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of Springer Nature 2022
N. V. Bergasa (ed.), Clinical Cases in Hepatology,
https://doi.org/10.1007/978-1-4471-4715-2_14
Chapter 14
Drug Induced Liver Injury
NoraV.Bergasa
A 60 year old man was seen in the hepatology clinic for follow up prior to initiating
treatment of chronic hepatitis C.The patient reported pruritus, which had started over
several days prior to the second visit. On exam, he had scleral icterus, excoriations
from chronic scratching, and hepatomegaly at the expense of the left lobe of the liver.
On the index visit, which had taken place eight weeks prior to the second visit,
no risk factors for viral hepatitis had been identied. The patient’s comorbidities
included hypertension, type 2 diabetes, and a remote cerebrovascular accident that
had left him emotionally labile without gross sensory or motor neurological decits.
He had been born outside the United States and was unemployed.
His medications included amlodipine and insulin. Three weeks prior to the index
visit, the patient had been treated for Helicobacter pylori infection with pantopra-
zole, clarithromycin, and metronidazole for fourteen days. The patient had not taken
any over the counter medications or herbal remedies.
A liver disease workup had not revealed any causes of liver disease other than
chronic hepatitis C. The liver sonogram was normal. The APRI score was 0.96,
consistent with advanced brosis.
Drug-induced liver injury (DILI) from clarithromycin was suspected. A sum-
mary of the liver prole over the course of his acute illness is shown in Table14.1.
The patient suffered from pruritus, which was treated with cholestyramine and
naloxone infusions in the hospital and subsequently managed with naltrexone and
pregabalin. Antipruritic medications were tapered and discontinued as pruritus
decreased. The serum activity (SA)s of AST, ALT, and AP and the serum bilirubin
N. V. Bergasa (*)
Department of Medicine, H+H/Metropolitan, New York, NY, USA
New York Medical College, Valhalla, NY, USA
Hepatology, H+H/Woodhull, Brooklyn, NY, USA
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concentration decreased gradually over eight weeks. He was started on sofosbuvir/
velpatasvir for the treatment of his HCV eight weeks after the rst documentation
of DILI.
The treatment of HCV was associated with a cure. He is enrolled in a surveil-
lance program for hepatocellular carcinoma. He has developed diabetic nephropa-
thy, which explains the increase in AP SA, which likely has a component of
bone origin.
Etiology
Hepatotoxicity is dened as toxic damage to the liver. The spectrum of hepatotoxic-
ity includes the nature of the hepatotoxic agent, the type and mechanism of liver
injury, the circumstances of the exposure, and the medical and social importance [1]
Hepatotoxic agents can be inorganic and organic. The inorganic agents include
metals, hydrazine derivatives, and iodides. The organic agents include plant toxins
such as pyrrolizidines and tannic acid, mycotoxins such as aatoxin, bacterial endo-
toxins and exotoxins, and synthetic compounds including nonmedicinal agents such
as organic amines and azo compounds, and medicinal agents used for diagnostic
and treatment purposes [1].
Table 14.1 Laboratory exams of the patient described over the course of illness
Liver Prole
Hepatitis C
Viral Load
and genotype T minus 21 T0 T12 T16
T20
(HCV
Rx
started) T32 T48 T144
Treatment of HP
with pantoprazole,
clarithromycin, and
metronidazole
started
AST (IU/ml) 70 101 86 78 45 24 25
ALT(IU/ml) 64 60 42 38 26 25 36
AP (IU/ml) 159 449 560 556 410 168 235
TB (mg/dl) 0.7 5.5 10.7 2.5 0.3 0.4 0.4
Albumin 9g/
dl)
3.9 3.0 2.7 2.5 2.7 4.0 3.8
PT (seconds)/
INR
10.9/
1.05
10.9 10.6 10.7 11.5
/1.12
11.5
HCV RNA
IU/ml/
Genotype
100,921/
1a
101 86 78 Not
detected
Not
detected
Not
Detected
T minus 21: 21days prior to the index visit to the clinic
T0: index visit
T12-T144: twelve to 144weeks post index visit
AST aspartate aminotransferase, ALT alanine aminotransferase, AP alkaline phosphatase, HCV
hepatitis C, INR international normalized ratio
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Hepatotoxicity can be associated with necrosis, steatosis, cirrhosis, and carci-
noma. Other forms of hepatotoxicity concern impaired bile ow and bilirubin excre-
tion. Vascular and degenerative lesions can also result from hepatotoxicity [1].
