Review

Drug-induced liver injury in older people

M Isabel Lucena, Judith Sanabria, Miren García-Cortes, Camilla Stephens, Raúl J Andrade

Lancet Gastroenterol Hepatol Drug-induced liver injury (DILI) is a rare, unpredictable, and potentially serious adverse reaction. It is induced by
2020; 5: 862–74 many drugs, herbs, and dietary supplements and represents a diagnostic challenge to clinicians. Older people
Servicio de Farmacología (aged 65 years and older) are often polymedicated, and their declining physiological function affects drug
Clínica (Prof M I Lucena MD,
pharmacokinetics. There is no consistent evidence that age is a general risk factor for DILI; however, age might be
J Sanabria MD, C Stephens PhD)
and Servicio de Ap Digestivo a risk factor with specific medications, with antimicrobials and cardiovascular drugs being the most likely
(M García-Cortes MD, medications to cause DILI in older people. Ageing influences DILI phenotypes, making cholestatic damage and
Prof R J Andrade MD), Instituto chronic DILI more likely. In older people with DILI, comorbidities act as confounding causes and account for
de Investigación Biomédica de
higher mortality unrelated to the liver. There are no specific therapies for DILI and supportive measures are still
Málaga-IBIMA, Hospital
Universitario Virgen de la the mainstay of management. This Review highlights current advances and gaps in DILI epidemiology,
Victoria, Universidad de mechanisms, and diagnosis that are pertinent to older individuals.
Málaga, Malaga, Spain;
Platform for Clinical Research
and Clinical Trials IBIMA,
Introduction confined to bed. Notably, there seems to be no
Spanish Clinical Research Drug-induced liver injury (DILI) mechanisms can be correlation between chronological and biological age in
Network (SCReN), Madrid, idiosyncratic, intrinsic, or indirect. Idiosyncratic (unex­ the pro­ gressive decline in physio­ logical functions,
Spain (Prof M I Lucena, pected, determined by host factors) DILI is a multifaceted, physical capacity, or mental capacity.7
J Sanabria); and Centro de
Investigación Biomédica en
potentially life-threatening adverse reaction that jeopar­ The size of the older population (ie, aged ≥80 years) is
Red de Enfermedades dises patient safety and represents a growing concern for projected to double by the middle of this century.8
Hepáticas y Digestivas patients, clinicians, regulatory agencies, and pharma­ Clinicians might question whether older people have
(CIBERehd), Madrid, Spain ceutical companies.1 Idiosyncratic DILI can affect indivi­ greater susceptibility to DILI, more severe DILI, and a
(Prof M I Lucena,
M García-Cortes, C Stephens)
duals at all ages, with hospitalisation required in 23% of greater risk of DILI-related mortality than younger
patients.2 It represents 3·5% of all hospital admissions people have. Above all, clinicians need to know how to
Correspondence to:
Prof M Isabel Lucena, owing to jaundice,3 and accounts for 11% of acute liver detect and manage DILI in this particularly complex
Departamento de Farmacología, failure cases in the USA. The main example of intrinsic clinical context.
Facultad de Medicina, (direct, predictable, dose-related) DILI is paracetamol
Universidad de Málaga,
29071 Malaga, Spain
poisoning, which accounts for approximately 50% of Epidemiology of DILI in older people
lucena@uma.es people with acute liver failure,4 typically occurring shortly A 2-year Icelandic study reported a crude annual
after exposure to high drug doses. Furthermore, 8% of incidence rate for DILI of 19 cases per 100 000 inhabitants.2
people with acute DILI progress to chronic liver injury.5 Older age appeared to be a risk factor for DILI in this
A third, emerging mechanism is indirect DILI, which is study, because the age-standardised incidence increased
based on the action of the drug (ie, what the drug does). from nine per 100  000 people in the group aged
An example of indirect DILI is injury caused by 15–29 years to 41 per 100 000 people in the group aged
antineoplastic immune checkpoint inhibitors, which 80 years and older. This increase in incidence paralleled
increase T-cell responses against the tumour by blocking that of polymedication associated with older age.
the main negative immune regulators, but which also put However, no other studies have provided similar figures
patients at risk of immune-mediated adverse reactions, and these data might not be generalisable because of
including hepatotoxicity.6 This Review highlights current small cohort size and the fact that 42% of the population
advances and knowledge gaps in idiosyncratic DILI that were aged 60 years and older. Also, the criterion for liver
are pertinent to older individuals. injury was concentration of alanine aminotransferase
A characteristic of the ageing population is the presence (ALT) more than three times the upper limit of normal
of multiple comorbid conditions that lead to polypharmacy. (ULN), and this threshold is no longer considered
When combined with age-related decline in physiological sufficient to qualify a case as clinically relevant DILI,
functions that affect drug pharmacokinetics, receptor partly because reversible minor increases of amino­
sensitivity, cardiac reserve, renal function, immunological transferases (known as adaptation) are observed with
response, and homoeostatic processes can increase the many drugs.9 In addition, comorbidities such as non-
risk of adverse drug reactions. Hence, this older age group alcoholic fatty liver disease, which characteristically
is considered to be a special at-risk population.7 manifests as mild alterations in liver tests, are increasingly
By convention, people aged 65 years and older diagnosed, particularly in an ageing population.
represent a heterogeneous population encompassing Overall, epidemiological information about DILI in
a spectrum of individuals ranging from healthy, older people is scarce, and data are mainly derived from
independent people aged 65–74 years to people aged prospective10–12 or retrospective patient cohorts that often
85 years and older who commonly have accompanying differ with regard to DILI definition criteria and sample
frailty (age-related decline across multiple physiological size.2,13–17 Also, specific information about the proportion
systems), cognitive impair­ ment, and who are often of older patients included in these cohorts is rarely

