Drug-Induced Liver Injury in OlderAdults

Ethan D. Miller, Hamzah Abu-Sbeih, and Naga P. Chalasani

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Patterns of Liver Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Medications in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Safety and Risks of Common Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Clinical Presentation and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Next Steps: Future Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

AbstractThe estimated incidence of idiosyncratic drug-induced liver injury (DILI) in the generalpopulation is 13.9 to 19.1 per 100,000 patientsper year. Age itself is not a risk factor, but olderadults appear to be at risk for DILI from a few,specific drugs, including several antibiotics.

Older adults with DILI do not have a highermortality compared to other age groups. Thepathogenesis of idiosyncratic DILI remainspoorly understood. Patients with suspectedDILI may present with a variety of clinicalsigns and symptoms. DILI remains a diagnosisof exclusion, and its identification involvesobtaining a careful history, select lab and imag-ing studies, and sometimes a liver biopsy.Older adults may exhibit a cholestatic bio-chemical profile compared to younger patientsin response to the same offending agent.The suspected drug should be discontinued,followed by close monitoring. Spontaneousresolution occurs in most, but normalizationof liver function may take days to months,while some progress to cirrhosis. Drug re-

E. D. Miller · H. Abu-SbeihDepartment of Gastroenterology, Hepatology andNutrition, The University of Texas MD Anderson CancerCenter, Houston, TX, USAe-mail: emiller1@mdanderson.org;habusbeih@mdanderson.org

N. P. Chalasani (*)Division of Gastroenterology and Hepatology, IndianaUniversity School of Medicine, Indianapolis, IN, USAe-mail: nchalasa@iu.edu

© Springer Nature Switzerland AG 2020C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology,https://doi.org/10.1007/978-3-319-90761-1_53-1

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challenge is not advisable but is on rare occa-sions unavoidable. Sometimes steroids areneeded to treat DILI, especially when there isan autoimmune hepatitis-like reaction. Bio-markers to predict and monitor DILIare needed. There is under-reporting ofDILI worldwide. More information regardingDILI in older adults is needed, includingfrom clinical trials and case reports inregistries.

KeywordsDILI · Hepatotoxicity · Hepatocellular ·Cholestatic · Antibiotics · Diclofenac · Steroidtherapy · Jaundice · Drug-induced hepatitis ·Liver biopsy · Autoimmune liver disease ·Idiosyncratic DILI · Supplement use · Liverinjury

Introduction

The topic of drug-induced liver injury (DILI) inthe elderly is important for several reasons.First, with increasing age come increasingcomorbidities, medical visits, and testing, withthe opportunity that test results concerning forliver injury may be identified. The clinicianneeds to have an approach to interpreting thesetests and how to respond: when to be alert tocertain medications which might pose a riskof liver injury and – just as important – when tobe alert to knowing which medications mightbe a risk if discontinued. Indeed, it has beenreported that older patients may be under-pre-scribed many medications, including statins(Barry et al. 2007). Second, “polypharmacy,”the presence of more than five medications ina routine regimen, has also been cited as a riskfactor for DILI in the elderly (Bell and Chalasani2009; Onji et al. 2009; Stine et al. 2013).Although it has been questioned as to whetherpolypharmacy itself a risk factor for DILI(Chalasani and Bjornsson 2010; Chalasani et al.2014), it is nevertheless a valid concern that with alonger list of medications, additional vigilance forthe risk of hepatotoxicity is needed to ensurehepatic issues do not overtake other medical

conditions as a primary focus. Third, manypatients, including the elderly, may take non-pre-scription medications and other supplements(Qato et al. 2016) that their providers may ormay not have been informed about or consideras possibly hepatotoxic. It is important to beaware of this possibility since these compoundscould be hepatotoxic and in fact have been cited ascommon causes of hepatotoxicity (Chalasani et al.2015; Navarro et al. 2017). Finally, it is of para-mount importance that registries around the worldreceive more cases of DILI in the elderly and thatmore studies include elderly patients, to improveour understanding of hepatotoxicity-related con-cerns in this important population.

DILI may be defined in several ways. Mainly itmay be defined by the pattern of hepatic-relatedbiochemistries observed after drug exposure(Danan and Benichou 1993). A hepatocellularpattern – in which the hepatocyte itself is injured– is characterized predominantly by elevatedaminotransferases, whereas a cholestatic pattern,with disruption of flow within the biliary system,is characterized predominantly by an elevatedalkaline phosphatase. A mixed pattern of injuryreflects hepatocellular and biliary injury.

DILI is also defined in terms of the character-istics known to result from exposure to a particu-lar drug. Drugs can cause intrinsic or idiosyncraticinjury. Specific drugs may elicit injury in apredictable, dose-dependent fashion, usually ata fixed latency. This “intrinsic” type of injuryis best typified by acetaminophen. While nottoxic to the liver when taken as intended, acet-aminophen can cause acute injury if taken inexcess, particularly in the context of significantalcohol consumption.

By contrast, idiosyncratic DILI from a partic-ular drug is not predictable with respect to dose,latency, or incidence. Idiosyncratic DILI tendsto be what can limit drug development and,while rare, can cause significant morbidity andmortality (Chalasani et al. 2015) and is responsi-ble for up to 17% of cases of acute liver failure(Nicoletti et al. 2017). Idiosyncratic DILI will bethe focus of this chapter.

