Chronic hepatitis: Pathogenesis and treatment

CHRONIC

HEPATITIS: PATkEOGENESIS AND TREATMENT

ABSTRACT.-Current therapies for chronic viral hepatitis, autoimmune “lupofd” chronic active hepatitis, and drug-induced chronic hepatitis are discussed in the context of recent advances in our understanding of the pathophysiology of chronic active liver disease. Accurate diagnosis is the cornerstone of proper treatment; the limitations and pitfalls of conventional techniques are discussed. Current theories of the pathogenesis of chronic hepatitis B are reviewed to provide a framework for the use of antiviral drugs. Data from the early results of therapy with adenine arabinoside, acyclovir, and immunomodtdatory agents are reviewed, and the theoretical basis for the use of alpha-interferon as well as prelimmary data supporting its efficacy is presented. Strategies for the treatment of chronic delta hepatitis and chronic non-A, non-B viral hepatitis are discussed as well. The immunological changes associated with autoimmune chronic active hepatftis are described to help define those patients with chronic active hepadtis who are likely to respond to immunosuppressive therapy. The reaogniaed haaards of long-term cordcosteroid therapy are indicated and guidelines for the management of these patients are suggested. Chronic drug-induced liver disease will usually improve with cessation of the offending agent. An ap preach to the patient with suspected drug-induced chronic hepatitis is indicated. Finally, the role of liver transplantation is mentioned as the ultimate treatment modality available for endstage liver disease.

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IN BFUEF Persistent inflammation of the liver for a minimum of six months is recognized as chronic hepatitis. Such a process can be perpetuated by several pathogenetic mechanisms, including several viral infections, autoimmune processes, and certain drugs. The morphologic expression of chronic hepatitis will usually be categorized as chronic persistent hepatitis, a generally benign variant, or chronic active hepatitis, a form that is associated with progressive liver dysfunction and death. Less commonly seen lesions are the chronic lobular hepatitis, in which hepatic inflammation may last for years without significant scar formation, or the lesion of chronic hepatitis with bile duct destruction, in which features of cholestasis and eventual biliary cirrhosis predominate over the initially mild parenchymal injury. Chronic liver injury will usually produce an alteration of hepatic blood flow through “capillarization” of the sinusoids, collagen deposition in the Space of Disse, and regenerative nodule formation. Hepatic atrophy results and liver failure is the ultimate outcome if therapy is unsuccessful. The goals of therapy are to reduce or eliminate the offending agent, to minimize the reactive changes that lead to cirrhosis, and to treat the metabolic effects of reduced liver function. The focus of this monograph is to review recent advances in the pathogenesis of chronic viral hepatitis and autoimmune chronic active hepatitis and the therapies that appear promising for these conditions. Chronic drug-induced liver disease is discussed briefly as well. Hepatitis B infection resolves spontaneously in 90% of cases contracted by adults with normal immune systems. In the remainder, as well as the vast majority of infants who contract the disease at parturition, a chronic carrier state is established in which infected liver cells are somehow protected from immune cytolysis. Thomas and colleagues have proposed that the conjoint expression of hepatitis B core antigen or hepatitis B e antigen with HLA-I antigen on the surface of infected hepatocytes is the receptor that allows sensitized cytotoxic T-lymphocytes to bind to and destroy the virus reservoir. Their model suggests that antibody to the viral proteins, antiHBc, or anti-HBe, may promote a carrier state by interfering with Tcell binding, thus allowing infected hepatocytes to persist in viral production. Additional modulation of the immune system may permit tolerance to the viral proteins to develop in the carrier infants. In keeping with this model, antiviral drugs such as adenine arabinoside, adenine arabinoside monophosphate, and acyclovir, which readily suppress intracellular viral replication, are relatively ineffective in clearing the infection because they do not eliminate the infected cells, and viral replication is resumed shortly after therapy is 114

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stopped. Modulation of the immune response by a short course of prednisone will occasionally induce clearance of the cohort of infected cells after steroid withdrawal. The alpha-interferons appear to be the most promising agents because of their multiple effects, which include suppression of the intracellular viral replication and enhancement of surface HLA-I antigen display. The latter effect promotes destruction of the infected liver cells and produces a cure in approximately 50% of adult-acquired, nonimmunosuppressed patients. Large-scale trials are underway to evaluate the efficacy of this treatment. Empiric trials of interferon for chronic delta hepatitis and chronic non-A, non-B viral hepatitis have suggested that these conditions may respond favorably to the drug, through undefined mechanisms. Autoimmune chronic active hepatitis is most likely caused by an aberrant immune response against normal hepatocytes. Numerous antibodies against cell membrane components, intracellular and intranuclear proteins have been described, but none seems to fill the requirements as the specific target antigen. Whatever the target antigen and the pathogenesis, the use of immunosuppression with corticosteroids, supplemented if necessary by azathioprine, will usually reduce liver inflammation and often leads to a sustained improvement in clinical condition. Unfortunately, many apparent responders will progress to cirrhosis, perhaps because of the advanced degree of parenchymal damage at the outset of therapy. Guidelines for the management of such patients are presented. Finally, the role of drug injury in the spectrum of chronic hepatitis is discussed. The identification of all drugs used by a patient found to have chronic hepatitis is essential, and potential offenders must be eliminated from the patient’s regimen. Resolution of hepatic inflammation will generally follow within six to eight weeks. Liver transplantation has evolved from an experimental dream to a practical treatment for advanced, refractory chronic liver disease. A brief discussion of the role of this drastic treatment concludes the comments on the pathogenesis and treatment of chronic hepatitis.

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John A. Payne, M.D., was graduated from Hamilton ColZege and the University of Rochester School of Medicine and Dentistry. He served an internship and residency in internal medicine at Rush-Presbyterian-St. Luke’s Medical Center and completed a fellowship in hepatology under the tutelage of Dr. A. William Holmes at the same institution. He completed his training in gastroenterology with Dr. John Galambos at Emory University before returning to Rush as a faculty member. He has been Chief of the Liver Unit since 1975 and is currently Associate Professor of Medicine. 116

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CHRONIC

HEPATITIS: PATHOGENESIS AND TREATMENT

The definition of chronic hepatitis is broadly constituted as any condition that causes persistent hepatic inflammation for a minimum of six months. The inflammatory reaction is due to direct injury caused by the inciting agent, an indirect immune response to the agent, or a combination of the two, and usually results in hepatic scarring, cirrhosis, and hepatic failure if spontaneous remission or therapeutic intervention does not occur. Once there has been sufficient permanent disturbance of the hepatic blood flow to impair parenchymal function, progressive atrophy must inevitably lead to failure. For many patients, this progression is silent and unappreciated until the liver reserve is exhausted and the signs and symptoms of decompensated liver disease become evident. The purpose of this monagraph is to review the current status of therapy for chronic inflammatory liver conditions, each capable of presenting in the asymptomatic patient as abnormalities in commonly performed serum chemistries. Hopefully the review will remind ourselves, in this era of cost-containment, of the importance of establishing a diagnosis to permit directed, specific therapy before liver failure occurs. DEFINITION

OF CHRONIC

HEPATITIS

Chronic hepatitis is defined, by convention, as a state of hepatic inflammation lasting a minimum of six months.* The degree of inflammation, measured by clinical, biochemical, and histological standards, is generally modest, with fluctuating intensity for periods of years to decades, but the occasional case may present as a fulminant hepatitis with rapid decompensation. The major untoward effect of the chronic inflammation is the promotion of collagen deposition in the perisinusoidal space, the space of Disse.’ A second complication is the production of a basement membrane by the sinusoidal lining cells, i.e., “capillarization,” converting the uniquely fenestrated cells to an apparent barrier to the exchange of metabolites and nutrients between sinusoidal lumen and parenchymal DM,

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cells3 (Fig 1). Both changes may contribute to the earliest stages of portal hypertension. A final alteration of the hepatic circulation occurs when regenerative nodules form in response to inflammatory destruction of parenchyma and atrophy of cells due to the capillarization of the sinusoids. As a consequence of the loss of sinusoids, the stiffening of the sinusoidal wall, and disruption of the local regulatory mechanisms of blood flow, portal hypertension develops and leads to diversion of blood from the liver. The resultant disruption of blood flow to the liver parenchyma inevitably leads to impaired hepatic clearance of metabolites, toxins, and nutrients, with a gradual reduction in hepatic function over time. The elevated levels of

FIG 1. Chronic active liver disease. Hepatic sinusoid outlined by an electron dense basal lamina (arrow) between hepatocyte (f-/j and endothelial cell (En) (~28,500). (From Bianchi FB, Biagini G, Ballardini G, et al: Basement membrane production by hepatocytes in chronic liver disease. Hepatology 1984; 4(2):1167-l 172. Used by permission.) 118

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serum glucagon commonly seen in cirrhotic patients probably reflect this impaired extraction, and contribute to perpetuation of the process by virtue of the vasodilatory effect of the hormone, an effect that may be instrumental in the development of portosystemic shunts .4 The general goals of therapy of chronic hepatitis are to reduce or eliminate the inciting agent, to minimize the reactive changes that lead to cirrhosis, and to anticipate and treat the metabolic effects of reduced liver function. When we fail in these efforts, liver transplantation may offer a reprieve, but clearly our patients’ best interests are served by accurate diagnosis and early intervention whenever feasible. Exciting developments in the virology and immunologv of chronic hepatitis have opened new avenues of therapeutic approach. Improved techniques of cell separation and culture, as well as sophisticated morphologic studies, have enhanced our knowledge of the biology of the stromal cells of the liver; from these insights may come the key to controlling hepatic fibrogenesis. For all who have experienced the frustration of our limited ability to palliate the suffering of a patient with advanced cirrhosis, the prospect of significant intervention and even possible reversal is to be greeted with greatest enthusiasm! PATHOLOGY

OF CHRONIC

HEPATITIS

The hallmark of chronic hepatitis is the presence of mononuclear cells infiltrating the portal triads on liver biopsy. Additional features include variable amounts of portal fibrosis, ductular injury, periportal inflammation (piecemeal necrosis), and alterations of the parenchyma with lobular inflammation, bridging necrosis or fibrosis, and eventual development of regenerative nodules. These changes are somewhat nonspecific and require an understanding of the duration of illness as well as supporting radiological, biochemical, and serologic data before a diagnosis can be established. The transition from acute to chronic hepatitis is indistinct. Features such as periportal inflammation and bridging necrosis are probably present quite often in acute hepatitis, only to resolve as liver regeneration and healing take place.5 Persistence of these features, with the added formation of scar tissue, indicates an inability of the liver to regenerate and heal, and the longer such features are found after an acute insult, the more significant they become.” Two major variants of chronic hepatitis are recognized: chronic persistent hepatitis and chronic active hepatitis.* In addition, unusual forms have been identified: chronic hepatitis with bile duct destruction and chronic lobular hepatitis. Chronic persistent hepatitis is characterized by a mononuclear DM,