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 Review

Spanish DILI ALFSG10 DILIN11 Japanese registry12 LATINDILIN* Pro-Euro DILI*

Registry*
Registry characteristics
Type National National National National International International
Participants (n) 843 1198 (133 with DILI) 899 307 359 92
Location Spain USA USA Japan Latin America Europe
Time period 1994 1998–2007 2003 2010–18 2011 2014
Demographics
Inclusion criteria CIOMS consensus ALF: encephalopathy, Age >2 years; and (1) ALT or AST ALT ≥150 IU/L or ALP New consensus criteria‡; New consensus criteria‡;
criteria (1994–2010)†; INR ≥1·5, and acute >5 × ULN or ALP >2 × ULN on ≥2 × ULN no paracetamol no paracetamol
new consensus criteria onset of illness two consecutive occasions; overdose hepatotoxicity
(from 2011 onwards)‡; <26 weeks or (2) total bilirubin ≥2·5 mg/dL
no paracetamol and elevated AST, ALT, or ALP; or
overdose (3) INR >1·5 and elevated AST,
ALT, or ALP
Sex
Men 439 (52%) 39 (29%) 369 (41%) 125 (41%) 140 (39%) 53 (58%)
Women 403 (48%) 94 (71%) 530 (59%) 182 (59%) 219 (61%) 39 (42%)
Age at DILI onset, years
Mean (SD) 54 (18) 44 (14) 49 (17) 59 (16) 49 (18) 55 (19)
Range 11–89 17–73 NA 17–86 14–89 19–90
Age ≥60 years 378 (45%) 20 (15%) NA 172 (56%) 118 (33%) 38 (41%)
Men 206 (55%) NA NA 84 (49%) 53 (45%) 18 (47%)
Women 172 (45%) NA NA 88 (51%) 65 (55%) 20 (53%)
Age ≥65 years 278 (33%) 8 (6%) 149 (17%) NA 80 (22%) 32 (35%)
Men 156 (56%) NA 60 (40%) NA 35 (44%) 17 (53%)
Women 122 (44%) NA 89 (60%) NA 45 (56%) 15 (47%)
Causative agents
Drugs 792 (94%) 118 (89%) 754 (84%) 246 (80%) 316 (88%) 85 (92%)
Herbal and dietary 51 (6%) 15 (11%) 145 (16%) 61 (20%) 43 (12%) 7 (8%)
supplements
Data are n (%), mean (SD), or median (IQR), unless otherwise specified. ALF=acute liver failure. ALFSG=Acute Liver Failure Study Group. ALT=alanine aminotransferase. ALP=alkaline phosphatase. AST=aspartate
aminotransferase. CIOMS=Council for International Organizations of Medical Sciences. DILI=drug-induced liver injury. DILIN=Drug-Induced Liver Injury Network. INR=international normalised ratio.
LATINDILIN=Latin Drug-Induced Liver Injury Network. NA=not available. ULN=upper limit of normal. *Unpublished data. †(1) ALT or conjugated bilirubin >2 × ULN; or (2) a combined increase in AST, ALP, or total
bilirubin, provided that one of them is >2 × ULN. ‡(1) ALT ≥5 × ULN; (2) ALP ≥2 × ULN; or (3) ALT ≥3 × ULN + total bilirubin >2 × ULN.

Table 1: Characteristics, patient demographics, and causative agents in prospective DILI registries

disclosed. In tables 1 and 2, the proportion of patients
aged 65 years and older ranged from 17% to 35%,
whereas the proportion of patients aged 60 years and
older ranged from 15% to 59%. The highest proportions
of older people in these cohorts were in two studies
from Japan,12,17 a country where the proportion of older
people is more than 30%.8 Similar figures were found
when analysing reports of DILI using the WHO
VigiBase safety dataset—62% of liver injury events
reported were in adults aged 18–64 years, 32% were in
patients aged 65 years and older, and only 6% were in
children.18
Available epidemiological data do not show that people
aged 65 years and older are more susceptible to DILI
than younger people. However, when focusing on
specific drugs, risk by age group can differ. For example,
in a UK population-based cohort study,19 patients older
than 70 years had a greater risk of DILI caused by
flucloxacillin than younger people who received
consecutive flucloxacillin prescriptions,19 and patients
older than 60 years were at higher risk of liver injury
caused by antituberculous therapy than patients aged 60
years or younger.20,21 Mortality from isoniazid-related
DILI is also age-dependent.22 By contrast, drugs such as
valproic acid, minocycline, and salicylates are more
hepatotoxic in younger patients than in the older
population.18
Antimicrobial drugs were most frequently implicated
in hepatotoxicity in older populations in the Spanish
DILI Registry23 and US Drug-Induced Liver Injury
Network (DILIN),11 whereas Chinese herbal drugs or
health foods were the most common causative agents in
a Japanese study.17
Age-related changes in pharmacokinetics
Changes in the pharmacokinetic processes of drug
absorption, distribution, metabolism, and excretion—as
a consequence of the decline in physiological functions
during ageing—impair drug disposition and drug
sensitivity. Ultimately, these age-related changes could

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Iceland2 South Korea13 Turkey14 India15 Mainland China16 Japan17

Study characteristics
Type Prospective Prospective Retrospective Retrospective Retrospective Retrospective
Participating hospital units Multiple hospitals Multiple hospitals Single hospital Single hospital Multiple hospitals Single hospital
Patients with DILI (n) 96 371 170 313 25 927 142
Time period 2010–12 (2 years) 2005–07 (2 years) 2001–07 (6·5 years) 1997–2008 (12 years) 2012–14 (2 years) 1997–2007 (10 years)
Demographics
Inclusion criteria Age >15 years; Hospitalised adults; Age >15 years; alcohol Total bilirubin No inclusion Did not follow accepted
ALT >3 × ULN or ALT >3 × ULN or total per day <15 g (women) >2 mg/dL; AST or criteria based on liver criteria based on liver
ALP >2 × ULN; and no bilirubin >2 × ULN or 20 g (men); CIOMS ALT >3 × ULN or chemistry values; biochemistry values
paracetamol toxicity consensus criteria*; ALP >2 × ULN included cases of mild
no herbal and dietary liver injury not
supplement toxicity represented in other
registries
Sex
Men 42 (44%) 136 (37%) 75 (44%) 183 (58%) 12 930 (51%) 59 (42%)
Women 54 (56%) 235 (63%) 95 (56%) 130 (42%) 12 507 (49%) 83 (58%)
Age at DILI onset, years
Mean (SD) or median (IQR) 55† (38−69) 49† (16–79) 43‡ (14) 39‡ (16) NA 60‡ (18)
Range 16–91 16–79 15–77 12–84 40–59§ NA
Age ≥60 years 40 (42%) 92 (25%) NA NA 5694 (22%) 84 (59%)
Causative agents
Drugs 81 (84%) 100 (27%) 170 (100%) 310 (99%) 18 927 (73%) 119 (84%)
Herbal and dietary supplements 15 (16%) 271 (73%) NA 3 (1%) 7000 (27%) 23 (16%)

Data are n (%), or mean (SD), or median (IQR), unless otherwise specified. ALT=alanine aminotransferase. ALP=alkaline phosphatase. AST=aspartate aminotransferase. CIOMS=Council for International Organizations of
Medical Sciences. DILI=drug-induced liver injury. INR=international normalized ratio. NA=not available. ULN=upper limit of normal. *(1) ALT or conjugated bilirubin 2 × ULN, or (2) a combined increase in AST, ALP, or
total bilirubin, provided one of them is >2 × ULN. †Median. ‡Mean. §The most frequent of several age ranges given in the study.

