should we genetically test everyonefor haemochromatosis? · haemochromatosis, however, is adisease...

Journal ofMedical Ethics 1999;25:209-2 14

Should we genetically test everyone forhaemochromatosis?Katrina Allen and Robert Williamson The Murdoch Institute, Royal Children's Hospital, Melbourne, Australia

AbstractThe increasing availability ofDNA-based diagnostictests has raised issues about whether these should beapplied to the population at large in order to identify,treat or prevent a range of diseases. DNA tests raiseconcerns in the community for several reasons. Thereis the possibility of stigmatisation and discriminationbetween those who test positive and those who don't.High-risk individuals may be identifiedfor whom noproven effective intervention is possible, or converselymay test "positive "for a disease that does noteventuate. Controversy concerning prenatal diagnosisand termination of affected pregnancies may arise.Haemochromatosis, however, is a disease that is notonly treatable but also preventable if those at highrisk are identified presymptomatically. This paperwill identify and discuss key issues regardingDNA-based population screeningforhaemochromatosis, and argue that population-basedgenetic screening for haemochromatosis should besupported when a number of contentious issues areaddressed. In the context of a health system withlimited resources haemochromatosis is the paradigmof a disorder where there is an ethical and clinicalimperative to encourage presymptomatic DNA testingfor all in ethnically relevant communities.(Journal ofMedical Ethics 1999;25:209-214)Keywords: Haemochromatosis; gene test; populationscreening; genetic predictive testing

IntroductionTraditionally, disease diagnosis and managementare initiated by the presentation of a patient withsymptoms. A number of technologies now allowmedical practitioners to identify an individual'spropensity to a wide range of diseases and act toprevent their onset. Examples of such preventivemanagement range from the identification ofhypothyroidism and phenylketonuria throughnewborn screening to prevent mental deficiency,cervical screening to identify those with early-stage cervical cancer amenable to therapy, to thecessation of smoking to prevent lung cancer. Thisparadigm shift from treatment to prevention hasresulted from the exponential increase in therange of diagnostic tests available to the physician,

including biochemical and haematological bloodtests, microbiology, histology and radiology. Newadvances using DNA data from molecular genet-ics extend this by allowing medical practitionersnot only to diagnose a disease at an early stage, butalso to predict the likelihood of a disease develop-ing in the future.The increasing availability of DNA-based tests

throws into relief questions of when geneticscreening of the general population for commonand treatable diseases is ethically sound, medicallyappropriate and financially cost-effective.' Therehave been many contributions discussing theappropriate times and contexts in which to offercarrier and presymptomatic testing.6 Presympto-matic identification of Huntington's disease isavailable to high-risk families, but this disease issevere and untreatable. Carrier testing for cysticfibrosis is offered to help couples make a decisionabout whether to continue a pregnancy. Incontrast, haemochromatosis is both preventableand treatable, and it is unlikely that couples willwish to make decisions regarding the continuationof a pregnancy based on fetal genetic status. Thushaemochromatosis is an excellent example of agenetic test that offers presymptomatic geneticidentification of a preventable adult-onset disease.

Since the discovery of the gene for haemochro-matosis and the ability to identify homozygotespresymptomatically, many countries are consider-ing whether haemochromatosis is an appropriatedisease for which to employ population geneticscreening. Critical issues of "how", "when", and,more importantly "who" should be screenedremain to be resolved.

Hereditary haemochromatosisHereditary haemochromatosis (HH) is a reces-sively inherited metabolic disorder caused by adefect in the cells lining the intestine which leadsto excessive and unregulated absorption of ironfrom the diet. HH (referred to as haemochroma-tosis in this paper) describes an iron overload syn-drome without any external cause such as seenfollowing repeated blood transfusions, prolongedinappropriate administration of iron, or in associ-

on June 21, 2020 by guest. Protected by copyright.

