9. Heme Synthesis Breakdown Hb

8/21/2019 9. Heme Synthesis Breakdown Hb

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HEME SYNTHESIS AND BREAKDOWN

HEMOGLOBIN

Questions:

1. Exp!in t"e st#u$tu#! o#%!ni&!tion o' "!e(o%o)in. Exp!in "o* t"e

st#u$tu#e o' "e(o%o)in is $!##+in% out its 'un$tions, -on M!+ /1

. A)no#(! "e(o%o)ins0 No 12213 M!#$" //4. St#u$tu#e o' "e(o%o)in 5 Au% //66. W"!t 7oes t"e s"i't o' ox+57isso$i!tion $u#e o' "e(o%o)in to t"e #i%"t

(e!n, -on M!+ /18. He(o%o)inop!t"ies 5 M!#$" //9. Si$e $e !ne(i! -on M!+ /14;. A 4 +e!# o7 %i# *it" $o(p!ints o' et"!#%+< *e!ness !n7 '#e=uent

episo7es o' !)7o(en !n7 )on p!in *!s )#ou%"t to t"e "ospit!. On

ex!(in!tion s$e#! *!s +eo* !n7 speen en!#%e7. T"e )oo7 s(e!#

s"o*e7 $#es$ent s"!pe7 RB$s !n7 t"e in7i#e$t !n 7en Be#% test *!s

positie. W"!t is t"e p#o)!)e 7i!%nosis, Ho* *ou7 +ou $on>#( +ou#

7i!%nosis, -on No /11?. Si$e $e !ne(i! is 7ue to !n !)no#(! %o)in $"!in in H). Dis$uss ots

(oe$u!# )!sis. -on No //92. W"!t is t"e (oe$u!# 7e'e$t in HBS !n7 H)M, -on M!+ //61/. Ho* 7oes H)S !n7 H)S 7i@e# in t"ei# p#i(!#+ st#u$tu#e,11. W"!t is $!#)ox+ H), In *"!t $on7itions 7oes it in$#e!se in )oo7, -on

M!+ //;1. W#ite ! note on HBA1$ !n7 its si%ni>$!n$e. -on No /11

St#u$tu#e o' "e(o%o)in:

1. Hemoglobin is found exclusively in red blood cells (RBCs), where is m!in funcion is

o r!ns"or oxygen (#$ ) from he lungs o he c!"ill!ries of he issues. %orm!l level

of Hemoglobin (Hb) in blood in m!les is 1&'1 gdl !nd in fem!les, 1*'1+ g dl.$. Hb is globul!r in sh!"e. Hemoglobin h!s ! mol. w. & &+. Hb is ! con-ug!ed

"roein, con!ining globin !nd he heme.*. Go)in

!. /he globul!r "roein unis of Hb is m!de u" of four (wo idenic!l "!irs)

"oly"e"ide ch!ins!. /wo idenic!l !l"h! (0) ch!ins con!ining 1&1 !mino !cids !ndb. /wo idenic!l non' 0 ch!ins (be!(),g!mm!(2),del!(3) or e"silon (4) ch!ins.c. 5n !dul hum!ns he non' 0 ch!ins !re be! (), con!ining 1& !mino !cids.d. /he "!iring of one !l"h! ch!in !nd one non'!l"h! ch!in "roduces !

hemoglobin dimer (wo ch!ins).e. /wo dimers combine o form ! hemoglobin er!mer, which is he funcion!l

form of hemoglobin.&. He(e

f. Heme con!ins ! "or"hyrin molecule n!mely "roo"or"hyrin l6, wih iron ! iscener. 7roo"or"hyrin l6 consiss of four "yrrole rings o which four mehyl,

wo "ro"ionyl !nd wo vinyl grou"s !re !!ched.g. 7or"hyrins !re cyclic com"ounds formed by fusion of & "yrrole rings lined by

mehenyl (CH:) bridgesh. /he "yrrole rings !re n!med !s 5, 55, 555, 5; !nd he bridges !s !l"h!, be!,

g!mm! !nd del!.i. Heme is ! "rosheic grou" !nd is "resen in

i. cyochromeii. C!!l!se


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iii. /ry"o"h!n "yrol!seiv. Chloro"yll

