Autoimmune hepatitis (AIH) is a rare disease, yet it. Fulminant Hepatic Failure as the Initial Presentation of Acute Autoimmune Hepatitis

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2004;2: Fulminant Hepatic Failure as the Initial Presentation of Acute Autoimmune Hepatitis WILLIAM R. KESSLER,* OSCAR W. CUMMINGS, GEORGE ECKERT, NAGA CHALASANI,* LAWRENCE LUMENG,* and PAUL Y. KWO* Departments of *Gastroenterology and Hepatology, Pathology, and Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana Background & Aims: Autoimmune hepatitis is a common cause of chronic hepatitis, and acute presentation is thought to be uncommon. The aim of this study was to compare clinical, biochemical, and histological features in patients with autoimmune hepatitis presenting with either acute or chronic hepatitis. Methods: Retrospective review of all patients with autoimmune hepatitis presenting to a University medical center from 1993 to Results: One hundred fifteen patients with autoimmune hepatitis were identified. Ten patients with autoimmune hepatitis were identified as having acute presentation (group I), and 20 patients with a classic presentation as chronic hepatitis (group II) served as age- and sex-matched controls. All patients met criteria published by the International Autoimmune Hepatitis Group. Patients with acute presentation differed significantly with regard to encephalopathy, albumin levels, and bilirubin levels. Blinded liver biopsy review demonstrated that those with acute presentation had significantly less fibrosis, and significantly greater interface hepatitis, lobular disarray, lobular hepatitis, hepatocyte necrosis, zone III necrosis, and submassive necrosis. Conclusions: In our study, patients with an acute presentation of autoimmune hepatitis differed from patients with a classical presentation clinically, biochemically, and histologically. In our review, a majority of patients with acute autoimmune hepatitis presented with fulminant hepatic failure. The pattern of zone 3 necrosis may be a specific finding in those with acute autoimmune hepatitis. Autoimmune hepatitis (AIH) is a rare disease, yet it is a relatively common cause of chronic hepatitis. Although the estimated mean annual incidence among whites of Northern European descent is only 1.9 cases per 100,000, it is the cause of approximately 20% of cases of chronic hepatitis. 1,2 Generally regarded as a chronic liver disease (originally named chronic autoimmune hepatitis), acute presentations of AIH account for up to 25% of all cases. 2 Case reports with both subacute and acute presentations of AIH have been reported in the pediatric literature. Three pediatric cases, all of which were type II AIH, presented acutely and responded to steroid and immunosuppressive therapy. 3 In addition, a case report describing a pediatric case of type II AIH with fulminant hepatic failure on presentation has also been reported. 4 In this case, liver biopsy specimen was found to demonstrate the absence of cirrhosis along with evidence of acute damage including inflammatory infiltrates and reticular collapse. A retrospective report reviewed 26 cases of recent-onset AIH, defined as clinical disease duration of less than 1 month, and suggested that acute presentations were in fact flares of chronic disease. 5 The question as to whether acute presentation of AIH reflects acute disease or, rather, a flare of a chronic illness has served as the grounds for debate. Although additional reports have been published, a conclusion has yet to be drawn as to whether AIH with acute presentation is a distinct clinical entity. Furthermore, although the exact prevalence of fulminant hepatic failure on presentation has yet to be delineated, it is generally believed to be uncommon. In this study we sought to determine whether clinical, biochemical, and histologic variables differ in patients with an acute presentation of AIH compared to those with the classic presentation of chronic hepatitis by using established criteria described for those with AIH. Materials and Methods Selection Criteria Charts were retrospectively reviewed for all patients presenting or referred to the Indiana University Medical Center who were diagnosed with AIH. This database reviewed included charts from inpatient referrals, the referral-based hepatology and pre liver transplant clinic, and post-transplant clinic. All clinical data were obtained before the initiation of Abbreviations used in this paper: AIH, autoimmune hepatitis; ANA, antinuclear antibody; LKM, liver-kidney microsomal antibody; OLT, orthotopic liver transplantation; SMA, smooth muscle antibody by the American Gastroenterological Association /04/$30.00 PII: /S (04)

