Levetiracetam Liver Injury: A Benign Antiepileptic Agent?

Levetiracetam is a commonly prescribed antiepileptic agent and has rarely been linked to hepatotoxicity. This case describes a patient with drug-induced autoimmune hepatitis secondary to levetiracetam.

Videoconference microscopy is a reliable alternative to conventional microscopy in the evaluation of Barrett's esophagus: Zooming into a new era.

Telepathology, practicing pathology from a distance, allows experts to review cases without the need to transfer glass slides. Due to significant intra- and inter-observer variabilities in the histological evaluation of Barrett's esophagus (BE), current guidelines recommend expert consultation in cases of dysplasia. We aimed to determine whether telepathology using microscope videoconferencing can be reliably used for evaluation of BE. Biopsies from 62 patients with endoscopic findings of salmon colored mucosa extending ≥1 cm proximal to the gastroesophageal junction were randomly selected to represent benign esophagus, non-dysplastic BE, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma. Three gastrointestinal-trained pathologists reviewed the cases via videoconference microscopy followed by conventional microscopy. Intra-observer and pairwise inter-observer agreements between the conventional microscopy and videoconference methodologies were calculated for each of the three pathologists using Fleiss-Cohen weighted kappa (K) analysis. The intra-observer agreement for each pathologist's assessment of videoconference microscopy and glass slide readings showed very good reliability (K = 0.94, 95% confidence interval = 0.89-0.99; 0.88, 95% confidence interval = 0.79-0.98; 0.93, 95% confidence interval = 0.90-0.97). Mean pairwise inter-observer agreement was 0.90 for videoconference and 0.91 for conventional microscopy. Diagnosis and grading of BE using videoconference microscopy show similar reliability as conventional microscopy. Based on our findings, we propose that videoconferencing pathology is a valid instrument for evaluating BE.

Hospitalizations for Acute on Chronic Liver Failure at Academic Compared to Non-academic Centers Have Higher Mortality.

BACKGROUND AND AIM: Acute on chronic liver failure (ACLF) in patients with cirrhosis has high short-term mortality. Data comparing ACLF admissions to academic centers (AC) and non-academic centers (NAC) are scanty. METHODS: National Inpatient Sample (2006-2014) was queried for admissions with cirrhosis and ACLF using the ICD-09 codes, and was stratified to AC or NAC. RESULTS: Of 1,928,764 admissions with cirrhosis (2006-2014), 112,174 (5. 9%) had ACLF. 6.7% of 1,018,568 cirrhosis admissions to AC had ACLF versus 5% of 910,196 admissions to NAC, P < 0.0001. Proportion of ACLF admissions to AC increased from 49% during 2006-2008 to 59% during 2012-2014. In a cohort of 73,630 ACLF admissions (36,615 each to AC and NAC) matched for patient demographics, cirrhosis etiology, number of comorbidities, elective versus emergent admission, ACLF grade, and type of organ failure. In-hospital mortality declined by 7% over the study period, but remained higher in AC (46% vs. 42%, P < 0.001), with 11% increased odds for in-hospital mortality compared to admission to NAC. Further admissions to AC versus NAC had higher median (IQR) length of stay at 13 (6-25) versus 11 (5-20) days, with higher median (IQR) hospital charges: 138,239 (66,772-275,603) versus 116,209 (55,767-232,699) USD, P < 0.001 for both. CONCLUSION: Patients with ACLF have high in-hospital mortality. Further, this is higher among admissions to AC. Although the in-hospital mortality is improving, strategies are needed on early identification of patients with futility of care for early discussion on goals of care, and optimal utilization of hospital resources among admissions with ACLF.

Extra-Hepatic Manifestations of Nonalcoholic Fatty Liver Disease: A Review.

Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease worldwide with a strong association with metabolic syndrome. NAFLD is truly a systemic disease and is associated with a plethora of extra-hepatic manifestations or comorbidities. These are either related to secondary effects of associated obesity or from pathophysiological effects of insulin resistance in NAFLD. Three most common causes of increased morbidity and mortality associated with NAFLD are cardiovascular disease, liver disease, and cancer. In this narrative review, we will discuss comprehensively on cardiovascular disease, type 2 diabetes mellitus, and chronic kidney disease and will also highlight on malignancy especially colorectal cancer, pulmonary disorders including obstructive sleep apnea, endocrine disorders such as hypothyroidism and polycystic ovarian syndrome, dermatological disorders especially psoriasis, and hematological associations including iron overload and susceptibility to thrombosis. In addition to focusing on pathogenesis of these extrahepatic manifestations, we will highlight their clinical implications for physicians in routine clinical practice. Further, there remains an unmet need for safe and effective therapies and examining their benefits on these extra-hepatic manifestations among patients with NAFLD.

