Cryptogenic Chronic Hepatitis Research Articles

Granulomatous lipophagic panniculitis and temporal arteritis in a patient with cryptogenic chronic active hepatitis.

An elderly woman receiving long term treatment with prednisone and azathioprine for cryptogenic chronic active hepatitis developed granulomatous lipophagic panniculitis and temporal arteritis. The lymphoplasmahistiocytic inflammatory reaction pattern is common to this patient's three diseases. It is suggested that an aberration of the defence mechanisms, immunological or otherwise, is responsible for this unusual occurrence. The triple association of chronic active hepatitis, granulomatous panniculitis and temporal arteritis has not been reported previously.

Cryptogenic chronic liver disease and hepatitis C virus infection in children

The clinical features of ‘cryptogenic’ chronic liver disease and the prevalence of antibody to hepatitis C virus (HCV) in serum have been investigated in 33 Italian children (mean age 5 years). The diagnosis was based on the persistence of increased alanineaminotransferase values for longer than 6 months after the exclusion of biliary diseases, of extra-hepatic causes of hypertransaminasemia, of infection with known hepatotropic viruses and of autoimmune or metabolic disorders. Five patients had been transfused early in life, three had undergone surgery and one girl's mother had had acute non-A, non-B hepatitis during pregnancy. The remaining patients had no history of overt parenteral exposure. At presentation only 11 patients were symptomatic, the others had been referred after a check-up for intercurrent diseases. Liver histology performed in 21 cases showed persistent or mild active hepatitis in 18 cases and severe hepatitis or cirrhosis in three cases. Anti-HCV antibodies were found in 48% of the cases, including 88% with obvious exposure and 33% of the remaining cases. During a mean follow-up period of 5 years (range 1–14 years) only 11% of the cases achieved sustained biochemical remission, although none developed signs of liver failure. There was no significant difference in the clinical features and outcome of the disease between anti-HCV-positive and -negative patients. The results of this study suggest that HCV is implicated in most cases of ‘cryptogenic’ chronic liver disease observed in Italian children with a history of parenteral exposure and in at least one-third of the cases without overt exposure. Chronic hepatitis C, although mildly symptomatic, is associated with a wide range of liver lesions including cirrhosis, and with a low rate of spontaneous remission even In the long run.

Prevalence of antibodies to hepatitis C virus among patients with cryptogenic chronic hepatitis and cirrhosis.

Many cases of chronic hepatitis and cirrhosis cannot be attributed to a known cause and are collectively referred to as cryptogenic chronic liver disease. We have evaluated the role of the hepatitis C virus in the pathogenesis of this condition in a retrospective serum analysis for antibody to hepatitis C virus in 129 patients with cryptogenic liver disease. Other causes of chronic hepatitis and cirrhosis were ruled out by clinical, serum biochemical and serological techniques. All 129 patients were HBcAg negative, but 28 (22%) had antibody to HBcAg. Sera were tested by radioimmunoassays using recombinant peptides for antibodies to nonstructural (C100-3 and C33c) and structural regions (C22) of HCV. Among the 129 patients, 61 (47%) had antibody to C100-3, 76 (59%) had antibody to C33c and 74 (57%) had antibody to C22. Seventy-nine (61%) were reactive with at least one and 76 (59%) were reactive with at least two HCV peptides (this is the criterion used for hepatitis C virus antibody reactivity). A proportion of patients with chronic hepatitis and cirrhosis (55 of 91; 60%) similar to that of patients without cirrhosis (21 of 38; 55%) had hepatitis C virus antibody. No significant clinical, serum biochemical or histological differences were noted between the group of patients with hepatitis C virus antibody and those without this antibody reactivity. Thus more than half the patients with cryptogenic chronic liver disease had hepatitis C virus antibody, suggesting that chronic HCV infection plays a major role in the origin of cryptogenic chronic hepatitis and cirrhosis.

