Jaundice, or yellowing of the skin and eyes, is caused by elevated levels of bilirubin in the blood. Bilirubin is produced from the breakdown of red blood cells and processed by the liver. Elevated bilirubin levels can be due to excessive red blood cell breakdown (pre-hepatic), impaired liver function (hepatic), or blocked bile ducts (post-hepatic). The most common causes of jaundice are viral hepatitis infections which cause inflammation of the liver.
4. LiverLiver
• Largest internal organ
• Weighs about 1400-1800 gram
• Located on right side under
ribcage
• Ability to regenerate
• Has over 500 vital functions
• Involved in many digestive,
vascular and metabolic
activities
5. Introduction
• Bilirubin is the orange-yellow pigment derived from
senescent red blood cells.
• It is a toxic waste product in the body.
• It is extracted and biotransformed mainly in the liver, and
excreted in bile and urine.
• It is a bile pigment
• Elevations in serum and urine bilirubin levels are normally
associated with Jaundice.
6. Erythrocytes become “old” as they lose their flexibility
and become pikilocytes (spherical), increasingly rigid
and fragile. Once the cell become fragile, they easily
destruct during passage through tight circulation
spots, especially in spleen, where the intra-capillary
space is about 3 micron as compared to 8 micron of
cell size
RBCs useful life span is 100 to 120 days,After
which they become trapped and fragment in smaller
circulatory channels, particularly in those of the spleen.
For this reason, the spleen is sometimes called the “red
blood cell graveyard.”
Dying erythrocytes are engulfed and destroyed by
macrophages.
7. Formation of Bilirubin
• Primary site of synthesis:-
SPLEEN: The Graveyard
of Red Blood Cells
• Secondary site of synthesis:-
LIVER & BONE MARROW
8. An average person
produces about 4
mg/kg of bilirubin
per day.
The daily bilirubin
production from all
sources in man
averages from 250
to 300 mg.
TOTAL BILIRUBIN
HEMOGLOBIN
FROM SENESCENT
RBC’S DESTROYED IN
RETICULOENDOTHELIAL
CELLS OF
LIVER, SPLEEN &
BONE MARROW
RBC PRECURSORS
DESTROYED IN THE
BONE MARROW
85% 15%
CATABOLISM OF
HEME-CONTAINING
PROTEINS (MYOGLOBIN,
CYTOCHROMES &
PEROXIDASES)
9. Extravascular Pathway for RBC Destruction
(Liver, Bone marrow,
& Spleen)
Hemoglobin
Globin
Amino acids
Amino acid pool
Heme Bilirubin
Fe2+
Excreted
Phagocytosis & Lysis
Recycled
11. • The globin is recycled or converted into amino acids, which
in turn are recycled or catabolized as required.
• Heme is oxidized, with the heme porphyrin ring being
opened by the endoplasmic reticulum enzyme, heme
oxygenase.
• The oxidation occurs on a specific carbon producing
equimolar amounts of the biliverdin, iron , and carbon
monoxide (CO). This is the only reaction in the body that is
known to produce CO.
• Most of the CO is excreted through the lungs, with the
result that the CO content of expired air is a direct measure
of the activity of heme oxygenase in an individual.
12. III IVI II
Oxidation Heme Oxygenase
In the first reaction, a
bridging methylene
group is cleaved by
heme oxygenase to
form Linear Biliverdin
from Cyclic Heme
molecule.
Fe 2+ is released from
the ring in this process.
16. • In the next reaction, a second
bridging methylene (between
rings III and IV) is reduced by
biliverdin reductase,
producing bilirubin.
I
I III
III IV
IV
II
II
Reduction Biliverdin Reductase
17. • biliverdin causing a change in the color of the molecule
from blue-green (biliverdin) to yellow-red (bilirubin).
• The latter catabolic changes in the structure of tetrapyrroles
are responsible for the progressive changes in color of a
hematoma, or bruise, in which the damaged tissue changes
its color from an initial dark blue to a red-yellow and finally
to a yellow color before all the pigment is transported out of
the affected tissue.
• Peripherally arising bilirubin is transported to the liver in
association with albumin, where the remaining catabolic
reactions take place.
• biliverdin causing a change in the color of the molecule
from blue-green (biliverdin) to yellow-red (bilirubin).
