Improved Detection of Hereditary Haemochromatosis
Improved Detection of Hereditary Haemochromatosis
This study has shown that the large number of SF requests received from primary care can be used as a resource to improve the diagnosis of C282Y homozygous HH in areas of high prevalence.
Homozygosity for C282Y HH is estimated to affect 0.5% of North European populations. The proposed algorithm hugely enriches the detection of C282Y homozygous HH with detection rates of 16.4% in women and 18.8% in men. These rates approach those of family screening, which would predict for 25% detection in siblings of an index case from heterozygous parents. Other studies have already commented that screening based on both SF and Tsat would represent an effective approach to improve the diagnosis of HH, but to date an algorithm has not yet been developed.
The proposed algorithm would be triggered by SF values ≥200 μg/L (women) and ≥300 μg/L (men) taken in primary care from patients >30 years. As 28.4% of the female C282Y homozygotes were found to have SF 200–300 μg/L, we now regard 200 μg/L as the upper limit of normal for our female population in primary care.
The impact on laboratory workload from implementing this algorithm can be determined. In a high-risk North European population, SF values ≥200 μg/L (women) and ≥300 μg/L (men) were found in 10.6% and 17.2% of SF requests made from primary care on patients >30 years. We have now shown that 20% of these women and 35% of these men have Tsat >40% and >50%, respectively. Therefore, only 2.12% (10.6%×20%) of female and 6.02% (17.2%×35%) of male SF requests made from primary care on patients >30 years would generate HFE genotyping with detection rates of 16.4% and 18.8% for C282Y homozygous HH.
The clinical impact from implementing this algorithm is less easy to define. It is likely to be influenced by the threshold values of SF and Tsat at which individual clinicians would recommend venesection. These attitudes might also be influenced by factors such as patient age and comorbidities. The European Association for the Study of Liver guidelines however recommend target value of SF <50 μg/L to achieve optimum disease control. It is important to note however that the algorithm would not unnecessarily burden clinical services with a large number of C282Y/H63D compound heterozygotes who may develop elevations in SF particularly in relation to alcohol excess. The algorithm detected only 25 male and 30 female compound heterozygotes from a total of 1745 already highly selected patients with SF values >200 μg/L and Tsat >30%.
In summary, the laboratory algorithm developed in this study would link a GP-initiated SF request to a sequential reflex laboratory pathway that delivers a high percentage yield of patients with C282Y homozygous HH. This pathway would use samples that are currently in laboratories but that are simply discarded after FBC and SF measurements. The introduction of this algorithm in areas with a high prevalence of HH would help to overcome low awareness of HH in primary care and remove the risk of failure to act on a raised SF result.
Discussion
This study has shown that the large number of SF requests received from primary care can be used as a resource to improve the diagnosis of C282Y homozygous HH in areas of high prevalence.
Homozygosity for C282Y HH is estimated to affect 0.5% of North European populations. The proposed algorithm hugely enriches the detection of C282Y homozygous HH with detection rates of 16.4% in women and 18.8% in men. These rates approach those of family screening, which would predict for 25% detection in siblings of an index case from heterozygous parents. Other studies have already commented that screening based on both SF and Tsat would represent an effective approach to improve the diagnosis of HH, but to date an algorithm has not yet been developed.
The proposed algorithm would be triggered by SF values ≥200 μg/L (women) and ≥300 μg/L (men) taken in primary care from patients >30 years. As 28.4% of the female C282Y homozygotes were found to have SF 200–300 μg/L, we now regard 200 μg/L as the upper limit of normal for our female population in primary care.
The impact on laboratory workload from implementing this algorithm can be determined. In a high-risk North European population, SF values ≥200 μg/L (women) and ≥300 μg/L (men) were found in 10.6% and 17.2% of SF requests made from primary care on patients >30 years. We have now shown that 20% of these women and 35% of these men have Tsat >40% and >50%, respectively. Therefore, only 2.12% (10.6%×20%) of female and 6.02% (17.2%×35%) of male SF requests made from primary care on patients >30 years would generate HFE genotyping with detection rates of 16.4% and 18.8% for C282Y homozygous HH.
The clinical impact from implementing this algorithm is less easy to define. It is likely to be influenced by the threshold values of SF and Tsat at which individual clinicians would recommend venesection. These attitudes might also be influenced by factors such as patient age and comorbidities. The European Association for the Study of Liver guidelines however recommend target value of SF <50 μg/L to achieve optimum disease control. It is important to note however that the algorithm would not unnecessarily burden clinical services with a large number of C282Y/H63D compound heterozygotes who may develop elevations in SF particularly in relation to alcohol excess. The algorithm detected only 25 male and 30 female compound heterozygotes from a total of 1745 already highly selected patients with SF values >200 μg/L and Tsat >30%.
In summary, the laboratory algorithm developed in this study would link a GP-initiated SF request to a sequential reflex laboratory pathway that delivers a high percentage yield of patients with C282Y homozygous HH. This pathway would use samples that are currently in laboratories but that are simply discarded after FBC and SF measurements. The introduction of this algorithm in areas with a high prevalence of HH would help to overcome low awareness of HH in primary care and remove the risk of failure to act on a raised SF result.
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