Drug-Induced Autoimmune Hepatitis: Clinical

Characteristics and Prognosis

Einar Bjo rnsson,
1,2
Jayant Talwalkar,
2
Sombat Treeprasertsuk,
2
Patrick S. Kamath,
2
Naoki Takahashi,
3
Schuyler Sanderson,
4
Matthias Neuhauser,
2
and Keith Lindor
2
Drug-induced autoimmune hepatitis (DIAIH) has been reported to be caused by several
drugs. There is a lack of data comparing these patients with other patients with autoim-
mune hepatitis (AIH). A search was performed using the Mayo Clinic diagnostic medical
index for AIH patients and DIAIH patients identied over 10 years. Individuals with over-
lap syndromes and decompensated liver disease were excluded. Overall, 261 patients
(204 females, median age 52) were identied, and 24 (9.2%) were DIAIH cases with a
median age of 53 (interquartile range, 24-61). Two drugs, nitrofurantoin (n 5 11) and
minocycline (n 5 11), were the main causes. A similar proportion of DIAIH patients had
positive antinuclear antibodies (83% versus 70%) and smooth muscle antibodies (50%
versus 45%) as compared with AIH patients. Histological grade and stage were similar in
patients with DIAIH versus AIH; however, none of the DIAIH patients had cirrhosis at
baseline; this was present in 20% of matched AIH cases. Liver imaging was normal in all
minocycline cases. Eight of 11 (73%) nitrofurantoin patients had abnormalities on hepatic
imaging (mainly liver atrophy), a nding seen in only 8 of 33 (24%) of a random sample
of the rest of the AIH group (P 5 0.0089). Corticosteroid responsiveness was similar in
DIAIH and the AIH patients. Discontinuation of immunosuppression was tried and suc-
cessful in 14 DIAIH cases, with no relapses (0%), whereas 65% of the AIH patients had a
relapse after discontinuation of immunosuppression (P < 0.0001). Conclusion: A signi-
cant proportion of patients with AIH have drug-induced AIH, mainly because of nitrofur-
antoin and minocycline. These two groups have similar clinical and histological patterns.
However, DIAIH patients do not seem to require long-term immunosuppressive therapy.
(HEPATOLOGY 2010;51:2040-2048)
D
rug-induced immune-mediated liver injury is
an adverse immune response against proteins
within the liver that can lead to a syndrome
of autoimmune hepatitis (AIH).
1,2
Reactive metabo-
lites created through hepatic metabolism of some drugs
have been shown to bind to cellular proteins such as
cytochrome P450. These can then be recognized by
the immune system as neoantigens.
3,4
The underlying
mechanisms have been elucidated for some drugs able
to induce AIH but not currently in use, such as dihy-
dralazine
5,6
and tienilic acid.
7
Among drugs still widely
used, drug-induced AIH (DIAIH) has been well docu-
mented for nitrofurantoin,
8,9
which is widely pre-
scribed for urinary tract infections, and minocycline, a
treatment of acne.
10,11
However, available data on
drug-induced AIH consist mainly of case reports and a
few very small case series.
11-13
Autoimmune hepatitis
induced by nitrofurantoin was reported in a series of
ve patients from the 1970s in the United States
12
and six patients from the Netherlands from the
1980s.
9
These small case series had very limited fol-
low-up, and the long-term prognosis of patients with
nitrofurantoin-induced AIH remains uncertain. Mino-
cycline-induced hepatitis is associated with the appear-
ance of antinuclear antibodies, and smooth-muscle
antibodies, elevated gamma globulin levels, and histo-
logical features identical to those observed in
AIH.
11,14-16
Information about need for long-term
Abbreviations: AIH, autoimmune hepatitis; DIAIH, drug-induced
autoimmune hepatitis; IgG, immunoglobulin G.
From the
1
Department of Internal Medicine, Section of Gastroenterology and
Hepatology, Landspitali University Hospital, Reykjavik, Iceland;
2
Division of
Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN;
3
Department of Radiology; and
4
Department of Laboratory Medicine and
Pathology, Mayo Clinic Rochester, Rochester, MN.
Received October 2, 2009; accepted January 11, 2010.
