Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.

BACKGROUND & AIMS: N-acetylcysteine (NAC), an antidote for acetaminophen poisoning, might benefit patients with non-acetaminophen-related acute liver failure. METHODS: In a prospective, double-blind trial, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and assigned randomly to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation. RESULTS: A total of 173 patients received NAC (n = 81) or placebo (n = 92). Overall survival at 3 weeks was 70% for patients given NAC and 66% for patients given placebo (1-sided P = .283). Transplant-free survival was significantly better for NAC patients (40%) than for those given placebo (27%; 1-sided P = .043). The benefits of transplant-free survival were confined to the 114 patients with coma grades I-II who received NAC (52% compared with 30% for placebo; 1-sided P = .010); transplant-free survival for the 59 patients with coma grades III-IV was 9% in those given NAC and 22% in those given placebo (1-sided P = .912). The transplantation rate was lower in the NAC group but was not significantly different between groups (32% vs 45%; P = .093). Intravenous NAC generally was well tolerated; only nausea and vomiting occurred significantly more frequently in the NAC group (14% vs 4%; P = .031). CONCLUSIONS: Intravenous NAC improves transplant-free survival in patients with early stage non-acetaminophen-related acute liver failure. Patients with advanced coma grades do not benefit from NAC and typically require emergency liver transplantation.

False positive acetaminophen concentrations in patients with liver injury.

BACKGROUND: Acetaminophen toxicity is the most common form of acute liver failure in the U.S. After acetaminophen overdoses, quantitation of plasma acetaminophen can aid in predicting severity of injury. However, recent case reports have suggested that acetaminophen concentrations may be falsely increased in the presence of hyperbilirubinemia. METHODS: We tested sera obtained from 43 patients with acute liver failure, mostly unrelated to acetaminophen, utilizing 6 different acetaminophen quantitation systems to determine the significance of this effect. In 36 of the 43 samples with bilirubin concentrations ranging from 1.0-61.5 mg/dl no acetaminophen was detectable by gas chromatography-mass spectroscopy. These 36 samples were then utilized to test the performance characteristics of 2 immunoassay and 4 enzymatic-colorimetric methods. RESULTS: Three of four colorimetric methods demonstrated 'detectable' values for acetaminophen in from 4 to 27 of the 36 negative samples, low concentration positive values being observed when serum bilirubin concentrations exceeded 10 mg/dl. By contrast, the 2 immunoassay methods (EMIT, FPIA) were virtually unaffected. The false positive values obtained were, in general, proportional to the quantity of bilirubin in the sample. However, prepared samples of normal human serum with added bilirubin showed a dose-response curve for only one of the 4 colorimetric assays. CONCLUSIONS: False positive acetaminophen tests may result when enzymatic-colorimetric assays are used, most commonly with bilirubin concentrations >10 mg/dl, leading to potential clinical errors in this setting. Bilirubin (or possibly other substances in acute liver failure sera) appears to affect the reliable measurement of acetaminophen, particularly with enzymatic-colorimetric assays.

Influence of high body mass index on outcome in acute liver failure.

BACKGROUND & AIMS: Diabetes and obesity affect development of nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease increases susceptibility to hepatic injury and limits regenerative capacity, which might increase adverse outcomes in acute liver failure. There is no difference in the prevalence of diabetes in acute liver failure patients when compared with the general population, but no large studies have examined the relationship of obesity to incidence or outcome of acute liver failure. METHODS: Seven hundred eighty-two adult patients with acute liver failure were prospectively enrolled from 1998-2004. Body mass index, history of diabetes, and outcome were recorded. Multivariable logistic regression was used for the analysis. RESULTS: Compared with 30.4% of adults in the National Health and Nutrition Examination Survey III, 29.1% of adult patients with acute liver failure were obese (P=.542). Obese patients had 1.63 times the odds of transplantation or death as nonobese patients (1.04-2.55, P=.033). Severely obese patients had 1.93 times the odds of transplantation or death (1.02-3.62, P=.042). There were no differences in the proportion of patients listed for transplantation, with body mass index greater or less than 30, 35, or 40 (P=.264, P=.112, P=.244, respectively). Obese patients had 3.4 times the odds of dying after transplantation (1.29-8.87, P=.01). CONCLUSIONS: Obesity does not appear to be more prevalent in acute liver failure. However, obese and severely obese patients had significantly poorer outcomes when they developed acute liver failure. This difference is not explained by weight discrimination in listing patients for transplantation, despite evidence for poorer post-transplant outcomes.

Pseudohypocalcemia after magnetic resonance imaging with gadolinium in patients with cirrhosis.

