Asymptomatic Individuals at Genetic Risk of Haemochromatosis Take Appropriate Steps to Prevent Disease Related to Iron Overload

Katrina J. Allen; Amy E. Nisselle; Veronica R. Collins; Robert Williamson; Martin B. Delatycki

Liver International. 2008;28(3):363-369. 

Abstract and Introduction


Background/Aims: If community screening for hereditary haemochromatosis is to be considered, compliance with preventative measures and absence of significant psychological morbidity must be demonstrated.
Methods: Workplace screening for the HFE C282Y mutation and then clinical care for C282Y homozygotes was instituted. Data were collected on understanding of test results, perceived health status and anxiety for C282Y homozygotes compared with controls. Uptake of clinical care, compliance and response to treatment and changes in diet were monitored for up to 4 years for C282Y homozygotes.
Results: After 11 307 individuals were screened, 40/47 (85%) newly identified C282Y homozygotes completed questionnaires 12 months after diagnosis compared with 79/126 (63%) of controls. Significantly more C282Y homozygotes correctly remembered their test result compared with controls (95 vs 51%, P < 0.0001). No significant difference in perceived health status was observed within or between the two groups at 12 months compared with baseline. Anxiety levels decreased significantly for C282Y homozygotes at 12 months compared with before testing (P < 0.05). Forty-five of the 47 (95.8%) C282Y homozygotes accessed clinical care for at least 12 months. All 22 participants requiring therapeutic venesection complied with treatment for at least 12 months (range 12–47 months).
Conclusion: Individuals at a high genetic risk of developing haemochromatosis use clinical services appropriately, maintain their health and are not 'worried well'. Population genetic screening for haemochromatosis can be conducted in the work place in a way that is acceptable and beneficial to participants.


Knowledge emerging from the human genome project is providing opportunities to identify individuals in the community who are at a high genetic risk of preventable disease.

HFE-associated hereditary haemochromatosis (HH) is a common autosomal recessive iron (Fe) overload disorder most prevalent in northern Europeans, with about one person in 200 homozygous for the C282Y mutation.[1, 2] Untreated, HH can result in hepatic cirrhosis and hepatocellular carcinoma, cardiomyopathy, diabetes mellitus, arthritis, impotence and chronic fatigue.[2] In the Australian population, more than 90% of clinical HH is associated with C282Y homozygosity.[3, 4] Clinical disease can be prevented by maintaining Fe indices in the normal range by regular venesection.[5]

As the disease is common and preventable, community screening for HH has been advocated.[6, 7] This has led to international debate concerning the implications of a lack of complete knowledge about disease penetrance, the potential for discrimination in insurance and employment, whether anxiety would be caused by screening of individuals unaware of their genetic status and whether screening should be by Fe studies or genetic testing.[3, 8–11] Compliance with preventative strategies is critical for any screening programme to succeed and a barrier to screening for HH is the concern that those identified by genetic screening may not take appropriate action to prevent disease.[3]

We have identified asymptomatic homozygotes for the C282Y mutation in our population through genetic screening in the workplace.[12, 13] Here we report the long-term outcomes of screening for 47 newly identified C282Y homozygotes.

Patients and Methods

The methods of subject recruitment and data collection, by information sessions and genetic screening in the workplace, have been described previously.[12] Informed consent was obtained from each subject included in this study, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. This study was approved by the Human Research Committee of the Department of Human Services, Victoria.


Pretest (baseline) questionnaires were completed after an education session but before testing by all those who attended these sessions.[12] Follow-up questionnaires were sent 1 month and 12 months after receipt of test results to all C282Y homozygotes. Questionnaires were also sent to four age- and gender-matched non-homozygous participant controls per homozygote. The content of the baseline and follow-up questionnaires has been described previously, and included sociodemographical details, the General Health Perception subscale of the Medical Outcomes Survey, SF-36,[14] state component of the short form of the Spielberger State-Trait Anxiety Inventory (STAI), a measure of transitory anxiety[15, 16] plus questions about remembering and interpreting the test result.[13]

Clinical Management

All C282Y homozygotes were offered follow-up by one of two study physicians (K. J. A., M. B. D.), including genetic counselling, standardised medical history, a diet and lifestyle questionnaire and clinical evaluation of the recognised features of HH. The questionnaire elicited information about diet (including frequency of red meat intake), alcohol intake, medication and dietary supplements (including vitamin C and Fe) and a history of blood donation.

