EMA6_An Update on Drug Induced Liver Injury

Vol. 57 - No. 2 MINERVA GASTROENTEROLOGICA E DIETOLOGICA 213

MINERVA GASTROENTEROL DIETOL 2011;57:213-29

Funding.Dr. Rangnekar is supported by a Clinical and Translational Science Award from the Michigan Institute for Clinical and Health Research. Dr. Fontana is a member of DILIN and the ALFSG and supported, in part, by grants from the National Institutes of Diabetes and Digestive and Kidney Diseases (U01-DK-065184 and RO-1-DK-58369-01).

Corresponding author: R. J. Fontana, MD, Professor of Medicine, Medical Director of Liver Transplantation, 3912 Taubman Center, Ann Arbor, MI 48109-0362 USA.E-mail: [email protected]

Department of Internal MedicineUniversity of Michigan Medical Center

Ann Arbor, MI, USA

Drug induced liver injury (DILI) is an uncom-mon cause of acute and chronic liver injury of increasing importance to patients, clini-cians, and regulators. The incidence of DILI due to an individual agent is not well defined but population-based studies suggest that the overall incidence of DILI may be as high as 10 to 15 cases per 100000 patient years. Bona fide risk factors for DILI are also not well es-tablished, but ongoing multicenter registry studies such as the Drug Induced Liver Injury Network are attempting to identify the role of genetic, environmental, and immunological factors in DILI pathogenesis and outcomes. Acute hepatocellular injury (~50%) is more common than mixed or cholestatic liver injury but jaundiced DILI subjects with either type of liver injury have a ~10% risk of short-term mortality. Antibiotics are the most commonly implicated agents associated with DILI, but there are emerging reports of liver injury as-sociated with the use of a multitude of herbal and dietary supplements. Despite their wide-spread use, the HMG-CoA reductase inhibi-tors or statins are an uncommon cause of idi-osyncratic DILI. Furthermore, recent studies have shown that statins are actually safe and efficacious to use in hyperlipidemic patients with chronic liver disease. Acetaminophen

hepatotoxicity remains a leading cause of se-vere acute liver injury. Limiting the amount of acetaminophen in prescription narcotic products may help reduce the incidence of future non-intentional overdoses but educat-ing patients and providers of the multitude of over the counter products that contain aceta-minophen is also recommended.

Key words: Acetaminophen - Dietary supple-ments - Pharmacogenetics.

Drug-induced liver injury (DILI) is an increasingly recognized cause of acu-te and chronic liver injury. The overall inci-dence of DILI in western population-based studies ranges between 1 per 10 000 to 100000 individuals, although these values may be underestimated due to challenges in diagnosis and reporting.1 In the United States, idiosyncratic DILI accounts for 13% of adult acute liver failure (ALF) cases while acetaminophen (APAP) overdose accounts for 40-50% of cases. Since mortality from drug-induced jaundice may approach 10%, prompt discontinuation of the offending agent as well as early recognition of DILI patients with adverse prognostic factors is important for optimal outcomes.2, 3 Idiosyn-cratic DILI is also a leading reason for drugs

A. S. RANGNEKAR, R. J. FONTANA

An update on drug induced liver injury

Anno: 2011Mese: JuneVolume: 57No: 2Rivista: MINERVA GASTROENTEROLOGICA E DIETOLOGICACod Rivista: MINERVA GASTROENTEROL DIETOL

Lavoro: titolo breve: AN UPDATE ON DRUG INDUCED LIVER INJURYprimo autore: RANGNEKAR pagine: 213-29

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214 MINERVA GASTROENTEROLOGICA E DIETOLOGICA June 2011

RANGNEKAR AN UPDATE ON DRUG INDUCED LIVER INJURY

in development to fail to obtain regulatory approval or to be subsequently withdrawn or restricted in their use, as recently noted with troglitazone and telithromycin, respec-tively.4, 5 Acetaminophen, a dose-dependent hepatotoxin found in multiple over-the-counter and prescription products, is the most common cause of DILI in the western world.6 However, most other instances of DILI appear to be idiosyncratic reactions that are independent of the dose ingested. The aim of this review is to provide an

update on the epidemiology, natural histo-ry, and emerging causes of DILI in western patients. In addition, a summary of clinical, pharmacogenetic, and immunological risk factors involved in DILI pathogenesis from several ongoing multicenter registry studies is provided.

Epidemiology

The epidemiology of DILI has been diffi-cult to study for several reasons. First, DILI

Table I.Minimal elements required to make a diagnosis of DILI.

Feature Comments

Presenting clinical features Age Gender Indication for drug Fever, rash, itching Immunoallergic features frequently absent

Medication history Implicated drug or HDS with generic name, dose, and fre-

quency of administration Duration of therapy Other drugs taken in 2 months prior to DILI onset Prior implicated drug exposure

Difficult when taking multiple herbals

Difficult to determine in some cases

Rechallenge infrequently encountered and not al-ways reliable

Initial evaluation Time from drug start to symptoms or jaundice (if present) Time from drug start to first abnormal lab Eosinophils (number/L or %) at onset or early in course

of injury

Initial and serial AST and ALT levels

Initial and serial alk phos or GGT levels Initial and serial bilirubin levels Initial and serial INR

Some patients are asymptomatic

First lab value meeting diagnostic criteria is DILI on-set date

Eosinophilia defined as Absolute Eos > 500/ml or >5% on diff

Review available pretreatment, peak, and post-di-scontinuation lab values

Include direct bilirubin if available.