8. T#!nspo#t O' Ox+%en B+

He(o%o)in:!. Hemoglobin srucure h!s !ll he

re


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"henomenon is referred o !s $oope#!tie )in7in% of $ o Hb or

heme'heme iner!cion. /he rele!se of $ from one heme f!cili!es

he rele!se of $ from ohers. /here is ! communic!ion !mong heme

grou"s in he hemoglobin funcion.ii. 5n he lungs, where he concenr!ion of $ is high, he hemoglobin

ges fully s!ur!ed wih $. @ he issue level, where he $

concenr!ion is low, he oxyhemoglobin rele!ses is $ for cellul!r

res"ir!ion.f. / D R form /he four subunis (!$b$) of hemoglobin !re held ogeher by we!

forces. /he deoxy Hb exiss in ! / or !u (ense) form. /'form of Hb h!s low

oxygen !?niy. #xy Hb exiss in R (rel!xed) form !nd h!s more !?niy for

oxygen.g. Bohr e=ec

i. /he binding of oxygen o hemoglobin decre!ses wih incre!sing HE

concenr!ion (lower "H) or when he hemoglobin is ex"osed o

incre!sed "!ri!l "ressure of C#$ ("C#$). /his "henomenon is

nown !s Bohr e=ec. l is due o ! ch!nge in he binding !?niy of

oxygen o hemoglobin. Bohr e=ec c!uses ! shif in he oxygen

dissoci!ion curve o he righ.ii. Fech!nism of Bohr e=ec1. Fos of he C#$ "roduced in me!bolism is hydr!ed !nd

r!ns"ored !s bic!rbon!e ion. Gome C#$ is c!rried !s

c!rb!m!e bound o he %'ermin!l !minogrou"s of hemoglobin

(forming c!rb!minohemoglobin)$. hen he "C#$ is high in issues, C#$ di=uses ino he red

blood cells. /he c!rbonic !nhydr!se in he red cells f!vors he

form!ion of c!rbonic !cid (H$C#*). 5n RBC, he inr!cellul!r "H

f!lls. /his reduces he !?niy of Hb for #$ !nd #$ is rele!sed

o he issues.

C!rbonic !nhydr!se

C#$ E H$# ''''''''''''''''' H$C#* I HE E HC#* :*. /he binding of C#$ s!biliJes he / (!u) or deoxy form of

hemoglobin, resuling in ! decre!se in is !?niy for oxygen !nd

! righ shif in he oxygen dissoci!ion.&. 5n he lungs, C#$ dissoci!es from he hemoglobin, !nd is

rele!sed in he bre!h.h. Chloride shif

i. Chloride (Cl') is bound more ighly o deoxyhemoglobin h!n o

oxyhemoglobin. /his f!cili!es he rele!se of $ii. >rom issues, C#$ is !en u" by RBC !nd he HC#* K concenr!ion

wihin he cell incre!ses in RBC. /his would di=use ou ino he "l!sm!.

Gimul!neously, chloride ions from he "l!sm! would ener in he cell

o es!blish elecric!l neur!liy. /his is c!lled chloride shif orH!mburger e=ec.

iii. 5n he lung, C#$ ges ou of RBC !nd HC#* : eners RBC while Cl' ges

ou.i. L=ec of $,*.bis"hos"ho glycer!e on #$ !?niy of Hb

i. $,*'B7C is "roduced in he eryhrocyes from glycolysis hrough ! shor

"!hw!y, referred o !s R!"!"or'Meubering cycle. l s"ecic!lly binds

o deoxyhemoglobin (!nd no o oxyhemoglobin) !nd decre!ses he $

!?niy o Hb by s!biliJing he deoxygen!ed hemoglobin o /'form.


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/he binding of $,*'B7C wih hemoglobin is !ssoci!ed wih he rele!se

of $ o he issues. /he concenr!ion of $,*'B7C in eryhrocyes is

elev!ed in chronic hy"oxi! !nd severe !nemi!.ii. Gor!ge of blood in !cid cir!e'dexrose medium resuls in he

decre!sed concenr!ion of

$,*'B7C. Guch blood when r!nsfused f!ils o su""ly $ o he issues

immedi!ely.iii. /he binding of $,*'B7C o fe!l hemoglobin is very we!N /herefore, Hb> h!s higher