Blood was obtained for Fe studies and liver function tests (LFTs). Fe indices were considered to be abnormal if there was a raised fasting serum ferritin (SF) (men > 300 μg/L, women > 200 μg/L) indicative of elevated Fe stores. Recommendations related to initial SF are outlined in Figure 1, with recommendations for therapeutic venesection based on published guidelines.[17] Raised transferrin saturation (TS) alone was not considered to be an indication for venesection.

Figure 1.


Treatment algorithm for newly identified C282Y homozygous participants. †One female participant with normal iron indices at diagnosis chose not to participate further in this study and so is not included in Figure 2. ‡Individuals with moderate elevation in serum ferritin (SF) were counselled that there is little available evidence that elevated SF is dangerous in asymptomatic individuals identified through population screening, provided that SF is < 1000 μg/L. All participants in this category chose to normalize SF through prophylactic venesection.

If SF was normal, participants were advised to become voluntary blood donors and monitor their Fe levels annually but were not entered into a formal therapeutic venesection programme. If SF was raised, advice was given to participants that it was not possible to accurately predict their risk of developing Fe overload-associated disease at the time of the study but that their risk of developing disease would be minimised if Fe levels were normalised. Participants with SF values that were moderately elevated (men 301–999 μg/L, women 201–999 μg/L) were given the choice of annual prophylactic monitoring or normalising Fe levels through therapeutic venesection. If they chose to normalise their Fe levels, a tailored venesection programme was implemented until SF returned to normal and then each participant was offered an annual review. Participants were recommended to have a liver biopsy if they fulfilled the accepted criteria of SF >1000 μg/L, significantly elevated liver enzymes or evidence of hepatomegaly.[18, 19]

In addition to advice about therapeutic venesection, monitoring of Fe indices and LFTs, recommendations were made about lifestyle. Recommendations for those with normal SF were that no changes in alcohol or dietary Fe intake were required. For those with elevated SF, dietary Fe intake did not need to be altered but cessation of alcohol was recommended until SF was normalised through venesection. All homozygotes were told to avoid Fe supplementation unless they were under treatment for Fe deficiency anaemia.

Response to Treatment

At each review, the number of therapeutic venesections was noted. Fe indices at baseline and follow-up were used to calculate the amount of Fe removed from the body based on 0.5 g of Fe in 1 L of blood.[20]

Statistical Analysis

Data were analysed using spss 11.5 (Statistical Program for the Social Sciences, SPSS Inc., Chicago, IL, USA). Descriptive statistics were used to analyse the sociodemographical, clinical and psychological characteristics of the sample. Total numbers within categories differ slightly for each variable because of missing data for a few individuals for some questions. The statistical significance of differences in mean levels of continuous variables between genotype groups was assessed by independent sample t-tests. The statistical significance of group differences in categorical variables was assessed using χ2 tests or Fisher's exact test, as appropriate. The statistical significance of the mean differences between baseline and 12-month follow-up scores for anxiety and general health perception was assessed using paired t-tests. A P-value < 0.05 was considered to be statistically significant.