2 626 KESSLER ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 7 Table 1. Comparison of Initial Clinical Data of AIH Patients With Acute (Group I) and Chronic (Group II) Presentation Group I (n 10) Group II (n 20) P value Clinical features Age (yr) Gender (M:F) 2:8 4: Race (white:black) 8:2 17: Duration of illness 3.2 wk 57 wk Encephalopathy (present:absent) 8:2 0: Autoimmune score Jaundice (yes:no) 10:0 8: Comorbidities Hypothyroidism Hypertension Ulcerative colitis Multiple sclerosis Laboratory findings Elevated ammonia a Protime (sec) ALT (IU/L) Albumin (g/dl) Bilirubin (mg/dl) Autoimmune markers b ANA (positive:negative) 7:3 16: SMA (positive:negative) 7:2 11: Anti-LKM (positive:negative) 1:9 0: a Ammonia measured in mol/l. b Positive ANA and SMA defined as titer greater than 1:40. any therapy for AIH. A total of 115 cases of AIH were identified between the years 1993 and All of these patients met the published criteria published by the International Autoimmune Hepatitis Group. 6 Patients were divided into 2 groups according to duration of illness on presentation. With previously published criteria, duration of disease was defined as the time interval from the first biochemical changes or unequivocal signs of liver disease to the time of presentation to Indiana University. 7 Group I consisted of patients with acute presentation, defined as jaundice and abnormal liver enzymes for less than 8 weeks as determined by chart review and patient interview. Group II consisted of patients with chronic presentation of AIH, defined as abnormal liver enzymes for more than 3 months, irrespective of duration, or the presence of jaundice again determined by chart review and patient interview. All patients with acute presentation had complete clinical and biochemical data necessary for a diagnosis of AIH, as well as a liver biopsy available for review. From all cases of AIH seen during a 9-year period, 30 (26.1%), including 10 patients with acute presentation and 20 with chronic presentation, met all pre-established criteria and were used for analysis in the acute group (group I) or as a control (group II). Patients in both groups received therapy with corticosteroids with or without immunosuppressive agents as has been previously described. 8 Virologic Analysis All patients were tested for acute hepatitis A (anti- HAV IgM), hepatitis B (HBsAg, anti-hbc IgM), hepatitis C (anti-hcv, HCV RNA by polymerase chain reaction), Epstein Barr virus (heterophil antibody), and cytomegalovirus (cytomegalovirus shell vial assay). Immunoserologic Analysis Antinuclear antibody (ANA) and smooth muscle antibody (SMA) values were obtained in all patients by using previously published standard techniques. 9 A titer of at least 1:40 was considered positive. Anti liver-kidney microsomal antibody (anti-lkm) was performed on all patients in group I and 5 of 20 patients from group II by using previously published standards. 9 A titer of at least 1:10 was considered positive. For those patients with acute presentation, HLA typing was performed. This was performed by using previously published standard techniques. 10 Histologic Analysis Thirty liver biopsies were reviewed by a single pathologist in a blinded fashion and subsequently staged according to established criteria. Between 1 and 5 slides were available from each case with an average of 3 slides for each case. Reticulum and trichrome stains were available for most cases. A total of 10 cases did not have trichrome stains available for review (3 from group I, 7 from group II). One case was reviewed from Kodachrome slides (group I). Biopsy specimens were scored according to stage of fibrosis (0 4), piecemeal necrosis (0 3), degree of portal inflammation (0 3), lobular hepatitis (0 3), lobular disarray (0 3), central necrosis (0 3), hepatocyte necrosis (0 3), and submassive necrosis (present vs. absent). 5

3 July 2004 FULMINANT HEPATIC FAILURE AND ACUTE AUTOIMMUNE HEPATITIS 627 Clinical Data Analysis All patients had AST (aspartate transaminase), ALT (alanine transaminase), prothrombin time, international normalized ratio, partial thromboplastin time, albumin, globulin, and bilirubin values measured and extracted. In addition, patients in group I had Factor V and Factor VII levels performed. A pertinent history denying the consumption of excessive doses of acetaminophen along with an undetectable acetaminophen level from referring institution were required for inclusion in the review. Treatment outcomes were defined as complete response or failure to respond with death, orthotopic liver transplantation (OLT), or listing for OLT as subsets. The 2 groups were compared for differences in binary categorical variables by using Fisher exact tests, for differences in ordinal categorical variables by using Mantel Haenszel tests, and for differences in continuous variables by using 2-sample t tests. Results Demographics Group I: Acute presentation. The patient characteristics of the 10 patients who met our criteria for acute presentation are listed in Table 1. The average age was 40 years, with the average duration of clinical disease being 3 weeks. All 10 patients presented to our institution with jaundice; 8 of 10 patients met previously described criteria for fulminant hepatic failure, with the average interval between jaundice and encephalopathy being 2.7 weeks. 