Potential risk factors/ competing causes Alcohol use Risk factors for acute and chronic liver disease including

family history Exclusion of heart failure, shock, sepsis, parenteral nutri-

tion prior to DILI onset Blood tests to exclude other causes of acute liver disease IgM anti-HAV (or negative anti-HAV) HBsAg and IgM anti-HBc (or negative anti-HBc) Anti-HCV and HCV RNA ANA, SmAb (and titer if positive)

Imaging of the liver (type and results) Liver USN and abdominal CT/ MRI Liver histology

Amount and pattern of use in 2 months prior to drug start and thereafter

Include parenteral exposures Based on medical history and cardiac imaging

Consider anti-HEV IgM if possible

Quantitative immunoglobulins, anti-HIV, CPK, CMV DNA by PCR, and EBV-DNA by PCR of value in se-lected cases

MRCP and ERCP helpful in some Useful to review injury pattern and severity if availa-

ble

Adapted from Fontana RJ, et al. Hepatology August 2010.107

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AN UPDATE ON DRUG INDUCED LIVER INJURY RANGNEKAR

nal Registry of Hepatotoxicity in southern Spain represents a consortium of centers that gather clinical data and biological sam-ples on DILI patients. In addition, the U.S. Acute Liver Failure Study Group (ALFSG), and the Drug-Induced Liver Injury Network (DILIN) are multicenter networks enrolling patients with ALF and DILI, respectively. Between 1994 and 2004, the Regional Re-gistry of Hepatotoxicity in Spain identified 461 cases of DILI and estimated the annual incidence of DILI at approximately 34 cases per 1 million persons. Nearly 58% of the DILI patients exhibited a hepatocellular li-ver injury pattern at presentation and 12% of patients with drug-induced jaundice pro-gressed to liver transplant or death.11 The ALFSG, which collects data from 17 tertia-ry care centers across the U.S., has found that idiosyncratic DILI accounts for 12% of ALF cases with isoniazid and nitrofurantoin most commonly implicated.2, 6 From 2003 to 2006, DILIN enrolled 300 consecutive DILI patients and noted that 73% of the cases were attributed to a single medication, 9%

accounts for



initial use, and the majority of patients will recover with discontinuation but rare cases of ALF have been reported.13, 17 Catechins are polyphenols in green tea extract that are thought to lead to cellular injury throu-gh mitochondrial disruption and generation of reactive oxygen species, but the actual mechanism of liver injury remains unclear.18

Risk factors for DILI

Many experts believe that certain patients may have increased susceptibility to DILI. While early retrospective studies suggested that women were at higher risk of deve-loping DILI possibly due to reduced body weight and greater overall use of medica-tions,1, 2, 19 subsequent studies have shown no difference between men and women.11, 13, 20-22 Nonetheless, two recent studies sho-wed that women are more likely to present with hepatocellular liver injury,13, 21 and that women with DILI may be at higher risk of progressing to ALF.11, 21, 23The elderly (i.e. those over the age of

65) may be at increased risk for developing DILI, due to altered drug pharmacokineti-cs and inadvertent drug interactions asso-ciated with polypharmacy.24, 25 However, there is no clear and convincing evidence from prospective studies that advancing age confers a higher susceptibility to DILI per se, although the elderly may be at higher risk of developing DILI with certain medi-cations such as isoniazid.26 Elderly patients may also be more likely to present with a mixed or purely cholestatic liver injury pat-tern compared to younger patients.11, 13, 21, 27 However, it should also be noted that chil-dren may be at increased risk of developing valproate hepatotoxicity as well as Reyes syndrome from aspirin.28, 29 Underlying liver disease has long been

considered a risk factor for the develop-ment of DILI. Both chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection may predispose patients to developing DILI from several medications including anti-tuberculosis agents, methimazole, and ibu-profen.30, 31 Although an attenuated intra-

to herbal or dietary supplements (HDS), and 18% to multiple suspect agents. The most commonly implicated agents in this study include antimicrobials, central nervous sy-stem agents, and immunomodulatory medi-cations. Interestingly, both the Spanish and DILIN registries identified amoxicillin-cla-vulanate as the most commonly implicated individual agent (59 and 23 cases, respecti-vely). Of the initial 300 patients enrolled in DILIN, asymptomatic laboratory abnormali-ties, overall mortality, and liver-related mor-tality were reported in 14%, 8%, and 3%, respectively.12, 13

Herbal and dietary supplements

In recent years, there has been an increa-se in the use of over-the-counter herbal and dietary supplements due to the public per-ception that these natural products are ef-ficacious and safe to take in large quantities. Common indications to use these products include intentional weight-loss, muscle-building, and enhancement of general well being. However, regulation of the marke-ting and manufacturing of HDS products is currently limited, and there are increasing reports of hepatotoxicity associated with some of these agents. Since under-reporting of over-the counter product use is com-mon, it is difficult to accurately determine the rates of adverse events associated with their use. However, supplements containing Hydroxycut, Herbalife, green tea, black co-hash, and anabolic steroids have all been implicated with severe and life-threatening DILI.14Green tea is a common ingredient in

many herbal preparations. It is derived from the leaves of Camellia sinensis and is a pur-ported weight loss agent and energy enhan-cer. Multiple cases of hepatitis have been observed in patients consuming green tea extract.15, 16 In 2003, Exolise, a product con-taining green tea extract, was withdrawn from the market in France and Spain due to reports of hepatotoxicity. In most cases of green tea hepatotoxicity, acute hepato-cellular injury develops within 3 months of

