Negative conversion of autoantibody profile in chronic hepatitis B: A case report

BACKGROUNDAutoimmune antibodies are detected in many diseases. Viral infections are accompanied by several immunopathological manifestations. Some autoimmune antibodies have been associated with the immune response induced by virus or drugs. Thus, a comprehensive diagnosis of chronic hepatitis B combined with autoimmune hepatitis is required, and immunosuppressant or antiviral therapy should be carefully considered.CASE SUMMARYWe present a case of a patient who had negative transformation of autoimmune antibodies during chronic active hepatitis B. A 50-year-old female who had a history of asymptomatic hepatitis B virus carriers for more than 10 years presented to the hospital with the complaint of weakness for 1 wk. Blood tests revealed elevated liver enzymes; the detection of autoantibodies was positive. Hepatitis B viral load was 72100000 IU/mL. The patient started tenofovir alafenamide fumigate 25 mg daily. Liver biopsy was performed, which was consistent with chronic active hepatitis B. The final diagnosis of the case was chronic active hepatitis B. The autoimmune antibodies turned negative after 4 wk of antiviral therapy. The patient recovered and was discharged with normal liver function. There was no appearance of autoantibodies, and liver function was normal at regular follow-ups.CONCLUSIONAutoimmune antibodies may appear in patients with chronic active hepatitis. It is necessary to differentiate the diagnosis with autoimmune hepatitis.     

Autoimmune thyroid disease induced by interferon therapy]

Interferon therapy, widely used in chronic viral hepatitis and in various malignant diseases, has been known to induce autoimmune phenomena, the most frequent being autoimmune thyroid disease. We have studied the human leukocyte antigen (HLA) in patients who developed autoimmune thyroid dysfunction after interferon-alpha therapy for chronic hepatitis C. Seventeen of 439 patients (3.9%) developed symptomatic autoimmune thyroid dysfunction after interferon-alpha therapy, including nine cases of hyperthyroidism and eight cases of hypothyroidism. The incidence of HLA-A2 in those patients was significantly higher than that in general population in Japan. The present results suggest that HLA-A2 is associated with interferon-alpha therapy-induced autoimmune thyroid dysfunction in patients with chronic hepatitis C.     

Islet cell and thyroid antibody prevalence in patients with hepatitis C virus infection: effect of treatment with interferon

An increased prevalence of hepatitis C virus (HCV) infection in patients with diabetes and a higher prevalence of diabetes in HCV-infected patients have been reported. However, the relationship between these two conditions remains controversial. In addition, although the effect of interferon treatment on thyroid autoimmunity has been extensively reported, its influence on beta-cell autoantibodies has not been investigated. The aims of the study were (1) to evaluate whether autoimmune beta-cell damage could be involved in the development of diabetes mellitus in HCV-infected patients and (2) to determine whether interferon treatment influences the appearance of beta-cell and thyroid autoantibodies. The prevalence of islet cell autoantibodies (glutamic acid decarboxylase antibodies [GADAs], tyrosine phosphatase antibodies [IA-2s], islet cell antibodies [ICAs]) was assessed in 303 non-selected HCV-infected patients (277 non-diabetic and 26 type 2 diabetic patients) and in 273 sex- and age-matched control subjects. ICAs and thyroid autoantibodies were also determined before and 6 and 12 months after treatment with interferon for 24 weeks in a subgroup of 46 HCV-infected patients. GADAs were detected in 4 of 277 (1.4%) HCV-infected non-diabetic patients, 1 of 273 (0.3%) control subjects, and 0 of 26 (0%) HCV-infected patients with diabetes. Anti-IA2s and ICAs were negative in all subjects. Both GADAs and anti-IA2s were negative in all HCV-infected patients treated with interferon. After therapy, only thyroid antibodies became positive in 5 of 46 (10.9%) treated patients, disappearing in all but 1 of these at the 12-month follow-up. Our results suggest that beta-cell autoimmunity is not associated with HCV infection, thus making it unlikely that the increased diabetes mellitus prevalence among HCV-infected patients could be mediated by autoimmune mechanisms. In addition, interferon treatment induces a transient increase in thyroid autoantibodies but does not influence the appearance of beta-cell autoantibodies.     

