DEFINITION: Icterus A yellowish tint to the body tissues; yellowness of the skin and deep tissues

0.5 mg/dl of plasma

Above 1.5mg/dl- jaundice appears

Heme Anabolism & Heme Catabolism

Bilirubin metabolism (RES)

heme

Requires: O2, NADPH Catalysed by: Heme oxygenase

Requires: NADPH biliverdin Catalysed by: Biliverdin reductase Requires: albumin bilirubin For: Transport to liver through plasma

Conjugation of bilirubin (liver)

Unconjugated bilirubin

Binds to ligandin Z-proteins/Y-proteins

Requires: glucoronic acid Catalysed by: Glucoronyl transferase

Conjugated bilirubin

Bilirubin monoglucuronide Bilirubin diclucuronide excreted in bile

Disposal of bilirubin (GIT)

Degraded by: bacterial Bilirubin betaglucoronidase oxidized Color of stool and urine

stercobilin

Conjugated bilirubin

urobilinogen urobilin

Unconjugated Bilirubin Indirect Bilirubin Solubility Normal Amount in blood Lipid Soluble 1mg/dl

Conjugated Bilirubin Diglucuronide Direct Bilirubin Water Soluble Well below 1/2mg/dl

Also known as

Accumulation

Increased Hgb to salvage

Malfunction in hepatocyte/ biliary tree

Diagnostic tests

Not detected in urine

Detected in urine

Causes of Jaundice
Predominantly Unconjugated hyperbilirubinemia: I. Excess production of bilirubin II. Reduced hepatic uptake III. Impaired bilirubin conjugation

Predominantly Conjugated Hyperbilirubinemia

1. Deficiency of canalicular membrane transporters
Dubin-Johnson syndrome, Rotor syndrome

2. Impaired bile flow.

UGT, uridine diphosphate-glucuronyltransferase.

 Conjugated Hyperbilirubinemia
Unconjugated Hyperbilirubinemia

 Water soluble and is seen in urine at low levels Urobilinogen will be absent in urine with cholestasis Abnormal liver laboratory Elevated alkaline phosphatase and gammaglutamyl transpeptidase (GGTP) suggest intra/ extrahepatic obstruction

 Tightly bound to albumin and will not appear in the urine Should have normal liver laboratory, CBC and smear may show anemia and hemolysis Gilberts syndrome is most common cause
Increase bilirubin may be seen with fever, exertion, fasting, surgery, and heavy alcohol use

 CHOLURIC presence of bile derivatives in the urine

Occurs in regurgitation hyperbilirubinemia Obstructive type

ACHOLURIC absence of bile derivatives in urine

presence of an excess unconjugated bilirubin Retention hyperbilirubinemia Hemolytic type

Conjugated Bilirubinemia
Jaundice is choluric

Unconjugated bilirubinemia
Jaundice is acholuric

Jaundice is mostly due to Jaundice is mostly due to posthepatic causes. Hepatic causes prehepatic causes. Hepatic causes include infective hepatitis. include neonatal jaundice.

Kernicterus can never occur Stool may be clay colored Van den Berg reaction is direct

Kernicterus can occur Stool is never clay colored Van den berg reaction is indirect.

PRE- HEPATIC
Indicates events in the blood stream. Haemolysis - more bilirubin produced than can be conjugated and excreted.

HEPATIC
Signifies events in the Liver.

POST-HEPATIC
Refers to events in the biliary tree 'Cholestasis' or 'biliary obstruction' conjugation occurs, but bile cannot be excreted, as outflow is blocked. Conjugated hyperbilirubinaemia Dark : Urine Dark : Feaces

Acute hepatitis - hepatocytes function poorly, so have difficulty conjugating and excreting bilirubin.

Unconjugated hyperbilirubinaemia Normal : Urine Pale : Feaces

Mixed

Dark : Urine Dark : Feaces

CLINICAL Defect in uptake of bilirubin by liver cells Immature hepatic conjugating system BIOCHEMICAL Slight change in liver cells Severe increase of Alkaline Phospholipase (APL) Gilbert's syndrome is a congenital disorder of bilirubin metabolism

CLINICAL Presence of tumors, structures

BIOCHEMICAL Mild to severe increase of APL

CLINICAL Liver damage (hepatitis, cirrhosis)

BIOCHEMICAL With marked biochemical change in liver cells Marked increase in APL

 Bilirubin is produced by the normal breakdown of red blood cells. Jaundice occurs when bilirubin builds up faster than a newborn's liver can break it down and pass it from the body.

