DRUG,TOXIC AND METABOLIC DISORDERS

1. DRUG,TOXIC AND METABOLIC DISORDERS DRUGS AND THE LIVER

2. Summary of types of drug-induced liver disease • Necrosis - zonal (usually zone 3), diffuse, massive. • Hepatitis - acute hepatitis, indistinguishable from viral hepatitis. - acute cholestatic hepatitis. Pointers to a drug aetiology are, eosinophils, granulomas, fatty change. - chronic hepatitis, usually severe histologically; most improve on withdrawal of the drug. • Cholestasis “pure” cholestasis, ie no inflammation or necrosis. • Cirrhosis. • Steatosis/steatohepatitis. • Phospholipidosis. • Vascular lesions - venous occlusion, sinusoidal dilatation, peliosis hepatis. • Tumours - liver cell adenoma, hepatocellular carcinoma, angiosarcoma.

3. ALCOHOLIC LIVER DISEASE • Importance - the leading cause of liver disease in most Western countries. Causes acute and chronic liver disease. Causes about 60% of cases of cirrhosis. • Metabolism - via alc.dehydogenase, MEOS, catalase to acetaldehyde and acetate. Alcohol and acetaldehyde are hepatotoxic. Damage also caused by reactive oxygen species. • Morphology - 1. Steatosis (fatty change). Invariable. Reversible. There may be fibrosis around terminal venules extending along sinusoids. 2. Alcoholic hepatitis in +/- 30% of patients. Reversible. Liver cell swelling (hydropic change) and necrosis, Neutrophil polymorph infiltrate, Mallory’s hyaline, Perivenular fibrosis with sinusoidal fibrosis. Steatosis. Occasionally cholestasis or siderosis. 3. Cirrhosis. Occurs in 10 - 15% of alcoholics. Irreversible. Micronodular becoming macronodular if drinking stops. Risk of hepatocellular carcinoma.

8. Liver biopsy is required to distinguish the three morphological types. All three may have hepatomegaly. Steatosis tends to be mild clinically & biochemically; alcoholic hepatitis can be mild or have life-threatening liver failure. It may be superimposed on cirrhosis. Factors influencing alcoholic liver disease. Dose and duration. Continuous worse than binge drinking. Immune reaction to neo-antigens from hepatocellular proteins. Female gender. Genetic polymorphisms. Nutritional deficiencies. Chronic viral infections. Drugs and toxins. The relationship of steatosis, alcoholic hepatitis to cirrhosis is not clear. Perivenular sinusoidal fibrosis due to hepatic stellate cell activation is important. Alcohol is fibrogenic. Its perivenular (zone 3) location (and that of necroinflammation) can be explained by the localisation here of drug metabolising enzymes. Alcohol releases endothelins from sinusoidal endothelial cells which induce myofibroblasts to contract, constricting sinusoids and leading to localised hypoxia, a further damaging factor.

9. TOXINS • A few examples of other toxins encountered through occupation, in the home or elsewhere in the enviroment:- Carbon tetrachloride, phosphorus, paraquat. Mushroom poisoning (Amanita phalloides). Plants containing pyrrolizidine alkaloids. Herbal teas, herbal remedies.

11. METABOLIC LIVER DISEASE • NONALCOHOLIC FATTY LIVER DISEASE AND STEATOHEPATITIS • Known as NAFLD and NASH respectively. • A diagnosis of exclusion especially of heavy alcohol intake. • Equally common in males and females (alcoholic liver disease M>F). • Strong association with obesity, hyperlipidemia, hyperinsulinemia and insulin resistance and diabetes mellitus type 2. • Patients often asymptomatic and discovered on incidental finding of abnormal liver blood tests. Diagnosed with increasing frequency with the epidemic of obesity. • Morphologically steatosis (NAFL) and steatohepatitis (NASH) are indistinguishable from their counterparts due to alcohol. 10% to 30% of NASH progress to cirrhosis. (May be the most common cause of “cryptogenic” cirrhosis). Contributes to progression of other liver diseases such as HCV hepatitis.

