[Personalised follow-ups for patients curatively treated for squamous cell carcinoma in the oral cavity]. / Gepersonaliseerde nacontrole bij patiënten die curatief zijn behandeld voor een plaveiselcelcarcinoom in de mondholte.

As a result of an increase in the incidence of oral cancer and improving survival rates, the number of patients needing follow-up care will increase in the Netherlands. At present, these patients enroll in a 5-year follow-up programme aiming for early detection of recurrences or second primary tumors and improving their prognosis of life expectancy, among other things. Recurrences mostly occur in the first 2 years after treatment, whereas patients have a lifelong elevated risk of second primary tumors. 75% of second primary tumors occur outside the oral cavity and over 50% outside the head and neck area, places not routinely checked. There is no convincing evidence this 5-year follow-up programme yields survival benefits. It would therefore be better to limit follow-up care to 2 years and choose a subsequent follow-up programme better tailored to the individual patient's needs. This does not necessarily require the lead of a head and neck oncologist.

The glutathione transferase Mu null genotype leads to lower 6-MMPR levels in patients treated with azathioprine but not with mercaptopurine.

The conversion of azathioprine (AZA) to mercaptopurine (MP) is mediated by glutathione transferase Mu1 (GSTM1), alpha1 (GSTA1) and alpha2 (GSTA2). We designed a case-control study with data from the TOPIC trial to explore the effects of genetic variation on steady state 6-methylmercaptopurine ribonucleotide (6-MMPR) and 6-thioguanine nucleotide (6-TGN) metabolite levels. We included 199 patients with inflammatory bowel disease (126 on AZA and 73 on MP). GSTM1-null genotype carriers on AZA had two-fold lower 6-MMPR levels than AZA users carrying one or two copies of GSTM1 (2239 (1006-4587) versus 4371 (1897-7369) pmol/8 × 108 RBCs; P<0.01). In patients on MP (control group) 6-MMPR levels were comparable (6195 (1551-10712) versus 6544 (1717-11600) pmol/8 × 108 RBCs; P=0.84). The 6-TGN levels were not affected by the GSTM1 genotype. The presence of genetic variants in GSTA1 and GSTA2 was not related to the 6-MMPR and 6-TGN levels.

Overdiagnosis by mammographic screening for breast cancer studied in birth cohorts in The Netherlands.

A drawback of early detection of breast cancer through mammographic screening is the diagnosis of breast cancers that would never have become clinically detected. This phenomenon, called overdiagnosis, is ideally quantified from the breast cancer incidence of screened and unscreened cohorts of women with follow-up until death. Such cohorts do not exist, requiring other methods to estimate overdiagnosis. We are the first to quantify overdiagnosis from invasive breast cancer and ductal carcinoma in situ (DCIS) in birth cohorts using an age-period-cohort -model (APC-model) including variables for the initial and subsequent screening rounds and a 5-year period after leaving screening. Data on the female population and breast cancer incidence were obtained from Statistics Netherlands, "Stichting Medische registratie" and the Dutch Cancer Registry for women aged 0-99 years. Data on screening participation was obtained from the five regional screening organizations. Overdiagnosis was calculated from the excess breast cancer incidence in the screened group divided by the breast cancer incidence in presence of screening for women aged 20-99 years (population perspective) and for women in the screened-age range (individual perspective). Overdiagnosis of invasive breast cancer was 11% from the population perspective and 17% from the invited women perspective in birth cohorts screened from age 49 to 74. For invasive breast cancer and DCIS together, overdiagnosis was 14% from population perspective and 22% from invited women perspective. A major strength of an APC-model including the different phases of screening is that it allows to estimate overdiagnosis in birth cohorts, thereby preventing overestimation.

Donation intensity and metabolic syndrome in active whole-blood donors.

BACKGROUND AND OBJECTIVES: Increased iron and metabolic syndrome (MetS) go hand in hand. Frequent blood donation depletes iron stores. This study investigates whether high-intensity blood donation is associated with lower MetS prevalence compared with low-intensity blood donation, and whether iron acts as an intermediary factor. MATERIALS AND METHODS: A random sample of 422 male and 211 female active whole-blood donors ≥45 years of age was included in a cross-sectional study. Lipids, glucose and iron parameters were measured after overnight fasting. MetS was defined according to the joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention. Three groups of donation intensity were created by sex-specific tertiles of donation frequency per year and duration of donor career. RESULTS: MetS was present in 22·9% of donors. Prevalence of MetS was 1·46 (95% confidence interval [CI]: 0·93-2·30) times higher in men with high donation intensity, whereas in women MetS prevalence was 2·14 (95% CI: 0·94-4·86) times higher in donors with high donation intensity compared with those with low donation intensity. In men, increased prevalence of MetS was mainly associated with higher ferritin, whereas high hepcidin predominantly affected MetS prevalence in women. CONCLUSION: High-intensity blood donation is not associated with a decreased prevalence of MetS. In men and women, different iron parameters are associated with MetS prevalence. The temporal relationship between blood donation, iron and MetS, and gender differences herein need to be explored in future research.

