METABOLISM

Color index

• Important

• Further explanation

1 Contents

. Definition and metabolism steps of bilirubin……..3 . 1st step :Bilirubin formation…………………….....4 . 2nd Step: Transport of Bilirubin ……………………5 . 3rd Step :Hepatic phase(uptake & Conjuation steps) ………………………………………………..6 . Fat of conjugated bilrubin………………………….7 Bilirubin metabolism . Fate of ………………………………..7

. summary …………… ……………………..12&11 . MCQs……………………………………………….13 . SAQs………………………………………………14

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link will be used for all of our work Physiology Edit 2 DEFINITION OF BILIRUBIN URINE  It is the water insoluble 1breakdown product of normal catabolism has a greenish yellow color that excreted in BILE  It is toxic FECES  Serum bilirubin level is an important clinical marker

of hepatobiliary excretory function. The four steps are finely balanced. Reduction at any step may cause hyperbilirubinemia. Enhancement of the through put requires induction of BILIRUBIN METABOLISM multiple genes, probably coordinated by nuclear receptors involves four discernible steps

Formation From [Heme : iron + ] Hepatic Phase Heme source: Plasma 1.Hepatic uptake Intestine 80% from hemoglobin, 20% other hemo-protein: Transport 2.Conjugation Excretion (cytochrome, catalase, 3.Biliary excretion peroxidas, myoglobin) RBCs in RBCs blood BILIRUBINFORMATION 1 60 Life span span Life : - ST stream 120 days. days. 120

Step

in 1)

2) Extravascularly

intravascularly reticuloendothelial system or Old OldRBCs

phagocytosed lysis

in blood in blood stream

by: by:

in the in

Give

( principal principal component of Hemoglobin released RBCs RBCs )

(By (By heme oxygenize) Heme and form breakdown Amino Globin

Split into

pigments blood blood by transferrin Transported the in stored in acids the the body FreeIron Bile

FREE is1stpigment

into the plasma for for erythropoiesis as a reservoir BILIRUBIN BILIRUBIN Stored reductase biliverdin

4

TRANSPORT 2 Formed Formed Bilirubin ND free bilirubin in plasma in freebilirubin

in spleen (give a water soluble compound)

(mainly albumin and globulin) Step immediately combines with (hydrophobic for further metabolism metabolism forand further transported to hepatocytes plasma plasma proteins Conjugation Conjugation process (hydrophilic)

)

OF BILIRUBIN IN PLASMA

*still called*still free bilirubin indirectbilirubin unconjugated, Calledhemobilirubin,

2)Preventunconjugated freelybilirubincome 1)Increasesolubilitymolecule.the wholeof Significanceto bilirubinbindingof albumin intocausetissue,other damage

cancerebral cause palsy losshearing and

binding and displace bilirubin toenter bilirubin and displace binding (a type (a of damage brain that resultcan from drugs as as drugs high levels of bilirubin in a a baby’s in blood) levels high of bilirubin compete with bilirubin foralbumincompete withbilirubin increase the risk of risk increasethe intobraintheneonates in sulfonamidesand salicylates

kernicterus

?!!

5 3rd Step HEPATIC PHASE (3 STEPS) - ratestep limiting by 5 - - 4 protein 3 freealbumin 2 withcombined throughthe hepatic membrane, cell mediated by a 1 intestinewhereis ittransformed through bacterialintoaction 6 ------

Fate of conjugated bilirubin of Dissociation Bilirubin Seceretion Conjugationof ReuptakeHepatic liver hepatocytes by active transport “ intoneeds energy” bilecanaliculi, it’sa Dailybilirubin:of load 250 ofColorbilebilirubindueis ofthe rest20% bilirubin conjugate with conjugated formbilirubin”of that is watersoluble formingthe compound Bilirubin (UDPGA) freebilirubinof80%

- Albumin complex dissociate Albumin

catalyzed by enzyme the of conjugatedof bilirubin Y & proteinsYZ , susceptibleto impairment ,inliver disease hemebilirubin bilirubin “1 st conugate

Step”

“2 that that trap the bilirubininsidethe cells , - majorityofconjugated passes bilevia ducts to nd 300 mg adultsinnormalmg 300

Inside hepatocytes into freebilirubinfree and Bilirubin(without Step”

with Diglucurnoide glucuronyl

“ 2 liverofinplasma into Cholebilirubin Uridine sulphate

diphospho carrierprotein transferase the albumin)isabsorbedthe

“ Cholebilirubin

& othersubstances.

