Liver

• The liver is the largest single organ in the body weighing around 1.5kg in fully grown adult
• the liver sits tucked under the right side of the ribcage and has two lobes, a larger right lob and smaller left lobe
• the gall bladder is an associated organ with the liver which stores bile as it is released from the liver until it is required for digestion - when fatty food is ingested and reaches the small intestine, the gall bladder contracts and releases bile which helps emulsify fats for absorption
• The blood supply to the liver is unusual in that only 20% comes from the hepatic artery delivering O2 whereas 80% comes via the hepatic portal vein and delivers nutrient-rich blood which has circulated the GI tract (low in O2) nutrient-rich
• under a low power microscopic the structure of the liver appears as hexagonal lobules - at the junctions of each of there is a “triad” which consists of a branch of the hepatic artery, hepatic portal vein and the bile duct
• the particular arrangement of hepatocytes makes them look like spokes in a wheel.
• there is a close nature of the interaction of the blood from the hepatic artery and the hepatic portal vein at the outer corner towards the central vein - as it flows through the sinusoids (like capillaries in the liver) it is a single layer of cells allowing for easy movement of substances in and out of the hepatocytes.
• the ducting system involves the bile duct which gathers bile as it leaves the hepatocytes and flows from the centre of the hexagonal lobule towards the outer corner - the bile ducts all then join to form the common bile duct which transports bile to the gall bladder
• blood flow and bile flow in separate ducting systems and in the opposite direction
• there are 5 main functions of the liver:

  1. metabolism of carbohydrates, fats, proteins and hormones
  2. storage of glycogen vit A and B12 and iron
  3. synthesis of some plasma proteins
  4. metabolism of drugs and foreign compounds
  5. metabolism and excretion of bilirubin
• Diseases affecting liver can affect any/all of the functions, however it has a large functional reserve, thus tests are relatively insensitive indicators of disease
• metabolism of carbohydrates in the liver includes gluconeogenesis, glycogen synthesis and breakdown
• metabolism of fats in the liver include fatty acid synthesis, cholesterol synthesis and excretion, lipoprotein synthesis, ketogenesis, bile acid synthesis, and vitamin D hydroxylation
• metabolism of proteins in the liver include the synthesis of plasma proteins and degradation of amino acids to form urea
• the metabolism of hormones in the liver includes the metabolism and excretion of steroid hormones, and metabolism of peptide hormones
• The liver synthesises plasma proteins except for immunoglobulins and complement.
• the liver synthesises most coagulation factors - fibrinogen, prothrombin, V,VII,IX, X,XI,XII,XIII and some of these require vitamin K for their synthesis (prothrombin, VII, IX and X)
• Albumin is solely synthesised in liver
• the liver is the route of excretion for many non-water soluble compounds from the body, some of these are converted to water-soluble then excreted in urine, others are excreted in bile which is the main excretory product produced by the liver
• Cholesterol cannot be fully metabolised by humans so it is excreted unchanged in bile or converted to bile acids and excreted in bile
• Urea is breakdown product of amino acid metabolism, they are deaminated and urea is synthesised in liver, but excreted by kidneys
• Steroid hormones are metabolised and inactivated by conjugation with glucuronate and sulphate, and excreted in urine in these water-soluble forms
• Many drugs are metabolised and inactivated by enzymes of the endoplasmic reticulum system, and some are excreted in bile
• RBCs at the end of their life span are broken down by the cells of the reticuloendothelial system (mainly the spleen) - released Hb is degraded to globin which enters the general amino acid pool and the Fe is removed from haem and recycled, whilst the remaining porphyrin ring is cleaved to form bilirubin, which is yellow
• 80% of bilirubin formed is from haem breakdown from circulating senescent RBCs, 20% from bone marrow RBCs, myoglobin, cytochromes and peroxidase
• Bilirubin is insoluble in plasma so has to be solubilised to be transported to the liver, so it is attached to albumin - the major plasma protein
• Unconjugated bilirubin is taken up into hepatocytes in a specific carrier-mediated process.
• In the endoplasmic reticulum of the hepatocytes, the enzyme UDP-glucuronyl transferase conjugates bilirubin to glucuronic acid to form conjugated bilirubin (bilirubin glucuronides) which is water soluble and is secreted into bile ducts in an energy dependant process as it is against a concentration gradient
• Fats in the GI tract cause the gall bladder to contract, releasing bile - the conjugated bilirubin is degraded by bacterial action in the gut, to a mixture of colourless water-soluble compounds called urobilinogen which is further oxidised to urobilins and stercobilins - yellow to brown giving urine and faeces their colour
• Enterohepatic circulation can occur where small quantities of urobilinogen are reabsorbed and carried back to the liver via the hepatic portal circulation - most of this is cleared by the liver, but some is filtered by the kidney and is excreted in the urine, where it can be detected
• stercobilin is only present in faeces whilst urobilinogen is found in both faeces and urine
• The liver produces 300mg bilirubin/day but can handle up to 10 times this amount if and when the need arises.
• 95% of plasma bilirubin is normally unconjugated as it has not passed through the liver for conjugation and release into bile
• in liver disease due to the inability of the liver to dispose of unconjugated bilirubin the conjugated form may predominate - this will cause a rise and contributes to the total plasm bilirubin measurement
• in the clinical lab, the total bilirubin is measured (conjugated and unconjugated), with the reference range being 2-17micromol/L
• conjugated and unconjugated bilirubin is very difficult to separate and so there is only one reference range for the total ammount
• When plasma levels reach >50 micromol bilirubin/L (some books quote 35) it presents as jaundice (icterus) - a yellowing of the skin and sclera of the eye due to deposition of bilirubin in tissues.
• causes of hyperbilirubinemia (build-up of billirubin) can be prehepatic, hepatic, or post-hepatic (commonly the gallbladder)
• the major pre-hepatic causes of jaundice include:

  • excessive haemolysis
  • ineffective erythropoiesis - leukaemia
• the major post-hepatic causes of jaundice include:

  • gallstones
  • biliary stricture - blockage
  • carcinoma of the pancreas or biliary tree
  • cholangitis - inflammation of bile duct system