HCV-HBV infection

Chronic infection of hepatitis C (HCV) and B virus (HBV) frequently causes viral hepatitis. Patients with chronic viral hepatitis are at risk for liver cirrhosis and even hepatocellular carcinoma. In patients with chronic hepatitis C, the most effective therapy is elimination of HCV with interferon (IFN). The most effective initial IFN therapy is the combination of pegylated IFN alpha-2b plus ribavirin. Forty-eight weeks of this combination therapy produces sustained viral response rates of approximately 50%. Moreover, several reports showed that long-term IFN therapy also reduced the risk of liver carcinogenesis. In patients with chronic hepatitis B, seroconversion from HBeAg to anti-HBe antibodies suppresses viral replication and attenuates the hepatitis. Twenty-four weeks of IFN therapy produces HBeAg seroconversion rates approximately 30%.     

Therapy of viral hepatitis

Chronic viral hepatitis is a leading cause of chronic hepatitis, liver cirrhosis, hepatic decompensation and hepatocellular carcinoma worldwide. Here, we will briefly review common indications and current therapies for chronic hepatitis B and C and discuss practical aspects of these therapies. Current therapies for hepatitis C aim at viral eradication. With the introduction of pegylated interferon and ribavirin viral eradication is successful in about 55% of treated patients. The goal of therapy of HBe antigen positive chronic hepatitis B is seroconversion to anti-HBe which can be achieved with interferon alpha in 25-45% of patients. A loss of HBs can be achieved in approximately 10%. Responders proceed significantly less to cirrhosis or hepatocellular carcinoma. Anti-HBe positive patients can be treated with interferon alpha or lamivudine. The former requires longer treatment and the results are disappointing. Lamivudine is a promising agent in the treatment of chronic hepatitis B, but the success is hampered by a high relapse rate and the emergence of viral resistance.     

Treatment of viral hepatitis--2001

Chronic viral hepatitis may now be controlled and, in many cases, permanently eradicated. Rapid advances in the antiviral therapy of chronic hepatitis C infection have resulted in a greater than 50% sustained response rate, with genotypes 2 and 3 now considered 'curable diseases.' Current hepatitis B therapy leads to significant improvement in liver histology and overall survival. These advances, coupled with the fact that 8% of the world population is chronically infected with viral hepatitis, has sparked considerable interest in this condition on the part of the pharmaceutical industry. In 2001, the most effective therapy for chronic hepatitis C is the combination of pegylated interferon alpha and oral ribavirin. The treatment of hepatitis B consists of either interferon alpha or oral lamivudine, while newer nucleoside/nucleotide analogues, alone or in combination with existing therapy, are being explored.     

Treatment of viral hepatitis - 2001

Chronic viral hepatitis may now be controlled and, in many cases, permanently eradicated. Rapid advances in the antiviral therapy of chronic hepatitis C infection have resulted in a greater than 50% sustained response rate, with genotypes 2 and 3 now considered ‘curable diseases.’ Current hepatitis B therapy leads to significant improvement in liver histology and overall survival. These advances, coupled with the fact that 8% of the world population is chronically infected with viral hepatitis, has sparked considerable interest in this condition on the part of the pharmaceutical industry. In 2001, the most effective therapy for chronic hepatitis C is the combination of pegylated interferon alpha and oral ribavirin. The treatment of hepatitis B consists of either interferon alpha or oral lamivudine, while newer nucleoside/nucleotide analogues, alone or in combination with existing therapy, are being explored.     

Failure of interferon to prevent recurrent hepatitis B infection in hepatic allograft

Chronic liver disease associated with hepatitis B virus infection is both common and serious; no satisfactory treatment currently exists. Orthotopic liver transplantation is an option for patients with end-stage liver disease associated with hepatitis B virus infection despite the risk of allograft reinfection. Passive immunoprophylaxis has been attempted perioperatively to prevent graft infection but has not been beneficial. Some patients with chronic type B hepatitis have benefited clinically from antiviral therapy and, in particular, interferon, but its use has not previously been reported as an approach to prevent allograft infection. We administered recombinant leukocyte A interferon perioperatively to a patient who underwent liver transplantation for type B chronic active hepatitis and cirrhosis. Circulating hepatitis B virus DNA was found postoperatively while the patient was receiving interferon, and stainable viral antigen subsequently reappeared in the transplanted liver. Thus, the drug failed to prevent viral replication and allograft infection. Thus far, no evidence of progression of the chronic hepatitis has been noted.     

