GASTROENTEROLOGY 2001;120:1502–1517

Autoimmune Hepatitis: Clinical Challenges MICHAEL P. MANNS and CHRISTIAN P. STRASSBURG Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany

aldenstro¨m first described the disease entity now termed autoimmune hepatitis (AIH) in 1950, when he observed a chronic form of hepatitis in young women.1 This hepatitis led to cirrhosis and was associated with jaundice, elevated gamma globulins, and amenorrhea.2 The disease was found to be associated with other autoimmune syndromes3 and was later termed “lupoid hepatitis” because of the presence of antinuclear antibodies (ANA); however, the term “lupoid” hepatitis has been abandoned because AIH is not part of the organ manifestations of systemic lupus erythematosus. The identification and characterization of serum autoantibodies have been a driving force in the systematic evaluation, classification, and diagnosis of AIH.4 Beginning in the 1970s, the detection of autoantibodies against proteins of the endoplasmic reticulum (microsomes) expressed in liver and kidney (liver-kidney microsomal antibodies, LKM)5–9 led to the identification of a second form of AIH not characterized by ANA.8 Molecular analysis soon identified cytochrome P450 (CYP) monoxygenases as hepatocellular target antigens of LKM-1 autoantibodies found in this second form of AIH (AIH type 2).7,10,11 Finally, a third serologically defined group of AIH was categorized after the detection by radioimmunoassay of antibodies to a soluble liver antigen (SLA) identified in the 100,000 g supernatant of liver homogenates.12 It is evident from the chronology of events that AIH does not represent a homogeneous entity and that seroimmunologic and genetic markers discriminate among its subgroups.13,14 AIH is a chronic, mainly periportal hepatitis associated with hypergammaglobulinemia and circulating autoantibodies, which, in most cases, responds to immunosuppressive treatment. There is a striking prevalence among females,15 an immunogenetic association with the HLA A1-B8-DR3 or DR4 haplotype,16 and the presence of extrahepatic syndromes.17 This complex definition indicates that a single cause or a single test for the accurate diagnosis of AIH has not been found. In contrast, the diagnosis is established by a number of diagnostic criteria, as recently defined by the International Autoimmune Hepatitis Group (IAHG), and the exclusion of other causes of chronic hepatitis18,19 (Tables 1 and 2). However, AIH

W

frequently overlaps with other autoimmune liver diseases that affect the biliary tract: primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).20,21 The combination of seroimmunologic and molecular biologic tests4 with a recently revised diagnostic scoring system permits a precise discrimination between AIH and other causes of chronic hepatitis. The exclusion of replicating hepatitis virus infection together with female sex, hypergammaglobulinemia, and response to immunosuppressive treatment are the hallmarks of an accurate diagnosis.18,19

Definition of AIH As long as the trigger/cause of AIH is not known, the determination is required whether AIH represents an etiologically heterogeneous syndrome or a single disease entity with a clinically differing rate of progression. Attempts to subclassify AIH have been based on the serologic autoantibody profile or on genetic markers.4 The diagnosis of AIH cannot be based on characteristic histologic markers; however, the histologic assessment of liver tissue is required for grading and staging as well as for therapeutic monitoring.22 The exclusion of viral hepatitis is achieved by the use of reliable, commercially available tests and should minimally include hepatitis A, B, and C viruses. Exclusion of hepatitis E virus infection cannot be generally recommended.19 In addition, the exclusion of other hepatotropic viral pathogens (i.e., cytomegalovirus, Epstein–Barr virus, other herpes group

Abbreviations used in this paper: AIH, autoimmune hepatitis; AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic autoantibodies; APS-1, autoimmune polyendocrine syndrome type 1; ELISA, enzyme-linked immunosorbent assay; HCV, hepatitis C virus; HDV, hepatitis D virus; IAHG, International Autoimmune Hepatitis Group; LC-1, liver cytosolic antigen 1; LKM, liver-kidney microsomal antibodies; LP, liver-pancreas antigen; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SLA, soluble liver antigen; SMA, smooth muscle antibodies; tRNA, transfer RNA. © 2001 by the American Gastroenterological Association 0016-5085/01/$35.00 doi:10.1053/gast.2001.24227

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Table 1. The Diagnosis of AIH Is a Diagnosis of Exclusion Suspected differential diagnosis

Test performed to exclude

Hepatitis C infection (HCV) Anti HCV (HCV RNA) Hepatitis B and D (HBV, HDV) HBsAg, anti-HBc (HBV DNA) Anti-HDV, HDV RNA only when HBsAg positive Hepatitis A virus (HAV) Antibodies, serology: IgG, IgM Hepatitis E virus (HEV) Only if suspected Ebstein–Barr virus (EBV) Only if suspected Herpes simplex virus (HSV) Only if suspected Cytomegaly virus (CMV) Only if suspected Varizella zoster zirus (VZV) Only if suspected Drug-induced hepatitis History, if applicable withdrawal of drug LKM-2, LM autoantibody in selected cases Primary biliary cirrhosis (PBC) Antimitochondrial antibodies (AMA) Specificity of reactivity: PDH-E2, BCKD-E2 Liver histology: copper deposition in bile ducts Unresponsive to steroids Primary sclerosing cholangitis Cholangiography (PSC) Wilson’s disease Ceruloplasmin, urine copper, eye examination, quantitative copper in liver biopsy Hemochromatosis Serum ferritin, serum iron, transferrin saturation, liver histology: iron staining, quantitative iron in biopsy Genetic testing: C282Y, H63D mutation of HFE gene in Caucasoids Phenotype testing: ␣1-Antitrypsin deficiency PiZZ/PiSS/PiMZ/PiSZ

viruses) is only recommended in cases suspicious of such infections but may be helpful if the diagnosis of AIH based on the above criteria is unclear. Antibody testing should include immunofluorescence testing for antimitochondrial antibodies (AMA).23 If these are positive, testing for reactivity with the PBC-associated autoantigens E2 subunit of pyruvate dehydrogenase and E2 subunit of branched-chain ketoacid dehydrogenase may be helpful to exclude PBC or to document an overlap syndrome. If a cholestatic biochemical profile (alkaline phosphatase elevation) is present, cholangiography is required to exclude PSC or overlap of PSC and AIH, which is more frequent in children.20 Noninvasive magnetic resonance cholangiopancreaticography is under evaluation as a substitute for the more invasive endoscopic retrograde cholangiopancreatography. The following standard tests to exclude the major genetic causes of chronic liver disease may be necessary to complete the diagnostic evaluation: Wilson’s disease, hemochromatosis, and ␣1antitrypsin deficiency.

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Diagnostic Score of AIH The diagnosis of AIH is established with the aid of a revised scoring system devised by the IAHG and the International Association for the Study of the Liver.18,19 This model describes the probability of AIH (Table 2). Table 2. International Diagnostic Criteria for the Diagnosis of AIH Parameter Gender Female Male Serum biochemistry Ratio of elevation of serum alkaline phosphatase vs. aminotransferase ⬎3.0 1.5–3 ⬍1.5 Total serum globulin, ␥-globulin, or IgG Times upper normal limit ⬎2.0 1.5–2.0 1.0–1.5 ⬍1.0 Autoantibodies (titers by immunfluorescence on rodent tissues) Adults ANA, SMA, or LKM-1 ⬎1:80 1:80 1:40 ⬍1:40 Antimitochondrial antibody Positive Negative Hepatitis viral markers Negative Positive Other etiological factors History of drug usage Yes No Alcohol (average consumption) ⬍25 g/day ⬎60 g/day Genetic factors: HLA DR3 or DR4 Other autoimmune diseases Response to therapy Complete Relapse Liver histology Interface hepatitis Predominant lymphoplasacytic infiltrate Rosetting of liver cells None of the above Biliary changes Other changes Seropositivity for other defined autoantibodies

Score ⫹2 0

⫺2 0 ⫹2 ⫹3 ⫹2 ⫹1 0

⫹3 ⫹2 ⫹1 0 ⫺4 0 ⫹3 ⫺3 ⫺4 ⫹1 ⫹2 ⫺2 ⫹1 ⫹2 ⫹2 ⫹3 ⫹3 ⫹1 ⫹1 ⫺5 ⫺3 ⫺3 ⫹2

NOTE. Interpretation of aggregate scores: definite AIH, ⬎15 before treatment and ⬎17 after treatment; probable AIH, 10 –15 before treatment and 12–17 after treatment. Data from Alvarez et al.19

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The validity of the score has been confirmed in 6 major studies evaluating a total of 983 patients.19,24 –29 The overall sensitivity of the score to establish a diagnosis of definite or probable AIH was 89.8%, however, the specificity for discriminating AIH from overlapping syndromes such as with PBC and or with PSC was low. In a study applying the diagnostic criteria to patients with PSC, PBC, and autoimmune cholangitis (AMA-negative PBC), 37.1% were scored as probable AIH resulting in a specificity of only 60.8% for the exclusion of AIH in biliary disease.26 In the revised AIH score, patients with histologic and cholangiographic evidence of PBC or PSC should be viewed as variants of cholestatic diseases and not of AIH. Specifically, well-defined granulomas, typical bile duct pathology of PSC, and PBC and substantial marginal bile duct proliferation with cholangiolitis and copper accumulation exclude AIH. Cholangiography is recommended for all patients who score as definite or probable AIH but do not respond to standard steroid treatment.