Experiences with a self-test for Dutch breast screening radiologists: lessons learnt.

PURPOSE: To evaluate a self-test for Dutch breast screening radiologists introduced as part of the national quality assurance programme. METHODS AND MATERIALS: A total of 144 radiologists were invited to complete a test-set of 60 screening mammograms (20 malignancies). Participants assigned findings such as location, lesion type and BI-RADS. We determined areas under the receiver operating characteristics (ROC) curves (AUC), case and lesion sensitivity and specificity, agreement (kappa) and correlation between reader characteristics and case sensitivity (Spearman correlation coefficients). RESULTS: A total of 110 radiologists completed the test (76%). Participants read a median number of 10,000 screening mammograms/year. Median AUC value was 0.93, case and lesion sensitivity was 91% and case specificity 94%. We found substantial agreement for recall (κ = 0.77) and laterality (κ = 0.80), moderate agreement for lesion type (κ = 0.57) and BI-RADS (κ = 0.45) and no correlation between case sensitivity and reader characteristics. CONCLUSION: Areas under the ROC curve, case sensitivity and lesion sensitivity were satisfactory and recall agreement was substantial. However, agreement in lesion type and BI-RADS could be improved; further education might be aimed at reducing interobserver variation in interpretation and description of abnormalities. We offered individual feedback on interpretive performance and overall feedback at group level. Future research will determine whether performance has improved. KEY POINTS: • We introduced and evaluated a self-test for Dutch breast screening radiologists. • ROC curves, case and lesion sensitivity and recall agreement were all satisfactory. • Agreement in BI-RADS interpretation and description of abnormalities could be improved. • These are areas that should be targeted with further education and training. • We offered individual feedback on interpretative performance and overall group feedback.

Immediate and delayed effects of mammographic screening on breast cancer mortality and incidence in birth cohorts.

BACKGROUND: Trend studies investigating the impact of mammographic screening usually display age-specific mortality and incidence rates over time, resulting in an underestimate of the benefit of screening, that is, mortality reduction, and an overestimate of its major harmful effect, that is, overdiagnosis. This study proposes a more appropriate way of analysing trends. METHODS: Breast cancer mortality (1950-2009) and incidence data (1975-2009) were obtained from Statistics Netherlands, 'Stg. Medische registratie' and the National Cancer Registry in the Netherlands for women aged 25-85 years. Data were visualised in age-birth cohort and age-period figures. RESULTS: Birth cohorts invited to participate in the mammographic screening programme showed a deflection in the breast cancer mortality rates within the first 5 years after invitation. Thereafter, the mortality rate increased, although less rapidly than in uninvited birth cohorts. Furthermore, invited birth cohorts showed a sharp increase in invasive breast cancer incidence rate during the first 5 years of invitation, followed by a moderate increase during the following screening years and a decline after passing the upper age limit. CONCLUSION: When applying a trend study to estimate the impact of mammographic screening, we recommend using a birth cohort approach.

Likelihood of early detection of breast cancer in relation to false-positive risk in life-time mammographic screening: population-based cohort study.

BACKGROUND: Women require balanced, high-quality information when making an informed decision on screening benefits and harms before attending biennial mammographic screening. PATIENTS AND METHODS: The cumulative risk of a false-positive recall and/or (small) screen-detected or interval cancer over 13 consecutive screening examinations for women aged 50 from the start of screening were estimated using data from the Nijmegen programme, the Netherlands. RESULTS: Women who underwent 13 successive screens in the period 1975-1976 had a 5.3% cumulative chance of a screen-detected cancer, with a 4.2% risk of at least one false-positive recall. The risk of being diagnosed with interval cancer was 3.7%. Two decades later, these estimates were 6.9%, 7.3% and 2.9%, respectively. The chance of detection of a small, favourable invasive breast cancer, anticipating a normal life-expectancy, rose from 2.3% to 3.7%. Extrapolation to digital screening mammography indicates that the proportion of false-positive results will rise to 16%. CONCLUSION: Dutch women about to participate in the screening programme can be reassured that the chance of false-positive recall in the Netherlands is relatively low. A new screening policy and improved mammography have increased the detection of an early screening carcinoma and lowering the risk of interval carcinoma.