The estimated incidence of idiosyncratic DILIin the general population is 13.9 to 19.1 per

2 E. D. Miller et al.

100,000 patients per year (Bjornsson et al. 2013;Sgro et al. 2002), although estimates from differ-ent parts of the world vary, and global datareporting is incomplete (Ahmad and Odin 2017).Because of its infrequency and also incompleteand under-reporting, including in clinical trials(Chalasani and Bjornsson 2010), it is especiallydifficult to estimate the incidence amongthe elderly as a distinct population. Moreover,the median age of DILI patients from a numberof large studies ranges between 48 and 55 years(Fontana 2014), underscoring the paucity ofdata regarding the elderly.

It has long been an assumed that older patientsare at higher risk for DILI compared to youngeradults. Age greater than 50 years confersadditional points to a historical and widely- usedscale (RUCAM) for assessing for DILI (Dananand Benichou 1993), predicated on this belief.There is some evidence that the incidence ofDILI increases with age, but for unclear reasons,possibly related to increased number of prescrip-tions with age (Bjornsson et al. 2013). But a riskof DILI in older patients, in general, has not beendemonstrated on a consistent basis (Bell andChalasani 2009; Chalasani et al. 2015; Andradeet al. 2019; Lucena et al. 2009; Suk et al. 2012).However, there is more consistent evidence thatthe biochemical pattern of DILI may shift withincreasing age (Chalasani et al. 2015; Lucena etal. 2009) and that the elderly appear to be at riskfor DILI not as a general rule, but from a few,specific drugs (Chalasani and Bjornsson 2010; deLemos et al. 2016).

Pathophysiology

The pathogenesis of idiosyncratic DILIremains poorly understood and involves complexinteractions among patient- and drug-relatedfactors. Patient-related factors include geneticand non-genetic host susceptibility factors(Chalasani and Bjornsson 2010; Daly and Day2009; Fontana 2014; Tujios and Fontana 2011;Wilke et al. 2007) and innate and adaptive immu-nity (Chen et al. 2015). In the future as the path-ophysiology becomes clarified, this

understanding will be the basis for clinically use-ful tools in the care of DILI patients (Vuppalanchiet al. 2014).

The liver plays an important role in the clear-ance and biotransformation of drugs and may beadversely affected due to the generation of toxicmetabolites. Hepatic drug-metabolizing enzymesconvert lipid-soluble molecules into a water-solu-ble form, thus permitting their entry into theplasma and excretion in the urine or eliminationinto the bile. Most drugs are transformed byhepatic phase I (reactive metabolite production)and phase II (reactive metabolite detoxification)metabolic reactions. Oxidation (e.g., hydroxyl-ation and dealkylation) and reduction (e.g.,nitroreduction) are phase I reactions, whereasphase II reactions include conjugation via anendogenous compound (via glucuronidation,sulfation, or acetylation) of the parent compoundor a metabolite to make it more hydrophilic foreventual excretion into bile or urine (Fig. 1). Thecytochrome P450 superfamily (CYP) is involvedin the bioactivation and metabolism of drugs,mostly in phase I reactions. Factors that alterCYP activity increase toxicity by reducing drugconversion to nontoxic metabolites or by increas-ing conversion to toxic metabolites (Walgren et al.2005). CYP is abundant in the centrilobular zonecompared to the periportal area; centrilobularnecrosis is characteristic of DILI, suggesting thatdrug-metabolizing enzymes play a role in DILI.Most hepatically cleared substrates are metabo-lized by CYP1, CYP2, and CYP3 families.

It has been proposed that due to variousfactors, including changes in liver mass, hepaticcirculation and Phase I metabolism, the liver agesin clinically relevant ways (Tan et al. 2015).CYP3A is a prominent subfamily, and it hasbeen postulated that age-related reductions inhepatic blood flow, and hepatic volume mayhave an impact on the clearance of some CYP3Asubstrates (Cotreau et al. 2005). Yet, in practice,there is a lack of evidence that these alterations aresignificant or can be used to anticipate or manageDILI (Onji et al. 2009; Stine et al. 2013). Also,it has been pointed out that such changes would,if relevant to DILI, be expected to account forintrinsic rather than idiosyncratic DILI (Chalasani

Drug-Induced Liver Injury in Older Adults 3

and Bjornsson 2010). In addition, it does notappear that older patients are at higher riskof worse outcomes compared to youngerpatients when DILI occurs. Rather, the presenceof pre-existing liver disease is a risk factor forhigher mortality from DILI (Chalasani et al.2015).

In addition to Phase I and II reactions, othercomponents of hepatic metabolism have beenimplicated in DILI. Hepatic transport systemsmaintain uptake and efflux processes in bile for-mation and play a role in drug clearance (Corsiniand Bortolini 2013). Cholestatic DILI may resultfrom drug-mediated inhibition of hepatobiliarytransporter systems (Ho and Kim 2005; Pauli-Magnus and Meier 2006). Mutations andpolymorphisms of the exporter proteins causeintracellular accumulation of toxic bile constitu-ents with cholestatic liver injury (Lang et al. 2007;Noe et al. 2005). Some drugs (e.g., valproate,salicylate, antiretroviral agents) cause liverinjury via mitochondrial toxicity; alteration ofmitochondrial function in the liver mayinduce fat accumulation (microvesicular steatosis)(Begriche et al. 2011). Drugs can also cause dam-age to the endothelial cells, which may lead tonodular regenerative hyperplasia, sinusoidalinjury, and accompanying manifestations of portal

hypertension even in the absence of cirrhosis(Fontana 2014).