Histology Although a disease-specific histologic feature does not characterize AIH, percutaneous liver biopsy should be performed when coagulation studies permit the procedure. Usually, histologic assessment shows periportal hepatitis with lymphocytic infiltrates, plasma cells, and piecemeal necroses. A lobular hepatitis can be present but is only indicative of AIH in the absence of copper deposits or biliary inflammation. Also, granulomas and iron deposits argue against AIH.30 –32

Clinical Presentation of AIH Based on limited epidemiologic data, the prevalence of AIH is estimated to range between 0.1 and 1.2 cases per 100,000 in Western Europe and North America among the white population but only 0.08 – 0.015 cases per 100,000 in Japan.33 In the North American and Western European white population, AIH accounts for about 20% of chronic hepatitis cases, and in Brazil only 5%–10% of patients with chronic hepatitis suffer from AIH.34 In about 25% of patients with AIH, an acute onset of AIH is observed, and rare cases of fulminant AIH have been reported.35 In most cases, however, the clinical presentation does not differ from that in other forms of chronic hepatitis36 and is characterized by fatigue, right upper quadrant pain, jaundice, and occasionally also by palmar erythema and spider nevi. In later stages, the consequences of portal hypertension dominate, including ascites, bleeding esophageal varices, and encephalopa-

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Table 3. Extrahepatic Associations of AIH Are Present in 10%–50% of Patients Frequent Autoimmune thyroid disease Ulcerative colitis Synovitis Rare or individual reports Rheumatoid arthritis Lichen planus Diabetes mellitus CREST syndrome Autoimmune-thrombozytopenic purpura Vitiligo Nail dystrophy Alopecia

thy.31 A specific feature of AIH is the association of extrahepatic immune-mediated syndromes including autoimmune thyroiditis, rheumatoid arthritis, and diabetes mellitus17,37 (Table 3). Because many of the same extrahepatic manifestations are also present in chronic hepatitis C, hepatitis C virus (HCV) infection should be excluded.13,38,39

Natural History and Prognosis The natural history and prognosis of AIH are largely defined by the inflammatory activity present at presentation and by the presence or development of cirrhosis. With a 5–10-fold elevation of aspartate aminotransferase and 2-fold ␥-globulin elevation, mortality without treatment is 90% in 10 years.40,41 Of patients with periportal hepatitis, cirrhosis develops in 17% within 5 years, but cirrhosis develops in 82% when bridging necrosis or necrosis of multiple lobules is present. The presence of cirrhosis indicates a mortality of 58% in 5 years; however, the presence of cirrhosis at the beginning of treatment does not influence response or short-term outcome.42 The course of AIH is also significantly influenced by the HLA antigen profile of the affected individual. The presence of HLA B8 is associated with severe inflammation at presentation and a higher likelihood of relapse after treatment.43,44 Individuals with HLA DR3 have a lower probability of reaching remission, have more frequent relapses, and require transplantation more often. The HLA DR4 –positive subgroup is characterized by a higher age of onset and a more benign outcome. Limiting confidence in assessments of the natural history of AIH, however, is the fact that frequently cited reports on the prognosis of AIH were written in the “pre hepatitis C era” based on data in a limited number of centers. These studies include placebo-controlled immunosuppressive treatment trials, the last of which was

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Table 4. Molecular Definitions of the Most Important Autoantigens Relevant to the Serologic Diagnosis of Autoimmune Hepatitis Antibody

Kilodaltons

Target antigen

Autoantigens of the endoplasmic reticulum (microsomal autoantigens) LKM-1

50

Cytochrome P450 2D6

LKM-2 LKM-3

50 55

Cytochrome P450 2C9 UGT1A

LKM

50

Cytochrome P450 2A6

LM

52

Cytochrome P450 1A2

57 59 35 59 64 70

Disulfidisomerase Carboxylesterase ? ? ? ?

Autoantigens of the cytosol (soluble liver proteins) LC1

SLA/LP

58–62

Formiminotransferase Cyclodeaminase

50

UGA repressor tRNAassociated protein

published in 1980,45 at a time when only patients with severe chronic hepatitis were enrolled. Today, it is unethical to conduct placebo-controlled AIH trials, therefore, we may never accurately know the natural history of AIH diagnosed on the basis of contemporary internationally accepted diagnostic criteria that incorporate new autoantibody markers and sensitive diagnostic procedures for viral hepatitis.

Autoantibodies in AIH The serologic hallmark of AIH are autoantibodies detected by serologic in vitro assays. For screening purposes, ANA, smooth muscle antibodies (SMA), LKM, and AMA continue to be determined by indirect immunofluorescence on rodent liver, stomach, and kidney tissue. When these autoantibodies are undetectable and the suspicion of AIH remains, autoantibodies against cytosolic antigens, in particular the SLA/liver-pancreas (LP) antigen, may be helpful. These SLA/LP autoantibodies are detected by radioimmunoassay and enzyme-linked immunosorbent assays (ELISAs) because they cannot be observed by immunofluorescence.12,46 – 49 In approximately 10% of patients with AIH, SLA autoantibodies are present as the only marker in the absence of the above-mentioned autoantibodies.50 For scientific purposes, autoantibody profiles have been used as a means of subclassification of AIH. Ac-

Disease

Autoimmune hepatitis type 2 Hepatitis C Ticrynafen-induced hepatitis Hepatitis D–associated autoimmunity Autoimmune hepatitis type 2 Autoimmune polyglandular syndrome type 1 (APS-1) Hepatitis C Dihydralazine-induced hepatitis Hepatitis with autoimmune polyglandular syndrome type 1 (APS-1) Halothane hepatitis Halothan hepatitis Autoimmune hepatitis Chronic hepatitis C Autoimmune hepatitis Chronic hepatitis C

Autoimmune hepatitis type 2 Autoimmune hepatitis Hepatitis C? Autoimmune hepatitis (type 3)

cording to this approach, AIH type 1 is characterized by the presence of ANA and/or anti-SMA directed predominantly against smooth muscle actin. AIH type 2 is characterized by anti–LKM-1 directed against cytochrome P450 (CYP) 2D6 and with lower frequency against uridine 5⬘-diphosphate glucuronosyltransferases.51 AIH type 3 is characterized by autoantibodies against SLA/LP, which have recently been identified as being directed against UGA-suppressor transfer RNA (tRNA)-associated protein and not against the previously suggested candidate autoantigens cytokeratins 8 and/or 18,52 or glutathione-S-transferases.53 Antibodies against LP and SLA autoantibodies seem to exhibit reactivity with the same UGA-suppressor tRNA-associated protein and have recently been designated SLA/LP antibodies.49,54 In addition, many cases of AIH display autoantibodies that show reactivity toward the asialoglycoprotein receptor55 and some reactivity with the liver cytosolic antigen 1 (LC-1),56,57 although these autoantibodies are not routinely determined. LC-1 autoantibodies are found in AIH type 2 and have been characterized as recognizing formiminotransferase cyclodeaminase58 (Table 4). AIH type 1 (classical, lupoid AIH) represents the most common form of AIH, whereas AIH type 2 and 3 are rare entities.59,60 AIH type 2 displays a regionally variable prevalence with very low numbers in the United States

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but accounting for up to 20% of AIH cases in Western Europe. Clinically, the serologically defined AIH subtypes do not differ fundamentally. There is no good evidence that AIH type 1 and AIH type 3 are distinguishable on clinical grounds.61 However, the recognition of SLA/LP autoantibodies as markers of AIH in cases of ANA and LKM negativity, which is present in 10% of AIH cases, justifies recognition of this subset of patients and decreases the possibility of misdiagnosis.50 The differences between AIH type 1 and AIH type 2 are more apparent: In AIH type 2, patients are younger and more frequently display an acute onset of hepatitis with a more severe course and rapid progression than patients with AIH type 1 or 3.17 Although the IAHG strongly argues against a further subtyping of AIH, the distinction between type 1 and type 2 has already been widely adopted in clinical practice. Whether anti-SLA/LP antibodies characterize a special clinical subgroup will remain controversial62 until specific causative agents triggering AIH or subsets of the syndrome are identified. ANA are directed against functional and structural components of the cell nucleus, against nuclear membranes, or DNA.63– 67 The target antigens are heterogeneous and incompletely defined in AIH. For diagnostic purposes, the molecular characterization of target antigen specificity is not required. ANA are also detected in PBC, in which case they have been found to target gp 210, sp100, and nucleoporin p62.23 ANA are routinely determined by indirect immunofluorescence on cryostat sections of rat liver and on Hep.2 cell slides. Most commonly, a homogeneous or speckled immunofluorescence pattern is encountered. ANA have been found to be reactive with centromeres, ribonucleoproteins, cyclin A, and many other antigens. They represent the most common autoantibody in AIH and occur in high titers usually exceeding 1:160. A subtyping of the various ANA specificities, which nowadays can be based on recombinant antigens, has no clinical significance. So far, neither liver-specific nuclear antigens nor liver disease– specific ANA have been identified. Anti-SMA are directed against components of the cytoskeleton such as actin, troponin, and tropomyosin.68,69 They frequently occur in high titers in association with ANA. However, SMA autoantibodies also occur in advanced diseases of the liver of other causes, in infectious diseases, and rheumatic disorders. In these cases, titers are often lower than 1:80. SMA autoantibodies are also determined by indirect immunofluorescence on cryostat sections of rat stomach. SMA have been found to be generally associated with the HLA A1-B8-DR3 haplotype, and, possibly as a reflection of this HLA

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status, the affected patients are younger and have a poorer prognosis. Interestingly, the association of anti– actin-positive patients with HLA A1-B8-DR3 was stronger than the association of SMA-positive patients with this haplotype. Nonactin-positive patients with SMA showed a closer association with HLA DR4.69 LKM and Liver Microsomal Antibodies In 1973, Rizzetto discovered by indirect immunofluorescence autoantibodies reactive with the proximal renal tubule and the hepatocellular cytoplasm.9 These autoantibodies termed LKM-1 are regarded as markers of a second form of AIH.8 Between 1988 and 1991, the 50-kilodalton antigen of LKM-1 autoantibodies was identified as cytochrome P450 2D6 (CYP2D6).7,11,70 LKM-1 autoantibodies recognize a major linear epitope between amino acids 263 and 270 of the CYP2D6 protein.71 These autoantibodies inhibit CYP2D6 activity in vitro and are capable of activating liver infiltrating T lymphocytes.72,73 This observation suggests a combined humoral and cellular immune mechanism leading to the development of LKM autoantibodies. In addition to linear epitopes,71 LKM-1 autoantibodies have also been shown to recognize conformation-dependent epitopes.74 However, the recognition of epitopes located between amino acid 257–269 seems to be a specific autoimmune reaction associated with AIH and discriminates between LKM-1 autoantibodies associated with AIH and those associated with chronic HCV infection.71,75–77 CYP2D6 has been found to be expressed on the hepatocellular surface,78,79 and its expression seems to be regulated by cytokines.80 Antibodies against microsomal proteins form a heterogeneous group spanning several immune-mediated diseases including AIH, drug-induced hepatitis,81– 83 autoimmune polyglandular syndrome type 1 (APS-1),84,85 and chronic hepatitis C (HCV) and D (HDV)13 (Table 4). Antimicrosomal autoantibodies against CYP1A2 and CYP2A6 are found in patients with the autoimmune polyglandular syndrome type 1 (APS-1) with hepatic involvement.86 – 88 Anti–CYP2A6 autoantibodies also occur in HCV infection.77,89 Liver microsomal autoantibodies, which are characterized by an immunofluorescence pattern selectively staining the hepatocellular but not renal cytoplasm, have been found to be directed against CYP1A2.84,90,91 These autoantibodies are also found in APS-1 syndrome with hepatic involvement and occur in dihydralazine-induced hepatitis.86 A second type of LKM autoantibodies, LKM-2, is directed against CYP2C9 and are induced in ticrynafen-associated hepatitis.83,92 A third group of LKM autoantibodies, LKM-3, was identified in 6%–10% of patients with chronic HDV

