Accepted Article
Autoimmune Hepatitis: East Meets West1 Fan Yang1, Qixia Wang1, Jidong Jia2, Xiong Ma1
Affiliations: 1. State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology &Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Shandong Road, Shanghai 200001, China. 2. Liver Research Center & Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, P R China
Correspondence to: Xiong Ma, M.D. Ph.D., Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Shandong Middle Road, Shanghai, China, 200001, Tel: 86-21-63200874; Fax: 86-21-63266027, Email: [email protected]. Or
JidongJia, M. D. Liver Research Center & Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, P R China. Financial Support: This work was supported by grants from the National Natural Science Foundation of China (Nos. 81170380 and 81325002 to X.M; No. 81100271 to Q.W.).
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jgh.12952
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Abstract
Autoimmune hepatitis (AIH) is an inflammatory liver disease with diverse clinical spectrum, which predominantly affects females. This review provides detailed comparisons of epidemiology, genetic predispositions, clinical features, risk factors of hepatocellular carcinoma (HCC) and mortality in AIH patients between eastern and western countries. AIH prevalence and incidence are lower in Asia-Pacific area than in Europe and America. European and American patients seem to have more severe disease, characterized with HLA-DR3 haplotype, younger age, more AIH-induced “cirrhosis” at diagnosis, higher elevated serum immunoglobulin G (IgG) levels and positive rate of anti-soluble liver antigen/liver pancreatitis (anti-SLA/LP). The overall AIH diagnostic accuracy of revised original criteria and simplified scoring system are similar in European/American populations and Asian. Cirrhosis at presentation and non-response to immunosuppressive therapy within 1 year are the most important predictors for poor prognosis of AIH patients. Keywords: autoimmune hepatitis; autoimmune liver disease; liver disease; autoimmune disease.
Abbreviations AIH, autoimmune hepatitis; HCC, hepatocellular carcinoma; PBC, primary biliary cirrhosis; IAIHG, International Autoimmune Hepatitis Group; HLA, human leukocyte antigen; IgG, immunoglobulin G; LT, liver transplantation; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ANA, antinuclear antibodies; ASMA, anti-smooth muscle antibodies; AMA, anti-mitochondrial antibodies; MMF, mycophenolatemofetil; Anti-SLA/LP, anti-soluble liver antigen/liver pancreatitis.
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Introductions Autoimmune hepatitis (AIH) is characterised by increased serum alanine aminotransferase
(ALT) and aspartate aminotransferase (AST), presence of autoantibody, elevated serum IgG level and interface hepatitis in liver histology. Albeit most of landmark studies of AIH had been conducted by European and North American groups in recent decades, lots of countries in Asia-Pacific area are paying increasingly attentions to this disease, and numerous achievements have been made in the past few years. In this paper, we summarize recent studies of AIH and compare the difference of the epidemiology, genetic predispositions, clinical features, diagnosis, treatments between eastern and western countries. Epidemiology and Genetics The highest prevalence is noted in North America (Alaska),1which is 42.9 per 100,000 people.
The European countries own a relatively high prevalence from 10.7 to 23.9 per 100,000 people,2, 3
with the prevalence of Denmark the highest.3 In Asia-Pacific area, New Zealand demonstrated a
high prevalence of 24.5 per 100,000 people4 while other countries owned comparatively low prevalence.5-7 A recent trial revealed that the incidence in Denmark doubled during the study period, indicating a higher incidence of AIH recently.3 In North America and Europe, the dominant susceptible genes of AIH are HLA-DR3
(DRB1*0301) and HLA-DR4 (DRB1*0401).8In Asia, HLA-DR4 is more common than HLA-DR3. To be highlighted, the diversity of genetic predisposition is not only separated by oceans but also exists in the same continent. For example, the major gene in China and Japan is DRB1*04059, 10 whereas in western India is B27, cw411 and in Pakistan is DR6.12 The dominant gene in German is A2, B8 and C7,13 while none of Turkish has A1-B8-DR3 autoimmune haplotype.14In United States, there are different genetic predispositions between African American and White American, first nations and non-first nations.15 Most recently, a genome-wide study from Netherlands identified HLA-DRB1*0301 (P = 5.3×10-49) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8×10-18) as a secondary susceptibility genotype. AIH is also associated with variants of SH2B3 (P = 7.7×10-8) and CARD10 (P = 3.0×10-6).16
Clinical, laboratory, and histology features Clinical features Autoimmune hepatitis has some non-specific manifestations including fatigue, lethargy,
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anorexia, nausea, amenorrhea, weight loss, jaundice, itching. However, up to 25% AIH patients are asymptomatic.17Meanwhile, around 30% of AIH patients present “acute hepatitis”, which is
characterized by extremely elevated aminotransferase (≥10 times upper limits normal value),
patients of this kind are usually accompanied with jaundice and need to be treated promptly.18 Another noteworthy point is AIH-induced “cirrhosis”. The percentage of cirrhosis at accession
is very high in Middle-Asia countries like Iran (41.3%),19 Israel (22.2%)7 and Saudi Arabic (45.5%),20while relatively low in East-Asia countries such as Japan (6.4-12.8%)10,
21, 22
and
Korea (5.4%-12.8%).23However, the proportion of cirrhosis in China was reported as high as 24.8%.24 In America, the percentage of cirrhosis at accession of African American, Native
American and Brazilians is 85%25, 59%15 and 53%26 respectively. For most countries, the average age of AIH patients at accession is around 50 years old, while
