Autoimmune Hepatitis in Special Populations: In Pediatrics and Across Different Ethnicities/Races

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Abbreviations

AA

African American

AIH

autoimmune hepatitis

EC

European Caucasoid

HLA

human leukocyte antigen

INR

international normalized ratio

p‐ANCA

peri‐nuclear staining anti‐neutrophil cytoplasmic antibody

PAS

Periodic Acid Schiff

Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver characterized by: (1) elevated serum aminotransferases and immunoglobulin G, (2) the presence of non‐organ‐specific autoantibodies, (3) lymphoplasmacytic interface hepatitis, and (4) response to immunosuppression.1 It is a diagnosis of exclusion and can be seen in all ethnic groups. In this review, a short case report of an African American (AA) child with AIH has been used to discuss the clinical spectrum of AIH in children and across different ethnic groups/races.

AIH in Children and Adolescents

A six‐year‐old AA girl was referred with hepatomegaly and elevated serum aminotransferase concentration. No family history of autoimmune disease or lupus was elicited. At presentation, alanine aminotransferase concentration was 960 U/L, aspartate aminotransferase 1031 U/L, gamma‐glutamyltransferase 165 U/L, bilirubin 0.7/0.3 mg/dL, international normalized ratio (INR) 1.5, immunoglobulin G 2941 mg/dL, smooth muscle antibody 1:640, and antinuclear antibody 1:320. Thyroid and celiac screen was negative. First‐line screen was also negative for hepatitis A, B, and C, Wilson’s disease, and alpha‐1‐antitrypsin deficiency. Liver histology showed advanced interface hepatitis and bridging fibrosis, and a modified histological activity index of 14/18. No biliary changes were noted (Fig. 1). She was started on prednisone 2 mg/kg/day. Mycophenolate mofetil was added instead of azathioprine because she had advanced fibrosis. Five months into treatment, she has become Cushingoid, has not achieved remission, and remains on 30 mg daily of prednisone. She has been hospitalized twice for intercurrent viral infections, respiratory syncytial virus and influenza, respectively, with worsening of liver function and increase of INR to 2.4. After recovery from the infectious episode and reduction of INR to 1.5, she was switched to tacrolimus from mycophenolate mofetil, and prednisone tapering is being attempted again. She may become a candidate for liver transplantation, if she remains unresponsive to this regimen with persistent deterioration of liver function.

Figure 1.

Liver needle core biopsy with features consistent with AIH. (A) A portal tract at the bottom of this image has interface hepatitis (arrows) that extends into bridging fibrosis (asterisk), which is better seen in a trichrome stain (B). The presence of pseudorosetting (asterisks), a reactive change, is highlighted in a PAS with diastase stain (C). The presence of plasma cells (arrows) mixed with a lymphocytic infiltrate is helpful in the diagnosis of AIH (D). Degenerative hepatocytes (acidophil bodes, arrows in inset) are part of intralobular degeneration in hepatitis. (Courtesy Philip Katzman, M.D., Division of Pathology, University of Rochester Medical Center, Rochester, NY.)

The incidence of juvenile AIH appears to be on the rise both in Europe and America; this may be secondary to increased awareness of the condition or a true increase in AIH. Children and adolescents often present more acutely than middle‐aged or elderly patients. Type 1 AIH presents in both adults and children, whereas type 2 AIH presents mainly in children. The differences between type 1 and type 2 AIH are depicted in Table 1. Both types are associated with other autoimmune disorders, including thyroiditis, diabetes, vitiligo, and inflammatory bowel disease. Family history of autoimmune disease can be obtained in 40% of patients.

Table 1.

Differences Between Type 1 and Type 2 AIH

	AIH Type 1	AIH Type 2
Autoantibodies	Antinuclear antibody	Liver kidney microsomal antibody
	Smooth muscle antibody	Anti‐liver cytosol antibody
Age at presentation	Usually after 10 years of age	Early childhood
Type of presentation	Usually chronic; may have cirrhosis at presentation	Often acute; may have acute liver failure presentation
Overlap with sclerosing cholangitis	More common	Unusual
	p‐ANCA may be positive
	Inflammatory bowel disease may be present
Remission	Some can maintain remission off of immunosuppression	Majority need immunosuppression to maintain remission

Overlap of AIH with sclerosing cholangitis, known as autoimmune sclerosing cholangitis, is the occurrence of characteristic features of AIH with additional biliary changes of sclerosing cholangitis noted on cholangiography.2, 3 Biochemically, the gamma‐glutamyltransferase is often elevated, peri‐nuclear staining anti‐neutrophil cytoplasmic antibody (p‐ANCA) may be positive, and on histology, there may be biliary changes (e.g., ductular proliferation, damage). Ursodeoxycholic acid is often added to the immunosuppressive treatment regimen. Standard immunosuppression in AIH is usually with steroids and azathioprine. Second‐line agents include mycophenolate mofetil and calcineurin inhibitors such as tacrolimus and cyclosporine. Notably, the child in the earlier case report does not have autoimmune sclerosing cholangitis at this point.

