2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Current management strategies for hepatocellular carcinoma.

Hepatocellular carcinoma is the third leading cause of cancer death worldwide, and its frequency is expected to increase. The possibility of identifying early stage curative cancer has supported the recommendation of surveillance by hepatic ultrasonography every 6 months in individuals with an annual incidence of cancer that exceeds 1.5%. Computerized tomography or magnetic resonance imaging is diagnostic if contrast uptake within the nodule is demonstrated in the arterial stage and washout is evident. Liver tissue examination is warranted in indeterminate nodules larger than 1 cm, and stromal invasion is the pathological hallmark. The Barcelona Clinic Liver Cancer staging system indicates the most appropriate evidence-based therapy. Liver resection is preferred for nodules <2 cm in the absence of portal hypertension or hyperbilirubinemia, and liver transplantation is the choice in patients without cirrhosis or with Child-Pugh A or B cirrhosis who have portal hypertension or hyperbilirubinemia. Radiofrequency ablation should be performed if transplantation is not an option and the total number of nodules is less than 3 and all are smaller than 3 cm. Intermediate or advanced stage cancer, defined by multinodularity, macrovascular invasion or extrahepatic spread, should be palliated by transarterial chemoembolization, treatment with sorafenib, or symptomatic care. Early referral to a tertiary care center is encouraged if there are deficiencies in diagnostic or therapeutic expertise or resources. In regions with limited resources, strong preventive measures must be instituted and at least hepatic resection or tumor ablation must be developed.

Progress in the diagnosis and treatment of autoimmune hepatitis.

Autoimmune hepatitis has diverse clinical presentations which complicate its diagnosis and adverse outcomes which demand new treatments. The aims of this review are to indicate the progress that has been made in solving these problems and to illuminate the pathway for additional solutions. Prime source and review articles in English were selected through Medline from 1970-2008 and assimilated into a personal library spanning 31 years. Two diagnostic scoring systems with complementary virtues have been developed that are useful in evaluating patients with confusing features. Acute severe and fulminant presentations require prompt corticosteroid therapy, and coincidental bile duct changes and centrilobular zone 3 necrosis on histological examination do not discount the diagnosis. Cholangio-graphic changes may be present in children and adults with the disease, and antibodies to soluble liver antigen have prognostic value. Autoimmune hepatitis must be considered in patients without autoantibodies and with graft dysfunction after liver transplantation. Asymptomatic patients may not require immediate treatment, and the Model of End Stage Liver Disease identifies problematic patients early. Normal liver tests and tissue constitute the optimal end point of treatment, and the first relapse is an indication for long-term azathioprine therapy. Cyclosporine, tacrolimus and mycophenolate mofetil are promising salvage therapies, and budesonide with azathioprine can be used as frontline treatment in select patients. Progress has been made in the diagnosis and treatment of autoimmune hepatitis, but more work must be done. Multicenter clinical trials are essential before the incorporation of new drugs into the treatment algorithm.

Evolving concepts in the diagnosis, pathogenesis and treatment of autoimmune hepatitis.

The diagnostic criteria for autoimmune hepatitis have been codified, and a scoring system can quantify the strength of the diagnosis. Centrilobular (zone 3) necrosis signifies acute disease, and severe acute and fulminant presentations of autoimmune hepatitis are recognized. The absence of symptoms at presentation may identify some patients who do not require treatment, but therapeutic decisions must be based on disease activity not symptoms, especially since 26-70% of asymptomatic patients become symptomatic. Elderly patients have more advanced disease at presentation, but they respond well to treatment. Antibodies to soluble liver antigen/liver pancreas, asialoglycoprotein receptor, actin, and liver cytosol type 1 have prognostic value. Molecular mimicry between viral and self-antigens is the likely basis for the autoimmune response. Susceptibility alleles optimize antigen presentation. Polymorphisms influence immunocyte activation, counter-regulatory actions within the cytokine milieu, and apoptotic pathways for hepatocyte and immunocyte death. Perturbations in the populations of T regulatory cells and natural killer T cells disrupt immune homeostasis. Cyclosporine, mycophenolate mofetil, and budesonide afford new treatment opportunities, and molecular interventions at critical pathogenic pathways are feasible, especially within the cytokine network. Confident animal models of the human disease and a collaborative network of clinical investigators are the requisites for progress.