Iranians and Saudis in Asia, African American, Mexican and Brazilians in America demonstrate younger age around 30 years old. The male to female ratio in different countries also ranges in a large scale. Laboratory features The characteristic biochemical features of AIH are elevated AST and ALT levels, and the
important immunologic feature is elevated serum IgG level and autoantibodies positive test. Serum IgG level test is very important not only in aspect of establishing the diagnosis of AIH, but also in monitoring the treatment response and tapering the dosage of steroid in AIH patients. There are ethnic and racial disparities in the percentage of ANA- and ASMA-positive AIH
patients. In Asia-Pacific area, the proportion of ASMA positive AIH patients ranges from 19% to
45% in most countries10, 21, 23, 24 while Israel and Australia own much higher percentage around 55% and 90%.7, 27In Europe, nearly 70% AIH patients are ANA-positive, and the percentage of ASMA-positive AIH patients are from 30% to 60%.28-31In America, the ASMA-positive AIH patients are more common than any other populations, ranging from 45% to 84%.15, 26
25,
Anti-SLA/LP is correlated with more severe histological changes, higher rates of relapse and
greater risk of liver transplantation (LT) or death from liver failure.32 However, the prevalence of
anti-SLA/LP is quite low, especially in Asia.32 Recent study revealed that the persistence of high titers of ASMA (>1:80) and/or anti-actin antibody (>1:40) were associated with disease
activity.33 In addition, anti-ribosomal P protein antibody has been reported to have predictive value in two articles published recently.34
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Histology
The histological hallmark of AIH is “interface hepatitis of moderate or severe activity”, which
presents in 84%-98% of patients.35 Additionally, an abundance of plasma cells and eosinophils are frequently co-existed. Besides, panacinar hepatitis is occasionally observed. And the presence of bridging necrosis or multiacinar collapse indicates severe disease with a higher risk to develop cirrhosis. Other histological features include hepatocyte rosette, central necrosis and emperipolesis. Emperipolesis was observed in 65.3 % AIH patients in our group, which was significantly higher than controls.36To be noted, up to 24% of AIH patients had biliary changes in some degree.37 Diagnosis
The first diagnostic system was proposed by the IAIHG in 1993 and was subsequently revised in 1999.38, 39 In 2008, a simplified scoring system was proposed by the same group.40 This physician-friendly system has been demonstrated very reliable in highly heterogeneous populations among different regions of the world. The overall sensitivity for probable AIH was
ranging from 65% to 95%, and the specificity was 90% to 99%. In the Chinese patients, the simplified scoring system had sensitivity and specificity of 90% and 95% for probable AIH, and 62% and 99% for definite AIH, respectively41. To be noted, the diagnostic value of the simplified criteria is limited in atypical AIH patients and those co-existed with viral hepatitis.39, 41-43
Treatments Standard therapy There are two widely accepted treatment regimens to induce remission.44Begining with
prednisone alone (60 mg daily) or a lower dosage of prednisone (30 mg daily) combined with azathioprine. AASLD guideline recommends the termination of steroid therapy might be considered after at least 2-year treatment, only if the patients achieved normalization of lab test and liver tissue44. However, considering the histological improvement lags behind lab test improvement, and relapse is quite common in those withdraw therapy45. In Asia, where HLA-DR4 is the predominant disease-susceptible gene and clinical manifestations of those patients are milder, a lower initial dose with prednisone 0.5-1mg/kg per day can achieve a satisfactory response. Novel therapy
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Budesonide: In 2010, a European trial compared the combination regimen of budesonide (3mg
thrice daily) and azathioprine with classical dual therapy of prednisolone and azathioprine in 203 treatment-naïve patients with AIH.46 After 6-month therapy, the budesonide group had better biochemical response (60% v.s. 38%) and less steroid-related side effects (28% v.s. 53.4%) than prednisone group. MMF: A study demonstrated that MMF was well tolerated in patients who were intolerant to
conventional therapy but did not induce remission in those refractory to conventional therapy. 47 In 2011, Zachou K. et a l48 conducted a prospective study of 56 patients with AIH receiving MMF as initial therapy. Nearly 88% of patients achieved complete biochemical remission, and 37% of them reached steroid-sparing conditions. Infliximab: A tentative treatment of infliximab was conducted in 11 cases with refractory AIH
in Germany. The results showed remarkable biochemical improvements albeit high frequency (7/11 cases) of infection occurred.49 The limitation of infliximab is mainly due to its risk of infusion-related reactions, serious infection and autoimmune reactions. To be noted, several infliximab-induced AIH were reported recently.50 Promising therapy Maintaining the balance between regulatory T cells and Th17 cells has became the promising
strategy of future immune therapy. The transfusion of Ex-vivo expanded regulatory T cells might be a potential curative approach for autoimmune disease including AIH.51 The other promising candidate may be myeloid-derived suppressor cells (MDSCs), a heterogeneous cell population with remarkable immune suppressor function. Most recently, our group demonstrated that MDSC, especially monocytic MDSCs play a critical role in regulating immune–mediated hepatocyte injury in murine models.52 Our unpublished data provided support for a beneficial role of functional MDSCs in suppressing excessive T-cell responses in human autoimmune liver diseases, and show promise for further study as cellular therapy for autoimmune diseases. Liver transplantation AIH is the underlying cause for 4%-6% of adult liver transplants (LT) in the western countries.