Anti-HCV in patients wtih HBsAg positive or cryptogenic chronic hepatitis: Comparison between 1st and 2nd generation tests

Anti-HCV in patients wtih HBsAg positive or cryptogenic chronic hepatitis: Comparison between 1st and 2nd generation tests

Association of autoimmune hepatitis with HLA-Bw54 and DR4 in Japanese patients

Human leukocyte antigen-D region-related alleles (human leukocyte antigen DR and DQ) and human leukocyte antigen class I alleles were typed serologically in 31 Japanese patients with autoimmune hepatitis. These patients had increased serum levels of AST and IgG, high titers of autoantibodies, no history of blood transfusion and were negative for HBsAg and antibodies to HBc. Three hundred eighty-six healthy subjects and 30 patients with cryptogenic chronic hepatitis served as control groups. The frequency of DR4 was significantly higher in autoimmune hepatitis patients (90.3%) than in healthy subjects (38.6%) and in cryptogenic chronic hepatitis patients (30%). The frequency of Bw54 was significantly higher in autoimmune hepatitis patients (45.2%) than in healthy subjects (10.9%). The risk to DR4-positive subjects for autoimmune hepatitis was 14.8 relative to healthy subjects. Two of 31 patients (6.5%) with autoimmune hepatitis were positive for antibody to hepatitis C virus; both clearly satisfied criteria for autoimmune hepatitis and both had Bw54 and DR4. This study revealed a highly significant association of autoimmune hepatitis with human leukocyte antigen Bw54 and DR4 in Japanese patients. Among the DR4-positive patients with autoimmune hepatitis, no significant differences were seen between those positive or negative for Bw54 with regard to clinical or laboratory data, relapse of disease or efficacy of prednisolone. Thus human leukocyte antigen class II alleles contribute to susceptibility and resistance to autoimmune hepatitis in Japanese patients, with distinct racial differences from those in white patients.

Frequency and Significance of Antibody to Hepatitis C Virus in Severe Corticosteroid-Treated Cryptogenic Chronic Active Hepatitis

To determine the frequency and significance of antibody to hepatitis C virus (anti-HCV) in severe cryptogenic chronic active hepatitis (CAH), we tested sera from 17 corticosteroid-treated patients by an enzyme immunoassay. Specificity of the antibodies to HCV-encoded antigens was assessed by recombinant immunoblot assay. The findings in patients with and without anti-HCV were contrasted, and the frequency of seropositivity was compared with that in patients who had other types of chronic liver disease and in normal adults. Only three patients (18%) with severe cryptogenic CAH had anti-HCV. Sera from two of these patients were reactive by recombinant immunoblot assay; the other sample produced an indeterminate reaction. The frequency of seropositivity in patients with cryptogenic disease was not statistically different from that in patients with autoimmune CAH (6%), hepatitis B surface antigen-positive CAH (9%), or alcoholic liver disease (0%), but it was significantly less than in those with posttransfusion CAH (18% versus 75%; P less than 0.01). Seropositive patients tended to have lower serum aspartate aminotransferase, gamma-globulin, and bilirubin levels than seronegative counterparts, and they did not have histologic features of confluent necrosis at initial assessment. Two of the three seropositive patients, both of whom had been reactive by recombinant immunoblot assay, entered remission during therapy, and one, with an indeterminate reaction, died of liver failure. We conclude that anti-HCV occurs infrequently in severe corticosteroid-treated cryptogenic CAH. Seropositive patients may have less severe inflammatory activity than seronegative counterparts. Cryptogenic disease may improve during corticosteroid treatment, a result suggesting an underlying immunologic disorder in some patients.

Anti-HCV in cryptogenic acute and chronic hepatitis

Anti-HCV in cryptogenic acute and chronic hepatitis

Clinical Features and Prognostic Implications of Severe Corticosteroid-Treated Cryptogenic Chronic Active Hepatitis

To assess the nature and prognosis of severe chronic active hepatitis of unknown cause, we compared 26 patients who had been fully screened for etiologic factors with 112 patients who had autoimmune chronic active hepatitis after similar durations of corticosteroid therapy (17(+)/- 2 versus 23 (+)/- 2 months), and follow-up versus 103 +/- 7 months). Patients with cryptogenic disease could not be distinguished from those with autoimmune disease on the basis of age, sex distribution, duration of illness, immunoglobulin levels, frequency of concurrent immunologic disorders, or histologic findings. Serum gamma-globulin levels were higher (3.4 +/- 0.1 versus 2.5 +/- 0.2 g/dl, P = 0.007) and albumin levels were lower (2.9 +/- 0.1 versus 3.3 +/- 0.1 g/dl, P = 0.003) in patients with autoimmune disease than in those with cryptogenic disease, but individual findings did not differentiate the patients. Remission (69 versus 75%), treatment failure (23 versus 13%), relapse after drug withdrawal (67 versus 68%), progression to cirrhosis (57 versus 36%), and death from hepatic failure (12 versus 11%) occurred as commonly in patients with cryptogenic as in those with autoimmune disease. Patients with different constellations of immunoserologic findings were similar clinically. We conclude that patients with severe chronic active hepatitis who have been fully screened for etiologic factors cannot be distinguished from patients with autoimmune disease of comparable severity. These two groups of patients have a similar prognosis after corticosteroid therapy, and such treatment should be considered in these highly selected patients.

