Drug-Induced Liver Injury

Introduction

Allopathic medicines are an important part of our lives. They help treat and prevent innumerable diseases. Medicines have been used in treating diseases for a very long time. Studies on these medicines are a fairly new component of the use of drugs. As new research and studies are done, we have come in contact with the new pathologies/ damages that might get introduced in the body with the usage of drugs. Therefore, we can say that there are many drug induced injuries in the body that are seen in people who have consumed the drug. In this blog, we shall read about the common drugs that cause liver injuries. 

Approach to Drug-Induced Liver Injury(DILI)

• Whenever there is a history of drug usage or any kind of drug abuse, we can see the main clinical presentation of liver damage, which is jaundice.
• Classification depending on R-value

R value =ALT (pt)/ Upper limit of normal of ALT of labALP (pt)/ Upper limit of normal of ALP of lab

• Cholestatic type of liver damage 
  • R-value low (<2)
  • ALP is more than Liver enzymes
• Hepatocellular type of liver damage 
  • R-value high (>5)
  • Liver enzymes are more than ALP
• Mixed type of liver damage 
  • R-value is 2-5

Drugs causing different types of DILI

• Important drugs causing Hepatocellular Drug induced liver injury is caused by the following drugs:
  • Paracetamol
  • Isoniazid
  • Macrolides
  • Minocycline
  • Nitrofurantoin
  • Inhaled anesthetics
  • Phenytoin
  • Carbamazepine
  • Valproate
  • Sulfonamides
  • Amiodarone
  • Allopurinol
  • NSAIDs
  • Fluoroquinolones
• Mixed type of drug induced liver injury is caused by:
  • Azathioprine
  • Flavocoxib
  • Sulfasalazine
  • Phenytoin
  • Carbamazepine
  • Allopurinol
  • Amiodarone
  • Fluoroquinolones
• Important drugs causing cholestatic type of drug induced liver injury(DILI) are as follows:
  • Amoxicillin/clavulanate
  • Trimethoprim / Sulfamethoxazole
  • Anabolic/androgen-containing steroids
  • Chlorpromazine
  • Azathioprine
  • Phenytoin
  • Fluoroquinolones
  • Carbamazepine
  • Amiodarone
  • Sulfasalazine

Also Read: Cancers of Biliary Tract

Hepatotoxicity due to anti-tuberculosis treatment (ATT)

• Many patients have certain side effects directly on the liver as these medicines get absorbed by the action of liver enzymes. ATT causes a transitional elevation in ALT levels, so there is no need to stop the drugs always.
• The proper way to define hepatoxicity is 

Elevation in AST or ALT >3x Upper limit of normal with symptoms of liver dysfunction

(or)

Elevation in AST or ALT >5x Upper limit of normal without symptoms of liver dysfunction

• isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) and ATT induced Hepatotoxicity effects
  • Most toxic
    • Isoniazid (INH) > Pyrazinamide
    • R-value more than 5
  • Most safest
    • Ethambutol (not hepatotoxic)
  • Very less toxic
    • Rifampicin can cause isolated hyperbilirubinemia (jaundice is seen, but no significant elevation in ALT or AST)
    • However, medication is to be stopped, as hepatotoxicity may increase with subsequent intake of the drug.

Why Isoniazid (INH) is Toxic?

• 20% of INH treated pts will develop a mild transient elevation in liver enzymes and are asymptomatic 
• Improves on further continuation of INH
• No need to stop INH or reduce the dose
• But follow-up is to be done. If it falls under the criteria of 3x with symptoms or 5x without symptoms, then INH is to be withdrawn.
• The following image explains the Isoniazid (INH) metabolism.

• Usually this should form Diacethylhydrazine at the non-toxic end.
• Less amounts of NAT2 lead to hepatotoxicity due to INH. but this NAT2 activity varies from person to person
• Slow acetylators are at higher risk of hepatotoxicity due to INH.

Pyrazinamide Toxicity

• Hepatocellular pattern (R >5)

• The mechanism of action of pyrazinamide is that is converts Pyrazinoic acid to 5 OH pyrazinoic acid (xanthine oxidase enzyme)
• Allopurinol is contraindicated with Pyrazinamide, as it increases liver toxicity. If Allopurinol is given,
  • It inhibits the xanthine oxidase enzyme
  • Inhibits conversion
  • This leads to increased pyrazinoic acid (toxic)
  • Thus leading to hepatocellular injury

Frequently Asked Questions in drug induced liver Injury

Q. Administration of which of the following drugs, along with pyrazinamide, increases the risk of hepatotoxicity?

Answer- Allopurinol 

Q. What is the antidote for PCM poisoning?

Answer- Acetylcysteine is the antidote for paracetamol toxicity

Also Read: Achalasia Cardia- Clinical Features, Diagnosis And Treatment

Hope you found this blog helpful for your NEET SS Gastroenterology and Hepatobiliary preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.