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

Ynto S. de Boer, Andrzej S. Kosinski, Thomas J. Urban, Zhen Zhao, Nanye Long, Naga Chalasani, David E. Kleiner, Jay H. Hoofnagle

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)103-112.e2
JournalClinical Gastroenterology and Hepatology
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2017

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Chemical and Drug Induced Liver Injury
Autoimmune Hepatitis
Nitrofurantoin
Methyldopa
Hydralazine
Minocycline
Nuclear Antigens
Antibodies
Immunoglobulin G
Autoimmunity
Wounds and Injuries
Prospective Studies
Phenotype
Population Control
Serum
Gene Frequency
Smooth Muscle
Liver Diseases
Alleles
Liver

Keywords

  • Database Analysis
  • Hepatotoxicity
  • Immune Response
  • Immunoglobulin
  • Toxicity

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

de Boer, Y. S., Kosinski, A. S., Urban, T. J., Zhao, Z., Long, N., Chalasani, N., ... Hoofnagle, J. H. (2017). Features of Autoimmune Hepatitis in Patients With Drug-induced Liver Injury. Clinical Gastroenterology and Hepatology, 15(1), 103-112.e2. https://doi.org/10.1016/j.cgh.2016.05.043

Features of Autoimmune Hepatitis in Patients With Drug-induced Liver Injury. / de Boer, Ynto S.; Kosinski, Andrzej S.; Urban, Thomas J.; Zhao, Zhen; Long, Nanye; Chalasani, Naga; Kleiner, David E.; Hoofnagle, Jay H.

In: Clinical Gastroenterology and Hepatology, Vol. 15, No. 1, 01.01.2017, p. 103-112.e2.

Research output: Contribution to journalArticle

de Boer, YS, Kosinski, AS, Urban, TJ, Zhao, Z, Long, N, Chalasani, N, Kleiner, DE & Hoofnagle, JH 2017, 'Features of Autoimmune Hepatitis in Patients With Drug-induced Liver Injury', Clinical Gastroenterology and Hepatology, vol. 15, no. 1, pp. 103-112.e2. https://doi.org/10.1016/j.cgh.2016.05.043
de Boer, Ynto S. ; Kosinski, Andrzej S. ; Urban, Thomas J. ; Zhao, Zhen ; Long, Nanye ; Chalasani, Naga ; Kleiner, David E. ; Hoofnagle, Jay H. / Features of Autoimmune Hepatitis in Patients With Drug-induced Liver Injury. In: Clinical Gastroenterology and Hepatology. 2017 ; Vol. 15, No. 1. pp. 103-112.e2.
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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.",
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AU - de Boer, Ynto S.

AU - Kosinski, Andrzej S.

AU - Urban, Thomas J.

AU - Zhao, Zhen

AU - Long, Nanye

AU - Chalasani, Naga

AU - Kleiner, David E.

AU - Hoofnagle, Jay H.

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N2 - 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.

AB - 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.

KW - Database Analysis

KW - Hepatotoxicity

KW - Immune Response

KW - Immunoglobulin

KW - Toxicity

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