GASTROENTEROLOGY 1995;109:2049-2055
CORRESPONDENCE Readers are encouraged to write letters to the editor concerning articles that have been published in GASTROENTEROLOGY.Short, general comments are also considered, but use of the Correspondence section for publication of original data in preliminary form is not encouraged. Letters should be typewritten double-spaced and submitted in triplicate.
AnUneutrophil Cytoplasmic Antibodies in Autoimmune Hepatitis Dear Sir: In their recent article, Targan et al. 1 suggest that the presence of antineutrophil cytoplasmic antibodies (ANCA) is an independent and selective marker for type 1 autoimmune hepatitis (AIH) and differs in several respects from the ANCA of patients with primary sclerosing cholangitis (PSC). Namely, the ANCA of AIH is very high titer, is predominantly of the immunoglobulin (Ig) G1 isotype only, and is not neutrophil specific, because reactivity was also observed with monocytes. The ANCA prevalence of 96% in the AIH group in this study is also the highest reported to date, and the authors suggest that the lower prevalence in previous reports may be due to patient selection and methodology. In our unit, an alkaline phosphatase technique is used for ANCA detection; this has been shown to have greater specificity for PSC than the immunofluorescence method. 2 Recently, 3 we examined sera from 184 patients with chronic liver disease to determine the prevalence and specificity of ANCA for PSC in this group of patients. Using this method, ANCA was detected only in patients with autoimmune liver disease, namely, PSC, primary biliary cirrhosis, and AIH. The sensitivity of perinuclear ANCA for PSC was found to be 63% at a 1:5 serum dilution and 49% at 1:50, with a specificity of 89% at 1:30. In contrast, in AIH, ANCA was detected in 49% at 1:5 dilution and only 11% at 1:50, suggesting, in contrast to Targan et al., that ANCA titers are highest in PSC. The titers in the AIH group were not affected by concomitant use of immunosuppressive therapy. Determination of ANCA IgG subclass in 33 patients with PSC and 11 patients with AIH, using specific monoclonal antibodies, showed a predominance of IgG1 in both groups (94% and 82% of all ANCA, respectively) with a similar distribution of IgG2, IgG3, and IgG4 between the groups. In contrast to Targan et al., 1 only 64% of AIH ANCA were IgG1 (cf 80%), and this was also seen in 38% of PSC ANCA (cf 33%). Furthermore, in this study, 3 ANCA was noted to be neutrophil-specific in both patients with PSC and those with AIH, and no reactivity was observed with monocytes. In another recent tissue distribution study, 4 ANCA in PSC was again shown to be specific to mature neutrophils and their immediate precursors after the myeloblast differentiation stage. The reactivity of AIH sera with monocytes as well as neutrophils in the study by Targan et al. 1 suggests that they may be reporting a different antibody. In a previous study 5 comparing PSC ANCA with UC ANCA, the former was again noted to be of higher titer but differed in its IgG subclass specificity with significantly increased use of IgG3. In this study, 90% of UC ANCA was IgG1 only compared with 63% PSC + UC ANCA (P = 0.016; Fisher's Exact Test). Thus, in our study, 2 ANCA titers were highest in PSC and not in AIH and there was a similar IgG subclass distribution and cell specificity to AIH ANCA. We therefore suggest that perinuclear ANCA is not an independent and selective marker for AIH. Indeed, the cross-reactivity with monocyres together with differences in titer and IgG subclass suggests that the antibody reported by Targan et al. in AIH sera is clearly different from the ANCA reported by us and others in PSC and AIH. Ultimately, determination of the antigen(s)
against which this ANCA is/are directed will not only allow the development of a highly sensitive and specific diagnostic test for PSC but may also provide insight into its pathogenesis and relationship with AIH. D. S. BANSI K. A. FLEMING R. W. CHAPMAN
Department of Gastroenterology Joh~ Radcliffe Hospital Headington Oxford OX3 9DU England 1. Targan SR, Landers C, Vidrich A, Czaja AJ. High-titer antineutrophil cytoplasmic antibodies in type-1 autoimmune hepatitis. Gastroenterology 1995; 108:1159-1166. 2. Lo SK, Fleming KA, Chapman RW. Prevalence of antineutrophil antibody in primary sclerosing cholangitis and ulcerative colitis using an alkaline phosphatase technique. Gut 1992;33:13701375. 3. Bansi DS, Chapman RW, Fleming KA. Antineutrophil cytoplasmic antibody titer but not IgG subclass distinguishes between primary sclerosing cholangitis and autoimmune hepatitis (abstr). Gastroenterology 1995; 108:A1028. 4. Lo SK, Chapman RW, Fleming KA. Tissue distribution of an autoantigen specific for primary scterosing cholangitis. J Clin Pathol 1993; 46:246-249. 5. Bansi DS, Fleming KA, Chapman RW. IgG subclass distribution of antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis and ulcerative colitis. J Pathol 1995;175(Suppl):146A. Reply. We thank Drs. Bansi, Fleming, and Chapman for their comments regarding our recent article describing the ANCA associated with type 1 AIH.I These authors point out some not insignificant differences between our data and their findings, prompting our response. First, it must he pointed out that heterogeneity in patient populations precludes the ability to meaningfully compare the results of different studies, The type 1 AIH patient population used in our study (104 patients) was characterized by severe disease activity and was extensively defined with respect to clinical and laboratory features, histological findings, and the absence of anti-liver-kidney microsomal antibody titers supporting the designation of severe type 1 AIH. Our patient population may not be representative of all patients with AIH but rather comprises a subgroup of patients characterized by their severe disease activity. The study of Bansi et al. 2 examining ANCA in patients with chronic active hepatitis neither clinically defined the patient population nor stratified patients with respect to disease severity. Second, significant methodological differences between studies also preclude meaningful comparisons of data except to say that ANCA/perinuclear ANCA (pANCA) is or is not present. In all of our studies, the assessment of ANCA seropositivity is based on a fixed-neutrophil enzyme-linked immunoabsorbent assay (ELISA) 3 used to quantitate neutrophil binding by serum Igs; subsequently, the ELISA-positive samples are assayed further by indirect immunofluorescence to ascertain the ANCA binding pattern. ANCA tirers are determined using the ELISA assay. We would contend that