Pharmacology Lecture Slides on Hepatotoxicity by Sanjaya Mani Dixit Assistant Professor of Pharmacology at Kathmandu Medical College

1. Hepatotoxicity
Sanjaya Mani Dixit
Assistant Professor of Pharmacology

2. Contents
Introduction
Injury Types
Predictable (Direct/Indirect)
Unpredictable
Risk Factors For Susceptibility to DILI
Reye Syndrome
Alcoholic Liver Disease
Prevention/severity/
Management/ Treatment/
Conclusion

3. Hepatotoxicity
Introduction

4. Hepatotoxicity
The term hepatotoxicity implies, chemical driven
liver damage or Drug induced liver injury (DILI)
Some chemicals = Hepatotoxic agents
(directly/metabolic end products)
Liver major site of drug toxicity ???
Major site of drug metabolism
(Cytochrome P-450 enzymes are hemoproteins located in the smooth
endoplasmic reticulum of liver, which are induced/inhibited by drugs.(Phase-I))

5. Hepatotoxicity
The liver is highly susceptible to drug-induced injury
because of its high metabolic capacity (phase I and II
reactions) and the fact that many xenobiotics are
concentrated in the liver through transport mechanisms
(Organic Anion Transporter & Organic Cation Transporter)
(phase III reactions).
The liver toxicity of most drugs in humans seems to be
mediated by an adaptive immune response, with or
without the production of drug-specific antibodies
(Uetrecht, 2009).

6. Hepatotoxicity
Almost 1000 Drugs, Toxins and Herbs are known
to be Hepatotoxic
Drug hepatotoxicity, is the leading cause of acute liver failure
(ALF). [Approximately 50% of all cases, 1000 in US/yr.]
Drug-induced ALF is associated with high morbidity and
mortality [ Only a 20% survival in the absence of liver
transplantation.]
Drug-induced hepatic injury is the most common reason cited
for withdrawal of an approved drug.
A book on market
for body parts

7. Hepatotoxicity-US (Medscape)
In the United States, approximately 2000 cases of acute liver
failure occur annually and drugs account for over 50% of them (39%
are due to acetaminophen, 13% are idiosyncratic reactions due to other
medications).
Drugs account for 2-5% of cases of patients hospitalized with jaundice
and approximately 10% of all cases of acute hepatitis.
The US Food and Drug Administration (FDA) has withdrawn
following drugs from the market for causing severe liver injury.
Bromfenac [1997-1998, > 50 cases-severe hepatic damage]
 Now used as eye drops – following cataract surgery
Troglitazone [1997-2000, > 90 cases- hepatotoxicity]

8. LiverTox-
Information on the documented hepatotoxicity of drugs is
available at: LiverTox (http://livertox.nlm.nih.gov).
According to critical analysis of the hepatotoxicity of drugs in
LiverTox, 53% of drugs had at least one case report of
convincing reports of liver injury.
Only 48 drugs had more than 50 case reports of DILI.
Amoxicillin-clavulanate is the most commonly implicated
agent leading to DILI in the prospective series.
Other drugs with highest risk are Azathioprine and Infliximab.

9. LiverTox- Drugs associated with more than 100 cases of DILI.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783956/

10. Hepatotoxicity - DILI
DILI may be of two types:
Predictable (Direct/Indirect)
Unpredictable

11. Drug-induced Liver Injury (DILI)
Predictable
Dose related
Intrinsically hepatotoxic drugs
Acute (hours)
Injury pattern is usually necrosis
Clinically → Fulminant (Acute Hepatitis)
Example: Acetaminophen (high doses)
 Reactive intermediate: N-acetyl p-benzoquinoneimine

12. Drug-induced Liver Injury (DILI)
Unpredictable
Not dose related
Rare 0.01-1.0 %
Weeks to months after ingestion of drug
Idiosyncratic
Immune mediated idiosyncrasy (Hypersensitivity)
Rash, Fever
Arthralgia, Eosinophilia
Example: Phenytoin, Sulfonamides, Valproate
Metabolic idiosyncrasy (Production of toxic metabolites)
Example: INH, Ketoconazole, and Diclofenac

13. Clinical Manifestations of DILI
The manifestations of drug-induced hepatotoxicity are highly
variable, ranging from asymptomatic elevation of liver enzymes
to fulminant hepatic failure.
The injury may suggest:
a hepatocellular injury, with elevation of aminotransferase
levels as the predominant symptom, or
a cholestatic injury, with elevated alkaline phosphatase levels
(with or without hyperbilirubinemia) being the main feature.