HLA display and composition of the inflammatory infiltrate in non replicating HBV-related and cryptogenic chronic active hepatitis

HLA display and composition of the inflammatory infiltrate in non replicating HBV-related and cryptogenic chronic active hepatitis

Treatment of chronic active hepatitis and other liver diseases with corticosteroid agents.

The term chronic active hepatitis covers aetiologically different conditions with similar histological features. Autoimmune chronic active hepatitis - the type that was described originally - is the only type which responds well to prednisolone therapy. Autoimmune chronic active hepatitis can be differentiated from other types by serological and other markers. Treatment with prednisolone should be given for at least two years, with adjustment of dosage according to the serum levels of aspartate transaminase; maintenance does should be 8-12 mg a day. Azathioprine (50-100 mg a day) may be given concurrently as a corticosteroid-sparing agent. Prednisolone therapy in patients with autoimmune chronic active hepatitis enhances the quality of life and survival is prolonged greatly; currently the survival rate after 10 years for prednisolone-treated cases is at least 70%. Prednisolone is not effective in hepatitis B-associated chronic active hepatitis and may be deleterious. In cryptogenic chronic active hepatitis, in which markers of autoimmunity or hepatitis B viral infection are lacking, a trial of prednisolone therapy may be given for three months, and continued only if the indices of disease activity indicate a response. Corticosteroid agents have not proved of benefit in other liver diseases, including alcoholic hepatitis and acute liver failure, and a beneficial effect in primary biliary cirrhosis is yet to be established.

Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug.

"Anti-liver/kidney microsome" (anti-LKM) autoantibodies have been found in the serum of patients with cryptogenic chronic hepatitis and with immunoallergic drug-induced hepatitis, such as those induced by halothane or by tienilic acid (called anti-LKM2 in this case). So far the nature of the human microsomal macromolecules recognized by these antibodies has not been determined. Here we show, by using immunoblot techniques, that among the macromolecules present in human adult liver microsomes, one protein called cytochrome P-450-8 is specifically recognized by most sera of patients containing anti-LKM2 antibodies but not by control serum. Human fetal liver microsomes that do not contain cytochrome P-450-8 are not recognized by the anti-LKM2 antibodies. It is also shown that anti-cytochrome P-450-8 antibodies as well as human serum containing anti-LKM2 antibodies specifically inhibit the hydroxylation of tienilic acid by human liver microsomes. These results indicate that anti-LKM2 antibodies appearing in patients with hepatitis and concomitant administration of tienilic acid are directed against a cytochrome P-450 isoenzyme that catalyzes the metabolic oxidation of this drug. This suggests a possible mechanism for the appearance of anti-organelle antibodies in a drug-induced hepatitis.

Influence of Aetiology, Clinical and Histological Features on Survival in Chronic Active Hepatitis: An Analysis of 204 Patients

To determine which clinical and laboratory features may influence survival in patients with chronic active hepatitis, we undertook a retrospective study of 204 patients seen on this unit over a 15-year period and applied logistic regression analysis. One hundred and six patients had autoimmune chronic active hepatitis, 69 'cryptogenic' chronic active hepatitis (no autoimmune markers or other aetiological factors identified), and 29 were HBsAg-seropositive. Variceal haemorrhage, encephalopathy and ascites were common presenting features in the cryptogenic group while the presence of jaundice and other immunopathic diseases did not differ between the groups. Cirrhosis was more common at presentation in the cryptogenic group. Remission was induced with corticosteroids and azathioprine in 82 per cent of patients with autoimmune chronic active hepatis and in 77 per cent of patients with cryptogenic chronic active hepatitis and the annual relapse rate was similar in the autoimmune and cryptogenic groups. Five-year survival was 87 per cent in the autoimmune group, 65 per cent in the cryptogenic group, and 80 per cent in those with HBsAg-positive disease, and on logistic regression analysis, the presence of cirrhosis at presentation was the only independent factor which adversely affected survival. Overall survival in the cirrhotic patients at five and 12 years was 63 and 48 per cent respectively compared with 95 and 92 per cent in those without cirrhosis.

