Bashar Aqel

A Randomized, Double-Blinded, Placebo-Controlled Multicenter Trial of Etanercept in the Treatment of Alcoholic Hepatitis

BACKGROUND & AIMS Alcoholic hepatitis is a cause of major morbidity and mortality that lacks effective therapies. Both experimental and clinical evidence indicate that the multifunctional cytokine tumor necrosis factor-alpha (TNF-alpha) contributes to pathogenesis and clinical sequelae of alcoholic hepatitis. A pilot study demonstrated that the TNF-alpha-neutralizing molecule etanercept could be an effective treatment for patients with alcoholic hepatitis. METHODS Forty-eight patients with moderate to severe alcoholic hepatitis (Model for End-Stage Liver Disease score > or = 15) were enrolled and randomized to groups that were given up to 6 subcutaneous injections of either etanercept or placebo for 3 weeks. Primary study end points included mortality at 1- and 6-month time points. RESULTS There were no significant baseline differences between the placebo and etanercept groups in demographics or disease severity parameters including age, gender, and Model for End-Stage Liver Disease score. The 1-month mortality rates of patients receiving placebo and etanercept were similar on an intention-to-treat basis (22.7% vs 36.4%, respectively; OR, 1.8; 95% CI, 0.5-6.5). The 6-month mortality rate was significantly higher in the etanercept group compared with the placebo group (57.7% vs 22.7%, respectively; OR, 4.6; 95% CI, 1.3-16.4; P = .017). Rates of infectious serious adverse events were significantly higher in the etanercept group compared with the placebo group (34.6% vs 9.1%, respectively, P = .04). CONCLUSIONS In patients with moderate to severe alcoholic hepatitis, etanercept was associated with a significantly higher mortality rate after 6 months, indicating that etanercept is not effective for the treatment of patients with alcoholic hepatitis.

Donor age affects fibrosis progression and graft survival after liver transplantation for hepatitis C

Background. The use of liver allografts from an older donor (OD) (age >50 years) is a widespread strategy to manage the disparity between supply and demand of organs for liver transplantation. This study determines the effect of OD allografts on fibrosis progression and graft survival after liver transplantation in patients with and without infection caused by hepatitis C virus (HCV). Methods. All patients undergoing liver transplantation at our center from March 1998 to December 2001 were analyzed. Protocol liver biopsies were performed at 1, 16, and 52 weeks after transplantation and yearly thereafter. One liver pathologist scored all biopsy specimens for modified hepatic activity index (0–18) and fibrosis (0–6). Results. A total of 402 patients (167 with HCV and 235 without HCV) underwent liver transplantation during the study period. Among patients with HCV, baseline characteristics of OD recipients were similar to younger donor (YD) (age <50 years) recipients. In patients with HCV, graft survival was shorter in OD graft recipients than in YD recipients (P <0.001). In patients without HCV, graft survival was independent of donor age. In patients with HCV, a fibrosis score of 3 or greater was present in 17% of OD recipients at 4 months and in 26% at 12 months after transplantation, compared with 8% of YD recipients at 4 months and 13% at 12 months (P <0.001). Conclusions. Liver transplantation with OD grafts is associated with rapid progression of fibrosis and decreased graft survival in patients with HCV, but not in patients without HCV. OD grafts should be considered preferentially for patients without HCV.

Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 after liver transplant.

Treatment with an all‐oral interferon‐free antiviral regimen using simeprevir and sofosbuvir with or without ribavirin (RBV) for 12 weeks resulted in high sustained virologic response (SVR) rates along with minimal adverse events in non–liver transplant (LT) patients with hepatitis C virus (HCV) genotype 1 infection. This is the first multicenter report on the efficacy, safety, and tolerability of this regimen in LT recipients. A total of 123 patients (76% male, 74% white, 60% genotype 1a, 30% METAVIR F3‐F4, 4% decompensation, 11% cholestatic recurrence, 7% had kidney transplant, and 82% previously failed pegylated interferon/RBV‐based regimens) received treatment and were followed for a median of 30 weeks (range 12‐53 weeks). The median time from LT to treatment was 32 months (range 2‐317 months). Tacrolimus was the primary immunosuppression in 91% of patients. Minimal immunosuppression dose adjustments were required. An SVR 12 weeks after treatment completion (SVR12) was achieved in 90% of patients (95% confidence interval 84%‐96%). In patients with genotype 1a infection, the SVR12 rate was significantly lower in those with METAVIR F3‐F4 (71%) compared to those with F0‐F2 (91%). Half of the patients achieved undetected HCV RNA at treatment week 4, and their SVR12 rate was significantly higher (96%) compared to those with detectable HCV RNA (83%). Treatment was very well tolerated with mild degrees of adverse events, except for one death possibly due to drug‐induced lung injury. In the 25 patients who received RBV, 72% developed anemia requiring intervention. Conclusion: An all‐oral interferon‐free antiviral regimen using simeprevir and sofosbuvir with or without RBV for 12 weeks was very well tolerated and resulted in excellent SVR12 rates in LT recipients with HCV genotype 1 infection. (Hepatology 2015;61:1880–1886)

