Lipid Disorders Pathophysiology

7/23/2019 Lipid Disorders Pathophysiology

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Ivano-FrankivskIvano-Frankivsk

National MedicalNational Medical

UniversityUniversity


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1.1. Regulation of lipid metabolism.Regulation of lipid metabolism.2.2. Classes of lipoproteins.Classes of lipoproteins.

3.3. Hyperlipidemias.Hyperlipidemias.

4.4. Atherosclerosis.Atherosclerosis.5.5. Complications ofComplications of

atherosclerosis.atherosclerosis.

6.6. besitybesity

!.!. "enetic disorders"enetic disorders

#.#. $at%soluble$at%soluble

&itamins&itamins


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The knowledge of the reasonsThe knowledge of the reasons

and mechanisms of atherosclerosisand mechanisms of atherosclerosisdevelopment is necessary for thedevelopment is necessary for the

doctors of various profession fordoctors of various profession for

prophylaxis and treatment of thisprophylaxis and treatment of this

disease.disease.

According to modern notions,According to modern notions,main etiological factors ofmain etiological factors of

atherosclerosis is dyslipoproteinemiaatherosclerosis is dyslipoproteinemia

and increased permeability arterialand increased permeability arterial

wall for lipoproteins.wall for lipoproteins.

AtherosclerosisAtherosclerosis exceptionally widespread disease. On data WO, exceptionally widespread disease. On data WO,mortality of the patients in the age !"#$$ years for damages of heart andmortality of the patients in the age !"#$$ years for damages of heart and

vessels connected with atherosclerosis, increased lately by %&'.vessels connected with atherosclerosis, increased lately by %&'.


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Metabolic Rate -Metabolic Rate -tthe amount of energy liberated per unit of time. The amount of energy liberated by the catabolism of food in the body is the same as the amount liberated when

food is burned outside the body.The energy liberated by catabolic processes in the bodyis used for maintaining body functions, digesting and

metaboli(ing food, thermoregulation, and physical activity. )t appears as external work, heat, and energy storage*

+

)sotonic muscle contractions perform work at a peak efficiency approximating "&'*

+ -

CaloriesCaloriesThe standardThe standard unit of heat energyunit of heat ener

gyis theis the calorie (cal)calorie (cal),,defined as thedefined as the amount of heat energy necessary to raise theamount of heat ener

gy necessary to raise the

temperature of g of water degree, from " /0 to % /0tem

perature of g of water degree, from " /0 to % /0 . This unit is also called the gram calorie, small calorie,. This unit is also called the gram calorie, small calorie,

or standard calorie. The unit commonly used in physiology and medicine is theor standard calorie. The unit commonly used in physiology and medicine is the Calorie (Calorie (kilocalorie; kcalkilocalorie; kcal),),whichwhich

e1uals &&& cal.e1uals &&& cal.

ENERGYENERGY

OUTPUTOUTPUTEXTERNALEXTERNAL

WORKWORKENERGYENERGY

STORAGESTORAGEHEATHEAT

WORKWORKDONEDONE

TOTAL ENERGYTOTAL ENERGYEXPENDEDEXPENDED

EFFICIENCYEFFICIENCY


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Measuring the Metabolic RateMeasuring the Metabolic Rate)n determining the metabolic rate, O)n determining the metabolic rate, O33

consumption is usually measured withconsumption is usually measured with

some form of oxygen#filled spirometer andsome form of oxygen#filled spirometer anda 0Oa 0O33#absorbing system.#absorbing system.

The spirometer bell is connected to a penThe spirometer bell is connected to a pen

that writes on a rotating drum as the bellthat writes on a rotating drum as the bell

moves up and down. The slope of a linemoves up and down. The slope of a line

4oining the ends of each of the spirometer4oining the ends of each of the spirometer

excursions is proportionate to the Oexcursions is proportionate to the O33consumption.consumption.

The amount of OThe amount of O335in milliliters6 consumed5in milliliters6 consumed

per unit of time is corrected to standardper unit of time is corrected to standard

temperature and pressure and thentemperature and pressure and then

converted to energy production byconverted to energy production by

multiplying by $.73 kcal-8 of Omultiplying by $.73 kcal-8 of O33consumed.consumed.


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2 The metabolic rate determined at rest in a room at aThe metabolic rate determined at rest in a room at acomfortable temperature in the thermoneutral (one 3#$ hourscomfortable temperature in the thermoneutral (one 3#$ hoursafter the last meal is called theafter the last meal is called the basal metabolic rate (BMR).basal metabolic rate (BMR).

2 ThisThis value falls about !" #uring slee$value falls about !" #uring slee$and up toand up to %!"%!"#uring $rolonge# starvation#uring $rolonge# starvation. The rate during normal daytime. The rate during normal daytimeactivities is, of course, higher than the 9:; because ofactivities is, of course, higher than the 9:; because of

muscular activity and food intake.muscular activity and food intake.2 TheThe ma&imum metabolic ratema&imum metabolic ratereached during exercise is oftenreached during exercise is often

said to be ten times the 9:;, but trained athletes can increasesaid to be ten times the 9:;, but trained athletes can increasetheir metabolic rate as much as 3fold.their metabolic rate as much as 3fold.

2 'he BMR of a man of average sie is about !!! kcal*#.'he BMR of a man of average sie is about !!! kcal*#.


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LipidsLipids

Fatty acidsFatty acids

and theiand theidei!ati!esdei!ati!es

SaturatedSaturated"n# d#$%&e"n# d#$%&e

%#nds'%#nds'

Ste#&s "Ste#&s "ste#idh#(#nes )ch#&este#&''

Ph#s*h#&i*idsPh#s*h#&i*ids

and e&atedand e&atedc#(*#$ndsc#(*#$nds

Ne$ta& +atsNe$ta& +ats

"ti,&yceide"ti,&yceide

s's'

UnsaturatedUnsaturated"dehyd#,enated-"dehyd#,enated-

.ith !ai#$s n$(%es #+ d#$%&e.ith !ai#$s n$(%es #+ d#$%&e

%#nds'%#nds'


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+i$o$rotein

Com$osition (")

ie

(nm)rotein

ree

Cholesterol

Cholesteryl

/sters'riglyceri#e hos$holi$i# 0rigin

ChylomicronsChylomicrons12-

!!! 3 4! 3 5ntestine

ChylomicronChylomicron

remnantsremnants3!-6! . . . . . . . . . . . . . . . Ca$illaries

7ery lo87ery lo8#ensity#ensity

li$o$roteinsli$o$roteins

(7+9+)(7+9+)

3!-6! 6 % : 22 1+iver an#

intestine

5nterme#iate-5nterme#iate-

#ensity#ensity


(59+)(59+)

2-%! ! 2 2 %! ! 7+9+

+o8-#ensity+o8-#ensity


(+9+)(+9+)

! ! 1 %: : 59+

igh-#ensityigh-#ensity


(9+)(9+)

1.2-! 2! % : 2 2+iver an#

intestine


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Transports diet#derived triglyceride 5T 5!60holesterol 50>!'6> 5$6 =hospholipid 57'6

@ynthesi(ed in intestinal epithelium

56 ;e1uires apolipoprotein 5apo6 9#$7 for assembly and secretion

536 ascent chylomicrons in the circulation obtain apo 0#)l and apo B from high

density lipoprotein 5C86Absent during fasting

)f increased, it forms a creamy supranate.

