Symposium on Gastroenterology for Internists
Chronic Hepatitis To Treat or Not to Treat? Albert J. Czaja, M.D., * and W. H. J. Summerskill, M.D. **
Chronic hepatitis connotes continuous or recurrent inflammation of the liver initiated by viral, drug, or unknown factors and perpetuated beyond an expected period of resolution. Continuation of the disease process for at least 10 weeks without clinical or biochemical improvement excludes self-limited acute hepatitis in most instances and indicates chronicity.16 Demonstration of ongoing activity for 6 months establishes the unresolving nature of the process 4 , 30, 45 and generates concern over possible progression to cirrhosis or liver failure. Although four controlled trials have demonstrated that prednisone with or without azathioprine can control the clinical manifestations and complications of severe chronic active liver disease,8, 9, 29, 42 the benefits and risks of such therapy have not been well studied in patients with less severe disease. In all patients, activity of the disease must be balanced against the potential for progression or spontaneous resolution, and the risks of long-term corticosteroid therapy. Thus, to treat or not to treat chronic hepatitis is a highly individualized judgment. A successful outcome depends on a thorough awareness of what has been diagnosed, why treatment is necessary, who should be treated, and how best to implement and monitor therapy.
WHAT IS THE DIAGNOSIS? The International Association for the Study of the Liver recently recognized two distinct types of chronic hepatitis, chronic persistent hepatitis (CPR) and chronic active hepatitis (CAR). For the latter, chronic active liver disease (CALD) is an acceptable synonym, whereas chronic aggressive hepatitis is limited to morphologic description. The lesions of subacute hepatitis or subacute hepatic necrosis have been omitted from the new nomenclature, and other types of chronic inflammatory liver disease, including Wilson's disease, primary biliary cirrhosis, and certain *Assistant Professor of Medicine, Mayo Medical School, Rochester, Minnesota **ProfessorofMedicine, Mayo Medical School, Rochester, Minnesota. Deceased March 9, 1977
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drug-related diseases, have been classified otherwise to emphasize their etiologic distinction. 13. 30. 44, 45 Differentiation of chronic persistent hepatitis from chronic active hepatitis can be difficult since clinical, biochemical and morphological features may be similar. Patients with chronic persistent"hepatitis may have hepatic enlargement and symptoms of easy fatigability, anorexia, and right upper quadrant pain. Elevations of serum aspartate transaminase levels to as high as 20 times normal are still consistent with the diagnosis, and hypergammaglobulinemia to twice normal and mild hyperbilirubinemia may be present initially.2 Although most biochemical abnormalities in chronic persistent hepatitis resolve spontaneously, serum transaminase levels may fluctuate between normal and three-fold normal, confusing the diagnosis. 2,46 Immunoserologic markers such as smooth muscle antibody, antimitochondrial antibody, antinuclear antibody, and positive lupus clot test identify patients likely to have chronic active hepatitis but these are not always present.4 Classification has been based mainly on histologic findings. The salient morphologic feature of chronic active hepatitis is the presence of moderate to severe periportal ("piecemeal") necrosis while limitation of the inflammatory round cell infiltrate to the portal tract with mild or absent periportal necrosis characterizes chronic persistent hepatitis,13 Needle biopsy of the liver with expert interpretation of the morphologic features is essential in establishing the diagnosis and will reproducibly disclose the degree ofhepatitis in over 90 per cent of cases. Sampling error however limits the effectiveness of needle biopsy in diagnosing cirrhosis,41 Other chronic inflammatory conditions of the liver are accepted as being etiologically distinct from chronic active hepatitis but may have abnormalities of serum transaminases and gamma globulin, positive immunoserology, and patterns of necrosis on liver biopsy identical to those encountered in chronic active hepatitis. Wilson's disease,43 primary biliary cirrhosis 6,17 and certain drug-related (oxyphenisatin,35 methyldopa,18,49 and isoniazid27 ) hepatic disorders must be distinguished from chronic active hepatitis since different forms oftherapy may be indicated. Screening tests for Wilson's disease are now mandatory in the evaluation of all patients suspected of having chronic active hepatitis and should include slit lamp examination of the eyes for Kayser-Fleischer rings, serum ceruloplasmin concentration and urinary copper excretion. Primary biliary cirrhosis may be a particular source of diagnostic confusion since there are many overlapping features with chronic active hepatitis. The presence of antimitochondrial antibody does not necessarily differentiate the two disorders 2l ,24 and, in the absence of characteristic bile duct lesions (stage 1 florid ductal damage)6 on liver biopsy, the histology may not be discriminating. A course of prednisone therapy may be necessary to make this differentiation since failure of a therapeutic response increases the likelihood of primary biliary cirrhosis.1 7 A careful clinical history will usually identify those patients with drug-induced hepatic disease. Withdrawal of the drug will usually improve the condition although complete resolution in severe cases may not be certain. 18
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WHY IS TREATMENT NECESSARY? The goals of therapy for chronic hepatitis are to control symptoms, prevent cirrhosis, and prolong survival. Treatment is justified only if the likelihood of achieving these ends is greater with medication than without and the consequences of untreated disease are greater than the potential complications of therapy. The benefit-risk factors must be carefully analyzed in each patient and therapy initiated only after all aspects of the disease have been evaluated. Generally, chronic persistent hepatitis is considered a benign disease for which specific therapy is unwarranted, while chronic active hepatitis is regarded as a progressive disorder for which treatment may be life saving.4,7 Controlled clinical trials have shown that corticosteroid therapy alone or in combination with azathioprine can improve certain biochemical abnormalities (serum bilirubin, total globulin, and albumin levels),8, 9, 42 control the complications of portal hypertension, 12, 29 and increase immediate life-expectancy in patients with severe chronic active hepatitis. 8, 42 In the majority of these patients, prednisone secures clinical, biochemical, and histologic remission of the disease. 44, 46 Treatment however is usually required for approximately 18 months 46 and is associated with major side effects in up to 44 per cent of patients, depending on the type and duration of therapy.47, 51 Patients with disease of less severity may have less to gain from such treatment.
Chronic Persistent Hepatitis This disease is virtually asymptomatic, typically nonprogressive, and generally associated with a good prognosis. In one series of 20 patients who were followed for up to 14 years (mean, 6 years), all clinical evidence of liver disease resolved in 16. Four were well when lost to follow-up. Corticosteroid therapy was not found to influence the clinical course and a propensity for the development of cirrhosis was not observed. 2 Systematic long-term studies, however, have not been conducted and the ultimate prognosis of chronic persistent hepatitis remains uncertain. The potential for increased disease activity and progression must be recognized. The histologic features of chronic persistent hepatitis are identical to those of the inactive or remission phase of chronic active hepatitis, 1,46 and deterioration to more severe inflammation is common in this phase of chronic active hepatitis.!. 37 Indeed, in one experience, 17 per cent of patients with chronic persistent hepatitis who were followed for at least 2 years realized this progression. 52 Because ofits usually benign nature, chronic persistent hepatitis does not require treatment with corticosteroids. Regular follow-up, however, is encouraged for all symptomatic patients, especially those with serum transaminase concentrations greater than five times normal or with positive immunoserologic tests. Such close observation may be the only means of identifying patients within the spectrum of chronic active hepatitis who progress to other stages of histologic activity and subsequently require specific therapy.