Genetic risk factors have been identified inassociation with idiosyncratic DILI, includingrelated to specific Phase I CYP enzymes, PhaseII enzymes, drug transporters, and mitochondrialDNA, as well as immunologic factors such asHLA alleles (Chalasani and Bjornsson 2010).Genome-wide association studies, which can beespecially useful in screening the genome for pos-sible genetic risk factors for a variety of condi-tions, have been done to identify DILI-relatedpolymorphisms, which has led to the identifica-tion of HLA-related risk factor for DILI forseveral drugs, including amoxicillin-clavulanate(Lucena et al. 2011), flucloxacillin (Daly etal. 2009), and also for statins (Nicoletti etal. 2017), but not pertaining specifically to age-related DILI. There is also evidence forassociations between the HLA haplotype anda cholestatic or mixed biochemistry patternin response to injury from amoxicillin-clavulanicacid (Hautekeete et al. 1999). Such studies mayreveal more polymorphisms related to specificdrugs and help shed light on the mechanismsunderlying DILI.

Specific immune pathways that may influencethe occurrence of liver injury have alsobeen investigated. For example, diclofenac, a

Fig. 1 Phases I, II, and III drug metabolism. (Abbre-viations: CYP1A1/2: Cytochrome P450 1A1 and 1A2;CYP2C8/9: Cytochrome P450 2C8/2C9; CYP2D6:

Cytochrome P450 2D6; and CYP3A4/5: CytochromeP450 3A4/3A5)

4 E. D. Miller et al.

non-steroidal anti-inflamatory drug (NSAID) thathas been reported to cause hepatotoxicity includ-ing in the elderly, may suppress TNF-alpha,thereby leading to apoptosis (Fredriksson et al.2011).

Various drug properties play a role in DILI.As one might expect, DILI is more likely tooccur for drugs that are metabolized by the liver,although there are exceptions (Lammert et al.2010). In one study, among a group of drugs thatcan cause DILI, ones that were reported morefrequently among the elderly, as comparedto a pediatric population, tended to have higherlipophilic indices (Hunt et al. 2014), possibly bycausing increased metabolic demands on the liver(Fontana 2014). It has been observed that doseof an oral medication, regardless of its class orindication, is also a factor for causing liver injury,with higher oral dose presenting an increased riskof DILI, especially in daily doses exceeding50 mg (Lammert et al. 2008). There also may bea connection between higher lipophilicity andhigher drug dose in leading to DILI (Chen et al.2013). When a variety of drug characteristicswere assessed together, drug dose >50 mg wasassociated with a shorter latency to DILI, but drugproperties were not helpful in determiningoutcomes (Vuppalanchi et al. 2014). While idio-syncratic DILI is not dose-related, there may bea threshold dose of 50–100 mg/day for DILI tobe more likely (Andrade et al. 2019). However, itis not clear how to apply information about bio-chemical properties or dose, other than to note thatidiosyncratic DILI can occur even when drugs aretaken according to standard dosing.

Patterns of Liver Injury

DILI is a pattern of injury with characteristics thatencompass a range of biochemical, histologic, andother clinical features (such as fever or rash,which may signal an allergic-based reaction).The “R” value (Table 1), the ratio of ALT/ULNto alkaline phosphatase/ULN, is used to

categorize the pattern of presenting biochemis-tries as reflective of injury that is hepatocellular(R > 5), cholestatic (R < 2), or mixed (R = 2–5).Irrespective of what is “classically” expected interms of a biochemical profile from a particulardrug, older adults appear to be more likely toexhibit a cholestatic or mixed biochemical patternof injury in response to a given drug, whencompared to younger adults who may exhibita hepatocellular pattern (Bjornsson et al. 2013;Chalasani et al. 2015; Onji et al. 2009) (Andradeet al. 2019; Hunt et al. 2014; Lucena et al. 2009)(Table 1).

There are a variety of histologic patterns thatmay be seen in the setting of DILI, includingacute or chronic hepatocellular or cholestaticinjury, granuloma formation, steatosis, macro-and micro-vesicular steatohepatitis, necrosis,vascular injury, and nodular regenerative hyper-plasia. Regarding histologic patterns, in a largecohort, there were five patterns that were seen inthe majority of cases: acute hepatitis, chronic hep-atitis, acute cholestasis, chronic cholestasis, andcholestatic hepatitis. There was limited correla-tion between histologic and biochemical patternsat the time of injury when it came to classificationinto hepatocellular, cholestatic, or mixed patternsof injury based on the “R” value (Kleiner et al.2014). Caution is urged in predicting the patternof histologic changes based on the pattern ofbiochemistries.