http://jme.bm

j.com/

J Med E

thics: first published as 10.1136/jme.25.2.209 on 1 A

pril 1999. Dow

nloaded from

http://jme.bmj.com/

210 Should we genetically test everyone for haemochromatosis?

ation with alcoholic liver disease. If haemochro-matosis is left undiagnosed and untreated, theexcess iron stored in the parenchymal cells ofmajor organs, primarily the liver, pancreas, heart,pituitary and joints, eventually leads to severe tis-sue damage and premature death from liver andcardiac failure. A few grams of iron are normallystored in the liver but accumulation of more than16 grams is associated with serious symptoms ofiron overload.Haemochromatosis has protean manifestations

and a patient may present to any number of clini-cal specialties with signs of liver disease, heartfailure, diabetes, hypogonadism, arthritis or evenchronic fatigue. Because symptoms of haemo-chromatosis are often non-specific, have a gradualonset and can mimic other common disorders,diagnosis is frequently delayed. Liver disease maypresent as an abnormal elevation in liver enzymes,clinical signs of cirrhosis or hepatocellularcarcinoma.7 Patients usually present with symp-toms in the 5th or 6th decade of life though therehave been reports of individuals presenting withcirrhosis as early as the 3rd decade of life.7With the possible exception of arthritis, the

clinical manifestations ofHH can be prevented byprophylactic phlebotomy.7 Regular phlebotomycan also prevent progression of disease in patientspresenting with symptomatic iron overload.8When phlebotomy is started prior to the develop-ment of cirrhosis or diabetes, affected people havea normal life expectancy.9 Preventive phlebotomy(giving one 500ml unit of blood - approximately 1gram of iron - every few months) is not usuallyrecommended until the individual is in his/her 3rddecade, although this may change with definitivepresymptomatic diagnosis. Avoidance of alcohol isalso often advised for patients with HH since aheavy alcohol intake may be a synergistic cofactorin the development of liver fibrosis.'0The gene mutated to cause haemochromatosis,

HFE, has recently been identified." A missensemutation (C282Y) is the most common genedefect and affects more than 85% of HH patientsofNorthern European descent,'2-14 while a secondmutation (H63D) is possibly associated with a lesssevere form of the disease.'2The prevalence ofHH in certain populations is

very high. Recent research estimates that 10% ofpeople of Northern European ancestry areheterozygous for HH, and one person in 300 fromthis ethnic group expresses the disease,'5 making ita significant public health problem in communi-ties of Northern European extraction.

Environmental factors impact on whetherand/or when homozygous individuals developclinical haemochromatosis. It is well established

that women with haemochromatosis usuallypresent later in life than men, probably becauseblood loss through menstruation retards the accu-mulation of pathological iron stores. Supplemen-tal iron and vitamin C (which increases ironabsorption) are likely to precipitate earlier pheno-typic expression, whereas blood donation andphysiological or pathological blood loss will lowerthe amount of iron stored in the liver and delayphenotypic expression.'6 Associations betweenseveral diseases (porphyria cutanea tarda, alco-holic liver disease, non-alcoholic steatohepatitisand hepatitis B)"' and haemochromatosis havebeen noted. Investigations as to whether thesediseases are associated with haemochromatosisexpression in homozygotes are necessary.

Despite the identification of several factors thatcan influence the time of expression of the disease,there still appears to be a subgroup of people whoare homozygous for HH mutations but who donot develop symptoms.'8 While the clinicalexpression of symptomatic disease is variable,Powell et al state that approximately 90% of maleand 50-70% of female homozygotes will developorgan dysfunction and potentially life-threateningcomplications of haemochromatosis.

Regardless of the variability of disease manifes-tation in HH, the earlier the disease is identifiedthe better the prognosis.9 Many investigators haveshown the benefit of phlebotomy for diseaseprevention as well as retardation of diseaseprogression. In contrast, the prognosis for thosewith cirrhosis for many years is bleak. Up to 30%of male haemochromatotics with cirrhosis willdevelop hepatocellular carcinoma.'6 Since regularphlebotomy to prevent haemochromatosis is rela-tively benign and the potential consequences ofdeveloping disease are so serious, it is likely thatmost homozygotes would embark on a preventivemanagement strategy to minimise the risk ofdeveloping disease even if each has a small chanceof not developing symptoms.