AIH in Different Ethnicities/Races

With globalization and immigration, the patient population who is accessing health care services is multiethnic. The role of ethnicity in guiding management is likely to become more important with the increasing trend toward personalized medicine. Clinical characteristics and outcomes of AIH have sometimes been reported to be different in ethnic minorities compared with whites. In Caucasoid Northern Europeans and North Americans, human leukocyte antigen (HLA) DRB1*0301 and DRB1*0401 are associated with AIH. Compared with 20% and 32% of whites having the DR3 and DR4 phenotypes, respectively, 26% to 30% of AAs have the DR3 phenotype and 3% to 5% have the DR4 phenotype.4 Similarly, the major gene associated with AIH in Asian countries such as China and Japan is DRB1*0405, in India B27, and in Pakistan cw4 and DR6.5 This genetic variation may account for differences in the clinical characteristics of AIH in different ethnic groups.

Some studies that are investigating AIH across ethnic groups are summarized in Table 2, but a comprehensive list is out of the scope of this review. One of the earlier studies was performed in Atlanta, Georgia. In a tertiary center serving a large African American (AA) population, it was reported that 85% of AAs with AIH presented with cirrhosis on initial liver biopsy compared with 38% of whites.4 Although the autoimmune disease activity appeared more advanced in AAs with higher serum bilirubin levels and more prolonged prothrombin time, both groups similarly entered biochemical remission; it was noted, however, that AAs with AIH required higher immunosuppression to control the disease. In a single‐center study from the United Kingdom observing 101 patients with AIH, black patients were more likely to have advanced disease with higher incidence of cirrhosis, liver failure at first presentation, as well as increased need for liver transplantation. Also, the mortality rate in the study cohort was significantly higher in black versus nonblack patients (24.3% versus 6.2%; P = 0.009).6 The authors did not report HLA class II data on their patients.

In Alaska, in terms of race/ethnicity, Eskimos are in the majority at 55%, followed by Aleuts at 24% and Indians at 21%.7 A population‐based study to identify autoimmune diseases, including AIH, in Alaska was performed by Hurlburt et al.7 They examined records between 1984 and 2000, and calculated the point prevalence of AIH in Alaskan natives to be 42.9/100,000, which was comparable with reported rates in other populations.7 In San Francisco, a retrospective study conducted between 2002 and 2017 reported that a major finding was that black, Latino, and Asian/Pacific Islander race/ethnicity were associated with increased odds of having an AIH diagnosis, but that there was no significant difference in baseline alanine aminotransferase (P = 0.45), total bilirubin (P = 0.06), fibrosis (P = 0.74), and hospitalization (P = 0.27)8 in the different ethnic groups. However, another study that calculated the national rate of AIH hospitalization in the United States to be 0.73 per 100,000 population reported that blacks and Latinos were hospitalized for AIH at a rate of 69% (P < 0.001) and 20% higher (P < 0.001), respectively, than whites.9 In this study, black race was independently associated with higher odds of death during hospitalization, after controlling for age, gender, payer, residence, zip code income, region, and cirrhosis.

In conclusion, AIH can be more severe at presentation in the pediatric age group than in adults, and autoimmune overlap with sclerosing cholangitis is increasingly being recognized as a separate entity in children and adolescents. The fact that AIH manifests differently across the different ethnic groups is evident and not surprising given the genetic association of AIH and the variability in HLA across races/ethnicities.

Table 2.

Comparison of Clinical Features and Outcomes of AIH in Different Ethnicities/races in Some Centers in USA, UK and Europe

Authors	Location	Subjects	Clinical Features	Prescription and Outcomes
Lim et al. (2001)4	Atlanta, Georgia, USA	27 AA	AA patients presented at earlier age, with more severe disease, 85% with cirrhosis versus 38% at first biopsy	More prednisone was required in AA patients, but response to therapy was good in both groups
		24 white
Hurlburt et al. (2002)7	Anchorage, Alaska, USA	2000 Alaskan native: Eskimo, Inuit, and Indian	Epidemiology: prevalence of AIH, overlap syndrome similar to other populations; 42 definite, 7 probable AIH	‐
Zolfino et al. (2002)3	London, England, UK	180 EC, 6 African, 5 Asian, 1 Arabic	Non‐EC patients were younger, presented with cholestatic biochemistry, and morphological biliary features were more common	Non‐EC patients showed poorer response to standard therapy
Verma et al. (2007)6	Baltimore, Maryland, USA	101 AIH	Black patients had more aggressive disease (56.7% with cirrhosis versus 37.5%), liver failure at initial presentation (37.8% versus 9.3%), and need for liver transplantation (51.3% versus 23.4%)	Mortality was higher (24.3% versus 6.2%)
		37 AA		Black male patients had the worst outcomes in this cohort
Wong et al. (2012)10	San Francisco, California, USA	183 AIH; 81 definite AIH, 63 overlap syndromes	Hispanic patients had highest prevalence of cirrhosis; with lower serum albumin and platelet levels; Asian patients had higher INR	Asian patients had poorer survival outcomes compared with whites
Van Gerven et al. (2014)11	Netherlands, Europe	1313 AIH	Epidemiology: no significant difference between Caucasian and non‐Caucasian patients in cirrhosis, biochemical markers, or fibrosis	No significant difference in outcomes with respect to hepatocellular carcinoma or liver transplant
Lee et al. (2018)8	San Francisco, California, USA	2049 controls, 63 AIH	Black, Latino, or Asian/Pacific Islander ethnicity associated with increased odds of AIH diagnosis compared with white reference group	No difference reported