11 Seven of these 8 patients had grade III encephalopathy, and 1 patient had grade II. Five of 10 patients were hypothyroid; 2 of these patients had previously received radioactive iodine as treatment for Graves disease. The interval between treatment of thyroid disease and presentation was 2 years for one patient and 2 weeks for the second. At the time of presentation, 1 patient had been on beta-interferon for 1.5 years as treatment for multiple sclerosis. Two patients were hypertensive, although neither patient had recent changes to their antihypertensive regimens. All patients received corticosteroids, and 9 patients received immunomodulators as treatment for AIH including azathioprine, tacrolimus, mycophenolate, cyclosporine, and 6-mercaptopurine. These medications were dosed according to published treatment regimens for AIH (prednisone, azathioprine, 6-mercaptopurine) or for antirejection therapy after liver transplantation in the cases of mycophenolate, tacrolimus, and cyclosporine. 12 Group II: Chronic presentation. This age- and sex-matched control group was composed of patients referred to Indiana University Medical Center for management of chronic AIH, and their characteristics are also listed in Table 1. Of the 105 patients with chronic Table 2. Comparison of Liver Biopsy Findings of AIH Patients With Acute (Group I) and Chronic (Group II) Presentation Histologic feature Grade/ stage Group I (n 10) Group II (n 20) P value Fibrosis present Fibrosis stage Portal inflammation Lymphocyte piecemeal necrosis Lobular disarray Hepatocyte necrosis Central necrosis Submassive necrosis Yes No 5 20 Bridging necrosis Yes No 6 16 Lobular hepatitis presentation, 20 were selected as age- and sex-matched control subjects. The average duration of disease, defined as the interval from the first reported elevation in transaminase levels until the time of referral, was 14 months. Eight of 20 patients had jaundice; the average duration of jaundice at time of referral was 12.5 days. Hepatic encephalopathy was not observed in any patients from this group. With regard to comorbidities, 2 patients were hypothyroid, 1 patient had Graves disease, 2 patients had ulcerative colitis, and 1 patient had sarcoidosis. All but one patient received maintenance corticosteroids. Twelve patients received immunomodulator therapy (azathioprine) in addition to corticosteroids. Clinical and Laboratory Findings Patients with acute and chronic presentations were indistinguishable by gender, age, race, and autoimmune score (Table 1). Patients in group I had a significantly higher rate of hypothyroidism as well as a trend

4 628 KESSLER ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 7 0%; P ) (Table 2). Patients in group I also had significantly lower albumin levels (2.50 vs g/dl; P ) and significantly greater serum total bilirubin levels (17.0 vs mg/dl; P ). Immunoserologic Data The proportion of patients presenting with positive autoimmune markers (ANA, SMA, or anti-lkm) did not differ significantly (Table 1). In group I, seven patients had positive ANA, 7 had positive SMA, and 1 was anti-lkm positive. Five patients had both positive ANA and SMA. In group II, sixteen patients were found to have positive ANA, 11 had positive anti-sma, and none were anti-lkm positive. Eight patients had both positive ANA and SMA. For those patients found to be positive for ANA and/or SMA, the range in titers for group I and group II were 1:80 1:1280 (ANA) and 1:20 1:5120 (SMA) and 1:80 1:5120 (ANA) and 1:20 1:5120 (SMA), respectively. The titer for the sin- Figure 1. Acute autoimmune hepatitis. (A and B) There is marked zone 3 hepatocyte necrosis and collapse associated with a mixed chronic inflammatory cell infiltrate including eosinophils, plasma cells and lymphocytes. (C) The portal tract (right hand corner) shows no inflammation or fibrosis (trichrome stain). toward a higher rate of hypertension. The probability of having an elevated ammonia level on presentation was significantly higher in group I (90% vs. 5%; P ) as was the presence of encephalopathy (80% vs. Figure 2. Chronic autoimmune hepatitis. The portal tract is predominantly expanded by a chronic inflammatory cell infiltrate. (A) There is an interface hepatitis (B) with small buds of type-one collagen extending into the lobule (periportal fibrosis).

