Autoantibody presentation in Drug-Induced Liver Injury (DILI) and idiopathic Autoimmune Hepatitis (AIH): The influence of HLA alleles

Stephens, Camilla; Ortega‐Alonso, Aida; Medina‐Cáliz, Inmaculada; Robles‐Díaz, Mercedes; Castiella, Agustín; Otazua, Pedro; Zapata, Elizabeth; Gomez-Moreno, Eva; López-Nevot, Miguel-Ángel; Ruiz‐Cabello, Francisco; Soriano, Germán; Román, Eva; Hallal, Hacibe; Andrade, Raúl J.; Lucena, M. Isabel

doi:10.1016/j.clinthera.2015.05.342

Cited by 3 publications

(6 citation statements)

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“…Interestingly, in line with previous reports, [ 8,14 ] we noticed that AMA could also be detected in DILI patients. However, it remains unclear whether DILI can induce PBC, although it is well known that DILI can induce AIH.…”

Section: Discussionsupporting

confidence: 93%

The future risk of primary biliary cholangitis (PBC) is low among patients with incidental anti‐mitochondrial antibodies but without baseline PBC

Duan

Chen

et al. 2022

Hepatol Commun

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Anti‐mitochondrial autoantibodies (AMAs) are highly specific for the diagnosis of primary biliary cholangitis (PBC) but are also occasionally found in other diseases. In the present study, we evaluated the incidence of and predictors for PBC development in AMA‐positive patients with other liver or non‐liver diseases at baseline. In this retrospective study, we screened patients who tested positive for AMA and/or anti‐mitochondrial M2 antibody (AMA‐M2) at Beijing Friendship Hospital, Capital Medical University, from October 2005 to January 2017. They were categorized by their diagnosis at the baseline as patients with PBC or non‐PBC cases. We followed up on the non‐PBC cases through telephone interviews and reviewing of medical records to obtain laboratory results and clinical outcomes. In total, 139 patients were AMA‐positive but did not fulfill the diagnostic criteria of PBC at baseline, including 51 patients with non‐PBC liver diseases and 88 cases with non‐liver diseases. The titers of AMA‐M2, alkaline phosphatase, gamma‐glutamyl transpeptidase, and immunoglobulin M were significantly higher in patients with PBC compared to those with non‐PBC liver diseases and non‐liver diseases. After a median follow‐up of 4.6 (interquartile range: 2.4–7.6) years, 4.3% (6 of 139) developed PBC, with an accumulative 5‐year incidence rate of 4.2%. None of the patients with non‐PBC liver diseases developed PBC, whereas the 5‐year incidence rate of PBC was 7.8% among 88 patients with non‐liver diseases. Lower alanine aminotransferase and higher immunoglobulin M were independent predictors for developing PBC. Conclusion: Our results suggest a low risk of developing PBC over time in AMA‐positive patients with other liver and non‐liver diseases.

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Section: Discussionsupporting

confidence: 93%

The future risk of primary biliary cholangitis (PBC) is low among patients with incidental anti‐mitochondrial antibodies but without baseline PBC

Duan

Chen

et al. 2022

Hepatol Commun

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“…As patients who present with different acute and chronic liver diseases can have associated autoantibodies in serum, including patients with DILI, [12][13][14][15][16][17][18] it is obviously not sufficient for the diagnosis of DI-AILH to have a drug etiology and positive autoantibodies.…”

Section: Discussionmentioning

confidence: 99%

“…A total of 39 case reports with interferon-induced liver injury were retrieved; two were excluded due to the lack of data (Supporting Information [SI] 1 and 2), but 17 publications contained 37 case reports (SI [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Females made up 32 of 37 (86%); median age of 38 years (range 11-68) (Table 1).…”

Section: Interferonsmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8][9] There is at the current time no agreement on the definitions. [10,11] Autoantibodies can be found in many liver disorders other than autoimmune hepatitis (AIH), such as acute liver failure, [12] acute idiosyncratic DILI, [13,14] liver injury due to HDS, [15] and in chronic liver diseases. [16][17][18] Thus, autoantibodies are often secondary to liver injury, and it can be difficult to ascertain whether autoimmune mechanisms are involved in the pathogenesis of the liver injury.…”