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of competing etiologies, evidence of prior reports of liver injury, and re-challenge. While this model is quite comprehensive, it does have several limitations. First, missing data for most of the criteria automatically lowers the total score, which may be par-ticularly problematic when studying a new drug or HDS product. Secondly, several criteria require subjective decision-making such as use of other hepatotoxic drugs and the amount of alcohol consumed. Thirdly, inter-rater reliability has been low, even in instances when this tool is utilized by ex-perts for research purposes.37 Finally, the means by which competing causes of liver injury are to be excluded are not provided, and the instrument does not mandate te-sting for acute HCV or HEV infection that can mimic DILI.13, 40 Despite these limita-tions, the RUCAM continues to be the most commonly cited causality instrument in DILI studies. Historically, consensus expert opinion

has been regarded as the gold standard in diagnosing DILI. However, many studies have demonstrated low inter-observer relia-bility among experts, and this methodology is not widely available or generalizable.41, 42 In DILIN, a consensus opinion is determined by the site investigator as well as two addi-tional independent study investigators who review an extensive clinical narrative and prospectively assembled dataset that inclu-des serial serum alanine aminotransferase (ALT) values and a host of diagnostic tests in each case. In DILIN, expert opinion is further strengthened by involving multiple other investigators by conference call du-ring discussion of these cases.43 The pattern of liver injury is categorized by the R value which is calculated as the initial serum ALT/upper limit of normal (ULN) divided by the serum alkaline phosphatase (AP)/ULN. An R value 5 is hepatocellular, and all other R values are considered mixed. While expert opinion may be the gold

standard for diagnosing DILI, this is not a practical approach for most clinicians. A probabilistic approach to causality as-sessment requires the availability of a lar-

hepatic immune response and altered drug metabolism have been implicated, it can be very difficult to distinguish a chronic liver disease flare due to a surge in viral replica-tion versus a true DILI episode. Nonethe-less, multiple studies have shown that HBV or HCV coinfection appears to increase the risk of DILI in patients with human immu-nodeficiency virus (HIV) infection. In fact, treatment of HCV with interferon-based therapy may lower the risk of DILI due to highly active antiretroviral therapy (HAART) in HIV patients with HCV co-infection.32, 33In contrast to the above, most studies

have not found non-alcoholic fatty liver di-sease (NAFLD) to be an independent risk factor for DILI. Furthermore, patients with NAFLD do not have an increased suscepti-bility to statin-induced DILI.11, 13, 34, 35 Alco-hol consumption was previously conside-red to be a risk factor for DILI. However, despite its presumed role in exacerbating acetaminophen-induced hepatotoxicity, alcohol has not been shown to be a risk factor for developing idiosyncratic DILI in several studies.11, 13, 26, 36

Causality assessment

Establishing a diagnosis of DILI remains difficult given the lack of standardized dia-gnostic criteria and the fact that DILI is largely a clinical diagnosis of exclusion. Existing diagnostic algorithms are cumber-some and unfamiliar to most clinicians. De-veloping a single instrument to easily assess causality has been particularly problematic given the low incidence of DILI and its un-predictable onset and variable natural hi-story.37The Rousel Uclaf Causality Assessment

Model (RUCAM) algorithm, which was de-veloped in 1989, is the most widely used li-ver-specific causality assessment method.38, 39 The information domains of the RUCAM include a determination of the chronologi-cal relationship between the suspect medi-cation use and liver injury onset as well as changes after drug discontinuation, identifi-cation of concurrent risk factors, exclusion

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cib were recently associated with specific class I and class II human leukocyte anti-gen (HLA) genotypes.48 The delayed onset of DILI in many cases further supports the notion that the adaptive immune response may be involved in DILI pathogenesis. Ho-wever, most other idiosyncratic DILI cases have not been shown to correlate with HLA genotypes.49 Autoimmunity due to an al-tered host protein or drug-metabolite/host protein complex is another potential me-chanism of DILI.50 For example, several me-dications such as hydralazine, diclofenac, nitrofurantoin, and minocycline, are asso-ciated with both hepatotoxicity and autoim-mune syndromes. Although many of these DILI patients present with high titer auto-antibodies, the fundamental pathogenesis of sporadic autoimmune hepatitis unfor-tunately remains elusive. A third potential mechanism of hepatotoxicity involves poly-morphisms in metabolic and/or detoxifica-tion pathways leading to the development of toxic metabolites.50 However, it has been difficult to reliably identify reactive meta-bolites in humans as well as in in vitro and animal model test systems. Clarifying the role of host genetic factors

in DILI pathogenesis has proven difficult due to the variability of presentation, the large number of different drugs causing in-jury, and until recently, a lack of reliable

ge number of well-vetted cases wherein a pre-test odds can be determined as well as complex analytic methods to apply Baye-sian statistics.44, 45 Although Bayesian appro-aches are attractive for adverse drug events like DILI that frequently have missing data, the need for precise data from a large num-ber of cases is a limitation with a rare dise-ase like DILI. The identification of validated biomarkers may help make a more accurate and reliable diagnosis of DILI possible. In addition, use of computerized algorithms wherein available data elements can be analyzed in the setting of prior reports may lead to improved diagnostic instruments.

Pathogenesis

The overwhelming majority of DILI cases are thought to be idiosyncratic (i.e. inde-pendent of drug dose and due to a unique mixture of ones own characteristics). Ho-wever, a recent review of drugs that were withdrawn from the marketplace or recei-ved black-box warnings for hepatotoxicity showed that most were prescribed at doses exceeding 50 mg per day.46, 47 Recent stu-dies have also suggested that some DILI ca-ses may, in part, be immune-mediated. For example, hepatotoxicity due to amoxicillin-clavulanate, ximelagatran, and lumiracox-

Table III.Studies of genetic polymorphisms in DILI patients.