5 July 2004 FULMINANT HEPATIC FAILURE AND ACUTE AUTOIMMUNE HEPATITIS 629 Table 3. Comparison of Response to Therapy of AIH Patients With Acute (Group I) and Chronic (Group II) Presentation Group I (n 10) Group II (n 20) P value Clinical outcome Complete response Died OLT 3 2 Listed for OLT 1 2 gle patient in group I with a positive anti-lkm was 1:640. Histologic Data Blinded liver biopsy review demonstrated that patients in group I had a significantly higher degree of piecemeal necrosis (P ), lobular disarray (P ), hepatocyte necrosis (P ), central necrosis (P ), submassive necrosis (P ), and lobular hepatitis (P ) (Figure 1). In group II patients with a chronic presentation, a greater degree of fibrosis was noted (P ) (Figure 2). No differences in portal inflammation (P 0.24) or bridging necrosis (P 0.38) were noted between the 2 groups (Table 2). HLA Data HLA data were available for patients from group I. HLA DRB was found in 2 patients, HLA DRB was found in 2 patients, and HLA DRB was found in 3 patients. Treatment Outcome Significant differences in clinical outcome (complete response, death, OLT, listing for OLT) and treatment response (complete response, death, OLT, listing for OLT) were noted between the 2 groups (Table 3, chi-square). Four patients from group I responded completely to therapy with normalization of liver aminotransferase levels and no clinical evidence of advanced liver disease, whereas 2 patients died of complications of acute liver failure. Three patients in group 1 underwent OLT, and 1 patient is listed for OLT. Group II patients had a significantly greater degree of complete response to immunosuppressive therapy. In group II, sixteen patients responded completely to standard therapy with normalization of aminotransferase levels and no evidence of advanced liver disease. Of the remaining 4 patients, 2 underwent OLT for cirrhosis caused by AIH, and 2 patients are currently awaiting OLT with cirrhosis caused by AIH. No patients from this group died, although a trend toward higher mortality in group I patients was noted (P 0.1). Discussion In our study, we found that patients with an acute presentation of AIH are indeed clinically, biochemically, and histologically distinct from those who present with the more typical presentation as chronic hepatitis. More clinically severe disease was noted in those with acute presentation as evidenced by the presence of encephalopathy and by a significantly greater degree of hyperbilirubinemia and hypoalbuminemia. Hypoalbuminemia in patients with acute presentation of AIH most likely reflects the acute phase reactant properties of this variable rather than a marker of chronic liver disease. 13 This is supported clinically because differences in outcome and treatment response were noted. In addition, none of the patients with acute presentation had stigmata of chronic liver disease (data not shown). Patients in group I had a poorer response to standard immunosuppressive therapy, and a trend toward higher mortality rate was noted, likely because of the high prevalence of fulminant hepatic failure noted in group 1. Three patients required urgent OLT, and 2 patients died of complications of their acute liver disease. Elevation of bilirubin level might be used prognostically in those with fulminant hepatic failure as well in those with end-stage liver disease, but to date this has not been reported to differentiate between acute and chronic presentation of AIH. 14,15 Despite the clinical and biochemical differences between the 2 groups, the aggregate autoimmune scores were similar in patients from both groups. In fact, all of the patients in group II readily met the current diagnostic criteria for AIH. Our study suggests a distinct histologic pattern of injury for those with acute presentation of AIH compared with those who present with chronic hepatitis. Sixty percent of patients from group I had no evidence of fibrosis compared with 15% from patients from group II (P ). Bridging necrosis, seen in both acute hepatitis and exacerbations of chronic hepatitis, was not found to be significantly different. The severity of interface hepatitis was significantly higher in group I patients, graded as brisk (3/3 on an activity scale) in 70% of patients from group I (P ). In terms of a distinct pattern of injury, severe lobular inflammation with extensive hepatocellular necrosis was seen primarily in those with acute presentation. Severity of injury, measured as central necrosis, submassive necrosis, hepatocyte necrosis, and lobular disarray, were all significantly different between the 2 groups. Lobular disarray

