Drug induced liver injury (DILI) and Hepatotoxicity

DRUG INDUCED LIVER
INJURY (DILI) OR
HEPATOTOXICITY
By: Dr. Ankit Gaur
M.Sc, Pharm.D, RPh

LIVERPHYSIOLOGIC FUNCTION
Formation and
secretion of bile
Nutrient and
vitamin
metabolism
(amino acid, lipid,
glucose)
Detoxification &
inactivation of
various
substances (toxin,
drug)
Synthesis of
plasma proteins
(albumin, clotting
factor)
Immune system 
kupffer cells.
2

HEPATOTOXICITY
Hepatotoxicity refers to liver damage. Certain
medicinal agents, when taken in overdoses
and sometimes even when introduced
within therapeutic ranges, may injure the
organ.
Other chemical agents, such as those used in
laboratories and industries, natural chemicals
e.g., microcystins and herbal remedies can
also induce hepatotoxicity.
Chemicals that cause liver injury are called
hepatotoxin.

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.

CLASSIFICATION
1. Intrinsic Hepatotoxicity
2. Idiosyncratic Hepatotoxicity
Allergic
Non-Allergic
5

Intrinsic hepatotoxicity is regarded as dose-
dependent and predictable above an
approximate threshold dose.
Whereas idiosyncratic hepatotoxicity occurs
without obvious dose-dependency and in an
unpredictable fashion.
 Allergic idiosyncratic hepatotoxicity is
characterized by the presence of typical
symptoms and signs of adaptive immune
reactions, including fever, skin reactions,
eosinophilia, formation of autoantibodies, and
a short latency time particularly after re-
exposure. 6

RISK FACTORS OF LIVER INJURY
Pharmacokinetic
s – Metabolism
Specific immune
system
Initial liver injury
Progression of liver
injury
Cytokine,
TNF, ROS
Acute
liver
failure
Chronic
liver failure
Enviromental Risk
Factor
Genetic Risk Factor

8
FORMS OF LIVER TOXICITY:-
 Zonal Necrosis- This is the most common type of
drug induced liver cell necrosis where the injury is
largely confined to a particular zone of the liver
lobule.
 Hepatitis- Disease of the liver causing
inflammation.
 Cholestasis- Cholestasis is a condition where
bile cannot flow from the liver to the duodenum.
 Steatosis- Steatosis is a condition characterised
by the build up of fat within the liver, sometimes
triggering inflammation of the liver

9
• Granuloma- A granuloma is one of a number of
forms of localized nodular inflammation found in
tissues.
• Vascular lesions- They result from injury to the
vascular endothelium.
• Neoplasm- Neoplasm or tumor, tissue composed
of cells that grow in an abnormal way.

MECHANISM OF DRUG INDUCED LIVER INJURY:
10

1.Initial Mechanisms of Toxicity: Direct Cell Stress,
Direct Mitochondrial Impairment, and Specific
Immune Reactions
2. Direct and Death Receptor-Mediated Pathways
Leading to Mitochondrial Permeability Transition
3. Apoptosis and Necrosis 11

13
SIGNS AND SYMPTOMS:-
 Yellowing of the skin and whites of the eyes
(jaundice)
 Fatigue
 Loss of appetite
 Nausea and vomiting
 Weight loss
 Dark or tea-colored urine

PRACTICAL GUIDELINE FOR DIAGNOSIS &
EARLY MANAGEMENT OF DILI
Preplanned LFT,
evaluation of drug
Careful history taking/rule out other
etiologies, evualate the type of liver injury
DILI is unlikely DILI is suspected
Diagnosis of
DILI
Hepatocellular type
or mixed
Discontinue the
suspected drug
Cholestatic type
Careful
monitoring
ALT > 8 x ULN at any
one time or
ALT > 5 x ULN for
more than 2 wk or
ALT > 3 x ULN, and
total bilirubin > 2 x
ULN or PT-INR > 1.5
x UNL
Symptoms
related to liver
injury such as
jaundice or
Total bilirubin > 3
x ULN or
PT-INR > 1.5 x
ULN
When a drug is initiated
When liver dysfunction is
recognized

Drugs & its mechanisms to induce
liver injury
18

DRUGS CAUSING LIVER DAMAGE
Acetaminophen:-(Paracetamol, also known by the
brand name Tylenol and Panadol) is usually well
tolerated in prescribed dose but overdose is the
most common cause of drug induced liver disease
and acute liver failure worldwide.
20
Nonsteroidal anti-inflammatory drugs- Aspirin,
phenylbutazone, ibuprofen, sulindac,
phenylbutazone, piroxicam, diclofenac and
indomethacin.
20

Glucocorticoids- Glucocorticoids are so named
due to their effect on carbohydrate mechanism.
they promote glycogen storage in liver. The
classical effect of prolonged use both in adult
and paediatric population is steatosis.
Isoniazid- Isoniazide (INH) is one of the most
commonly used drug for tuberculosis; it is
associated with mild elevation of liver enzymes
in up to 20% of patients and severe
hepatotoxicity in 1-2% of patients

Natural products- Amanita mushroom, particularly
the destroying angels, aflatoxins.
Industrial toxin- Arsenic, Carbon tetraChloride, Vinyl
Chloride.
Herbal and alternative remedies- Ackee fruit,
Camphor, Pyrrolizidine alkaloids, Horse chestnut
leaf, Valerian, Comfrey (often used in herbal tea).
2
2

1- CARBON TETRA CHLORIDE
Carbon tetrachloride was widely used as a
cleaning solvent, fire extinguisher agent, and
anthelmintics.
Because of its liver toxicity and known
carcinogenicity in animals, its role has become
limited; it is now used mainly as an intermediate
in chemical manufacturing.