Drug (ref #) DILI cases (N.) Implicated Gene * Odds ratio P-value Comment

Isoniazid 54 26 CYP2E11 3.4 0.02 Involved in metabolite bioactivation

Isoniazid 53 49 CYP2E11 2.5 0.009

Isoniazid 52 33 NAT 21 3.7 0.003 Involved in detoxification of metabolite

Amoxicillin-clavulanate 56 22 HLA DRB1*15011 9.3 2.510-6

Valproate 61 17 POLG1 23.6 5.110-7 Included 6 children

Flucloxacillin 57 51 HLA B*57012 80.6 910-19 Replication cohort inclu-ded

Ximelagatran 48 74 HLA DRB1*072 N/a N/a Not approved for use

Lumiracoxib 60 139 HLA DRB1*15012 5.0 6.810-25 Not approved for use; Replication cohort in-cluded

*Studies with a 1 used a candidate gene approach while 2 denotes GWA study.

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The first successful GWA study in DILI identified a strong association between flucloxacillin-induced liver injury and the HLA-B*5701 allele.57 In this study, 51 case patients who experienced a typical chole-static hepatitis following the use of fluclo-xacillin in England were genotyped as well as 64 drug-exposed controls. In the initial cohort as well as a validation cohort, pos-session of the HLA-B*5701 allele was asso-ciated with an 80-fold increased risk of de-veloping DILI (P=910-19). Interestingly, this HLA allele has also been associated with abacavir-hypersensitivity in HIV patients.58 A subsequent analysis also revealed a se-cond gene, ST6GAL1, to be associated with flucloxacillin hepatotoxicity and a follow-up study suggested an independent role for polymorphisms in the promoter region of the pregnane X receptor (PXR) which is ac-tivated by flucloxacillin.57, 59 Another recent GWA study identified an association betwe-en the HLA class II allele, HLA-DRB1*07, and elevations in serum ALT levels in 74 subjects treated with ximelagatran, a throm-bin inhibitor that was withdrawn, and 130 treated controls.48 Finally, a GWA study was undertaken in 41 patients with lumiracox-cib induced liver injury and in a validation cohort of 98 patients. Fine mapping demon-strated a strong link between lumiracoxcib hepatotoxicity and a commonly occurring HLA haplotype, HLA-DRB1*150, with an odds ratio of 5.60 These studies show that GWA methodo-

logies promise to become an increasingly useful method for the evaluation of com-plex disease traits like DILI. In addition, use of whole exome and whole genome sequencing may prove to be even more in-formative in the future as the cost and fea-sibility of these studies improve. However, challenges will likely remain in applying these powerful genetic techniques to rare disease phenotypes like DILI due to the li-mited number of cases attributed to an in-dividual agent enrolled in the ongoing re-gistries worldwide. However, collection of even a small number of DILI cases can pro-ve very informative, as was recently shown in studies implicating rare polymorphisms

prospective data and samples to test. Pre-vious genetic association studies have lar-gely focused on evaluating candidate ge-nes involved in the uptake, metabolism, transport, or detoxification of a drug (Table III). For example, reduced activity in the NAT2 gene, which is involved in the me-tabolism of isoniazid, has been associated with isoniazid hepatotoxicity in multiple studies.51, 52 Isoniazid is initially metaboli-zed to acetylhydrazine, which can then be further metabolized by NAT2 to the less to-xic diacetylhydrazine, while CYP2E1 me-diated oxidative metabolism leads to the generation of an hepatotoxic intermediate metabolite. Polymorphisms in CYP2E1 ex-pression have been correlated with isonia-zid hepatotoxicity, although these results have not been consistently replicated53, 54. Amoxicillin-clavulanate hepatotoxicity has also been associated with HLA DRB1*1501 in at least 2 studies, with 57-64% of affected patients having this allele.55, 56 Both xime-lagatran and flucloxacillin have also been associated with specific HLA haplotypes.48, 57 Among the patients in the Spanish regist-ry, both HLA-DRB1*07 and DQB1*02 were less prevalent in DILI patients, and as such have been proposed to confer a generally protective effect.49 Several other genetic po-lymorphisms have been reported in the lite-rature, but many of these studies are small, and the findings have not been replicated.The recent advent of genome-wide asso-

ciation (GWA) methodologies has enhan-ced the ability of researchers to identify the genetic basis of several common and rare diseases. GWA studies involve comparing common single nucleotide polymorphisms (SNP) present in at least 1 to 5% of indivi-duals across the entire genome of case pa-tients to unselected population controls of the same ethnic background. A DNA sam-ple extracted from whole blood is plated onto a gene chip which can assess up to 1 million SNPs simultaneously using high throughput methods. Based on the frequen-cy of identifying associations by chance, GWA studies usually require a strict thre-shold for statistical significance that exceeds 1 x 10-6 or more.

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rates are similar between patients with ALF due to acetaminophen overdose and idio-syncratic DILI, a greater percentage of pa-tients with idiosyncratic DILI require tran-splantation for long-term survival (53% vs. 6%).2 The ALFSG recently published prospec-

tive data regarding idiosyncratic drug-in-duced ALF in the US over a 10 year pe-riod.62 Among a total of 1198 ALF patients, 133 were ultimately diagnosed with DILI by expert opinion. Of these patients, 70.7% were women and 57.1% white, with a mean age of 43.8 years (Table IV). Antimicrobials (46%) were the most commonly implicated class of drugs and the top cited agents were isoniazid, nitrofurantoin, and trimethoprim-sulfamethoxazole. Overall 3-week patient

in the mitochondrial gamma polymerase gene (POLG) in patients with valproate he-patotoxicity.61

Natural history

After discontinuation of the suspected drug, the majority of patients with DILI will achieve complete clinical and laboratory recovery. However, nearly 10% of patients with drug-induced jaundice will eventual-ly progress to transplant or death. Patients who progress to ALF with concomitant co-agulopathy and encephalopathy are at high risk of death, but independent predictors of poor outcome in DILI-induced ALF are yet to be elucidated. While overall survival

Table IV.Adult patients with acute liver failure due to idiosyncratic DILI from the US ALFSG 1998 to 2007.