Breast cancer risk prediction model: a nomogram based on common mammographic screening findings.

OBJECTIVES: To develop a prediction model for breast cancer based on common mammographic findings on screening mammograms aiming to reduce reader variability in assigning BI-RADS. METHODS: We retrospectively reviewed 352 positive screening mammograms of women participating in the Dutch screening programme (Nijmegen region, 2006-2008). The following mammographic findings were assessed by consensus reading of three expert radiologists: masses and mass density, calcifications, architectural distortion, focal asymmetry and mammographic density, and BI-RADS. Data on age, diagnostic workup and final diagnosis were collected from patient records. Multivariate logistic regression analyses were used to build a breast cancer prediction model, presented as a nomogram. RESULTS: Breast cancer was diagnosed in 108 cases (31 %). The highest positive predictive value (PPV) was found for spiculated masses (96 %) and the lowest for well-defined masses (10 %). Characteristics included in the nomogram are age, mass, calcifications, architectural distortion and focal asymmetry. CONCLUSION: With our nomogram we developed a tool assisting screening radiologists in determining the chance of malignancy based on mammographic findings. We propose cutoff values for assigning BI-RADS in the Dutch programme based on our nomogram, which will need to be validated in future research. These values can easily be adapted for use in other screening programmes. KEY POINTS: • There is substantial reader variability in assigning BI-RADS in mammographic screening. • There are no strict guidelines linking mammographic findings to BI-RADS categories. • We developed a model (nomogram) predicting the presence of breast cancer. • Our nomogram is based on common findings on positive screening mammograms. • The nomogram aims to assist screening radiologists in assigning BI-RADS categories.

The Breast Imaging Reporting and Data System (BI-RADS) in the Dutch breast cancer screening programme: its role as an assessment and stratification tool.

OBJECTIVES: To assess the suitability of the Breast Imaging Reporting and Data System (BI-RADS) as a quality assessment tool in the Dutch breast cancer screening programme. METHODS: The data of 93,793 screened women in the Amsterdam screening region (November 2005-July 2006) were reviewed. BI-RADS categories, work-up, age, final diagnosis and final TNM classification were available from the screening registry. Interval cancers were obtained through linkage with the cancer registry. BI-RADS was introduced as a pilot in the Amsterdam region before the nationwide introduction of digital mammography (2009-2010). RESULTS: A total of 1,559 women were referred to hospital (referral rate 1.7 %). Breast cancer was diagnosed in 485 women (detection rate 0.52 %); 253 interval cancers were reported, yielding a programme sensitivity of 66 % and specificity of 99 %. BI-RADS 0 had a lower positive predictive value (PPV, 14.1 %) than BI-RADS 4 (39.1 %) and BI-RADS 5 (92.9 %; P < 0.0001). The number of invasive procedures and tumour size also differed significantly between BI-RADS categories (P < 0.0001). CONCLUSION: The significant differences in PPV, invasive procedures and tumour size match with stratification into BI-RADS categories. It revealed inter-observer variability between screening radiologists and can thus be used as a quality assessment tool in screening and as a stratification tool in diagnostic work-up. KEY POINTS: • The BI-RADS atlas is widely used in breast cancer screening programmes. • There were significant differences in results amongst different BI-RADS categories. • Those differences represented the radiologists' degree of suspicion for malignancy, thus enabling stratification of referrals. • BI-RADS can be used as a quality assessment tool in screening. • Training should create more uniformity in applying the BI-RADS lexicon.

Increasingly strong reduction in breast cancer mortality due to screening.

BACKGROUND: Favourable outcomes of breast cancer screening trials in the 1970s and 1980s resulted in the launch of population-based service screening programmes in many Western countries. We investigated whether improvements in mammography and treatment modalities have had an influence on the effectiveness of breast cancer screening from 1975 to 2008. METHODS: In Nijmegen, the Netherlands, 55,529 women received an invitation for screening between 1975 and 2008. We designed a case-referent study to evaluate the impact of mammographic screening on breast cancer mortality over time from 1975 to 2008. A total number of 282 breast cancer deaths were identified, and 1410 referents aged 50-69 were sampled from the population invited for screening. We estimated the effectiveness by calculating the odds ratio (OR) indicating the breast cancer death rate for screened vs unscreened women. RESULTS: The breast cancer death rate in the screened group over the complete period was 35% lower than in the unscreened group (OR=0.65; 95% CI=0.49-0.87). Analysis by calendar year showed an increasing effectiveness from a 28% reduction in breast cancer mortality in the period 1975-1991 (OR=0.72; 95% CI=0.47-1.09) to 65% in the period 1992-2008 (OR=0.35; 95% CI=0.19-0.64). CONCLUSION: Our results show an increasingly strong reduction in breast cancer mortality over time because of mammographic screening.

