Pathogenesis Of Chronic Active Hepatitis Research Articles

Increased levels of IL‐21 responses are associated with the severity of liver injury in patients with chronic active hepatitis B

Interleukin-21 (IL-21) participates in tissue damage in various immune-mediated diseases. Its role in the pathogenesis of chronic active hepatitis B (CAHB) has not been clarified. The frequency of circulating IL-21(+) T cells and the levels of serum and intrahepatic IL-21 have been characterized in 70 CAHB patients, 32 inactive carrier (IC), 18 chronic hepatitis C (CHC) and 20 healthy controls (HC). Their potential association with liver injury was analysed. The percentages of IL-21(+) CD3(+) CD8(-) and IL-21(+) CD3(+) CD8(+) T cells and the levels of serum IL-21 in CAHB patients were significantly higher than that in the IC, CHC patients and HC (P < 0.001) and were correlated positively with the levels of serum alanine aminotransferase (ALT, r = 0.424, P < 0.001; r = 0.392, P = 0.001) and aspartate aminotransferase (AST, r = 0.388, P = 0.001; r = 0.329, P = 0.005) in CAHB patients, respectively. The levels of IL-21 expression in the liver tissues were associated significantly with increased degrees of inflammation and fibrosis in CAHB patients (P < 0.01 or P < 0.05). Our findings suggest that aberrant IL-21 responses may be associated with the progression of CHB.

Response to Combination Therapy with Interferon Alfa-2a and Ribavirin in Chronic Hepatitis C According to a TNF-α Promoter Polymorphism

Background: Tumor necrosis factor-α (TNF-α) is involved in the pathogenesis of chronic active hepatitis C. Polymorphisms in the promoter region of the TNF-α gene can alter the TNF-α expression and modify the host immune response. The present study aimed at the correlation of the G308A TNF-α polymorphism with the response to antiviral combination therapy in chronic hepatitis C. Patients and Methods: 62 patients with HCV and 119 healthy unrelated controls were genotyped for the G308A TNF-α promoter polymorphism. The patients received 3 × 3 million units of interferon alfa-2a and 1,000–1,200 mg ribavirin daily according to their body weight. A response was defined as absence of HCV-RNA and normalization of S-ALT after 6 months of combination therapy. Results: With respect to the allele and genotype frequency, a significant difference was not observed between controls and patients with chronic hepatitis C. Furthermore, such a difference was also not observed if responders and non-responders to antiviral therapy were compared. Conclusions: The promoter polymorphism of the TNF-α gene investigated herein is equally distributed in healthy individuals and patients with hepatitis C and does not seem to predict the response to therapy with interferon alfa-2a and ribavirin.

Modification of cellular immune responses in experimental autoimmune hepatitis in mice by maitake (Grifola frondosa)

Immune response to liver-specific lipoprotein (LSP) is involved in the pathogenesis of chronic active hepatitis. Experimental hepatitis could thus be prepared in C57BL/6 mice by injection of liver-specific protein in a syngeneic liver homogenate with Freund's complete adjuvant. In hepatitic mice treated with maitake (Grifola frondosa) fruit bodies, the values of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) values increased temporarily by 2.24–2.79 times and decreased rapidly thereafter. However, in the mice given normal feed, both values increased constantly. Thus, we examined T cell activities both in the exacerbation and remission stages of hepatitis. We suggest that the activation of CD8+ cells is more potentiated than that of CD4+ cells by administration of maitake or the D-Fraction-glucan (β-1,6 glucan having β-1,3 branches), which can enhance immuno-competent cells at the exacerbation stage. However, at the remission stage, marked potentiation of CD8+ cell activity was not observed. These results suggest that depressed suppressor T cell activity is revived by the X-Fraction-glucan (β-1,6 glucan having α-1,4 branched glucan), while the cytotoxic T cell activity, which is activated by the D-Fraction, is restricted, thereby creating a smooth shift from the exacerbation stage to the remission stage.

