This document provides an overview of drug-induced liver disease (DILD). It defines DILD and discusses its epidemiology and risk factors. Two main mechanisms of hepatotoxicity are described - intrinsic and idiosyncratic. Various types of DILD are outlined including hepatocellular necrosis, steatosis, cholestasis, granulomatous hepatitis, and fibrosis/cirrhosis. Clinical manifestations, investigations, and treatment approaches are summarized. Assessment involves a patient history, liver enzyme levels, biopsy, and nutritional status evaluation. Treatment focuses on diagnosis, drug withdrawal, supportive care, and use of antidotes/corticosteroids if needed.

1. Dr Merlin M
Assistant Professor
DRUG INDUCED LIVER
DISORDER

2. PROTOCOL
 DEFINITION
 EPIDEMIOLOGY
 AETIOLOGY
 RISK FACTORS
 VARIOUS DRUG INDUCED LIVER DISORDERS
 PATHOPHYSIOLOGY
 CLINICAL MANIFESTATIONS
 INVESTIGATIONS
 TREATMENT
 REFERENCES

3. DEFINITION
 Drug induced liver diseases (DILD) is
defined as Injury to liver that is associated
with impaired liver function caused by
exposure to a drug or another
noninfectious agent.

5. EPIDEMIOLOGY
Over all incidence:2-5% jaundiced hospital
inpatients & 25% fulminant hepatic failure
cases.
15-40% acute liver failure cases-drugs
ADR in liver-increased in patients with pre
existing liver disease-cirrhosis
Middle aged and elderly more suffering than
young.

6. AETIOLOGY
 Drug induced liver diseases can be acute or chronic.
Hepatotoxicity
Cytotoxic Cholestatic
(Cellular destruction) (Impaired bile flow)
Necrotic Steatic
(Cell death) (Fatty degeneration)

7. MECHANISM: 2 types
Intrinsic hepatotoxicity
(Type A)
1. Predictable
2. Reproducible
3. Dose dependent
4. Occurs in everyone
5. Short incubation(hours to
week)
6. Eg : paracetamol,
salicylates , tetracycline,
methotrexate.
Idiosyncratic hepatotoxicity
(Type B)
1. Less predictable
2. Not reproducible
3. Dose independent
4. Rarely occurs
5. Variable incubation(weeks
to months)
6. Eg : isoniazid,
halothane, chlorpromazine.

8. RISK FACTORS
HOST FACTOR DRUG EXAMPLE
Pre-existing liver disease. Methotrexate, aspirin, sodium valproate.
Age - older.
- younger.
Halothane, isoniazid, chlorpromazine
Aspirin, sodium valproate.
Gender -female.
-male.
Halothane, isoniazid, nitrofurantoin.
Sodium valproate.
Genetics. phenobarbital,Halothane, chlorpromazine, isoniazid
Enzyme-induction. Paracetamol, halothane, isoniazid, sodium valproate.
Polypharmacy. NSAIDs +other hepatotoxic drugs.
Isoniazid+rifampicin or pyrazinamide.
Sodium valproate+phenytoin.
Paracetamol+zidovudine.
Concurrent diseases.
DM.
Renal failure.
Malnutrition.
Methotrexate.
Allopurinol, IV tetracycline.
Paracetamol.

9. Various drug induced liver disorders
 Hepatocellular necrosis.
 Steatosis(Fatty liver).
 Cholestasis.
 Cholestasis with hepatitis.
 Granulomatous hepatitis.
 Acute hepatitis.
 Chronic active hepatitis.
 Fibrosis and cirrhosis.
 Vascular disorders.
 Hepatic Tumours.
PATHOPHYSIOLOGY

10. HEPATOCELLULAR NECROSIS
CHANGES
Presents with jaundice.
Modestly increased alkaline
phosphatase.
Increased alanine amino transferase.
Prolonged prothrombin time.

11. HISTOLOGY:
Necrosis of the hepatocytes
HISTOLOGY

12. :DRUGS
Paracetamol.
Propylthiouracil.
Salicylates.
Iron salts.
Allopurinol.
Dantrolene.
Halothane.
Ketoconazole.
Isoniazid.
Mithramycin.
Cocaine.

