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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e3181fc1e0b
Original Articles: Hepatology and Nutrition

Utility of Simplified Criteria for the Diagnosis of Autoimmune Hepatitis in Children

Hiejima, Eitaro; Komatsu, Haruki; Sogo, Tsuyoshi; Inui, Ayano; Fujisawa, Tomoo

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Author Information

From the Department of Pediatrics, Eastern Yokohama Hospital, Japan.

Received 14 July, 2010

Accepted 13 September, 2010

Address correspondence and reprint requests to Haruki Komatsu, Eastern Yokohama Hospital, Children's Center for Health & Development, 3-6-1 Simosueyoshi Tsurumi, Yokohama, Kanagawa 230-0012, Japan (e-mail: haruki-komatsu@chive.ocn.ne.jp).

The authors report no conflict of interests.

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Abstract

Background and Aim: Although the diagnostic scoring system of autoimmune hepatitis (AIH) has been used, these criteria are intended mainly as research tools and are complicated to apply. To resolve these difficulties and allow quick diagnosis, a simplified scoring system was proposed in 2007. We retrospectively compared the simplified AIH scoring system with the 1999 revised original AIH scoring system in children.

Patients and Methods: Twenty children (boys/girls 10/10, age 1–15 years, mean age ± SD 8.4 ± 4.4 years) who were diagnosed with AIH based on clinical, biochemical, immunological, and histological data were enrolled in this study. In addition, 36 children with non-AIH liver diseases (boys/girls 22/14, age 1–16 years, mean age ± SD 7.8 ± 4.4 years) were available for evaluation of both the simplified and the 1999 revised scoring system.

Results: The sensitivity and specificity of the 1999 revised scoring system were 100% and 81%, respectively. In contrast, the sensitivity and specificity of the simplified scoring system were 55% and 86%, respectively. Of the 20 children with AIH, 9 (45%) were classified as not having AIH using the simplified scoring system. Of the 9 children, 2 and 7 were classified as having definite AIH and probable AIH using the 1999 revised scoring system, respectively. All 5 children with primary sclerosing cholangitis were graded as having AIH using the simplified AIH criteria and the 1999 revised criteria.

Conclusions: Although the simplified AIH scoring system has low sensitivity for the diagnosis of AIH in children, the specificity of the simplified AIH scoring system is high. However, the simplified AIH scoring system could not differentiate between AIH and primary sclerosing cholangitis. Therefore, the simplified AIH scoring system does not seem to be a reliable diagnostic tool in children.

Autoimmune hepatitis (AIH) is a progressive inflammatory liver disorder characterized serologically by high levels of transaminases and immunoglobulin G (IgG), the presence of autoantibodies, histologically by interface hepatitis, and the absence of a known etiology. Juvenile AIH is divided into 2 types according to seropositivity for smooth muscle and/or anti-nuclear antibody (AIH type 1) or liver/kidney antibody (AIH type 2). Immunosuppressive treatment with corticosteroid is the first-line treatment for AIH (1–3). Without appropriate treatment, AIH generally progresses to cirrhosis. Liver cirrhosis is detected at the time of diagnosis in between 44% and 80% of children with AIH (1,2). Liver transplantation is indicated in patients who progress to end-stage liver disease and present with fulminant hepatic failure (1–3). However, the diagnosis of AIH is difficult in children and adults because the clinical picture is highly varied and there is no specific test applicable for all patients. In 1993, the International Autoimmune Hepatitis Group (IAIHG) proposed the diagnostic criteria, and the criteria were revised by IAIHG in 1999 (4). These criteria were intended mainly as a research tool to allow comparison of studies between different centers. Because of the complexity of the criteria, however, they are not easily applicable as a clinical tool. To resolve these difficulties and allow “bedside” diagnosis, the IAIHG proposed a simplified scoring system in 2007 (Table 1) (5,6). The new, simplified criteria incorporate only 4 parameters: presence of associated autoantibodies, IgG level, liver histological findings, and absence of viral hepatitis. Although several studies have been performed to evaluate the utility of the simplified diagnostic criteria, there is controversy about whether the simplified criteria are useful and reliable for diagnosis as a practical diagnostic tool (1,2). In addition, the utility of the simplified diagnostic criteria has not been evaluated in children. In this retrospective study, we compared the simplified scoring system with the revised original scoring system.

