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Received: 6 July 2016    Accepted: 26 October 2016

DOI: 10.1111/liv.13308

SPECIAL SECTION: DRUG-INDUCED LIVER INJURY

Hepatotoxicity of statins and other lipid-­lowering agents

Einar S. Björnsson1,2

1
Faculty of Medicine, The National University
Hospital of Iceland, Reykjavik, Iceland
Abstract
2
Faculty of Medicine, University of Iceland, Statins are generally well tolerated and adverse effects are relatively rare. Clinical trials
Reykjavik, Iceland are underpowered to detect uncommon adverse effects such as idiosyncratic drug-­

Correspondence induced liver injury. This review is aimed at covering the current knowledge on the
Einar Björnsson, Department of Internal hepatotoxicity associated with statins and other lipid lowering drugs. Both atorvasta-
Medicine, The National University Hospital of
Iceland, Reykjavik, Iceland. tin and simvastatin have been associated with more than 50 case reports of liver injury
Email: einarsb@landspitali.is and other statins have been implicated in this type of liver injury as well. Idiosyncratic

Handling Editor: Raúl Andrade liver injury due to statins has been reported to occur 1.9%-­5.5% of patients in pro-
spective series of drug-­induced liver injury. Atorvastatin and simvastatin have been
associated with positive rechallenge and some case reports have described liver injury
following dose escalation of the implicated statin. Mortality from liver injury and/or
liver transplantation has been documented in a few patients with statin induced liver
injury although the vast majority of patients with liver injury have recovered after ces-
sation of therapy.

KEYWORDS
atorvastatin, drug-induced liver injury, hepatotoxicity, simvastatin, statins

hepatoxicity from the literature was published.16 Furthermore, statins

1 |  INTRODUCTION
were among the causes of acute liver failure reported from the acute
liver failure study group in the USA.17 Since then three separate pa-
Statins are among the most commonly used type of drugs worldwide
pers on patients with statin suspected liver injury have been pub-
in patients with hypercholesterolaemia and other risk factors for car-
lished.18–20 Patients who are put on statins with elevated liver tests
diovascular disease, both in primary and secondary prevention.1–4 In
at baseline, with non-­alcoholic liver disease and hepatitis C are not at
early clinical trials, elevations of aminotransferases were observed in
higher risk of hepatotoxicity from these drugs than those with normal
up to 2% of patients.1–4 Despite this clinically apparent liver injury
liver tests at baseline.21,22 This review is aimed at covering the current
was very rarely observed in the statin trials.1–4 Although trials on the
knowledge on the hepatotoxicity associated with statins and other
efficacy and safety of statins have included several thousands of pa-
lipid lowering drugs.
tients, the trials are underpowered to detect uncommon side effects
such as DILI. Thus, DILI is generally detected in the post-­marketing
phase.5 Shortly after its marketing in Europe, three reports of simv-
2 | FREQUENCY OF LIVER INJURY THE
astatin suspected liver injury were published.6–8 All major prospec-
USE OF STATINS
tive and retrospective series on DILI have included statin suspected
hepatotoxicity.9–15 In 2009, summary of 40 cases of statin induced
In recent years, three prospective DILI studies have been undertaken
from Spain, USA and Iceland.10,14,15 In the Icelandic study, three pa-
Abbreviations: AIH, Autoimmune hepatitis; ALF, acute liver failure; ALP, Alkaline phospha- tients out of 96 recruited patients (3.1%) had liver injury asssociated
tase; ALT, alanine aminotransferase; DIAIH, Drug-induced autoimmune hepatitis; DILI,
with atorvastatin (n=2) and simvastatin (n=1).14 Analysis of the cases
drug-induced liver injury; DILIN, drug-induced liver injury network; ULN, upper limit of nor-
mal; US, United States. from the Spanish Hepatotoxicity Registry associated with statin use,