13. STEATOSIS(FATTY LIVER)

14. CHANGES
Abnormal LFTs.
Increased blood levels of ALT & AST
Hyperammonia
Hypoglycemia
Acidosis
Clotting factor deficiency
Tetracyclines +synthesis of
lipoproteins ------ STEATOSIS

15. HISTOLOGY
Small fat droplets in liver cells.

16. DRUGS
Tetracycline
Sodium valproate
Methotrexate.
Steroids.
 Alcohol
Amiodarone
Macrovesicular
Microvesicular

17. CHOLESTASIS

18. Increased bilirubin
Normal or minimally raised alanine amino
transferase
No inflammation or hapatocellular necrosis
CHANGES

19. HISTOLOGY
Bile plugs are present in canaliculi.

20. Oral contraceptives.
Carbimazole.
Anabolic steroids.
Cyclosporin.
DRUGS

21. CHOLESTASIS WITH HEPATITIS
Increased bilirubin.
Increased alanine amino transferase.
Increased alkaline phosphatase.
Certain liver damage.
CHANGES

22. DRUGS
• Chlorpromazine.
• Tricyclics.
• Erythromycin.
• ACE inhibitors.
• Ranitidine.
•Sulphonamides.
•Sulphonylureas.
•Phenytoin.
•NSAIDS.
•Cimetidine.

23. GRANULOMATOUS HEPATITIS

24. CHANGES
Modestly elevated LFTs.
Phenytoin.
Allopurinol.
Carbamazepine.
Clofibrate.
Hydralazine.
Sulphonamides.
Sulphonylureas.
HISTOLOGY
Granulomas and tissue eosinophilia.
DRUGS

25. ACUTE HEPATITIS
CHANGES:
• Elevation of LFTs.
• Increased prothrombin time.
HISTOLOGY
o Necrosis.
o Cellular degeneration.
o Inflammatory infiltrate
DRUGS
Dantrolene.
Isoniazid.
Phenytoin.

26. CHRONIC ACTIVE HEPATITIS
CHANGES
Increased serum transaminase.
Decreased albumin.
Circulating auto antibodies.
DRUGS
Methyldopa.
Nitrofurantoin.
Isoniazid.

27. FIBROSIS AND CIRRHOSIS

28. CHANGES
Slightly raised serum transaminase.
Fibrosis may proceed to cirrhosis.
Deposition of fibrous tissue.
Methotrexate (chronic use).
Vitamin A (dose dependent).
Methyldopa.
HISTOLOGY
DRUGS

29. VASCULAR DISORDERS

30. Non thrombotic narrowing of small centri -
lobular veins
Budd-chiari syndrome (obstruction of large
veins)
CHANGES

31. DRUGS
Azathioprine.
Dactinomycin.
Dacarbazine.
Oral contraceptives.
HISTOLOGY

32. TUMOURS
Oral contraceptives.
Danazol
Steroids
DRUGS

33. Examples of dose related drug induced
hepatotoxicity
DRUG TOXIC DOSE
Paracetamol. Single dose >10g.
Tetracycline. >2g daily(oral).
Methotrexate. Weekly dose >15mg.
6-Mercaptopurine. >2.5mg/kg.
Vitamin A. Chronic use 40,000 units daily.
Cyclophosphamide. Daily dose >400mg/sq.m.
Salicylates. Chronic use >2g daily.
Anabolic steroids. High dose >1 month.
Oral contraceptives. High dose , chronic use.
Iron. Single dose >1g.

34. CLINICAL MANIFESTATIONS
Anorexia , nausea , vomiting , malaise , lethargy ,
abdominal pain(1st indication of liver failure).
Oliguria and anuria-acute tubular necrosis.
Renal failure , myocardial injury , pancreatitis.
Fatigue , nausea & vomiting, hypoglycemia and confusion.
Jaundice in severe cases.
ACUTE HEPATOCELLULAR NECROSIS
STEATOSIS

35. :
Tiredness, lethargy, malaise.
GI-symptoms: ascites, bleeding oesophageal varices,
hepatic encephalopathy.
skin rash.
Extra hepatic features: lymphadenopathy, bone marrow
suppression.
ACUTE HEPATATIS
Drug allergy followed by anorexia, nausea & vomiting, dark
urine, pale stools and jaundice.
Weight loss.
CHRONIC ACTIVE HEPATITIS

