Drug Induced Liver Disease

Question 1

Question 2

What is an intrinsic hepatotoxin?

Answer 2

A toxin marked by predictable injury in a dose-dependent manner every time it is given (e.g. carbon tetrachloride)

Question 3

What is an Idiosyncratic Hepatotoxin?

Answer 3

A toxin marked by unpredictable response in humans (most meds fall under this category)

Question 4

Question 5

How do oral contraceptives cause liver injury?

Answer 5

They do so in an idiosyncratic manner mainly marked by bland cholestasis (below) by

1) decreased membrane fluidity
2) Decreasing NaKATPase activity and bile salt transport

Question 6

What other liver problems have been linked to OC use?

Answer 6

• Vascular complications
• Hepatic vein thrombosis (Budd-Chiari)
• Peliosis hepatis
• Focal nodular hyperplasia
• Hepatic adenomas
• Hepatocellular carcinoma – rare with current doses

Question 7

What is this?

Answer 7

Peritoneal hemorrhage due to Adenomas- sometimes women on OC can come in hypotensive from a ruptured adenoma

Question 8

Ruptured adenoma

Answer 8

Ruptured adenoma

Question 9

What is this?

Answer 9

Angiosarcoma, linked to polyvinyl chloride exposure

•Survival: 12 months

Question 10

What is this?

Answer 10

Acetaminophen overdose

Question 11

How is Tylenol metabolized?

Answer 11

The liver is the primary site in the body where acetaminophen is metabolized. In the liver, acetaminophen first undergoes sulphation (binding to a sulphate molecule) and glucuronidation (binding to a glucuronide molecule) before being eliminated from the body by the liver. The parent compound, acetaminophen, and its sulphate and glucuronide compounds (metabolites) are themselves actually not harmful.

Question 12

What happens during Tylenol OD?

Answer 12

An excessive amount of acetaminophen in the liver, however, can overwhelm (saturate) the sulphation and glucuronidation pathways. When this happens, the acetaminophen is processed through another pathway, the cytochrome P-450 system. From acetaminophen, the P-450 system forms an intermediate metabolite referred to as NAPQI, which turns out to be a toxic compound.

Ordinarily, however, this toxic metabolite is rendered harmless (detoxified) by another pathway, the glutathione system.

Question 13

How does alcohol affect the metabolism of Tylenol?

Answer 13

It reduces levels of GSH leading to increased P450 induction forming NAPQI

•As little as 2.5 – 4 gm may be hepatotoxic in Alcoholics

Question 14

Acetaminophen is unsafe at low doses in alcoholics but typically well tolerated in patients with non-alcoholic liver disease. What about in cirrhotic pts from other causes than EtOH?

Answer 14

•Patients with cirrhosis from other causes often have decreased P450 activity and normal glutathione level (safe!)

Question 15

What is the tx for suspected Tylenol OD?

Answer 15

•N-Acetylcysteine given 140 mg/kg then 70 mg/kg q 4 hours x 17 doses

Question 16

T or F. Tx for suspected Tylenol OD with N-Acetylcysteine can be effective even after several hrs

Answer 16

T.

• Do not rely on acetaminophen levels to decide on giving N-Acetylcysteine
• If you are not sure, give N-Acetylcysteine
• Dosing within 10-36 hours lowers mortality from 58% to 37%.
• Helpful in acute liver failure from non-acetaminophen etiologies

Question 17

How does N-acetylcysteine work?

Answer 17

In the treatment of acetaminophen overdose, acetylcysteine acts to maintain or replenish depleted glutathione reserves in the liver and enhance non-toxic metabolism of acetaminophen. These actions serve to protect liver cells from NAPQI toxicity.

It is most effective in preventing or lessening hepatic injury when administered within 8–10 hours after overdose.

Question 18

Answer 18

Question 19

Nutmeg liver

Answer 19

Question 20

Question 21

Answer 21

Question 22

Amiodarone can cause steatohepatitis, Mallory-Denk bodies or granulomas, but its most distinctive hepatotoxicity is ________

Answer 22

phospho-lipidosis.

Question 23

How does amiodarone cause phospho-lipidosis?

Answer 23

It binds to membrane phospholipids and messes up their recycling in lysosomes.

Question 24

What does this show?

Answer 24

Electron microscopy can reveal “myelin figures’ of lysosomes stuffed with phospholipid (arrows) and altered mitochondria with reduced cristae (Mi)

This form of toxicity is due to the amphiphilic nature of Amiodarone