DE JESUS, Vincent Patrick DE JOYA, Bernadette Chantle DE LEON, Erica Jane DEL MUNDO, Leandro DEL ROSARIO, Gracelle Ann DEL ROSARIO, Kariza Fabiola DELA CRUZ, Cathleen May DELA CRUZ, Jose Miguel GROUP 2 B1

At

the end of the conference the students would be able to: Discuss the catabolism of heme

Discuss the different phases of bilirubin metabolism Recognize cases of Jaundice

Differentiate the different types of jaundice Explain the occurrence of jaundice in the ff:

Physiologic jaundice of the newborn Hemolytic Jaundice Polycythemia Blood Extravasation Defects in conjugation Breast milk jaundice Obstruction of the biliary tract

Jaundice,

also known as icterus, refers to the yellowish discoloration of the skin or sclera yellow pigments begin to deposit in the sclera of the eyes and in the skin when the bilirubin concentration in the plasma is elevated (hyperbilirubinemia)

The

the

principal pigment in bile from the breakdown of hemoglobin

derived when

aged red blood cells are phagocytized by the reticuloendothelial systemspleen, liver and bone marrow

About

80% comes from the destruction of heme-containing proteins (myoglobin, cytochromes) and catabolism of heme

large

complex protein molecule comprises two major parts Heme

Globin

Within

the splenic phagocytic cells, or macrophages:hemoglobin loses its iron to transferrin globin chains return to the amino acid pool rest of the molecule is converted to bilirubin

Formation

of -aminolevulinic acid (ALA)

Glycine activated by pyridoxal phosphate(coenzyme) Reaction of Glycine with Succinyl CoA(from Kreb s Cycle) by ALA synthase forms -aminolevulinic acid (ALA) Occurs in the mitochondria Formation

of Porphobilinogen(PBG)

Two molecules of ALA are condensed by the enzyme ALA dehydratase to form porphobilinogen Occurs in the cytosol sensitive to inhibition by heavy metal ions

Formation of Hydroxymethylbilane(HMB) condensation of four porphobilinogens produces the linear tetrapyrrole, hydroxymethylbilane by PBG deaminase Formation of Uroporhyrinogen III Hydroxymethylbilane is isomerized and cyclized by uroporphyrinogen III synthase to produce the asymmetric uroporphyrinogen III by Uroporphyrinogen synthase

Formation of Coproporphyrinogen IIIUroporphyrinogen III undergoes decarboxylation of its acetate groups, generating coproporphyrinogen III by the enzyme Uroporphyrinogen decarboxylase All the acetate groups are changed into methyl substituents

Formation of Protoporphyrinogen IXCoproporphyrinogen III enters the mitochondria Two proprionate side chains are decarboxylated to vinyl groups, generating Protoporphyrinogen IX Enzyme is coproporphyrinogen oxydase

Formation of Protoporphyrin IX

protoporphyrinogen IX is oxidized to protoporphyrin IX by the enzyme protoporphyrinogen oxidase

Formation of Hemeintroduction of iron (as Fe+2) into protoporphyrin IX occurs randomly Enhanced by the enzyme ferrochelatase Like ALA ferrochelatase is inhibited by lead

Causes Hemolytic Jaundice of Erythroblastosis Fetalis Jaundice

Phases Causes of Jaundice of Jaundice

Hemolysis Non Hemolytic Jaundice Hematoma Resorption Neonatal Jaundice

Prehepatic

Hepatocellular Disorders Intrahepatic Alcohol Intake Drug Reactions

Hepatic

Causes of Obstructive Jaundice Obstruction

Post Hepatic

Test

used for estimating conjugated as well as unconjugated bilirubin levels in plasma diazo reagent (diazotized sulphanilic acid) is added to conjugated bilirubin a reddish brown coloration is obtained

Erlichs

direct Van den Berg reaction/ direct bilirubin

Unconjugated

bilirubin, which is waterinsoluble, has to be dissolved in methanol to complete the Van den Berg reaction is added to the solution to direct the presence of unconjugated bilirubinA reddish violet coloration obtained upon adding = presence of unconjugated bilirubina indirect Van den Berg reaction/ indirect bilirubin

Methanol

Hyperbilirubinemia

bilirubin levels in the blood are elevated above the normal range of 0.3-1 mg/dL

Jaundice

bilirubin level in the blood exceeds 2 mg/dL

rise

in the water-insoluble, unconjugated or indirect-reacting bilirubin in the blood not usually accompanied by a rise in urinary bilirubin

Urinary

bilirubin rise if the water-soluble, conjugated or direct-reacting bilirubin is in excess in the blood

Types

of hyperbilirubinemia:

(1)

Retention hyperbilirubinemia

overproduction of bilirubin (unconjugated bilirubin)

(2)

Regurgitation hyperbilirubinemia

reflux into the bloodstream secondary to biliary obstruction (conjugated bilirubin)

Unconjugated

hyperbilirubinemia

retention of unconjugated bilirubin in the blood production of bilirubin exceeds the capacity of the liver for its uptake, conjugation and biliary excretion may lead to acholuric jaundice with unconjugated hyperbilirubinemia

usually With

with no urinary bilirubin

increased urinary and fecal urobilinogens produced in excess from bilirubin may also arise from the crossing of the blood brain barrier by nonpolar unconjugated bilirubin (kernicterus)

Encephalopathy

Unconjugated

hyperbilirubinemia occurs in several conditionHemolytic jaundice Crigler-Najjar syndromes

Type I Crigler-Najjar Type II Crigler-Najjar

Gilberts disease Neonatal jaundice Toxic hepatic jaundice

In

liver dysfunctions, liver cells fail to remove unconjugated bilirubin from blood and to conjugate and excrete it in bile increases serum unconjugated bilirubin producing jaundice.

