Hepatotoxicity

Question 1

Alcoholic Liver Disease (ALD)

Answer 1

affects a lot of people yo

Question 2

How is alcohol metabolised

Answer 2

Primarily in the liver at a fixed metabolic rate irrespective of blood conc

Question 3

How is the liver organised?

Answer 3

In lobules, hepatocytes and portal triad.

Blood flows along the portal/sinusoidal tracts into a central venule

Question 4

Give the spectrum of liver damage

Answer 4

Fatty liver - fat accumulates
non-alcoholic liver disease (NASH) - fat plus inflammation and scarring
cirrhosis - scar tissue replaces cells

Question 5

What are NSAIDs?

e.g. aspirin, acetaminophen and ibuprofen

Answer 5

Analgesic, anti-pyretic and anti-inflammatory
COX-inhibitors, inhibit PG production
Cause GI problems & damage via PG inhibition and mucosal damage - can cause ulceration

Question 6

How does aspirin work?

Answer 6

Hydrolysed by esterases in blood and tissues to salicylate and acetic acid
Converted in liver to water-soluble conjugates, excreted by kidney
High dose for anti-inflammatory action may not be tolerated

Question 7

Ibuprofen

Answer 7

Propionic derivative - more often for anti-inflammatory as well as analgesic

Question 8

Paracetamol - acetaminophen

Answer 8

no sig anti-inflammatory action, mild analgesic
associated w intentional or accidental poisoning
–> overdose causes hepatotoxicity

Question 9

Metabolism of acetaminophen

Answer 9

Rapidly absorbed
Metabolised to non-toxic agents, eliminated in urine
Metabolised by P450 enzymes to become N-acetyl-p-benzoquinone-imine (NAPQI/NABQI) - toxic, rapidly conjugated with GSH

Question 10

What conditions might promote hepatotoxicity

Answer 10

.NAPQI can bind proteins and lipids in hepatocytes, trigger hepatocyte death and centrilobular liver necrosis

Question 11

Four phases of clinical presentation

Answer 11

Day 1 - asymptomatic or may have nausea /vomiting
Days 2-3 - pain may resolve, increase in LFT enzymes
Days 3-4, abdominal pain, hepatic necrosis, jaundice, renal failure
Days 4-21, resolution of symptoms or organ failure

Question 12

Assessment of treatment

Answer 12

Obtain plasma acetaminophen level as a marker of damage
Consider history of ingestion, quantity and formulation
Any co-ingested agents?
LFTs - bilirubin, electrolytes MONITOR PT TIME!

Question 13

What is antidotal therapy?

Answer 13

Most effective within 8hr post-ingestion
activated charcoal if acute
N-acetylcysteine (NAC) drug of choice for prevention and treatment

Question 14

HOW DOES NAC PROVIDE A TREATMENT?

Answer 14

*

Question 15

Tests to assess liver damage/function

Answer 15

No single test displays absolute specificity
TRANSAMINASES - tells cell injury
ALT (alanine aminotransferase)
AST (aspartate transaminase)
(with) lactate dehydrogenase (LDH) measures hepatocyte integrity
ALKALINE PHOSPHATASE (AP)
- removed via liver so increased in disorders affecting bile duct/ liver
GAMMA GLUTAMYL TRANSPEPTIDASE
- to transport aa and peptides to liver - increases w alcohol
Synthetic function - albumin, clotting screen
Excretory function - plasma bilirubin, urine bilirubin and urine urobilinogen