Metabolic diseases of the liver

1. Metabolic diseases of the liver • Central role in metabolism • Causes and mechanisms of dysfunction • Clinical patterns of metabolic disease • Clinical approach to problem-solving • Specific disorders

2. Liver’s central role in metabolism Pathways involve CHO, protein, lipid, trace element and vitamin metabolism • Synthesis e.g. serum proteins • Detoxification/degradation e.g. ammonia • Regulation e..g. blood glucose

3. Metabolic function of the liver Reactions disturbed by • Congenital deficiency of enzymes • Nutritional deficiency/excess of substrate • Toxic/chemical damage to organelles • Hypoxic/ischaemic insult • Secondary to metabolic effects of disease

4. Metabolic disorders • of amino acid metabolism • of bile acid synthesis and metabolism • of carbohydrate metabolism • of bile flow and excretion • of mitochondrial function • of peroxisomal function • of copper metabolism

5. Metabolic dysfunction : inherited disease • Essential product deficit e.g. G-6-P deficiency (Glycogen storage I) • Precursor accumulation e.g. OTC deficiency (Hyperammonaemia) • Alternative pathway activation e.g. Aminoacidopathy • Combinations of above

6. Mitochondrial damage • Inhibition of beta oxygenation of fatty acids leads to microvesicular steatosis • Interference with oxidative phosphorylation leads to insufficient ATP generation • Impairment of the respiratory chain leads to excess ROS with lipid peroxidation • Increase in permeability transition leads to cell death (apoptosis)

7. Mitochondrial dysfunction • Inborn enzyme deficiencies involving: fatty acid oxygenation organic acids lactate metabolism oxidative phosphorylation urea cycle Episodic decompensation precipitated by intercurrent stress

8. Toxic damage to liver • Mitochondrial damage Drugs (antivirals, salicylate, valproate, tetracycline) Toxins (hypoglycin, atractyloside) • Endothelial damage to hepatic veins Drugs (cytotoxic drugs) Toxins (Senecio, aflatoxin, pyrrolizidine) • Glutathione depletion and cell death Drugs (paracetamol) Hypoxic ischaemia

9. Mechanisms of centrilobular necrosis • Sepsis • Shock induced ischaemia • Congestive heart failure • Toxicity from drugs and poisons made worse by Malnutrition Infection Fasting Exercise

10. Pathologic manifestations of metabolic disease of the liver • No structural abnormalities evident but severe functional disturbance • Hepatocyte injury leading to apoptosis, necrosis, cirrhosis or tumours • Storage of lipid, glycogen or other products manifesting as hepatomegaly

11. Clinical patterns of metabolic disease involving the liver • Newborn acute metabolic crisis mimics sepsis • Severe vomiting and failure to thrive • Recurrent episodes of vomiting and encephalopathy with acidosis • Progressive retardation or seizures with hepatomegaly • Hepatomegaly with/without jaundice and failure to thrive/grow normally

12. Inherited metabolic disease presenting with acute onset liver failure “Reye-like”

13. Inherited metabolic disease presenting with acute onset liver failure “Reye-like”