Abstract
Autoimmune Hepatitis (AIH) is a poorly understood disease. There has been a paucity of reports on the epidemiology and clinical course of AIH in multiethnic populations. The aim of this study is to examine the clinical and serologic features of AIH in the multiethnic population of Hawai‘i. This was a retrospective, cross-sectional study of a cohort of patients seen between 2010–2013 in a tertiary referral center in Hawai‘i. All 32 patients were diagnosed according to International Autoimmune Hepatitis Group (IAIHG) criteria. The mean (SD) age of diagnosis was 49.4 (17.5) years, 75% of patients were female, 72% were Asian, 19% were Caucasian, 6% were Pacific Islander, and 3% were African American. When compared to Caucasians, Asians had lower transaminase levels and international normalized ratio (INR), and were more likely to have anti-nuclear antibody (ANA) seropositivity at presentation. Asians were also older at diagnosis and more likely to achieve complete or partial remission. Patients diagnosed before the age of 40 had higher levels of total bilirubin at presentation compared to those diagnosed after the age of 40. No significant differences were observed between genders. Asian patients with type I AIH present later in life with more favorable laboratory values, and have a superior treatment response compared to Caucasians. Diagnosis before the age of 40 is associated with less favorable laboratory values at diagnosis. Further studies are necessary to validate these findings and determine the reason for the ethnic differences.
Introduction
Autoimmune hepatitis (AIH) is a disease of unknown etiology characterized by a loss of immune tolerance to the liver, resulting in chronic hepatocellular inflammation, autoantibodies, and hypergammaglobuminemia.1,2 Despite its discovery in the 1950's, the pathogenesis underlying AIH and many of its clinical features remains unclear.3
The diagnosis of AIH is based on the criteria established by the International Autoimmune Hepatitis Group (IAIHG), established in 1993 and revised in 1999.1 The disease is classified into two types based on the presence of circulating autoantibodies. Type 1 is defined by the presence of anti-nuclear antibody (ANA) and/or anti-smooth muscle antibody (SMA). Type 2 is defined by the presence of anti-liver/kidney microsomes (LKM-1) and/or anti-liver cytosol antigen (LC-1).1 Treatment for AIH is based on the 2010 American Association for the Study of Liver Disease (AALSD) Practice Guidelines, which recommend a regimen of prednisone with azathioprine or prednisone monotherapy. Treatment results in the remission of disease in 65%–80% of patients.2,4 However, up to 86% of patients experience a relapse after withdrawal of corticosteroids, thus potentially reverting to the natural history of AIH of progressive liver dysfunction.1,5
AIH has a strong female predominance, and commonly occurs in concurrence with other autoimmune diseases including thyroiditis, inflammatory bowel disease, and systemic lupus erythematosus.1,3,6,7 AIH presents with a bimodal distribution and a variable clinical presentation that ranges from asymptomatic to acute liver failure.2,5,8–10 Prevalence rates differ between ethnicities, with previous studies reporting a prevalence rate of 1 in 5,000 to 10,000 in Western countries compared to much lower rates in Japanese populations.11–12 Current data suggests that many of the characteristics of AIH vary between ethnicities. Several studies have found that Japanese have a milder form of the disease with a later onset when compared to Caucasians.8,13–14 Despite these reports, overall epidemiologic data of AIH remain sparse, especially in the United States. The multiethnic population of Hawai‘i provides a unique opportunity to elucidate differences in the characteristics of AIH between ethnic groups and will allow clinicians to better diagnose and manage this disease. Thus, the aim of this retrospective study is to investigate the clinical and serological features of AIH and treatment response in the multiethnic population of Hawai‘i.
Methods
In this retrospective, cross-sectional study, medical records of 32 patients clinically determined to have AIH were reviewed. These patients presented to our tertiary referral center from January 1, 2010 through August 31, 2013. Patients with concurrent primary biliary cirrhosis were excluded. All patients were diagnosed with AIH according to the IAIHG scoring system.2
Data including age, gender, and self-identified ethnicity were obtained from patient charts. Laboratory data was obtained at presentation and throughout treatment, and included alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), total bilirubin, international normalized ratio (INR), albumin, gamma-glutamyl transferase (GGT), ANA, and SMA. Reference ranges for these are as follows: ALT is 0–41 IU/L, AST 0–40 IU/L, total bilirubin is 0–1.2 mg/dl, INR is ≤ 1, GGT is 8–61 IU/L, ANA is ≤ 40, and SMA is < 20.