NASH Is the Most Rapidly Growing Etiology for Acute-on-Chronic Liver Failure-Related Hospitalization and Disease Burden in the United States: A Population-Based Study.

Acute-on-chronic liver failure (ACLF) is characterized by multiple organ failure (OF) with high short-term mortality. There is lack of population-based data on trends on etiology specific ACLF related burden. National Inpatient Sample (2006-2014) was queried using ICD-09 codes for admissions with cirrhosis and ACLF (≥2 extrahepatic OF). Of 1,928,764 admissions for cirrhosis between 2006 and 2014, 112,174 (5.9%) had ACLF (4.5%, 1.2%, and 0.2% with ACLF 1, 2, and 3, respectively). The brain was the most common OF in 11.9%, followed by respiratory failure in 7.7%, cardiac failure in 6.3%, and renal failure in 5.6%. ACLF increased by 24% between 2006 and 2014 with a 63% increase in 179,104 patients with nonalcoholic steatohepatitis (NASH) cirrhosis (3.5% to 5.7%); a 28% increase in patients with 429,306 alcoholic cirrhosis (5.6% to 7.2%); a 25% increase in patients with 1,091,053 with other etiologies (5.2% to 6.5%); and no significant change in 229,301 patients with viral hepatitis (VH) (4.0% to 4.1%). In-hospital mortality was higher among ACLF patients compared with patients without ACLF (44% versus 4.7%; P < 0.0001). Each NASH-related ACLF patient compared with other etiologies had a longer mean length of stay (14 versus 12 days), was associated with higher median total charges (US $151,196 versus US $134,597), and had more frequent use of dialysis (45% versus 36%) and longterm care (32% versus 26%; P < 0.0001 for all). Results remained similar in a subgroup analysis after including half of admissions with cryptogenic cirrhosis as NASH. In conclusion, NASH cirrhosis is the most rapidly growing indication for ACLF-related hospitalization and use of hospital resources. In the setting of improved treatment options for chronic hepatitis, the health care burden of chronic viral-related liver disease remains stable. Population-based strategies are needed to reduce the health care burden of cirrhosis, particularly related to NASH.

Decreasing frequency and improved outcomes of hepatitis C-related liver transplantation in the era of direct-acting antivirals - a retrospective cohort study.

Benefit of direct-acting antivirals (DAA) for hepatitis C virus (HCV) on clinical outcomes is unclear. We examined temporal trends in liver transplant (LT) listings, receipt of LT, re-LT, and survival between pre-DAA (2009-2012) and DAA era (2013-2016) using UNOS database. Of 32 319 first adult LT, 15 049 (47%) were performed for HCV. Trends on listing, first LT, and of re-LT for HCV showed 23%, 20%, and 21% decrease in DAA compared to pre-DAA era (P < 0.0001). One-year liver graft and patient survival among HCV LT improved in DAA era (90% vs. 86% and 92% vs. 88%, respectively, P < 0.0001). Non-HCV LT showed no improvement in survival (89% vs. 89% and 92% vs. 92.4%, P = NS). On cox regression, compared to non-HCV LTs in DAA era, LT for HCV in pre-DAA era had worse patient survival (HR 1.56 [1.04-2.35]). The outcome was similar when compared to LTs for HCV in DAA era and for non-HCV in pre-DAA era. Burden of HCV-related LT waitlist and LT is declining in DAA era, with improved post-transplant outcomes, more so in later than earlier DAA era. Our findings negate recent Cochrane meta-analysis on DAA therapy and encourage studies to examine HCV clinical outcomes outside LT setting.

Epidemiology of Alcohol Consumption and Societal Burden of Alcoholism and Alcoholic Liver Disease.

Alcohol abuse is a major determinant of public health outcomes. Worldwide data from 2016 indicate that alcohol is the seventh leading risk factor in terms of disability-adjusted life years, an increase of more than 25% from 1990 to 2016. Understanding the epidemiology of alcoholic liver disease, including the regional variations in consumption and public policy, is an area of active research. In countries where the per capita consumption of alcohol decreases, there appears to be an associated decrease in disease burden. Given alcohol's health burden, an increased focus on alcohol control policies is needed.

A Validated Score Predicts Acute Kidney Injury and Survival in Patients With Alcoholic Hepatitis.

