Autoantibodies and their Antigens in Autoimmune Hepatitis

ABSTRACT

Autoantibody detection assists in the diagnosis and allows differentiation of autoimmune hepatitis (AIH) type 1 (AIH-1), characterized by antinuclear antibody (ANA) and/or smooth muscle antibody (SMA), and type 2 (AIH-2), distinguished by the presence of antibodies to liver-kidney microsome type 1 (anti-LKM1) and/or antibodies to liver cytosol type 1 (anti-LC1). Detection of atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) and anti-soluble liver antigen (SLA) antibodies can act as an additional pointer toward the diagnosis of AIH, particularly in the absence of the conventional autoantibodies. Routine autoantibody testing by indirect immunofluorescence has been recently complemented by molecular assays based on purified or recombinant antigens. Although the AIH-1-specific ANA and SMA targets need better definition, those of anti-LKM1 and anti-LC1 in AIH-2 have been clearly identified; the fine specificity of antibody reactivity and its clinical relevance to disease pathogenesis are the focus of ongoing investigation. This article critically discusses the current knowledge of the diagnostic and clinical significance of AIH-related autoantibody reactivities, focusing on key issues that the physician needs to be aware of to be able to request the appropriate testing and to interpret correctly the laboratory results within the clinical context of the patient.

KEYWORDS

Antibody - autoantigen - autoimmunity - disease - liver

REFERENCES

• 1 Bogdanos D P, Invernizzi P, Mackay I R, Vergani D. Autoimmune liver serology: current diagnostic and clinical challenges.  World J Gastroenterol. 2008;  14(21) 3374-3387
• 2 Vergani D, Alvarez F, Bianchi F B International Autoimmune Hepatitis Group et al. Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group.  J Hepatol. 2004;  41(4) 677-683
• 3 Alvarez F, Berg P A, Bianchi F B et al.. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis.  J Hepatol. 1999;  31(5) 929-938
• 4 Hennes E M, Zeniya M, Czaja A J International Autoimmune Hepatitis Group et al. Simplified criteria for the diagnosis of autoimmune hepatitis.  Hepatology. 2008;  48(1) 169-176
• 5 Gregorio G V, Portmann B, Reid F et al.. Autoimmune hepatitis in childhood: a 20-year experience.  Hepatology. 1997;  25(3) 541-547
• 6 Duchini A, McHutchison J G, Pockros P J. LKM-positive autoimmune hepatitis in the western United States: a case series.  Am J Gastroenterol. 2000;  95(11) 3238-3241
• 7 Bogdanos D P, Mieli-Vergani G, Vergani D. Liver-kidney microsomal antibody-positive autoimmune hepatitis in the United States.  Am J Gastroenterol. 2001;  96(12) 3447-3448
• 8 Waldenstrom J. Leber, blutproteine und Nahrungsweiss.  Dtsch Z Verdau Stoffwechselkr. 1950;  15 113-119
• 9 Zimmerman H J, Heller P, Hill R P. Extreme hyperglobulinemia in subacute hepatic necrosis.  N Engl J Med. 1951;  244(7) 245-249
• 10 Mackay I R. Historical reflections on autoimmune hepatitis.  World J Gastroenterol. 2008;  14(21) 3292-3300
• 11 Leoni A. [The specificity of L.E. phenomenon].  Minerva Med. 1954;  45(30) 1022-1027
• 12 Joske R A, King W E. The L.E.-cell phenomenon in active chronic viral hepatitis.  Lancet. 1955;  269(6888) 477-480
• 13 Hargraves M M, Richmond H, Morton R. Presentation of two bone marrow elements; the tart cells and the L.E cell.  Mayo Clin Proc. 1948;  23 25-28
