Liver injury is a possible consequence of ingestion of any xenobiotic, including industrial toxins, pharmacologic agents, and complementary and alternative medications (CAMs). Among patients with acute liver failure, drug-induced liver injury (DILI) is the most common cause.

1. Drug induced liver injury-
pathophysiology and causes
Dr. jyoti verma
Associate professor
Medicine

2. Introduction
Liver injury is a possible consequence of
- ingestion of any xenobiotic, including industrial toxins, pharmacologic
agents, and
- complementary and alternative medications (CAMs).
- Among patients with acute liver failure, drug-induced liver injury
(DILI) is the most common cause.

3. Pathophysiology
• Hepatotoxic drugs can injure the hepatocyte directly, for example, via
a free-radical or metabolic intermediate that causes peroxidation of
membrane lipids and that results in liver cell injury.
• Alternatively, a drug or its metabolite may
-activate components of the innate or adaptive immune system,
-stimulate apoptotic pathways,
-or initiate damage to bile excretory pathways

5. Potential mechanisms of drug-induced liver injury
The normal hepatocyte may be affected adversely by drugs through
(A) disruption of intracellular calcium homeostasis that leads to the disassembly of actin fibrils at the surface of the
hepatocyte, resulting in blebbing of the cell membrane, rupture, and cell lysis;
(B) disruption of actin filaments next to the canaliculus (the specialized portion of the cell responsible for bile
excretion), leading to loss of villous processes and interruption of transport pumps such as multidrug
resistance–associated protein 3 (MRP3), which, in turn, prevents the excretion of bilirubin and other organic
compounds;
(C) covalent binding of the heme-containing cytochrome P450 enzyme to the drug, thus creating nonfunctioning
adducts;
(D) migration of these enzyme drug adducts to the cell surface in vesicles to serve as target immunogens for
cytolytic attack by T cells, stimulating an immune response involving cytolytic T cells and cytokines; (
(E) activation of apoptotic pathways by tumor necrosis factor α (TNF-α) receptor or Fas (DD denotes death
domain), triggering the cascade of intercellular caspases, resulting in programmed cell death; or
(F) inhibition of mitochondrial function by a dual effect on both β-oxidation and the respiratory-chain enzymes,
leading to failure of free fatty acid metabolism, a lack of aerobic respiration, and accumulation of lactate and
reactive oxygen species (which may disrupt mitochondrial DNA). Toxic metabolites excreted in bile may damage
bile-duct epithelium.

6. Some Features of Toxic and Drug-Induced
Hepatic Injury:

7. Principal Alterations of Hepatic Morphology Produced by Some
Commonly Used Drugs and Chemicals

10. Risk factors for drug-induced liver injury
• Race
Some drugs appear to have different toxicities based on race. For example,
blacks and Hispanics may be more susceptible to isoniazid (INH) toxicity. The
rate of metabolism is under the control of P-450 enzymes and can vary from
individual to individual.
• Age
Apart from accidental exposure, hepatic drug reactions are rare in children.
Elderly persons are at increased risk of hepatic injury because of decreased
clearance, drug-to-drug interactions, reduced hepatic blood flow, variation in
drug binding, and lower hepatic volume. In addition, poor diet, infections,
and multiple hospitalizations are important reasons for drug-induced
hepatotoxicity.

11. • Sex
Although the reasons are unknown, hepatic drug reactions are more
common in females.
• Drug formulation
• Long-acting drugs may cause more injury than shorter-acting drugs.