Table 2: Characteristics, patients demographics, and causative agents in large DILI cohorts from epidemiological studies

influence variability in drug response and toxicity in
older people.
Age-related changes in body composition, with a
decrease of water (decrease in lean body mass) and higher
adipose tissue content, translate into higher distribution
volumes for lipophilic compounds and a prolonged half-
life. Highly lipophilic drugs given at high daily doses are
more likely to be involved in adverse hepatic reactions in
older than in younger people, suggesting greater hepatic
exposure to the drug in older people.18
Biotransformation of drugs occurs largely in the liver,
although other organs (such as the gastrointestinal tract,
kidneys, lungs, and skin) present some metabolic activity.
This location of biotransformation might explain organ-
specific toxicities related to some drugs (ie, drug reaction
with eosinophilia and systemic symptoms [DRESS] with
frequent combined involvement of the skin and liver, or
paracetamol hepatotoxicity and accompanying renal
injury). With advancing age, there is a progressive
reduction in liver volume and liver blood flow. Although
activities of the drug-metabolising CYP450 enzymes
remain stable with normal ageing, these ageing-related
changes in liver blood flow and mass can decrease
elimination of high clearance drugs and increase drug
exposure. In contrast, among the detoxifying reactions,
glucuronidation (the main route in paracetamol meta­
bolism) appears preser­ved at age 65 years and older.24,25
Additionally, ageing is associated with moderate changes
in biliary function, including decreased bile flow and bile
acid secretion.26 Notably, drugs involved in liver toxicity in
older people were associated with an increase in biliary
excretion and bile salt export pump (ABCB11), and MRP2
(ABCC2) transporter inhibition.27 P-glycoprotein 1 (ABCB1)
functional activity, however, seems to be unaffected.25
Reduction of renal clearance with age is the most
relevant and predictable change in drug pharmaco­kinetics.
With advancing age there is a progressive decline in renal
function, including renal blood flow, glomerular filtration
rate, and active tubular secretion. Thus, renal clearance of
drugs primarily excreted by the kidney correlates with
creatinine clearance. Disease conditions prevalent in older
people, such as diabetes and hypertension, can further
compromise renal function.
Co-morbidities, polypharmacy, and potential
for drug interactions
Common chronic non-communicable diseases that lead
to polypharmacy in older people are the reason for the
increase in the rate of adverse drug reactions in this
population.8,28
Notably, in a population-based case-control study using
the UK General Practice Research Database,29 the risk of
developing acute, clinically relevant DILI was increased
by a factor of six when a combination of two or more

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Microbiota

CYP

Covalent binding Reactive

metabolites Intestinal permeability
HLA presentation
PAMPs (eg, LPS)
Cellular damage

APCs
Cellular Innate or adaptive
Mitochondrial damage
stress immune response
DAMPs (danger signals)
Neoantigen
Uregulation
ROS HLA
Nrf2 of gene HSP, HMGB 1, DNA, RNA
expression
TCR
GSH
Immune
JNK tolerance
Mild liver injury
Adaptation
No liver injury

Severe liver injury

Regeneration
Resolution
Clearance Proinflammatory and protective
cytokine balance
Acute liver failure

Figure: Current understanding of the underlying mechanism of idiosyncratic drug-induced liver injury
Intermediate drug metabolites formed during drug metabolism undergo conjugation with hydrophilic groups to aid drug clearance. The inability to detoxify reactive
drug metabolites can cause mitochondrial damage and oxidative stress and subsequently activate prodeath and prosurvival signalling pathways. Reactive
metabolites can also function as haptens and form neoantigens. The presentation neoantigens on specific HLA molecules could cause an adaptive immune response.
Because of its biological role with constant exposure to foreign antigens, the liver has a strong natural predisposition towards immune tolerance. This tolerance
prevents a substantial immune response in the presence of a drug-related neoantigen, causing, at most, a mild liver injury that resolves spontaneously despite
continued drug intake (ie, adaptation). Clinically relevant drug-induced liver injury is believed to result from a breakdown in hepatic immune tolerance. Concomitant
inflammation (whether sterile or infectious) can change the cytokine environment in favour of an immune response. Changes to the intestinal microbiota
(ie, dysbiosis) can increase intestinal permeability and release bacterial products into the blood stream. These molecules can be detected as PAMPs, which play an
important role in helping to stimulate immune activation. APCs=antigen-presenting cells. CYP=cytochrome P450. DAMPs=damage-associated molecular patterns.
GSH=glutathione. HMGB1=high-mobility group 1. HSP=heat shock protein. JNK=c-Jun N-terminal kinase. LPS=lipopolysaccharide. Nrf2=nuclear factor erythroid
2-related factor 2. PAMP=pathogen-associated molecular pattern. ROS=reactive oxygen species. TCR=T-cell receptor.

hepatotoxic drugs was present. An in-vitro analysis—
using monocyte-derived hepatocyte-like cells from
patients with DILI who were taking two drugs at the time
of DILI onset—supports this hypothesis by showing that
combinations of drugs increased toxicity, although the
mechanisms are still unknown.30
Concurrently administered drugs given to patients
with hepatotoxicity caused by statins did not appear to
influence the DILI risk.31 However, the term therapeutic
misadventure has been used to describe severe cases of
acute liver injury with paracetamol given at therapeutic
doses in chronic alcohol consumers or patients receiving
isoniazid treatment. This acute liver injury was
presumably caused by the generation of large amounts
of toxic metabolites through the induction of the drug-
metabolising enzyme CYP2E1 together with a depletion
in the hepatic glutathione content, malnutrition, and
fasting (reduced glycogen deposits).32 The absence of
pre-existing conditions has also been shown to influence
the characteristics of DILI presentation, in particular
delayed onset (ie, symptoms appearing after drug
cessation).33 These findings underscore the relevant and
complex interactions between drug properties and host
factors in DILI development,34 highlighting the need to
investigate further pharmacokinetic and pharmaco­
dynamic changes associated with older age, particularly
in the presence of comorbidities and when patients are
polymedicated.35
A long-debated issue is whether underlying liver
disease makes patients more prone to DILI. There is
some evidence that chronic viral hepatitis B and C,
particularly in people with HIV, increase the risk of
hepatotoxicity with antituberculosis and antiretroviral
drugs.36 Similarly, a report using a pharmacoepidemiology
database suggested that patients with features of non-
alcoholic fatty liver disease were at increased risk of DILI
from some prescription medications,37 but not statins.38
Nevertheless, DILI can have more severe consequences
if a patient has pre-existing liver disease.11
Mechanisms
The underlying mechanism of idiosyncratic DILI is not
yet fully understood but is generally believed to be a
multifactorial process (figure). As such, drug properties,
host factors, and environmental conditions interact to
determine DILI susceptibility, phenotypic expression,