The 10-year post-transplant survival for AIH is around 75%.44 The recurrence after LT has been reported in 20% to 42 % patients53, 54.The post-transplant recurrence affects approximately 25 % and 50% of liver allografts within the first 5 years and after 10 years. It should be mentioned that chronic patients have a higher risk of recurrent than fulminant patients with autoimmune
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hepatitis,55 and the risk is particularly high in those patients transplanted when the disease is active.56 Most recurrent AIH patients respond to reintroduction of corticosteroids and azathioprine, thus, the therapy should be implemented as soon as the diagnosis is made. De novo AIH, which has been reported in 3-10% of patients transplanted for non-autoimmune
disorders, shares the identical characteristics of classical AIH.57 We can differentiate it from acute rejection by its histological features. Recipients of female or older donor grafts, or recipients using tacrolimus or MMF as part of their immunosuppressive regimen have a higher risk of de novo AIH, whereas LT recipients maintained on cyclosporine A have a lower risk.57Most recently, a patient with IgG4-associated de novo AIH after liver transplantation was reported for the first time.58To be noted, De novo AIH does not respond to anti-rejection
regimens. It should be treated by standard regimen in combination with low dose of calcineurin inhibitor.59
Risk factors of Mortality and HCC Mortality and LT predictors In Asia, a Japanese trail revealed the 10-year survival rate of AIH patients was 94.9 % and
liver-related mortality was 3.4%. 10A study of AIH in New Zealand showed the 10-year survival
ranged from 80% to 100% in different groups divided by age.60 It regarded failure to normalize ALT within 6 month therapy, low serum albumin < 36 g/L and age ≤ 20 years or age ≥ 60 years at accession as risk factors of mortality. In Europe, a Swedish study showed the 10-year LT free survival rate of AIH was 84%.
Cirrhosis or elevated INR at accession and non-responders turned out to be the predictors of poor prognosis.60 In 2011, a study revealed that the 10-year survival rate in the UK was 84%, while the 20 year survival rate was only 48%.28 Histological cirrhosis, decompensation at accession, failure to normalize ALT in a year and relapses > 4 times per decade were proved to be the risk factors of poor outcome. Most recently, in a study including 1721 AIH patients in Denmark, the 10-year mortality was 26.4% and the liver-related mortality was 10.2%, and male gender and
cirrhosis at accession were listed as the risk factors of mortality.3 In America, a study of Mayo clinic revealed that the 10-year survival rate of AIH patients with
and without cirrhosis at accession were not significantly different, with 89% and 90% respectively.61A Canadian trial showed the 10-year overall survival was 83.0% and 10-year
liver-related mortality is 14.9%. In this study, the 10-year survival rates of cirrhosis and
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non-cirrhosis patients were significantly different, with 61.9% and 94% respectively.17 HCC risk factors It has been noted that the HCC risk of AIH patients is comparable to HCC frequency among
patients with cirrhosis secondary to other chronic liver disease.62 Several trials have demonstrated that cirrhosis at diagnosis is independently associated with HCC development. In Asia-Pacific area, most studies of HCC in AIH patients were conducted in Japan, and had the similar conclusions62-65.
Summary
We have reviewed AIH in East and West, and highlighted the disparities in genetic predispositions and clinical features. Since there is no epidemiologic data from China and India, AIH prevalence and incidencemay be underestimated. Further study is needed to confirm. We hold the point that the diagnosis criteria and therapies should be more variable according to distinguishing features in different area. Liver histology is very important not only for the accurate diagnosis of AIH especially in simplified scoring system, but also for the evaluation of severe disease activity and risk factors of poor outcomes, i.e. bridging necrosis, multiacinar
collapse, hepatocyte rosette, central necrosis, emperipolesis and cirrhosis at accession.
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Tables:
Table 1 Epidemiology of AIH in Asia-pacific and Europe/America area. Country
Prevalence /100,000
Incidence /100,000
Asia-Pacific New Zealand 20104 24.5 2 Brunei Darussalam 5.61 NM 20095 Singapore 20016 4.0 NM Israel 20137 11 0.67 Australia 201027 8 NM AIH, autoimmune hepatitis; NM, no mentioned.
Prevalenc e /100,000 Europe and America Sweden 20082 10.7 Spain 200466 11.61
0.85 0.83
Norway 198867 Denmark 20143 US (Alaska) 20021
1.9 1.68 NM
Country
16.9 23.9 42.9
Incidence /100,000
Europe and America
Asia-Pacific
Table 2 The clinical features of patients with AIH in Asia-pacific and Europe/America area. Area Country No Age F:M IgG (g/L) ANA SMA Cirrhosis % China24 193 53 9:1 19.3 90% 19% 24.8% Japan21 1056 60 6:1 24 89% 43% 6.4% Korea23 343 53 8:1 23.6 94% 23% 5.4% Iran19 102 29 3:1 25.5 50% NM 41.3% Israel7 100 48 19:1 41 91% 55% 22.2% Saudi Arabia20 33 32 3:1 28.8 NM NM 45.5% 27 Australia 42 53 31:11 NM NM 90% 23.8% UK28 256 56 5:1 NM 80% 36% 36% German29 103 46 5:1 NM 67% 53% 29.1% 30 Italy 125 42 5:1 1.73ULN 61% 67% 24% Spain31 81 48 15:1 NM NM NM 32.4% 15 US Native 150 47 7:1 23.2 88% 49% 37% US25 12:1 29.2 88% 82% 85% 27/24 34/41 African/White 3:1 29 78% 69% 38% 26 Mexico 30 32 9:1 NM 57% 53% NM AIH, autoimmune hepatitis; F, female; M, male; IgG, immunoglobulin G; ANA, antinuclear antibodies; SMA, smooth muscle antibodies; ULN, upper limits of normal; NM, no mentioned.
