Current concepts of chronic hepatitis

Pathology

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Current Concepts of Chronic Hepatitis Malcolm Mackinnon, W. G. E. Cooksley, W. D. Reed & P. De La M. Hall To cite this article: Malcolm Mackinnon, W. G. E. Cooksley, W. D. Reed & P. De La M. Hall (1981) Current Concepts of Chronic Hepatitis, Pathology, 13:2, 277-288 To link to this article: http://dx.doi.org/10.3109/00313028109081667

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Pathology (1981). 13. pp. 277 88

CURRENT CONCEPTS OF CHRONIC HEPATITIS* MALCOLM MACKINNON, W. G. E. COOKSLEY, W. D. REEDA N D P. DE LA M. HALL The Flinckrs Medicul Cmtrr Dppurtnietits o j Merlicinc unrl Histopritliolo~~~., Depurtnien f of' Medicine Utiivrrsitj. of' W~srcvnA ustruliu urirl D(>purtnw t i t of Biochemi.rtr.y, Univrrsitj. of Quc~nslutzcl '

K e i , Word\: hepatitis, chronic persistent hepatitis, chronic active hepatitis

The major problem limiting our understanding of chronic hepatitis relates to the definition of the disease. Semantic confusion has led t o difficulties in interpreting therapeutic trials' and limits the usefulness of comparing studies in different geographic locations. At the present time the most satisfactory approach to the concept of chronic hepatitis is based on the Fogarty Proceedings' definition. DEFl NITION Although the term chronic hepatitis in reality describeschronic inflammatory liver disease of any aetiology, the term is usually restricted to those diseases that follow viral hepatitis or are of unknown aetiology.' Identical clinical, functional and morphological features may be found also in chronic liver disease of other aetiologies such as drug induced,3alcoholic liver disease,4 CI 1 antitrypsin deficiency5 and Wilson's disease." These latter conditions, albeit associated with chronic liver inflammation, are excluded by definition from the working classification of chronic hepatitis. Thus, the first aspect of the definition of chronic hepatitis has aetiological overtones. The second consideration in the definition concerns temporal aspects. SInce the time of onset is often unclear, the arbitrary figure of6 mth is now accepted as the minimum duration of documrntcrldisease before the term chronic hepatitis is applied. The shorter time o f 3 mth' is n o longer considered appropriate. Because of the lack of specificity of clinical and laboratory features the third aspect of definition is morphological. Chronic,por.si.rfcnt Iwputitis denotes the histological pattern of ;I disease which is rarely progressive, while chronic m f i w Iwprititis refers to the histological pattern of a disease which has the potential to progress to fibrosis, cirrhosis and liver failure. Because of the wide spectrum of clinical disease, the absence of known aetiology in many cases and the disputed significance of certain histological and laboratory parameters, other * Based on a seminar by the Australian Liver Research G r o u p a t the Annual Scicntific Meeting o l t h c Australian Society Ibr Medical Rescarch ( A S M R ) in December 1979.

278 M A C K I N N O N ct a/. I'arliology (1981). 13. April classifications' of chronic hepatitis cxist with terms such as chronic lobular hepatitis. lupoid hepatitis and the more embracing term chronic active liver disease. possibly including primary biliary cirrhosis. Furthermorc, the different prognosis and response to treatment of chronic active hepatitis due to the hepatitis B virusX has led to the introduction of the subgroups hepatitis B positive and hepatitis B negative chronic active hepatitis. As a result, the improvement in prognosis due to effective therapy in patients with chronic active hepatitis is set against ii nosological nomenclature which lcaves much to be desired.' The definition ofchronic hepatitis is, therefore, primarily morphological with a secondary aetiological classification, and at the present time chronic kepcititis refers to active liver disease with specific histological features, present for more than 6 rnth and not due to diseases such as Wilson's disease or alcoholism. CLINICAL FEATURES

