Chapter 44: Liver Metabolism

The liver functions as the body's metabolic processing center, receiving nutrient-dense blood from the portal vein and oxygenated blood from the hepatic artery, positioning it perfectly to regulate circulating compounds before they distribute systemically. Structurally organized into functional lobules with sinusoids containing specialized cells, the liver enables hepatocytes to perform uptake, transformation, secretion, and excretion of metabolites and foreign substances. The liver maintains blood glucose homeostasis through glycogen storage and mobilization, gluconeogenesis from amino acids and glycerol, and ketone body synthesis during prolonged fasting or carbohydrate restriction. It synthesizes and exports lipoproteins including VLDL and cholesterol, produces bile salts for lipid digestion, and metabolizes amino acids while converting excess nitrogen into urea through the urea cycle to prevent ammonia accumulation. The liver's detoxification capacity relies heavily on cytochrome P450 enzymes, which catalyze phase I oxidation of xenobiotics and drugs, rendering them susceptible to phase II conjugation reactions that enhance water solubility for urinary or biliary excretion. Notable examples include the conversion of acetaminophen to reactive intermediates amplified by alcohol-induced CYP2E1 upregulation, activation of aflatoxin B1 to carcinogenic metabolites, and vinyl chloride metabolism to toxic epoxides. Peroxisomes within hepatocytes oxidize very-long-chain fatty acids that mitochondria cannot process efficiently, while medium-chain fatty acids provide alternative energy sources in certain malabsorption disorders. Hepatic lipid metabolism is regulated through PPAR-alpha signaling, which increases fatty acid oxidation and is targeted by fibrate drugs for managing hypertriglyceridemia. Liver disease disrupts these coordinated functions, impairing glucose regulation to produce hepatogenous diabetes, reducing clearance of aromatic amino acids and ammonia to precipitate hepatic encephalopathy, and altering lipid composition through changes in lipoprotein lipase and lecithin-cholesterol acyltransferase activity. Fibrosis develops when stellate cells accumulate and deposit fibrillar collagen in response to hepatic injury, eventually progressing to cirrhosis characterized by portal hypertension, esophageal varices, and hemorrhagic complications.