12. IRON OVERLOAD • Iron overload due to excess from the diet, via parenteral route, or combination of both. • Classification:- Hereditary haemochromatosis. - Iron overload due to chronic anaemias, with or without blood transfusions, excess oral iron, cirrhosis (especially alcoholic), porphyria cutanea tarda, neonatal haemochromatosis. • With transfusional or excess oral iron overload, haemosiderin accumulates predominantly in Kupffer cells. Fibrosis does not develop. • Cases of chronic anaemias with iron overload may develop fibrosis and eventually cirrhosis. There is no risk of hepatocellular carcinoma.

13. HEREDITARY HAEMOCHROMATOSIS • Inherited defect whereby iron is absorbed from the diet in excessive amounts throughout life. Autosomal recessive inheritance. • The haemochromatosis gene HFE on chromosome 6. Most common mutation cysteine-to-tyrosine substitution at amino acid 282 (C282Y). Linked with HLA-A3. • Males:females as 7:1. Frequency of C282Y 10% in Caucasians, especially Northern Europe. Low penetrance. • Often detected by finding of a high serum ferritin. • Excess iron directly toxic via reactive free radicals and is fibrogenic. • Iron is deposited as haemosiderin in liver, pancreas, myocardium, endocrine organs, synovium, skin. Known as “bronzed diabetes.”

17. Hereditary haemochromatosis • In the liver, brown haemosiderin pigment accumulates first in periportal hepatocytes (zone 1), extending in time to all hepatocytes, Kupffer cells, bile duct epithelium, portal tract macrophages and encrusts portal tract collagen. • Stained with Perl’s Prussian blue stain, it can be graded 1-4. • Fibrosis commences in portal tracts, eventually linking tracts, but true cirrhosis only develops late in the disease ( a micronodular cirrhosis). • There is a high risk of hepatocellular carcinoma (200 fold greater than in the general population. Treatment reduces iron but not this risk. • Early diagnosis and treatment before irreversible tissue damage and screening of family members is important. • Genotyping for C282Y and liver biopsy to assess grading of siderosis and degree of fibrosis are important.

18. WILSON DISEASE • Inherited abnormality of copper metabolism. • Autosomal recessive inheritance. Age of onset over 6 years. • Gene ATP7B on chromosome 13 encodes for transmembrane copper-transporting ATPase on hepatocyte canalicular membrane. • Mutations lead to decreased biliary copper excretion. Excess copper accumulates, toxic via Cu-catalysed reactive oxygen species. Disease prevelance 1:30,000. • Low plasma caeruloplasmin; high urinary copper. • Copper deposited in liver, brain, and cornea (resulting in characteristic Kayser-Fleischer rings) = liver disease and neuropsychiatric features. • Pathological changes in liver very variable - fatty change, acute hepatitis, massive necrosis, chronic hepatitis, steatonecrosis, cirrhosis. Risk of hepatocellular carcinoma low. Distinctive mitochondrial changes on electron microscopy. Copper or its binding protein can be demonstrated in the liver. • Early diagnosis and treatment have markedly improved prognosis.

19. ALPHA-1-ANTITRYPSIN DEFICIENCY • Inherited abnormality of this anti-protease and acute phase reactant. • Autosomal recessive inheritance. • Gene is on chromosome 14. • Normal allele PiMM. Numerous variants; most important is Z allele. PiZZ causes substitution of lysine for glutamic acid at 342 position. • Leads to abnormal molecular folding and accumulation of abnormal AAT in endoplasmic reticulum. • Not toxic; possibly autophagocytic response within hepatocytes causes liver injury. • Seen as PAS positive globules in periportal (zone 1) hepatocytes. Can be stained specifically by immunoperoxidas method. • Serum AAT is low. Causes cholestasis in neonates and infants; can lead to cirrhosis. Chronic hepatitis-like picture in adults leading to cirrhosis.

21. OTHER METABOLIC DISEASES • Numerous metabolic disease affect the liver including those of:- carbohydrate metabolism (eg glycogen storage diseases) protein & amino acid metabolism lipid metabolism (eg Gaucher’s disease) porphyrin metabolism and others.