2 6 Test tube must be left upright in a refrigerator overnight,

2 36 0hylomicron floats on top of plasma because it has very little protein 5low

density6.@ource of fatty acids and glycerol

2 Dsed to synthesi(e T< in the liver and adipose

ydrolysisby capillary lipoprotein lipase 50=86 leaves a chylomicron remnant,

2 0hylomicron remnants arc removed by apo B receptors in the liver.


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+i$o$rotein unctions A$o$roteins unctions

Chylomicrons

Transport dietary triglyceride and

cholesterol from intestine totissues

a$oB-%6

a$oC-55a$o/

@ecreted by intestine

Activates lipoprotein lipaseDptake of remnants by theliver

7+9+

Transports triglyceride from liverto tissues

a$oB-!!a$oC-55a$o/

@ecreted by liverActivates lipoprotein lipaseDptake of remnants 5)C86 by

liver

59+(7+9+remnants)

=icks up cholesterol from C8 tobecome 8C8=icked up by liver

a$o/a$oB-!!

Dptake by liver

+9+

Celivers cholesterol into cells A$oB-!! Dptake by liver and othertissues via 8C8 receptor

5apo9#&& receptor6

9+

=icks up cholesterol accumulatingin blood vesselsCelivers cholesterol to liver andsteroidogenic tissues viascavenger receptor 5@;#96

@huttles apo0#)) and apoB inblood

a$oA- Activates lecithin cholesterolacyltransferase 580AT6 toproduce cholesterol esters


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Transportsliver#synthesi(ed T< in the blood

# ;e1uires apolipoprotein 9#&& for assembly and secretion

Com$osition3"; hence,fasting #oesfasting #oes not have anot have ame#ically significant effect onme#ically significant effect onthe serum level.the serum level.


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J


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2 )n the body, fatty acids are broken down to)n the body, fatty acids are broken down to acetyl-CoAacetyl-CoA, which enters the, which enters the citric aci# cyclecitric aci# cycle..

2 The main breakdown occurs in the mitochondria by M#oxidation.The main breakdown occurs in the mitochondria by M#oxidation.

2 atty aci# o&i#ationatty aci# o&i#ation begins with activation of the fatty acid, a reaction that occurs both inside andbegins with activation of the fatty acid, a reaction that occurs both inside andoutside the mitochondria.outside the mitochondria.

2 :edium# and short#chain fatty acids can enter the mitochondria without difficulty, but long#chain:edium# and short#chain fatty acids can enter the mitochondria without difficulty, but long#chain

fatty acids must be bound tofatty acids must be bound to carnitinecarnitinein ester linkage before they can cross the innerin ester linkage before they can cross the inner

mitochondrial membrane.mitochondrial membrane.

2 CarnitineCarnitine is M#hydroxy#N#trimethylammonium butyrate, and it is synthesi(ed in the body fromis M#hydroxy#N#trimethylammonium butyrate, and it is synthesi(ed in the body from

lysine and methionine.lysine and methionine.

2 A translocase moves the fatty acid#carnitine ester into the matrix space in exchange for freeA translocase moves the fatty acid#carnitine ester into the matrix space in exchange for free

carnitine.carnitine.

2 )n the matrix space, the ester is hydroly(ed, making the activated fatty acid molecule available for)n the matrix space, the ester is hydroly(ed, making the activated fatty acid molecule available for

M#oxidation and providing free carnitine for further exchange.M#oxidation and providing free carnitine for further exchange.

2 -0&i#ation-0&i#ation proceeds by serial removal of two carbon fragments from the fatty acid. The energyproceeds by serial removal of two carbon fragments from the fatty acid. The energy

yield of this process is large.yield of this process is large.


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2 Ceficient M#oxidation of fatty acids can beCeficient M#oxidation of fatty acids can beproduced byproduced by carnitine deficiencycarnitine deficiency oror geneticgenetic

defects in the translocasedefects in the translocaseoror other en(ymesother en(ymes

involved in the transfer of long#chain fattyinvolved in the transfer of long#chain fattyacids into the mitochondria.acids into the mitochondria.

2 This causesThis causes cardiomyopathycardiomyopathy..2 )n addition, it causes)n addition, it causes hy$oketonemichy$oketonemic

hy$oglycemiahy$oglycemiawithwith comacoma, a serious and, a serious and

often fatal condition triggered by fasting, inoften fatal condition triggered by fasting, in

which glucose stores are used up because ofwhich glucose stores are used up because of

the lack of fatty acid oxidation to providethe lack of fatty acid oxidation to provideenergy, andenergy, and ketone bodiesketone bodies are not formed inare not formed innormal amountsnormal amountsbecause of thebecause of the lack oflack of

ade1uate 0oA in the liverade1uate 0oA in the liver..


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)n many tissues, acetyl#0oA unitsacetyl#0oA units condense to form acetoacetyl#0oAform acetoacetyl#0oA.

)n the liverliver, which 5unlike other tissues6 contains a deacylasecontains a deacylase, free aceto-acetate is formed.

This M#keto acidM#keto acid is converted to -hy#ro&ybutyrate-hy#ro&ybutyrateand acetoneacetone, and because these compounds aremetaboli(ed with difficulty in the liver, they diffuse into the circulation.

AcetoacetateAcetoacetateis also formed in the liver via the formation of !#hydroxy#!#methylglutaryl#0oA, and this

pathway is 1uantitatively more important than deacylation.

AcetoacetateAcetoacetate, -hy#ro&ybutyrate-hy#ro&ybutyrate, and acetoneacetoneare called ketone bo#ies (B)ketone bo#ies (B).

Tissues other than liver transfer 0oA from succinyl-CoA to acetoacetateand metaboli(e the active

acetoacetate to C0an# 0 via the citric aci# cycle. There are also other pathways whereby ketone

bodies are metaboli(ed.

AcetoneAcetoneis discharged in the urine and expired air.

