Richard T. Stravitz

SIMILARITIES AND DIFFERENCES IN OUTCOMES OF CIRRHOSIS DUE TO NONALCOHOLIC STEATOHEPATITIS AND HEPATITIS C

The objective of this study was to prospectively define outcomes of cirrhosis due to nonalcoholic steatohepatitis (NASH) and compare them with those associated with hepatitis C virus (HCV) infection. We compared 152 patients with cirrhosis due to NASH with 150 matched patients with cirrhosis due to HCV. Over 10 years, 29/152 patients with cirrhosis due to NASH died compared with 44/150 patients with HCV (P < .04). This was mainly due to the lower mortality rate in patients with Child class A cirrhosis due to NASH versus HCV (3/74 vs. 15/75; P < .004). There were no significant across‐group differences in mortality in patients with Child class B or C cirrhosis. Sepsis was the most common cause of death in both groups; patients with NASH had a higher cardiac mortality (8/152 vs. 1/150; P < .03). Patients with Child class A cirrhosis due to NASH also had a significantly lower risk of decompensation, defined by a 2‐point increase in Child‐Turcotte‐Pugh score (P < .007). Cirrhosis due to NASH was associated with a lower rate of development of ascites (14/101 vs. 40/97 patients at risk; P < .006). NASH also had a significantly lower risk of development of hepatocellular carcinoma (10/149 vs. 25/147 patients at risk; P < .01). In conclusion, compensated cirrhosis due to NASH is associated with a lower mortality rate compared with that due to HCV. It is also associated with a lower rate of development of ascites, hyperbilirubinemia, and hepatocellular carcinoma. However, cardiovascular mortality is greater in patients with NASH. (HEPATOLOGY 2006.)

Surveillance for Hepatocellular Carcinoma in Patients with Cirrhosis Improves Outcome

OBJECTIVE Liver transplantation has become an effective treatment for cirrhotic patients with early-stage hepatocellular carcinoma. We hypothesized that the quality of surveillance for hepatocellular carcinoma influences prognosis by affecting access to liver transplantation. METHODS A total of 269 patients with cirrhosis and hepatocellular carcinoma were retrospectively categorized into 3 groups according to quality of surveillance: standard-of-care (n=172) (group 1); substandard surveillance (n=48) (group 2); and absence of surveillance in patients not recognized to be cirrhotic (n=59) (group 3). RESULTS Three-year survival in the 60 patients who underwent liver transplantation was 81% versus 12% for patients who did not undergo transplantation (P<.001). The percentages of patients who underwent transplantation according to tumor stage at diagnosis (T1, T2, T3, and T4) were 58%, 35%, 10%, and 1%, respectively. Hepatocellular carcinoma was diagnosed at stages 1 and 2 in 70% of patients in group 1, 37% of patients in group 2, and only 18% of patients in group 3 (P <.001). Liver transplantation was performed in 32% of patients in group 1, 13% of patients in group 2, and 7% of patients in group 3 (P<.001). Three-year survival from cancer diagnosis in patients in group 3 (12%) was significantly worse than in patients in group 1 (39%) or group 2 (27%) (each P<.05). Eighty percent of patients in group 3 had subtle abnormalities of cirrhosis on routine laboratory tests. CONCLUSION The quality of surveillance has a direct impact on hepatocellular carcinoma stage at diagnosis, access to liver transplantation, and survival.

Adult Living Donor Versus Deceased Donor Liver Transplantation: A 6‐Year Single Center Experience

No long‐term (>3 years) prospective comparison of adult‐to‐adult living donor liver transplantation (A2ALLTx) to adult deceased donor liver transplantation (ADDLTx) has been reported.

Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis.

Safety of individual probiotic strains approved under Investigational New Drug (IND) policies in cirrhosis with minimal hepatic encephalopathy (MHE) is not clear.

The impact of fat distribution on the severity of nonalcoholic fatty liver disease and metabolic syndrome.