!?niy for $ com"!red o !dul hemoglobin (Hb@).. Binding of C# C!rbon monoxide (C#) binds ighly (bu reversibly) o he hemoglobin

iron, forming c!rbon monoxy hemoglobin (or c!rboxyhemoglobin). hen C# binds o

one or more of he four heme sies, hemoglobin shifs o he rel!xed conform!ion,

c!using he rem!ining heme sies o bind oxygen wih high !?niy. /his shifs he

oxygen dissoci!ion curve o he lef, !nd ch!nges he norm!l sigmoid!l sh!"e

ow!rd ! hy"erbol!. @s ! resul, he !=eced hemoglobin is un!ble o rele!se oxygen

o he issues.O. /+pes o' no#(! H)

!. Hb @ /his is denoed !s !$)$ !nd ermed hemoglobin @.

b. Hb > /he combin!ion of wo !l"h! ch!ins !nd wo g!mm! ch!ins form fe!lhemoglobin, ermed hemoglobin >.

c. Hb @$ /he "roduc of he del! globin gene is c!lled hemoglobin @$.

He(o%o)in Go)in "!in

o(position

A7ut

on$ent#!tion

Hb@ !$)$ 9'98P

Hb@$ !$d$ $.*'*.+P

Hb> !$r$ Q$P

Hb@lc !$b$' glucose Q +P

8. Hb deriv!ives Hemoglobin (s"ecic!lly heme) combines wih di=eren lig!nds !nd

forms hemoglobin deriv!ives. /he norm!l blood con!ins oxyHb !nd deoxyHb.

Besides hese, mehemoglohin (meHb) !nd c!rboxyhemoglobin !re he oher

im"or!n Hb deriv!ivesN /he Hb deriv!ives h!ve ch!r!cerisic colour !nd hey c!n

be deeced by !bsor"ion s"ecr!.


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Met"e(o%o)in

1. hen he ferrous (>eEE) iron is oxidiJed o ferric (>eEEE) s!e, me'Hb is formed.

Gm!ll


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hemoglobino"!hies h! c!n h!ve severe clinic!l conse


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&. He(o%o)in 7ise!se!. CooleyNs hemoglobinemi! (HbC) is ch!r!ceriJed by subsiuion of glu!m!e

by lysine in he sixh "osiion of b'ch!in. ue o he "resence of lysine, Hb C

moves more slowly on elecro"horesis com"!red o Hb@ !nd HbG, HbC dise!se

occurs only in bl!cs.b. Boh homoJygous !nd heeroJygousin dividu!ls of Hb C dise!se !re nown.

/his dise!se is ch!r!ceriJed by mild hemolyic !nemi!. %o s"ecic her!"y is

recommended.8. He(o%o)in D:

!. /his is c!used by he subsiuion of glu!mine in "l!ce of glu!m!e in he

1$1s "osiion of B'ch!in.). Gever!l v!ri!ns of Hb !re idenied from di=eren "l!ces indic!ed by he

su?x. >or ins!nce, Hb (7un-!b), Hb (Mos @ngeles). Hb , on

elecro"horesis moves !long wih Hb G.9. He(o%o)in E:

!. /his is he mos common !bnorm!l hemoglobin !fer HbG. l is esim!ed h!

!bou 1#P of he "o"ul!ion in Gouh'L!s @si! (B!ngl!desh, /h!il!nd,

Fy!nm!r) su=er from HbL dise!se. 5n 5ndi!, i is "rev!len in es Beng!l.). HbL is ch!r!ceriJed by re"l!cemen of glu!m!e by lysine ! $h "osiion of

B'ch!in. /he individu!ls of HbL (eiher homoJygous or heeroJygous) h!ve no clinic!l m!nifes!ions.

THALASSEMIAS

1. /h!l!ssemi!s !re ch!r!ceriJed by ! defec in he "roducion of !'or b'globin ch!in.

/here is however, no !bnorm!l iy in he !mino !cids of he individu!l ch!ins.

/h!l!ssemi!s occur due o ! v!riey of molecul!r defecs1. Sene deleion or subsiuion,$. Xnder"roducion or ins!biliy of mR%@,*. efec in he inii!ion of ch!in synhesis,&. 7rem!ure ch!in ermin!ion

$. Reducion in !l"h! ch!in synhesis is c!lled !l"h! h!l!ssemi!, while decien be! ch!insynhesis is he be! h!l!ssemi!. #her y"es lie del!'be! h!l!ssemi!, Hb Me"ore,

heredi!ry "ersisence of Hb> (H7>) !re rel!ed condiions.*. Be! h!l!ssemi! is more common h!n !l"h! v!riey. Be! y"e is ch!r!ceriJed by !

