DILI

Question 1

What is the annual incidence of DILI?

Answer 1

1-10 per 100,000 people exposed
accounts for up to 10% of adverse drug reactions
most common cause of acute liver failure in the US

Question 2

What are the patterns of acute liver injury caused by DILI?

Answer 2

cholestasis
hepatocellular
- confluent necrosis
mixed
steatosis (less common)

Question 3

What are the common causes of cholestatic DILI?

Answer 3

Augmentin
Carbamazepine
Erythromycin
Ketoconazole
Rifampicin
Flucloxacillin

Question 4

What are the features of a cholestatic DILI?

Answer 4

Predominantly elevated ALP, GGT and bilirubin
Aminotransferases are only mildly elevated (less than 8-fold)
overall good prognosis

Question 5

What are the features of hepatocellular DILI?

Answer 5

Predominantly riased aminotransferases - similar to acute viral hepatitis
Histology: acute hepatocellular necrosis, apoptosis
can affect single hepatosyts or groups
confluent necrosis can result in acute liver failure

zonal necrosis: characteristic of compunds with predictable, dose-dependent toxicity e.g. Paracetamol
Non-zonal necrosis: viral hepatitis like pattern. More common with compounds that cause non-dose related injury e.g. Phenytoin, Diclofenac

Question 6

Which drugs cause a hepatocellular type of DILI?

Answer 6

Paracetamol
Phenytoin
Diclofenac

Question 7

What drugs cause a mixed pattern of DILI?

Answer 7

Phenyotin

Fluoroquinolones

Question 8

Which drugs cause steatosis?

Answer 8

Drugs that disrupt beta-oxidation of lipids and oxidative energy production e.g. Amiodarone

Question 9

What features suggest DILI?

Answer 9

exposure to drug prior to liver injury
exclusion of underlying liver disease
improvement after cessation of the drug

there are no specific markers and histological can resemble autoimmune hepatitis

Question 10

What are the features of chronic DILI?

Answer 10

Abnormal LFTs > 3-6 months
Chronic hepatocellular damage tends to occurs in chronic drug use and resolves once drug is stopped
May progress to cirrhosis or liver failure

chronic DILI is serologically and morphologically indistinguishable from type1 autoimmune hepatitis
- more common in females, raised auto-immune markers (ANA, anti-SM Abs)

Question 11

What are the features of Flucloxacillin induced DILI?

Answer 11

cholestatic pattern
idiosyncratic reaction - mechanism poorly understoof
HLA B5701 association
most recover within several months after stopping the drug
can develop into chronic liver disease
vanishing bile duct syndrome can occue - prolonged damage leads to loss of bile ducts and over ductopaenia -> liver failure

Question 12

What types of drug reactions can cause DILI?

Answer 12

Predictable
- reaction occurs in any individual at a sufficient dose, e.g. Paracetamol

Idiosyncratic

• no dose-response relationship
• the adverse reaction cannot be predicted from a drug’s pharmacological profile or from pre-clinical toxicology tests
  e. g. Flucloxacillin

Question 13

What is the typical pattern of LFTs in alcoholic liver disease?

Answer 13

AST > ALT, ratio 2-3

Question 14

What are the histological changes possible with alcoholic liver disease?

Answer 14

steatosis -> cirrhosis

Question 15

How long will it take alcoholic fatty liver disease to normalise upon cessation of alcohol?

Answer 15

4-6 weeks

Question 16

How much does ongoing alcohol comsumption increase the risk of developing cirrhosis?

Answer 16

40g/day increases the risk of progression to cirrhosis by 30%

Question 17

How should alcoholic liver disease be treated?

Answer 17

Cessation support
Severe alcoholic liver disease may benefit from treatment with short-term prednisolone or pentoxifylline (if corticosteroid therapy is contraindicated by infection or kidney failure)

Question 18

How is alcoholic liver disease severity quantified?

Answer 18

Maddrey discriminant function (MDF)
MDF = 4.6 (prothrombin time [s] – control prothrombin time [s]) + total bilirubin (mg/dL)

Patients with MDF scores of 32 or greater (indicating severe alcoholic hepatitis) have short-term mortality risks as high as 50%

MELD score of 18+ has similar prognostic implications