The patterns of fat distribution and their relationship to severity of nonalcoholic fatty liver disease (NAFLD) are unknown. The objectives of this study were to define the fat distribution patterns and their relationship to histological severity and metabolic parameters in subjects with NAFLD. Anthropometric indices and total body fat were measured in 123 subjects. Fat distribution patterns were defined as: general, abdominal, limb, truncal, and dorsocervical lipohypertrophy (DCL) a novel finding in NAFLD. Eighty‐one (66%) of the subjects were obese, and 94 (76%) had abdominal obesity. Thirty‐five (28.5%) had DCL. Whereas body mass index (BMI) correlated best with the presence of diabetes (r = 0.22, P < 0.05), waist circumference (WC) correlated best with hypertension (r = 0.2, P < 0.05), hypertriglyceridemia (r = 0.37, P < 0.001), and insulin resistance (homeostasis model of assessment for insulin resistance [r = 0.68, P < 0.0001]). None of the patterns of fat distribution were significantly associated with severity of hepatic steatosis. Abdominal obesity (WC) correlated with inflammation (r = 0.2, P < 0.05) only. DCL correlated significantly with the severity of all histological parameters except steatosis. Whereas DCL was the single greatest contributor to the variability in severity of histological parameters, a model combining BMI, WC, and DCL showed the greatest contribution to the variability in severity of individual histological parameters. The addition of steatosis grade to the model significantly increased its contribution to the range of lobular inflammation. Conclusion: WC predicts metabolic risk profile with the most significance. However, DCL is most strongly associated with severity of steatohepatitis. WC and BMI added modestly to the contribution of DCL to severity of nonalcoholic steatohepatitis. (HEPATOLOGY 2007.)

The Stroop smartphone application is a short and valid method to screen for minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) detection is difficult because of the unavailability of short screening tools. Therefore, MHE patients can remain undiagnosed and untreated. The aim of this study was to use a Stroop smartphone application (app) (EncephalApp_Stroop) to screen for MHE. The app and standard psychometric tests (SPTs; 2 of 4 abnormal is MHE, gold standard), psychometric hepatic encephalopathy score (PHES), and inhibitory control tests (ICTs) were administered to patients with cirrhosis (with or without previous overt hepatic encephalopathy; OHE) and age‐matched controls from two centers; a subset underwent retesting. A separate validation cohort was also recruited. Stroop has an “off” state with neutral stimuli and an “on” state with incongruent stimuli. Outcomes included time to complete five correct runs as well as number of trials needed in on (Ontime) and off (Offtime) states. Stroop results were compared between controls and patients with cirrhosis with or without OHE and those with or without MHE (using SPTs, ICTs, and PHES). Receiver operating characteristic analysis was performed to diagnose MHE in patients with cirrhosis with or without previous OHE. One hundred and twenty‐five patients with cirrhosis (43 previous OHE) and 134 controls were included in the original cohort. App times were correlated with Model for End‐Stage Liver Disease (Offtime: r = 0.57; Ontime: r = 0.61; P < 0.0001) and were worst in previous OHE patients, compared to the rest and controls. Stroop performance was also significantly impaired in those with MHE, compared to those without MHE, according to SPTs, ICTs, and PHES (all P < 0.0001). A cutoff of >274.9 seconds (Ontime plus Offtime) had an area under the curve of 0.89 in all patients and 0.84 in patients without previous OHE for MHE diagnosis using SPT as the gold standard. The validation cohort showed 78% sensitivity and 90% specificity with the >274.9‐seconds Ontime plus Offtime cutoff. App result patterns were similar between the centers. Test‐retest reliability in controls and those without previous OHE was good; a learning effect on Ontime in patients with cirrhosis without previous OHE was noted. Conclusion: The Stroop smartphone app is a short, valid, and reliable tool for screening of MHE. (Hepatology 2013;58:1122‐1132)

A US multicenter study of hepatitis C treatment of liver transplant recipients with protease-inhibitor triple therapy