Table 1
Table 1
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PATIENTS AND METHODS

Patients

Between April 2007 and May 2010, we followed 20 children with AIH (boys/girls 10/10, age 1–15 years, mean age ± SD 8.4 ± 4.4 years) who were diagnosed based on the criteria proposed by IAIHG in 1999. All 20 children were classified into type 1 AIH according to the autoantibody profile. In addition, all 20 children fulfilled the criteria for the diagnosis of AIH in children, which was proposed by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) (Table 2) (1). Between April 2007 and May 2010, a liver biopsy was performed in 111 children with non-AIH liver diseases in our department. Of the 111 children with non-AIH liver diseases, 36 (boys/girls 22/14, age 1–16 years, mean age ± SD 7.8 ± 4.4 years) were available for the evaluation of both the 1999 IAIHG and the simplified scoring system. The 36 children with non-AIH chronic liver diseases were diagnosed as having hepatitis C infection (n = 18, boys/girls 10/8, age 4–17 years, mean age ± SD 7.7 ± 3.4 years), primary sclerosing cholangitis (PSC) (n = 5, boys/girls 2/3, age 5–14 years, mean age ± SD 9.4 ± 3.8 years), hepatitis B (n = 2, 1-year-old and 2-year-old boys), chronic Epstein-Barr-related hepatitis (n = 2, 1-year-old girl and 16-year-old boy), nonalcoholic fatty liver disease (n = 2, 10-year-old and 13-year-old boys), glycogen storage disease (n = 1, 1-year-old boy), Wilson disease (n = 1, 13-year-old boy), and cryptogenic hepatitis (n = 5, boys/girls 3/2, age 4–15 years, mean age ± SD 7.8 ± 4.9 years). Of the 18 children with chronic hepatitis C, 4 (22%) were positive for anti-nuclear antibody. However, none of the children with chronic hepatitis C were positive for anti-liver/kidney microsomal antibody type 1. The diagnosis of PSC was based on the demonstration of specific cholangiographic changes that were detected in endoscopic retrograde cholangiography. Of the 5 children with PSC, 1 was diagnosed as having small duct PSC. Because there were no histological findings of interface hepatitis in the 5 children with PCS, they were not regarded as having AIH/PSC overlap.

Table 2
Table 2
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We compared the performance parameters between the 1999 IAIHG revised system and the simplified scoring system. In addition, we analyzed factors of the discrepant diagnoses for AIH using both scoring systems. The pretreatment scores were applied as the 1999 revised criteria for the diagnosis of AIH in this study. A score of 10 to 15 points supports a probable diagnosis and a score of more than 15 points supports a definite diagnosis by the 1999 revised scoring system. On the contrary, the simplified scoring system is based on 4 components: autoantibody titers, Ig/IgG levels, liver histology, and viral hepatitis. A score of 6 points constituted a probable diagnosis of AIH and a score of 7 or more points constituted a definite diagnosis of AIH (Table 1) (5,6). Autoantibodies were detected by indirect immunofluorescence.

Sensitivity, specificity, positive predictive value, and negative predictive value were the performance parameters for diagnosis that were assessed for each scoring system. The clinical diagnoses based on the 1999 revised criteria for AIH pretreatment (4) and the criteria of AIH in childhood devised by ESPGHAN and NASPGHAN (Table 2) (1), and on conventional clinical criteria for the other chronic liver diseases, were regarded as the criterion standard of diagnosis.

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RESULTS

Comparison of Scoring Systems for AIH

The comparison of clinical diagnoses and scoring diagnoses using each system is shown in Table 3. Of the 20 children with AIH, 11 (55%) were classified as having definite AIH (score range 16–21 points) and 9 (45%) were classified as having probable AIH (score range 12–15 points) using the 1999 revised scoring system. In contrast, the simplified scoring system made the diagnosis of definite AIH and probable AIH in 8 (40%) (score of 7 points, n = 2; score of 8 points, n = 6) and 3 (15%) of the 20 children with AIH, respectively. The remaining 9 (45%) children with AIH were not graded as having AIH using the simplified scoring system. Of the 11 children classified as having definite AIH using the 1999 revised scoring system, 7 (64%) and 2 (18%) were graded as having definite AIH and probable AIH using the simplified AIH scoring system, respectively. The remaining 2 (18%) children were graded as not having AIH. Of the 9 children diagnosed with probable AIH using the 1999 revised scoring system, 1 (11%) was graded as having probable AIH and 1 (11%) definite AIH using the simplified scoring system. The remaining 7 (78%) were classified as not having AIH.