The clinical features of chronic hepatitis have recently been reviewed," and generally they are non-specific with occasional association of other diseases such a s ulcerative colitis, thyroiditis, rheumatoid arthritis and glomerular and tubular renal disease." It is of interest to stress, however, that the clinical pattern of chronic active hepatitis appears t o be changing. Fifteen yr ago the disease was one of young females with hyperglobulinaeiiiia and positive autoantibodies."' In our recent experience this presentation is much less common, and this suggests that the aetiology of the disease may be changing. With a wide spectrum of clinical disease histological examination of liver tissue to dist i ng u ish clzronic uctivc lwpa tit is from chronic ,wrsistcn I hrpcrtitis is ma nd a t ory . Every attempt should be made to provide a n aetiological diagnosis in patients whose liver disease histologically mimics chronic active hepatitis, and of particular importance is the recognition that drugs such as methyldopa, isoniazid, nitrofurantoin and possibly aspirin and paracetainol may induce chronic hepatic inflammation." PATHOLOGY

The diagnosis of chronic hepatitis is based on the pattern of damage seen in the liver biopsy. However, since an identical picture may be seen in the liver during an episode of acute viral hepatitis," knowledge of the clinical and biochemical findings is necessary to establish the chronic nature of the process. Chronic hepatitis is classified as clzronic prrsistcnt or chronic activr hepititis." I t is sometimes difficult to differentiate between the two patterns of liver damage, particularly if the liver biopsy is technically poor o r the amount of tissue inadequate for evaluation. Serial biopsies are often necessary for accurate diagnosis, assessment of progression or recovery and to follow the effects of specific treatment. Accurate diagnosis is essential because of the different prognosis of chronic persistent and chronic active hepatitis.", I s

(i) Chronic Persistent Hepatitis The histological changes are in the portal tracts, the architecture of the liver is undisturbed and there is minimal hepatocyte damage in the liver lobules. The portal tracts contain an infiltrate of lymphocytes with occasional plasma cells or macrophages. There is little or no increase in the amount of fibrous tissue in the portal tracts. Of greatest importance is the absence of 'piecemeal' necrosis of hepatocytes in the region of the limiting plate, i.e. the

FIG. I Portion of a liver biopsy showing 'piecemeal necrosis' o f hepatocytes and extension of a chronic inflammatory cell infiltrate into the periphery of a liver lobule. H & E x 450

hepatocytes a t the periphery o f t h e liver lobule. In a number ofcases the aetiology m a y be reflected by iinmuno-histochemical demonstration of HBsAg in the hepatocyte cytoplas111,"' and when a large amount of HBsAg is present the cells have an abundant eosinophilic cytoplasm and appear as 'ground-glass' hepatocytes." The cells usually stain positively with orcein." In general the prognosis is good, progression to cirrhosis does not occur and with time (he liver rnay return to normal. However, occasionally progression to chronic active hepatitis may occur without apparent clinical o r biochemical deterioration''. "' emphasizing the importance of serial biopsy in the inanageinent of these patients.

(ii) Clironic Activc Hepatitis The clinical, biochemical arid serological features may be suggestive of this form of chronic hepatitis, but a definite diagnosis can only be made on the basis of histological features in the liver biopsy. The presence of 'piecemeal necrosis'20is necessary for this diagnosis. This lesion is characterized by foci of lymphocytes and plasma cells destroying hepatocytes in the region of the limiting plate (Fig. 1). It is unusual t o see the dead or damaged hepatocytes, but a reticulin stain will demonstrate the disruption of the limiting plate and focal collapse of the reticulin framework in the areas where hepatocytes have been destroyed (Fig. 2). The portal tracts contain an infiltrate of lymphocytes and plasma cells with an occasional macroph;tge. However, the intensity ofthis infiltrate does not appear to correlate particularly well with the rate of progression to cirrhosis, possibly because the degree of activity may fluctuate Several studies have suggested that a relatively slow progressioil to hepatic