Table 3 Poor outcome predictors of AIH Country
A s i a P a c i f i c
Area
Japan
No 203
Survival rate (5-year, 10-year, or 20-year) 10-year: 94.9 %
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Poor outcome predictors Relapse >2 times
Europe and America
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201210 New Zealand 201360 Israel 20137
100
Liver-related: 96.6% 10-year: 60 yrs: 80%; 21-40 yrs: 93%; 41-60 yrs: 100%. 10-year: 89.7 %
UK28 2011
256
133
Denmark 20143 Sweden 201068
1721
Canada 200517
135
473
10-year: 82% Liver-related: 91%; 20-year: 48% Liver-related: 70%. 10-year: 73.6% Liver-related: 89.8% 10-year LT-free: 84%; 5-year LT-free: 93%.
Normalize ALT > 6 months; Low serum albumin< 36 g/L; Age ≤20 years or age ≥60 year. Liver fibrosis: bridging fibrosis (F3) and cirrhosis (F4) ; Level of serum albumin. Histological cirrhosis; Decompensation; Abnormal ALT level in a year; Relapses > 4 times per decade. Male gender; Cirrhosis at accession. Cirrhosis at accession; Non-responder; Elevated INR values.
5-year: 89.6%; 10-year:83%; 10-year survival rate: Histological cirrhosis at accession Cirrhosis group: 61.9%; Non-cirrhosis group: 94%. United 128 10-year survival rate: Cirrhosis at accession is not a risk States Cirrhosis group: 89%; factor 199661 Non-cirrhosis group: 90%. AIH, autoimmune hepatitis; ALT, alanine aminotransferase; INR, nternational normalized ratio; LT, liver transplantation; NM, no mentioned.
Asia-Pacific
Table 4 HCC in patients with AIH Area Country No Japan Ohira 127 201264 Japan Migita 7 201222 Japan 6 Hino-Arinaga 201265
Eu ro pe an d A m eri ca
United Kingdom
15
Incidence 0.64% 0.45%
Duration AIH to HCC: 96 months HCC to death: 40 months NM
0.5%
NM
Risk factors of HCC Presence of cirrhosis; Elderly patients Presence of cirrhosis
Presence of cirrhosis; Non-responder; Abnormal ALT at final observation. Presence of cirrhosis; (No gender differences).
0.56%; 1.1%*
Cirrhosis to HCC: 102.5 months
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200863 HCC to death:19 months United States 6 1.9%* Cirrhosis to HCC: 120 NM 201162 months * AIH patients with cirrhosis at accession. HCC, hepatocellular carcinoma; AIH, autoimmune hepatitis; ALT, alanine aminotransferase; LC, liver cirrhosis;NM, no mentioned.
Figure legend: Fig. 1 Histological features of autoimmune hepatitis (HE staining). (A) Interface hepatitis (magnification 200); (B) Plasma cells infiltration (magnification 400); (C) Hepatocyte rosette (magnification 400); (D) Emperipolesis (magnification 400). JGH_12952_F1
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Autoimmune Hepatitis: East Meets West1 Fan Yang1, Qixia Wang1, Jidong Jia2, Xiong Ma1
Affiliations: 1. State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology &Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Shandong Road, Shanghai 200001, China. 2. Liver Research Center & Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, P R China
Correspondence to: Xiong Ma, M.D. Ph.D., Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Shandong Middle Road, Shanghai, China, 200001, Tel: 86-21-63200874; Fax: 86-21-63266027, Email: [email protected]. Or
JidongJia, M. D. Liver Research Center & Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, P R China. Financial Support: This work was supported by grants from the National Natural Science Foundation of China (Nos. 81170380 and 81325002 to X.M; No. 81100271 to Q.W.).
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jgh.12952
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Abstract
Autoimmune hepatitis (AIH) is an inflammatory liver disease with diverse clinical spectrum, which predominantly affects females. This review provides detailed comparisons of epidemiology, genetic predispositions, clinical features, risk factors of hepatocellular carcinoma (HCC) and mortality in AIH patients between eastern and western countries. AIH prevalence and incidence are lower in Asia-Pacific area than in Europe and America. European and American patients seem to have more severe disease, characterized with HLA-DR3 haplotype, younger age, more AIH-induced “cirrhosis” at diagnosis, higher elevated serum immunoglobulin G (IgG) levels and positive rate of anti-soluble liver antigen/liver pancreatitis (anti-SLA/LP). The overall AIH diagnostic accuracy of revised original criteria and simplified scoring system are similar in European/American populations and Asian. Cirrhosis at presentation and non-response to immunosuppressive therapy within 1 year are the most important predictors for poor prognosis of AIH patients. Keywords: autoimmune hepatitis; autoimmune liver disease; liver disease; autoimmune disease.