Liver International 2017; 37: 173–178 wileyonlinelibrary.com/journal/liv © 2016 John Wiley & Sons A/S.  |  173
Published by John Wiley & Sons Ltd
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174       BJÖRNSSON
revealed that 5.5% (47/858) of all cases were due to statins.19 In the
DILIN study from the USA, 1.9% (22/1188) of cases recruited from
2004 to 2014, having at least a probable likelihood relationship was
associated with statins.20 In general, it is very difficult to obtain infor-
mation on the exact numbers of individuals taking different drugs in
different countries. Thus, in almost all studies on DILI, the numbers
needed to harm have not been available. A notable exception is the
prospective and population based study from Iceland.14 The propor-
tion of patients taking amoxicillin-­clavulanate (the most commonly
implicated agent) who developed liver injury, was approximately one
out of 2300 users,14 whereas the largest risk with individual drugs
was 1 of 148 and 1 of 133 with infliximab and azathioprine respec-
tively.14 As a result of the small numbers of patients with hepato-
toxicity associated with statin use, reliable calculations of patients at
risk are very difficult. During this study period of 2 years in Iceland,14
overall 27 845 patients were treated with simvastatin and one was
diagnosed with liver injury, whereas 7385 patients were treated with
atorvastatin and two developed DILI, leading to a risk of liver injury in
14
one patient of approximately 3700 treated patients. As mentioned
above, it has to be acknowledged that the numbers are small. A ret-
rospective study based on spontaneous reporting of adverse drug
reactions to the Swedish authorities showed much lower incidence
18
figures. Based on the sale of statins in Sweden during this study
period and spontaneous reporting, a statin-­related DILI episode was
observed in 1.6/10 000 person-­years and in 1.2 per 100 000 users.18
However, it is well known that there is a huge underreporting of ad-
verse drug reactions and these figures are likely to be a large underes-
timation of the frequency of these reactions. In a small retrospective
cases, series from Iceland consisting of four patients with well docu-
mented histologically documented liver injury associated with statin
use, one new case per approximately 17 000 users.23 If both simvas-
tatin and atorvastatin, cases are added in the prospective Icelandic
study, one new case per 11 000 users could be estimated.14 Patients
on statin treatment within a health maintainance organization in the
USA who were found to have more than 10-­fold elevation in ami-
notransferases were identified.24 Among 23 000 patients, 62 (0.3%)
were identified with an alanine aminotransferase (ALT) greater than
10 times the upper limit of normal during this study period. Overall
17/230 000 patients (0.1%) had significant ALT elevations consid-
24
ered directly attributable to statin use. In total, 76% (13/17) cases
were considered to be due to drug interactions.24 However, analysis
of patients with hepatotoxicity attributed to statins in a study from
Sweden could not find evidence for clinically relevant interactions
that could explain statin induced liver injury.18 Among patients put
on the liver transplant list with acute liver failure (ALF) 1990-­2002 in
25
the USA, three were identified as having liver failure due to statins.
Moreover, among patients with ALF (ALF), with liver failure in the
USA (1998-­2007), statins were the implicated agent in 6/133 (4.5%)
cases.17
The largest study of liver injury with statins as the implicated
agents is based on analysis of spontaneous reporting to the Swedish