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Pathology (1981), 13, April

FIG. 2 Portion of a liver biopsy showing foci of condensation of the reticulin framework in areas where ‘piecemeal‘ necrosis of hepatocytes has occurred. Gordon & Sweet’s impregnation for reticulin x 450

fibrosis and cirrhosis may occur when ‘piecemeal necrosis’ is mild and confluent hepatocyte necrosis is not seen.” Indeed, the hypothetical but unproven key to the likelihood of progression to cirrhosis (and the need for treatment) may lie, as suggested by Boyer,22 with the lesion of bridging necrosis. This pattern of damage is due lo the presence ofconfluent areas of liver cell necrosis which extend between adjacent portal tracts, o r from a portal tract to an adjacent central vein resulting in reticulin framework collapse and ‘passive’ septum formation (Fig. 3). A heavy infiltrate of lymphocytes and plasma cells with lesser numbers of macrophages is present in the septa. Piecemeal necrosis of hepatocytes often occurs on either side of the septa, and the inflammatory process extends into the adjacent parenchyma. In 1963 Schaffner & Popper23described the presence of a basement membrane around the sinusoids that remain in these septa. This process they called ‘capillarization’, and suggested that this vascular abnormality may play a part in the intrahepatic shunting of blood within the microcirculation of the liver, which may in turn contribute to progression of the liver disease. New fibrous tissue appears soon after the development of passive septa, at which stage these areas of bridging are referred to as ‘active’ septa. Very occasionally there may be a prominent cholangitic type of lesion.’4 This pattern of damage may suggest primary biliary cirrhosis, but while the bile duct epithelium may be infiltrated by inflammatory cells, it does not become degenerative, and the serological test for anti mitochondria1 antibody is negative. Mixed patterns of chronic active hepatitis and primary biliary cirrhosis have been described.’’

(

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FIG. 3 Portion of :I liver biopsy rhonsing ’bridging’ necrosih. A p a s \ ~ v eseptum consisting of collapsed reticulum li-arncwork extends lrom ii portal tract across the core of liver and partially ,urrouiids scvcral groups of likcr cells. Gordon & Sweet’s impregnation for i-cticulin x I80

Other changes described in chronic active hepatitis include lobular disarray, increased mitotic activity and pleomorphism of liver cells, evidence of liver cell regeneration often with the formation of ‘pseudo acini’, and K upffer cell hyperplasia.

(iii) Chronic A c t i w Heputitis and cirrhosis The initial biopsy may show the features of an established cirrhosis with chronic active hepatitis. This is seen most commonly i n relatively asymptomatic patients who present late in the course of their discase.12 On the other hand chronic active hepatitis may progress to cirrhosis over a variable period of time.”.’” If the cirrhosis is micronodulai-. the diagnosis can be made on needle biopsy of the liver: with macronodular cirrhosis the biopsy may suggest but not necessa r i I y est a b 1i s h the d i a gii o s i s . An increasingly common and consequently important complication ofchronic hepatitis B virus infection is the development of primary hepatocell~ilai-carcinoma. The tuinours develop in associalion with chronic active hepatitis with cirrhosis. but also may develop in the asymptomatic young carriers of hepatitis B who have littlc or no evidence of hepatitis,’x. 3

’’

PATHOGENESIS Although the pathogenetic mechanisms leading t o chronic hepatitis have not been established, the characteristic histological picture and response to corticosteroid therapy implicate abnormalities of the immune syslem. Recent evidence suggests that inany oft hese patients have a genetically determined increase in their immune responsiveness. T he evidence for H BsAg negative and positive disease will be considered separately.

