These slides describe in short about the conditions in which Hyperbilirubinemia can occur.

1. HYPERBILIRUBINEMIA

2. INTRODUCTION
• Hyperbilirubinemia :- An elevated level of the pigment bilirubin in the blood.
• Occurs when ,serum bilirubin >2 mg/dl
• Yellowing of the skin, scleras (white of the eye), and mucous membranes (jaundice)
• A sufficient elevation of bilirubin produces jaundice.
• Hyperbilirubinemia is a biochemical finding but jaundice is a clinical finding for increased
bilirubin levels in the blood.

3. BILIRUBIN METABOLISM

4. BILIRUBIN
FORMATION

5. HEPATOCELLULAR
BILIRUBIN TRANSPORT
 Transfer of bilirubin from blood to
bile involves four distinct but interrelated steps, as
follows:
 Hepatocellular Uptake
 Intracellular Binding
 Conjugation
 Biliary Excretion

6. BILIRUBIN AND
ITS BREAKDOWN

7. ENTEROHEPATIC
CIRCULATION

9. HEPATOCELLULAR CONDITIONS
THAT MAY PRODUCE JAUNDICE
1. Viral hepatitis
• Hepatitis A, B, C, D, and E
• Epstein-Barr virus
• Cytomegalovirus
• Herpes simplex
2. Alcohol
3. Drug toxicity
• Predictable, dose-dependent (e.g., acetaminophen)
• Unpredictable, idiosyncratic (e.g., isoniazid)
4. Environmental toxins
• Vinyl chloride
• Jamaica bush tea—pyrrolizidine alkaloids
• Kava Kava
• Wild mushrooms—Amanita phalloides or A. verna
5. Wilson's disease
6. Autoimmune hepatitis

10. CHOLESTATIC CONDITIONS THAT
MAY PRODUCE JAUNDICE
• 1. Intrahepatic
• Viral hepatitis
• 1. Fibrosing cholestatic hepatitis—hepatitis B and C
• 2. Hepatitis A, Epstein-Barr virus, cytomegalovirus
• Alcoholic hepatitis
• Drug toxicity
• 1. Pure cholestasis—anabolic and contraceptive steroids
• 2. Cholestatic hepatitis—chlorpromazine, erythromycin
estolate
• 3. Chronic cholestasis—chlorpromazine and
prochlorperazine
• Primary biliary cirrhosis
• Primary sclerosing cholangitis
• Vanishing bile duct syndrome
• 1. Chronic rejection of liver transplants
• 2. Sarcoidosis
• 3. Drugs
• Inherited
• 1. Progressive familial intrahepatic cholestasis
• 2. Benign recurrent cholestasis
• Cholestasis of pregnancy

11. CHOLESTATIC CONDITIONS THAT
MAY PRODUCE JAUNDICE
• 1. Intrahepatic
• Total parenteral nutrition
• Nonhepatobiliary sepsis
• Benign postoperative cholestasis
• Paraneoplastic syndrome
• Venoocclusive disease
• Graft-versus-host disease
• Infiltrative disease
• 1. TB
• 2. Lymphoma
• 3. Amyloid
• Infections
• 1. Malaria
• 2. Leptospirosis

12. CHOLESTATIC CONDITIONS THAT
MAY PRODUCE JAUNDICE
• 2. Extrahepatic
• A. Malignant
• 1. Cholangiocarcinoma
• 2. Pancreatic cancer
• 3. Gallbladder cancer
• 4. Ampullary cancer
• 5. Malignant involvement of the porta hepatis lymph nodes
• B. Benign
• 1. Choledocholithiasis
• 2. Postoperative biliary structures
• 3. Primary sclerosing cholangitis
• 4. Chronic pancreatitis
• 5. AIDS cholangiopathy
• 6. Mirizzi's syndrome
• 7. Parasitic disease (ascariasis)

13.  Hemolysis
 Increased destruction of RBCs
 eg sickle cell anemia, thalassemia
 Drastic increase in the amount of bilirubin produced
 Unconj. bilirubin levels rise due to liver’s inability to catch
up to the increased rate of RBC destruction
 Prolonged hemolysis may lead to precipitation of bilirubin
salts in the gall bladder and biliary network
 result in formation of gallstones and conditions such as
cholecystitis and biliary obstruction
UNCONJUGATED HYPERBILIRUBINEMIA