Presentation of disease was stratified into three categories: acute, insidious, or asymptomatic. Acute included persons with features of icteric hepatitis. Insidious included persons with vague or non-specific symptoms (eg, fatigue, malaise, nausea, abdominal pain). Asymptomatic included persons who presented with abnormal liver function tests in the absence of symptoms.
Treatment response at one year was stratified into three categories: complete, partial, or no remission. Complete remission was defined as the normalization of liver function tests below 40 IU/L. Partial remission was defined as ALT less than two times the upper limit of normal. No remission was defined as the lack of normalization such that ALT was greater than two times the upper limit of normal (80 IU/L).
Determination of histology consistent with AIH was based on liver biopsy. Histology consistent with AIH was defined as the presence of interface hepatitis, lobular hepatitis, rosettes, or plasma cell infiltration.2,11
The study was approved by the University of Hawai‘i Human Studies Program CHS #20525 and The Queen's Medical Center RA-2014-050.
One-way analysis of variance was used to test the differences in the means of continuous variables, and chi-squared tests were used to test differences between categorical variables. Statistical analyses were performed with SPSS, Version 21 (SPSS Inc, Chicago IL).
Results
The study population consisted of 32 patients, diagnosed according to criteria issued by the IAIHG. The clinical, serological, immunological, and histological features at presentation are reported in Table 1. The mean (SD) age at diagnosis was 49.4 (17.5) years, and the majority of patients were female (75%). Most patients identified as Asian (72%), followed by Caucasian (19%), Pacific Islander (including Native Hawaiian) (6%), and African American (3%). Of those who identified as Asian, the majority were Japanese or Okinawan (47%).
Table 1.
Cohort Characteristics of Patients with Autoimmune Hepatitis at Presentation
| Cohort | |
| N | 32 |
| Mean age at diagnosis, years, (SD) | 49.4 (17.5) |
| Female gender, no. (%) | 24 (75%) |
| Ethnicity, no. (%) | |
| Caucasian | 6 (19%) |
| Asian | 23 (72%) |
| African American | 1 (3%) |
| Pacific Islander | 2 (6%) |
| Concomitant autoimmune disease, no. (%) | 8 (25%) |
| ALT, IU/L, Mean (SD) | 501.6 (595.7) |
| AST, IU/L, Mean (SD) | 484.4 (640.0) |
| Total bilirubin, mg/dL, Mean (SD) | 7.6 (13.1) |
| INR, Mean (SD) | 1.2 (0.2) |
| Albumin, g/dL, Mean (SD) | 4.1 (0.4) |
| GGT, IU/L, Mean (SD) | 101.4 (128.1) |
| ANA positive, no. (%) | 17 (77%) |
| SMA positive, no. (%) | 8 (47%) |
| Histology consistent with AIH, no. (%) | 18 (86%) |
| Cirrhosis present on biopsy, no. (%) | 16 (50%) |
| Presentation, no. (%) | |
| Acute | 7 (28%) |
| Insidious | 12 (48%) |
| Asymptomatic | 6 (24%) |
| Treatment response, no. (%) | |
| Complete remission | 24 (75%) |
| Partial remission | 5 (16%) |
| No remission | 3 (9%) |
Abbreviations: standard deviation (SD), alanine aminotransferase (ALT), aspartate aminotransferase (AST), International normalized ratio (INR), gamma-glutamyl transferase (GGT), anti-nuclear antibody (ANA), smooth muscle antibody (SMA), autoimmune hepatitis (AIH).
Concomitant autoimmune diseases were present in 25% of patients. Four patients had hypothyroidism, two patients had hyperthyroidism, and two patients had psoriatic arthritis. Other reported autoimmune disorders included one patient with thrombocytopenia not related to portal hypertension and one patient with systemic lupus erythematosus.