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cellular infiltrate that is confined to the portal triads.* Occasionally, dramatic lymphoid follicles may be seen within the expanded portal tracts. Lobular inflammation is minimal, and scarring is sparse. An exceptional case may progress to chronic active hepatitis and cirrhosis, but the vast majority of patients will have a benign resolution of the hepatitis over a period of years.187-10 When hepatitis B is the etiologic agent, spontaneous clearance of the replicating virus is marked by an increase in serum transaminases and an increase in lobular inflammation, followed by a resolution of hepatic inflammation with residual scarring or cirrhosis indicating the extent of prior damage .I1 Continued circulation of hepatitis B surface antigen (HBsAg) after clearance of the infection indicates that viral integration has occurred. Chronic active hepatitis is a progressive lesion associated with eventual cirrhosis, liver failure, and death. Mild disease, without cirrhosis, lobular collapse, bridging hepatic necrosis, or florid parenchymal inflammation, may resolve or persist without clinical detriment, but severe disease, indicated by the presence of one of the above features, leads to death for nearly half the patients within a few years if treatment is not undertaken.l’ Bile duct injury may be seen in chronic persistent and chronic to the overall active hepatitis .13,I4 In general, the lesion is incidental degree of hepatic inflammation, but in occasional patients, portends a poor prognosis with severe cholestatic features and progression to cirrhosis. When widespread, the histologic differentiation from primary biliary cirrhosis can be extremely difficult. In these cases, the clinician is forced to rely upon serologic findings such as circulating antimitochondrial antibody or elevated IgM antibodies to distinguish primary biliary cirrhosis from chronic hepatitis with bile duct destruction. Treatment is supportive, with care being taken to supplement fat-soluble vitamins, calcium, and antipruritic medications as required. Chronic lobular hepatitis, on the other hand, does not appear to have a bad effect on prognosis?5-17 Patients are usually anicteric and mildly symptomatic, and since there is no tendency to progress to cirrhosis, therapeutic intervention is not required. In general, such patients must undergo at least two biopsies to establish the diagnosis, and may be candidates for antiviral therapy in the future. If hepatitis B is the etiologic agent, then appropriate counseling to restrict the transmission of the disease is indicated. The expression of hepatic injury generally does not indicate etiology. It does serve to indicate the extent of injury and likelihood of progression, and probably reflects the overriding role of immune mechanisms in the pathogenesis of chronic hepatitis. In addition, supportive therapy can be appropriately modified if, for instance, 120

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significant cholestasis should be appreciated. Once a diagnosis has been established, there seems to be little rationale for frequent follow-up biopsies unless the patient is participating in a clinical trial or a significant change in clinical status occurs. The liver biopsy is generally reliable in assessing the pattern of inflammation. Occasionally, through sampling error, intercurrent disease, or change in immune response, the histologic features will deteriorate from chronic persistent hepatitis to chronic active hepatitis or cirrhosis, but changes are more commonly seen in a favorable way when patients respond to therapy. Intriguing work by Zajicek and colleaguesl’ has indicated that liver regeneration occurs in the periportal zone of the liver acinus, with subsequent migration of the parenchymal cells and adjacent sinusoidal lining cells and macrophages toward the central veins, where the aged cells are eliminated. The significant lesions of chronic hepatitis that have a serious prognosis are those that affect the periportal zone-piecemeal necrosis and “sleeve necrosis.“1 Destruction of the progenitor cells must inevitably lead to atrophy and liver failure, processes usually attributed to altered hepatic blood flow, and as the pathogenesis of the periportal inflammation is understood, it may become possible to retard or prevent chronic liver failure. The timing of the liver biopsy is important. For patients with protracted viral hepatitis, biopsy should be deferred for at least six months in cases of hepatitis B, and for nine to 12 months in cases of non-A, non-B viral disease. Hepatitis A has never been linked with chronic hepatitis, so that biopsy would be done in this condition to evaluate intercurrent disease. A disease that may masquerade as chronic hepatitis is primary sclerosing cholangitis. Two studies have shown that liver biopsy of primary sclerosing cholangitis may often have the appearance of chronic hepatitis or cirrhosis, and that endoscopic retrograde cholangiopancreatography (ERCP) is necessary to establish the correct diagnosis.*‘, ” The helpful features of periductal fibrosis and inflammation may be subtle or absent. An argument could be made for evaluating most patients with unexplained liver inflammation with ERCP, but the yield will be enhanced if restricted to those patients with cholestatic chronic liver disease, inflammatory bowel disease, or young adult males with unexplained chronic hepatitis or cirrhosis. The discovery of patients with classic radiologic and histologic changes in the absence of biochemical alteration attests to the insidious nature of the sclerosing process.2’ It has been fashionable for some physicians to minimize the use of percutaneous liver biopsy as a diagnostic tool. Certainly the typed reports of our radiologic colleagues have an authoritative air and at times seem to provide histologic evaluations. The pressures from DM,

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governmental agencies, “health maintenance” organizations, and insurance carriers to minimize health care also encourage the passive observation of asymptomatic elevations of serum transaminases. For the patient with treatable disease such as Wilson’s disease, hemachromatosis, chronic viral hepatitis, alcoholic liver disease, drug-induced liver disease, porphyria cutanea tarda, obstructive biliary tract lesions, fatty liver, primary biliary cirrhosis, sclerosing cholangitis, and numerous other conditions, early, accurate diagnosis is most easily achieved by liver biopsy supported by appropriate serologic, biochemical, and radiologic studies. DLAGNOSZS It is evident that patients with chronic liver disease will be seen for medical attention because of symptomatic illness or routine screening programs that discover serum enzyme abnormalities. Evaluation of the asymptomatic patient with persistent liver inflammation includes a search for potentially offending drugs, infection with hepatitis B and D, cytomegalovirus, Epstein-Barr virus, Wilson’s disease (in patients younger than 35 years with inapparent neurological disease), alpha-,-antitrypsin deficiency, sclerosing cholangitis, granulomatous liver disease, fatty liver, biliary tract disease, alcoholic liver disease, hemachromatosis, and malignancy. Should the patient have symptomatic illness with historical evidence of autoimmune disorders, or physical findings of jaundice, splenomegaly, ascites, spider telangiectasias, palmar erythema, i.e., evidence of chronic liver disease, then the need to demonstrate illness of six months’ duration before obtaining a liver biopsy is set aside, for if the patient has deteriorating autoimmune or hepatitis B hepatitis, early therapeutic intervention may produce a substantial improvement in wellbeing. The decision to treat is easiest in patients with documented chronic hepatitis B or the female patient with hyperglobulinemia and high titers of autoantibodies, whose liver biopsy shows flamboyant piecemeal necrosis and bridging necrosis with early collapse. If the patient has substantial hyperglobulinemia without the standard autoantibodies, treatment may still be effective, and a diagnosis of “steroid-responsive” chronic hepatitis can be established. The arbitrary criteria developed for the Mayo Clinic trials to identify patients with severe chronic liver disease, namely, serum transaminases elevated fivefold and serum globulins elevated twofold, are useful in defining patients with enough liver inflammation to warrant a trial of immunosuppression. In practice, the need for such an empiric trial is unusual, and the risk to the patient from steroid side effects is acceptable, for responders will usually show clinical and biochemical improvement within three to six weeks. 122

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PATHOGENESIS

HEPATITIS

AND TREATMENT

OF CHRONIC

HEPATITIS

B VIRUS

The prototype of chronic hepatitis is the lesion produced by chronic hepatitis B viral infection. Approximately 10% of patients infected with this virus will develop chronic infection, with approximately half progressing to cirrhosis.” Integration of the viral genome occurs at random and may be causally related to the development of hepatocellular carcinoma,23 but the relationship of the phenomena of genetic integration and of inflammatory response to chronic infection to tumor formation has not been established. Clearly, HBV carriers without inflammatory response can develop hepatocellular carcinoma, so the processes must be separable. Following entry into the bloodstream, the hepatitis B virus is taken up by hepatocytes, possibly by means of the proposed polymerized human albumin receptor (pHSA-19. The viral genome, a partially double-stranded DNA capable of producing a limited number of proteins, is transported to the hepatocyte nucleus. Viral replication is enabled by HBV DNA polymerase, and various forms of DNA that reflect the replication process can be identified in liver tissue and circulating plasma.24 Coincidently, mRNA drives the production of the viral proteins, surface antigen (HBsAg), core antigen (HBcAg), and DNA polymerase. Additional polypeptides are formed, but whether these proteins have biologic significance is currently under study. Following assembly of the complete virus, it is extruded through the sinusoidal cell membrane into the circulation. Viral protein manufacture is not efficiently coordinated; a tremendous excess of HBsAg is produced that has no direct infectious ability, but serves as a handy marker for HBV infection. HBcAg is also produced in excess, but to a lesser degree. This protein spontaneously converts to e antigen (HBeAg) when released to the plasma unless contained within the HBsAg.” The various HBV proteins and molecular forms of replicating DNA can be detected within hepatocytes and do not appear to cause cell damage. The currently favored hypothesis is that hepatocyte injury is caused by T-lymphocytes, sensitized to HBcAg and/or HBeAg, when the HBcAgHBeAg is present on the hepatocyte surface adjacent to native human leukocyte antigen (HLA).Zfi The combined presentation of HLA antigen and core/e antigen allows the T-lymphocyte to adhere to the hepatocyte and rupture the cell membrane by release of lysozymes and other lymphokines (Fig 2). The fascinating phenomenon of chronic HBV infection is under study. In general, most carriers have normal immune function when subjected to standard stimuli. Proposed mechanisms invoke the possible modulation of viral antigen expression by antibody or an DM,

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i)LYSlS OF HEPATOCYES SUPPORTING HRV REPLICATION

iilLYSlS OF WWlCylES CONTAIN INC INTEGRAL

HBV

iii)FAlUJRE OF LYSIS OF HEMTOCYTES CONTAINING INTEGRATED HRV

Evasion d immune lyrir

Malignant Iranslermatim Tc * Cyiotoaic T cell TH * Helper 1 cell Ts * Suppressor 1 cell fl * 0 * A ’

A

HLA class 1 protein HBV relaled ant&en displayed during regkatim HRV rehM antigm diwhyed m cells containing integrata Intqdim d HRV sequence into live genome

HBV

FIG 2. Hypothetical immunopathogenesis of liver disease in chronic HBV infection. Cytotoxic Tcells cause immune lysis of hepatocytes on which viral antigens are displayed in association with HLA proteins. Panels i and ii show lysis by T-lymphocytes of hepatocytes supporting HBV replication or containing integrated HBV. In panel iii, some hepatocytes containing integrated HBV, in which (a) the viral antigens are not displayed in association with HLA proteins or (b) are not expressed at all, evade immune lysis, continue to proliferate, and may subsequently undergo malignant transformation. (From Thomas HC, Pignatelli M, Goodall A, et al: Immunological mechanisms of cell lysis in hepatitis B virus infection. Semin Liver Dis 1984; 4(26):42. Used by permission.)

