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MOLECULAR MECHANISM OF DRUG
INDUCED HEPATOTOXICITY
1
FACILITATED BY PRESENTED BY
Dr Shivalinge Gowda Madhavapriya B N
HOD 1st MPharm
Dept of Pharmacology Dept of Pharmacology
CONTENTS Introduction
Classification
Mechanism of Liver damage
Patterns of Injury
Specific drug or toxin which leads to
hepatotoxicity
References
2
INTRODUCTION Hepatotoxicity (from hepatic toxicity) implies
chemical-driven liver damage
The liver plays a central role in transforming
and clearing chemicals and is susceptible to the
toxicity from these agents 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
(eg microcystins) and herbal remedies can
also induce hepatotoxicity Chemicals that
cause liver injury are called hepatotoxins
3
Classification1 Intrinsic Hepatotoxicity
2 Idiosyncratic Hepatotoxicity
Allergic
Non-Allergic
4
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-exposure5
6
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
MECHANISM OF DRUG INDUCED LIVER INJURY
7
1Initial 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
8
9
PATTERNS OF LIVER INJURYPatterns of drug-induced liver disease
Type of injury Hepatocellular Cholestatic Mixed
ALT ge Twofold rise Normal ge Twofold rise
ALP Normal ge Twofold rise ge Twofold rise
ALT ALP ratio High ge5 Low le2 2-5
Examples
Acetaminophen
Allopurinol
Amiodarone
HAART
NSAID
Anabolic steroid
Chlorpromazine
Clopidogrel
Erythromycin
Hormonal
contraception
Amitriptyline
Enalapril
Carbamazepine
Sulfonamide
Phenytoin
10
11
12
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
13
bull Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues
bull Vascular lesions- They result from
injury to the vascular endothelium
bull Neoplasm- Neoplasm or tumor tissue
composed of cells that grow in an
abnormal way
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
CONTENTS Introduction
Classification
Mechanism of Liver damage
Patterns of Injury
Specific drug or toxin which leads to
hepatotoxicity
References
2
INTRODUCTION Hepatotoxicity (from hepatic toxicity) implies
chemical-driven liver damage
The liver plays a central role in transforming
and clearing chemicals and is susceptible to the
toxicity from these agents 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
(eg microcystins) and herbal remedies can
also induce hepatotoxicity Chemicals that
cause liver injury are called hepatotoxins
3
Classification1 Intrinsic Hepatotoxicity
2 Idiosyncratic Hepatotoxicity
Allergic
Non-Allergic
4
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-exposure5
6
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
MECHANISM OF DRUG INDUCED LIVER INJURY
7
1Initial 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
8
9
PATTERNS OF LIVER INJURYPatterns of drug-induced liver disease
Type of injury Hepatocellular Cholestatic Mixed
ALT ge Twofold rise Normal ge Twofold rise
ALP Normal ge Twofold rise ge Twofold rise
ALT ALP ratio High ge5 Low le2 2-5
Examples
Acetaminophen
Allopurinol
Amiodarone
HAART
NSAID
Anabolic steroid
Chlorpromazine
Clopidogrel
Erythromycin
Hormonal
contraception
Amitriptyline
Enalapril
Carbamazepine
Sulfonamide
Phenytoin
10
11
12
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
13
bull Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues
bull Vascular lesions- They result from
injury to the vascular endothelium
bull Neoplasm- Neoplasm or tumor tissue
composed of cells that grow in an
abnormal way
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
INTRODUCTION Hepatotoxicity (from hepatic toxicity) implies
chemical-driven liver damage
The liver plays a central role in transforming
and clearing chemicals and is susceptible to the
toxicity from these agents 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
(eg microcystins) and herbal remedies can
also induce hepatotoxicity Chemicals that
cause liver injury are called hepatotoxins
3
Classification1 Intrinsic Hepatotoxicity
2 Idiosyncratic Hepatotoxicity
Allergic
Non-Allergic
4
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-exposure5
6
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
MECHANISM OF DRUG INDUCED LIVER INJURY
7
1Initial 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
8
9
PATTERNS OF LIVER INJURYPatterns of drug-induced liver disease
Type of injury Hepatocellular Cholestatic Mixed
ALT ge Twofold rise Normal ge Twofold rise
ALP Normal ge Twofold rise ge Twofold rise
ALT ALP ratio High ge5 Low le2 2-5
Examples
Acetaminophen
Allopurinol
Amiodarone
HAART
NSAID
Anabolic steroid
Chlorpromazine
Clopidogrel
Erythromycin
Hormonal
contraception
Amitriptyline
Enalapril
Carbamazepine
Sulfonamide