14. Clinical manifestation
• Unconjugated hyperbilirubinemia
• Normal serum level of transaminases,alkaline phosphatase,proteins
• Acholuric jaundice (bile pigment absent in urine)
• Dark brown color in stool
• Increased urinary excretion of urobilinogen

15. Ineffective erythropoiesis
develoing erythroid cells destroyed in bone marrow
fraction of total bilirubin production increased
unconjugated hyperbilirubinemia
Occurs in
• thalassemia major
• Megaloblastic anemia
• Congenital erythropoietic porphyria
• Lead poisoning
 Other
 Degradation of Hb
originating from areas of
tissue infarctions and
hematomas

16.  Several drugs have been reported to inhibit bilirubin
uptake by the liver
 e.g. novobiocin, flavopiridol, Rifampicin
Bile
MRP2
B + GST
CB
Plasma Hepatic cell
Alb
B
Alb :GSTB
sER
B + UDPGA
UGT1A1
Impairment in dissociation of bilirubin from albumin
Dearrangement of binding to cytoplasmic protein –GST

17. due to defect or deficiency in the enzyme bilirubin-UDP glucurunosyl transferase
Physiological jaundice of Newborn
incompletely developed hepatic physiologic processes
decreased UGT1A1 in neonates,alternate excretory pathway
unconjugated bilirubin in the gut
(intestinal flora under-developed;bilirubin urobilinogen)
enterohepatic circulation of unconjugated bilirubin
unconjugated hyperbilirubinemia (5-10mg/dl) in 2-5 days
 In pre-term infants,profound hepatic dysfunction can lead to higher levels of unconjugated
hyperbilirubinemia(>20mg/dl)
 Complication:kernicterus
 t/t:Phototherapy,exchange transfusion
3)

18. Impaired bilirubin conjugation
Acquired conjugation defects
• Breast milk jaundice
bilirubin conjugation inhibited by certain fatty acid present in breast milk
EGF in breast milk is also associated
• Diffuse hepatocellular disease
Hepatitis
cirrhosis
• Drugs inhibiting UGT1A1 activity
pregnanediol
Novobiocin
Chloramphenicol
Gentamicin

20. HEREDITARY DEFECTS IN BILIRUBIN
CONJUGATION
• Three familial disorders characterized by differing degrees of unconjugated
hyperbilirubinemia have long been recognized.
• Differing degrees of deficiency in the ability to conjugate bilirubin.
• Some of the disorders are as follows :-
• Crigler Najjar Syndrome
• Gilbert’s Syndrome

22. CRIGLER-NAJJAR SYNDROME
• This syndrome is of two types:-
• Crigler Najjar Syndrome Type 1
• Crigler Najjar Syndrome Type 2

23. CRIGLER NAJJAR SYNDROME TYPE 1
• Characterised by unconjugated hyperbilirubinemia of about 20-45 mg/dL.
• Rare disorder – Shows Autosomal Recessive Inheritence.
• Usually appears in Neonatal period and persists for life.
• Mutation in UGT1 gene.
• Conventional hepatic function tests are normal.
• Hepatic histology is normal but sometimes bile plugs can develop in canaliculi.
• Bilirubin glucuronides – Absent in the bile.
• No detectable constitutive expression of UGT1A1 activity in hepatic tissue.
• Unconjugated bilirubin accumulation (but can be excreted via alternative
pathways)
• No response to Phenobarbital or other enzyme inducers.
• Early liver transplantation remains the best hope to prevent brain injury and death.

24. Crigler Najjar
Syndrome
Type IB
Defect is limited
largely to bilirubin
conjugation
Mutation is in the
bilirubin-specific exon
A1
Type IA
Defects in the
glucuronide
conjugation of a
spectrum of substrates
Mutations in one of
the common exons
(2–5) of the UGT1
gene
Type II

25. CRIGLER NAJJAR SYNDROME TYPE 2
• Similar presentation to Crigler Najjar Syndrome Type 1
• Differences:
• Average bilirubin concentrations are lower in CN-II
• CN-II is only infrequently associated with kernicterus
• Bile is deeply colored
• Bilirubin glucuronides are present (Characteristic increase in the
proportion of monoglucuronides)
• UGT1A1 in liver is usually present at reduced levels (typically ≤10% of
normal)
• Reduction of serum bilirubin concentrations by >25% in response to enzyme
inducers such as phenobarbital distinguishes CN-II from CN-I.
• Incidence of kernicterus in CN-II is low