idiosyncratic variance in the membrane display of HBeA#HBcAg in juxtaposition with the HLA antigen. Clearly, patients with impaired immune activity, whether due to drugs or disease, would be less able to eliminate the MS and therefore have a milder liver injury. While there may be a group of patients with advanced liver disease where promotion of the carrier state might be beneficial, current evidence suggests that immune suppression with prednisone increases mortality because the risks of steroid therapy outweigh any potential benefits !’ Thomas and colleagues have proposed that the presence of “excess” anti-HBc, whether derived from a vigorous native response or transmitted from mother to fetus across the placenta, may coat the HBcAg expressed at the cell surface of infected hepatocytes, effectively blocking the binding of cytolytic T-cells and promoting the persistence of infection” (Fig 3). Supporting data for this view are 124

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CARRIER HDTHER (HEs+ve,HBeAg+ve)

NEONATE

PLACENTA

BLOOD

LIVER

BLOOD

Anti nit modu4eation

Induction of sumressors

0

HBV HBsAg (2011~1) IgC Anti-IlBc Cytotoxic T cells

0 -

Tc

sensitiscd

to HBcAg

FIG 3. Postulated mechanisms of neonatal centa into the neonatal circulation. maternal IgG blocks recognition of to soluble virus protein (HBe) may specific suppressor cells inhibiting AML, Scully LJ, et al: Approaches liver disease. Semin Liver Dis 1986;

carrier state. Maternal IgG anti-HE% crosses the plaHBV infection of the neonatal liver is thus facilitated as virus-infected cells by cytotoxic T-cells. Early exposure induce a state of antigenic tolerance to the virus with the host defense mechanism. (From Thomas HC, Lever to the treatment of hepatitis B virus and delta-related 6(28):35. Used by permission.)

found in the early and prompt elevation in IgM anti-HBc in patients destined to become carriersz9 and the effects of giving exogenous anti-HBc to animals at the time of HBV inoculation.” This notion is also consistent with the observation that although anti-HBs, whether induced by previous infection or vaccination, or given as hyperimmune globulin, will usually prevent HBV infection, it has little effect on the course once infection has been established.30 ANTNIRAL

THERAPY

FOR

HEPATITIS

B VIRUS

Antiviral therapy can be achieved by preventing cell entry by the virus, disrupting viral nucleic acid synthesis, destroying infected cells, and interfering with viral assembly. These effects may be produced by drug action on cellular metabolism or through modification of the immune system, Through the combined efforts of reDM,

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searchers who have defined the mechanisms of hepatitis B viral infection and replication on the one hand, and have demonstrated the complexity of the host response on the other, a composite picture of hepatitis B infection has emerged that indicates several avenues of therapeutic intervention. Early efforts at modulating the global immune response with nonspecific agents such as levamisole,31 transfer factor,32 and corticosteroids,27, 33 while demonstrating that immune modulation clearly affects the severity of disease expression, also indicated that viral reproduction and hepatic inflammation were inversely correlated. Furthermore, studies have indicated that patients vary in ability to respond to treatment because of inherent genetic factors and coincidental infections.” Finally, one must appreciate the limitations of characterizing the patient’s status solely by the use of serologic markers for hepatitis B, for these markers do not indicate whether viral antigens are originating from cells with integrated viral DNA, episomal DNA, or a combination of the two populations.25 The success of therapy in HBV infections can be judged in two dimensions: eradication of the virus and healing of the liver. At present, the detection of circulating HBV DNA by methods sensitive enough to identify minute numbers of virus represent the “gold standard” of virus detection. These assays will have to be adapted for general clinical use as a necessary condition for widespread use of antiviral agents. The current reliance on HBeAg as a marker of viral reproduction in clinical practice, while a reasonable cost-effective approximation, is not adequate to monitor antiviral effect and will produce confusing results if not supported by the HBV DNA assays.34’ 35 Hepatic healing is monitored by the traditional use of serum transaminases and liver biopsy. Whether newer assays reflecting hepatic fibrogenesis and treatment designed to limit or reverse hepatic fibrosis will emerge as significant adjunctive measures remains to be seen. Presently, elimination of the HBV reservoir requires the destruction of all infected hepatocytes. Since these cells are presumably able to function normally and contribute to normal hepatic function, their elimination represents a threat to survival to the extent that liver function is dependent upon this cohort of cells. One of the important aspects of patient evaluation is the estimation of the extent of hepatocyte infection. Patients with minimal baseline hepatic inflammation are most likely to have more extensive hepatic infection; in the extreme, HBV carriers who are immunosuppressed because of organ transplantation may have demonstrable virus in nearly every hepatocyte. On the other hand, patients with a vigorous immune response, and severe liver damage as a consequence, may not have sufficient reserve to tolerate the removal of the infected cells. Restriction of therapy to patients with demonstrable hepatic inflammation, compensated liver disease, and circulating virus 1243

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would appear to be a reasonable compromise that presences patient safety and yet allows for drug efficacy. As experience accrues, it may be possible to modify these guidelines to broaden the therapeutic application of the antiviral drugs. Agents used include the interferons, arabinoside A and its monophosphate esther, acyclovir, levamisole, and transfer factor.3fi INTERFERON The interferons are a family of proteins naturally produced in response to viral infections and constitute a fundamental cellular defense mechanism. A comprehensive review by Peters and colleagues provides a wealth of information that is used in the following remarks.“7 Alpha-interferon is produced by stimulated leukocytes, primarily monocytes and transformed B lymphocytes, most often in response to a viral infection. Genetic analysis indicates that there are at least 16 genes, located on chromosome 9, that produce the alpha-interferon(s). Beta-interferon is a single glycosylated molecule produced by fibroblasts. The cell surface receptor for alpha- and beta-interferon is shared. Early studies with this protein are difficult to interpret because of erratic absorption from intramuscular sites. Gamma-interferon is an acid-labile protein produced by stimulated T-cells. The gene for gamma-interferon resides on chromosome 12 and the cell membrane receptor for gamma-interferon is distinct from that of alpha- and beta-interferon. Interferon binds to an asymmetric, specific cell-surface receptor. All subsequent intracellular events appear to depend upon cell uptake of the interferon-receptor complex, an event that renders the cell unresponsive to additional interferon stimulation for several hours until receptors can be renewed at the cell surface. Alpha- and beta-interferon promote the expression of several enzymes, including 2’5’ oligoadenylate synthetase (2’,5’OAS), and protein kinase (Table 1). It appears that the production of short strands of oligoadenTABLE

1.

Selected

Effects

Effect

Intranuclear

Induction of 2’5’ OAS Suppression of hepatocyte replication Inhibition of viral protein synthesis Enhanced HLA-1 display

Intracytoplasmic Cell membrane

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of Interferon

Location

127

ylate by 2’,5’OAS stimulates an endonuclease that destroys the viral messenger RNA and prevents viral reproduction. A second, detrimental, effect of 2’,5’OAS induction is the impairment of hepatocyte regeneration by interference with putrescine production.38 A buildup of this protein seems to be a prerequisite for hepatocyte reproduction. Activation of protein kinase phosphorylates several proteins, including an initiator of protein synthesis, eIF2, blocking the production of proteins.3s In addition to the intranuclear effects, alpha- and beta-interferon alter the hepatocyte membrane to enhance the display of the Class I HLA antigens, usually expressed poorly by normal hepatocytes; gamma-interferon preferentially promotes Class II HLA antigens as well. Early studies of serum interferon levels in acute and chronic hepatitis were puzzling because of inconsistent results.40 More recently, however, when evidence of tissue interferon production was sought in histologic specimens of acute and chronic hepatitis B, marked immunofluorescence of infiltrating mononuclear cells, circulating polymorphonuclear cells, and portal fibroblasts demonstrated local inferferon production41 (Fig 4). Such availability of interferon would promote lysis of infected hepatocytes because sensitized cytolytic T-cells are able to bind to and destroy infected hepatocytes when HBcAg/HBeAg is present at the cell surface adjacent to the enhanced HLA antigen(s) display. In addition to local cellular effects, the interferons have profound effects on immune function. Lymphocyte proliferation, cytotoxic activity, and immunoglobulin production are influenced.3s These effects are most pronounced at high doses and may limit the beneficial local effects of viral suppression. Several studies support the proposed pathogenetic role of interferon in hepatitis B liver disease. The first link is the description of the distribution of HBV antigens within the infected liver. Chu and Liaw”’ studied the intrahepatic distribution of HBsAg and HBcAg in 32 patients with chronic hepatitis. In patients with circulating HBeAg and mild liver inflammation, intranuclear HBcAg was present. When HBeAg was present and the liver disease was active, less intranuclear HBcAg was found and HBcAg could be seen on hepatocyte membranes in areas of cell necrosis. All patients with circulating anti-HBe failed to demonstrate HBcAg in the nucleus or on the hepatocyte membrane. Finally, all patients had HBsAg present on hepatocyte membranes regardless of HBeAg or anti-HBe status; the membrane HBsAg did not correlate with focal inflammation. As noted earlier, interferon has been demonstrated in the inflammatory cells adjacent to hepatocytes with cytoplasmic HBcAg.41 This relation was examined more closely in an elegant study by van den Oord and colleagues,43 who used double-staining immunohistochemical techniques to show the distribution of HL4 class I and II 128

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FIG 4. Sections of HBV-infected human liver stained by indirect immunofluorescence using antiIFN-alpha monoclonal antibody (6C3) viewed by light microscopy (left-hand side) and the same field by fluorescence (right-hand side). (A) Fibrous tissue from a patient showing IFN-alpha-positive mononuclear cells and fibroblasts (arrow). ((3) Liver tissue from a patient showing IFN-alpha-positive portal tract cells (PT) and negative hepatocytes (I+). Calibration bar, 50 km. (From Jilbert AR, Burrell CJ, Gowans EJ, et al: Cellular localization of alpha-interferon in hepatitis B virus-infected liver tissue. Hepatology 1986; 6(39):957961. Used by permission.)

antigens and to characterize the types of T-cells present in the inflammatory infiltrate. They showed that in areas of spotty necrosis, all hepatocytes had surface Class I antigens and the cellular infiltrate was primarily cytotoxic-suppressor T-lymphocytes. Furthermore, 11 of 14 cases with intranuclear HBcAg in these areas had Class II antigens on the hepatocyte membranes. Since Class II antigen display is an effect of gamma-interferon produced by cytotoxic-suppressor T-cells, a link between the viral stimulation of interferon and the inflammatory reaction can be established. A second phenomenon noted in this study was the enhanced display of Class I antigens on periportal hepatocytes without regard to viral protein presence. In these areas of piecemeal necrosis, there was a mixture of helper-inducer T cells and cytotoxic-suppressor Tcells closely applied to branching dendritic processes of sinusoidal lining cells that enclosed clumps of hepatocytes. The sinusoidal lining cells strongly stained for Class II HLA antigens. The reason that DM,