Antibodies against human cytochrome P-450db1 in autoimmune hepatitis type II.

In a subgroup of children with chronic active hepatitis, circulating autoantibodies occur that bind to liver and kidney endoplasmic reticulum (anti-liver/kidney microsome antibody type I or anti-LKM1). Anti-LKM1 titers follow the severity of the disease and the presence of these antibodies serves as a diagnostic marker for this autoimmune hepatitis type II. We demonstrate that anti-LKM1 IgGs specifically inhibit the hydroxylation of bufuralol in human liver microsomes. Using two assay systems with different selectivity for the two cytochrome P-450 isozymes catalyzing bufuralol metabolism in human liver, we show that anti-LKM1 exclusively recognizes cytochrome P-450db1. Immunopurification of the LKM1 antigen from solubilized human liver microsomes resulted in an electrophoretically homogenous protein that had the same molecular mass (50 kDa) as purified P-450db1 and an identical N-terminal amino acid sequence. Recognition of both purified P-450db1 and the immunoisolated protein on western blots by several monoclonal antibodies confirmed the identity of the LKM1 antigen with cytochrome P-450db1. Cytochrome P-450db1 has been identified as the target of a common genetic polymorphism of drug oxidation. However, the relationship between the polymorphic cytochrome P-450db1 and the appearance of anti-LKM1 autoantibodies as well as their role in the pathogenesis of chronic active hepatitis remains speculative.

Significant autoimmune markers of autoimmune liver disorders: Current status

AbstractChronic inflammatory liver diseases are classified as chronic active hepatitis (CAH) or primary biliary cirrhosis (PBC) on the basis of clinical and pathological criteria. Autoantibodies allow the distinction between autoimmune forms of CAH and virally induced forms, in particular CAH non‐A, non‐B. Three different subgroups of autoimmune‐type CAH have been defined so far. Classical autoimmune “lupoid” CAH is characterized by antinuclear antibodies (ANA) and liver‐membrane autoantibodies (LMA). Antibodies against a liver‐kidney‐microsomal antigen (LKM) are found in a small group of generally young patients and are associated with a progressive form of autoimmune CAH. The target antigen as defined by immunoblotting is a protein at 50 kilodaltons (KD), and it has been detected on phenobarbital‐inducible isoenzymes of cytochrome P‐450. The third subgroup, clinically similar to “lupoid” CAH, is characterized by antibodies against a soluble cytoplasmic liver antigen (anti‐SLA). These antibodies cannot be diagnosed by routine methods, i.e., immunofluorescence, but are only found by radioimmunoassay or enzyme immunoassay. In primary biliary cirrhosis (PBC) the immune reactions are directed against the intrahepatic bile ducts rather than hepatocytes. Antimitochondrial antibodies (AMA), traditionally diagnosed by immunofluorescence, are found in up to 100% of PBC patients. Complement‐fixation test, radioimmunoassay, and enzyme immunoassay allow the distinction of disease‐specific subtypes of AMA. Immunoblotting allows the characterization at the molecular level of two PBC‐specific AMA subtypes, anti‐p48 and anti‐p62. The latter corresponds to the anti‐M2 antibodies described previously. All these antibodies are important tools in the differential diagnosis of chronic inflammatory liver diseases. Patients with autoimmune‐type CAH benefit from immunosuppressive therapy, while those with virally induced CAH do not. The role of these autoantibodies in the pathogenesis of CAH or PBC is not known as yet, but they are sensitive and specific diagnostic markers.

Trial of specific antigen-mediated leukocyte adherence inhibition test in patients with chronic active hepatitis and hepatitis B carrier.