• The latter catabolic changes in the structure of tetrapyrroles
are responsible for the progressive changes in color of a
hematoma, or bruise, in which the damaged tissue changes
its color from an initial dark blue to a red-yellow and finally
to a yellow color before all the pigment is transported out of
the affected tissue.
• Peripherally arising bilirubin is transported to the liver in
association with albumin, where the remaining catabolic
reactions take place.
18. Bilirubin is not very water-soluble, so most of it is carried to the liver bound to
albumin.
19. In cells of the liver, bilirubin undergoes modification to
increase its water solubility so that it can be excreted more
easily.
a.Bilirubin is conjugated to two
molecules of glucuronic acid, creating
bilirubin diglucuronide.
b. Bilirubin diglucuronide is transported
out of the hepatocytes into the bile
canaliculi and is thus excreted in bile.
In cells of the liver, bilirubin undergoes modification to
increase its water solubility so that it can be excreted more
easily.
a.Bilirubin is conjugated to two
molecules of glucuronic acid, creating
bilirubin diglucuronide.
b. Bilirubin diglucuronide is transported
out of the hepatocytes into the bile
canaliculi and is thus excreted in bile.
20. In Blood
• The bilirubin synthesized in
spleen, liver & bone marrow
is unconjugated bilirubin.
• It is hydrophobic in nature so
it is transported to the liver
as a complex with the
plasma protein, albumin.
Unconjugated bilirubin
– Lipid soluble
– : limits excretion
– 1 gm albumin binds 8.5
mg bilirubin
– Fatty acids & drugs can
displace bilirubin
– Indirect positive reaction
in van den Bergh test
Unconjugated bilirubin
– Lipid soluble
– : limits excretion
– 1 gm albumin binds 8.5
mg bilirubin
– Fatty acids & drugs can
displace bilirubin
– Indirect positive reaction
in van den Bergh test
21. Role of Blood Proteins in the
Metabolism of Bilirubin
1. Albumin
Dissolved in Blood
23. In Endoplasmic Reticulum
In the microsomes of the endoplasmic reticulum,
unconjugated bilirubin is converted to water soluble
mono- or di- conjugates by sequential covalent
coupling with glucuronic acid.
34. In the Intestine
• In the small intestine, conjugated bilirubins are poorly
reabsorbed, but are partly hydrolyzed back to unconjugated
bilirubin by catalytic action of bacterial ß-glucuronidases.
• In the distal ileum and colon, anaerobic flora mediate further
catabolism of bile pigments:
a) hydrolysis of conjugated bilirubin to unconjugated bilirubin by
bacterial β-glucuronidases;
b) multistep hydrogenation (reduction) of unconjugated bilirubin to
form colorless urobilinogens; and
c) oxidation of unconjugated bilirubin to brown colored
mesobilifuscins.
35. • Urobilinogens is a collective
term for a group of 3
tetrapyrroles;
– Stercobilinogen (6H)
– Mesobilinogen (8H)&,
– Urobilinogen (12H)
• Upto 20 % of urobilinogen
produced daily is reabsorbed
from the intestine & enters the
entero-hepatic circulation.
Urobilinogen Structure
36. • Most of the reabsorbed urobilinogen is taken up by the liver
& is re-excreted in the bile.
• A small fraction (2 % - 5 %) enters the general circulation &
appears in the urine.
• In the lower intestinal tract, the 3 urobilinogens
spontaneously oxidize to produce the corresponding bile
pigments;
– Stercobilin
– Mesobilin &
– Urobilin;
which are orange-brown in color and are the major
pigments of stool.
41. SYMPTOMSSYMPTOMS
o Yellowing of the skin, scleras (white of the eye), andYellowing of the skin, scleras (white of the eye), and
mucous membranes (jaundice)mucous membranes (jaundice)
o Detectable when total plasma bilirubin levels exceedDetectable when total plasma bilirubin levels exceed
2mg/100mL2mg/100mL
AHHH!!! I have symptoms
of hyperbilirubinemia!!!
42. Clinical Significance
Hyperbilirubinemia & Types of Jaundice
• Hyperbilirubinemia : Increased plasma concentrations
of bilirubin (> 3 mg/dl) occurs when there is an
imbalance between its production and excretion.
• Recognized clinically as jaundice.
• Also known as icterus, a yellow discoloration of the
skin, sclerae and mucous membrane.
43.
44.
45. • Jaundice becomes clinically evident when the serum
bilirubin level exceeds 2.5mg/dL.