• 14 Cowling D C, Mackay I R, Taft L I. Lupoid hepatitis.  Lancet. 1956;  271(6957) 1323-1326
• 15 Mackay I R, Weiden S, Hasker J. Autoimmune hepatitis.  Ann N Y Acad Sci. 1965;  124(2) 767-780
• 16 Johnson P J, McFarlane I G. Meeting report: International Autoimmune Hepatitis Group.  Hepatology. 1993;  18(4) 998-1005
• 17 Holborow E J, Asherson G L, Johnson G D, Barnes R D, Carmichael D S. Antinuclear factor and other antibodies in blood and liver diseases.  BMJ. 1963;  1(5331) 656-658
• 18 Czaja A J, Morshed S A, Parveen S, Nishioka M. Antibodies to single-stranded and double-stranded DNA in antinuclear antibody-positive type 1-autoimmune hepatitis.  Hepatology. 1997;  26(3) 567-572
• 19 Parveen S, Morshed S A, Arima K et al.. Antibodies to Ro/La, Cenp-B, and snRNPs antigens in autoimmune hepatitis of North America versus Asia: patterns of immunofluorescence, ELISA reactivities, and HLA association.  Dig Dis Sci. 1998;  43(6) 1322-1331
• 20 Czaja A J, Homburger H A. Autoantibodies in liver disease.  Gastroenterology. 2001;  120(1) 239-249
• 21 Johnson G D, Holborow E J, Glynn L E. Antibody to smooth muscle in patients with liver disease.  Lancet. 1965;  2(7418) 878-879
• 22 Whittingham S, Irwin J, Mackay I R, Smalley M. Smooth muscle autoantibody in “autoimmune” hepatitis.  Gastroenterology. 1966;  51(4) 499-505
• 23 Bottazzo G F, Florin-Christensen A, Fairfax A, Swana G, Doniach D, Groeschel-Stewart U. Classification of smooth muscle autoantibodies detected by immunofluorescence.  J Clin Pathol. 1976;  29(5) 403-410
• 24 Toh B H. Smooth muscle autoantibodies and autoantigens.  Clin Exp Immunol. 1979;  38(3) 621-628
• 25 Gabbiani G, Ryan G B, Lamelin J P et al.. Human smooth muscle autoantibody. Its identification as antiactin antibody and a study of its binding to “nonmuscular” cells.  Am J Pathol. 1973;  72(3) 473-488
• 26 Kurki P, Linder E, Miettinen A, Alfthan O. Smooth muscle antibodies of actin and “non-actin” specificity.  Clin Immunol Immunopathol. 1978;  9(4) 443-453
• 27 Lidman K, Biberfeld G, Fagraeus A et al.. Anti-actin specificity of human smooth muscle antibodies in chronic active hepatitis.  Clin Exp Immunol. 1976;  24(2) 266-272
• 28 Czaja A J, Cassani F, Cataleta M, Valentini P, Bianchi F B. Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis.  Hepatology. 1996;  24(5) 1068-1073
• 29 Liaskos C, Bogdanos D P, Davies E T, Dalekos G N. Diagnostic relevance of anti-filamentous actin antibodies in autoimmune hepatitis.  J Clin Pathol. 2007;  60(1) 107-108
• 30 Granito A, Muratori L, Muratori P et al.. Antibodies to filamentous actin (F-actin) in type 1 autoimmune hepatitis.  J Clin Pathol. 2006;  59(3) 280-284
• 31 Zamanou A, Tsirogianni A, Terzoglou C, Balafas A, Economidou I, Lymberi P. Anti-smooth muscle antibodies (ASMAs) and anti-cytoskeleton antibodies (ACTAs) in liver diseases: a comparison of classical indirect immunofluorescence with ELISA.  J Clin Lab Anal. 2002;  16(4) 194-201
• 32 Villalta D, Bizzaro N, Da Re M, Tozzoli R, Komorowski L, Tonutti E. Diagnostic accuracy of four different immunological methods for the detection of anti-F-actin autoantibodies in type 1 autoimmune hepatitis and other liver-related disorders.  Autoimmunity. 2008;  41(1) 105-110
• 33 Rizzetto M, Swana G, Doniach D. Microsomal antibodies in active chronic hepatitis and other disorders.  Clin Exp Immunol. 1973;  15(3) 331-344