BACKGROUND & AIMS NS3/4A protease inhibitors, boceprevir or telaprevir, combined with peginterferon and ribavirin was the standard treatment for HCV genotype 1 and remains the only available direct antiviral drug based therapy in some countries. Efficacy and safety data in liver transplant recipients are limited. METHODS This was a retrospective cohort study of 81 patients with genotype 1 HCV treated with boceprevir (10%) or telaprevir (90%) plus peginterferon and ribavirin at 6 US transplant centers (53% stage 3-4/4 fibrosis, 57% treatment experienced). The primary end point was undetectable HCV RNA 12 weeks after treatment completion (SVR12). RESULTS The intent-to-treat SVR12 rate was 63% (51/81). Patients with an extended rapid virologic response, (undetectable HCV RNA at 4 and 12 weeks after starting boceprevir or telaprevir), had a higher rate of SVR12 than all other patients (85% vs. 15%, p<0.001). Adverse effects were common; 21% of patients experienced hemoglobin <8g/dl and 57% required blood transfusions during the first 16 weeks. Twenty seven percent were hospitalized and 9% died; all were liver-related. CONCLUSIONS The addition of boceprevir or telaprevir to peginterferon and ribavirin yields SVR12 of 63% in liver transplant recipients with genotype 1 recurrent HCV, despite a high prevalence of advanced fibrosis and prior non-response to peginterferon and ribavirin. Rapid virologic response predicted a high likelihood of SVR. Despite a doubling of SVR rates, poor tolerability and high rates of adverse events were frequent and pose barriers to its widespread application.

Effect of hyponatraemia on outcomes following orthotopic liver transplantation.

Background: Hyponatraemia increases risk of adverse outcomes following orthotopic liver transplantation (OLT), but it is unclear whether improvement of pretransplant hyponatraemia ameliorates post‐transplant complications.

Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure

Summary.  Background:  It has been well established that hemostatic potential in patients with chronic liver disease is in a rebalanced status due to a concomitant decrease in pro‐ and antihemostatic drivers. The hemostatic changes in patients with acute liver injury/failure (ALI/ALF) are similar but not identical to the changes in patients with chronic liver disease and have not been studied in great detail.

Severity of Nonalcoholic Fatty Liver Disease and Progression to Cirrhosis Are Associated With Atherogenic Lipoprotein Profile

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is associated independently with increased cardiovascular mortality. Although NAFLD is associated with dyslipidemia, it is not clear whether recently identified markers of cardiovascular risk indicate liver disease progression in patients with histologically confirmed NAFLD. We evaluated an extensive panel of serum markers of cardiovascular risk in nondiabetic patients with histologically proven NAFLD. METHODS We performed a case-control study in which we compared serum levels of laboratory markers of cardiovascular risk among 81 nondiabetic subjects with histologically confirmed NAFLD vs lean (N = 81) and obese (N = 81) individuals without NAFLD (based on liver fat score, controls). For ex vivo studies, liver tissues were obtained from subjects undergoing elective cholecystectomy or from a tissue repository. RESULTS Subjects with NAFLD had increased serum levels of insulin, triglycerides, and apolipoprotein B; increased size and concentration of very large density lipoprotein particles; increased concentrations of low-density lipoprotein (LDL) particles and small dense LDL (sdLDL) cholesterol, and an increased percentage of sdLDL, compared with controls. Although nonalcoholic steatohepatitis was associated with a worse profile of serum atherogenic markers than NAFLD, these differences did not reach statistical significance. Despite hyperinsulinemia, triglyceride and apolipoprotein B levels, concentrations of LDL particles and LDL cholesterol, and sdLDL-related parameters decreased significantly in patients with cirrhosis. Ex vivo studies showed that patients with NAFLD had increased sensitivity of hepatic triglyceride levels and cholesterol synthesis to insulin, and that sensitivity increased the development of cirrhosis. CONCLUSIONS Atherogenic dyslipidemia is related to increased insulin-induced hepatic lipid synthesis in patients with NAFLD. Reduced dyslipidemia in patients with cirrhosis is associated with increased insulin resistance and possibly failed lipid synthesis.