Accuracy of Non-invasive Indices for Diagnosing Hepatic Steatosis Compared to Imaging in a Real-World Cohort.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease is common and under-diagnosed. This study evaluated the accuracy of several previously reported indices, including hepatic steatosis index, alanine aminotransferase (ALT) method, Framingham steatosis index, and Dallas steatosis index, to diagnose hepatic steatosis in a real-world cohort. METHODS: This study included 701 randomly selected adult patients seen in our integrated healthcare system between 2015 and 2020 with appropriate abdominal imaging and routine outpatient laboratory studies. Information on demographics, comorbidities and existing liver disease, anthropometrics, laboratory studies, and abdominal imaging was collected. The sensitivity, specificity, and C-statistic of each method in detecting hepatic steatosis based on abdominal imaging were determined. RESULTS: 202/701 patients (28.8%) had hepatic steatosis on abdominal imaging. These patients were more likely to have metabolic syndrome components and higher body mass index. All indices performed similarly with moderate accuracy in detecting hepatic steatosis based on the C-statistic (95% confidence interval): Hepatic steatosis index 0.76 (0.72-0.79), Framingham steatosis index 0.78 (0.74-0.82), and Dallas steatosis index 0.80 (0.76-0.83). ALT method had sensitivity 44.7% (36.9-52.7%) and specificity 88.6% (85.0-91.7%). Several sensitivity analyses were performed, which did not significantly alter the performance of any index. CONCLUSION: The findings support both the clinical utility of these indices in diagnosing hepatic steatosis in the absence of imaging in real-world settings and the research utility of these indices in generating reliable electronic medical record-based nonalcoholic fatty liver disease cohorts.

Microbiome therapeutics for hepatic encephalopathy.

Hepatic encephalopathy (HE) is a complication of cirrhosis characterised by neuropsychiatric and motor dysfunction. Microbiota-host interactions play an important role in HE pathogenesis. Therapies targeting microbial community composition and function have been explored for the treatment of HE. Prebiotics, probiotics and faecal microbiota transplant (FMT) have been used with the aim of increasing the abundance of potentially beneficial taxa, while antibiotics have been used to decrease the abundance of potentially harmful taxa. Other microbiome therapeutics, including postbiotics and absorbents, have been used to target microbial products. Microbiome-targeted therapies for HE have had some success, notably lactulose and rifaximin, with probiotics and FMT also showing promise. However, there remain several challenges to the effective application of microbiome therapeutics in HE, including the resilience of the microbiome to sustainable change and unpredictable clinical outcomes from microbiota alterations. Future work in this space should focus on rigorous trial design, microbiome therapy selection, and a personalised approach to HE.

Opioid Use Is More Common in Nonalcoholic Fatty Liver Disease Patients with Cirrhosis, Higher BMI, and Psychiatric Disease.

BACKGROUND: Opioid use is a topic of growing concern among patients with nonalcoholic fatty liver disease (NAFLD). Given safety concerns of opioids, proactively identifying subgroups of patients with an increased probability of opioid use may encourage practitioners to recommend alternative therapies for pain, thus reducing the likelihood of opioid misuse. This work assessed the prevalence and patient characteristics associated with opioid use in a real-world cohort of patients with NAFLD. METHODS: TARGET-NASH, an observational study of participants at 55 academic and community sites in the United States, includes patients with NAFLD defined by pragmatic case definitions. Opioid use was defined as any documented opioid prescriptions in the year prior to enrollment. The association between patient characteristics and the odds of opioid use were modeled with stepwise multivariable logistic regression and tree ensemble methods (Classification and regression tree/Boosted Tree). RESULTS: The cohort included 3,474 adult patients with NAFLD including 18.0% with documented opioid use. Variables associated with opioid use included presence of cirrhosis (OR 1.51, 95% CI 1.16-1.98), BMI ≥32 kg/m2 (OR 1.29, 95% CI 1.05-1.59), depression (OR 1.87, 95% CI 1.50-2.33), and anxiety (OR 1.59, 95% CI 1.27-1.98). In the boosted tree analysis, history of back pain, depression, and fibromyalgia had the greatest relative importance in predicting opioid use. CONCLUSION: Prescription opioids were used in nearly 1 of 5 patients with NAFLD. Given the safety concerns of opioids in patients with NAFLD, alternative therapies including low-dose acetaminophen and nonpharmacologic treatments should be considered for these patients.

Alcohol, tobacco and coffee consumption and liver disease severity among individuals with Chronic Hepatitis B infection in North America.