26. GILBERT SYNDROME
• Mild unconjugated hyperbilirubinemia.
• Serum bilirubin concentrations are most often <3 mg/dL
• M>F
• Normal values for standard hepatic biochemical tests
• Normal hepatic histology but modest increase in lipofuscin.
• Association with other conditions like stress, fatigue, alcohol use, etc. can aggrevate
the bilirubin levels
• Relieving factors :- enzyme inducing agents
• UGT1A1 activity is reduced to about 10-35% of normal.
• Phenobarbital normalizes serum bilirubin concentration and hepatic bilirubin
clearance
• Defect in bilirubin uptake as well as in conjugation

28. DISORDERS OF BILIRUBIN METABOLISM LEADING TO MIXED
OR PREDOMINANTLY CONJUGATED HYPERBILIRUBINEMIA

29.  Dubin–Johnson Syndrome
 mild conj. hyperbilirubinemia, but can increase with concurrent illness,
pregnancy, and use of oral contraceptives; otherwise asymptomatic
 Inability of hepatocytes to secrete CB after it has formed
 Due to mutation in the MRP2 gene (autosomal recessive trait)
 Liver histology shows black pigmentation
Bile
MRP2
B + GST
CB
Plasma Hepatic cell
Alb
B
Alb :GSTB
sER
B + UDPGA
UGT1A1

31. Rotor Syndrome
• Autosomal recessive condition
• Characterized by increased total bilirubin levels due to a rise in CB
• Caused by a defect in transport of bilirubin into bile
• Similar to Dubin –johnson , but no pigmentation in liver histology
• Total urinary coproporphyrin excretion is substantially increased in Rotor syndrome

33. BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS(BRIC)
• Autosomal recessive
• FIC1 gene mutated
• Characterised by recurrent attacks of pruritis and jaundice
• Typical episode
malaise
elevation in serum aminotransferase
rise in alkaline phosphatase and conjugated bilirubin
onset of jaundice and itching
• Benign because it does not lead to cirrhosis or end-stage liver disease

34. Progressive familial
intrahepatic cholestasis
Byler’s Disease
(Progressive FIC type 1)
Infancy
Progresses to
malnutrition, growth
retardation, and end-
stage liver disease
during childhood
FIC1 mutation
Progressive FIC type 2
Mutation in the protein
named Sister of p-
glycoprotein (aka
BSEP)
Progressive FIC type 3
Mutation of MDR3
Required for hepato
celluar excretion of
phospholipids
High serum levels of γ-
glutamyltransferase
activity

35. CHOLESTATIC CONDITIONS

36. CHOLESTATIC DISEASES :
CHOLESTASIS
• Cholestasis is caused by:
• impaired bile formation and
• bile flow
• Gives rise to accumulation of bile pigment in the hepatic parenchyma.
• Can be caused by:
• extrahepatic or intrahepatic obstruction of bile channels or
• defects in hepatocyte bile secretion.

37. CHOLESTATIC DISEASES :
CHOLESTASIS• Morphologic features of
cholestasis:
1. Cholestatic
hepatocytes are
enlarged
2. With dilated
canalicular spaces
3. Apoptotic cells may
be seen
4. Kupffer cells frequently
contain regurgitated
bile pigments

38. CHOLESTATIC DISEASES :
CHOLESTASIS
• Morphologic features of
cholestasis:
5. Bile plug (arrow)
showing the expansion
of bile canaliculus by
bile.
6. FEATHERY
DEGENERATION:
Droplets of bile
pigment also
accumulate within
hepatocytes, which
can take on a fine,
foamy appearance.

39. CHOLESTATIC DISEASES :
LARGE BILE DUCT OBSTRUCTION
• Most common cause of bile duct obstruction in adults:
• Extrahepatic cholelithiasis (gallstones) followed by
• Malignancies of the biliary tree or head of the pancreas, and
• Strictures resulting from previous surgical procedures.
• Obstructive conditions in children include:
• biliary atresia
• cystic fibrosis
• choledochal cysts
• syndromes in which there are insufficient intrahepatic bile
ducts.