282 MACKINKON et [ I / . H BSA g twgot iw C/Iron ic A c t i

Pathology ( 1 0 X l ) 3 13. April

H q m t it is Hyperglobulinaemia is a common finding in inany forins o f chronic liver disease, particularly where cirrhosis is present. In most cases, this is thought to be the result of reduced hepatic phagocytosis and unrelated t o aetiology?” However, i n HBsAg negative chronic active hepatitis ( C A H ) marked elevation of serum gamma globulin, mostly IgG, is an early feature of the disease, and family studies have shown that many first degree relatives of these patients have raised serum immunoglobulin levels in the absence of any clinical or biochemical signs of liver disease.”.” The observation of a positive lupus erythematosus (L.E.)cell phenomenon in some cases” and the presence of autoantibodies i n serum of both patients and relatives3’.’‘ lend further support to the concept of an inherited defect in immune regulation. Further convincing evidence o f a genetic component to the disease came from the discovery of a strong association with the histocompatibility antigen HLA-BX. MacKay & Morrisi4 detected this antigen in more than 600, oftheir patients with C A H , and the association was strongest in those cases with high titre autoantibodies in the serum. Recently Opelz et ul.’5 have reported a n even stronger association with the D locus antigen HLA-Dw3. Histocompatibility antigens are known to be quite closely linked t o genes determining some aspects of regulation and intensity of immune response in mice,’6 and similar associations have been sought in man. Triger et ~ 1 . have ~ ’ reported that many patients with C A H have antibodies to measles and rubella in high titre without evidence of recent infection, suggesting a defect in control of antibody production. Galbraith Ct u1.j’ have shown that the highest titres of rubella and smooth muscle antibodies are found in patients possessing HLA-BX and that another second locus antigen HLA-B12 is associated with a similar increase in measles and antinuclear antibodies. Eddleston & Williams3”have shown that there is an inverse correlation between length of survival and rubella antibody titre in patients with HBsAg negative chronic active hepatitis. suggesting that the antibody titres may reflect the intensity of an immune assault against hepatocytes. They have also shown that the presence of HLA-B12 and to a lesser extent HLA-BX in patients with CAH is associated with increased mortality. In contrast, possession of HLA-B7 was associated with lower titres of antibody to rubella and smooth muscle and decreased mortality. I n another family study“’ titres of rubella antibodies were significantly higher and serum autoantibodies more frequent in the first degree relatives of patients with CAH. However they were unrelated to the inheritance of HLA-BX o r t o each other. This finding argues strongly against the simple inheritance of an immune response gene linked to HLA in patients with CAH and is more consistent with the presence of a generalized non-specific increase in immune responsiveness under polygenic control. H B.vAg posifivc C‘liroiiic, Active Hepatiris

The genetic background in patients with HBsAg positive chronic active hepatitis appears to be quite different. Certainly there is n o association with HLA-BX.4’ but the frequency of this antigen is also low in control populations in areas where H BsAg positive disease is prevalent. Positive associations with HLA-BW17 and HLA-BW35 have been reported i n patients with HBsAg positive chronic active he pa ti ti^.^' In antigen positive chronic active hepatitis lymphocyte sensitization to HBsAg has been demonstrated.43However, it is unclear whether this or other HBV antigens are the target of cytotoxic responses against infected hepatocytes. Similarly, no direct pathogenetic role has been demonstrated for antiviral antibodies. An

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alternative explanation for the role of persistent HBV may be virus-induced loss of immune regulation leading to uncontrolled autoimmune reaction against liver, in contrast with the genetically determined defect in immunoregulation of H BsAg negative cases. The reason for the increased susceptibility of males t o chronic infection with HBsAg is not known. It applies to both healthy carriers and patients with liver disease, and in a study of H BsAg positive patients with hepatoina n o generalized defect in either cellular or humoral immune responses was found.44 The possibility of a specific immune defect remains. Liwr-specific. uutoinimunitj,