The prevalence, clinical features and response to antiviral therapy of patients with chronic hepatitis C who are seropositive for liver-kidney microsome type 1 antibodies

BACKGROUND: Antibodies to liver-kidney microsome type 1 (anti-LKM-1), which are a marker of autoimmune hepatitis, are found in a minority of patients with chronic hepatitis C virus (HCV) infection. Whether interferon/ribavirin therapy is safe and effective in these patients is unclear. AIM: To describe the prevalence, clinical features and response to interferon/ribavirin therapy of anti-LKM-1 seropositive patients with chronic hepatitis C. PATIENTS AND METHODS: All anti-LKM-1 seropositive patients with chronic hepatitis C who between 1997 and 2002 underwent a diagnostic liver biopsy at the Liver Center Maggiore Hospital, Milan, were studied. Serum HCV RNA was tested by in-house PCR with a limit sensitivity of 50 IU/ml. Tissue antibodies were assessed by indirect immunofluorescence on cryostat sections from rat liver, kidney and stomach. Liver biopsies were graded and staged by the Ishak score. Autoimmune hepatitis was defined according to the International Autoimmune Hepatitis Grading (IAHG) score. RESULTS: Forty-eight (1.8%) of 2675 HCV patients circulated anti-LKM-1 (30 females, 55 years of age). Twenty-eight had genotype 2, 18 genotype 1, and two genotype 3. Aminotransferase levels had been high for 23 + 12 years, on average. Using IAHG, autoimmune hepatitis was excluded in 44 patients (92%) and found to be probable in 4 patients (8%). Chronic hepatitis was histologically mild in 34 patients (70%), moderate to severe in 7 patients (15%) and with cirrhosis in 7 patients (15%). A sustained virological response (SVR) was achieved in 20 of the 27 patients who received interferon/ribavirin (13 genotype 2c with 87% SVR, and 7 genotype 1b with 58% SVR). None of the patients had serum aminotransferases, immunoglobulins or anti-LKM-1 levels flaring following therapy. CONCLUSIONS: LKM-1 antibodies rarely occur in patients with chronic hepatitis C and do not predict autoimmune hepatitis, interferon/ribavirin hyporesponsiveness or immune-related reactions to therapy.     

Auto-antibodies in hepatitis C.

Hepatitis C virus (HCV) has been implicated in the development of a variety of autoimmune phenomena, some of which are well documented and include a panel of auto-antibodies shared with autoimmune hepatitis (AIH). Anti-nuclear (ANA) and smooth muscle (SMA) antibodies (markers of AIH type 1 [AIH-1]), have been demonstrated in 9-38% and 5-91% of cases respectively, whereas anti-liver/kidney microsomal type 1 (anti-LKM-1) and anti-liver cytosol type 1 antibodies (anti-LC1) (markers of AIH type 2 [AIH-2]), are definitely rarer, especially in adults. The presence of these auto-reactivities in chronic hepatitis C generates clinical overlaps and dilemmas in the correct classification and treatment of such patients. The immunopathological characterization of the auto-antibodies, anti-nuclear and smooth muscle antibodies in particular, combined with internationally defined criteria for the diagnosis of AIH is helpful in this clinical process. Thyroid auto-antibodies and cryoprecitable rheumatoid factors are also commonly detected in hepatitis C, while the occurrence of other auto-antibodies still awaits confirmation.     

Managing chronic hepatitis. Recent advances in diagnosis and treatment

A variety of effective therapies are now available for chronic hepatitis of various causes. Most patients with autoimmune chronic active hepatitis respond to immunosuppressive therapy, and those with Wilson's disease respond to copper-chelating therapy. Patients with drug-induced chronic hepatitis improve with cessation of the medication. About 30% to 40% of patients with chronic hepatitis B infection respond to interferon alfa, as do about 50% of those with chronic hepatitis C infection.     