Age may be a risk factor for the developmentof chronic DILI, but findings have not been con-sistent. Defining chronic DILI as persistentlyabnormal biochemistries, histology, or imaginglasting a year or more after drug withdrawal,older age was a risk factor in one study (Medina-Caliz et al. 2016). However, using abnormal bio-chemistries, imaging, or exam findings noted atleast 6 months after drug withdrawal to definechronicity, a separate study found that olderpatients are actually less likely to have chronicDILI compared to other age groups (Chalasani etal. 2015).

Drug-Induced Liver Injury in Older Adults 5

Medications in Older Adults

The majority of DILI cases are caused by asingle prescription medication, and the rest arecaused by multiple agents or dietary supplements(Bjornsson et al. 2013).

Medication, herbal preparation, and supple-ment use is common throughout the world.Most older adults in the US take prescription andover-the-counter medications and supplements(Qato et al. 2016). While older adults compriseless than 15% of the US population (Hunt et al.2014), over 30% of serious medication-relatedadverse events are reported in adults >65 yearsold (Sonawane et al. 2018).

Several large, prospective, registry-basedstudies have consistently shown that by class,antibiotics are the most common cause of idiosyn-cratic DILI in the general population (Andrade etal. 2005; Bjornsson et al. 2013; Chalasani et al.2015). Other common classes of medicationscausing DILI include herbal agents and dietarysupplements, cardiovascular drugs (includingsome statins), antineoplastic agents, centralnervous system medications, and NSAIDs (espe-cially diclofenac) (Andrade et al. 2005; Bjornssonet al. 2013; Chalasani et al. 2015).

Safety and Risks of Common Drugs

The risk of DILI (Table 2) is higher for olderadults for certain drugs, such as amoxicillin-clavulanate (Chalasani et al. 2014), but age itselfis not a risk factor for DILI related to all drugs(Chalasani et al. 2015; Leise et al. 2014). For

example, in one study comparing categoriesof drugs causing DILI in those under age 65 tothose age 65 or older, the four of the five mostcommon categories of drugs were the same (i.e,antimicrobials, cardiovascular drugs, herbals anddietary supplements, and antineoplastics). Thetwo groups differed in that analgesics were listedfor the older age group, whereas central nervoussystem agents were listed for the younger agegroup. Also, except for antimicrobials toppingthe lists in frequency in both groups, the relativefrequencies of the other categories differed(Chalasani et al. 2015). Importantly, older adultsdo not have higher mortality compared to otherage groups when DILI does happen (Chalasani etal. 2015).

Below are highlighted some common medica-tions and categories of medications which arerelevant to older adults. There are online resourcesavailable with information regarding liver toxic-ities associated with specific agents. In the USA,the Drug-Induced Liver Injury Network (DILIN)maintains LiverTox, a National Institutes ofHealth (NIH) online database that can be searchedfor information on hepatotoxicity for an expan-sive and increasing number of available medica-tions, herbal preparations, and supplements.LiverTox searches include associated mono-graphs and case reports, describing expected clin-ical, biochemical, and, when available, histologicpatterns of injury, described treatments, with ref-erences (Hoofnagle et al. 2013). There are alsoinstructions about submitting DILI cases toLiverTox and to the US Federal Drug Adminis-tration. The LiverTox website can be accessed at:https://livertox.nih.gov/.

Table 1 Patterns of liver injury in drug induced liver injury

R-value Pattern Key feature Comment

<2 Cholestatic Predominantly elevatedalkaline phosphatase

Amoxicillin-clavulanate is the prototype. Elderlyindividuals are at higher risk for cholestatic DILI

>5 Hepatocellular Predominantly elevatedalkaline aminotransferase

Isoniazid is the prototype

2<R<5 Mixed Equally elevated alkalinephosphatase and alkalinephosphatase

Interestingly, and for entirely unknown reasons, DILIwith mixed pattern injury appears to be associated withlower mortality than other patterns of liver injury

The R-value is defined as serum ALT/ULN divided by serum alkaline phosphatase/ULN (ULN, upper limit of normal)

6 E. D. Miller et al.

AntibioticsCertain antibiotics are more likely to be hepato-toxic among elderly patients, compared toyounger adults and children (Hunt et al. 2014;Medina-Caliz et al. 2016). Older age has beenshown to be a risk factor for susceptibility toamoxicillin-clavulanate, which is more likelyto cause a cholestatic pattern or mixed biochem-istry pattern of injury in older patients, comparedto the hepatocellular pattern seen in youngerpatients (Bjornsson et al. 2013; de Lemos et al.2016; Hunt et al. 2014). Liver biopsy may showcholestasis and portal inflammation with ductinjury (Figs. 2a and b).

Isoniazid also poses increased risk of DILIwith age (Chalasani and Bjornsson 2010), aswell as when it is used in the combination anti-

tuberculosis regimen of isoniazid, rifampin, andpyrazinamide. Flucloxacillin, an antibiotic usedin many parts of the world, may also cause DILImore frequently in elderly patients (Chalasani andBjornsson 2010; Wing et al. 2017). Erythromycinand nitrofurantoin have also been cited as causingDILI more commonly in older patients (Chalasaniand Bjornsson 2010). Nitrofurantoin has cancause a chronic, autoimmune hepatitis-like histo-logic pattern (Fig. 3) (Stricker et al. 1988) (Fig. 3).