Review article: next-generation transformative advances in the pathogenesis and management of autoimmune hepatitis.

BACKGROUND: Advances in autoimmune hepatitis that transform current concepts of pathogenesis and management can be anticipated as products of ongoing investigations driven by unmet clinical needs and an evolving biotechnology. AIM: To describe the advances that are likely to become transformative in autoimmune hepatitis, based on the direction of current investigations. METHODS: Pertinent abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and a secondary bibliography was developed. The discovery process was repeated, and a tertiary bibliography was identified. The number of abstracts reviewed was 2830, and the number of full-length articles reviewed exceeded 150. RESULTS: Risk-laden allelic variants outside the major histocompatibility complex (rs3184504, r36000782) are being identified by genome-wide association studies, and their gene products are potential therapeutic targets. Epigenetic changes associated with environmental cues can enhance the transcriptional activity of genes, and chromatin re-structuring and antagonists of noncoding molecules of ribonucleic acid are feasible interventions. The intestinal microbiome is a discovery field for microbial products and activated immune cells that may translocate to the periphery and respond to manipulation. Epidemiological studies and controlled interview-based surveys may implicate environmental and xenobiotic factors that warrant evidence-based changes in lifestyle, and site-directed molecular and cellular interventions promise to change the paradigm of treatment from one of blanket immunosuppression. CONCLUSIONS: Advances in genetics, epigenetics, pathophysiology, epidemiology, and site-directed molecular and cellular interventions constitute the next generation of transformative advances in autoimmune hepatitis.

Spontaneous resolution of pancreatic masses (pseudocysts?)--Development and disappearance after acute alcoholic pancreatitis.

To determine the incidence and the natural history of retroperitoneal masses complicating acute pancreatitis, 104 cases of acute alcoholic pancreatitis were evaluated prospectively for mass formation. Abdominal masses detected by physical examination and serial x-ray films of the upper portion of the gastrointestinal tract were localized to the retroperitoneum by additional contrast studies, including abdominal angiography. Nonoperative management was urged only for patients with an asymptomatic mass. An abdominal mass developed in 19 patients (18%). In eight of these, it disappeared rapidly, but in 11 (11%), it persisted, and was considered to be a pancreatic pseudocyst. Eight of the 11 patients were treated nonoperatively, and the mass resolved without complication three weeks to three months after diagnosis. In three patients, a pseudocyst was confirmed at laparotomy. Exploration was justified by an unstable clinical course in only one instance. A routine surgical approach to an asymptomatic retroperitoneal mass developing after acute alcoholic pancreatitis may not be necessaary in patients who are improving clinically because the mass may resolve without complication.

Viral hepatitis. A population-based study in Rochester, Minn, 1971-1980.

The incidence of acute viral hepatitis among Rochester, Minn, residents 1971-1980 was 28.6 per 100,000 person-years (p-y) (age- and sex-adjusted to the 1980 white population in the United States). The adjusted incidence of hepatitis B (12.9 per 100,000 p-y) was somewhat less than for hepatitis non-B (15.6 per 100,000 p-y). Each type was more frequent among young adults, especially males. The incidence of hepatitis was greater among those employed in the health service industry than among nonmedical employees (53.4 vs 20.0 per 100,000 p-y). Medical employees had nearly a fivefold increased incidence of hepatitis B and a twofold increased incidence of hepatitis non-B. Exposure to known hepatitis cases was common, but other possible causative factors were not frequent. In this midwestern community, the incidence of acute viral hepatitis is substantial, with medical employees at significantly increased risk.

Diverse manifestations and evolving treatments of autoimmune hepatitis.