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 Review
and outcome.34 Increased understanding of paracetamol
hepatotoxicity has provided insights into idiosyncratic
DILI, which is no longer believed to be a passive process
directly due to overwhelming biochemical injury, but
rather an active process involving the recruitment of cell
death signalling pathways and immune responses.39
Cellular stress in hepatocytes—induced by reactive
metabolites, mitochondrial dysfunction, and oxidative
stress—is believed to be an important event in the
initiation of DILI. Reactive metabolites are often formed
during drug metabolism and cellular exposure to these
compounds is dependent on the efficacy of phase 1
(bioactivation), phase 2 (detoxification), and phase 3
(elimination) reactions. The effect of ageing on drug
metabolism can vary depending on the drug, as well as on
patient factors, such as comorbidities and polypharmacy,
affecting the threshold dose needed to initiate cellular
damage.
Mitochondria are a common target of DILI reactions. It
has been suggested that the high incidence of DILI
resulting from antibiotics could be related to the bacterial
ancestry of mitochondria. As such, mitochondria share
many genetic and structural similarities with bacteria,
and antibiotics might therefore damage mitochondria.39
Mitochondria are influenced by age both quantitatively
and qualitatively, with decreasing mitochondrial DNA
copy number and heteroplasmy accumulation occurring
with increasing age.40 Therefore, older patients could be
at increased risk of reaching the threshold for
mitochondrial dysfunction and subsequent hepatocyte
injury when exposed to drugs with mitochondrial liability
(ie, can directly damage mitochondria).
Mitochondrial dysfunction leads to perturbation of the
electron transport chain, resulting in increased reactive
oxygen species generation. Reactive drug metabolites can
also induce reactive oxygen species and oxidative stress,
and the inability to restore redox homoeostasis carries
the risk of substantial cell damage. Cellular stress
activates adaptive signalling pathways, such as upregu­
lation of the transcription factor nuclear factor erythroid
2-related factor 2, which leads to increased expression of
antioxidant genes, including those encoding glutathione
S-transferases. The intracellular level of reduced gluta­
thione is therefore of high importance to maintain redox
homoeostasis. A decreased concentration of gluta­thione
has been reported in erythrocytes and lymphocytes of
healthy older people, and potentially could also occur in
hepatocytes.41 This decrease in glutathione concen­tration
suggests that older patients could be more prone to
elevated oxidative stress than younger patients, which in
conjunction with drug treatment might initiate DILI
development. As cellular stress reaches a critical hepato­
cyte injury threshold, cell death signalling pathways are
induced (eg, activation of the mitogen-activated protein
kinase JNK), eventually causing apoptosis and necrosis
through mitochondrial permea­bility transition and outer
membrane permea­bilisation.39 A typical delay of weeks or
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months from drug treatment initiation to DILI detection
can therefore be explained by a gradual accumulation of
initially silent hepatocyte injury.
Findings point towards the immune system also
playing a crucial role in DILI, because the liver readily
adapts to situations of drug-induced stress (figure). The
role of the immune system in DILI has become apparent
with the discovery of associations between specific HLA
risk alleles and DILI susceptibility to different causative
agents, of which many do not normally cause clinical
signs of immunopathology.42 On the basis of the hapten
theory, reactive metabolites are able to bind to
endogenous proteins and form neoantigens, with the
potential to elicit an adaptive immune response when
presented on specific HLA molecules. Alternatively,
reactive metabolites might form non-covalent inter­
actions with HLA molecules or T-cell receptors. Because
of its biological role, the liver is constantly exposed to
foreign antigens, and therefore has a strong natural
predisposition towards immune tolerance that needs to
be broken for clinically relevant liver injury to occur.43
The role of immune tolerance in the liver is becoming
apparent with new cancer immunotherapies that
specifically target immune checkpoints that regulate self-
tolerance. However, most patients tolerate drugs and
might experience mild, often transient, asymptomatic
liver enzyme elevations (eg, with statins or isoniazid)
because of activated protective pathways that limit further
damage—a phenomenon known as adaptation.43
The immune system undergoes age-related changes
(immunosenescence) that affect its efficiency, with a
general decline in immune function in older people.44 It is
unknown if such changes have any clinically significant
effect on susceptibility to DILI. One of the characteristics
of immunosenescence is persistent low-grade inflam­
mation (inflammaging), with increased secretion of
proinflammatory mediators, such as cytokines, chemo­
kines, growth factors, and proteases. Inflammaging is
also thought to be implicated in the pathogenesis of a
number of diseases in older people, such as osteoporosis,
type 2 diabetes, and rheumatoid arthritis.44 Concomitant
inflam­mation in general is thought to potentially increase
the risk of DILI, because of the heightened state of the
immune system and the ability to more readily activate an
immune response. Inflammatory stimuli could also
come from the intestinal microbiota. Older people have a
different microbiota profile compared with younger
adults. However, this change appears to occur gradually
throughout life, and is heavily dependent on differences
in factors such as diet, lifestyle, and comorbidities.45
Ageing has been associated with increased intestinal
permeability, mainly because the intestinal epithelial
barrier becomes impaired with age.46 This increase in
permeability allows proinflammatory bacterial products
to be released into the bloodstream. These molecules can
be detected as pathogen-associated molecular patterns
and contribute to chronic immune activation. Age-
 Review

Spanish DILI Registry23 (n=603) US DILIN11 (n=899) Japanese single centre17 (n=142)
Age <60 years Age ≥60 years Age <65 years Age ≥65 years Age <65 years Age ≥65 years
(n=750) (n=149) (n=76) (n=66)
Men (n=152) Women (n=175) Men (n=158) Women (n=118)
Demographics
Sex
Men 152 (49%) ·· 158 (51%) ·· 307 (41%) 60 (40%) 32 (42%) 27 (41%)
Women ·· 175 (60%) ·· 118 (40%) 443 (59%) 89 (60%) 44 (58%) 39 (59%)
Age, years (SD) 39 (NA) 43 (NA) 71 (NA) 70 (NA) 44 (14) 73 (6) NA NA
BMI (kg/m2) 25 (3·3) 25 (4·6) 26 (2·8)* 28 (4·4)* 28 (6·8) 27 (5·0) NA NA
DILI characteristics
Jaundice 100 (66%) 100 (57%) 124 (78%)* 90 (76%)* 533 (71%) 100 (67%) NA NA
Hospitalisation 80 (53%) 80 (46%) 97 (61%)* 70 (59%)* 221 (29·5%) 43 (29%) 76 (100%) 66 (100%)
Eosinophilia 38 (25%) 43 (25%) 31 (20%)† 30 (25%)† 83 (11%) 16 (11%) 26 (34%) 32 (48%)
Pattern of liver injury
Hepatocellular 93 (61%) 114 (65%) 68 (43%)* 54 (46%)* 428 (57%) 58 (39%)* 62 (82%) 48 (73%)
Cholestatic or mixed 59 (39%) 61 (35%) 90 (57%)* 64 (54%)* 323 (43%) 91 (61%)* 14 (18%) 18 (27%)
Liver biochemistries at DILI recognition
Total bilirubin, mg/dL 13 × ULN (NA)* 6 × ULN (NA)* 13 × ULN (NA)* 9 × ULN (NA)* 6·6 (6·6) 7 (6·7)* 3·5 (4·6) 5·8 (7·9)*‡
Alanine aminotransferase, 22 × ULN (NA)* 22 × ULN (NA)* 22 × ULN (NA)* 14 × ULN (NA)* 866 (1144) 620 (861)* 560 (449) 648 (567)*‡
IU/L
Alkaline phosphatase, IU/L 1·9 × ULN (NA)* 3·2 × ULN (NA)* 1·9 × ULN (NA)* 3·2 × ULN (NA)* 264 (220) 410 (361) 442 (396) 783 (842)*‡
Fulminant liver failure or liver 2 (1%) 11 (6%) 2 (1%) 8 (7%) 33 (4%) 3 (2%) liver 0 3 (5%)
transplantation transplantations
Data are n (%), or mean (SD). BMI=body-mass index. DILI=drug-induced liver injury. DILIN=Drug-Induced Liver Injury Network. NA=not available. ULN=upper limit of normal. *Significant difference compared
with younger patients. †Hypersensitivity features present (ie, one or more positive features, such as fever, rash, arthralgia, peripheral eosinophilia, or lymphopenia). ‡Weighted mean.

