6. The Liver Notes
- 2. Normal liver
- 3. Normal liver • The liver is a large, meaty organ that sits on the right side of the belly. • The liver is reddish-brown in colour and feels rubbery to the touch. Normally you can't feel the liver, because it's protected by the rib cage. • The liver has two large sections, called the right and the left lobes. • The gallbladder sits under the liver, along with parts of the pancreas and intestines. The liver and these organs work together to digest, absorb, and process food.
- 4. Functions of the Liver • The liver's main function is to filter the blood coming from the digestive tract, before passing it to the rest of the body. • The liver also detoxifies chemicals and metabolizes drugs. As it does so, the liver secretes bile that ends up back in the intestines. • The liver also makes proteins important for blood clotting and other functions
- 5. Disease symptoms • The classic symptoms of liver damage include the following: • Pale stools occur when stercobilin, a brown pigment, is absent from the stool. Stercobilin is derived from bilirubin metabolites produced in the liver. • Dark urine occurs when bilirubin mixes with urine • Jaundice (yellow skin and/or whites of the eyes) This is where bilirubin deposits in skin, causing an intense itch. Itching is the most common complaint by people who have liver failure. Often this itch cannot be relieved by drugs.
- 6. Disease symptoms • Swelling of the abdomen, ankles and feet occurs because the liver fails to make albumin. • Excessive fatigue occurs from a generalized loss of nutrients, minerals and vitamins. • Bruising and easy bleeding are other features of liver disease. The liver makes substances which help prevent bleeding. When liver damage occurs, these substances are no longer present and severe bleeding can occur.
- 7. Liver Tests • Liver Function profile: • Total protein, • Albumin, • Total bilirubin, • Conjugated bilirubin, • Unconjugated bilirubin, • AST, ALT, GGT & ALP
- 8. Plasma proteins • Total protein and albumin levels are usually included in the routine liver function tests but are not specific indicators of liver disease. • Transaminases: Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) are commonly used to indicate hepatocellular destruction. Both are present within the hepatocyte and are released during cell damage. ALT is the more specific enzyme as AST is found in cardiac muscle, skeletal muscle, and erythrocytes as well as in hepatocytes.
- 9. Hepatocellular vs. Cholestasis • In hepatocellular disease, plasma ALT rises before jaundice appears, reaches levels in excess of 100 times normal and fails in parallel with the plasma bilirubin concentration, if the disease resolves. • In obstructive(cholestatic) liver disease there may be only minimal damage to hepatocytes and the ALT level may not rise. However, in most obstructive disorders, there is some liver cell destruction(due to back pressure of bile) and a modest rise in the plasma level of this enzyme of ALT is seen(< 10 times ULN).
- 10. Alkaline phosphatase (ALP): • Levels usually very high in obstructive disease ( > 3 times ULN), whereas in hepatocellular disease the level may be normal or only moderately raised (<3 times ULN). • The latter reflects mild cholestasis due to obstruction of bile canaliculi by swollen hepatocytes. • ALP may also be raised in bone- and other nonhepatic diseases.
- 11. Gamma-qlutamyltransferase (GGT): • Has a wide distribution in the body (including the liver) but raised plasma levels usually indicate a hepatic origin. • Plasma level may be raised due to induction of the liver enzyme by alcohol and a variety of drugs. • An increase GGT confirms that an increase in ALP is of the liver origin and an increased ALP accompanied by a normal GGT indicate bone origin.
- 12. Clinical significance: • Cholinesterase levels in serum are useful as an indicator of possible insecticide poisoning, for the detection ofpatients with atypical forms of the enzyme, or as a test of liver function. THE ONLY ENZYME THAT IS DECREASED WHEN ABNORMAL. • Among the organic phosphorus compounds that inhibit cholinesterase activity are many insecticides, such as Parathion, Sarin, and tetraethyl pyrophosphate. • Workers in agriculture and in organic chemical industries are subject to poisoning by inhalation of these materials or by contact with them.
- 13. Evaluate the source, transport and metabolism of bilirubin. • Destruction of red cells releases haem (the red pigment of blood). • Metabolism of haem, in the reticuloendothelial system by haem oxygenase, produces carbon monoxide, iron and a tetrapyrrole compound called biliverdin. • Biliverdin is converted by biliverdin reductase to form bilirubin (a yellow-orange pigment which is extremely insoluble in aqueous solutions).