Section: Introductionmentioning

confidence: 99%

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Setting up criteria for drug‐induced autoimmune‐like hepatitis through a systematic analysis of published reports

et al. 2022

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Nitrofurantoin, minocycline, methyldopa and infliximab, have been found to induce autoimmune‐like hepatitis (DI‐AILH). Evidence for other drugs and herbal and dietary supplements (HDS) is unclear. The aims of the study were to establish criteria to define and review the published evidence of suspected DI‐AILH. Search was undertaken in Pubmed using search terms “drug‐induced liver injury,” “autoimmune hepatitis,” and “drug‐induced autoimmune hepatitis.” DI‐AILH was defined as (1) drug as a potential trigger of liver injury with autoimmune features and histological findings compatible with AIH; (2) no or incomplete recovery or worsening of liver tests after discontinuation of the drug; (3) corticosteroids requirement or spontaneous recovery; (4) follow‐up without immunosuppression (IS) and no relapse of AIH at least 6 months after discontinuation of IS; and (5) drugs potentially inducing AILH with a chronic course. Cases fulfilling the first four criteria were considered probable DI‐AILH with three possible DI‐AILH. A total of 186 case reports were identified for conventional drugs (n = 148; females 79%; latency 2.6 months) and HDS (n = 38; females 50%). The most commonly reported agents of DI‐AILH were interferons (n = 37), statins (n = 24), methylprednisolone (MPS) (n = 16), adalimumab (n = 10), imatinib (n = 8), and diclofenac (n = 7). Tinospora cordifolia and Khat were the only HDS with probable DI‐AILH cases. No relapses of AIH were observed when IS was stopped after interferons, imatinib, diclofenac, and methylprednisolone. Conclusion: Beyond well‐recognized nitrofurantoin, methyldopa, hydralazine, minocycline, and infliximab as causes of DI‐AILH, interferons, imatinib, adalimumab, and MPS were the best‐documented agents leading to probable DI‐AILH. Khat and Tinospora cordifolia were the only HDS found to be able to induce DI‐AILH. Long‐term immunosuppression appears to be rarely required in patients with DI‐AILH due to these drugs.

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“…(29,30) Formation of autoantibodies may be dependent on the human leukocyte antigen (HLA; also major histocompatibility complex) locus and associated risk alleles, as observed in patients within a Spanish DILI registry. (31) HLA genotype has been shown to influence progression of autoimmune disease among those with the presence of specific autoantibodies, possibly by an antigen-specific T-cell response (such as in RA and anti-citrullinated protein antibodies (32) ). However, top HLA risk alleles (HLA-class II, DR beta 1 [DRB1]*03:01 and DRB1*04:01) in de novo AIH have not been shown to be enriched in drug-induced AIH (5) and may represent differences in autoantibody formation between the two clinical entities.…”

Section: Discussionmentioning

confidence: 99%

Exploratory Study of Autoantibody Profiling in Drug‐Induced Liver Injury with an Autoimmune Phenotype

et al. 2020

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Drug‐induced liver injury (DILI) sometimes presents with an autoimmune hepatitis‐like phenotype (AI‐DILI), and it is challenging to distinguish it from de novo autoimmune hepatitis (AIH). We conducted a study to identify autoantibodies unique to AI‐DILI by profiling serum autoantibodies. Autoantibodies were quantified using an autoantigen array containing 94 autoantigens from four groups: AI‐DILI (n = 65), DILI controls (n = 67), de novo AIH (n = 17), and healthy controls (HCs; n = 30). In 37 patients with AI‐DILI, samples were also collected 6 months after presentation. AI‐DILI and de novo AIH had similar anti‐neutrophil antibody and anti‐smooth muscle antibody prevalence. Compared to HCs, de novo AIH had an increase in many immunoglobulin G (IgG; 35 [46.1%]) and IgM (51 [70%]) autoantibodies, whereas AI‐DILI had an increase of IgM (40 [54.8%]) but not IgG autoantibodies. DILI controls had a similar IgG and IgM profile compared to HCs. Comparing de novo AIH to AI‐DILI identified 18 (23.7%) elevated IgG but only one (1.4%) IgM autoantibodies, indicating the unique IgG autoantibody profile in de novo AIH. Compared to DILI and HCs, increased IgM autoantibodies in AI‐DILI and de novo AIH were common; however, AI‐DILI induced by different drugs showed different frequencies of IgM autoantibodies, with nitrofurantoin‐related AI‐DILI showing a higher number of increased IgM autoantibodies. AI‐DILI autoantibody levels at diagnosis and at 6 months showed a significant decline in 37 IgM autoantibodies. A model with highly correlated IgG and IgM was fitted into multivariate logistic regression and revealed an area under the curve of 0.87 (95% confidence interval, 0.79‐0.95) to distinguish de novo AIH from AI‐DILI. Conclusion: The unique IgG and IgM autoantibody signature appears to be a promising biomarker for distinguishing AI‐DILI from de novo AIH.

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Autoantibody presentation in Drug-Induced Liver Injury (DILI) and idiopathic Autoimmune Hepatitis (AIH): The influence of HLA alleles

Cited by 3 publications

References 0 publications

The future risk of primary biliary cholangitis (PBC) is low among patients with incidental anti‐mitochondrial antibodies but without baseline PBC

The future risk of primary biliary cholangitis (PBC) is low among patients with incidental anti‐mitochondrial antibodies but without baseline PBC

Setting up criteria for drug‐induced autoimmune‐like hepatitis through a systematic analysis of published reports

Exploratory Study of Autoantibody Profiling in Drug‐Induced Liver Injury with an Autoimmune Phenotype

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