Abbreviations AIH, autoimmune hepatitis; HCC, hepatocellular carcinoma; PBC, primary biliary cirrhosis; IAIHG, International Autoimmune Hepatitis Group; HLA, human leukocyte antigen; IgG, immunoglobulin G; LT, liver transplantation; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ANA, antinuclear antibodies; ASMA, anti-smooth muscle antibodies; AMA, anti-mitochondrial antibodies; MMF, mycophenolatemofetil; Anti-SLA/LP, anti-soluble liver antigen/liver pancreatitis.
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Introductions Autoimmune hepatitis (AIH) is characterised by increased serum alanine aminotransferase
(ALT) and aspartate aminotransferase (AST), presence of autoantibody, elevated serum IgG level and interface hepatitis in liver histology. Albeit most of landmark studies of AIH had been conducted by European and North American groups in recent decades, lots of countries in Asia-Pacific area are paying increasingly attentions to this disease, and numerous achievements have been made in the past few years. In this paper, we summarize recent studies of AIH and compare the difference of the epidemiology, genetic predispositions, clinical features, diagnosis, treatments between eastern and western countries. Epidemiology and Genetics The highest prevalence is noted in North America (Alaska),1which is 42.9 per 100,000 people.
The European countries own a relatively high prevalence from 10.7 to 23.9 per 100,000 people,2, 3
with the prevalence of Denmark the highest.3 In Asia-Pacific area, New Zealand demonstrated a
high prevalence of 24.5 per 100,000 people4 while other countries owned comparatively low prevalence.5-7 A recent trial revealed that the incidence in Denmark doubled during the study period, indicating a higher incidence of AIH recently.3 In North America and Europe, the dominant susceptible genes of AIH are HLA-DR3
(DRB1*0301) and HLA-DR4 (DRB1*0401).8In Asia, HLA-DR4 is more common than HLA-DR3. To be highlighted, the diversity of genetic predisposition is not only separated by oceans but also exists in the same continent. For example, the major gene in China and Japan is DRB1*04059, 10 whereas in western India is B27, cw411 and in Pakistan is DR6.12 The dominant gene in German is A2, B8 and C7,13 while none of Turkish has A1-B8-DR3 autoimmune haplotype.14In United States, there are different genetic predispositions between African American and White American, first nations and non-first nations.15 Most recently, a genome-wide study from Netherlands identified HLA-DRB1*0301 (P = 5.3×10-49) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8×10-18) as a secondary susceptibility genotype. AIH is also associated with variants of SH2B3 (P = 7.7×10-8) and CARD10 (P = 3.0×10-6).16
Clinical, laboratory, and histology features Clinical features Autoimmune hepatitis has some non-specific manifestations including fatigue, lethargy,
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anorexia, nausea, amenorrhea, weight loss, jaundice, itching. However, up to 25% AIH patients are asymptomatic.17Meanwhile, around 30% of AIH patients present “acute hepatitis”, which is
characterized by extremely elevated aminotransferase (≥10 times upper limits normal value),
patients of this kind are usually accompanied with jaundice and need to be treated promptly.18 Another noteworthy point is AIH-induced “cirrhosis”. The percentage of cirrhosis at accession
is very high in Middle-Asia countries like Iran (41.3%),19 Israel (22.2%)7 and Saudi Arabic (45.5%),20while relatively low in East-Asia countries such as Japan (6.4-12.8%)10,
21, 22
and
Korea (5.4%-12.8%).23However, the proportion of cirrhosis in China was reported as high as 24.8%.24 In America, the percentage of cirrhosis at accession of African American, Native
American and Brazilians is 85%25, 59%15 and 53%26 respectively. For most countries, the average age of AIH patients at accession is around 50 years old, while
Iranians and Saudis in Asia, African American, Mexican and Brazilians in America demonstrate younger age around 30 years old. The male to female ratio in different countries also ranges in a large scale. Laboratory features The characteristic biochemical features of AIH are elevated AST and ALT levels, and the
important immunologic feature is elevated serum IgG level and autoantibodies positive test. Serum IgG level test is very important not only in aspect of establishing the diagnosis of AIH, but also in monitoring the treatment response and tapering the dosage of steroid in AIH patients. There are ethnic and racial disparities in the percentage of ANA- and ASMA-positive AIH
patients. In Asia-Pacific area, the proportion of ASMA positive AIH patients ranges from 19% to
45% in most countries10, 21, 23, 24 while Israel and Australia own much higher percentage around 55% and 90%.7, 27In Europe, nearly 70% AIH patients are ANA-positive, and the percentage of ASMA-positive AIH patients are from 30% to 60%.28-31In America, the ASMA-positive AIH patients are more common than any other populations, ranging from 45% to 84%.15, 26
25,
Anti-SLA/LP is correlated with more severe histological changes, higher rates of relapse and
greater risk of liver transplantation (LT) or death from liver failure.32 However, the prevalence of
anti-SLA/LP is quite low, especially in Asia.32 Recent study revealed that the persistence of high titers of ASMA (>1:80) and/or anti-actin antibody (>1:40) were associated with disease
activity.33 In addition, anti-ribosomal P protein antibody has been reported to have predictive value in two articles published recently.34
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Histology
The histological hallmark of AIH is “interface hepatitis of moderate or severe activity”, which
presents in 84%-98% of patients.35 Additionally, an abundance of plasma cells and eosinophils are frequently co-existed. Besides, panacinar hepatitis is occasionally observed. And the presence of bridging necrosis or multiacinar collapse indicates severe disease with a higher risk to develop cirrhosis. Other histological features include hepatocyte rosette, central necrosis and emperipolesis. Emperipolesis was observed in 65.3 % AIH patients in our group, which was significantly higher than controls.36To be noted, up to 24% of AIH patients had biliary changes in some degree.37 Diagnosis
