HEMOCHROMATOSIS

This is a slide presentation for MBBS students. a brief overview of hemochromatosis, an iron overload condition. overview of hemochromatosis, pathophysiology, clinical features, approach, and management

1. Hepatology lectures for
5
th
Sem;MBBS
Pratap Sagar Tiwari
MBBS,MD (Medicine),DM (Hepatology)

2. Hereditary
Hemochromatosis

3. BACKGROUND
•Thenormaldailydietcontainsabout10–20mgofiron.Ofthis,1–1.5mg(10%)is
absorbed.
•Theaverageadultmalehasabout1,000mgofstorediron(enoughforaboutthree
years),whereaswomenonaveragehaveonlyabout300mg(enoughforaboutsix
months).
•About70percentofyourbody'sironisfoundintheredbloodcellsofyourbloodcalled
hemoglobinandinmusclecellscalledmyoglobin.
•Oneunitoftransfusedbloodcontainsabout200-250mgofiron.

4. NORMAL IRON PHYSIOLOGY
•Thenormaldailydietcontainsabout10–20mgofiron.Ofthis,1–1.5mg(10%)is
absorbed.
•Thisamountdependsonbodystoresanddemandsoftheerythroidprogenitors,more
beingabsorbedifstoresarereducedandastheneedincreases.
•Theabsorptionprocess,sitedintheduodenumanduppersmallintestine.
Heme iron
Non Heme iron
PrincipallyfoundinmeatasHbormyoglobin.Easilyabsorbedbecauseitisnot
influencedbythemanyligandsinthediet;directlytakenupintoenterocytesbyan
absorptionpathway.
Accountsforthemajorityoftheironinplants,islesswellabsorbed.
Foundinantioxidant-richplantfoodsthathaveproventoprotectagainst
inflammationandchronicdiseases.

5. IRON ABSORPTION AND TRANSPORT:
REGULATORS
(1)theHFEgene
(2)theDivalentmetaltransporter‐1(DMT‐1)
(3)theintracellularmechanismsforcontrollingtheexpressionoftransportandstorage
proteins,inparticularironregulatoryproteins(IRPs)
(4)theBasolateralirontransporter(calledIREG‐1orferroportin)
(5)Hepcidin,apolypeptidethatplaysapivotalroleinironregulation

6. 4.Fe2+istransportedintomucosalcellsbythedivalentmetallictransporter1(DMT1).
5.TheFe2+inmucosalcellsiseithersequesteredawayasmucosalferritininenterocytes,whichislaterlostby
sheddingofepithelialcells,orcrossesthebasolateralmembraneviaferroportin(FPN).
6.Fe2+isconvertedtoFe3+byhephaestinlocatedonthebasolateralmembraneoftheenterocyte.
7.Fe3+entersintothecirculationandistransportedboundtoplasmatransferrin(TF).
8.Transferrin-boundironstimulatesthesynthesisofhepcidinintheliver,whichinturninhibitsferroportin
functionandblocksthereleaseofironfromenterocytes.
MECHANISM OF IRON ABSORPTION 1.Hemeironistransportedinto
mucosalcellsviatheheme
transporter.
2.Hemeironisreleasedfromits
porphyrinnetworkandentersa
commonpathwaywithnonheme
iron.
3.Nonhemeironisreducedfrom
ferricion(Fe3+)toferrousion
(Fe2+)viatheenzymaticactionof
ferrireductaseorascorbicacid
(Duodenalcytochromeb-related
ferricreductase(dcytb))presenton
theapicalsurfaceofthe
enterocyte.

7. FERRITIN
•Ferritinisthemajorcellularironstorage
protein.
•Plasmaferritinisalsoanindirectmarker
ofthetotalamountofironstoredinthe
body;hence,serumferritinisusedasa
diagnostictest.
Highserumferritinlevelsarealsoseenwithhypoxiaand
inflammatoryconditions,suchashepatitis,alcoholexcess,
fattyliver,andsomecancers.
➢Ferritinthatisnotcombinedwithironiscalledapoferritin.
➢Ironisstoredinaproteincomplexasferritinortherelatedcomplexhemosiderin
(digestedferritinandlysosomes).ForegThebreakdownofhemegivesriseto
biliverdinandiron.Thebodythentrapsthereleasedironandstoresitashemosiderin
intissues.