Autoimmune hepatitis has a global occurrence and diverse manifestations. Patients are frequently asymptomatic (34%), and an acute, even fulminant, presentation is possible. Concurrent immune disorders may obscure the liver disease, and perivenular (Rappaport zone 3) necrosis is within the histological spectrum. Clinical phenotypes and outcomes vary among different ethnic groups, and genetic factors strongly affect susceptibility. Non-disease specific autoimmune modifiers include female gender and gene polymorphisms that affect immunocyte activation and differentiation. Antibodies to soluble liver antigen/liver pancreas may have prognostic importance and reflect a genetic propensity for severe disease. Subtypes based on serological profiles do not have distinctive outcomes or therapies. Variant forms include patients with bile duct injury or loss, absence of conventional serological markers, abnormal cholangiograms, or coincidental hepatitis C. Treatment is empiric and based on the predominant manifestations (hepatitic, cholestatic, or viral). New treatment strategies must be strengthened by predictive indices that accurately forecast individual differences in disease outcome. Drugs with site-specific actions on immunocyte activation and proliferation (cyclosporine, tacrolimus and myco-phenolate mofetil) must be assessed by clinical trial, and site-specific molecular interventions (blocking peptides, recombinant immune modulators, T cell vaccination, oral tolerance, gene silencing and gene therapy) require confident experimental animal models for evaluation. Better prognostic indices, new immunosuppressive agents, and site-specific molecular interventions promise to improve care.

Recent-onset autoimmune hepatitis. Biopsy findings and clinical correlations.

Whereas the histologic findings in clinically "chronic" autoimmune hepatitis have been well established, with piecemeal necrosis as a hallmark lesion, the histologic findings of clinically "acute" or recent-onset autoimmune hepatitis remain undefined. The goal of this study was to define more fully the liver histomorphology in patients with recent-onset autoimmune hepatitis. Twenty-six patients were identified at our institution who had well-characterized autoimmune hepatitis and had undergone a liver biopsy within 6 months of clinical presentation. A detailed histologic evaluation revealed evidence of chronic liver disease in 25 (of 26) patients despite the lack of correlating clinical chronicity. The histologic evidence of chronicity included, in addition to a portal lymphoplasmacytic infiltrate, bridging (septal) fibrosis (11 patients) and overt cirrhosis (four patients). Eighteen of these 25 cases with evidence of chronicity also showed zone 2 and 3 lobular hepatitis, including disarray and hepatocyte necrosis. A single case showed lobular hepatitis with confluent hepatocyte necrosis (submassive hepatocellular necrosis), but no evidence of chronic liver disease. Although autoimmune hepatitis remains in the differential diagnosis of lobular hepatitis, these data show that most patients with autoimmune hepatitis who undergo biopsy early in its clinical course will have histologic evidence of chronic liver disease. Most of these patients probably have a lobular "flare" in disease activity, which likely precipitated the clinical presentation. The findings herein reinforce the concept that autoimmune hepatitis is by definition a chronic disease and supports the proposal that the modifier "chronic" be eliminated from autoimmune hepatitis.

Drug therapy in the management of type 1 autoimmune hepatitis.

Prednisone alone or in combination with azathioprine is the treatment of choice for severe type 1 autoimmune hepatitis. The combination regimen is preferred, especially in the elderly, because of a lower incidence of corticosteroid-related complications. Only patients with sustained severe laboratory abnormalities, bridging necrosis or multilobular necrosis on histological assessment, and/or incapacitating symptoms, have absolute indications for treatment based on controlled clinical trials. The institution of therapy must be individualised in other patients, based mainly on symptoms and disease behaviour. Serum aspartate aminotransferase and gamma-globulin levels are the most useful indices to monitor during therapy. Liver tissue examination is the best method of evaluating completeness of response. Most patients enter remission, but relapse occurs in 50 to 86% after drug withdrawal. Maintenance therapy with low dosages of prednisone or azathioprine can be used long term in patients who have relapsed repeatedly. Inability to achieve remission after 3 years (incomplete response), deterioration during therapy (treatment failure) and drug toxicity are unsatisfactory responses that warrant alternative strategies. Liver transplantation is effective in managing decompensated disease, but recurrence of autoimmune hepatitis after transplantation is possible. Tacrolimus and budesonide are promising new drugs.

Current problems in the diagnosis and management of chronic active hepatitis.

Although corticosteroids have been shown to be effective in the treatment of most forms of severe chronic active hepatitis, many problems remain in the diagnosis and management of patients with this disease. Difficulties in determining chronicity, establishing the correct diagnosis, and deciding when and how to initiate and stop therapy jeopardize successful management. Mechanisms of drug action, pharmacokinetics, long-term sequelae of therapy, and optimum treatment schedules have been incompletely described. A satisfactory program of management remains undefined for patients with less than severe disease, hepatitis B surface antigenemia, and suboptimal results after conventional treatment. The goals of this review are to identify problem areas and to indicate directions for future investigation and improvement.