” in the bile the in

- Urobilinogen glucuronic

inER,the smooth hemebilirubin (receptor)& . , the ,

“3

acid rd

Step”

&

6 Urobilinogen excreted excreted in the feces as as causes causes dark brown *Majority conjugated of extracted by the liver extracted the by liver cells and conjugate again and excreted the in bile ( Converted Converted small in color of the feces. color of feces. the *Small portion *Small portion returns plasmato and bound tightly less to *Small oxidized oxidized and intestine intestine into 70% of 70% of amount is

that that , FATE OF

deconjugated blirubin FATE portion portion the of bilirubin the in be ECF to the of conjugated type. Urobilinogen the the intestinal mucosa Reabsorbed Reabsorbed through and and re the the hepatic cells in into the into the portal vein

passes passes via bile to ducts intestine the whereit’s transformed through bacterial action UROBILINOGEN ( enterohepatic 20% of 20% of circulation). circulation).

and and absorbed by small the intestine the into portal blood the to liver whereis it OF CONJUGATED BILIRUBIN the the bile - excreted excreted by into into U robilinogen

which is highly which is highly soluble Urobilinogen where where it isoxidized to and and excreted by the kidneys kidneys the in urine albumin albumin &excreted in is urine. the causes this a small urine is exposed urine isexposed to general circulation

Escapes Escapes to the 10% of 10% of air.

when when the

enterohepatic

circulation circulation bile of pigments).

7 OTHER SUBSTANCES   increase in hepaticincreasein anticonvulsants markedproliferationendoplasmic thesmooth of In addition severalIn addition reticulum in the hepatic cells, with a concurrenta withcells, hepatic inthereticulum bilirubinthefor systemenzyme theywhenarepresentin appreciable The formationofthe The list list steroids includes&various glucuronyl

and other compounds can cause cause can compoundsother and glucuronyl barbiturates

transferase glucuronides

transferase , antihistamines, CONJUGATED BY

system inthesystem endoplasmicsmooth reticulum catalyzes the

ofa variety ofsubstances in toaddition bilirubin.

activity. drugs,these

treatment a of congenitaldisease whichin thereis Phenobarbital (type 2 UDP a relativedeficiency of GLUCOURONYL other compounds can competewithcompoundscan other - glucuronyl

has been used successfully for the

transferase glucuronyl

TRANSFERASE amounts.

transferase deficiency).

8 Totalbilirubin= Directbilirubin+ Indirectbilirubin Knowing level of each type of bilirubin has diagnosticbilirubinofof type eachlevel Knowing TYPES OF BILIRUBIN IN SERUM Direct Direct bilirubin “Conjugated” Reacts rapidly Reacts Water Water soluble with reagents importance

“Unconjugated”

with reagents Reacts bilirubin Indirect Indirect insoluble insoluble Water Water

sowly

NORMAL RANGE OF BILIRUBIN <1mg/dl Normal 1~16 • •

1/5 1/5 are 4/5 are unconjugated bilirubin, micromol/l 1 - Occult 2 mg/dl2 conjugated conjugated bilirubin. Hyperbilirubinemia

(0.1~1mg/dl) > 2 mg/dl

9 . . OTHER SUBSTANCES EXCRETED IN THE BILE obstructive toisthejaundice duewhen A substancesusually levels2 bloodthe theseduct,of bile extraor hepatic In much patients with jaundice due topatients intraduejaundicewith Cholesterol& alkaline smaller risesmaller phosphatase

hepatocellular obstruction rise is generallyseen .

disease.

non of of the

. hormones & a number of drugsof & anumberhormones (enterohepaticcirculation) subsequentlyreabsorbed Adrenocortical,steroidother excretedbiletheandin

10 Transport of bilirubin in plasma occurs in two forms twoTransportin occurs in plasma bilirubinof Transport of bilirubin in plasma occurs in two forms forms twoin occurs in plasma Transportbilirubin of (biliverdin) Small Small amount RBCs RBCs ( small small combines combines with(mainly albumin and globulin) cholebilirubin bacterial bacterial action Bilirubin Bilirubin absorbed through the lysis majority majority of conjugated bilirubin transformed through (by glucuronyl (by glucuronyl transferase) Cholebilirubin bound bound less tightly to Unconjugated Unconjugated bilirubin normally not excreted in bile amountof Bilirubin Bilirubin 2+

--

in in spleen or blood (by (by biliverdin reductase) Transport Plasma in Bilirubin of Bilirubin Bilirubin in spleen transport transport process into the bile traped deconjugated

unconjugated unconjugated bilirubin Fateof conjugated bilirubin , direct, conjugated bilirubin) Bilirubin Secretion inBile Secretion Bilirubin

conjugated conjugated bilirubin returns to the plasma and into Bilirubin formationBilirubin

inside inside the cell by Y &Z proteins

secreted by the liver cells by an active uridine  Hepatic uptakeHepatic Hepatic phase Hepatic urobilinogen Conjugation

circulation albumin

back by

strem diphospho  go go to  hepatiocytes

 

 circulation bilirubin bilirubin  (hydrophilic)

hemoglobin hemoglobin excreted

bood free bilirubin bilirubin free stercobilin - glucuronic

canaliculi

strem (highly (highly hydrophilic)

diglucuronide

 

in in the urine membrane membrane and hemobilirubin,

enterohepatic

  

acid

( feces

bile bile pigment

hydrophopic

–

.