36. Severe Pruritus with or without dark urine,pale stools and jaundice.
Abdominal pain , influenza- like illness.
Painful hepatomegaly, ascites and jaundice.
Abdominal pain, feeling of fullness after eating , weight loss,
fatigue, anorexia, nausea and vomiting.
CHOLESTASIS
CHOLESTATIC HEPATITIS:
VENO-OCCLUSIVE DISEASE
HEPATIC TUMOURS

37. INVESTIGATIONS
Liver function tests (LFTs).
Radiological investigations.
Liver biopsy and histological evaluation.
Serological markers for Hepatitis A , B & C.

38. Include serum bilirubin, AST ,ALT, alkaline
phosphatase,gamma glutamyl transferase , albumin.
AST & ALT- high levels in acute liver failure.
Highest serum levels of alkaline phosphatase seen in
cholestasis.
Total protein ,albumin, prothrombin time- normal
function of liver.
Alpha Feto protein- to exclude malignancy.
Conjugate bilirubin- biliary obstruction.
LIVER FUNCTION TEST

39. Ultra sound, computed tomography,
percutaneous cholangiograms, endoscopic
retrograde cholangiopancreatography- physical
obstruction of bile duct by gallstones, masses
or strictures.
RADIOLOGICAL INVESTIGATIONS

41.  They are useful in the diagnosis of acute
hepatocellular dysfunction.
 Serological tests for hepatitis A, B and C should be
determined in patients with symptoms of hepatitis
to exclude an infective cause.
LIVER BIOPSY AND HISTOLOGICAL EVALUATION
SEROLOGICAL INVESTIGATIONS

42. ASSESSMENT
Assessment and monitoring of DILD is important.
DILD may cause death if they are not treated.
Assessment done based on various factors like:
1. Patients History
• Social habits – alcohol.
• Previous medications/ previous reactions.
• Occupation/Environmental factors.
• Arsenic, CCl4 – lab, agriculture, construction.
• Vinylchlorides – plastic workers.
• Alternative/ Non-drug therapy.
• Clove oil, maragosa oil, pennyroyal oil etc..

43. 2.Liver enzyme levels

44. 3.Liver Biopsy
4.Nutritional status
o Low serum levels of vitamins E and C are
associated with asymptomatic elevations in
transaminases.
o High serum iron, transferrin, and selenium
levels are also associated with asymptomatic
elevations of transaminases.

45. TREATMENT
I. Diagnosis.
II. Withdrawal of the causative drug.
III.Supportive therapy.
DIAGNOSIS
 Detailed drug history including the use of oral
contraceptives,OTC medicines, vitamins, herbs and illicit
drugs should be obtained.
 Predisposing factors should be noted.
WITHDRAWL
 Once drug induced hepatotoxicity has been recognized,
therapy should be stopped.

46. 1. ANTIDOTES
 N-acetyl cysteine & methionine for paracetamol
over dose.
 Desferrioxamine (5 to 10g in 100 ml water orally)
for iron overdose.
2.CORTICOSTEROIDS
 For immuno suppression.
MANAGEMENT

47. 3.SUPPORTIVE TREATMENT
 Fluid & electrolyte balance.
 Nutritional support-high carbohydrate , low fat diet-
relief from anorexia, nausea and diarrhoea.
4. PRURITIS
Light clothing (avoid wool).
Cooling the skin with tepid bath or calamine
lotion

48. 5. COAGULATION DISORDERS
Can be treated by correcting vitamin K deficiency
with iv phytomenadione injection.
Infusion of fresh frozen plasma or clotting factor
concentrates are indicated if profused bleeding occurs.
6.LIVER PROTECTIVES
LIV52.
Livna.
Liv Atharva liq.

49.  Clinical Pharmacy and Therapeutics- Fourth Edition-
Roger Walker, Page NO: 199-214.
 Pharmacotherapy. A Pathophysiologic Approach-
Joseph. T. Dipiro 6th Edition, Page NO:713-720.
REFERENCES