LIVER, PANCREAS, AND BILIARY TRACT: CASE REPORT
Autoimmune Hepatitis Triggered by Statins
Vamsee Alla, MD,*w Joseph Abraham, MD,* Junaid Siddiqui, MD,*w Dimple Raina, MD,*w
George Y. Wu, MD, PhD,*w Naga P. Chalasani, MD,yJ and Herbert L. Bonkovsky, MD*w z
Abstract: Although the cause of autoimmune hepatitis (AIH) is
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unknown, drugs are believed to be potential triggers in some
patients. In isolated case reports, statins have been considered
such triggers. Here we describe 3 patients in whom it is probable
that statins initiated the development of AIH. Two men (aged
47 and 51) and one woman (aged 57) developed AIH after the
initiation of statin therapy. They developed positive titers of
antinuclear antibodies, antismooth muscle antibodies (1/40 to
1/160), and hypergammaglobulinemia. Features of all 3 patients
met the criteria for AIH according to the International
Autoimmune Hepatitis Panel. Liver biopsies in all 3 showed
varying stages of fibrosis and plasma cell infiltration, compatible
with AIH. The woman developed hepatitis due to statins on
2 separate occasions: the first in 1999, due to simvastatin, and
the second in 2001 to 2002, due to atorvastatin, which was severe
and persisted even after discontinuing medication. Similarly, in the
2 other cases, exposure to statins preceded development of AIH,
which persisted despite discontinuing medications. All 3 patients
responded well to prednisone and azathioprine or mycophenolate
therapy. 3 similar previously reported cases are reviewed. We
conclude that the 3 cases reported here and 3 similar previously
reported cases, indicate that severe, ongoing AIH on rare occasions
can be triggered by statins.
Key Words: autoimmune hepatitis, drug-induced liver injury,
HMG-CoA reductase inhibitors, immunosuppressive, stains
(J Clin Gastroenterol 2006;40:757–761)
A lthough the cause of autoimmune hepatitis (AIH) is
unknown, drugs and chemicals are believed to be
potential triggers in some patients. Statins are very widely
prescribed medications. In isolated case reports, statins
Received for publication January 17, 2006; accepted March 24, 2006.
From the Departments of *Medicine; zMolecular, Microbial and
Structural Biology; wThe Liver-Biliary-Pancreatic Center; yUniver-
sity of Connecticut Health Center, Farmington, CT 06030; and JThe
Department of Medicine, Indiana University School of Medicine,
Indianapolis, IN 46202.
Supported by the following contracts and grants from NIH, MO1
RR06192, NO1 DK 92326, RO1 DK 38825 and 14, UO1 DK065193.
Dr Abraham is deceased.
Current address: Dr Siddiqui, Division of Gastroenterology and
Hepatology, University of Iowa Hospitals and Clinic, Iowa City, IA.
Copyright r 2006 by Lippincott Williams & Wilkins
J Clin Gastroenterol  Volume 40, Number 8, September 2006
have been considered such triggers. Here we describe
three patients in whom it is probable that statins triggered
the development of AIH. The key features of these cases,
and 3 similar previously reported cases are summarized in
the Table 1.
CASE SUMMARIES
Case 1 (B.B.)
A 51-year-old woman accountant with familial hyper-
cholesterolemia, strong family history of coronary artery
disease, hypothyroidism, and hyperlipidemia, was first treated
in 1999 with fluvastatin (Lescol) for 12 weeks. She developed
marked elevations of serum alanine aminotransferase (ALT),
and aspartate aminotransferase (AST). Even after discontinua-
tion of fluvastatin, serum aminotransferases remained elevated
for about 4 months (Fig. 1A). Viral hepatitis serologies,
antinuclear antibodies (ANA), antimitochondrial antibodies
(AMA), antismooth muscle antibodies (ASMA), antiliver
kidney-microsomal-1 antibodies (anti-LKM-1) were negative.
Serum globulins were mildly elevated (3.6 g/dL, reference range,
2.3 to 3.5 g/dL). A liver biopsy (performed September 29, 1999)
showed lobular hepatitis with infiltration of lymphocytes and
plasma cells, spotty hepatocytic oncosis and apoptosis, and mild
(Ishak stage 1) portal fibrosis.
