Carlo H. Tamburro

A Randomized, Controlled Trial of Interferon Alfa-2b Alone and after Prednisone Withdrawal for the Treatment of Chronic Hepatitis B

Abstract Background and Methods. Chronic hepatitis B is a common and often progressive liver disorder for which there is no accepted therapy. To assess the efficacy of treatment with interferon, we randomly assigned patients with chronic hepatitis B to one of the following regimens: prednisone for 6 weeks followed by 5 million units of recombinant interferon alfa-2b daily for 16 weeks; placebo followed by 5 million units of interferon daily for 16 weeks; placebo followed by 1 million units of interferon daily for 16 weeks; or observation with no treatment. Results. Hepatitis B e antigen and hepatitis B viral DNA disappeared from serum significantly more often in the patients given prednisone plus interferon (16 of 44 patients, or 36 percent) or 5 million units of interferon alone (15 of 41; 37 percent) than in the untreated controls (3 of 43; 7 percent; P<0.001); the difference between those given 1 million units of interferon (7 of 41; 17 percent) and the controls was not significant. The strongest indep...

Pathological diagnosis of chronic hepatitis C: A multicenter comparative study with chronic hepatitis B

BACKGROUND Hepatic histological responses described in hepatitis C virus (HCV) infection include bile duct damage, lymphoid follicles and/or aggregates in portal tracts, large- and small-droplet fat, Mallory body-like material in hepatocytes, liver cell dysplasia and multinucleation, and activation of sinusoidal inflammatory cells. The specificity of these lesions for HCV infection is uncertain. METHODS In two multicenter trials of recombinant interferon alfa therapy for chronic hepatitis C and B, the frequency of these eight lesions in pretherapy and posttherapy liver biopsy specimens was examined to determine the set of features, if any, that distinguishes HCV from hepatitis B virus (HBV) infection. The lesions were scored in 317 HCV biopsy specimens and 299 HBV specimens. RESULTS Stepwise logistic regression determined a set of three features more likely to be seen in HCV than in HBV infection: bile duct damage [odds ratio (OR), 4.7; 95% confidence interval (Cl), 1.8-12.3], lymphoid follicles and/or aggregates (OR, 2.4; 95% Cl, 1.2-4.7), and large-droplet fat (OR, 2.4; 95% Cl, 1.4-4.1). A fourth lesion, Mallory body-like material, was seen only in HCV biopsy specimens (OR, 71.6; 95% Cl, 4.4-996.1). CONCLUSIONS These four histological lesions are useful pathological parameters in the diagnosis of liver disease caused by HCV.

Short-Term and Long-Term Survival in Patients with Alcoholic Hepatitis Treated with Oxandrolone and Prednisolone

A cooperative study was conducted to determine the efficacy of 30 days of treatment with either a glucocorticosteroid (prednisolone) or an anabolic steroid (oxandrolone) in moderate or severe alcoholic hepatitis. One hundred thirty-two patients with moderate disease and 131 with severe disease were randomly assigned to one of three treatments: prednisolone, oxandrolone, or placebo. During the 30 days, mortality in the groups receiving steroid therapy was not significantly different from mortality in the placebo group. Thirteen per cent of the moderately ill patients and 29 per cent of the severely ill patients died. Although neither steroid improved short-term survival, oxandrolone therapy was associated with a beneficial effect on long-term survival. This was especially true in patients with moderate disease: among those who survived for one or two months after the start of treatment the conditional six-month death rate was 3.5 per cent after oxandrolone and 19 to 20 per cent after placebo (P = 0.02). No consistent long-term effect was associated with prednisolone therapy.

Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus

BACKGROUND & AIMS Interferon therapy has been associated with a number of severe side effects when administered to patients with decompensated cirrhosis caused by chronic hepatitis B. The safety and potential efficacy of a low-dose, titratable regimen of interferon alfa-2b in patients with decompensated liver disease caused by chronic hepatitis B virus infection were studied. METHODS Twenty-six patients were treated at five medical centers. Five patients had Childs class A status, 15 had Childs B status, and 6 had Childs C status. Treatment was continued for 24 weeks whenever possible. Dose adjustments were made according to predefined safety criteria. RESULTS All patients with Childs A status responded with a sustained loss of serum hepatitis B virus DNA, reduction in aminotransferase activity, and clinical stabilization. Only 5 patients with Childs B (33%) and no patients with Childs C status reached similar end points. The probability of survival was greater in responders than in nonresponders (P = 0.017). Three patients each developed serious infections or greater than twofold increases in serum aminotransferase levels during therapy. CONCLUSIONS Low-dose, titratable interferon therapy is safer than previously reported regimens. Nonetheless, serious infections were observed relatively frequently, and this therapy should be reserved for individuals with mild to moderate hepatic decompensation, preferably patients with Childs A status.

