cell expansion is part of the disease process itself and may contribute to disease severity, mainly related to fibrosis. As the majority of these progenitor cells tend to acquire a biliary phenotype, their role in liver repair and improvement in liver function remains to be addressed. Present data on stem cell therapy are heterogeneous in terms of methods and endpoints; thus, results need to be carefully examined prior to drawing a conclusion on possible benefits.

Metabolic abnormalities are common in HIV-infected individuals on antiretroviral therapy (ART), but the biochemical details and underlying mechanisms of these disorders have not been defined.Untargeted metabolomic profiling of plasma was performed for 32 HIV patients with low nadir CD4 counts (<300 cells/ul) on protease inhibitor (PI)-based ART and 20 healthy controls using liquid or gas chromatography and mass spectrometry. Effects of Hepatitis C (HCV) co-infection and relationships between altered lipid metabolites and markers of inflammation, microbial translocation, and hepatic function were examined. Unsupervised hierarchical clustering, principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), Random forest, pathway mapping, and metabolite set enrichment analysis (MSEA) were performed using dChip, Metaboanalyst, and MSEA software.A 35-metabolite signature mapping to lipid, amino acid, and nucleotide metabolism distinguished HIV patients with advanced disease on PI-based ART from controls regardless of HCV serostatus (p<0.05, false discovery rate (FDR)<0.1). Many altered lipids, including bile acids, sulfated steroids, polyunsaturated fatty acids, and eicosanoids, were ligands of nuclear receptors that regulate metabolism and inflammation. Distinct clusters of altered lipids correlated with markers of inflammation (interferon-α and interleukin-6), microbial translocation (lipopolysaccharide (LPS) and LPS-binding protein), and hepatic function (bilirubin) (p<0.05). Lipid alterations showed substantial overlap with those reported in non-alcoholic fatty liver disease (NALFD). Increased bile acids were associated with noninvasive markers of hepatic fibrosis (FIB-4, APRI, and YKL-40) and correlated with acylcarnitines, a marker of mitochondrial dysfunction.Lipid alterations in HIV patients receiving PI-based ART are linked to markers of inflammation, microbial translocation, and hepatic function, suggesting that therapeutic strategies attenuating dysregulated innate immune activation and hepatic dysfunction may be beneficial for prevention and treatment of metabolic disorders in HIV patients.

The case of a patient who developed toxic epidermal necrolysis (TEN) after treatment with rifaximin for hepatic encephalopathy is reported.A 62-year-old Caucasian woman with a history of alcohol abuse arrived at the emergency room with complaints of abdominal pain and acute onset of jaundice, likely secondary to alcoholic hepatitis. Laboratory tests and multiple imaging studies conducted in the emergency department revealed signs of chronic liver disease and common bile duct dilation with ascites. At admission, she had low concentrations of serum sodium, serum chloride, serum creatinine, and serum albumin and elevated liver function test values. On hospital day 7, the patient developed an altered mental status, which was diagnosed as toxic metabolic encephalopathy, primarily hepatic in origin. The patient was given lactulose 20 g via nasogastric tube every 12 hours and rifaximin 400 mg orally every 8 hours. The patient received only two doses of the rifaximin before it was discontinued. On hospital day 27, oral rifaximin 550 mg twice daily was initiated. After 12 days of rifaximin therapy, the patient developed a diffuse, erythematous, maculopapular, and desquamating cutaneous reaction on her chest, arms, and legs. The suspected diagnosis was determined to be a severe cutaneous adverse drug reaction, possibly TEN. Use of the Naranjo et al. scale revealed that rifaximin was a possible cause of the reaction. Rifaximin was discontinued, and antihistamines and i.v. corticosteroids were initiated. The reaction completely resolved after one week.A 62-year-old woman developed possible TEN after receiving rifaximin to treat hepatic encephalopathy.

Purpose:

To compare the diagnostic performance of acoustic radiation force impulse (ARFI) elastography with that of FibroScan M and XL probes and FibroTest in the staging of fibrosis in patients with chronic liver disease.Materials and

Methods:

This study received ethics approval, and all participants provided written informed consent. A total of 321 consecutive patients with chronic liver disease who underwent liver biopsy were prospectively enrolled from April 2010 to May 2012. Liver disease was caused by viral hepatitis (n = 136), alcoholic or nonalcoholic steatohepatitis disorders (n = 113), or some other disease (n = 72). In each patient, liver stiffness was evaluated with ARFI elastography, M and XL probes, and FibroTest within 1 month before liver biopsy. Histologic staging of liver fibrosis served as the reference standard.

Results:

Liver stiffness measurement failure rates were 11.2% with the M probe (36 of 321 patients), 2.3% with the XL probe (six of 260 patients), and 0% with ARFI elastography (0 of 321 patients). Unreliable results with ARFI elastography were more frequent in obese patients (those with a body mass index of 30 kg/m(2) or more) (42 of 86 patients [48.8%] vs 34 of 235 patients [14.5%], P < .0001). No significant difference was found between ARFI elastography and the M probe in the diagnosis of cirrhosis (area under under the receiver operating characteristic curve [Az], 0.88 vs 0.91; P = .12) or severe fibrosis (Az, 0.85 vs 0.89; P = .15); however, the M probe demonstrated better results in the diagnosis of moderate fibrosis (Az, 0.81 vs 0.88; P = .008). No significant difference was found between ARFI elastography and the XL probe in the diagnosis of moderate fibrosis, severe fibrosis, or cirrhosis. The diagnostic performance of ARFI elastography improved when it was applied in nonobese patients (Az of ARFI for cirrhosis and severe fibrosis = 0.92 and 0.91, respectively, in nonobese patients [P = .0002] and 0.63 and 0.63, respectively, in obese patients [P < .0001]).

Conclusion:

ARFI elastography is reliable in the assessment of liver fibrosis in patients with chronic liver disease, especially nonobese patients.© RSNA, 2013.

Despite high recidivism rates in those treated for alcoholism, recurrent episodes of severe alcoholic hepatitis (SAH) have not been described. Our aim was to assess the clinical characteristics and outcomes in recurrent SAH.A retrospective review of patient records was carried out. Recurrent SAH was defined as two or more discrete episodes of SAH (discriminant function≥32) coinciding with recidivism in the same patient, with documented improvement/resolution of jaundice during intervening periods of abstinence.Of 56 patients with recidivism following index presentation with SAH, 10 (17.9%) developed recurrent SAH. We report on 17 episodes in seven patients with complete data. The mean age and duration of alcohol use were 47.9±7.4 and 16.1±5.2 years, respectively. Compared with those without recurrence, the cohort with recurrent SAH were more likely to be women (57.1 vs. 34.8%, P=0.405), had higher alcohol consumption during relapse (16.0±15.3 vs. 11.3±8.1 U/day, P=0.591) and a recidivism pattern of alcohol relapse after initial abstinence rather than continuous alcohol use. Recurrent episodes were more severe compared with the index one (discriminant function 70.4±27.9 vs. 50.5±10.9; MELD score 26.2±3.7 vs. 22.1±1.5, P<0.05), the overall mortality being 57.1%. Treatment responses to corticosteroids were consistent in 66.7% of patients.Approximately 18% of patients, especially women, develop recurrent SAH because of recidivism, with increasing disease severity and mortality approaching 60%. Our data underscore the urgent need to develop strategies to prevent recidivism following index presentation with SAH.