Breast cancer screening case-control study design: impact on breast cancer mortality.

BACKGROUND: Recent case-control studies on the effectiveness of population-based breast cancer screening show differences in the magnitude of breast cancer mortality reduction. We investigated the role played by aspects of the case-control study design on these differences, e.g. the definition of cases and exposure to screening. MATERIAL AND METHODS: We investigated six case-control studies conducted in East Anglia (UK), Wales, Iceland, central and northern Italy, South Australia and The Netherlands. RESULTS: The breast cancer mortality reduction in the different case-control studies ranged from 38% to 70% in the screened versus the nonscreened women. We identified differences in design, e.g. the inclusion or exclusion of the first years of screening, and the correction factor for self-selection bias. CONCLUSIONS: Overall, the design of the case-control studies was similar. The differences in the magnitude of breast cancer mortality reductions are therefore unlikely to be caused by variations in the design of the case-control studies. These differences must be due to other factors, like the organisation of the service screening programme and the attendance rate. The reduction in breast cancer mortality estimated in these case-control studies indicates that the impact of current mammographic screening is at least consistent with the effect reported by the former randomised screening trials.

Less mammographic density after nasal versus oral administration of postmenopausal hormone therapy.

OBJECTIVE: Nasal administration gives a more acute but shorter rise in serum hormone levels than oral administration and may therefore have less effect on the fibroglandular tissue in the breasts. We studied the change in mammographic breast density after nasal vs. oral administration of postmenopausal hormone therapy (PHT). METHODS: We studied participants in a randomized, controlled trial on the impact of nasal vs. oral administration of PHT (combined 17ß-estradiol plus norethisterone) for 1 year. Two radiologists classified mammographic density at baseline and after 1 year into four categories. Also, the percentage density was calculated by a computer-based method. The main outcome measure was the difference in the proportion of women with an increase in mammographic density category after 1 year between the nasal and oral groups. Also, the change in the percentage density was calculated. RESULTS: The study group comprised 112 healthy postmenopausal women (mean age 56 years), of whom 53 received oral and 59 intranasal PHT. An increase in mammographic density category after 1 year was seen in 20% of the women in the nasal group and in 34% of the oral group. This resulted in a non-significant difference in the proportion of women in whom mammographic breast density had increased by 214% (95% confidence interval (CI) 230% to 2.7%). The mean change in percentage density was 21.2% in the nasal group and + 1.2% in the oral group, yielding a 22.4% differential effect (95% CI 27.3% to 2.5%). CONCLUSIONS: One year of nasal PHT gave a smaller, although not statistically significant, increase in mammographic density than oral PHT. Remaining issues are the relation between the route of administration of PHT and breast complaints and breast cancer risk.

In primary breast cancer the mitotic activity yields similar prognostic information as the histological grade: a study with long-term follow-up.

We evaluated with long-term follow-up, the prognostic value of the mitotic activity index (MAI) and the volume corrected mitotic index (M/V-index) compared with that of the histological grade in breast cancer patients not treated with adjuvant systemic therapy. Of 739 consecutive patients living in the city of Nijmegen, the Netherlands, 477 patients with primary unilateral breast cancer were not treated with adjuvant systemic therapy and eligible for the study. In multivariate survival analyses the MAI and M/V-index showed similar hazard ratios (HRs) compared to HRs of histological grade for overall survival (OS) (HR: 1.45, 1.48, and grade II versus grade I (GII/GI) 1.34, grade III versus grade I (GIII/GI) 1.53, respectively) and for breast cancer specific survival (BCSS) (HR: 1.27, 1.57, and (GII/GI) 1.57 (GIII/GI) 2.32, respectively). Other independent prognostic variables for OS and BCSS were age at diagnosis, tumour size, and number of positive lymph nodes. In the present study with long term follow-up, we compared the prognostic value of mitotic activity with that of histological grade and found no advantage for the mitotic activity in predicting either BCSS or OS and concluded that histological grade and the mitotic activity were equally informative in predicting patient outcome. As histological grade is a well established and widely used prognosticator we do not have arguments to replace the histological grade by the mitotic indices MAI or M/V-index.

