Drug Induced Liver Injury

Ema Rachmawati
FKK Farmasi UNEJ
Liver
 Largest solid organ
 1,4 (W) – 1,6 (M)
kg
 Located in the
right upper
quadrant of the
abdomen
 Composed of cells
called hepatocytes
Liver function
• Albumin, coagulation • Vitamins, mineral,
factors carbohydrates etc
• Carbohydrate, Fat &
Protein SYNTHESIS
& STORAGE
METABOLISM

PROTEKSI SECRETORY
& &
DETOXIFICATION EXCRETORY
• Toxins, ammonia, etc • Bile, Bile acids, salts
• Bilirubin, drugs, hormon & pigments
Liver injury
 May caused by:
 Infection (virus, bacteria)
 Autoimmune
 Toxin (drugs, alcohol, poison)

Drug induced liver injury (DILI)

Drug induced liver injury
 a liver injury due to xenobiotics, herbs, or medications
that leads to either liver dysfunction or abnormal liver
serology, in the setting of no other identifiable cause.
 Intrinsic / Dose dependent DILI
 Idiosyncration DILI
Drug metabolism and DILI
 Phase I  cyt450
 Phase II 
biotransformasi
(konjugasi)
Liver injury and its pattern
 Hepatocellular  injury to hepatocytes
(necrosis/apoptosis)
 Cholestasis  impaired bile formation/bile flow
 Mixed Hepatocellular and cholestasis

May lead to fibrosis and cirrhosis

 Drug induced
hepatitis Drug induced
cholestasis

Hepatocytes Inflammation

↑ aspartate amino transferase (AST) ↑bilirubin darah and

and alanine aminotransferase (ALT) alkali phosphatase

Anorexia, fatique, nausea, vomitus Jaundice, itching

Hepatocellular
 Hepatocellular injury manifest
 Steatosis / fatty liver  fat droplets within hepatocytes
 Microvesicular and macrovesicular
 Hepatitis / inflammation  inflammatory cell with oedema
and congestion around hepatocytes
 RE will be damaged and healing process resulting scar tissue
(fibrosis and cirrhosis)
 Necrosis / cell death  resulting fibrosis and cirrhosis
Steatosis
 Microvesicular steatosis
 tiny fat vesicles filling
the hepatocytes

 Macrovesicular steatosis
 large clear vacuoles
in the cytoplasm of
hepatocytes which push
the nucleus to one side
Fibrosis and cirrhosis
 In extensive
hepatocellular
injury 
deposition of
collagen
 Factors that may predispose to DILI
 Gender
 DILI more common in females than in males
 Age
 DILI more commmon in the elderly due to altered pharmacokinetics and polypharmacy
 During adult life, the expression of some CYPs declines by up to 10% with advancing
age. Expression of CYP 3A4 and 2E1 seem to be different among men and women,
which may explain the enhanced metabolism of certain drugs, however it’s still unclear
whether this increases the risk of hepatic drug reaction.
 Pre-existing liver disease
 Concurrent disease
 DM, HIV, renal failure, malnutrition, obesity
 Diseases that alter the expression of CYPs include DM (increased CYP2E1), and
hypothyroid (decreased CYP3A4)
 polypharmacy
 Genetics
 Genetic differences in drug metabolism may predispose certain patient to
hepatotoxicity
 polymorphisms in this setting explains the four-fold or greater differences in
rates of metabolism among healthy individuals. Genetic alterations may
contribute to diminished metabolism, lack of metabolism, or excessive
metabolism of a drug.
 polymorphisms of CYP2C9- affects the metabolism of S-warfarin,
omeprazole, tolbutamide
 polymorphism of CYP2C19- affects the metabolism of S-mephenytoin
 polymorphism of glutathione s-transferase can affect metabolism of
acetaminophen
 HLA (human leukocyte antigen)- association between certain HLA
haplotypes and the development of DILI from fluclox-, augmentin
Mekanisme drug induce liver injury
 Direct injury of hepatocytes  covalen binding with cell membrane
cause cell membrane rupture
 Imunologic reaction active metabolite activate APC (antigen
presenting cell)
 Inhibition of cellular pathway of drug metabolism  covalen
binding with cyt P450
 Activation of apoptosis pathways
 Disruption of bile acid transport
 Inhibition of mitochondrial function  increased concentration of
ROS, ATP depletion, inhibit beta oxidation leading to steatosis
A. Direct cell stress 
rupture cell membrane
B. Disruption of transport
pumps of bile acid
C. Covalen binding to P450
D. Immunologic reaction
E. Activation of apoptosis
pathway by TNF/Fas
F. Inhibition of mitochondrial
function
 Diagnosis

 Gejala (mual, muntah, lemah, lesu,

mudah capek, dark urine, jaundice)
 Riwayat penggunaan alkohol
 Riwayat penggunaan obat
 Pemeriksaaan virus hepatitis
 Pemeriksaan adanya autoimun
disease
 Penyakit yg memicu perubahan
hemodinamik
RUCAM (Roussel Uclaf Causality Assessment Method)
 Method to assess cause of hepatotoxicity
 Score :
 0  DILI excluded
 1-2  unlikely
 3-5  possible
 6-8  probable
 > 8  highly probable
Clinical presentation
Liver disease akut Liver disease kronik
 Malaise may present with signs of
 Low-grade fever cirrhosis or decompensation
 Anorexia
 Jaundice
 Nausea and Vomiting
 RUQ pain  Palmer erythema
 Jaundice  Ascites
 Acholic stools
 Dark urine  HE
Liver disease severity (CPS score)

 CPS grade A : 1-6 poin

 CPS grade B : 7-9 poin
 CPS grade C : 10-15
poin
Manajemen Terapi

 Withdrawal obat yg diduga menyebabkan liver injury

 Diberikan antidotum  utk ketoksikan karena
overdosis obat
 Pemberian kortikosteroid  imunosupresi pada DILI
 Antiprutirus  jika px mengalami gejala itching
 Pada kasus berat  transplantasi