Response to Questionnaires

Over 95% (11 307) of those attending screening sessions (11 841) chose to have cheek brush testing for the HFE C282Y mutation.[13] Fifty-three per cent were female, and the mean age was 36 years (range 18–65 years). Fifty-one participants (one in 221) were found to be homozygous for the C282Y mutation. Four C282Y homozygotes already aware of their genetic status, were taking steps to maintain Fe indices in the normal range and were therefore excluded from further analysis. Follow-up questionnaires were administered at 1 month to all 47 newly identified C282Y homozygotes and 378 controls, with 42 (89.4%) homozygotes (23 males and 19 females) and 157 (41.5%) controls (77 males and 80 females) returning the questionnaires. Twelve-month follow-up questionnaires were sent to all newly identified C282Y homozygotes plus a subset of controls who returned a 1-month questionnaire (n = 126). Questionnaires were returned by 40 (85.1%) C282Y homozygotes (20 males and 20 females) and 79 (62.7%) controls (36 males and 43 females) ( ). At both follow-up time points, C282Y homozygous participants had a significantly higher response rate than that of controls. The mean age was similar for responders and non-responders at 12 months (39.5 and 38.7 years respectively). A comparison of characteristics between C282Y homozygotes and controls showed similar mean anxiety scores and general health perception scores at baseline for responders compared with non-responders of the 1- and 12-month questionnaires.

Table 1.  Characteristics of Participants who Completed the 12-month Follow-up Questionnaire

Clinical Management of C282Y Homozygotes

Of the 47 newly identified C282Y homozygotes, 46 (97.9%) had initial Fe indices measured. One person elected not to receive clinical management through this study and did not provide any further medical management details. Sixteen of the 23 (69.6%) males and 6/23 (26.1%) females had a raised SF (Fig. 1), while 19/23 (82.6%) males and 9/23 (39.1%) females had a raised fasting TS. Biochemical penetrance based on elevated SF in the context of elevated fasting TS was 20/46 (43.5%) with 15/23 (65.2%) for males and 5/23 (21.7%) for females. The mean age for males with elevated SF at diagnosis was 40±10 years and for females this was 46±10 years. Two female participants with Fe deficiency anaemia were advised not to venesect. Forty-four of the 47 (93.6%) attended at least one dedicated follow-up clinic, with a further two electing to have ongoing management by primary care physicians and to copy test results and study pro formas for inclusion in this study.

Figure 1 outlines the management algorithm for newly identified C282Y homozygous participants, based on SF levels at diagnosis. Twenty-four participants with normal SF were given the option of donating blood if they desired, or alternatively to follow a ‘wait and watch’ approach with repeat Fe studies annually.

The 15 participants with moderately elevated SF (≤1000 μg/L) but normal liver tests donated blood every 1–3 months. Three male participants with moderately elevated SF (301–999 μg/L) and abnormal LFTs had a liver biopsy recommended. Of these, two refused liver biopsies, preferring to undergo therapeutic venesection to return SF to the normal range, and one had a liver biopsy that showed mild portal fibrosis and mild elevation in Fe stores.

Four men with severely elevated SF (>1000 μg/L) had a liver biopsy recommended. Of these, one chose to venesect his SF to the normal range without liver biopsy. Two liver biopsies showed severe precirrhotic fibrosis with 3+ and 4/4 hepatocellular siderosis, respectively, and one showed mild portal fibrosis and moderate (2+) haemosiderosis.

Information relating to diet, alcohol intake and history of blood donation was compared for all newly identified C282Y homozygotes with normal SF levels with those with raised SF at the initial examination (Fig. 1). Of the seven men with raised SF, six (85.7%) reported moderate alcohol consumption (>20 g/day, range 21–46 g) and one (14.3%) reported an excessive alcohol consumption of 105 g/day (initial SF 4036 μg/L). Of the six women with raised SF, three (50%) reported a very low alcohol intake (median 3 g/day, range 1–9 g), two (33.3%) reported a moderate alcohol consumption of 21 g/day and one (16.7%) reported an excessive alcohol consumption of 150 g/day (initial SF 550 μg/L). All participants with normal SF reported a low alcohol intake of <20 g/day.

Eight men (50.0%) with raised SF reported eating red meat at least four times per week compared with two (28.6%) of those with normal SF. In women, this level of meat intake was reported by 1/6 (16.7%) and 3/17 (17.6%) for raised and normal SF groups respectively.

