Features of Autoimmune Hepatitis in Patients With Drug-induced Liver Injury

Abstract

Background & aims: Drug-induced liver injury (DILI) has features similar to those of other liver diseases including autoimmune hepatitis (AIH). We aimed to characterize the clinical and autoimmune features of liver injury caused by nitrofurantoin, minocycline, methyldopa, or hydralazine.

Methods: We analyzed data from 88 cases of DILI attributed to nitrofurantoin, minocycline, methyldopa, or hydralazine included in the Drug-Induced Liver Injury Network prospective study from 2004 through 2014. Sera were collected from patients at baseline and follow-up examination and tested for levels of immunoglobulin G (IgG), antibodies to nuclear antigen (ANA), smooth muscle (SMA), and soluble liver antigen (SLA). An autoimmune score was derived on the basis of increases in levels of IgG, ANA, SMA, and SLA (assigned values of 0, 1+, or 2+). AIH-associated HLA-DRB1*03:01 and HLA-DRB1*04:01 allele frequencies were compared with those of the general population (controls).

Results: Of the 88 cases, 80 were women (91%), 74% had hepatocellular injury, and 25% had severe injury. At the onset of DILI, 39% of cases had increased levels of IgG, 72% had increased levels of ANA, 60% had increased levels of SMA, and none had increases in SLA. A phenotype of autoimmunity (autoimmune score ≥2) was observed in 82% of cases attributed to nitrofurantoin and 73% of cases attributed to minocycline (73%) but only 55% of cases attributed to methyldopa and 43% of cases attributed to hydralazine (P = .16 for nitrofurantoin and minocycline vs methyldopa and hydralazine). We observed a decrease in numbers of serum samples positive for ANA (P = .01) or SMA (P < .001) and in autoimmune scores (P < .001) between DILI onset and follow-up. Similar percentages of patients with DILI had HLA-DRB1*03:01 (15%) and HLA-DRB1*04:01 (9%) as controls (12% and 9%, respectively).

Conclusions: In analysis of data from the DILIN prospective study, we found that most cases of DILI attributed to nitrofurantoin or minocycline and about half of cases that were due to methyldopa and hydralazine have a phenotype of autoimmunity similar to AIH. These features decrease with recovery of the injury and are not associated with the typical HLA alleles found in patients with idiopathic AIH.

Keywords: Database Analysis; Hepatotoxicity; Immune Response; Immunoglobulin; Toxicity.

Figure 1

Frequencies of ANA, SMA, and IgG positivity and autoimmune phenotype at baseline. Frequencies of ANA, SMA positivity, IgG levels, and autoimmune (AI) score in 65 DILI cases due to nitrofurantoin- (n = 29), minocycline- (n = 19), methyldopa- (n = 10), and hydralazine- (n = 7) induced liver injury with available stored serum samples.

Figure 2

Comparison of autoimmune features with reference cohort. Comparison of ANA, SMA positivity, IgG levels, and autoimmune (AI) score between 65 cases due to nitrofurantoin (n = 29), minocycline (n = 19), methyldopa (n = 10), and hydralazine (n = 7) (Mit/Myn/Met/Hyd) and 67 reference cases due to amoxicillin/clavulanate (n = 33), isoniazid (n = 24), and diclofenac (n = 10) (Aug/INH/Dic).

Figure 3

Comparison of autoimmune features at baseline and 6 months of follow-up. Frequencies of ANA, SMA positivity, IgG levels, and autoimmune (AI) score at baseline and 6 months of follow-up of 39 cases due to nitrofurantoin-, minocycline-, hydralazine-, and methyldopa-induced with available samples.

Figure 4

Latency and pattern of injury. Time of onset to DILI in days (capped at 12 months) in nitrofurantoin (A), minocycline (B), methyldopa (C), and hydralazine (D) cases with available serum samples, stratified according to drug, pattern of injury, and autoimmune and/or immunoallergic phenotype. C, cholestatic; HC, hepatocellular; M, mixed.