18
Adverse Drug Reactions Advisory Committe during 1988-­2010.
The inclusion crteria were based on reported and suspected statin
Key points
• Statins can lead to idiosyncratic liver injury.
• More than 50 cases of liver injury have been reported in
association with atorvastatin and simvastatin.
• In prospective studies of patients with DILI, statins have
been the cause in approximately 2%-5% of patients.
• Statins, mainly atorvastatin can induce autoimmune
hepatitis.
• Mortality from liver injury has only been associated with
atorvastatin and simvastatin.
injury, >5 × upper limit of normal (ULN) in aminotransferases and/or
alkaline phosphatase >2 × ULN.18 Overall 73 patients fulfilled the pre-­
determined criteria. Other series with a significant number of patients
with statin induced hepatotoxicity included 47 patients and 22 pa-
tients recruited prospectively in the Spanish Hepatotoxicity Registry
and the DILIN Registry respectively.19,20 The following parts on phe-
notypes, clinical characteristics and outcomes are based on these ap-
proximately 140 patients reported in these three series.18–20 Similar
definitions for liver injury associated with statins were used in these
three studies.18–20 The Swedish and the DILIN studies both had the
same threshold for liver injury, ALT or AST >5 times ULN and/or ALP
>2 ULN and although initially in the Spanish Registry the threshold
in ALT/AST was >2 × ULN, later on it was changed to >5 × ULN, in
2011.19 In the Swedish and Spanish studies, RUCAM was the causal-
ity assessment tool but in the DILIN study expert opinion was mainly
used apart from RUCAM.20
3 | PHENOTYPES, DURATION OF THERAPY
AND HISTOLOGY
The age range, gender proportions, type of liver injury and the differ-
ent statins implicated in the three largest series are demonstrated in
Table 1. However, other patients with DILI in the Spanish Registry
were significantly younger.19 Females were predominant in the DILIN
study whereas in Sweden and Spain the injury was similar in males and
females (Table 1). The clinical phenotype in the three studies was very
variable. The median latency from start of statin duration of treatment
varied widely in the three studies. The median duration of treatment
was longest in the DILIN study, with 155 days,20 57 days in Spain 19
18
and 90 days in the Swedish study. The shortest latency reported in
the DILIN study was 34 days and the majority developed liver injury
within 6 months. Compared with other DILI patients the Spanish pa-
tients with statin induced liver injury did not have significantly longer
latency than other DILI patients.19 Most patients with statin induced
liver injury were symptomatic although a minority (13%) were asymp-
tomatic in the DILIN study.20
Jaundice was present in 35% in the Swedish study, 53% in the
Spanish study and in 68% in the DILIN study, of whom 18% had
BJÖRNSSON |
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T A B L E   1   Median age, gender proportion, type of liver injury, which reproduced a similar pattern of liver injury as the original liver in-
median dose, proportion with jaundice, as well as the proportion of jury.18 These patients were rechallenged inadvertently, as the respon-
statins reported in the three large on statin induced liver injury sible physicians were either uncertain of the cause of the previous liver
Sweden Spain (n=47), USA (n=22), injury or did not take it seriously.18 The liver injury was of cholestatic
(n=73), ref. 18 ref. 19 ref. 20 type in one of these patients but hepatocellular in the other two who
Age 64 62 60 had ALT elevations more than 50 times the ULN in comparison with