Cutoff value determines the performance of a semi-quantitative immunochemical faecal occult blood test in a colorectal cancer screening programme.

BACKGROUND: The cutoff of semi-quantitative immunochemical faecal occult blood tests (iFOBTs) influences colonoscopy referrals and detection rates. We studied the performance of an iFOBT (OC-Sensor) in colorectal cancer (CRC) screening at different cutoffs. METHODS: Dutch screening participants, 50-75 years of age, with average CRC risk and an iFOBT value >or=50 ng ml(-1) were offered colonoscopy. The detection rate was the percentage of participants with CRC or advanced adenomas (>or=10 mm, >or=20% villous, high-grade dysplasia). The number needed to scope (NNTScope) was the number of colonoscopies to be carried out to find one person with CRC or advanced adenomas. RESULTS: iFOBT values >or=50 ng ml(-1) were detected in 526 of 6157 participants (8.5%) and 428 (81%) underwent colonoscopy. The detection rate for advanced lesions (28 CRC and 161 with advanced adenomas) was 3.1% (95% confidence interval: 2.6-3.5%) and the NNTScope was 2.3. At 75 ng ml(-1), the detection rate was 2.7%, the NNTScope was 2.0 and the CRC miss rate compared with 50 ng ml(-1) was <5% (N=1). At 100 ng ml(-1), the detection rate was 2.4% and the NNTScope was <2. Compared with 50 ng ml(-1), up to 200 ng ml(-1) CRC miss rates remained at 16% (N=4). CONCLUSIONS: Cutoffs below the standard 100 ng ml(-1) resulted in not only higher detection rates of advanced lesions but also more colonoscopies. With sufficient capacity, 75 ng ml(-1) might be advised; if not, up to 200 ng ml(-1) CRC miss rates are acceptable compared with the decrease in performed colonoscopies.

Towards evidence-based follow-up intervals for breast cancer survivors: Estimates of the preclinical detectable phase of contralateral second breast cancer.

PURPOSE: Follow-up schemes in breast cancer survivors are predominantly consensus-based. To determine evidence-based follow-up intervals, estimates of sensitivity of the screening test(s) and duration of the preclinical detectable phase (PCDP) are key. We estimated the sensitivity and the duration of the PCDP of clinical breast examination (CBE) and mammography for the detection of contralateral second breast cancers (CBC) in breast cancer survivors. METHODS: Women with a CBC (N = 589) diagnosed in Florence between 1980 and 2005 were included. Test sensitivity and the duration of PCDP were estimated using a simple exponential model of PCDP duration. Analyses were stratified by follow-up period (0-5 vs. >5 years after primary diagnosis) and age at CBC diagnosis (<50 vs. ≥50 years). RESULTS: For CBE, test sensitivity was 55% and the duration of the PCDP 16 months. Mammography sensitivity was 91% and duration of the PCDP 35 months. Stratified analyses showed a higher test sensitivity for CBE for women aged <50 (70% vs. 51%). No difference in the duration of PCDP of CBE was found. For mammography, test sensitivity and the duration of the PCDP were higher for women with longer follow-up and in older women. CONCLUSIONS: Poor test sensitivity for CBE with a shorter duration of the PCDP compared with mammography were observed. Mammography had high test sensitivity and the potential to detect CBCs early. The estimated duration of the PCDP (35 months) was considerably longer than the recommended follow-up interval (12 months). Future studies are needed to determine whether a longer follow-up interval is appropriate.

Metastases but not cardiovascular mortality reduces life expectancy following surgical resection of apparently benign pheochromocytoma.