ALF DILI cases (N.=133)

Mean age 44

% Female 71%

Ethnicity (%) Caucasian African American Hispanic Other

57%16%15%12%

Labs at presentaton Median ALT (IU/ml) Mean Alk phos (IU/ml) Mean Bilirubin (mg/dl) Median INR

574166212.6

% Rash at presentation 8%

% Eosinophilia at presentation 11%

Duration of drug use prior to ALF 1-8 weeks

Causality score * % Highly likely % Probable % Possible

81%15%4%

3-week outcomes % Spontaneous survival % Transplanted % Died

27%42%31%

Implicated drugs, (N.) ^ Isoniazid (21)Nitrofurantoin (12)

TMP/SMX (9)Phenytoin (8)

Antifungal agents (azoles) (6)Various HDS products (12)

*Determined by expert opinion. ^Most frequently implicated agents.

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defines chronic DILI as persistently eleva-ted liver biochemistries on at least 2 occa-sions, abnormal liver histology, or radiolo-gical evidence of persistent liver injury at 6 months or more after DILI onset.43 Patients who present with a cholestatic injury pat-tern may be at increased risk of developing chronic DILI but confirmatory prospective studies are needed.36 To date, neither cor-ticosteroids nor ursodeoxycholic acid have been convincingly shown to improve pro-gnosis or outcomes or reduce the likeliho-od of developing chronic DILI.67 N-acetylcysteine (NAC) is an approved

treatment for patients with acetaminophen overdose at risk for liver injury. In 2009, the ALFSG reported the results of a ran-domized, double-blind, placebo-controlled trial which demonstrated the benefit of a 72-hour infusion of intravenous NAC in pa-tients with non-acetaminophen ALF.68 Spe-cifically, transplant-free survival was signifi-cantly higher for patients receiving NAC as compared to placebo (40% vs. 27% respec-tively, P=0.043) and this benefit was prima-rily confined to patients with early stage ALF, defined as coma grade I-II. Interestin-gly, patients with idiosyncratic DILI appe-ared to experience the greatest benefit in transplant-free survival (58% vs. 27%). The-refore, additional studies of NAC or other anti-oxidants/hepatoprotective agents are needed in patients with severe DILI.

Liver histopathology

While liver biopsy may be useful to de-termine the pattern and degree of liver in-jury, no specific histological changes are considered diagnostic of DILI. However, certain patterns of injury are associated with specific drugs, and a liver biopsy is frequently obtained to exclude other pos-sible competing etiologies of liver injury. For example, isolated non-necrotizing gra-nulomas are associated with phenytoin and allopurinol hepatotoxicity.69, 70 In addition, tamoxifen, amiodarone, and HAART may cause macrovesicular steatohepatitis,71-73 while tetracycline and valproic acid have

survival was 66.2%, but transplant-free sur-vival was only 27.1%. Information regarding medication factors

in the outcomes of patients with DILI is sparse. In general, a longer duration of the-rapy with an offending medication is asso-ciated with increasing severity of liver injury as well as an increased risk of developing chronic DILI.13, 36, 65 In addition, specific drugs such as halothane may be associated with a higher case fatality rate in compari-son to other agents such as erythromycin and amoxicillin-clavulanate which are gene-rally associated with self-limited disease.66 Patients with underlying diabetes mellitus are more likely to develop severe DILI and perhaps even ALF.13, 63 The role of chronic alcohol consumption in DILI remains lar-gely unclear and has not been associated with development of DILI or evolution into chronic liver injury.11, 36 A past history of DILI due to any medication increases the risk of future DILI.64 However, the role of other factors such as diet, smoking, and un-derlying illnesses in the development and outcome of DILI are largely unknown. In regards to clinical presentation, early

studies suggested that hepatocellular liver injury may portend a poorer prognosis,11, 13, 66 although recent prospective data do not support this observation.22 In patients with hepatocellular injury, the ratio of aspartate aminotransferase (AST) to ALT may corre-late with progression to ALF, transplanta-tion, and death.65, 66 The combination of hepatocellular injury and jaundice has been associated with higher mortality (i.e. Hys rule), and several recent studies have con-firmed higher rates of death and liver tran-splantation in patients with this clinical pre-sentation.11, 13, 66

Treatment of DILI

The vast majority of patients with DILI will achieve complete recovery after cessa-tion of the suspect medication. However, approximately 5% to 14% of patients may develop chronic DILI which has been va-riably defined in different studies.2, 36 DILIN

