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



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).



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).



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.
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: y.deboer@vumc.nl.
Ynto S
YS
de Boer
Duke Clinical Research Institute, Durham, North Carolina.
Andrzej S
AS
Kosinski
Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina, Chapel Hill, North Carolina.
Thomas J
TJ
Urban
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland.
Zhen
Z
Zhao
Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina, Chapel Hill, North Carolina.
Nanye
N
Long
Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana.
Naga
N
Chalasani
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
David E
DE
Kleiner
Liver Disease Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Electronic address: hoofnaglej@extra.niddk.nih.gov.
Jay H
JH
Hoofnagle
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000890:Anti-Infective Agents / Q000009:adverse effects; D000959:Antihypertensive Agents / Q000009:adverse effects; D001323:Autoantibodies / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications*; D005260:Female; D006680:HLA Antigens / Q000235:genetics; D019693:Hepatitis, Autoimmune / Q000473:pathology*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012720:Severity of Illness Index; D055815:Young Adult
D000890:Anti-Infective Agents; D000959:Antihypertensive Agents; D001323:Autoantibodies; D006680:HLA Antigens
Database Analysis; Hepatotoxicity; Immune Response; Immunoglobulin; Toxicity