14. Pathological Manifestations of DILI
Besides the use of clinical and laboratory data, the pattern of liver
histology may be classified into different categories:
Acute hepatocellular injury
Chronic hepatocellular injury
Acute cholestasis
Chronic cholestasis
Granulomatous hepatitis
Autoimmune hepatitis
Vascular lesions/venoocclusive disease
Neoplastic lesions

16. Diagnosis of DILI
When a single agent is involved, the diagnosis may be relatively
simple, but with multiple agents, implicating a specific agent as
the cause is difficult.
The latency period of idiosyncratic drug reactions is highly
variable; hence, obtaining a history of every drug ingested in the
past 3 months is essential.
The onset is usually within 5-90 days of starting the drug.
Performing laboratory tests to assess and diagnose the effects of
the suspected medication is essential.
Classify DILI as hepatocellular, cholestatic, or mixed according
to the pattern of elevation of liver enzymes based on the first set
of laboratory tests available.

17. Diclofenac- Extreme toxicity in vultures
Diclofenac hepatotoxicity is typically associated with an acute hepatitis-like histology
with necrosis that may be most prominent centrally. There is usually focal necrosis
and inflammation, but with severe cases the injury can be confluent or submassive.

18. Drug Induced Liver Injury
Hepatic-related side effects of NSAIDs have been
reported to occur in 3% of patients receiving the drugs.
The mechanism by which almost all NSAIDs produce
hepatoxicity seems to be immunologic or metabolic,
with dose-related toxicity being seen in aspirin
and acetaminophen.

19. Drug Induced Liver Injury
Acetaminophen
It is almost entirely metabolized in the liver, and the minor
metabolites(NAPBQI) are responsible for the hepatotoxicity
seen in overdoses.
Mechanisms of acetaminophen hepatotoxicity include depletion
of hepatocyte glutathione, accumulation of the toxic metabolite
NAPBQI, mitochondrial dysfunction, and alteration of innate
immunity.
The lowest dose of acetaminophen to cause hepatotoxicity is
believed to be between 125 and 150 mg/kg. The threshold dose to
cause hepatotoxicity is 10 to 15 g of acetaminophen for adults and
150 mg/kg for children.
NAC is the antidote for acetaminophen.

20. Drug Induced Liver Injury
Reye syndrome

Reye's (Ryes) syndrome is a rare but serious
condition that causes swelling in the liver and brain
and results in severe damage in children recovering
from viral infection.

Predominantly in children given acetylsalicylic
acid

Mitochondrial dysfunction in liver and some other
organs.

Produces microvesicular steatosis(fat
accumulation) with severe liver dysfunction.

21. DILI
Alcoholic Liver Disease
Alcoholic liver disease occurs after years of heavy
drinking.
Alcohol can cause inflammation in the liver.
Over time, scarring and cirrhosis can occur.
Cirrhosis is the final phase of alcoholic liver disease.
Women are more predisposed to ALD, because alcohol
metabolism is slower in females.

22. Effect of Alcohol in Liver
Mobilizes peripheral fat and increases fat synthesis in liver in a
dose-dependent manner.
Regular alcohol- induces microsomal enzymes
Chronic alcoholism subjects liver to oxidative stress and
causes cellular necrosis followed by fibrosis.
Alcohol-Acetaldehyde-hepatocyte damage, inflammation (Chronic-
large amounts)
Alcoholic cirrhosis – vitamin and nutritional deficiencies

23. Hepatotoxicity in TB patients
INH, Rifampin, and PZA all are associated with
DILI (drug-induced liver injury)
Only one case of DILI has been reported for
Ethambutol
Risk of DILI in active TB treatment studies ranges
from 5 to 33%
Concomitant use of Rifampin increases the risk

24. Risk Factors For Susceptibility to DILI
Methotrexate
Alcohol
Obesity
D.M
Chronic hepatitis
INH (Isoniazid)
HBV,HCV,HIV
Alcohol
Older age
Female
Acetaminophen
Alcohol
Fasting
INH
Valproate
Young age
Anticonvulsants
Diclofenac
Female
Osteoarthritis

