Protracted, But Not Acute, Hepatitis A Virus Infection Is Strongly Associated With Hla–Drb1*1301, A Marker for Pediatric Autoimmune Hepatitis

Abstract

HLA alleles are known to be associated with susceptibility to develop autoimmune hepatitis (AH), and hepatitis A virus (HAV) infection is postulated as a putative trigger for AH. We investigated whether HLA may influence the outcome of the HAV infection by studying 67 children with self-limited and 39 children with protracted forms of this infection. HLA typing of the uncomplicated forms showed no significant increase of any HLA class I or II alleles. In contrast, DRB1*1301 was present in 46.1% of the children with protracted forms (vs. 9.8% in healthy controls; relative risk [RR]: 7.6; 2 ‫؍‬ 33.3; P ‫؍‬ 2 ؋ 10 ؊9 ). In uncomplicated hepatitis, 45% developed anti-smooth muscle antibody (SMA)/actin antibodies, but only 1 child had detectable antibodies after 3 months of infection onset. In contrast, after 1 year, 69% of the patients suffering protracted forms had titers of anti-SMA/actin antibodies that ranged between 1:40 and 1:160. Within their follow-up, 2 patients developed a Hashimoto's thyroiditis, but the remaining patients showed no signs of developing autoimmune hepatitis. We conclude that the DRB1*1301 haplotype is strongly associated with the protracted forms of HAV infection and suggest that the infection allows a sustained release of liver self-antigens. However, other still-unknown susceptibility genes are required for the full development of pediatric AH. (HEPATOLOGY 2001;33:1512-1517

Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly

“…By defining the susceptibility alleles for type 1 autoimmune hepatitis within different subgroups of the same population and between populations with different ethnic and geographic characteristics, indigenous etiologic agents that naturally select genetically susceptible individuals to develop the disease may be discovered. 21,22,33 Our elderly patients entered remission, relapsed after drug withdrawal, and sustained a long term remission without medication as commonly as the young adults, and these findings are in accord with other experiences that have emphasized the responsiveness of the elderly to conventional treatments. [11][12][13]15 Histological cirrhosis in the absence of clinical decompensation is not associated with an impaired treatment response, 37,38 and our findings re-emphasize these earlier observations.…”

“…HLA distinctions between the young and old in this geographic region may not only affect clinical features and outcome but generate hypotheses about etiologic mechanisms. 21,22 In this retrospective analysis of prospectively acquired data, we determined the frequency of definite type 1 autoimmune hepatitis in white North American adults within different age ranges, and we assessed age-related distinctions in clinical features, treatment outcome, and HLA phenotype for DR3 and DR4. In this fashion, we evaluated age as a factor in disease expression and outcome in adult patients and as a surrogate for a genetic propensity that might affect disease behavior or reflect its cause.…”

A comparative review of HLA associations with hepatitis B and C viral infections across global populations

“…Hepatitis A viral infection (HAV) is suspected to trigger AIH in genetically susceptible patients carrying HLA DRB1*0401 [101] . Strong association of DRB1*1301 haplotype with protracted forms of HAV infection that further developed to AIH in pediatric patients is reported [102] . Extensive investigation of HAV infected individuals worldwide will contribute to the limited information regarding its HLA association and its relation to HLA associations of HBV and HCV infections.…”

Autoimmune hepatitis after liver transplantation and other lessons of self-intolerance

“…A triggering factor, such as a virus or toxin, is presumed, 27,28 and a genetic predisposition that ensures the optimal presentation of self-antigens or foreign antigens to immunocytes 29,30 or enhances susceptibility to the etiologic agent has been proposed. 31,32 Genetic polymorphisms can affect the cytokine microenvironment 33,34 and/or immune regulators that influence immunocyte activation, 35 and there may be disturbances in activation-induced cell death that perpetuate the immune response. 36 Mechanisms for loss of selftolerance remain speculative, but defects in the negative selection of autoreactive immunocytes 5,37 and clonal expansion of immunocytes cross-reactive to homologous antigens (molecular mimicry) [38][39][40] are the most promising considerations (Table 1).…”

“…82 In Argentina and Brazil, children have the susceptibility allele DRB1*1301, which distinguishes them from adult counterparts. [83][84][85][86] This allele may influence their reactivity to environmental or infectious agents, such as hepatitis A, 31 which in turn may trigger autoimmune hepatitis. 87,88 Different geographic regions may have indigenous infections or toxins that affect particular populations preferentially because of certain susceptibility alleles.…”