Winston Dunn

MELD accurately predicts mortality in patients with alcoholic hepatitis

Assessing severity of disease in patients with alcoholic hepatitis (AH) is useful for predicting mortality, guiding treatment decisions, and stratifying patients for therapeutic trials. The traditional disease‐specific prognostic model used for this purpose is the Maddrey discriminant function (DF). The model for end‐stage liver disease (MELD) is a more recently developed scoring system that has been validated as an independent predictor of patient survival in candidates for liver transplantation. The aim of the present study was to examine the ability of MELD to predict mortality in patients with AH. A retrospective cohort study of 73 patients diagnosed with AH between 1995 and 2001 was performed at the Mayo Clinic in Rochester, Minnesota. MELD was the only independent predictor of mortality in patients with AH. MELD was comparable to DF in predicting 30‐day mortality (c‐statistic and 95% CI: 0.83 [0.71‐0.96] and 0.74 [0.62‐0.87] for MELD and DF, respectively, not significant) and 90‐day mortality (c‐statistic and 95% CI: 0.86 [0.77‐0.96] and 0.83 [0.74‐0.92] for MELD and DF, respectively, not significant). A MELD score of 21 had a sensitivity of 75% and a specificity of 75% in predicting 90‐day mortality in AH. In conclusion, MELD is useful for predicting 30‐day and 90‐day mortality in patients with AH and maintains some practical and statistical advantages over DF in predicting mortality rate in these patients. MELD is a useful clinical tool for gauging mortality and guiding treatment decisions in patients with AH, particularly those complicated by ascites and/or encephalopathy. (HEPATOLOGY 2005;41:353–358.)

Influence of Serum Sodium on MELD-Based Survival Prediction in Alcoholic Hepatitis

OBJECTIVE To compare the Model for End-Stage Liver Disease (MELD) with the modified model including sodium (MELDNa) for predicting 180-day mortality in patients with alcoholic hepatitis (AH) and determine the subset in whom serum sodium may enhance 180-day mortality prediction. PATIENTS AND METHODS We examined 26 patients with AH enrolled in a prospective trial between June 1, 2004, and June 30, 2007, at Mayo Clinic. Logistic regression analysis was done to assess the effect of MELD and MELDNa scores on 180-day mortality. The C statistic was derived to compare MELD with MELDNa in patients with and without ascites. RESULTS MELD (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.05-1.47; P = .007; C statistic, 0.81) and MELDNa (OR, 1.24; 95% CI, 1.05-1.56; P = .008; C statistic, 0.78) were significant predictors of 180-day mortality in patients with AH. A MELD score of 27.0 and a MELDNa score of 28.0 had sensitivity of 76.5% and 87.5% and specificity of 64.9% and 52.5%, respectively. In patients with AH and ascites, MELDNa (OR, 2.27; 95% CI, 1.22-36.68; P = .008; C statistic, 0.97) was a better predictor of 180-day mortality than MELD (OR, 1.37; 95% CI, 1.07-2.12; P = .006; C statistic, 0.90). A MELD score of 29.0 and a MELDNa score of 34.0 had sensitivity of 85.7% and 83.3% and specificity of 31.0% and 16.7%, respectively. CONCLUSION MELD and MELDNa were similar predictors of 180-day mortality; however, MELDNa was a better predictor of mortality than MELD in patients with ascites. Hyponatremia in patients with AH without ascites is not a predictor of mortality because it may have a dilutional basis secondary to excessive intake of low-osmolar alcohol.