8. TRANSFERRIN
•Transferrinisabloodplasmaglycoproteinthat
playsacentralroleinironmetabolismandis
responsibleforferric-iondelivery.
•Theyareproducedintheliverandcontainbinding
sitesfortwoFe3+ions.Humantransferrinis
encodedbytheTFgene.
•Whennotboundtoiron,transferrinisknownas
"apotransferrin"
•Transferrinregulatestheabsorptionofironinto
theblood. Transferrinexistsinrelationshiptotheneedforiron:
Whenironstoresarelow,transferrinlevelsincrease,
whereastransferrinislowwhenthereistoomuchiron.
Transferrinsaturation,measuredasapercentage,isamedicallaboratoryvalue.
Itisthevalueofserumirondividedbythetotaliron-bindingcapacityoftheavailabletransferrin,thisvaluetellshow
muchserumironisbound.

9. TRANSFERRIN
↓ Transferrin
↑ Transferrin
Iron deficiency anemia
Pregnancy (↑ iron delivery to placenta)
Oral contraceptives (↑ synthesis)
Iron overload diseases
Protein malnutrition
Note:Anabsenceoftransferrin:atransferrinemia,aconditioncharacterizedbyanemiaandhemosiderosisin
theheartandliverthatleadstoheartfailureandmanyothercomplications.Ferritin,getssecretedmoreinto
thebloodstreamsoastobindwiththeexcessivefreeironandhenceserumferritinlevelsrises.
Whenplasmatransferrinlevelsrise,thereisareciprocaldecreaseinpercenttransferrin
ironsaturation,andacorrespondingincreaseintotalironbindingcapacityiniron
deficientstates.
TRANSFERRIN ∞ TIBC
↑ TRANSFERRIN SATURATION

10. EXTRA NOTE
IDA AOCD Iron overload
Serum Iron level ↓ ↓ ↑
Ferritin ↓ ↑/N ↑
Transferrin ↑ N/↓(ample iron but
not available)
↓
TIBC ↑ N/↓ ↓
Transferrin saturation ↓ ↓ (dt low serum iron) ↑
Hepcidin ↓ ↑ ↑

11. CAUSES OF INHERITED HEPATIC IRON OVERLOAD

12. HAEMOCHROMATOSIS: definition
•Aconditioninwhichtheamountoftotalbodyironisincreased;theexcess
ironisdepositedin,andcausesdamageto,severalorgans,includingtheliver.
Itmaybeprimaryorsecondarytootherdiseases.

14. PATHOPHYSIOLOGY OF HH
•TheHFEproteinregulatestheproductionofaproteincalledhepcidin.
•Approx90%ofptsarehomozygousforasinglepointmutationresultingin
acysteinetotyrosinesubstitutionatposition282(C282Y)intheHFE
protein.
•Ahistidine-to-asparticacidmutationatposition63(H63D)inHFEcausesa
lesssevereformofhaemochromatosis.
•Fewerthan50%ofC282Yhomozygoteswilldevelopclinicalfeaturesof
haemochromatosis.

15. APPROACH
TS
N/↓ TS ↑ TS
Rule out
•Alcohol
•Inflammation
•Cell necrosis
•Cancer
•Metabolic
syndrome
>300 ug/l male
>200 ug/l female
FerroportinDisease, Aceruloplasminemia, atransferrinemia, DMT-1 deficiency,etc
Hyperferritinemia-
cataract syndrome
No Iron Overload Iron Overload
MRI/Liver biopsy
↑Ferritin
> 45%< 45%
None HFE
Hemochromatosis
C282Y/C282Y
C282Y/H63D
HFE gene testing

17. CLINICAL FEATURES
•Overthaemochromatosisis10timesmorefrequentinmalesthanfemales.
•Womenaresparedbyironlosswithmenstruationandpregnancy.Female
ptswithhaemochromatosisusually,butnotalways,haveabsentorscanty
menstruation,havehadahysterectomy,oraremanyyearspostmenopausal.
•Haemochromatosisisrarelydiagnosedbeforetheageof20years,andthe
peakincidenceperiodisbetween40and60yearsofage.