• Several types of Jaundice:
– Hemolytic
– Hepatocellular
– Obstructive
• Symptoms:
– Yellow discoloration of the skin, sclerae and mucous
membranes
– Itching (pruritus) due to deposits of bile salts on the skin
– Stool becomes light in color
– Urine becomes deep orange and foamy
46. Different Causes of Jaundice
• Excessive Production of Bilirubin
• Reduced Hepatocyte Uptake
• Impaired Bilirubin conjugation
• Impaired Bile Flow
50. 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
• High plasma concentrations of
unconjugated bilirubin (normal
concentration ~0.5 mg/dL)
51. Hepatic 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
52. What is Hepatitis?
• Inflammation of the liver
• Caused by viruses, alcohol, medications, and
other toxins
• This training will focus on viral hepatitis
Hepatitis A Virus (HAV)Hepatitis A Virus (HAV)
Hepatitis B Virus (HBV)Hepatitis B Virus (HBV)
Hepatitis C Virus (HCV)Hepatitis C Virus (HCV)
Hepatitis D Virus (HDV)Hepatitis D Virus (HDV)
Hepatitis E Virus (HEV)Hepatitis E Virus (HEV)
Hepatitis F
Hepatitis G (not confirmed yet).
These viruses all affect the liver but otherwise are unique
53. Acute Hepatitis
• Hepatitis can be defined as a constellation of
signs & symptoms resulting from
inflammation & hepatic cell necrosis
• In a previously asymptomatic individual the
term “acute” is applied
• Virus is the most common cause of
hepatitis.
– Only occasionally can bacterial infections like
syphilis or TB be considered
• Most cases of acute hepatitis are sub-clinical
& usually undiagnosed
54. Hepatitis A (HAV)Hepatitis A (HAV)
At one time, hepatitis A was referred to as "infectious hepatitis" because it could be
spread from person to person like other viral infections. Infection with hepatitis A virus
can be spread through the ingestion of food or water, especially where unsanitary
conditions allow water or food to become contaminated by human waste containing
hepatitis
Found in the stool (feces) of persons infectedFound in the stool (feces) of persons infected
with hepatitis A viruswith hepatitis A virus
HAV is usually spread by “fecal-oralHAV is usually spread by “fecal-oral
transmission”transmission”
– Putting something in the mouth (food,Putting something in the mouth (food,
water, hands) that has been contaminatedwater, hands) that has been contaminated
with the stool of a person with hepatitis Awith the stool of a person with hepatitis A
– Most infections come from contact with aMost infections come from contact with a
household member or sex partner who hashousehold member or sex partner who has
hepatitis Ahepatitis A
Highly infectious and stable in environment forHighly infectious and stable in environment for
monthsmonths
55. Signs and Symptoms of HAV
• jaundice
• fatigue
• abdominal pain
• loss of appetite
• nausea
• diarrhea
• fever
Adults have signs and symptoms more
often than children
Incubation Period: 15-50 days
(average 28 days)
56. Hepatitis B (HBV)Hepatitis B (HBV)
Type B hepatitis was at one time referred to as "serum hepatitis," because it was
thought that the only way hepatitis B virus (HBV) could spread was through blood
or serum
About 6-10% of patients with hepatitis B develop chronic HBV infection (infection
lasting at least six months and often years to decades) and can infect others as
long as they remain infected. Patients with chronic hepatitis B infection also are at
risk of developing cirrhosis, liver failure and liver cancer.
HBV is spread throughHBV is spread through
unprotected sex with an infectedunprotected sex with an infected
personperson
by sharing drugs, needles, or "works"by sharing drugs, needles, or "works"
when using drugswhen using drugs
through needlesticks or sharpsthrough needlesticks or sharps
exposures on the jobexposures on the job
from an infected mother to her babyfrom an infected mother to her baby
during birthduring birth
The best way to protect against HBV isThe best way to protect against HBV is
vaccinationvaccination
57. HBV Structure & Antigens
Dane particleDane particle
HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr)
HBcAg = inner core protein (a single serotype)
HBeAg = secreted protein; function unknown
58. There are 4There are 4 open reading framesopen reading frames derived from the same strand (thederived from the same strand (the
incomplete + strand)incomplete + strand)
• SS - the 3 polypeptides of the surface antigen (- the 3 polypeptides of the surface antigen (preS1, preS2 and SpreS1, preS2 and S --
produced from alternative translation start sites.produced from alternative translation start sites.
