Jaundice - Etiology, pathogenesis, Clinical features, Investigation, Treatment and Outcome

Jaundice - Etiology, pathogenesis, Clinical features, Investigation, Treatment and Outcome

1. Jaundice
Dr. M. N. Astagimath, M.D.
Associate Professor
Department of Biochemistry
KIMS, Hubli

2. Jaundice
•Jaundice, or icterus, is a yellowish
discoloration of tissue resulting from the
deposition of bilirubin.
•Tissue deposition of bilirubin occurs
only in the presence of serum
hyperbilirubinemia and is a sign of
either liver disease or, less often, a
hemolytic disorder.

3. Differential Diagnosis
•The differential diagnosis for yellowing of
the skin is limited. In addition to jaundice, it
includes carotenoderma, the use of the
drug quinacrine, and excessive exposure
to phenols.

4. Indicator of increased serum
hyperbilirubinemia
•The presence of scleral icterus indicates a
serum bilirubin of at least 3.0 mg/dl
•Underneath the tongue
•Darkening of the urine
•The skin will eventually become yellow

5. Sources of Bilirubin
•A tetrapyrrole pigment, is a breakdown
product of heme (ferroprotoporphyrin IX)
•250 to 300 mg of bilirubin produced each
day
•70 to 80% derived from the breakdown of
hemoglobin in senescent red blood cells
•Remainder comes from prematurely
destroyed erythroid cells and from the
turnover of hemoproteins

6. Bilirubin

7. Formation of bilirubin
•Formation of bilirubin occurs in
reticuloendothelial cells.
•First reaction, catalyzed by the enzyme
heme oxygenase, oxidatively cleaves
the abridge of the porphyrin group and
opens the heme ring.
•The end products of this reaction are
biliverdin, carbon monoxide, and iron.

9. Formation of bilirubin
•The second reaction, catalyzed by the
cytosolic enzyme biliverdin reductase,
reduces the central methylene bridge of
biliverdin and converts it to bilirubin

11. Transport to Liver
•Bilirubinis virtually insoluble in water
•Aqueous solubility 0.1-5 mg/dl
•Transportof unconjugated bilirubin in the
bloodis accomplished by its reversible, non-
covalent binding to albumin
•Each molecule of albumin has
-one “high affinity binding site
(binds about 25mg/dl)
-one “low affinity” binding site
•The excess bilirubin is loosely bound and
thus easily detached, which diffuses into
tissues.

12. Uptake by Liver
•Bilirubin most likely enters the hepatocyte both by a facilitated
transport mechanism and by passive diffusion
•Unconjugated bilirubin bound to albumin, but not the albumin,
is taken up by hepatocytes
•Carrier-mediated facilitated membranetransport is the
predominant process
•Several putative bilirubin transporters have been identified
•Lateral extension of plasma membrane of liver cells facing
hepatic sinusoids has specific “receptor sites” for bilirubin

13. Intracellular Binding
•Having crossed the plasma membrane to
enter the cell, bilirubin partitions between
the lipid environment of intracellular
membranes
•In the aqueous cytosol, in which it is kept
in solution by binding as a nonsubstrate
ligand to several of the glutathione-s-
transferases, formerly called ligandins.

14. Conjugation
•When the carboxyl groups are esterified by
conjugation with glucuronic acid residues, the
internal hydrogen bonding is disrupted,
rendering the resulting mono-and
diglucuronide conjugates highly soluble in
aqueous solution
•Catalyzed by a specific UDP-
glucuronosyltransferase

15. Bilirubin Diglucuronide

17. UDP-glucuronosyltransferase
•Various first exons encode the specific
substrate-binding sites for each isoform, while
the shared exons encode common
glycosylation, UDP-glucuronic acid-binding,
transmembrane, and stop transfer domains.
•Encoded by the Exon A1 and the four common
exons, collectively designated the UGT1A1
gene.
•Mutation in one of the first exons will affect
only a single enzyme isoform. By contrast, a
mutation in exons 2 to 5 will alter all isoforms
encoded by the UGT1gene complex.

18. Biliary Excretion
•Normal bile
-less than 5% unconjugated bilirubin
-7% bilirubin monoconjugates
-90% bilirubin diconjugates.
•Bilirubin mono-and diglucuronides are
excreted across the canalicular plasma
membrane into the canaliculus by an ATP-
dependent transport process mediated by a
canalicular membrane protein called
multidrug resistance-associated protein 2
(MRP2).

19. BILIRUBIN IN PLASMA
•Indeed, when the direct-reacting fraction is
less than 15% of total bilirubin at virtually
any total bilirubin concentration, the
bilirubin in the sample can be considered
as essentially all unconjugated.

