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Hepatitis C Virus Antibody in Patients With Chronic Autoimmune Hepatitis: Pitfalls in Diagnosis and Implications for Treatment

1991; Elsevier BV; Volume: 66; Issue: 6 Linguagem: Inglês

10.1016/s0025-6196(12)60526-6

1942-5546

Gary L. Davis,

Liver Diseases and Immunity

Chronic hepatitis is an etiologically diverse clinical syndrome characterized by a sustained increase in serum aminotransferase levels for at least 3, and usually 6, months and histologic evidence of portal or periportal inflammation on liver biopsy. Chronic hepatitis is most commonly a consequence of infection by hepatotropic viruses such as hepatitis B, hepatitis C (formerly referred to as non-A, non-B hepatitis), or hepatitis D (delta agent) but may also result from certain hepatotoxic drugs or inherited metabolic disorders such as Wilson's disease (hepatolenticular degeneration), α1-antitrypsin deficiency, or hemochromatosis. Chronic hepatitis is thought to be autoimmune in origin when no serologic evidence of viral or metabolic causes of hepatitis is noted and autoantibodies are present in the serum. Several forms of autoimmune hepatitis exist, based on the type of autoantibody present.1Davis GL Chronic hepatitis.in: Kaplowitz N Liver and Biliary Diseases. Williams & Wilkins, Baltimore1991Google Scholar Most cases, including those previously studied in the large Mayo Clinic corticosteroid treatment trial, are categorized as the classic form (type I) of the disease associated with antinuclear antibody or anti-smooth muscle (anti-actin) antibody (or both). The cause of chronic hepatitis can usually be determined by review of the history and serologic tests.1Davis GL Chronic hepatitis.in: Kaplowitz N Liver and Biliary Diseases. Williams & Wilkins, Baltimore1991Google Scholar Drug-induced chronic hepatitis is suspected on the basis of the drug history and confirmed by the response to discontinuation of the implicated agent. Metabolic forms of the disease are suspected by substantiating decreased α1-antitrypsin levels (α1-antitrypsin deficiency), reduced levels of ceruloplasmin (Wilson's disease), or increased iron saturation (genetic hemochromatosis). The last two diagnoses are confirmed by quantification of increased levels of the implicated metal in the liver biopsy specimen. Viral causes can usually be diagnosed on the basis of serologic tests alone—for instance, the detection of hepatitis B surface antigen in chronic hepatitis B or both hepatitis B surface antigen and IgG antibody to the hepatitis D virus in chronic hepatitis D (either as coinfection with or superinfection of chronic hepatitis B). Both chronic autoimmune hepatitis and chronic hepatitis C are diagnosed by exclusion of other potential causes of hepatitis. Chronic autoimmune hepatitis is supported by the presence of autoantibodies (such as antinuclear antibody or anti-smooth muscle [anti-actin] antibody), a positive lupus erythematosus cell preparation, or hypergammaglobulinemia. In patients without these features, chronic hepatitis C should be considered. Risk factors for infection are evident in about 60% of cases of hepatitis C.2Alter MJ Hadler SC Judson FN Mares A Alexander WJ Hu PY Miller JK Moyer LA Fields HA Bradley DW Margolis HS Risk factors for acute non-A, non-B hepatitis in the United States and association with hepatitis C virus infection.JAMA. 1990; 264: 2231-2235Crossref PubMed Scopus (582) Google Scholar These factors include a history of intravenous use of drugs with shared paraphernalia, blood transfusion, occupational exposure to blood, or intimate exposure to someone with hepatitis. No identifiable risk factor is present in the other approximately 40% of patients with hepatitis C. These cases are termed “sporadic hepatitis.” The agent thought to be responsible for most cases of hepatitis C (non-A, non-B), now labeled as the hepatitis C virus (HCV), was recently isolated and its genome was cloned.3Choo Q-L Kuo G Weiner AJ Overby LR Bradley DW Houghton M Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome.Science. 1989; 244: 359-362Crossref PubMed Scopus (6250) Google Scholar A commercially available enzyme-linked immunosorbent assay for an antibody to a nonstructural peptide of the HCV was licensed for general use in May 1990. This antibody is present in about 90% of cases of hepatitis C due to intravenous use of drugs or blood transfusion and in 60 to 70% of cases of sporadic hepatitis C.4Kuo G Choo Q-L Alter HJ Gitnick GL Redeker AG Purcell RH Miyamura T Dienstag JL Alter MJ Stevens CE Tegtmeier GE Bonino F Colombo M Lee W-S Kuo C Berger K Shuster JR Overby LR Bradley DW Houghton M An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis.Science. 