Address reprint requests to: Einar Bjornsson, Landspitali University Hospital,
Hringbraut, 101 Reykjavik, Iceland. E-mail: [email protected]; fax:
354-543-4834.
Copyright VC
2010 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.23588
Potential conict of interest: Nothing to report.
2040
immunosuppression in these patients is unclear, and
none of these reports have described long-term con-
sequences for liver damage. We aimed to assess the
proportion of drug-induced AIH among consecutive
well-characterized patients with AIH. Furthermore,
we sought to compare the clinical, biochemical, and
histological characteristics of these two groups of
AIH patients. Lastly, we wanted to investigate the
prognosis in terms of liver-related mortality and
compare the results of drug withdrawal in these
patients.
Patients and Methods
We performed a search in the diagnostic medical
index at the Mayo Clinic for the diagnosis AIH in the
period 1997 to 2007. The search is based on the pres-
ence of AIH in the text, and the search will retrieve all
patients that have AIH mentioned in the medical
charts, such as the primary diagnosis, differential diag-
nosis, family history of AIH, and liver transplantation
for AIH. By this method we identied 1536 patients.
Only patients with available clinical and biochemical
components of the new simplied criteria at baseline
were included.
17
Thus, information on the presence of
autoantibodies, immunoglobulin G (IgG) or gamma-
globulins, viral serologies, and a liver biopsy were
obtained before initiation of immunosuppressive ther-
apy. Patients seen at the Mayo Clinic only for a second
opinion, but who were diagnosed earlier and who had
already started treatment, were excluded. Also, patients
undergoing transplants for AIH and patients with
decompensated liver disease at presentation were
excluded as well as pediatric cases (younger than
16 years of age). The reason for excluding patients
with liver failure or those who required transplantation
was because the diagnosis of AIH is more uncertain in
these conditions. Some features of AIH such as auto-
antibodies can be present in patients with liver failure
and decompensated liver disease, probably secondary
to the chronic liver injury. Furthermore, most patients
with decompensated liver disease had been started on
treatment for AIH elsewhere, and therefore there was
often a lack of important biochemical parameters such
as gammaglobulins or IgG and autoantibodies, making
a diagnostic score almost impossible.
Furthermore, patients with a diagnosis of primary
biliary cirrhosis and primary sclerosing cholangitis
were excluded, as were patients with clinical suspicion
of overlap syndromes (AIH/primary biliary cirrhosis
and AIH/primary sclerosing cholangitis).
A retrospective review was performed on patients
fullling the inclusion criteria. The following variables
were obtained by the chart review: age, sex, date of
liver biopsy, titers of antinuclear antibodies, smooth
muscle antibodies, liver kidney microsomal, antimito-
chondrial antibodies, antinuclear cytoplasmic antibod-
ies, IgG, gammaglobulins, aspartate aminotransferase,
alanine aminotransferase, alkaline phosphatase, total
bilirubin, albumin, and international normalized ratio
at baseline. Furthermore, aspartate aminotransferase,
alanine aminotransferase, alkaline phosphatase, total
bilirubin, albumin, international normalized ratio,
IgG, gamma globulins at 1 to 2 weeks, 2 months, 6
months, 1 year, and at last follow-up after start of
immunosuppressive treatment were recorded. The
presence of a suspicion of drug etiology in triggering
the AIH was recorded. The liver biopsy results were
analyzed, and histology compared between the DIAH
patients and age (65 years of age at the diagnosis of
AIH) and sex-matched patients (n 24) randomly
chosen from the rest of the AIH patients. Sex was bal-
anced, and no signicant age difference was found at
diagnosis. Furthermore, patients with nitrofurantoin-
induced and minocycline-induced AIH were com-
pared. All biopsy materials were reviewed by a single
liver pathologist (S.O.S.), blinded to the clinical con-
text of the biopsy as well as the patients outcomes.
The overall inammatory activity (grade) of the
whole specimen, portal, and interface inammation
as well as brosis (stage) were recorded from the
available materials on a scale from 0 to 4 and ana-
lyzed according to Batts and Ludwig.
18
Interface hep-
atitis was graded as none, minimal, mild, moderate,
and severe interface hepatitis and brosis stage as no
brosis, to portal, periportal, bridging, and cirrhosis.
Additionally, perivenular (zone 3) necrosis and con-
uent necrosis were evaluated in the biopsy materials
review.