20. Bilirubin in the Gut
•An appreciable fraction is converted to
urobilinogen and related compounds by
bacterial metabolism within the ileum and
colon.
•Urobilinogen is reabsorbed from these sites,
reaches the liver via the portal circulation,
and is reexcreted into bile, undergoing an
enterohepatic circulation.
•Urobilinogen not taken up by the liver
reaches the systemic circulation, from which
some is cleared by the kidneys.

21. Renal Excretion of Bilirubin Conjugates
•Unconjugated bilirubin is not excreted in
urine no matter how high its plasma
concentration, since it is too tightly bound to
albumin for effective glomerular filtration
and there is no tubular mechanism for its
renal secretion.
•polar bilirubin conjugates are far less tightly
bound to albumin and are readily filtered at
the glomerulus
•bilirubinuria indicates the presence of
conjugated bilirubin in plasma and,
therefore, hepatobiliary dysfunction.

22. Liver Diseases
Inherited hyperbilirubinemia•
Gilbert's syndrome
•
Crigler
-
Najjar syndrome, types I and II
•
Dubin
-
Johnson syndrome
•
Rotor syndrome
Viral hepatitis•
Hepatitis A
•
Hepatitis B
•
Hepatitis C
•
Hepatitis D
•
Hepatitis E
•
Others (mononucleosis, herpes, adenovirus hepatitis)
•
Cryptogenic hepatitis
Immune and autoimmune liver diseases•
Primary biliary cirrhosis
•
Autoimmune hepatitis
•
Sclerosing cholangitis
•
Overlap syndromes
•
Graft
-
vs
-
host disease
•
Allograft rejection

23. Liver Diseases
Genetic liver diseases
A
1 Antitrypsin deficiency
•
Hemochromatosis
•
Wilson's disease
•
Benign recurrent intrahepatic cholestasis
•
Familial intrahepatic cholestasis (FIC)
•
Others (galactosemia, tyrosinemia, cystic fibrosis, Newman
-
pick, Gaucher's
disease)
Alcoholic liver disease•
Acute fatty liver
•
Acute alcoholic hepatitis
•
Laennec's cirrhosis
Nonalcoholic fatty liver•
Steatosis and Steatohepatitis

24. Liver Diseases
Liver involvement in systemic
diseases
•
SarcoidosisAmyloidosis, glycogen storage diseases, celiac disease, tuberculosis
Cholestatic syndromes•
Benign postoperative cholestasis
•
Jaundice of sepsis
•
Total parenteral nutrition (TPN)
-
induced jaundice
•
Cholestasis of pregnancy
•
Cholangitis and cholecystitis
•
biliary obstruction (stone, stricture, cancer)
•
Biliary atresia
•
Caroli's disease

25. Liver Diseases
Drug
-
induced liver disease
•
Hepatocellular patterns (isoniazid, acetaminophen)
•
Cholestatic patterns (methyltestosterone)
•
Mixed patterns (sulfonamides, phenytoin)
•
Micro
-
and macrovesicular
steatosis (methotrexate, fialuridine)
Vascular injuryMass lesionsCysts

26. Over production
Hemolysis.
Icreased destruction of erythrocytes leads
to increased bilirubin turnover and
unconjugated hyperbilirubinemia.
Normal liver function.
Direct-reacting fraction as measured in a
typical clinical laboratory being 15% of
the total serum bilirubin.

27. Over production
Ineffective Erythropoiesis.
•Megaloblastic anemias, congenital
erythropoietic porphyria, lead poisoning,
and various dyserythropoietic anemias.
•Total bilirubin production derived from
ineffective erythropoiesis is increased,
reaching as much as 70% of the total, and
may be sufficient to produce modest
degrees of unconjugated
hyperbilirubinemia.

28. Uptake by Liver
•Decreased hepatic bilirubin uptake is
believed to contribute to the
unconjugated hyperbilirubinemia of
Gilbert's syndrome (GS).
•Drugs, including flavispidic acid,
novobiocin, and various
cholecystographic contrast agents,
have been reported to inhibit bilirubin
uptake.

29. Impaired Conjugation
•Physiologic neonatal jaundicebirth. Peak
levels are typically less than 85 to 170
umol/l (5 to 10 mg/dl) and decline to normal
adult concentrations within 2 weeks.
•Prematurity -absolute levels in excess of
340 umol/l (20 mg/dl), puts the infant at risk
for bilirubin encephalopathy, or kernicterus,
in which bilirubin crosses an immature
blood-brain barrier and precipitates in the
basal ganglia and other areas of the brain.