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Chronic Active Hepatitis Progression is likely but not inevitable in patients with chronic active hepatitis. Prognosis, and thereby the need for treatment, depends on the severity of the disease process as reflected in clinical, functional, and morphologic findings. Sustained elevation of serum glutamic oxalacetic transaminase (SGOT) levels to ten-fold normal or more, or five-fold increases in conjunction with at least twice-normal serum gamma globulin concentrations identify disease of such severity that most patients die within 3 years. 16 Application of these biochemical criteria prospectively indicates that 40 per cent of patients die within 6 months ifuntreated. 42 In other studies, only 6 per cent of 183 patients with severe chronic active hepatitis survived for more than 10 years. 28 • 33 Disease of this degree of severity obviously warrants therapy. Piecemeal necrosis is the hallmark of chronic active hepatitis,13 but further separation of patients according to morphologic features is justified by differences in response to treatment and prognosis.!. 37 Hepatocellular necrosis can be restricted to the portal area with moderate to severe erosion of the limiting plate (piecemeal necrosis) or it can extend from contiguous central veins and portal tracts (bridging necrosis) or be confluent with adjacent lobules (multilobular necrosis). Inactive hepatitis represents a remission stage of the disease and is indistinguishable histologic ally from nonspecific or chronic persistent hepatitis. Cirrhosis can be associated with any of the patterns of necrosis but is more accurately described as active or inactive, depending on the presence of piecemeal necrosis. These patterns of necrosis represent fluctuations in the degree and extent of disease activity at any given time during the course of chronic active hepatitis and, although each is potentially progressive, some are more consistently associated with a poor prognosis than others and more clearly dictate the need for treatment. 1, 37 The presence of bridging or multilobular necrosis presages progression of disease 5 , 56 and justifies treatment despite lack of other clinical and biochemical indices of disease activity. Cirrhosis developed in 37 per cent and death occurred in 19 per cent of 52 patients with these histologic findings following acute hepatitis during a mean observation period of 4 years. 5 In our own experience, 25 of 66 such patients developed cirrhosis (39 per cent) and 13 died of hepatic failure (20 per cent) after up to 5 years of follow-up. 37 Conversely, limitation of necrosis to the periportal area is less apt to deteriorate rapidly or progress to cirrhosis. Only one of 32 patients with periportal necrosis developed cirrhosis during a mean observation period of 4% years and none died of hepatic failure. 37 In these patients, the severity of the symptoms, not the prognosis, primarily influences the decision to treat. Documentation of cirrhosis in patients with severe disease activity does not preclude the need for treatment. Although these patients have a poorer long-term prognosis than others with chronic active hepatitis, over 50 per cent do enter remission, 37 and therapy may diminish the likelihood of varix formation and hemorrhage. 12 , 29
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WHO SHOULD BE TREATED? All patients with chronic active hepatitis are candidates for corticosteroid treatment. Clinical and histologic, rather than etiologic, findings most directly influence prognosis and are the major factors dictating therapy. Histologic evaluation is essential in all patients with chronic abnormalities of liver function since symptomatology and biochemical tests do not accurately reflect morphologic changes. Chronic active hepatitis may be impossible to distinguish from chronic persistent hepatitis by clinical findings alone, and anicteric chronic active hepatitis may progress to cirrhosis, especially in postmenopausal women without significant symptomatology.23 In patients with severe clinical disease, the histologic patterns of necrosis cannot be reliably predicted without tissue sampling although the presence of vascular spiders, impressive elevation 'of SGOT and hypoalbuminemia are more frequently associated with bridging or multilobular necrosis and cirrhosis than with the less aggressive periportal disease. 37 Severe Chronic Active Hepatitis Currently, corticosteroid therapy is most clearly indicated in patients with severe disease as characterized by duration of symptoms for longer than 3 months, sustained elevations of SGOT more than 10 times normal or 5 times normal in conjunction with an elevation in gamma globulin to twice normal and chronic active hepatitis documented by liver biopsy. Survival is significantly increased by prednisone therapy in this group and is warranted in all patients with disease of this severity, even though spontaneous resolution may be anticipated in 20 per cent.42 The presence of hepatitis B surface antigenemia, ascites or cirrhosis does not preclude a satisfactory response although the consistency of the response may be reduced in patients with hepatitis B surface antigenemia or decompensated cirrhosis with endogenous encephalopathy. 36, 38 The presence of bridging or multilobular necrosis identifies a precirrhotic condition and implies a poor prognosis. Accordingly, corticosteroid therapy is justified in these patients regardless of associated clinical or biochemical findings. Our experience indicates that corticosteroid therapy will diminish the incidence of cirrhosis and death from hepatic failure. 37 Necrosis limited to the periportal area does not have the same propensity for progression as the bridging or confluent lesions; however, patients with periportal necrosis who fulfill all criteria for disease severity should be treated, since there is the potential for deterioration to more severe necrosis and since resolution of symptoms can be more rapidly achieved with treatment. 37 Serious clinical deterioration with the development of ascites and other features of hepatic failure warrants therapeutic intervention even though the efficacy of such treatment is uncertain.
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Mild Chronic Active Hepatitis
These patients undoubtedly comprise the majority with chronic active hepatitis and yet indications for therapy are not well defined. Although studies showing a beneficial effect of steroids have included such patients,8.9 no clinically controlled trial has yet been published specifically evaluating the role of prednisone in the management ofthis group. That mild disease can progress to cirrhosis is unquestioned 23 but the frequency with which this occurs and whether corticosteroids can alter progression of disease and influence survival is unknown. The risks to be balanced against the possible benefits of treatment include the likelihood of severe side effects after more than 1 year of therapy and the unknown potential for mild disease to spontaneously resolve. Extrapolating from the experience with severe chronic active hepatitis, the presence of bridging or multilobular necrosis justifies treatment. However, patients at both ends of the histologic spectrum, i.e., those having periportal necrosis or cirrhosis, require careful consideration. The best guideline to therapy is the severity of symptoms. Fatigability, arthralgias, and anorexia may be severe in patients with mild disease. Marked improvement in these symptoms may be induced by prednisone. Since major side effects of corticosteroids do not accrue until after 1 year of treatment, a 6 month trial of prednisone therapy offers an adequate assessment of its efficacy in symptomatic patients. There is no objective evidence that treatment of asymptomatic patients with mild periportal necrosis or cirrhosis with mild activity is beneficial. Special Considerations The role of corticosteroids in the management of patients with hepatitis B surface antigen CHBsAg) is controversial. Uncontrolled observations in patients unselected by uniform criteria of severity of disease suggest that HBsAg positive patients with chronic active hepatitis, if untreated, have slower progression, longer survival, and fewer relapses with jaundice than HBsAg negative patients. 4o This relatively good prognosis and the possibility that steroid-induced impairment of host defense mechanisms may perpetuate the antigenemia and ac!:ually be deleterious have been offered as caveats against corticosteroid therapy in this group. Convincing evidence, however, that prednisone facilitates disease chronicity or progression in HBsAg positive patients is lacking. In acute hepatitis B, indices of viral replication are not affected by steroid administration 20 and corticosteroid treatment has been beneficial in those antigen-positive patients who have been regularly followed, albeit in an uncontrolled fashion. 15 Currently, clinical and histologic findings remain the most secure indications for treatment. Etiologic considerations are important primarily as prognostic rather than therapeutic indices. HBsAg positive patients with severe chronic active hepatitis enter remission less frequently and treatment fails more often, than is the case with HBsAg negative patients with disease of comparable severity.38 Determination of the e-antigen status allows further characterization of HBsAg positive patients, and identifies a subgroup prone to therapeutic recalcitrance. 54 Positivity of e-antigen corre-
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lates with inability to eliminate HBsAg from the serum or produce detectable amounts of antibody to surface antigen and may reflect an impaired immune response to hepatitis B virus. Failure of conventional prednisone therapy to control disease activity may be anticipated in these patients, and higher than usual maintenance doses administered over longer periods of time may be required to suppress the disease. 38 , 54 Although a genetic predisposition to chronic active hepatitis has been postulated because of a higher than normal incidence of histocompatibility antigens (HLA1, HLA8, DW3) in these patients, 53 a definite association between genetic factors and prognosis or therapeutic responsiveness has not been established. Most recently, high levels of cell-mediated cytotoxicity have been found in those HBsAg negative patients who possess HLA1, HLA8 or DW3,55 further implicating genetic influences (possible abnormalities in the immunoregulatory genes) in the pathogenesis ofthe liver disease. The importance of cell-mediated cytotoxicity in the perpetuation of chronic active hepatitis and the effect of prednisone on this cytotoxicity require further definition, but at present these etiologic mechanisms should not deter initiation of corticosteroid therapy when clinically indicated.
HOW SHOULD TREATMENT BE IMPLEMENTED? Conventional Treatment Controlled clinical trials have demonstrated that two therapeutic regimens are of equal effectiveness in the management of severe chronic active hepatitis (Table 1),47 High initial dose prednisone followed by a fixed daily maintenance dose (Pred) or a smaller amount of prednisone in combination with a fixed daily dose of azathioprine (Comb) are each able to induce clinical, biochemical and histologic remission of severe chronic active hepatitis. Eighty per cent of patients treated with these programs enter remission between 6 and 36 months (mean 24 months) after the start of therapy. 44, 47 Combination therapy with prednisone and azathioprine is currently the treatment of choice since it is as effective as prednisone alone in controlling the liver disease and is associated with fewer side effects.47 Alternate day doses of prednisone titrated to secure resolution ofbiochemical abnormalities alleviates symptoms, increases early survival, and has fewer side effects than the Pred program but does not as reliably produce histologic remission. 47 Contraindications to Treatment Diabetes, severe osteoporosis, peptic ulcer disease, cataracts, and moderate hypertension are partial contraindications to prednisone therapy. All of these conditions may be aggravated by administration of corticosteroids, although each is manageable if such therapy is indicated. Utilization of the small dose of prednisone in combination with azathioprine is the preferred treatment for these patients.