AntineoplasticsDILI from antineoplastic agents can occur and canlimit cancer therapy (Bjornsson et al. 2013). Agehas been identified as one factor that can increasethe risk of hepatotoxicity (Vincenzi et al. 2018),often when agents are used in combination

Table 2 Drugs commonly associated with DILI in the elderly

Medication Comment

Amoxicillin-clavulanate Most common cause for DILI in the Western world. Elderly are more susceptible.

Erythromycin Cholestatic pattern.

Flucloxacillin Not available in the USA. HLA-B�57:01 is a very strong risk factor for DILI due toflucloxacillin.

Nitrofurantoin Used chronically for prophylaxis against urosepsis, nitrofurantoin is associated withautoimmune like liver injury.

Isoniazid Hepatocellular pattern liver injury. Elderly are more susceptible for liver injury from anti-TB medications.

Diclofenac Diclofenac consumed systemically is associated with chronic hepatitis - like picture.Topical creams are not associated with liver injury.

Fig. 2 Panel A: Liver injury due to amoxicillin-clavulanate. Portal area with inflammation and bile ductinjury (arrow), 400x. Panel B: Amoxicillin-clavulanate-induced liver injury. Canalicular cholestasis (arrows) near

central vein, 600x. (Courtesy of David E. Kleiner, MD,PhD at the Laboratory of Pathology/ National CancerInstitute, USA)

Drug-Induced Liver Injury in Older Adults 7

(Bjornsson et al. 2013). The patterns of injury arewidely variable. Immune checkpoint inhibitors,which are increasingly being used due to theirimpressive efficacy against a large and growinglist of malignancies, are thought to cause injurythrough immune mechanisms and thus may causean autoimmune-like form of liver injury (Postowet al. 2018), although histologic findings can varywidely (De Martin et al. 2018), as with all DILI.Typically, they can lead to elevated aminotrans-ferases, with or without elevated alkaline phos-phatase. Antineoplastics can also lead to chronicand progressive injury, not always apparent fromroutine biochemistries. For example, oxaliplatin,a drug used to treat colorectal cancer, may causesinusoid injury and portal hypertension (Overmanet al. 2018). Oxaliplatin injury can thus mimicclinical signs and symptoms of cirrhosis (varices,enlarges spleen, thrombocytopenia) in theabsence of cirrhosis. Tamoxifen, a widely-usedtreatment for breast cancer, can cause or worsenfatty liver disease (Pan et al. 2016), can be super-imposed upon non-alcohol-related steatohepatitis,and can even lead to cirrhosis. While vigilance forantineoplastic-related DILI is important, it is alsoimportant to not be overly cautious in limitinguse of these drugs. Risk/benefit analysis is chal-lenging, and further studies are needed.

SteroidsSteroids can cause liver injury, even acute liverfailure in high doses (Sisti et al. 2015). Two ste-roids, cyproterone and danazol, have beenreported as causing DILI in elderly, althoughit is not clear that the risk is actually higheramong older patients (Hunt et al. 2014). However,steroids in general are the mainstay of treatmentin a variety of conditions, including in the man-agement of autoimmune hepatitis (Manns et al.2010) or immune checkpoint inhibitor-relatedliver injury (Brahmer et al. 2018). Their useshould always be carefully considered with a thor-ough discussion with the patient regardingthe many risks. When possible, a liver biopsyshould be considered before starting steroids totreat DILI.

Nonsteroidal Anti-inflammatory DrugsNSAIDs may lead to liver injury. While theelderly are not always at higher risk of DILIfrom these medications, it has been reported thatolder patients, especially women, may be moresusceptible (O’Connor et al. 2003). Diclofenac,a potent NSAID, may cause DILI more frequentlyin older adults (Banks et al. 1995), typically afterchronic use rather than as a result of acute expo-sure (Medina-Caliz et al. 2016). Aspirin, widelyused and often thought of as not hepatotoxic,occasionally causes elevated ALT levels and can(rarely) lead to hepatic failure with extremely highblood levels (O’Connor et al. 2003), but is notof higher risk for DILI specifically among olderpatients.

Alcohol and Drug InteractionsAlcohol consumption, especially heavy drinking(defined as consumption of over 2 drinks/day or14 drinks/week for women or over 3 drinks/dayor 21 drinks/week for men), is a risk factor foralcohol-related acute and chronic liver disease,including cirrhosis. Indeed, in the USA, the rela-tive contribution of alcohol-related liver disease tocirrhosis-related death is anticipated to increase(Crabb et al. 2019). Heavy alcohol consumptionincreases the risk of acetaminophen hepatotoxic-ity (Schmidt et al. 2002).

