1. REVIEW
Presented at : Pediatric Sp-1 Program, Dept. of Pediatrics,
Airlangga Univ-Dr.Soetomo Teaching Hospital
DRUG-INDUCED
LIVER INJURY (dili)
PRESENTER : MADE ARY SARASMITA, S.FARM, APT
HUBBY H.P, S.Si, APT
JOSEPHINE P. A., S.FARM, APT
ATIKA VITASARI, S.FARM, APT
RENNIE PUSPA N., S.FARM, APT
A. ADELSA D., S.FARM., APT
EMA PRISTI YUNITA, S.FARM., APT
POSTGRADUATED PROGRAM MASTER OF CLINICAL PHARMACY
FACULTY OF PHARMACY AIRLANGGA UNIVERSITY
2011 1

2. LIVER physiologic function
Detoxification &
Nutrient and
inactivation of
Formation and vitamin
various substances
secretion of bile metabolism (amino
(toxin, drug)
acid, lipid, glucose)
Synthesis of plasma
Immune system 
proteins (albumin,
kupffer cells.
clotting factor)
(Barret, E.K., Barman, S.M., Boitano, S., Brooks, H.L., 2010, Ganong’s Review
of Medical Physiology, 23rd edition, USA: The McGraw-Hills Comp.) 2

3. DRUG-INDUCED LIVER INJURY / DISEASE (DILI)
Liver injury may be produced by a large
variety of chemical substances
The type and degree of injury produced is
extremely varied, and may mimic the entire
spectrum of hepatobiliary disorders.
The central role played by the liver in the
clearance and biotransformation of chemical
 susceptibility to drug-induced injury.
Drugs can initiate progressive chronic liver
disease and are the single leading cause of
acute liver failure.
3
Friedman, S.L., McQuaid K.R., 2003, Current Diagnosis and Treatment in Gastroenterology, USA: The McGraw-Hills, Comp.

4. Risk factors of liver injury
Enviromental Risk Factor Genetic Risk Factor
Pharmacokinetics
– Metabolism
Specific immune
system
Initial liver injury
Cytokine, TNF,
ROS
Progression of liver injury
Chronic liver Acute liver
failure failure
• Grattagliano, I., Bonfrate, L. et al., Biochemical mechanisms in drug-induced liver injury: certainly
and doubts, World J Gastroenterol 2009 October 21;15(39):4865-4876 4

5. Environmental Hepatotoxin &
Associated Occupations at Risk
for Exposure
Kirchain, WR & Allen, RE 2008, ‘Drug-Induced Liver Disease’, In: Joseph T.Dipiro, Barbara, G.Wells, et al.,
Pharmacotherapy: A Pathophysiologic Approach , 7th Ed., The McGraw-Hill Companies, Inc , New York.
5

6. A General Diagram of
biotransformation Of Drugs
Kirchain, WR & Allen, RE 2008, ‘Drug-Induced Liver Disease’, In: Joseph T.Dipiro, Barbara, G.Wells, et al.,
Pharmacotherapy: A Pathophysiologic Approach , 7th Ed., The McGraw-Hill Companies, Inc , New York. 6

7. Pathway of Drug Hepatic Metabolism
• A, B, and C represent three different drugs.  Drugs may undergo primary phase 2 biotransformation
(A) or initial phase 1 and subsequent phase 2 metabolism (B). Drug C is secreted from the hepatocyte
following phase 1 metabolism only.
• The oxidation-reduction & hydrolytic reactions  referred to as phase 1 reactions  increase the
polarity or water solubility of a molc.  through the generation of metabolically active moieties
(hydroxyl groups) in the parent comp.
7
Friedman, S.L., McQuaid K.R., 2003, Current Diagnosis and Treatment in Gastroenterology, USA: The McGraw-Hills, Comp.

8. MECHANISMS OF LIVER INJURY
William, M.Lee, Review Article : Medical Progress Drug-Induced Hepatotoxicity. N Engl J Med 2003;349:474-85)
8

9. Schematic Representation of Toxic Damage of Hepatocyte in
Response to High Dose of Drugs
Drug can impair MC function  by the impairment of the OXPHOS, inhibition of FAO  can induce vesicular
steatosis. Reactive oxygen species (ROS)  responsible for oxidative stress and lipid peroxidation (trigger the
production of different cytokines that favor necroinflammation and fibrosis).
• Grattagliano, I., Bonfrate, L. et al., Biochemical mechanisms in drug-induced liver injury: certainly and
doubts, World J Gastroenterol 2009 October 21;15(39):4865-4876 9