Phenytoin
10
11
12
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
13
bull Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues
bull Vascular lesions- They result from
injury to the vascular endothelium
bull Neoplasm- Neoplasm or tumor tissue
composed of cells that grow in an
abnormal way
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
Classification1 Intrinsic Hepatotoxicity
2 Idiosyncratic Hepatotoxicity
Allergic
Non-Allergic
4
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-exposure5
6
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
MECHANISM OF DRUG INDUCED LIVER INJURY
7
1Initial 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
8
9
PATTERNS OF LIVER INJURYPatterns of drug-induced liver disease
Type of injury Hepatocellular Cholestatic Mixed
ALT ge Twofold rise Normal ge Twofold rise
ALP Normal ge Twofold rise ge Twofold rise
ALT ALP ratio High ge5 Low le2 2-5
Examples
Acetaminophen
Allopurinol
Amiodarone
HAART
NSAID
Anabolic steroid
Chlorpromazine
Clopidogrel
Erythromycin
Hormonal
contraception
Amitriptyline
Enalapril
Carbamazepine
Sulfonamide
Phenytoin
10
11
12
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
13
bull Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues
bull Vascular lesions- They result from
injury to the vascular endothelium
bull Neoplasm- Neoplasm or tumor tissue
composed of cells that grow in an
abnormal way
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
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-exposure5
6
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
MECHANISM OF DRUG INDUCED LIVER INJURY
7
1Initial 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
8
9
PATTERNS OF LIVER INJURYPatterns of drug-induced liver disease
Type of injury Hepatocellular Cholestatic Mixed
ALT ge Twofold rise Normal ge Twofold rise
ALP Normal ge Twofold rise ge Twofold rise
ALT ALP ratio High ge5 Low le2 2-5
Examples
Acetaminophen
Allopurinol
Amiodarone
HAART
NSAID
Anabolic steroid
Chlorpromazine
Clopidogrel
Erythromycin
Hormonal
contraception
Amitriptyline
Enalapril
Carbamazepine
Sulfonamide
Phenytoin
10
11
12
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
13
bull Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues
bull Vascular lesions- They result from
injury to the vascular endothelium
bull Neoplasm- Neoplasm or tumor tissue
composed of cells that grow in an
abnormal way
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
6
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
MECHANISM OF DRUG INDUCED LIVER INJURY
7
1Initial 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
8
9
PATTERNS OF LIVER INJURYPatterns of drug-induced liver disease
Type of injury Hepatocellular Cholestatic Mixed
ALT ge Twofold rise Normal ge Twofold rise
ALP Normal ge Twofold rise ge Twofold rise
ALT ALP ratio High ge5 Low le2 2-5
Examples
Acetaminophen
Allopurinol
Amiodarone
HAART
NSAID
Anabolic steroid
Chlorpromazine
Clopidogrel
Erythromycin
Hormonal
contraception
Amitriptyline
Enalapril
Carbamazepine
Sulfonamide
Phenytoin
10
11
12
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
13
bull Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues
bull Vascular lesions- They result from
injury to the vascular endothelium
bull Neoplasm- Neoplasm or tumor tissue
composed of cells that grow in an
abnormal way
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
MECHANISM OF DRUG INDUCED LIVER INJURY
7
1Initial 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
8
9
PATTERNS OF LIVER INJURYPatterns of drug-induced liver disease
Type of injury Hepatocellular Cholestatic Mixed
ALT ge Twofold rise Normal ge Twofold rise
ALP Normal ge Twofold rise ge Twofold rise
ALT ALP ratio High ge5 Low le2 2-5
Examples
Acetaminophen
Allopurinol
Amiodarone
HAART
NSAID
Anabolic steroid
Chlorpromazine
Clopidogrel
Erythromycin
Hormonal
contraception
Amitriptyline
Enalapril
Carbamazepine
Sulfonamide
Phenytoin
10
11
12
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
13
bull Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues
bull Vascular lesions- They result from
injury to the vascular endothelium
bull Neoplasm- Neoplasm or tumor tissue
composed of cells that grow in an
abnormal way
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
1Initial 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
8
9
PATTERNS OF LIVER INJURYPatterns of drug-induced liver disease
Type of injury Hepatocellular Cholestatic Mixed
ALT ge Twofold rise Normal ge Twofold rise
ALP Normal ge Twofold rise ge Twofold rise
ALT ALP ratio High ge5 Low le2 2-5
Examples
Acetaminophen
Allopurinol
Amiodarone
HAART
NSAID
Anabolic steroid