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ber of case studies have described severe statin-induced hepatotoxicity.77 The dura-tion of time to development of DILI in the-se case reports was highly variable, ranging from 5 days to 4 years. Mortality has also been rare, and most patients seem to expe-rience resolution of laboratory abnormali-ties within weeks to months. Among 51741 adult American liver transplant recipients, only 3 had probable statin-induced liver fai-lure. Of note, 2 of these 3 cases were attri-buted to cerivastatin, an agent which was subsequently withdrawn from the market.23 Among 598 cases of severe or fatal DILI in Sweden, simvastatin was only linked to one death and another statin-treated patient re-quired liver transplantation.46 Serious statin-induced hepatotoxicity has also been rarely identified in two ongoing prospective stu-dies. The DILIN group reported that 3.4% of the first 300 collected DILI cases were attributed to lipid-lowering agents. Among these patients, one patient with cirrhosis ta-king ezetimibe and simvastatin died of liver failure, while another patient taking lova-statin as well as concurrent leflunomide for rheumatoid arthritis subsequently required liver transplantation.13 In the Spanish regist-ry, 11 of 461 DILI cases were related to sta-tins.11 Of the 28 cases of chronic DILI in this registry, 2 were attributed to lipid-lowering agents, and interestingly a cholestatic pat-tern of liver injury was seen in both cases.36In several case reports of statin-induced

liver injury, the patients were exposed to other potential hepatotoxic medications, which may have directly induced liver in-jury. Alternatively several drugs such as diltiazem and amiodarone may potentiate statin-induced hepatotoxicity by competi-tively inihibiting CYP3A4, the enzyme re-sponsible for metabolizing statins.77 Among the reported cases of statin-induced hepato-toxicity, a subset has been associated with development of autoantibodies, including antinuclear, anti-smooth muscle, and anti-histone antibodies.77 Whether the statin it-self acts as a hapten in the development of an autoimmune response, or whether these cases reflect sporadic autoimmune hepatitis remains unclear.

been associated with microvesicular steato-hepatitis.74 Vascular injury of the liver may occur after use of estrogens (Budd-Chiari syndrome), chemotherapeutic agents (sinu-soidal obstruction syndrome), and immuno-modulators (nodular regenerative hyperpla-sia).74 The presence of hepatic necrosis has been associated with a higher mortality rate in published reports of DILI. In addition, it has also been observed that hepatic or peri-pheral eosinophilia may be associated with more favorable outcomes and a greater abi-lity to regenerate, but confirmatory studies are needed.75

Statin hepatotoxicity

The statins or hydroxymethylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors are used to lower circulating LDL choleste-rol levels, and are among the most frequen-tly prescribed medications in the world. In clinical trials, less than 3% of patients recei-ving statins developed elevated serum AST and ALT levels, defined as 3 times the ULN. However, few if any developed progres-sive liver injury or jaundice even despite continued dosing. As such, statin-induced aminotransferase elevation is a commonly identified phenomenon of unclear clinical significance. In addition, nearly 30% of pa-tients on statins can also develop asympto-matic elevations in serum creatinine pho-sphokinase (CPK) levels. Therefore, serum aminotransferase elevations in some pa-tients may actually be due to statin-induced CPK elevations, rather than liver injury.35 Recently, a GWA study identified a SNP in the SLCO1B1 gene which was associa-ted with an increased risk of statin-induced myopathy which occurs in



pravastatin 80 mg daily or placebo. No si-gnificant difference in the frequency of se-rum ALT elevation was noted between the two groups.80 A post-hoc analysis of another large multicenter randomized controlled study also demonstrated the efficacy and safety of statins in coronary artery disease patients with abnormal baseline liver bio-chemistries.81 Other studies have reported potential benefits of statin use in NAFLD, including improvement of aminotransfera-se levels,82-85 as well as a reduction in both hepatic steatosis and progression of hepa-tic fibrosis.86 In the US, the National Lipid Association Safety Task Force, a group of experts in cardiology and hepatology, has concluded that statins are safe for use in pa-tients with compensated chronic liver disea-se including NAFLD. In addition, this group determined that compensated cirrhosis is not a contraindication to statin therapy, but use of these drugs in patients with decom-pensated liver disease is not recommended due to altered pharmacokinetics.87

Statins in patients with liver disease

There is a common misconception that statins may be unsafe to use in patients with underlying liver disease. However, the ma-jority of evidence supports the use of statins in hyperlipidemic patients with stable chro-nic liver disease. In general, patients with NAFLD are known to have a substantially elevated risk of cardiovascular mortality.78 Furthermore, patients with chronic HCV have a higher incidence of insulin resistan-ce and metabolic syndrome, which may also increase their risk of cardiovascular mortality.79 In retrospective studies, patients with abnormal baseline liver biochemistri-es did not demonstrate a higher incidence of further laboratory abnormalities after 12 months of statin therapy compared to un-treated controls.34 In addition, a randomi-zed, double-blind, placebo-controlled trial by Lewis et al. confirmed the safety of sta-tin use in patients with liver disease (Table V). In this study, patients with underlying liver disease were randomized to receive

Table V.Efficacy and safety of statins in hyperlipidemic patients with liver disease.

Lewis et al.80 (2007) Athyros et al.81 (2010)

Number of pts N.=326 N.=437

Patient characteristics Chronic liver disease with LDL cholesterol Coronary artery disease with LDL choleste-rol

Mean age (yrs) 50 60

% Male 52% 80%

Liver disease % Chronic HCV % NAFLD % Other

25%64%11%

100% presumed NAFLD with AST/ALT 2 X baseline 7.5% 12.5% NA NA

% ALT change% AST change% GGTP change

NA NA -35%-47%-46%

+12%*+12%*+16%*

% Jaundice 0% 0% 0% 0%

*P



Serum acetaminophen levels can be useful in estimating the risk of liver inju-ry after a single time point ingestion. Ho-wever, an initially low serum acetamino-phen level may be unreliable, especially in patients with a delayed presentation or in those that overdose over several days. In addition, serum bilirubin levels greater than 10 grams per deciliter can lead to fal-se positive serum acetaminophen levels in some assays.98 Based on these limitations, there has been ongoing investigation into identifying more reliable serum markers of acetaminophen hepatotoxicity. In ear-ly studies, acetaminophen protein adducts were detected in the serum up to 12 days after ingestion. If a point of care test could be developed, this new assay may serve as a more specific and even potentially sensi-