Five (31.3%) men with raised SF reported having given blood in the past and none were presently giving blood, while five (71.4%) of those with normal SF reported giving blood either now or in the past. None of the women with raised SF levels reported giving blood now but four (66.6%) had done so in the past. For women with normal SF levels, eight (47.0%) had given blood either now or in the past.

Long-term Follow-up of C282Y Homozygotes

Of the 40 C282Y homozygotes who returned a 12-month questionnaire, 38 (95.0%) correctly answered questions about test result knowledge, compared with 40/79 (50.6%) of controls (P<0.0001). All 40 C282Y homozygotes continued to interpret the risks of associated disease correctly, compared with 71/79 (89.9%) of controls (P = 0.050). There was a significant decrease in anxiety levels for C282Y homozygotes 12 months after being informed of their result when compared with levels at the time of testing but there was no significant change for controls ( ). There was no significant change in health perception scores in C282Y homozygotes or controls at 12 months.

Table 2.  Mean Scores for Anxiety and Perceived Health Status for Respondents Who Completed Questionnaires both before Testing (Baseline) and 12 Months after Receipt of the Test Result

Forty-five of the 47 newly identified homozygotes (95.7%) had Fe indices measured both at diagnosis and at least 12 months after diagnosis, to gauge the response to therapeutic venesection if indicated (Fig. 2). All 44 individuals who attended an initial clinic have been followed up for at least 12 months after receiving their test result (median 21 months, range 12–47 months). Of the 23 participants with normal Fe indices at diagnosis, 6/16 women and 6/7 men became blood donors. Of those people with raised SF, 5/6 women and all men have commenced therapeutic venesection and 68.2% (15/22) now have an SF in the normal range. SF levels have normalised for 10 (62.5%) men after a median of 16 venesections (range 1–54) and five (83.3%) women after a median of five venesections (range 0–13). TS levels in these groups have normalised for four (25.0%) men and four (66.7%) women. All four men with an initial SF >1000 μg/L have reduced their SF levels through therapeutic venesection programmes for at least 12 months, and 3/4 now have SF levels in the normal range. One male who had a liver biopsy recommended, but refused (initial SF 789 μg/L and ALT 89 U/L), had an SF of 974 μg/L at annual review. He had only venesected twice in the 12 months, due to feeling faint each time, and then was lost to further follow-up.

Figure 2.


Iron indices for the 45 newly identified C282Y homozygotes who had iron indices retested for at least 12 months. Data are grouped by gender and age. Baseline is at diagnosis and follow-up is the latest iron study performed, up to 47 months after diagnosis. Errors bars indicate one standard deviation.

No women with raised SF (n = 6) reported altering their intake of red meat, vitamin supplements or alcohol, which was initially low for three women, moderate for two and very high for one. Of the 16 men with raised SF, three men (18.8%) reported reducing their intake of red meat by one to two portions per week and stopping daily multivitamin tablets that contain Fe. Five men (31.3%) had reduced their alcohol consumption by a median 29 g/day (range 1–60).

With respect to life insurance, 3/40 (7.5%) newly identified C282Y homozygous participants reported having difficulties in obtaining new or amended policies on follow-up questionnaires. Following clarification with the participants' insurer of the current Insurance Industry guidelines negotiated as part of instituting this study,[21] policies for all three were granted at standard rates based on normalised Fe indices.


There has been considerable debate as to whether community genetic screening for HH is warranted. Major concerns include lack of knowledge about disease penetrance, possible increased anxiety in individuals who may never develop disease, cost effectiveness, insurance and workplace discrimination and compliance with clinical management.[3, 9–11]

If screening programmes are to achieve their aim of preventing disease, it is important that the programmes demonstrate long-term and appropriate retention of knowledge as well as sustained compliance with appropriate therapy.[22] Those identified as being at a high risk of developing HH in our programme were clearly motivated as all but one C282Y homozygote undertook appropriate clinical follow-up, with 21/22 (96%) of those with elevated SF entering into a therapeutic venesection programme. Furthermore homozygotes were counselled that there is little available evidence that elevated SF is dangerous in asymptomatic individuals identified through population screening, provided that SF is <1000 μg/L.[11] Staunch critics of screening to detect Fe overload and haemochromatosis have used the proposition that those identified by screening may not take action to prevent disease as a justification to dissuade public health authorities that screening is not a worthy activity. In contrast to such concerns, and despite provision of information to participants that the risk of disease in this scenario was unclear, almost all chose to normalise their Fe studies.