• CC - the core protein- the core protein
• PP - the polymerase- the polymerase
• XX - a transactivator of viral transcription (and cellular genes?).- a transactivator of viral transcription (and cellular genes?).
HBx is conserved in all mammalian (but not avian) hepadnaviruses.HBx is conserved in all mammalian (but not avian) hepadnaviruses.
Though not essential in transfected cells, it is required for infectionThough not essential in transfected cells, it is required for infection
in vivo.in vivo.
Open Reading Frames
59. Type C hepatitis was previously referred to as "non-A, non-B hepatitis,
Patients with chronic hepatitis C infection are at risk for developing cirrhosis, liver
failure, and liver cancer.
The hepatitis C virus (HCV) usually is spread by shared needles among drug
abusers, blood transfusion, hemodialysis, and needle sticks. Approximately 90% of
transfusion-associated hepatitis is caused by hepatitis C
Hepatitis C (HCV)
Preventing HCV InfectionPreventing HCV Infection
There isThere is nono vaccinevaccine
Best prevention is behaviorBest prevention is behavior
changechange
Do not shoot drugsDo not shoot drugs
Do not share personal itemsDo not share personal items
such as razors or toothbrushessuch as razors or toothbrushes
Avoid tattoos or body piercingAvoid tattoos or body piercing
60. Symptoms of HCV
• jaundice
• fatigue
• dark urine
• abdominal pain
• loss of appetite
• nausea
80% of persons have no signs or symptoms80% of persons have no signs or symptoms
Incubation Period: 14-180 days (average 45 days)Incubation Period: 14-180 days (average 45 days)
• HCV disease does not appear to accelerate HIV diseaseHCV disease does not appear to accelerate HIV disease
• Higher toxicity fromHigher toxicity from Highly Active Antiretroviral TherapyHighly Active Antiretroviral Therapy
((HAART)HAART)
• As people live longer with HIV, manyAs people live longer with HIV, many more HIV deaths aremore HIV deaths are
caused by HCV-related end stage liver diseasecaused by HCV-related end stage liver disease
• There is still a lot of research to be done on these effectsThere is still a lot of research to be done on these effects
Potential Co-Infection Effect ofPotential Co-Infection Effect of HCVHCV on HIV Diseaseon HIV Disease
61. Types D, E, F, and G HepatitisTypes D, E, F, and G Hepatitis
There also are viral hepatitis types D, E, F (not confirmed yet), and G. The most
important of these at present is the hepatitis D virus (HDV), also known as the delta virus
or agent. It is a small virus that requires concomitant infection with hepatitis B to survive.
HDV cannot survive on its own because it requires a protein that the hepatitis B virus
makes (the envelope protein, also called surface antigen) to enable it to infect liver cells.
Hepatitis D OverviewHepatitis D Overview
Caused by hepatitis D virus (HDV)Caused by hepatitis D virus (HDV)
Coined “Delta Hepatitis”Coined “Delta Hepatitis”
Rarely seen in the United StatesRarely seen in the United States
FoundFound onlyonly in persons infected with HBVin persons infected with HBV
and has similar routes of transmission as HBVand has similar routes of transmission as HBV
Prevention is vaccination for HBVPrevention is vaccination for HBV
Hepatitis E OverviewHepatitis E Overview
Caused by hepatitis E virusCaused by hepatitis E virus
Primarily a disease of importPrimarily a disease of import
Very similar to hepatitis A with fecal-oral transmissionVery similar to hepatitis A with fecal-oral transmission
Transmitted like HAV with the same symptomsTransmitted like HAV with the same symptoms
No vaccination available
62.