The first diagnostic system was proposed by the IAIHG in 1993 and was subsequently revised in 1999.38, 39 In 2008, a simplified scoring system was proposed by the same group.40 This physician-friendly system has been demonstrated very reliable in highly heterogeneous populations among different regions of the world. The overall sensitivity for probable AIH was
ranging from 65% to 95%, and the specificity was 90% to 99%. In the Chinese patients, the simplified scoring system had sensitivity and specificity of 90% and 95% for probable AIH, and 62% and 99% for definite AIH, respectively41. To be noted, the diagnostic value of the simplified criteria is limited in atypical AIH patients and those co-existed with viral hepatitis.39, 41-43
Treatments Standard therapy There are two widely accepted treatment regimens to induce remission.44Begining with
prednisone alone (60 mg daily) or a lower dosage of prednisone (30 mg daily) combined with azathioprine. AASLD guideline recommends the termination of steroid therapy might be considered after at least 2-year treatment, only if the patients achieved normalization of lab test and liver tissue44. However, considering the histological improvement lags behind lab test improvement, and relapse is quite common in those withdraw therapy45. In Asia, where HLA-DR4 is the predominant disease-susceptible gene and clinical manifestations of those patients are milder, a lower initial dose with prednisone 0.5-1mg/kg per day can achieve a satisfactory response. Novel therapy
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Budesonide: In 2010, a European trial compared the combination regimen of budesonide (3mg
thrice daily) and azathioprine with classical dual therapy of prednisolone and azathioprine in 203 treatment-naïve patients with AIH.46 After 6-month therapy, the budesonide group had better biochemical response (60% v.s. 38%) and less steroid-related side effects (28% v.s. 53.4%) than prednisone group. MMF: A study demonstrated that MMF was well tolerated in patients who were intolerant to
conventional therapy but did not induce remission in those refractory to conventional therapy. 47 In 2011, Zachou K. et a l48 conducted a prospective study of 56 patients with AIH receiving MMF as initial therapy. Nearly 88% of patients achieved complete biochemical remission, and 37% of them reached steroid-sparing conditions. Infliximab: A tentative treatment of infliximab was conducted in 11 cases with refractory AIH
in Germany. The results showed remarkable biochemical improvements albeit high frequency (7/11 cases) of infection occurred.49 The limitation of infliximab is mainly due to its risk of infusion-related reactions, serious infection and autoimmune reactions. To be noted, several infliximab-induced AIH were reported recently.50 Promising therapy Maintaining the balance between regulatory T cells and Th17 cells has became the promising
strategy of future immune therapy. The transfusion of Ex-vivo expanded regulatory T cells might be a potential curative approach for autoimmune disease including AIH.51 The other promising candidate may be myeloid-derived suppressor cells (MDSCs), a heterogeneous cell population with remarkable immune suppressor function. Most recently, our group demonstrated that MDSC, especially monocytic MDSCs play a critical role in regulating immune–mediated hepatocyte injury in murine models.52 Our unpublished data provided support for a beneficial role of functional MDSCs in suppressing excessive T-cell responses in human autoimmune liver diseases, and show promise for further study as cellular therapy for autoimmune diseases. Liver transplantation AIH is the underlying cause for 4%-6% of adult liver transplants (LT) in the western countries.
The 10-year post-transplant survival for AIH is around 75%.44 The recurrence after LT has been reported in 20% to 42 % patients53, 54.The post-transplant recurrence affects approximately 25 % and 50% of liver allografts within the first 5 years and after 10 years. It should be mentioned that chronic patients have a higher risk of recurrent than fulminant patients with autoimmune
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hepatitis,55 and the risk is particularly high in those patients transplanted when the disease is active.56 Most recurrent AIH patients respond to reintroduction of corticosteroids and azathioprine, thus, the therapy should be implemented as soon as the diagnosis is made. De novo AIH, which has been reported in 3-10% of patients transplanted for non-autoimmune
disorders, shares the identical characteristics of classical AIH.57 We can differentiate it from acute rejection by its histological features. Recipients of female or older donor grafts, or recipients using tacrolimus or MMF as part of their immunosuppressive regimen have a higher risk of de novo AIH, whereas LT recipients maintained on cyclosporine A have a lower risk.57Most recently, a patient with IgG4-associated de novo AIH after liver transplantation was reported for the first time.58To be noted, De novo AIH does not respond to anti-rejection
regimens. It should be treated by standard regimen in combination with low dose of calcineurin inhibitor.59
Risk factors of Mortality and HCC Mortality and LT predictors In Asia, a Japanese trail revealed the 10-year survival rate of AIH patients was 94.9 % and
liver-related mortality was 3.4%. 10A study of AIH in New Zealand showed the 10-year survival
ranged from 80% to 100% in different groups divided by age.60 It regarded failure to normalize ALT within 6 month therapy, low serum albumin < 36 g/L and age ≤ 20 years or age ≥ 60 years at accession as risk factors of mortality. In Europe, a Swedish study showed the 10-year LT free survival rate of AIH was 84%.