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these sinusoidal cells are reactive is unknown, It is tempting to speculate that cellular debris may instigate a localized autoimmune phenomenon leading to the pathologic lesion common to all of the chronic liver diseases, but there is insufficient evidence in the various diseases to establish such an hypothesis at present. The interplay between viral antigen production and interferon effect is a dynamic process that is modulated during the course of the disease. In the early phase of viral replication when HBeAg circulates, liver tissue homogenates contain increased levels of 2’,5’OAS and the density of HLA-I antigen is not increased. Once seroconversion to anti-HBe occurs, 2’,5’OAS activity is relatively decreased and HLA display is markedly increased. The data are consistent with the view that a shift from alpha/beta interferon effect to gamma-interferon effect is responsible for the variations.37 THERAPE

UTIC

TRZALS

Long before it was possible to establish the scientific basis for interferon as a therapeutic agent in chronic HBV, trials were instigated because of the central role of interferons in viral diseases in general. The early trials were limited because of the extraordinary expense and technical difficulties in preparing sufficient quantities of interferon for clinical use. The first trial was conducted at Stanford University and reported in 1976 by Greenberg and his colleagues44 They followed the serum levels of HBsAg, HBeAg, HBV DNA, and DNA polymerase in three patients with biopsy-documented chronic active hepatitis B in response to courses of alpha (leukocyte) interferon of varying dosages and duration. A fourth patient, who had no DNA polymerase and had anti-HBe, was studied in a limited fashion and showed no change in antibody titers in response to therapy. In the first patient, therapy was begun at 17 X lo4 unit/kg/day, given subcutaneously in divided doses for the first two courses and once a day for subsequent doses. As shown in Figure 5, DNA polymerase activity showed a prompt response to therapy, and an equally prompt relapse when short-term (
1975

I

1976

FIG 5. Effect of three separate courses (A, B, C-H) of human leukocyte interferon on Dane-particle-associated DNA polymerase, HBsAg (by complement fixation) and HBcAg (by radioimmunoassay) in Case 1. Circles denote mean and 2 SDS of a minimum of four separate values in serum samples obtained at regular intervals during the two months before study. Letters A through H denote individual interferon treatment courses at specific dosages with the units of interferon per kilogram per day x lo4 as shown. (From Greenberg HB, Pollard RP, Lutwick LI, et al: Effect of human leukocyte interferon on hepatis B virus infection in patients with chronic active hepatitis. N Engl J Med 1976; 295(42):517-522. Used by permission.)

The third patient showed a transient depression in DNA polymerase activity in response to a short course of 1.2 X lo3 unit/kg/day. These three patients showed that parenteral alpha-interferon could successfully block viral replication and subsequent production of viral proteins. The degree of serum transaminase activity was sufficiently mild that little effect could be seen in this small sample. The time of follow-up did not allow seroconversion to occur. Side effects were limited to low-grade fever and myalgias in the one patient with the highest doses. Further progress in developing interferon therapy awaited the availability of enough drug to permit therapeutic trials defining dosage schedules, toxicity, and characteristics of the patient population who might best benefit from therapy. Interpretation of therapeutic results is confounded by the ability of the HBV genome to become integrated, in whole or in part, into DM,

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3216 ~88r,

319

I

I

I

15

21

21

I

1

I

1 12 1976

I

18

1

1

1

I -

22 28

30

5110

FIG 6. Effect of three separate courses (A, B, and C) of human leukocyte interferon on Daneparticle-associated DNA polymerase, HBsAg and HBcAg in Case 2. Circles denote mean and 2 SDS of a minimum of four separate values in serum samples obtained at regular intervals during the two months before study. Letters A through C denote individual interferon treatment courses at specific dosages with the units of interferon per kilogram per day x IO3 as shown. (From Greenberg HB, Pollard RP, Lutwick LI, et al: Effect of human leukocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis. N Engl J Med 1976; 295(42):517-522. Used by permission.)

the hepatocyte genome. Integration may produce clones of cells that are capable of producing surface antigen, clones that produce core antigen, and clones that produce the entire virus, within the same liver. The immune mechanisms that permit selective destruction of hepatocytes expressing HBcAg and HBeAg on the cell surface will have no effect on the cloned cells producing pure surface antigen, and the persistence of circulating HBsAg has been considered a treatment failure, or only a partial therapeutic response. A more reasonable index of efficacy is to measure virus replication with HBV 132

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DNA, DNA polymerase, or HBeAg, and to attribute continued circulation of HBsAg in the absence of viral replication to the integrated genome. Early pilot studies identified several variables that influenced the response to treatment .37,45 Women, patients with more intense inflammatory activity, and those with lower levels of DNA polymerase were likely to eliminate the virus. Concurrent immunosuppressive therapy reduced the therapeutic response, while cessation of immunosuppressive therapy prior to antiviral therapy markedly enhanced viral clearance. Orientals, who presumably have contracted hepatitis at birth or in childhood and are more likely to have integrated virus because of the duration of infection, do not respond as well as non-Orientals to interferon therapy. Male homosexuals, who fail to respond to treatment with adenine arabinoside, are able to clear hepatitis B with alpha-interferon about half the time.45 Hepatitis B carriers with HIV (HTLV-III) antibodies do not respond to alphainterferon.46 Alpha-interferon has been given in three forms: lymphoblastoid (derived from stimulated buify coat preparations and containing many alpha-interferons), alpha-A (a monoclonal, highly purified, single species of alpha-interferon), and alpha-, (a second monoclonal alpha-interferon) .36 There is general agreement that the drug must be given parenterally at least three times a week, and the suggestion by some that daily injection may produce better tolerance to the side effects than intermittent use. High-dose therapy (Xen million units/day) does not yield better results and is associated with more toxicity than more moderate doses.47 Finally, the duration of therapy appears to be optimized in the range of 12 to 20 weeks. Response, as indicated by the disappearance of replicative viral markers, occurs within eight weeks and is often accompanied by a flare in serum transaminases and increased hepatic inflammation.z8 Dushieko et al. treated 14 patients with 18 to 50 million units of alpha-A interferon three times a week for eight weeks after a severalday induction period.@ Six patients (43%) had a clinical and serologic remission with loss of HBeAg, HBV DNA, and DNA polymerase, and subsequently normal serum transaminases. Five sustained the remission for a follow-up of up to three years. An additional three patients had a transient drop in viral markers, but returned to pretreatment values while continuing therapy. The remaining five did not respond at all. Scully et al. achieved a response rate of 53% (19/32) in males treated with lymphoblastoid interferon given as a five-day induction dose of five to ten million units/sq m followed by ten million units/ sq m three times weekly for 12 or 24 weeks4’None of eight women in this trial responded to treatment. Five women were Oriental and presumed to have acquired the infection in early life. The men inDM,

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eluded heterosexuals and homosexuals; only four were HTLV-III positive and one of these responded to treatment. Table 2 summarizes the results of therapeutic trials with interferon. TOXICITY When used in low to moderate doses of less than ten million units/day, the alpha-interferons are reasonably well tolerated. Virtually all patients experience fever, chills, and myalgias on commencement of therapy. Headaches, fatigue, anorexia, and nausea are also noted. Long-term therapy may produce irritability, depression, loss of concentration, hair loss, bone marrow suppression, weight loss, and increased need for sleep. Pyogenic abscesses have also been noted.37 All side effects appear to remit shortly after cessation of the drug, and may be reduced to tolerable levels by reduction in dosage. Toxicity is minimized by excluding patients with low blood counts, preexistent symptomatic depression, or severe head trauma, and significant co-morbid disease states. Acetaminophen may be given to mitigate the febrile response to the initiation of therapy. Blood counts should be monitored weekly in the initial months of therapy and once a month thereafter, with dose reduction if persistent leukopenia, anemia, or thrombocytopenia develop. ACYCLOVIR The antiviral property of acyclovir and its prodrug, deoxyacyclovir, depends on the metabolism of the drugs by thymidine kinase to the active moiety.50 Despite the absense of viral thymidine kinase in the hepatitis B virus, activity against hepatitis B replication has been claimed, apparently by partial inhibition of HBV DNA polymerase.51J” The major appeal of acyclovir is the limited toxicity of the drug which precipitates in urine if hydration is not well maintained. TABLE Therapeutic

134

2. Trials

With

Alpha-Interferon

Source

Dose,

mIJ/sq

m

Lok et al.‘37 Dooley et aI.‘38 Dushieko et a1.48 Scully et a1T9 Barbara et aI.’ Hess et al.14’ *Clearance of markers

10 18-100 18-50 5-10 2.5-5 lo-30 of viral replication.

Duration, 4-8 2 9 12-24 24 24

wk

Response* S/11 z/9 6/14 19/40 8/9 19/32

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Whether acyclovir will assume a role for patients with low-level viral replication, e.g., anti-HBe-positive patients with mild ongoing hepatic inflammation, or in combination with other, more potent antivirals, remains to be seen.53, 54 AZIENZNE ARABZNOSZDE AND ADENZNE ARAZ3ZNOSZDE MONOPHOSPHATE Adenine arabinoside WA-A) and its monophosphate (ARA-AMP) have been shown to effectively reduce the activity of either the HBV mRNA or DNA polymerase.55 The monophosphate form of the drug allows it to be administered intramuscularly, whereas ARA-A must be given intravenously (IV). A recent review by Hoofnagle summarizes the therapeutic trials with ARA-A and ARA-AILIP.~~ Adenine arabinoside was used initially by Pollard et a1.57 for two HBeAg-positive patients with circulating DNA polymerase. With each nine to 14 day course of IV ARA-A, 15 mg/kg/day, the DNA polymerase activity was markedly reduced for the duration of therapy. In one patient, viral replication resumed following cessation of drug use; in the other, clinical remission ensued. Several subsequent studies showed a similar effect, namely, a prompt suppression of viral replication with a rebound to pretreatment levels once therapy was stopped.58-60 Use of ARA-AMP, which simplified administration and permitted longer courses of therapy to be given, did not improve upon the results except for a trial by Trepo et al., which found a remarkable sustained clearance of HBeAg/DNA polymerase activity in 66.6% of 18 patients, eight of whom had received two courses of therapy.“’ Histologic remission was attained as well. These patients may have had a stronger immune response independent of the antiviral therapy, based on the exclusion of male homosexuals, the high rate of spontaneous remission in the placebo group (26.3%70),and the requirement for symptomatic disease for inclusion in the study. Most recently, a study by Alexander and colleagues6’ showed that the disappearance of DNA polymerase activity was accompanied by persistent low-level viral DNA levels. These authors believed that the continued circulation of viral DNA indicated an incomplete inhibition of viral synthesis, and that a rebound to baseline levels was to be expected in that circumstance. The major limitation to the use of ARA-A and ARA-AMP is the substantial toxicity of these drugs. Patients commonly experience nausea, anorexia, fatigue, diarrhea, and vomiting. Reversible bone marrow suppression with thrombocytopenia can be expected. The most vexing side effect is a peculiar neuromuscular pain syndrome that produces pain and cramping, most pronounced at the site of injection, sometimes lasting for months after cessation of the drug. DM,