Haemochromatosis and heterozygosityIt is still not clear whether there is any phenotypeassociated with HH heterozygosity. A study ofproband relatives performed before the gene wasidentified found that a small proportion ofpresumed heterozygotes (from family studies)presented with elevated serum iron measures.Very few of these individuals had documentediron overload or clinical symptoms. Among thosewho did, other contributing factors such asalcohol abuse were present. '-` These data suggestthat clinical HH occurs rarely in heterozygotes,and possibly only in the presence of otherenvironmental risk factors.


http://jme.bm

j.com/

J Med E


pril 1999. Dow

nloaded from

http://jme.bmj.com/

Allen, Williamson 211

Compound heterozygote individuals, on theother hand, can express haemochromatosis with-out a precipitating cofactor. Compound heterozy-gotes are those individuals who carry both knownHH mutations, C282Y and H63D. Several largeseries of haemochromatosis patients have identi-fied a small number of compound heterozygoteswho express disease. These individuals probablyhave a lower risk of disease expression thanC282Y/C282Y homozygote patients since theproportion of C282Y/H63D genotypes amongHH cases is low despite an equal frequency ofcarrier rate for the H63D and C282Y mutation.'7

Why screen for haemochromatosis?Because the presymptomatic phase of haemo-chromatosis is prolonged, there is a large windowof opportunity in which to diagnose risk of diseasewell before disease onset. For those who arepresymptomatic, disease prevention is possible.For those who present with early symptoms,treatment to retard disease progression is avail-able. In contrast, untreated haemochromatosiscan result in serious morbidity and early death.

Population-based screening has the potential toprevent the development of disease, but will onlybe effective if appropriate education and treat-ment strategies are implemented alongside ascreening programme. Such a programme wouldrepresent a cost-effective use of the ever-diminishing health care dollar. Bassett et alestimate the cost of screening in Australia to beAU$4,943-AU$ 1 1,016 per case detected depend-ing on the screening strategy and method of con-firmation of diagnosis.2' This compares favourablywith other public health screening initiativesalready in use such as cervical cancer screening(AU$30,782 adjusted cost per life year) andbreast cancer screening (AU$6,600-1 1,000).22

How should we screen forhaemochromatosis?The starting point for identifying individuals whowould participate in a screening programme couldbe based on phenotype or genotype. Phenotype isassessed by investigating liver function or haema-tological iron values. Genotype is determined byidentifying a gene mutation in HFE, either by cas-cade screening of relatives of index cases, or in thecommunity without preselection.

In the past, phenotypic screening of first degreerelatives has occurred on an ad hoc basis followingthe identification of a symptomatic proband. Sus-picion of disease is based on abnormal iron stud-ies (ie elevated serum ferritin and transferrinsaturation) and confirmed by an elevated hepaticiron index on liver biopsy. Liver biopsy is also

undertaken to identify the presence or absence ofcirrhosis, a hallmark of irreversible and advanceddisease.23 Phenotypic identification of presympto-matic homozygotes using serum iron markers isless reliable, particularly in women, and heterozy-gotes can only be identified using genetic analysisrather than phenotype.

Current genotype assessment in Australia isbased on cascade screening of first degree relativesof affected homozygote probands. Although this isan effective way to identify further cases of haemo-chromatosis, siblings of affected patients mayalready have severe iron loading and early or evenadvanced symptoms of disease. In addition, ethicalissues arise around the possibility of coercive inter-action within a family when genetic testing in anaffected relative is necessary before screening canbe provided to other family members.There are two important reasons why we

believe population-based genotype screening forHH should not be delayed. Firstly, the prospectivediagnosis of many homozygous HH individualswill be missed if widespread screening is notimplemented before complete information isknown about penetrance. Secondly, incompletedata regarding disease penetrance and prevalenceis not an a priori reason not to screen since peopleare likely to cope well with a degree of uncertaintywhen counselled about risk of disease expressionif the disease is preventable and/or treatable.The ability to identify homozygous HH before

disease onset is the greatest advantage of DNA-based testing. With the identification of the muta-tions responsible for haemochromatosis, DNAtesting has become the method of choice to iden-tify those with HH. DNA samples from individu-als can be obtained easily, cheaply and reliablyeither from blood or mouthwash samples.24

Who is affected by a decision to screen thegeneral population?The arguments for and against genetic screeningcan be viewed from the individual perspective, orfrom the point of view of public health policy.Both need to be considered.

