Hepatic Failure Due to Cholestatic Hepatitis C in an Immunosuppressed Patient Treated With Elbasvir and Grazeprevir.

Hepatitis C-induced cholestatic hepatitis is a well-known fatal complication of postorthotropic liver transplantation and prolonged immunosuppression. Recent studies on direct-acting antiviral agents have shown promising results in terms of morbidity and mortality of this condition in postorthotropic liver, heart, and renal transplant patients. However, hepatitis C-induced cholestatic hepatitis remains a highly fatal condition in non-transplant patients. We report the first-ever use of the oral direct-acting antiviral combination, elbasvir and grazeprevir, in the treatment of a non-liver transplant patient with cholestatic hepatitis.

Reversal of fibrosis in patients with nonalcoholic steatohepatosis after gastric bypass surgery.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) improves the pathophysiology that contributes to obesity-related nonalcoholic steatohepatitis (NASH). Whether obesity-related fibrosis improves is unclear. We hypothesized that RYGB reverses NASH and fibrosis, and indocyanine green (ICG) clearance provides a sensitive measure for detecting asymptomatic fatty liver disease. METHODS: One hundred six obese adults scheduled for RYGB had preoperative liver function assessed using standard tests and ICG clearance and core liver biopsies obtained during RYGB. Once patients lost 60% of their preoperative weight or weight loss plateaued, liver function was reassessed. Repeat liver biopsies were obtained on patients with NASH at the time of RYGB. RESULTS: RYGB improved steatosis, lobular inflammation, hepatocyte ballooning and fibrosis. Serum albumin, AST, and ALT decreased the most in patients with NASH and NASH plus fibrosis. Twenty seven (26%) patients had normal baseline liver histology and 45 (43%) had NASH or NASH plus fibrosis. Nine of 13 patients with substantial fatty liver had normalized histology after weight loss, while severity of disease in the rest had stabilized or was reduced. Mean ICG clearance in patients with normal/mild fatty liver disease and those with histological fatty livers did not differ significantly. CONCLUSIONS: RYGB surgery reverses NASH and liver fibrosis. Underlying mechanisms that facilitate improvement remain unclear.

Ohio solid organ transplantation consortium criteria for liver transplantation in patients with alcoholic liver disease.

AIM: To evaluate risk of recidivism on a case-by-case basis. METHODS: From our center's liver transplant program, we selected patients with alcoholic liver disease who were listed for transplant based on Ohio Solid Organ Transplantation Consortium (OSOTC) exception criteria. They were considered to have either a low or medium risk of recidivism, and had at least one or three or more months of abstinence, respectively. They were matched based on gender, age, and Model for End-Stage Liver Disease (MELD) score to controls with alcohol-induced cirrhosis from Organ Procurement and Transplant Network data. RESULTS: Thirty six patients with alcoholic liver disease were approved for listing based on OSOTC exception criteria and were matched to 72 controls. Nineteen patients (53%) with a median [Inter-quartile range (IQR)] MELD score of 24 (13) received transplant and were followed for a median of 3.4 years. They were matched to 38 controls with a median (IQR) MELD score of 25 (9). At one and five years, cumulative survival rates (± standard error) were 90% ± 7% and 92% ± 5% and 73% ± 12% and 77% ± 8% in patients and controls, respectively (Log-rank test, P = 0.837). Four (21%) patients resumed drinking by last follow-up visit. CONCLUSION: Compared to traditional criteria for assessment of risk of recidivism, a careful selection process with more flexibility to evaluate eligibility on a case-by-case basis can lead to similar survival rates after transplantation.

Prevalence of celiac disease in cirrhosis and outcome of cirrhosis on a gluten free diet: a prospective study.

