Hepatic physiology

Synthesis

• 90% of plasma proteins (albumin, factors, compliment)
• Regulatory proteins (thrombopoetin, angiotensinogen, herceptin)
• Nutrients (gluconeogenesis, ketones, non-essential amino acids)

Storage

• Energy (glycogen and lipid droplets)
• Fat soluble vitamins (ADEK + B12)
• Minerals (ferritin, copper)
• Blood (25% of total blood volume)

Metabolism

• Glucose \(\leftrightarrow\) Glycogen
• Triglycerides \(\leftrightarrow\) FFAs \(\to\) ketones
• Amino acids \(\to\) ammonia + \(\alpha\)-keto acid
• Lactate \(\to\) glucose (Cori cycle)
• Ammonia \(\to\) urea
• Phase 1 + phase 2 metabolism of xenobiotics

Immunological

• Synthesis of compliment
• IL6 \(\to \ \uparrow\)herceptin \(\to\ \ \downarrow\)ferroportin to deny iron to bacteria
• Kuffner cells (liver macrophages) phagocytose opsonised pathogens
• IgA and IgG in bile

Excretion (via bile)

• Bile acids (95% enterohepatically cycled)
• Cholesterol (1g/day)
• Conjugated bilirubin
• Drugs (e.g. ceftriaxone)
• Heavy metals (lead, arsenic)

Composition

95% water, 5% solutes

Organic solutes: bile salts (40mM), cholesterol (4mM), conjugated bilirubin (2mM), lipids, de minimus protein. Bile salts formed from neutralization of bile acids; primary = made by hepatocytes, secondary = made by intestinal bacteria

Inorganic solutes: similar ionic profile to plasma

Formation of bile

95% of bile salts reabsorbed in terminal ileum

Recirculate to hepatocytes and actively transported into bile

H2O follows by osmosis ("bile-salt dependent")

Other substances (conjugated xenobiotics, bilirubin) are also actively excreted, with H2O following by osmosis ("bile-salt independent")

Bile ducts \(\to\) water added

Gall bladder \(\to\) ions + H2O reclaimed, concentrating bile

Functions of bile

Emulsify lipids: \(\uparrow\)SA \(\to \ \uparrow\)lipid absorption + \(\uparrow\)absorption of fat-soluble vitamins

Excrete xenobiotics, cholesterol, bilirubin

Immune functions (IgA and IgG)

Growth factors for enterocytes

Synthesis failure

Hypoalbuminaemia

Thrombocytopenia and macrocytic anaemia

Coagulopathy

Storage failure

Hypoglycaemia

Metabolism failure

Accumulation of lactate

Accumulation of ammonia (hepatic encephalopathy)

Accumulation of drugs normally hepatically conjugated

Accumulation of unconjugated bilirubin

Immunological

Loss of compliment \(\to\) susceptibility to sepsis

Loss of hepatic macrophages \(\to\) susceptibility to translocation

Excretion (via bile)

Accumulation of conjugated bilirubin

Accumulation of drugs normally excreted in bile

Sources

Protein deamination: amino acid \(\to\ \ \alpha\)keto acid + ammonia

Purine metabolism in skeletal muscle

Renal ammoniagenesis from glutamate

Distribution

98% ionized and largely ion trapped

Metabolism

Exclusively in liver

2NH3+ CO2 \(\to\) urea + H2O

Elimination

Urea mostly excreted renally

~15% enterohepatically cycled (metabolized by flora back to ammonia and returned by first-pass to the liver; lactulose ion traps ammonia in the GIT)