Protein energy malnutrition in severe alcoholic hepatitis : diagnosis and response to treatment

Background: Active nutrition therapy and the anabolic steroid oxandrolone (OX), in selected patients with severe alcoholic hepatitis, significantly improved liver status and survival. We report here on the changes in their nutritional parameters. Methods: Protein energy malnutrition (PEM) was evaluated and expressed as percent of low normal in 271 patients initially, at 1 month and at 3 months. Active therapy consisted of OX plus a high caloric food supplement vs a matching placebo and a low calorie supplement. Results: PEM was present in every patient; mean PEM score 60% of low normal. Most of the parameters improved significantly from baseline on standard care; the largest improvement seen in visceral proteins, the smallest in fat stores (skinfold thickness). Total PEM score significantly correlated with 6 month mortality (p=.0012). Using logistic regression analysis, creatinine height index, hand grip strength and total peripheral blood lymphocytes were the best risk factors for survival. When CD lymph...

VA Cooperative Study on Alcoholic Hepatitis III: Changes in Protein-Calorie Malnutrition Associated with 30 Days of Hospitalization with and without Enteral Nutritional Therapy

Patients with moderate to severe alcoholic hepatitis and features of protein-calorie malnutrition were studied with respect to changes in their nutritional status during 30 days of hospitalization. Thirty-four patients served as controls, were given a 2500 kcal hospital diet and allowed to eat ad libitum. Twenty-three patients were given, in addition to the hospital diet, a nutrition supplement high in calories, protein, and branched-chain amino acids (Hepatic Aid). Because of anorexia, the controls consumed lesser amounts of both calories and protein while those given the nutritional therapy exceeded their estimated energy requirements (116.1%) and consumed a mean of 98.3 g of protein per day. This was well tolerated despite the fact that portal systemic encephalopathy was present in 72% of the patients. Mortality associated with the liver disease was comparable in both groups, 16.7% in the treated vs 20.6% in the controls. In those patients that survived the 30 days of hospitalization, clinical and biochemical tests of liver injury improved in both groups. With respect to their nutritional status, those given nutritional therapy showed significant improvement in six of the nine parameters (67%) used to assess nutrition. In the controls significant improvement was observed in only two nutritional parameters (22%) while three parameters (33%) deteriorated further. These three were all associated with calorie deprivation (marasmus). This study suggests that patients with acute alcoholic hepatitis require additional nutritional therapy to maintain and improve their nutrition parameters, especially those related to marasmus; and that Hepatic Aid is well tolerated for this purpose.

Cell-mediated hepatic injury in alcoholic liver disease

BACKGROUND The mechanism responsible for the initiation and perpetuation of alcoholic liver disease (ALD) remains poorly understood. This investigation attempted to elucidate the role of cell-mediated immune phenomena in the pathogenesis of ethanol-induced liver injury. METHODS Frozen liver biopsy specimens from 144 patients with moderate to severe ALD were examined by the avidin-biotin immunoperoxidase technique for the expression of antigenic markers of T and B lymphocytes, natural killer cells, and class I and II MHC molecules in the tissue. RESULTS Expression of CD3 by lymphocytes correlated significantly with regenerating nodules, intralobular inflammation, central sclerosis, and abnormalities of Kupffer cells. B cells were rarely present, and natural killer cells were absent. CD3+ lymphocytes expressed either CD4 or CD8 surface molecules. Enhanced class I MHC expression correlated significantly with portal inflammation, limiting plate erosion, vascular abnormalities, and hemosiderosis. Expression of class II MHC molecules correlated significantly with necrosis, bile stasis, and Mallory bodies. CONCLUSIONS The distribution and persistence of CD4+ and CD8+ cells in actively advancing ALD, the enhanced MHC expression on hepatocytes, and their relationship to alcoholic hyalin and necrosis lend support to the hypothesis that a cytotoxic T lymphocyte-hepatocyte interaction plays a role, perhaps via lymphokine production, in the genesis or perpetuation of ALD.