30. HEREDITARY DEFECTS IN
BILIRUBIN CONJUGATION
Crigler-Najjar syndrome, type I (CN-I).
•Unconjugated hyperbilirubinemia (20 to 45
mg/dl) that appears in the neonatal period
and persists for life.
•Absent bilirubin-UDP-glucuronosyltransferase
enzymatic activity.
Crigler-Najjar syndrome, type II (CN-II).
•Lower bilirubin, characteristic increase in
monoglucuronides.
•UGT1A1 is usually present at reduced levels.

31. Gilbert's syndrome
•Mild unconjugated hyperbilirubinemia,
•Normal biochemical tests, and histology.
•UGT1A1 activity is typically reduced to 10
to 35% of normal,
•A characteristic increase in bilirubin
monoglucuronides.
•That hepatic bilirubin clearance is reduced
to an average of one-third of normal.

32. Acquired Conjugation Defects
•Advanced hepatitis or cirrhosis.
•However, conjugation is better preserved
than canalicular excretion.
•Various drugs, including pregnanediol,
novobiocin, chloramphenicol, and
gentamicin, may produce unconjugated
hyperbilirubinemia by inhibiting UGT1A1
activity.
•Breast milk jaundice-certain FAs and the
progestational steroid 3a,20b-pregnanediol.
•Lucey-Driscoll syndrome).

33. DEFECTS IN HEPATIC
EXCRETION
Dubin-Johnson syndrome
•Benign,low-grade (2 and 5 mg/dl),
predominantly conjugated
hyperbilirubinemia.
•A cardinal feature of Dubin-Johnson
syndrome is the accumulation in the
lysosomes of centrilobular hepatocytes of
dark, coarsely granular pigment. As a
result, the liver may be grossly black in
appearance.

34. Rotor Syndrome
•Liver in patients with rotor syndrome has
no increased pigmentation and appears
totally normal.
•The only abnormality in routine
laboratory tests is an elevation of
predominant total serum conjugated
bilirubin.
•No reflux of conjugated BSP back into
the circulation as seen in Dubin-Johnson
syndrome.

35. Benign Recurrent Intrahepatic
Cholestasis (BRIC)
•Recurrent attacks of pruritus and
jaundice.
•Begins with mild malaise and
elevations in serum aminotransferase
levels, followed rapidly by rises in
alkaline phosphatase and bilirubin
and onset of jaundice and itching.

36. Differential Diagnosis of Jaundice
Tests Pre
Hepatic Hepatic
Post
Hepatic
Conj. BilirubinAbsent  
AST & ALT N  N
ALP N Normal 
Urine BilirubinAbsent Present Present
Urine
Urobilinogen
Present Present Absent

37. NORMAL BILIRUBIN
METABOLISM
Uptake of bilirubin by the liver is mediated by
a carrier protein (receptor)
Uptake may be competitively inhibited by
other organic anions
On the smooth ER, bilirubin is conjugated with
glucoronic acid, xylose, or ribose
Glucoronic acid is the major conjugate -
catalyzed by UDP glucuronyl tranferase
“Conjugated” bilirubin is water soluble and is
secreted by the hepatocytes into the biliary
canaliculi
Converted to stercobilinogen (urobilinogen)
(colorless) by bacteria in the gut
Oxidized to stercobilin which is colored
Excreted in feces
Some stercobilin may be re-adsorbed by the
gut and re-excreted by either the liver or
kidney

38. Prehepatic (hemolytic) jaundice
•Results from excess
production of bilirubin
(beyond the livers ability
to conjugate it) following
hemolysis
•Excess RBC lysis is
commonly the result of
autoimmune disease;
hemolytic disease of the
newborn (Rh-or ABO-
incompatibility);
structurally abnormal
RBCs (Sickle cell disease);
or breakdown of
extravasated blood
•

39. Intrahepatic jaundice
•Impaired uptake,
conjugation, or
secretion of bilirubin
•Reflects a generalized
liver (hepatocyte)
dysfunction
•In this case,
hyperbilirubinemia is
usually accompanied by
other abnormalities in
biochemical markers of
liver function

40. Posthepatic jaundice
•Caused by an obstruction
of the biliary tree
•Plasma bilirubin is
conjugated, and other
biliary metabolites, such
as bile acids accumulate in
the plasma
•Characterized by pale
colored stools (absence of
fecal bilirubin or urobilin),
and dark urine (increased
conjugated bilirubin)
•In a complete obstruction,
urobilin is absent from the