Burton Combes

Methylprednisolone Therapy in Patients with Severe Alcoholic Hepatitis: A Randomized Multicenter Trial

STUDY OBJECTIVE To determine the efficacy of a corticosteroid in reducing the short-term mortality of patients with severe alcoholic hepatitis. DESIGN Randomized, double-blind, placebo-controlled multicenter trial. SETTING Four university teaching hospitals. PATIENTS We enrolled 66 patients with alcoholic hepatitis and either spontaneous hepatic encephalopathy or a discriminant function value greater than 32, calculated using the formula: 4.6 (prothrombin time - control time) + serum bilirubin [in mumol/L]/17.1. Fifty-nine patients (89%) completed the study. Two patients withdrew from the trial. The other 64 patients were hospitalized for the duration of the trial; however, treatment was discontinued in 5 patients because of potential drug toxicity. INTERVENTIONS Patients were randomly assigned to receive either methylprednisolone (32 mg) or placebo within 7 days of admission. Treatment was given for 28 days. The doses were then tapered over 2 weeks and discontinued. MEASUREMENTS AND MAIN RESULTS The endpoint of the study was death. Of the 31 recipients of placebo, 11 (35%) died within 28 days of randomization compared with 2 (6%) of the 35 patients given methylprednisolone (P = 0.006). The 95% CI for the difference in mortality was 12% to 70%. In the patients with spontaneous hepatic encephalopathy at entry, 9 of 19 recipients of placebo died (47%) compared with 1 (7%) of the 14 patients given methylprednisolone (P = 0.02). The 95% CI for the difference in mortality was 14% to 66%. The Cox proportional hazards regression model showed the advantage of methylprednisolone over placebo after adjustment for other potentially important prognostic variables (P = 0.004). CONCLUSIONS Methylprednisolone therapy decreases short-term mortality in patients with severe alcoholic hepatitis manifested either by spontaneous hepatic encephalopathy or a markedly elevated discriminant function value.

GLOMERULONEPHRITIS WITH DEPOSITION OF AUSTRALIA ANTIGEN-ANTIBODY COMPLEXES IN GLOMERULAR BASEMENT MEMBRANE

Abstract A patient with persistent Australia (Au) antigenaemia after post-transfusion hepatitis developed membranous glomerulonephritis. Immunofluorescent staining of kidney tissue revealed glomerular deposits of IgG, complement C 3 , and Au antigen in a pattern characteristic of immune complex deposition. These findings suggest that Au antigen was involved in the formation of immune complexes whose glomerular deposition initiated the pathologic process leading to the development of diffuse membranous glomerulonephritis.

A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis

One hundred fifty-one patients with primary biliary cirrhosis (PBC) grouped into four strata based on entry serum bilirubin ( or +2 (strata 3 and 4). Histology was favorably affected by ursodiol in patients in strata 1 and 2 but not in strata 3 and 4. Ursodiol enrichment in fasting bile obtained at the conclusion of the trail was approximately 40% and comparable in all strata. Thus, differences in ursodiol enrichment of the bile acid pool do not explain better responses of laboratory tests and histology found in patients with less advanced PBC. Patients treated will ursodiol tended to develop a treatment failure less frequently that those who received placebo, particularly in strata 1 and 2 (ursodiol 42%, placebo 60%, P = .078). Development of severe symptoms (fatigue/pruritus) and doubling of serum bilirubin were reduced significantly in ursodiol-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Prediction of clinical outcomes in primary biliary cirrhosis by serum enhanced liver fibrosis assay

Primary biliary cirrhosis (PBC) is sometimes diagnosed based on a positive antimitochondrial antibody in the appropriate clinical setting without a liver biopsy. Although a liver biopsy can assess the extent of liver fibrosis and provide prognostic information, serum fibrosis markers avoid biopsy complications and sampling error and provide results as a continuous variable, which may be more precise than categorical histological stages. The current study was undertaken to evaluate serum fibrosis markers as predictors of clinical progression in a large cohort of PBC patients. Serial liver biopsy specimens and serum samples were collected every 2 years in 161 PBC subjects for a median of 7.3 years. Clinical progression was defined as development of one or more of the following events: varices, variceal bleed, ascites, encephalopathy, liver transplantation, or liver‐related death. Serum hyaluronic acid, tissue inhibitor of metalloproteinase 1, and procollagen III aminopeptide were measured and entered into the previously validated enhanced liver fibrosis (ELF) algorithm. The ability of ELF, histological fibrosis, bilirubin, Model for End‐Stage Liver Disease (MELD), and Mayo Risk Score to differentiate between individuals who would experience a clinical event from those who would not was evaluated at different time points. Event‐free survival was significantly lower in those with high baseline ELF. Each 1‐point increase in ELF was associated with a threefold increase in future complications. The prognostic performance of all tests was similar when performed close to the time of the first event. However, at earlier times in the disease process (4 and 6 years before the first event), the prognostic performance of ELF was significantly better than MELD or Mayo R score. Conclusion: The ELF algorithm is a highly accurate noninvasive measure of PBC disease severity that provides useful long‐term prognostic information. (HEPATOLOGY 2008.)