10. •Drugs & its
mechanisms to
induce liver injury
10

11. IDIOSYNCRATIC DRUG REACTIONS
(William M. Lee, M.D. Review Article : Medical Progress Drug-Induced Hepatotoxicity, N Engl J Med
2003;349:474-85). 11

12. ANTICONVULSANT DRUG-INDUCED LIVER INJURY
Virtually all of the major antiepileptic drugs can cause hepatotoxicity,
although a fatal outcome is rare.
• Larrey, D., Drug Induced Liver Disease, Journal of Hepatology 2000;32 (Suppl.1): 77-88
Once hepatotoxicity develops, mortality rates are 10–38% with
phenytoin and about 25% with carbamazepine. Elderly patients may be
at higher risk.
• Aronson, J.K, 2005, Meyler ‘s Side Effect of Drugs: The International Encyclopedia of
Adverse Drug Reactions and Interaction, 5 th ed, USA: Elsevier.
Fatal valproate hepatotoxicity may occur with greater frequency in
children under the age of 2 years who are receiving multiple drug
therapy  monitoring of LFT
• Ahmed, N., Siddiqi, Z.A., Antiepileptic drugs and liver disease, Seizure (2006)15,156-164
12

13. …..Phenytoin-Induced Hepatotoxicity
• The interval between the initiation of phenytoin
therapy and the onset of clinical abnormalities ranges
from 1 to 6 weeks in the vast majority of patients.
• Presenting symptoms  fever, rash and lymph-
adenopathy, Jaundice and hepato-splenomegaly.
• Biochemical features  abnormal serum bilirubin,
transaminases, and ALP levels
• The morphologic and pathologic abnormalities are
non-specific  primary hepatocellular degeneration
and/or necrosis.
Ahmed, N., Siddiqi, Z.A., Antiepileptic drugs and liver disease, Seizure (2006)15,156-164 13

14. …..Valproic Acid-Induced Hepatotoxicity
• The incidence of valproac acid- induced fatal hepatic dysfunction is 1 :
500, in children under 2 years
• The risk declines with age with a rate of 1/12,000 when used in
polytherapy and 1/37,000 when used in monotherapy after the first 2
years of life.
• Certain risk factors  Younger age, mental retardation, polypharmacy,
stress, infection underlying liver disease, and history of metabolic
disorders of metabolism.
• The idiosyncratic hepatic toxicity to valproic acid usually occurs during the
first 2—3 months of therapy  leads to vomiting, hemorrhage, increased
seizures, anorexia, jaundice, edema, and ascites.
Ahmed, N., Siddiqi, Z.A., Antiepileptic drugs and liver disease, Seizure (2006)15,156-164 14

15. Mechanisms of valproic acid-induced inhibition of
mitochondrial fatty acid ß-oxidation.
VPA is an analogue of medium-chain fatty acid  freely enters the mitochondrion and generates
a coenzyme A ester (VPA-CoA)  VPA-CoA inhibit carnitine palmitoyltransferase-1 (CPT 1),
an enzyme catalyzing the step of MC entry and b-oxidation of long-chain fatty acids 
reduces mitochondrial levels of CoA (cofactor for FAO).
• Begriche, K., Massart, J., Robin, M.A., Review: Drug induced toxicity on mitochondria and lipid metabolism: Mechanistic 15
diversity and deleterious consequences for the liver, Journal of Hepatology 2011 vol 54;773-794

16. Antituberculosis Drug-Induced Hepatotoxicity
• The incidence of ATDH during standard multidrug TB treatment has been
variably reported as between 2% and 28%.
• Isoniazid, rifampicin and PZA are potentially hepatotoxic drugs. No
hepatotoxicity has been described for ethambutol or streptomycin.
• The risk of hepatotoxicity was associated with female sex (OR =4,1; 95% CI = 1.2,
14) and presumed recent infection (OR = 14,3; 95% CI = 1.8, 115)
(Aronson, J.K, 2005, Meyler ‘s Side Effect of Drugs: The International Encyclopedia of Adverse Drug Reactions
and Interaction, 5 th ed, USA: Elsevier).
(Alma Tostmann, Martin J Boeree,Rob E Aarnoutse, Wiel C M de Lange, Andre J A M van der Vens and Richard
Dekhuijzen, Review : Antituberculosis drug-induced hepatotoxicity: Concise up-to-date review. Journal of
Gastroenterology and Hepatology 23 (2008) 192–202 © 2007 The Authors) 16

