ANA-H and/or SMA-AA does not exclude AIH, the characterAntibodies to nuclei (ANA), smooth muscle (SMA), and ization of ANA and SMA may help to discriminate between liver/kidney microsomes type 1 (anti-LKM1) may occur in the two conditions. As compared with the seronegative counchronic hepatitis C. Distinct subspecificities, including ANA terpart, autoantibody-positive chronic hepatitis C is more with the homogeneous pattern (ANA-H) and SMA with anticommon in females and exhibits a more severe biochemical actin specificity (SMA-AA), are found in autoimmune hepatiand histological activity. The response to IFN therapy, howtis (AIH). This study was performed to characterize the hepaever, is similar. (HEPATOLOGY 1997;26:561-566.) titis C virus (HCV)-associated autoantibodies and to evaluate their influence on the profile of the disease. Two hundred ninety consecutive patients with chronic hepatitis C and 35A variety of immunological abnormalities has been decontrol cases with AIH were screened for autoantibodies by scribed in patients with chronic hepatitis C. In particular, indirect immunofluorescence (IFL) at 1:40 serum dilution. the occurrence of serum non-organ-specific autoantibodies The ANA pattern was defined by IFL on HEp-2 cells and the has been extensively studied: smooth muscle (SMA) and anti-SMA-AA identified by the presence of at least two of the nuclear (ANA) antibodies have been detected in approxifollowing elements: 1) SMA T or SMA G pattern by IFL on mately one third of the cases, 1,2 while antibodies to liver/ kidney sections; 2) XR 1 precipitating system by counterimmu-kidney microsomes type 1 (anti-LKM1) have been found noelectrophoresis; or 3) typical pattern by IFL on liver sec-more rarely (from 0% to 5%). [2][3][4] Variations in the autoantitions from phalloidin-intoxicated rats. ANA, SMA, and anti-body prevalence among the reports so far published 1-7 have LKM1 occurred in 9%, 20%, and 6% of chronic hepatitis C been attributed both to different experimental conditions in cases, respectively. The overall prevalence of autoantibodies the immunofluorescence (IFL) procedure and to ethnical and was 30% (87 of 290). Compared with AIH, HCV-associated geographical differences in the study populations. ANA and SMA exhibited ANA-H and SMA-AA at a lower Most reports agree that the autoantibody positivity does prevalence (38% vs. 71%, P Å .04 and 8% vs. 87%, P õ not influence either the clinical and biochemical profile of .000001, respectively) and had a lower median titer (1:80 vs. chronic hepatitis C or the response to interferon (IFN) alfa. 1:320, P õ .001 and 1:40 vs. 1:320, P õ .000001, respec-Some data, however, have been published on the occurrence tively). The concomitant positivity for ANA-H and SMA-AA of disease activity exacerbations in patients with serum autowas detected in none of the HCV cases, but in 46% of AIH antibodies during IFN treatment. 8-10 sera (P õ .000001). Two parameters were independently asThe major impact of the above autoantibodies in the hepasociated with the autoantibodie...

tionally, multiple reactivities can be present concurrently in Antibodies to actin have been proposed as diagnostic the same patient. 10,11markers for type 1 autoimmune hepatitis. Our aims were Recent studies have suggested that anti-actin have specito determine 1) if testing for antibodies to actin is supeficity for autoimmune liver disease, 12-14 and they have been rior to testing for smooth muscle antibodies (SMA); 2) if advocated as better markers for autoimmune hepatitis than these antibodies identify patients with distinctive clini-SMA. 4,15,16 Indeed, the designation, ''anti-actin hepatitis,'' has cal features; and 3) if the production of antibodies to already been used to describe the condition. 16 The SMA found actin is associated with genetic risk factors for autoimin patients with viral infections, including viral hepatitis, are mune hepatitis. Sera from 99 patients with type 1 autoreactive mainly against non-actin cytofilaments (intermediimmune hepatitis were tested. The frequencies of HLA ate filaments), whereas the SMA described in infectious B8, DR3, DR4, and A1-B8-DR3 in patient subsets were compared with those in 80 normal subjects. Seventy-mononucleosis are reactive mainly against tubulin. 4,17 In conthree patients (74%) had antibodies to actin. Antibodies trast, the SMA in autoimmune hepatitis are typically reactive to actin were found more commonly in patients with against actin, 4,15 and this reactivity is either absent or infre-SMA than in patients without them (86% vs. 7%, P õ quent in other chronic liver diseases. 15,[17][18][19] Not all patients .0001). Screening only for antibodies to actin and antinu-with autoimmune hepatitis and SMA, however, have anticlear antibodies (ANA) failed to establish the diagnosis actin, and the frequency of actin immunoreactivity may be of autoimmune hepatitis in 5 patients. Patients with an-as low as 38% in such patients. 15,20 These observations sugtibodies to actin were younger than seronegative pa-gest that anti-actin determinations can enhance diagnostic tients. They were also more commonly DR3-positive specificity, but at a reduced sensitivity when compared with than normal subjects and more frequently B8-positive conventional SMA screening. The advantages of a more prethan patients with non-actin-associated SMA (49% vs. cise diagnosis by anti-actin testing have not been weighed 0%, P Å .004). Only patients with antibodies to actin died against the disadvantages of a missed diagnosis. of liver failure (6% vs. 0%), and 10 of 11 patients requiring Subclassifications of autoimmune hepatitis have been proliver transplantation were seropositive for these anti-posed based on immunoserological findings.21,22 Differentiabodies. Indeed, death and liver transplantation occurred tion of patient subsets by their seropositivity for SMA and/ more frequently in these patients than in actin-negative or ANA or antibodies to liver/kidney microsome type 1 has patients with ANA (19% vs. 0%, P Å .03). We conclude identified individuals who have distinctive clinical, labor...