BACKGROUND & AIMS: Current consensus suggests CD to be a multi-systemic disease that could affect any organ system including the liver. It remains under-diagnosed in the US and its prevalence and management in cirrhotic patients has not been studied. Our aim was (1) to estimate the prevalence of CD in cirrhosis, (2) to characterize cirrhotic patients with abnormal celiac serology and normal small bowel biopsy and (3) to evaluate the effect of a GFD on the liver. METHODS: A total of 204 consecutive patients with biopsy proven cirrhosis scheduled for an upper endoscopy (EGD) to assess and treat gastro-esophageal varices (GEV) at the Cleveland Clinic between 5/1/2008 and 5/30/2010 were enrolled in the study and followed for 2 years. RESULTS: CD affects 2.5% of cirrhotic patients and more than twice the prevalence in the general population. Abnormal EMA >1/10 and high hTTG levels >20 IU can be used to diagnose CD in cirrhosis. Sensitivities and specificities are 100% for EMA and 80% and 94% for hTTG, respectively. After a GFD, patients with CD showed a return to normal levels of their celiac serology, small bowel biopsy and liver enzyme abnormalities. CONCLUSIONS: CD is at least twice more common in cirrhotic patients than in the general population and GFD improves liver tests. CD can occur coincidentally with other liver disorders and screening may be warranted during the evaluation of patients with cirrhosis. Abnormal EMA and high hTTG levels can be used to diagnose CD in cirrhosis.

Cargo, "infection," and the logic of quarantine in the nineteenth century.

In the nineteenth century, maritime quarantine officials often paid more attention to ships' cargo than they did to the health of passengers or crew members. Based on a close reading of the everyday practice of quarantine at Philadelphia's Lazaretto (1801-1895), this article suggests that the historical significance of quarantine has been distorted by its association with the etiological debate over contagion and with xenophobic responses to immigration. In fact, the practice of quarantine rested neither on contagionist medical doctrine nor on nativism. Rather, it was based on the danger of infection, an elusive but fundamental concept in nineteenth-century public health. The concern about cargo rather than people-and the logic of infection it reflects-bespeak a widely shared set of perceptions of illness and public health in the first three-quarters of the nineteenth century that is not captured by discussions of contagion or of anti-immigrant bias.

High prevalence of normal serum albumin in NASH patients with ascites: a retrospective analysis.

BACKGROUND: Ascites usually occurs in the setting of end-stage liver disease and low serum albumin and is associated with increased mortality. However, some patients develop ascites despite normal serum albumin (NSA), when a higher portal pressure and/or enhanced renal sodium retention would be expected. This study investigated the relationship between the hepatic venous pressure gradient (HVPG) and serum albumin in ascitic patients with different etiologies of cirrhosis and mortality. METHODS: Records of all patients with non-malignant ascites who underwent HVPG measurement from 2005 to 2009 were reviewed. RESULTS: One hundred and thirty-eight 138 patients met inclusion criteria; 18.8% had NSA. No difference in sodium excretion or diuretic use was noted in patients with and without NSA. NASH patients were more likely to have a NSA (34.2% vs 12.4%; P=0.001) as well as lower HVPG (15 vs 17.9 mmHg; P=0.009) compared to other etiologies. MELD and HVPG predicted overall survival. However, mortality did not differ by disease etiology, though NASH patients had lower CTP (7.6 vs 8.5; P<0.001) and MELD (15.6 vs 18.1; P=0.09) scores, particularly among patients who died. CONCLUSIONS: In patients with ascites and NSA, there were no increase in HVPG or urinary sodium retention. NASH patients with ascites had lower HVPG and a higher prevalence of NSA. They also had a higher mortality relative to MELD and CTP scores in other patients. In these patients, mechanisms other than portal and oncotic pressures and sodium retention play a role in ascites development, and increase mortality rate when complicated by low albumin.

Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.

This placebo-controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig's histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone.

Pegylated interferon alpha-2b, ribavirin and amantadine for chronic hepatitis C.