The normal bloo# ketone level in humans is lo8 (about mg*#+)andless than mg is e&crete# $er

% hours, because the ketones are normally metaboli(ed as rapidly as they are formed. owever, if the

entry of acetyl#0oA into the citric acid cycle is depressedentry of acetyl#0oA into the citric acid cycle is depressed because of a decreased supply of the products ofdecreased supply of the products of

glucose metabolismglucose metabolism, or if the entry #oes not increase when the supply of acetyl#0oA increases, acetyl#

0oA accumulates, the rate of condensation to acetoacetyl#0oA increases, and more acetoacetate ismore acetoacetate is

formed in the liverformed in the liver.

The ability of the tissues to oxidi(e the ketonesoxidi(e the ketones is soon exceeded, and they accumulate in the bloodstream

(ketosis).

Acet#neAcet#ne

%eath%eathK/ in $ineK/ in $ine

KETONURIAKETONURIA

K/ in the %#dK/ in the %#d

KETONE0IAKETONE0IA $ -$ -Aci#osisAci#osis 9ehy#ra-9ehy#ra-tationtation

AreAre

osmoticDosmoticD


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High-fat mealHigh-fat meal80 g TGs80 g TGs

recommended dailyrecommended dailymaxmax

TT

GG

/i&e "&i!e'/i&e "&i!e'

Panceatic &i*asePanceatic &i*aseC#&i*ase "*#tects &i*ase +#( the %i&e'C#&i*ase "*#tects &i*ase +#( the %i&e'

1 2 0G1 2 0G

33 1 FA1 FA

INTESTINEINTESTINE

MOOGL!"#$!%#MOOGL!"#$!%#

TGTG

"H&LOM!"$O"H&LOM!"$OSS L&M'L&M'HH

Via thoracic

duct

"an(t pass mem)rane )y they"an(t pass mem)rane )y theyo*n+ they need )e di,ided )yo*n+ they need )e di,ided )y

)reado*n)reado*n

.lood.lood

streamstream

SteatorrheaSteatorrhea //Fatty st##& "45 #+Fatty st##& "45 #+

+ats'+ats'


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therosclerosistherosclerosisis a form ofis a form of arteriosclerosisarteriosclerosisin *hichin *hich thiceningthiceningandand hardeninghardeningof theof the,essel,essel ae ca$sed %y theae ca$sed %y the acc$($&ati#n #+ &i*id6acc$($&ati#n #+ &i*id6&aden (ac#*ha,es&aden (ac#*ha,es .ithin the ateia& .a&&-.ithin the ateia& .a&&-

.hich &eads t# the +#(ati#n #+ a &esi#n ca&&ed a.hich &eads t# the +#(ati#n #+ a &esi#n ca&&ed apla1ue2pla1ue2

therosclerosistherosclerosis isis not a single disease %$t%$tathe a *ath#,ic *#cess that canathe a *ath#,ic *#cess that can a7ecta7ect

!asc$&a syste(s!asc$&a syste(s th#$,h#$t the %#dy- es$&tin,th#$,h#$t the %#dy- es$&tin,in ische(ic synd#(es that can !ay .ide&y inin ische(ic synd#(es that can !ay .ide&y inthei se!eity and c&inica& (ani+estati#ns8thei se!eity and c&inica& (ani+estati#ns8

It is the &eadin, c#nti%$t# t#It is the &eadin, c#nti%$t# t# c##nay ateyc##nay ateyandand cee%#!asc$&a diseasecee%#!asc$&a disease88


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2 A d t i t l fAnd yet ancient people of


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The ($((i9ed E,y*tians- .ee &i:e&y t# ha!e %een .ea&thy- andThe ($((i9ed E,y*tians- .ee &i:e&y t# ha!e %een .ea&thy- and

thee+#e *#%a%&y c#ns$(ed a t #+ sat$ated +at8 This is in +act n#t the 9stthee+#e *#%a%&y c#ns$(ed a t #+ sat$ated +at8 This is in +act n#t the 9st

ti(e that hadened ateies .ee identi9ed in E,y*tian ($((ies8 And yetti(e that hadened ateies .ee identi9ed in E,y*tian ($((ies8 And yet

the Unan,ans- #+ the A&$etian Is&ands in A&as:a- s$%sisted a&(#st entie&y #nthe Unan,ans- #+ the A&$etian Is&ands in A&as:a- s$%sisted a&(#st entie&y #n

(aine &i+e8 They- and the #the ($((ies- .ee *ese!ed nat$a&&y th#$,h(aine &i+e8 They- and the #the ($((ies- .ee *ese!ed nat$a&&y th#$,hc&i(ate +act#s- n#t %eca$se they had attained any s*ecia& stat$s that .#$&dc&i(ate +act#s- n#t %eca$se they had attained any s*ecia& stat$s that .#$&d

ha!e *i!i&e,ed the( .ith e;ta6ich +##ds8ha!e *i!i&e,ed the( .ith e;ta6ich +##ds8

/$t that ancient *e#*&e- t##- had ca&ci9ed ateies- =s$,,ests that the/$t that ancient *e#*&e- t##- had ca&ci9ed ateies- =s$,,ests that the

disease is an inheent c#(*#nent #+ h$(an a,in, and n#t necessai&ydisease is an inheent c#(*#nent #+ h$(an a,in, and n#t necessai&y

ass#ciated .ith any s*eci9c diet # &i+esty&e8= Indeed- the ($((ies .ithass#ciated .ith any s*eci9c diet # &i+esty&e8= Indeed- the ($((ies .ith

si,ns #+ ca&ci9cati#n tended t# %e #&de- # .hat in th#se days c#$nted assi,ns #+ ca&ci9cati#n tended t# %e #&de- # .hat in th#se days c#$nted asa,e> they died at a#$nd ?@ yeas as #**#sed t# @18 F# each decade #+ &i+ea,e> they died at a#$nd ?@ yeas as #**#sed t# @18 F# each decade #+ &i+e

Hatiay+ a male #gyptian scri)e *ho li,ed during

the e* 3ingdom 45670-59: ."#;+ enters the "Tscanner2


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2Role of bloo# monocytes. 'hough bloo# monocytes #o

not possess receptors for normal 8C8, 8C8 does appear in

the monocyte cytoplasm to form foam cell. lasma +9+ on

entry into the intima undergoes oxidation. The Poxidised

8C8Q formed in the intima performs the following all#

important functions on monocytes and endothelium*2For monocytes: Oxidised LDL acts to attract, proliferate,

immobilise and activate them as well as is readily taken up

by scavenger receptor on the monocyte to transform it to a

lipid#laden foam cell.2Ior endothelium: Oxidised LDL is cytotoxic.2Ceath of foam cell by apoptosis releases lipid to form lipidcore of pla1ue.


