2. JAUNDICE
The common causes of jaundice are
1. Bilirubin overproduction,
2.Hepatitis,
3.Obstruction of the flow of bile.
3. Hepatic bile serves two major functions:
(1)The emulsification of dietary fat in the
lumen of the gut through the detergent
action of bile salts, and
(2) The elimination of bilirubin, excess
cholesterol.
4. Alterations of bile formation become clinically
evident as
yellow discoloration of the skin and sclera
(jaundice and icterus, respectively) due to
retention of bilirubin.
5. The metabolism of bilirubin by the liver consists of
four events: USCE
1.uptake from the circulation;
2. intracellular storage;
3.conjugation with glucoronic acid;
4.biliary excretion.
6. Bilirubin and Bile Formation
Bilirubin is the end product of heme
degradation.
• The majority of daily production (0.2 to 0.3
gm, 85%) is derived from breakdown of
senescent red cells by the mononuclear
phagocytic system, especially in the spleen,
liver, and bone marrow.
7. • Most of the remainder (15%) of bilirubin is
derived from the
• turnover of hepatic heme or hemoproteins
(e.g., the P-450 cytochromes) and
• from premature destruction of red cell
precursors in the bone marrow
8. • Intracellular heme oxygenase oxidizes heme
to biliverdin (step 1 ), which is immediately
reduced to bilirubin by biliverdin reductase.
9. • Bilirubin thus formed outside the liver is
released and bound to serum albumin (step
2).
10. • Albumin binding is necessary to transport
bilirubin because bilirubin is virtually
insoluble in aqueous solutions at physiologic
pH.
11. • Hepatic processing of bilirubin involves
carrier-mediated
uptake at the
sinusoidal membrane (step 3),
12. •conjugation
with one or two molecules of glucuronic acid by
bilirubin uridine diphosphate (UDP)–
glucuronyltransferase (UGT1A1, step 4) in the
endoplasmic reticulum, and
excretio
nof the water-soluble, nontoxic bilirubin
13. • Most bilirubin glucuronides are
deconjugated in the gut
lumen by bacterial β-glucuronidases and
degraded to colorless
urobilinogens (step 5).
14. • The urobilinogens and the residue of intact
pigment are largely excreted in feces.
15. • Approximately 20% of the urobilinogens
formed are reabsorbed in the ileum and
colon, returned to the liver, and re-excreted
into bile.
16. • A small amount of reabsorbed urobilinogen
is excreted in the urine.
17. Bilirubin metabolism and elimination.
(1) Normal bilirubin production from heme (0.2–0.3
gm/day) is derived primarily from the breakdown of
senescent circulating erythrocytes.
(2) Extrahepatic bilirubin is bound to serum albumin and
delivered to the liver.
(3) Hepatocellular uptake and
(4) glucuronidation in the endoplasmic reticulum
generate bilirubin monoglucuronides and
diglucuronides, which are water soluble and readily
excreted into bile.
(5) Gut bacteria deconjugate the bilirubin and degrade
it to colorless urobilinogens. The urobilinogens and
the residue of intact pigments are excreted in the
feces, with some reabsorption and excretion into
urine.
18.
19. Pathophysiology of Jaundice
• Both unconjugated bilirubin and conjugated
bilirubin (bilirubin glucuronides) may
accumulate systemically. There are two
important pathophysiologic differences
between the two forms of bilirubin.
20. • Unconjugated bilirubin is virtually
insoluble in water at physiologic pH and
exists in tight complexes with serum albumin.
This form cannot be excreted in the urine
even when blood levels are high.
21. • Normally, a very small amount of
unconjugated bilirubin is present as an
albumin-free anion in plasma. This fraction of
unbound bilirubin may diffuse into tissues,
particularly the brain in infants, and produce
toxic injury.
22. • The unbound plasma fraction may increase in
severe hemolytic disease or when protein-
binding drugs displace bilirubin from
albumin. Hence, hemolytic disease of the
newborn (erythroblastosis fetalis) may lead
to accumulation of unconjugated bilirubin in
the brain, which can cause severe neurologic
damage, referred to as kernicterus.
23. • In contrast, conjugated bilirubin is water-
soluble, nontoxic, and only loosely bound to
albumin. Because of its solubility and weak
association with albumin, excess conjugated
bilirubin in plasma can be excreted in urine.
24. • With prolonged conjugated
hyperbilirubinemia, a portion of circulating
pigment may become covalently bound to
albumin; this is termed the bilirubin delta
fraction.
25. • Serum bilirubin levels in the normal adult
vary between 0.3 and 1.2 mg/dL, and
• the rate of systemic bilirubin production is
equal to the rates of hepatic uptake,
conjugation, and biliary excretion.
26. • Jaundice becomes evident when the serum
bilirubin levels rise above 2.0 to 2.5 mg/dL;
levels as high as 30 to 40 mg/dL can occur
with severe disease.
27. Jaundice occurs when the equilibrium between
bilirubin production and clearance is disturbed by
one or more of the following mechanisms :
(1) excessive extrahepatic production of bilirubin;
(2) reduced hepatocyte uptake;
(3) impaired conjugation;
(4) decreased hepatocellular excretion; and
(5) impaired bile flow.
28. • The first three mechanisms produce
unconjugated hyperbilirubinemia, and the
latter two produce predominantly
conjugated hyperbilirubinemia.
29.
30.
31. Neonatal Jaundice
Because the hepatic machinery for conjugating and
excreting bilirubin does not fully mature until
about 2 weeks of age, almost every newborn
develops transient and mild unconjugated
hyperbilirubinemia, termed neonatal jaundice or
physiologic jaundice of the newborn.
32. • This may be exacerbated by breastfeeding, as
a result of the presence of bilirubin-
deconjugating enzymes in breast milk.
Nevertheless, sustained jaundice in the
newborn is abnormal.
33. Cholestasis
Cholestasis denotes a pathologic condition of
impaired bile formation and bile flow,
leading to accumulation of bile pigment in
the hepatic parenchyma.
34. It can be caused by extrahepatic or
intrahepatic obstruction of bile channels, or
by defects in hepatocyte bile secretion.
35. • Patients may have jaundice, pruritus, skin
xanthomas (focal accumulation of
cholesterol), or symptoms related to
intestinal malabsorption, including
nutritional deficiencies of the fat-soluble
vitamins A, D, or K.
36. • A characteristic laboratory finding is elevated
serum alkaline phosphatase and γ-glutamyl
transpeptidase (GGT), enzymes present on
the apical membranes of hepatocytes and
bile duct epithelial cells.