The new simplied score was calculated. Histologi-
cal features were considered typical, compatible, or
atypical according to Hennes et al.
17
The biopsy was
considered typical if the biopsy demonstrated interface
hepatitis with a lymphoplasmacytic inltrate extending
from the portal areas into the lobular parenchyma
with associated rosette formation. The biopsy was con-
sidered compatible if the biopsy revealed features of
chronic hepatitis without all of the typical features
listed. Additionally, the designation of atypical was
applied if the biopsy demonstrated distinct features of
different diagnosis. In medical records with lack of in-
formation about the IgG levels, we used the gamma-
globulin level for calculation.
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RNSSON ET AL. 2041

Because obvious imaging abnormalities were seen
in most of the nitrofurantoin cases (none in the mino-
cycline cases), we compared the appearance of the liver
on imaging between these patients and other AIH
patients. We matched three AIH patients for sex and
age (65 years of age) with each nitrofurantoin patient
(33 versus 11) for this purpose and analyzed results of
imaging between the two groups.
The type of immunosuppressive treatment and its
duration was recorded. Information on whether immu-
nosuppressive therapy was discontinued during follow-
up and the results of the discontinuation were
obtained. Discontinuation was considered successful if
no relapse was observed biochemically or histologically
in patients with at least 12 months of follow-up. Bio-
chemical remission was dened as alanine aminotrans-
ferase and aspartate aminotransferase values that were
less than 1.5 times the upper limit of normal. The
date of last follow-up was recorded, and the duration
of follow-up was calculated. Complications of liver dis-
ease, clinical cirrhosis, ascites, esophageal or gastric
varices, need for liver transplantation, and death were
obtained. Response to therapy at 1 to 2 weeks and 2,
6, and 12 months as well as at last follow-up was
determined.
Statistical Analysis. Continuous variables are pre-
sented as medians and interquartile range. Dichoto-
mous variables were compared using the Fischer exact
test, and the Mann-Whitney test was used for continu-
ous variables. All tests were two-tailed and conducted
at a 5% level of signicance.
Results
General Characteristics of the Patients. A total of
261 well-characterized AIH cases were identied with
the available clinical, laboratory, and histological data
required for diagnosis according to the new simplied
criteria. Overall, 560 cases were excluded because of
an earlier diagnosis of AIH outside the Mayo Clinic,
and many of these patients were on treatment when
rst seen at the Mayo Clinic. Decompensated liver dis-
ease at presentation was found in 125 patients, and 70
had undergone transplantation for AIH, 57 had not
undergone a liver biopsy, 39 did not have available
data on autoantibodies or gamma globulins, three had
only family history of AIH, and 256 did not have
AIH as their nal diagnosis. Other cases excluded were
for suspicion of overlap syndromes with primary bili-
ary cirrhosis and primary sclerosing cholangitis (n
97) and pediatric cases (n 68).
Drugs were suspected to have induced the AIH in
24 of 261 (9.2%) cases: minocycline (n 11), nitro-
furantoin (n 11), and cephalexin and Prometrium,
in one case each. These were suspected on clinical
grounds because of current use of these drugs at the
time of diagnosis. None of the patients continued with
the drugs past the date of presentation, and none were
rechallenged.
The demographic and biochemical data in the study
cohort of the 24 DIAIH patients and the 237 other
AIH patients is demonstrated in Table 1. The median
follow-up of the DIAIH patients was 36 months
(13-77); and in the other AIH patients, 36 months
(15-79) (P NS).
The DIAIH patients were referral patients from
states other than Minnesota in 19 of 24 (79%) and in
160 of 237 (68%) in the other AIH patients (P
NS).
A similar proportion of patients had antinuclear
antibodies and smooth muscle antibody seropositivity
among the two groups (Table 1). Trial of discontinua-
tion of immunosuppression was only tried in 14 of 24
(58%) of the DIAIH patients. A signicantly higher
proportion of patients with DIAIH were able to dis-
continue their immunosuppressive therapy compared
with other AIH patients (100% versus 35%) (P <
0.0001) (Table 1) and showed no relapse at 36
(12-58) months in the DIAIH patients.
In general, liver tests at presentation were higher and
jaundice more common in the DIAIH group, but the
differences were not signicantly different (Table 1).