Gender (male %) 55% 47% 32% 10-­15 times elevations during the previous injury with concomitant
bilirubin elevation.18 All of these patients recovered.18 One of the pa-
Dose (median), mg – – 20
tients in the DILIN statin study was restarted on the same statin and
Hepatocellular 59% 51% 55%
quickly re-­developed similar type of acute liver injury.20
Latency (median) 90 57 155
Drug-­induced autoimmune hepatitis (DIAIH) has been well doc-
Jaundice 35% 53% 68%
umented for several drugs such as nitrofurantoin,32 minocycline,32
Autoantibodies – 25% 27%
infliximab33 and also statins, mainly atorvastatin.16 Drug-­induced
Chronicity – 19% 18% autoimmune hepatitis seems to have similar clinical, biochemical and
Atorvastatin 41% 34% 36% histological patterns as AIH not induced by drugs, but in the largest
Simvastatin 38% 28% 23% series, these patients did not seem to require long-­term immunosup-
Fluvastatin 15% 25% 9% pression.32,33 Thus, although these patients required immunosuppres-
Lovastatin – 4% 5% sion initially they were very unlikely to relapse after discontinuation
Rosuvastatin 3% – 18% of immunosuppression.32,33 However, a relapse has been reported in
Pravastatin 3% 8% 9% a patient with atorvastatin induced AIH after discontinuation of cor-
ticosteroids and azathioprine.16 Although most drug-­induced DIAIH
HC, hepatocellular, ref., reference.
have been associated with atorvastatin,19,20,34–38 this has also been
18–20
concomitant coagulopathy with elevation in INR. More patients associated with fluvastatin37 and rosuvastatin.20 Thus, it clear that
with statin induced liver injury had hepatocellular than cholestatic or statins are increasingly recognized as drugs that can induce the so
mixed liver injury (Table 1). However, the type of liver injury seems called drug-­induced autoimmune hepatitis.19,20,34–38
to vary widely. Alkaline phosphatase (ALP) levels times upper limit of In a recent analysis from the Spanish Hepatotoxicity Registry,
normal were significantly more elevated in the statin group than other statins were the most frequent type of drugs that were associated
DILI patients.19 Cholestatic/mixed pattern was more common with with chronic liver injury.39
atorvastatin in 56% of patients than among Simvastatin induced liver
injury in 24% (P=.018) in this study from Sweden.18 The other studies
have probably not had enough power to compare the different statin 4 | COMPARISON OF THE DIFFERENT
in that respect. STATINS
Interestingly, two patients had dose increase within a few months
of developing liver injury.20 In a recent case report, a dose escalation Atorvastatin has been the most frequently implicated statin in all of
of atorvastatin was associated with acute liver failure.26 An 85-­year the series of statin induced hepatotoxicity as shown in Table 1.18–20
old woman had been treated with 40 mg daily of atorvastatin for ap- Categorization of drugs leading to liver injury based on the number
proximately 15 months without adverse effect when the dose was of published case reports was recently undertaken.40 Atorvastatin
increased to 80 mg daily due to inadequate lipemic control.26 Five and simvastatin both belong to category A, which consists of drugs
months later, she developed jaundice and elevated alanine amino- with more than 50 well-­documented cases of hepatotoxicity (Table 2).
transferase (909 IU/L) asparate aminotransferase (1157 IU/L) and Apart from these, fluvastatin seems to be the statin apart from atorv-
ALP (415 IU/L), creatine kinase (4753 IU/L) as well as elevated INR astatin and simvastatin that has also well-­documented hepatotoxicity
(1.71) and she also developed hepatic encephalopathy.26 Atorvastatin with almost 30 cases reported and also reported positive rechallenge
induced liver injury was suspected, the drug discontinued and she re- (Table 2). Interestingly, in a Swedish retrospective study on spontane-
covered.26 A liver biopsy a few months later revealed portal hepatitis, ous reporting of DILI, fluvastatin was according to sale figures asso-
with an inflammatory infiltrate with predominance of lymphocytes and ciated with the highest incidence of statin induced hepatotoxicity.18
eosinophils.26 The authors speculated that as atorvastatin is a highly Other statins have according to this recent categorization had 11-­13
lipophilic drug, extensively metabolized by CYP3A4 might increase the reports of liver injury reported but not been associated with positive
risk of hepatotoxicity from this drug.26 Extensive hepatic metabolism rechallenge or mortality.18 However, it should be acknowledged that
and lipophilicity has indeed been documented to increase the risk of it is difficult to compare the risk of hepatotoxicity associated with the
hepatotoxicity in general.27,28 Moreover, a high oral daily dose is asso- different statins. Only the Icelandic study has been population based
ciated with an increased risk of DILI.29 Atorvastatin,18 Simvastatin18,30 but lacks power in this context. Atorvastatin and simvastatin may
and pravastatin31 have had documented positive rechallenge. In the have been more frequently reported because they have been more
Swedish study, three patients were rechallenged with the same statin, frequently prescribed.
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176       BJÖRNSSON