63. HbsAHbsA
gg
Anti-Anti-
HH
BsBs
Anti-Anti-
HH
BcBc
HBeHBe
AgAg
Anti-Anti-
HH
BeBe
InterpretationInterpretation
++ -- IgMIgM ++ -- Acute HBV, high infectivityAcute HBV, high infectivity
++ -- IgGIgG ++ -- Chronic HBV, high infectivityChronic HBV, high infectivity
++ -- IgGIgG -- ++ Late-acute or chronic HBV infection, lowLate-acute or chronic HBV infection, low
infectivityinfectivity
++ ++ ++ +/-+/- +/-+/- Heterotypic anti-HBs with HBsAg;Heterotypic anti-HBs with HBsAg;
usually indicates chronic HBV carrierusually indicates chronic HBV carrier
statestate
-- -- IgMIgM +/-+/- +/-+/- Acute HBV infection (anti-HBc window)Acute HBV infection (anti-HBc window)
-- ++ IgGIgG -- +/-+/- Recovery from HBV infectionRecovery from HBV infection
-- -- IgGIgG -- +/-+/- Low-level HBsAg carrier or remote pastLow-level HBsAg carrier or remote past
infectioninfection
-- ++ -- -- -- Immunization for HBV (with HBsAg)Immunization for HBV (with HBsAg)
64. Alcoholic Hepatitis
• An acute or chronic illness involving the liver
with necrosis, inflammation & scarring
• 95% develop a fatty liver which is a reversible
process
• Encephalopathy & death 20%
• 30% go on to cirrhosis within 6 mo
• 50% of those abstaining for 6 mo recover
completely
65. Alcoholic Hepatitis
Symptoms
• Most patients are symptomatic. The most
common complaints are:
– Anorexia, nausea, vomiting
– Abdominal pain (RUQ)
– Fever (due to infection or inflammation of liver)
– Weight loss due to anorexia
– Jaundice is usually mild
– Diarrhea which is due to portal hypertension
66. Alcoholic Liver DiseaseAlcoholic Liver Disease
Alcoholic HepatitisAlcoholic Hepatitis
• Characteristics:Characteristics:
1.1. Hepatocyte swelling & necrosisHepatocyte swelling & necrosis ballooning dueballooning due
to accumulation of fat, water & proteinsto accumulation of fat, water & proteins
2.2. Mallory bodies – eosinophilic cytoplasmicMallory bodies – eosinophilic cytoplasmic
inclusions in degenerating hepatocytesinclusions in degenerating hepatocytes
3.3. Neutrophilic reaction – accumulate aroundNeutrophilic reaction – accumulate around
degenerating hepatocytes (“satellitosis”)degenerating hepatocytes (“satellitosis”)
4.4. Fibrosis – (+) activation of sinusoidal stellate cellsFibrosis – (+) activation of sinusoidal stellate cells
& portal tract fibroblasts& portal tract fibroblasts
67. • Hemolytic jaundice arises as a
consequence of excessive destruction
of RBCs.
• – This overloads the capacity of the RE
system to metabolize heme.
• – Failure to conjugate bilirubin to
glucuronic acid causes accumulation of
bilirubin in the unconjugated form in the
blood.
68. • Hepatocellular jaundice arises from
liver disease, either inherited or
acquired.
• – Liver dysfunction impairs conjugation of
bilirubin.
• – Consequently, unconjugated bilirubin
spills over into the blood.
• –In addition, urobilinogen is elevated in
the urine.
69.
70. Ongoing liver damage with liver cell necrosis
followed by fibrosis and hepatocyte
regeneration results in cirrhosis. This
produces a nodular, firm liver. The nodules
seen here are larger than 3 mm and, hence,
this is an example of "macronodular"
73. Obstructive jaundice
Definition :
Is a condition
characterized by
Yellow discoloration
of the skin , sclera &
mucous membrane as
a result of an elevated
Sr. Bilirubin conc. due
to an obstructive cause.
74. Posthepatic(Obstructive) 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
urine.
75. • • Obstructive jaundice, as the name implies,
is caused by blockage of the bile duct by a
gallstone or a
• tumor (usually of the head of the pancreas).
• – This prevents passage of bile into the intestine
and consequently conjugated bilirubin builds up
in the blood.
• – Patients with this condition suffer severe
abdominal pain associated with the
obstruction (if due togallstone) and their feces
are gray in color due to lack of stercobilin.
76. Pre-hepatic Hepatic Post hepatic
cause Excessive break down
Of RBC’s
Malaria,HS
Gilbert Syndrome
Infective
Liver Damage
Bile Duct Obstruction
Serum Bilirubin unconjugated Both conj+unconj. conjugated
Urine bilirubin Absent
Achloric jaundice
Bilirubinemia +
Deep yellow urine
As in hepatic jaundice
++
Urine
urobilinogen
Increases
Because of increased
stercobilinogen
Decreases
Because of decreased
stercobilinogen
Absent(-)
Fecal
stercobilinogen
20-250mg/day
Markedly increased
Dark brown stool
Reduced
Pale coloured stool
Absent
clay colored stool
Fecal fat 5-6% normal Increased 40-50%
Bulky,pale greasy foul
smelling faeces
As hepatic jaundice
Liver functions normal Impaired SGOT/SGPT Normal
Alkaline phosphatase++
Vonden burg test Indirect+ biphasic Direct+
78. Neonatal Jaundice
• Common, particularly in premature infants.