Patients with nitrofurantoin-induced and minocycline-
induced AIH are shown in Table 2.
Histology. A very similar proportion of the DIAIH
and the rest of the AIH group had typical and com-
patible histology according to the histological charac-
terization presented by Hennes et al.
17
(Table 3).
None of the DIAIH patients had atypical histology,
and only one patient from the rest of the AIH group
had atypical histology. This patient fullled diagnostic
criteria for AIH, although histology was similar to
histology observed in primary biliary cirrhosis. The
severity of inammation and brosis was not signi-
cantly different between the two groups (Table 3).
There was a tendency toward a higher stage score in
the AIH than in the DIAIH group, but the differ-
ence was not signicant (Table 3). However, cirrhosis
was not present in any of the DIAH patients,
whereas cirrhosis was found among 5 of 24 (20.8%)
in the rest of the AIH patients (P 0.049). When
divided into none and mild versus moderate and
severe activity in terms of grade, portal inammatory
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RNSSON ET AL. HEPATOLOGY, June 2010

activity, interface, and portal hepatitis in DIAH versus
AIH, no signicant differences were found (data not
shown). A total of six patients with DIAIH had a
follow-up liver biopsy, and all had either very mild
or no inammatory activity in the follow-up biopsy.
Comparison between the histological features in the
Table 2. Comparison of the Demographics, Seropositivity, AIH Score, Histology, Treatment and Liver Tests at Presentation in
Patients with Nitrofurantoin-Induced and Minocycline-Induced AIH
Nitrofurantoin AIH (n 5 11) Minocycline AIH (n 5 11) P value
Age 61 (54-66) 24 (18-38) 0.0019
Sex, females (%) 11 (100%) 10 (91%) NS
Duration of therapy (months) 24 (8-36) 12 (9-36) NS
ANA positive (%) 8/11 (73%) 10/11 (91%) NS
SMA positive (%) 6/11 (55%) 5/11 (45%) NS
Both ANA and SMA (%) 4/11 (36%) 4/11 (36%) NS
Seronegative (%) 1/11 (9%) 0/11 (0%) NS
Simplied AIH score:
Probable or denite (%) 7/9 (78%) 10/10 (100%) NS
Compatible histology (%) 6/11 (55%) 2/11 (18%) NS
Typical histology (%) 5/11 (45%) 9/11 (82%) NS
Immunosuppressive therapy (%) 11/11 (100%) 9/11 (82%) NS
Steroids and azathioprine (%) 3/11 (27%) 8/9 (89%) 0.0098
Steroids alone (%) 8/11 (73%) 1/11 (11%) 0.0098
Trial of discontinuation successful (%) 9/9 (100%) 5/5 (100%) NS
AST (<48 U/L) 827 (516-1401) 329 (168-726) 0.0235
ALT (<55 U/L) 778 (448-1159) 380 (213-871) NS
ALP (115 U/L) 426 (314-503) 188 (110-1081) NS
TB (<1.0 mg/dL) 7 (2.7-21.0) 1.5 (0.8-7.5) NS
Albumin (>3.5 g/dL) 2.9 (2.6-3.4) 3.4 (2.8-3.5) NS
INR (<1.2) 1.2 (1.0-1.4) 1.1 (0.9-1.3) NS
IgG (<1500 g/dL) 1835 (1275-2455) 1905 (1790-2580) NS
Gamma globulins (<1.7 g/dL) 2.5 (1.9-2.6) 2.8 (2.3-3.8) NS
Jaundice at presentation 8/11 (73%) 3/11 (27%) NS
In two nitrofurantoin cases and one minocycline case, gamma globulin levels were not available, which made it possible to calculate the AIH score in 19
patients.