Distribution of the HLA class I allele in chronic hepatitis C and its association with serum ALT level in chronic hepatitis C

An essential process for resolution of viral infections is the efficient recognition and elimination of intracellular virus. Recognition of viral antigens in the form of short peptides associated with HLA class I molecule is a major task of CD8+ cytotoxic T lymphocytes. In this study, we have evaluated the frequency of the HLA class I alleles in patients with chronic hepatitis C. HLA-B51, -B52, -B55, -B56, -B61, B70, -Cw1, -Cw3, and -Cw4 are less frequent in patients with chronic hepatitis C than in Japanese individuals. The frequency of HLA-A2 is slightly lower in the patients but tends to be higher in patients with normal alanine aminotransferase (ALT) level than in those with elevated ALT level (p = 0.07). Other HLA alleles are not significantly different between two groups. Comparison of HLA homozygosity at HLA-A and -B or -C or at two or three loci did not show a significant association with levels of serum ALT or with the clinical outcome of interferon therapy in patients with hepatitis C. These results suggest a possibility that the alterations of host response, which depends on genetic background, influence disease activities of HCV infection.     

Chronic hepatitis: pathogenesis and treatment

Current therapies for chronic viral hepatitis, autoimmune "lupoid" chronic active hepatitis, and drug-induced chronic hepatitis are discussed in the context of recent advances in our understanding of the pathophysiology of chronic active liver disease. Accurate diagnosis is the cornerstone of proper treatment; the limitations and pitfalls of conventional techniques are discussed. Current theories of the pathogenesis of chronic hepatitis B are reviewed to provide a framework for the use of antiviral drugs. Data from the early results of therapy with adenine arabinoside, acyclovir, and immunomodulatory agents are reviewed, and the theoretical basis for the use of alpha-interferon as well as preliminary data supporting its efficacy is presented. Strategies for the treatment of chronic delta hepatitis and chronic non-A, non-B viral hepatitis are discussed as well. The immunological changes associated with autoimmune chronic active hepatitis are described to help define those patients with chronic active hepatitis who are likely to respond to immunosuppressive therapy. The recognized hazards of long-term corticosteroid therapy are indicated and guidelines for the management of these patients are suggested. Chronic drug-induced liver disease will usually improve with cessation of the offending agent. An approach to the patient with suspected drug-induced chronic hepatitis is indicated. Finally, the role of liver transplantation is mentioned as the ultimate treatment modality available for endstage liver disease.     

A possible role of human leukocyte antigen(HLA) typing for predicting response to interferon therapy in chronic hepatitis C

Hepatitis C viral load, genotype and/or staging of liver fibrosis are known to be factors for predicting response to interferon(IFN) therapy in patients with chronic hepatitis C. The aim of this study is to investigate if human leukocyte antigen(HLA) typing is related to the response to IFN therapy. The seventy six Japanese patients were studied and categorized into two groups: 46 patients with chronic hepatitis C (Group A) and 30 with liver disease unrelated to HCV infection(Group B). In addition, 39 patients who were treated with IFN were classified into complete responders(CR) and non-complete responders (NR). There was not any differences in HLA typing between group A and B, but the frequency of HLA class I B51(5) was higher in CR than in NR patients(p = 0.045). When restricted to those who had low viral load(under 10(55) copies/ml) and genotype 2a or 2b, HLA class I CW1 was found in 7 responders(70%) and in 1 non-responder(14%) (p = 0.023). HLA class II DR9 was not found in responders but in 3 non-responders(p = 0.022). These preliminary results suggest that HLA types may be related response to IFN therapy in patients with chronic hepatitis C.     

干扰素α致甲状腺功能异常21例临床分析

目的探讨干扰素α治疗慢性丙型病毒性肝炎(丙肝)时对甲状腺功能的影响及治疗对策。方法对我院2007年6月—2011年6月的309例慢性丙肝患者应用干扰素α治疗过程中出现甲状腺功能异常21例的临床资料进行分析。结果本组甲状腺功能异常发生率6.8%(21/309),21例在应用干扰素α治疗前甲状腺功能均正常,治疗2周~6个月后出现甲状腺功能异常,其中甲状腺功能亢进症(甲亢)11例,甲状腺功能减退症(甲减)7例,亚临床甲减3例。明确诊断后2例甲亢停用干扰素,余继续用药,同时予相应治疗,病情好转出院。随访半年,预后良好。结论干扰素α治疗慢性丙肝可诱发甲状腺功能异常,故治疗过程中应密切监测甲状腺功能,以及时采取处理措施。     