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A novel strategy being explored by Shouval et al.63 is to link monoclonal antibodies to HBsAg to the antiviral agents cytosine arabinoside or ARA-A. The antibody portion of the conjugate would then serve to bind the antiviral drug specifically to the infected cell, permitting a great reduction in systemic exposure to the drug and, presumably, a major reduction in toxicity. Although many problems must be surmounted in the application of such an approach, the recent strides in genetic engineering and immunological manipulation seem to make such a technique feasible. PREDNISONE

WITHDRAWAL

During the course of untreated hepatitis B infection, patients have been observed to develop spontaneous increases in serum transaminases accompanied by a significant increase in liver parenchymal inflammation. Seroconversion from HBeAg to anti-HBe often follows, viral replication ceases, and subsequent biopsies show a marked histological improvement with residual s~arring.~~’ A similar phenomenon was noted in patients with chronic hepatitis B receiving immunosuppressive chemotherapy shortly after the course of therapy ended, occasionally with the precipitation of a fulminant hepatitis.“a70 In view of the apparent response of the infection to immune manipulation, Nair and colleagues” treated 20 patients with chronic active hepatitis B with a short course of prednisone, starting at 60 mg/day and tapering to zero over ten weeks. The patients were compared with 24 patients who refused treatment during the study period but were otherwise comparable with respect to clinical, serological, and histological parameters. The treated group had a significant rise in serum DNA polymerase and fall in transaminases while on therapy, followed by a precipitous fall in DNA polymerase accompanied by a bump in serum transaminases upon steroid withdrawal (Fig 7). Fourteen of 16 patients became persistently negative for DNA polymerase. Ten of 14 became negative for HBeAg and five seroconverted to anti-HBe. In four male homosexual patients, HBeAg and DNA polymerase reappeared between 14 and 24 months after the study had been completed. In the untreated group, only three of 1.5 with circulating DNA polymerase spontaneously lost enzyme activity and only one of 14 became HBeAg-negative. Five patients developed signs of decompensation associated with the steroid withdrawal: two developed ascites, two developed ascites and hepatic encephalopathy, and one had a hemorrhage from esophageal varices. These patients differed from the compensated study population with lower albumin levels, prothrombin activity and platelet counts, and higher bilirubin levels at baseline. The four 136

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A I Pr&luM

I

G vi +I I

3t

W

Prrdnisons

Group

.- - - untmotsd Gmup

4+-

-

I

-4

-2

0

2

4

6

I,

”

I

I

9

12

Months

7oo

e t

PrrdnisOna

Group

- - Untraated Group

600

f 3 5 a

Months

FIG 7. A, comparison between the sequential changes in serum HBV DNA in the prednisonetreated patients (n = 16) with that of the untreated patients (n = 15). A score from negative to 4 + was assigned by comparison of the intensity of hybridization of the test sample with various concentrations of the HBV DNA standard as follows: 4+= z2oopg 3+ = ,100 - <200 pg 2+= 12.5 -
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with ascites responded to a short course of diuretics and stabilized without further medications. In a second study, Hoofnagle and colleagues treated ten patients with a Z&day course of prednisolone in doses reduced from 60 mg to zero over 28 days, and compared the clinical, serological, and biochemical outcome with a randomized sample of five control patients.72 As anticipated, the steroid-treated group developed significant transient improvement in inflammation while receiving a drug, followed by a substantial rebound in transaminase activity four to ten weeks after withdrawal. In three patients, the exacerbation was symptomatic and prolonged, and in four of seven treated patients with serial biopsies, a deterioration in liver histology was seen. In contrast to the previous study, no significant short-term or longterm effect on serum DNA polymerase activity or viral markers was noted. The failure to affect viral replication may have been due to the short period of immunosuppression, four weeks, or the long duration of the carrier state, nearly three years, in the treatment group. The time course of membrane expression of viral antigen in response to immune suppression is unknown and it is conceivable that the failure to eradicate the infection could be due to erratic HBcAg/HBeAg display. In addition, there is no reliable way to assess the number of hepatocytes infected in an individual. Presumably, patients with a longer duration of infection have a larger reservoir of infected cells that must be eliminated, and would be at greater risk for severe liver damage with a smaller chance of eliminating the infection. The Hoofnagle study emphasizes the inherent risks involved when the clinician attempts to fool Mother Nature. Indeed, at least one patient has died from decompensated liver disease as a result of short-term immune suppression.73 Patient selection is clearly crucial to the safe execution of immune manipulation in chronic hepatitis B. The important parameters of hepatic reserve and regenerative capability, number and distribution of infected hepatocytes, and potential vigor of the immune response can only be estimated at the present time. The uncontrolled use of this modality should be avoided. MISCELIANEOUS

AGENTS

Additional agents that have been used to treat chronic hepatitis B in small trials are the immunostimulating agents transfer factor,74 levamisole,75 and interleukin .z.~~ Antiviral agents have included ribavirin” and quinacrine.78 There does not seem to be any current enthusiasm for further investigation with these agents. 138

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COMBINATION

THERAPY

The chemotherapeutic approaches already discussed attempt to eradicate the hepatitis B virus by directly suppressing intracellular viral synthesis (AFIA-A, AR&, acyclovir, interferon1 or by destroying infected hepatocytes (interferon, prednisone withdrawal). A logical extension of these approaches is the use of agents in tandem or simultaneously, with the hope of increasing the response rate while maintaining an acceptable incidence of side effects. Combinations used to date include acyclovir and interferon, interferon and adenine arabinoside, and prednisone withdrawal followed by an antiviral agent. Two studies using acyclovir and lymphoblastoid alpha-interferon have produced conflicting results. Schalm et al.” used IV acyclovir (15 mg/kg twice daily for two weeks) and interferon (2.5 mU/sq m/ day) to induce a fall in DNA polymerase activity and continued with an additional six weeks of daily parenteral interferon. The combination produced a rapid fall in DNA polymerase and a slower decrease in HBeAg. Four of five patients lost DNA polymerase activity and three of five lost HBeAg for the duration of follow up, which was six months. The study did not have a control group to establish that the combination was more effective than interferon alone. Such a trial is currently underway. In contrast, Guarascio and colleaguesso used a short course of intramuscular (IM) lymphoblastoid interferon (5 mU/ sq m/day for three days followed by 7.5 mU/sq m/day for seven days) to reduce viral replication followed with a six-week course of oral acyclovir, 800 mg, four times a day. This regimen produced a fall in viral replication that slowly returned to baseline despite the acyclovir. This pilot study also did not include controls to determine if any benefit could be ascribed to the addition of acyclovir. The combination of adenine arabinoside and interferon was used by Sacks et ala1 While the combination was clearly more effective in eliminating viral replication than either agent alone, the toxicity was unacceptable. Combination therapy using a short course of prednisone followed by an antiviral agent, adenine arabinoside, its phosphorylated derivative, or one of the alpha-interferons, has also been studied in a preliminary fashion and seems promising.82-84 Omata et al. studied small groups with ARA-A and alpha-interferon, singly and following a pulse of prednisone, and were able to demonstrate that nine of 14 patients receiving combination therapy cleared HBeAg, and an unspecified additional number of patients lost DNA polymerase and HBV DNA activity, as compared with three of 35 treated with a single agent. Perrillo et al. treated 11 patients with an eight-week course of tapering prednisone followed by 28 days of AKA-AMP and achieved a response rate of 73% (8/11), in patients who lost serum DNA polyDM,

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merase activity. Of these, five of eight patients cleared the HBeAg as well, remaining negative for at least six months in follow-up. A major multicenter trial is underway to evaluate the effects of pulse prednisone in combination with alpha-, interferon, 1 or 5 mU/ day, administered for 16 weeks. Early experience suggests that drug toxicity is reasonably tolerated by most patients. We await the results with great anticipation. SUMA4ARY

Considerable progress has been made in understanding the pathogenesis of chronic hepatitis B viral disease. The application of antiviral and immunomodulatory agents clearly modifies the natural history of the disease and can eliminate the infection in a substantial number of patients, especially those with disease of relatively recent duration, who lack coincidental illnesses that cause immune suppression, and are sufficiently reactive to the HBcAgHBeAg to generate at least a modest inflammatory response. Care must be taken to assure that liver reserve is adequate to withstand the destruction of the reservoir of infected hepatocytes with successful treatment. As treatment strategies continue to evolve and less toxic agents become available, one can anticipate a substantial, favorable impact on epidemiology of this serious disease. HEPATITIS

D VIRUS

The hepatitis D virus (delta agent, HDV) is an incomplete RNA virus that closely resembles plant viruses, i.e., introns, in genetic comcells in the position.85 Hepatitis D virus cannot enter mammalian absence of HBsAg, and therefore cannot cause liver infection unless an antecedent or concomitant HBV infection with persistent HBsAg production occurs, allowing encapsidation and subsequent entry into hepatocytes (Fig 8). In contrast to hepatitis B, hepatitis D is thought to be cytopathic and to produce cell injury in the absence of virus-specific immune mechanisms. Although the addition of HDV to a liver with an established HBV infection reduces the titer of circulating HBV viral proteins and the number of HBV virions in the liver by destroying infected hepatocytes directly, the usual overall effect on the liver is to worsen liver damage-at times to a dramatic extent ?6 Within hepatocytes infected with HDV and HBV, the delta viral RNA is reproduced by reverse transcriptase and transported to the cytoplasm where viral assembly occurs with HDV enclosed by HBsAg. The immune events that may participate in viral clearance have not been fully elucidated, but preliminary evidence suggests 140

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FIG 8. Delta particles purified from the serum of a chimpanzee. They contain delta antigen and RNA inside on HBsAg coat. (From Rizzeto M, Verme G, Gerin JL, et al: Hepatitis Delta virus disease, in Popper H, Schaffner F (eds): Progress in Liver Diseases. New York, Grune & Stratton Inc, 1986, vol 8, pp 417-431. Used by permission.)

that autoimmune mechanisms that are not virus-specific more important in delta infection than in hepatitis B.85 ANTIVIRAL

may be

THERAPY FOR HDV (DELTA AGENT)

Special care must be taken in evaluating claims of drug effect in the therapy of HDV, for this virus is found only in the presence of HBsAg. Selection of patients with inactive chronic hepatitis B (no demonstrable HBV DNA, DNA polymerase, or HBeAg), whose persistent HBsAg is presumably due to integrated HBV genetic sequences, permits such an evaluation without the confounding effects of coincidental active hepatitis B infection. The first description of treatment of chronic HDV was given by Rizzeto and colleagues.87 Utilizing biopsy tissue and serum specimens stored over a period of years, a retrospective analysis was undertaken to identify any potential benefit from the use of corticosteroids, azathioprine, or the combination of the two in the progression of chronic HDV disease. Eighty-one percent of the subjects were anti-HBe positive. No stratification for disease activity, homosexual activity, medication dosage, or degree of HDV infection of hepatocytes was possible. The overall rate of progression to cirrhosis, as DM,

