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Underdiagnosis of hereditary haemochromatosis: reflects lack of clinical not biochemical penetrance
  1. D Thorburn1,
  2. A J Morris1,
  3. A J Stanley1,
  4. P R Mills2
  1. 1Gastroenterology Unit, Glasgow Royal Infirmary, 84 Castle St, Glasgow G4 0SF, UK
  2. 2Gastroenterology Unit, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK
  1. Correspondence to:
    Dr A J Stanley, Ward 8/9, 84 Castle St, Glasgow G4 0SF, UK;

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In their paper, Ryan et al (

) reported that 78% of men (mean age 42 years) and 36% of women (mean age 39 years) who were identified to be C282Y homozygotes by family screening had evidence of biochemical iron overload. They concluded that underdiagnosis of hereditary haemochromatosis may be the result of failure to diagnose the phenotype in patients with iron overload.

In Glasgow, the prevalence of the C282Y homozygous state is high at approximately 1 in 180 of the population, of whom only 5.1% had been diagnosed by August 2001.1 Of these known cases we identified 42 (20 males) C282Y homozygotes who had been diagnosed by predictive genetic testing of family members of affected probands. At diagnosis, all 20 males (mean age 46) had evidence of biochemical iron overload, defined as a transferrin saturation of ≥45% (transferrin detected immunochemically) or a serum ferritin of ≥300 μg. Both parameters were elevated in 15 (75%) individuals, with three having an isolated elevated transferrin saturation and two an isolated elevated ferritin.

Of the 22 females (mean age 44) identified, 18 (81%) had evidence of biochemical iron overload at diagnosis, with 10 (45%) having raised transferrin saturation and ferritin, as defined above. A further seven patients had an isolated elevation in transferrin saturation and one had an elevated ferritin alone. Only four (9.5%) C282Y homozygotes identified by family testing had no evidence of biochemical iron overload. All of these individuals were female (age range 17–48 years). Unfortunately, due to the retrospective nature of the analysis, it was not possible to assess symptoms at diagnosis.

The prevalence of biochemical iron overload in our predominantly Celtic population is high and comparable with that reported from Dublin by Ryan et al. However, the proportion that will develop clinical “disease” related to hereditary haemochromatosis remains uncertain. Ryan et al proposed that underdiagnosis of hereditary haemochromatosis might be due to the non-specific nature of the symptoms early in the disease. They noted that fatigue, arthropathy, and male impotence were common complaints in these C282Y homozygotes identified by family screening. However, they provided no evidence that these symptoms were due to iron excess as they appeared to be as common in their biochemically non-expressing control group. It would be interesting to know whether any of these non-specific symptoms improved with phlebotomy.

In a recent large population screening study from the USA, Beutler et al reported the prevalence of biochemical iron overload in C282Y homozygotes to be similar to that observed by the Dublin group and ourselves. However, they found no evidence of more frequent symptoms in C282Y homozygotes compared with controls, even if biochemical iron overload was present.2 It appears that these individuals have iron overload and a number of unrelated non-specific symptoms, similar to those seen in the general population. Prospective longitudinal studies are required to establish the proportion of C282Y homozygotes who will eventually exhibit the clinical phenotype of hereditary haemochromatosis.