Cell Death and Prognosis of Mortality in Alcoholic Hepatitis Patients Using Plasma Keratin-18

Alcoholic liver disease encompasses the progressive stages of liver dysfunction that culminates in alcoholic cirrhosis (AC) and in severe cases alcoholic hepatitis (AH). Currently, prognostic scores have limited specificity and sensitivity. Plasma keratin-18 (K18) levels are elevated during liver disease and may be biomarkers of outcome. The objective of this study was to determine if total K18 (M65) or caspase-cleaved K18 (M30) levels were different between AC and AH patients. M65 and M30 levels were measured in the plasma of consented healthy controls and patients with AC and AH. Cell death was assessed by TUNEL staining and caspase activity. M65 and M30 values were significantly higher in AC patients compared to healthy controls and further increased in AH patients. The M65 values and the M30/M65 ratios of nonsurviving AH patients were significantly elevated above their surviving counterparts and healthy controls. Statistical analysis indicated that M30/M65 ratios outperformed current indices for accurately distinguishing the prognosis of AH patients. These scores occurred with minimal increase in plasma cell death markers such as ALT and AST. Serum caspase activity, TUNEL staining, and M30 immunohistochemistry in biopsies indicated that serum and tissue values may not correlate well with overall cell death. In conclusion, both M65 and M30 differentiate AH from AC patients, and M65 values and the M30/M65 ratio are capable of predicting early stage mortality; however, they may not accurately reflect pure hepatocyte cell death in these populations, as they do not strongly correlate with traditional cell death markers.

Is it worthy of switching to PegIFN alfa-2a in patients achieving virological suppression with entecavir?

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Response to Doganay et al.

To the Editor: We appreciate the interest shown in our paper (1) by Doganay et al. (2). Above all, we thank Doganay et al. for emphasizing that excessive alcohol intake (referred to as “alcohol” in this letter) does not prevent fibrosis. Alcohol leads to cirrhosis, and cirrhosis-related mortality and morbidity in a number of large-scale population studies (3,5). Our study focused on interactions among the rs738409 polymorphism, obesity, and alcohol intake. When we published our finding of the negative interaction between alcohol and obesity on fibrosis risk, we chose our words carefully in an attempt to avoid the misconception that alcohol intake prevents fibrosis.

The Interaction Between Obesity and Alcohol: A Population-Based Autopsy Study

Introduction: As the childhood obesity epidemic grows, an increasing number of children are diagnosed with non-alcoholic fatty liver disease (NAFLD) and type 2 non-alcoholic steatohepatitis (NASH). One common finding in NASH patients is increased levels of free fatty acids (FFA). Peroxidation of FFA by reactive oxygen species (ROS) has been shown to cause damage to cellular membranes and organelles such as mitochondria. Studies in humans and animals have demonstrated that oxidative stress, which produces ROS, is a critical player in the pathogenesis of NASH. PON1 is an enzyme exclusively synthesized in the liver and functions as an antioxidant preventing the oxidation of High Density Lipoproteins (HDL). Studies in adults have shown comparable activity of PON1 in both liver and serum, thus making it a potential biomarker for evaluating liver disease. Adult human and animal studies have demonstrated decreased or depleted PON1 activity with diseased liver architecture and changes in plasma lipoprotein subclass distribution. This can lead to increased production of oxidative stress and subsequent atherosclerotic risk. Currently the relationships between PON1 and pediatric (type 2) NASH, is unknown. This study focuses on the gene expression of PON1 in type 2 NASH. Methods and Results: NASH was diagnosed according to Kleiners criteria. Data mining on NASH microarray database [1] showed a difference in the relative expression of PON1 among insulin resistant (1.77x) and non insulin resistant (2.24x) pediatric NASH patients compared to normal controls (NC). Additional quantitative analysis of the PON1 expression in liver tissue of NASH (n=18) and NC (n= 4) with GAPDH as the housekeeping gene was performed with real time PCR. PON1 mRNA expression level was found to be 8.18 times that of the NC (p< 0.005). Conclusion: The increase in the expression of PON1 in pediatric NASH livers suggests a shift in the balance between antioxidants and oxidative stress. This finding is in contrast to adult NASH studies where a decreased level of PON1 activity in serum was reported with NASH type I. Our findings suggest that the hepatic damage involved in type 2 NASH is not as extensive compared to the hepatic damage noted in type 1 NASH. In addition this data suggests that serum levels of PON1 are likely inadequate surrogate for liver biopsy when assessing pediatric liver disease, additional studies are necessary.