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infection by Crivelli 1983.93 These autoantibodies are directed against family 1 uridine 5⬘-diphosphate glucuronosyltransferases (UGT1A),51 which are also a superfamily of drug metabolizing proteins located in the endoplasmic reticulum.94 LKM-3 autoantibodies have been identified in HDV infection but also in AIH type 2 patients.95,96 They can also occur in LKM-1–negative and ANA-negative AIH.96 In addition, LKM-positive sera display reactivity with a number of currently undefined antigens with molecular weights of 35, 57, 59, and 70 kilodaltons. These autoantibodies are predominantly found in AIH, HCV infection, and halothane hepatitis.97 LKM autoantibodies are visualized by indirect immunofluorescence on rodent cryostat sections. Subclassification is achieved by ELISA and Western blot, preferably with recombinant antigens. Antibodies against SLA/LP were detected in a patient with ANA-negative AIH12 and are directed against UGA-suppressor tRNA-associated protein.46,48,49 The exact function of this protein and its role in autoimmunity are unclear. In earlier reports, reactivity with cytokeratins 8 and 18 as well as with glutathione-S-transferase were detected, which was not confirmed in later studies.49,52,53 SLA autoantibodies are highly specific for AIH. Recent studies have also shown that SLA autoantibodies are reactive with the same antigen as the independently described liver-pancreas autoantibodies (antiLP).49,54 This has led to the designation of SLA/LP autoantibodies that are detected by ELISA (Table 5). In about 75% of cases, SLA/LP autoantibodies occur simultaneously with other autoantibodies such as SMA and more rarely with AMA.12,61,98,99 In ANA-positive patients, SLA autoantibodies appear in 11% of cases. SLA/LP autoantibodies are detected by ELISA (Table 4).

Other Autoantibodies in AIH The asialoglycoprotein receptor is a liver-specific glycoprotein located in the cell membrane. Autoimmunity targeting this antigen is observed in 88% of all patients with AIH100; however, anti–asialoglycoprotein receptor antibodies are also found in chronic hepatitis B and C, alcoholic liver disease, and PBC. The levels of anti–asialoglycoprotein receptor antibodies fluctuate according to inflammatory activity of the disease and can be viewed as an additional marker to monitor therapeutic efficacy.101 Anti–asialoglycoprotein receptor seems to be a general marker of liver autoimmunity. They are not routinely used for diagnostic purposes. Anti– cytosol autoantibodies type 1 (anti–LC-1) antibodies are viewed as a second marker of AIH type 2, in

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Table 5. Adverse Effects of Standard Treatment Regimens in AIH Prominent side effects of corticosteroid administration Acne Moon-shaped face Striae Dorsal hump Obesity Weight gain Osteoporosis Avascular bone necrosis Psychiatric symptoms (euphoria, psychosis, depression) Diabetes mellitus Cataract Hypertension Prominent side effects of azathioprine administration Nausea Vomiting Abdominal discomfort Hepatotoxicity Rash Arthralgia Myalgia Leukocytopenia Lymphadenopathy Teratogenicity? Oncogenicity?

which they have been detected in up to 50% of LKMpositive sera.102 Other data indicate their occurrence in combination with ANA and SMA autoantibodies and in chronic hepatitis C.57 Contrary to LKM autoantibodies, LC-1 autoantibodies seem to correlate with disease activity. The molecular antigen target has been identified to be formiminotransferase cyclodeaminase,58 but the clinical significance has not yet been completely defined. Antineutrophil cytoplasmic autoantibodies (ANCA) are detected in 65%–96% of sera103,104 from patients with AIH type 1. Immunofluorescence distinguished 2 major ANCA patterns: cANCA with a diffuse cytoplasmic staining of neutrophils and pANCA, which exhibit a rim-like staining of the perinuclear cytoplasm. Among the major autoantigen targets with diagnostic clinical relevance are myeloperoxidase (pANCA), which are detected in 60%– 80% of patients with microscopic polyangiitis, and proteinase 3 (classical cANCA), which is closely associated with Wegener’s granulomatosis. In AIH, atypical pANCA (also termed xANCA) are usually detected that display a pANCA immunofluorescence pattern but do not show reactivity with myeloperoxidase. ANCA are rarely detected in AIH type 2. The discrimination of ANCA and ANA is difficult because ANA frequently also stain ethanol-fixed neutrophils. Most likely the presence of ANCA is only accurate if the ANCA titer exceeds that of ANA by 2-fold. The role of ANCA in AIH is not clear and their routine determination is not recommended.

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Classification and Subclassification of AIH as a Clinical Challenge For years, the existence of AIH as a separate hepatic disease was a matter of intense debate. Currently, however, controversy surrounds the question of whether AIH is heterogeneous in nature, as discussed above. There are 2 ways to define heterogeneity in AIH: for many years, autoantibodies have been used to distinguish subtypes of AIH; however, the IAHG regards such distinctions to be too premature for routine use in everyday practice. The other way to classify the heterogeneity of AIH is based on immunogenetics.

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AIH Type 2 Serum immunoglobulin levels are moderately elevated with a reduction of immunoglobulin A. AIH type 2 is a rare disorder that affects 20% of AIH patients in Europe but only 4% in the United States.8,59 There is a female predominance. The number of extrahepatic immune syndromes such as diabetes, vitiligo, and autoimmune thyroid disease is more prevalent than in AIH type 1. The average age at the time of diagnosis is around 10 years, but AIH type 2 is also observed in adults, especially in Europe. AIH type 2 carries a higher risk of progression to cirrhosis and of a fulminant course at onset. AIH Type 3

The Challenge of Genetic Heterogeneity Not only the prevalence of but also the immunogenetic associations with AIH vary regionally. AIH in whites has an association with HLA DRB1*0301.105 In Japan, the A1-B8-DR3 haplotype is almost absent, and a typical association with HLA DRB1*0405 has been found.106 Argentinean adults with AIH have an increased frequency of HLA DRB1*0405107 and Mexicans of HLA DRB1*0404.108 In children from Argentina and Brazil, a strong association with HLA DRB1*1301 and a weaker association with DRB1*0301 have been demonstrated.109 –111 These data suggest evolutionary differences in the prevalence of and susceptibility to AIH. From these findings, it can be expected that a number of genetic associations are responsible for AIH. However, the genetic data presently available argue strongly for a genetic predisposition for disease progression rather than disease susceptibility. AIH is a polygenetic disease. Many genetic markers are being identified, each of which contributes a small piece of the puzzle.112

The Challenge of Immunoserological Heterogeneity AIH Type 1 Representing 80% of the cases of AIH, this form is the most prevalent subclass. Seventy percent of patients are female with a peak incidence between ages 16 and 30 years. However, 50% are older than 30 years. An association with other immune syndromes is observed in 48%, including autoimmune thyroid disease, synovitis, and ulcerative colitis. The clinical course is often unremarkable, and acute onset is very rare. About 25% have cirrhosis at the time of diagnosis.

AIH type 3 is the most controversial of all serologic subgroups.62 AIH type 3 has a lower prevalence than AIH type 2, 90% of cases are females, and the age maximum is between 20 and 40 years. This subclass of AIH resembles AIH type 1 with respect to clinical characteristics, immunogenetic markers, and treatment response.12,48,49,54,61 The detection of autoantibodies against UGA-suppressor tRNA-associated protein, which is very specific for AIH, makes this defined entity an attractive model to study the molecular origin of AIH.

Differential Diagnosis Cryptogenic hepatitis is an etiologically undefined chronic hepatitis. Patients with cryptogenic hepatitis are negative for viral as well as autoantibody markers. It is not established how many of these patients suffer from AIH without detectable autoantibodies. In about 13% of patients, initially seronegative when tested by indirect immunofluorescence for ANA, SMA, and LKM, detection of SLA autoantibodies contributed to their diagnostic clarification.50 Clinically this group of patients with cryptogenic hepatitis resembles AIH type 1 with respect to age and sex distribution, HLA antigen types, inflammatory activity, and response to therapy. Overlap syndromes are conditions in which there are leading symptoms of AIH, but additional markers and symptoms point to other liver diseases. The “overlap syndrome” is a descriptively vague designation of syndromes in which patients present with clinical, histologic, and immunoserological signs of AIH and one of the cholestatic autoimmune liver diseases, either PBC or PSC. The following terms have been used: immune cholangitis, PBC/CAH overlap syndrome, or AIH/PSC overlap syndrome.

