DRUG INDUCED LIVER DISORDERS

Drug induced liver disease is a rare but potentially fatal, often debilitating and largely
unpredictable outcome of drug treatment.
Drugs can cause liver disease in several ways, some drugs are directly injurious to the liver, and
others are transformed by the liver into chemicals that can cause injury to liver directly or
indirectly.
Drug-induced liver disease can have many different clinical presentations: idiosyncratic
reactions, allergic hepatitis, toxic hepatitis, chronic active toxic hepatitis, toxic cirrhosis, and
liver vascular disorders.
The liver function affects almost every other organ system in the body, but there are no specific
diagnostic tests for drug induced liver disease.
PATTERNS OF DRUG INDUCED LIVER DISEASE
A. Hepatocellular injury
● Centrolobular necrosis
● Steatohepatitis
● Phospholipidosis
● Generalized hepatocellular necrosis
B. Toxic cirrhosis
C. Cholestatic injury
D. Liver vascular disorders
E. Mixed hepatocellular and cholestatic injury
Hepatocellular injury
Hepatocellular injury is characterized by significant elevations in the serum aminotransferases,
which usually precede elevations in total bilirubin levels and alkaline phosphatase levels.
Hepatocellular injury can lead to fulminant hepatitis.
Centrolobular Necrosis
Centrolobular necrosis is often a dose-related, predictable reaction.
It also can be associated with idiosyncratic reactions.
Also called direct or metabolite-related hepatotoxicity, centrolobular necrosis is usually the result
of the production of a toxic metabolite
Steatohepatitis
Also known as steatonecrosis. It results from the accumulation of fatty acids in the hepatocyte.
Drugs or their metabolites that cause steatonecrosis by affecting fatty-acid esterification and
oxidation rates within the mitochondria of the hepatocyte. This eventually disrupts the
homeostasis of the hepatocyte.
The liver biopsy is marked by a massive infiltration by polymorphonuclear leukocytes,
degeneration of the hepatocytes, and the presence of Mallory bodies.
Phospholipidosis
Phospholipidosis is the accumulation of phospholipids instead of fatty acids. The phospholipids
usually engorge the lysosomal bodies of the hepatocyte.
Generalized Hepatocellular Necrosis
It mimics the changes associated with the more common viral hepatitis. Many drugs that are
associated with toxic hepatitis produce metabolites that are not inherently toxic to the liver.
Instead, they act as haptens, binding to specific cell proteins and inducing an autoimmune
reaction.
Toxic Cirrhosis
The scarring effect of hepatitis in the liver leads to the development of cirrhosis. Methotrexate
causes periportal fibrosis in most patients who experience hepatotoxicity. The lesion results from
the action of a bioactivated metabolite produced by CYP450.
Cholestatic Injury
It primarily involves the bile canalicular system
The inability of the liver to remove bile causes intrahepatic accumulation of toxic bile acids and
excretion products, this leads to cholestatic injury.
In some cases, progressive destruction of the cholangiocytes leads to the vanishing bile duct
syndrome.
Drug induced cholestasis can occur as an acute disorder or as a chronic disorder.
Liver Vascular Disorders
Focal lesions in hepatic venules, sinusoids, and portal veins occur with various drugs.
Peliosis hepatitis is a rare type of hepatic vascular lesion that can be seen as both an acute and a
chronic disease.

Liver disorders Drugs inducing liver disorders

Hepatocellular injury Acarbose ,allopurinol, losartan
Centrolobular necrosis Acetaminophen
Steatohepatitis Alcohol , sodium valproate
Phospholipidosis Amiodarone
Generalized hepatocellular necrosis Isoniazid,ketoconazole
Toxic cirrhosis Methotrexate
Cholestatic injury Erythromycin , tetracycline,
Liver vascular disorders Androgens ,estrogens ,tamoxifen

MECHANISMS OF DRUG INDUCED LIVER DISEASE

1. Acetaminophen
Over dose of acetaminophen leads to liver injury by the formation of toxic metabolites
Acetaminophen
Bioactivated

N –acetyl P-benzoquinone imine(NAPQI)

(Toxic metabolite)

Production of high energy metabolites by the CYP450

These form covalent bonds with cellular proteins &nucleic acids

Adduct formation
 Cellular damage or injury

Centrolobular necrosis

2. ALCOHOL
​Alcohol
Converts to
Acetaldehyde

Increased fatty acid synthesis

Accumulation of fatty acids in the hepatocyte

Hepatocytes becomes necrotic

Steatohepatitis
3. ISONIAZID
Isoniazid stimulates autoimmunity
It involves antibody mediated cytotoxicity or direct cellular toxicity
Toxic metabolites of isoniazid are directly toxic to the cellular proteins in the hepatocyte.
Isoniazid induces generalized hepatocellular necrosis.
ISONIAZID
N acetyl transferase
Acetylisoniazid
Hydrolysis
Acetyl hydrazine
Oxidation Acetylation
Hepatotoxic metabolite Diacetyl hydrazine
(Non toxic)

Generalized hepatocellular necrosis

4​.​ SODIUM VALPROATE
Parent drug or its metabolites can trigger outer mitochondrial rupture
These drugs disrupt beta oxidation of lipids and oxidative energy production within the
hepatocyte.
In acute cases, interruption of beta oxidation leads to micro vesicular steatosis
In chronic disease, micro vascular disease is present
Interruption of beta oxidation leads to depletion of ATP which can cause liver cell necrosis &
further leads to hepatic failure and death.
MECHMECHANOF DUG-INDUCED
LIVER DISEASE​MECHANISMS OF DRUG INDUCED LIVER DISEASE
STIMULATION OF AUTOIMMUNITY
Autoimmune injuries involve antibody mediated cytotoxicity or direct cellular toxicity. This type
of injury occurs when enzymedrug adducts migrate to the cell surface and form neoantigens. The
neoantigens serve as targets for cytolytic attack by T cells. The injury may be exacerbated by the
recruitment of inflammatory cells. Halothane, sulfamethoxazole, carbamazepine, and nevirapine
are associated with autoimmune injuries.
DISRUPTION OF CALCIUM HOMEOSTASIS AND CELL MEMBRANE INJURY
Drug-induced damage to the cellular proteins that are involved with calcium homeostasis can
lead to an influx of intracellular calcium that causes a decline in adenosine triphosphate levels
and disruption of the actin fibril assembly. The resulting impact on the cell is blebbing of the cell
membrane, rupture, and cell lysis. Lovastatin, venlafaxine, and phalloidin, which is the active
component of mushrooms, impair calcium homeostasis.
METABOLIC ACTIVATION OF THE CYTOCHROME P450 ENZYMES
Most hepatocellular injuries involve the production of high-energy reactive metabolites by the
CYP450 system. ​_ ​These reactive metabolites are capable of forming covalent bonds with
cellular proteins (enzymes) and nucleic acids that lead to adduct formation. In the case of acute
toxicity, the enzyme-drug adduct can cause cell injury or cell lysis. Adducts that form with DNA
can cause long term consequences such as neoplasia. Acetaminophen, furosemide, and
diclofenac are examples of this mechanism of liver injury.
MITOCHONDRIAL INJURY
Drugs that impair mitochondrial structure, function, or DNA synthesis can disrupt β-oxidation of
lipids and oxidative energy production within the hepatocyte. In acute disease, prolonged
interruption of β-oxidation leads to microvesicular steatosis, whereas, in chronic disease,
macrovesicular disease is present. Severe damage to the mitochondria eventually leads to hepatic
failure and death. Aspirin, valproic acid.