INTRODUCTION AND OBJECTIVES: The prevalence of alcohol, tobacco, and coffee use and association with liver health among North Americans with Chronic Hepatitis B (CHB) infection has not been well described. MATERIALS AND METHODS: The Hepatitis B Research Network includes an observational study of untreated CHB adults enrolled at 21 sites in the United States and Canada. Alcohol use was categorized as none, moderate, and at-risk based on the definition from the National Institute on Alcohol Abuse and Alcoholism; tobacco use as never, current and former; coffee use as none, 1-2 cups/day, and ≥3 cups/day. Linear regression and linear mixed models were used to associate lifestyle behaviors with ALT and FIB-4 values. RESULTS: 1330 participants met eligibility: 53% males, 71% Asian and the median age was 42 years (IQR: 34-52). Median ALT was 33U/L (IQR: 22-50), 37% had HBV DNA <103IU/mL, 71% were HBeAg negative, and 65% had a FIB-4 <1.45. At baseline, 8% of participants were at-risk alcohol drinkers, 11% were current smokers and 92% drank <3 cups of coffee/day. Current tobacco and 'at-risk' alcohol use, were significantly associated with elevated ALT levels in univariable analyses, however, these associations were not statistically significant when controlling for sociodemographic and HBV characteristics. CONCLUSIONS: In this large diverse cohort of untreated CHB participants, at-risk alcohol use, current tobacco use and limited coffee consumption did not have an association with high ALT and FIB-4 values. In contrast, significant associations were found between the frequency of these lifestyle behaviors and sociodemographic factors.

Models to Predict Hepatitis B Virus Infection Among Patients With Cancer Undergoing Systemic Anticancer Therapy: A Prospective Cohort Study.

PURPOSE: Most patients with cancer are not screened for hepatitis B virus (HBV) infection before undergoing anticancer therapy, and optimal screening strategies are unknown. We sought to develop selective HBV screening strategies for patients who require systemic anticancer therapy. METHODS: This prospective cohort study included adults age ≥ 18 years with solid or hematologic malignancies who received systemic anticancer therapy at a comprehensive cancer center during 2013 and 2014. Patients underwent hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface antibody testing, and completed a 19-question modified Centers for Disease Control and Prevention (CDC) HBV survey. Multivariable models that predict chronic or past HBV infection were developed and validated using bootstrapping. RESULTS: A total of 2,124 patients (mean age, 58 ± 13 years) completed the risk survey and HBV testing. Of these, 54% were women; 77% were non-Hispanic white, 11% Hispanic, 8% black, and 4% Asian; and 20% had a hematologic malignancy and 80% a solid tumor. Almost 12% were born outside the United States. The prevalence was 0.3% for chronic HBV infection and 6% for past HBV infection. Significant predictors of positive hepatitis B surface antigen or hepatitis B core antibody tests were as follows: men who had sex with men, black or Asian race, birthplace outside the United States, parent's birthplace outside the United States, household exposure to HBV, age ≥ 50 years, and history of injection drug use. The area under the receiver operating characteristic curve of the model on the basis of these seven predictors was 0.79 (95% CI, 0.73 to 0.82). The modified CDC survey and brief tools with fewer than seven questions yielded similar false-negative rates (0% and 0% to 0.7%, respectively). CONCLUSION: An internally validated risk tool performed as well as the modified CDC survey; however, more than 90% of patients who completed the tool would still require HBV testing. Universal HBV testing is more efficient than risk-based screening.

Population-Based Analysis and Projections of Liver Supply Under Redistricting.

BACKGROUND: To reduce the geographic heterogeneity in liver transplant allocation, the United Network of Organ Sharing has proposed redistricting, which is impacted by both donor supply and liver transplantation demand. We aimed to determine the impact of demographic changes on the redistricting proposal and characterize causes behind geographic heterogeneity in donor supply. METHODS: We analyzed adult donors from 2002 to 2014 from the United Network of Organ Sharing database and calculated regional liver donation and utilization stratified by age, race, and body mass index. We used US population data to make regional projections of available donors from 2016 to 2025, incorporating the proposed 8-region redistricting plan. We used donors/100 000 population age 18 to 84 years (D/100K) as a measure of equity. We calculated a coefficient of variation (standard deviation/mean) for each regional model. We performed an exploratory analysis where we used national rates of donation, utilization and both for each regional model. RESULTS: The overall projected D/100K will decrease from 2.53 to 2.49 from 2016 to 2025. The coefficient of variation in 2016 is expected to be 20.3% in the 11-region model and 13.2% in the 8-region model. We found that standardizing regional donation and utilization rates would reduce geographic heterogeneity to 4.9% in the 8-region model and 4.6% in the 11-region model. CONCLUSIONS: The 8-region allocation model will reduce geographic variation in donor supply to a significant extent; however, we project that geographic disparity will marginally increase over time. Though challenging, interventions to better standardize donation and utilization rates would be impactful in reducing geographic heterogeneity in organ supply.