Hepatitis non A, non B. Manifestations and implications of acute and chronic disease.

Application of sensitive radioimmunoassays for the detection of hepatitis A and B viruses has demonstrated that up to 25% of cases of acute sporadic hepatitis and up to 90% of cases of posttransfusion hepatitis cannot be classified by etiologic agent and warrant designation as non-A, non-B hepatitis. Epidemiologic studies have indicated a pattern of transmission similar to that of hepatitis B virus, with predominance of parenteral routes of spread. Spontaneous resolution of acute infection fails to occur in up to 60% of patients; a chronic asymptomatic but infectious carrier state is recognized. Although the chronic hepatitis is usually mild, a potential for progression to cirrhosis has been described. Transmission studies in chimpanzees have suggested the existence of at least two non-A, non-B agents, which produce strain-specific ultrastructural changes in the hepatocyte and confer a homologous immunity. Multiple assay systems for detecting putative viral antigens have been developed, but their specificity has not been confirmed. Elimination of blood procured by contract from commercial blood banks diminishes the risk of posttransfusion hepatitis and is recommended for prophylaxis. Although the effectiveness of immune serum globulin in the prevention of sporadic disease has not been established, its administration should be considered after exposure to incriminated blood, in spouses during the acute illness, and in neonates of infected mothers.

Clinical features and prognostic implications of severe corticosteroid-treated cryptogenic chronic active hepatitis.

To assess the nature and prognosis of severe chronic active hepatitis of unknown cause, we compared 26 patients who had been fully screened for etiologic factors with 112 patients who had autoimmune chronic active hepatitis after similar durations of corticosteroid therapy (17(+)/- 2 versus 23 (+)/- 2 months), and follow-up versus 103 +/- 7 months). Patients with cryptogenic disease could not be distinguished from those with autoimmune disease on the basis of age, sex distribution, duration of illness, immunoglobulin levels, frequency of concurrent immunologic disorders, or histologic findings. Serum gamma-globulin levels were higher (3.4 +/- 0.1 versus 2.5 +/- 0.2 g/dl, P = 0.007) and albumin levels were lower (2.9 +/- 0.1 versus 3.3 +/- 0.1 g/dl, P = 0.003) in patients with autoimmune disease than in those with cryptogenic disease, but individual findings did not differentiate the patients. Remission (69 versus 75%), treatment failure (23 versus 13%), relapse after drug withdrawal (67 versus 68%), progression to cirrhosis (57 versus 36%), and death from hepatic failure (12 versus 11%) occurred as commonly in patients with cryptogenic as in those with autoimmune disease. Patients with different constellations of immunoserologic findings were similar clinically. We conclude that patients with severe chronic active hepatitis who have been fully screened for etiologic factors cannot be distinguished from patients with autoimmune disease of comparable severity. These two groups of patients have a similar prognosis after corticosteroid therapy, and such treatment should be considered in these highly selected patients.

Current concepts in the diagnosis, pathogenesis, and treatment of autoimmune hepatitis.

Autoimmune hepatitis has a global distribution and affects all ages. Genetic factors strongly influence susceptibility, clinical expression, and treatment response. The diagnosis of autoimmune hepatitis has been codified by an international panel. An acute or fulminant presentation is recognized but not a cholestatic form. Subclassifications by predominant autoantibody profile have been proposed, but they lack etiologic and prognostic differences. Autoantibodies continue to be characterized to improve diagnostic specificity, predict outcome, and identify pertinent antigenic targets. Cytosolic enzymes are prime candidates as autoantigens. DRB1*0301 and DRB1*0401 are the susceptibility alleles in Caucasoid Northern Europeans and North Americans, and they also affect clinical expression and treatment outcome. Other autoimmune promoters affecting cytokine production and immunocyte activation may act in synergy with the susceptibility alleles to affect disease behavior. Cell-mediated and antibody-dependent forms of cytotoxicity are probably interactive pathogenic mechanisms, and novel site-specific therapies are feasible because these mechanisms are defined. Potent new immunosuppressive agents are emerging from the transplantation arena, but prednisone alone or in combination with azathioprine remains the mainstay of treatment. Corticosteroid therapy is effective but not ideal.