25. Risk Factors For Susceptibility to DILI
Sulfonamide
HIV
Slow acetylator
Genetic defect in defense
Anticonvulsants
Genetic defect in
detoxification
Rifampicin
Slow acetylators
INH
Pyrazinamide
Slow acetylators
INH

28. Hepatotoxicity in Liver Impairment
Drugs that cause dose-related toxicity may do so at
lower doses in the presence of hepatic impairment
than in individuals with normal liver function.
Some drugs that produce reactions of the
idiosyncratic kind do so more frequently in patients
with liver disease.
These drugs should be avoided or used very
carefully in patients with liver disease.

29. Drugs to be avoided or used with caution in liver disease

30. Prevention of drug-induced liver injury
includes:
Vigilance,
 Identification of risk factors,
 ALT monitoring with certain drugs, and
 Safer marketing strategies.
The most useful way to prevent DILI would be to
educate our patients about the warning signs of severe
drug injury such as abdominal pain, nausea, vomiting
and jaundice.

31. Indicator of severity
There is usually poor correlation between degree of
ALT elevation and the severity of the liver disease.
 Histology being a more accurate indicator.
However, jaundice is a good predictor of mortality in
drug-induced hepatitis.

32. MANAGEMENT
Prompt discontinuation of the offending drug,
Supportive and symptomatic therapy,
Monitoring for the development of ALF.
In case of drug-induced acute liver failure (ALF),
consider liver transplantation as a therapeutic option.
Adults with idiosyncratic drug-induced ALF should
receive N-acetylcysteine early in the course (coma
grade I-II).

33. Treatment
Use of glucocorticoids for immune-mediated
reactions and ursodeoxycholic acid (UDCA) for
cholestatic liver injury remain controversial therapies.
In the subset with DILI, there was a trend towards a
worse prognosis in those on steroid therapy
It may be reasonable to treat prolonged cholestasis due
to DILI with UDCA in a dose of 13–15 mg/kg.
In drug-induced hepatitis with allergic features, with
no improvement after drug withdrawal, a short course of
steroids may be justifiable.

34. Treatment
Antioxidants have also been proposed as a
treatment modality for severe DILI
N-acetylcysteine (NAC) is the treatment of choice
for paracetamol overdose.
At the earliest signs of liver failure (INR.1.5,
development of ascites, or any grade of hepatic
encephalopathy), prompt referral to a liver transplant
unit is indicated.

36. CONCLUSION
Drug-induced liver injury must be included as a
differential diagnosis in all patients with an abnormal
liver panel.
Management of patients with drug induced liver
injury needs increased vigilance, as once liver failure
develops spontaneous survival (in the absence of liver
transplantation) is rare, except in those with paracetamol-induced
hepatotoxicity

38. Cytochrome P450
Cytochrome P450 stands for a superfamily of haem-containing
mono-oxygenases that protect the individual against potentially
harmful substances by modifying these substances by oxidation,
hydroxylation, dealkylation, or dehalogenation, thereby increasing
polarity and solubility and thus facilitating excretion from the
body.
CYP, followed by a number (family), then a letter (subfamily),
and another number (protein); e.g. CYP3A4 is the fourth protein
in family 3, subfamily A. The designation P450 is derived from
the specific spectral absorbance at 450 nm of these proteins.

39. Cytochrome P450
Cytochrome P450 stands for a superfamily of more than 50 (58 identified
2020) closely related heme-containing enzymes, which can be divided into
families (with at least 40% sequence homology on the amino acid level) and
subfamilies (with at least 55% sequence homology), each with their own
substrate specificity.
They are found in all kingdoms of life. In mammals, these proteins are found
primarily in microsomes of hepatocytes and other cell types, where they
oxidise steroids, fatty acids and xenobiotics, and are important for the
detoxification and clearance of various compounds, as well as for hormone
synthesis and breakdown, cholesterol synthesis and vitamin D metabolism.
In plants, these proteins are important for the biosynthesis of several
compounds such as hormones, defensive compounds and fatty acids. In
bacteria, they are important for several metabolic processes, such as the
biosynthesis of antibiotic erythromycin in Saccharopolyspora erythraea
(Streptomyces erythraeus).

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