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In one of the series reported, patients had serologic markers of PBC in 8% with serum AMA and histologic signs of nonsuppurative cholangitis, PSC in 6% with typical changes of the biliary tree by cholangiography, and autoimmune cholangitis in 10% with ANA, SMA, and histologic inflammation of the biliary system.20 Virus-Associated Autoimmunity Another clinically relevant overlap situation is virus-associated autoimmunity, characterized by the occurrence of significant titers of autoantibodies in viral hepatitis.4,13 Autoantibodies are found in all types of viral hepatitis, and the prevalence varies geographically. Autoantibodies, including antithyroid antibodies, may occur at significant titers spontaneously or during interferon treatment.113 The coexistence of AIH and viral hepatitis is a very rare event although documented in the literature. Also, subclinical autoimmune liver disease may become manifest very rarely when patients with viral hepatitis, in particular those with hepatitis C, are treated with cytokines.89 On the other hand, it has been well documented that several patients with chronic hepatitis C and significant titers of autoantibodies, in particular those from France, Spain, Italy, Japan, Germany, and other countries, may experience an increase of aminotransferase levels, and some of these patients may require immunosuppression. Autoimmune mechanisms are being considered as an explanation for these rare exacerbations. In general, patients with replicating chronic viral hepatitis should be treated initially with antivirals, but should be monitored more carefully than those without significant autoantibody titers detectable in serum. The best-studied associations at a molecular level are HCV and HDV infections in which LKM autoantibodies can be detected in 2%–5% and 6%–12% of cases, respectively. AIH type 2 and HCV infection with LKM autoantibodies are clinically distinct entities.114,115 LKM autoantibodies in virus infection are present at lower titers and recognize more conformational and diverse epitopes than those in genuine AIH. This distinction is relevant because it forms the basis for mutually exclusive therapeutic strategies, immunosuppresssion in AIH, and interferon in chronic virus hepatitis.77 APS-1 Hepatitis has also been described in 10%–15% of patients with APS-1.116,117 This syndrome is characterized by mucocutaneous candidiasis, hypothyroidism, Addison’s disease, and other endocrinopathies.118,119 In patients with APS-1, autoantibodies to CYP1A2 and CYP2A6 have been described as markers of an autoim-

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mune liver disease.86,87 Anti-CYP1A2 antibodies are associated with the occurrence of hepatitis, whereas anti CYP2A6, a cytochrome that is not exclusively expressed in liver, also occurs in patients with APS-1 that do not suffer from liver disease.

Indications for Therapy: The Challenge of Whom to Treat An absolute indication for treatment is present in acute-onset or fulminant AIH, when aminotransferase levels exceed 5–10 times the upper normal value, upon histologic evidence of bridging or multilobular necrosis, as well as when severe hepatic and extrahepatic symptoms (fatigue, upper right quadrant pains, associated immune-mediated symptoms) are present.31 In the presence of mild disease activity such as aminotransferase levels below 5–10-fold elevation, hepatitis lacking fibrosis, and mild symptoms of hepatitis, the indications for treatment must be weighed individually against the risks associated with therapy. Analyses have shown that hepatitis in the absence of fibrosis is associated with only a low risk of developing cirrhosis and therefore may result in unaltered life expectancies even if left untreated. When aminotransferase levels are only mildly elevated, histology shows inactive cirrhotic changes, but when active inflammation is absent, an indication for immunosuppressive therapy is not present. Liver failure inevitably leads to a consideration for liver transplantation as the definitive therapeutic measure.31

Treatment of AIH AIH was the first chronic liver disease in which medical treatment was shown to prolong survival. Two fundamental goals are distinguished: induction of remission and maintenance of remission. Induction of Remission: Standard Immunosuppressive Treatment The standard initial treatment of AIH is prednisone monotherapy or combination therapy with prednisone and azathioprine.120 Both are equally effective.41,121 Prednisolone or prednisone can both be used and are equally effective. Decrease of liver function in cirrhosis does not affect the metabolism from prednisone to prednisolone. Combination therapy is generally preferred because of the marked reduction in unwanted side effects in this group. The decision for either strategy involves the consideration of patient profiles (Table 5): combination therapy is best suited for elderly, osteoporotic patients, patients with a metabolic syndrome (diabetes, hypertension, obesity), and with psychiatric labil-

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Table 6. Treatment Regimen and Follow-Up Examinations of AIH Regardless of Autoantibody Type Monotherapy Prednis(ol)one Azathioprine

Combination therapy

60 mg reduction within 4 weeks to 30 mg reduction within 4 weeks to maintenance dose 20 mg or lower maintenance dose 10 mg or lower NA 50 mg (maintenance with azathioprine: monotherapy: 2 mg/kg body wt) After remission is reached (treatment length 12–24 months, histology, avoid premature reduction)

Prednis(ol)one

Reduction of daily dose by 2.5 mg per week NA

Azathioprine

Examination Physical Liver biopsy Blood count Aminotransferases ␥-Glutamyltransferase ␥-Globulin Bilirubin Coagulation studies Autoantibodies Thyroid function tests

Before therapy ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹

During therapy before remission q 4 weeks

⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹/⫺ ⫹/⫺

Remission under therapy q 3–6 months ⫹ (⫹/⫺) ⫹ ⫹ ⫹ ⫹ ⫹ ⫹

Reduction: 25 mg every 3 weeks

Cessation of therapy q 3 weeks (⫻4)

Remission post therapy q 3–6 months

Evaluation of relapse

⫹

⫹

⫹ ⫹

⫹ ⫹

⫹ ⫹

⫹ ⫹ ⫹

⫹ ⫹ ⫹

⫹ ⫹ ⫹ ⫹ ⫹

NOTE. In the elderly patient with low inflammatory activity, the indication to treat must be weighed against side effects and many of these patients may best remain untreated. The table reflects the Mayo approach.122,152 In our experience, monotherapy with prednisone beginning with 50 mg and tapered by 10 mg every 10 days to a maintenance dose of 15–20 mg, and alternatively combination therapy with 1 mg/kg body wt of azathioprine for 3 weeks and tapering to 50 mg daily combined with prednisone therapy tapered to 10 mg daily, are equally effective. There is no published evidence of an advantage of an individual tapering regimen, and different tapering and dosing regimens are used by different centers. In the individual young patient without severe symptoms and with low inflammatory activity (biopsy, ALT ⬍ 5 ⫻ upper limit of normal), treatment can be initiated with maintenance doses. NA, not applicable.

ity. Conversely, monotherapy with steroids would be preferred in patients with hematologic abnormalities (cytopenia), for short treatment trials when response to immunosuppressive treatment is used as a diagnostic procedure and in young patients when fertility becomes an issue. While corticosteroids are as effective as combination treatment to induce remission, azathioprine monotherapy is ineffective for inducing remission. The issue of azathioprine teratogenicity and oncogenicity requires discussion with young patients. Although in animal models teratogenicity and oncogenicity have been observed, this has not been conclusively shown in humans. Nevertheless, teratogenicity and oncogenicity cannot be ruled out and therefore azathioprine therapy during pregnancy cannot be recommended. Treatment should generally follow defined therapeutic schedules (Table 6).31 However, in individual patients therapy is best tailored to the patient’s presentation. This is particularly true in elderly patients without severe inflammatory activity who may best remain under medical observation but not treated. In younger patients with low inflammatory activity (alanine aminotransferase levels ⱕ5 ⫻ upper limit of normal), the initiation of

therapy may be sufficient with the maintenance dose rather than by applying an induction and tapering regimen. In any case, the goal of treatment is a complete biochemical and histologic resolution of inflammation as well as the clinical remission of symptoms. This is achieved in 87% of patients within 3 years of treatment. Beyond 3 years, only about 7% of patients reach remission per additional treatment year. Usually, if the diagnosis is correct, aminotransferase levels normalize within a few weeks and months, usually in up to 3– 6 months. It is important to note that histologic remission lags 3– 6 months behind normalization of biochemical markers. Therefore, biopsy-proven remission is the ultimate goal of all treatment courses. Early termination of treatment may lead to frequent relapse episodes, which may lead to higher rates of cirrhosis, esophageal varices, and liver failure as well as to a substantially higher frequency of unwanted drug side effects. An important treatment goal, therefore, is the prevention of relapse episodes. Performing a liver biopsy is the only means to determine histologic remission in discontinuing treatment but is not necessarily required for decision making.121 If normalization of hepatic architecture under immunosup-

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pressive therapy is documented, the risk of relapse is only 20%.121 In biopsy specimens showing portal hepatitis, relapse occurs in 50% within 6 months after end of treatment. However, if treated patients progress to cirrhosis or show signs of interface hepatitis, relapse is invariably observed after the end of treatment. Overall, the frequency of relapse is 50% in 6 months and 70% in 3 years after withdrawal of immunosuppressive therapy.122 A sustained response is achieved in only 17% of patients. Azathioprine maintenance after prednisone withdrawal reduces the likelihood of relapse.121 Drug withdrawal should proceed gradually over a period of 3– 6 months.

AUTOIMMUNE HEPATITIS: CLINICAL CHALLENGES

Treatment Options in Difficult-to-Treat Patients The therapy of AIH with prednis(ol)one and azathioprine is not ideal, and the search for drugs with a favorable risk-benefit ratio is ongoing. For most of the alternative approaches, the results have been disappointing and the adverse effects severe. Therapeutic goals include the prevention of treatment failure, the achievement of long-term remission with the prevention of corticosteroid side effects, and the treatment of overlap disorders.

No or Incomplete Remission With Standard Immunosuppression: The Difficult-to-Treat Patient as a Particular Challenge (Role of Maintenance Therapy) Other typical treatment end points in AIH are an incomplete response in which no remission is reached within 2 years of treatment, treatment failure in which biochemical and clinical signs of AIH deteriorate during therapy, and intolerance of the administered drugs. The standard treatment schedules have to be altered in these situations. When incomplete responses are present, immunosuppression is usually required indefinitely at the lowest possible dose to maintain aminotransferase levels below 5 times the upper limit of normal or to reach histologic remission. This can be achieved by combination therapy with prednisone and azathioprine, or by indefinite therapy with azathioprine alone (2 mg 䡠 kg⫺1 䡠 day⫺1).123 Treatment failure usually requires a trial with highdose corticosteroids (60 mg/day) or combination therapy (30 mg prednis(ol)one and 150 mg azathioprine per day) for 4 – 6 weeks. In 20% of patients, liver failure is a risk that leads to consideration of liver transplantation. Drug intolerance calls for an immediate reduction of the implicated drug and the determination of the single tolerated drug capable of controlling the disease. Usually, vertebral compression, psychosis, diabetic decompensation, or severe weight gain are complications of steroid therapy, which can be overcome by increasing the azathioprine dose or by azathioprine maintenance therapy. Severe cytopenia, arthralgia, and myalgia may be complications of azathioprine (Table 5). If treatment results are unsatisfactory, alternative drugs such as cyclosporin A, tacrolimus, cyclophosphamide, mercaptopurine, mycophenolate mofetil, or the addition of ursodeoxycholic acid can be considered; however, efficacy in clinical trials has not been shown (see below).