decre!se or !bsence of synhesis of be! ch!ins. @s ! com"ens!ion, g!mm! or del!

ch!in synhesis is incre!sed. 5 c!n exis in homoJygous(m!-or) !nd heeroJygous(minor)

!nd inermedi!e forms. @l"h! h!l!ssemi!s !re c!used by ! decre!sed synhesis or o!l

!bsence of !'globin ch!in of Hb. /here !re four co"ies of !'globin gene, wo on e!ch one

of he chromosome 1. >our y"es of !'h!l!ssemi!s occur which de"end on he number

of missing !'globin genes!. Gilen c!rrier s!e is due o loss of one of he four !'globin genes wih no "hysic!l

m!nifes!ions.b. !'/h!l!ssemi! r!i c!used by loss of wo genes. Finor !nemi! is observed.c. Hemoglobin H dise!se, due o missing of hree genes, is !ssoci!ed wih

moder!e !nemi!.d. Hydro"s fe!lis is he mos severe form of !'h!l!ssemi!s due o l!c of !ll he

four genes. /he feus usu!lly survives unil birh !nd hen dies.e. HomoJygous be! h!l!ssemi! is ch!r!ceriJed by severe !nemi!, hy"ers"lenism

!nd he"!os"lenomeg!ly. /he m!rrow in he sull bones ex"!nd "roducing he

Ah!ir'on'endf. !""e!r!nce described in 6'r!y.


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g. Re"e!ed r!nsfusion is he only !v!il!ble re!men. /his m!y le!d o iron

overlo!d.h. G"lenecomy m!y !lso lessen he !nemi!.i. F!rrow r!ns"l!n!ion h!s been successfully ried in ! few c!ses.

HEME

1. N!(e t"e #!te i(itin% en&+(e o' "e(e s+nt"esis. W"!t is its $oen&+(e, -on

//2. He(e 7e%#!7!tion 5 Au% //834. He(e $!t!)ois( 5 Ap#i //13 -on /16

He(e Bios+nt"esis :

1. l is "rim!rily synhesiJed in he liver !nd he eryhrocye'"roducing cells of bone

m!rrow (eryhroid cells). Heme synhesis !lso occurs o some exen in oher issues.$. Ge" 1 @M@ synhesis /he synhesis s!rs wih he condens!ion of succinyl Co@

!nd glycine in he "resence of "yridox!l "hos"h!e o form del! !mino levulinic !cid

(@M@). /he enJyme @M@ synh!se is loc!ed in he miochondri! !nd is he #!te5i(itin% en&+(e of he "!hw!y. /his re!cion re


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con!ining cyochrome "&+ for heir me!bolism. #u of he o!l heme

synhesiJed, wo hirds !re used for cyochrome "&+ "roducion.O. /he se"s c!!lyJed by ferrochel!!se !nd @M@ dehydr!!se !re inhibied by le!d.8. 5%H (5sonicoinic !cid hydr!Jide) h! decre!ses he !v!il!biliy of "yridox!l

"hos"h!e m!y !lso !=ec heme synhesis.9. High cellul!r concenr!ion of glucose "revens inducion of @M@ synh!se. /his is

he b!sis of !dminisr!ion of glucose o relieve he !cue !!c of "or"hyri!s.

!t!)ois( o' He(e: De%#!7!tion o' He(e

5n RL Gysem

1. Lryhrocyes h!ve ! life s"!n of 1$ d!ys. @ he end of his "eriod, hey !re !en

u" !nd degr!ded by he m!cro"h!ges of he reiculoendoheli! (RL) sysem in he

s"leen !nd liver. /he hemoglobin is cle!ved o he "roein "!r globin !nd non'"roein

heme. @bou g of hemoglobin "er d!y is broen down, !nd resynhesiJed in !n

!dul m!n$. /he globin m!y be reuiliJed !s such for he form!ion of hemoglobin or degr!ded o

he individu!l !mino !cids.