A) THE PUBLIC PERSPECTIVEFrom the public perspective, screening to preventa common disease is usually a cost-effective use ofthe health dollar. The cost of identifying morehomozygotes through DNA screening than bycurrent phenotypic measures would be offset bythe fact that it should be cheaper to preventdisease through a health maintenance programmethan to treat and manage HH patients as theypresent to a specialist unit. If all persons werescreened and agreed to enrol in a prevention pro-


http://jme.bm

j.com/

J Med E


pril 1999. Dow

nloaded from

http://jme.bmj.com/


gramme, it is probable that symptomatic haemo-chromatosis would become a very rare disease. Inaddition, blood donated regularly to transfusionservices by homozygous but healthy presympto-matic individuals as part of a health maintenanceprogramme would be a valuable public resource.

Another important public issue is the possibilitythat a group is created within the population thatcould be discriminated against because of theirgenotype, even in the absence of clinical symp-toms. There are data indicating that women withfamilial breast cancer are reluctant to acceptgenetic screening because of fears of discrimina-tion in insurance.25 In the case ofhaemochromato-sis, we suggest that discrimination would beirrational and based on a misunderstanding ofdisease progression, as the individual would behealthier and have a longer lifespan if tested,provided a prevention programme was accepted.Many countries are implementing legislation oragreements which prevent discrimination in insur-ance or employment due to genetic testing.26-27

It must be emphasised that a major educationalprogramme of both the lay and medical commu-nities would need to be implemented to raiseawareness of issues surrounding diagnosis andmanagement of haemochromatosis. Educationalprogrammes would assist implementation of asuccessful screening programme as well as helpminimise any misinformation and resultant inap-propriate discrimination. Such programmeswould not be simple or cheap, but any advances inunderstanding of genetics in one area, such ashaemochromatosis, would also provide benefits inother areas of gene testing.

B) THE HOMOZYGOTE'S PERSPECTIVEThe homozygous individual clearly benefits fromthe implementation of screening, as developmentof disease can be prevented. Since compound het-erozygote individuals also appear to be susceptibleto disease expression, we believe these individualsalso stand to benefit from having their HH geneticstatus identified.

It is possible that a small proportion ofindividuals with symptomatic haemochromatosismay have alternate genetic mutations to thosealready identified and thus would be missed byscreening programmes that identify only the twocommon mutations. This proportion is likely to bevery small in Anglo-Celtic populations, but maybe greater in Southern Europeans.28 Identificationof any further disease-causing mutations willincrease our ability to screen for presymptomatichomozygotes.A further issue is that unless catch-up screening

is administered to the whole population, a cohort

of people will be unaware of their HH status andmay remain unidentified until presentation withadvanced disease. The increased level of educa-tion in the community following the implementa-tion of a population-based screening programmewould, however, serve to benefit these individualsby increasing the vigilance for HH disease identi-fication.

C) THE HETEROZYGOTE 'S PERSPECTIVEFrom the perspective of the heterozygote, infor-mation regarding predisposition to iron loading orother diseases is central to whether identificationof the heterozygote status is beneficial to the indi-vidual, though it must be remembered thatheterozygosity may equally be associated with aselective advantage. For instance, it has been sug-gested that heterozygote women may have areproductive advantage, as they are less likely tohave iron deficiency.19Data on the incidence of iron loading in hetero-