Table 3: Phenotypic characteristics of drug-induced liver injury in people aged 65 years and older

dependent increases in intestinal permeability might be
preceded by microbiota dysbiosis, which could lead to a
second, more clinically significant, change in the
microbiota com­position.47 Use of non-steroidal anti-
inflammatory drugs, which can increase intestinal
permeability, is often accompanied by use of proton-
pump inhibitors, which reduce stomach acid production,
resulting in changes to the intestinal microbiota.48 We
might speculate that the frequent use of antibiotics by
older patients could affect the microbiota and increase the
risk of dysbiosis, leading to intestinal permeability,
bacterial translocation, and increased susceptibility to
DILI. The outcome of DILI is highly dependent on the
liver’s capacity to regenerate, a process that requires the
activation of a specific cell cycle and mitogenic genes. It is
well known that ageing impairs liver regeneration,
potentially because of a diminished rate, rather than
capacity, of liver regeneration.26 This diminished rate of
liver regeneration is unlikely to affect DILI susceptibility,
but is of importance for DILI outcome. Hence, older
patients developing DILI are at increased risk of a more
severe outcome than are younger patients.
Phenotypes of DILI
DILI varies widely in its phenotypic expression and
severity, which range from asymptomatic liver test
abnormalities to acute liver failure. Clinical features of
acute DILI include vomiting, right upper quadrant pain,
dark urine, and jaundice, which are similar to features of
acute hepatitis or cholestasis resulting from other causes.
Approximately a quarter of patients manifest drug allergy
features (eg, fever, rash, arthralgia, eosinophilia, or
lymphocytosis), which prompt suspicion of DILI.49 In
more severe cases, erythema multiforme, drug reaction
with eosinophilia and systemic symptoms, Stevens-
Johnson syndrome, or toxic epidermal necrolysis can
accompany the liver damage.50
By convention, acute DILI should be considered,
irrespective of the presence of symptoms, when any one
of the following thresholds of liver enzymes are met:
(1) ALT (or aspartate aminotransferase [AST] in the
absence of ALT values) increase of at least five times
ULN; (2) alkaline phosphatase (ALP) elevation at least
two times ULN; or (3) total bilirubin concentration
exceeding two times ULN associated with ALT or AST
elevation of at least three times ULN. Elevation of ALT or
AST at least three times ULN in the presence of
symptoms is deemed sufficient to consider DILI.9,51 The
pattern of DILI is defined using the ratio (ie, the R value)
of ALT (or AST) activity to ALP activity, with activity
expressed as the number of times higher than the ULN
of the laboratory range. The pattern of DILI is
(1) hepatocellular when ALT alone is elevated to at least
five times ULN, or the R value is at least 5, (2) cholestatic

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 Review

Epidemiology Chemical properties Phenotype presentation Host risk factors Proposed mechanisms
Amoxicillin– 17% of cases in the High solubility; ≤50% hepatic Cholestatic or mixed damage related HLA risk alleles: A*02:01, A*30:02 Alterations in innate and
clavulanic acid Spanish DILI Registry and metabolism; renal and biliary to older age, male sex, and (hepatocellular), B*18:01 adaptive immune
11% in DILIN excretion; reactive metabolite prolonged amoxicillin–clavulanic (hepatocellular), DRB1*15:01- regulations; delayed
formation; mitochondrial liability acid therapy; hepatocellular damage DQB1*06:02 (cholestatic or mixed), onset explained by
related to younger age, female sex, DRB1*07 (protective); a missense interactions between
and shorter treatment duration; variant in PTPN22 (reduced immune drug properties and host
48% of patients present with tolerance of T cells) is a risk factor for factors (high daily dose,
delayed onset (after treatment DILI caused by amoxicillin–clavulanic absence of pre‐existing
discontinuation)31 acid; a low level of ERAP2 gene conditions)
expression (which encodes a protein
that trims peptides to fit into the
antigen binding site of HLA proteins)
is also a risk factor for amoxicillin–
clavulanic acid-induced DILI
Antituberculosis DILI incidence increases Isoniazid: hydrophilic, hepatic Mainly hepatocellular; median time HLA-DQA1*01:02 (protective); Immune-mediated DILI;
drugs: isoniazid, with age; patients aged metabolism (by CYP2E1, NAT2), to onset 6 weeks to 6 months; can HLA-DQB1*0201 (risk); associations generation and
rifampicin, and ≥60 years are 3·5 times reactive metabolites, mitochondrial lead to ALF and death; up to 20% of not GWAS confirmed; older age, accumulation (through
pyrazinamide more likely to have DILI; liability; rifampicin: lipophilic, high users develop transient female sex, alcohol consumption, reduced clearance) of
isoniazid is the most hepatic metabolism, potent enzyme asymptomatic liver enzyme malnutrition, NAT2 ultra slow reactive metabolites
hepatotoxic; isoniazid– inducer, potentiates hepatotoxicity of elevations acetylators; viral hepatitis and HIV
rifampicin combination other antituberculosis drugs; co-infection
has highest DILI rate pyrazinamide: hydrophilic, high
hepatic metabolism, long half-life
(9·5 h), which is longer in patients
with underlying liver disease
Atorvastatin Statin that most High lipophilicity; extensively Often asymptomatic Aged ≥65 years Potential threshold dose
commonly causes DILI in metabolised by CYP3A4; forms aminotransferase elevations;
different cohort studies reactive metabolites typically a cholestatic or mixed
pattern; about 30% of
hepatocellular cases show
autoimmune features; statins are
overrepresented among chronic DILI
cases; can develop ALF leading to
death or liver transplantation
Diclofenac Diclofenac caused DILI in Hydrophilic; extensive metabolism; Predominantly hepatocellular; time Associations reported in a candidate Impairment in drug-
180 (71%) aged formation of reactive metabolites to onset 2–6 months; commonly gene study: UGT2B7*2 and ABCC2; metabolising enzymes
≥60 years56 presents with jaundice; frequently GWAS: PPARG (risk);57 non- and hepatocanalicular
prescribed for chronic inflammatory synonymous PTSG1 and PTGS2 transporters; alterations
conditions (osteoarthritis); associated with DILI onset after long- in intestinal mucosal
intestinal toxicity term NSAID therapy58 barrier and gut
microbiome leading to
bacterial translocation
and enhanced hepatic
inflammation
Flucloxacillin DILI risk increases from Low hepatic metabolism; metabolic Presents with jaundice; HLA‐B*57:01 and HLA‐B*57:03, HLA testing for presence
8·5 per 100 000 people activation to toxic metabolite predominantly cholestatic; course is HLA-B protein positive for valine at of risk alleles might help
prescribed flucloxacillin, (5’hydroxymethyl flucloxacillin); generally severe and protracted; position 97, female sex, age >70 years, confirm (if present) or
to 110·5 per 100 000 in reduced clearance in patients with histological findings of centrizonal and longer treatment duration refute the diagnosis of
people aged >70 years diminished renal function bile stasis with portal tract DILI; impaired renal
who have received two or inflammation and variable loss of function might increase
more consecutive bile ducts drug concentrations
prescriptions of
flucloxacillin
ABCC1/ABCC2=ATP binding cassette subfamily C member 1/2. ALF=acute liver failure. CYP2E1=cytochrome P450 family 2 subfamily E member 1. CYP3A4=cytochrome P450 family 3 subfamily A member 4.
DILI=drug-induced liver injury. DILIN=Drug-Induced Liver Injury Network. ERAP2=endoplasmic reticulum aminopeptidase 2. GWAS=genome-wide association study. NAT2=N-acetyltransferase 2. NPV=negative
predictive value. NSAID=nonsteroidal anti-inflammatory drug. OR=odds ratio. PPARG=peroxisome proliferator activated receptor gamma. PTPN22=protein tyrosine phosphatase non-receptor type 22.
PTGS1/PTGS2=prostaglandin-endoperoxide synthase 1/2. UGT2B7=UDP glucuronosyltransferase family 2 member B7.