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A'0E50+0=EA'0E50+0=E

2 . )n4ured endothelial cells. )n4ured endothelial cells become inflamedbecome inflamedandandcannot make normal amounts of antithromboticcannot make normal amounts of antithrombotic

and vasodilating cytokines.and vasodilating cytokines.

2 3. umerous3. umerous inflammatory cytokines are releasedinflammatory cytokines are released,,

includingincluding tumor necrosis factor#alpha 5TI#R6,tumor necrosis factor#alpha 5TI#R6,

interferongammainterferongamma 5)I#5)I#N6,N6, interleukin# 5)8#6, toxicinterleukin# 5)8#6, toxic

oxygen radicals, and heat shock proteins.oxygen radicals, and heat shock proteins.2 !.!. :acrophages adhere to in4ured endothelium:acrophages adhere to in4ured endothelium byby

way of adhesion molecules, such as vascular cellway of adhesion molecules, such as vascular cell

adhesion molecule# 5E0A:#6.adhesion molecule# 5E0A:#6.

2 $. These$. These macrophagesmacrophagesthen release en(ymes andthen release en(ymes and

toxic oxygen radicals thattoxic oxygen radicals that create oxidative stresscreate oxidative stress,,oxidi(e 8C8oxidi(e 8C8, and, and further in4ure the vessel wallfurther in4ure the vessel wall..

2 "".


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Endothelial Dysfunction in Atherosclerosis

;oss ;. N n!l " #edGGG> !$&*"3%.

Macro$hages $lay main

rolendings

' Chy(ic#ns ae *i(ai&y inceasedin ea&y chi&dh##d8

1' LDL inceases &ate in &i+e8@' Pesents .ith ac$te *anceatitis Panceatic !esse&s 9&&ed .ith

chy(ic#ns $*t$e8

d2 La)oratory >ndings' Incease in se$( TG (,JdL

"*i(ai&y chy(ic#ns'1' T$%id s$*anate "chy(ic#ns' and

c&ea in+anate "ea&y chi&dh##d'

@' N#(a& "$s$a& case' t# (#deate&y

inceased se$( CH

A* 8ateral borders of thickened

AchillesU tendons are shown with

arrows.

9* Tendinous xanthomas can also

occur in the extensor tendons of

the hands 5shown6, feet, elbowsand knees.

0* anthelasmas are cholesterol

deposits in the eyelids.

C* Arcus cornealis results from

cholesterol infiltration around the

corneal rim 5arrow6.


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a. +aboratory fin#ings

6 @erum 8C8 H G& mg-d8

36 @erum 0 H 3%& mg-d8

a6 @erum T< F !&& mg-d8 5called type ))a6b6 @erum T< H !&& mg-d8 5called type l)b6

b. athogenesis

2 Cecreased synthesis of 8C8 receptors.

c. AcKuire# causes of hy$ercholesterolemia

6 =rimary hypothyroidism

2 Cecrease in 8C8 receptor synthesis orfunction

36 ephrotic syndrome

2 )ncrease in 8C8 correlates with the degree ofhypoalbuminemia

!6 Bxtrahepatic cholestasis 5obstruction of bile6

2 9ile contains 0 for excretion

#. amilial hy$ercholesterolemia

6 Autosomal dominant 5AC6 disorder

36 Ceficiency of 8C8 receptors

!6 0linical findings

a6 =remature coronary# artery# disease andstroke

b6 Tendon xanthomas

2 0holesterol deposit located over tendons5e.g. Achilles6 and extensor surfaces of 4oints

c6 anthelasma

2 Vellow, raised pla1ue on the eyelid

e. olygenic hy$ercholesterolemia (ty$e 5la)

6 :ost common hereditary cause 57"' ofcases6

36 :ultifactorial 5polygenic6 inheritance

!6 Alteration in regulation of 8C8 levels

$6 ormal serum T 300 mg/L

2) Serum CH 250 to 500 mg/dL

3) LDL< 190 mg/dL Familial dysbetalipoproteinemia ("remnant disease")

1) AD inheritance

2) Deficiency of apo E

3) Decreased liver uptake of chylomicron remnants and IDL Clinical findings

1) Palmar xanthomas in flexor creases

2) Increased risk for coronary artery disease

3) Increased risk for peripheral vascular disease (unlike type II disorders) Laboratorv findings

1) Serum CH and TG > 300 mg/dL

2) Serum CH 250 to 500 mg/dL

3) LDL< 190 mg/dL4) Confirm diagnosis with ultracentrifugation to identify remnants Lipoprotein electrophoresis and identification of apo E gene defect are other studiesthat can be used.

Treatment Fibric acid derivatives


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+aboratory fin#ings

6 @erum T< H !&& mg-d8> 36 @erum 0 3"& to "&& mg-d8> !6 @erum 8C8 F G& mg-d8>

$6 Turbid infranate after refrigeration

5ncrease in 7+9+ - due to increase in synthesis or decrease in catabolism

AcKuire# causes of hy$ertriglyceri#emia

6 Bxcess alcohol intake

36 Oral contraceptives # estrogen increases synthesis of E8C8

!6 Ciabetes mellitus # decreased muscle and adipose 08=

$6 0hronic renal failure # increased synthesis of E8C8

"6 Thia(ides, M#blockers # possible inhibition of 0=8

amilial hy$ertriglyceri#emia

6 Autosomal dominant disorder

36 0linical findings

a6 Bruptive xanthomas # yellow, papular lesions

5b6 )ncreased risk for coronary artery# and peripheral

vascular disease

T$%e#6e$ ti!e


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a. Pathogenesis

1) Increase in chylomicrons and VLDL

2) Due to decreased activation and release of CPL

b. Familial hypercholesterolemia (type IV) + exacerbating disorder

Exacerbating disorders diabetic ketoacidosis (DKA: most common),alcohol

c. Increased serum TG > 1000 mg/dL; normal CH and LDL.

d. Turbid plasma

1) Supranate after refrigeration, due to increased chylomicrons

2) Infranate after refrigeration, due to increased VLDL.e. Hyperchylomicronemia syndrome

1) Eruptive xanthomas

2) Increased incidence of acute pancreatitis

3) Lipemia retinalis - retinal vessels look like milk: blurry vision

4) Dyspnea and hypoxemia - impaired gas exchange in pulmonarycapillaries

5) Hepatosplenomegaly

6) Increase in serum TG (usually >1000 mg/dL)

7) Normal serum CH and LDL

8) Turbid supranate and infranate after refrigeration

f. Treatment

(1) Treat exacerbating disorder (e.g.. DKA)

(2) Nicotinic acid or fibric acid derivatives


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A$oli$o$rotein B #eficiency(abetali$o$roteinemia)

a. Autosomal recessiveb. 9eficiency of a$oli$o$rotein B-%6 an# B-!!