17. ISONIAZID PIRAZINAMID RIFAMPICIN
• Isoniazid-induced • PZA  to pyrazinoic • The major pathway 
hepatotoxicity is acid and oxidized to 5- desacetylation into
considered hydroxypyrazinoic acid desacetylrifampicin,
idiosyncratic. by xanthine oxidase separately hydrolysis
• can affect any organ • In a rat study, PZA produces a 3-formyl
system  include IgE- inhibited the activity of rifampicin.
mediated reactions as several CYP450 • Rifampicin  a potent
well as reactive isoenzymes (2B, 2C, inducer of the hepatic
metabolite syndromes 2E1, 3A), but a study in CYP450S  increasing
human liver metabolism of many
microsomes showed other compounds.
that PZA has no
inhibitory effect on the
CYP450 isoenzymes.
Among 148 patient who were given the combination PZA + Rifampicin for 2 month  grade 3
hepatotoxicity (transaminase >5-20 times the upper limit of reference range) and grade 4
hepatotoxicity (transaminase >20 times) were reported in 10 and 4 patient respectively.
Monitoring of LFT and patient’s linical symptoms.
Aronson, J.K, 2005, Meyler ‘s Side Effect of Drugs: The International Encyclopedia of Adverse Drug Reactions
and Interaction, 5 th ed, USA: Elsevier). 17

18. ANTIRETROVIRAL DRUG-INDUCED LIVER INJURY
• The frequency of hepatic injury associated with ARV is at least 10%
• Because co-infection with HBV or HCV in HIV patients increases the risk of
toxicity, all patients should be screened for viral hepatitis before starting ARV
Spengler, U., Lichterfeld, M., Rockstroh, K.J., Review: Antiretroviral drug toxicity,
Journal of Hepatology 36 (2002) 283–294 18

19. ACETHAMINOPHEN-INDUCED LIVER INJURY
• Most common cause of DILI, and is an important cause of
acute liver failure
• Single doses exceeding 7 to 10 g (140 mg/kg of body
weight in children)  liver injury severe (as indicated by
serum ALT levels > 1000 U/L) or fatal liver injury
• Among persons with an untreated acetaminophen OD,
severe liver injury occurred in only 20% among those
with severe liver injury, the mortality rate was 20%.
• Risk factors for acetaminophen hepatotoxicity
– Age
– Dose: >150 mg/kg in children; Severe toxicity possible with
dose >15 g
Kirchain, WR & Allen, RE 2008, ‘Drug-Induced Liver Disease’, In: Joseph T.Dipiro, Barbara, G.Wells, et al.,
Pharmacotherapy: A Pathophysiologic Approach , 7th Ed., The McGraw-Hill Companies, Inc , New York. 19

20. Mechanism of Acetaminophen-induced Hepatotoxicty
At usual therapeutic dosages, acetaminophen is metabolized  conjugation reactions. The capacity becomes
saturated at higher dosages  diversion of the drug to the P-450-mediated pathway  generates reactive
electrophile N-acetyl-p-benzoquinone imine (NAPQI)  undergoes phase 2 conjugation with glutathione 
glutathione depletion  allowing the electrophile to exert damaging effects within the cell via covalent binding.
Friedman, S.L., McQuaid K.R., 2003, Current Diagnosis and Treatment in Gastroenterology, USA: The McGraw-Hills, Comp.
20

21. Practical Guideline for Diagnosis &
Early Management of DILI
Preplanned LFT, evaluation
When a drug is initiated
of drug
Careful history taking/rule out other etiologies,
evualate the type of liver injury When liver dysfunction is
recognized
DILI is unlikely DILI is suspected
Diagnosis of DILI
Symptoms related
ALT > 8 x ULN at any
Hepatocellular type to liver injury such
one time or Cholestatic type as jaundice or
ALT > 5 x ULN for more or mixed
Total bilirubin > 3 x
than 2 wk or
ULN or
ALT > 3 x ULN, and total
PT-INR > 1.5 x ULN
bilirubin > 2 x ULN or Discontinue the
PT-INR > 1.5 x UNL Careful monitoring
suspected drug
Ignazio G., Leonilde B., Catia V.D, Biochemical mechanisms in drug-induced liver injury, World J Gastroenterol 2009
October 21; 15(39): 4865-4876 21

22. Child-Pugh Scores for Patients
with Liver Disease
Child-Pugh Scores for Patients with Liver Disease
Score 8-9 : 25 % normal dose
Score > 10 : 50 % normal dose
Bauer L.A. et al, 2008, Applied Clinical Pharmacokinetics, 5TH edition, USA: McGraw-Hill. 22