Table 4: Overview of drugs frequently involved in DILI in older people

when ALP alone is elevated at least two times ULN, or
the R value is at least 2, and (3) mixed when the R value
is 2–5.51 It is important to use the first set of laboratory
tests available in relation to the clinical event, because
the pattern of elevated liver enzymes can evolve over the
course of the event, owing to differences in the rate of
improvement between amino­ transferases and ALP.
Thus, a hepatocellular pattern often becomes mixed or
cholestatic over time.52 Other patterns of DILI should be
characterised according to imaging or histological
findings, or both (ie, sinusoidal obstruction syndrome,
non-alcoholic steatohepatitis).

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Although some drugs have a typical signature
(eg, isoniazid causes hepatocellular injury, anabolic
steroids cause cholestatic injury), the DILI phenotype
from the same drug can differ among individuals
(eg, amoxicillin–clavulanic acid). The biological basis for
such a difference is not yet clear. A candidate gene study
showed that the frequencies of HLA-DRB1*15 and
HLA-DQB1*06 alleles were significantly increased and
HLA-DRB1*07 and HLA-DQB1*02 alleles were reduced in
patients with DILI who had cholestatic or mixed damage,
when compared with a healthy control group.53 This
finding was later confirmed for patients with amoxicillin–
clavulanic acid hepatotoxicity,54 which suggests that HLA
class II alleles could partially explain why a given drug
causes different types of liver damage in patients, and
supports the concept of an immunoallergic-based
mechanism of cholestatic and mixed DILI.
Age is a strong determinant of DILI phenotypic
presentation, with older age consistently favouring the
cholestatic phenotype across several DILI cohorts.11,23 This
higher proportion of the cholestatic phenotype in older
age groups was also apparent in the DILI cohorts
presented in table 3, in addition to an increased proportion
of people with jaundice. A previous analysis of amoxicillin–
clavulanic acid cases from the Spanish DILI Registry
confirmed an age-related phenotypic expression.55
An overview of specific causative agents most
frequently involved in DILI in older people is presented
in table 4. It encompasses epidemiological data, chemical
properties, phenotype presentations, and associated host
risk factors that might help clinicians to reach a reliable
diagnosis.
Diagnosis and causality assessment
Diagnosis of DILI is one of the most challenging tasks in
the hepatology field because DILI can mimic almost all
other acute or chronic liver diseases, and diagnostic tests
specific to DILI have not yet been developed. As a result,
the diagnosis of DILI depends on a high degree of
awareness of the condition and the exclusion of alternative
causes of liver damage.9 Such a clinical exercise is complex
and requires skills and a wide knowledge of liver disorders.
A clinician facing a potential DILI case often requires the
help of an experienced hepatologist. This expertise is
particularly needed when suspicion of DILI occurs in a
clinical trial run by a local investigator not familiar with
liver diseases.
The diagnostic approach to DILI is initiated after
detection of liver biochemistry abnormalities (including
elevated ALT or AST, ALP, total bilirubin, or a combination
of these) that meet the criteria for liver injury51 during an
investigation for non-specific symptoms, or by the
occurrence of a viral hepatitis or obstructive jaundice-like
syndrome, which are the most common presentations of
overt DILI in clinical practice. If there is a high degree of
suspicion, clinicians should have a detailed interview with
the patient and caregivers (of particular importance in
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Review
older, frail patients) about exposure to prescription drugs
and over-the-counter medications, recording drug start
and stop dates, as well as any exposure to herbal and
dietary supplements (which is often overlooked by the
physician)—all of which are key elements for DILI
ascertainment.49 Although every drug in common use has
been implicated in DILI,59 antimicrobials rank as the first
causative drug class in several large cohorts of patients
with DILI, and antimicrobial usage is much higher in
individuals aged 65 years and older.2,11,23 It is crucial to
retrieve information about latency (ie, time from drug
initiation to liver damage detection), to monitor the course
of the reaction during discontinuation of the suspected
drug, and to establish time to resolution to confirm a
compatible temporal relationship with the suspected
causative agent. The time to DILI onset varies considerably
among different drugs and patients. Most individuals with
DILI develop it within the first 3 months of therapy,
although some drugs (eg, amoxicillin–clavulanic acid) can
cause DILI that develops a considerable time after
treatment cessation in a small proportion of patients.55,60
Whether older age can influence time to onset has not
been shown for the majority of drugs causing hepato­
toxicity. However, one study analysing a large series of
patients who developed DILI after taking amoxicillin–
clavulanic acid showed that patients older than 55 years
had a longer latency period than did younger individuals.55
Defining the phenotype is an essential next step in DILI
assessment, as it provides guidance for further investi­
gations. Older people in particular have a propensity to
manifest DILI with a cholestatic phenotype.3,23 Hence,
cholestasis in older people should prompt clinicians to
search for exposure to drugs or other compounds, aside
from excluding benign and malignant causes of obstructive
jaundice.
The diagnostic tests needed in older people with
suspected DILI (table 5) should be tailored according to
the phenotype of presentation and to comorbidities.
Although old age is a risk factor for cardiovascular
disorders, and hepatic ischaemia is an obvious alternative
possibility in individuals with hepatocellular damage and
very high aminotransferases, patients with a previous
diagnosis of cardiac failure, coronary artery disease, or
stroke are at greater risk of ischaemic hepatitis. A history
of syncope or a hypotensive episode can be a clue for a
diagnosis of this condition. Routine evaluation of all
patients with liver injury includes liver imaging studies.
Patients with suspected DILI, regardless of the type of
damage, should undergo abdominal ultrasonography to
exclude biliary obstruction and focal lesions.1 Patients
with a hepatocellular or mixed type of liver damage and a
normal abdominal ultrasound do not normally require
further imaging assessments. Patients with a cholestatic
type of liver injury, or associated abdominal pain, might
warrant additional imaging, such as magnetic resonance
cholangiography or CT. This approach is of paramount
importance in older individuals, who more frequently
 Review