Alpha-1-antitrypsin MZ phenotype and cryptogenic chronic liver disease in adults.

Intrahepatocytic inclusions of alpha-1-antitrypsin as markers of Z allele were searched by histochemical and immunohistochemical (peroxidase-antiperoxidase) methods in needle biopsy specimens from 80 consecutive cases of cryptogenic cirrhosis and chronic active hepatitis - HBsAg-negative - in adults. All positive cases and 26% of the negative ones were phenotyped in order to determine the frequency of heterozygous (MZ) deficiency. At variance with previous studies, no prevalence of heterozygous (MZ) deficiency could be demonstrated. This result indicates that further investigations are mandatory to establish if heterozygous (MZ) subjects are predisposed to chronic liver disease.

Geographic differences in HBV related, autoimmune, and cryptogenic chronic active hepatitis.

To clarify the importance of ethnic and geographic factors in chronic active hepatitis (CAH), HBV markers and autoantibodies (AMA, ANA, SMA), have been compared in 158 patients with biopsy-proven CAH from New York City and in 92 patients with CAH from Milan. HBsAg-positive CAH was more frequently observed in Milan (49%) than in New York City (27%). However, among HBsAg-positive patients, HBcAg, HBeAg, and epidemiologic risk factors for acquisition of HBV infection were more frequently found in New York than in Italy. The prevalence of HBsAg-negative, anti-HBc-positive CAH and cryptogenic CAH was similar in the two cities, while autoimmune CAH was more frequently observed in New York (20%) than in Milan (2%). In particular, the prevalence of autoimmune hepatitis was higher among Jewish patients than among patients of Anglo-Saxon or Latin ethnic background in New York. Thus, environmental and/or ethnic factors may influence the prevalence of the four major types of CAH.

Outcome of chronic active hepatitis: influence of histocompatibility antigens and triggering factors.

Twenty-five patients with chronic active hepatitis triggered by external factors (viruses or drugs) and 20 patients with cryptogenic chronic active hepatitis were studied for two to five years. The first group showed a significantly higher frequency of clinical and biochemical resolution at the end of the observation period than did the second group. The group with cryptogenic disease had a predominance of females carrying the histocompatibility antigen HLA-B8, whereas the group with virus- or drug-induced hepatitis did not differ from normal controls in regard to the distribution of HLA antigens. HLA-B8 and HLA-B12 were found in all but two patients in the group with cryptogenic hepatitis; this group of patients had elevated levels of gamma-globulin and autoantibodies in their sera more frequently than did the group with virus- or drug-induced disease. The results suggest that there are at least two types of chronic active hepatitis: one genetically determined, with signs of enhanced immunoreactivity and with a low degree of healing in five years; and another type triggered by external factors and without predisposing genetic factors. The data suggest that the clinical outcome is more favorable for patients with the second type of chronic active hepatitis.

Measurement of portal pressure and its clinical application

Estimates of portal pressure in unanesthetized man can be obtained by needling the spleen, by cannulating the umbilical vein remnant, by inserting a needle directly into the hepatic parenchyma or by wedging a catheter into an hepatic vein. In recording pressures as low as those in the portal system, it is essential to have an accurate baseline that reflects the pressure in the major hepatic veins. An external zero reference point is not entirely satisfactory since it is not possible to compensate for increase in intra-abdominal pressure that may accompany ascites or bowel distention. Only wedged hepatic vein catheterization allows recording of an accurate internal zero pressure reference point. Using umbilical cannulation for entry into the portal vein, two groups of investigators have recently shown that wedged hepatic vein pressure and portal vein pressure are essentially identical in alcoholic liver disease and probably in cryptogenic cirrhosis and chronic active hepatitis. For these reasons hepatic vein catheterization should be the method of choice for accurate measurement of portal pressure. A high wedged hepatic vein pressure does not indicate that the hepatic vascular resistance increase is all postsinusoidal; this term should be abandoned. Portal pressure measurement is clinically useful in several situations. A high value can be decisive in the diagnosis of chronic liver disease in patients with unexplained bleeding from the upper gastrointestinal tract, splenomegaly or ascites. In chronic liver disease the level of portal pressure can be used to follow the course of the disease and the effects of treatment. It is still uncertain whether portal pressure is useful in predicting variceal bleeding.