The treatment of choice for non-metastatic pheochromocytoma is surgical resection. Its goals are to abolish catecholamine hypersecretion, normalize blood pressure, and prevent further tumor growth or progression to metastatic disease. Data on long-term mortality and morbidity after pheochromocytoma surgery are limited. We here report a retrospective study on the long-term outcome after surgery for apparently benign pheochromocytoma at the Radboud University Nijmegen Medical Centre. Data on clinical presentation, treatment, post-surgical blood pressure and recurrence, metastasis and death were collected of 69 consecutive patients (January 1966-December 2000; follow-up: until death or January 2006). Survival was compared with survival of a matched reference population. Two patients died of surgical complications. All ten patients with metastatic disease (including three diagnosed at first surgery) died. At follow-up, 40 patients were alive and recurrence free and three patients were lost to follow up. Two patients experienced a benign recurrence. Mean+/-s.d. follow-up was 10.2+/-7.5 (median 9, range 1-38) years. Kaplan-Meier estimates for 5- and 10-year survival since surgery were 85.8% (95% CI: 77.2-94.4%) and 74.2% (95% CI: 62.0-86.4%) for patients versus 95.5 and 89.4% in the reference population (P<0.05). Sixty-four percent of all patients with hypertension prior to surgery showed a significant decrease in blood pressure, but remained hypertensive after surgery. In conclusion, compared with the general population patients have a reduced life expectancy following pheochromocytoma surgery, due to their risk of developing metastatic disease. Only one-third becomes normotensive without antihypertensive medication. Therefore, lifelong follow-up is warranted.

Large increase in a Dutch woman's lifetime risk of developing breast cancer.

A large increase in the incidence of breast cancer has been observed in many countries over the last two decades. On the other hand, however, breast cancer mortality has decreased. The prominent burden of breast cancer in the female population induces a lot of discussion about incidence and mortality rates, whereas lifetime risks are less mentioned. This study provides information on the changes in risks for Dutch women with regards to being diagnosed with breast cancer (both invasive and in situ) or dying from this disease during the screening era. We used the life table method to calculate lifetime risks for the period 1989-2003. The lifetime risk for developing breast cancer increased from 1 in 10 in 1989 to 1 in 7 in 2003; the risk of dying from breast cancer decreased respectively from 1 in 22 to 1 in 26. The increasing incidence is alarming but has to be seen in perspective; the decreasing mortality is promising and shows that, at most, one third of the breast cancer cases are fatal.

Follow-up after curative treatment for oral squamous cell carcinoma. A critical appraisal of the guidelines and a review of the literature.

The oral cavity is the commonest subsite of head and neck squamous cell carcinoma (HNSCC). Because of the rising incidence and increasing survival, more patients will be enrolled in a routine follow-up program. This review gives an overview of the evidence and guideline recommendations concerning follow-up after oral squamous cell carcinoma (OSCC). There is limited evidence concerning the effectiveness of follow-up after OSCC. This lack of evidence is reflected in a variation in guideline recommendations with respect to test interval and duration (i.e. for 3-5 years or lifelong). Most studies on the value of routine follow-up after curative treatment include all HNSCC subsites. The available literature shows, that these subsites have a different timing of recurrence and a different risk of second primary tumors at different locations. This leaves no rationale for applying the same follow-up program to each of the HNSCC subsites. There is agreement in the literature that OSCC follow-up can either be discontinued after two or three years or should be lifelong based on the risk of second primary tumors. Many authors advocate a personalized follow-up regimen that is based on the risk of new disease rather than a one-size-fits-all surveillance program. The literature is conflicting about the survival benefits of asymptomatic detection of new disease for HNSCC. To aid the development of evidence-based follow-up advise after OSCC, future research should focus on risk stratification, the value of symptom-free detection of recurrences and the active role that patients might play in determining their own follow-up regimen.

Changing aspects of HFE-related hereditary haemochromatosis and endeavours to early diagnosis.

HFE-related hereditary haemochromatosis (HH) is an iron overload disease attributed to the highly prevalent homozygosity for the C282Y mutation in the HFE gene. The pathophysiology of this error in iron metabolism is not completely elucidated yet, although deficiency of the iron regulatory hormone hepcidin appears to play a role. Ways of diagnosing iron overload include measurement of the serum iron parameters, i.e. serum transferrin saturation and serum ferritin, by a liver biopsy or by calculating the amount of mobilisable body iron withdrawn by phlebotomies. Clinical signs attributed to HFE-related HH include liver failure, arthralgia, chronic fatigue, diabetes mellitus and congestive heart failure. organ failure can be prevented by phlebotomies starting before irreversible damage has occurred. Therefore, screening to facilitate early diagnosis is desirable in individuals at risk of developing HFE-related iron overload. over time it appeared that the clinical penetrance of the HFE mutations was much lower than had previously been thought. This changed the opinion about a suitable screening modality from case detection, via population screening, to family screening as the most appropriate method to prevent HFE-related disease. However, before the implementation of family screening it is vital to have thorough information on the relevance of the specific health problem involved, on the clinical penetrance of C282Y homozygosity and on the effectiveness of the screening approach.