• 34 Rizzetto M, Bianchi F B, Doniach D. Characterization of the microsomal antigen related to a subclass of active chronic hepatitis.  Immunology. 1974;  26(3) 589-601
• 35 Homberg J C, Abuaf N, Bernard O et al.. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of “autoimmune” hepatitis.  Hepatology. 1987;  7(6) 1333-1339
• 36 Homberg J C, Andre C, Abuaf N. A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis.  Clin Exp Immunol. 1984;  55(3) 561-570
• 37 Crivelli O, Lavarini C, Chiaberge E et al.. Microsomal autoantibodies in chronic infection with the HBsAg associated delta (delta) agent.  Clin Exp Immunol. 1983;  54(1) 232-238
• 38 Clemente M G, Meloni A, Obermayer-Straub P, Frau F, Manns M P, De Virgiliis S. Two cytochromes P450 are major hepatocellular autoantigens in autoimmune polyglandular syndrome type 1.  Gastroenterology. 1998;  114(2) 324-328
• 39 Gueguen M, Meunier-Rotival M, Bernard O, Alvarez F. Anti-liver kidney microsome antibody recognizes a cytochrome P450 from the IID subfamily.  J Exp Med. 1988;  168(2) 801-806
• 40 Manns M P, Johnson E F, Griffin K J, Tan E M, Sullivan K F. Major antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450db1.  J Clin Invest. 1989;  83(3) 1066-1072
• 41 Zanger U M, Hauri H P, Loeper J, Homberg J C, Meyer U A. Antibodies against human cytochrome P-450db1 in autoimmune hepatitis type II.  Proc Natl Acad Sci U S A. 1988;  85(21) 8256-8260
• 42 Manns M P, Obermayer-Straub P. Cytochromes P450 and uridine triphosphate-glucuronosyltransferases: model autoantigens to study drug-induced, virus-induced, and autoimmune liver disease.  Hepatology. 1997;  26(4) 1054-1066
• 43 Martini E, Abuaf N, Cavalli F, Durand V, Johanet C, Homberg J C. Antibody to liver cytosol (anti-LC1) in patients with autoimmune chronic active hepatitis type 2.  Hepatology. 1988;  8(6) 1662-1666
• 44 Lenzi M, Manotti P, Muratori L et al.. Liver cytosolic 1 antigen-antibody system in type 2 autoimmune hepatitis and hepatitis C virus infection.  Gut. 1995;  36(5) 749-754
• 45 Muratori L, Cataleta M, Muratori P, Lenzi M, Bianchi F B. Liver/kidney microsomal antibody type 1 and liver cytosol antibody type 1 concentrations in type 2 autoimmune hepatitis.  Gut. 1998;  42(5) 721-726
• 46 Lapierre P, Hajoui O, Homberg J C, Alvarez F. Formiminotransferase cyclodeaminase is an organ-specific autoantigen recognized by sera of patients with autoimmune hepatitis.  Gastroenterology. 1999;  116(3) 643-649
• 47 Muratori L, Sztul E, Muratori P et al.. Distinct epitopes on formiminotransferase cyclodeaminase induce autoimmune liver cytosol antibody type 1.  Hepatology. 2001;  34(3) 494-501
• 48 Berg P A, Stechemesser E, Strienz J. Hypergammaglobulinamische chronisch aktive Hepatitis mit Nachweis von leberpankreas-spezifischen komplementbindenden Autoantikorpern.  Verh Dtsch Ges Inn Med. 1981;  87 921-927
• 49 Stechemesser E, Klein R, Berg P A. Characterization and clinical relevance of liver-pancreas antibodies in autoimmune hepatitis.  Hepatology. 1993;  18(1) 1-9
• 50 Manns M, Gerken G, Kyriatsoulis A, Staritz M, Meyer zum Büschenfelde K H. Characterisation of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen.  Lancet. 1987;  1(8528) 292-294
• 51 Wies I, Brunner S, Henninger J et al.. Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis.  Lancet. 2000;  355(9214) 1510-1515