Acetaminophen hepatotoxicity

Acetaminophen overdose is the leading cause of ALF in Western countries, and the majority of patients overdose on acetamino-phen due to suicidal ideation.2 However, an increasing proportion of patients are pre-senting with unintentional overdoses, like-ly due to the ubiquity of APAP in multiple products and its often under-recognized hepatotoxic potential.88, 90 Acetaminophen is well known to exhibit dose-dependent hepatotoxicity. With stable dosing, only a small proportion of APAP is oxidatively me-tabolized by cytochrome P450 to N-acetyl-P-benzoquinone imine (NAPQI) which can then be detoxified in the liver by gluta-thione transferase. However, when exces-sive doses are ingested, there is an incre-ased amount of NAPQI generated which can covalently bind to hepatic proteins to form adducts, deplete glutathione stores, and subsequently lead to pericentral ne-crosis.91 Chronic consumption of alcohol or ingestion of agents such as isoniazid and phenytoin can increase the formation of NAPQI through induction of CYP2E1.92, 93 Recent animal and human studies have also implicated a potential role of the innate im-mune response in explaining the variable susceptibility to acetaminophen hepatoto-xicity. Interestingly, subjects with reduced CD44 expression on lymphocytes may be at increased risk of developing acetamino-phen hepatotoxicity.94, 95A high index of suspicion is necessary to

diagnose acetaminophen overdose inclu-ding a careful review of all over-the-counter medication use since acetaminophen is an ingredient in several hundred products. Acetaminophen doses greater than 4 grams per day generally increase the risk of hepa-totoxicity.96 The classic laboratory findings associated with acetaminophen liver injury include elevated serum aminotransferase le-vels, prolonged prothrombin time, metabo-lic acidosis, and renal failure in up to 50% of patients with ALF (Figure 1). However, it should be noted that serum bilirubin levels at presentation are most commonly normal or minimally elevated.97

Figure 1.Non-intentional acetaminophen overdose case. A 28 year old Caucasian woman with a history of chronic abdominal pain and depression presented with nausea, vomiting, and altered mental status. She had ta-ken 4 to 8 tablets per day of Vicodin (5 mg hydroco-done-500 mg acetaminophen) for several months and recently took additional vicodin and tylenol tabs for worsening pain. Her initial serum acetaminophen level was 95 mcg/ml with a pH of 7.12, ALT of 2600 IU/ml, and INR of 5.6. After 2 days of N-acetylcysteine therapy, she required intubation for worsening mental status and cerebral edema on head CT. Although her serum ALT and INR continued to improve, she required placement of an intracranial pressure monitor on hospital day #4 and induction of a pentobarbital coma. Following a pro-longed and complicated hospital course, she eventually improved and was discharged home on hospital day #30 with a normal ALT, bilirubin, and INR.

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thorities have been looking at efforts to re-duce the frequency of this avoidable cause of liver injury. For example, there are an estimated 56000 acetaminophen overdose cases, 26000 hospitalizations, and greater than 500 deaths due to acetaminophen overdose each year in the United States alone.88 In the United Kingdom where the majority of APAP overdose cases appear to be intentional/suicidal circumstances, bli-ster packaging and dispensing restrictions have led to a significant reduction in the number of patients with intentional over-dose.104 In the United States, an advisory panel to the FDA made a series of recom-mendations to reduce the incidence of both intentional and non-intentional APAP hepatotoxicity.105 On January 13th, 2011 the FDA announced that they will requi-re all manufacturers of prescription drug products to limit the maximum amount of APAP to 325 mg per tablet and to place Black-Box warnings on these products.106 Hopefully, these actions and others direc-ted at the multitude of over-the-counter products containing acetaminophen will reduce future instances of acetaminophen hepatotoxicity.

Riassunto

Attualit sul danno epatico indotto da farmaci Il danno epatico indotto da farmaci (drug indu-

ced liver injury, DILI) una causa non comune di danno epatico acuto o cronico, che sta acquistan-do sempre maggiore importanza per i pazienti, i medici e gli organismi di controllo. Lincidenza di DILI legato ad un singolo agente non definita con precisione, ma studi basati sulla popolazione sugge-riscono che lincidenza complessiva del DILI possa essere nellordine di 10-15 casi per 100000 anni/pa-ziente. Anche i fattori di rischio per DILI non sono ben definiti, ma studi multicentrici basati su registro attualmente in corso, come il Drug Induced Liver Injury Network, stanno cercando di identificare il ruolo dei fattori genetici, ambientali ed immunolo-gici nella patogenesi e negli outcome del DILI. Il danno epatocellulare acuto (~50%) pi comune del danno epatico di tipo misto o colestatico; i sog-getti itterici con DILI, indipendentemente dal tipo di danno epatico, hanno un rischio di mortalit a breve termine del 10% circa. Gli antibiotici sono gli agenti pi comunemente implicati nello sviluppo di

tive biomarker of acetaminophen hepato-toxicity.99, 100 Initial management of suspected APAP