The mechanisms of liver injury can be true hepatotoxicity or secondary to the
host susceptibility to an agent. True hepatotoxicity refers to an agent’s ability to
cause liver injury in most recipients of different species. An idiosyncratic reaction is
mediated by the host’s immune or metabolic response to an agent. There is a mix of
host susceptibility and idiosyncrasy supporting liver injury [1].
The circumstances under which liver injury occurs have been divided into (1)
toxicologic, including: (i) occupational: routine exposure or accidental, (ii) domes-
tic: accidental or suicidal exposure, ingestion of contaminated food, recreational
drug use, e.g., euphorogenic substances, (iii) environmental: pollution, natural hep-
atotoxins, and (2) pharmaceutical: (i) iatrogenic, and (ii) self-medication [1].
The focus of this chapter is drug-induced liver injury (DILI). The most important
intervention in DILI cases is to identify the agent and to discontinue its use.
Rechallenge should not be done because of the risk of inducing a worse reaction
than the rst one, including liver failure. Livertox.NIH.gov is a search database with
extremely valuable information, which should be accessed to evaluate a patient in
whom DILI is being considered [2].
DILI is the injurious effect to the liver by an agent, natural or produced [3],
exhibited by an increase in the SA of the liver associated enzymes, alanine and
aspartate aminotransferases (ALT and AST), and alkaline phosphatase (AP) activi-
ties, which can be accompanied by hyperbilirubinemia and hepatic synthetic dys-
function, including acute liver failure (ALF) [4].
Risk Factors forDili
Genetics
Individualization of treatment based on comprehensive new generation sequencing
(NGS) genotyping data provides the opportunity to prescribe effective and safe
medications to individuals according to their genetic predisposition to efcacy and
side effects, i.e. the prescribed drug should be chosen according to the patient’s
probability of benet and their susceptibility to developing side effects [5].
Accordingly, the inclusion of pharmacogenetics is of great importance in drug
development. Pharmacogenetics is a eld in evolution that will lead to a decrease in
adverse reactions to drugs, as a genetic predisposition is proposed in cases of idio-
syncratic DILI, and support for this idea has been provided.
A study of cultured T cells provided the immunological basis for ucloxacillin-
induced liver injury. Flucloxacillin-responsive CD4+ and CD8+ T cells in patients
with DILI from this medication were identied. Naive CD45RA+ CD8+ T cells
expressing HLA-B*57:01 from normal volunteers were activated with
14 Drug Induced Liver Injury
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ucloxacillin when dendritic cells presented the agent antigen. The production of
interferon gamma, T helper (Th) 2 cytokines, perforin, granzyme B, and FasL was
reported in association with T-cell clones’ exposure expressing CCR4 and CCR9
that migrated towards CCL17 and CCL 25in response to stimulation by the drug.
The activation of CD8+ clones with ucloxacillin was restricted by HLA-B*57:01
and related to HLA-B*58:01 and dependent on antigen processing. Additional reac-
tivity to β-lactam antibiotics, including oxacillin, cloxacillin, and dicloxacillin, was
documented by the clones [6].
A genetic predisposition to ucloxacillin-induced DILI was conrmed by a
genome-wide association study (GWAS) in 51 cases with this condition versus 282
control samples. The study documented an association peak in the major histocom-
patibility complex (MHC) region with the strongest association noted for
rs2395029[G], a marker in complete linkage disequilibrium with HLA-B*5701 [7].
Amoxicillin-clavulanate induced DILI has been signicantly associated with the
DRB1*1501-DRB5*0101-DQB1*0602 haplotype [8]. A genetic predisposition for
amoxicillin-clavulanate induced DILI was conrmed and expanded by a GWAS
study that included 822,927 single nucleotide polymorphism (SNP) markers from
201 white subjects in Europe and the United States versus 532 well-matched control
subjects. The main nding was with an HLA class II SNP (rs9274407,
P = 4.8 × 10(−14)), which correlated with rs3135388, a tag SNP of HLA-
DRB1*1501-DQB1*0602 [9].
The absence of HLA-DQA1*0102 and the presence of HLA-DQB1*0201 were
independent risk factors for DILI in a group of 56 patients from 346 who developed
DILI in association with antituberculous therapy with isoniazid, rifampicin, and
pyrazinamide and ethambutol and streptomycin from North India [10, 11].