Table 1. Comparison of the Demographics, Seropositivity, AIH Score, Histology, Treatment, and Liver Tests at Presentation in
Patients with Autoimmune Hepatitis (AIH) and Those with Drug-Induced Liver Injury (DIAIH)
AIH Patients (n 5 237) DIAIH (n 5 24) P Value
Age 52 (37-62) 53 (24-61) NS
Sex, females (%) 184 (78%) 20 (92%) NS
ANA positive (%) 165/237 (70%) 20 (83%) NS
SMA positive (%) 106/237 (45%) 12/24 (50%) NS
Both ANA and SMA (%) 69/237 (29%) 9/24 (38%) NS
Seronegative (%) 29/237 (12%) 1/24 (4%) NS
Simplied AIH score:
Probable or denite (%) 181/237 (76%) 19/21 (90.5%) NS
Immunosuppressive therapy (%) 222/237 (94%) 21/24 (88%) NS
Steroids and azathioprine (%) 191/222 (86%) 12/21 (57%) 0.0024
Steroids alone (%) 31/222 (14%) 9 (43%) 0.0024
Trial of discontinuation successful (%) 18/52 (35%) 14/14 (100%) <0.0001
AST (<48 U/L) 392 (154-1031) 679 (291-956) NS
ALT (<55 U/L) 480 (185-1141) 728 (255-1141) NS
ALP (115 U/L) 241 (138-350) 376 (229-514) 0.0166
TB (<1.0 mg/dL) 2.0 (1.0-8.0) 4.0 (1.0-12.0) NS
Albumin (>3.5 g/dL) 3.4 (2.95-3.7) 3.1 (2.6-3.6) NS
INR (<1.2) 1.1 (1.0-1.3) 1.1 (1.0-1.3) NS
IgG (<1500 g/dL) 2020 (1618-2702) 1905 (1600-2455) NS
Gamma globulins (<1.7 g/dL) 2.5 (2.0-3.2) 2.55 (2.2-3.1) NS
Jaundice at presentation 110/237 (46%) 12/24 (50%) NS
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RNSSON ET AL. 2043

nitrofurantoin-induced and minocycline-induced AIH
patients showed similar grade and stage in these
patients (Table 4). In general the necroinammatory
activity was found to be higher in the nitrofurantoin-
induced AIH than in the AIH induced by minocy-
cline (Table 4).
Imaging. Changes on radiological images were evi-
dent in 8 of 11 (73%) of the nitrofurantoin-induced
AIH cases, whereas this was not observed in any of the
minocycline patients (P 0.0010). Furthermore, other
AIH patients had abnormalities on imaging in only
24% (8/33) of cases versus 73% of the nitrofurantoin
patients (P 0.0089). In most of the AIH patients
with abnormalities on imaging, the liver showed mild
atrophy (n 4), clear signs of cirrhosis (atrophy and
signs of portal hypertension such as ascites) (n 2),
or coarsening of the liver architecture compatible
with chronic liver disease (n 2). In several nitrofur-
antoin patients, the appearance of the liver was consid-
ered cirrhotic on imaging but cirrhosis was not
shown to be present histologically in any of the nitro-
furantoin (or the minocycline) patients. Two patients
had left lobe liver atrophy, two patients had right lobe
liver atrophy, and two patients had diffuse general liver
atrophy.
In ve patients, computed tomography or magnetic
resonance imaging showed conuent area of abnormal-
ity with distortion of surrounding liver parenchyma
(Figs. 1-3). The conuent abnormal area showed
retention of contrast on delayed-phase images, consist-
ent with conuent brosis or massive brotic bands.
In some cases when images were obtained at presenta-
tion, the conuent area showed fairly intense enhance-
ment during the portal phase of enhancement. This
early enhancement is somewhat unusual for typical
conuent brosis, but may have been due to active or
subacute phase of the disease. The appearance of con-
uent brosis or massive brotic bands (Figs. 1-3) was
only seen in the nitrofurantoin patients and in none of
the AIH patients.
One of the patients with right liver atrophy also
had a large mass in the right lobe and hypertrophy of
the left liver lobe. Another patient had heterogeneous
echotexture, with a subtle 3-cm mass in the right lobe
that on the original imaging was similar to focal nodu-
lar hyperplasia but was clinically considered secondary
to the nitrofurantoin-induced liver damage, and the
patient was in clinical and biochemical remission at
follow-up.