In September 2002, due to elevated serum cholesterol,
and, after a discussion with her primary care physician, the
patient decided to start simvastatin (Zocor), 20 mg daily. Within
2 weeks of starting simvastatin, she felt extremely fatigued with
generalized itching, and in 6 weeks noticed discomfort in the
right upper quadrant of her abdomen. By December 14, 2002,
she was extremely fatigued and hypersomnic. Serum liver
enzymes were markedly elevated [ALT 1749 U/L (reference
range 10 to 39), AST 1459 U/L (reference range 10 to 36)],
although serum albumin [3.8 g/dL (reference range 3.5 to 5.5)],
and total bilirubin [1.0 mg/dL (reference range 0.3 to 1.2)] were
normal. Simvastatin was discontinued. On December thirtieth
repeat liver chemistries showed persistent elevations of ALT and
AST, and hyperbilirubinemia (serum total bilirubin, 7.3 mg/dL,
direct-reacting bilirubin, 6.0 mg/dL) (Fig. 1A). She was referred
to the Liver Center at The University of Connecticut Health
Center (UCHC) for further evaluation. In January 2003, her
serum AST was 1748 U/L (10 to 42 U/L), ALT was 1420 U/L
(10 to 40 U/L), total bilirubin was 11.3 mg/dL (0.2 to 1.2
mg/dL), direct bilirubin was 6.5 mg/dL (0 to 0.4 mg/dL), and
albumin was 3.3 g/dL (3.5 to 5.5 g/dL) (reference ranges in
parentheses).
An abdominal ultrasound showed mild dilatation of the
common bile duct (8 mm). An endoscopic retrograde cholan-
giopancreatogram was normal, showing no intrahepatic or
extrahepatic obstruction. It was felt that drug-induced liver
injury due to an idiosyncratic reaction to simvastatin was the
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TABLE 1. Features of Subjects With Autoimmune Hepatitis Triggered by Statins

Subjects Reported in This Paper Previously Reported Subjects
Patient 1 (B.B.) Patient 2 (J.K.) Patient 3 (B.J.) Patient 1 (Ref. 9) Patient 2 (Ref. 1) Patient 3 (Ref. 11)
Age 57 47 51 58 65 46
Sex Female Male Male Female Female Female
Medication Simvastatin* Atorvastatin Atorvastatin Atorvastatin Atorvastatinw Rosuvastatin
Duration of drug 4 mo* 4 mo 4 mo 7 mo 4 mo 2 mo
therapy before
onset of AIH
Peak serum ALT 1749 1170 1555 352 510 2539
(U/L)
Peak serum total 11.3 3.4 5.5 32 5.3 7.9
bilirubin
(mg/dL)
Peak serum ALP 228 160 203 270 481 151
(U/L)
Peak ASMA titer 1:40 1:40 1:160 Negative >1:1280 1:160
AIH score 20z 17z 14 19 15yJ NR
HLA type DR-4 DR- 4, 7 NA DR- 3, 4 DR-7 NR
Ishak fibrosis 5-6 4-5 4 NR 5-6 NR
score
Response to Serum ALT, AST Serum AST, ALT Serum AST, ALT Serum liver tests Serum ALT, AST Serum AST, ALT
therapy normal after 1 y normal after normal after normal and <3x ULN <3x ULN
of treatment 3 mo of 7 mo of compensated after 67 d of after 6 mo of
with treatment with treatment with cirrhosis after 1 y treatment with treatment with
azathioprine azathioprine prednisone and of treatment with prednisone prednisone
and prednisone and prednisone mycophenolate tacrolimus,
prednisolone, and
mycophenolate
*Previously treated with fluvastatin for 12 wk in 1999, simvastatin was started in 11/2002.
wPreviously treated with pravastatin (1996) and fluvastatin (1997). Atorvastatin was started in 04/2000.
zPostimmunosuppressive therapy.
yPreimmunosuppressive therapy.
JPelli, N., personal communication.
NA indicates not available; NR, not reported; ULN, upper limit of normal.