Table 3
Table 3
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Scoring Discrepancies for AIH

Of the 11 children diagnosed as having definite AIH using the 1999 revised scoring system, 4 were downgraded using the simplified scoring system. Of the 4 downgraded children, 2 were classified as having probable AIH and the remaining 2 had nondiagnostic scores by the simplified criteria. Of the 9 children diagnosed with probable AIH using the 1999 revised scoring system, 7 were downgraded, 1 upgraded, and 1 had no change. All of the 7 downgraded children had nondiagnostic scores using the simplified scoring system. In the upgraded case, the points using the 1999 revised and simplified scoring system were 14 and 7, respectively. In this case, a 10-year-girl had high IgG levels (1.16 upper normal limit) and high titers of anti-nuclear autoantibodies (1:320). These parameters contributed to the upgrade of AIH classification. Of the 20 children with AIH, 8 had acute illness at onset. All 8 children had acute presentation, but 1 was downgraded using the simplified AIH. Of the 8 children with acute presentation, 4 (50%) were diagnosed with fulminant hepatic failure. Of the 4 children with fulminant hepatic failure, 3 had no points in the component of the presence of autioantibodies and 3 had no points in IgG levels.

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Treatment Outcomes of Probable and Definite AIH

Twenty children diagnosed with definite or probable AIH using the 1999 revised scoring system were treated with immunosuppressive therapy. All but 1 responded well to prednisolone combined with azathioprine. A 3-year-old boy who did not respond to prednisolone combined with azathioprine was classified as having definite AIH using both the 1999 revised and simplified scoring system. Because the elevation of transaminases was not improved, cyclosporine A was added to the treatment with prednisolone and azathioprine.

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Comparison of Scoring for Excluding Other Diagnoses

The 1999 revised scoring system graded all 5 of the children with PSC as having probable AIH. Additionally, 1 child (6-year-old girl) with chronic hepatitis C and 1 child (3-year-old girl) with cryptogenic hepatitis were graded as having probable AIH using the 1999 revised scoring system. Similarly, using the simplified scoring system, the 3 children with PSC were graded as having definite AIH. The remaining 2 children with PSC were classified as having probable AIH. However, the simplified scoring system did not grade any of the children with chronic hepatitis C, chronic related Epstein-Barr infection, chronic hepatitis B, nonalcoholic liver disease, glycogen storage disease, Wilson disease, or cryptogenic chronic hepatitis as having AIH.

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Performance Parameters for Diagnosing AIH

The sensitivity, specificity, positive predictive value, and negative predictive values of the simplified AIH criteria are shown in Table 4. The sensitivity and specificity of the 1999 revised scoring system were 100% and 81%, respectively. In contrast, the sensitivity and specificity of the simplified scoring system were 55% and 86%, respectively. The sensitivity of the simplified scoring system was approximately half that of the 1999 revised scoring system. Of the 20 children with AIH, 9 (45%) were classified as not having AIH using the simplified scoring system. Of the 9 children, 2 and 7 were classified as having definite AIH and probable AIH using the 1999 revised scoring system, respectively. Therefore, there is concern that the simplified scoring system could overlook AIH in pediatric patients. However, the specificity (86%) of the simplified scoring system was superior to that (81%) of the 1999 revised scoring system. All 11 children classified as having AIH using the simplified scoring system were graded as having AIH by the 1999 revised scoring system. These findings suggest that high specificity of the simplified scoring system has the potential to make an accurate diagnosis of AIH in children if PSC could be excluded.

Table 4
Table 4
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DISCUSSION

The scoring system for the diagnosis of AIH developed by IAIHG has focused on adult patients since the 1990s (4,7). Because the scoring system was made based on data from adults, there is controversy about whether the scoring system is appropriate to use as diagnostic criteria for AIH in children. In this study, the children used as a criterion standard were diagnosed as having AIH based on clinical, biochemical, immunological, and histological data as well as the scoring system. They also met the criteria for the diagnosis of AIH in childhood (1). Moreover, they responded well to immunosuppressive therapy. Therefore, we thought that our pediatric patients with AIH were suitable as a criterion standard to compare the utility of the 1999 revised scoring system with that of the simplified scoring system.