Table 2 stratifies patients by ethnicity. Due to the limited patient population, only Caucasians and Asians were analyzed. Compared to Caucasians, Asians were more likely to be diagnosed at a later age, and present with lower levels of ALT, AST, and GGT, and significantly higher levels of albumin. Additionally, Asians had significantly higher proportion of ANA seropositivity compared to Caucasians (93% and 40%). Lastly, treatment response in Asians was associated with higher rates of remission compared to Caucasians.
Table 2.
Clinical, Serologic, and Histologic Characteristics by Ethnicity
| Caucasian | Asian | P-value | |
| n | 6 | 23 | |
| Age at diagnosis, years, Mean (SD) | 36.2 (14.3) | 54.9 (15.2) | .013 |
| Female gender, no. (%) | 5/6 (83%) | 18/23 (78%) | .79 |
| Concomitant autoimmune disease, no. (%) | 2/6 (33%) | 5/23 (22%) | .55 |
| ALT, IU/L, Mean (SD) | 1137.5 (525.0) | 409.7 | .033 |
| AST, IU/L, Mean (SD) | 1285.3 (883.8) | 337.4 | .008 |
| Total bilirubin, mg/dL, Mean (SD) | 6.6 (7.6) | 6.2 (13.1) | .95 |
| INR, Mean (SD) | 1.4 (0.1) | 1.1 (0.0) | .067 |
| Albumin, g/dL, Mean (SD) | 3.7 (0.4) | 4.3 (0.3) | .004 |
| GGT, IU/L, Mean (SD) | 230.0 (199.3) | 65.1 (78.0) | .011 |
| ANA positive, no. (%) | 2/5 (40%) | 14/15 (93%) | .004 |
| SMA positive, no. (%) | 2/4 (50%) | 6/11 (54%) | .88 |
| Histology consistent with AIH, no. (%) | 4/4 (100%) | 12/14 (85%) | .42 |
| Cirrhosis present on biopsy, no. (%) | 2/4 (50%) | 6/16 (37%) | .92 |
| Presentation, no. (%) | .185 | ||
| Acute | 2/5 (40%) | 4/17 (23%) | |
| Insidious | 3/5 (60%) | 7/17 (41%) | |
| Asymptomatic | 0/5 (0%) | 6/17 (35%) | |
| Treatment response, no. (%) | .014 | ||
| Complete remission | 3/6 (50%) | 19/23 (82%) | |
| Partial remission | 1/6 (16%) | 4/23 (17%) | |
| No remission | 2/6 (33%) | 0/23 (0%) | |
Abbreviations: standard deviation (SD), alanine aminotransferase (ALT), aspartate aminotransferase (AST), International normalized ratio (INR), gamma-glutamyl transferase (GGT), anti-nuclear antibody (ANA), smooth muscle antibody (SMA), autoimmune hepatitis (AIH).
The three patients whose ethnicities were not identified as Caucasian or Asian were excluded from this analysis. One-way analysis of variance was used to test the differences in the means of continuous variables, and chi-squared tests were used to test differences between categorical variables.
To determine the effect of age at diagnosis on disease course, patients were grouped into two categories—those diagnosed before the age of 40, and those diagnosed after the age of 40 (Table 3). Patients diagnosed before the age of 40 had significantly higher levels of total bilirubin (9.4 mg/dL and 7.0 mg/dL) and GGT (117 IU/L and 95.8 IU/L) compared to those diagnosed after the age of 40. Improved treatment response in patients diagnosed before the age of 40 compared to those diagnosed after the age of 40 was numerically higher but not statistically significant (P = .09).
Table 3.