In an attempt to improve the efficacy of antiviral therapy for chronic hepatitis C, a three-drug combination of pegylated interferon alpha-2b, ribavirin, and amantadine has been suggested. Despite the initial enthusiasm, the role of amantadine in the treatment of chronic hepatitis C remains controversial. In a multi-center, open-label clinical trial, the potential efficacy and safety of this triple combination regimen were assessed. In this open-label pilot study, two separate patient populations with chronic hepatitis C and viremia were enrolled: treatment-naive and those who had failed a previous course of treatment. Patients were started on pegylated interferon alpha-2b at a dose of 1.5 microg/kg weekly with ribavirin, 1000-1200 mg/day, and amantadine, 200 mg/day, for 4 weeks, followed by pegylated interferon alpha-2b, 0.5 microg/kg weekly, ribavirin, 1000-1200 mg/day, and amantadine, 200 mg/day, for another 20 weeks. Patients with undetectable HCV RNA at week 24 continued this regimen for a total of 48 weeks and were followed for another 24 weeks. Patients with undetectable virus (<50 IU/mL) after 24 weeks of follow-up were considered to have SVR. Health-related quality of life and safety data were also collected. Sixty-nine treatment-naive and 99 nonresponder patients with chronic hepatitis C were enrolled in the study. Of all patients enrolled, 74% were male, aged 47.27+/-5.76 years; their body mass index (BMI) was 28.87+/-5.05 kg/m2, 79.4% were white, 85% had HCV genotypes 1 and 4, and 36% had cirrhosis. Their baseline HCV RNA was 689,242+/-698,030 IU/mL, with a baseline ALT of 107.25+/-79.08. Of the entire cohort, 35 (21%) discontinued early due to side effects or loss to follow-up. Significant anemia (hemoglobin, < 10 g/dL) occurred in 11% (19/168), while severe anemia (hemoglobin, <8.5 g/dL) occurred in 0.6% (1/168). In the treatment-naive group, sustained virologic response (SVR) was 34.3%, versus 19.4% for the group who had previously failed to respond to a course of treatment (P = 0.01). For both groups combined, virologic response after 24 weeks of therapy was 40.5%, with an end-of-treatment virologic response of 35.7% and a SVR of 26.2%. Patients with genotypes 1 and 4 had lower response rates than those with genotypes 2 and 3 (SVR, 21 vs. 46%; P = 0.001). Patients with advanced fibrosis (Metavir stages 3 and 4) tended to have lower response rates than those with minimal or mild fibrosis (Metavir stages 0-2) (SVR, 10 vs. 30%; P = 0.08). African-American patients with HCV had lower response rates than Caucasians or other ethnic groups (SVR, 4 vs. 29 vs. 20%; P = 0.04). Age, gender, and BMI did not affect SVR. The addition of amantadine to pegylated interferon alpha-2b and ribavirin does not seem to increase the efficicacy of this regimen.

Obesity and non-alcoholic fatty liver disease in chronic hepatitis C.

BACKGROUND: Superimposed non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) may affect HCV-related fibrosis. We performed a study to determine the relationship between NAFLD and chronic hepatitis C. METHODS: One hundred and twenty patients with chronic hepatitis C and available liver biopsies were included. Baseline liver biopsies were read by 1 hepatopathologist using Metavir, as well as a fatty liver pathology protocol. Patients' baseline clinical, demographic, and virologic data were associated with the extent of steatosis (>33% vs. < or =33%), the type of fatty liver (no steatosis vs. steatosis only vs. NASH), and the stage of fibrosis seen on the liver biopsy. RESULTS: Seventy percent of patients were men and 80% were white. The mean age was 47.48+/-5.70 years, mean BMI was 29.01 +/-5.01 kg/m, and mean waist to hip ratio (W/H) was 0.90+/-0.08. Patients with higher grade of steatosis had higher BMI (32.83+/-6.26 vs. 28.49+/-4.62, P = 0.034), more likely to have genotype 3 (21.4% vs. 5.7%, P = 0.037) and advanced fibrosis (92.9% vs. 62.3%, P = 0.033) than those with lower grade of steatosis. Of these, only HCV-genotype 3 remained independently associated with higher grade of steatosis. When patients with superimposed NASH (n = 22) were compared with those with only steatosis (n = 49) and those without steatosis (n = 49), patients with superimposed NASH had more evidence of obesity (BMI: 30.64+/-5.23 vs. 29.90+/-5.35 vs. 27.33+/-4.07, P = 0.008; W/H: 0.97+/-0.06 vs. 0.91+/-0.08 vs. 0.87+/-0.07, P < 0.001), more commonly infected with HCV genotype 3 (14% vs. 12% vs. 0%, P = 0.036) and had more advanced fibrosis (95.5% vs. 75.5% vs. 42.9%, P < 0.001). Race, gender, and age did not affect extent of steatosis or presence of superimposed NASH. CONCLUSION: In conclusion, markers of obesity (BMI and W/H) and HCV genotype 3 are associated with the extent of steatosis and type of fatty liver. Higher grade of steatosis and presence of superimposed NASH are both associated with advanced hepatic fibrosis.