• Transient (resolves in the first 10 days).
• Due to immaturity of the enzymes involved in bilirubin
conjugation.
• High levels of unconjugated bilirubin are toxic to the
newborn – due to its hydrophobicity it can cross the
blood-brain barrier and cause a type of mental
retardation known as kernicterus
• If bilirubin levels are judged to be too high, then
phototherapy with UV light is used to convert it to a
water soluble, non-toxic form.
79.
80. • If necessary, exchange blood transfusion is used to remove
excess bilirubin
• Phenobarbital is oftentimes administered to Mom prior to
an induced labor of a premature infant – crosses the
placenta and induces the synthesis of UDP glucuronyl
transferase
• Jaundice within the first 24 hrs of life or which takes longer
then 10 days to resolve is usually pathological and needs
to be further investigated
81. CLINICAL FEATURES
• Severe unconjugated hyperbilirubinemia at birth
Prior to phototherapy:
• Kernicterus
• Death in infancy
82. Phototherapy
•Phototherapy is usually not needed
unless the bilirubin levels rise very
quickly or go above 16-20 mg/dl in
healthy, full term babies.
• During phototherapy, the
treatment of choice for
jaundice, babies are placed
under blue lights that convert
the bilirubin into compounds
that can be eliminated from
the body.
84. Bilirubin Toxicity - Kernicterus
• Kernicterus or brain encephalopathy refers to the yellow
staining of the deep nuclei (i.e., the kernel) of the brain
namely, the basal ganglia.
• It is a form of permanent brain damage caused by
excessive jaundice.
• The concentration of bilirubin in serum is so high that it can
move out of the blood into brain tissue by crossing the fetal
blood-brain barrier.
• This condition develops in newborns with prolonged
jaundice due to:
– Polycythemia
– Rh incompatibility between mother & fetus
86. Isolated increased serum bilirubin
Ruling out of hemolysis, subsequent fractionation of the bilirubin
Possibility of the
following syndromes:
• Dublin-Johnson
• Rotor
Possibility of following syndromes
based on the bilirubin concentration:
• Gilbert’s - <3 mg/dl
• Crigler-Najjar (Type I) - >25 mg/dl
• Crigler-Najjar (Type II) - 5 to 20 mg/dl
• Lucey-Driscoll - Transiently ~ 5 mg/dl
Algorithm for differentiating the familial causes of
Hyperbilirubinemia
Conjugated Unconjugated
87. Crigler-Najjar Syndrome (Type I)
• Crigler-Najjar Syndrome (Type I) is a rare genetic disorder
caused by complete absence of UDP-
glucuronyltransferase and manifested by very high levels of
unconjugated bilirubin.
• It is inherited as an autosomal recessive trait.
• Most patients die of severe brain damage caused by
kernicterus within the first year of life.
• Early liver transplantation is the only effective therapy.
88. Crigler-Najjar Syndrome (Type II)
• This is a rare autosomal dominant disorder.
• It is characterized by partial deficiency of UDP-
glucuronyltransferase.
• Unconjugated bilirubin is usually 5 – 20 mg/dl.
• Unlike Crigler-Najjar Type I, Type II responds
dramatically to Phenobarbital & a normal life can be
expected.
89. Gilbert’s Syndrome
• Gilbert’s syndrome is also called as familial non-hemolytic
non-obstructive jaundice.
• mild unconjugated Hyperbilirubinemia.
• It affects 3% – 5% of the population. It is often misdiagnosed
as chronic Hepatitis.
• The concentration of Bilirubin in serum fluctuates between 1.5
& 3 mg/dl.
• In this condition the activity of hepatic glucuronyltransferase is
low as a result of mutation in the bilirubin-UDP-
glucuronyltransferase gene(UGT1A1).
90. Dubin-Johnson Syndrome
• It is a benign, autosomal recessive
condition characterized by jaundice
with predominantly elevated
conjugated bilirubin and a minor
elevation of unconjugated bilirubin.