• 52 Volkmann M, Martin L, Bäurle A et al.. Soluble liver antigen: isolation of a 35-kd recombinant protein (SLA-p35) specifically recognizing sera from patients with autoimmune hepatitis.  Hepatology. 2001;  33(3) 591-596
• 53 Ma Y, Okamoto M, Thomas M G et al.. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease.  Hepatology. 2002;  35(3) 658-664
• 54 Gelpi C, Sontheimer E J, Rodriguez-Sanchez J L. Autoantibodies against a serine tRNA-protein complex implicated in cotranslational selenocysteine insertion.  Proc Natl Acad Sci U S A. 1992;  89(20) 9739-9743
• 55 McFarlane I G, Hegarty J E, McSorley C G, McFarlane B M, Williams R. Antibodies to liver-specific protein predict outcome of treatment withdrawal in autoimmune chronic active hepatitis.  Lancet. 1984;  2(8409) 954-956
• 56 Czaja A J, Pfeifer K D, Decker R H, Vallari A S. Frequency and significance of antibodies to asialoglycoprotein receptor in type 1 autoimmune hepatitis.  Dig Dis Sci. 1996;  41(9) 1733-1740
• 57 van der Woude F J, Rasmussen N, Lobatto S et al.. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis.  Lancet. 1985;  1(8426) 425-429
• 58 Hagen E C, Andrassy K, Chernok E EEC/BCR Group for ANCA Assay Standardization et al. The value of indirect immunofluorescence and solid phase techniques for ANCA detection. A report on the first phase of an international cooperative study on the standardization of ANCA assays.  J Immunol Methods. 1993;  159(1-2) 1-16
• 59 Terjung B, Herzog V, Worman H J et al.. Atypical antineutrophil cytoplasmic antibodies with perinuclear fluorescence in chronic inflammatory bowel diseases and hepatobiliary disorders colocalize with nuclear lamina proteins.  Hepatology. 1998;  28(2) 332-340
• 60 Terjung B, Spengler U, Sauerbruch T, Worman H J. “Atypical p-ANCA” in IBD and hepatobiliary disorders react with a 50-kilodalton nuclear envelope protein of neutrophils and myeloid cell lines.  Gastroenterology. 2000;  119(2) 310-322
• 61 Terjung B, Worman H J, Herzog V, Sauerbruch T, Spengler U. Differentiation of antineutrophil nuclear antibodies in inflammatory bowel and autoimmune liver diseases from antineutrophil cytoplasmic antibodies (p-ANCA) using immunofluorescence microscopy.  Clin Exp Immunol. 2001;  126(1) 37-46
• 62 Terjung B, Bogsch F, Klein R et al.. Diagnostic accuracy of atypical p-ANCA in autoimmune hepatitis using ROC- and multivariate regression analysis.  Eur J Med Res. 2004;  9(9) 439-448
• 63 Terjung B, Spengler U. Atypical p-ANCA in PSC and AIH: a hint toward a “leaky gut”?.  Clin Rev Allergy Immunol. 2009;  36(1) 40-51
• 64 Gregorio G V, McFarlane B, Bracken P, Vergani D, Mieli-Vergani G. Organ and non-organ specific autoantibody titres and IgG levels as markers of disease activity: a longitudinal study in childhood autoimmune liver disease.  Autoimmunity. 2002;  35(8) 515-519
• 65 Frenzel C, Herkel J, Lüth S, Galle P R, Schramm C, Lohse A W. Evaluation of F-actin ELISA for the diagnosis of autoimmune hepatitis.  Am J Gastroenterol. 2006;  101(12) 2731-2736
• 66 Gregorio G V, Portmann B, Karani J et al.. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.  Hepatology. 2001;  33(3) 544-553
• 67 Hov J R, Boberg K M, Karlsen T H. Autoantibodies in primary sclerosing cholangitis.  World J Gastroenterol. 2008;  14(24) 3781-3791
• 68 Kerkar N, Hadzić N, Davies E T et al.. De-novo autoimmune hepatitis after liver transplantation.  Lancet. 1998;  351(9100) 409-413