1989; 244: 362-364Crossref PubMed Scopus (3051) Google Scholar Although the specificity of the antibody is good in the clinical setting of a patient with chronic liver disease, neutralization and immunoblot assays to recombinant viral proteins provide supportive evidence that the antibody is truly specific. Additionally, a high antibody absorbance in the enzyme-linked immunosorbent assay is much more likely to be specific for a viral infection. HCV infection is confirmed by immunoblot reactivity to recombinant HCV-associated peptides in only about 16% of samples when the absorbance is between the cutoff limit and twice the cutoff limit (optical density ratio between 1 and 2). In contrast, immunoblot reactivity is present in about 76% of samples with an optical density absorbance ratio of more than 2.5HCV slide set and text. Raritan, New Jersey, Ortho Diagnostic SystemsGoogle Scholar Although investigators must work within the limitations of specificity of the current antibody assay, the technology for serologic diagnosis of HCV infection is evolving rapidly, and more sensitive and specific tests will most likely become available in the near future. Unfortunately, the serologic diagnosis of chronic hepatitis is not always straightforward. Common epidemiologic risk factors may occasionally result in coinfection with multiple hepatitis viruses. Furthermore, coincidental infection with hepatotropic viruses may occur in patients with nonviral types of chronic hepatitis because hepatitis B and C are relatively prevalent (approximately 0.5 to 1%) in the US population. Recent studies have found that the currently available antibody to the hepatitis C virus (anti-HCV) is present in a substantial proportion of patients with chronic autoimmune hepatitis.6Esteban JI Esteban R Viladomiu L López-Talavera JC González A Hernández JM Roget M Vargas V Genescà J Buti M Guardia J Hepatitis C virus antibodies among risk groups in Spain.Lancet. 1989; 2: 294-297Abstract PubMed Scopus (827) Google Scholar, 7McFarlane IG Smith HM Johnson PJ Bray GP Vergani D Williams R Hepatitis C virus antibodies in chronic active hepatitis: pathogenetic factor or false-positive result?.Lancet. 1990; 335: 754-757Abstract PubMed Scopus (402) Google Scholar Several explanations for this observation have been proposed. The suggestion that HCV may be etiologically implicated in the development of autoimmune hepatitis seems doubtful because anti-HCV (usually at extremely low titer) is present in only a subset of patients, its specificity is not confirmed by supportive tests such as immunoblot assays of other HCV peptides, and it frequently disappears after successful immunosuppressive treatment of the liver disease. Another explanation is that the HCV shares epitopes with the liver cell membrane target that presumably results in development of autoimmune hepatitis. The lack of correlation between the presence or titer of anti-HCV and the severity of hepatic inflammation also makes this theory unlikely. The presence of nonspecific (false-positive) anti-HCV in patients with chronic autoimmune hepatitis is best explained by the presence of hypergammaglobulinemia.7McFarlane IG Smith HM Johnson PJ Bray GP Vergani D Williams R Hepatitis C virus antibodies in chronic active hepatitis: pathogenetic factor or false-positive result?.Lancet. 1990; 335: 754-757Abstract PubMed Scopus (402) Google Scholar, 8Boudart D Lucas J-C Muller J-Y Carrer DL Planchon B Harousseau J-C False-positive hepatitis C virus antibody tests in paraproteinaemia (letter to the editor).Lancet. 1990; 336: 63Abstract PubMed Scopus (52) Google Scholar Anti-HCV reactivity correlates directly with the serum globulin level. High levels of immunoglobulin, particularly IgG, are associated with binding of a small amount of a low-avidity globulin in the current enzyme-linked immunosorbent assay. These antibodies are easily dissociated by urea and are not specific for HCV by immunoblot assays. High globulin levels may also result from prolonged freezer storage of samples, which can result in desiccation and concentration of sera.9Taswell HF, Rabe D, Schimek C, Czaja AJ, Rakela J: False positive anti-HCV enzyme-linked immunoassay in frozen sera (abstract). In Program and Abstracts of the Second International Symposium on HCV, 1990, p 89Google Scholar More commonly, hyperglobulinemia occurs as a manifestation of chronic autoimmune hepatitis itself. Anti-HCV reactivity disappears coincident with the decrease in globulin noted during successful corticosteroid treatment of the hepatitis.7McFarlane IG Smith HM Johnson PJ Bray GP Vergani D Williams R Hepatitis C virus antibodies in chronic active hepatitis: pathogenetic factor or false-positive result?.Lancet. 