Michel H. Mendler

Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis

BACKGROUND & AIMS The diagnosis of hemochromatosis is now possible for C282Y homozygous patients using noninvasive molecular genetic tests. The aim of this study was to define noninvasive factors predictive of severe fibrosis (bridging fibrosis or cirrhosis) to avoid unnecessary liver biopsies in such patients. METHODS Clinical and biological data were recorded at the time of diagnosis in 197 French C282Y homozygous patients, 52 (26%) of whom had severe fibrosis. Variables significantly linked to severe fibrosis using univariate analysis were entered into a multivariate stepwise analysis. These variables were combined to obtain a simple index allowing for prediction of severe fibrosis. RESULTS Serum ferritin, hepatomegaly, and serum aspartate aminotransferase were selected using multivariate analysis. Their combination applied to the 96 patients with ferritin level of </=1000 microgram/L, normal aspartate aminotransferase values, and absence of hepatomegaly showed that no severe fibrosis was encountered in this subgroup of patients. The results were validated in 113 C282Y homozygous patients in Canada with a good reproducibility of negative prediction but a poor reproducibility of the positive prediction of severe fibrosis. CONCLUSIONS In C282Y homozygous patients, the diagnosis of severe fibrosis relies on liver biopsy, but absence of severe fibrosis can be accurately predicted in most patients on the basis of simple clinical and biochemical variables.

Factors Predicting Relapse and Poor Outcome in Type I Autoimmune Hepatitis: Role of Cirrhosis Development, Patterns of Transaminases During Remission and Plasma Cell Activity in the Liver Biopsy

AIM:To determine factors predicting relapse and poor outcome in patients with type I autoimmune hepatitis (AIH).METHODS:Patients with AIH were retrospectively recruited. Definitions—remission: AST/ALT < 2 ULN; relapse: AST/ALT ≥ 2 ULN; poor outcome: cirrhosis complications, transplantation (OLTx), and death; abnormal transaminases: AST/ALT > ULN but within the remission range; abnormal transaminases index (ATI): number of occasions AST/ALT abnormal/years of remission. Liver biopsies were assessed by Ishak system, and additional score given for portal and parenchymal plasma cells. Data are presented as median (range).RESULTS:Seventy-one patients were identified. Twenty (28%) had cirrhosis at presentation, 14 (20%) developed it during follow-up of 52 months (18–336). Of the 14, four had histological confirmation, and the remainder had clinical/radiological evidence of cirrhosis. Factors independently associated with cirrhosis development were inability to have consistently normal transaminases during remission, OR 19.3 (95% CI 2.2–40), p= 0.002. Treatment was discontinued in 40/69 patients of whom 30 (75%) relapsed within 2 months (1–23), culminating in one death. Factors independently associated with relapse were: time to initial remission, OR 5.5, 95% CI 1.3–22, p= 0.01; failure to have consistently normal transaminases during remission OR 11.8, 95% CI 1.3–100, p= 0.02; and portal plasma cell score (PPCS) OR 10.6 (95% CI 1.0–107), p= 0.04. Time to remission ≥ 5 months, PPCS ≥ 3 and ATI ≥ 2 was associated with >90% probability of relapse (PPV 100%). Fifteen percent had a poor outcome. Independent predictors of poor outcome were: globulins at onset OR 3.4 (95% CI 1.1–10.1), p= 0.02 and cirrhosis development, OR 23 (95% CI 1.7–307), p= 0.CONCLUSIONS:Seventy percent of patients with AIH relapse upon drug cessation. Time to remission ≥ 5 months, ATI ≥ 2 and PPCS ≥ 3 were associated with >90% probability of relapse. Factors predicting poor outcome were globulins at onset and cirrhosis development.

Abnormal hepatic methionine and glutathione metabolism in patients with alcoholic hepatitis.

BACKGROUND Abnormal methionine metabolism occurs in animals fed ethanol and in end-stage cirrhotic patients. Expected consequences of these abnormalities include reduced hepatic S-adenosylmethionine and glutathione (GSH) levels, impaired transmethylation, and reduced homocysteine catabolism, resulting in the often-observed hyperhomocystinemia in cirrhotic patients. These parameters have not been examined simultaneously in patients with less advanced alcoholic liver disease. METHODS Six patients hospitalized for alcoholic hepatitis were studied. Plasma was analyzed for homocysteine, methionine, and GSH levels. Liver biopsies diagnosed acute alcoholic hepatitis and underlying fibrosis. Liver specimens were processed for messenger RNA (mRNA) levels and various metabolites and were compared with those of six normal controls. RESULTS Three patients had cirrhosis, and three had only portal fibrosis. Plasma levels of homocysteine and methionine were increased in two of the three patients with cirrhosis but not in the patients with fibrosis. All patients had markedly lower plasma GSH levels (mean +/- SD: 0.27 +/- 0.19 microM, which is at least 10-fold lower than the normal range). Hepatic S-adenosylmethionine levels were reduced by 50%, whereas methionine, GSH, and cysteine levels were reduced by 70-80%. The mRNA levels of most enzymes involved in methionine metabolism and GSH synthesis were decreased, whereas albumin expression was unchanged. Despite the well known induction of cytochrome P450 2E1 in chronic alcoholics, its mRNA levels were nearly 70% lower in these patients. CONCLUSIONS In alcoholic hepatitis, abnormal hepatic gene expression in methionine and GSH metabolism occurs and often contributes to decreased hepatic methionine, S-adenosylmethionine, cysteine, and GSH levels. It may be important to replenish these thiols in patients hospitalized with alcoholic hepatitis.