• 69 Bogdanos D P, Mieli-Vergani G, Vergani D. Non-organ-specific autoantibodies in hepatitis C virus infection: do they matter?.  Clin Infect Dis. 2005;  40(4) 508-510
• 70 Bogdanos D P, Baum H, Vergani D. Antimitochondrial and other autoantibodies.  Clin Liver Dis. 2003;  7(4) 759-777, vi
• 71 Rigopoulou E I, Davies E T, Pares A et al.. Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis.  Gut. 2005;  54(4) 528-532
• 72 Vergani D, Bogdanos D P. Positive markers in AMA-negative PBC.  Am J Gastroenterol. 2003;  98(2) 241-243
• 73 Maggiore G, Bernard O, Homberg J C et al.. Liver disease associated with anti-liver-kidney microsome antibody in children.  J Pediatr. 1986;  108(3) 399-404
• 74 Muratori L, Parola M, Ripalti A et al.. Liver/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane.  Gut. 2000;  46(4) 553-561
• 75 Cassani F, Cataleta M, Valentini P et al.. Serum autoantibodies in chronic hepatitis C: comparison with autoimmune hepatitis and impact on the disease profile.  Hepatology. 1997;  26(3) 561-566
• 76 Lenzi M, Bellentani S, Saccoccio G et al.. Prevalence of non-organ-specific autoantibodies and chronic liver disease in the general population: a nested case-control study of the Dionysos cohort.  Gut. 1999;  45(3) 435-441
• 77 Muratori L, Lenzi M, Cataleta M et al.. Interferon therapy in liver/kidney microsomal antibody type 1-positive patients with chronic hepatitis C.  J Hepatol. 1994;  21(2) 199-203
• 78 Bortolotti F, Vajro P, Balli F et al.. Non-organ specific autoantibodies in children with chronic hepatitis C.  J Hepatol. 1996;  25(5) 614-620
• 79 Bogdanos D P, Mieli-Vergani G, Vergani D. Virus, liver and autoimmunity.  Dig Liver Dis. 2000;  32(5) 440-446
• 80 Ferri S, Muratori L, Quarneti C et al.. Clinical features and effect of antiviral therapy on anti-liver/kidney microsomal antibody type 1 positive chronic hepatitis C.  J Hepatol. 2009;  , March 26 (Epub ahead print)
• 81 Vergani D. LKM antibody: getting in some target practice.  Gut. 2000;  46(4) 449-450
• 82 Baeres M, Herkel J, Czaja A J et al.. Establishment of standardised SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics.  Gut. 2002;  51(2) 259-264
• 83 Bogdanos D P, Gilbert D, Bianchi I et al.. Antibodies to soluble liver antigen and alpha-enolase in patients with autoimmune hepatitis.  J Autoimmune Dis. 2004;  1(1) 4
• 84 Vitozzi S, Djilali-Saiah I, Lapierre P, Alvarez F. Anti-soluble liver antigen/liver-pancreas (SLA/LP) antibodies in pediatric patients with autoimmune hepatitis.  Autoimmunity. 2002;  35(8) 485-492
• 85 Xu X M, Carlson B A, Mix H et al.. Biosynthesis of selenocysteine on its tRNA in eukaryotes.  PLoS Biol. 2007;  5(1) e4
• 86 Kerkar N, Ma Y, Davies E T, Cheeseman P, Mieli-Vergani G, Vergani D. Detection of liver kidney microsomal type 1 antibody using molecularly based immunoassays.  J Clin Pathol. 2002;  55(12) 906-909
• 87 Vergani D. NOSA in HCV infection: markers or makers of disease?.  Gut. 1999;  45(3) 328-329
• 88 Vergani D, Choudhuri K, Bogdanos D P, Mieli-Vergani G. Pathogenesis of autoimmune hepatitis.  Clin Liver Dis. 2002;  6(3) 727-737
• 89 Vergani D, Mieli-Vergani G. The impact of autoimmunity on hepatocytes.  Semin Liver Dis. 2007;  27(2) 140-151