1990; 335: 754-757Abstract PubMed Scopus (402) Google Scholar How often do autoantibodies and anti-HCV coexist? Of note, low-titer nonspecific antinuclear antibodies may occasionally occur in otherwise healthy persons. It would be expected that they would also occur in patients with HCV infection, although such coexistence seems to be uncommon.10Mackay IR Frazer IH Toh B-H Pedersen JS Alter HJ Absence of autoimmune serological reactions in chronic non A, non B viral hepatitis.Clin Exp Immunol. 1985; 61: 39-43PubMed Google Scholar Because neither a definitive serologic test nor a generally agreed on set of diagnostic criteria exists for autoimmune hepatitis, determining how many patients with this disease are positive for anti-HCV is difficult with use of the currently available serologic assay. On the basis of my own outpatient clinical experience and discussions with colleagues who have large hepatology practices, however, I believe that this is a common clinical problem. Low-level anti-HCV has been reported to occur in 44 to 65% of autoantibody-positive patients who are clinically suspected, because of the absence of risk factors for hepatitis C, to have autoimmune hepatitis.7McFarlane IG Smith HM Johnson PJ Bray GP Vergani D Williams R Hepatitis C virus antibodies in chronic active hepatitis: pathogenetic factor or false-positive result?.Lancet. 1990; 335: 754-757Abstract PubMed Scopus (402) Google Scholar, 8Boudart D Lucas J-C Muller J-Y Carrer DL Planchon B Harousseau J-C False-positive hepatitis C virus antibody tests in paraproteinaemia (letter to the editor).Lancet. 1990; 336: 63Abstract PubMed Scopus (52) Google Scholar Similarly, anti-HCV may occur in patients with chronic idiopathic or cryptogenic hepatitis (seronegative autoimmune hepatitis). The study by Czaja and colleagues reported in this issue of the Proceedings (pages 572 to 582) no doubt underestimates the number of patients with coexisting antibodies because the study group included only patients with extremely active disease (a subgroup that probably represents only about 15% of patients with autoimmune hepatitis), excluded patients with potential risk factors for viral hepatitis, and included samples from patients who had already been treated with prednisone and were therefore more likely than others to have cleared a falsely increased anti-HCV. Why is the occurrence of anti-HCV in patients with autoimmune hepatitis or the presence of antinuclear antibodies in patients with chronic hepatitis C a problem? A clear identification of the cause of disease is essential for selection of the appropriate therapeutic modality for patients with chronic hepatitis. Thus, coexistence of serologic evidence in support of two different types of chronic hepatitis complicates decisions about treatment. Immunosuppression with corticosteroids with or without azathioprine is effective treatment for classic autoimmune hepatitis.11Soloway R Summerskill WHJ Baggenstoss AH Geall MG Gitnick GL Elveback LR Schoenfield LJ Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis.Gastroenterology. 1972; 63: 820-833PubMed Google Scholar A response to treatment is manifested by amelioration of symptoms, normalization or near-normalization of serum aminotransferase levels, and histologic evidence of improvement. In contrast, corticosteroids have little or no effect on serum aminotransferase levels in patients with chronic hepatitis C.12Stokes P Lopez WC Balart LA Effects of short-term corticosteroid therapy in patients with chronic non-A non-B hepatitis (NANB) (abstract).Gastroenterology. 1987; 92: 1783Google Scholar Recombinant interferon alfa-2b is an antiviral agent that was recently approved for the treatment of chronic hepatitis C. When used at currently recommended doses, it effectively normalizes serum aminotransferase levels and reduces lobular and periportal inflammation in liver biopsy specimens in approximately 40% of patients.13Davis GL Balart LA Schiff ER Lindsay K Bodenheimer Jr, HC Perrillo RP Carey W Jacobson IM Payne J Dienstag JL VanThiel DH Tamburro C Lefkowitch J Albrecht J Meschievitz C Ortego TJ Gibas A Hepatitis Interventional Therapy Group Treatment of chronic hepatitis C with recombinant interferon alfa: a multicenter randomized, controlled trial.N Engl J Med. 1989; 321: 1501-1506Crossref PubMed Scopus (1633) Google Scholar It is critical to recognize, however, that interferon is also a potent immunomodulatory agent. Autoantibodies commonly develop during the course of treatment and on rare occasion have been associated with development of autoimmune disorders such as thyroid disease or idiopathic thrombocytopenic purpura.14Mayet WJ Hess G Gerken G Rossol S Voth R Manns M Meyer zum Büschenfelde KH Treatment of chronic type B hepatitis with recombinant alpha-interferon induces autoantibodies not specific for autoimmune chronic hepatitis.Hepatology. 