*. 8P of he heme comes from he eryhrocyes !nd he res ($#P) comes from

imm!ure RBC, myoglobin !nd cyochromes

&. Heme oxygen!se !nd %@7H !nd #$ com"lex cle!ves he mehyl bridges of "yrrolerings o form biliverdin !nd C!rbon monoxide. Heme oxygen!se uiliJes %@7H !nd

$ o form biliverdin. Gimul!neously, ferrous iron (>e$E) is oxidiJed o ferric form

(>e*E) !nd rele!sed. /he "roducs of heme oxygen!se re!cion !re biliverdin (!

green "igmen), >e*E !nd c!rbon monoxide (C#).+. Biliverdin is reduced by biliverdin reduc!se o Bilirubin (yellow "igmen). #ne gr!m

of hemoglobin on degr!d!ion n!lly yields !bou *+ mg biliruhin. /he erm bile

"igmens is used o collecivelyre"resen bilirubin !nd is deriv!ives

5n 7l!sm!

. Bilirubin is bound o !lbumin !nd r!ns"ored o liver. #ne molecule of !lbumin c!n

bind $ molecules of bilirubin. Cer!in drugs lie sulfon!mides D s!licyl!es c!n

dis"l!ce bilirubin from !lbumin. ue o his, bilirubin c!n ener he cenr!l nervous

sysem !nd c!use d!m!ge o neurons.5n Miver

O. @s he !lbumin'bilirubin com"lex eners he liver , bilirubin dissoci!es !nd is !en

u" by sinusoid!l surf!ce of he he"!ocyes by ! c!rrier medi!ed !cive r!ns"or.

5nside he he"!ocyes, bilirubin binds o ! s"ecic inr!cellul!r "roein n!mely

lig!ndin.8. 5n liver Bilirubin is rele!sed !nd con-ug!ed wih wo molecules of glucuron!e

su""lied by X7'glucuron!e c!!lysed by glucuronyl r!nsfer!se o form w!er

soluble Bilirubin diglucuronide. /he enJyme bilirubin glucuronyl r!nsfer!cs!enbe

induced by ! number of drugs (e.g. 7henob!rbi!l). rugs lie "rim!


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Bilirubin diglucuronide

5n Bili!ry Gysem

9. Con-ug!ed Bilirubin is excreed o bile !nd eners inesine hrough g!ll bl!dder !nd

bile duc. /he r!ns"or of hilirubin diglucuronide is !n !cive, energy'de"enden !nd

r!e limiing "rocess. Lxcreion of con-ug!ed bilirubin ino bile is medi!ed by !n @/7binding c!ssee "roein which is c!lled Fulis"ecic org!nic !nion r!ns"orer

(F#@/), loc!ed in he "l!sm! membr!ne of he bili!ry c!n!liculi. /his se" is

susce"ible o !ny im"!irmen in liver funcion. Bile con!ining bilirubin is colleced

by g!ll bl!dder !nd r!ns"ored o 1s "!r of duodenu!m by bileduc.

5n 5nesine Lnerohe"!ic circul!ion

1. 5n inesine con-.bilirubin is hydrolysed by b!ceri!l b'glucuronid!se o form free

Bilirubin .11. >ree bilirubin is !g!in convered o urobilinogen in inesinesV "!r of Xrobilinogen is

re!bsorbed !nd excreed in urine !s urobilin. @nd m!-or "!r is convered o

sercobilin by b!ceri! !nd excreed in feces.1$. Lnerohe"!ic circul!ion $P urobilinogen is re!bsorbed from he inesine !nd

reurned o liver. 5 is re excreed in o inesine hrough bile. /his is c!lled

enerohe"!ic circul!ion. Gm!ll "orion is excreed in urine. Boh urobilin !nd

sercobilin !re "resen in urine !nd feces.1*. 5f inesin!l Wor! is decre!sed by "rolonged !dminisr!ion of !nibioics, bilirubin is

no reduced o bilinogens, !nd in he l!rge gu, i is re'oxidiJed by #$ o form

biliverdin. /hen green inged feces is seen, es"eci!lly in children.

curonide


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-OR-HYRINS

!. -o#p"+#i!s 5 Ap#i ///). A$ute inte#(itt!n po#p"+#i!. -on (!+ /14

!. 7or"hyrins !re cyclic com"ounds com"osed of & "yrrole rings held ogeher by mehenyl

(CH') bridges. Heme is !n iron'con!ining "or"hyrin . /he srucure of "or"hyrins h!s

four "yrrole rings n!mely l, 55, lll !nd l;. >or"hyrins in c!ncer her!"yb. /he "hoodyn!mic "ro"eries of "or"hyrins c!n be used in he re!men of cer!in

c!ncers. /his is c!rried ou by ! echni


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b. 5 is inheried !s !n !uosom!l domin!n r!i. l is usu!lly ex"ressed !fer "ubery.