zygotes is currently inconclusive. The likelihoodof a heterozygote developing haemochromatosisin the absence of a second aggravating diseaseappears to be very low. Bulaj et al studied over onethousand heterozygotes. Although 4% of femalesand 8% of males had abnormal haematologicaliron profiles, only one patient had evidence ofmild liver damage on biopsy in the absence of anyfurther identifiable precipitating factor.'9 Thiswould suggest that heterozygotes are unlikely todevelop primary iron loading, but that they mayhave an increased risk of developing iron loadingin the presence of a second disease. It has beensuggested that phlebotomy may prevent ironaccumulation in heterozygote patients with a pre-cipitating environmental factor.20 Until there isdefinitive research about the propensity fordisease expression in heterozygotes and whetherphlebotomy in such situations is beneficial to theindividual then it is difficult to inform heterozy-gotes appropriately. As new research is carried outthis situation may change.The question of whether to inform heterozy-

gotes of their genetic status remains a difficultethical dilemma that warrants further study andconsideration. Such consideration applies to manycommonly inherited diseases, since we all carry anumber of recessive genes that are not clinicallyimportant unless two persons with the samerecessive mutation have children.With regard to reproductive issues, since

haemochromatosis is a preventable disease, it isunlikely that a heterozygote couple at risk of hav-ing a child who is homozygous for the mutationwould choose prenatal diagnosis and terminate anaffected pregnancy. It is unlikely that either the


http://jme.bm

j.com/

J Med E


pril 1999. Dow

nloaded from

http://jme.bmj.com/

Allen, Williamson 213

medical or lay community would support termi-nation of an affected fetus since the disease isadult-onset and can be compatible with normalhealth if preventive strategies are appropriatelyimplemented.We believe the current cost of informing

heterozygotes in both financial and psychologicalterms is too high. Not only would the number ofpeople needing counselling increase greatly butthe complexity of counselling would increase dra-matically because not enough is known about therisk of disease expression. In the future thecommunity may desire such information and bebetter equipped to deal with such complex geneticdata, but the initial introduction of population-based heterozygote screening alongside homo-zygous screening would only serve to confuse sucha programme.

Offering information on carrier status wouldmassively increase the cost of education and coun-selling, and risk creating a group of "worried well".When more is known about the medical implica-tions of heterozygosity, decisions about whether toinform individuals of their status should becomeclearer. Cascade screening of relatives of probandscurrently identifies heterozygotes, but whetherindividuals are informed of their carrier statusappears to be individualised by the caring physi-cian. At this point we would not advocate informingheterozygotes identified by population screening oftheir status unless requested by the individual ordictated by the clinical setting.

Who and when should we screen?It is not clear whether it is discriminatory to offerscreening only to those who are in a high-risk eth-nic group, omitting to screen those in other groups.Even if it appears costly to offer screening to thosein low-risk populations (which, in the Australiancontext, would include those of Aboriginal, SouthEast Asian and African origin) this may havesignificant implications in a city with much ethnicmixing, such as Melbourne. Although the cost ofneedless screening is an issue, so too is perceivedand real discrimination against those who are notscreened, with all the problems in defining ethnicityin a multicultural environment.

Implementation of population-based geneticscreening will be most beneficial if administeredto a receptive population and at a time when thecost-benefit ratio is most favourable. Screening todetect presymptomatic homozygotes can be di-rected at three main groups: neonates, adolescentsand young adults.Neonates are an easy group to target because

efficient and acceptable screening is already inplace for phenylketonuria and other serious

diseases affecting neonates. It would be logisticallysimple to add a further test to those currently per-formed. Screening in the neonatal period ensuresthat homozygotes identified will definitely bepresymptomatic. However, neonatal screeningmeans there is a long lead time before theinformation is relevant and preventive measurescan be implemented, as regular phlebotomywould be unlikely to be organised before theinfant was at least 20 years of age. Parents ofpresymptomatic homozygous individuals mayperceive their child as unwell. Parents may alsoimplement inappropriate care such as eliminatingiron from a growing child's diet. Many years ofindividual follow-up will be required to ensurethat appropriate preventive strategies are imple-mented at the appropriate age.

If we compare haemochromatosis with cysticfibrosis (CF), a disease for which neonatal screen-ing for all is already in place in Australia, we cansay:* HH is more common than CF (1 in 300 v 1 in

2,500);* HH is a preventable disease while CF is not;* prenatal testing for HH is not likely to be

implemented because (unlike CF) it is bothpreventable and treatable;

* a single mutation accounts for more than80-90% unlike CF where there are manymutations, the most common of which ac-counts for about 70% of mutations.