Identifying patients at high risk for acute kidney injury (AKI) during hospitalization among patients admitted with severe alcoholic hepatitis (AH) is an unmet clinical need. We performed a multicentric prospective cohort study using data from 4 different cohorts on well-characterized patients hospitalized with severe AH. Data collected on 773 AH patients from 4 cohorts across the globe were randomly split into test (n = 390) and validation (n = 383) cohorts. We found that 32% of the patients developed inpatient AKI in the test cohort. Approximately 60% of patients met criteria for systemic inflammatory response syndrome (SIRS) at admission. Hepatic encephalopathy, SIRS, and Model for End-Stage Liver Disease score at admission predicted inpatient AKI with odds ratios of 3.86, 2.24, and 1.14, respectively. The AKI risk score developed using these predictors stratified risk of inpatient AKI to low (score <3), moderate (3-4), and high (>4). These findings were replicated in the validation cohort. In the whole study cohort, patients with AKI had a lower 90-day survival (53% versus 77%; P < 0.001). Those with AKI risk score of >4 had significantly lower 90-day survival as compared with those with risk scores between 3 and 4 and <3 (47% versus 68% versus 88%; P < 0.001). In conclusion, AKI occurs frequently in AH patients and negatively impacts short-term mortality. The AKI risk score is useful in identifying patients at high risk for inpatient AKI and may be useful for developing new therapeutic strategies to prevent AKI in patients with AH.

Correction: Patients with stage 3 compared to stage 4 liver fibrosis have lower frequency of and longer time to liver disease complications.

[This corrects the article DOI: 10.1371/journal.pone.0197117.].

Patients with stage 3 compared to stage 4 liver fibrosis have lower frequency of and longer time to liver disease complications.

BACKGROUND AND AIMS: Advanced liver fibrosis is an important predictor of liver disease progression and mortality, and current guidelines recommend screening for complications of cirrhosis once patients develop F3 fibrosis. Our study compared liver disease progression and survival in patients with stage 3 (F3) and stage 4 (F4) fibrosis on liver biopsy. METHODS: Retrospective study of patients with F3 or F4 on liver biopsy followed for development of liver disease complications (variceal bleeding, ascites, and hepatic encephalopathy); hepatocellular carcinoma, and survival (overall and transplant free survival). RESULTS: Of 2488 patients receiving liver biopsy between 01/02 and 12/12, a total of 294 (171 F3) were analyzed. Over a median follow up period of 3 years, patients with F4 (mean age 53 years, 63% male) compared to F3 (mean age 49 years, 43% male) had higher five year cumulative probability of any decompensation (38% vs. 14%, p<0.0001), including variceal bleed (10% vs. 4%, p = 0.014), ascites (21% vs. 9%, p = 0.0014), and hepatic encephalopathy (14% vs. 5%, p = 0.003). F4 patients also had lower overall 5-year survival (80% vs. 93%, p = 0.003) and transplant free survival (80% vs. 93%, p = 0.002). Probability of hepatocellular carcinoma in 5 years after biopsy was similar between F3 and F4 (1.2% vs. 2%, p = 0.54). CONCLUSIONS: Compared to F4 stage, patients with F3 fibrosis have decreased risk for development of liver disease complications and better survival. Prospective well designed studies are suggested with large sample size and overcoming the limitations identified in this study, to confirm and validate these findings, as basis for modifying guidelines and recommendations on follow up of patients with advanced fibrosis and stage 3 liver fibrosis.

Hepatitis C Virus and Hepatocellular Carcinoma: A Narrative Review.

Hepatocellular carcinoma (HCC) is a leading cause of liver-related death worldwide. Hepatitis C virus (HCV) infection is a major cause of advanced hepatic fibrosis and cirrhosis, with significantly increased risk for development of HCC. The morbidity and mortality of HCV-related HCC remains high, as rates of HCV cirrhosis continue to increase. The long-term goal of antiviral therapy for chronic HCV is to reduce complications from cirrhosis, including HCC. The advent of new direct-acting antivirals with high rates of virological clearance has revolutionized cure of HCV infection. While the development of HCC in HCV patients who achieve disease sustained virologic response is reduced, these patients remain at risk for HCC, particularly those patients with advanced fibrosis and cirrhosis. This review outlines the epidemiology of HCC in chronic HCV, various mechanisms, risk factors and pathophysiology that contribute to this disease process, screening recommendations, and the available data on the impact of new direct-acting antiviral treatment on the development on HCC.

Heavy Alcohol Use Among Deceased Donors Does Not Impact Recipient Outcomes After Liver Transplantation.