most likely diagnosis, and the patient was followed closely as an
outpatient. Serum AST and total bilirubin remained high,
1760 U/L and 11 mg/dL, respectively in mid-January 2003
(Fig. 1A). Due to persistent elevations of serum aminotrans-
ferases and bilirubin, with further rise on July 20, 2003, a second
liver biopsy was done on July 24, 2003. The architecture of liver
was distorted due to formation of frequent fibrosis septa and
regenerative nodules. The fibrosis score (Ishak scoring system)
was 6. Marked piecemeal necrosis was noted around all fibrous
septae. Severe lobular hepatitis was also noted. Minimal fatty
metamorphosis was present. The inflammatory cells were chiefly
composed of plasma cells, lymphocytes, and histiocytes/proli-
ferating Kupffer cells. Occasional apoptotic (acidophilic) bodies
were present. Bile ductules showed proliferation and reactive
changes. There was no lymphoid nodule formation. Central
veins were obliterated and incorporated into regenerative
nodules. The overall features were consistent with markedly
active postnecrotic cirrhosis, due to AIH. She again had
negative viral serologies (hepatitis A, B, and C), but now serum
ANA was positive at a titer of 1:80, ASMA was 1:40, and serum
globulins were increased 1.5 times the upper limit of normal
value. On the basis of the history, clinical picture, liver biopsy,
and laboratory testing a diagnosis of AIH, triggered by
simvastatin, was made and she was treated with prednisone
(60 mg/d) and azathioprine (50 mg/d). She improved both
symptomatically and biochemically (Fig. 1A). After 3 months
on these drugs, serum aminotransferases and total bilirubin were
normal. The dose of prednisone was gradually reduced and then
stopped while she remained on azathioprine alone. In March
2005, azathioprine was stopped as she had had normal serum
aminotransferases and bilirubin for an extended period of time.
However, soon thereafter, her serum aminotransferases rose
again, and she was retreated with combination prednisone and
azathioprine therapy. Within 1 month, her serum aminotrans-
ferases had again fallen into normal range, and prednisone again
was tapered. The patient remains on azathioprine 50 mg/d. Her
HLA type was found to be positive for HLA-DR4, but
negative for HLA-DR3 and DR7 (HLA typing was done by
polymerase chain reaction-based methods at ARUP labora-
tories, Salt Lake City, UT).
Case 2 (J.K.)
A 57-year-old white, man with primary hypercholeste-
rolemia was started on fluvastatin (Lescol) 40 mg/d, in October
2000, because serum total cholesterol was 326 mg/dL and LDL
cholesterol was 198 mg/dL. After 14 months of fluvastatin
therapy, at the end of 2001, the patient for an unknown reason
was switched to atorvastatin (Lipitor), 40 mg/d. Atorvastatin
was continued for 5 months, but was discontinued in May 2002,
because the serum ALT and AST were noted to climb from
31 U/L and 26 U/L (in December 2001), to 424 U/L and 109
U/L, respectively (Fig. 1B). The patient denied any significant
alcohol intake. Despite cessation of atorvastatin, liver enzymes
remained elevated prompting a referral to the Liver Center of

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J Clin Gastroenterol  Volume 40, Number 8, September 2006
FIGURE 1. A, Clinical and biochemical course of patient B.B.
ALT indicates serum alanine aminotransferase; Aza, azathio-
prine; Fluva, fluvastatin; Pred, prednisone; Simva, simvastatin;
TBili, serum total bilirubin. B, Clinical and biochemical course
of patient J.K. Ator indicates atorvastatin.
UCHC in December 2002. At that time serum ALT and AST
were still increased at 109 U/L and 50 U/L, respectively.
Appropriate studies excluded viral hepatitis, a-1-antitrypsin
deficiency, hemochromatosis, and Wilson disease. The ANA
and AMA were negative, but ASMA was noted to be positive
with a titer of 1:40. Abdominal ultrasound was normal. In
January 2003, the patient received a trial of gemfibrozil because
of a persistently high serum cholesterol. Gemfibrozil was
discontinued in April, 2003, because the patient’s serum ALT
and AST had risen further to 940 U/L and 355 U/L, and alkaline
phosphatase (ALP) had climbed to 143 U/L (reference range 25
to 125 U/L). During the follow-up period of more than a year,
although the patient received no lipid lowering drugs, or other
drugs, liver enzymes remained at least 3 to 4 times above the
upper limit of normal (ULN) with peak ALT, AST, and ALP
1170 U/L, 786 U/L, and 160 U/L, respectively. In April 2004, the
serum total bilirubin, which had been normal previously, was
elevated at 3.4 mg/dL. The serum globulin level, which had been
2.0 g/dL (reference range 2.3 to 4.5 g/dL) in 2002, showed an
increase to 4.1 g/dL around the same time.
