1. LIVER DAMAGE The majority of cases of liver damage are due to:
1. Infections: Hepatitis A, B, C. EBV, etc.
2. Structural disease of the liver:
Infiltration
Metastases

2. Most common causes of Liver Damage (Cont.)
3. Interference with function:
Biliary drainage
Blood supply - arterial
Hepatic venous drainage
Relatively few (<10%) are due to toxic injury
50% in subjects over >50 years =
Alcohol, drugs, chemicals, nutritional toxins

3. Assessing liver function
Most routine tests reflect liver damage
The tests of function are those which reflect synthetic capacity – eg albumin and prothrombin time
LFTs may be grossly deranged when function is normal and may be normal when function is grossly deranged

4. Drug Induced Liver Damage
1. Role of the liver in biotransformation
2. Metabolites themselves may be toxic
3. Role of mixed function oxidase (cytochrome(s) P450-dependent)
4. Depletion of conjugating substances

5. Categorisation of drugs
Predictable (intrinsic hepatotoxins)
Unpredictable (idiosyncratic hepatotoxins)

6. Intrinsic Hepatotoxins
Cholestatic eg. Anabolic steroids
Selective interference with mechanisms and structures involved in excretion of bile
Little actual cell damage
Sometimes predictable cholestatic toxins give a mixed picture of cholestasis and hepatocyte damage

7. Intrinsic Hepatotoxins
Cytotoxic
- Phosphorus - Carbon Tetrachloride - Paracetamol (O/D)
Necrosis (mechanisms unclear)
lipid peroxidation
generation of toxic oxygen species
glutathione depletion
covalent binding with functionally important molecules
Steatosis
interference with mechanisms for transport if lipid from liver
impaired mitochondrial metabolism of fatty acids

8. Idiosyncratic Liver Damage
Small proportion of recipients special susceptibility -
(1) Hypersensitivity-immune
(2) Aberrant metabolism
Fever, rash, eosinophilia granulomata in liver.
Drug or metabolite acts as a hapten
Carbamazepine
Penicillin
Sulphonamide
Inherited tendency to produce toxic metabolites, eg. Isoniazid, Valproate, Halothane, Perhexiline
1 & 2 may combine, eg. phenytoin hapten - reactive metabolite

9. Plant and Fungal Toxins
Peptides of amanita Phalloides - mushrooms
Alfatoxin - fungal contaminant of some crops
Herbal teas
Generally uncommon in Australia - but common in some countries

10. Alcohol
Correlation between per capita alcohol consumption and mortality from cirrhosis.
However, pathogenesis is still unclear
Not related to type of beverage
Is related to ‘dose’
Women more susceptible - lower body weight
- lower relative lean body mass
- lower gastric ethanol dehydrogenase

11. Possible Mechanisms of Toxicity
Acetaldehyde
• damages hepatocytes
• acting as neoantigen
• reduces glutathione levels
Enzyme induction
increases amount of mixed function oxidase
?increases production of toxic metabolites

12. Possible Mechanisms of Alcohol Toxicity (Cont.)
Fat - storing para-sinusoidal cells transform into myofibroblasts
Animal studies suggest that alcohol metabolites directly hepatotoxic even in the presence of adequate nutrition

13. Stages of Alcoholic Liver Disease
1. Fatty liver (steatosis) synthesis oxidation transport
2. Acute alcoholic hepatitis
Neutrophil infiltrate
Perivenular fibrosis
Alcoholic hyaline (eosinophile substance)
Cholestasis
Inflamed portal tracts

14. Stages of Alcoholic Liver Disease (Cont.)
3. Cirrhosis
Disturbed lobular architecture
Increased fibrous tissue
Reduced functioning hepatocyte mass
Shunting

15. Clinical Outcomes 1. Acute Injury eg. Paracetamol Usually mild
Occasionally severe - acube/subacute liver failure
Jaundice, ascites, coagulation disorder, encephalopathy
2. Subacute/persisting eg. Flucloxacillin
Cholestatic features - itching jaundice
3. Chronic eg. Methotrexate
Fibrosis/cirrhosis
4. Others – Hepatic venous thrombosis, hepatocellular adenoma

16. Clinical Approach
Always suspect drugs/toxins in any case of liver damage no matter how ‘clear-cut’ the cause is.
Check whether the drug has been reported to cause this rather than remembering lists of drugs.

17. Drugs currently reported to cause liver damage
Clavulanate
Diclofenac
Flucloxacillin
Amiodorone
Nefazodone (withdrawn)
Trovafloxacin
Statins
Carbamazepine
Paracetamol