Clinical assessment of cirrhosis in severe chronic active liver disease: specificity and sensitivity of physical and laboratory findings.

The usefulness of certain physical and laboratory findings in predicting the morphologic diagnosis of cirrhosis in severe chronic active liver disease was determined in 101 patients, 39 of whom had cirrhosis. Hypoalbuminemia (69%) and hypergammaglobulinemia (67%) were the most common findings in cirrhosis, but they lacked specificity. Thrombocytopenia, hepatic encephalopathy, and ascites, which were the most specific and sensitive abnormalities, implicated cirrhosis with 85% assurance when present and occurred in the majority of patients with cirrhosis (56%). No single feature was pathognomonic of cirrhosis, although absence of all clinical findings excluded the diagnosis; Eight or more clinical abnormalities were invariably associated with cirrhosis, but only 18% of patients had such florid manifestations. The presence of at least five abnormalities was associated with a 76% likelihood of cirrhosis and was encountered in 56% of cirrhotic patients. Patients with three or fewer findings seldom had cirrhosis (24%), and only the presence of ascites reliably implicated the lesion in these patients. We conclude that in severe chronic active liver disease, recognition of certain specific findings or a constellation of abnormalities permits confident identification of cirrhosis in the majority of patients with this disorder.

Viral genotypes as determinants of autoimmune expression in chronic hepatitis C.

OBJECTIVE: To correlate viral genotypes with the immune manifestations of chronic hepatitis C and evaluate the effect of immune features on disease expression and response to antiviral treatment. DESIGN: We undertook a retrospective analysis of 67 patients with chronic hepatitis C. MATERIAL AND METHODS: Patients were selected for study if they had been screened for autoantibodies and concurrent immune diseases and if viral genotyping had been performed or was possible. Concurrent immune manifestations and responses to interferon therapy were determined. RESULTS: Of the 67 patients, 18 (27%) had one or more immune features. Immune manifestations occurred as commonly in patients with genotype 1 as in those with other genotypes (30% versus 14%; P = 0.3). Concurrent immune features did not distinguish patients, and responses to interferon therapy were similar between patients with and those without immune manifestations. None of the 14 patients with concurrent immune diseases or high-titer autoantibodies (serum titers, 1:320 or more) entered remission during interferon treatment. In contrast, 6 of 53 patients without concurrent immune diseases and no or low-titer autoantibodies had treatment-related remission. These differences, however, were not statistically significant (0% versus 11%; P = 0.3). CONCLUSION: Autoantibodies and concurrent immune diseases are not associated with a particular viral genotype, clinical profile, or treatment outcome. Larger studies are necessary for complete assessment of the influence of prominent immune manifestations on treatment response.

Frequency and significance of antibody to hepatitis C virus in severe corticosteroid-treated autoimmune chronic active hepatitis.

To determine the frequency and significance of antibody to hepatitis C virus (anti-HCV) in severe autoimmune chronic active hepatitis, we tested sera from 85 cortico-steroid-treated patients by an enzyme immunoassay. Seropositive patients were assessed for specific antibodies to hepatitis C virus-encoded antigens by recombinant immunoblot assay. The findings in patients with and without anti-HCV were contrasted, and the frequency of seropositivity was compared with that in patients who had other types of chronic liver disease and in normal adults. Only 5 of the 85 patients with autoimmune hepatitis (6%) were seropositive for anti-HCV, and only 2 of these patients were reactive by recombinant immunoblot assay. The frequency of seropositivity in autoimmune hepatitis was not significantly different from that in hepatitis B surface antigen-positive (9%) and cryptogenic (18%) disease, but it was significantly less than that in posttransfusion chronic active hepatitis (6% versus 75%; P less than 0.001). Two patients became seronegative after corticosteroid therapy; both had been nonreactive by recombinant immunoblot assay. Four of the seropositive patients entered remission during corticosteroid therapy, including three whose sera were nonreactive to virus-encoded antigens. We conclude that anti-HCV occurs infrequently in corticosteroid-treated severe autoimmune hepatitis and that antibodies detected by enzyme immunoassay may be nonreactive to hepatitis C virus-encoded antigens. Seropositive patients who are nonreactive by immunoblot assay may still respond to corticosteroid therapy and become seronegative during treatment.