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Table 1. Effective Treatment Schedules for Severe Chronic Active Hepatitis COMBINATION
STANDARD PREDNISONE
Drugs (daily doses) Prednisone
Azathioprine
60 mg 40mg 30 mg 20 mg None
x 1 week x 1 week x 2 weeks maintenance
30 mg 20mg 15 mg 10 mg 50 mg
x 1 week x 1 week x 2 weeks maintenance maintenance
Laboratory tests' SGOT, bilirubin, gamma globulin Leukocytes and platelets
2 weeks, 3 months, then every 6 months Every 6 months
2 weeks, 3 months, then every 6 months Weekly x 3 months, every 2 weeks x 9 months, every 3 weeks thereafter
Complete evaluation
Every 6 months""
Every 6 months·*
Indications
Leukopenia Thrombocytopenia
Preferred, since fewer sideeffects
"To monitor response and identify treatment failure **Liver biopsy if clinical and biochemical resolution
Leukopenia and thrombocytopenia are absolute contraindications to treatment with azathioprine. Prednisone alone should be administered to these patients even though the risks of corticosteroid side effects are greater than with combination therapy.42, 51 Subsequent improvement in the liver disease may be associated with normalization of leukocyte and platelet levels permitting conversion to combination therapy later. Rarely, contraindications to effective doses of both drugs are encountered. In order to utilize the lower dose schedule of prednisone, splenectomy has been suggested to improve cytopenia and permit the addition of azathioprine to the program. 3 A past history of malignancy is a relative contraindication to both drugs since oncogenic effects of the medications have been suggested. 31
Drug Side Effects Corticosteroid therapy can produce cosmetic changes (obesity, facial rounding, acne, dorsal hump and hirsutism) as well as severe debilitating complications (diabetes, hypertension, cataracts, psychosis and osteoporosis with aseptic necrosis of the hip or vertebral collapse). The frequency of side effects depends on the dose and duration of steroid administration. Eighty per cent of patients treated with prednisone for an average of2 years manifest cosmetic side effects which occur with equal frequency in all regimens containing steroids. 51 Severe complications usually develop only after 18 months oftreatment and at doses ofprednisone above 10 mg daily. They occur less often with combination therapy (10 per cent) than with prednisone in fixed daily dose (44 per cent) or in titrated alternate day doses (36 per cent), and are more common in patients with continuing hypoalbuminemia (less than 3 gm per 100 ml for
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more than 5 months) and/or hyperbilirubinemia (greater than 1.3 mg per 100 ml for more than 5 months).51 Increased serum levels of unbound corticosteroid have been demonstrated in these patients and may result from reduced availability of the albumin carrier (hypoalbuminemia) or competitive displacement of the bound drug by organic anions (hyperbilirubinemia).50 The unbound fraction of serum corticosteroid is the pharmacologically effective fraction and is most likely responsible for the development of side effects. Unfortunately the patients most in need of therapy are those most likely to suffer major steroid complications. Azathioprine may cause hepatotoxicity, gastrointestinal upset, skin rashes, leukopenia, and thrombocytopenia. Many of these complications are difficult to distinguish from those of the liver disease itself and occur in less than 10 per cent of patients receiving the low dose of 50 mg daily.47 In higher doses, an oncogenic potential has been ascribed to azathioprine and is best characterized by the development of lymphomas at a young age in individuals receiving high doses against a background of renal disease, chronic azotemia, transplantation, and general immunosuppression.31. 47 In our experience with 121 patients treated on one or more occasions for at least 6 months (mean 33 ± 2 months) and followed for over 482 patient years of observation (mean 48 ± 1 months), malignancies developed in 7 per cent after treatment periods totalling 42 ± 8 months. Carcinomas were usually low grade and operable involving the skin, bladder, penis, ovary, and liver. Patients developing neoplasms differed from others only in that they were older (60 ± 3 years versus 36 ± 2 years) and at a naturally higher risk for malignancy.ll The oncogenic property of azathioprine has not been established while the life-saving effect of the medication in combination with prednisone remains secure.
Duration of Treatment Therapy is continued until an endpoint is reached comprising full remission of the disease, serious drug toxicity, or treatment failure and death. Remission has been arbitrarily defined as complete absence of symptoms, resolution of all biochemical abnormalities except for trivial (less than twice normal) elevation of SGOT, and disappearance of morphologic features of aggressive disease activity (piecemeal necrosis). The presence of cirrhosis or inflammation indistinguishable from nonspecific or chronic persistent hepatitis does not preclude remission. Symptoms and clinical features of disease activity usually resolve within 6 months after initiation of treatment. Abnormal biochemical and immunoserologic studies normalize after 1 year, and by 2 years 70 per cent of patients demonstrate histologic resolution. Only a minority of patients require therapy for 3 years or more. 44 Remission must be established by liver biopsy since clinical and biochemical abnormalities commonly resolve completely during therapy while successive liver biopsies continue to show significant disease activity. When remission is achieved, medications are slowly discontinued by tapering dosages over a 6 week period (Table 2). Liver function tests are monitored at 3 week intervals for the first 12 weeks and at 6 month
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Table 2. Gradual Discontinuation of Conventional Therapy STANDARD PREDNISONE
Drugs (daily doses) Prednisone
Azathioprine
Laboratory tests* SCOT, bilirubin, gamma globulin Leukocytes and platelets Complete evaluation with liver biopsy
15 mg 10 mg 5 mg 2.5 mg Off None
x x x x
1 1 2 2
week week weeks weeks
COMBINATION
7.5 mg x 2 weeks 5 mg x 2 weeks 2.5 mg x 2 weeks Off 50 mg x 3 weeks 25 mg x 3 weeks Off
3, 6, 9, 12 weeks, then every 6 months As necessary
3, 6, 9, 12 weeks, then every 6 months As necessary
Every 6 months until normal biopsy or two consecutive biopsies showing chronic persistent hepatitis, then annually
Every 6 months until normal biopsy or two consecutive biopsies showing chronic persistent hepatitis, then annually
'To document continuing remission and identify relapse
intervals thereafter. The patient is evaluated every 6 months until a normal liver biopsy or two consecutive biopsies showing chronic persistent hepatitis are obtained and then at annual intervals to ensure against delayed relapse. Complete disappearance of disease activity, including all histologic features of chronic inflammation, occurs slowly, eventuating in 12 per cent of patients with severe disease after almost 4% years offollow-up.1° Normal hepatic architecture or totally inactive cirrhosis is usually documented 1% years after medication has been discontinued, and in many patients (43 per cent) occurs only after multiple courses of treatment. Patients whose histologic findings return entirely to normal have not had a relapse as yet after up to 4% years of further follow-up (mean 2 years) and may indeed by "cured."lo Relapse, however, is common in patients with cirrhosis even if the inflammatory component of their disease is inapparent on liver biopsy. Manifestations of serious drug toxicity or deterioration of the liver disease on standard therapy (treatment failure) justify termination of conventional treatment. Prompt initiation of other measures designed to control these special problems is necessary.
Treatment Problems FAIL URE. Approximately 20 per cent of patients with severe chronic active hepatitis fail to improve on conventional therapy and require higher than usual doses of medication for control. Treatment failure has been arbitrarily characterized as the development of endogenous encephalopathy, increasing ascites, or biochemical deterioration with increments of at least 67 per cent in the serum bilirubin and/or SGOT
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abnormalities while on therapy. Failure usually develops within 2 months after initiation of treatment but may occur 8 or more months later.36 The majority will respond if their medication is increased to 60 mg of prednisone daily or 30 mg of prednisone in combination with 150 mg of azathioprine daily (Table 3). Improvement usually follows within 6 weeks and the doses of medication can then be reduced at monthly intervals by 10 mg decrements of prednisone and, when applicable, 50 mg decrements of azathioprine until conventional maintenance levels are reached. Dose reduction is indicated by at least a 33 per cent improvement in SGOT during a 4 week period of observation. 36 DRUG TOXICITY. The development of serious drug toxicity warrants modification or discontinuation of therapy. If prednisone alone has been administered, conversion to combination therapy with low dose prednisone should be attempted. Azathioprine toxicity justifies dose reduction or elimination. If neither drug can be given in its customary dosage, administration of prednisone, 10 mg daily or 20 mg on alternate days, will usually prevent clinical and biochemical progression of the disease without aggravating already established side effects. SLOW RESPONSE. Patients may improve clinically and biochemically on conventional therapy but not achieve complete remission after more than 2 years of continuous treatment. In our experience, up to 24 per cent of patients do not reach a therapeutic endpoint after a mean period of treatment of26 months. The likelihood of ultimate remission in these patients is not fully defined and whether increments in their medication will hasten resolution is unstudied. The majority are completely asymptomatic but require continuous medication and follow-up. In each patient, possible reasons for the slow response must be carefully investigated. Compliance to the therapeutic program should be evaluated and a detailed drug history taken. The accuracy of the original diagnosis should Table 3. Management of Treatment Failure HIGH PREDNISONE
Drugs (daily doses) Prednisone Azathioprine
HIGH COMBINATION
60mg None
30mg 150mg
Monthly
Monthly
Every 6 months
Weekly
Dose decrements' Prednisone Azathioprine
10mg/month None
10 mg/month 50mg/month
Complete evaluation Liver biopsy
Every 6 months If needed diagnostically
Every 6 months If needed diagnostically
Laboratory tests SGOT, bilirubin, gamma globulin Leukocytes and platelets
*For each monthly improvement of SGOT by 33 per cent until maintenance level is achieved
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be re-established. Unless serious drug toxicities intervene, therapy should be continued unaltered. RELAPSE. Fifty per cent of patients with severe chronic active hepatitis who enter remission suffer relapse within 6 months after discontinuation of medication and require another course of therapy. 44, 47 Remission sustained for longer than 6 months is associated with an 8 per cent relapse rate. Fatigue, arthralgias, and elevation of SGOT to at least three-fold normal invariably indicate histologic deterioration. In 10 per cent of patients, however, histologic relapse occurs without characteristic clinical and biochemical signs, emphasizing the need for follow-up liver biopsy within the first year of remission. 44 Reinstitution of therapy is usually followed by prompt improvement in all indices of activity and the likelihood of the patient again achieving remission is 80 per cent. 44 , 47 No patients who have relapsed have failed to respond to subsequent courses of therapy. The relapse rate after one or more remissions remains constant at 50 per cent. The two major reasons for an unsatisfactory response to therapy are wrong diagnosis and inadequate treatment. All patients who respond poorly to therapy must be re-evaluated to exclude primary biliary cirrhosis, Wilson's disease, alpha. antitrypsin deficiency, hepatic carcinoma, and drug-induced liver disease. If confirmed, these diagnoses may indicate the need for another more effective form of therapy. Lower than recommended doses of prednisone or too rapid, arbitrary alterations in medication most commonly account for an unsuccessful resolution of activity. Institution of a therapeutic program of proven efficacy as outlined in Table 1 will usually control the disease process. Recent studies indicate that hepatic conversion of prednisone to its active metabolite, prednisolone, remains adequate even in severe disease. 39 Failure of response cannot be attributed to inadequate utilization of the drug and administration of prednisolone instead of prednisone is not necessary. Novel Treatments Several new approaches to the management of chronic active hepatitis are currently being evaluated. INTERFERON. This is a cellular protein which inhibits viral replication at the level of transcription. Although optimum protection requires cellular exposure to interferon before viral infection, perpetuation of chronic disease implies a steady stream of viruses continuously infecting previously uninvolved cells. Patients with acute or chronic hepatitis B disease do not produce interferon in amounts normally encountered after other viral infections, suggesting that the B virus is a poor inducer of endogenous interferon production.1 4 Administration of exogenous interferon to these patients or stimulation of endogenous production may facilitate control of disease activity. Preliminary studies in animals and humans chronically infected with hepatitis B virus have shown immediate and reproducible reduction by interferon of indices of viral replication. 14, 19, 32 Definite improvements, however, in liver function tests and histology have not been demonstrated during short periods of administration. Suppression of viral replication is
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only transient and the frequency ofhematologic effects, febrile reactions and hepatotoxicity, observed in animal studies,32 require further elucidation. TRANSFER FACTOR. Correction of a possible defect in cell-mediated immunity by administration of transfer factor has been attempted in one patient with HBsAg positive chronic active hepatitis. 48 Although cellmediated immunity, as measured by lymphocyte response to HBsAg, was enhanced, there was no correlation with clinical course or appearance of viral markers. Additional studies are needed to evaluate the full potential of this approach. PENICILLAMINE. This drug has had a vast uncontrolled experience in Europe where its administration has been associated with an improvement in the biochemical abnormalities of chronic active hepatitis. 25 Inhibition of collagen cross-linkage has been demonstrated in animal studies and the potential antifibroblastic action of penicillamine might prove beneficial in the management of precirrhotic conditions. Such an influence has been suggested in controlled studies involving alcoholic liver disease, although overall survival was unaffected by the drug. 34 Currently, the experience in chronic active hepatitis indicates only an anti-inflammatory effect of penicillamine which may be attributable to cupresis. Carefully controlled trials are obviously necessary. Its greatest benefit may be in those patients with chronic active hepatitis and copper overload 26 or as an adjunct to corticosteroids in the management of treatment failure. COLCHICINE. This drug has also generated interest as a potential antifibrogenic agent. Controlled clinical trials in patients with cirrhosis have yielded only preliminary, inconclusive results. An antiinflammatory action is apparent from improvements in biochemical studies but beneficial effects on histology and early survival have yet to be demonstrated. 22 The development of primary hepatic tumors in some of the patients treated with colchicine emphasizes the need for continued careful evaluation of this drug in an investigational setting.