Interferons in the management of viral hepatitis

Since their discovery in 1957, interferons (IFNs) have been noted to have protective effects against human viral infections. The use and safety of IFNs in patients with acute or chronic hepatitis B or C infections have evolved over the last 20 years. The most studied IFN for the management of viral hepatitis is IFN-alpha, but others have recently been evaluated through controlled clinical trials. IFN treatment is not currently indicated for patients with acute hepatitis B, but has proven beneficial in chronic hepatitis B. The success of treatment in this group of patients has been measured by the normalization of liver enzymes, loss of hepatitis B e antigen and loss of detectable serum DNA of hepatitis B. It has been estimated in several clinical trials that as many as 40% of treated patients will respond to therapy, as defined above. Although only a few and limited studies have evaluated the use of IFNs in acute hepatitis C, treatment appears to decrease the likelihood of chronicity, and should be considered. In chronic hepatitis C, treatment has been effective in achieving sustained viral eradication in up to 20% of patients taking the FDA-approved dosage of three million units, three times weekly for 6-12 months. However, higher doses, longer duration of treatment or combining IFN with other antiviral agents may improve the rate of response. It has become clear during the last two decades that IFNs have beneficial effects for patients with viral hepatitis B or C. Much more effort is needed to establish the optimal dose and duration of therapy. Studies addressing the pharmacokinetics of IFNs in patients with viral hepatitis are needed, and methods to improve the bioavailability of these products to affected tissues such as the liver may improve efficacy and minimize side-effects.     

Antibodies to Hepatitis C Virus and Chronic Liver Disease among Finnish Patients with Haemophilia

Antibodies to hepatitis C virus, hepatitis B serology and liver enzymes were examined in 137 Finnish haemophiliac patients to detect signs of chronic viral hepatitis and its possible aetiological associations. The prevalence of raised alanine aminotransferase values was 37%. These were significantly associated with hepatitis C seropositivity but not with hepatitis B antibodies, severity of haemophilia or the type of clotting factor used in replacement therapy. The prevalence of hepatitis C seropositivity was 50%; it was significantly associated with severe haemophilia and with the use of large pool concentrates. The hepatitis C virus seems to be the major cause of chronic liver disease transmitted by clotting factors also in Finland, despite a somewhat lower seroprevalence than described elsewhere so far.     

Antibodies to hepatitic C virus and chronic liver disease among Finnish patients with haemophilia

Antibodies to hepatitis C virus, hepatitis B serology and liver enzymes were examined in 137 Finnish haemophiliac patients to detect signs of chronic viral hepatitis and its possible aetiological associations. The prevalence of raised alanine aminotransferase values was 37%. These were significantly associated with hepatitis C seropositivity but not with hepatitis B antibodies, severity of haemophilia or the type of clotting factor used in replacement therapy. The prevalence of hepatitis C seropositivity was 50%; it was significantly associated with severe haemophilia and with the use of large pool concentrates. The hepatitis C virus seems to be the major cause of chronic liver disease transmitted by clotting factors also in Finland, despite a somewhat lower seroprevalence than described elsewhere so far.     

Interferon therapy for acute hepatitis C during pregnancy

OBJECTIVE: Due to their antiproliferative activity, the probable effects of interferons on a fetus are a concern. We report on a pregnant patient who developed acute hepatitis C during pregnancy and was treated with a short course of interferon alfa therapy with a successful outcome. CASE SUMMARY: A 26-year-old woman was diagnosed with acute hepatitis C at the 16th week of pregnancy. She received a total dose of 72 million units of interferon alfa-2b during a 2 1/2 month period. Although the therapy was discontinued due to adverse effects, a complete biochemical and virologic response was obtained. Premature labor occurred and healthy, but growth-restricted, twin infants were born transvaginally. At 18 months of age, they had normal development, with a negative hepatitis C serology. DISCUSSION: The rate of transmission of hepatitis C virus from mother to infant is within the range of 1-5%. Although acute hepatitis C during pregnancy is a very rare occurrence, the mother is at a great risk for chronic infection. There is scarce literature about the probable effects of interferon use during pregnancy due to a lack of controlled studies in this special population. A total of 8 infants, including ours, exposed to interferon alfa and/or ribavirin during pregnancy showed no congenital anomalies or malformations. CONCLUSIONS: Patients with chronic hepatitis whose therapy can be delayed should not be treated with interferon due to a lack of controlled studies. However, women exposed to interferon inadvertently during pregnancy may be encouraged to continue pregnancy. In patients with acute hepatitis C during pregnancy, the use of interferon therapy should be considered with close monitoring.