In the pathogenesis of chronic active hepatitis, the importance of cell mediated immunity (CMI) has been emphasized. Leukocyte adherence inhibition (LAI) assay, which is one of the methods for analysis of the reaction of CMI, has been used to analysie the CMI of cancer patients.The authors tried the specific antigen-mediated LAI assay in 40 patients with chronic active hepatitis, 19 patients carriers of hepatitis B virus, and in the 5 persons who have no anti-HBs in spite of receiving vaccination against HBV, and these were compared with 7 normal control subjects who had been exposed to hepatitis B virus previously.The results were as follows: The NAI was 52.4±14 (mean ± standard deviation) in 7 normal control subjects who had been exposed to hepatitis B virus previously.The NAI was 20.6 ± 11 (mean ± standard deviation) in 40 patients with chronic active hepatitis. The value was significantly lower than that of the normal control group (P<0.001).The NAI was 49.7±17.8 (mean ± standard deviation) in 19 patients carriers of hepatitis B virus. The value was not significantly different from that of the normal control group (P>0.05).The NAI was 25.1±11 (mean ± standard deviation) in 5 persons who have no anti-HBs in spite of receiving vaccination against HBV. The value was significantly lower than that of the normal control group (P<0.05).In patients with chronic active hepatitis and hepatitis B virus carriers, we checked the LAI assay serially. The value of NAI was increased according to the improvement of clinical symptoms and normalization of transaminase, but the value of NAI was decreased according to the worsening of clinical symptoms and elevation of transaminase.

Serologic Markers of Hepatitis A and B in Chronic Active Hepatitis

Sera from 44 patients with a well-documented diagnosis of chronic active hepatitis (CAH) were analysed for antibodies to hepatitis A virus (anti-HAV), hepatitis B surface antigen (HBsAg) and anti-HBs, e-antigen (HBeAg) and anti-HBe, as well as antibodies to hepatitis B core antigen (anti-HBc). Twenty-two patients had serologic evidence of hepatitis A infection. The frequency of anti-HAV was low in patients under 50 years of age (21%) but high among older patients (72%). There was, however, no significant difference between patients and age-matched controls regarding the prevalence of anti-HAV in serum. Markers for hepatitis B virus were found in 10 patients or 23% as compared with about 10% in Swedish blood donors. The results indicate that hepatitis A virus is of little importance in the pathogenesis of CAH and confirm the association between hepatitis B virus and development of chronic active hepatitis.

AUSTRALIA ANTIGEN IN ACUTE AND CHRONIC LIVER DISEASE

The sera of 389 patients with biopsy-documented acute and chronic liver disease and of 135 healthy controls were tested for Australia (Au) antigen by a modification of the micro-Ouchterlony double-diffusion technique. The two sera used as antibody, which contained a high titre of anti-Au, were obtained from a multiply-transfused hæmophiliac and a chronic-hæmodialysis-unit nurse who had been exposed to viral hepatitis, but had never had the disease. These anti-Au sera, when tested against reference sera containing Au antigen, gave reactions of identity with human and rabbit anti-Au sera and human anti-SH serum. Au antigen was detected in the serum of 46 (52%) of 88 patients with acute viral hepatitis, 11 (38%) of 29 with prolonged viral hepatitis, 6 (25%) of 24 with chronic active hepatitis, but in none of the 135 controls and in only 3 of the remaining 248 patients with other forms of acute and chronic liver disease. In each of the latter 3 cases, Au antigen was detected in the serum a few days after multiple transfusions of whole blood. In viral hepatitis, Au antigen was encountered most frequently in infections of unknown type (67%), less commonly in "serum-hepatitis " infections (49%), and least commonly in " infectious-hepatitis " infections (25%). The data confirm previous reports that Au antigen can be detected in the serum of a high proportion of patients with acute viral hepatitis, and demonstrate that, in prolonged viral hepatitis, the antigen may persist for months or years, disappearing only when the disease becomes inactive. In addition, they attest to the specificity of the Au antigen for viral hepatitis, and provide supporting evidence for the view that persistent infection with the hepatitis virus may play an important role in the pathogenesis of chronic active hepatitis.