Clinical, Serologic, and Histologic Features by Age at Diagnosis
| Diagnosis <40 years of age | Diagnosis >40 years of age | P-value | ||
| n | 10 | 19 | ||
| Female gender, no. (%) | 9/9 (90%) | 12/19 (63%) | .124 | |
| Ethnicity, no. (%) | .63 | |||
| Caucasian | 5/10 (50%) | 1/19 (5%) | ||
| Asian | 3/10 (30%) | 17/19 (90%) | ||
| African American | 1/10 (10%) | 0/19 (0%) | ||
| Pacific Islander | 1/10 (10%) | 1/19 (5%) | ||
| Concomitant autoimmune disease, no. (%) | 4/10 (40%) | 3/19 (16% | .148 | |
| ALT, IU/L, Mean (SD) | 527.4 (607.6) | 527.8 (655.7) | .71 | |
| AST, IU/L, Mean (SD) | 606.9 (863.5) | 445.0 (545.5) | .46 | |
| Total bilirubin, mg/dL, Mean (SD) | 9.4 (13.9) | 7.0 (13.6) | .026 | |
| INR, Mean (SD) | 1.3 (0.2) | 1.1 (0.0) | >.99 | |
| Albumin, g/dL, Mean (SD) | 3.9 (0.5) | 4.2 (0.4) | .56 | |
| GGT, IU/L, Mean (SD) | 117.4 (134.6) | 95.8 (138.5) | .004 | |
| ANA positive, no. (%) | 5/9 (55%) | 11/12 (92%) | .019 | |
| SMA positive, no. (%) | 2/7 (29%) | 5/9 (56%) | .28 | |
| Histology consistent with AIH, no. (%) | 5/7 (71%) | 13/14 (93%) | .186 | |
| Cirrhosis present on biopsy, no. (%) | 4/7 (57%) | 5/12 (42%) | .52 | |
| Presentation, no. (%) | .60 | |||
| Acute | 1/8 (13%) | 5/16 (31%) | ||
| Insidious | 5/8 (63%) | 7/16 (44%) | ||
| Asymptomatic | 2/8 (25%) | 4/16 (25%) | ||
| Treatment response, no. (%) | .093 | |||
| Complete remission | 5/8 (63%) | 13/18 (72%) | ||
| Partial remission | 2/8 (25%) | 3/18 (17%) | ||
| No remission | 1/8 (13%) | 2/18 (11%) | ||
Abbreviations: standard deviation (SD), alanine aminotransferase (ALT), aspartate aminotransferase (AST), International normalized ratio (INR), gamma-glutamyl transferase (GGT), anti-nuclear antibody (ANA), smooth muscle antibody (SMA), autoimmune hepatitis (AIH). Three patients had an unknown age of diagnosis and were excluded from this analysis.
One-way analysis of variance was used to test the differences in the means of continuous variables, and chi-squared tests were used to test differences between categorical variables.
No statistically significant gender differences were observed (data not shown)
Discussion
We describe the clinical and serological features as well as clinical course of a multiethnic cohort of 32 patients diagnosed with type I AIH at a tertiary referral center in Hawai‘i. The majority of the patients were Asian, and had a milder form of the disease compared to Caucasians. More specifically, Asians had milder presenting symptoms, more favorable laboratory values, and higher remission rates compared to Caucasians. Asians were diagnosed at a later age and were more likely to have a positive ANA. A comparison of age at diagnosis also revealed significant differences. A diagnosis before the age of 40 was associated with higher bilirubin and GGT values, while older patients were more likely to report ANA positivity. Lastly, no statistically significant differences were found between genders.
AIH has a strong female predominance. The current study found that 75% of the patients were female, concordant with previous reports that 75% of persons with AIH are female.1–3,15 Concomitant autoimmune disorders are commonly associated with AIH, and 25% of the patients in our population reported extra-hepatic autoimmune disorders, with thyroid disorders being the most common. This is consistent with previous studies, reporting extra-hepatic autoimmune disease in 20% of AIH patients.3,16 Furthermore, thyroid disorders were the most commonly concurrent extra-hepatic autoimmune disease.3,13
Most patients presented with an insidious onset, following previous data that demonstrated that the majority of patients initially present with vague, non-specific symptoms.14,15 However, it is important to note that nearly a quarter of our patients presented acutely, while nearly a quarter of patients were asymptomatic. Thus, nearly half our patients presented with vague, nonspecific symptoms, making it important to keep autoimmune hepatitis in the differential diagnosis of any patient with acute hepatitis, acute liver failure or elevated liver function tests, as clinical manifestations may vary widely. However, these results may be biased as we are a tertiary referral center with a liver transplant program.
