Physiology
Liver Function
Detoxification, synthesis, metabolism — the body's biochemical hub
The liver is the largest internal organ (~1.5 kg in adults) and the body's central biochemical factory. Functions span synthesis (albumin ~12 g/day, all clotting factors except factor VIII, urea, cholesterol, bile, glucose via gluconeogenesis), detoxification (Phase I CYP450 oxidation, Phase II conjugation with glucuronide/sulfate/glutathione, ammonia → urea via Krebs-Henseleit cycle), metabolism (glycogen storage ~100 g, lipid handling, drug clearance), storage (vitamins A, D, E, K, B12; iron as ferritin; copper), and immune surveillance (Kupffer cells filter portal blood). Dual blood supply: 75% from portal vein (nutrient-rich from gut), 25% from hepatic artery. Cirrhosis (scarring from chronic injury — alcohol, hepatitis B/C, NAFLD/MASLD), the end-stage of liver disease, kills ~2 million globally per year.
- Weight~1.5 kg (adult)
- Albumin synthesis~12 g/day
- Glycogen storage~100 g (~400 kcal)
- Blood flow~1.5 L/min (25% of cardiac output)
- Portal vein contribution~75% of liver blood (gut, spleen, pancreas drainage)
- Cirrhosis deaths~2 million/yr globally
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Why liver function matters
- Drug metabolism. Most oral drugs cleared hepatically — dose adjustment in cirrhosis.
- Coagulation. INR rises in liver failure; bleeding risk.
- Glucose homeostasis. Gluconeogenesis between meals; fasting hypoglycemia in failure.
- Bilirubin clearance. Jaundice signals dysfunction or obstruction.
- Ammonia clearance. Failure causes encephalopathy.
- Storage. Iron overload (hemochromatosis), copper (Wilson), glycogen storage diseases.
- Cancer. HCC is 6th most common cancer worldwide; HBV/HCV/MASLD-driven.
Common misconceptions
- Liver enzymes (AST/ALT) reflect function. They reflect injury — synthesis is gauged by albumin, INR, bilirubin.
- Detox teas help the liver. No evidence; some cause hepatotoxicity (kava, comfrey, green tea extract).
- Cirrhosis is reversible. Early fibrosis can regress; established cirrhosis usually permanent though some HCV cure data show regression.
- Only alcohol causes liver disease. MASLD/NAFLD (metabolic) is leading cause in obese populations.
- Acetaminophen is always safe. Overdose causes acute liver failure; max 3-4 g/day adult, lower in alcoholics or fasting.
- Bilirubin elevation = liver problem. Hemolysis and Gilbert syndrome (~5% population) cause indirect hyperbilirubinemia without liver disease.
Frequently asked questions
How does the liver detoxify drugs?
Two phases. Phase I — cytochrome P450 enzymes (mainly CYP3A4, CYP2D6, CYP2C9, CYP1A2 in ER of hepatocytes) introduce or unmask polar groups via oxidation, reduction, hydrolysis. Phase II — conjugation with glucuronic acid (UGTs, most common), sulfate, glutathione, glycine, acetyl groups, increasing water solubility. Conjugates excreted in bile (enterohepatic recirculation possible) or urine. CYP450 induction (rifampin, phenytoin, St. John's wort) accelerates metabolism — drug-drug interactions; inhibition (erythromycin, grapefruit juice, ritonavir) raises levels.
What does the liver synthesize?
Albumin (most abundant plasma protein, maintains oncotic pressure, drug binding) ~12 g/day. Clotting factors (I/fibrinogen, II, V, VII, IX, X, XI, XII; protein C and S) — vitamin K-dependent ones require γ-carboxylation; warfarin blocks this. Acute phase proteins (CRP, haptoglobin, ferritin, fibrinogen) under IL-6 control. Bile salts from cholesterol — emulsify dietary fat. Glucose via gluconeogenesis from lactate, glycerol, amino acids during fasting. Lipoproteins (VLDL → LDL).
What is bile and why does it matter?
~600-1000 mL/day produced by hepatocytes. Components: bile salts (cholate, chenodeoxycholate; conjugated to glycine or taurine), phospholipids, cholesterol, bilirubin, electrolytes. Stored and concentrated in gallbladder; ejected into duodenum after meals via CCK. Function: emulsify fats for lipase digestion, absorb fat-soluble vitamins (ADEK), excrete cholesterol and bilirubin. Gallstones — cholesterol or pigment — affect ~10-15% adults; cholecystectomy is one of most common surgeries.
What does jaundice mean?
Yellow discoloration of skin, sclera, mucosa from bilirubin >2-3 mg/dL. Pre-hepatic: hemolysis (unconjugated/indirect rises) — ineffective erythropoiesis, sickle, hereditary spherocytosis. Hepatic: hepatocyte injury (hepatitis, cirrhosis) — both rise. Post-hepatic: obstruction (gallstones, pancreatic head cancer, cholangiocarcinoma) — conjugated/direct rises with pale stools, dark urine, pruritus. Neonatal jaundice common (immature UGT); kernicterus if unconjugated bilirubin crosses BBB.
How does the liver handle ammonia?
Amino acid catabolism produces NH3, which is neurotoxic. Urea cycle (Krebs-Henseleit) in periportal hepatocytes converts 2 NH3 + CO2 → urea (excreted by kidney). Inherited urea cycle defects (OTC deficiency most common) cause hyperammonemia in neonates. Cirrhosis impairs cycle — hyperammonemia → hepatic encephalopathy (asterixis, confusion, coma). Treated with lactulose (acidifies colon, traps NH4+) and rifaximin (reduces ammonia-producing gut bacteria).
What causes cirrhosis?
Chronic hepatocellular injury → fibrosis → architectural distortion with regenerative nodules. Top causes globally: alcohol-related liver disease, chronic hepatitis B and C, MASLD/NAFLD (now leading cause in many countries due to obesity), autoimmune hepatitis, hemochromatosis, Wilson disease, primary biliary cholangitis. Complications: portal hypertension (esophageal varices, ascites, splenomegaly), hepatic encephalopathy, coagulopathy, hepatorenal syndrome, hepatocellular carcinoma. Child-Pugh and MELD scores stage severity; transplant for end-stage.
How does the liver regenerate?
Remarkable regenerative capacity — can regrow to full mass after up to 70% partial hepatectomy in weeks. Differentiated hepatocytes re-enter cell cycle (rather than relying on stem cells primarily). Drivers: HGF, TGF-α, EGF, IL-6, TNF-α. Why living donor liver transplant works — donor liver regenerates within ~6-8 weeks. Acetaminophen toxicity overwhelms glutathione (Phase II), generating NAPQI which causes massive necrosis; N-acetylcysteine within 8-10 hr is antidote.