Compared with the 1999 revised scoring system, the simplified scoring system showed low sensitivity (100% on the 1999 criteria, 55% on the simplified criteria) but high specificity (81% on the 1999 criteria, 86% on the simplified criteria) in this study. The simplified AIH criteria lacked high sensitivity in children. The lack of high sensitivity is a crucial problem as a diagnostic tool, because 7 of 9 children classified as having probable AIH by the 1999 revised scoring system were graded as not having AIH. These findings suggest that the simplified AIH scoring system often makes a false-negative diagnosis of AIH in children. In contrast, the specificity of the simplified scoring system was 86% in children. In children, the specificity was relatively superior to the 1999 revised criteria. The specificity of the simplified criteria was 90% in adult studies (8,9). Thus, the specificity of the simplified AIH criteria in children was as high as that in adults. This is a striking finding of the simplified AIH scoring system in children. All of the children graded as having AIH using the simplified scoring system were also classified as having AIH using the 1999 revised system. However, care must always be taken to avoid misdiagnosing PSC for AIH. The simplified scoring system classified all 5 children with PSC as having AIH in this study. These findings indicate that the simplified scoring system cannot differentiate between PSC and AIH. Pediatric patients with PSC often have autoimmunological characteristics resembling AIH, including positive autoantibodies (ANA, SMA), high IgG levels, and infiltration of cells in portal tracts. Although the definition is obscure, an overlapping syndrome between AIH and PSC has been reported both in children and adults (10). In a previous pediatric cohort study, the 1999 revised scoring system classified all 27 patients with the overlapping syndrome as having AIH (10). Although we studied a small number of children, the previous and the present study suggest that the 1999 revised and the simplified criteria can lead to the misdiagnosis of AIH. To make a correct diagnosis of AIH, a cholangiogram must inevitably be performed to distinguish PSC from AIH in children.

ESPGHAN and NASPGHAN proposed the criteria for the diagnosis of AIH in childhood (1), although the criteria were not a scoring system. The criteria includes 7 components, elevated transaminases, positive autoantibodies, elevated IgG, liver histology, exclusion of viral hepatitis, exclusion of Wilson disease, and normal cholangiogram. However, all 4 components in the simplified scoring system are included in the pediatric criteria. Consequently, the simplified AIH criteria are the same as the pediatric criteria of AIH when Wilson disease is excluded and the cholangiogram is normal. Therefore, not only the simplified AIH criteria but also the evaluation of copper metabolism and cholangiogram are required to diagnose AIH in children.

The majority of downgraded patients with AIH had acute onset of illness in this study. This finding is consistent with the previous adult study (9). The performance parameter of the scoring systems is influenced by the clinical pattern of disease presentation in children and adults. The sensitivity of the 1999 revised and simplified criteria was >90% in the adult patients with chronic onset (8,9). However, the sensitivity in adult patients with fulminant hepatic failure was 40% using the 1999 revised criteria (9). Moreover, the sensitivity was decreased to 24% using the simplified criteria (9). These findings suggest that acute onset of AIH should not be evaluated using the simplified criteria.

In conclusion, the simplified AIH scoring system has low sensitivity and high specificity for the diagnosis of AIH in children. However, the simplified AIH scoring system could not exclude PSC. Evaluation by performing a cholangiogram is indispensable even if the simplified scoring system classifies a child as having AIH. Therefore, the simplified AIH scoring system seems inappropriate to use as a “bedside” clinical diagnostic tool.

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REFERENCES

1. Mieli-Vergani G, Heller S, Jara P, et al. Autoimmune hepatitis. J Pediatr Gastroenterol Nutr 2009; 49:158–164.

2. Mieli-Vergani G, Vergani D. Autoimmune hepatitis in children: what is different from adult AIH? Semin Liver Dis 2009; 29:297–306.

3. Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51:2193–213.

4. Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999; 31:929–938.

5. Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008; 48:169–176.

6. Choi G, Peters MG. The challenge of diagnosing autoimmune hepatitis: less is more. Hepatology 2008; 48:10–12.

7. Johnson PJ, McFarlane IG. Meeting report: International Autoimmune Hepatitis Group. Hepatology 1993; 18:998–1005.

8. Czaja AJ. Performance parameters of the diagnostic scoring systems for autoimmune hepatitis. Hepatology 2008; 48:1540–1548.

9. Yeoman AD, Westbrook RH, Al-Chalabi T, et al. Diagnostic value and utility of the simplified International Autoimmune Hepatitis Group (IAIHG) criteria in acute and chronic liver disease. Hepatology 2009; 50:538–545.

10. Gregorio GV, Portmann B, Karani J, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology 2001; 33:544–553.

Cited By:

This article has been cited 1 time(s).

Minerva Pediatrica
Autoimmune liver diseases
Della Corte, C; Sartorelli, MR; Comparcola, D; Alterio, A; Giorgio, V; Papadatou, B; Nobili, V
Minerva Pediatrica, 64(6): 595-606.

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Keywords:

autoimmune hepatitis; children; primary sclerosing cholangitis; simplified criteria

Copyright 2011 by ESPGHAN and NASPGHAN

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