- 14. • In circulation, bilirubin binds to albumin and is transported to the liver. • Once the albumin-bilirubin complex reaches the liver, the bilirubin is separated from the albumin and diffuses across the plasma membrane into the hepatocyte cytosol where it is conjugated with uridine diphosphate (UDP)-glucuronic acid in the presence of UDP-glucuronyl transferase.
- 15. • The glucuronide bilirubin(conjugated bilirubin) is soluble in an aqueous solution and excreted through the bile duct to the intestinal lumen where it is hydrolyzed by intestinal microorganisms to form compounds known as urobilinogens. • These compounds are then either reabsorbed into the circulation or excreted into the lower intestine.
- 16. • Reabsorption of urobilinogens into the circulation leads to its reuse or its excretion into the urine by the kidney. • Excretion of urobilinogens into the lower intestine leads to its excretion into the faeces. • Urobilinogens in urine or faeces are oxidized in the presence of oxygen and lead to the production of urobilinogen derivatives, which contribute to the normal colour of urine and faeces.
- 17. Disorders of Bile Pigment Metabolism • Bilirubin Reference ranges: • Total bilirubin:0-17 umol/L • Conjugated Bilirubin: 0-4 umol/L • Unconjugated Bilirubin: 3.5- 14 umol/L
- 18. • An increase in the bilirubin concentration in blood leads to the deposition of bilirubin pigment in the sclera of the eyes and in the skin. This yellowish pigmentation in the skin or the sclera is known as jaundice or icterus. • Although jaundice is most often linked to viral hepatitis, there are other causes for increased bilirubin in the circulation. • In general jaundice can be classified by the underlying site or cause of the jaundice: Prehepatic, hepatic, and posthepatic jaundice.
- 19. Prehepatic jaundice • Increased production of bilirubin due to excessive red cell destruction eg in Haemolytic disease. • The conjugated bilirubin concentration is normal, while the unconjugated bilirubin concentration is increased. • The increased bilirubin production leads to an increase in the amount of bilirubin that is conjugated in the liver and excreted into the gut where it is converted into urobilinogen.
- 20. Prehepatic jaundice • As a result of the formation of excessive amounts of urobilinogen , faecal urobilinogen and urobilin are greatly increased, whereas urine urobilinogen is moderately increased. • Total bilirubin is usually < 85 umol/L.
- 21. Intrahepatic jaundice • Gilbert's disease • There is an inability of the hepatocytes to take up bilirubin from the blood due to a congenital malfunction of the transport system. • Affected individuals have no symptoms but a mild jaundice is seen. Bilirubin levels is usually < 50 umol/L and is unconjugated.
- 22. Crigler-Najjar syndrome • A more serious disease, there is a deficiency of the UDPD Transferase Enzyme system. • In Type I, in which there is a complete absence of the enzyme in the liver, is very rare. • No conjugated bilirubin is formed and the bile is colourless. This type is fatal. • In Type II there is a less severe deficiency of the enzyme, and some conjugated bilirubin is formed.
- 23. • Dubin-Johnson syndrome and Rotor's syndrome are two hereditary disorders characterized by conjugated hyperbilirubinaemia from defective excretion by the liver cell (cholestasis).
- 24. Physiologic Jaundice of the Newborn • The UDP6 Transferase Enzyme system is not fully developed at birth. In full-term infants, several days pass before the enzyme is produced in sufficient quantity to conjugate the bilirubin presented to it. • The serum bilirubin may rise as high as 137 umol/L in normal full-term infants by the 3rd to the 6th day of life as a result of the immature enzyme system before falling to normal adult levels; this condition is known as physiologic jaundice of the newborn. This process is aggravated in premature infants, who must wait a longer time for generation of the conjugating enzyme.
- 25. Haemolytic Disease of the Newborn (HDN) • This disease is caused by an Rh, ABO, or other blood system incompatibility between mother and fetus. • If the mother has been previously sensitized to a surface antigen present on fetal red cells, maternal antibodies cross the placenta and bind to the specific surface antigens; activated complement binds to the attached IgG and destroys the red cell membrane by lytic, enzymatic action.