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The Challenge of Preventing Treatment Failures Tacrolimus FK506 is a potent macrolide lactone compound with immunosuppressive capabilities exceeding those of cyclosporin A. The application of 3 mg twice a day in 21 patients treated for 1 year led to an improvement of aminotransferase and bilirubin levels.124 Although FK506 represents a promising immunosuppressive candidate drug, larger randomized trials are required to assess its role in the therapy of AIH. Cyclosporin A Cyclosporin A is a lipophylic cyclic peptide of 11 residues produced by Tolypocladium inflatum that acts on calcium-dependent signaling and inhibits T-cell function via the interleukin 2 gene. In a recent study, treatment of 32 children with AIH type 1 and 4 children with AIH type 2 resulted in histologic improvement at doses of 2–3 mg⫺1 䡠 kg⫺1 䡠 day⫺1.125 There was no difference in response between AIH type 1 and AIH type 2. Although relapses did not occur in a separate study of 15 patients with AIH type 2,126 this was not observed in an earlier trial.127 Cyclosporin A seems to be well tolerated in AIH. Cyclophosphamide The induction of remission with 1–1.5 mg⫺1 䡠 䡠 day⫺1 in combination with steroids has been reported.128 However, the dependency of continued application of cyclophosphamide with its potentially severe hematologic side effects renders it a highly experimental treatment option.

kg⫺1

Mycophenolate Mycophenolate-mofetil has received attention as a transplant immunosuppressant with an important role in the steroid-free immunosuppressive therapy of patients

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transplanted with chronic hepatitis C infection. In a recent pilot study, 7 patients with AIH type 1 who either did not tolerate azathioprine or did not respond to standard therapy with a complete normalization of aminotransferase levels were treated with 1 g of mycophenolate-mofetil twice a day in addition to steroids, and followed for a median of 46 months.129 In 5 of 7 patients, normalization of aminotransferase levels was achieved within 3 months. One patient developed leukocytopenia. These preliminary data suggest that mycophenolatemofetil may represent another alternative strategy of preventing treatment failure. Larger studies are required to provide more evidence for a beneficial effect.

The Challenge of Achieving Long-term Remission Without Corticosteroid Side Effects Budesonide Budesonide is a synthetic steroid with high firstpass metabolism in the liver, which should limit systemic side effects compared with conventional steroids. It is a common drug for allergic pulmonary disease. In a study treating 13 AIH patients with 6 – 8 mg of budesonide per day over a period of 9 months, the drug was well tolerated and aminotransferase levels were normalized.130 Our own experiences have confirmed that budesonide is effective but does not offer an advantage over conventional steroids when cirrhosis and portosystemic shunts are present.131 Remission can be achieved when budesonide is used instead of prednisolone. However, the main advantage of budesonide for the future treatment of AIH is to replace predniso(lo)ne in long-term maintenance therapy to reduce steroid side effects. This potential benefit has not been realized in clinical trials.132 Azathioprine Azathioprine is effective in maintaining remission after remission has been achieved by combination or corticosteroid monotherapy and represents a corticosteroid-free alternative as discussed above.123 Induction of remission with azathioprine monotherapy is not effective, as discussed above.

The Challenge of Cholestatic Disease and AIH Ursodeoxycholic Acid Ursodeoxycholic acid is a hydrophilic bile acid with putative immunomodulatory capabilities. It is presumed to alter HLA class I antigen expression on cellular surfaces and to suppress immunoglobulin production.133

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Uncontrolled trials have shown a reduction in histologic abnormalities and clinical and biochemical improvement but not a reduction of fibrosis in 4 patients with AIH type 1 given 600 mg/day over 2 years.134 In contrast, no benefit was reported when 13–15 mg 䡠 kg⫺1 䡠 day⫺1 was given.135 Ursodeoxycholic acid is a well-tolerated drug; however, its role in AIH therapy or in combination with immunosuppressive therapy136 is still unclear.

Non-Liver Disease–Specific Therapy, Therapy of Complications Demineralization Steroid treatment has a negative impact on bone mineralization. Supplementation with vitamin D, calcium, and regular physical activity should accompany therapy routinely. In postmenopausal women, hormone replacement therapy is indicated. Whether bisphosphonate therapy of symptomatic osteoporosis is beneficial in chronic liver disease of noncholestatic cause is presently unclear. Vitamin Replacement Vitamin K (if indicated by coagulation studies) and multivitamin supplements should be administered.

Liver Transplantation Transplantation is the treatment option of choice in end stage AIH.137–141 There is no single indicator that predicts that liver transplantation will be required in patients with AIH. Candidates for liver transplantation are usually among the treatment failure group in whom cirrhosis progresses despite immunosuppressive therapy.142 Patients who do not reach remission within 4 years of continuous therapy are at elevated risk for liver failure and should therefore be evaluated for liver transplantation. Indicators of a high mortality associated with liver failure are histologic evidence of multilobular necrosis and progressive hyperbilirubinemia. In Europe, 4% of liver transplants are for AIH.143 The 5-year survival is 92%,138,140,144 and the recurrence of AIH is estimated to range between 11% and 35%.145–149 The persistence of autoantibodies does not indicate or predict recurrence of AIH.150 Individual adjustment of immunosuppressive therapy after transplantation in patients with AIH is necessary to prevent or control recurrence of AIH.149 De novo development of AIH after retransplantation has been reported.151

References 1. Waldenstro¨m J. Leber, Blutproteine und Nahrungseiweisse. Dtsch Gesellsch Verd Stoffw 1950;15:113–119.

May 2001

2. Kunkel HG, Ahrens EHJ, Eisenmenger WJ. Extreme hypergammaglobulinemia in young women with liver disease of unknown ethiology. J Clin Invest 1951;30:654. 3. Mackay IR, Taft LI, Cowling DC. Lupoid hepatitis. Lancet 1956; 2:1323–1326. 4. Strassburg CP, Obermayer-Straub P, Manns MP. Autoimmunity in liver diseases. Clin Rev Allergy Immunol 2000;18:127–139. 5. Guenguen M, Yamamotoh AM, Bernard O, Alvarez F. Anti-liver kidney microsome antibody type 1 recognizes human cytochrome P450 db1. Biochem Biophys Res Commun 1989;159: 542–547. 6. Manns M, Meyer zum Bu¨schenfelde KH, Slusarczyk J, Dienes HP. Detection of liver-kidney microsomal autoantibodies by radioimmunoassay and their relation to antimitochondrial antibodies in inflammatory liver disease. Clin Exp Immunol 1984;54: 600 – 608. 7. Zanger UM, Hauri HP, Loeper J, Homberg JC, Meyer UA. Antibodies against human cytochrome P-450db1 in autoimmune hepatitis type 2. Proc Natl Acad. Sci U S A 1988;85:8256 – 8260. 8. Homberg JC, Abuaf N, Bernard O, Islam S, Alvarez F, Khalil SH, Poupon R, Darnis F, Levy VG, Grippon P. Chronic active hepatitis associated with anti liver/kidney microsome type 1: a second type of “autoimmune” hepatitis. Hepatology 1987;7:1333– 1339. 9. Rizzetto M, Swana G, Doniach D. Microsomal antibodies in active chronic hepatitis and other disorders. Clin Exp Immunol 1973;15:331–344. 10. Guenguen M, Boniface O, Bernard O, Clerc F, Cartwright T, Alvarez F. Identification of the main epitope on human cytochrome P450IID6 recognized by anti-liver kidney microsome antibody. J Autoimmun 1991;4:607– 615. 11. Manns MP, Johnson EF, Griffin KJ, Tan EM, Sullivan KF. Major antigen of liver kidney microsomal antibodies in idiopathic autoimmune hepatitis is cytochrome P450db1. J Clin Invest 1989; 83:1066 –1072. 12. Manns M, Gerken G, Kyriatsoulis A, Staritz M, Meyer zum Bu¨schenfelde KH. Characterization of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen. Lancet 1987;1:292–294. 13. Strassburg CP, Obermayer-Straub P, Manns MP. Autoimmunity in hepatitis C and D virus infection. J Viral Hepatol 1996;3:49 – 59. 14. Obermayer-Straub P, Strassburg CP, Manns MP. Autoimmune hepatitis. J Hepatol 2000;31:181–197. 15. Johnson PJ, McFarlane IG, Eddleston ALWF. The natural course and heterogeneity of autoimmune-type chronic active hepatitis. Semin Liver Dis 1991;11:187–196. 16. Manns MP, Kru¨ger M. Genetics in liver diseases. Gastroenterology 1994;106:1676 –1697. 17. Gregorio GV, Portman B, Reid F, Donaldson PT, Doherty DG, McCartney M, Vergani D, Mieli-Vergani G. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology 1997;25:541– 547. 18. Johnson PJ, McFarlane IG. Meeting report: international autoimmune hepatitis group. Hepatology 1993;18:998 –1005. 19. Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WG, Czaja AJ, Desmet VJ, Donaldson PT, Eddleston AL, Fainboim L, Heathcote J, Homberg JC, Hoofnagle HH, Kajumu S, Krawitt EL, Mackay IR, MacSween RN, Maddrey WC, Manns MP, McFarlane IG, Meyer zum Bu¨schenfelde KH, Zeniya M. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatology 1999;31:929 –938. 20. Czaja AJ. Frequency and nature of the variant syndromes of autoimmune liver disease. Hepatology 1998;28:360 –365. 21. Boberg KM, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H.

AUTOIMMUNE HEPATITIS: CLINICAL CHALLENGES

22. 23.

24.

25.

26.

27. 28.

29.

30. 31.

32.

33.

34. 35.

36.

37. 38.

