Transcript LIVER DAMAGE

LIVER DAMAGE
The majority of cases of liver damage
are due to:
Infections: Hepatitis A, B, C. EBV,
etc.
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2.
Structural disease of the liver:
Infiltration
Metastases
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
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
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
Categorisation of drugs
1. Predictable (intrinsic hepatotoxins)
2. Unpredictable (idiosyncratic
hepatotoxins)
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
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
Idiosyncratic Liver Damage
1.
Small proportion of recipients special susceptibility (1) Hypersensitivity-immune
(2) Aberrant metabolism
Fever, rash, eosinophilia granulomata in liver.
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Drug or metabolite acts as a hapten
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2.
Carbamazepine
Penicillin
Sulphonamide
Inherited tendency to produce toxic metabolites, eg.
Isoniazid, Valproate, Halothane, Perhexiline
1 & 2 may combine, eg. phenytoin hapten - reactive
metabolite
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
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
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
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
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
Stages of Alcoholic Liver Disease (Cont.)
3. Cirrhosis
Disturbed lobular architecture
Increased fibrous tissue
Reduced functioning hepatocyte mass
Shunting
Clinical Outcomes
1. Acute Injury eg. Paracetamol
Usually mild
Occasionally severe - acute/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
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.
Drugs currently reported to cause
liver damage
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Clavulanate
Diclofenac
Flucloxacillin
Amiodorone
Nefazodone (withdrawn)
Trovafloxacin
Statins
Carbamazepine
Paracetamol