Differences between ethnicities were investigated due to the diverse, multiethnic population of Hawai‘i. Although AIH is an overall rare disease, rates of disease have been found to differ by ethnicity, with Caucasians having a higher incidence than Asians.17 Incidence rates in Japan have been reported at 0.15 cases per 100,000 people per year, in contrast with Western countries such as England, reporting incidence rates of 3.0 cases per 100,000 people per year.12,13 In this study, the majority of patients diagnosed with AIH were Asian, likely reflecting the large Asian population in Hawai‘i. The majority of Asians identified as Japanese or Okinawan.
Asians were also diagnosed at a later age and had higher rates of remission compared to Caucasians. This follows with previous studies reporting a later diagnosis and improved treatment response in Asians compared to Caucasians.2,8,11,18 Asians had significantly lower serum levels of GGT and INR, as well as lower serum levels of ALT, AST, and albumin. The milder laboratory values correlate with the trend toward the insidious and asymptomatic presentations observed in Asians, although this was not statistically significant. These features may also indicate a less severe form of the disease, which correlates with the greater rates of remission observed in the Asian patients compared with Caucasians. All Asian patients responded to treatment with at least partial remission, while 33% of Caucasians had no remission of their disease, consistent with previous reports from Miyake, et al, showing that Japanese patients had superior treatment response from corticosteroids compared to Caucasians.18 Treatment response is integral in the prevention of severe liver-related complications, and these results suggest that patients with AIH, especially Caucasians, should be monitored closely in their response to treatment. Interestingly, ANA seropositivity was higher in Asians (93%), compared to Caucasians (40%). Low prevalence of ANA in our Caucasian population may be due to the small sample size.19, 20 The etiology for the differences in presentation and treatment response is still unclear, but may be due to underlying genetic factors. Several studies have suggested that differing human leukocyte antigen (HLA) alleles are correlated with gender, ethnicity, and prognosis.19,21–23 Patients with HLA DR3 and HLA DR4 are at increased risk for type 1 AIH.19 HLA DR4 has also been associated with increased response to treatment compared to DR3, and is the dominant HLA allele in Japanese patients with type 1 AIH.13 As HLA alleles have been shown to be associated with AIH in various forms, it is possible that they may also explain the differences observed between ethnicities in this study. HLA genotyping was not available in our study, and it certainly should be incorporated in future studies. It is also possible that differing intestinal microbiomes may play a role in the pathogenesis of AIH in a manner similar to other autoimmune diseases such as diabetes mellitus type 1 and rheumatoid arthritis.24,25 However, these features have not been investigated in patients with autoimmune hepatitis to our knowledge.
Age of diagnosis varied widely in the present study, with the youngest patient diagnosed at 18 years, and the oldest at 80 years. A bimodal distribution was not observed, but the sixth and fourth decades of life were the most common age at diagnosis. Interestingly, a diagnosis of AIH after the age of 40 was associated with higher bilirubin and GGT levels, and lower rates of ANA seropositivity. Presentation of AIH did not differ by age, which was consistent with previous reports.8,26 While not reaching the level of statistical significance, in this study, patients with an older age at diagnosis appeared to have higher rates of remission (79% achieved complete remission and 13% partial remission compared to 63% and 25%, respectively among their younger counterparts, P = .09). This is in contrast with previous studies that reported persons over the age of 50 with a worse treatment response.15, 27 These results may be explained by the finding that 90% of those diagnosed over the age of 40 were Asian, compared to 30% under the age of 40, with Asians showing a good response to treatment. Patients under the age of 20 have been reported to have a particularly poor treatment response and prognosis.15 Among the thirty-two patients in our study, three were diagnosed before age 20, of which two had evidence of cirrhosis on biopsy at the time of diagnosis.
The effect of gender on the clinical features of AIH remains controversial. In the present study, no significant differences were found between genders, supporting previous evidence that gender is independent of clinical characteristics of AIH.7,19,28–31 However, Czaja, et al, suggested that some differences between genders may be mediated by differing HLA status.19
The limitations of our study include the small sample size, the fact that this data was collected at a tertiary referral center, and lack of longitudinal data due to the recent establishment of this referral center. Further studies with a larger number of patients are necessary to validate the current findings.
Conclusion
The results of our study indicate that clinical and serological features of AIH were significantly different between Asians and Caucasians. Asians were diagnosed at a later age, had better laboratory values, and higher rates of remission compared to Caucasians. Patients diagnosed before the age of 40 had worse serologic values compared to those diagnosed after the age of 40. Finally, gender was not significantly associated with differences in clinical, serological, and prognostic features of AIH.