40. CHOLESTATIC DISEASES :
LARGE BILE DUCT OBSTRUCTION
• Acute biliary obstruction, either intrahepatic or extrahepatic, causes
• Distention of upstream bile ductsbecome dilated.
• Bile ductules proliferate at the portalparenchymal interface, accompanied by
stromal edema and infiltrating neutrophils. These labyrinthine ductules reabsorb
secreted bile salts, serving to protect the downstream obstructed bile ducts from their
toxic detergent action.
• Histologic hallmark of ascending cholangitis is the influx of these periductular
neutrophils directly into the bile duct epithelium and lumen

41. CHOLESTATIC DISEASES :
LARGE BILE DUCT OBSTRUCTION
• Chronic biliary obstruction and ductular reactions: Secondary inflammation
initiate
• Periportal fibrosis, eventually leading to hepatic scarring and
• Nodule formation, generating secondary or obstructive biliary cirrhosis.

44. CHOLESTATIC DISEASES :
LARGE BILE DUCT OBSTRUCTION
• Chronic biliary obstruction and ductular reactions:Cholestatic features in the
parenchyma may be severe with:
• Extensive feathery degeneration of periportal hepatocytes
• Cytoplasmic swelling often with Mallory-Denk bodies (periportal predominance)
• Formation of bile infarcts from detergent effects of extravasated bile.
• Ascending cholangitis may be superimposed on this chronic process as well,
sometimes triggering acute on-chronic liver failure.

45. CHOLESTATIC DISEASES :
CHOLESTASIS OF SEPSIS
• Sepsis may affect the liver by several mechanisms:
• Through direct effects of intrahepatic bacterial infection (e.G., Abscess formation or
bacterial cholangitis),
• Ischemia relating to hypotension caused by sepsis (particularly when the liver is
cirrhotic), or
• In response to circulating microbial products (LPS).

46. CHOLESTATIC DISEASES :
CHOLESTASIS OF SEPSIS
• Two forms:
1. Canalicular cholestasis:
• Bile plugs within predominantly
centrilobular canaliculi.
• Associated with activated kupffer
cells and mild portal inflammation,
• But hepatocyte necrosis is scant or
absent

47. CHOLESTATIC DISEASES :
CHOLESTASIS OF SEPSIS
2. Ductular cholestasis:
• More ominous finding
• Dilated canals of hering and bile
ductules at the interface of portal
tracts and parenchyma become
dilated and contain obvious bile
plugs
• Often accompanies or even
precedes the development of
septic shock.

48. CHOLESTATIC DISEASES :
PRIMARY HEPATOLITHIASIS
• Hepatolithiasis is a disorder of intrahepatic gallstone formation that leads to
• Repeated bouts of ascending cholangitis
• Progressive inflammatory destruction of hepatic parenchyma
• Predisposes to biliary neoplasia.

49. CHOLESTATIC DISEASES :
PRIMARY HEPATOLITHIASIS
• Hepatolithiasis has pigmented
calcium bilirubinate stones in
distended intrahepatic bile ducts.
• The ducts show chronic
inflammation, mural fibrosis, and
peribiliary gland hyperplasia, all in
the absence of extrahepatic duct
obstruction.
• Biliary dysplasia may be seen and
may evolve to invasive
cholangiocarcinoma.

50. CHOLESTATIC DISEASES :
NEONATAL CHOLESTASIS
• Prolonged conjugated hyperbilirubinemia in the neonate beyond 14-21 days
after birth.
• Major causes:
• Neonatal Hepatitis
• Biliary Atresia
• Differentiation between two must: surgical correction for Biliary Atresia

52. CHOLESTATIC DISEASES :
NEONATAL CHOLESTASIS
• Neonatal hepatitis is not a specific
entity
• Nor are the disorders necessarily
inflammatory.
• Morphologic findings
• Lobular disarray with focal liver cell
apoptosis and necrosis
• Panlobular giant-cell transformation
of hepatocytes
• Prominent hepatocellular and
canalicular cholestasis

53. CHOLESTATIC DISEASES :
NEONATAL CHOLESTASIS
• Morphologic findings
• Mild mononuclear infiltration of the
portal areas;
• Reactivechanges in kupffer cells;
and
• Extramedullary hematopoiesis.
• Parenchymal pattern of injury may
blend into a ductal pattern of injury:
• With ductular reaction
• And fibrosis of portal tracts
• In these cases distinction froman
obstructive biliary atresia may
therefore be difficult.