Fig. 3 Nitrofurantoin-induced liver injury. Portalinflammation with interface hepatitis and plasma cells(arrows) 400x. (Courtesy of David E. Kleiner, MD, PhDat the Laboratory of Pathology/ National Cancer Institute,USA)

8 E. D. Miller et al.

Although acetaminophen is safe in usual ther-apeutic doses, hepatic and other organ damageoccur with overdose. Acetaminophen overdoseis responsible for nearly half of all cases of acuteliver failure in the USA (Ramachandran andJaeschke 2019). Older age has been shown tobe an independent risk factor for developinghepatotoxicity from acetaminophen (Schmidt etal. 2002). In contrast to drugs that causeidiosyncratic DILI, liver damage from acetamin-ophen is dose-dependent. Overdose may beintentional, as in acute ingestion in suicideattempt. Or ingestion may be unintentional,as in consumption of excess dosage of a medica-tion regimen, often through use of multiple acet-aminophen-containing medications. Indeed, inearly 2011, the US Food and Drug Administrationasked manufacturers to limit the strengthof acetaminophen to 325 mg in acetaminophen-containing medications, since acetaminophenis often a constituent of several drug combina-tions, especially opioids. In addition, the maxi-mum daily dose of extra-strength acetaminophen(500 mg) is 3000 mg/day, also to reduce overuse,although most if not all physicians consider4000 mg/day to be the maximum acetaminophendose. Prognosis is better when acetaminophenliver injury is treated with N-acetylcysteine withinhours of ingestion.

The role that alcohol consumption plays inthe occurrence of idiosyncratic DILI is less clearthan in acetaminophen toxicity but has beeninvestigated. Alcohol use can increase the riskof DILI from isoniazid and halothane (two drugsalso more likely to be hepatotoxic in olderpatients) (Dakhoul et al. 2018) as well as metho-trexate (Malatjalian et al. 1996). In a recentstudy of heavy alcohol drinkers compared tonon-alcohol drinkers, alcohol was not linkedto worse outcomes when DILI was known orsuspected. Interestingly, anabolic steroids weresignificantly linked to DILI among heavydrinkers, possibly because it was younger, maleadults who were the heavy drinkers, althoughthe causative role was not investigated (Dakhoulet al. 2018).

Cardiovascular DrugsAs a class, these agents have been implicatedamong the top causes of DILI in the elderly ata frequency higher than for younger adults(Chalasani et al. 2015). Many of these drugshave been reported to cause DILI, including com-mon drugs such as amlodipine, atenolol, enalapril,labetalol, lisinopril, valsartan, and verapamil(Fontana et al. 2014). Amiodarone, a widelyused antiarrhythmic drug, has long been knownto pose a risk of DILI (Chalasani et al. 2008;Lewis et al. 1989). It causes elevated aminotrans-ferases in a quarter of recipients, can cause injurylong after drug withdrawal (Lewis et al. 1989),and has been linked to liver failure and cirrhosis(Bratton et al. 2019; Lewis et al. 1989). Casesof jaundice have been reported as well (Brattonet al. 2019). It also has a long latency (Chalasani etal. 2015), which means that a high indexof suspicion for amiodarone-related toxicityis needed in the setting of elevated aminotransfer-ases. A liver biopsy may show steatohepatitis,in a pattern similar to alcohol or non-alcoholicsteatohepatitis (Fig. 4).

Hydralazine, an antihypertensive drug, isanother cardiovascular drug that can cause avariety of liver injuries, including an autoimmunehepatitis-like pattern of serologic findings (deBoer et al. 2017), and can cause both cholestaticand hepatocellular patterns of injury.

StatinsAmong older adults in the USA, the most com-monly prescribed medications include severalstatin medications (Qato et al. 2016). Medicationsin this class (atorvastatin, rosuvastatin, simva-statin, pravastatin, fluvastatin, and lovastatin)have been cited among the top 100 drugs respon-sible for DILI (Chalasani et al. 2015). Yet olderadults do not appear to be at higher risk than otherage groups for experiencing DILI from any ofthese statins. Because of the proven efficacyof these drugs, caution should be used in makinga decision to discontinue a statin.

OtherIt has been reported that older adults may be atincreased risk from halothane use (Chalasani and

Drug-Induced Liver Injury in Older Adults 9

Bjornsson 2010). This drug carries the risk ofhepatotoxicity in the general population, and isoften actively avoided for that reason.

Herbals and Dietary SupplementsThis is a heterogeneous group of productsthat includes multivitamins, natural extracts,and other botanicals as well as weight loss andbodybuilding preparations. The use of herbalsand dietary supplements is common worldwide.Hepatotoxicity may occur with their use(Bjornsson et al. 2013; Bunchorntavakul andReddy 2013; Navarro et al. 2017), accountingfor up to 20% of reported cases in the USA, withwide variations in rates reported in registriesaround the world (Navarro et al. 2017). Due topoor regulation and oversight of these products,there could be significant variations between thelisted ingredients and contents of the supplement,including batch-to-batch differences. And givenhow available and common and potentially under-reported these products are, it is worthwhileto remain aware that supplements are not alwayssafe and should not be considered so, despitethe perception that they are harmless (Navarro etal. 2014). To this point, one study of emergencydepartment visits identified that micronutrients,such as vitamins or multivitamins, calcium, iron,and potassium supplements accounted for two-thirds of ER visits among elderly patients (Geller

et al. 2015). Common supplements taken amongthe elderly in the USA include vitamins, omega-3fish oil, calcium, vitamin D, and saw palmetto(Qato et al. 2016). While none of these com-pounds in general has been linked to DILI in theelderly, it is important to maintain some degree ofsuspicion toward any compound whenDILI is suspected.