Survival and cost-effectiveness of sorafenib therapy in advanced hepatocellular carcinoma: An analysis of the SEER-Medicare database.

Sorafenib is the only chemotherapeutic approved for treatment of advanced hepatocellular carcinoma (HCC). However, its effectiveness in patients with Child-Pugh class B cirrhosis and any moderating effects of health system characteristics are unclear. We examined the survival and cost-effectiveness associated with sorafenib in elderly patients with advanced HCC. We performed an analysis of Medicare beneficiaries with HCC diagnoses from 2007 to 2009. We compared advanced stage patients with HCC (American Joint Committee on Cancer stage III/IV) who received sorafenib within 6 months of diagnosis (and were otherwise untreated) to advanced stage patients with HCC who received no therapy (control). We performed univariate and multivariate analyses to identify predictors of survival. Incremental cost-effectiveness ratios (ICERs) were calculated for sorafenib-treated and control patients. We included 228 sorafenib-treated patients and 870 control patients. The median survival of the sorafenib-treated patients was 150.5 days versus 62 days for control patients. On multivariate analysis, significant predictors of improved survival were treatment with sorafenib (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.57-0.77), being seen at a National Cancer Institute-designated cancer center (HR, 0.77; 95% CI, 0.62-0.97), and being seen at a transplantation center (HR, 0.77; 95% CI, 0.65-0.93). Predictors of worse survival included stage IV disease (HR, 1.40; 95% CI, 1.24-1.58), decompensated cirrhosis (HR, 1.49; 95% CI, 1.30-1.70), and treatment in an urban setting (HR, 1.45; 95% CI, 1.21-1.73.) Although sorafenib use was associated with a survival benefit (HR, 0.61; 95% CI, 0.47-0.79) among patients with decompensated cirrhosis, the median survival benefit was 31 days, and it was not cost-effective (ICER, $224,914 per life year gained). CONCLUSION: Sorafenib is associated with improved survival in elderly patients with advanced HCC; however, it is not cost-effective among those with hepatic decompensation. (Hepatology 2017;65:122-133).

Trends in hepatitis B virus screening at the onset of chemotherapy in a large US cancer center.

BACKGROUND: National organizations recommend screening for hepatitis B virus (HBV) before chemotherapy but differ regarding which patients should be screened. We aimed to determine contemporary screening rates at a cancer center and the possible influence on these rates of publication of national recommendations. METHODS: We conducted a retrospective cohort study of HBV screening in cancer patients registered during the period from January 2004 through April 2011. Screening was defined as HBsAg and anti-HBc tests ordered around the time of initial chemotherapy. We compared screening rates for 3 periods: January 1, 2004, through December 18, 2008 (Food and Drug Administration and American Association for the Study of Liver Diseases 2007 recommendations); December 19, 2008, through September 30, 2010 (Centers for Disease Control and Prevention, National Comprehensive Cancer Network, American Association for the Study of Liver Diseases 2009, Institute of Medicine, and American Society of Clinical Oncology recommendations); and October 1, 2010, through April 30, 2011. Logistic regression models were used to identify predictors of screening. RESULTS: Of 141,877 new patients, 18,688 received chemotherapy, and 3020 (16.2%) were screened. HBV screening rates increased over the 3 time periods (14.8%, 18.2%, 19.9%; P <0.0001), but <19% of patients with HBV risk factors were screened. Among patients with hematologic malignancies, over 66% were screened, and odds of screening nearly doubled after publication of the recommendations (P <0.0001). Less than 4% of patients with solid tumors were screened, although odds of screening increased 70% after publication of the recommendations (P =0.003). Other predictors of screening included younger age, planned rituximab therapy, and known risk factors for HBV infection. CONCLUSIONS: Most patients with solid tumors or HBV risk factors remained unscreened, although screening rates increased after publication of national recommendations. Efforts are needed to increase awareness of the importance of HBV screening before chemotherapy to identify patients who should start antiviral prophylaxis.

Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C.