Predicting outcome after cardiac surgery in patients with cirrhosis: a comparison of Child-Pugh and MELD scores.

BACKGROUND & AIMS: This study aims to quantify the risk of cardiac surgery in patients with cirrhosis. METHODS: Records of all adult patients with cirrhosis undergoing cardiac surgery using cardiopulmonary bypass at the Cleveland Clinic (Cleveland, OH) from January 1992 to June 2002 were analyzed for any relationship of Child-Pugh class and/or score and Model for End-Stage Liver Disease (MELD) score with outcome measures of hepatic decompensation and death during the first 3 months after surgery. RESULTS: Forty-four patients underwent coronary artery bypass grafting (16 patients), valve surgery (16 patients), a combination of the 2 procedures (10 patients), or pericardiectomy (2 patients). Twelve patients (27%) developed hepatic decompensation, and 7 patients (16%) died. Proportions of hepatic decompensation were 3 of 31, 8 of 12, and 1 of 1 patients, and death, 1 of 31, 5 of 12, and 1 of 1 patients in Child-Pugh classes A, B, and C, respectively. The association of hepatic decompensation and mortality with Child-Pugh class, Child-Pugh score, and MELD score was significant (P < 0.005). Areas under the receiver operating characteristic curves for mortality were similar for Child-Pugh (0.84 +/- 0.09) and MELD scores (0.87 +/- 0.09). A cutoff Child-Pugh score >7 was found to have a sensitivity and specificity of 86% and 92% for mortality, with a negative predictive value of 97% (95% confidence interval [CI], 83-99) and positive predictive value of 67% (95% CI, 31-91), respectively. However, a similar cutoff value for MELD score could not be established. CONCLUSIONS: Child-Pugh score and/or class and MELD score are significantly associated with hepatic decompensation and mortality after cardiac surgery using cardiopulmonary bypass in patients with cirrhosis. Such surgery can be conducted safely in patients with a Child-Pugh score /=8 have a significant risk for mortality.

Triple combination of interferon alpha-2b, ribavirin, and amantadine for treatment of chronic hepatitis C.

Retreatment of interferon-resistant chronic hepatitis C represents a significant clinical challenge. In an open-label, pilot study, the safety and efficacy of interferon alpha-2b, ribavirin, and amantadine were assessed. Twenty patients with chronic hepatitis C who had previously failed to respond to a course of interferon monotherapy followed by a course of combination therapy (10 patients received interferon alpha-2b [3 million units three times a week] plus ribavirin [800 mg/d] and 10 patients received interferon alpha-2b [3 million units three times a week] plus amantadine [200 mg/d]) were enrolled in this retreatment protocol. One month after discontinuation of their last regimen, patients started treatment with interferon alpha-2b (3 million units three times a week), ribavirin (1,000-1,200 mg/d), and amantadine (200 mg/d). Biochemical and virologic end points were monitored. Patients with hepatitis C virus (HCV) RNA levels of <100 copies/mL at the end of 24 weeks of therapy completed a 48-week course of interferon alpha-2b, ribavirin, and amantadine treatment. Of the enrolled subjects, 60% were male, 85% were white, 85% had HCV genotype 1, and 20% had histologic cirrhosis. The mean age +/- SD of the patients was 44.1 +/- 4.9 years, the mean baseline HCV RNA level +/- SD was 1,845,150 +/- 1,279,069 copies/mL, and the mean baseline alanine aminotransferase level +/- SD was 130 +/- 100 U/L. Five patients (25%) became HCV RNA negative (<100 copies/mL) after 24 weeks of treatment, with only three patients (15%) remaining HCV RNA negative at the end of 48 weeks of treatment. This end of treatment response was sustained 6 months after the discontinuation of treatment in only two patients (10%). In this interferon-resistant group, a treatment regimen of interferon alpha-2b, ribavirin, and amantadine was associated with only a 10% sustained viral eradication rate.