Individual Patients. The clinical characteristics of
the individual patients with nitrofurantoin-induced
and minocycline-induced AIH are shown in Tables 5
and 6. A total of 8 of 11 (73%) nitrofurantoin cases
had jaundice at presentation (Table 5), whereas only 3
of 11 (27%) of the minocycline cases had jaundice at
presentation (Table 6). All patients with nitrofuran-
toin-induced AIH were treated with immunosuppres-
sion (Table 5), whereas two minocycline patients were
not treated (Table 6). In one case attributable to rap-
idly improving jaundice, liver tests before therapy were
instituted, and not in another case attributable to mild
liver enzyme abnormalities (Table 6). All cases with all
parameters available to make a score for the likelihood
of AIH received at least a probable score; however,
in three cases, information about gamma globulins was
not available for the AIH score.
Outcome. At the end of follow-up, among those
who had at least 6 months follow-up at the Mayo
Table 3. Comparison Between DILI/AIH and AIH Alone
DIAIH AIH P Value
Grade (Batts and Ludwig) 3 (2-3) 3 (2-3) NS
Portal inammation 2 (2-3) 2 (2-3) NS
Lymphoplasmacytic
(absent/present) 19/23 (83%) 22/23 (96%) NS
Interface hepatitis 2.5 (1.5-3.0) 2.0 (1.0-3.0) NS
Lobular hepatitis 2.0 (1.0-3.0) 2.0 (1.0-3.0) NS
Zone 3 necrosis 15/23 (65%) 12/22 (55%) NS
Conuent necrosis 7/23 (30.4%) 2/22 (9%) NS
Rosette formation 7/22 (31.8%) 5/22 (22.7%) NS
Stage 0 (0-2) 1 (0-3) 0.06
Compatible 8/24 (33%) 8/24 (33%) NS
Typical 16/24 (66%) 15/24 (63%)
Atypical 0 1/24 (4%)
Results are expressed as medians and interquartile range. Grade, portal inam-
mation, interface, and lobular hepatitis as well as stage are scored as none, mild,
moderate, and severe. Lymphoplasmacytic occurrence, zone 3 necrosis, conuent
necrosis, and rosette formation are classied as present or absent.
Table 4. Comparison Between Nitrofurantoin and
Minocyclin-Induced AIH
Nitrofurantoin Minocycline P Value
Grade (Batts and Ludwig) 3 (3-3.8) 2 (2-3) 0.0082
Portal inammation 3 (2-3) 2 (2-3) 0.08
Lymphoplasmacytic
(absent/present) 10/10 (100%) 9/11 (82%) NS
Interface hepatitis 3.0 (3.0-3.0) 2.0 (1.0-2.8) 0.0053
Lobular hepatitis 3.0 (2.0-4.0) 1.0 (1.0-2.0) 0.0072
Zone 3 necrosis 9/10 (90%) 6/11 (55.5%) NS
Conuent necrosis 6/10 (30.4%) 1/11 (9%) 0.024
Rosette formation 6/9 (66%) 1/11 (9%) 0.0166
Stage 0 (0-2) 0 (0-1.8) NS
Compatible 6/11 (55%) 2/11 (18%) NS
Typical 5/11 (45%) 9/11 (82%)
Atypical 0 0
Results are expressed as medians and interquartile range. Grade, portal
inammation, interface, and lobular hepatitis as well as stage are scored as
none, mild, moderate, and severe. Lymphoplasmacytic occurrence, zone 3 ne-
crosis, conuent necrosis, and rosette formation are classied as present or
absent.
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RNSSON ET AL. HEPATOLOGY, June 2010

clinic, 22 of 23 (96%) of the DIAIH patients were in
biochemical remission, as were 159 of 177 (90%) of
the other AIH patients (NS). None of the DIAIH
patients developed cirrhosis during follow-up, and all
were alive at last follow-up, whereas 18 of 257 (7%)
AIH patients had developed cirrhosis clinically (P
NS). Overall, ve of these patients had decompensated
liver cirrhosis with mild ascites in most, and 13
patients had nonbleeding esophageal varices. Among
the seven patients who died during the study period,
only two deaths were liver related. One patient died of
fulminant hepatic failure on the liver transplantation
list a few months after presentation, and one other
patient died in chronic liver failure and with a dissemi-
nated breast cancer. Others died of stroke, heart fail-
ure, and colon cancer, and two had unknown causes
of death. At the end of follow-up, one of the above-
mentioned patients with cirrhosis had undergone liver
transplantation, two were listed, and one was evaluated
for transplantation.
