Chronic Active Liver Disease Research Articles

T and B lymphocytes in patients with chronic active liver disease and in healthy HBsAg carriers.

E-rosette and surface Ig tests were used to study circulating T and B lymphocytes in 65 patients with chronic active liver disease (CALD), 15 healthy HBsAg carriers and 30 healthy controls. No significant variation in B lymphocytes was observed in CALD and in healthy HBsAg carriers. On the other hand, the absolute number and the percentage of T lymphocytes were significantly decreased in CALD, especially in cases negative for HBV infection markers.

Immunoregulatory T-cell function in acute and chronic liver disease

The suppressor function of T cells separated from the peripheral blood lymphocytes of patients with acute or chronic liver disease was evaluated by using, as an indicator system, pokeweed mitogen-induced immunoglobulin synthesis in vitro. Suppressor activity of T cells was enhanced during the recovery phase in 13 of 17 patients who have recovered from acute viral hepatitis. When such T cells were irradiated before coculture, the suppressor function was selectively eliminated, but the helper T-cell function remained unchanged. In serial studies, normalization of the excess suppressor function of T cells was observed when the liver function of an acute viral hepatitis patient returned to the normal range. Except for chronic active liver disease, in which the suppressor activity of T cells was substantially reduced in 50% of the patients studied, the studies indicated normal T-cell functions, both suppressor and helper, in other liver diseases such as chronic persistent hepatitis, inactive cirrhosis, and fatty liver disease. These data suggest that the host immunoregulatory mechanism might be important in recovering from acute viral hepatitis and in perpetuating hepatocyte injury in chronic active liver disease.

Peptic ulceration in patients with chronic liver disease

A prospective study was undertaken to determine the frequency of peptic ulceration in different forms of chronic liver disease and the effect of corticosteroid treatment. One hundred sixty-three patients with chronic liver disease underwent upper gastrointestinal endoscopy, 106 for investigation of dyspeptic symptoms and the remaining 57 for assessment of the presence of varices. Twenty-four peptic ulcers were found (14.7%), 12 duodenal, 8 gastric, and 4 prepyloric. Ulcers were found in 5 of 15 patients with hepatitis B surface-antigen-positive chronic active liver disease (33%), 10 of 46 patients with alcoholic liver disease (22%), 5 of 35 with primary biliary cirrhosis (14%), 2 of 19 with miscellaneous chronic liver diseases (10%), and 2 of 25 with cryptogenic cirrhosis (8%). Ulcers were not demonstrated in any of the 23 patients with hepatitis B surface-antigen-negative chronic active hepatitis. Thirty-one patients were receiving prednisolone therapy, 5 had peptic ulcer compared with 19 of the remaining 132 patients. This difference was not significant. Fifty-nine patients presented with gastrointestinal bleeding on 88 separate occasions. Peptic ulcer was the cause in 6% of these. In chronic liver disease peptic ulcers occurred with differing frequencies in different forms of the disease. This was unaffected by corticosteroid therapy. Peptic ulcers were rarely the cause of gastrointestinal bleeding.

Acute non-A, non-B hepatitis--clinical, epidemiological and histological characteristics.

Among 73 consecutive patients with biopsy documented acute non-toxic hepatitis, half of the patients (49%) had acute type B hepatitis, while 27 patients (37%) had acute type A infection. One patient had a significant rise in antibodies against cytomegalovirus. The remaining 10 patients (14%) fulfilled the criteria of hepatitis type non-A, non-B. The main type of exposure for hepatitis A was visit to endemic hepatitis areas (41%), and for type B it was drug addiction (46%). Half of the patients with hepatitis non-A, non-B had no known hepatitis exposure while some had visited endemic hepatitis areas or were drug addicts. The patients with non-A, non-B hepatitis had significantly less biochemical changes as compared to the patients with hepatitis B. In contrast, the histological findings showed the greatest activity in the biopsies from patients with hepatitis B and non-A, non-B. Follow-up liver biopsies in half of the patients with non-A, non-B hepatitis showed no signs of chronic active liver disease. It is concluded that hepatitis type non-A, non-B is a significant problem in Denmark.

Complement metabolism in chronic liver disease: Catabolism of C1q in chronic active liver disease and primary biliary cirrhosis

The fractional catabolic rate of C1q was increased markedly in primary biliary cirrhosis, and in HBsAg-positive chronic liver disease. In 3 out of 4 patients with HBsAg-negative chronic active liver disease C1q catabolism was normal. The rate of synthesis of the protein was increased in primary biliary cirrhosis, but it was normal in patients with chronic active liver disease. The fractional catabolic rate and synthetic rate of albumin were normal in these subjects. These data provide further evidence for the activation of the classical pathway of complement in primary biliary cirrhosis and HBsAg-positive chronic active liver disease. In HBsAg-negative chronic active liver disease, the presence of C1q binding macromolecules was not associated with increased C1q catabolism.