18. CLINICAL FEATURES
•Symptomaticdiseaseusuallypresentsinmenover40yearsofagewith
featuresofliverdisease(oftenwithhepatomegaly),type2diabetesor
heartfailure.
•Fatigueandarthropathyareearlysymptomsbutarefrequentlyabsent.
•Leaden-greyskinpigmentationduetoexcessmelaninoccurs,especiallyin
exposedparts,axillae,groinsandgenitalia:hencetheterm‘bronzed
diabetes’.
•Impotence,lossoflibidoandtesticularatrophyarerecognised
complications,asareearly-onsetosteoarthritistargetingunusualsitessuch
asthemetacarpophalangealjoints,chondrocalcinosisandpseudogout.
•Cardiacfailureorcardiacdysrhythmiamayoccurduetoirondepositionin
theheart.

19. CLINICAL PRESENTATION HH

20. MANAGEMENT
•Treatmentconsistsofweeklyvenesectionof500mLblood(250mgiron)
untiltheserumironisnormal;thismaytake2yearsormore.
•Therequiredfrequencyofmaintenancephlebotomydependsontherateof
ironaccumulation(generallyonceevery2–4months).
•Theaimistoreduceferritintounder50μg/L(5μg/dL).Thereafter,
venesectioniscontinuedasrequiredtokeeptheserumferritinnormal.

21. •Ptsmustbeadvisedtomaintainadequateintakeofdietaryprotein,vitaminB12,and
folate,whileavoidingiron-richfoodsandascorbicandcitricacids,whicharethoughtto
increasetheabsorptionofiron.
•Alcoholshouldbeavoidedwhileirondepletiontherapyisinprogress,particularlygiven
thatheavyalcoholintakeisa/withhigherserumironmarkers,increasedseverityof
clinicaldisease,andincreasedriskofcirrhosisandHCCinC282Yhomozygotes.
•Phlebotomycanresultinimprovedcardiacfunction,bettercontrolofdiabetes,
heightenedenergylevels,reductionofabdominalpain,andresolutionofskin
hyperpigmentation.
•However,somecomplicationsofHHareirreversible,includingarthropathy,
hypogonadism,advancedcirrhosis,andHCC.
•Hypogonadism may lessen in men aged less than 40 years at diagnosis.

22. ASYMPTOMATIC DISEASE
•First-degreefamilymembersshouldbeinvestigated,preferablybygenetic
screeningandalsobycheckingtheplasmaferritinandtransferrin
saturation.
•LiverbiopsyisindicatedinasymptomaticrelativesonlyiftheLFTsare
abnormaland/ortheserumferritinisgreaterthan1000μg/L(100μg/dL)
becausethesefeaturesarea/withsignificantfibrosisorcirrhosis.
•Asymptomaticdiseaseshouldalsobetreatedbyvenesectionuntilthe
serumferritinisnormal.

23. PROGNOSIS
•Pre-cirrhoticpatientswithHHChaveanormallifeexpectancy,andeven
cirrhoticpatientshaveagoodprognosiscomparedwithotherformsof
cirrhosis(three-quartersofpatientsarealive5yearsafterdiagnosis).
•Screeningforhepatocellularcarcinomaismandatorybecausethisisthe
maincauseofdeath,affectingone-thirdofpatientswithcirrhosis,
irrespectiveoftherapy.
•VenesectionreducesbutdoesnotabolishtheriskofHCCinthepresenceof
cirrhosis.

24. OTHERS:
•IRONCHELATORS:Deferoxamine&Deferasirox
•StudieshavedemonstratedthatPPIsreduceintestinalabsorptionofnonhemeironand
maythusdecreasetherequirementforfrequentphlebotomy.
•Erythrocytapharesisisanextracorporealbloodseparationmethodwherebywholeblood
isextractedfromadonororpt,theredbloodcellsareseparated,andtheremaining
bloodisreturnedtothecirculation.
•Hepcidinadministrationhasbeenshowntodiminishironaccumulationinmice,implying
thatincreasinghepcidinlevelsmightbeabletomitigateironoverloadinHH.
•Patientswithend-stageliverdiseaseduetoHHshouldbeevaluatedforliver
transplantation.Thesurvivalofpatientswithgenetichaemochromatosisafterliver
transplantmaybelessthanthatofotherrecipients(53versus81%survivalat25
months).

25. END OF SLIDES

26. ETC