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judged by needle biopsy, was the same in treated (W/50) as in untreated (12/25) groups. A second study compared the effects of levamisole, an immunostimulant drug, on four patients with intrahepatic HBcAg and four with intrahepatic delta antigen (HDAgl, with an identical number of controls .88 No change in serum ALT or clinical status was identified in the HDAg-positive patients, whereas all of the treated HBcAg patients demonstrated a sustained elevation in serum transaminases for a one- to two-month period after levamisole was discontinued. The success of alpha-interferon in modifying the course of hepatitis B and other viral infections has made it a logical choice for empiric therapy of HDV. Rizzeto and colleagues next randomized 11 patients to receive alpha-, interferon or no treatment.8g Ten of 11 had no evidence of HBV viral replication; the 11th had low titers of HBeAg and intermittent weakly positive HBV DNA in the serum. Six patients were treated with alpha-, interferon, 5 MLJ/sq m subcutaneously three times a week for 12 weeks. Serum levels of HDV DNA were measured semiquantitatively by visual inspection of an autoradiograph produced by a cDNA probe of HDV-genomic RNA. HDAg in liver biopsy tissue was demonstrated by immunofluorescence techniques. In five of six patients, serum HDV DNA diminished; in four of five no DNA was detectable at the end of the treatment period. After an initial rise in transaminase activity, serum enzymes fell in parallel with decreased HDV DNA. One patient with a biphasic course of HDV DNA experienced a similar pattern of serum enzyme activity. With long-term follow-up, only one patient has been free of HDV DNA activity; the others returned to pretreatment levels. Thomas and Hoofnagle have informally reported similar responses in trials that are underway. NON-A,

NON-B

VIRUSES

Little is known about the pathogenesis of non-A, non-B hepatitis because of the frustrating inability to identify the causative agents. At least two short-incubation and two long-incubation filterable, transmissable agents have been identified in cross-challenge studies using chimpanzees.” The short-incubation viruses have accounted for major waterborne epidemics in India; the long-incubation viruses are the major source of posttransfusion viral hepatitis. Although fulminant and subfolminant hepatitis occurs, the usual course with these viruses is mildly symptomatic with fluctuating biochemical evidence of liver disease. One third to one half of posttransfusion non-A, non-B hepatitis will last for at least a year, and will generally subside over the next several years, although occasional patients will have abnormalities persist for decades. An estimated 50% of the cases will progress to cirrhosis. 142

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ANTIVIRAL,

THERAPY FOR NON-A,

NON-B

VZRAL HEPATITIS

A single pilot study has been reported to date on the use of alpha-, interferon in the treatment of non-A, non-B viral hepatitis.‘* Nine patients had exposure to transfused blood products or illicit IV drugs as the presumed source of the hepatitis. All patients had demonstrated elevated serum transaminase activity for 1.4 to 19.5 years and biopsy-proven chronic liver disease. Other causes of chronic liver disease were excluded by history and biochemical findings. Eight of ten patients demonstrated a prompt reduction of serum transaminases to normal on institution of interferon. In two patients receiving short courses (four months), inflammatory activity resumed within two months of cessation of therapy, and rapidly improved on resumption of interferon therapy. The improvement in transaminase activity was maintained with reduction of interferon to 1 mU three times per week. Follow-up liver biopsies in three patients showed a corresponding improvement in liver histology. A nationwide multicenter trial is currently underway to evaluate low-dose protracted treatment of chronic non-A, non-B viral hepatitis. Major problems that must be confronted in the therapy of non-A, non-B viral hepatitis are deciding who has the disease and whether the several non-A, non-B agents respond in a similar fashion. Treatment for a disease that is often asymptomatic must be acceptable in terms of side effects and cost, and it will probably be difficult to sharply define the patients who will benefit most. Nonetheless, one must be encouraged by the early attempts to bring these viral hepatitides under control. AUTOIMMUNE

‘ZUPOID”

HEPATITIS

Since the mid-fifties, clinicians have recognized a group of patients with liver inflammation, marked hyperglobulinemia, and a variety of associated diseases categorized as autoimmune disorders. Shortly after the initial description by Waldenstrom et al,s2-s4 MacKay noted a strong association of chronic active liver disease with the lupus erythematosus (LE) cell phenomenon, and postulated that forbidden clones of lymphocytes were instrumental in the pathogenesis of the disorder.s5 The term “lupoid hepatitis” was introduced to reflect the LE cell characteristic, but has served as a major source of confusion because of the implied association between systemic lupus erythematosus (SLE) and autoimmune chronic hepatitis. SLE is a form of vasculitis that affects many organ systems and usually produces trivial hepatic injury; autoimmune hepatitis is a process that attacks the liver primarily, with inconsequential effects on the vascular tree.Y6 As our understanding of immunology has expanded, it has become clear that autoimmune events are commonplace and play an DM,

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instrumental role in the repair of organs on a daily basis. The earliest autoantibodies described included several that are often found in chronic active hepatitis: antinuclear antibody (ANA), smooth-muscle antibody @MA), and antimitochondrial antibody (AMA). Refinements in technique have shown that such tests do not measure an antibody against a specific protein, but rather a family of antibodies that react against parts of the nuclear proteins, actin, and other elements of the cytoskeleton, and mitochondrial ATPase, respectively.s6,g7 Recently, autoantibodies against calmodulin, a protein that regulates intracellular metabolism by binding calcium and plays an important role in the metabolism of the cytoskeleton, were described and shown to have a predilection for patients with chronic liver disease.s8 Given the heterogeneity of antigens, antibodies, and test conditions, as well as the absence of any link between the presence of the antibodies and the pathogenesis of chronic active hepatitis, the role of such antibodies is relegated to a marker of potential disease only, and cannot be used to establish the diagnosis. Nonetheless, attempts to establish a pathogenetic link have continued because of the strong association of membrane-associated antigens and autoimmune liver disease. Jensen et al.” showed the frequent occurrence of antibodies against an antigen prepared from partially autolysed hepatic tissue called liver-specific protein (LSP) in the course of viral hepatitis. AntiLSP titers were usually low and transient, except in those patients who developed chronic viral hepatitis. In the patients with protracted infection, the anti-LSP titers rose substantially and persisted for the duration of the study. In the case of viral hepatitis, these autoantibodies appear to be an epiphenomenon that resolves with clearance of the infection. In contrast, those patients who develop the autoimmune diseases seem to share an inability to regulate the repair process. Once organ injury has been initiated, progressive organ damage ensues and persists, long after the inciting agent has been eliminated.lOO”O1 The damage is mediated by lymphocytes activated by an unidentified target antigen on the surface of normal hepatocytes. The means by which the immune system distinguishes “self’ from ‘non-self’ proteins is one of the central problems in immunology, and although some intriguing clues have been discovered, the process remains enigmatic. Most patients with autoimmune chronic active hepatitis share a common genotype, HIA-B8 and Dr3.l” A congenital deficiency of complement component four ((241 has been recently associated with autoimmune chronic hepatitis.lo3 Relatives of patients with chronic active hepatitis have an increased incidence of autoantibodies.1o4’1o5 As indicated by MacKay in a recent review of immunologically mediated liver disease, it is surprising that so few 144

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families express overt autoimmune hepatitis, given the strong genetic influence identiIied.‘06 A number of antibodies have been identified that are directed against components of the liver cell membrane, including anti-LSP, liver membrane antigen &MA), and liver-kidney-microsomal antigen (LKM). Antibodies against a cytosolic protein, soluble liver antigen (SLA), have also been described.“’ The association of so many hepatocyte-related antigens indicates that the fundamental defect in autoimmune chronic active hepatitis is a disordered immune surveillence mechanism that allows the uncontrolled expression of an autoantibody. Whatever the precise defect may prove to be, impaired immune suppression by T-cells is the final result. The autoantibodies bind to the hepatocyte membrane and fix complement. In turn, cytotoxic T-cells bind to the complement and cell destruction follows, a process that is called antibodydependent cellular cytotoxicity.*07 Fortunately, this process usually can be turned off by the use of immunosuppressive drugs in doses that are reasonably well tolerated, and as indicated previously, the patient’s response to immunosuppression may be the strongest clue to establish the diagnosis of autoimmune chronic active hepatitis. THERAPY

OF AUTOIMMUNE

CHRONIC

ACTZVE

HEPATITIS

In his thoughtful and comprehensive review of chronic active hepatitis written in 1981, Czaja indicated several decisions that must be made before instituting immunosuppressive therapy for chronic active liver disease.“’ These include the need to establish that the disease is chronic and unlikely to subside spontaneously, that the disease is likely to respond to immunosuppression, that the morbidity and mortality of the untreated disease will be greater than the side effects of treatment, and that the patient can comply with the necessary monitoring to assure safe use of the immunosuppressant drugs. The simplest way to establish disease chronicity is to document abnormal transaminase values for a period of six months and obtain a liver biopsy to rule in chronic active hepatitis and eliminate the many other causes of chronic liver disease that require a different therapeutic approach. A slavish adherence to a six-month observation period may be harmful to the patient with florid disease activity who presents acutely and has the potential to rapidly progress to liver failure.12’ log The presence of high titers of anti-smooth muscle and antinuclear antibodies, twofold increase in gamma-globulin, splenomegaly, or a history of previous autoimmune disorders should lead the clinician to advocate a prompt liver biopsy and early therapeutic intervention. DM,

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The diagnosis of chronic active “lupoid” hepatitis requires biopsy documentation of significant piecemeal necrosis in mild to moderate disease and bridging necrosis, multilobular collapse, or established cirrhosis in severe disease. The exclusion of disorders such as Wilson’s disease, primary biliary cirrhosis, and chronic viral or drug hepatitis must always be done, as indicated earlier, Sclerosing cholangitis may present a histologic picture of mild chronic active hepatitis, and should be investigated with a retrograde cholangiogram, for the radiogram is diagnostic and the effects of steroid therapy in sclerosing cholangitis potentially devastating on the skeleton. Mild to moderate disease does not always require treatment. At the very least, such patients must be followed up in case there is a change in biochemical activity, but the toxic effects of immunosuppression in asymptomatic, “biochemical” disease may outweigh any benefit .lXo On the other hand, patients with extreme hyperglobulinemia may require plasmapheresis for control of hyperviscosity symptoms,*11 although we have successfully treated such a patient with immunosuppression al0ne.l” THERAPEUTIC

REGIMENS

Early controlled trials of immunosuppression for the treatment of severe chronic active hepatitis demonstrated a consistent favorable response to therapy with prolongation of life.‘2,113 The dose regimens have varied, from high-dose (60 mgday) to moderate (30 mg/ day) steroid induction tapered to maintenance levels of 10 to 20 mg/ day, or with the inception of therapy at a maintenance level of 10 to 20 mg/day. Azathioprine is ineffective alone, but permits the effective dose of prednisone to be reduced.114’115 The usual dose of azathioprine is 50 mgday. Withdrawal of azathioprine from patients in remission has resulted in relapse,l16 substantiating its contribution to disease control. The role of immune modulation is different in autoimmune chronic active hepatitis than in chronic viral hepatitis. In the latter case, immunomodulation permits the destruction of infected liver cells; in the former, the goal of therapy is the prevention of disease expression. It is not surprising, therefore, that reappearance of autoimmune disease should follow a reduction in immune suppression therapy with a high degree of regularity. When treatment is discontinued, 50% to 87% of patients will have a relapse, and the rate increases with the duration of follow-up therapy.117’118 Most patients will show a rise in serum transaminases of immunosuppression.108 After two relapses, it is highly unlikely that the patient can be weaned from steroids. Most often, however, maintenance doses can be reduced to a level that minimizes side effects. Although it has been established that corticosteroids with or with146