REFERENCES 1. Baggenstoss, A. H., Soloway, R. D., Summerskill, W. H. J., et al.: Chronic active liver disease. The range of histologic lesions, their response to treatment and evolution. Human Pathol., 3:183-198, 1972. 2. Becker, M. D., Scheuer, P. J., Baptista, A., et al.: Prognosis of chronic persistent hepatitis. Lancet, 1 :53-57, 1970. 3. Boye, N. P., Nordoy, A., and Gjone, E.: Splenectomy in active chronic hepatitis. Scand. J. Gastroent., 7:747-750, 1972. 4. Boyer J. L.: Chronic hepatitis-a perspective on classification and determinants ofprognosis. Gastroenterology, 70:1161-1171,1976. 5. Boyer, J. L., and Klatskin, G.: Pattern of necrosis in acute viral hepatitis. New Eng. J. Med., 283:1063-1071, 1970. 6. Christoffersen, P., Poulsen, H., and Scheuer, P. J.: Abnormal bile duct epithelium in chronic aggressive hepatitis and primary biliary cirrhosis. Human Pathol., 3:227-235, 1972. 7. Conn, H. 0.: Chronic hepatitis: reducing an iatrogenic enigma to a workable puzzle. Editorial. Gastroenterology, 70:1182-1184, 1976. 8. Cook, G. C., Mulligan, R., and Sherlock, S.: Controlled prospective trial of corticosteroid therapy in active chronic hepatitis. Quart. J. Med., 40:159-185, 1971. 9. Copenhagen Study Group for liver Diseases: Effect of prednisone on the survival of patients with cirrhosis of the liver. Lancet, 1: 119-121, 1969.
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10. Czaja, A. J., and Summerskill, W. H. J.: Can severe chronic active liver disease treated with steroids be cured? Abstract. Gastroenterology, 72:1042, 1977. 11. Czaja, A. J., and Summers kill, W. H. J.: Malignancy in chronic liver disease. Gastroenterology, in press. 12. Czaja, A. J., Wolf, A. M., and Summerskill, W. H. J.: A prospective study of development and prognosis of esophageal varices in treated chronic active liver disease. Abstract. Gastroenterology, 71 :901, 1976. 13. de Groote, J., Desmet, V. J., Gedigk, P., et al.: A classification of chronic hepatitis. Lancet, 2:626-628, 1968. 14. Desmyter, J., Ray, M. B., de Groote, J., et al.: Administration of human fibroblast interferon in chronic hepatitis-B infection. Lancet, 2:645-647, 1976. 15. Dudley, F. J., Scheuer, P. J., and Sherlock, S.: Natural history of hepatitis-associated antigen-positive chronic liver disease. Lancet, 2:1388-1393, 1972. 16. Geall, M. G., Schoenfield, L. J., and Summerskill, W. H. J.: Classification and treatment of chronic active liver disease. Gastroenterology, 55:724-729, 1968. 17. Geubel, A. P., Baggenstoss, A. H., and Summerskill, W. H. J.: Responses to treatment can differentiate chronic active liver disease with cholangitic features from the primary biliary cirrhosis syndrome. Gastroenterology, 71 :444-449, 1976. 18. Goldstein, G. B., Lam, K C., and Mistilis, S. P.: Drug-induced active chronic hepatitis. Amer. J. Dig. Dis., 18:177-184, 1973. 19. Greenberg, H. B., Pollard, R B., Lutwick, L. I., et al.: Effect ofhumanleukocyte interferon on hepatitis B infection in patients with chronic active liver disease. New Eng. J. Med., 295:517-522,1976. 20. Greenberg, H. B., Robinson, W. S., Knauer, C. M., etal.: Hepatitis B viral markers in severe viral hepatitis: influence of steroid therapy. Abstract. Gastroenterology, 71 :909, 1976. 21. Kaplowitz, N., Finlayson, N. D. C., Walmsley, P., et al.: Hepatobiliarydiseases associated with serum antimitochondrlal antibody (AMA). Amer. J. Med., 54:725-730,1973. 22. Kershenobich, D., Uribe, M., and Rojkind, M.: A trial of colchicine in liver cirrhosis. Abstract. Gastroenterology, 68:1078, 1975. 23. Klatskin, G.: Subacute hepatic necrosis and postnecrotic cirrhosis due to anicteric infections with the hepatitis virus. Amer. J. Med., 25 :333-358, 1958. 24. Klatskin, G., and Kantor, F. S.: Mitochondrial antibody in primary biliary cirrhosis and other diseases. Ann. Intern. Med., 77:533-541, 1972. 25. Lange, J., Schumacher, K, and Witscher, H. P.: Die Behandlung der Chronischaggressiven Hepatitis mit D-Penicillamin. Deutsche Med. Wschr., 96:139-145, 1971. 26. LaRusso, N. F., Summerskill, W. H. J., and McCall, J. T.: Abnormalities of chemical tests for copper metabolism in chronic active liver disease: differentiation from Wilson's disease. Gastroenterology, 70:653-656, 1976. 27. Maddrey, W. C., and Boitnott, J. K: Isoniazid hepatitis. Ann. Intern. Med., 79:1-12,1973. 28. Mistilis, S. P., and Blackburn, C. R B.: The treatment of active chronic hepatitis with 6-mercaptopurine and azathioprine. Aust. Ann. Med., 16:305-311, 1967. 29. Murray-Lyon, 1. M., Stern, R B., and Williams, R: Controlled trial of prednisone and azathioprine in active chronic hepatitis. Lancet, 1 :735-737, 1973. 30. Nomenclature, Diagnostic Criteria and Diagnostic Methodology for Diseases of the Liver and Biliary Tract. Fogarty International Proc., No. 22, U. S. Government Printing Office, 1976, pp. 1-11. 31. Penn, 1., Hammond, W., Brettschneider, L., et al.: Malignant lymphomas in transplantation patients. Transplant. Proc., 1 :106-112, 1969. 32. Purcell, RH., Gerin, J. L., London, W. T., et al.: Modification of chronic hepatitis-B virus infection in chimpanzees by administration of an interferon inducer. Lancet, 2: 757-761, 1976. 33. Read, A. E., Sherlock, S., and Harrison, C. V.: Active "juvenile" cirrhosis considered as part of a systemic disease and the effect of corticosteroid therapy. Gut, 4 :378-393, 1963. 34. Resnick, R. H., Boitnott, J., lber, F. L., et aI.: Preliminary observations ofd-penicillamine therapy in acute alcoholic liver disease. Digestion, 11 :257-265, 1974. 35. Reynolds, T. B., Peters, R L., and Yamada, S.: Chronic active and lupoid hepatitis caused by a laxative, oxyphenisatin. New Eng. J. Med., 285:813-820, 1971. 36. Schalm, S. W., Ammon, H. V., and Summerskill, W. H. J.: Failure of customary treatment in chronic active liver disease: causes and management. Ann. Clin. Res., 8:221-227, 1976. 37. Schalm, S. W., Korman, M. G., Summerskill, W. H. J., et al.: Severe chronic active liver disease: prognostic significance of initial morphologic patterns. Amer. J. Dig. Dis., in press. 38. Schalm, S. W., Summerskill, W. H. J., Gitnick, G. L., et al.: Contrasting features and responses to treatment of severe chronic active liver disease with and without hepatitis B, antigen. Gut, 17:781-786,1976.
