Normal Liver Function

Structure of the Liver

Blood flows through the liver at low pressure and high flow (Ý surface area), slowly percolating through hepatocytes

Functional unit of the liver:

histological appearance: hepatic lobule – central vein surrounded by six portal triads (vein, artery, duct)
basic physiological unit: rappaport acinus – each portal triad feeds several central veins

Blood flows from the hepatic artery Þ zone 1 Þ zone 2 Þ zone 3 Þ central vein

areas nearer the hepatic artery have more O₂, are less affected during shock, and have more metabolic enzymes
blood flows through capillary finestrae (holes), and interacts with liver cell surfaces (arranged in parallel sheet)

sinusoids separate rows of hepatocytes; the space of disse separates hepatocytes from cells lining sinusoids
cirrhosis and fibrosis involve loss of blood flow to the liver – hepatocytes usually remain functional

Kuppfer cells – macrophages inside liver vessels – immunological effects, also degrade hemoglobin to bilirubin

Biliary Function

Bile – two functions:

(1) enhance intestinal absorption of lipids through bile acids (which are also involved in cholesterol elimination)
(2) excrete lipophilic waste products (cholesterol and bilirubin, also xenobiotics, plant sterols, Antibody/Antigen complexes, IgA)

pumped between hepatocytes through canilicular apparatus – only bile salts, liquids, and ions are allowed through
moves through portal ducts countercurrent (opposite direction) to blood, emerging at the common hepatic duct

gall bladder – concentration, storage, and controlled delivery of bile – contracts with cholecystokinin

cystic duct – joins common hepatic to make common bile duct (blockage: cholestasis)

Cholestasis is defined as a problem in bile flow, and has several possible causes:

blockage – blocked caniliculus, scarring or stone impaction of bile ducts, cancer of bile ducts, liver, or pancreas
autoimmune attack on small bile ducts – primary biliary cirrhosis

damage to hepatocytes (acute viral hepatitis produces jaundice)

Three Major Liver Functions

(1) Glucose Regulation – storage, synthesis, and control of plasma glucose levels

fatty acid metabolism and gluconeogenesis are tightly controlled; also can store up to 75 g of glycogen

(2) Amino Acid Interconversion and Protein Synthesis – amino acids produced from corresponding keto acids

liver makes 50 g protein per day; half of this is secreted – most plasma proteins come from the liver
most significant protein is albumin (25% of total liver output), also transferrin, lipoproteins, coagulation proteins

(3) Excretion – clearance/detoxification of drugs, hormones, alcohol, bilirubin, cholesterol, ammonia (via urea cycle)

two-phase biotransformation to make lipid soluble compounds water soluble (modification then conjugation)
waste molecules diffuse through pores, taken up by carrier proteins, transformed – most secreted into bile

some re-released into blood; now water-soluble due to biotransformation – filtered by kidney

major waste product of liver: bilirubin – see below

bile acids (bile salts at physiological pH) – only practical major role for elimination of cholesterol from body

make cholesterol soluble (mixed micelles in bile of lecithin, cholesterol, and bile salts)

Bilirubin – major waste product eliminated by liver

produced from breakdown of hemoglobin (by heme oxygenase) in reticular endothelial cells

6 g hemoglobin broken down per day (80% from old RBC’s) Þ 30 mg bilirubin

native bilirubin (unconjugated bilirubin) is electrophilic and very toxic – absorbed into liver for processing

metabolism involves conjugation to glucuronic acid to produce conjugated bilirubin Þ secreted in bile

some conjugated bilirubin is deconjugated in the colon by bacteria to produce unconjugated bilirubin, which returns to the liver, or urobilinogen, which is re-excreted unchanged

Note: conjugated bilirubin was previously known as "direct," and unconjugated as "indirect"

blood-brain barrier in newborns permeable to unconjugated bilirubin Þ can produce brain damage (kernicterus)

some causes of too much bilirubin in blood (hyperbilirubinemias):

(1) Gilbert’s Syndrome (cannot conjugate unconjugated bilirubin) – inherited, very common (10% of population), normal liver, high unconjugated bilirubin

deficiency in glucuronidase, which conjugates bilirubin with glucuronic acid

(2) Dubin-Johnson Syndrome – inherited, rare, dark pigment in liver, high conjugated bilirubin

problem with transport into biliary apparatus (also occurs with tumors and certain drugs)

(3) Drug Induced Hyperbilirubinemia – e.g. rifampin competes with bilirubin’s liver uptake system

sulfa drugs – displace bilirubin from albumin (some fatty acids also do this)

(4) Cholestasis – blocked or non-functional bile duct

cholestasis of pregnancy – from old birth control (estrogen), also 10-20% of South Americans