overdose includes inducing emesis with ipe-cac syrup, gastric lavage of pill fragments, and administering activated charcoal to mi-nimize absorption in patients presenting within 12 to 24 hours of a single time point ingestion.101 The likelihood of hepatotoxi-city can be assessed with the Rumack no-mogram, which takes into account the time since overdose as well as the serum ace-taminophen level. Patients with known or suspected acetaminophen overdose should be admitted to the hospital for assessment of suicidality as well as initiation of NAC therapy. Patients with hemodynamic insta-bility, acute renal failure, or altered mental status should be directly admitted to the in-tensive care unit and urgently referred for liver transplant evaluation.102 NAC should be administered immediately to patients at risk for hepatotoxicity, as based on initially elevated serum acetaminophen, aminotran-sferase, or INR levels. Oral NAC is given as an initial loading dose of 140 mg/kg follo-wed by 70 mg/kg every 4 hours for a total of 72 hours or until the INR is less than 1.5.91 Patients who are unable to tolerate oral NAC can be given intravenous NAC as a continuous infusion until the INR is less than 1.5. Mild to moderate hypersensitivity reactions develop in up to 5% of patients receiving NAC and can be managed by a re-duction in the rate of NAC infusion and/or concurrent administration of antihistamines and corticosteroids for patients with more severe reactions.103With supportive care, the majority of pa-

tients with acetaminophen overdose can be successfully treated. However, amongst those who progress to ALF, 3-week spon-taneous survival is only 60% with 5-10% of patients requiring liver transplantation and the remainder dying of ALF.

Prevention of acetaminophen overdose

Due to increasing reports of APAP over-dose in multiple countries, regulatory au-

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injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastro-enterology 2005;129:512-21.

12. Hoofnagle JH. Drug-induced liver injury network (DILIN). Hepatology 2004;40:773.

13. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J et al. Causes, clinical fea-tures, and outcomes from a prospective study of drug-induced liver injury in the United States. Gas-troenterology 2008;135:1924-34, 34 e1-4.

14. Navarro VJ. Herbal and dietary supplement hepato-toxicity. Semin Liver Dis 2009;29:373-82.

15. Gloro R, Hourmand-Ollivier I, Mosquet B, Mosquet L, Rousselot P, Salame E et al. Fulminant hepatitis during self-medication with hydroalcoholic ex-tract of green tea. Eur J Gastroenterol Hepatol 2005;17:1135-7.

16. Jimenez-Saenz M, Martinez-Sanchez Mdel C. Acute hepatitis associated with the use of green tea infu-sions. J Hepatol 2006;44:616-7.

17. Mazzanti G, Menniti-Ippolito F, Moro PA, Cassetti F, Raschetti R, Santuccio C et al. Hepatotoxicity from green tea: a review of the literature and two unpub-lished cases. Eur J Clin Pharmacol 2009;65:331-41.

18. Galati G, Lin A, Sultan AM, OBrien PJ. Cellular and in vivo hepatotoxicity caused by green tea phenolic acids and catechins. Free Radic Biol Med 2006;40:570-80.

19. De Valle MB, Av Klinteberg V, Alem N, Olsson R, Bjornsson E. Drug-induced liver injury in a Swed-ish University hospital out-patient hepatology clinic. Aliment Pharmacol Ther 2006;24:1187-95.

20. Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. Clin Liver Dis 2007;11:477-505, v.

21. Lucena MI, Andrade RJ, Kaplowitz N, Garcia-Cortes M, Fernandez M, Romero-Gomez M et al. Pheno-typic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatol-ogy 2009;49:2001-9.

22. Ibanez L, Perez E, Vidal X, Laporte JR. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epi-demiological and clinical features, and exposure to drugs. J Hepatol 2002;37:592-600.

23. Russo MW, Galanko JA, Shrestha R, Fried MW, Wat-kins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl 2004;10:1018-23.

24. Abboud G, Kaplowitz N. Drug-induced liver injury. Drug Saf 2007;30:277-94.

25. Schenker S, Bay M. Drug disposition and hepatotox-icity in the elderly. J Clin Gastroenterol 1994;18:232-7.

26. Fountain FF, Tolley E, Chrisman CR, Self TH. Iso-niazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7-year evalua-tion from a public health tuberculosis clinic. Chest 2005;128:116-23.

27. Onji M, Fujioka S, Takeuchi Y, Takaki T, Osawa T, Yamamoto K et al. Clinical characteristics of drug-induced liver injury in the elderly. Hepatol Res 2009;39:546-52.

28. Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH et al. Drug-induced hepatic injury in children: a case/non-case study of sus-pected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010;70:721-8.

29. Schror K. Aspirin and Reye syndrome: a review of the evidence. Paediatr Drugs 2007;9:195-204.

30. Wong WM, Wu PC, Yuen MF, Cheng CC, Yew WW,

DILI; tuttavia, report recenti riferiscono danni epati-ci associati alluso di una molteplicit di integratori alimentari e prodotti a base di erbe. Nonostante la loro grande diffusione, gli inibitori della HMG-CoA reduttasi (statine) sono una causa non frequente di DILI idiosincratico. Inoltre, recenti studi hanno mo-strato che le statine possono essere effettivamente usate in modo sicuro ed efficace in pazienti iperli-pidemici con epatopatia cronica. Lepatotossicit del paracetamolo continua ad essere una casa prima-ria di danno epatico acuto severo. Una limitazio-ne della quantit di paracetamolo nelle specialit contenenti stupefacenti pu contribuire a ridurre lincidenza di sovradosaggi non intenzionali, ma si consiglia anche di promuovere uninformazione adeguata sia nei pazienti che nei soggetti che ven-dono gli innumerevoli prodotti da banco contenenti paracetamolo.

Parole chiave: Acetaminofene - Integratori alimenta-ri - Farmacogenetica.

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