Conflict of Interest
None of the authors identify a conflict of interest.
References
- 1.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(5):929–938. doi: 10.1016/s0168-8278(99)80297-9. [DOI] [PubMed] [Google Scholar]
- 2.Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51(6):2193–2213. doi: 10.1002/hep.23584. [DOI] [PubMed] [Google Scholar]
- 3.Liberal R, Grant CR, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: A comprehensive review. Journal of Autoimmunity. 2013;41:126–139. doi: 10.1016/j.jaut.2012.11.002. [DOI] [PubMed] [Google Scholar]
- 4.Czaja AJ. Drug therapy in the management of type 1 autoimmune hepatitis. Drugs. 1999;57(1):49–68. doi: 10.2165/00003495-199957010-00005. [DOI] [PubMed] [Google Scholar]
- 5.Czaja AJ. Difficult treatment decisions in autoimmune hepatitis. World Journal of Gastroenterology. 2010;16(8):934. doi: 10.3748/wjg.v16.i8.934. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Floreani A, Niro G, Rosa Rizzotto E, et al. Type I autoimmune hepatitis: clinical course and outcome in an Italian multicentre study. Aliment Pharmacol Ther. 2006;24(7):1051–1057. doi: 10.1111/j.1365-2036.2006.03104.x. [DOI] [PubMed] [Google Scholar]
- 7.Al-Chalabi T, Underhill JA, Portmann BC, McFarlane IG, Heneghan MA. Impact of gender on the long-term outcome and survival of patients with autoimmune hepatitis. J Hepatol. 2008;48(1):140–147. doi: 10.1016/j.jhep.2007.08.013. [DOI] [PubMed] [Google Scholar]
- 8.Miyake Y, Iwasaki Y, Takaki A, et al. Clinical features of Japanese elderly patients with type 1 autoimmune hepatitis. Intern Med. 2007;46(24):1945–1949. doi: 10.2169/internalmedicine.46.0420. [DOI] [PubMed] [Google Scholar]
- 9.Boberg KM, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol. 1998;33(1):99–103. doi: 10.1080/00365529850166284. [DOI] [PubMed] [Google Scholar]
- 10.Werner M, Prytz H, Ohlsson B, et al. Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: a nationwide study. Scand J Gastroenterol. 2008;43(10):1232–1240. doi: 10.1080/00365520802130183. [DOI] [PubMed] [Google Scholar]
- 11.Fallatah HI, Akbar HO. Autoimmune hepatitis as a unique form of an autoimmune liver disease: immunological aspects and clinical overview. Autoimmune Dis. 2012:2012. doi: 10.1155/2012/312817. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Whalley S, Puvanachandra P, Desai A, Kennedy H. Hepatology outpatient service provision in secondary care: a study of liver disease incidence and resource costs. Clin Med. 2007;7(2):119–124. doi: 10.7861/clinmedicine.7-2-119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Toda G, Zeniya M, Watanabe F, et al. 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(6):1207–1212. doi: 10.1016/s0168-8278(97)80453-9. [DOI] [PubMed] [Google Scholar]
- 14.Abe M, Mashiba T, Zeniya M, et al. Present status of autoimmune hepatitis in Japan: a nationwide survey. J Gastroenterol. 2011;46(9):1136–1141. doi: 10.1007/s00535-011-0421-y. [DOI] [PubMed] [Google Scholar]
- 15.Ngu JH, Gearry RB, Frampton CM, Stedman CAM. Predictors of poor outcome in patients with autoimmune hepatitis: a population-based study. Hepatology. 2013;57(6):2399–2406. doi: 10.1002/hep.26290. [DOI] [PubMed] [Google Scholar]
- 16.Liberal R, Vergani D. Effect of ethnicity on the clinical presentation and outcome of autoimmune hepatitis. Expert Rev Gastroenterol Hepatol. 2012;6(3):267–269. doi: 10.1586/egh.12.17. [DOI] [PubMed] [Google Scholar]
