7. Pathway of bilirubin synthesis and breakdown? Causes of Jaundice?

• Bilirubin is a waste product excreted via bile, generated from the break-down
of worn out RBCs – more specifically, the degradation of heme (iron-
containing part of Hb). This bilirubin is extracted from the blood by
hepatocytes and excreted via bile.
• Most of the breakdown of bilirubin is from senescent erythrocytes (worn out
RBCs), but also from the turnover of hepatic hemoproteins from premature
destruction of newly formed erythrocytes in BM.
• The pathway involves: heme oxygenase oxidises heme to biliverdin which is
then reduced to biliverdin reductase. Bilirubin is formed outside the liver in
cells of mononuclear phagocytes/reticuloendothelial cells (such as in spleen,
macrophages etc) is released and bound to serum albumin. This bilirubin is
unconjugated and is not water soluble in the blood. Therefore purpose of liver
processes is conjugation to make it soluble in bile for excretion. Liver
processes includes;
1. carrier mediated uptake at the sinusoidal membrane (transport)
2. cytosolic protein binding and delivery to endoplasmic reticulum
(absorption, conversion)
3. conjugation with 1 or 2 molecules of glucoronic acid by bilirubin
uridine diphosphate-glucuronosyltransferase (conjugation – made
water soluble for bile)
4. Excretion of the water-soluble non-toxic bilirubin glucuronides into
bile.
5. gut bacteria deconjugates the bilirubin and degrade it to colourless
urobilinogens which is then excreted in urine. It is further oxidise to
form stercobilins which is excreted in feces. Feces darkens by
oxidation in air to give its proper colour…
• Bilirubin is a yellow pigment that gives bile its yellow colour. In gut though it
goes colourless due to bacteria, hence feces colour isn’t that yellowish
• A small amount is normally reabsorbed by the intestine back into the blood,
also excreted through urine and responsible for yellow colour. It can only be
excreted by kidneys after modification in liver and intestine.
• If bilirubin is formed more rapidly that it can be cleared, it accumulates in
body = jaundice – patients appear yellowish esp in whites of eyes (sclera).

Types and causes of Jaundice:

Types

• Prehepatic – or haemolytic – jaundice due 2 excessive breakdown of RBC,

liver’s capabilities stretched. Often medical treatment
• Hepatic – liver itself is diseased and cant deal with normal load
• Posthepatic – or obstructive, processing is fine, but elimination is hindered by
obstruction such as gallstone i.e. cant excrete in feces properly. Often surgical.

Causes

1. excessive production of bilirubin, normal is 0.2-0.3 g a day e.g. haemolytic

anaemia, internal haemorrhage
 2. reduced hepatic uptake e.g. drug interference, viral hep
3. impaired conjugation e.g. newborns…
4. decreased hepatocellular excretion e.g. deficiency in transporters,
hepatocellular damage etc
5. impaired bile flow (intra and extra hepatic) e.g. obstruction

• 1-3 are called unconjugated hyperbilirubinemia (pre and hepatic), 4-5, are
conjugated hyperbilirubinemia – refers to post.

• Also inborn errors in metabolism – gilbert syndrome- inherited and dubin-

johnson syndrome – autosomal recessive defect. Both effect pathway at some
point.

Sherwood, Robbins pathology