2 () 9eficiency of chylomicrons, 7+9+ an# +9+

2 () 9ecrease in serum C an# '=

c. Clinical fin#ings

) Malabsor$tion

a) Chylomicrons accumulate in villi an# $reventreabsor$tion of micelles.

b) Marke# #ecrease in vitamin /

) Ata&ia(s$inocerebellar #egeneration),hemolytic anemia 8ith thorny RBCs(acanthocytes) relate# to vitamin / #eficiency.

#. 'reatment - vitamin /


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ObesityObesityan excess of adipose tissue that imparts healthan excess of adipose tissue that imparts healthrisk; a body weight of 20% excess over ideal weight for age,risk; a body weight of 20% excess over ideal weight for age,

sex and height is considered a health risk.sex and height is considered a health risk.

1. Body mass index (BMI)

> 30kg/m2 (normal, 19.5-24.9kg/m2)

1) Excess fat n t!e "ast an# flanks s morem$ortant t!an an excess n t!e t!g!s an#

%&ttocks.

2) Excess 'sceral fat n t!e a%#omnalca't !as greater sgnfcance t!an excesss&%c&taneo&s fat.

agnetc resonance magng s &se# to

access t!e amo&nt of 'sceral fat.

/#dy (ass inde; "/#dy (ass inde; ".M!.M!' .hich is e$a& t#' .hich is e$a& t# .ei,ht in.ei,ht in:,Jhei,ht in (1:,Jhei,ht in (1


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#T!OLOGT!OLOG& ObesityObesityresults when caloric intakeresults when caloric intake

exceeds utilisation.exceeds utilisation.

The imbalance of these twoThe imbalance of these two

components can occur in thecomponents can occur in the

following situations*following situations*

.. 'nadequate'nadequatepushin! of oneself a(ay from the dinin! ta&lepushin! of oneself a(ay from the dinin! ta&le causingcausing

overeating.overeating.

3.3. 'nsufficient'nsufficientpushin! of oneself out of the chair leadin! topushin! of oneself out of the chair leadin! to inactivity andinactivity and

sedentary life style.sedentary life style.

!.!. )enetic)eneticpredisposition to de*elop o&esity.predisposition to de*elop o&esity.

$.$. DietsDietslar!ely deri*ed from car&ohydrates and fats thanlar!ely deri*ed from car&ohydrates and fats than protein#rich diet.protein#rich diet.

".". Secondary obesitySecondary obesity may result follo(in! a num&er of underlyin!may result follo(in! a num&er of underlyin! diseasesdiseases

such as hypothyroidism, 0ushingQs disease, insulinoma and hypothalamicsuch as hypothyroidism, 0ushingQs disease, insulinoma and hypothalamic

disorders.disorders.


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+e$tin@atiety 5hunger-appetite

suppression6 and regulation of eating

behavior by hypothalamus@ympathoactivation)nsulin sensiti(ing:odulating role in reproduction,

angiogenesis, immune response,

blood pressure control, and

osteogenesis

A#i$onectin)nsulin sensiti(ingAnti#inflammatoryAnti#atherogenic

Resistin

=romotes insulin resistance andincreased blood glucose levels)nhibits adipocyte differentiation

and may function as a feedback

regulator of adipogenesis

7isfatin 5from visceral fat6:imics insulin and binds to insulin

receptors in rats

7as$inmay be insulin sensiti(ing

ormones 5Adipokinesormones 5Adipokines6

Li*#*#tein &i*aseA*#&i*#*#tein ECh#&este#& este tans+e*#tein

Re,$&at#s #+ Li*#*#teinRe,$&at#s #+ Li*#*#tein

0eta%#&is(0eta%#&is(

Ina((at#yIna((at#y

Cyt#:inesCyt#:inesTumor necrosis factor#alpha)nterleukins 5)8#%, )8#7, )8#&6=lasminogen activator inhibitor#:onocyte chemoattractant protein#

Othe H#(#nes andOthe H#(#nes and

Cyt#:inesCyt#:inesBstrogenAngiotensinogen

Tissue factorTransforming growth factor#beta)nsulin#like growth factoritric oxide synthaseAcylation stimulating proteinAdipophilinAdipoX:onobutyrin

Agouti protein


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Re,$&ati#n #+ a**etite and satiety #cc$s th#$,hRe,$&ati#n #+ a**etite and satiety #cc$s th#$,hne$#end#cine e,$&ati#n #+ eatin, %eha!i#- ene,yne$#end#cine e,$&ati#n #+ eatin, %eha!i#- ene,y(eta%#&is(- and %#dy +at (ass8 The syste( is c#(*&e; and(eta%#&is(- and %#dy +at (ass8 The syste( is c#(*&e; and

c#nt#&&ed %y a dyna(ic cic$it #+ si,na&in, (#&ec$&es +#( thec#nt#&&ed %y a dyna(ic cic$it #+ si,na&in, (#&ec$&es +#( the*ei*hey actin, #n centa& c#nt#&s inc&$din, the %ain ste(-*ei*hey actin, #n centa& c#nt#&s inc&$din, the %ain ste(-hy*#tha&a($s- and a$t#n#(ic ne!#$s syste(8 An i(%a&ance inhy*#tha&a($s- and a$t#n#(ic ne!#$s syste(8 An i(%a&ance inthis syste( is $s$a&&y ass#ciated .ith e;cessi!e caic inta:e inthis syste( is $s$a&&y ass#ciated .ith e;cessi!e caic inta:e ine&ati#n t# e;ecise .ith the c#nse$ence #+ .ei,ht ,ain ande&ati#n t# e;ecise .ith the c#nse$ence #+ .ei,ht ,ain and#%esity8#%esity8

TheThe arcuate nucleus 4$";arcuate nucleus 4$";in the hy*#tha&a($s has t.# setsin the hy*#tha&a($s has t.# sets#+ ne$#ns .ith #**#sin, e7ects that inteact t# e,$&ate and#+ ne$#ns .ith #**#sin, e7ects that inteact t# e,$&ate and%a&ance +##d inta:e and ene,y (eta%#&is(8%a&ance +##d inta:e and ene,y (eta%#&is(8

One set #+ ne$#ns *#d$cesOne set #+ ne$#ns *#d$ces neuropeptide & 4'&;neuropeptide & 4'&;andandagoutirelated protein 4G$';agoutirelated protein 4G$';- .hich- .hich stimulates eatingstimulates eatingandand decreases meta)olismdecreases meta)olism"ana%#&ic'8"ana%#&ic'8