/he sym"oms include !bdomin!l "!in, vomiing !nd c!rdiov!scul!r !bnorm!liies.

/he neuro"sychi!ric disrub!nces observed in hese "!iens !re believed o be

due o reduced !civiy of ry"o"h!n "yrrol!se resuling in he !ccumul!ion of

ry"o"h!n !nd +'hydroxyry"!mine.c. /he sym"oms !re more severe !fer !dminisr!ion of drugs (e.g.b!rbiur!es)

h! induce he synhesis of cyochrome 7&+. /his is due o he incre!sed !civiyo

f @M@ synh!se c!using !ccumul!ion of 7BS !nd @M@. /hese "!iens !re no

"hoosensiive since he enJyme defec occurs "rior o he form!ion of

uro"or"hyrinogen.d. @cue inermien "or"hyri! is re!ed by !dminisr!ion of hem!in which inhibis

he enJyme'@M@ synh!se !nd he !ccumul!ion of "or"hobilinogen.

&. Congeni!l eryhro"oieic "or"hyri!

!. /his disorder is due o ! defec in he enJyme uro"or"hyrinogen 555 cosynh!se. l

is ! r!re congeni!l disorder c!used by !uosom!l recessive mode of inheri!nce

mosly conned o eryhro"oieic issues.b. /he individu!ls excree uro"or"hyrinogen 5 !nd co"ro"or"hyrinogen 5 which

oxidiJed res"ecively o uro"or"hyrin 5 !nd co"ro"or"hyrin Y (red "igmens).

c. /he "!iens !re "hoosensiive (iching !nd burning of sin when ex"osed ovisible ligh) due o he !bnorm!l "ro"hyrins h! !ccumul!e. 5ncre!sed

hemolysis is !lso observed in he individu!ls !=eced by his disorder.d. 7or"hyri! cu!ne! !rd!e. /his is !lso nown !s cu!neous he"!ic "or"hyri! !nd is he mos common

"or"hyri!, usu!lly !ssoci!ed wih liver d!m!ge c!used by !lcohol

overconsum"ion !nd iron overlo!d.f. /he "!ri!l deciency of he enJyme uro"or"hyrinogen dec!rboxyl!se is

res"onsible for he defec.g. /here is incre!sed excreion of uro"or"hyrins (l !nd lll) !nd r!rely

"or"hobilinogen.h. Cu!neous "hoosensiiviy is he mos im"or!n clinic!l m!nifes!ion of hese

"!iens. Miver exhibis Wuorescence due o high concenr!ion of !ccumul!ed

"or"hyrins.

+. Heredi!ry co"ro"or"hyri!

!. /his disorder is due o ! defec in he enJvme co"ro"or"hyrinogen oxid!se. @s !

resul of his, co"ro"or"hyrinogen lll !nd oher inermedi!es (@M@ !nd 7BS) of

heme synhesis "rior o he bloc!de !re excreed in urine !nd feces.b. /he vicims of heredi!ry co"ro"or"hyri! !re "hoosensiive. /hey exhibi he

clinic!l m!nifes!ions observed in he "!iens of !cue inermien "or"hyri!.

5nfusion of hem!in is used o conrol his disorder. Hem!in inhibis @M@ synh!se

!nd hus reduces he !ccumul!ion of v!rious inermedi!es.

. ;!rieg!e "or"hyri!

!. /he enJyme "roo"or"hyrinogen oxid!se is defecive in his disorder. ue o his

bloc!de, "roo"or"hyrin l6 re


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bio"sy exhibi red Wourescence.b. @c$!tion o' H+pe#)ii#u)ine(i! o# !un7i$e!. Hemolyic -!undice Llev!ed serum uncon-ug!ed bilirubin, !nd incre!sed

urin!ry excreion of urobilinogen.b. #bsrucive -!undice Llev!ed serum con-ug!ed bilirubin !nd incre!sed

http://en.wikipedia.org/wiki/Pyrrolehttp://en.wikipedia.org/wiki/Pyrrole


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!civiies of !l!line "hos"h!!se (@M7), !l!nine r!ns!min!se (@M/) !nd

!s"!r!e r!ns!min!se (@G/)c. He"!ic -!undice Llev!ed serum uncon-ug!ed !nd con-ug!ed bilirubin, !nd

incre!sed !civiies of @M/ !nd @G/.9. He(o+ti$ !un7i$e:

!. /his condiion is !ssoci!ed wih incre!sed hemolysis of eryhrocyes. /his

resuls in he over"roducion of bilirubin beyond he !biliy of he 5iver o

con-ug!e !nd excree he s!me.b. Cu!ses

i. Congeni!l Hemolyic -!undice occurs due o1. Hemoglobin defec /h!l!ssemi!sV sicele cell dise!se$. LnJyme defec S7 D "yruv!e in!se deciency*. Fembr!ne defec Cong. G"h!erocyosis

ii. 5mmune hemolyic -!undice1. Rh incom"!ibiliy$. @B# incom"!ibiliy

iii. @c


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iii. !r coloured urine due o elev!ed excreion of bilirubin !nd cl!y

coloured feces due o !bsence of sercobilinogen. >eces con!in excess

f! indic!ing im"!irmen in f! digesion !nd !bsor"ion in he

!bsence of bile (s"ecic!lly bile s!ls).iv. /he "!iens ex"erience n!use! !nd g!sroinesin!l "!in.

9. %eon!!l ' "hysiologic -!undice!. l is c!used by incre!sed hemolysis cou"led wih imm!ure he"!ic sysem for

he u"!e, con-ug!ion !nd secreion of bilirubin.b. /he !civiy of he enJyme X7'glucuronylr!nsfer!se is low in he newborn.

>urher, here is ! limi!ion in he !v!il!biliy of he subsr!e X7'glucuronic

!cid for con-ug!ion. /he ne e=ec is h! in some inf!ns he serum

unco-ug!ed bilirubin is highly elev!ed from d!y $ of life bu does no go

beyond oxic leveles h! "roduce ernicerus.1. Z!undice due o geneic defecs Congeni!l %on hemolyic Hy"erbilirubinemi!s. /hey

resul from !bnorm!l u"!e, con-ug!ion or excreion of bilirubin due o inheried

defecs.!. Crigler'%!--!r Gyndrome

i. Here he defec is in con-ug!ion.1. 5n /y"e 1, here is severe deciency of X7 glucuronyl

r!nsfer!se. /he dise!se is ofen f!!l !nd he children diebefore he !ge of $. Z!undice usu!lly !""e!rs wihin he rs $&

hours of life. Xncon-ug!ed bilirubin level incre!ses o more

h!n $ mgdl, !nd hence ernicerus resuls.$. /he /y"e $ dise!se is ! milder formV only he second s!ge of

con-ug!ion is decien. hen b!rbiur!es !re given, some

res"onse is seen !nd -!undice im"roves. Bilirubin level in blood

exceeds $ mgdl in Crigler'%!--!r syndrome /y"e 1 !nd does

no exceed $ mgdl in Crigler'%!--!r syndrome /y"e $.b. SilberNs ise!se

i. 5 is inheried !s !n !uosom!l domin!n r!i. /he defec is in he

u"!e of bilirubin by he liver !nd !n im"!irnren in con-ug!ion due o

reduced !civiy of X7'glucuronylr!nsfer!se.ii. Bilirubin level is usu!lly !round * mgdl, !nd "!ien is !sym"om!ic,

exce" for he "resence of mild -!undice.c. ubin'Zohnson Gyndrome

i. 5 is !n !uosom!l recessive r!i le!ding o defecive excreion of

con-ug!ed bilirubinV so con-ug!ed bilirubin in blood is incre!sed.ii. /he dise!se resuls from he defecive @/7de"enden org!nic !nion

r!ns"or in bile c!n!liculi. /here is ! mu!ion in he FR7'$ "roein

which is res"onsible for r!ns"or of con-ug!ed bilirubin ino bile. /he

bilirubin ges de"osied in he liver !nd he liver !""e!rs bl!c,

referred o !s Bl!c liver -!undice.iii. Roor Gyndrome 5 is ! simil!r condiion, bu he ex!c defec is no

idenied. Bilirubin excreion is defecive, bu here is no s!ining of heliver. 5 is !n !uosom!l recessive condiion.

11. B#e!st (i !un7i$e:!. L!rly onse /his y"e indirec hy"erbilirubinemi! is due o l!c of !de


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c. /hese !re mosly benign !nd self'limiing condiions.1. I((une "e(o+ti$ !un7i$e:

!. Rh 5ncom"!ibiliyi. /his condiion resuls from incom"!ibiliy beween m!ern!l !nd fe!l

blood grou"s. Rh Eve feus m!y "roduce !nibodies in Rh :ve moher.