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39. Schalm, S. W., Summerskill, W. H. J., and Go, V. L. W.: Prednisone for chronic active liver disease: pharmacokinetics, including conversion to prednisolone. Gastroenterology, 72:910-913, 1977. 40. Sherlock, S.: Chronic hepatitis. Gut, 15:581-597,1974. 41. Soloway, R. D., Baggenstoss, A. H., Schoenfield, L. J., et al.: Observer error and sampling variability tested in evaluation of hepatitis and cirrhosis by liver biopsy. Amer. J. Dig. Dis., 16:1082-1086, 1971. 42. Soloway, R. D., Summerskill, W. H. J., Baggenstoss, A. H., et al.: Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis. Gastroenterology, 63:820-833, 1972. 43. Sternleib, 1., and Scheinberg, 1. M.: Chronic hepatitis as a first manifestation of Wilson's disease. Ann. Intern. Med., 76:59-64, 1972. 44. Summerskill, W. H. J.: Chronic active liver disease re-examined: prognosis hopeful. Gastroenterology, 66:450-464, 1974. 45. Summerskill, W. H. J.: Chronic hepatitis-1975. Editorial. Amer. J. Dig. Dis., 20:10871090, 1975. 46. Summerskill, W. H. J., Ammon, H. V., and Baggenstoss, A. H.: Treatment of chronic hepatitis. In Schaffner, F., Shedock, S., and Leevy, C. M., eds.: The Liver and its Diseases. New York, International Medical Book Corp., 1974, pp. 216-226. 47. Summerskill, W. H. J., Korman, M. G., Ammon,H. V., etal.: Prednisone for chronic active liver disease: dose titration, standard dose, and combination with azathioprine compared. Gut, 16:876-883, 1975. 48. Tong, M. J., Nystrom, J. S., Redeker, A. G., et al.: Failure of transfer-factor therapy in chronic active type B hepatitis. New Eng. J. Med., 295:209-211,1976. 49. Tysell, J. E., and Knauer, C. M.: Hepatitis induced by methyldopa (Aldomet). Amer. J. Dig. Dis., 16:849-855, 1971. 50. Uribe, M., Summers kill, W. H. J., Go, V. L. W.: Why hyperbilirubinemia and hypoalbuminemia predispose to steroid side effects during treatment of chronic active liver disease. Abstract. Gastroenterology, 72: 1143, 1977. 51. Uribe, M., Wolf, A. M., and Summerskill, W. H. J.: Steroid side effects during therapy of chronic active liver disease (CALD): what to expect. Abstract. Gastroenterology, 71 :932, 1976. 52. Vido, 1., Selmair, H., Wildhirt, E., et al.: Zur Prognose derchronischen Hepatitis. Deutsche Med. Wschr., 94:2215-2220, 1969. 53. Vogten, A. J. M., Schalm, S. W., Summerskill, W. H. J., et al.: Prevalence ofDW3 determinant in chronic active liver disease: relationship to etiology and response to treatment. Abstract. Gastroenterology, 70:996, 1976. 54. Vogten, A. J. M., Schalm, S. W., Summerskill, W. H. J., et al.: Behavior ofe-antigen and antibody during chronic active liver disease. Lancet, 2:126-128, 1976. 55. Vogten, A. J. M., Summerskill, W. H. J., Shorter, R. G., et al.: Evidence for a genetic contribution to cell mediated cytotoxicity in chronic active liver disease. Abstract. Gastroenterology, 72:1145, 1977. 56. Ware, A. J., Eigenbrodt, E. H., Combes, B.: Prognostic significance of subacute hepatic necrosis in acute hepatitis. Gastroenterology, 68:519-524, 1975. Gastroenterology Unit St. Mary's Hospital Rochester, Minnesota 55901
Chronic Hepatitis To Treat or Not to Treat? Albert J. Czaja, M.D., * and W. H. J. Summerskill, M.D. **
Chronic hepatitis connotes continuous or recurrent inflammation of the liver initiated by viral, drug, or unknown factors and perpetuated beyond an expected period of resolution. Continuation of the disease process for at least 10 weeks without clinical or biochemical improvement excludes self-limited acute hepatitis in most instances and indicates chronicity.16 Demonstration of ongoing activity for 6 months establishes the unresolving nature of the process 4 , 30, 45 and generates concern over possible progression to cirrhosis or liver failure. Although four controlled trials have demonstrated that prednisone with or without azathioprine can control the clinical manifestations and complications of severe chronic active liver disease,8, 9, 29, 42 the benefits and risks of such therapy have not been well studied in patients with less severe disease. In all patients, activity of the disease must be balanced against the potential for progression or spontaneous resolution, and the risks of long-term corticosteroid therapy. Thus, to treat or not to treat chronic hepatitis is a highly individualized judgment. A successful outcome depends on a thorough awareness of what has been diagnosed, why treatment is necessary, who should be treated, and how best to implement and monitor therapy.
WHAT IS THE DIAGNOSIS? The International Association for the Study of the Liver recently recognized two distinct types of chronic hepatitis, chronic persistent hepatitis (CPR) and chronic active hepatitis (CAR). For the latter, chronic active liver disease (CALD) is an acceptable synonym, whereas chronic aggressive hepatitis is limited to morphologic description. The lesions of subacute hepatitis or subacute hepatic necrosis have been omitted from the new nomenclature, and other types of chronic inflammatory liver disease, including Wilson's disease, primary biliary cirrhosis, and certain *Assistant Professor of Medicine, Mayo Medical School, Rochester, Minnesota **ProfessorofMedicine, Mayo Medical School, Rochester, Minnesota. Deceased March 9, 1977
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drug-related diseases, have been classified otherwise to emphasize their etiologic distinction. 13. 30. 44, 45 Differentiation of chronic persistent hepatitis from chronic active hepatitis can be difficult since clinical, biochemical and morphological features may be similar. Patients with chronic persistent"hepatitis may have hepatic enlargement and symptoms of easy fatigability, anorexia, and right upper quadrant pain. Elevations of serum aspartate transaminase levels to as high as 20 times normal are still consistent with the diagnosis, and hypergammaglobulinemia to twice normal and mild hyperbilirubinemia may be present initially.2 Although most biochemical abnormalities in chronic persistent hepatitis resolve spontaneously, serum transaminase levels may fluctuate between normal and three-fold normal, confusing the diagnosis. 2,46 Immunoserologic markers such as smooth muscle antibody, antimitochondrial antibody, antinuclear antibody, and positive lupus clot test identify patients likely to have chronic active hepatitis but these are not always present.4 Classification has been based mainly on histologic findings. The salient morphologic feature of chronic active hepatitis is the presence of moderate to severe periportal ("piecemeal") necrosis while limitation of the inflammatory round cell infiltrate to the portal tract with mild or absent periportal necrosis characterizes chronic persistent hepatitis,13 Needle biopsy of the liver with expert interpretation of the morphologic features is essential in establishing the diagnosis and will reproducibly disclose the degree ofhepatitis in over 90 per cent of cases. Sampling error however limits the effectiveness of needle biopsy in diagnosing cirrhosis,41 Other chronic inflammatory conditions of the liver are accepted as being etiologically distinct from chronic active hepatitis but may have abnormalities of serum transaminases and gamma globulin, positive immunoserology, and patterns of necrosis on liver biopsy identical to those encountered in chronic active hepatitis. Wilson's disease,43 primary biliary cirrhosis 6,17 and certain drug-related (oxyphenisatin,35 methyldopa,18,49 and isoniazid27 ) hepatic disorders must be distinguished from chronic active hepatitis since different forms oftherapy may be indicated. Screening tests for Wilson's disease are now mandatory in the evaluation of all patients suspected of having chronic active hepatitis and should include slit lamp examination of the eyes for Kayser-Fleischer rings, serum ceruloplasmin concentration and urinary copper excretion. Primary biliary cirrhosis may be a particular source of diagnostic confusion since there are many overlapping features with chronic active hepatitis. The presence of antimitochondrial antibody does not necessarily differentiate the two disorders 2l ,24 and, in the absence of characteristic bile duct lesions (stage 1 florid ductal damage)6 on liver biopsy, the histology may not be discriminating. A course of prednisone therapy may be necessary to make this differentiation since failure of a therapeutic response increases the likelihood of primary biliary cirrhosis.1 7 A careful clinical history will usually identify those patients with drug-induced hepatic disease. Withdrawal of the drug will usually improve the condition although complete resolution in severe cases may not be certain. 18
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WHY IS TREATMENT NECESSARY? The goals of therapy for chronic hepatitis are to control symptoms, prevent cirrhosis, and prolong survival. Treatment is justified only if the likelihood of achieving these ends is greater with medication than without and the consequences of untreated disease are greater than the potential complications of therapy. The benefit-risk factors must be carefully analyzed in each patient and therapy initiated only after all aspects of the disease have been evaluated. Generally, chronic persistent hepatitis is considered a benign disease for which specific therapy is unwarranted, while chronic active hepatitis is regarded as a progressive disorder for which treatment may be life saving.4,7 Controlled clinical trials have shown that corticosteroid therapy alone or in combination with azathioprine can improve certain biochemical abnormalities (serum bilirubin, total globulin, and albumin levels),8, 9, 42 control the complications of portal hypertension, 12, 29 and increase immediate life-expectancy in patients with severe chronic active hepatitis. 8, 42 In the majority of these patients, prednisone secures clinical, biochemical, and histologic remission of the disease. 44, 46 Treatment however is usually required for approximately 18 months 46 and is associated with major side effects in up to 44 per cent of patients, depending on the type and duration of therapy.47, 51 Patients with disease of less severity may have less to gain from such treatment.