An#the set #+ ne$#ns synthesiesAn#the set #+ ne$#ns synthesies pro-opiomelanocortinpro-opiomelanocortin4'OM";4'OM";6*#d$cin, *e*tide and6*#d$cin, *e*tide and cocaineand-amphetamine-cocaineand-amphetamine-regulated transcript 4"$T;regulated transcript 4"$T;- c#&&ecti!e&y :n#.n as- c#&&ecti!e&y :n#.n asPO0CJCARTPO0CJCART ne$#ns8 Theyne$#ns8 They inhi)it eatinginhi)it eating andand increaseincreasemeta)olismmeta)olism"cata%#&ic'8"cata%#&ic'8

/#th sets #+ ne$#ns e;*ess thei e7ects %y acti!atin, sec#nd6/#th sets #+ ne$#ns e;*ess thei e7ects %y acti!atin, sec#nd6#de ne$#ns in the hy*#tha&a($s- .hich inceases ##de ne$#ns in the hy*#tha&a($s- .hich inceases #deceases a**etite and ene,y (eta%#&is(8deceases a**etite and ene,y (eta%#&is(8


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?at cell mass

and

stimulates 0MC*CAR' gene expression with resulting N-M release and decrease in appetite and food

intake. With le$tin resistanceas occurs in obesity, these effects are depressed and food intake increases in

excess of energy expenditure. A!", a!outi-related peptide+ #$%SH, alpha-melanocyte stimulating hormone>?E, neuropeptide V> "O%C&CA!', proopiomelanocortincocaine#and#amphetamine#related transcript

rcuatenucleus

'ara,entricular

nucleus


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Ne$#*e*tide Y"NPY'0e&anin6c#ncentatin, h#(#ne"0CH'

A,#$ti6e&ated*#tein "AGRP'Ghe&inGa&aninOe;ins A and /

Pe*tide YY "PYY'

Le*tinIns$&inCh#&ecyst#:inin "CCK'C#tic#t#*in6e&easin,h#(#ne "CRF'U#c#tin "a CRF satietysi,na&in, h#(#ne'C#caine6 and

a(*heta(ine6e,$&atedtansci*t "CART'A&*ha6(e&an#cyte6sti($&atin, h#(#ne "60SH'/#(%esin

Se#t#nin

(#&ec$&es that sti($&ate eatin,(#&ec$&es that sti($&ate eatin,

(#&ec$&es that inhi%iteatin,

hrelinhrelinis produced &y the stomach in response to hun!eris produced &y the stomach in response to hun!erand stimulatesand stimulates

food intake and induces metabolic changes leadingfood intake and induces metabolic changes leading to an increase in bodyto an increase in body


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food intake and induces metabolic changes leadingfood intake and induces metabolic changes leadingto an increase in bodyto an increase in body

weight and body fat mass.weight and body fat mass. =hrelin=hrelinalso stimulates release of growth hormonealso stimulates release of growth hormone

5


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'athogenesis'athogenesisa2 Genetic factorsa2 Genetic factors account for 60A to 80A of eases2account for 60A to 80A of eases2BB #xamplesCdefects in the leptin gene+ syndrome D 4o)esity+#xamplesCdefects in the leptin gene+ syndrome D 4o)esity+

hypertension+ dia)etes;hypertension+ dia)etes;

)2 c1uired causes)2 c1uired causes 45; #ndocrine disordersChypothyroidism+ dishing syndrome45; #ndocrine disordersChypothyroidism+ dishing syndrome 4; Hypothalamic lesions+ menopause4; Hypothalamic lesions+ menopausec2 Leptinc2 Leptin5; Leptin is a hormone25; Leptin is a hormone2

a; Secreted )y adipose tissuea; Secreted )y adipose tissue

); Maintains energy )alance 4intae and output;); Maintains energy )alance 4intae and output;; Leptin increases *hen adipose stores are ade1uate2; Leptin increases *hen adipose stores are ade1uate2

a; %ecreases food intae 4inhi)its satiety center;a; %ecreases food intae 4inhi)its satiety center;

); !ncreases energy expenditure 4stimulates 4); !ncreases energy expenditure 4stimulates 4EE-oxidation of-oxidation offatty- acids;fattyacids;

:; Leptin decreases *hen adipose stores are inade1uate2:; Leptin decreases *hen adipose stores are inade1uate2 a; !ncreases food intae 4stimulates the satiety center;a; !ncreases food intae 4stimulates the satiety center;

); %ecreases energy expenditure 4inhi)its); %ecreases energy expenditure 4inhi)its EE-oxidation of-oxidation offatty acids;fatty acids;

F; O)esity related to leptin dysfunction may )e caused )y theF; O)esity related to leptin dysfunction may )e caused )y thefollo*ingfollo*ing

a; $esistance to leptin eectsa; $esistance to leptin eects

); Mutations resulting in inhi)ition of leptin release); Mutations resulting in inhi)ition of leptin release


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1. Hyperinsulinaemia. Increasedinsulin secretion is a feat&re ofo%est. an o%ese n#'#&als ex!%t

!$erglcaema or frank #a%etes #es$te!$erns&lnaema. *!s s #&e to a stateof ns&ln-resstance conse+&ent totss&e nsenst't.

2. Type 2 diabetes mellitus. There

is a strong association of t$e 2#a%etes mellt&s "t! o%est. %estoften exacer%ates t!e #a%etc state an#n man cases "eg!t re#&cton oftenlea#s to ameloraton of #a%etes.

. Hypertension. ! strongassociation bet"een hypertensionan# o%est s o%ser'e# "!c! s $er!a$s#&e to ncrease# %loo# 'ol&me. eg!tre#&cton lea#s to sgnfcant re#&ctonn sstolc %loo# $ress&re.


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%. y$erli$o$roteinaemia.'he $lasmacholesterol circulates in the blood as low#density lipoprotein 58C86 containing most ofthe circulating triglycerides. Obesity is stronglyassociated with E8C8 and mildly with 8C8.Total blood cholesterol levels are alsoelevated in obesity.

2. Atherosclerosis.0besity $re#is$oses to#evelo$ment of atherosclerosis. As a resultof atherosclerosis and hypertension, there isincreased risk of myocardial infarction andstroke in obese individuals.

:. ?onalcoholic fatty liver #isease(?A+9). 0besity contributes todevelopment of AI8C which may progressfurther to cirrhosis of the liver.

1. Cholelithiasis.'here is si& times higherinci#ence of gallstones in obese persons,mainly due to increased total bodycholesterol.