Discussion
The results of the current study suggest that among
consecutive patients with well-characterized AIH,
drug-induced AIH makes up a signicant proportion,
approximately 9%, of AIH cases. More than 90% of
these DIAIH cases were associated with two drugs,
nitrofurantoin and minocycline. Overall, the histologi-
cal features of DIAIH seem to be identical to those of
AIH. Severe imaging abnormalities with liver lobe and
general liver atrophy were also commonly observed in
nitrofurantoin but not in minocycline cases, indicating
postnecrotic scarring.
None of the patients with DIAIH developed cirrho-
sis during follow-up, and these patients seem to have a
generally favorable prognosis. All patients with DIAIH
in whom discontinuation of immunosuppressive ther-
apy was tried could withdraw drug therapy without a
relapse, whereas only approximately one third of the
Fig. 1. Conuent necrosis in both right and left liver lobe.
Fig. 2. Conuent brosis in both right and left lobe in another
patient but with another distribution.
Fig. 3. Conuent brosis centrally with general liver atrophy.
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RNSSON ET AL. 2045

other AIH patients did not experience a relapse after
withdrawal of immunosuppression. Taken together,
our results suggest that DIAIH is a distinct phenom-
enon, and a trial of withdrawal of immunosuppression
should be undertaken in these patients.
Previous literature on DIAIH consist only of case
reports and small case series. Our series of 24 well-
characterized patients is by far the largest study on the
clinical aspects of drug-induced AIH. No previous
study has been able to assess the proportion of DIAIH
out of AIH cases in general. We found that 9.2% of
AIH patients were by denition induced by drugs. It
is conceivable that this reects referral bias, but no sig-
nicant difference was found between the proportion
of referral patients among the DIAIH versus the other
AIH patients.
Nitrofurantoin can lead to a broad spectrum of liver
injury with mild liver test abnormalities, acute liver
failure with fatal outcome, or need for liver transplan-
tation
9,12,19-21
and also liver cirrhosis.
21
Nitrofurantoin
is still widely used in many countries and was recently
found to be one of the most common single agents
associated with drug-induced liver injury (DILI) in a
recent prospective study in the United States.
21
Nitro-
furantoin has been documented to induce AIH previ-
ously in a number of reports.
8,9,12,13,22-24
All cases in
the current series with laboratory parameters available
to score the AIH by the new simplied criteria
17
had a
score of at least probable. Zone 3 necrosis was
observed in our DIAIH cohort and has been described
in nitrofurantoin-induced liver injury
12
but has also
been reported in AIH without drug involvement.
25,26
It seems that DIAIH caused by other drugs than nitro-
furantoin and minocycline is a rare cause of AIH.
Interestingly, one of the two other drugs suspected to
have caused AIH, cephalexin, was also taken by one
patient with minocycline-induced AIH in one series.
10
Cirrhosis was not found to develop in any of the
DIAIH cases in the current study, whereas this was
found in 20% of the other AIH patients at baseline.
Table 5. Clinical Characteristic of the Individual Patients with Nitrofurantoin-Induced AIH
Subject, Duration of Therapy (months) ANA SMA IgG Gamma-globulins Score AST ALT ALP TB Therapy Response to Therapy
F55 (27) neg 1:40 282 336 327 2.7 Steroids Fair*
F55 (36) neg 1:20 2069 1479 426 37.1 Steroids Good
F53 (6) 1:320 1:160 2850 2.9 7 827 1059 1.8 Steroids Good
F64 (7) neg 1:80 1.8 6 436 188 341 1.1 Steroids Good
F55 (4) 5.6 neg 1440 2.2 6 918 1165 470 7.8 Steroids Good
F75 (60) 5.3 1:20 2.5 7 1725 1141 1195 20.6 Steroids Good
F52 (36) >12 1:1280 1750 1.8 7 814 778 499 4.5 Steroids Good
F67 (36) 1.8 1:20 3.6 6 1538 1652 229 30.9 SterAza Good
F67 (12) >12 neg 1.3 6 993 729 276 10.6 SterAza Good
F66 (36) 1:80 1:80 - 1.8 6 300 450 0.9 SterAza Good
F64 (24) 6.3 1:40 2230 2.6 7 757 448 514 3.5 SterAza Good
F, female; M, male.