5n Rh incom"!ibiliy, he rs child ofen esc!"es. Bu in he second

"regn!ncy, he Rh !nibodies will "!ss from moher o he feus. /hey

would s!r desroying he fe!l red cells even before birh.ii. Gomeimes he child is born wih severe hemolyic dise!se, ofen

referred o !s eryhrobl!sosis fe!lis. hen blood level is more h!n $

mgdl, he c!"!ciy of !lbumin o bind bilirubin is exceeded. 5n young

children before he !ge of 1 ye!r, he blood'br!in b!rrier is no fully

m!ured, !nd herefore free bilirubin eners he br!in ([ernicerus). 5 is

de"osied in br!in, le!ding o men!l re!rd!ion, s, oxic ence"h!liis

!nd s"!siciy.iii. 5f he child develo"s hemolyic dise!se, child m!y be given exch!nge

r!nsfusion !long wih "hooher!"y !nd b!rbiur!es. 7hooher!"y

wih blue ligh (&& nm w!ve lengh) isomeriJes he insoluble bilirubin

o more soluble isomers. /hese c!n be excreed hrough urine wihou

con-ug!ion.b. @B# incom"!ibiliy /his is due o mosly # E moher !nd @ or B grou" feus.

/he dise!se is milder h!n Rh y"e. Bu even rs "regn!ncy is !=eced.1*. O)st#u$tie !un7i$e

!. #bsrucion c!n occur due o inrhe"!ic c!use lie he"!iisb. Bile duc obsrucion m!y be congeni!l or due o c!lculus D c!ncer he!d of

"!ncre!s.16. Tests 'o# Bie -i%(ents

!. Bilinogens (XBS !nd GBS) re!c wih LhrlichNs !ldehyde re!gen ("!r!

dimehyl !mino benJ!ldehyde) o form red color.b. 5n >oucheNs es, urine is he!ed wih b!rium sul"h!e which !dsorbs bilirubin.

>erric chloride oxidiJes bilirubin o "roduce ! green color.

c. 5n SmelinNs es, niric !cid is used !s he oxidiJing !gen.d. /he bilinogens (XB !nd GB) form com"lexes wih Jinc ions which exhibi

brilli!n green Wuorescence. /his is he b!sis for GchlesingerNs re!cion. 5 is

neg!ive in norm!l urine.1+. F!n Den Be#% Re!$tion

!. /he es idenies incre!se in serum Bilirubin !nd is neg!ive in norm!l level.

5 idenies con-ug!ed !nd uncon-ug!ed bilirubins.b. B!sis /he regen is ! mixure of e


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MYOGLOBIN M)C

1. 5 is seen in muscles. Fyoglobin conen of sele!l muscle is $.+ gl gV of c!rdi!c

muscle is 1.& gP !nd of smooh muscles .*gP.$. Fb is ! single "oly"e"ide ch!in. Hum!n Fb con!ins 1+$ !mino !cids wih !

molecul!r weigh of 1O,+ !lons.*. #ne molecule of Fb c!n combine wih 1 molecule of oxygen. /he Hb c!rries oxygen

from lungs o issue c!"ill!ries, from where oxygen di=uses ino issues. 5n he

muscles, he oxygen is !en u" by Fb for he s!e of issue res"ir!ion.&. Fb h!s higher !?niy for oxygen h!n h! of Hb.+. 5n severe "hysic!l exercise, "#$ in muscles lowers o + mm Hg, when myoglobin

rele!ses !ll he bound oxygen.. Fb h!s ! high oxygen !?niy while Bohr e=ec, co'o"er!ive e=ec !nd $,*'B7S

e=ec !re

!bsen.

O. Fyoglobin in Xrine !nd Blood Gevere crush in-ury c!uses rele!se of myoglobin from

he d!m!ged muscles. Being ! sm!ll molecul!r weigh "roein, Fb is excreed

hrough urine (myoglobinuri!). Xrine color becomes d!r red.8. Fyoglobin will be rele!sed from myoc!rdium during myoc!rdi!l inf!rcion (F5), !nd is

seen in

serum. Gerum myoglobin esim!ion is useful in e!rly deecion of myoc!rdi!l

inf!rcion


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9. Heme Synthesis Breakdown Hb

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