UNLABELLED: Higher coffee consumption has been associated inversely with the incidence of chronic liver disease in population studies. We examined the relationship of coffee consumption with liver disease progression in individuals with advanced hepatitis C-related liver disease. Baseline coffee and tea intake were assessed in 766 participants of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had hepatitis C-related bridging fibrosis or cirrhosis on liver biopsy and failed to achieve a sustained virological response to peginterferon plus ribavirin treatment. Participants were followed for 3.8 years for clinical outcomes and, for those without cirrhosis, a 2-point increase in Ishak fibrosis score on protocol biopsies. At baseline, higher coffee consumption was associated with less severe steatosis on biopsy, lower serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, alpha-fetoprotein, insulin, and homeostatic model assessment (HOMA2) score, and higher albumin (P < 0.05 for all). Two hundred thirty patients had outcomes. Outcome rates declined with increasing coffee intake: 11.1/100 person-years for none, 12.1 for less than 1 cup/day, 8.2 for 1 to fewer than 3 cups/day, and 6.3 for 3 or more cups/day (P-trend = 0.0011). Relative risks (95% confidence intervals) were 1.11 (0.76-1.61) for less than 1 cup/day; 0.70 (0.48-1.02) for 1 to fewer than 3 cups/day; and 0.47 (0.27-0.85) for 3 or more cups/day (P-trend = 0.0003) versus not drinking. Risk estimates did not vary by treatment assignment or cirrhosis status at baseline. Tea intake was not associated with outcomes. CONCLUSION: In a large prospective study of participants with advanced hepatitis C-related liver disease, regular coffee consumption was associated with lower rates of disease progression.

Herbal product use by persons enrolled in the hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial.

Herbal products, used for centuries in Far Eastern countries, are gaining popularity in western countries. Surveys indicate that persons with chronic hepatitis C (CHC) often use herbals, especially silymarin (milk thistle extract), hoping to improve the modest response to antiviral therapy and reduce side effects. The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial, involving persons with advanced CHC, nonresponders to prior antiviral therapy but still willing to participate in long-term pegylated interferon treatment, offered the opportunity to examine the use and potential effects of silymarin. Among 1145 study participants, 56% had never taken herbals, 21% admitted past use, and 23% were using them at enrollment. Silymarin constituted 72% of 60 herbals used at enrollment. Among all participants, 67% had never used silymarin, 16% used it in the past, and 17% used it at baseline. Silymarin use varied widely among the 10 participating study centers; men were more frequent users than women, as were non-Hispanic whites than African Americans and Hispanics. Silymarin use correlated strongly with higher education. No beneficial effect of silymarin was found on serum alanine aminotransferase or hepatitis C virus (HCV) RNA levels. Univariate analysis showed significantly fewer liver-related symptoms and better quality-of-life parameters in users than nonusers, but after reanalysis adjusted for covariates of age, race, education, alcohol consumption, exercise, body mass index, and smoking, only fatigue, nausea, liver pain, anorexia, muscle and joint pain, and general health remained significantly better in silymarin users. In conclusion, silymarin users had similar alanine aminotransferase and HCV levels to those of nonusers but fewer symptoms and somewhat better quality-of-life indices. Because its use among these HALT-C participants was self-motivated and uncontrolled, however, only a well-designed prospective study can determine whether silymarin provides benefit to persons with chronic hepatitis C.

Monitoring drug resistance in chronic hepatitis B virus (HBV)-infected patients during lamivudine therapy: evaluation of performance of INNO-LiPA HBV DR assay.

Sensitive and early detection of emerging hepatitis B virus (HBV) drug resistance may not only help monitor the viral dynamics associated with lamivudine treatment but could also improve therapeutic decision making. This is especially important when new antivirals effective against lamivudine-resistant HBV become available. A total of 159 serum samples from 33 chronic HBV patients receiving lamivudine treatment were analyzed at four centers for the presence of lamivudine-resistant mutations at codons 528 [180] (proposed revised nomenclature according to Stuyver et al. [Hepatology 33:751-757, 2001] shown in brackets), 552 [204], and 555 [207] of the HBV polymerase. Sequencing data were compared with results generated by the INNO-LiPA HBV DR line probe assay (LiPA), an assay based on reverse hybridization of amplified HBV DNA fragments with specific nucleotide probes immobilized on nitrocellulose strips. LiPA provided at least the same information as sequencing for 97.5% of all codons analyzed for codon 528 [180], 95% for codon 552 [204], and 100% for codon 555 [207]. The most common reason for discrepant or indeterminate results (0.4% and 1.5%, respectively) in a small percentage of the population tested could be attributed to polymorphisms not yet covered by LiPA probes. In at least five patients, a mutant could be detected earlier by LiPA than by sequencing. In 15 patients, LiPA detected mixed wild-type and mutant virus populations before viral breakthrough. These results demonstrate that INNO-LiPA HBV DR is a highly sensitive and easily applicable assay for the detection and monitoring of lamivudine-resistant mutations in chronic hepatitis B patients and that the assay is more sensitive than sequencing in detecting mixed mutant and wild-type sequences.