• 90 Gregorio G V, Choudhuri K, Ma Y et al.. Mimicry between the hepatitis C virus polyprotein and antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis C virus infection.  Clin Exp Immunol. 2003;  133(3) 404-413
• 91 Kerkar N, Choudhuri K, Ma Y et al.. Cytochrome P4502D6(193-212): a new immunodominant epitope and target of virus/self cross-reactivity in liver kidney microsomal autoantibody type 1-positive liver disease.  J Immunol. 2003;  170(3) 1481-1489
• 92 Bogdanos D P, Dalekos G N. Enzymes as target antigens of liver-specific autoimmunity: the case of cytochromes P450s.  Curr Med Chem. 2008;  15(22) 2285-2292
• 93 Mullighan C G, Bogdanos D P, Vergani D, Bardy P G. Cytochrome P450 1A2 is a target antigen in hepatitic graft-versus-host disease.  Bone Marrow Transplant. 2006;  38(10) 703-705
• 94 Granito A, Stanzani M, Muratori L et al.. LKM1-positive type 2 autoimmune hepatitis following allogenic hematopoietic stem-cell transplantation.  Am J Gastroenterol. 2008;  103(5) 1313-1314
• 95 Obermayer-Straub P, Perheentupa J, Braun S et al.. Hepatic autoantigens in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.  Gastroenterology. 2001;  121(3) 668-677
• 96 Lanzavecchia A. How can cryptic epitopes trigger autoimmunity?.  J Exp Med. 1995;  181(6) 1945-1948
• 97 Bogdanos D P, McFarlane I G. Cytochrome P450 2A6 meets P450 2D6: an enigma of viral infections and autoimmunity.  J Hepatol. 2003;  39(5) 860-863
• 98 Beaune P, Pessayre D, Dansette P, Mansuy D, Manns M. Autoantibodies against cytochromes P450: role in human diseases.  Adv Pharmacol. 1994;  30 199-245
• 99 Hasler J A. Pharmacogenetics of cytochromes P450.  Mol Aspects Med. 1999;  20(1-2) 12-24 25-137
• 100 Lin J H, Lu A Y. Interindividual variability in inhibition and induction of cytochrome P450 enzymes.  Annu Rev Pharmacol Toxicol. 2001;  41 535-567
• 101 Bogdanos D P, Choudhuri K, Vergani D. Molecular mimicry and autoimmune liver disease: virtuous intentions, malign consequences.  Liver. 2001;  21(4) 225-232
• 102 Dalekos G N, Wedemeyer H, Obermayer-Straub P et al.. Epitope mapping of cytochrome P4502D6 autoantigen in patients with chronic hepatitis C during alpha-interferon treatment.  J Hepatol. 1999;  30(3) 366-375
• 103 Manns M P, Griffin K J, Sullivan K F, Johnson E F. LKM-1 autoantibodies recognize a short linear sequence in P450IID6, a cytochrome P-450 monooxygenase.  J Clin Invest. 1991;  88(4) 1370-1378
• 104 Yamamoto A M, Cresteil D, Homberg J C, Alvarez F. Characterization of anti-liver-kidney microsome antibody (anti-LKM1) from hepatitis C virus-positive and -negative sera.  Gastroenterology. 1993;  104(6) 1762-1767
• 105 Bogdanos D P, Lenzi M, Okamoto M et al.. Multiple viral/self immunological cross-reactivity in liver kidney microsomal antibody positive hepatitis C virus infected patients is associated with the possession of HLA B51.  Int J Immunopathol Pharmacol. 2004;  17(1) 83-92
• 106 Ma Y, Bogdanos D P, Hussain M J et al.. Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2.  Gastroenterology. 2006;  130(3) 868-882
• 107 Ma Y, Thomas M G, Okamoto M et al.. Key residues of a major cytochrome P4502D6 epitope are located on the surface of the molecule.  J Immunol. 2002;  169(1) 277-285
• 108 Manns M, Zanger U, Gerken G et al.. Patients with type II autoimmune hepatitis express functionally intact cytochrome P-450 db1 that is inhibited by LKM-1 autoantibodies in vitro but not in vivo.  Hepatology. 1990;  12(1) 127-132