All parents of homozygote HH infants would beobligate heterozygotes and a small percentagewould be homozygous for HH by chance. Anadded benefit of neonatal screening would be theidentification through reverse cascade screeningof further presymptomatic homozygous individu-als since parents, as well as aunts and uncles, ofnewborns are likely to be young adults. Neonataltesting may be an option in the future when moreis known about disease prevalence and penetranceand if and when there is increased awareness ofHH in the community.The advantage of screening adolescents is their

potential to take responsibility for their own healthand any preventive strategies that need implemen-tation. Unfortunately adolescents can be suscepti-ble to stigmatisation through peer pressure.Knowledge of HH homozygosity may initiateinappropriate reactionary high-risk behaviour inthe individual. In addition, this group is difficult toaccess since school-based screening may not beacceptable to parents or school authorities.

Screening of young adults (20-30 year olds) hasmany ethical advantages. Young adults are au-tonomous and capable of giving consent, and ifthey have counselling will be aware of the useful-


http://jme.bm

j.com/

J Med E


pril 1999. Dow

nloaded from

http://jme.bmj.com/


ness of the test and the possible implications forrelatives and with regard to insurance. They alsoare likely to be motivated to enter into aprevention programme. However, a small minor-ity of cases may already have liver damage belowthe age of 30.We favour screening of young adults with the

proviso that health maintenance programmes beimplemented for individuals identified as homo-zygous for HH. Ongoing support, education andcounselling would help ensure that homozygousindividuals remain informed of the latest researchdevelopments and have ready access to infor-mation regarding health maintenance. However,public education programmes and resolution ofissues of stigmatisation need to be addressedbefore implementation of population-basedscreening. Participation in a screening programmewould need to be completely voluntary.

ConclusionsHaemochromatosis is an ideal disease in which toimplement population-based genetic screeningbecause it is both common and preventable. Onbalance, the public and the individual stand togain from the implementation of genetic screen-ing. At this point in time, screening of youngadults would be the most readily accepted by thecommunity and the most efficient to implement.Education of the medical and lay communitieswould be vital to the success of such a programmeand pilot studies of population-based screeningwould help address many of these issues. Before awidely applied programme could be imple-mented, issues regarding funding and implemen-tation of health maintenance programmes for allhomozygous individuals identified would need tobe fully explored. In addition, issues around thehealth status of heterozygotes need furtherconsideration. Finally legislation against genetic-based discrimination and misuse of genetic infor-mation should be given priority before embarkingon a programme of population-based screening.

Katrina Allen MBBS, BMedSc, FRACP is aPaediatric Gastroenterologist at The MurdochInstitute, Royal Children's Hospital, Parkville,Victoria, Australia. Robert Williamson PhD,FRCPath, FRCP (Edin), is Director of TheMurdoch Institute.

References1 Modell B, Moddell M. Towards a healthy baby: congenital disor-

ders and the new genetics in primary health care. New York:Oxford University Press, 1992.

2 WHO scientific group report. Control of hereditary diseases.Geneva: WHO, 1996.

3 Burke W, Thomson E, Khoury M et al. Genetic testing forhereditary hemochromatosis and its implications. Journal of theAmerican Medical Association 1998;280,2: 172-7.

4 Williamson R. Universal community carrier screening forcystic fibrosis. Nature Genetics 1993;3:195-201.

5 DudokdeWit AC, Tibben A, Duivenvoorden HJ et al. Distressin individuals facing predictive DNA testing for autosomaldominant late-onset disorders: comparing questionnaire resultswith in-depth interviews. American Journal of Medical Genetics1998; 75,1:62-74.

6 Morris MJ, Tyler A, Lazarou L et al. Problems in genetic pre-diction for Huntington's disease. Lancet 1982;2(8663):601-3.

