Thesis (MSc)--Stellenbosch University, 2000. / ENGLISH ABSTRACT: Hereditary haemochromatosis (HH) is an autosomal recessive iron storage disease where
the accumulation of iron in parenchymal organs may lead to diabetes, heart failure, liver
cirrhosis, arthropathy, weakness and a variety of other ailments if preventive measures are
not taken. HH is often not considered as a cause of these conditions, particularly not in the
elderly where the background frequencies of type II diabetes, osteoarthritis and heart
failure are generally high. Heterozygosity for C282Y, the HFE-mutation causing HH in
approximately 80% of affected individuals worldwide, has been linked to a raised
incidence of malignancies of the colon and rectum, stomach and the haematological
system. One of the highest carrier-frequencies (116) in the world for this mutation has been
reported in the South-African Afrikaner population, resulting in C282Y-homozygosity in
approximately 1 in every 115 people in this group.
A sample of 197 elderly Afrikaner volunteers was recruited for genotype/phenotype
association studies. Their clinical presentation was denoted, biochemical iron-status
determined and HFE genotyping performed. Either an increase or decrease in survival, or
both, were proposed, depending on possible gender effects. HH has been positively
associated with various cancer types, but may also protect against iron-deficiency anaemia
which is by far the most frequent cause of anaemia in the older person.
This study has led to the following findings:
1. The carrier frequency of mutation C282Y was found to be 1/8 in the elderly population
(similar in males and females), which is slightly lower than the 1/6 reported in younger
adults from the same population. Only one C282Y homozygote and two C282YIH63D
compound heterozygotes were detected, all of them female.
2. The prevalence of diabetes, heart disease, arthropathy or a combination of these
conditions did not differ significantly in C282Y heterozygotes and the mutationnegative
group.
3. Among 24 C282Y heterozygotes only one individual with rectal carcmoma was
detected compared with two cases with rectal- and seven with colonic malignancies in
153 mutation-negative individuals. The single female C282Y homozygote identified
suffered from both rectal and colon carcinoma and died approximately 6 months ago as
a consequence of her colon malignancy.
4. Serum ferritin appears to be a highly unreliable parameter of iron status, particularly in
the elderly where a variety of factors that may influence the levels are often present in
elderly individuals. This may be due to ageing alone or as a result of multiple comorbidities.
5. Serum ferritin levels were lower than expected in elderly subjects with mutation
C282Y and compound heterozygotes with both C282Y and H63D, which may be
related to a variable penetrance of the HFE gene mutations. It is possible that variation
in other genes exist that confer protection against iron-loading by gene-gene
interaction. The probability that environmental factors (e.g. a low iron diet) are more
important in this respect cannot be excluded, although this is considered less likely in
the light of the fact that the same trend was observed in all mutation-positive elderly individuals. It is therefore highly likely that C282Y -positive subjects with significant
iron loading have died before reaching their seventies, particularly since none of the
males included in this study were homozygous or compound heterozygous for the
mutations analysed.
In conclusion, possession of a mutant HFE gene does not appear to confer a survival
advantage in old age, neither does it seem that mutation carriers with significant ironloading
are overlooked by the medical fraternity. Further investigations are warranted to
shed more light on the contributions of gene-gene and gene-environment interaction in the
clinical manifestation of Hll, and how these processes can be manipulated to prevent the
symptoms of this largely underdiagnosed disease. / AFRIKAANSE OPSOMMING: Oorerflike hemochromatose (OH) is 'n outosomaal resessiewe yster-oorladingssiekte waar
akkumulasie van yster in parenkimale organe kan lei tot suikersiekte, hartversaking, lewer
sirrose, artropatie, moegheid en 'n verskeidenheid van ander probleme indien
voorkomende maatreëls nie getref word nie. OH word gewoonlik nie oorweeg as
moontlike oorsaak vir hierdie toestande nie, veral nie in ouer mense nie waar die
agtergrond-frekwensie van tipe II diabetes, osteoartritis en hartversaking in elk geval hoog
is. Heterosigositeit vir die HFE mutasie C282Y, wat OH veroorsaak in ongeveer 80% van
geaffekteerde gevalle wêreldwyd, is geassosieer met 'n verhoogde voorkoms van kanker
van die kolon, rektum, maag en ook die hematologiese sisteem. Van die hoogste draer
frekwensies ter wêreld vir hierdie mutasie (1/6) is gevind in die Afrikaner populasie van
Suid-Afrika, wat daarop dui dat 1 uit elke 115 mense in die groep homosigoties vir die
C282Y mutasie kan wees.