In addition to recommendations about venesection and monitoring of Fe studies, medical management included recommendations to decrease alcohol intake while SF remained elevated. One-third of men with raised SF complied with this advice. Interestingly, despite recommendations that it was unnecessary, 18.8% of men with raised SF reduced their red meat intake. Alcohol intake and diet was unchanged in all the women with raised SF, although this is probably owing to the fact they did not have excessive alcohol or red meat intake initially and none had an SF level in the severe range (>1000 μg/L).

Of those recommended to have a liver biopsy based on current guidelines, only four of seven proceeded, with three choosing to normalise SF by venesection without biopsy. Because our study participants were identified through workplace screening, they may not have been as motivated to undergo liver biopsy as patients who present with symptoms in a healthcare setting.

Our study was not designed to examine clinical penetrance in those homozygous for the C282Y mutation. We chose to undertake screening in the workplace setting where individuals are expected to be well, unlike those presenting in a healthcare setting such as a hospital or a general practice. The average age of our participants was 36 years, which is below the average age of symptom onset in HH of 41±14 years.[23] Nevertheless, the rate of biochemical penetrance (raised SF in the presence of TS) in this study, at 20/46 (43.5%), is lower than that of other population-based studies [11, 24] but in keeping with the young mean age of this cohort. The percentage of men with elevated SF alone was 69.6% and the percentage of women was 26.1%.

We identified 2/46 (4.3%) asymptomatic individuals with severe hepatic fibrosis who were at a significant risk of progressing to cirrhosis and developing hepatocellular carcinoma without treatment, and a further 5/46 (10.9%) individuals with biochemical evidence of liver disease.[19] These findings are in line with the results of Powell et al.,[25] who found a significant rate of cirrhosis (5.6% of men and 1.9% of women) in a cohort of 672 asymptomatic C282Y homozygous individuals. In addition, our recently completed study of 30 000 northern Europeans yielded 158 C282Y homozygotes where data were available and of whom 28% of males (but only 1% of females) had Fe overload-related disease.[26] Both our results and the study by Powell and colleagues highlight that serious and sometimes irreversible disease can occur in asymptomatic individuals.

Other studies of individuals identified through opportunistic screening have found lower compliance with medical recommendations. For example, 67% of screened blood donors in Italy with raised Fe indices did not return for definitive testing.[27] In order to ensure that fear of discrimination was not an issue in this study, before commencing testing, we obtained an agreement with the Australian Life and Disability Insurance Industry that those who are C282Y homozygous would not be discriminated against in life insurance and would be insured at non-loaded rates, provided they entered a clinical programme to restore their Fe indices to normal levels.[21] This policy is in line with the belief that genetic disease predisposition alone should not be the basis for insurance policy loading. While some individuals were initially offered insurance with a loading on the basis of their genetic test result, all received non-loaded policies once the agreement was brought to the attention of the insurance company. A study from North America, however, suggested that concern about genetic discrimination varies substantially by race and other demographical factors and by nationality.[28] Other studies have suggested that the psychosocial impact of screening in North America is qualitatively different from Australia[29, 30] and this may be related to the universal provision of healthcare in Australia.

In conclusion, population genetic screening for HH is well accepted, knowledge is retained and screening in a workplace setting does not cause an increase in anxiety in those found to be at a high risk of developing disease related to Fe overload. Most importantly, those at risk comply with measures to ensure that they do not develop the Fe overload-related disease.

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