CAPÍTULO V EL DIA FELIZ
4. La colección de libros
ADH release may be impaired by certain substances (eg, ethanol, phenytoin) and central diabetes insipidus
Water intake decreases serum osmolality. Low serum osmolality inhibits ADH secretion, allowing the kidneys to produce dilute urine.
32) ON BILIRUBIN METABOLISM Dear Yin Ling,
when we see a patient with jaundice, the physiology of Bilirubin metabolism must be at the back of our minds in order to think of differential diagnosis. This separates medicine from quackery. Not all jaundice is due to liver diseases and liver diseases are not always accompanied with jaundice!!
Bilirubin, a physiological product of RBC, is metabolized in the liver and excreted into bile ducts; an appearance of jaundice means that there is a breakdown of balance of bilirubin metabolism and the patient may have a problem in the liver, or RBC
production and destruction, or excretion of bilirubin. eg hemolytic diseases: Always keep it in mind when managing a patient with jaundice.
Bilirubin is an end product of heme metabolism, coming mainly, 70 ~ 80 %, from hemoglobin of senescent red blood cells; it splits to heme and globin, then further split to iron and biliverdin, and the biliverdin converts to bilirubin.
Bilirubin combines with albumin in the blood stream, only separated just before being uptaken into liver cells. The bilirubin in the hepatocytes conjugates with
glucuronic acid to become conjugated bilirubin, which is excreted to the biliary tract and intestines and finally excreted.
The bilirubin from hemoglobin is free unconjugated bilirubin in the blood stream and is not soluble in water. After being taken into hepatocytes, it is converted to soluble conjugated form and excreted into bile ducts.
The bilirubin is divided into two types, direct reacting bilirubin and indirect reacting bilirubin, according to its mode of reaction during the test process. It can be
recognized that direct reacting bilirubin is the conjugated bilirubin and the indirect reacting bilirubin as unconjugated bilirubin.
Conjugated bilirubin is absorbed in the distal portion of the ileum after its hydrolyzed and converted to URObilinogen by the intestinal pathogens.
About 15 ~ 20 % of the urobilinogen is reabsorbed from the intestine into portal veins and finally 90% of them return to the liver and is re-‐excreted in the bile, the entero-‐hepatic circulation of bilirubin. The remaining 10 % gets into the systemic circulation and finally excreted in the urine through kidney. Thus urine urobilinogen increases in hemolytic disease.
Hyperbilirubinemia -‐-‐ jaundice occurs when the bilirubin balance between production and excretion breaks down.
the possible causes of hyperbilirubinemia:
1. over production of bilirubin from hemolysis
2. the impairment in bilirubin uptake and conjugation in the liver, 3. impaired excretion from the liver cells or the liver
4. the unconjugated and conjugated bilirubin that is leaked into the blood stream from damaged liver cells.
High-‐unconjugated-‐bilirubinemia
(1) Overproduction:
Normal liver can handle the amount of seven times of normal daily bilirubin production.
When the production of bilirubin is increased due to hemolysis and and Ineffective erythropoiesis beyond the ability of normal liver to handle, the serum indirect
bilirubin will increase and this is prehepatic jaundice. AST, ALT and Alk-‐P, that reflect the damage of hepatocytes will remain normal and predominantly indirect bilirubin is increased. Note that The conjugated bilirubin may increase slightly because of the high turnover.
(2) Abnormality in uptake and conjugation:
Serum indirect bilirubin may increase when there is problems of uptake and conjugation in the liver cells of bilirubin. This is non-‐hemolytic unconjugated hyperbilirubinemia.
Crigler-‐Najjar syndrome (congenital non-‐hemolytic jaundice) is caused by the deficiency of glucuronyl transferase. The symptoms will appear in the infant stage, and there are two types, Type I is more severe than Type II, and may induce
kernicterus.
Gilbert's syndrome or idiopathic unconjugated hyperbilirubinemia is caused by the similar mechanism as Crigler-‐Najjar syndrome, and only different in degree.
High-‐conjugated-‐bilirubinemia:
unconjugated-‐bilirubin conjugates with glucuronic acid to become conjugated-‐
bilirubin.
When transportation of conjugated-‐bilirubin is impaired in the liver during the
excretion process from liver cells or during passage from bile ductules, the condition is called cholestatic jaundice.
(1) Intrahepatic causes of cholestasis:
The jaundice in drug-‐induced hepatitis and in pregnancy is intra-‐hepatic cholestasis.
Dubin-‐Johnson Syndrome and Rotor Syndrome are congenital causes of intrahepatic cholestasis. The increase of serum bilirubin is mainly conjugated-‐bilirubin, and Rotor syndrome is considered as a variant of Dubin-‐Johnson syndrome. Morphologically, melanin pigments deposit in the liver cells are noted in Dubin-‐Johnson syndrome but not in Rotor Syndrome.
Primary biliary cirrhosis shows obstruction of biliary ductules and inter-‐lobular bile ductules.
Primary/secondary sclerosing cholangitis will induce hyper-‐conjugated-‐
bilirubinemia.
In hepatocyte diseases, i.e. acute and chronic liver diseases including cirrhosis, the uptake, conjugation and excretion of bilirubin in the hepatocytes are impaired and induce an intra-‐hepatic cholestasis. Therefore, the serum bilirubin elevation is a mixed type.
(2) Extrahepatic cholestasis:
Stones, parasites, tumours in the biliary tract, biliary obstruction due to external compression from Ca Pancreas will induce elevation in serum conjugated-‐bilirubin.
No conjugated bilirubin is present in normal urine. Only conjugated-‐bilirubin will pass through renal glomeruli. Serum level of bilirubin does not parallel to the amount of urinary bilirubin.
Urobilinogen-‐ only a small part of urobilinogen absorbed from the intestinal tract is excreted out of the body through the kidney, and most of the urobilinogen return to the liver and are re-‐excreted to the intestinal tract.
The amount of urinary urobilinogen is affected by the amount of conjugated-‐
bilirubin in the biliary duct and also intestinal pathogens that convert bilirubin to urobilinogen.
Urobilinogen is a colourless product of bilirubin reduction. This constitutes the
"enterohepatic urobilinogen cycle".
Increased amounts of bilirubin are formed in haemolysis, which generates increased
urobilinogen in the gut.
In liver disease (such as hepatitis), the intrahepatic urobilinogen cycle is inhibited also increasing urobilinogen levels.
Urobilinogen is converted to the yellow pigmented urobilin apparent in urine.
The urobilinogen is reduced to stercobilinogen in the intestine and is then oxidized to brown stercobilin, which gives the feces their characteristic color.
In biliary obstruction, below-‐normal amounts of conjugated bilirubin reach the intestine for conversion to urobilinogen. With limited urobilinogen available for reabsorption and excretion, the amount of urobilin found in the urine is low. High amounts of the soluble conjugated bilirubin enter the circulation where they are excreted via the kidneys. These mechanisms are responsible for the dark urine and pale stools observed in biliary obstruction.
Low urine urobilinogen may result from complete obstructive jaundice or treatment with broad-‐spectrum antibiotics, which destroy the intestinal bacterial flora.
(Obstruction of bilirubin passage into the gut or failure of urobilinogen production in the gut.)
33) on LIVER ENZYMES