Six‐minute walk distance predicts mortality in liver transplant candidates

The 6‐minute walk distance (6MWD) is a simple test measuring global physical function. It is commonly used to predict mortality in patients with cardiac and pulmonary diseases, but it is also useful in assessing the functional status of patients with a variety of other medical conditions. We sought to determine (1) the characteristics of the 6MWD in patients listed for liver transplantation (LT), (2) the existence of a relationship between the 6MWD and the quality of life, and (3) the relationship between the 6MWD and survival in LT candidates. The 6MWD was prospectively measured in all patients listed for LT. The 6MWD was determined when the listed Model for End‐Stage Liver Disease (MELD) score was ≥15. Patients were followed until LT, death, removal from the wait list, or the end of the study period. Quality of life was assessed with the Short Form 36 (SF‐36). In 121 patients, the mean 6MWD was 369 ± 122 m; it was not related to age, height, weight, body mass index, albumin level, or etiology of liver disease and showed a moderate correlation with the physical component score (PCS) on the SF‐36 (r = 0.4) and a moderate inverse correlation with the native MELD score (r = −0.61). In an unadjusted analysis, a high native MELD score, a low 6MWD, and a low PCS were associated with mortality, with only the 6MWD retaining significance after adjustment for covariates. Each 100‐m increase in the 6MWD was significantly associated with increased survival (hazard ratio = 0.48, P = 0.0001), with 6MWD < 250 m being associated with an increased risk of death (P = 0.0001). In conclusion, the 6MWD is significantly reduced in patients awaiting LT and is inversely correlated with the native MELD score. A pretransplant 6MWD < 250 m is a risk for death on the wait list. Liver Transpl 16:1373–1378, 2010.

Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis.

Background Autoimmune hepatitis (AIH) is an immune mediated chronic liver disease with a prevalence of 17 cases/100,000. Resistance to the standard treatment of AIH (prednisone and azathioprine) occurs in 15% to 20%. There is currently no standard treatment of patients with steroid refractory AIH. Goals Determine the efficacy of tacrolimus in the treatment of steroid refractory AIH. Methods This is a retrospective study evaluating the efficacy of Tacrolimus in the treatment of steroid refractory AIH. Results Between October 1998 and February 2002, 11 patients with steroid refractory AIH were treated with tacrolimus. Mean age was 63 years. Median duration of steroid treatment before starting tacrolimus was 9 months. Median duration of tacrolimus treatment was 25 months. Median follow-up period was 16 months. Median baseline ALT, AST were 77 U/L and 68 U/L and became 21 U/L and 32 U/L respectively at end of follow-up (P = 0.005 and 0.01 respectively). Significant weight reduction was seen in all patients (P = 0.02). Tacrolimus treatment was safe and well tolerated. Conclusion Use of low dose tacrolimus led to successful biochemical and histologic remission and weaning off prednisone in patients with steroid refractory AIH. This data supports further studies in evaluating the use of tacrolimus in the treatment of AIH.

Natural History of Post-Liver Transplantation Hepatitis C: A Review of Factors That May Influence Its Course

Our aim was to assess long‐term survival in patients transplanted for HCV‐related end‐stage liver disease (ESLD) and evaluate potentially modifiable predictors of survival. We performed a retrospective analysis of adult liver transplants (LT) at our institution for HCV‐related ESLD since the programs inception. Pertinent demographic, clinical, and biochemical information was retrieved from electronic medical records and histological data from 990 per‐protocol liver biopsies were collected. Three hundred eighty LT were performed at our institution during the study period, 206 patients were transplanted for HCV‐related ESLD; 6 died within 30 days of transplantation and were not included. The remaining 200 recipients (DDLT 168 LDLT 32) constituted the evaluable population. The demographics were as follows: 150 males, median age 53 years; median donor age 39 years; hepatocellular carcinoma (HCC) in 26%. Overall 1‐, 5‐, and 7‐year survival: 95%, 81%, and 79%; median survival 43 months, mortality 15%. Significant HCV recurrence (HAI ≥6 and/or fibrosis ≥2) was present in 49%, “early recurrence” (within 1 year of LT) in 30.5% and biopsy‐proven acute rejection was present in 27%. Factors with a significant negative impact on patient survival included: fibrosis stage ≥2 at 12‐month biopsy, advanced donor age, history of HCC and early acute rejection. Survival was similar regardless of the donor type (DDLT vs. LDLT). Early and aggressive HCV recurrence has a very heavy toll on patient survival. Prompt recognition and treatment of “rapid fibrosers” may impart benefit. As has been described before, avoidance of rejection and selection of young donors for HCV‐positive recipients will also improve survival in this population. On the basis of our findings, LDLT is a good option for HCV‐positive recipients. Liver Transpl 15:1872–1881, 2009.

