DRUG INDUCED
LIVER DISEASES
Introduction
Drug induced liver diseases (DILD) are the diseases which are caused by taking drug or any
medication. Drugs can induce almost all forms of acute or chronic liver disease, with some
drugs producing more than one type of hepatic reaction such as
• Hepatocellular necrosis
• Fatty liver
• Cholestasis
• Acute hepatitis
• Chronic active hepatitis
• Fibrosis and cirrhosis
Pathophysiology
Hepatocellular necrosis
In severe cases, acute hepatocellular necrosis presents with jaundice and LFT abnormalities,
including a modestly raised alkaline phosphatase and a markedly elevated alanine
aminotransferase level of up to 200 times the upper limit of the reference range.
Drugs involved
Paracetamol
Propylthiouracil
Allopurinol
Dantrolene
Steatosis
Steatosis (fatty liver) is the accumulation of fat droplets within liver cells and is associated with
abnormal LFTs, although the elevation of alanine aminotransferase is not as high as that seen in
acute hepatocellular necrosis.
Drugs involved
Tetracyclines
Steroids
Fibrosis
In patients with fibrosis, the serum transaminase levels may be only slightly raised, and are not
good predictors of hepatic damage. Fibrosis may proceed to cirrhosis.
Drugs involved
Methyldopa
Vitamin A (dose-related)
Cholestasis
• Cholestasis without hepatitis is associated with a raised bilirubin and a normal or
minimally raised alanine aminotransferase level.
• Cholestasis associated with hepatitis presents with raised bilirubin, alanine
aminotransferase and alkaline phosphatase levels and a certain amount of liver damage.
Drugs involved
Oral contraceptives
Carbimazole
Anabolic steroids
Ciclosporin
Granulomatous hepatitis
Granulomatous hepatitis occurs with modestly elevated LFTs and, usually, normal synthetic
liver function. Histology reveals granulomas and tissue eosinophilia.
Drugs involved
Phenytoin
Allopurinol
Carbamazepine
Acute hepatitis
Acute hepatitis resembles viral hepatitis with LFTs raised in proportion to the severity of the
hepatocellular damage.
Drugs involved
Dantrolene
Isoniazid
Paracetamol-induced hepatotoxicity
Severe hepatotoxicity is traditionally defined as alanine aminotransferase (ALT) elevation >
1000 IU/L.
Paracetamol causes a dose-related toxicity resulting in centrilobular necrosis.
In overdose, paracetamol causes dose-dependent hepatotoxicity through the formation of a
toxic metabolite called NAPQI (N-acetyl-p-benzoquinone imine).
The threshold dose to cause hepatotoxicity is 10-15 g for adults and 150 mg/kg for children.
Factors that increase risk include chronic alcohol use, malnutrition, advanced age, chronic
pulmonary disease, cardiac dysfunction, chronic liver disease, and drug interactions.
Effective antidote is Acetylcysteine
Risk factors
Host factors that predispose to drug hepatotoxicity
1)Pre existing liver disease: Methotrexate, aspirin, sodium valproate
2)Age:Older: Halothane, isoniazid, chlorpromazine. Younger: Aspirin, sodium valproate
3)Gender:Female: Halothane, isoniazid, nitrofurantoin. Male: Sodium valproate, co-amoxiclav
4)Genetics: Halothane, chlorpromazine, phenytoin, carbamazepine, phenobarbital.
5)Enzyme induction: Paracetamol, halothane, isoniazid, sodium valproate
6)HIV positive with hepatitis C or B co-infection: Antiretroviral agents
7)Concurrent diseases:
Diabetes mellitus: Methotrexate
Renal failure: Allopurinol, i.v. tetracycline
Malnutrition: Paracetamol
Investigations
Various types of investigation are used in the diagnosis of drug-induced hepatotoxicity:
Biochemical tests
LFTs are measured, which generally include :
total bilirubin, alanine transaminase and alkaline phosphatase, γ-glutamyl transpeptidase.
α-Fetoprotein may be measured to exclude malignancy.
Serological markers
Serological markers for hepatitis A, B and C and other viruses such as the Epstein–Barr virus should
be determined
Radiological investigations
Following techniques are used to look for physical obstruction of bile ducts by gallstones
• Ultrasound
• Computed tomography
• Percutaneous cholangiograms
• endoscopic retrograde cholangiopancreatography (ERCP)
Liver biopsy
Specific diagnostic tests for drug-induced disease exist for few drugs, with halothane being a
notable exception.
Management
Antidotes
• acetyl cysteine and methionine for Paracetamol
• desferrioxamine for iron overdose.(5-10g orally or IV)
Corticosteroids
Immunosuppressants with corticosteroids has been used in the management of drug-induced
hepatotoxicity.
Supportive treatment
A low-fat, high-carbohydrate diet provides relief from the anorexia, nausea and diarrhea that
may accompany cholestasis.
Pruritis
Measures for pruritis management include:
• light clothing (avoid wool)
• cooling skin with tepid baths or calamine lotion
• moisturising agent such as aqueous cream
Coagulation disorders
These are treated by :
• correcting vitamin K deficiency with intravenous phytomenadione injection
• by giving Menadiol sodium phosphate, the water-soluble vitamin K analogue
Liver transplantation can also be considered for acute hepatic failure patients.
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