Cirrhosis or elevated INR at accession and non-responders turned out to be the predictors of poor prognosis.60 In 2011, a study revealed that the 10-year survival rate in the UK was 84%, while the 20 year survival rate was only 48%.28 Histological cirrhosis, decompensation at accession, failure to normalize ALT in a year and relapses > 4 times per decade were proved to be the risk factors of poor outcome. Most recently, in a study including 1721 AIH patients in Denmark, the 10-year mortality was 26.4% and the liver-related mortality was 10.2%, and male gender and
cirrhosis at accession were listed as the risk factors of mortality.3 In America, a study of Mayo clinic revealed that the 10-year survival rate of AIH patients with
and without cirrhosis at accession were not significantly different, with 89% and 90% respectively.61A Canadian trial showed the 10-year overall survival was 83.0% and 10-year
liver-related mortality is 14.9%. In this study, the 10-year survival rates of cirrhosis and
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non-cirrhosis patients were significantly different, with 61.9% and 94% respectively.17 HCC risk factors It has been noted that the HCC risk of AIH patients is comparable to HCC frequency among
patients with cirrhosis secondary to other chronic liver disease.62 Several trials have demonstrated that cirrhosis at diagnosis is independently associated with HCC development. In Asia-Pacific area, most studies of HCC in AIH patients were conducted in Japan, and had the similar conclusions62-65.
Summary
We have reviewed AIH in East and West, and highlighted the disparities in genetic predispositions and clinical features. Since there is no epidemiologic data from China and India, AIH prevalence and incidencemay be underestimated. Further study is needed to confirm. We hold the point that the diagnosis criteria and therapies should be more variable according to distinguishing features in different area. Liver histology is very important not only for the accurate diagnosis of AIH especially in simplified scoring system, but also for the evaluation of severe disease activity and risk factors of poor outcomes, i.e. bridging necrosis, multiacinar
collapse, hepatocyte rosette, central necrosis, emperipolesis and cirrhosis at accession.
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and the International Liver Transplantation Society. 2009; 15 Suppl 2: S25-34. [54] Duclos-Vallee JC, Sebagh M, Rifai K, et al. A 10 year follow up study of patients transplanted for autoimmune hepatitis: histological recurrence precedes clinical and biochemical recurrence. Gut. 2003; 52: 893-7. [55] Ayata G, Gordon FD, Lewis WD, et al. Liver transplantation for autoimmune hepatitis: a long-term pathologic study. Hepatology. 2000; 32: 185-92. [56] Milkiewicz P, Hubscher SG, Skiba G, Hathaway M, Elias E. Recurrence of autoimmune hepatitis after liver transplantation. Transplantation. 1999; 68: 253-6. [57] Montano-Loza AJ, Vargas-Vorackova F, Ma M, et al. Incidence and risk factors associated with de novo autoimmune hepatitis after liver transplantation. Liver international : official journal of the International Association for the Study of the Liver. 2012; 32: 1426-33. [58] Zhao XY, Rakhda MI, Wang TI, Jia JD. Immunoglobulin G4-associated de novo autoimmune hepatitis after liver transplantation for chronic hepatitis B- and C-related cirrhosis and hepatocellular carcinoma: a case report with literature review. Transplantation proceedings. 2013; 45: 824-7. [59] Mieli-Vergani G, Vergani D. De novo autoimmune hepatitis after liver transplantation. Journal of hepatology. 2004; 40: 3-7. [60] Ngu JH, Gearry RB, Frampton CM, Stedman CA. Predictors of poor outcome in patients w ith autoimmune hepatitis: a population-based study. Hepatology. 2013; 57: 2399-406. [61] Roberts SK, Therneau TM, Czaja AJ. Prognosis of histological cirrhosis in type 1 autoimmune hepatitis. Gastroenterology. 1996; 110: 848-57. [62] Wong RJ, Gish R, Frederick T, Bzowej N, Frenette C. Development of hepatocellular carcinoma in autoimmune hepatitis patients: a case series. Digestive diseases and sciences. 2011; 56: 578-85. [63] Yeoman AD, Al-Chalabi T, Karani JB, et al. Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: Implications for follow-up and screening. Hepatology. 2008; 48: 863-70. [64] Ohira H, Abe K, Takahashi A, Zeniya M, Ichida T. Clinical features of hepatocellular carcinoma in patients with autoimmune hepatitis in Japan. Journal of gastroenterology. 2013; 48: 109-14. [65] Hino-Arinaga T, Ide T, Kuromatsu R, et al. Risk factors for hepatocellular carcinoma in Japanese patients with autoimmune hepatitis type 1. Journal of gastroenterology. 2012; 47: 569-76. [66] Primo J, Merino C, Fernandez J, Moles JR, Llorca P, Hinojosa J. [Incidence and prevalence of autoimmune hepatitis in the area of the Hospital de Sagunto (Spain)]. Gastroenterologia y hepatologia. 2004; 27: 239-43. [67] 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. Scandinavian journal of gastroenterology. 1998; 33: 99-103. [68] Werner M, Wallerstedt S, Lindgren S, et al. Characteristics and long-term outcome of patients with autoimmune hepatitis related to the initial treatment response. Scandinavian journal of gastroenterology. 2010; 45: 457-67.