Frequency and significance of antibody to hepatitis C virus in severe corticosteroid-treated cryptogenic chronic active hepatitis.

To determine the frequency and significance of antibody to hepatitis C virus (anti-HCV) in severe cryptogenic chronic active hepatitis (CAH), we tested sera from 17 corticosteroid-treated patients by an enzyme immunoassay. Specificity of the antibodies to HCV-encoded antigens was assessed by recombinant immunoblot assay. The findings in patients with and without anti-HCV were contrasted, and the frequency of seropositivity was compared with that in patients who had other types of chronic liver disease and in normal adults. Only three patients (18%) with severe cryptogenic CAH had anti-HCV. Sera from two of these patients were reactive by recombinant immunoblot assay; the other sample produced an indeterminate reaction. The frequency of seropositivity in patients with cryptogenic disease was not statistically different from that in patients with autoimmune CAH (6%), hepatitis B surface antigen-positive CAH (9%), or alcoholic liver disease (0%), but it was significantly less than in those with posttransfusion CAH (18% versus 75%; P less than 0.01). Seropositive patients tended to have lower serum aspartate aminotransferase, gamma-globulin, and bilirubin levels than seronegative counterparts, and they did not have histologic features of confluent necrosis at initial assessment. Two of the three seropositive patients, both of whom had been reactive by recombinant immunoblot assay, entered remission during therapy, and one, with an indeterminate reaction, died of liver failure. We conclude that anti-HCV occurs infrequently in severe corticosteroid-treated cryptogenic CAH. Seropositive patients may have less severe inflammatory activity than seronegative counterparts. Cryptogenic disease may improve during corticosteroid treatment, a result suggesting an underlying immunologic disorder in some patients.

HLA-DQ associations in type 1 autoimmune hepatitis.

OBJECTIVE: To determine whether, in patients with type 1 autoimmune hepatitis and human leukocyte antigen (HLA) DR3 and DR4 positivity, any DQ antigen is disease-specific. MATERIAL AND METHODS: HLA class II typing was performed by restriction fragment length polymorphism in 103 patients with type 1 autoimmune hepatitis, 104 patients with chronic viral hepatitis, and 80 normal subjects. A shared association with a disease-specific DQ antigen was sought in patients with HLA-DR3, DR4, and DR3-DR4. RESULTS: Patients with HLA-DR3 and DR4 shared positivity for DQ2, DQ4, DQ5, DQ6, and DQ7, but the associations reflected established linkages or were of low frequency. Patients heterozygous for DR3-DR4 or homozygous for either DR3 or DR4 did not have a shared DQ antigen. Only the DR3-DQ2 haplotype distinguished patients with autoimmune hepatitis from normal subjects or those with chronic viral hepatitis. CONCLUSION: The DR3 and DR4 antigens are not associated with a single disease-specific DQ antigen in type 1 autoimmune hepatitis. The DR3-DQ2 haplotype is the principal risk factor for the disease at our referral center. Analyses by restriction fragment length polymorphism do not implicate a single susceptibility gene at the DQ locus.

Prognostic and therapeutic implications of extreme serum aminotransferase elevation in chronic active hepatitis.

Extreme elevation of the serum aspartate aminotransferase level typically suggests acute hepatocellular necrosis and may militate against the diagnosis of chronic active hepatitis. However, we found that 26 of 160 patients (16%) with chronic active hepatitis had aminotransferase elevations of more than 1,000 IU/liter. These patients were younger and more often jaundiced than the others, but they exhibited signs of chronic liver disease as often. In only 2 of 26 patients with extreme aminotransferase abnormality were features of chronic disease absent. Patients with extreme enzyme elevation had histologic findings of confluent necrosis (P greater than 0.005) and features associated with acute viral infection (P greater than 0.005) more often than others, but they as often had cirrhosis on biopsy specimens. Virologic markers did not distinguish the patients or correlate with viral features in liver tissue. Corticosteroids improved immediate survival (P greater than 0.005) and the likelihood of remission (P greater than 0.005). Although chronic active hepatitis may present with extreme aminotransferase elevation and histologic features associated with acute viral infection, ancillary features of chronic disease facilitate the correct diagnosis and the initiation of appropriate therapy.