Contribution of Ascites to Impaired Gastric Function and Nutritional Intake in Patients With Cirrhosis and Ascites

BACKGROUND & AIMS Protein calorie malnutrition and weight loss are common among patients with cirrhosis and ascites. The cause of these symptoms is unclear, with several putative mechanisms proposed. The primary aims of this study were to compare gastric volumes and accommodation between patients with cirrhosis complicated by ascites and healthy controls, and to evaluate the effect of large-volume paracentesis in the patient group. METHODS Patients with cirrhosis and ascites underwent assessment of gastric volumes as measured by single-photon emission computed tomography, gastric sensation assessed by a validated nutrient drink test, and a 3-day assessment of caloric intake before and after large-volume paracentesis. Age- and sex-adjusted linear regression models were used to compare gastric volumes and accommodation ratios between patients and healthy volunteers. Paired Wilcoxon rank-sum tests were used to compare gastric measures before and after paracentesis among the patient group. RESULTS Fifteen patients (median age, 54 y) were compared with 112 healthy (age- and sex-matched) controls. Median postprandial gastric volumes (627 mL patients vs 721 healthy controls) and gastric accommodation were reduced significantly in patients compared with healthy controls (P = .02 and .006, respectively). After paracentesis: (1) fasting gastric volumes were increased (median 312 mL post- vs 241 mL pre-, P = .04), (2) patients tolerated ingestion of larger maximum volumes (median 964 mL post- vs 738 mL pre-, P = .04), and (3) caloric intake was increased (median 34% kcal post- vs 3110 kcal pre-, P = .005). CONCLUSIONS Postprandial gastric volumes and accommodation ratios are reduced in patients with cirrhosis and ascites compared with healthy controls. In addition, large-volume paracentesis increases fasting gastric volumes, volumes ingested until maximal satiation, and caloric intake.

Nuclear receptors and nonalcoholic fatty liver disease

Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 in patients with cirrhosis

Interferon (IFN)‐free regimens are needed to treat hepatitis C virus (HCV) infection. Combined simeprevir (SMV) and sofosbuvir (SOF) with or without ribavirin (RBV) results in high sustained virological response (SVR) rates along with minimal adverse events (AEs) in patients with hepatitis C genotype 1 (HCV GT1). The aim of this study was to report on the virological response, safety, and tolerability of SOF and SMV with or without RBV in compensated and decompensated patients with cirrhosis with HCV GT1 infection. Patients treated with standardized clinical protocol utilizing SMV+SOF with or without RBV at three transplant centers were retrospectively reviewed. A total of 119 patients (61% male, 87% white, 69% subtype 1a, 30% Child‐Pugh‐Turcott [CPT]‐B liver cirrhosis [LC], and 82% were treatment experienced) received treatment and were followed for a median of 38 weeks (range, 12‐58). Sustained virological response (SVR) at week 12 (SVR12) was achieved in 78% (92 of 118) of patients (95% confidence interval: 69‐85). Lower pretreatment Model for End Stage Liver Disease (MELD) score was a predictor of SVR12 (P = 0.018). Baseline viral load, previous treatment status, RBV use, or GT1 subtype did not impact SVR 12. The majority of patients with SVR12 showed stability or improvement in MELD score. Treatment was very well tolerated with mild degrees of AEs. Conclusions: The regimen of SMV+SOF with or without RBV for 12 weeks was very well tolerated and resulted in high SVR12 rates (78%) in HCV GT1 patients with LC. SVR12 was inversely related to pretreatment MELD. SVR12 had favorable short‐term impact on MELD score. Long‐term impact on disease stability is yet to be determined. Longer treatment duration or the use of different regimen may still be needed in this population. (Hepatology 2015;62:1004‐1012)

Relationship between sarcopenia, six-minute walk distance and health-related quality of life in liver transplant candidates.

Sarcopenia, or loss of skeletal muscle mass, is associated with increased mortality and morbidity in liver transplant (LT) candidates. Six‐minute walk distance (6MWD) and health‐related quality of life (HRQOL) as assessed by short form 36 scores (SF‐36) also impact clinical outcomes in these patients. This study explored the relationship between the sarcopenia, 6MWD, and HRQOL in LT candidates. Sarcopenia was evaluated based on skeletal muscle mass index (SMI) quantified from abdominal computed tomography. Patients were followed until death, removal from the wait list or the end of the study period. Two hundred and thirteen patients listed for LT were included. The mean SMI, 6MWD and mean gait speed were 54.3 ± 9.7, 370.5 m and 1 m/s, respectively. Sarcopenia was noted in 22.2% of LT candidates. There was no correlation between sarcopenia, 6MWD, and SF‐36 scores. The 6MWD, but not sarcopenia, was an independent predictor of mortality (hazard ratio = 2.1 [0.9–4.7]). In summary, sarcopenia did not emerge as a significant predictor of waitlist mortality and also failed to correlate with either functional capacity or HRQOL in LT candidates. In patients with ESLD awaiting LT, 6MWD appears to be a more useful prognostic indicator than the presence of sarcopenia.