- 17.Koay L-B, Lin C-Y, Tsai S-L, et al. Type 1 autoimmune hepatitis in Taiwan: diagnosis using the revised criteria of the International Autoimmune Hepatitis Group. Dig Dis Sci. 2006;51(11):1978–1984. doi: 10.1007/s10620-005-9068-y. [DOI] [PubMed] [Google Scholar]
- 18.Miyake Y, Yamamoto K. Current status of autoimmune hepatitis in Japan. Acta Med Okayama. 2008;62(4):217–226. doi: 10.18926/AMO/30943. [DOI] [PubMed] [Google Scholar]
- 19.Czaja AJ, Donaldson PT. Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis. Am J Gastroenterol. 2002;97(8):2051–2057. doi: 10.1111/j.1572-0241.2002.05921.x. [DOI] [PubMed] [Google Scholar]
- 20.Nakamura K, Yoneda M, Yokohama S, et al. Efficacy of ursodeoxycholic acid in Japanese patients with type 1 autoimmune hepatitis. J Gastroenterol Hepatol. 1998;13(5):490–495. doi: 10.1111/j.1440-1746.1998.tb00674.x. [DOI] [PubMed] [Google Scholar]
- 21.Czaja AJ. Advances in the current treatment of autoimmune hepatitis. Dig Dis Sci. 2012;57(8):1996–2010. doi: 10.1007/s10620-012-2151-2. [DOI] [PubMed] [Google Scholar]
- 22.Czaja AJ. Genetic factors affecting the occurrence, clinical phenotype, and outcome of autoimmune hepatitis. Clin Gastroenterol Hepatol. 2008;6(4):379–388. doi: 10.1016/j.cgh.2007.12.048. [DOI] [PubMed] [Google Scholar]
- 23.Montano-Loza AJ, Carpenter HA, Czaja AJ. Clinical significance of HLA DRB103-DRB104 in type 1 autoimmune hepatitis. Liver Int. 2006;26(10):1201–1208. doi: 10.1111/j.1478-3231.2006.01387.x. [DOI] [PubMed] [Google Scholar]
- 24.Brown CT, Davis-Richardson AG, Giongo A, et al. Gut Microbiome Metagenomics Analysis Suggests a Functional Model for the Development of Autoimmunity for Type 1 Diabetes. PLoS ONE. 2011;6(10):e25792. doi: 10.1371/journal.pone.0025792. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Mathis D. A gut feeling about arthritis. eLife. >2013. p. 2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816613/ [DOI] [PMC free article] [PubMed]
- 26.Verslype C, George C, Buchel E, Nevens F, van Steenbergen W, Fevery J. Diagnosis and treatment of autoimmune hepatitis at age 65 and older. Aliment Pharmacol Ther. 2005;21(6):695–6999. doi: 10.1111/j.1365-2036.2005.02403.x. [DOI] [PubMed] [Google Scholar]
- 27.Yokokawa J, Kanno Y, Saito H, et al. Risk factors associated with relapse of type 1 autoimmune hepatitis in Japan. Hepatol Res. 2011;41(7):641–646. doi: 10.1111/j.1872-034X.2011.00812.x. [DOI] [PubMed] [Google Scholar]
- 28.Muratori P, Granito A, Quarneti C, et al. Autoimmune hepatitis in Italy: the Bologna experience. J Hepatol. 2009;50(6):1210–1218. doi: 10.1016/j.jhep.2009.01.020. [DOI] [PubMed] [Google Scholar]
- 29.Czaja AJ. Autoimmune hepatitis in special patient populations. Best Practice & Research Clinical Gastroenterology. 2011;25(6):689–700. doi: 10.1016/j.bpg.2011.09.011. [DOI] [PubMed] [Google Scholar]
- 30.Vierling JM. Diagnosis and treatment of autoimmune hepatitis. Curr Gastroenterol Rep. 2012;14(1):25–36. doi: 10.1007/s11894-011-0236-2. [DOI] [PubMed] [Google Scholar]
- 31.Miyake Y, Iwasaki Y, Sakaguchi K, Shiratori Y. Clinical features of Japanese male patients with type 1 autoimmune hepatitis. Alimentary Pharmacology & Therapeutics. 2006;24(3):519–523. doi: 10.1111/j.1365-2036.2006.03013.x. [DOI] [PubMed] [Google Scholar]