Significance of megamitochondria in alcoholic liver disease

The significance of megamitochondria in the alcoholic liver injury of humans was investigated as part of a large Veterans Administration cooperative study of the natural history of alcoholic hepatitis. Two hundred twenty patients were clinically stratified into the following three groups according to disease severity using serum bilirubin and prothrombin time as indicators: Group 1 (mild disease), serum bilirubin levels less than 5 mg/dl and prothrombin time prolonged for less than 4 s; group 2 (moderate disease), serum bilirubin levels greater than 5 mg/dl but prothrombin time prolonged for less than 4 s; and group 3 (severe disease), serum bilirubin levels greater than 5 mg/dl and prothrombin time prolonged for greater than 4 s. Megamitochondria were observed in 20% of the patients (45 of 220). Of these, 43 patients were in groups 1 and 2 of severity and only 1 patient belonged in group 3. The association of megamitochondria with cirrhosis was infrequent (33%, 15 of 45 patients). The differences in severity correlated with the differences in mortality: in patients with megamitochondria, only 1 had died at 6 mo compared with 40 deaths in patients without megamitochondria. By 12 mo, there were two deaths in patients with megamitochondria versus 51 deaths in those patients without. No complications were present in 72% of patients with megamitochondria versus 39% for those without. Infection, gastrointestinal bleeding, pancreatitis, hyperglycemia, azotemia, delirium tremens, seizures, and hepatic encephalopathy were all more common in patients without megamitochondria. The patients with megamitochondria appear to represent a subcategory of alcoholic hepatitis with a milder degree of clinical severity, lower incidence of cirrhosis, fewer complications, and good long-term survival.

Clinical predictors of response to recombinant interferon-α treatment in patients with chronic non-A, non-B hepatitis (hepatitis C)

SUMMARY. Chronic non‐A, non‐B hepatitis (NANBH) is a common and often progressive liver disease. Based on current serological tests, hepatitis C virus (HCV) infection is responsible for most cases. Interferon‐α (IFN) treatment at a dose of 3 × 106 units given three times per week for 24 weeks has been shown to be effective in normalizing serum alanine aminotransferase (ALT) levels and reducing hepatic inflammation in approximately 40% of these patients. The purpose of this study was to identify pretreatment characteristics in patients with chronic hepatitis C(CH‐C) which would best predict a favourable response to IFN treatment (normalization of serum ALT). One hundred and sixty‐three adult patients who had participated in a large multi‐centre treatment trial were included in the study group: 84 had been treated with 3 × 106 units of recombinant IFN‐α‐2b (rIFN) subcutaneously three times per week for 24 weeks and 79 patients had been treated with 1 × 106 units rIFN in the same dosage schedule. Forty‐one pretreatment historical, clinical, laboratory and histological variables were evaluated. In addition, early biochemical improvement during treatment was evaluated as a predictor of ultimate response. Univariate analysis identified six variables (dose, dose m‐2, weight, body surface area, ongoing ethanol use, white blood cell count and the presence of symptoms) as potential predictors of response (two‐tailed, P < 0.15). By multivariate analysis, however, only the 3 × 106 dose of rIFN was independently predictive of response (P < 0.01). When the analysis of response was confined to those patients who received treatment with 3 × 106 units of rIFN, seven variables [body weight, surface area, dose m‐2, current ethanol use, serum albumin and the presence of chronic persistent hepatitis (CPH) on entry liver biopsy] were more frequent in patients who responded to therapy. In a multivariate model, only CPH and body weight predicted an increased likelihood of response (P < 0.01). However, the model was not a sensitive predictor of response as only 18% of the study group had CPH on liver biopsy. A decrease in serum ALT levels within the first 12–16 weeks of rIFN treatment was found to be the strongest indicator of an ultimate response to treatment. Thus, assessment of early response to IFN treatment is the only practical means of predicting complete response and avoiding prolonged and unnecessary therapy in those with little chance of response.

Chemical hepatitis: pathogenesis, detection and management.

The toxic effects of many nonmedicinal chemicals include serious hepatic injury, often accompanied by various degrees of damage to other organs. Some chemicals produce only mild damage. Others are capable of producing injury only after ingestion of large amounts, after severe exposure, or in combination with another agent such as alcohol.