Chlorpromazine
Clopidogrel
Erythromycin
Hormonal
contraception
Amitriptyline
Enalapril
Carbamazepine
Sulfonamide
Phenytoin
10
11
12
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
13
bull Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues
bull Vascular lesions- They result from
injury to the vascular endothelium
bull Neoplasm- Neoplasm or tumor tissue
composed of cells that grow in an
abnormal way
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
9
PATTERNS OF LIVER INJURYPatterns of drug-induced liver disease
Type of injury Hepatocellular Cholestatic Mixed
ALT ge Twofold rise Normal ge Twofold rise
ALP Normal ge Twofold rise ge Twofold rise
ALT ALP ratio High ge5 Low le2 2-5
Examples
Acetaminophen
Allopurinol
Amiodarone
HAART
NSAID
Anabolic steroid
Chlorpromazine
Clopidogrel
Erythromycin
Hormonal
contraception
Amitriptyline
Enalapril
Carbamazepine
Sulfonamide
Phenytoin
10
11
12
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
13
bull Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues
bull Vascular lesions- They result from
injury to the vascular endothelium
bull Neoplasm- Neoplasm or tumor tissue
composed of cells that grow in an
abnormal way
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
PATTERNS OF LIVER INJURYPatterns of drug-induced liver disease
Type of injury Hepatocellular Cholestatic Mixed
ALT ge Twofold rise Normal ge Twofold rise
ALP Normal ge Twofold rise ge Twofold rise
ALT ALP ratio High ge5 Low le2 2-5
Examples
Acetaminophen
Allopurinol
Amiodarone
HAART
NSAID
Anabolic steroid
Chlorpromazine
Clopidogrel
Erythromycin
Hormonal
contraception
Amitriptyline
Enalapril
Carbamazepine
Sulfonamide
Phenytoin
10
11
12
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
13
bull Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues
bull Vascular lesions- They result from
injury to the vascular endothelium
bull Neoplasm- Neoplasm or tumor tissue
composed of cells that grow in an
abnormal way
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
11
12
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
13
bull Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues
bull Vascular lesions- They result from
injury to the vascular endothelium
bull Neoplasm- Neoplasm or tumor tissue
composed of cells that grow in an
abnormal way
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
12
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
13
bull Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues
bull Vascular lesions- They result from
injury to the vascular endothelium
bull Neoplasm- Neoplasm or tumor tissue
composed of cells that grow in an
abnormal way
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
13
bull Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues
bull Vascular lesions- They result from
injury to the vascular endothelium
bull Neoplasm- Neoplasm or tumor tissue
composed of cells that grow in an
abnormal way
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
GENETIC AND NONGENETIC RISK
FACTORS
14
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
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
15
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
Nonsteroidal anti-inflammatory drugs-Aspirin phenylbutazone ibuprofen sulindac phenylbutazone piroxicam diclofenac and indomethacin
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 paediatricpopulation 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 16
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
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)
17
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
18
Images showing liver damage
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
19
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
20
Ultrastructural Images
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
85
4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
References
22
21
1 Donald Blumenthal Laurence Brunton Keith Parker Lazo John S Iain Buxton
(2006) Goodman and Gilmans Pharmacological Basis of Therapeutics Digital
EditionMcGraw-Hill Professional ISBN 0-07-146804-8
2 PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann Gerd A Kullak-Ublick and Ignazio Grattagliano
3 William M Lee MD Drug-Induced Hepatotoxicity N Engl J Med 2003 349474-
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4 Aashish Pandit Tarun Sachdeva and Pallavi Bafna Drug-Induced Hepatotoxicity A
Review Journal of Applied Pharmaceutical Science 02 (05) 2012 233-243
Wikipedia httpenwikipediaorgwikiLiver_disease
Medicine Net httpwwwmedicinenetcomliver_diseasearticlehtm
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