Etiology of Liver Disease in Renal-Transplant Patients

The etiology of 72 episodes of liver disease that developed in 62 of 162 renal-transplant recipients was evaluated. Infection with hepatitis B virus was a minor problem, and none of our patients had evidence of infection with hepatitis A. Cytomegalovirus infection was ubiquitous in the population and probably accounted for many episodes of acute liver disease. This agents role in causing chronic hepatitis is less secure. Infections with other viruses including Epstein-Barr virus, adenovirus, and the herpes viruses were only rarely associated with hepatic disease. Azathioprine was responsible for some episodes of acute cholestasis but could not be incriminated as a direct cause of chronic disease. A cause could be identified for the majority of episodes of acute hepatic dysfunction, but the cause of most of the chronic hepatitis remains undetermined. It is likely that infection with non-A, non-B hepatitis virus accounts for much of this serious, often fatal, complication of renal transplantation.

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 Ludwigs 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. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2005;42:1184–1193.)

Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis

OBJECTIVES:Generalized pruritus is a common complication of cholestatic liver diseases, although its pathogenesis remains elusive. Current treatments are often inadequate and may be poorly tolerated, so the clinician is sometimes faced with a patient in misery and no good therapeutic options. Because, in our experience, several patients with primary biliary cirrhosis (PBC) claimed that sertraline had improved their pruritus, we sought to determine whether sertraline use was associated with changes in pruritus medications or self-reported severity of pruritus in a large cohort of patients with PBC.METHODS:The self-reported severity of pruritus was followed prospectively in 40 patients with PBC for a mean of 7.5 ± 1.3 yr. These data were then retrospectively examined to determine the effect of sertraline on pruritus in all subjects who had received sertraline at some time during the study.RESULTS:For 28 of 32 patients with pruritus, itching was stable or fluctuated slightly over the follow-up period. No patient experienced rapid progression of pruritus, and four patients experienced a sustained resolution of their pruritus. Ten subjects started sertraline and continued it long enough (>6 months) to determine its lasting effect on pruritus. Three of these individuals did not have significant pruritus before or after sertraline. Of the seven patients with pruritus, six (86%) recorded a significant reduction or resolution of pruritus in their weekly diaries and also decreased or completely stopped other medications for pruritus.CONCLUSIONS:Sertraline use is associated with an improvement in cholestatic pruritus. This novel observation implies that serotonergic fibers are important in regulating the perception of itch.

Hepatotoxicity of Mercaptopurine

The appearance of jaundice in patients with acute leukemia treated with mercaptopurine has been described in several reports and attributed to a toxic effect of the therapeutic agent on the liver.1-6A number of possible causes of jaundice unrelated to therapy exist in the leukemia patient, and it is difficult to be certain whether all reported instances are indeed produced by the drug. Nevertheless, it is generally accepted that mercaptopurine is potentially hepatotoxic. Recently, we have observed jaundice develop in two nonleukemic patients during therapy with mercaptopurine. Because of increasing current interest in the use of purine analogues for treatment of a variety of diseases, we are reporting our observations in order to direct attention to this important therapeutic complication. Patient Summaries Patient 1. —A 45-year-old man was admitted to Parkland Memorial Hospital on Dec 14, 1966, for evaluation of jaundice. He had been well until July 1964 when

Prognostic Significance of Subacute Hepatic Necrosis in Acute Hepatitis

A retrospective analysis has been made of 57 patients with subacute hepatic necrosis demonstrated on a liver biopsy obtained during the course of an episode of acute hepatitis. Fourteen patients have been lost to follow-up. One patient died acutely with massive hepatic necrosis, while 8 have developed chronic active liver disease. Two of nine biopsies subsequently performed on patients who had shown complete clinical and biochemical resolution revealed an inactive postnecrotic cirrhosis. The incidence of these complications developing in patients with subacute hepatic necrosis was approximately 30%. These findings add qualitative support to the position that liver biopsy findings bear important prognostic value in patients with acute hepatitis.

MATURATION OF THE SULFOBROMOPHTHALEIN SODIUM-GLUTATHIONE CONJUGATING SYSTEM IN RAT LIVER*

Sulfobromophthalein sodium, hereafter referred to as BSP, has frequently been employed to appraise hepatic function in the newborn infant (1-7). With but one exception (2), many studies have demonstrated delayed disappearance of BSP from blood and increased BSP retention in both the full-term and premature infant in the immediate postpartum period (1, 3-7). Subsequently, the rate of removal of BSP from blood gradually increased, and within a few weeks after birth, approached values found in older children and adults. In general, the impairment of BSP clearance in the first few days after delivery has been attributed to immaturity, and the gradual improvement to maturation of the factors involved in the hepatic removal of BSP from blood and the subsequent excretion of BSP into bile. Based on a considerable body of evidence which has been accumulated within the past few years (8-15), it is now known that a major fraction of the BSP which is removed from blood and excreted into bile undergoes metabolic transformation within the liver. There appears to be general agreement that the major pathway of BSPmetabolism in man, rat, dog, and other species involves conjugation with the tripeptide glutathione in thioether linkage (12-15). Recently, we identified an enzyme in the soluble supernatant fraction of liver that catalyzes BSP-glutathione conjugation (15). During conjugation, whether enzymecatalyzed or not, bromine is released from BSP, and the sulfur group of glutathione attaches to BSP at the site of bromine removal (13, 15).