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Tables:
Table 1 Epidemiology of AIH in Asia-pacific and Europe/America area. Country
Prevalence /100,000
Incidence /100,000
Asia-Pacific New Zealand 20104 24.5 2 Brunei Darussalam 5.61 NM 20095 Singapore 20016 4.0 NM Israel 20137 11 0.67 Australia 201027 8 NM AIH, autoimmune hepatitis; NM, no mentioned.
Prevalenc e /100,000 Europe and America Sweden 20082 10.7 Spain 200466 11.61
0.85 0.83
Norway 198867 Denmark 20143 US (Alaska) 20021
1.9 1.68 NM
Country
16.9 23.9 42.9
Incidence /100,000
Europe and America
Asia-Pacific
Table 2 The clinical features of patients with AIH in Asia-pacific and Europe/America area. Area Country No Age F:M IgG (g/L) ANA SMA Cirrhosis % China24 193 53 9:1 19.3 90% 19% 24.8% Japan21 1056 60 6:1 24 89% 43% 6.4% Korea23 343 53 8:1 23.6 94% 23% 5.4% Iran19 102 29 3:1 25.5 50% NM 41.3% Israel7 100 48 19:1 41 91% 55% 22.2% Saudi Arabia20 33 32 3:1 28.8 NM NM 45.5% 27 Australia 42 53 31:11 NM NM 90% 23.8% UK28 256 56 5:1 NM 80% 36% 36% German29 103 46 5:1 NM 67% 53% 29.1% 30 Italy 125 42 5:1 1.73ULN 61% 67% 24% Spain31 81 48 15:1 NM NM NM 32.4% 15 US Native 150 47 7:1 23.2 88% 49% 37% US25 12:1 29.2 88% 82% 85% 27/24 34/41 African/White 3:1 29 78% 69% 38% 26 Mexico 30 32 9:1 NM 57% 53% NM AIH, autoimmune hepatitis; F, female; M, male; IgG, immunoglobulin G; ANA, antinuclear antibodies; SMA, smooth muscle antibodies; ULN, upper limits of normal; NM, no mentioned.
Table 3 Poor outcome predictors of AIH Country
A s i a P a c i f i c
Area
Japan
No 203
Survival rate (5-year, 10-year, or 20-year) 10-year: 94.9 %
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Poor outcome predictors Relapse >2 times
Europe and America
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201210 New Zealand 201360 Israel 20137
100
Liver-related: 96.6% 10-year: 60 yrs: 80%; 21-40 yrs: 93%; 41-60 yrs: 100%. 10-year: 89.7 %
UK28 2011
256
133
Denmark 20143 Sweden 201068
1721
Canada 200517
135
473
10-year: 82% Liver-related: 91%; 20-year: 48% Liver-related: 70%. 10-year: 73.6% Liver-related: 89.8% 10-year LT-free: 84%; 5-year LT-free: 93%.
Normalize ALT > 6 months; Low serum albumin< 36 g/L; Age ≤20 years or age ≥60 year. Liver fibrosis: bridging fibrosis (F3) and cirrhosis (F4) ; Level of serum albumin. Histological cirrhosis; Decompensation; Abnormal ALT level in a year; Relapses > 4 times per decade. Male gender; Cirrhosis at accession. Cirrhosis at accession; Non-responder; Elevated INR values.
5-year: 89.6%; 10-year:83%; 10-year survival rate: Histological cirrhosis at accession Cirrhosis group: 61.9%; Non-cirrhosis group: 94%. United 128 10-year survival rate: Cirrhosis at accession is not a risk States Cirrhosis group: 89%; factor 199661 Non-cirrhosis group: 90%. AIH, autoimmune hepatitis; ALT, alanine aminotransferase; INR, nternational normalized ratio; LT, liver transplantation; NM, no mentioned.
Asia-Pacific
Table 4 HCC in patients with AIH Area Country No Japan Ohira 127 201264 Japan Migita 7 201222 Japan 6 Hino-Arinaga 201265
Eu ro pe an d A m eri ca
United Kingdom
15
Incidence 0.64% 0.45%
Duration AIH to HCC: 96 months HCC to death: 40 months NM
0.5%
NM
Risk factors of HCC Presence of cirrhosis; Elderly patients Presence of cirrhosis
Presence of cirrhosis; Non-responder; Abnormal ALT at final observation. Presence of cirrhosis; (No gender differences).
0.56%; 1.1%*
Cirrhosis to HCC: 102.5 months
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200863 HCC to death:19 months United States 6 1.9%* Cirrhosis to HCC: 120 NM 201162 months * AIH patients with cirrhosis at accession. HCC, hepatocellular carcinoma; AIH, autoimmune hepatitis; ALT, alanine aminotransferase; LC, liver cirrhosis;NM, no mentioned.
Figure legend: Fig. 1 Histological features of autoimmune hepatitis (HE staining). (A) Interface hepatitis (magnification 200); (B) Plasma cells infiltration (magnification 400); (C) Hepatocyte rosette (magnification 400); (D) Emperipolesis (magnification 400). JGH_12952_F1
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