12. • Alcohol ingestion
Alcoholic persons are susceptible to drug toxicity because alcohol induces liver injury and cirrhotic changes that alter drug
metabolism. Alcohol causes depletion of glutathione (hepatoprotective) stores that make the person more susceptible to toxicity
by drugs.
• Liver disease
Preexisting liver disease has not been thought to make patients more susceptible to drug-induced liver injury, [5, 6] but it may be
that a diminished liver reserve or the ability to recover could make the consequences of injury worse. Although the total
cytochrome P-450 is reduced in chronic liver disease, some may be affected more than others. The modification of doses in
persons with liver disease should be based on the knowledge of the specific enzyme involved in the metabolism. Patients with
HIV infection who are co-infected with hepatitis B or C virus are at increased risk for hepatotoxic effects when treated with
antiretroviral therapy. Similarly, patients with cirrhosis are at increased risk of decompensation by toxic drugs.
• Genetic factors
A unique gene encodes each P-450 protein. Genetic differences in the P-450 enzymes can result in abnormal reactions to drugs,
including idiosyncratic reactions. Debrisoquine is an antiarrhythmic drug that undergoes poor metabolism because of abnormal
expression of P-450-II-D6. This can be identified by polymerase chain reaction amplification of mutant genes. This has led to the
possibility of future detection of persons who can have abnormal reactions to a drug. [8]
• Other comorbidities
Persons with AIDS, persons who are malnourished, and persons who are fasting may be susceptible to drug reactions because of
low glutathione stores.

13. Pathophysiology and mechanisms of drug-induced liver injury
Pathophysiologic mechanisms
• The pathophysiologic mechanisms of hepatotoxicity are still being explored and
include both hepatocellular and extracellular mechanisms. The following are some
of the mechanisms that have been described:
• Disruption of the hepatocyte: Covalent binding of the drug to intracellular proteins
can cause a decrease in ATP levels, leading to actin disruption. Disassembly of actin
fibrils at the surface of the hepatocyte causes blebs and rupture of the membrane.
• Disruption of the transport proteins: Drugs that affect transport proteins at the
canalicular membrane can interrupt bile flow. Loss of villous processes and
interruption of transport pumps such as multidrug resistance–associated protein 3
prevent the excretion of bilirubin, causing cholestasis.
• .

14. Cont..
• Cytolytic T-cell activation: Covalent binding of a drug to the P-450 enzyme acts as an immunogen,
activating T cells and cytokines and stimulating a multifaceted immune response.
• Apoptosis of hepatocytes: Activation of the apoptotic pathways by the tumor necrosis factor-
alpha receptor of Fas may trigger the cascade of intercellular caspases, which results in
programmed cell death.
• Mitochondrial disruption: Certain drugs inhibit mitochondrial function by a dual effect on both
beta-oxidation energy production by inhibiting the synthesis of nicotinamide adenine
dinucleotide and flavin adenine dinucleotide, resulting in decreased ATP production.
• Bile duct injury: Toxic metabolites excreted in bile may cause injury to the bile duct epithelium

15. Drug toxicity mechanisms
• The classic division of drug reactions is into at least two major groups, (1) drugs that directly affect the liver
and (2) drugs that mediate an immune response, as follows:
• Intrinsic or predictable drug reactions: Drugs that fall into this category cause reproducible injuries in animals,
and the injury is dose related. The injury can be due to the drug itself or to a metabolite. Acetaminophen is a
classic example of a known intrinsic or predictable hepatotoxin at supertherapeutic doses. Another classic
example is carbon tetrachloride.
• Idiosyncratic drug reactions: Idiosyncratic drug reactions can be subdivided into those that are classified as
hypersensitivity or immunoallergic and those that are metabolic-idiosyncratic. Regarding hypersensitivity
reactions, phenytoin is a classic, if not common, cause of hypersensitivity reactions. The response is
characterized by fever, rash, and eosinophilia and is an immune-related response with a typical short latency
period of 1-4 weeks. A metabolic-idiosyncratic reaction occurs through an indirect metabolite of the offending
drug. Unlike intrinsic hepatotoxins, the response rate is variable and can occur within a week or up to one year
later. It occurs in a minority of patients taking the drug, and no clinical manifestations of hypersensitivity are
noted. INH toxicity is considered to fall into this class. Not all drugs fall neatly into one of these categories, and
overlapping mechanisms may occur with some drugs (eg, halothane).

16. Last slide..