Hypocalcemia in patients with cirrhosis may be due to a number of causes. We noted a relationship between injection with gadodiamide, a particular gadolinium chelate, during magnetic resonance imaging of the liver and the development of a falsely low serum total calcium level in a patient with cirrhosis. A cross-reference and retrospective chart review identified 10 additional patients in whom this phenomenon was noted. We describe the temporal relationship and clinical characteristics of these patients. Pseudohypocalcemia following magnetic resonance imaging with gadodiamide contrast should be considered in the differential diagnosis of hypocalcemia in patients with cirrhosis.

A correlation between the pretransplantation MELD score and mortality in the first two years after liver transplantation.

The Model for End-Stage Liver Disease (MELD) score is now the criteria for allocation in liver transplantation for patients with chronic disease. Although the score has been effective in the prediction of mortality in patients awaiting liver transplantation, its abilities to predict posttransplantation outcome need study. The aim of this study is to compare outcome in the first 2 years after liver transplantation according to the pretransplantation MELD score. The study includes 669 consecutive patients who underwent primary liver transplantation between December 1993 and October 1999 in a single transplant center. Patients who died of malignancy were excluded from the series. Pretransplantation MELD score was calculated using the United Network for Organ Sharing formula. Patients were stratified according to MELD score less than 15, 15 to 24, and 25 and higher. Posttransplantation survival at 3, 6, 12, 18, and 24 months was significantly lower in the groups with a higher MELD score. The difference was significant for hepatitis C and noncholestatic liver diseases, but not cholestatic diseases. In patients with a MELD score between 15 and 24, survival was significantly greater with cholestatic diseases and lower in patients with hepatitis C. In our study, pretransplantation MELD score correlates with survival in the first 2 years after transplantation. There is a survival advantage for patients with cholestatic diseases compared with those with hepatitis C. These findings suggest the need to readjust MELD score-based allocation decisions to consider patient outcome.

The changing clinical presentation of recurrent primary biliary cirrhosis after liver transplantation.

BACKGROUND: Recurrent disease after liver transplant is a significant problem. Recurrent primary biliary cirrhosis (RPBC) is a histologic diagnosis. Clinical data is unreliable in predicting or diagnosing recurrence. RPBC appears to have a changing clinical presentation in recent years. MATERIALS AND METHODS: The diagnosis of RPBC after liver transplantation was made histologically. Data were obtained from our prospectively maintained liver-transplant database and evaluated statistically. RESULTS: Between 1985 and 1999, 1,835 liver transplants were performed, 169 for PBC. One hundred fifty-six patients were evaluated (one patient received retransplantation, and 13 were excluded). Seventeen (10.9%) experienced recurrence. Median posttransplantation follow-up time was 72.1 months. Median time to recurrence was 49.6 months. Median follow-up time after recurrence was 11.5 months. Neither acute rejection episodes (P=0.34) nor OKT3 use (P=0.36) before diagnosis of recurrence was significant. The combination of cyclosporine, azathioprine, and prednisolone demonstrated recurrence in 6 of 71 (8.4%). Six of 49 (12.2%) patients treated with cyclosporine with or without mycophenolate mofetil and prednisolone experienced recurrence. Six of 36 (16.7%) patients treated with tacrolimus and prednisolone with or without mycophenolate mofetil experienced recurrence. Patients treated with cyclosporine had numerically fewer recurrences than those treated with tacrolimus (P=0.11). CONCLUSIONS: Patients with RPBC demonstrated prolonged survival. Clinical factors did not aid in predicting RPBC. The clinical course of RPBC appears to be different than in the earlier years of liver transplantation. Immunosuppression may play a role. The use and type of antimetabolite drugs had no affect on recurrence. RPBC demonstrated a different clinical course with tacrolimus treatment (shorter time to recurrence) and increased incidence when compared with cyclosporine treatment. Controlled randomized studies are necessary to determine differences between tacrolimus and cyclosporine treatment, if any.

Incidence and recurrence of autoimmune/alloimmune hepatitis in liver transplant recipients.

We prospectively collected data on 1,429 liver transplant recipients between December 1984 and December 1998. Fifty-five patients (3.8%; 10 men, 45 women; median age, 44.5 +/- 13 [SD] years) with autoimmune hepatitis (AIH) underwent orthotopic liver transplantation (OLT). Transplant recipients with AIH were younger, more likely to be women, and had a greater likelihood of rejection in the first 3, 6, and 12 months. There was no difference in patient survival or graft survival. There were 11 biopsy-proven recurrences (1 man, 10 women) of AIH after OLT. Almost half the episodes occurred within the first year after OLT. No patient required re-OLT because of recurrent disease. AIH has an incidence of 4% and a recurrence rate of 20% in OLT. Transplant recipients are more likely to be young women and have an increased incidence of acute cellular rejection (ACR) during the first post-OLT year. Recurrence should be suspected in those with abnormal liver function test results in the absence of ACR, especially during the first year after OLT. We cannot establish with certainty whether the observed process represents recurrence of the original autoimmune disease, an alloimmune phenomenon, or allograft dysfunction mimicking AIH.