6 630 KESSLER ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 7 has been previously observed in patients with acute presentation of AIH and has been historically described as an inconsistent feature in those with chronic AIH. 2,5 Also in contrast to those with chronic AIH, a pattern of centrizonal (zone III) injury was noted. This pattern of injury differs from that described for acetaminophen toxicity, because a substantial inflammatory infiltrate, which is minimal in acetaminophen toxicity, was present in patients with acute presentation of AIH. 16,17 Seven of 10 patients with acute presentation had moderate to severe zone III necrosis in contrast to 6 of 20 patients with chronic presentation (P ). Zone III necrosis was recently described in a case report of an individual with an acute onset of AIH. In this case, an initial liver biopsy performed 1 month after the onset of symptoms demonstrated centrizonal injury with complete sparing of the portal tracts. Repeat biopsy performed 7 months later (without the institution of therapy) showed portal inflammation, hepatocellular loss, and bridging inflammation consistent with AIH, which suggested that centrilobular injury can evolve into the classic pattern of injury described for AIH Our case series would also suggest that patients with acute presentation of AIH might have a different histologic presentation from those presenting with chronic AIH. In a case series describing 3 pediatric patients with type I AIH with subfulminant hepatic failure at initial presentation, 2 of the 3 liver biopsies demonstrated only acute histologic changes, whereas the third case revealed focal micronodular cirrhosis, suggesting that AIH could present in the absence of histologic changes associated with chronic liver disease. 21 Our data suggest that patients with acute presentation have significantly different serum albumin and bilirubin levels, a different histologic pattern of injury, and do not respond to therapy as well as those patients with chronic presentation. This is, in part, a reflection of the clinical severity of disease as can be seen in a variety of other causes of hepatitis with acute and chronic presentations including hepatitis B and Wilson s disease. In our review, patients with acute presentation had significantly more zone III injury along with a significantly lower degree of fibrosis. Although this likely does not reflect an independent disease entity, the findings of zone III injury with the lack of fibrosis typically described in AIH support the acute presentation of AIH as de novo disease rather than a flare of a chronic disease process. Rather than a distinct entity, this might represent the uncommon acute phase of a disease that normally presents in a chronic form. If other studies confirm our findings that zone III necrosis might reflect a more severe form of acute AIH, then this variable might warrant inclusion in a revised scoring system. Although not a specific aim of our study, follow-up data on patients in group I revealed that of the 5 patients who responded to medical therapy, only 1 exhibited histologic evidence of progression. No evidence of recurrent disease was apparent on repeat liver biopsies for those patients who had undergone OLT for acute AIH. Neither of these findings lend themselves to much speculation, because half of the patients in the group who responded to medical therapy had underlying cirrhosis on initial biopsy, and therefore progression of disease would be difficult to document. In terms of the lack of recurrence noted in the patients who required OLT, post-transplantation immunosuppression might be a confounding factor, because potent immunosuppressive drugs are used, which might keep the AIH in clinical remission. The prognostic importance of HLA typing is becoming ever more apparent. 22 Consistent with recently published data, 80% of patients in group I were found to be either HLA DRB or 0401 positive. 23,24 Although the importance of these alleles has been convincingly portrayed in the literature, the small number of patients who underwent HLA typing in this study did not allow for such analysis. Although it is accepted that the presentation of AIH is acute in up to 25% of cases, whether this signifies a distinct entity has remained unclear. This retrospective review suggests that patients with acute presentation differ clinically, biochemically, and histologically from patients with more typical presentation. A pattern of zone III necrosis might be specific for acute AIH. Our review also suggests that fulminant hepatic failure is not an uncommon form of acute presentation of AIH. When patients present with an acute hepatitis or fulminant hepatic failure, AIH should be considered in the initial differential diagnosis, and corticosteroids and OLT should be considered, if appropriate. References 1. Al-Khalidi JA, Czaja AJ. Current concepts in the diagnosis, pathogenesis, and treatment of autoimmune hepatitis. Mayo Clin Proc 2001;76: Manns MP, Strassburg CP. Autoimmune hepatitis: clinical challenges. 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