- 26. HDN • The haemolysis produce a large amount of bilirubin for excretion by an immature liver. • The load is too large to handle effectively, So the plasma bilirubin concentration rises rapidly and the jaundice may be severe. • Plasma albumin has a limited capacity for binding bilirubin, and when primary binding sites are saturated, the bilirubin becomes less tightly bound to secondary sites
- 27. HDN • When the blood circulates to the brain, the unbound bilirubin enters the brain cells and causes irreversible damage to the basal ganglia. • Nuclear staining of brain cells is known as kernicterus. • Historically, the critical concentration of plasma bilirubin for possible brain damage in newborns was considered to be ± 340 umol/L.
- 28. • Any cause of Severe hepatocelluiar damage may also interfere with uptake, conjugation, or secretion of bilirubin. • Examples are viral hepatitis, hepatitis produced by toxins and cirrhosis. • This will lead to unconjugated as well as conjugated hyperbilirubinaemia.
- 29. Posthepatic jaundice • Results from the impaired secretion of bilirubin caused by mechanical obstruction of the flow of bile into the intestines. • This may due to the presence of gallstones or a tumour. • When bile ceases to flow into the intestines, there is a rise in the serum level of conjugated bilirubin, and the faeces looses its source of normal pigmentation and becomes clay-coloured. • Conjugated bilirubin appears in the urine, and urine urobiiinogen levels decrease.
- 30. COMMON LABORATORY TESTS TYPES OF JAUNDICE PREHEPATIC INTRAHEPATIC POSTHEPATIC HDN Haemolytic Acute injury Chronic injury Cholestasis Cirrhosis Obstruction (Cholestasis) Total biiirubin ↑↑↑ ↑ ↑↑ N↑ ↑↑↑ ↑ ↑↑↑ Conjugated biiirubin N N ↑↑ N↑ ↑↑↑ ↑ ↑↑↑ Urine biiirubin 0 0 ↑↑↑ ↑ ↑↑↑ ↑ ↑↑↑ Urine urobilinogen 0 ↑ ↑ ↑ N↑ N↑ ↓↓ Faecal urobilinogen 0 ↑↑↑ ↓ ↓ ↓ N↓ ↓↓ Albumin - - N ↓ N ↓↓ N y-globulin - - ↑ ↑↑ N ↑↑ N Prothrombin Time - - ↑↑ ↑ ↑ N ↑ ALP - - ↑ ↑ ↑↑ N ↑↑↑ AST - - ↑↑↑↑ ↑ ↑↑ ↑ ↑↑ ALT - - ↑↑↑↑ ↑ ↑ N ↑
- 31. Clinical significance • Total bilirubin is increased mildly in chronic haemolytic disease (below 86 umol/L), moderately to severely in hepatocellular disease (170 to 510 umol/L) and markedly in cholestasis (internai or external obstruction of blood to bile flow, where the concentration would vary from 170 to 1030 umol/L). • Conjugated bilirubin: • Conjugated bilirubin is increased in both hepatocellular disease and cholestasis.
- 32. Unconjugated bilirubin • The increase in bilirubin concentration in haemolytic disease, including HDN, is almost entirely in this fraction. • It also accounts for about 30 - 50% of the bilirubin rise in hepatocellular disease or cholestasis. • Clinical Significance: Decreased concentration Total bilirubin : No clinical significance Conjugated bilirubin: No clinical significance Unconjugated bilirubin: No clinical significance
- 33. Urine Bilirubin • Bilirubin is not detectable by conventional methods in the urine of a normal, healthy person. • When present, urinary bilirubin indicates some pathologic condition of the liver or biliary system. • The bile pigment found in the urine in these conditions is conjugated bilirubin, the water- soluble fraction of total bilirubin. • The presence of any bilirubin in the urine is abnormal.
- 34. Urine Urobilinogen • The excretion of urinary urobilinogen is normally 1-4 mg/24hr. This excretion is elevated in haemolytic disease (excess production from bilirubin), in hepatocellular Liver disease(decreased removal by hepatocytes), and in congestive cardiac failure • (impaired circulation to the liver).
- 35. Faecal Urobilinogen • Decreased in hepatocellular disease, as well as in obstructions to the biliary tree. • Visual inspection of the faeces usually suffices to detect decreased urobilinogen, because the stools become pale or clay-coloured with decreasing amounts of pigment.