Until recently substantial evidence of organ-specific immune reactions i n chronic hepatitis has not been available. However, the isolation by Meyer zum Buschenfelde & Miescher” o f 2 organ-specific proteins from human liver has allowed the demonstration of both cellmediated immune responses‘” and organ-specific antibodies in patients with chronic active hepatitis.” This liver-specific lipoprotein (LSP) is species cross-reactive and can induce both autoantibody production and the histological lesion of chronic active hepatitis progressing to cirrhosis when injected into rabbits.4xThoinson et u / . ~ have ’ shown that lymphocytes from patients with CAH are cytotoxic to isolated rabbit hepatocytes in tissue culture. This reaction is specifically inhibited by addition of purified LSP, suggesting that this lipoprotein is the principal target antigen on the liver-cell membrane. More recently it has been shown that cytotoxic lymphocytes from patients with chronic active hepatitis are non-T cells”’ and normal moiionuclear cells become cytotoxic when prc-incubated in C A H sera.” On the basis of these observations it has been suggested that specific antibody to LSP acts to focus lymphoid killer cells to produce the ongoing damage to periportal hepatocytes in chronic active hepatitis in an antibody-dependent cellular cytotoxicity (ADCC) reaction. These findings have recently been confirmed in a system employing autologous hepatocytes from patients with H BsAg negative chronic active hepatitis.” Decreased suppressor T-cell activity has been put forward to explain continued autoantibody production to LSP and liver cell damage in HBsAg negative chronic active hepatitis.’j A suppressor T-cell defect related to HLA antigens has been reported in other autoimmune disease in man54and in CAH there is some evidence of both a generalized defect in suppressor T-cell function” and a specific defect in T-cell response to liver-specific lipoprotein.” Such a defect in suppressorlymphocyte function may provide the link between the specific immune effector mechanism involved in disease progression in H BsAg negalive chronic active hepatitis and the genetic lack of immune regulation related t o HLA. The proposed organ specificity of the liver cell membrane lipoprotein has recently been questioned by Behrens & P a r ~ n e t t o . ~In’ view of the large size and complexity of the LSP molecule it s e e m likely that it contains several antigenic subunits soine of which are tissuespecific while others are not. Mice injected with homologous liver protein. unlike rabbits immunized with heterologous material, produce autoantibodies which react only with the cell membrane of hepatocytes and not with other tissues. Thus, while much positive evidence implicating the immune system in the pathogenesis of C A H is accumulating, the primary role of this system remains t o be established.

THERAPEUTIC CONSIDERATIONS

A number of controlled clinical trials have demonstrated that corticosteroids have a beneficial effect in chronic active hepatitis. Nevertheless, the problems associated with these

284 RIACKINNON P I a/. Pathology ( l % l ) ? 13. April major studies have been presented by Wright r t (11.' who conclude that faults in study design and problems with definition of the disease have resulted in a soinewhat confused picture. At the present time the following approaches to the treatment of chronic hepatitis would appcur to be valid. ( a ) N o activc treatment is required for chronic persistent hcpatitis. However. since progression to chronic active liepatitis may occur without apparent deterioration in clinical o r bioclieimical parameters," careful follom-up is mandatory. This must include serial liver biopsy, until such time as the liver is morphologically normal. (b) Corticosteroids ( kazathioprine) are indicated in patients with chronic active hepatitis who are:' (i) symptomatic ( i i ) havc severe histological lesions, e.g. inultilobular or bridging necrosis on biopsy ( i i i ) H BsAg negative. The major areas of concern are the indications for active treatment in patients with chronic active hepatitis but without bridging necrosis, and the response to treatment of patients who are HBsAg positive. The problem of chronic active hepatitis without bridging necrosis has been analysed by Boyer" and Conn.'x Evidence at present suggests that chronic active hepatitis with piecemeal necrosis but without bridging necrosis is much less likely to progress to cirrhosis than is the case when the lesion is associated with bridging necrosis.". " While the most easily definable treatment goal is that of prolonged survival, it would be logical to assume that mortality in this disease relates to the devclopinent of irreversible damage and cirrhosis. If this is so, i t may be difficult to justify treating patients who d o not demonstrate bridging necrosis and thus a likelihood of progression to cirrhosis. Clearly further studies to define the indications for corticosteroid treatment in chronic active hepatitis without bridging necrosis are needed. Similarly, the indications Tor treatment in patients with HBsAg positive chronic active hepatitis are far from clear. In ii small subseries froin the Mayo Clinic studyXthe following indications emerged from the 13 HBsAg positive patients studied: ( i ) Treatment response was less likely, and particularly histological remission was much less common. in antigen positive patients than in age, sex and severity matched HB,Ag negative patients: ( i i ) Corticosteroid requirements were greater: (iii)Death was more common in the HBsAg positive treated group (4'13 vs. 1 13 HBsAg negative). Overall, the response to corticosteroid treatment in HBsAg positive patients with chronic active hepatitis appears to be less gratifying than in antigen-negative patients. Nevertheless, I proportion of antigen-positive patients d o respond to treatment, and a critical question deinandiiig an answer at the present time concerns the definition of patients who are likely to benefit from corticosteroid treatment. Since corticosteroid dosage may have to be high and sustained. side effects froin treatment may be inore common. Furthermore, preliminary data from Scullard c't ~ 1 . 'indicate ~ that corticosteroid steroid treatment in antigen-positive patients inay increase the indices of HB virus infectivity. Treatment of antigen-positive patients must becarefully considered in the light o f t h e above observations until the situation is clarified by further controlled clinical studies. The above problems with antigen-positive chronic active hepatitis apply to some extent to chronic active hepatitis generally. Certainly some patients. indeed many patients, with