A liver biopsy was performed on June 28, 2004. It showed
advanced bridging fibrosis (stage 4/6 Ishak scoring system) with
r 2006 Lippincott Williams & Wilkins
AIH Triggered by Statins
portal, interface, and lobular hepatitis. The inflammatory cells
were chiefly lymphocytes and plasma cells, with occasional
polymorphonuclear leukocytes and eosinophils. There was
evidence of lobular unrest, cell swelling, and pseudo-rosette
formation (Figs. 2C, D). On the basis of the patient’s clinical
course, laboratory results, and liver biopsy findings, a diagnosis
of autoimmune hepatitis was made; and the patient was started
on prednisone 30 mg/d and azathioprine 100 mg/d in July, 2004.
The patient responded well to this treatment with the normal-
ization of the liver tests by September 2004. The dose of
prednisone was tapered and discontinued in December 2005.
Liver tests have remained normal. The plan is to continue
azathioprine for a duration of 2 years. HLA typing, done at
ARUP Laboratories as in the case of B.B., showed that the
patient is positive for both HLA-DR4 and DR7.
Case 3 (B.J.)
A 51-year-old White man with history of hyperlipidemia
was noted to have mildly elevated serum aminotransferases in
1997 and an evaluation at that time (including viral serologies
and autoimmune markers) was unremarkable. An abdominal
ultrasound showed increased echogenicity of the liver and no
other abnormal findings. A liver biopsy, performed in 1997,
showed moderate steatosis (B50%) with some ballooning of
hepatocytes. From 1997 until the spring of 2003, B.J. was
treated with gemfibrozil. Serum ALT and AST, although mildly
increased, remained <3 times the upper limit of normal. In
May 2003, gemfibrozil was stopped and atorvastatin (Lipitor),
20 mg/d was started. In September 2003, serum ALT was found
to be 527 U/L with serum total bilirubin 0.8 mg/dL. A repeat
liver biopsy in September 2003, showed moderate steatosis with
lobular inflammation, focal necrosis, and mild lymphocytic and
eosinophilic infiltration. This was felt to be most consistent with
drug-induced liver injury; atorvastatin was discontinued on
September 20, 2003.
Subsequently, serum liver enzymes remained elevated in
November 2003 (ALT 498 U/L), and were higher in February
2004 (ALT 662 U/L). Serum ALT and total bilirubin continued
to rise reaching 1555 U/L, and 2.2 mg/dL, respectively, in
August, 2004. At this time, B.J. was referred to the Liver
Center at Indiana University. In September 2004, at this Center
he appeared icteric and serum AST was 1111 U/L, ALT 1550
U/L, total bilirubin 5.5 mg/dL (direct 2.2 mg/dL), and alkaline
phosphatase 203 U/L. His medications included paroxetine,
pantoprazole, zolpidem, iron, and insulin, all of which he had
taken for 2 or more years. Viral hepatitis serologies were
negative. Serum IgA and IgM were normal, but IgG was
increased (2.7 g/dL). His ANA and ASMA titers were positive at
1:160 dilution. Serum anti-LKM-1 antibody was negative.
Serum ceruloplasmin and a-1 antitrypsin levels had been within
the normal range in 1997. A liver biopsy, performed in August
2004, showed marked chronic inflammation within the portal
tracts including numerous plasma cells associated with extensive
piecemeal necrosis. There was moderate steatosis. There was
marked inflammatory activity within the lobule, associated with
patchy foci of bridging necrosis. The trichrome stain revealed
bridging fibrosis (Ishak fibrosis score 3).
A diagnosis of AIH, precipitated by atorvastatin was
made, and immunosuppressive therapy, consisting of prednisone
40 mg/d, and mycophenolate mofetil, 500 mg twice daily was
started, on October 6, 2004. Within 2 weeks, serum AST fell to
301 U/L, ALT to 762 U/L, and total bilirubin to 2.1 mg/dL
(direct 0.9). Serum liver tests became normal in 7 months,
and have remained normal since. In June 2005, serum AST was
759
Alla et al
FIGURE 2. Photomicrographs of liver
biopsy no. 2 of B.B. (A, B) and of J.K.