Eenhonderd sewe-en-negentig bejaarde Afrikaner vrywilligers het aan die studie
deelgeneem wat daarop gemik was om genotipe/fenotipe korrelasies uit te voer. Die kliniese
beeld van elke individu is gedokumenteer, die yster status biochemies bepaal en HFE
genotipering uitgevoer. Die a priori veronderstelling was dat oorlewing sou toeneem of
afneem, of beide, afhangende van die geslag van die individu. Daar is voorheen 'n verband
gevind tussen OH en die ontwikkeling van bogenoemde maligniteite, maar aan die ander
kant kan dit moontlik ook beskerm teen anemie as gevolg van yster gebrek, wat juis die
mees algemene oorsaak van anemie in die ouer persoon is. Hierdie studie het tot die volgende bevindings gelei:
1. Die draer frekwensie van mutasie C282Y was 1/8 in die bejaardes (dieselfde in mans
en vrouens), wat effens laer is as die 1/6 wat gerappoteer is in jonger volwassenes.
Slegs een C282Y homosigoot en twee C282YIH63D saamgestelde heterosigote is
opgespoor, en al drie was vroulik.
2. Die voorkoms van suikersiekte, hartsiekte, gewrigspyne of 'n kombinasie van hierdie
aandoenings het nie betekenisvol verskil tussen die C282Y heterosigote en die mutasienegatiewe
groep nie.
3. Daar was slegs een persoon met rektum karsinoom in die groep van 24 bejaarde C282Y
heterosigote, terwyl daar twee gevalle met rektum kanker en sewe gevalle met kolon
kanker gevind is onder die 153 mutasie-negatiewe individue. Die enkele vroulike
C282Y homosigoot wat opgespoor is het beide rektum- en kolonkanker gehad en is
ongeveer 6 maande vóór voltooing van die tesis oorlede aan haar kolon karsinoom.
4. Dit wil voorkom asof serum ferritien veral in bejaardes 'n hoogs onbetroubare maatstaf
is vir yster status, aangesien dit deur 'n verskeidenheid faktore beïnvloed word wat
dikwels in bejaardes aanwesig is as gevolg van veroudering of veelvuldige komorbiditeite.
5. Die serum ferritien vlakke was laer as verwag in sowel die bejaarde C282Y-homosigoot
as in die twee saamgestelde heterosigote met mutasies C282Y en H63D,
wat moonlik die gevolg is van die wisselende graad van penetrasie van HFE mutasies.
Dit is moontlik dat variasie in ander gene beskerming bied teen yster-oorlading deur
middel van geen-geen interaksie. Die moontlikheid dat omgewingsfaktore (soos 'n lae-yster
dieet) 'n belangrike rol speel in hierdie verband kan nie uitgesluit word nie,
hoewel dit minder waarskynlik lyk te wees in die lig van die feit dat dieselfde neiging waargeneem is in alle mutasie-positiewe bejaardes. Die kans is dus redelik groot dat
individue met die C282Y mutasie en betekenisvolle yster oorlading oorlede is voordat
hulle die sewentiger jare kon bereik, veral omdat geeneen van die mans wat ingesluit is
in die studie homosigoot of 'n saamgestelde heterosigoot was vir die mutasies wat
geanaliseer is nie.
Opsommend wil dit voorkom asof die teenwoordigheid van 'n mutante HFE geen nie 'n
beter oorlewingskans bied op ouer leeftyd nie, en dit blyk ook dat mutasie draers met
betekenisvolle ysteroorlading nie deur dokters misgekyk word nie. Verdere navorsing is
nodig om meer lig te werp op die bydrae van geen-geen- en geen-omgewing interaksie in
die kliniese manifestasie van OH, en ook hoe hierdie prosesse gemanipuleer kan word om
die simptome van hierdie onder -gediagnoseerde siekte te voorkom.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/51584 |
| Date | 12 1900 |
| Creators | Bouwens, C. S. H. |
| Contributors | Kotze, M. J., Maritz, F. J., De Villiers, J. N. P., Stellenbosch University. Faculty of Medicine & Health Sciences. Dept. of Pathology. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | Unknown |
| Type | Thesis |
| Format | 101 leaves : ill. |
| Rights | Stellenbosch University |
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