*Information not available on discontinuation of immunosuppression.
Discontinuation of immunosuppression successful.
Discontinuation of immunosuppression not tried.
Table 6. Clinical Characteristic of the Individual Patients with Minocycline Induced AIH
Subject, Duration of Therapy (months) ANA SMA IgG Gamma-globulins Score AST ALT ALP TB Therapy Response to Therapy
F24 (36) 1:40 neg 1820 2.4 6 449 728 595 0.8 SterAza Good*
F39 (-) 2.9 neg 2.0 7 785 1035 1243 11.1 SterAza Good
F60 (8) neg 1:160 1670 2.8 7 178 283 188 0.5 Steroids Good
F25 (42) 1:320 1:160 1990 2.88 7 329 213 1963 1.5 SterAza Good
F17 (-) 1:80 1:40 4.6 7 328 478 0.9 SterAza Good
F55 (2) 1:80 1:40 1.2 6 769 871 151 13.3 None -
F33 (4) >12 1:640 3170 3.5 7 1412 2079 122 3.5 SterAza Good
F25 (-) 1.5 1:20 1760 6 267 389 0.9 SterAza Good*
F17 (12) >12 neg 1620 1.7 7 600 0.7 SterAza Good*
F18 (36) >12 neg 2.2 7 165 245 106 0.9 SterAza Good*
M18 (12) 3.6 neg 78 127 0.5 None -
F, female; M, male.
*Discontinuation of immunosuppression not tried.
Discontinuation of immunosuppression successful.
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Our results are in agreement with Stricker et al.,
9
who
found no cases of nitrofurantoin-induced cirrhosis
among 52 reported cases of suspected liver injury
reported to the Netherlands Centre for Monitoring of
Adverse Reactions to Drugs. Most of the patients with
DIAIH in our study had been treated for a long pe-
riod with the drug, with a median duration of 24 and
12 months in the nitrofurantoin-induced and minocy-
cline-induced AIH, respectively. This long duration of
treatment has been the experience in other series.
9,12
Interestingly, severe abnormalities were seen on imag-
ing in 8 of 11 (73%) of the nitrofurantoin cases,
whereas this was not found to occur in the other
DIAIH cases. This has not been reported previously,
but a recent case report revealed low attenuation
patches in the liver parenchyma.
27
This unusual pat-
tern of brosis was seen in the nitrofurantoin cases
with conuent brosis and massive brotic bands not
seen in other AIH patients. The appearance of this
type of brotic process on imaging might raise a suspi-
cion of nitrofurantoin-induced liver injury. However, it
is not clear whether these changes are specic for
nitrofurantoin-induced liver damage. Inadvertent
rechallenge of nitrofurantoin has been reported to
induce chronic liver injury
28
and severe liver injury
17 years after an initial hepatitis-like illness,
29
which
underlines the importance of careful history in assess-
ing chronic test abnormalities and changes seen on
imaging.
One of the most important ndings of the analysis
of the DIAIH cases in our series is that corticosteroid
therapy could be discontinued without relapse.
The need for continuous immunosuppressive therapy
has not been analyzed in previous series on
DIAIH.
9,10,12,13,15,30
In all cases of the current studies
when this was tried, no relapse was found to occur
during a median follow-up of 36 months. This argues
for induction of AIH by nitrofurantoin and minocy-
cline and not simply unmasking otherwise sporadic
cases of AIH. To our knowledge, relapse after discon-
tinuation of immunosuppressive therapy has only been
reported in a single case of minocycline-induced AIH
previously.
31
Our results indicate that DIAIH patients
have a generally favorable prognosis, although our fol-
low-up was rather limited. None of the DIAIH
patients had histological cirrhosis at presentation, and
none developed cirrhosis clinically during follow-up,
and all except one patient (who only had 6 months
follow-up) were in biochemical remission and experi-
enced lack of relapse after immunosuppression with-
drawal. A recent study analyzing chronic liver injury
after a previous episode of severe DILI revealed devel-
opment of AIH in several patients associated with sev-
eral different drugs. In these patients, immunosuppres-
sion could also be discontinued without a relapse,
32
which is in line with the results of the current series.
Our results suggest that in patients with DIAIH a trial
of discontinuation of immunosuppression should be
undertaken in all patients.
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