BACKGROUND: Data on liver transplant (LT) outcomes using deceased donors with heavy drinking (HD) (>2 drinks per day) are scanty. METHODS: Using the United Network for Organ Sharing database (2002-2014), we examined outcomes after LT in adults comparing deceased HD donors with non-HD (ND) donors. RESULTS: Of 56 182 first LTs performed in the United States for 10 common indications using deceased donors, 47 882 with available information on alcohol use were analyzed. Of these 47 882 LT recipients, 7298 (15%) were from HD donors, with similar proportion over time (2002-2014, Armitage trend test P = 0.75) and for recipient liver disease etiology (χ P = 0.42). Proportion of liver organ used for LT was lower for HD donors compared with ND donors (63% vs 78%; P < 0.001). Five-year outcomes on first LT comparing 7166 HD donors and 21 498 ND donors matched based on propensity score were similar for liver graft (73.7% vs 73.7%, log rank P = 0.98) and patient survival (77.6% vs 77.0%, P = 0.36). On Cox regression analysis, history of HD in deceased donors did not affect liver graft 1.02 (0.97-1.08) or patient survival 1.03 (0.97-1.09). CONCLUSIONS: Among LT recipients using select liver grafts, history of HD in deceased donors does not impact outcomes after LT.

Biomarkers of Renal Injury in Cirrhosis: Association with Acute Kidney Injury and Recovery after Liver Transplantation.

BACKGROUND: To define urine or serum biomarkers in predicting renal function recovery after liver transplantation (LT). METHODS: Adults listed for LT (February 2011-July 2014) and with modified diet for renal disease-6 (MDRD-6) <60 mL/min provided urine/blood samples at baseline and serially until LT for biomarkers in serum (pg/mL) and urine (pg/mg creatinine). RESULTS: Of 271 LT listed patients (mean age 57 years, 63% males, median listing MELD 17.5), 1 year acute kidney injury (AKI) probability was 49%, with odds of 1.3-, 3.0-, 4.6-, and 8.5-fold times for listing MELD 16-20, 21-25, 26-30, and >30, compared to MELD <16. Thirty-seven people died over 1 year from the time of listing, with twofold increased odds with AKI. Among 67 patients with MDRD <60, only urinary epidermal growth factor was different comparing AKI (increase in serum creatinine ≥0.3 mg/dL from baseline within past 3 months) vs. no AKI (2,254 vs. 4,253, p = 0.003). Differences between acute tubular necrosis (ATN) and hepatorenal syndrome could not be ascertained for a small sample of 3 patients with ATN. Analyzing 15 of 43 receiving LT and MDRD-6 <30 prior to LT, biomarkers were not different comparing 5 patients recovering renal function (MDRD-6 >50 mL/min) at 6 months vs. 10 without recovery. CONCLUSIONS: AKI is common among LT listed patients, with a negative impact on transplant-free survival. Serum and urine biomarkers are not associated with the recovery of renal function after LT. Multicenter studies are suggested to (a) develop strategies to reduce the development of AKI and (b) derive novel biomarkers for use in accurately predicting renal recovery after LT.

Text messaging approach improves weight loss in patients with nonalcoholic fatty liver disease: A randomized study.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is emerging as the most common liver disease. The only effective treatment is 7%-10% weight loss. Mobile technology is increasingly used in weight management. This study was performed to evaluate the effects of text messaging intervention on weight loss in patients with NAFLD. METHODS: Thirty well-defined NAFLD patients (mean age 52 years, 67% females, mean BMI 38) were randomized 1:1 to control group: counselling on healthy diet and exercise, or intervention group: text messages in addition to healthy life style counselling. NAFLD text messaging program sent weekly messages for 22 weeks on healthy life style education. Primary outcome was change in weight. Secondary outcomes were changes in liver enzymes and lipid profile. RESULTS: Intervention group lost an average of 6.9 lbs. (P = .03) compared to gain of 1.8 lbs. in the control group (P = .45). Intervention group also showed a decrease in ALT level (-12.5 IU/L, P = .035) and improvement in serum triglycerides (-28 mg/dL, P = .048). There were no changes in the control group on serum ALT level (-6.1 IU/L, P = .46) and on serum triglycerides (-20.3 mg/dL P = .27). Using one-way analysis of variance, change in outcomes in intervention group compared to control group was significant for weight (P = .02) and BMI (P = .02). CONCLUSIONS: Text messaging on healthy life style is associated with reduction in weight in NAFLD patients. Larger studies are suggested to examine benefits on liver histology, and assess long-term impact of this approach in patients with NAFLD.

Severe Alcoholic Hepatitis: Atypical Presentation with Markedly Elevated Alkaline Phosphatase.

Alcoholic hepatitis (AH) is an acute inflammatory liver disease with poor prognosis. Infections in AH are difficult to detect and contribute to short-term mortality. Intrahepatic cholestasis and elevated alkaline phosphatase levels are also associated with worse outcomes. This report describes an uncommon presentation of severe AH.