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chronic active hepatitis benefit from treatment; nevertheless studies to date have not clearly defined the need for treatment, for example, in patients with the histological lesion of piecemeal necrosis alone compared to patients with bridging or niultilobular necrosis. The problem is partly semantic, for any assessment of treatment will be dependent on the criteria accepted to define the disease. The current solution is to define the disease arbitrarily. Tlie clinical and histological features will, to a large extent, simply reflect the criteria for diagnosis of the disease. Some of the problems with this classification have been outlined above. An aetiologically based classification is the most rational answer. Our progression towards this end is occurring slowly, albeit in a somewhat haphazard fashion. Classification based primarily on aetiology would enable us to define a disease aetiologically, e.g. viral hepatitis B, qualified by its duration, its morphology and its complications. Tlie problem with this approach to classification is that many, if not m o s t , patients with chronic active hepatitis have at present an unknown aetiology. However, in some series the use of anti H B core antibody is increasing the proportion of patients with an hepatitis B aetiology, and it is anticipated that markers for viral hepatitis non-A, nonB will further reduce the number with a n unknown aetiology. The establishment of an aetiological diagnosis must be our major long-term goal. A prognostic-therapeutic classification. Since the current definition is directed at prognostic considerations, one may modify the present classification in an attempt to predict those who will respond to treatment. As indicated, there is evidence that patients with HB,Ag positive chronic active hepatitis have a different prognosis and response to treatment than those with other forms.* Further critical analysis of the relationship of morphology to prognosis and treatment response is indicated. A final approach to re-classification would be the use of numerical taxonomy (cluster analysis). In this approach, used by Jones e t ~ l . ~in' )inflammatory bowel disease, each patient is compared with each other patient for every variable to see if clusters appear that reflect a group which could be called a disease entity. There are no preconceived definitions; however one may unwittingly overlook critical variables, and the homogeneity necessary for classification may mask the heterogeneity of the disease. I f the different aetiologies of chronic active hepatitis are not clarified in the near future, the possibility that numerical taxonomy might allow a classification into groups characterized by their similarities should be considered. Over the past decade, with the recognition of HB virus as a cause of chronic active (and chronic persistent) hepatitis, progress has been made towards a rational aetiological classification. Nevertheless, semantics still confuse the therapeutic approach; it more critical analysis of therapy, particularly related to aetiological and morphological facets, is needed. Adr1rr.s.~ ,fbr c ~ ~ e s p o n t l e n c eM.M., t Department of Gastroenterology, Flinders Medical Centrc. Bedford Park. South Australia 5042

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2. LEFVY. C. M . & TYGsrRur, N . (1976): Standardisation of nomenclature, diagnostic criteria and diagnostic morphology. I n Diciwc,.s of the Liwr and Biliurj. Trur,/. Karger, Basel. pp. 9-10,