39.

40.

41.

1513

Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol 1998;33:99 –103. Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 1995;19:1409 –1417. Strassburg CP, Jaeckel E, Manns MP. Anti-mitochondrial antibodies and other immunological tests in primary biliary cirrhosis. Eur J Gastroenterol Hepatol 1999;11:595– 601. Miyakawa H, Kitazawa E, Abe K, Kawaguchi N, Fuzikawa H, Kikuchi K, Kako M, Komatsu T, Hayashi N, Kiyosawa K. Chronic hepatitis C associated with anti-liver/kidney microsome-1 antibody is not a subgroup of autoimmune hepatitis. J Gastroenterol 1997;32:769 –776. Bianchi FB, Cassani F, Lenzi M, Ballardini G, Muratori L, Giostra F, Zauli D. Impact of international autoimmune hepatitis group scoring system in definition of autoimmune hepatitis. An Italian experience. Dig Dis Sci 1996;41:166 –171. Boberg KM, Fausa O, Haaland T, Holter E, Mellbye OJ, Spurkland A, Schrumpf E. Features of autoimmune hepatitis in primary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis. Hepatology 1996;23: 1369 –1376. Czaja A, Carpenter HA. Validation of scoring system for diagnosis of autoimmune hepatitis. Dig Dis Sci 1996;41:305–314. Dickson RC, Gaffey MJ, Ishitani MB, Roarty TP, Driscoll CJ, Caldwell SH. The international autoimmune hepatitis score in chronic hepatitis C. J Viral Hepatol 1997;4:121–128. Toda G, Zeniya M, Watanabe F, Imawari M, Kiyosawa K, Nishioka M, Tsuji T, Omata M. Present status of autoimmune hepatitis in Japan: correlating the characteristics with international criteria in an area with a high rate of HCV infection. Japanese National Study Group of Autoimmune Hepatitis. J Hepatol 1997; 26:1207–1212. Scheuer PJ, Lefkowitch JH. Liver biopsy interpretation. Philadelphia: Saunders, 1994. Manns MP, Strassburg CP. Autoimmune hepatitis. In: O’Grady JG, Lake JR, Howdle DP, eds. Comprehensive clinical hepatology. London: Mosby, 2000;16:1–14. Dienes HP, Popper H, Manns M, Baumann W, Thoenes W, Meyer zum Bu¨schenfelde K-H. Histologic features in autoimmune hepatitis. Z Gastroenterol 1989;27:327–330. Nishioka M, Morshed SA, McFarlane IG. Geographical variation in the frequency and characteristics of autoimmune liver diseases. Amsterdam: Elsevier, 1998. Cancado ELR, Porta G. Autoimmune hepatitis in South America. Boston: Kluwer Academic, 2000. Nikias GA, Batts KP, Czaja AJ. The nature and prognostic implications of autoimmune hepatitis with acute presentation. J Hepatol 1994;21:866 – 871. Desmet VJ, Gerber M, Hoofnaagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19:1513–1520. Strassburg CP, Manns MP. Autoimmune hepatitis versus viral hepatitis C. Liver 1995;15:225–232. Pawlotsky JM, Ben Yahia M, Andre C, Voisin M-C, Intrator L, Roudot-Thoraval F, Deforges L, Duvoux C, Zafrani E-L, Duval J, Dhumeaux D. Immunological disorders in C virus chronic active hepatitis: a prospective case-control study. Hepatology 1994; 19:841– 848. Lunel F, Cacoub P. Treatment of autoimmune and extrahepatic manifestations of hepatitis C virus infection. J Hepatol 1999; 31(Suppl 1):210 –216. Geall MG, Schoenfield LJ, Summerskill WHJ. Classification and treatment of chronic active liver disease. Gastroenterology 1968;55:724 –729. Soloway RD, Summerskill WHJ, Baggenstoss AH, Geall MG,

1514

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

MANNS AND STRASSBURG

Gitnick GL, Elveback ER, Schoenfield LJ. Clinical, biochemical and histologic remission of severe chronic active liver disease: a controlled study of treatments and early prognosis. Gastroenterology 1972;63:820 – 833. Roberts SK, Therneau TM, Czaja AJ. Prognosis of histological cirrhosis in type 1 autoimmune hepatitis. Gastroenterology 1996;110:848 – 857. Donaldson PT, Doherty DG, Hayllar KM, Mc Farlane IG, Johnson PJ, Williams R. Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR 4 and A1-B8-DR-3 are independent risk factors. Hepatology. 1991;13:701–706. Czaja AJ, Rakela J, Hay JE, Moore SB. Clinical and prognostic implications of human leucocyte antigen B8 in corticosteroidtreated severe chronic active hepatitis. Gastroenterology 1990; 98:1587–1593. Kirk AP, Jain S, Pocock S, Thomas HC, Sherlock S. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis. Gut 1980;21:78 –93. Gelpi CSE, Rodriguez-Sanchez JL. Autoantibodies against a serine tRNA-protein complex implicated in cotranslational selenocysteine insertion. Proc Natl Acad Sci U S A 1992;89: 9739 –9743. Costa M, Rodriguez-Sanchez JL, Czaja AJ, Gelpi C. Isolation and characterization of cDNA encoding the antigenic protein of the human tRNP(Ser)Sec complex recognized by autoantibodies from patients with type-1 autoimmune hepatitis. Clin Exp Immunol 2000;121:364 –374. Volkmann MML, Ba¨urle A, Heid H, Strassburg CP, Trautwein C, Fiehn W, Manns MP. Soluble liver antigen: isolation of a 35 kD recombinant protein (SLA-P35) specifically recognizing sera from patients with autoimmune hepatitis type 3. Hepatology 2001;33:591–596. Wies I, Brunner S, Henninger J, Herkel J, Kanzler S, Meyer zum Bu¨schenfelde KH, Lohse AW. Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis. Lancet 2000; 355:1510 –1515. Czaja AJ, Carpenter HA, Manns MP. Antibodies to soluble liver antigen, P450IID6, and mitochondrial complexes in chronic hepatitis. Gastroenterology 1993;105:1522–1528. Philipp T, Durazzo M, Trautwein C, Alex B, Straub P, Lamb JG, Johnson EF, Tukey RH, Manns MP. Recognition of uridine diphosphate glucuronosyl transferases by LKM-3 antibodies in chronic hepatitis D. Lancet 1994;344:578 –581. Wa¨chter B, Kyriasoulis A, Lohse AW, Gerken G, Meyer zum Bu¨schenfelde KH, Manns M. Characterization of liver cytokeratin as a major antigen of anti-SLA antibodies. J Hepatol 1990; 11:232–239. Wesierska-Gaedek J, Frimm R, Hitchman E, Penner E. Members of the glutathione S-transferase gene family are antigens in autoimmune hepatitis. Gastroenterology 1998;1998:329 –335. Stechemesser E, Klein R, Berg PA. Characterization and clinical relevance of liver-pancreas antibodies in autoimmune hepatitis. Hepatology 1993;18:1–9. Treichel U, McFarlane BM, Seki T, Krawitt EL, Alessi N, Sickel F, McFarlane IG, Kiosawa K, Furuta S, Freni MA, Gerkem G, Meyer zum Bu¨schenfelde K-H. Demographics of anti-asialoglycoprotein receptor autoantibodies in autoimmune hepatitis. Hepatology 1994;107:799 – 804. Muratori L, Cataleta M, Muratori P, Manotti P, Lenzi M, Cassani F, Bianchi FB. Detection of anti-liver cytosol antibody type 1 (anti-LC1) by immunodiffusion, counterimmunoelectrophoresis and immunoblotting: comparison of different techniques. J Immunol Methods 1995;187:259 –264. Martini E, Abuaf N, Cavalli F, Durand V, Johanet C, Homberg JC. Antibody to liver cytosol (anti-LC1) in patients with autoimmune chronic active hepatitis type 2. Hepatology 1988;8:1662–1666.