Reasons for this: Too large an amount of bilirubin is reabsorbed from the intestines before the baby gets rid of it in the stool. A newborn baby's still-developing liver may not yet be able to remove adequate bilirubin from the blood. Newborns make more bilirubin than adults do since they have more turnover of red blood cells.

 High levels of bilirubin usually above 25 mg can cause deafness, cerebral palsy, or other forms of brain damage in some babies. Jaundice may indicate the presence of another condition, such as an infection or a thyroid problem.

 Also called hematogenous jaundice. Massive lysis of red blood cells may produce bilirubin faster than it can be conjugated. Normally that liver produces 300 mg of bilirubin per day but has the capacity to excrete over 3 000 mg.

 Under these conditions there is an increase bilirubin is excreted into the bile, the amount of urobilinogen entering the enterohepatic circulation is increased, and urinary urobilinogen is increased. Hemolytic jaundice is the presentation of an increase in unconjugated bilirubin levels in the blood.

 The common causes of hemolytic jaundice include Rh hemolytic disease, ABO incompatibility, G-6-PD deficiency and minor blood group incompatibility. Rh hemolytic disease
A baby born to an Rh-negative mother (and Rh-positive father) should have Rh typing and a Direct Coombs test (DCT) on cord blood.

ABO Incompatibility
Babies born to women with O blood group should be closely monitored for jaundice and discharged after 72 hours.

 Other hemolytic states

G6PD deficiency, hereditary spherocytosis, minor group incompatibilities should be managed similar to ABO incompatibility.

 also known as plethora. A condition where there is an increase in Red Blood Cells in relation to the blood volume. As the blood cells begin to breakdown after its normal lifespan, there will be increase of bilirubin production than normal due to the abnormally high amounts of red blood cells in the circulation.

 There will be increase of bilirubin production than normal due to the abnormally high amounts of red blood cells in the circulation.

This will cause an accumulation of bilirubin in the blood leading to jaundice.

 Leakage of blood from the blood vessels into the tissues. Does not cause an increase in neither conjugated nor unconjugated bilirubin in the blood.

 It causes local accumulation of bilirubin in the affected tissue and subsequently causes local jaundice in that area. This in turn will be phagocytosed by cell macrophages for further breakdown to biliverdin then to unconjugated bilirubin

 Conjugated hyperbilirubinemia commonly results from blockage of the hepatic or common bile ducts, most often due to a gallstone or to cancer of the head of the pancreas. Once biliburin sent to the liver, it will be conjugated to bind with glucoronic acid or sulfate before it is excreted into the bile and finally the intestines.

 The conversion of free bilirubin to the conjugated form requires a specific enzyme called UDP glucoronyltransferase.

Some disorders that is conjugated bilirubin: Dubin Johnson Syndrome, Cholestatic jaundice of pregnancy, and Alcoholic liver diseases.

 A condition wherein there is jaundice in an exclusively breast fed baby who is otherwise healthy. It develops after the first week of life and continues up to the sixth week of life. The presence of the progesterone called 3-alpha20 beta pregnanediol in the breast milk of some women.

 3 alpha 20 beta pregnanediol counteracts the effect of UDP- glucoronyltransferase, the enzyme responsible for conjugating free bilirubin in the liver. Caused by factors in the breast milk, which block certain proteins in the liver that break down bilirubin.

 Bile duct obstruction is a blockage in the tubes that carry bile from the liver to the gallbladder and small intestine. When the bile ducts become blocked bile builds up in the liver.

 Jaundice develops due to the increasing levels of bilirubin in the blood. Patients with Dubin-Johnson Syndrome, Hepatic tumor or common bile stones suffer from obstructive jaundice.

 http://www.gpnotebook.co.uk/simplepage.cfm?I D=-536477635&linkID=7340&cook=no DISORDERS OF BILIRUBIN METABOLISM Namita Roy Chowdhur Irwin M. Arias Allan W. Wolkoff Jayanta Roy Chowdhury Color Atlas of Physiology by Stephan Silbernagl and Agamemnon Despopoulos