• Excretion of various conjugated
anions and bilirubin into bile is
impaired, reflecting the underlying
defect in canalicular excretion.
• The Liver has a characteristic
greenish black appearance and liver
biopsy reveals a dark brown melanin-
like pigment in hepatocytes and
kupffer cells.
91. Rotor’s Syndrome
• It is another form of conjugated hyperbilirubinemia.
• It is similar to dubin-johnson syndrome but without
pigmentation in liver.
Hinweis der Redaktion
Classical anatomic landmarks in the average 1400-1800 gram adult liver. Structure The liver is encased in a fibroelastic capsule called Glisson's capsule and is grossly separated into right and left lobes. Glisson's capsule contains blood vessels, lymph vessels, and nerves. The two liver lobes consist of many smaller units called lobules. The lobules contain the liver cells (hepatocytes) that line up together in plates. The hepatocytes are considered to be the functional units of the liver. Liver cells are capable of cell division and readily reproduce when needed to replace damaged tissue.
The liver is nothing more than an array of cells between the portal and caval venous systems. This shows the direction of flow. The liver gets about 80% of its blood supply from the portal veins and 20% from the hepatic arterial system. The IDEAL three-dimensional diagram: Hexagonal Hepatic “LOBULE” From the point of view of anatomy, physiology, and pathology, you must clearly understand the DIRECTION is: Portal vein Sinusoids Central vein Hepatic Veins IVC Crucially important concept worth repeating. KNOW the difference between an acinus and a lobule. The best tip to understanding liver disease is to understand the direction of blood flow. TOXIC injuries generally do more damage in the part of the liver closest to the PORTAL vein, and HYPOXIC injuries generally do more damage in the parts of the liver around the CENTRAL vein, i.e., centrolobular necrosis.
The classical view of liver tissue from a liver biopsy, H&E stained. The FIRST part of the lobule, i.e., portal triad is the FIRST to get blood flow, so it is also the FIRST to get the brunt of general toxic effects, and the LAST to get the brunt of ischemic effects. The LAST part of the lobule, central vein!
Bilirubin Biotransformation Bilirubin is a product of red blood cell breakdown. When a red blood cell has lived out its 120-day life span, the cell membrane becomes fragile and ruptures. Hemoglobin is released and is acted upon by circulating phagocytic cells to form free bilirubin. Free bilirubin binds to plasma albumin and circulates in the bloodstream to the liver. Free bilirubin is considered unconjugated in that, although it is bound to albumin, the binding is reversible. Once in the liver, bilirubin releases from albumin and, because free bilirubin is lipid soluble, moves easily into the hepatocytes. Once inside the hepatocytes, bilirubin is rapidly bound to another substance, usually glucuronic acid, and is now considered conjugated. Conjugated bilirubin is water soluble, not lipid soluble. Most conjugated bilirubin is actively transported into the bile canaliculi. From there it is delivered along with the other components of bile to the gallbladder or small intestine. A small amount of conjugated bilirubin does not go to the intestine as a bile component, however, but rather is absorbed back into the bloodstream. Therefore, in the bloodstream, there is always a small amount of conjugated bilirubin present, along with unconjugated bilirubin on its way to the liver. Once in the intestine, conjugated bilirubin is acted upon by bacteria and changed into urobilinogen. Most urobilinogen enters the bloodstream and is excreted by the kidneys in the urine, some is excreted in the stool, and some is recycled back to the liver in the enterohepatic (intestinal to liver) circulation. Figure shows the steps involved in the conjugation and excretion of bilirubin. The conjugation of bilirubin is essential for its excretion. Without conjugation, bilirubin cannot be excreted by either the kidneys or the intestines. The handling of bilirubin by the liver is a form of metabolic detoxification. Without conjugation, unconjugated bilirubin would build up in the bloodstream to toxic levels.
- Coinfection with HIV and Hepatitis C is a significant problem, especially among injection drug users In the United States it estimated that 240,000 persons are infected with both HCV and HIV. Studies estimate that as many as 25-30% of HIV positive people in the United States are coinfected with HCV and up to 10% of HCV positive person are infected with HIV. In urban areas of the US, up to 90% of person who acquired HIV infection from injection drug use also have HCV. HCV accelerated in the setting of HIV: Increased risk for cirrhosis HCV frequently “drives prognosis” in co-infected pts: making treatment more difficult