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out azathioprine clearly improve short-term survival for those with severe chronic active hepatitis, a second goal of therapy, to prevent cirrhosis, has met with less success. Many patients will progress to cirrhosis despite continued immunosuppression,lls but these patients may have had such damage at the onset of disease that progression was inevitable. The majority of patients developed histologic evidence of cirrhosis within the first three years, and in many, the response to corticosteroids at standard doses was suboptimal. Until markers for the various non-A, non-B viral hepatitis agents become available, it will be impossible to separate out this group from those with autoimmune disease, and to determine the extent to which the outcome has been biased by their inclusion. In the Mayo Clinic study, the development of cirrhosis did not alter life expectancy. Complications of cirrhosis were generally not seen, even with an average of five years of systematic observation. It seems reasonable to attribute the benign outcome to the careful suppression of inflammatory disease, and it is important to emphasize that this group of patients had severe chronic active hepatitis at the onset of therapy. The late results of the study from the Royal Free Hospital confirmed the beneficial effect of corticosteroids in the early years of treatment, but also indicated several instances of decompensated cirrhosis developing as a late consequence of the disease .I” TOXICITY

OF

CORTZCOSTEROZDS

AND

AZATHIOPRINE

The toxic effects of the corticosteroids are dose-related and can be minimized by maintaining the patient on the lowest effective dose. Cosmetic changes such as facial fullness, steroid “hump,” acne, and hair growth are usually well tolerated provided the liver disease is controlled. Decreased glucose tolerance, obesity, hypertension, and peptic ulcer disease can be managed in the usual fashion. Cataracts may develop prematurely and require extraction. Thrombocytopenia may necessitate cessation of therapy. In general, side effects appear within the first 18 months of therapy; those patients who tolerate the initial stages of therapy are likely to continue without problems.‘21 The most devastating side effect of long-term corticosteroid therapy is osteopenia. The loss of bone is accelerated in patients with chronic liver disease for unknown reasons, and the addition of corticosteroids can be catastrophic, with vertebral collapse and aseptic necrosis of the femoral head creating severe limitations and discomfort for the patient. There are no satisfactory methods for predicting which patients will have bone collapse, and there is no satisfactory treatment once it has developed. Wang and Czaja,“’ in reviewing the Mayo Clinic experience, concluded that the incidence of corticosteDM,

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roid side effects was similar for pre- and postmenopausal women, and that the response to treatment was generally favorable, so that the intuitive notion that postmenopausal women should not be treated because of a predilection for side effects does not seem to be borne out. Azathioprine is generally well tolerated, especially at a dosage of 50 mgday, but may cause bone marrow suppression, hepatitis, nausea, and vomiting. The drug is teratogenic and should be avoided in women without suitable birth contro1.123 Complete blood counts must be monitored biweekly during the initial three months of therapy and three to four times per year thereafter. Long-term use of azathioprine in doses larger than those generally used for chronic active hepatitis has resulted in an increased risk for malignancy. Surveillance of the Mayo Clinic patients receiving corticosteroids with or without azathioprine disclosed a slight increase in the occurrence of extrahepatic malignancy when compared with the expected rate for a normal population.124 There did not appear to be a specific organ system that was predisposed to malignant change, and therapy of tumors after discovery appeared to be reasonably effective, so that careful attention to changes in the patient’s clinical condition with care to exclude malignancy seems to be the most appropriate means of management. PATIENT

MONITORING

AND

FOLLOW-

UP

Most patients will respond to immunosuppressive therapy with a marked improvement in sense of well-being and reduction in serum transaminase activity, globulin levels, and serum bilirubin within several weeks. Should a patient not respond, the possibility of chronic non-A, non-B viral hepatitis should strongly be considered. Within the first three months, the patient will often demonstrate a susceptibility to the side effects of the immunosuppressive drugs, so that attention to blood glucose, blood counts, blood pressure (BP), and stool guaiac is indicated. Additional drugs may be required to counteract side effects. Energetic attempts to prevent weight gain may be required to offset the steroid-induced hyperphagia. Moderate salt restriction should be instituted to minimize fluid retention and elevation of BP. Alcohol use should be minimized to avoid the potential for hepatic fibrosis in a setting of low-grade inflammation. Exercise should be encouraged and a regular program instituted. Increased muscle mass and bone density provide important reserves for patients with advanced liver disease, and must be developed when the patient is feeling well enough to exercise. After the induction of therapy, patients can be seen quarterly for brief visits to establish their continued response to therapy. If high14s

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1988

dose corticosteroid therapy was initially chosen, the dose is reduced monthly in decreasing increments to achieve a maintenance dose of 10 mg or less daily. The steroid taper is usually carried out over a six- to eight-month period. Spontaneous flares in transarninase activity may occur without apparent detriment to the patient, but if symptoms of the presenting illness, malaise, and fatigue recur, an increase in steroids to a level that had previously provided control is indicated. When normal or near normal transaminases have been maintained for three to six months, a gradual taper to discontinuance of steroids may be tried. If the patient is successfully withdrawn from immunosuppression, monthly follow-up for the next six months will identify the majority of those who are destined to relapse.*17’*‘8 Late relapses occur as well, but are more difficult to anticipate. A satisfactory response to reinstitution of therapy is usually achieved. In some cases, the liver disease remits, but the autoimmune process appears to attack other organ systems in sequence. With treatment, the five-year survival rate for autoimmune chronic active hepatitis is approximately 85%, despite the fact that many patients will have developed cirrhosis.‘25 Adverse factors are those of decompensated liver disease, including ascites, variceal hemorrhage, hepatic encephalopathy, and hypoalbuminemia. For those patients who do decompensate, the possibility of liver transplantation is now a widely available option. Treatment of the patient should be chosen so that a future liver transplantation will not be compromised. Surgical shunts, whether vascular or peritoneovenous, will not usually prevent subsequent liver transplantation, but if the portal vein is destroyed by surgery or subsequent thrombosis, or the patient develops a serious infection associated with a peritoneovenous shunt, then chances of a successful transplantation are severely impaired. The choice of therapy for decompensated patients must depend on available expertise; it is increasingly important to consider the impact of therapy on the immediate problem and to consider the long-range consequences as well. DRUG-INDUCED

CHRONZC

HEPATITIS

Prescription drugs are believed to produce chronic hepatitis by direct hepatocyte toxicity, immune-mediated injury, or a combination of the tw~.“~ Most acute drug reactions resolve without residual damage once the offending agent has been removed. Patients are most susceptible to chronic drug injury when drug-induced symptoms are tolerable and the patient is diligent, enabling the continued use of the offending agent. Drugs, such as halothane, which have a high lipid solubility and may therefore be stored in adipose tissue, DM,

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can be mobilized from tissue stores and provide an ongoing stimulus for liver injury even though the drug is no longer administered. The metabolism of a drug is influenced by many factors. The addition or subtraction of drugs from an established regimen may occasionally trigger an hepatotoxic reaction, as can alterations in alcohol use or nutritional status.lz7 Toxic metabolites such as reactive free radicals that bind to intracellular macromolecules are often supposed to be the mediators of liver damage.lz8 The frequent occurrence of autoantibody production in some drug reactions, e.g., alpha-methyldopa chronic active hepatitis, raises the possibility that an altered immune response may be drug-induced as welll” Models of drug toxicity provide plausible explanations for a mechanism of necrosis in selected cases, but proof of drug toxicity is rarely established in clinical circumstances. A peculiar phenomenon is noted with many drugs, illustrated by surveys of patients taking Isoniazid. Approximately 20% of patients will demonstrate a mild biochemical effect with an increase in serum transaminase levels during the initial months of therapy.130-132 The hepatic inflammation will subsequently resolve without change in drug regimen and without apparent residual injury. Hepatic morphology is usually described as a nonspecific “reactive” hepatitis, and occasionally, for drugs known to stimulate enzyme induction, a proliferating endoplasmic reticulum may be seen, but in most instances the mechanism of hepatic adaptation is obscure. The diagnosis of drug-induced chronic liver disease is presumed when improvement in inflammatory parameters occurs following cessation of the drug. Drug toxicity will generally resolve within six weeks, but worsening of liver damage can occur in the early days after drug cessation, creating diagnostic uncertainty. If the toxic target includes the biliary tree, continued nonspecific damage may accrue to the hepatocytes denied biliary drainage by the transient insult, and if the damage is widespread, secondary biliary cirrhosis can develop .133 The diagnosis of drug-induced chronic active hepatitis requires a liver biopsy with significant histologic lesions as well as demonstration of prolonged transaminase elevations. Furthermore, evidence of inflammation must subside within six to eight weeks of cessation of the drug, and if a repeat liver biopsy is performed, disappearance of periportal inflammation is required. Drugs that have been implicated as causes of chronic active hepatitis include Isoniazid, alpha-methyldopa, nitrofurantoin, chlorpromazine, halothane, sulfonamides, and oxyphenisatin.134 The latter was the first drug noted to cause chronic hepatitis, and although banned in many countries, may still be available in parts of the world. 150

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Liver transplantation is an established option for patients with decompensated liver disease.135 The procedure carries a risk that is directly related to the illness of the patient at the time of transplant (Williams JW, personal communication) and therefore requires a difficult judgment of the optimal time of transplantation. A successful transplantation obligates the patient to a lifelong regimen of immunosuppression, medical monitoring, and concern for personal wellbeing that is not tolerable for everyone. Side effects of cyclosporine, including renal damage, hypertension, seizures, tremors, gingival hyperplasia, hair growth, rhinorrhea, susceptibility to viral infections, and perhaps malignancies, are added to the previously described effects of corticosteroids. The financial cost of follow-up care may be prohibitive, particularly in a climate where Health Maintainence Organizations and insurance carriers have become adept at avoiding payment for transplantation-related expenses. The psychological imon patient and family may have surprising pact of “resurrection” effects. Despite these many real concerns, a successful liver transplantation and subsequent excellent quality of life can be anticipated for the majority of patients.13” The criteria for patient selection vary from center to center, but generally follow the same guidelines. Patients with chronic liver disease should be considered when there is evidence of recurrent variceal hemorrhage, chronic hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, or parenchymal failure with hypoalbuminemia, hypocoagulability, and jaundice. Patients with chronic viral hepatitis present a special problem, for if the virus is replicating at the time of transplantation, infection of the grafted liver is a virtual certainty with potentially devastating long-term consequences of recurrent hepatitis or even malignancy. Alpha-interferon, although reasonably effective in clearing the replicating virus, seems likely to stimulate liver rejection by increasing the HLA display on the grafted liver cells. Whether such a concern is justified, and whether reinfection of the graft can be avoided by a pretreatment program remains to be seen. Perhaps a role for acyclovir or additional antiviral agents will be developed for this particular setting. SUMMARY The last three decades have witnessed considerable progress in our understanding of the pathogenesis and treatment of chronic hepatitis. Although much remains to be established regarding speDM,