Diagnostic tests Comments

Viral hepatitis − exclude for hepatocellular ·· Viral hepatitis is a major cause of liver injury and affects people
or mixed worldwide. Except for pure cholestatic injury, viral hepatitis
can present as DILI and should be excluded in patients with
hepatotoxicity suspicion
Hepatitis A Anti HAV-IgM HAV outbreaks in communities; more severe in older people
Hepatitis B Anti HBV-IgM ··
Hepatitis C Anti-HCV, RNA-HCV ··
Hepatitis E Anti HEV, RNA-HEV HEV in European countries (genotype 3 and 4) is a zoonosis
and typically affects older men
Alcoholic hepatitis − exclude for Ratio of AST to ALT >1, AST <300 U/L; raised GGT History of regular alcohol intake
hepatocellular, cholestatic, or mixed and mean corpuscular volume
Autoimmune hepatitis − exclude for Antinuclear antibody and ASMA titres, raised IgG 25% of patients present with acute hepatocellular damage
hepatocellular and gamma globulins resembling viral hepatitis; incidence peak is around age
70 years for both sexes61
Ischaemic hepatitis − exclude for A rapid increase in ratio of AST to ALT Acute or chronic congestive heart failure, hypotension,
hepatocellular ≥800 IU/L;62 ultrasound or MRI hypoxia, hepatic venous occlusion
Biliary tract disease − exclude for Ultrasound and MRI, endoscopic retrograde Choledocolithiasis and cancer (biliary tract, pancreatic cancer)
cholestatic, mixed, or very rarely cholangiopancreatography as appropriate are more frequent in older people; abdominal pain, chills,
hepatocellular passage of calculi can be associated with transient marked
elevations of aminotransferases (hepatocellular pattern)
Non-alcoholic steatohepatitis − exclude Ratio of AST to ALT <1; ultrasound or MRI Prevalence of non-alcoholic steatohepatitis increases with age
for hepatocellular
Haemochromatosis − exclude for Ratio of AST to ALT <1; ferritin, transferrin Men of any age and older women are more likely to be affected
hepatocellular saturation

The pattern of liver injury can be hepatocellular, cholestatic, or mixed and is determined by calculating the ratio (R) of ALT to alkaline phosphatase from the first available
blood analysis after DILI recognition, using multiples of the upper limit of normal for both values, with R ≥5 for hepatocellular; R ≤2 for cholestatic; and R >2 and <5 for
mixed.51 ALT=alanine aminotransferase. ASMA=anti-smooth muscle antibody. AST=aspartate aminotransferase. GGT=γ-glutamyl transferase. HAV=hepatitis A virus.
HBV=hepatitis B virus. HCV=hepatitis C virus. HEV=hepatitis E virus.

Table 5: Investigations of liver disease according to type of liver damage in older patients with suspected DILI

have obstructive jaundice. Thus, acute cholestasis should
be carefully assessed by imaging techniques before a
DILI diagnosis is made.
Liver histology is not essential for DILI diagnosis, as
histological features are seldom indicative of toxic liver
damage. Notable exceptions include sinusoidal obstruction
syndrome relating to chemotherapy (oxaliplatin). Hence,
liver biopsy is more useful for diagnosing an alternative
liver disorder (eg, autoimmune hepatitis) than for
establishing hepatotoxicity. Additionally, liver biopsy can
provide data of prognostic value that could be used to
inform clinical decisions.63 In progressive cholestatic DILI,
a liver biopsy can provide evidence for bile duct loss, which
has important prognostic implications.64
We advocate the use of causality assessment tools
(clinical scales) to quantify the strength of association in
hepatotoxicity research and reporting. The Roussel Uclaf
Causality Assessment Method (RUCAM) scale (also
known as the Council for International Organizations of
Medical Sciences [CIOMS] scale) is the most widely used
in post-marketing DILI causality assessment.1 This scale
contains seven domains: time to onset, course after drug
cessation, DILI risk factors, exclusion of relevant causes of
liver injury, potential influence of associated medications,
known hepatotoxic potential of the drug, and recurrence
of liver injury after drug re-exposure. These domains are
rated individually and the total sum provides a final score
that is translated into a predefined category (highly
probable, probable, possible, unlikely, and excluded).
RUCAM arbitrarily considers age 55 years and older to be
a risk factor for DILI, adding one point to the score.65
Although no study has systematically explored the
performance of the scale in older people, no differences
were found between scores obtained from younger and
older patients in a US study.11
Genome-wide association studies have identified some
genetic variants (mostly HLA class I and II alleles)
associated with the risk of DILI due to specific drugs.66–69
The rarity of DILI, and the fact that it is a polygenic
disorder, make genetic testing impractical as a predictive
biomarker because of the low positive predictive values.
Nevertheless, in selected clinical scenarios, the high
negative predictive value of genotype-based tests might
help in strengthening the diagnosis, or with excluding
particular drugs as a cause of DILI.42 For example,
HLA*33:01 (a rare allele, found in 1% of the general
population) was found in 80% of people with DILI
attributed to ticlopidine (an antiplatelet drug frequently
used by older people to prevent strokes and coronary stent
occlusions) in a genome-wide association study.68 Genetic
testing that shows the absence of HLA*33:01 in a person
with liver damage taking ticlopidine should encourage the
search for competing causes of DILI. Furthermore,
genetic testing in a patient taking more than one drug