This

Conjugated

hyperbilirubinemia

Conjugated

or direct-reacting bilirubin may rise in the serum may appear in the urine, producing choluric jaundice

bilirubin

Regurgitation

of conjugated bilirubin into the blood from the biliary duct system may occurobstructed by a tumor or gallstone (regurgitation hyperbilirubinemia)

May

be due to the ff. conditions

Obstructive jaundice Dubin-Johnson syndrome hepatocellular diseases

Hepatocellular impaired:

disease

uptake of bilirubin conjugation of bilirubin excretion of bilirubin

Excretion

= most affected

leading to conjugated rather than unconjugated bilirubinemia

choluric

and is associated with pale stools

urine

urobilinogen levels

first increase decrease with increasing severity Initial

rise in urine urobilinogen

reduction in hepatic reuptake of the urobilinogen urobilinogen is eliminated in larger amounts in urine urine

urobilinogen decrease

reduced excretion of bilirubin into the intestine with consequent reduction in the intestinal urobilinogen synthesis

For

the same reason, a rising urinary urobilinogen level in a patient with jaundice under treatment is a good sign

UNCONJUGATED Water-insoluble Non-polar Indirect reacting Hemobilirubin Prehepatic bilirubin

CONJUGATED Water-soluble Polar Direct reacting Cholebilirubin Posthepatic/Obstructive Regurgitative bilirubin

Type 1/B1

Type 2/B2

Pre-hepatic

- The pathology is occurring prior to the liver. - The pathology is located within the liver.

Hepatic

Post-hepatic

- The pathology is located after the conjugation of bilirubin in the liver.

also

called physiologic jaundice of the newborn 5 mg/dl of hyperbilirubinemia present normally may be

appears within 2 to 5 days of birth and last for about a week yellowing of the skin and other tissues of a newborn infant

In

the fetus, bilirubin is removed from circulation by the placenta. birth, the newborn has to suddenly excrete its own bilirubin but its hepatic conjugation of bilirubin is still inadequate due to reduced UDP-glucuronyltransferase activity. As a result, hyperbilirubenimia occurs.

At

can

be reduced by phototherapy

Exposure

of skin to white or blue lights causes photoisomerization of bilirubin to water-soluble bilirubin excreted in bile without requiring any conjugation

rapidly

Bilirubin

levels that deviate from the normal range and requiring intervention would be defined as pathological jaundice. of jaundice within 24 hours

Appearance

Increase

in serum bilirubin beyond 5 mg/dl/day

peak

levels above the expected normal range of clinical jaundice beyond 2 weeks bilirubin (dark urine staining the

presence

conjugated

clothes)

unconjugated hyperbilirubinemia develops after the first week and continues up to the sixth week of life Yellowing of the skin and sclera (white part of the eye) 3-alpha-20-beta pregnanediol uridine diphosphoglucuronic acid (UDPGA) glucuronyl transferase Phototherapy

Hemo

blood ; Lytic breakdown of cells

excess breakdown of red blood cells. rupture of red cells is followed by the release of hemoglobin Increase in unconjugated bilirubin Level

The

also

called Plethora

hyperbilirubinemia, in which there are too many red blood cells in the blood circulation Polycythemia vera Secondary polycythemia reddish-purple coloring, respiratory distress, and low blood sugar are the symptoms of Polycythemia

Deep

leakage of blood from a vessel into tissues surrounding it occur in injuries or burns or allergic reaction

can

After

bleeding has started, the bruise continues to deepen in color until bleeding stops. Bruising of the skin develops

biliary obstruction refers to the blockage of any duct occurs when bilirubin cannot reach the intestinal area gallstones, malignancy, infection, and biliary cirrhosis pale stools conjugated bilirubin

Increase

1. Conjugation Deficit Crigler-Najjar Syndrome

rare autosomal recessive disorders are characterized by genetic defects of hepatic bilirubin-conjugating enzymes.

Crigler-Najjar Type I Crigler-Najjar Type II

results from the genetic deficiency of the bilirubin-UDP glucuronyl transferase for converting bilirubin monoglucuronide unconjugated or indirect-reacting bilirubin rises in the serumk high unconjugated bilirubin in the serum damages the corpus striatum and other cerebral ganglia, leading to toxic encephalopathy

results from the genetic deficiency of the hepatic glucuronyl transferase for glucuronidating bilirubin Unconjugated or indirect-reacting bilirubin also rises in the serum Jaundice is milder, not necessarily fatal

2. Bilurubin transport deficit

Gilberts diseasemay result from rare autosomal dominant genetic deficiencies in the hepatic uptake of unconjugated bilirubin from blood or in the hepatic bilirubin-UDP glucuronyl transferase benign congenital jaundice with a mild unconjugated hyperbilirubinemia

3. Bilirubin Excretion deficit

Dubin-Johnson Syndrome rare

congenital jaundice also called the chronic idiopathic jaundice an autosomal recessive trait genetic deficiency of the liver in secreting conjugated bilirubin leads to its reflux into the blood and the consequent conjugated hyperbilirubinemia