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cific causes and treatments, therapeutic intervention with immunosuppression and antiviral agents can be effective, and will be increasingly so as our understanding of the diseases increases. Additidnal studies on the pathophysiology of hepatic fibrosis and liver regeneration will hopefully broaden our therapeutic options in the near future. Until then, our best efforts are directed at careful assessment and diagnosis, with such intervention as is possible. REFERENCES 1. DeGroote J, Desmet VJ, Gedegk P, et al: A classification of chronic hepatitis. Lancer 1968; 2:626-628. 2. Bianchi FB, Biagini G, Ballardini G, et al: Basement membrane production by hepatocytes in chronic liver disease. Hepatology 1984; 4:1167-1172. 3. Schaffner F, Popper H: Capillarization of hepatic sinusoids in man. Gastroenterology 1963; 44:239-242. 4. Benoit JN, Zimmerman B, Premen AJ, et al: Role of glucagon in splanchnic hyperemia of chronic portal hypertension. Am J Physiol 1986; 251G674G677. 5. Ware AJ, Cuthbert JA, Shorey J, et al: A prospective trial of steroid therapy in severe viral hepatitis: The prognostic significance of bridging necrosis. Gastroenterology 1981; 80:219-224. 6. Boyer JL, Klatskin G: Pattern of necrosis in acute viral hepatitis: Prognostic value of bridging (subacute hepatic) necrosis. N Engl J Med 1970; 283:10631071. 7. Chung WK: Chronic hepatitis in Korea, in Popper H, Schaffner F teds): Progress in Liver Diseases. New York, Grune & Stratton Inc, 1986, vol 8, pp 469484. 8. Weissberg JI, Andres LL, Smith CI, et al: Survival in chronic hepatitis B: An analysis of 379 patients. Ann Intern Med 1984; 101:613-616. 9. Anderson MG, Murray-Lyon IM: Natural history of the HBsAg carrier. Gut 1985;26:848-860. 10. Sanchez-Tapias JM, Vilar JH, Costa J, et al: Natural history of chronic persistent hepatitis B: Relationship between hepatitis B virus replication and the course of the disease. J Hepatol 1984; 1:15-27. 11. Liaw YF, Chu CM, Su IJ, et al: Clinical and histological events preceding hepatitis Be antigen seroconversion in chronic type B hepatitis. Gastroenterobgy 1983; 84:216-219. 12. Soloway RD, Summerskill WHJ, Baggenstoss AH, et al: Clinical, biochemical, and histological remission of severe chronic active liver disease: A controlled study of treatments and early prognosis. Gastroenterology 1972; 63:820-833. 13. Christofferson P, Poulson H, Winkler K: Clinical findings in patients with hepatitis and abnormal bile duct epithelium. Stand J Gastroenterol 1970; 5:117-121. 14. Popper H, Schaffner F: Chronic hepatitis: Taxonomic, etiologic, and therapeutic problems, in Popper H, Schtier F (eds): Progress in Liver Diseases. New York, Grune & Stratton Inc, 1976, vol 5, pp 531-5.58. 15. Popper H, Schaffner F: The vocabulary of chronic hepatitis. N Engl J Med 1971;284:1154-1156. 16. Wilkinson SP, Portmann B, Cochrane AMG, et al: Clinical course of chronic lobular hepatitis: Report of five cases. Q J Med 1978; 188:421429. 152

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17. Liaw YF, Chu CM, Chen TJ, et al: Chronic lobular hepatitis: A clinicopathological and prognostic study. Hepatology 1982; 2258-262. 18. Zajicek G, Oren R, Weinreb M Jr: The streaming liver. Liver 1985; 5293-300. 19. Chapman RWG, Arborgh BAM, Rhodes JM, et al: Primary sclerosing cholangitis: A review of its clinical features, cholangiography, and hepatic histology. Gut 1980; 21870-877. 20. Weisner RH, Larusso NF: Clinicopathologic features of the syndrome of primary sclemsing cholangitis. Gastroenterology 1980; 79:200-206. 21. Balasubramaniam K, Weisner RH, LaRusso NF: Can serum alkaline phosphatase levels be normal in primary sclemsing cholangitis? Gastroenterology 1987; 92:1303. 22. Redeker AG: Viral hepatitis: Clinical aspects. Am .I Med Sci 1975; 270:9-16. 23. Sharfitz DA, Rogler CE: Molecular characterization of viral forms observed in persistent hepatitis infections, chronic liver disease and hepatocellular carcinoma in woodchucks and humans, in Vyas GN, Dienstag JL, Hoofnagle JH (eds): Viral Hepatitis and Liver Disease. New York, Grune & Stratton Inc, 1984, pp 225-243. 24. Summers J: Replication of hepatitis B viruses, in Vyas GN, Dienstag JL, Hoofnagle JH teds): Viral Hepatitis and Liver Disease. New York, Grune & Stratton Inc, 1984, pp 87-96. 25. Tiollais P, Dejean A, Brechot C, et al: Structure of hepatitis B virus DNA, in Vyas GN, Dienstag JL, Hoofnagle JH teds): Viral Hepatitis and Liver Disease. New York, Grune & Stratton Inc, 1984, pp 49-65. 26. Thomas HC, Pignatelli M, Goodall A, et al: Immunological mechanisms of cell lysis in hepatitis B virus infection, in Vyas GN, Dienstag JL, Hoofnagle JH (eds): Viral Hepatitis and Liver Disease. New York, Grune & Stratton Inc, 1984, pp 167-177. 27. Lam KC, Lai CL, Trepo C, et al: Deleterious effect of prednisolone in HBsAgpositive chronic active hepatitis. N Engl J Med 1981; 304:380-386. 28. Thomas HC, Lever AML, Scully LJ, et al: Approaches to the treatment of hepatitis B virus and delta-related liver disease. Semin Liver Dis 1986; 6:3441. 23. Pignatelli M, Waters J, Lever A, et al: Cytotoxic T-cell responses to the nucleocapsid proteins of HBV in chronic hepatitis: Evidence that antibody modulation may cause protracted infection. J Hepatol 1987; 4:15-21. 30. Reed WD, Eddleston ALWF, Cullens H, et al: Infusion of hepatitis B antibody in antigen-positive active chronic hepatitis. Lancet 1973; 2:1347-1351. 31. Nilius R, Schentke U, Otto L, et al: Levamisole therapy in chronic hepatitis: Results of a multicentric double blind trial. Hepatogastroentero/ogy 1383; 30:90-92.

32. Shulman ST, Hutto JH, Ayoub EM, et al: A double-blind evaluation of transfer factor therapy of HBsAg-positive chronic aggressive hepatitis: Pmliminary report of efficacy. Cell Immunol 1979; 43:352-361. 33. Sagnelli E, Piccinino F, Manzillo G, et al: Effect of immunosuppressive therapy on HBsAg-positive chronic active hepatitis in relation to presence or absence of HBeAg and antiHBe. Hepatology 1983; 3:690-695. 34. Karayiannis P, Fowler MJF, Lok ASF, et al: Detection of serum HBV-DNA by molecular hybridization: Correlation with HBeAg/anti-HBe status, racial origin, liver histology and hepatocellular carcinoma. J Hepatol 1985; 1:99-106. 35. Matsuyama Y, Omata M, Yokosuka 0, et al: Discordance of hepatitis Be antigen/antibody and hepatitis B virus deoxyribonucleic acid in serum: Analysis of 1063 specimens. Gastroenterology 1985; 98:1104-1108. 36. Gregory P: Treatment of chronic viral hepatitis, in Vyas GN, Dienstag JL, DM,

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HBeAg-positive hepatitis with acyclovir: A controlled trial. J Hepatol 1986; 3:s143-s147. Omata M, Hirota K, Yokosuka 0: In vivo study of the mechanism of action of antiviral agents against hepadna virus replication in the liver: Resistance of supercoiled viral DNA. J Hepatoll986; 3:S49-S55. Hoofnagle JH: J Hepatol 1986; 3(suppl Z):S73-SBO. Pollard RB, Smith JL, Neal A, et al: Effects of vidarabine on chronic hepatitis B infection. JAMA 1976; 239:X%48-1650. Scullard GB, Pollard RB, Smith JL, et al: Antiviral treatment of chronic hepatitis B virus infection: I. Changes in viral markers with interferon combined with adenine arabinoside. J Infect Dis 1981; 143:772-783. Scullard GB, Andres LL, Greenberg HB, et al: Antiviral treatment of chronic hepatitis B virus infection: Improvement in liver disease with interferon and adenine arabinoside. Hepatofogy 1981; 1228-232. Chadwick RG, Basendine MF, Crawford EM, et al: HBsAg-positive chronic liver disease: Inhibition of DNA polymerase activity by vidarabine. Br Med J 1987; 2:531-533. Trepo C, Hantz 0, Ouzan D, et al: Therapeutic efficacy of ARA-AMP in symptomatic, HBeAg positive C&H: A randomized, placebo control study. Hepatology 1984; 4:1055. Alexander GJM, Fagan EA, Roland0 N, et al: Differential effect of ARA-AMP on serum DNA polymerase activity and serum HBV-DNA in chronic hepatitis B virus infection: A possible reason for lack of efficacy. J Hepatol 1986; 3(suppl 2):S81-586. Shouval D, Adler R, Wands JR, et al: Conjugates between monoclonal antibodies to HBsAg and cytosine arabinoside. J Hepatof 1986; 3(suppl 2l:S87s95. Realdi G, Alberti A, Rugge M, et al: Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection. &.StFOenteFO~Ogy 1980; 79:195-199. Hoofnagle JH, Dushieko GM, Seeff LB, et al: Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med 1981; 941744-748. Burrell CH, Gowans EJ, Rowland R, et al: Correlation between liver histology and markers of hepatitis B virus replication in infected patients: A study by in situ hybridization. Hepatology 1984; 420-24. Liaw YF, Chu CM, Su IJ, et al: Clinical and histologic events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis. &StFoenterology 1983; 84:216-219. Rakela J, Redeker AG, Welicky B: Effect of short term prednisone therapy on aminotransferase levels and hepatitis B virus markers in chronic type B hepatitis. &StFOenteFO~Ogy 1983; 84:954-960. Scullard GH, Smith CL, Merigan TC, et al: Effects of immunosuppressive therapy on viral markers in chronic active hepatitis B. Gastroentero~ogy 1981; 81:987-991. Hoofnagle JH, Dushieko GM, Schafer DF, et al: Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med 1982; 96:447-449. Nair PV, Tong MJ, Stevenson D, et al: A pilot study on the effects of prednisone withdrawal on serum hepatitis B virus DNA and HBeAg in chronic active hepatitis B. Hepatology 1986; 6:1319-1324. Hoofnagle JH, Davis GL, Pappas C, et al: A short course of prednisolone in

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