7 Adams PC, Kersatz AE, Valberg LS. Clinical presentation ofhemochromatosis. American Journal of Medicine 1991;90:445-9.

8 Powell LW. Hemochromatosis, the impact of early diagnosisand therapy. Gastroenterology 1996;110: 1304-7.

9 Niederau C, Fischer R, Purschell A et al. Long-term survival inpatients with hereditary haemochromatosis. Gastroenterology1996;110:1 107-1119.

10 Adams PC, Agnew S. Alcoholism in hereditary hemochroma-tosis revisited: prevalence and clinical consequences amongsthomozygous siblings. Hepatology 1996;23:724-7.

11 Feder JN, Gnirke A, Thomas W et al. A novel MHC class I-likegene is mutated in patients with hereditary hemochromatosis.Nature Genetics 1996;13:399-408.

12 Jouanolle AM, Fergelot P, Gandon G et al. A candidate gene forhemochromatosis: frequency of the C282Y and H63Dmutations. Human Genetics 1997;100:544-7.

13 Jazwinska EC, Cullen LM, Busfield F et al. Haemochromatosisand HFE. Nature Genetics 1996;13:399-408.

14 The UK Haemochromatosis Consortium. A simple genetic testidentifies 90% of UK patients with haemochromatosis. Gut1997;41,6:841 -4.

15 Legget BA, Halliday JW, Brown NN et al. Prevalence ofhaemochromatosis amongst asymptomatic Australians. BritishJ7ournal of Haematology 1990;74:525-30.

16 Powell LM, Bassett ML. Haemochromaotisis: diagnosis andmanagement after the cloning of the HFE gene. Australian andNew Zealand Journal ofMedicine 1998;28: 159-63.

17 Burke W, Press N, McDonell SM. Hemochromatosis: geneticshelps to define a multifactorial disease. Clinical Genetics1998;54: 1-9.

18 Crawford HG, Jazwinska EC, Cullen LM et al. Expression ofHLA-linked hemochromatosis in subjects homozygous or het-erozygous for the C282Y mutation. Gastroenterology 1998;1 14:1003-8.

19 Bulaj ZJ, Griffen LM, Jorde LB et al. Clinical and biochemicalabnormalities in people heterozygous for hemochromatosis.New England Journal ofMedicine 1996;335:1799-1805.

20 George DK, Goldwurm S, MacDonald GA et al. Increasedhepatic iron concentration in nonalcoholic steatohepatitis isassociated with increased fibrosis. Gastroenterology 1998;114:311-18.

21 Bassett ML, Leggett BA, Halliday JW et al. Analysis of the costof population screening for haemochromatosis using biochemi-cal and genetic markers. Journal ofHepatology 1997;27: 517-24.

22 Carter R, Glasziou P, van Oortmarssen G et al. Cost-effectiveness of mammographic screening in Australia. Austral-ian Journal of Public Health 1993;17,1:42-50.

23 Bacon BR. Diagnosis and management of haemochromatosis.Gastroenterology 1997;113: 995-9.

24 Lench N, Stanier P, Williamson R. Simple non-invasive methodto obtain DNA for gene analysis. Lancet 1988;1:1356-8.

25 Bekendorf JL, Reutenauer JE, Hughes CA et al. Patients'attitudes about autonomy and confidentiality in genetic testingfor breast-ovarian cancer susceptibility. American Journal ofMedical Genetics 1997:73:296-303.

26 Otlowski M, Chalmers D, Skene L et al. Discussion paper.Implications of the human genome project for Australian insurancelaw and practice. Canberra: Australian Research Council, 1998.

27 Hudson KL, Rothenberg KH, Andrews LB et al. Geneticdiscrimination and health insurance: an urgent need forreform. Science 1995;270:391-3.

28 Piperno A, Sampietro M, Pietrangelo A et al. Heterogeneity ofhemochromatosis in Italy. Gastroenterology 1998;114:996-1002.


http://jme.bm

j.com/

J Med E


pril 1999. Dow

nloaded from

http://jme.bmj.com/

should we genetically test everyonefor haemochromatosis? · haemochromatosis, however, is adisease...

Documents