Clinical features and prognosis of severe chronic active liver disease (CALD) after corticosteroid-induced remission

Disappearance of symptoms, resolution of most biochemical abnormalities, and histologic improvement to mild chronic inflammation were accomplished in 69 of 123 patients (56%) with severe chronic active liver disease treated with corticosteroids for up to 6.5 yr. Remission of at least 6 mo duration was possible in 35 of the 69 (51%) after discontinuation of therapy while others relapsed promptly and required retreatment. The likelihood of sustained remission was not predicted by initial clinical or biochemical features, although patients developing cirrhosis during treatment invariably relapsed. Subsequent courses of treatment after relapse were equally effective in again inducing remission, but the probability of another relapse increased after each successive therapy and was 86% after three treatments. Six of twenty-two patients (27%) followed for at least 4 yr after initial remission had three or more relapses. Although patients who relapsed were more likely to develop cirrhosis, manifestations of portal hypertension and immediate survival were not affected by relapse. Complete disappearance of all manifestations of active disease was possible in 12 of the patients entering remission (17%), but only patients without cirrhosis consistently sustained this improvement. We conclude that relapse after cessation of therapy frequently follows corticosteroid-induced remission of severe CALD, especially if cirrhosis develops, but does not jeopardize response to subsequent treatments or alter early prognosis.

The role of acute hepatitis type A, B, and non-A non-B in the development of chronic active liver disease.

In 19 patients followed from biopsy-verified acute viral hepatitis to chronic active liver disease and 74 patients followed to complete resolution verified by a normal liver biopsy, sera from the acute phase were studied for serologic evidence of hepatitis type A and B. Eleven of the 19 patients who developed chronic active liver disease progressed from acute hepatitis type B and 7 from acute hepatitis type non-A non-B. One patient could not be classified because the sera were exhausted. None had serological markers of actual hepatitis type A infection. Of the 74 patients with a histologically complete resolution, the acute episode could be classified as type B hepatitis in 47 and type A hepatitis in 13 patients. The remaining 14 patients were classified as having acute viral hepatitis type non-A non-B. Our findings confirm that type B and non-A non-B hepatitis may give rise to chronic liver disease, whereas type A hepatitis so far has not been demonstrated to initiate a chronic liver disease.

Rapid determination of fibronectin by laser nephelometry. Fibronectin concentrations is plasma in human diseases, I.

Fibronectin (Synonyms: cold-insoluble globulin, antigelatin factor) is a cell surface glycoprotein. It has been shown that remarkably large amounts of fibronectin are present in human plasma. Owing to the difficult and expensive radioimmunoassays, only a few reports on the relation of fibronectin and human diseases have so far been published. In this communication a rapid and easily handled immunoassay, using the light scattering effect, is described. The first results on the measurement of fibronectin concentrations in the plasma of patients with chronic active liver diseases are reported.

Autoantibodies to Collagen in Patients with Chronic Liver Diseases

Sera of patients with various liver diseases were investigated for the presence of autoantibodies to type I collagen with a sensitive radioimmunoassay employing 3H-labelled collagen type I. A high percentage (69%) of patients with chronic liver diseases, equally distributed between chronic active hepatitis and alcoholic liver disease, was found to possess antibodies to denatured type I collagen, while no antibodies against native collagen were found. These antibodies belonged predominantly to the IgA immunoglobulin class. None of the patients with acute hepatitis or cholestatic liver disease, nor the healthy individual investigated had IgA-anticollagen antibodies. These findings may be useful as a parameter for the detection of chronic liver disease.

Acetaminophen associated hepatic injury: Report of two cases showing unusual portal tract reactions

Two patients experienced acute transient hepatic and renal failure following ingestion of substantial but less than the usually toxic doses of acetaminophen, in both cases associated with heavy acute alcohol intake. One patient developed transient clinical features of chronic active liver disease one month later. Liver biopsy specimens from both patients taken after the acute episodes revealed, in addition to the well recognized centrilobular hepatic injury of acetaminophen, unusual portal tract lesions, which resembled chronic active hepatitis in one case. In some patients therapeutic doses of acetaminophen, if taken together with alcohol, may produce acute and chronic liver disease.

