Improved Detection of Hereditary Haemochromatosis
Improved Detection of Hereditary Haemochromatosis
Aims There is high prevalence of hereditary haemochromatosis (HH) in North European populations, yet the diagnosis is often delayed or missed in primary care. Primary care physicians frequently request serum ferritin (SF) estimation but appear uncertain as how to investigate patients with raised SF values. Our aim was to develop a laboratory algorithm with high predictive value for the diagnosis of HH in patients from primary care with raised SF values.
Methods Transferrin saturation (Tsat) was measured on SF samples sent from primary care; 1657 male and 2077 female patients age ≥30 years with SF ≥200 μg/L. HFE genotyping was performed on all 878 male and 867 female patients with Tsat >30%.
Results This study identified 402 (206 men; 196 women) C282Y carriers and 132 (58 men; 74 women) C282Y homozygotes. Optimal limits for combined SF and Tsat values for HH recognition were established. The detection rate for homozygous C282Y HH for male patients with both SF ≥300 μg/L and Tsat >50% was 18.8% (52/272) and 16.3% (68/415) for female patients with both SF ≥200 μg/L and Tsat >40%.
Conclusions The large number of SF requests received from primary care should be used as a resource to improve the diagnosis of HH in areas of high prevalence.
Hereditary haemochromatosis (HH) is an autosomal-recessive genetic disorder of iron metabolism. It has been recognised as a clinical disorder for >100 years and is one of the most common inherited conditions in populations of North European descent. Clinical complications include liver cirrhosis, cardiomyopathy and diabetes. Treatment is simple and effective, but diagnosis is often either delayed or missed. HH is typically associated with the C282Y mutation in the HFE gene. Large population studies have determined global distribution of the C282Y mutation with highest prevalence (0.5% C282Y homozygotes) in North European populations. The H63D mutation of HFE is found in 20% of the UK population and can be associated with HH when inherited in combination with C282Y. Clinical iron overload however is less severe and far less frequent. Rarer mutations causing HH have been described. These include mutations in hemojuvelin, hepcidin (HAMP) genes, transferrin receptor 2 (TRF2), ferroportin and rare mutations in HFE. In the absence of C282Y homozygosity or C282Y/H63D compound heterozygosity, further investigation of raised serum ferritin (SF) and transferrin saturation (Tsat) can include screening for these less common mutations.
Clinical penetrance as defined by biochemical evidence of iron overload is not complete in C282Y homozygotes. Estimates vary considerably, but it is found more commonly in male than in female homozygotes. In a study of Danish male C282Y homozygotes, 89% had Tsat ≥50% and 94% SF ≥300 μg/L. Other studies suggest that 38–50% of C282Y homozygotes may develop iron overload. Estimates of clinical penetrance as defined by iron overload-related morbidity also vary considerably from 10% to 30% of men and much less frequently in women.
In health, SF is a reliable marker of reticuloendothelial iron stores and is highly sensitive to iron overload in HH. It is the most frequently measured haematinic in the UK, and since its general introduction in the 1980s, SF has replaced the measurements of serum iron and transferrin in primary care. Primary care physicians are familiar with the investigation and treatment of low SF values and iron deficiency but are much less comfortable with investigating patients with high SF values even when these values are grossly elevated. Transferrin is responsible for iron transport and raised Tsat reflects the potential for parenchymal iron loading and tissue damage. The liver, heart, pancreas, pituitary gland, joints and skin are most susceptible to tissue damage. In the liver, iron deposition initially causes a non-specific inflammation that can then progress to cirrhosis, particularly when SF >1000 μg/L.
Timely diagnosis and treatment with simple venesection prevents organ damage. HH is however poorly recognised in primary care. The aim of this study was to develop a hospital laboratory pathway to improve the diagnosis of HH in primary care.
Abstract and Introduction
Abstract
Aims There is high prevalence of hereditary haemochromatosis (HH) in North European populations, yet the diagnosis is often delayed or missed in primary care. Primary care physicians frequently request serum ferritin (SF) estimation but appear uncertain as how to investigate patients with raised SF values. Our aim was to develop a laboratory algorithm with high predictive value for the diagnosis of HH in patients from primary care with raised SF values.
Methods Transferrin saturation (Tsat) was measured on SF samples sent from primary care; 1657 male and 2077 female patients age ≥30 years with SF ≥200 μg/L. HFE genotyping was performed on all 878 male and 867 female patients with Tsat >30%.
Results This study identified 402 (206 men; 196 women) C282Y carriers and 132 (58 men; 74 women) C282Y homozygotes. Optimal limits for combined SF and Tsat values for HH recognition were established. The detection rate for homozygous C282Y HH for male patients with both SF ≥300 μg/L and Tsat >50% was 18.8% (52/272) and 16.3% (68/415) for female patients with both SF ≥200 μg/L and Tsat >40%.
Conclusions The large number of SF requests received from primary care should be used as a resource to improve the diagnosis of HH in areas of high prevalence.
Introduction
Hereditary haemochromatosis (HH) is an autosomal-recessive genetic disorder of iron metabolism. It has been recognised as a clinical disorder for >100 years and is one of the most common inherited conditions in populations of North European descent. Clinical complications include liver cirrhosis, cardiomyopathy and diabetes. Treatment is simple and effective, but diagnosis is often either delayed or missed. HH is typically associated with the C282Y mutation in the HFE gene. Large population studies have determined global distribution of the C282Y mutation with highest prevalence (0.5% C282Y homozygotes) in North European populations. The H63D mutation of HFE is found in 20% of the UK population and can be associated with HH when inherited in combination with C282Y. Clinical iron overload however is less severe and far less frequent. Rarer mutations causing HH have been described. These include mutations in hemojuvelin, hepcidin (HAMP) genes, transferrin receptor 2 (TRF2), ferroportin and rare mutations in HFE. In the absence of C282Y homozygosity or C282Y/H63D compound heterozygosity, further investigation of raised serum ferritin (SF) and transferrin saturation (Tsat) can include screening for these less common mutations.
Clinical penetrance as defined by biochemical evidence of iron overload is not complete in C282Y homozygotes. Estimates vary considerably, but it is found more commonly in male than in female homozygotes. In a study of Danish male C282Y homozygotes, 89% had Tsat ≥50% and 94% SF ≥300 μg/L. Other studies suggest that 38–50% of C282Y homozygotes may develop iron overload. Estimates of clinical penetrance as defined by iron overload-related morbidity also vary considerably from 10% to 30% of men and much less frequently in women.
In health, SF is a reliable marker of reticuloendothelial iron stores and is highly sensitive to iron overload in HH. It is the most frequently measured haematinic in the UK, and since its general introduction in the 1980s, SF has replaced the measurements of serum iron and transferrin in primary care. Primary care physicians are familiar with the investigation and treatment of low SF values and iron deficiency but are much less comfortable with investigating patients with high SF values even when these values are grossly elevated. Transferrin is responsible for iron transport and raised Tsat reflects the potential for parenchymal iron loading and tissue damage. The liver, heart, pancreas, pituitary gland, joints and skin are most susceptible to tissue damage. In the liver, iron deposition initially causes a non-specific inflammation that can then progress to cirrhosis, particularly when SF >1000 μg/L.
Timely diagnosis and treatment with simple venesection prevents organ damage. HH is however poorly recognised in primary care. The aim of this study was to develop a hospital laboratory pathway to improve the diagnosis of HH in primary care.