GASTROENTEROLOGY Vol. 120, No. 6

58. Lapierre P, Hajoui O, Homberg J-C, Alvarez F. Fomiminotransferase cyclodeaminase is an organ specific autoantigen recognized by sera of patients with autoimmune hepatitis. Gastroenterology 1999;116:643– 649. 59. Czaja AJ, Manns MP, Homburger HA. Frequency and significance of antibodies to liver/kidney microsome type 1 in adults with chronic active hepatitis. Gastroenterology 1992;103:1290 –1295. 60. Czaja AJ. Behavior and significance of autoantibodies in type 1 autoimmune hepatitis. J Hepatol 1999;30:394 – 401. 61. Kanzler S, Weidemann C, Gerken G, Lo¨hr HF, Galle PR, Meyer zum Bu¨schenfelde KH, Lohse AW. Clinical significance of autoantibodies to soluble liver antigen in autoimmune hepatitis. J Hepatol 1999;31:635– 640. 62. McFarlane IG. Lessons about antibodies in autoimmune hepatitis. Lancet 2000;355:1475–1476. 63. Tan MT. Autoantibodies in pathology and cell biology. Cell 1991; 67:841– 842. 64. Strassburg CP, Manns MP. Antinuclear antibody (ANA) patterns in hepatic and extrahepatic autoimmune disease. J Hepatol 1999;31:751. 65. Strassburg C, Alex B, Zindy F, Gerken G, Lu¨ttig B, Meyer zum Bu¨schenfelde KH, Bre´chot C, Manns M. Identification of cyclin A as a molecular target of antinuclear antibodies (ANA) in hepatic and non-hepatic diseases. J Hepatol 1996;25:859 – 866. 66. Czaja AJ, Nishioka M, Morhed SA, Haciya T. Patterns of nuclear immunofluorescence and reactivities to recombinant nuclear antigens in autoimmune hepatitis. Gastroenterology 1994;107: 200 –207. 67. Czaja AJ, Ming C, Shirai M, Nishioka M. Frequency and significance of antibodies to histones in autoimmune hepatitis. J Hepatol 1995;23:32–38. 68. Toh BH. Smooth muscle autoantibodies and autoantigens. Clin Exp Immunol 1979;38:621– 628. 69. Czaja AJ, Cassani F, Cataleta M, Valenti P, Bianchi FB. Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis. Hepatology 1996;24:1068 –1073. 70. Gueguen M, Meunier-Rotival M, Bernard O, Alvarez F. Anti–liverkidney microsome antibody recognizes a cytochrome P450 from the IID subfamily. J Exp Med 1988;168:801– 806. 71. Manns MP, Griffin KJ, Sullivan KF, Johnson EF. LKM-1 autoantibodies recognize a short linear sequence in P450IID6, a cytochrome P-450 monooxygenase. J Clin Invest 1991;88:1370 – 1378. 72. Manns M, Zanger U, Gerken G, Sullivan KF, Meyer zum Bu¨schenfelde KH, Eichelbaum M. Patients with type II autoimmune hepatitis express functionally intact cytochrome P450 db1 that is inhibited by LKM1 autoantibodies in vitro but not in vivo. Hepatology 1990;12:127–132. 73. Lo¨hr HF, Schlaak JF, Lohse AW, Bo¨cher WO, Arenz M, Gerken G, Meyer zum Bu¨schenfelde K-H. Autoreactive CD4⫹ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibody-positive autoimmune hepatitis. Hepatology 1996;24:1416 –1421. 74. Duclos-Vallee JC, Hajoui O, Yamamoto AM, Jacqz-Aigrin E, Alvarez F. Conformational epitopes on CYP2D6 are recognized by liver/kidney microsomal antibodies. Gastroenterology 1995;108: 470 – 476. 75. Yamamoto AM, Cresteil D, Boniface O, Clerc FF, Alvarez F. Identification and analysis of cytochrome P450IID6 antigenic sites recognized by anti-liver-kidney microsome type-1 antibodies (LKM1). Eur J Immunol 1993;23:1105–1111. 76. Ma Y, Peakman M, Lobo-Yeo A, Wen L, Lenzi M, Gaken J, Farzaneh F, Mieli-Vergani G, Bianchi FB, Vergani D. Differences in immune recognition of cytochrome P4502D6 by liver kidney microsomal (LKM) antibody in autoimmune hepatitis and chronic hepatitis C virus infection. Clin Exp Immunol 1994;97: 94 –99. 77. Dalekos GN, Wedemeyer H, Obermayer-Straub P, Kayser A,

May 2001

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92. 93.

94.

Barut A, Frank H, Manns MP. Epitope mapping of cytochrome P4502D6 autoantigen in patients with chronic hepatitis C during ␣-interferon treatment. J Hepatol 1999;30:366 –375. Muratori L, Parola M, Ripalti A, Robino G, Muratori P, Bellomo G, Carini R, Lenzi M, Landini MP, Albano E, Bianchi FB. Liver/ kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane. Gut 2000;46:553–561. Loeper J, Descartoire V, Maurice M, Beaune P, Belghiti J, Houssin D, Ballet F, Feldman G, Guenguerich FP, Pessayre D. Cytochromes P450 in human hepatocyte plasma membrane: recognition by several autoantibodies. Gastroenterology 1993;104: 203–216. Trautwein C, Ramadori G, Gerken G, Meyer zum Bu¨schenfelde KH, Manns MP. Regulation of cytochrome P450 2D by acute phase mediators in C3H/HeJ mice. Biochem Biophys Res Commun 1992;182:617– 623. Beaune PH, Pessayre D, Dansette P, Mansuy D, Manns MP. Autoantibodies against cytochromes P450: role in human diseases. Adv Pharmacol 1994;30:199 –245. Homberg JC, Abuaf N, Helmy-Khalil S, Bijour M, Poupon R, Islam S, Darnis F, Levy VG, Opolon P, Beaugrand M. Drug induced hepatitis associated with anticytoplasmic organelle autoantibodies. Hepatology 1985;5:722–725. Zimmerman HJ, Lewis JH, Ishak KG, Maddrey W. Ticrynafenassociated hepatic injury: analysis of 340 cases. Hepatology 1984;4:315–323. Manns MP, Griffin KJ, Quattrochi L, Sacher M, Thaler H, Tukey R, Johnson EF. Identification of cytochrome P450 IA2 as a human autoantigen. Arch Biochem Biophys 1990;280:229 –232. Obermayer-Straub P, Strassburg CP, Manns MP. Autoimmune polyglandular syndrome type 1. Clin Rev Allergy Immunol 2000; 18:167–183. Clemente MG, Obermayer-Straub P, Meloni A, Strassburg CP, Arangino V, Tukey RH, De Virgiliis S, Manns MP. Cytochrome P450 1A2 is a hepatic autoantigen in autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metabol 1997;82:1353– 1361. Clemente MG, Meloni A, Obermayer-Straub P, Frau F, Manns MP, DeVirgiliis S. Two cytochromes P450 are major hepatocellular autoantigens in autoimmune polyglandular syndrome type 1. Gastroenterology 1998;114:324 –328. Gebre-Medhin G, Husebye ES, Gustafsson J, Winqvist O, Goksoyr A, Rorsman F, Ka¨mpe O. Cytochrome P450IA2 and aromatic L-amino acid decarboxylase are hepatic autoantigens in autoimmune polyendocrine syndrome type I. FEBS Lett 1997; 412:439 – 445. Dalekos GN, Obermayer-Straub P, Maeda T, Tsianos EV, Manns MP. Antibodies against cytochrome P4502A6 (CYP2A6) in patients with chronic viral hepatitis are mainly linked to hepatitis C virus infection (abstr). Digestion 1998;59:S36. Bourdi M, Larrey D, Nataf J, Bernuau J, Pessayre D, Iwasaki M, Guengerich FP, Beaune PH. Anti-liver endoplasmic reticulum antibodies are directed against human cytochrome P-450IA2. A specific marker of dihydralazine hepatitis. J Clin Invest 1990; 85:1967–1973. Sacher M, Blu¨mel P, Thaler H, Manns M. Chronic active hepatitis associated with vitiligo, nail dystrophy, alopecia and a new variant of LKM antibodies. J Hepatol 1990;10:364 –369. Van Pelt F, Straub P, Manns M. Molecular basis of drug-induced immunological liver injury. Semin Liv Dis 1995;15:283–300. Crivelli O, Lavarini C, Chiaberge E, Amoroso A, Farci P, Negro F, Rizzetto M. Microsomal autoantibodies in chronic infection with HBsAg associated delta (delta) agent. Clin Exp Immunol 1983; 54:232–238. Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 2000;40:581– 616.

AUTOIMMUNE HEPATITIS: CLINICAL CHALLENGES

1515

95. Philipp T, Straub P, Durazzo M, Tukey RH, Manns MP. Molecular analysis of autoantigens in hepatitis D. J Hepatol 1995;22: 132–135. 96. Strassburg C, Obermayer-Straub P, Alex B, Durazzo M, Rizzetto M, Tukey RH, Manns MP. Autoantibodies against glucuronosyltransferases differ between viral hepatitis and autoimmune hepatitis. Gastroenterology 1996;11:1582–1592. 97. Durazzo M, Philipp T, Van Pelt FNAM, Lu¨ttig B, Borghesio E, Michel G, Schmidt E, Loges S, Rizzetto M, Manns MP. Heterogeneity of microsomal autoantibodies (LKM) in chronic hepatitis C and D virus infection. Gastroenterology 1995;108:455– 462. 98. Manns M, Gerken G, Kyriatsoulis A, Trautwein C, Reske K, Meyer zum Bu¨schenfelde K-H. Two different subtypes of antimitochondrial antibodies are associated with primary biliary cirrhosis: identification and characterization by radioimmunoassay and immunoblotting. Hepatology 1987;5:893– 899. 99. Lohse AW, Gerkem G, Mohr H, Lo¨hr HF, Treichel U, Dienes HP, Meyer zum Bu¨schenfelde KH. Relation between autoimmune hepatitis and viral hepatitis: clinical and serological characteristics in 859 patients. Z Gastroenterol 1995;33:527–533. 100. Portalla T, Treichel U, Lo¨hr H, Fleischer B. The asialoglycoprotein receptor as target structure in autoimmune liver diseases. Semin Liver Dis 1991;11:215–222. 101. Treichel U, Gerken G, Rossol S, Rotthaue HW, Meyer zum Bu¨schenfelde K-H, Portalla T. Autoantibodies against the human asialoglycoprotein receptor: effects of therapy in autoimmune and virus-induced chronic active hepatitis. J Hepatol 1993;19:55– 63. 102. Lenzi M, Manotti P, Muratori L, Cataleta M, Ballardini G, Cassani F, Bianchi FB. Liver cytosolic 1 antigen-antibody system in type 2 autoimmune hepatitis and hepatitis C virus infection. Gut 1995;36:749 –754. 103. Mulder AHL, Horst G, Haagsma EB, Limburg PC, Kleibeuker JH, Kallenberg GM. Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases. Hepatology 1993;17:411– 417. 104. Targan SR, Landers C, Vidrich A, Czaja AJ. High titer antineutrophil cytoplasmic antibodies in type-1 autoimmune hepatitis. Gastroenterology 1995;108:1159 –1166. 105. Doherty DG, Donaldson PT, Underhill JA, Farrant JM, Duthie A, Mieli-Vergani G, McFarlane IG, Johnson PJ, Eddleston AL, Mowat AP. Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis. Hepatology 1994;19:609 – 615. 106. Seki T, Ota M, Furuta S, Fukushima H, Kondo T, Hino K, Mizuki N. HLA class II molecules and autoimmune hepatitis susceptibility in Japanese patients. Gastroenterology 1992;103:1041– 1047. 107. Marcos Y, Fainboim HA, Capucchio M, Findor J, Daruich J, Reyes B, Pando M, Theiler GC, Mendez N, Satz ML. Two locus involvement in the association of human leukocyte antigen with the extrahepatic manifestations of autoimmune chronic active hepatitis. Hepatology 1994;19:1371–1374. 108. Vazquez-Garcia MN, Alaez C, Olivo A, Debaz H, Perez-Luque E, Burguete A, Cano S, de la Rosa G, Bautisa N, Hernandez A, Bandera J, Torres LF, Alvarez F, Gorodezky C. MHC class II sequences of susceptibility and protection in Mexicans with autoimmune hepatitis. J Hepatol 1998;28:985–990. 109. Fainboim L, Marcos Y, Pando M, Cappuchio M, Reyes GB, Galoppo C, Badia I, Remondino G, Cioccha M, Ramonet M. Chronic active autoimmune hepatitis in children: strong association with a particular HLA-DR6 (DRB1*1301) haplotype. Hum Immunol 1994;41:146 –150. 110. Pando M, Larriba J, Fernandez GC, Fainboim H, Ciocca M, Ramonet M, Badia I, Daruich J, Findor J, Tanno H, CaneroVelasco C, Fainboim L. Pediatric and adult forms of type I

1516

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122. 123.