(C, D). A, There is expansion of portal areas
with moderately severe inflammation and
bridging fibrosis. (low power, Masson
trichrome). B, There is moderate-to-severe
lobular hepatitis, with prominent plasma-
cytic infiltration (medium power, hemato-
xylin and eosin). C, There are bridging
fibrosis and moderate inflammation (low
power, Masson trichrome). D, There is
severe portal, interface, and lobular
hepatitis with mixed lymphocytic and
plasmacytic infiltration (medium power,
hematoxylin and eosin).
36 U/L, ALT 20 U/L, and total bilirubin 0.6 mg/dL.
A posttreatment liver biopsy, done in February 2005, showed
much improved inflammation and hepatocytic oncosis and
apoptosis, but septal and focal bridging fibrosis (Ishak fibrosis
score = 3). The patient has been maintained on mycophenolate
mofetil 500 mg twice daily alone. HLA DR typing was
attempted, but due to laboratory error was not completed
successfully, and the patient has declined further testing.
DISCUSSION
Autoimmune hepatitis is a chronic necroinflamma-
tory disease of unknown etiology, characterized by the
presence of circulating autoantibodies, elevated serum
globulins and histologic features of interface hepatitis
with lympho-plasmacytic infiltration. Autoimmune hepa-
titis may be triggered by various environmental factors,
including viruses (eg, measles, hepatitis C and HSV), and
drugs (eg, minocycline, hydralazine, procainamide) in
genetically predisposed patients. It is important to
diagnose AIH early and differentiate it from other liver
diseases because appropriate immunosuppression will
usually improve this condition and delay or prevent
development of hepatic decompensation or the need for
liver transplantation. There may be overlap features with
other autoimmune liver diseases like primary biliary
cirrhosis and primary sclerosing cholangitis.1
HMG-CoA reductase inhibitors (statins) are among
the most widely used drugs.2 Although they are generally
considered safe,3 they may rarely produce serious adverse
reactions. Asymptomatic elevations in serum aminotrans-
ferases are common in patients taking statins, but severe
hepatic toxicity is rare. Nevertheless, since the early 1990s
there have appeared sporadic reports of statins triggering
autoimmune diseases. These diseases include lupus
erythematosus, dermatomyositis, lichen planus, and
others.4–9 Statin-induced autoimmune hepatitis pre-
viously was reported by Graziadei et al10 Pelli et al11
and Wolters and van Buuren.12 Key features of our 3
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J Clin Gastroenterol  Volume 40, Number 8, September 2006
cases and those reported by others are summarized in the
Table 1. Among the 6 reported cases of AIH triggered by
statins, 4 were women and 2 were men; all were aged >45
years. All developed a predominantly hepatocellular
pattern of injury. HLA typing was available on 4 patients
and all 4 were positive for DR 3, 4, or 7, types known to
be associated with increased risk of AIH.1
A striking feature in our case series and in the 3
previously described cases is the apparent class effect of
statins to unmask or trigger an autoimmune process
resulting in clinically significant hepatitis. In B.B.,
relatively brief exposure to fluvastatin led to marked
elevation in serum ALT, which improved spontaneously
(Fig. 1A). Later exposure to simvastatin led to a prompt
and dramatic recurrence of severe AIH, with persistence
of active hepatitis for nearly a year and marked
progression of hepatic fibrosis and inflammation on liver
biopsy (Fig. 1A). More likely than not, the initial
exposure to fluvastatin led to initial immuno-allergic
response, and the subsequent brief exposure to simvasta-
tin led to a more rapid and severe, self-sustaining
anamnestic response.
Our 3 patients and the 2 previously reported with
data sufficient for analysis had ‘‘definite’’ or ‘‘likely’’
AIH, according to the International Autoimmune Hepa-
titis Group scoring system (Table 1).13
Although statins exhibit immunosuppressive act-
ions, including down-regulation of MHC class 2 antigen
expression in response to interferon g,14–16 in rare
instances, perhaps, in particularly susceptible patients,
statins may still trigger autoimmune responses (Refs. 5 to
14 and this paper). Perhaps, absent the immunosuppres-
sive properties of statins, such responses would be more
frequent.
In summary, although statins are generally safe
medications, the 3 cases reported here, and 3 similar
previously reported cases (Table 1), indicate that severe,
persistent AIH can be triggered by statins.
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J Clin Gastroenterol  Volume 40, Number 8, September 2006
ACKNOWLEDGMENT
The authors thank Jean Clark for her help with typing
and preparing the manuscript.
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