Clinical Presentation and Diagnosis

DILI remains a diagnosis of exclusion.Identifying DILI involves taking a careful historyand obtaining select lab and imaging studies andsometimes a liver biopsy. Patients with suspectedDILI may present with a variety of clinical signsand symptoms, such as jaundice, fever, abdominalpain, nausea and vomiting, and also of liver failure(altered mental status/confusion), and a range ofabnormal laboratory results. Obtaining a thoroughhistory is essential (Table 3). It is particularlyimportant to review the patient’s medicationswith them. This involves confirming with themall the medications listed in their medical recordsand their own lists. If possible, patients shouldbring records of recent hospitalizations and havebottles with their own medications with themwhen a history is obtained. Do not rule out drugsthey may not have taken for some time, as laten-cies can vary and may be as long as 12 months forcertain medications (e.g., nitrofurantoin andstatins). Include questions about any medicationstaken for a short time (e.g., analgesics and antibi-otics) or that were stopped recently and why. It isalso important to ask about herbal and dietarysupplements. Even under the best of circum-stances, lists and memories may be erroneous,and it can be valuable to enlist the assistance of apatient’s family and friends – to help recall briefillnesses, treatments, and hospitalizations thatmay have involved drug exposure. Be sure toobtain information about comorbid illness thatmay cause liver injury. Physical exam may revealsigns of other causes of liver injury (Table 3).

It is helpful to review the pattern of abnormalhepatic biochemistry studies. The R value (Table1) should be obtained if there is any question

Fig. 4 Amiodarone-induced liver injury. Periportalballooning with numerous Mallory-Denk bodies (arrows),200x. (Courtesy of David E. Kleiner, MD, PhD at theLaboratory of Pathology/ National Cancer Institute, USA)

10 E. D. Miller et al.

about whether the pattern of injuryis hepatocellular (elevated ALT and/or AST) orcholestatic (elevated alkaline phosphatase) or amix.

There are several caveats in assessing for DILI.It should be kept in mind that the R value canchange with time, and also that, as mentionedabove, older patients may present with a chole-static pattern in the setting of DILI irrespectiveof the pattern expected by the inciting agent,based on the agent’s listed side effect profile orpublished literature. Additionally, not all drugsfall neatly into one category or another, and itis often helpful to begin with a broad investigationinto possible causes of liver injury rather than tofocus on one pattern of injury alone.

When hepatocellular or mixed injury issuspected, assessment may be focused on rulingout other possible causes of such injury. Thisincludes serology for viral hepatitis (HAV, HBV,HCV). If HEV PCR is available, it may beobtained. Other considerations include HSV,

EBV, and CMV. (Ischemic hepatopathy and evengallstone disease may present as hepatocellular ormixed injury as well, depending on the timingof injury). Serology for autoimmune hepatitisshould be obtained (either to assess for possibleautoimmune hepatitis or for a high titer ofantinuclear antibody, which can be seen withnitrofurantoin and minocycline (Chalasani et al.2015)). Assessment for Wilson’s disease shouldbe considered. Sometimes the markers do notreflect liver injury at all: skeletal muscle injurycan cause elevated AST and even ALT. Considercreatine kinase and aldolase to assess for myositis.

To assess for cholestatic injury, imaging shouldbe obtained to assess for biliary disease, includingobstruction. Consider serology for primary biliarycholangitis.

The severity of DILI, generally for hepatocel-lular injury, should not be estimated by the degreeof elevation of aminotransferases (which arenot in general a good indicator of liver function,although there are exceptions, such as acutesevere hepatitis with acetaminophen toxicity,Wilson’s disease or HSV infection) but ratheron whether there is evidence of impaired liversynthetic function associated with the injury.Biochemical clues to impaired synthetic functioninclude acute changes such as elevated INR ortotal bilirubin and decline in albumin or platelets.Hy’s law is a useful guideline, and postulatesthat those who develop bilirubin >2x ULN inthe setting of AST or ALT >3x the upper limitof normal have an approximately 10–50% risk ofDILI-related mortality or need for liver transplant(Temple 2006). This rule, in fact, is the basisfor the model used by the US Federal DrugAdministration in drug development, to determinewhether a compound proceeds through the drugapproval process (Senior 2014), highlighting itsimportance in considering DILI.

A liver biopsy is useful in certain circum-stances but is by no means a required element inthe evaluation of any possible DILI. Histologicfindings of DILI, as mentioned, are diverse andnot pathognomonic. However, a biopsy may beneeded for one of several reasons. First, it can helpdiagnostically to identify a pattern of injury whenone or more possible causes of liver injury

Table 3 Assessment for DILI in individuals presentingwith acute or chronic liver injury

Obtain careful current and past medication history

Dose, duration, and timing of drug ingestion

Temporal relationship between exposure to knownhepatotoxic agent and injury

Use of herbal medications, nutritional supplements,and over-the-counter medications

History of chronic liver diseases

Alternate causes of liver injury

Viral hepatitis (HAV, HBV, HCV, HEV, HSV, CMV,EBV)

Autoimmune hepatitis (separate from DILI)

Iron overload (hemochromatosis or transfusion-related)

Wilson disease

Primary biliary cholangitis

Wilson’s disease

Gallstone-related diseases

Exclusion of other causes of abnormal biochemistries

Alcohol use

Ischemic liver injury, including congestive heart failure

Sepsis

Muscle disease/injury

Budd-Chiari syndrome

Hemolysis

Drug-Induced Liver Injury in Older Adults 11

are being considered, usually to rule out a cause.Second, it can help to establish the severityof injury. This information is often needed, par-ticularly to serve as a baseline if serial biopsiesare being considered, or when the patientalready has a known chronic liver disease, or ifre-challenge with the suspected or known causeof DILI is being considered.