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6.6. y$oventilation syn#rome (ick8ickiany$oventilation syn#rome (ick8ickiansyn#rome).syn#rome). This is characterised byThis is characterised byhypersomnolence, both at night and during dayhypersomnolence, both at night and during day

in obese individuals along with carbon dioxidein obese individuals along with carbon dioxideretention, hypoxia, polycythaemia andretention, hypoxia, polycythaemia andeventually right#sided heart failure. 5:r =ickwickeventually right#sided heart failure. 5:r =ickwickwas a character, the fat boy, in 0harles CickensQwas a character, the fat boy, in 0harles CickensQic/(ic/ apers. 0he term pic/(ic/ianic/(ic/ apers. 0he term pic/(ic/iansyndrome was first used by @ir William Osler forsyndrome was first used by @ir William Osler forthe sleepapnoea syndrome6.the sleepapnoea syndrome6.

4.4. 0steoarthritis.0steoarthritis. 'hese in#ivi#uals are more'hese in#ivi#uals are more$rone to$rone to develop degenerative 4oint diseasedevelop degenerative 4oint diseasedue to wear and tear following trauma to 4ointsdue to wear and tear following trauma to 4ointsas a result of large body weight.as a result of large body weight.

!.!. Cancer.Cancer.9iet rich in fats, $articularly9iet rich in fats, $articularly#erive# from animal#erive# from animal fats and meats, isfats and meats, isassociated with higher incidence of cancers ofassociated with higher incidence of cancers of

colon, breast, endometrium and prostate.colon, breast, endometrium and prostate.


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C+5?5CA+ 5?95?=C+5?5CA+ 5?95?= C0MM/?'C0MM/?'

CancerCancer5ncrease# inci#ence of estrogen-relate# cancers (e.g., en#ometrial, breast)

because of increase# aromatiation of an#rogens to estrogens in a#i$ose tissue

CholelithiasisCholelithiasis5ncrease# inci#ence of cholecystitis an# cholesterol stones< bile is

su$ersaturate# 8ith cholesterol

9iabetes me9iabetes melllitus,litus,

ty$ety$e ))

5ncrease# a#i$ose #o8nregulates insulin rece$tor synthesis

y$erinsulinemia increases a#i$ose stores

Oeight re#uction u$regulates insulin rece$tor synthesis

e$atomegalye$atomegalyatty change accom$anie# by liver cell inIury an# re$air by fibrosis

y$ertensiony$ertensiony$erinsulinemia increases so#ium retention, lea#ing lo increase in $lasma

volume

+eft venlricular hy$ertro$hy an# stroke com$licate hy$ertension

y$ertriglyceri#emiay$ertriglyceri#emiay$ertriglyceri#emia #ecreases serum high-#ensity li$o$rotein levels,

increasing risk of coronary artery #isease

5ncrease# lo8-#ensity5ncrease# lo8-#ensityli$o$rotein levelsli$o$rotein levels

y$ercholesterolemia $re#is$oses lo coronary artery #isease

0bstructive slee$0bstructive slee$

a$neaa$nea

Oeight of a#i$ose tissue com$resses u$$er air8ays causing res$iratory

aci#osis an# hy$o&emia

otential for #evelo$ing cor $ulmonale ($ulmonary hy$ertension an# right

ventricular hy$ertro$hy)

0steoarthritis0steoarthritis 9egenerative arthritis in 8eight-bearing Ioints (e.g., femoral hea#s)


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ra#er-Oilli syn#romera#er-Oilli syn#rome 5=W@6 is a single gene imprinting disorder5=sora- @yphilis6 caused by defects in chromosome ". These defects

may be of two types* . =aternally inherited deletion or disruption of genes in the proximal arm

of chromosome ". 5@yphilis6

3. :aternal disomy in the proximal arm of chromosome ". 5=sora6

Relate# 8or#sRelate# 8or#s

0ryptorchidism#dwarfism#subnormal mentality> hypogenital dystrophywith diabetic tendency> hypotonia#hypomentia#hypogonadism#obesitysyndrome> 8abhart#Willi syndrome> =rader#8abhart#Willi Ianconesyndrome> Willi#=rader syndrome.

istorical Backgroun#istorical Backgroun#

The first patient with =rader#Willi syndrome was described by 8angdon#Cown )n77? as an adolescent girl with mental impairment 5=sora6, short stature 5=sora6,hypogonadism 5=sora6, obesity 5=sora6. e called these symptoms to polysarcia.

)n G"%, =rader et al reported some patients with similar phenotypes.

)n G7, 8edbetter et al identified microdeletions 5@yphilis6 within chromosome "and determined it to be the site for =rader#Willi syndrome.

2 atho$hysiologyat

ho$hysiology


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atho$hysiology$ y gy

2 ra#er-Oilli syn#romera#er-Oilli syn#rome is the firstis the firsthuman disorder recogni(ed tohuman disorder recogni(ed to

genomic imprinting. )n suchgenomic imprinting. )n such

disorders, genes are expresseddisorders, genes are expresseddifferentially based on the parent ofdifferentially based on the parent of

origin. )t results from the loss oforigin. )t results from the loss of

imprinted genomic material withinimprinted genomic material withinthethe paternalpaternal "1.3#! locus."1.3#! locus.

2 The loss ofThe loss of maternalmaternalgenomicgenomic

material 5@yphilis6 at the "1.3#!material 5@yphilis6 at the "1.3#!locus results inlocus results in AngelmanAngelmansyn#romesyn#rome..

2 :ost cases of =rader#Willi:ost cases of =rader#Willi

syndrome that involve deletionssyndrome that involve deletions

5@yphilis6, unbalanced5@yphilis6, unbalancedtranslocations 5=sora6, andtranslocations 5=sora6, anduniparental 5maternal6 disomyuniparental 5maternal6 disomy

5=sora6 are sporadic.5=sora6 are sporadic.


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Chi&denChi&den2 Hy*e*ha,iaHy*e*ha,ia"Ps#a' .ith"Ps#a' .ith

*#,essi!e de!e*(ent #+ #%esity*#,essi!e de!e*(ent #+ #%esity"Ps#a'8"Ps#a'82Sh#t stat$eSh#t stat$e "Ps#a' .ith &ac: #+"Ps#a' .ith &ac: #+

*$%eta& ,#.th sh#t "Sy*hi&is'8*$%eta& ,#.th sh#t "Sy*hi&is'82S&ee* dist$%ancesS&ee* dist$%ances "Ps#a'-"Ps#a'-

