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Published byHilary Gwen Fields Modified over 8 years ago
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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
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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
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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
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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
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Categorisation of drugs
Predictable (intrinsic hepatotoxins) Unpredictable (idiosyncratic hepatotoxins)
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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
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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
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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
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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
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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
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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
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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
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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
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Stages of Alcoholic Liver Disease (Cont.)
3. Cirrhosis Disturbed lobular architecture Increased fibrous tissue Reduced functioning hepatocyte mass Shunting
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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
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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.
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Drugs currently reported to cause liver damage
Clavulanate Diclofenac Flucloxacillin Amiodorone Nefazodone (withdrawn) Trovafloxacin Statins Carbamazepine Paracetamol
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