23. Key Guideline in the Recognition & Prevention
of Hepatotoxicity in Clinical Practice
Remove Monitoring
Do not Take a
the • Symptom
ignore the careful
causative • LFT
symptoms history
agent
Victor J. Navarro, M.D., and John R. Senior, M.D., 2006, Drug-Related Hepatotoxicity, The New England Journal
of Medicine, vol. 354, pp. 731-739. 23

24. …THANK YOU…
…TERIMA KASIH
24

25. Fig. 2. Metabolic consequences of severe inhibition of mitochondrial fatty acid b-oxidation. A
severe impairment of mitochondrial fatty acid oxidation (FAO) can induce accumulation of
free fatty acids and triglycerides , reduced ATP synthesis and lower production of ketone
bodies. Inhibition of FAO also decreases gluconeogenesis through mechanisms including 
lower ATP production and reduced pyruvate carboxylase (PC). The accumulation of free
fatty acids (and some of their metabolites such as dicarboxylic acids) could play a major
25
role in the pathophysiology of microvesicular steatosis.

26. Mechanisms of Drug-Induced Liver Injury
• The clinical features of some cases of DILI (Drug-Induced Direct Hepatotoxicity) strongly suggest an
involvement of the adaptive immune system. These clinical characteristics include (1) concurrence
of rash, fever, and eosinophilia; (2) delay of the initial reaction (1-8 weeks) or requirement of
repeated exposure to the culprit drug; (3) rapid recurrence of toxicity on reexposure to the drug;
and (4) presence of antibodies specifi c for native or drug-modifi ed hepatic proteins.
• Drugs suspected to induce these types of reactions include halothane, tienilic acid, dihydralazine, 26
diclofenac, phenytoin, and carbamazepine

27. Mechanism of Drug Hepatotoxicity
27
Friedman, S.L., McQuaid K.R., 2003, Current Diagnosis and Treatment in Gastroenterology, USA: The McGraw-Hills, Comp.

28. Victor J. Navarro, M.D., and John R. Senior, M.D., 2006, Drug-Related Hepatotoxicity, The New England Journal of
28
Medicine, vol. 354, pp. 731-739.

29. 29

30. (The new england journal of medicine. N Engl J Med 2003;349:474-85. Review Article : Medical Progress
30
Drug-Induced Hepatotoxicity. William M. Lee, M.D.)

31. 31

32. • Begriche, K., Massart, J., Robin, M.A., Review: Drug induced toxicity on mitochondria and lipid metabolism:
32
Mechanistic diversity and deleterious consequences for the liver, Journal of Hepatology 2011 vol 54;773-794

33. PENJELASAN GAMBAR DI ATAS  ini kamu baca aja
mita jangan dimasukkan ppt
A general diagram of biotransformation. (1) The drug is actively transported into the
hepatocyte by the organic anion transport pump, a transmembrane protein. (2) The
metabolite (drug) interacts with one of a number of enzymes, the most common being
CYP2C9, 2C19, 2D6, and 3A4. This family of enzymes is regulated by the complementary
DNA xenobiotic receptor. The xenobiotic receptor is in turn upregulated by other drugs,
changes in cholesterol catabolism, and bile acids. (3) The immediate result of the action of
these phase I enzymes is the production of an unstable metabolite. (4) The unstable
metabolite then reacts with glucuronidase, various transferases, or hydroxylases to form a
conjugated metabolite. The efficacy of these enzymes is affected by the patient’s
nutritional state and genetic polymorphism, leading to variations in individual risk for
toxicity. (5) The conjugated metabolite is removed from the hepatocyte by the canalicular
membrane export pump, one of a large family of membrane proteins (other members of
this family pump conjugated metabolites back into the blood for excretion by the kidney).
These proteins are subject to genetic polymorphism as well, again leading to somAe
patients having an increased risk for toxicity. (6) If unable to form a conjugate, the
unstable metabolite can participate in oxidative reactions that damage lipids, proteins, or
even DNA. (7) Alternatively the unstable metabolite may form damaging covalent bonds
with available anions or cations. (SNP, indicates points in this process that are influenced
by an individual’s single nucleotide polymorphisms.) 33