Development and early prognosis of esophageal varices in severe chronic active liver disease (CALD) treated with prednisone

The prevalence of gastroesophageal varices and gastrointestinal hemorrhage was determined in 124 patients with severe chronic active liver disease (CALD) receiving prednisone and followed regularly for up to 10 yr. Varices were demonstrated by contrast radiography in only 19 patients (15%). Ten had varices before therapy and nine developed them after 12–102 mo of observation (mean, 38 ± 9 mo.). The likelihood of developing varices within 5 yr after therapy was 8% in all patients and 13% after documentation of cirrhosis. Hemorrhage from varices occurred in only 1 patient, who had varices and bled once before treatment. Bleeding from other sites was commoner in the presence of varices (P < 0.025), but mortality was not increased by bleeding from any site. The probability of upper gastrointestinal bleeding was only 6% within 5 yr after therapy and the 5 yr survival was 93%. In severe CALD, varices are an uncommon initial finding and do not develop quickly or hemorrhage early after steroid therapy.

Electron microscopy of hepatitis B virus components in chronic active liver disease.

Eighteen liver biopsy specimens from patients with hepatitis B surface antigen (HBsAg) positive chronic aggressive hepatitis were studied by electron microscopy. All cases were selected on the basis of positive liver cell membrane fluorescence for HBsAg on immunohistochemical investigation. Striking changes in the morphology of the liver cell membrane were observed in nearly all cases. Furthermore, a dual aspect of hepatitis B core antigen (HBcAg) is described. HBcAg particles may occur as either 'naked' or 'cloudy' particles surrounded by semi electron dense material. The nature of the 'cloud' remains to be identified.

Metabolism of the Third Component of Complement in Acute Type B Hepatitis, HBs Antigen Positive Glomerulonephritis, Polyarteritis Nodosum, and HBs Antigen Positive and Negative Chronic Active Liver Disease

The contribution of complement consuming immune mechanisms to the various syndromes which follow HBV infection has been studied by measuring the catabolism of radioiodinated, purified, hemolytically active C3. Albumin catabolism has been studied in parallel to determine whether changes in C3 catabolism are specific and therefore consistent with complement activation, or merely a result of a generalized state of hypercatabolism of all plasma proteins. Two patients studied during the 1st wk of acute type B hepatitis showed increased fractional catabolic rates (FCR) of both C3 and albumin; the ratio of the FCR C3/FCR ablumin was normal. Six patients with HBsAg-positive chronic active liver disease (CALD) showed increased FCR of C3 but normal FCR albumin; the ratio of FCR C3/albumin was significantly increased. In contrast six patients with HBsAg-negative CALD showed normal FCR of C3. Three patients with chronic persistent hepatitis, one with membranous glomerulonephritis and one with polyarteritis nodosum, showed increased catabolism of C3 but normal albumin catabolism. The ratio of FCR C3/FCR of albumin was greater than in patients with HBsAg-positive CALD. These data demonstrate that C3 catabolism is specifically increased in HBsAg-positive CPH and CALD but is normal in HBsAg-negative CALD. This is consistent with recruitment of complement fixing immune mechanisms in the HBV-related chronic disease states. In contrast, in early acute type B hepatitis and in HBs-negative CALD there is no evidence of increased immune catabolism of C3.

Chronic Active Liver Disease: Definition, Diagnosis, and Management

Chronic Active Liver Disease: Definition, Diagnosis, and Management

Hepatocellular carcinoma in the U.S.A., etiologic considerations: Localization of hepatitis B antigens

The serologic and tissue markers of hepatitis B virus (HBV) were studied in 50 patients in whom hepatocellular carcinoma (HCC) was confirmed at autopsy. Serologic and tissue markers included serum hepatitis B surface antigen (HBsAg), tissue HBsAg, tissue hepatitis core antigen (HBcAg), and serum antibody to HBcAg (anti-HBc). Twenty-two patients had HCC arising in alcoholic cirrhosis; 2 of the 22 (9.1%) had one or more of the HBV tissue and serologic markers. This infection rate is similar to the rate of 7.9% observed in 63 control alcoholic cirrhotic patients without HCC. In contrast, 15 of 20 (75.0%) patients with HCC in nonalcoholic chronic active liver disease showed evidence of active HBV infection. One of 8 patients with HCC in normal liver had serum HBV markers. This result indicates that there is an extremely high prevalence of HBV infection among HCC patients with nonalcoholic chronic liver disease in the U.S.A. The prevalence of HBV infection in these patients is as high as that observed in Asia and Africa. Thus, it can be concluded that the lower prevalence rate of active HBV infection in HCC patients in the U.S.A. is the result of statistical dilution of HCC-B-viral disease by the large numbers of the alcoholic cirrhotic patients with HCC, and that if chronic active hepatitis type B were as common in the United States as it is in Africa and Asia, the frequency of occurrence of HCC might also be as high.