Management

When DILI is suspected, the first step is todiscontinue the causative drug(s). Most casesimprove upon withdrawal of the suspectedmedication(s) with no long-term sequelae(Hayashi et al. 2017). Normalization of liverfunction may take days to months, and somedevelop chronic DILI, with an incidence of5–10% (Hayashi and Bjornsson 2018). Regularmonitoring of labs and, when relevant, signsor symptoms of possible persistence or progres-sion of DILI is advised (Bessone et al. 2019;Reuben et al. 2010; Andrade et al. 2019; EuropeanAssociation for the Study of the Liver 2016; Mar-tin et al. 2014)

Sometimes steroids are needed, especiallywhen there may be an autoimmune-like reaction(Stine and Chalasani 2015), including for immunecheckpoint inhibitors which are increasinglybeing used for a variety of cancers (Brahmer etal. 2018). Steroid use should be limited to situa-tions in which they are specifically indicated, andnot as part of the general management of DILI.

N-acetylcysteine is a well-known treatmentof acetaminophen-related DILI (Ramachandranand Jaeschke 2019). Its use for other causes ofliver failure in DILI is controversial, largely dueto lack of clear evidence of efficacy. There issome evidence that it can improve survival ifadministered to adults with acute liver failure notdue to acetaminophen (Lee et al. 2009). USA andEuropean guidelines recommend its use in ALFdue to idiosyncratic DILI early on (e.g., comagrade I–II) (Chalasani et al. 2014; Andrade et al.2019). With its low side-effect profile and lackof other definitive and safe treatments of DILI,its administration is encouraged when available.

Prior history of DILI increases the riskof injury on re-exposure to the same or structur-ally similar agents. Re-challenge is not advisable,since recurrent injury may be more severe thanthe initial insult, especially with immunologicinjury. Ideally, re-challenge should be avoided.It is essential to closely monitor hepatic functionin those with a prior history of DILI if re-exposureis necessary.

The presence of jaundice, coagulopathy, new-onset fluid retention, and encephalopathy or comais evidence of DILI-related acute liver failure(Reuben et al. 2010). DILI can be associatedwith significant mortality, and is one of the mostcommon causes of liver failure leading to death orliver transplant (Bessone et al. 2019). Comparedto other causes of acute liver failure, it leads toa lower transplant-free survival (Andrade et al.2019). When there are features concerning forliver failure, it is important to consider whetherliver transplant is an option, based on patientfactors and access to a transplant center. It isimportant to recognize that older age is nota contraindication to liver transplantation basedon the most recent USA (Martin et al. 2014) andEuropean guidelines (European Association forthe Study of the Liver 2016), with liver transplantshaving been successfully performed in olderadults. However, for this population, assessmentof comorbidities is essential due to the risk ofposttransplant cardiovascular complications.

Next Steps: Future Goals

The prediction and monitoring of the course ofDILI remains a challenge. Novel biomarkers areneeded and have been the subject of recent work(Barnhill et al. 2018; Church et al. 2018). There isalso a computer-based modeling system,DILIsym, used to characterize the effects ofdrugs on a selected patient population by mathe-matically simulating its mechanism of injury(Church and Watkins 2018). Another modelincorporates lab values and comorbidities to esti-mate 6-month mortality in DILI. The study thatled to this model was also novel in providinginsight into the context in which DILI occurs:

12 E. D. Miller et al.

higher burden of comorbid illness (particularly forolder males) was an independent risk factor for 6-month mortality in DILI (Ghabril et al. 2019).This observation merits additional investigationinto the role comorbid diseases play in DILI,especially in older patients.

Finally, better data for elderly patients andinclusion in clinical trials are needed (Mitchelland Hilmer 2010). Older adults are often under-represented in clinical trials (Stine et al. 2013; vanRiet-Nales et al. 2016). There is an initiativeby the NIH in the USA that trials include patientsacross the life span, with the goal of requiringexpanded age criteria in new grants (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-116.html). It is also essential for registries,worldwide, to include cases of DILI amongolder patients (Haugen et al. 2019).

Key Points

• Older adults are not, in general, at higher riskof drug-induced liver injury compared to otherage groups.

• A few medications, including antibiotics(amoxicillin-clavulanate, erythromycin,flucloxacillin, isoniazid) and diclofenac, maybe more likely to cause DILI in older adults.

• DILI may present more commonly with a cho-lestatic biochemical pattern in the elderly agegroup compared to younger adults or children.

• Although statins can cause DILI, they are notriskier to use as age increases.

• Cessation of the offending agent and clinicalmonitoring are needed when DILI is suspected.

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