#%st$cti!e s&ee* a*nea and#%st$cti!e s&ee* a*nea and

nac#&e*sy "Ps#a'8nac#&e*sy "Ps#a'82G#.th h#(#ne de9ciencyG#.th h#(#ne de9ciency "Ps#a'8"Ps#a'82Pe(at$e ,#.thPe(at$e ,#.th #+ *$%ic and#+ *$%ic and

a;i&&ay hai "Ps#a' %$t #thea;i&&ay hai "Ps#a' %$t #the

+eat$es #+ Pade6Wi&&i synd#(e ae+eat$es #+ Pade6Wi&&i synd#(e ae

$s$a&&y de&ayed # inc#(*&ete8$s$a&&y de&ayed # inc#(*&ete82 Testic$&a descent &ateTestic$&a descent &ate "Ps#a' (enache (ay #cc$ as &ate as a,e @"Ps#a' (enache (ay #cc$ as &ate as a,e @

"Ps#a'8"Ps#a'82 Feat$es #+ *sych#sisFeat$es #+ *sych#sis and %eha!i#$a& *#%&e(s6 te(*e #$t%$sts "Ps#a'-and %eha!i#$a& *#%&e(s6 te(*e #$t%$sts "Ps#a'-

st$%%#n "Ps#a'- and #%sessi!e6c#(*$&si!e %eha!i#$ "Ps#a'- eatin,st$%%#n "Ps#a'- and #%sessi!e6c#(*$&si!e %eha!i#$ "Ps#a'- eatin,

,a%a,e "Ps#a' and +#en +##d "Ps#a'- and stea&in, es#$ces t# #%tain,a%a,e "Ps#a' and +#en +##d "Ps#a'- and stea&in, es#$ces t# #%tain

+##d "Ps#a' &eadin, t# ,astic c#(*&icati#ns- ,astic nec#sis "Ps#aJSy*hi&is'+##d "Ps#a' &eadin, t# ,astic c#(*&icati#ns- ,astic nec#sis "Ps#aJSy*hi&is'

and e!en death8and e!en death82 0i&d (enta& etadati#n "Ps#a'80i&d (enta& etadati#n "Ps#a'8


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S'!GOL!'!%S2


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S'!GOL!'!%S2%!SO$%#$S

0lasses of sphingolipids and their hydrophilic groups include* @phingomyelin* phosphorylcholine

0erebrosides* galactose or glucose


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9isease+ysosomal

/nyme Missing

ubstrateAccumulating in5nclusion Bo#y

ym$toms

'ay-achs exosaminidase A Yebrabodies in inclusions>0haracteristic foamymacrophages> Barly death


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The %i,ht &i,ht at i,ht entes th#$,h the *$*i& #+ theeye at &e+t- the ed s*#tQ in dia,n#sis #+Tay6Sachs disease

A#ult onset ?iemann-ic

k #isease ty$e C $resen

ting 8ith $sychosis
http://www.ninds.nih.gov/disorders/taysachs/taysachs.htmhttp://jnnp.bmj.com/cgi/content/full/74/4/528http://jnnp.bmj.com/cgi/content/full/74/4/528http://jnnp.bmj.com/cgi/content/full/74/4/528http://jnnp.bmj.com/cgi/content/full/74/4/528http://jnnp.bmj.com/cgi/content/full/74/4/528http://jnnp.bmj.com/cgi/content/full/74/4/528http://www.ninds.nih.gov/disorders/taysachs/taysachs.htm


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7itamin7itamin //C' 0 9/5C5/?CE//C' 0 9/5C5/?CE //C' 0 '0P5C5'E//C' 0 '0P5C5'E

AARetinolRetinol

0cular lesions< night blindness, xerophthalmia# dry andscaly scleral con4unctiva> keratomalacia# corneal ulcersmay occur which may get infected> 9itotQs spots # focaltriangular areas of opacities due to accumulation ofkeratinised epithelium> blindness # s1uamous metaplasiaof corneal epithelium6Cutaneous lesions0ther lesions< s1uamous metaplasia of respiratoryepithelium, pneumonia> urothelium and pancreatic ductalepithelium, subse1uent anaplasia> retarded bone growth>renal calculi

=apilledema and sei(ures 5due to

an increase )n intracranial

pressure6, hepatitis, bone pain 5due

to periosteal proliferation6

99CalcitriolCalcitriol

=athologic fractures, excess osteoid, bow legs

Chil#ren< rickets> craniotabes5soft skull bones6> rachitic

rosary 5defective minerali(ation and overgrowth of

epiphyseal cartilage in ribs6

A#ults< called osteomalacia

0ontinuous muscle contraction 5hypocalcaemictetany6

ypercalcemiawith metastatic

calcification, renal calculi


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7itamin7itamin //C' 0 9/5C5/?CE//C' 0 9/5C5/?CE //C' 0 '0P5C5'E//C' 0 '0P5C5'E

//NN--

'oco$he-'oco$he-

rolrol

emolytic anemia 5damage to ;90 membrane6, reduced red cell

lifespan>

=eripheral neuropathy, degeneration of posterior column 5poor 4ointsensation6 and spinocerebellar tract 5ataxia6, retinal pigments,

degeneration axons of peripheral nerves> denervation of muscles@terility in male and female animals

Cecreased synthesis of

vitamin Z#dependent

procoagulant factors>

synergistic effect with

warfarin anticoagulation

?e8borns< ypoprothrombinaemia in hemorrhagic disease of newborn

50@ bleeding, ecchymoses6>

A#ults< gastrointestinal bleeding, ecchymoses> prolonged $rothrombin

time and partial thrombo$lastin timebiliary obstruction # bile is prevented from entering the bowel due to

biliary obstruction which prevents the absorption of this fat#solublevitamin. @urgery in patients of obstructive 4aundice, therefore, leads tomarked tendency to bleeding.malabsorption of fat develop vitamin Z deficiency e.g. coeliac

disease, sprue, pancreatic disease, hypermotility of bowel etc.anticoagulant therapy # patients on warfarin group of anticoagulants

have impaired biosynthesis of vitamin Z#dependent coagulation factors.antibiotic therapy # the use of broad#spectrum antibiotics and sulfadrugs reduces the normal intestinal flora.diffuse liver disease # 5e.g. cirrhosis, amyloidosis of liver,

hepatocellular carcinoma, hepatoblastoma6 havehypoprothrombinaemia due to impaired synthesis of prothrombin.Administration of vitamin Z to such patients is of no avail since liver,

where prothrombin synthesis utilising vitamin Z takes place, isdiseased.

emolytic anemia and

4aundicein newborns if

mother receives excess

vitamin Z


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. 0opstead 8ee#Bllen 0. =athophysiology - 8ee#Bllen 0. 0opstead, Sac1uelyn 8. 9anasic-- Blsevier )nc. 3&&.

3. ;O99)@ 9A@)0 =ATO8O section editors, Ealentina 8.9rashers, eal @. ;ote # %th ed. 3&&.

$. =athophysiology, 0oncepts of Altered ealth @tates, 0arol :attson =orth,


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Lipid Disorders Pathophysiology