Genetic susceptibility to DILI from diclofenac has been reported in association
with rs17036170 upstream of the gene peroxisome proliferator-activated receptor
gamma (PPARG), which participates in lipid metabolism [12] and with rs7574865,
near the signal transducer and activator of transcription 4 gene (STAT4). The latter
has been implicated in autoimmune diseases [13, 14].
Idiosyncratic drug reactions also concern metabolic pathways of detoxication
and hence the genetics behind drug metabolism. In this regard, studies have explored
associations with the cytochrome p450 family because of its role in phase I drug
metabolism [15], UDP-glucuronosyltransferases, the role of which is glucuronida-
tion to end the biological actions of drugs and to facilitate the renal excretion of
lipophilic medications [16].
N-acetyltransferases, which are drug-metabolizing enzymes that acetylate drugs
and carcinogens [17], and glutathione S-transferases, the function of which includes
to catalyzing the conjugation of electrophilic substrates to glutathione and protec-
tion of cells from peroxidation [18].
Susceptibility genes identied in association with DILI in the context of drug
metabolism include: (i) in the cytochrome p450 group, CYP2E1 for isoniazid [19]
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and CYP2C9 for bosentan, (ii) the UDP-glucuronosyltransferases UGT2B7 for
diclofenac [20], (iii) the N-acetyltransferases NAT2 for isoniazid [21], and in the
glutathione S-transferases, GSTM1 for troglitazone [22] and GSTT1 for amoxicillin-
clavulanate [23].
A GWAS included 55 subjects from India and 70 European with DILI and 1199
Indian and 10,397 European controls. The study found a signicance for the HLA-
B*52:01 and the rs117491755 in ASTN2, which was found in Europeans. The
NAT2*5 frequency was lower in DILI cases than in controls. NAT2*6 and NAT2*7
were the most common genes, homozygotes for NAT2*6 or NAT2*7 or both, the
more common in cases than in the control group. These results were interpreted to
suggest that the HLA genotype makes a small contribution to DILI from anti-tuber-
culosis medications. An impact from NAT2 was documented when the metabolic
effect of NAT2*5 and NAT2*6 and NAT2*7 was taken into consideration [24].
Transport proteins may be involved in DILI because of their function in uptake
of drugs into the hepatocyte and biliary excretion of metabolites [25]. In this con-
text, the C-24T variant of ABCC2, which codes for the multidrug resistance pro-
tein 2 (MRP2) [26], was identied in association with DILI from diclofenac [20],
and the ABCB1, which codes for P-glycoprotein [27], with DILI from nevirap-
ine [28].
A genetic predisposition to DILI from certain drugs has been conrmed; there-
fore, it is important to determine if an individual is at risk for DILI before initiating
treatment with a given drug. The use of drugs at high risk for DILI should be
avoided if other options are available, in the author’s opinion. In clinical practice, it
may not be feasible to check genetic predisposition to DILI from certain drugs;
however, there is precedent for the inclusion of HLA typing prior to prescribing
abacavir to treat HIV.In this regard, “100% of those who develop it [hypersensitiv-
ity reaction] are positive for HLA-B*57:01,” which has resulted in the recommen-
dation by drug regulators worldwide for genotyping for HLA-B*57:01 prior to
prescribing this drug [29]. Amoxicillin/clavulanate induced DILI has been signi-
cantly associated with the HLA class II antigen DRB1*1501-DRB5*0101-
DQB1*0602 haplotype [8]. Accordingly, an alternative medication can be used to
avoid a devastating DILI, which can result in ductopenia and tremendous suffering
from pruritus, and other complications from hepatobiliary disease. HLA-B*1502
has been reported more frequently in patients who develop Stevens–Johnson’s syn-
drome in association with carbamazepine; thus, alternative anticonvulsants can be
prescribed. Clearly, signicant efforts to facilitate testing for genetic predisposi-
tion, including clinical availability from commercial laboratories and pricing, must
be made.
A search for studies on the subject of epigenetics, a phenomenon that may pre-
dispose to hepatotoxicity, and DILI did not yield any results; however, this is an area
of research that will provide valuable information and will improve patient care
when used in the clinical arena [5].
14 Drug Induced Liver Injury
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