Autoantibodies and Serum Immunoglobulins in Chronic Liver Diseases

In a prospective consecutive study, 68 patients with various liver diseases and 67 control persons were examined for the occurrence of smooth muscle antibodies (SMA), antinuclear antibodies (ANA) and mitochondrial antibodies (MTA) of IgG, IgA and IgM class. A determination of serum immunoglobulins (S-IgG, S-IgA and S-IgM) was also performed. IgG-SMA in titres of greater than 80 occurred in 8 of 12 patients (67%) with hepatitis B antigen (HBag)-negative chronic active liver disease (CALD) and not in other diseases. Apart from one patient with primary biliary cirrhosis (PBC), IgG-ANA in titres of greater than 40 were likewise detected only in HBag-negative CALD (33%). The titres of IgG-SMA and IgG-ANA varied analogously with the biochemical liver parametres. There was a mutual exclusion between HBag and IgG-SMA/-ANA in titres of greater than 20, while IgM-SMA occured in titres of 80 in two patients with HBag-positive CALD. The incidence and titres of IgM-SMA and -ANA were not higher than in the controls. IgA-SMA and -ANA were detected only sporadically. The MTA demonstrated were of IgG PCLASS AND TITRES OF GREATER THAN 40 WERE FOUND ONLY IN PATIENTS WITH PBC (4 of 5). Som of the patients in all groups had an increased conenctration of one or more of the serum immunoglobulins. S-IgG levels were found to be significantly higher in CALD than in the other groups

K-Cell-Mediated Antibody-Dependent Cellular Cytotoxicity in Chronic Active Liver Disease

These studies were designed to determine the ability of antihepatocyte antibodies from patients with chronic active liver disease to induce killing of rabbit hepatocytes by normal lymphocytes. Normal subjects and patients with chronic persistent hepatitis or chronic active liver disease served as sources of sera, and normal human peripheral lymphocytes and their subsets (T-enriched, K-enriched, and B) served as effectors. Only sera from patients with chronic active liver disease possessed membrane-reactive IgG directed against the surface of rabbit or human hepatocytes. After pretreatment of rabbit hepatocytes with sera from patients with chronic active liver disease, marked cytotoxicity mediated by normal lymphocytes was observed. K-enriched cells mediated the antibody-dependent cellular cytotoxicity, whereas T-enriched cells and B-cells did not. Heat-aggregated human IgG blocked the antibody-dependent cellular cytotoxicity. These data suggest that sera from patients with chronic active liver disease contain IgG antihepatocyte antibodies, which are capable of inducing normal K-cells to kill rabbit hepatocytes in vitro.

Normal lymphocyte interferon production in adult HBsAg-positive chronic active liver disease.

To challenge the hypothesis that interferon (IF) production in chronic hepatitis-B virus liver disease is defective, lymphocytes from 14 patients with chronic active liver disease (CALD); from nine patients with chronic inactive liver disease (CILD), and from six healthy chronic carriers (HCC) were stimulated by Newcastle Disease virus. The patients with CILD showed a weak IF response by comparison with the controls (P less than 0.0005), whereas IF production by CALD patients and the HCC did not statistically differ from IF production in the healthy hepatitis-B surface antigen negative subjects who served as controls. These results indicate that IF treatment of CALD does not rely on a completely proved background.

Corticosteroid Pharmacokinetics in Liver Disease

Among the corticosteroids, prednisone is the most commonly used in the treatment of chronic active liver disease. However, its pharmacokinetics have only recently been investigated. Prednisone is effectively absorbed and converted to its active therapeutic derivative, prednisolone, in healthy volunteers and in patients with liver disease; the bioavailability of oral prednisone approximates 100% of an intravenous dose and is comparable after administration of either prednisone or prednisolone. Patients with liver disease and hypoalbuminaemia are more likely to suffer major side effects of prednisone as a consequence of decreased protein binding and delayed clearance of prednisolone. Dosage in such patients should be reduced in accordance with serum albumin concentration.

Liver Allograft

A patient suffering from chronic active hepatitis with macronodular cirrhosis, positive for hepatitis B surface antigen (HBsAg), was treated with an orthotopic liver allograft. The HBs antigenemia, as measured with several precipitation tests and by complement fixation, became negative after transplantation and remained so for about 2 1/2 months. During the interval, very low titers of the antigen were detectable by radioimmunoassay. At about three months after transplantation, she had an attack of acute hepatitis, at which time HBsAg became detectable by all tests. She recovered, but progressive liver disease developed during the remaining 1 1/2 years of her life. She died of disseminated nocardiosis and candidiasis with deteriorating hepatic function. The homograft at autopsy showed no evidence of rejection, but was the site of chronic active liver disease, although of a different pathologic pattern than that affecting her native liver. The differences in histology may reflect the influence of chronic immunosuppression on the features of chronic active hepatitis.