Chronic Persistent Hepatitis This disease is virtually asymptomatic, typically nonprogressive, and generally associated with a good prognosis. In one series of 20 patients who were followed for up to 14 years (mean, 6 years), all clinical evidence of liver disease resolved in 16. Four were well when lost to follow-up. Corticosteroid therapy was not found to influence the clinical course and a propensity for the development of cirrhosis was not observed. 2 Systematic long-term studies, however, have not been conducted and the ultimate prognosis of chronic persistent hepatitis remains uncertain. The potential for increased disease activity and progression must be recognized. The histologic features of chronic persistent hepatitis are identical to those of the inactive or remission phase of chronic active hepatitis, 1,46 and deterioration to more severe inflammation is common in this phase of chronic active hepatitis.!. 37 Indeed, in one experience, 17 per cent of patients with chronic persistent hepatitis who were followed for at least 2 years realized this progression. 52 Because ofits usually benign nature, chronic persistent hepatitis does not require treatment with corticosteroids. Regular follow-up, however, is encouraged for all symptomatic patients, especially those with serum transaminase concentrations greater than five times normal or with positive immunoserologic tests. Such close observation may be the only means of identifying patients within the spectrum of chronic active hepatitis who progress to other stages of histologic activity and subsequently require specific therapy.
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Chronic Active Hepatitis Progression is likely but not inevitable in patients with chronic active hepatitis. Prognosis, and thereby the need for treatment, depends on the severity of the disease process as reflected in clinical, functional, and morphologic findings. Sustained elevation of serum glutamic oxalacetic transaminase (SGOT) levels to ten-fold normal or more, or five-fold increases in conjunction with at least twice-normal serum gamma globulin concentrations identify disease of such severity that most patients die within 3 years. 16 Application of these biochemical criteria prospectively indicates that 40 per cent of patients die within 6 months ifuntreated. 42 In other studies, only 6 per cent of 183 patients with severe chronic active hepatitis survived for more than 10 years. 28 • 33 Disease of this degree of severity obviously warrants therapy. Piecemeal necrosis is the hallmark of chronic active hepatitis,13 but further separation of patients according to morphologic features is justified by differences in response to treatment and prognosis.!. 37 Hepatocellular necrosis can be restricted to the portal area with moderate to severe erosion of the limiting plate (piecemeal necrosis) or it can extend from contiguous central veins and portal tracts (bridging necrosis) or be confluent with adjacent lobules (multilobular necrosis). Inactive hepatitis represents a remission stage of the disease and is indistinguishable histologic ally from nonspecific or chronic persistent hepatitis. Cirrhosis can be associated with any of the patterns of necrosis but is more accurately described as active or inactive, depending on the presence of piecemeal necrosis. These patterns of necrosis represent fluctuations in the degree and extent of disease activity at any given time during the course of chronic active hepatitis and, although each is potentially progressive, some are more consistently associated with a poor prognosis than others and more clearly dictate the need for treatment. 1, 37 The presence of bridging or multilobular necrosis presages progression of disease 5 , 56 and justifies treatment despite lack of other clinical and biochemical indices of disease activity. Cirrhosis developed in 37 per cent and death occurred in 19 per cent of 52 patients with these histologic findings following acute hepatitis during a mean observation period of 4 years. 5 In our own experience, 25 of 66 such patients developed cirrhosis (39 per cent) and 13 died of hepatic failure (20 per cent) after up to 5 years of follow-up. 37 Conversely, limitation of necrosis to the periportal area is less apt to deteriorate rapidly or progress to cirrhosis. Only one of 32 patients with periportal necrosis developed cirrhosis during a mean observation period of 4% years and none died of hepatic failure. 37 In these patients, the severity of the symptoms, not the prognosis, primarily influences the decision to treat. Documentation of cirrhosis in patients with severe disease activity does not preclude the need for treatment. Although these patients have a poorer long-term prognosis than others with chronic active hepatitis, over 50 per cent do enter remission, 37 and therapy may diminish the likelihood of varix formation and hemorrhage. 12 , 29
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WHO SHOULD BE TREATED? All patients with chronic active hepatitis are candidates for corticosteroid treatment. Clinical and histologic, rather than etiologic, findings most directly influence prognosis and are the major factors dictating therapy. Histologic evaluation is essential in all patients with chronic abnormalities of liver function since symptomatology and biochemical tests do not accurately reflect morphologic changes. Chronic active hepatitis may be impossible to distinguish from chronic persistent hepatitis by clinical findings alone, and anicteric chronic active hepatitis may progress to cirrhosis, especially in postmenopausal women without significant symptomatology.23 In patients with severe clinical disease, the histologic patterns of necrosis cannot be reliably predicted without tissue sampling although the presence of vascular spiders, impressive elevation 'of SGOT and hypoalbuminemia are more frequently associated with bridging or multilobular necrosis and cirrhosis than with the less aggressive periportal disease. 37 Severe Chronic Active Hepatitis Currently, corticosteroid therapy is most clearly indicated in patients with severe disease as characterized by duration of symptoms for longer than 3 months, sustained elevations of SGOT more than 10 times normal or 5 times normal in conjunction with an elevation in gamma globulin to twice normal and chronic active hepatitis documented by liver biopsy. Survival is significantly increased by prednisone therapy in this group and is warranted in all patients with disease of this severity, even though spontaneous resolution may be anticipated in 20 per cent.42 The presence of hepatitis B surface antigenemia, ascites or cirrhosis does not preclude a satisfactory response although the consistency of the response may be reduced in patients with hepatitis B surface antigenemia or decompensated cirrhosis with endogenous encephalopathy. 36, 38 The presence of bridging or multilobular necrosis identifies a precirrhotic condition and implies a poor prognosis. Accordingly, corticosteroid therapy is justified in these patients regardless of associated clinical or biochemical findings. Our experience indicates that corticosteroid therapy will diminish the incidence of cirrhosis and death from hepatic failure. 37 Necrosis limited to the periportal area does not have the same propensity for progression as the bridging or confluent lesions; however, patients with periportal necrosis who fulfill all criteria for disease severity should be treated, since there is the potential for deterioration to more severe necrosis and since resolution of symptoms can be more rapidly achieved with treatment. 37 Serious clinical deterioration with the development of ascites and other features of hepatic failure warrants therapeutic intervention even though the efficacy of such treatment is uncertain.
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Mild Chronic Active Hepatitis
These patients undoubtedly comprise the majority with chronic active hepatitis and yet indications for therapy are not well defined. Although studies showing a beneficial effect of steroids have included such patients,8.9 no clinically controlled trial has yet been published specifically evaluating the role of prednisone in the management ofthis group. That mild disease can progress to cirrhosis is unquestioned 23 but the frequency with which this occurs and whether corticosteroids can alter progression of disease and influence survival is unknown. The risks to be balanced against the possible benefits of treatment include the likelihood of severe side effects after more than 1 year of therapy and the unknown potential for mild disease to spontaneously resolve. Extrapolating from the experience with severe chronic active hepatitis, the presence of bridging or multilobular necrosis justifies treatment. However, patients at both ends of the histologic spectrum, i.e., those having periportal necrosis or cirrhosis, require careful consideration. The best guideline to therapy is the severity of symptoms. Fatigability, arthralgias, and anorexia may be severe in patients with mild disease. Marked improvement in these symptoms may be induced by prednisone. Since major side effects of corticosteroids do not accrue until after 1 year of treatment, a 6 month trial of prednisone therapy offers an adequate assessment of its efficacy in symptomatic patients. There is no objective evidence that treatment of asymptomatic patients with mild periportal necrosis or cirrhosis with mild activity is beneficial. Special Considerations The role of corticosteroids in the management of patients with hepatitis B surface antigen CHBsAg) is controversial. Uncontrolled observations in patients unselected by uniform criteria of severity of disease suggest that HBsAg positive patients with chronic active hepatitis, if untreated, have slower progression, longer survival, and fewer relapses with jaundice than HBsAg negative patients. 4o This relatively good prognosis and the possibility that steroid-induced impairment of host defense mechanisms may perpetuate the antigenemia and ac!:ually be deleterious have been offered as caveats against corticosteroid therapy in this group. Convincing evidence, however, that prednisone facilitates disease chronicity or progression in HBsAg positive patients is lacking. In acute hepatitis B, indices of viral replication are not affected by steroid administration 20 and corticosteroid treatment has been beneficial in those antigen-positive patients who have been regularly followed, albeit in an uncontrolled fashion. 15 Currently, clinical and histologic findings remain the most secure indications for treatment. Etiologic considerations are important primarily as prognostic rather than therapeutic indices. HBsAg positive patients with severe chronic active hepatitis enter remission less frequently and treatment fails more often, than is the case with HBsAg negative patients with disease of comparable severity.38 Determination of the e-antigen status allows further characterization of HBsAg positive patients, and identifies a subgroup prone to therapeutic recalcitrance. 54 Positivity of e-antigen corre-
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lates with inability to eliminate HBsAg from the serum or produce detectable amounts of antibody to surface antigen and may reflect an impaired immune response to hepatitis B virus. Failure of conventional prednisone therapy to control disease activity may be anticipated in these patients, and higher than usual maintenance doses administered over longer periods of time may be required to suppress the disease. 38 , 54 Although a genetic predisposition to chronic active hepatitis has been postulated because of a higher than normal incidence of histocompatibility antigens (HLA1, HLA8, DW3) in these patients, 53 a definite association between genetic factors and prognosis or therapeutic responsiveness has not been established. Most recently, high levels of cell-mediated cytotoxicity have been found in those HBsAg negative patients who possess HLA1, HLA8 or DW3,55 further implicating genetic influences (possible abnormalities in the immunoregulatory genes) in the pathogenesis ofthe liver disease. The importance of cell-mediated cytotoxicity in the perpetuation of chronic active hepatitis and the effect of prednisone on this cytotoxicity require further definition, but at present these etiologic mechanisms should not deter initiation of corticosteroid therapy when clinically indicated.