124.

125.

126.

127.

128.

MANNS AND STRASSBURG

autoimmune hepatitis in Argentina: evidence for differential genetic predisposition. Hepatology 1999;30:1374 –1380. Bittencourt PL, Goldberg AC, Cancado EL, Porta G, Carrilho FJ, Farias AQ, Palacios SA, Chiarella JM, Abrantes-Lemos CP, Baggio VL, Laudanna AA, Kalil J. Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2. Am J Gastroenterol 1999;94:1906 –1913. Manns MP, Jaeckel E. Searching for the needle in the haystack: another candidate needle in autoimmune hepatitis? Gastroenterology 1999;117:728 –732. Mayet WJ, Hess G, Gerken G, Rossol S, Voth R, Manns M, Meyer zum Bu¨schenfelde KH. Treatment of chronic type B hepatitis with recombinant alpha-interferon induces autoantibodies not specific for autoimmune chronic hepatitis. Hepatology 1989;10:24 –28. Lunel F, Abuaf N, Lionel F, Grippon P, Perrin M, Coz YL, Valla D, Borotto E, Yamamoto AM, Huraux JM, Opolon P, Homberg JC. Liver/kidney microsome antibody type 1 and hepatitis C virus infection. Hepatology 1992;16:630 – 636. Michel G, Ritter A, Gerken G, Meyer zum Bu¨schenfelde KH, Decker R, Manns MP. Anti-GOR and hepatitis C virus in autoimmune liver diseases. Lancet 1992;339:267–269. Ahonen P, Mylla¨rniemi S, Sipila¨ I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 1990;322:1829 –1836. Michele TM, Fleckenstein J, Sgrignoli AR, Tuluvath PJ. Chronic active hepatitis in the type I polyglandular autoimmune syndrome. J Postgrad Med 1994;70:128 –131. Aaltonen J, Bo¨rses P, Sandkuijl L, Perheentupa J, Peltonen L. An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21. Nat Genet 1994;8:83– 87. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Horm Metab Res 1996;28:353– 356. Summerskill WHJ, Korman MG, Ammon HV, Baggenstoss AH. Prednisone for chronic active liver disease: dose titration, standard dose and combination with azathioprine compound. Gut 1975;16:876 – 883. Czaja AJ, Davis GL, Ludwig J, Tashwell HF. Complete resolution of inflammatory activity following corticosteroid treatment of HBsAg-negative chronic active hepatitis. Hepatology 1984;4: 622– 627. Czaja AJ. Therapy of autoimmune diseases: state of the art. Boston: Kluwer Academic, 2000. Johnson PJ, McFarlane IG, Williams R. Azathioprine for longterm maintenance of remission in autoimmune hepatitis. N Engl J Med 1995;333:958 –963. Van Thiel DH, Wright H, Carroll P, Abu-Elmagd K, Rodriguez-Rilo H, McMichael J, Irish W, Starzl TE. Tacrolimus: a potential new treatment for autoimmune chronic active hepatitis: results of an open-label preliminary trial. Am J Gastroenterol 1995;90:771– 776. Alvarez F, Ciocca M, Canero-Velasco C, Ramonet M, de Davila MT, Cuarterolo M, Gonzalez T, Jara-Vega P, Camarena C, Brochu P, Drut R, Alvarez E. Short-term cyclosporine induces a remission of autoimmune hepatitis in children. J Hepatol 1999;30: 222–227. Debray D, Maggiore G, Giradet JP, Mallet E, Bernard O. Efficacy of cyclosporin A in children with type 2 autoimmune hepatitis. J Pediatr 1999;135:111–114. Fernandez NF, Redeker AG, Vierling JM, Villamil FG, Fong T-L. Cyclosporine therapy in patients with steroid resistant autoimmune hepatitis. Am J Gastroenterol 1999;94:241–248. Kanzler S, Gerken G, Dienes HP, Meyer zum Bu¨schenfelde K-H, Lohse AW. Cyclophosphamide as alternative immunosuppres-

GASTROENTEROLOGY Vol. 120, No. 6

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139. 140.

141.

142.

143. 144.

145.

146.

147.

sive therapy for autoimmune hepatitis: report of three cases. Z Gastroenterol 1996;35:571–578. Richardson PD, James PD, Ryder SD. Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine. J Hepatol 2000;33: 371–375. Danielson A, Prytz H. Oral budesonide for treatment of autoimmune chronic hepatitis. Aliment Pharmacol Ther 1994;8:585– 590. Schu¨ler A, Manns MP. Treatment of autoimmune hepatitis. In: Arroyo V, Bosch J, Rode´s J, eds. Treatment in hepatology. Paris: Masson, 1995:375–383. Czaja AJ, Lindor KD. Failure of budesonide in a pilot study of treatment-dependent autoimmune hepatitis. Gastroenterology 2000;119:1312–1316. Calmus Y, Gane P, Rouger P, Poupon R. Hepatic expression of class I and class II major histocompatibility complex molecules in primary biliary cirrhosis: effect of ursodeoxycholic acid. Hepatology 1990;11:12–15. Nakamura K, Yoneda M, Yokohama S, Tamori K, Sato Y, Aso K, Aoshima M, Hasegawa T, Makino I. Efficacy of ursodeoxycholic acid in Japanese patients with type 1 autoimmune hepatitis. J Gastroenterol Hepatol 1998;13:490 – 495. Czaja AJ, Carpenter HA, Lindor KD. Ursodeoxycholic acid as adjunctive therapy for problematic type 1 autoimmune hepatitis: a randomized placebo-controlled treatment trial. Hepatology 1999;30:1381–1386. van Hoogstraten HJ, Vleggaar FP, Boland GJ, van Steenbergen W, Griffioen P, Hop WC, van Hattum J, van Berge Henegouwen GP, Schalm SW, van Buuren HR. Budesonide or prednisone in combination with ursodeoxycholic acid in primary sclerosing cholangitis: a randomized double-blind pilot study. BelgianDutch PSC Study Group. Am J Gastroenterol 2000;95:2015– 2022. Ahmed M, Mutimer D, Hathaway M, Hubscher S, McMaster P, Elias E. Liver transplantation for autoimmune hepatitis: a 12year experience. Transplant Proc 1997;29:496. Prados E, Cuervas-Mons V, De La Mata M, Fraga E, Rimola A, Prieto M, Clemente G, Vicente E, Casanovas T, Fabrega E. Outcome of autoimmune hepatitis after liver transplantation. Transplantation 1998;66:1645–1650. Neuberger J. Incidence, timing, and risk factors for acute and chronic rejection. Liver Transpl Surg 1999;5:S30 –S36. Sanchez-Urdazpal L, Czaja AJ, Van Holk B. Prognostic features and role of liver transplantation in severe corticoid-treated autoimmune chronic active hepatitis. Hepatology 1991;15:215– 221. Tillmann HL, Jackel E, Manns MP. Liver transplantation in autoimmune liver disease: selection of patients. Hepatogastroenterology 1999;46:3053–3059. Czaja AJ, Rakela J, Ludwig J. Features reflective of early prognosis in corticosteroid-treated severe autoimmune chronic active hepatitis. Gastroenterology 1988;95:448 – 453. European Liver Transplant Registry 1996. Ratziu V, Samuel D, Sebagh M, Farges O, Saliba F, Ichai P, Farahmand H, Gigou M, Feray C, Reynes M, Bismuth H. Longterm follow-up after liver transplantation for autoimmune hepatitis: evidence of recurrence of primary disease. J Hepatol 1999;30:131–141. Milkiewicz P, Hubscher SG, Skiba G, Hathaway M, Elias E. Recurrence of autoimmune hepatitis after liver transplantation. Transplantation 1999;68:253–256. Wright HL, Bou-Abboud CF, Hassanenstein T, Block GD, Demetris AJ, Starzi TE, Van Thiel DH. Disease recurrence and rejection following liver transplantation for autoimmune chronic active liver disease. Transplantation 1992;53:136 –139. Devlin J, Donaldson P, Portman B, Heaton N, Tan KC, Williams

May 2001

148.

149.

150.

151.

R. Recurrence of autoimmune hepatitis following liver transplantation. Liver Transpl Surg 1995;1:162–165. Go¨tz G, Neuhaus R, Bechstein WO, Lobeck H, Berg T, Hopf U, Neuhaus P. Recurrence of autoimmune hepatitis after liver transplantation. Transplant Proc 1999;31:430 – 431. Manns MP, Bahr MJ. Recurrent autoimmune hepatitis after liver transplantation: when non-self becomes self. Hepatology 2000; 32:868 – 870. Conti F, Dousset B, Levillayer H, Gruska J, Weill B, Calmus Y. Autoantibodies after liver transplantation: a marker of allograft disease? (abstr). J Hepatol 1997;26:150. Kerkar N, Hadizic N, Davies E, Portman B, Donaldson PT, Rela M,

AUTOIMMUNE HEPATITIS: CLINICAL CHALLENGES

1517

Heaton ND, Vergani D, Mieli-Vergani G. De-novo autoimmune hepatitis after liver transplantation. Lancet 1998;351:409 – 413. 152. Czaja AJ. Diagnosis and therapy of autoimmune liver disease. Med Clin North Am 1996;80:973–995.

Received October 23, 2000. Accepted February 26, 2001. Address requests for reprints to: Michael Manns, M.D., Department of Gastroenterology and Hepatology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany. e-mail: MANNS. [email protected].