1989; 10: 24-28Crossref PubMed Scopus (201) Google Scholar A few reports have noted an abrupt increase in serum aminotransferase levels during interferon treatment, a finding that suggests the possibility that autoimmune hepatitis was either precipitated or exacerbated.15Willems B, Villeneuve JP, Vincelette J, Paradis K, Feinman SV, Layrargues GP: Autoimmune hepatitis and peak transaminases during the treatment of chronic hepatitis C with interferon (abstract). In Program and Abstracts of the Second International Symposium on HCV, 1990, p 125Google Scholar, 16Vento S Di Perri G Garofano T Cosco L Concia E Ferraro T Bassetti D Hazards of interferon therapy for HBV-seronegative chronic hepatitis (letter to the editor).Lancet. 1989; 2: 926Abstract PubMed Scopus (90) Google Scholar Thus, interferon treatment is specifically contraindicated in patients with suspected autoimmune hepatitis.17Intron® A (interferon alfa-2b recombinant) (package insert). Schering Corporation, Kenilworth, New Jersey, February 1991Google Scholar How should the clinician approach the patient in whom the distinction between autoimmune hepatitis and hepatitis C is unclear? Of primary importance, one must remember that neither the anti-HCV test nor the serologic criteria for autoimmune hepatitis are perfect. Anti-HCV is not present in 10 to 20% of patients with well-characterized hepatitis C (non-A, non-B) who have risk factors for infection, and it is absent in as many as 40% of patients with sporadic hepatitis C who have no identifiable risk factor for infection. Autoantibodies are absent in 20 to 30% of patients with corticosteroid-responsive autoimmune hepatitis (idiopathic or cryptogenic hepatitis). The approach to the patient should include elicitation of a detailed history of potential risk factors for viral hepatitis and assessment for the presence of other manifestations of autoimmune disease. Anti-HCV positivity by the enzyme immunosorbent assay should be confirmed by either a high absorbance ratio or, preferably, a supportive test such as neutralization or an immunoblot assay. Similarly, the titer of antinuclear antibodies and the γ-globulin level should be considered. Liver biopsy should be performed in all patients in order to ascertain the degree of histologic inflammation and, therefore, the need for treatment. Certain histologic features such as portal lymphoid follicles, bile duct lesions, and steatosis, although not diagnostic, may provide additional support for a diagnosis of hepatitis C.18Lefkowitch JH Apfelbaum TF Non-A, non-B hepatitis: characterization of liver biopsy pathology.J Clin Gastroenterol. 1989; 11: 225-232Crossref PubMed Google Scholar Treatment should be diagnosis-specific. Treatment with recombinant interferon alfa should be confined to those patients with a definite diagnosis of chronic hepatitis C (non-A, non-B). Patients with chronic hepatitis C (non-A, non-B) who are negative for anti-HCV should be considered for interferon treatment only after autoimmune hepatitis has been confidently excluded, inasmuch as such therapy in patients with autoimmune hepatitis is potentially hazardous (for the aforementioned reasons). Corticosteroids with or without azathioprine should be used in patients in whom the diagnosis of chronic autoimmune hepatitis is supported by serologic findings. Patients in whom the distinction between autoimmune hepatitis and hepatitis C cannot be confidently made on the basis of serologic or clinical evaluation should be managed cautiously. A 2- or 3-month trial of prednisone therapy is the most prudent first step. Patients with autoimmune hepatitis would be expected to have a dramatic reduction in serum aminotransferase levels, whereas those with chronic hepatitis C should have a minimal change (less than a 50% decrease in aminotransferase levels). In the latter group, corticosteroid therapy can be discontinued and interferon therapy can be initiated without fear that occult autoimmune disease has been missed.