HOW SHOULD TREATMENT BE IMPLEMENTED? Conventional Treatment Controlled clinical trials have demonstrated that two therapeutic regimens are of equal effectiveness in the management of severe chronic active hepatitis (Table 1),47 High initial dose prednisone followed by a fixed daily maintenance dose (Pred) or a smaller amount of prednisone in combination with a fixed daily dose of azathioprine (Comb) are each able to induce clinical, biochemical and histologic remission of severe chronic active hepatitis. Eighty per cent of patients treated with these programs enter remission between 6 and 36 months (mean 24 months) after the start of therapy. 44, 47 Combination therapy with prednisone and azathioprine is currently the treatment of choice since it is as effective as prednisone alone in controlling the liver disease and is associated with fewer side effects.47 Alternate day doses of prednisone titrated to secure resolution ofbiochemical abnormalities alleviates symptoms, increases early survival, and has fewer side effects than the Pred program but does not as reliably produce histologic remission. 47 Contraindications to Treatment Diabetes, severe osteoporosis, peptic ulcer disease, cataracts, and moderate hypertension are partial contraindications to prednisone therapy. All of these conditions may be aggravated by administration of corticosteroids, although each is manageable if such therapy is indicated. Utilization of the small dose of prednisone in combination with azathioprine is the preferred treatment for these patients.
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Table 1. Effective Treatment Schedules for Severe Chronic Active Hepatitis COMBINATION
STANDARD PREDNISONE
Drugs (daily doses) Prednisone
Azathioprine
60 mg 40mg 30 mg 20 mg None
x 1 week x 1 week x 2 weeks maintenance
30 mg 20mg 15 mg 10 mg 50 mg
x 1 week x 1 week x 2 weeks maintenance maintenance
Laboratory tests' SGOT, bilirubin, gamma globulin Leukocytes and platelets
2 weeks, 3 months, then every 6 months Every 6 months
2 weeks, 3 months, then every 6 months Weekly x 3 months, every 2 weeks x 9 months, every 3 weeks thereafter
Complete evaluation
Every 6 months""
Every 6 months·*
Indications
Leukopenia Thrombocytopenia
Preferred, since fewer sideeffects
"To monitor response and identify treatment failure **Liver biopsy if clinical and biochemical resolution
Leukopenia and thrombocytopenia are absolute contraindications to treatment with azathioprine. Prednisone alone should be administered to these patients even though the risks of corticosteroid side effects are greater than with combination therapy.42, 51 Subsequent improvement in the liver disease may be associated with normalization of leukocyte and platelet levels permitting conversion to combination therapy later. Rarely, contraindications to effective doses of both drugs are encountered. In order to utilize the lower dose schedule of prednisone, splenectomy has been suggested to improve cytopenia and permit the addition of azathioprine to the program. 3 A past history of malignancy is a relative contraindication to both drugs since oncogenic effects of the medications have been suggested. 31
Drug Side Effects Corticosteroid therapy can produce cosmetic changes (obesity, facial rounding, acne, dorsal hump and hirsutism) as well as severe debilitating complications (diabetes, hypertension, cataracts, psychosis and osteoporosis with aseptic necrosis of the hip or vertebral collapse). The frequency of side effects depends on the dose and duration of steroid administration. Eighty per cent of patients treated with prednisone for an average of2 years manifest cosmetic side effects which occur with equal frequency in all regimens containing steroids. 51 Severe complications usually develop only after 18 months oftreatment and at doses ofprednisone above 10 mg daily. They occur less often with combination therapy (10 per cent) than with prednisone in fixed daily dose (44 per cent) or in titrated alternate day doses (36 per cent), and are more common in patients with continuing hypoalbuminemia (less than 3 gm per 100 ml for
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more than 5 months) and/or hyperbilirubinemia (greater than 1.3 mg per 100 ml for more than 5 months).51 Increased serum levels of unbound corticosteroid have been demonstrated in these patients and may result from reduced availability of the albumin carrier (hypoalbuminemia) or competitive displacement of the bound drug by organic anions (hyperbilirubinemia).50 The unbound fraction of serum corticosteroid is the pharmacologically effective fraction and is most likely responsible for the development of side effects. Unfortunately the patients most in need of therapy are those most likely to suffer major steroid complications. Azathioprine may cause hepatotoxicity, gastrointestinal upset, skin rashes, leukopenia, and thrombocytopenia. Many of these complications are difficult to distinguish from those of the liver disease itself and occur in less than 10 per cent of patients receiving the low dose of 50 mg daily.47 In higher doses, an oncogenic potential has been ascribed to azathioprine and is best characterized by the development of lymphomas at a young age in individuals receiving high doses against a background of renal disease, chronic azotemia, transplantation, and general immunosuppression.31. 47 In our experience with 121 patients treated on one or more occasions for at least 6 months (mean 33 ± 2 months) and followed for over 482 patient years of observation (mean 48 ± 1 months), malignancies developed in 7 per cent after treatment periods totalling 42 ± 8 months. Carcinomas were usually low grade and operable involving the skin, bladder, penis, ovary, and liver. Patients developing neoplasms differed from others only in that they were older (60 ± 3 years versus 36 ± 2 years) and at a naturally higher risk for malignancy.ll The oncogenic property of azathioprine has not been established while the life-saving effect of the medication in combination with prednisone remains secure.
Duration of Treatment Therapy is continued until an endpoint is reached comprising full remission of the disease, serious drug toxicity, or treatment failure and death. Remission has been arbitrarily defined as complete absence of symptoms, resolution of all biochemical abnormalities except for trivial (less than twice normal) elevation of SGOT, and disappearance of morphologic features of aggressive disease activity (piecemeal necrosis). The presence of cirrhosis or inflammation indistinguishable from nonspecific or chronic persistent hepatitis does not preclude remission. Symptoms and clinical features of disease activity usually resolve within 6 months after initiation of treatment. Abnormal biochemical and immunoserologic studies normalize after 1 year, and by 2 years 70 per cent of patients demonstrate histologic resolution. Only a minority of patients require therapy for 3 years or more. 44 Remission must be established by liver biopsy since clinical and biochemical abnormalities commonly resolve completely during therapy while successive liver biopsies continue to show significant disease activity. When remission is achieved, medications are slowly discontinued by tapering dosages over a 6 week period (Table 2). Liver function tests are monitored at 3 week intervals for the first 12 weeks and at 6 month
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Table 2. Gradual Discontinuation of Conventional Therapy STANDARD PREDNISONE
Drugs (daily doses) Prednisone
Azathioprine
Laboratory tests* SCOT, bilirubin, gamma globulin Leukocytes and platelets Complete evaluation with liver biopsy
15 mg 10 mg 5 mg 2.5 mg Off None
x x x x
1 1 2 2
week week weeks weeks
COMBINATION
7.5 mg x 2 weeks 5 mg x 2 weeks 2.5 mg x 2 weeks Off 50 mg x 3 weeks 25 mg x 3 weeks Off
3, 6, 9, 12 weeks, then every 6 months As necessary
3, 6, 9, 12 weeks, then every 6 months As necessary
Every 6 months until normal biopsy or two consecutive biopsies showing chronic persistent hepatitis, then annually
Every 6 months until normal biopsy or two consecutive biopsies showing chronic persistent hepatitis, then annually
'To document continuing remission and identify relapse
intervals thereafter. The patient is evaluated every 6 months until a normal liver biopsy or two consecutive biopsies showing chronic persistent hepatitis are obtained and then at annual intervals to ensure against delayed relapse. Complete disappearance of disease activity, including all histologic features of chronic inflammation, occurs slowly, eventuating in 12 per cent of patients with severe disease after almost 4% years offollow-up.1° Normal hepatic architecture or totally inactive cirrhosis is usually documented 1% years after medication has been discontinued, and in many patients (43 per cent) occurs only after multiple courses of treatment. Patients whose histologic findings return entirely to normal have not had a relapse as yet after up to 4% years of further follow-up (mean 2 years) and may indeed by "cured."lo Relapse, however, is common in patients with cirrhosis even if the inflammatory component of their disease is inapparent on liver biopsy. Manifestations of serious drug toxicity or deterioration of the liver disease on standard therapy (treatment failure) justify termination of conventional treatment. Prompt initiation of other measures designed to control these special problems is necessary.