Histologic Features of the Liver in Insulin Resistance-Associated Iron Overload A Study of 139 Patients

The aim of the present study was to describe histologic features of the liver in insulin resistance-associated hepatic iron overload (IR-HIO), defined as the association of metabolic disorders and hepatic iron overload. We included 139 patients in the study on the basis of one or more metabolic disorders and liver iron overload unrelated to usual causes. Liver biopsy specimens were reviewed, and histologic data were compared with those of a previously published, well-defined population with genetic hemochromatosis. Iron overload was characterized by a mixed pattern with iron deposits in hepatocytes and sinusoidal cells. Steatosis was present in 59.7% of patients with inflammation in 32.4% of cases. Periportal fibrosis was found in 67.4% of patients. These patients were older, had higher sinusoidal iron scores, and had a higher prevalence of steatosis and inflammation than patients without fibrosis. Iron overload in IR-HIO was histologically different from that in genetic hemochromatosis.

Proposal for a histological scoring and grading system for non-alcoholic fatty liver disease

Abstract: Aim/Background: The spectrum of histopathological features in non‐alcoholic fatty liver disease (NAFLD) has been well described. At least two scoring systems have been established. We propose here a system in which numerical scores are obtained using the different features.

Instant diagnosis of spontaneous bacterial peritonitis using leukocyte esterase reagent strips: Nephur-Test vs. MultistixSG.

Background/Aim: Spontaneous bacterial peritonitis (SBP), defined by an ascites neutrophil count >250/μl, is a severe complication of cirrhosis and demands prompt diagnosis. Leukocyte esterase reagent strips can rapidly detect leukocytes in physiological fluids. We compared the performance of two leukocyte esterase reagent strips in the diagnosis of SBP.

Prevalence of septic events, type 1 hepatorenal syndrome, and mortality in severe alcoholic hepatitis and utility of discriminant function and MELD score in predicting these adverse events.

We sought to assess prevalence, and utility of discriminant function (DF) and MELD score in predicting septic events (SE), type 1 hepatorenal syndrome (HRS), and short-term mortality in severe alcoholic hepatitis (AH). Charts of patients with AH (group 1) and cirrhosis without AH (group 2) were retrospectively reviewed. Severe AH, discriminant function (DF) ≥ 32 was treated with pentoxifylline. One hundred ninety-five patients were enrolled in the study and divided into 2 groups: group 1, n=99, and group 2, n=96. Of those with AH, 82% had a DF ≥ 32 at presentation. Group 1 patients had a higher prevalence of SE (38% versus 25%, P=.04), type 1 HRS (30% versus 9%, P=.0003), and short-term mortality (28% versus 7%, P=.0001). In patients with AH, a MELD score ≥20 (but not a DF ≥ 32) at presentation was an independent predictor of a SE (odds ratio [OR] 2.8 [1.0–7.9], P=.04), HRS (OR 4.0, 95% confidence interval [CI] 1.0–16.6, P=0.05), and short-term mortality (OR 6.4, 95% CI 1.1–37.6, P=.03). Kaplan-Meier survival curves confirmed that that a MELD ≥ 20 but not a DF ≥ 32 was associated with a poorer survival (P = .005 and .5, respectively). In conclusion, patients with severe AH have higher prevalence of SE, HRS, and short-term mortality compared to those with cirrhosis without AH. A MELD score ≥20 at presentation is an independent predictor of these adverse events in patients with AH who have been treated with pentoxifylline.

Choosing the location for non‐image guided abdominal paracentesis

Abstract: Objectives: The optimal location for paracentesis has not been studied scientifically. The evolving obesity epidemic has changed the physique of many patients with cirrhosis and ascites such that needles inserted into the abdominal wall may not reach fluid. We aimed to determine the location for paracentesis that would have the thinnest abdominal wall and the deepest amount of fluid.

A new highly sensitive point of care screen for spontaneous bacterial peritonitis using the leukocyte esterase method

BACKGROUND & AIMS Urine reagent strips measuring leukocyte esterase activity have been studied to screen spontaneous bacterial peritonitis (SBP) but are insensitive. We calibrated a strip specifically for ascitic fluid to achieve high sensitivity in this diagnosis. METHODS Experiments were conducted on ascitic fluid from patients with cirrhosis. Samples with SBP were diluted with native acellular ascitic fluid to achieve PMN counts below, above, and close to the diagnostic threshold of 250 PMN/microl. A model of SBP was created by spiking negative ascitic fluid samples (<250 PMN/microl) with activated PMN from blood of patients with sepsis, and diluted to achieve a range of PMN. Aliquots were tested at 2, 3, 4, and 10 min with the Periscreen leukocyte esterase strip. PMN/microl was correlated to timings and color scales: white defined negative (PMN <250/microl); and shades of brown, purple, and pink defined positive. Ascitic fluid samples were obtained from 58 patients. Negative ascitic fluid was used from 32 to generate the model SBP. RESULTS One thousand three hundred and four experiments were performed with a median PMN count of 492/microl (0-7510). After exclusion of uninterpretable colorimetric results, 1089 experiments were analyzed [PMN of 444/microl (0-7510)]. The best result was obtained at 3 min (n=299), with Se: 100%, Sp: 57.9%; NPV: 100%, PPV: 76.5%. The test was not interpretable in bloody, chylous or bilious ascitic fluid, or concurrent imipenem treatment. CONCLUSIONS This new leukocyte esterase strip calibrated to an ascitic fluid PMN count 250/microl is a robust screening tool when the strip turns any hue of tan/brown at 3 min.

A pilot study of iron depletion as adjuvant therapy in chronic hepatitis C patients not responding to interferon

The aim of this study was to assess the efficacy of iron depletion obtained by phlebotomy to enhance interferon response in 11 patients who had failed to respond to a standard 3-month interferon treatment. Despite a significant effect on serum aminotransferase levels, there was no effect on viremia, and iron depletion was unable to trigger interferon response.