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Background-Liver/kidney microsomal antibody type 1 (LKM1) and liver cytosol antibody type 1 (LC1) are the serological markers of type 2 autoimmune hepatitis (AIH). Aims-Since LKM1 and LC1 react against two distinct liver specific autoantigens (cytochrome P450IID6 (CYP2D6) and a 58 kDa cytosolic polypeptide respectively), the aim was to see whether LKM1 and LC1 concentrations correlate with liver disease activity. Patients-Twenty one patients with type 2 AIH were studied.Methods-All sera were tested by indirect immunofluorescence, counterimmunoelectrophoresis, and immunoblotting visualised by enhanced chemiluminescence. To evaluate LKM1 and LC1 levels, the 50 kDa microsomal reactivity (corresponding to CYP2D6) and the 58 kDa cytosolic reactivity were quantified by densitometric analysis. Results-Seven patients were positive for LKM1, nine for LC1, and five for both. Serial serum samples at onset and during immunosuppressive treatment were analysed in 13 patients (four positive for LKM1, six positive for LC1 and three positive for both). During remission, LKM1 concentration remained essentially unchanged in six of seven patients, and decreased in only one. Conversely, in two of nine patients, LC1 was completely lost, and, in the remaining seven, LC1 concentration was reduced by more than 50%. After immunosuppression tapering or withdrawal, flare ups of liver necrosis ensued with increasing LC1 concentration, but not LKM1. Conclusions-LC1 concentration, at variance with that of LKM1, parallels liver disease activity, and its participation in the pathogenic mechanisms of liver injury can be hypothesised. (Gut 1998;42:721-726)

Within the multiform liver/kidney microsomal (LKM) family, a subgroup of sera that reacts with a liver cytosolic (LC) protein has been isolated and the new antigen-antibody system is called LC1.

Liver/kidney microsomal antibody type 1 (LKM-1), the serological marker of a subset of autoimmune hepatitis, is also present in a proportion of patients with hepatitis C virus (HCV) related chronic liver disease. To characterise further this autoreactivity and to evaluate whether an autoantibody giving an identical immunofluorescence staining, and detected in two different clinical conditions, involves the same antigenic target(s), sera from autoimmune and HCV infected patients were tested with native, recombinant, and synthetic antigens. Sixty five sera were selected on the basis of the typical immunofluorescence pattern: 50 patients had serological markers of HCV infection, the remaining 15 suffered from autoimmune hepatitis. The reactivity of each serum with rat and human microsomal fractions, full length human recombinant CYP2D6, and two synthetic peptides spanning the amino acid regions 257-269 and 373-398 of CYP2D6 was systematically investigated by immunoblotting. Fourteen (93%) sera from autoimmune hepatitis patients and 39 (78%) from HCV infected patients reacted with rat and/or human microsomal polypeptides of 39 kD, 50 kD, 58 kD, and 66 kD in different associations, the 50 kD band being the most frequently observed. Reactivity to CYP2D6 and its amino acid sequence 257-269 was significantly more common in autoimmune hepatitis than in HCV infected patients (p<0.001 and p<00003, respectively). LKM-1 reactivity is directed against heterogeneous and not entirely defined autoantigens. The main target in autoimmune sera is CYP2D6 and its 257-269 amino acid region, while sera from patients with HCV infection are more likely to recognise other microsomal targets, the molecular identity of which is currently unknown. (Gut 1995; 37: 406-412)

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