54. CHOLESTATIC DISEASES :
NEONATAL CHOLESTASIS
• Biliary Atresia:
• Biliary atresia is defined as a complete or partial obstruction of the lumen of the
extrahepatic biliary tree within the first 3 months of life.
• Two forms:
1. Fetal form:
• aberrant intrauterine development of the extrahepatic
biliary tree
1. Perinatal form:
 presumed normally developed biliary tree is destroyed
following birth.
 Etiology unknownviral infection (Reovirus, rotavirus,and
cytomegalovirus) and autoimmunereactions are leading
suspects.

55. CHOLESTATIC DISEASES :
NEONATAL CHOLESTASIS
• Variability in the anatomy of biliary atresia:
• Common duct (type I)
• Right and/or left hepatic bile ducts (type II)
• Obstruction of bile ducts at or above the porta hepatis(type III)
• Salient features of biliary atresia:
• Inflammation and fibrosing stricture of the hepatic or common bile ducts
• Periductular inflammation may progress into the intrahepatic bile ductsprogressive
destruction of the intrahepatic biliary tree

56. • Primary Biliary Cirrhosis
• PBC is an autoimmune disease characterized by nonsuppurative, inflammatory
destruction of small and medium sized intrahepatic bile ducts. Large intrahepatic
ducts and the extrahepatic biliary tree are not involved.
• Pathogenesis
• AMA : recognize the E2 component of the pyruvate dehydrogenase complex (PDC-E2)
• PDC-E2–specific T cells
• Aberrant expression of MHC class II molecules on bile duct epithelial cells, accumulation of
autoreactive T cells around bile ducts, and antibodies against other cellular components
CHOLESTATIC DISEASES :
AUTOIMMUNE CHOLANGIOPATHIES

57. • Primary Biliary Cirrhosis:
• Sagittal section: liver enlargement,
nodularity indicative of cirrhosis,
and green discoloration due to
cholestasis.
CHOLESTATIC DISEASES :
AUTOIMMUNE CHOLANGIOPATHIES

58. • Primary Biliary Cirrhosis:
• Ductular reactions follow duct
injury, and these in turn
participate in the development
of portal-portal septal fibrosis
CHOLESTATIC DISEASES :
AUTOIMMUNE CHOLANGIOPATHIES

59. • Primary Biliary Cirrhosis:
• THE FLORID DUCT LESION:
Interlobular bile ducts are actively
destroyed by lymphoplasmacytic
inflammation with or without
granulomas
CHOLESTATIC DISEASES :
AUTOIMMUNE CHOLANGIOPATHIES

61. • Primary Sclerosing Cholangitis (PSC)
• PSC is characterized by inflammation and obliterative fibrosis of intrahepatic and
extrahepatic bile ducts with dilation of preserved segments.
• Pathogenesis:
• Immunologically mediated injury to bile ducts:
• T cells in the periductal stroma
• Presence of circulating autoantibodies
• Association with HLA-B8 and other MHC antigens
• Linkage to ulcerative colitis
• It has been proposed that T cells activated in the damaged mucosa of patients with
ulcerative colitis migrate to the liver where they recognize a cross-reacting bile duct
antigen.
• Autoantibody profiles in PSC are not as characteristic as they are in PBC
CHOLESTATIC DISEASES :
AUTOIMMUNE CHOLANGIOPATHIES

62. • Primary Sclerosing Cholangitis (PSC):
• Large duct inflammation:
• Similar to ulcerative colitis
• Acute, neutrophilic infiltration of
the epithelium superimposed on a
chronic inflammatory
background.
• Inflamed areas develop strictures
because edema and
inflammation narrows the lumen or
because of subsequent scarring.
• Smaller ducts:
• Little inflammation
• Striking circumferential
“onion skin” fibrosis
around an increasingly
atrophic duct lumen
eventually leading to
obliteration by a
“tombstone” scar.
CHOLESTATIC DISEASES :
AUTOIMMUNE CHOLANGIOPATHIES

63. • Primary Sclerosing Cholangitis (PSC):
• Because the likelihood of sampling smaller duct lesions on a
random needle biopsy is miniscule, diagnosis depends on
radiologic imaging of the extrahepatic and larger
intrahepatic ducts.
CHOLESTATIC DISEASES :
AUTOIMMUNE CHOLANGIOPATHIES