Treatment Problems FAIL URE. Approximately 20 per cent of patients with severe chronic active hepatitis fail to improve on conventional therapy and require higher than usual doses of medication for control. Treatment failure has been arbitrarily characterized as the development of endogenous encephalopathy, increasing ascites, or biochemical deterioration with increments of at least 67 per cent in the serum bilirubin and/or SGOT
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abnormalities while on therapy. Failure usually develops within 2 months after initiation of treatment but may occur 8 or more months later.36 The majority will respond if their medication is increased to 60 mg of prednisone daily or 30 mg of prednisone in combination with 150 mg of azathioprine daily (Table 3). Improvement usually follows within 6 weeks and the doses of medication can then be reduced at monthly intervals by 10 mg decrements of prednisone and, when applicable, 50 mg decrements of azathioprine until conventional maintenance levels are reached. Dose reduction is indicated by at least a 33 per cent improvement in SGOT during a 4 week period of observation. 36 DRUG TOXICITY. The development of serious drug toxicity warrants modification or discontinuation of therapy. If prednisone alone has been administered, conversion to combination therapy with low dose prednisone should be attempted. Azathioprine toxicity justifies dose reduction or elimination. If neither drug can be given in its customary dosage, administration of prednisone, 10 mg daily or 20 mg on alternate days, will usually prevent clinical and biochemical progression of the disease without aggravating already established side effects. SLOW RESPONSE. Patients may improve clinically and biochemically on conventional therapy but not achieve complete remission after more than 2 years of continuous treatment. In our experience, up to 24 per cent of patients do not reach a therapeutic endpoint after a mean period of treatment of26 months. The likelihood of ultimate remission in these patients is not fully defined and whether increments in their medication will hasten resolution is unstudied. The majority are completely asymptomatic but require continuous medication and follow-up. In each patient, possible reasons for the slow response must be carefully investigated. Compliance to the therapeutic program should be evaluated and a detailed drug history taken. The accuracy of the original diagnosis should Table 3. Management of Treatment Failure HIGH PREDNISONE
Drugs (daily doses) Prednisone Azathioprine
HIGH COMBINATION
60mg None
30mg 150mg
Monthly
Monthly
Every 6 months
Weekly
Dose decrements' Prednisone Azathioprine
10mg/month None
10 mg/month 50mg/month
Complete evaluation Liver biopsy
Every 6 months If needed diagnostically
Every 6 months If needed diagnostically
Laboratory tests SGOT, bilirubin, gamma globulin Leukocytes and platelets
*For each monthly improvement of SGOT by 33 per cent until maintenance level is achieved
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be re-established. Unless serious drug toxicities intervene, therapy should be continued unaltered. RELAPSE. Fifty per cent of patients with severe chronic active hepatitis who enter remission suffer relapse within 6 months after discontinuation of medication and require another course of therapy. 44, 47 Remission sustained for longer than 6 months is associated with an 8 per cent relapse rate. Fatigue, arthralgias, and elevation of SGOT to at least three-fold normal invariably indicate histologic deterioration. In 10 per cent of patients, however, histologic relapse occurs without characteristic clinical and biochemical signs, emphasizing the need for follow-up liver biopsy within the first year of remission. 44 Reinstitution of therapy is usually followed by prompt improvement in all indices of activity and the likelihood of the patient again achieving remission is 80 per cent. 44 , 47 No patients who have relapsed have failed to respond to subsequent courses of therapy. The relapse rate after one or more remissions remains constant at 50 per cent. The two major reasons for an unsatisfactory response to therapy are wrong diagnosis and inadequate treatment. All patients who respond poorly to therapy must be re-evaluated to exclude primary biliary cirrhosis, Wilson's disease, alpha. antitrypsin deficiency, hepatic carcinoma, and drug-induced liver disease. If confirmed, these diagnoses may indicate the need for another more effective form of therapy. Lower than recommended doses of prednisone or too rapid, arbitrary alterations in medication most commonly account for an unsuccessful resolution of activity. Institution of a therapeutic program of proven efficacy as outlined in Table 1 will usually control the disease process. Recent studies indicate that hepatic conversion of prednisone to its active metabolite, prednisolone, remains adequate even in severe disease. 39 Failure of response cannot be attributed to inadequate utilization of the drug and administration of prednisolone instead of prednisone is not necessary. Novel Treatments Several new approaches to the management of chronic active hepatitis are currently being evaluated. INTERFERON. This is a cellular protein which inhibits viral replication at the level of transcription. Although optimum protection requires cellular exposure to interferon before viral infection, perpetuation of chronic disease implies a steady stream of viruses continuously infecting previously uninvolved cells. Patients with acute or chronic hepatitis B disease do not produce interferon in amounts normally encountered after other viral infections, suggesting that the B virus is a poor inducer of endogenous interferon production.1 4 Administration of exogenous interferon to these patients or stimulation of endogenous production may facilitate control of disease activity. Preliminary studies in animals and humans chronically infected with hepatitis B virus have shown immediate and reproducible reduction by interferon of indices of viral replication. 14, 19, 32 Definite improvements, however, in liver function tests and histology have not been demonstrated during short periods of administration. Suppression of viral replication is
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only transient and the frequency ofhematologic effects, febrile reactions and hepatotoxicity, observed in animal studies,32 require further elucidation. TRANSFER FACTOR. Correction of a possible defect in cell-mediated immunity by administration of transfer factor has been attempted in one patient with HBsAg positive chronic active hepatitis. 48 Although cellmediated immunity, as measured by lymphocyte response to HBsAg, was enhanced, there was no correlation with clinical course or appearance of viral markers. Additional studies are needed to evaluate the full potential of this approach. PENICILLAMINE. This drug has had a vast uncontrolled experience in Europe where its administration has been associated with an improvement in the biochemical abnormalities of chronic active hepatitis. 25 Inhibition of collagen cross-linkage has been demonstrated in animal studies and the potential antifibroblastic action of penicillamine might prove beneficial in the management of precirrhotic conditions. Such an influence has been suggested in controlled studies involving alcoholic liver disease, although overall survival was unaffected by the drug. 34 Currently, the experience in chronic active hepatitis indicates only an anti-inflammatory effect of penicillamine which may be attributable to cupresis. Carefully controlled trials are obviously necessary. Its greatest benefit may be in those patients with chronic active hepatitis and copper overload 26 or as an adjunct to corticosteroids in the management of treatment failure. COLCHICINE. This drug has also generated interest as a potential antifibrogenic agent. Controlled clinical trials in patients with cirrhosis have yielded only preliminary, inconclusive results. An antiinflammatory action is apparent from improvements in biochemical studies but beneficial effects on histology and early survival have yet to be demonstrated. 22 The development of primary hepatic tumors in some of the patients treated with colchicine emphasizes the need for continued careful evaluation of this drug in an investigational setting.
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39. Schalm, S. W., Summerskill, W. H. J., and Go, V. L. W.: Prednisone for chronic active liver disease: pharmacokinetics, including conversion to prednisolone. Gastroenterology, 72:910-913, 1977. 40. Sherlock, S.: Chronic hepatitis. Gut, 15:581-597,1974. 41. Soloway, R. D., Baggenstoss, A. H., Schoenfield, L. J., et al.: Observer error and sampling variability tested in evaluation of hepatitis and cirrhosis by liver biopsy. Amer. J. Dig. Dis., 16:1082-1086, 1971. 42. Soloway, R. D., Summerskill, W. H. J., Baggenstoss, A. H., et al.: Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis. Gastroenterology, 63:820-833, 1972. 43. Sternleib, 1., and Scheinberg, 1. M.: Chronic hepatitis as a first manifestation of Wilson's disease. Ann. Intern. Med., 76:59-64, 1972. 44. Summerskill, W. H. J.: Chronic active liver disease re-examined: prognosis hopeful. Gastroenterology, 66:450-464, 1974. 45. Summerskill, W. H. J.: Chronic hepatitis-1975. Editorial. Amer. J. Dig. Dis., 20:10871090, 1975. 46. Summerskill, W. H. J., Ammon, H. V., and Baggenstoss, A. H.: Treatment of chronic hepatitis. In Schaffner, F., Shedock, S., and Leevy, C. M., eds.: The Liver and its Diseases. New York, International Medical Book Corp., 1974, pp. 216-226. 47. Summerskill, W. H. J., Korman, M. G., Ammon,H. V., etal.: Prednisone for chronic active liver disease: dose titration, standard dose, and combination with azathioprine compared. Gut, 16:876-883, 1975. 48. Tong, M. J., Nystrom, J. S., Redeker, A. G., et al.: Failure of transfer-factor therapy in chronic active type B hepatitis. New Eng. J. Med., 295:209-211,1976. 49. Tysell, J. E., and Knauer, C. M.: Hepatitis induced by methyldopa (Aldomet). Amer. J. Dig. Dis., 16:849-855, 1971. 50. Uribe, M., Summers kill, W. H. J., Go, V. L. W.: Why hyperbilirubinemia and hypoalbuminemia predispose to steroid side effects during treatment of chronic active liver disease. Abstract. Gastroenterology, 72: 1143, 1977. 51. Uribe, M., Wolf, A. M., and Summerskill, W. H. J.: Steroid side effects during therapy of chronic active liver disease (CALD): what to expect. Abstract. Gastroenterology, 71 :932, 1976. 52. Vido, 1., Selmair, H., Wildhirt, E., et al.: Zur Prognose derchronischen Hepatitis. Deutsche Med. Wschr., 94:2215-2220, 1969. 53. Vogten, A. J. M., Schalm, S. W., Summerskill, W. H. J., et al.: Prevalence ofDW3 determinant in chronic active liver disease: relationship to etiology and response to treatment. Abstract. Gastroenterology, 70:996, 1976. 54. Vogten, A. J. M., Schalm, S. W., Summerskill, W. H. J., et al.: Behavior ofe-antigen and antibody during chronic active liver disease. Lancet, 2:126-128, 1976. 55. Vogten, A. J. M., Summerskill, W. H. J., Shorter, R. G., et al.: Evidence for a genetic contribution to cell mediated cytotoxicity in chronic active liver disease. Abstract. Gastroenterology, 72:1145, 1977. 56. Ware, A. J., Eigenbrodt, E. H., Combes, B.: Prognostic significance of subacute hepatic necrosis in acute hepatitis. Gastroenterology, 68:519-524, 1975. Gastroenterology Unit St. Mary's Hospital Rochester, Minnesota 55901