T A B L E   2   Number of case reports of DILI with different statins onset.20 Interestingly, very similar proportions of patients fulfilled
and whether cases of positive rechallenge and fatality from the liver these criteria for chronicity, that is 18% and 19% respectively 19,20

injury has been reported (modified from reference)40 (Table 1). In the Spanish study, chronicity associated with statin in-
Fatal liver duced liver injury was similar to that observed with other treatments
Number of injury (21.4%).19 In a separate study on chronicity, seven of 298 (2.3%) DILI
cases Positive reported cases without pre-­existing liver disease and with at least 1 year of
reported rechallenge (yes/no)
follow-­up were found to have cirrhosis on a liver biopsy, of whom two
Simvastatin 68 yes yes (29%) had atorvastatin induced liver injury.39
Atorvastatin 65 yes yes
Fluvastatin 28 yes no
Rosuvastatin 13 no no 7 | OTHER LIPID LOWERING AGENTS
Lovastatin 12 no no
Pravastatin 11 no no Before the statins discussed above became the dominating lipid low-
ering agents, both niacin and fibrates were frequently used as lipid
lowering therapy. Niacin has well documented hepatotoxicity.43–46
Limited data exist on tolerance of other statins in patients who This can be serious and has been associated with fatality.40 According
have experienced statin induced liver injury. A case has been reported to a recent categorization of drugs implicated in liver injury, niacin
who recovered after liver injury from fluvastatin also developed liver was found to be a direct hepatotoxin.40 This category consisted of
20
injury with atorvastatin. However, in five cases information was pharmaceuticals that had not been implicated in causing liver injury at
available about switch to another statin in the Swedish statin study, standard doses, but are clearly hepatotoxic in high concentrations or
after they recovered from liver injury.18 This was possible in all cases with drug overdoses, for example, both niacin and acetaminophen. All
without reported liver injury during follow-­up.18 In three patients, three fibrates that have been used to lower lipids: fenofibrate, gemfi-
atorvastatin was replaced pravastatin and in one by simvastatin and brazole and clofibrate have been linked to cases with clinically appar-
two patients could use simvastatin and atorvastatin instead of rosu- ent liver injury.10,11,47–49 Fenofibrate is the best documented with 24
18
vastatin that lead to the original liver reaction. cases of hepatotoxicity according to a recent review.40 Among cases
with Fenofibrate induced liver injury there has been a case of positive
rechallenge.40 Gemfibrazole has only been implicated in six published
5 |  OUTCOMES cases and clofibrate in only three and none of these two agents had
cases with positive rechallenge.40 Therefore, the hepatotoxicty of
As in other patients with DILI, the prognosis of patients with statin gemfibrazole and clofibrate is questionable. Fibrates were reported
induced liver injury is generally favourable. Only atorvastatin and sim- in 11/461 (2.4%) in the original large cohort paper from the Spanish
vastatin have been associated with fatality from statin induced liver Registry.10 The acute liver injury was relatively mild, with a mean el-
18,20,40–42
injury, whereas patients reported to have liver injury from evation in serum bilirubin of 2.4.10 Interestingly, two cases of fibrate
fluvastatin, lovastatin, pravastatin and rosuvastatin have all recov- induced liver injury, 2/28 (7%) with chronic liver injury at long-­term
ered (Table 2). In the retrospective study from Sweden, two patients follow-­up were associated with fibrates and the same number with
died as a result of the statin induced liver injury and one required statins (7%).50 No cases of other lipid lowering agents than statins
18
liver transplantation. Among patients reported from the Spanish were observed in the prospective DILi study from Iceland.14 Among
Hepatotoxicity there were two deaths among the 47 cases but the 899 patients in the DILIN study four patients with liver injury associ-
deaths were not liver related.19 In the DILIN study, four of the 22 ated with fenofibrate were reported and one with gemfibrazole.15
patients were considered to have severe statin induced liver injury, In summary, clinically important liver injury from statins is very
presenting with apart from jaundice, prolongation of INR but only one rare, but use of statins can be associated with liver injury and some-
patient died.20 The fatality was observed in a patient with pre-­existing times severe hepatotoxicity. Among statins, only atorvastatin and sim-
alcoholic cirrhosis.20 vastatin induced liver injury has been associated with fatal outcome.
Although liver injury can occur in patients treated with statins this is
rare. If patients have a good indication for statin therapy, even those
6 |  CHRONICITY who have underlying liver pathology such as non-­alcoholic steatohep-
atitis, patients should be treated with statins as many of these patients
Both this study from the Spanish Hepatotoxicity Registry and the have greater risk of cardiovascular mortality than suffering from liver
DILIN study included follow-­up of patients with statin induced liver disease.
injury.19,20 The term chronic liver injury was reserved for the cases
in whom the damage persisted biochemically for more than 1 year.19
CO NFL I C T O F I NT ER ES TS
Chronic injury in the DILIN study was defined as liver biochemical or
histological abnormalities that persisted for 6 months or more after The author has no conflict of interests.
BJÖRNSSON
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