R.A. Fox

CELLULAR IMMUNITY AND HEPATITIS-ASSOCIATED, AUSTRALIA ANTIGEN LIVER DISEASE

Abstract After contact with material containing hepatitis-associated Australia antigen (H.A.A.), a complex set of interactions between both the related infective agent and the immune response of the host, both cellular and humoral, ensues. Evidence is presented which suggests the predominant importance of the cellular immune response in this interaction. Although immune complexes of H.A.A. and antibody are thought important in producing some of the varied clinical manifestations, the cellular immune response seems to determine the severity and persistence of the associated liver-cell damage. It is suggested that the competence of the cell-mediated (T-lymphocyte-dependent) immune system would decide whether the infection is self-limited or persists with varying degrees of liver damage.

CHRONIC LIVER DISEASE AND PRIMARY LIVER-CELL CANCER WITH HEPATITIS-ASSOCIATED (AUSTRALIA) ANTIGEN IN SERUM

Abstract Seventeen patients, all males, are Summary described with chronic liver disease and a positive serological test for hepatitis-associated (H.A.) Australia antigen. Two came from the U.K., eight from Greece, three from North or South America, one from Belgium, one from Italy, and two from Africa. Seven presented during follow-up of a severe attack of virus hepatitis. All had received corticosteroid therapy. The other ten had no past history of the acute disease. Liver biopsy was done in sixteen patients. One patient showed only evidence of a recent viral hepatitis, and four showed persistent hepatitis or inactive post-necrotic scarring. These five patients are symptom-free and the prognosis is considered good. Six patients showed histological features of chronic aggressive hepatitis and in four there was also cirrhosis. They differed from classic active chronic (lupoid) hepatitis in being males of an older age-group. Serum bilirubin, aspartate transaminase, and globulin levels tended to be lower. The smooth-muscle antibody was absent from the serum or present only in low titre. Hepatic histological differences were not absolute although three of the H.A. group showed evidence of a recent acute hepatitis. Five patients had primary liver cancer, and in four of these, underlying cirrhosis was demonstrated. Serum-α-fetoprotein was present in two of these five patients. These observations suggest, but do not prove, that acute hepatitis with positive H.A. antigen may be followed by chronic liver disease and cirrhosis and that this can proceed to liver-cell cancer.

Impaired delayed hypersensitivity in primary biliary cirrhosis.

Abstract Primary biliary cirrhosis is a granulomatous disease. Intrahepatic granulomas were found in 29 out of 69 patients, and in 5 of these patients granulomas were found in lymph-nodes from various sites. This indicates that the granulomatous response can be widespread. Skin testing revealed a high incidence of Mantoux negatives in primary biliary cirrhosis compared with controls. Delayed hypersensitivity could be induced with dinitrochlorobenzene in only 46% of patients compared with 94% of controls. Most patients had impaired in-vitro lymphocyte transformation in response to phytohaemagglutinin. These findings indicate that in primary biliary cirrhosis there may be impairment of the normal mechanisms of delayed hypersensitivity. It is suggested that this is a result of the disease process rather than an aetiological factor.

HEPATITIS-ASSOCIATED ANTIGEN IN CHRONIC LIVER DISEASE

Abstract The finding of hepatitis-associated antigen in patients with acute viral hepatitis has been confirmed. 218 patients with various forms of liver disease were studied and the antigen was not found in drug-associated jaundice (8 cases), chronic persistent hepatitis (19 cases), active chronic hepatitis (32 cases), primary biliary cirrhosis (39 cases), or alcoholic liver disease (31 cases). It was found in 3 of 7 patients with prolonged viral hepatitis—a Greek patient with cryptogenic cirrhosis and 2 patients (1 a Greek) with primary liver-cell carcinoma. It is concluded that persistence of the hepatitis virus, as judged by a positive test for hepatitis-associated antigen, is unlikely to be an important factor in the aetiology of chronic liver disease in Great Britain.

Relationship of hepatitis-associated antigen (H.A.A.) to acute and chronic liver injury.