MECHANISM OF TOXICITY
Carbon tetrachloride is a potent hepatic and renal
toxin. The mechanism is thought to be a result of a
toxic free-radical intermediate of metabolism.
(CCl4) undergoes hepatic reductive metabolism to
CCl3 and CCl3OO free radicals toxic intermediates
which may initiate hepatocellular damage..
Chronic use of metabolic enzyme inducers such as
phenobarbital and ethanol increase the toxicity of
carbon tetrachloride. Carbon tetrachloride is a
known animal and suspected human carcinogen.

SIGN & SYMPTOMS
 Nausea
 Vomiting
 Dizziness
 Depression of conscious level
 Cardiac Arrythmias
 Coma
 Hapatic necrosis
 Renal Damage

MANAGEMENT
 Remove the subject from exposure area.
 Maintain normobaric or hyperbaric oxygen.
 In case of ingestion administer activated charcoal.
 Ipecac induced vomiting may be useful for initial
treatment.
 N-acetylcysteine may minimize hepatic and renal
toxicity by providing a scavenger for the toxic
intermediate.

2- ACETAMINOPHEN
Acetaminophen is a widely used drug found in many
over the counter and prescription analgesics
medication.
In adults, toxicity may occur by ingestion of greater
than 7.5-10g (24 regular strength or 15 extra
strength caplets or tablets) over a period of 8 hours
or less.

Acetaminophen is metabolized in the liver by
conjugation to non-toxic glutathione. The
conjugated product is eliminated in the urine. But in
an acute overdose, the liver's normal glutathione
reserves are depleted; the excess acetaminophen
is then metabolized to highly toxic metabolite: N-
acetyl-p-benzoquinone (NABQI). NABQI is very
reactive causing hepatocellular death and
subsequent massive liver cell necrosis.

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.

SIGN & SYMPTOMS
 Anorexia
 Nausea
 Vomiting
 Altered mental status
 Increased Transaminase level
 Heaptic failure
 Renal failure

MANAGEMENT
 Ipecac Syrup
 Activated Charcoal
 N-Acetyl Cysteine (loading dose is 150mg/kg in
200ml of 5% dextrose infused over 15-60
minutes).
 Methionine can also be given.

3- ETHANOL
Commercial beer, wine, and liquors contain various
amounts of ethanol. Ethanol is also found in a variety of
perfumes, mouthwashes, many food flavorings (eg,
vanilla, almond, and lemon extracts), pharmaceutical
preparations (eg, elixirs), and many other products.
Ethanol is frequently ingested recreationally and is the
most common co-ingestant with other drugs in suicide
attempts. Ethanol may also serve as an antidote in the
emergency treatment of methanol and ethylene glycol
poisonings.

Ethanol is also oxidized in liver by an ethanol-inducible
cytochrome P-450 enzyme that converted the contents
to toxic radicals. Induction also results in energy
wastage and increased production of acetaldehyde
that results in injury to cells and mitochondria with a
striking impairment of oxygen utilization.
Acetaldehyde also causes glutathione depletion and
lipid peroxidation, and stimulates hepatic collagen
synthesis, thereby promoting fibrosis and cell damage.

SIGN & SYMPTOMS
 Euphoria
 Impairment of balance & muscle coordination
 Nausea
 Vomiting
 Hypoglycemia
 Ketoacidosis
 Respiratory Depression
 Pale, bluish, cold and clammy skin due to insufficient
oxygen
 Coma

MANAGEMENT
 Protect the airway and provide supportive treatment.
 Don’t induce vomiting or activated charcoal
 Give glucose & thiamine to treat alcoholic ketoacidosis
 Correct hypothermia with gradual rewarming
 No specific antidote available
 Perform hemodylasis for efficient ethanol removal.

4- AFLATOXINS
The aflatoxins are a group of structurally related toxic
compounds produced by certain strains of the fungi
Aspergillus flavus and A. parasiticus.
Aflatoxicosis is poisoning that results from ingestion of
aflatoxins in contaminated food. Among 18 different
types of aflatoxins identified, major members are
aflatoxin B1, B2, G1 and G2. Aflatoxin B1 is the most
toxic and most prevalent among this family.

The major target for the toxicity of aflatoxins is the
liver. Oxidation by cytochrome P450, aflatoxins then
bind to DNA or proteins and impair their functions.
Aflatoxins produce necrosis of liver cells, damage
to mitochondria, and proliferation of bile ducts.
Aflatoxin also suppress the immune system of the
body.

SIGN & SYMPTOMS
 Vomiting
 Abdominal Pain
 Mental Impairment
 Convulsion
 Hemorrhaging
 Disruption of food digestion & metabolism
 Liver damage
 Coma

MANAGEMENT
 The FDA’s goal for aflatoxins has been to minimize
contamination by the cause.
 Provide supportive treatment.
 There is no specific antidote for toxicity of aflatoxins.
Timely administration of methionine (200 mg/kg) and
sodium thiosulfate (50 mg/kg), at eight hour intervals,
is proven to be of therapeutic value.

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.
40

Drug induced liver injury (DILI) and Hepatotoxicity

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