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with hepatotoxic potential might point to the causative
agent (eg, the absence of HLA B*57:01 in a patient taking
flucloxacillin and diclofenac will incriminate the latter).
A number of new soluble candidate biomarkers hold
promise for enhanced liver specificity and prognostic
value in DILI.70 These include biomarkers of liver injury
(microRNA 122), mitochondrial dysfunction, and necrosis
(glutamate dehydrogenase), necrosis (high mobility group
protein B1), necrosis and apoptosis (the ratio of cleaved
cytokeratin-18 [KRT18] to full length cytokeratin), and
immune activation and inflammation (macrophage
colony stimulating factor receptor and osteopontin).70,71
DILI in older patients is in special need of biomarkers of
cholestasis and bile duct injury because currently there
are no markers, and markers would be particularly helpful
in this population.
Management
Immediately after suspicion of DILI, the key step is
withdrawal of the suspected drug or drugs, followed by
prognostic assessment of the patient. Although most
patients with DILI will recover completely, a small
proportion can progress to liver failure and death within
the first few months after DILI has been recognised.
Continuing to take the hepatotoxic drug after toxic liver
injury might result in a worsening of the clinical outcome
and an increase in the risk of acute liver failure or death.9
However, in a large US cohort (602 people in the Acute
Liver Failure Study Group) of paracetamol-related and
non-paracetamol cases of acute liver failure, including
127 patients with idiosyncratic drug-induced acute liver
failure, older age (≥60 years) was shown to have no
influence on spontaneous survival rate once acute liver
failure had occurred.72 In contrast, a prospective follow-
up study found that older age was a risk factor for
chronicity in people with idiosyncratic DILI.5 Similarly,
persistent liver biochemistry abnor­malities were more
common in older patients and patients with cholestatic
DILI than in patients with spontaneous recovery.73
The pattern of liver damage also has prognostic
implications. Hepatocellular injury is associated with a
higher risk of death than cholestatic or mixed liver
injury.52,74 When the hepatocellular pattern is associated
with jaundice, the patient might fulfil Hy’s law, which
predicts that the patient will have a 10% or higher risk of
death owing to liver failure or the need for liver
transplantation.75 Hy’s law is now used by the US Food
and Drug Administration during drug development to
predict risk of hepatotoxicity. An optimised definition52 of
Hy’s law for predicting the risk of acute liver failure was
validated in 2017.74
A long-term conception in the DILI field is that
cholestatic liver injury is associated with a better prognosis
than hepatocellular damage.76,77 A notable exception,
however, was benoxaprofen, a drug removed from the
market in 1982 because it induced serious photosensitivity
skin reactions and cholestatic jaundice with fatal outcomes
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Review
in older women. The signature of benaxoprofen-induced
cholestasis was the development of impending liver
failure in most of the patients with associated kidney
failure despite immediate treatment discontinuation.78
Notably, in the first report of the DILIN prospective study,
patients with cholestatic jaundice had a higher mortality
rate (14%) compared with patients with hepatocellular
injury (7∤5%), but the difference was not significant.79 The
reasons for this higher mortality are unclear, but a large
proportion of deaths could have been non-liver-related,
with comor­bidities contributing to the deaths. Indeed, a
later analysis in a subpopulation of the DILIN cohort
confirmed that patients with serious comorbidities had
greater 6-month mortality, were older in age, and
predominantly had cholestatic patterns of liver injury.28
Analysis of the DILI cohorts, however, shows that female
sex, regardless of age, is a risk factor for acute liver
failure.23 In older people, drug-induced cholestasis, if long-
lasting, can be more serious than in younger people, as it
is frequently associated with renal insufficiency and the
development of malnutrition. Indeed, patients with
obstructive jaundice, leading to a high concentration of
total bilirubin, are at increased risk of aminoglycoside
nephrotoxicity.80 This increased risk has also been shown
in patients with cholestatic DILI due to illicit use of
anabolic androgenic compounds, in whom markedly
elevated serum bilirubin concentration was a distinct
predisposing factor for acute kidney injury.81
In the absence of guidelines, practical management of
DILI in older people implies that physicians should pay
attention to coexisting diseases (eg, chronic kidney failure)
that can worsen in the setting of toxic acute liver injury
and therefore need careful scrutiny. Indeed, DILI
management is mainly supportive, as there is no specific
therapy for toxic liver injury. Corticosteroids are often
given empirically in serious DILI, but no randomised trial
has shown benefits to support its use, even in drug-
induced acute liver failure.9 Corticosteroids did not
improve overall survival; in a retrospective analysis of
patients with severe liver injury (MELD score >40),
patients given corticosteriods had a lower survival rate
than patients not given corticosteroids (survival was 30%
with corticosteroids vs 57% without).82 Nevertheless,
steroid use can be justified when autoimmune hepatitis
(irrespective of whether or not it is induced by a drug) is
suspected, and to treat hepatotoxicity caused by immune
checkpoint inhibitors.9 In addition, drug-related chole­
static hepatitis associated with hypersensitivity features is
often treated empirically with corticosteroids.83 The
efficacy of acetylcysteine (which remains the mainstay for
managing paracetamol-related acute liver failure) has
been tested in a randomised placebo-controlled trial of
patients with non-paracetamol-induced acute liver failure
that included patients with DILI as one of the subgroups.
The trial showed significantly higher transplant-free
survival rates for patients given acetylcysteine compared
with patients given placebo, but only if individuals were at
 Review
Search strategy and selection criteria
We searched PubMed for studies published from database
inception up to Sept 30, 2019, using specific terms such as
“drug-induced liver injury”, “hepatotoxicity”, “cholestasis”,
and “acute liver failure”, combined with “elderly”, and “older
patients”. Articles were further identified on the basis of the
subheadings used in this Review. No language or article type
restrictions were applied.
early stages (I–II) of hepatic encepha­lopathy (58 [52%]
with acetylcysteine vs 56 [30%] with placebo; p=0·010).84 In
people with cholestatic DILI, ursodeoxycholic acid is also
frequently used because of its good safety profile, although
so far no randomised trial has been done to support its
use. In people with cholestatic DILI, pruritus is often
severe and protracted, justifying (by analogy with primary
biliary cholangitis and other chronic cholestatic disorders)
the use of bile acid resins (eg, colestyramine) or
antihistamines. These drugs, and second-line or third-line
recommended therapies such as rifampicin (a pregnane
X receptor agonist) or naltrexone (opioid μ-receptor
antagonist), have never been adequately tested in patients
with DILI. New and promising alternatives for improving
pruritus in patients with primary biliary cholangitis
include bezafibrate (an agonist of the transcription factor
PPAR), which could also be tried in older patients with
cholestatic DILI and refractory pruritus.85
Conclusions
The oldest age group (≥80 years) among the older
population is expected to be the fastest growing age
segment by 2050. Traditionally, older adults (≥65 years)
are under-represented in clinical trials, but this global
demographic trend means that we need better evidence
on which to base decisions in pharmacotherapy and
greater participation of older patients in clinical drug
develop­ment. This approach would probably change the
understanding of adverse drug reactions, including DILI,
in this population.86
DILI, which affects individuals of all ages, does not
seem to be more frequent in older people, although it
might be more common in older people taking specific
drugs. Future studies exploring liver safety of drugs in
old, frail individuals need to consider the heterogeneity
of this population, so that they can better characterise
the phenotype and severity of DILI. The effects of ageing
on drug disposition, immune system, and intestinal
microbiota are not clear. Little evidence is available to
support an effect on DILI susceptibility, although older
patients with DILI who have comorbidities might have a
worse outcome more frequently than younger patients
without comorbidities. Bio­ markers of cholestasis and
bile duct injury in particular are warranted in older
patients, because increasing age is a risk factor for
cholestatic DILI.
872 www.thelancet.com/gastrohep Vol 5 September 2020
Contributors
MIL, RJA, CS, JS, and MG-C participated in the writing of the different
sections of the manuscript; MIL and RJA wrote the summary, read the
combined sections to ensure consistency, supervised the work, and are
the guarantors.
Declaration of interests
We declare no competing interests.
Acknowledgments
We acknowledge the support of Estefanía Caballano-Infantes and
Alejandro Cueto-Sanchez in the preparation of this manuscript and from
European Cooperation in Science & Technology (COST) Action CA17112
Prospective European Drug-Induced Liver Injury Network. This study
was supported by grants from the Instituto de Salud Carlos III,
cofounded by Fondo Europeo de Desarrollo Regional—FEDER (contract
numbers: PI 18_01804 and PT17/0017/0020) and Agencia Española del
Medicamento. Spanish Clinical Research Network (SCReN) and Centro
de Investigación Biomédica en Red de Enfermedades Hepáticas y
Digestivas (CIBERehd) are funded by Instituto de Salud Carlos III.
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