. . .

energy glucuronyl glucuronyl transferase  deficiency deficiency ) *20% conjugate with

enter enter 20 %of urobilin & small amount impairment in liver – limiting limiting step with with - circulation sulphate disease. dependent, rate enterohepatic urobilinogen

 ureine  excreted jaundice

glomeruli Transport plasma in occursformstwo in of bilirubin The chief The chief form of bilirubin Indirect reacting bilirubin Not filtered Not filtered through renal insoluble )high affinity to Unconjugatedbilirubin Affinity Affinity to brain tissue Lipid lipid ( lipid (kernicterus), (kernicterus), toxic Bound Bound to albumin (Hemobilirubin) hemobilirubin in the in the blood

soluble soluble (water hydrophopic  absent

in in urine

)

-

No Bound Bound to Direct reacting bilirubin glomeruli Present lowconc. in in Conjugated bilirubin filtered filtered through renal Summary

Affinity Affinity to brain tissue ( Cholebilirubin Water cholebilirubin less less toxic the blood urine urine glucuronicacid 

soluble soluble

present present in

)

-

11 Antihistamines,anticonvulsants Phenobarbital peroxidas

Sulfonamides salicylatesand Steroids congenitaldeficiency of  bilirubin for glucuronylbilirubin glucuronyltransferase Cytochrome, catalase,  transferase activity drugs drugs increase of risk increase glucuronyl sources of heme transferase kernicterus  , myoglobin, Summary 2 Summary can can compete with 

treatment of a

other

12 D. Only in Only D. bloodstream C. reticuloendothelial system and blood stream .Liver B A.Pancreas bloodand stream lysis 2 D)Increase bilirubin C)anemia B) A)hyperbilirubinemia bilirubinmetabolism? 1 D.Asprine C.amoxacilin B.Cephalocporin A. sulfonamides ? neonatein 4 Biliverdin D. activator C.Bilirubin biliverdinB. reductase A.Bilirubin ? bilirubin 3 - - - - hypobilirubinemia which one of the following drugs drugs kernicterus followingthe mayof cause one which stepof resultonethe from of be wouldreductionwhat which one of the following are the main sites of old RBCs oldRBCs of following the sites are mainthe of one which enzyme enzyme responsibleto biliverdinchange into free ?

anhydrease

solubility

D C B A 7 D C B A. Catalase 6 D. C. B. A. Bilirubin 5 - - - . . Jaundice . Occult . Bilirubin . . . Normal level . . Anemia .

Hemebilirubin Glucuronyl Insetinal Presence of mg/dl 3 bilirubin in the is body a condition called Dark Color of feces is caused by Glucuronyl Sterocobili Enzymeresponsible of conjugation reaction

Bacteria

tranferase deaminase

7 6 5 4 3 2 1 key:Answer ------

C B D A B C A

MCQs

13 Hyperbilirubenemia Range 0.1“ Normal Q5 Q4 Q3 Ironstoredwillalso inthe ,bilebody pigment (biliverdin) converted to bilirubin by biliverdin reductase ? degradation hemoglobinproductsof theexplain brief Q2:In ?: bindingalbumin of bilirubin importancemainis the Q1what bilethe in conjugatedofbilirubinSecretionStep3: bilirubinConjugationStepof2: reuptakeHepaticStep1: first give will andglobin,(iron heme andpigment bile ) 2 1 to increaseto bilirubin solubilityand avoid its accumulation in the becausetissues it’s toxic - - : What is the normal range of bilirubin in the body? And what happens in case of any increase of amount? of anythisincase of increase happenswhatAnd body? inthe range of normalbilirubin is the What: theserumin bilirubinof aretypes the What : briefly? one each explainand metabolism bilirubinof phase hepaticstepstheof Mention :

Direct bilirubin “Conjugated”bilirubinDirect Indirect bilirubin “Unconjugated”Indirectbilirubin

– “increase” 1 “increase”

1 mg/dl” 1

Cholebilirubin -

Occult 1 Occult Hemobilirubin -

2 mg/dl or 2 mg/dl 2

the globinthe give willacidsthat amino storedwill inthe body -

Jaundice > 2 mg/dl mg/dl 2 > Jaundice

SAQs

14 Lina Amal Amal by:Done Aljurf

Afrah Aseeri Good Luck Thanks Thanks work for checkingour

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