34. MECHANISMS OF DRUG-INDUCED LIVER DISEASE
1) STIMULATION OF AUTOIMMUNITY
Autoimmune injuries involve antibody mediated cytotoxicity or direct cellular toxicity  This
type of injury occurs when enzymedrug adducts migrate to the cell surface and form
neoantigens  The neoantigens serve as targets for cytolytic attack by T cells  The injury
may be exacerbated by the recruitment of inflammatory cells  Halothane,
sulfamethoxazole, carbamazepine, and nevirapine are associated with autoimmune injuries
 Stimulation of autoimmunity is often associated with some stage of all fulminant
presentations
Dantrolene, isoniazid, phenytoin, nitrofurantoin, and trazodone are associated with a type
of autoimmune-mediated disease in the liver called chronic active hepatitis  Antinuclear
antibodies appear in most patients  These drugs appear to form antiorganelle antibodies
2) IDIOSYNCRATIC REACTIONS
Idiosyncratic drug-related hepatotoxicity is rare and usually occurs in a small proportion of
individuals.
These adverse reactions are often categorized into allergic and nonallergic reactions  The
allergic reactions are characterized by fever, rash, and eosinophilia. They are usually dose-
related and have a short latency period (<1 month). Upon reexposure to the offending agent,
the patient will experience rapid recurrence of hepatotoxicity. Studies show that
minocycline, nitrofurantoin, and phenytoin can cause allergic reactions.
The nonallergic idiosyncratic reactions are devoid of the hypersensitivity features and usually
have a long latency period (several months). These patients often have normal liver function
tests for 6 months or longer and then suddenly develop hepatotoxicity. Dependent on the
medication, the incident can be independent of dose or dose-related. Amiodarone, isoniazid,
and ketoconazole are associated with nonallergic drugrelated hepatotoxicity.
34

35. 3) DISRUPTION OF CALCIUM HOMEOSTASIS AND CELL MEMBRANE INJURY
Drug-induced damage to the cellular proteins that are involved with calcium homeostasis can
lead to an influx of intracellular calcium that causes a decline in adenosine triphosphate
levels and disruption of the actin fibril assembly  The resulting impact on the cell is
blebbing of the cell membrane, rupture, and cell lysis  Lovastatin, venlafaxine, and
phalloidin which is the active component of mushrooms  impair calcium homeostasis
4) METABOLIC ACTIVATION OF THE CYTOCHROME P450 ENZYMES
Most hepatocellular injuries  the production of high-energy reactive metabolites by the
CYP450 system  These reactive metabolites are capable of forming covalent bonds with
cellular proteins (enzymes) and nucleic acids that lead to adduct formation
In the case of acute toxicity  the enzyme-drug adduct can cause cell injury or cell lysis 
Adducts that form with DNA can cause longterm consequences such as neoplasia.
Acetaminophen, furosemide, and diclofenac are examples of this mechanism of liver injury.
Individual genetic differences can play a role in the significance of this process  patients
with a single nucleotide polymorphism (SNP) that codes for slow-reacting variants of CYP450
will react differently from those with a SNP that codes for very-fast-reacting variants
35

36. ANATOMY OF LIVER
Tank, Patrick W.; Gest, Thomas R.2009. Atlas of Anatomy, USA: Lippincott Williams & Wilkins. 36

37. Mechanisms of Drug-Induced Macrovacuolar
Steatosis and Steatohepatitis.
• The progression of steatosis into steatohepatitis in some patients involves the production of reactive oxygen
species (ROS)  responsible for oxidative stress and lipid peroxidation (trigger the production of different
cytokines such as TNFa and TGFb that favor necroinflammation and fibrosis).
• Begriche, K., Massart, J., Robin, M.A., Review: Drug induced toxicity on mitochondria and lipid metabolism: Mechanistic 37
diversity and deleterious consequences for the liver, Journal of Hepatology 2011 vol 54;773-794

38. KEY POINTS OF
DRUG-INDUCED LIVER
DISEASE Drug induced lipid
dysmetabolism &
macrov. steatosis
• Drug can impair MC function 
mechanism: impairment of the
OXPHOS, inhibition of FAO
• Can induce necrosis/apoptosis  • Drug also alter lipid
cytolytic hepatitis metabolism in liver by
• A severe inhibition of MC FAO can increasing de novo fatty acid
induce vesicular steatosis synthesis
• Impairment of MC FAO can be • Lipid accumulate within the
direct / indirect hepatocytes as large
vacuoles  macv. steatosis
Drug induced mitcochondrial dysfunction
• Begriche, K., Massart, J., Robin, M.A., Review: Drug induced toxicity on mitochondria and lipid metabolism: Mechanistic
diversity and deleterious consequences for the liver, Journal of Hepatology 2011 vol 54;773-794 38