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3. Cooasiru, W. G . E.. ow^"^. A. E. & POWFLL, I-. W . ( 1973): The incidence of oxyphenisatin ingestion in active chronic hepatitis: a prospective controlled study o f 2 9 patients. Au.rt. N.Z. J .Mcd. 3, 124-128. 4.GOLI)BLK(;. s. J.. MtNIlP"rHA1.L. c. L., CO%VELL, A . M . & Circorn. A. (1977): 'Non nlcoholic' chronic hepatitis in the alcoholic. Gu.str.ocn/rro/o,q.12, 598- 604. 5. r R l ( i f l < . D . R.. M I L IW.\I
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22. BOYER, J . L. (1976): Chronic hepatltis -a perspective on cl~issificationand determinants of prognosis. G a s / r o r n / c ' r o / i ~70, ~ ~ ,1161- 1171. 23. SCHAbrNER, F. & POPPER. H. (1963): Capillarization of hepatic sintisoids in inan. ~;u.srrori~IPr.o/t~~~i. 44, 239-242. 24. P ~ C L S F N H . . BL CHRISTOF~EKSHN, P. (1972): Abnormal bile duct epithelitini in chronic aggressive hepatitis and cirrhosis. Hum. PufI7o1. 3, 217- 225. 25. Ki.orPLL. G., SIEI-FIIT,G.. LIIINFR.H. P I u/.( 1977): Histopathological features i n mixed types of chronic aggressive hepatitis and primary biliary cirrhosis. V/rc.hon..s ,4r(,/i. i Prrtliol 4nor.) 373, 143 160. 26. DtGKOOTt. J., F F V E K Y . J . & LtPOL'TKT. L. (1978): Long term follow up of chronic active hepatitis of moderate severity. Gut 19, 510-513. 27 Sc HEUFR. P. J . (1973): Lircar. I3iop.s) Inrc~'prc~ruf/(~n. 2nd ed. Bailliere Tindall. London. pp. 78 X4. 28. HADLIYANNIS,S. J . (1080): Hepatocellular carcinoina and type B hepatitis. In C'linic,.s / n G ~ ~ . s / r . ~ i ~ ~ ~ f Eds r r o /I.o gA. l ~ D. Bouchier. B. N . Brooke, W . Cleutzfeldt. N . C. Hightower and H. Worming. Saunders, London. pp. 1 17- t34. 29. SUMITHRAN. E. & M r S w t n , R. N. M. (1979): An appraisal of the relationship between primary hepatocellular carcinoma and hepatiti5 B virus. Ifi.sto/~cr/ho/o,~i, 3, 447 458. 30. TKKER.D. K . (1976): The liver as a n immunological Orgall. G~/.Sfrc/c,/7Ic'r.o/iJ~1' 71, 162-164. 31. JOSKE. R. A. Cyr LAUKtMT, R. H. (1970): Familial cirrhosis with autoimmune features and raised i i n ni u n ologica I level s . Ga.vtrocafi'r.o/og.i. 59, 546-552.

(7HROKIC' EIEPA~I'ITIS

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~Al.BKAlTI1.

A.. BIAS.W. B. ef a/.(1977): 42. H I I LIS. W. D.. HILLIS, Associations of hepatitis B Surface antigenacmia with HLA locus B specificitie,. N. Eng/. J . Mcd. 296, 1310-1314. 43. LEE. W. M.. R w i , W. D , MIT('HEI.1.. C. G. ('I ul. ( 1975): Cellular and humoral iiiiinunitq t o liepatitis-B surface antigen in aclive chronlc hepatitis. Br. Mctl. J . I , 705-708. A,. V o w . C. L. & BARKER,L. F. 44. PKIMA(,K. (1973): linniunolopical studies in Ugandan patients with hepatocellular carcinom'i. Br. Med. J I , 16-19. 45. MrYtK 7 ~ 1 1 BUSCHEUP~LDE. K. H. & M i t s c i i t i ~ , P. A . (1972): Liver specific antigens: purification and characterization. C'/in. Evp. Ininwnol. 10, 89-102.

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