Abstract The serum titres of hepatitis-associated antigen (H.A.A.) and third component of complement have been measured in 87 patients with H.A.A. in their serum and in 18 patients with massive necrosis of the liver. An inverse relationship was found between the H.A.A. titre and liver damage. In acute hepatitis the lowest titres (concentration of H.A.A.) were found in fulminant viral hepatitis. When antigen was present chronically in the serum, titres were highest in the carriers, lower in chronic persistent hepatitis, and lowest in chronic aggressive hepatitis. In one patient with chronic aggressive hepatitis, prednisone therapy was followed by a marked rise in titre associated with a concomitant fall in serum-transaminases. These results suggest that the liver injury in these patients may be due to variations of the immune response to H.A.A. rather than the amount of infective agent present. Liver-cell injury could not be related to serum C 3 (β 1C /β 1A ) levels except in massive hepatic necrosis, where it was uniformly low independent of aetiology. This implies that the low C 3 (β 1C /β 1A ) levels are due to decreased synthesis by the liver rather than increased consumption by immune complexes. These results support the concept that the liver injury and clinical course in H.A.A.-positive patients is related to variations in the patients cellular immune response to H.A.A. rather than to immune complex formation or the amount of infective agent present.

Lymphocyte transformation in response to phytohaemagglutinin in primary biliary cirrhosis: The search for a plasma inhibitory factor

The aim of this study was to determine the importance of plasma inhibitory factors in producing the impaired phytohaemagglutinin (PHA)-induced lymphocyte transformation that is seen in some patients with primary biliary cirrhosis. Twenty-six normal subjects and 12 patients with primary biliary cirrhosis were studied. The lymphocytes from each subject were cultured in the presence of autologous plasma and also in the presence of homologous plasma from a normal subject or from a patient with primary biliary cirrhosis. The results confirm that a proportion of patients with primary biliary cirrhosis are anergic and that the impaired lymphocyte transformation to PHA in vitro can be partially accounted for by the presence of inhibitory factors in the plasma. However, these factors are unlikely to account completely for the impaired transformation, it being probable that there are also abnormalities of the T lymphocytes themselves.

Asymptomatic primary biliary cirrhosis

Four asymptomatic patients are described with raised serum alkaline phosphatase values and a positive serum mitochondrial antibody test. In all four needle liver biopsy showed destructive bile duct lesions. Lymphocyte transformation to phytohaemagglutinin was normal in three and impaired in one who also suffered from rheumatoid arthritis. Two patients showed normal skin and serological test responses to dinitrochlorobenzene and haemocyanin. These four patients are believed to be suffering from asymptomatic primary biliary cirrhosis.

IMMUNOLOGICAL STUDIES IN AN EPIDEMIC OF INFECTIVE, SHORT-INCUBATION HEPATITIS

Abstract Immunological studies were performed on 75 patients from an epidemic of short-incubation infective hepatitis, in which hepatitis-associated antigen was consistently absent. Epidemic hepatitis-associated antigen was detected in over 90% of the patients in the first two weeks of illness, while sera from convalescents were all negative for this antigen. Smooth-muscle antibodies were found in 74% of the patients. The frequency of this antibody was higher in the first week. Titres reached a maximum of 1/80 in the acute phase and all became negative after 14 weeks. Serum IgM levels were raised in the first week and fell during convalescence.

The serum concentration of the third component of complement β1C/β1A in liver disease

Serum C3 (β1C/β1A) has been measured in normal individuals and the range found is in agreement with findings of other authors (85-370 mg/100 ml). In 18 patients with acute hepatitis and massive necrosis serum C3 was consistently reduced to below 50% of normal. In other patients with acute hepatitis the serum C3 concentration was normal. In the majority of the 150 patients with chronic liver disease serum C3 concentration was normal. However, 10 patients (six with active chronic hepatitis, four with cryptogenic cirrhosis) had hypocomplementaemia. The reason for the depression is not clear but could reflect either decreased synthesis or increased consumption, or a combination of the two.

THE ANERGIC STATE AND OTHER IMMUNOLOGICAL CHANGES IN PRIMARY BILIARY CIRRHOSIS

This chapter describes the anergic state and other immunological changes in primary biliary cirrhosis. The results demonstrate that there is a degree of anergy in a proportion of patients with primary biliary cirrhosis. The abnormality appears to be in the delayed hypersensitivity mechanisms related to thymic derived lymphocytes. Most of the granulomas are found within the portal zones but in one patient studied, there were a number of granulomas and they were found in central and portal zones. The granulomas are found within the liver and in extrahepatic sites in primary biliary cirrhosis. A significant proportion of patients are anergic as demonstrated by negative tuberculin skin tests, failure to be sensitized with 2, 4-dinitro 1-chlorobenzene and impaired lymphocyte transformation to phytohaemagglutinin. There is impairment of normal mechanisms of delayed hypersensitivity, which occurs as a result of the disease and is probably not aetiologically related.