Development of a Laboratory Pathway to Assist the Diagnosis of Hereditary Haemochromatosis in Primary Care
Authors: Ogilvie Catherine E , Gaffney Dairena , Murray Heather , Kerry Andrew , Bissett Heather , Cuthbertson Grace , Wickremesinghe Sahara , Spooner Richard , Fitzsimons Edward J 
Published: October 2019

Abstract
Abstract 994
Hereditary Haemochromatosis (HH) is a common, treatable condition. It is autosomal recessive and usually associated with the C282Y mutation in the HFE gene. Large population studies have determined global distribution of the C282Y mutation with highest prevalence in North European populations: 0.5% C282Y homozygotes. Clinical penetrance, defined by biochemical evidence of iron overload, is around 50%. Because earlier symptoms of HH can be non-specific, the condition is poorly recognised and there is a need to improve detection of clinically relevant HH. The aim of this study was to develop a hospital laboratory pathway to improve the diagnosis in Primary Care.
Serum ferritin (SF) is a reliable marker of body iron stores and is highly sensitive to iron overload in HH. It is also the most frequently measured haematinic in the UK. Greater Glasgow and Clyde (GG&C) is the largest Health Board in Scotland with a predominantly ‘Celtic’ population of 1.4 million. GG&C annually processes some 70,000 serum ferritin samples from Primary Care. These samples provided the study population.
Samples were recruited from 5 hospital laboratories across GG&C from Jan 2011 to July 2012. Samples were selected from patients aged ≥30years with serum ferritin >200μmol/l (normal range 20–300μmol/l). Iron studies (serum iron and transferrin saturation (Tsat)) were performed on all samples. HFE genotyping was carried out on samples with Tsat ≥30%. This value was chosen as parenchymal iron loading and clinically relevant HH can only occur if Tsat is elevated >30%.
At interim analysis in May 2012, 3269 samples had been analysed. Males n=1373 (42%), median values; age 64yrs, SF 443μmol/l, Tsat 31.4%. Females n=1896 (58%), median values; age 69yrs, SF 304μmol/l, Tsat 27.6%. The 1553 samples with Tsat >30% were HFE genotyped (899 Tsat 30–40%; 654 Tsat >40%). 95 patients were homozygous C282Y (6.1% of those genotyped). 92% (87 of 95 patients) of C282Y homozygotes had Tsat >40%.

Males:
748 patients genotyped. 342(46%) Tsat >40%, 406(54%) Tsat 30–40%. 38 C282Y homozygotes detected; 35(92%) Tsat >40%, 3(8%) Tsat 30–40%. The detection rate was 10.2% (35/342) for patients with Tsat >40% and 0.7% (3/406) for Tsat 30–40%.

Females:
805 patients genotyped. 312(39%) Tsat >40%, 493(61%) Tsat 30–40%. 57 C282Y homozygotes detected; 52(91%) Tsat >40%, 5(9%) Tsat 30–40%. The detection rate was 16.7% (52/312) for patients with Tsat >40% and 1% (5/493) for Tsat 30–40%.

Serum ferritin:
1028 (31%) patients had serum ferritin 200–300μmol/l. 147 males (14%), 881 females (86%). There were 15 C282Y homozygotes; 1 male and 14 female patients (5 aged 30–50yrs, 9 aged >50yrs). Of the female C282Y homozygotes, 13 (93%) had Tsat >40%. The detection rate for C282Y homozygote females was 10% (13/130) for Tsat >40% and 0.5% (1/207) for Tsat 30–40%.
There were 1226 males with SF >300μmol/l. HFE genotyping of those samples with Tsat >40% revealed 10% C282Y homozygotes i.e. 1 in 10 patients genotyped was affected; an approximate 40 fold enrichment over general population screening (0.5% HFE homozygotes with 50% penetrance). In female patients with SF >200μmol/l and Tsat >40% the detection rate was 16.7% (67 fold enrichment). These enrichment figures do not include those relatives diagnosed from family studies after diagnosis in the index case.

We now propose:

Disclosures:
Ogilvie: Chief Scientist Office, Scottish Government: Research Funding. Fitzsimons:Chief Scientist Office, Scottish Government: Research Funding.