HFE Genotype, Ferritin Levels and Transferrin Saturation in Patients with Suspected Hereditary Hemochromatosis

Sandnes, Miriam; Vorland, Marta; Ulvik, Rune J.; Reikvam, Håkon

doi:10.3390/genes12081162

Cited by 7 publications

(5 citation statements)

References 36 publications

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“…Elevated levels of liver enzymes may be an early sign of this organ's injury due to iron accumulation. In agreement with a previous study [4], liver enzyme levels were correlated with the ferritin level (Table 1). Moreover, ALP is related to bone disease, and Pb is known to accumulate in bones [43].…”

Section: Liver Function Testssupporting

confidence: 92%

“…In most cases, the disorder is associated with mutations of the High FErrum (HFE) gene. Homozygosity for C282Y is the most prevalent variant in patients with symptoms, although other variants like H63D homozygosity or compound heterozygosity C282Y/H63D may contribute to disease manifestations [4]. Routine treatment involves bloodlettings of 450-500 mL weekly, up to 20-40 times, to remove excess iron from the body.…”

Section: Introductionmentioning

confidence: 99%

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Bloodlettings in Hemochromatosis Result in Increased Blood Lead (Pb) Concentrations

Yazdani

Distante

Mørkrid

et al. 2022

Biol Trace Elem Res

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Hemochromatosis is a hereditary disorder, most often associated with mutations of the HFE (High FErrum) gene. If left untreated, it can result in severe parenchymal iron accumulation. Bloodletting is the mainstay treatment. We have previously shown that treatment of hemochromatosis by repeated bloodlettings may induce changes in the serum levels of several trace elements. The aim of this work was to evaluate if whole blood concentrations of the environmental pollutants lead (Pb), mercury (Hg), and cadmium (Cd) could be affected by bloodlettings. We recruited 28 patients and 21 healthy individuals (control group). Whole blood and urine levels of Pb, Hg, and Cd were measured before the start and after the completion of treatment using inductively coupled plasma mass spectrometry, together with serum iron and liver function tests. Concentrations of blood Pb, but not Hg or Cd, were significantly increased after treatment. The increase in Pb was higher in C282Y homozygous patients than in the other patients, and it was positively correlated with the serum concentration of alkaline phosphatase. Bloodlettings in hemochromatosis result in an increase in the blood concentration of Pb. Augmented absorption due to iron loss or Pb mobilization from bone may contribute to the higher blood Pb level.

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Section: Liver Function Testssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Bloodlettings in Hemochromatosis Result in Increased Blood Lead (Pb) Concentrations

Yazdani

Distante

Mørkrid

et al. 2022

Biol Trace Elem Res

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“…Progressive increases in serum levels are markers of increased iron absorption and are amongst the earliest signs of hemochromatosis. [ 25 ] Progressively increasing serum ferritin (hyperferritinemia) is also characteristic of hemochromatosis, [ 25 ] reflecting increasing iron storage; although ferritin levels are raised in several conditions including acute inflammation, which may have resulted in the weaker association trends between a higher polygenic score for ferritin (or TIBC) and an increase in risk of liver disease or comorbidities. Raised serum iron biomarkers are reported in other HFE genotype groups, especially in p.C282Y/p.H63D compound heterozygotes compared with noncarriers; [ 26 ] however, evidence for the impact on clinical diagnosis and morbidity is variable.…”

Section: Discussionmentioning

confidence: 99%

Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: Associations in a large community cohort

2022

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Background:The iron overload condition hereditary hemochromatosis (HH) can cause liver cirrhosis and cancer, diabetes, and arthritis. Males homozygous for the p.C282Y missense mutation in the Homeostatin Iron Regulator (HFE) gene have greatest risk; yet, only a minority develop these conditions.We aimed to determine whether common genetic variants influencing iron levels or liver disease risk in the general population also modify clinical penetrance in HFE p.C282Y and p.H63D carriers. Methods:We studied 1294 male and 1596 female UK Biobank HFE p.C282Y homozygous participants of European ancestry with medical records up to 14 years after baseline assessment. Polygenic scores quantified genetic effects of blood iron biomarkers and relevant diseases (identified in the general population).Analyses were also performed in other HFE p.C282Y/p.H63D genotype groups.Results: In male p.C282Y homozygotes, a higher iron polygenic score increased the risk of liver fibrosis or cirrhosis diagnoses (odds ratio for the top 20% of iron polygenic score vs. the bottom 20% = 4.90: 95% confidence intervals, 1.63-14.73; p = 0.005), liver cancer, and osteoarthritis but not diabetes. A liver cirrhosis polygenic score was associated with liver cancer diagnoses. In female p.C282Y homozygotes, the osteoarthritis polygenic score was associated with increased osteoarthritis diagnoses and type-2 diabetes polygenic score with diabetes. However, the iron polygenic score was not robustly associated with diagnoses in p.C282Y female homozygotes or in other p.C282Y/p.H63D genotypes.Conclusions: HFE p.C282Y homozygote penetrance to clinical disease in a large community cohort was partly explained by common genetic variants that influence iron and risks of related diagnoses in the general population, including polygenic scores in HH screening and diagnosis, may help in estimating prognosis and treatment planning.

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“…Higher PRS for serum iron and for transferrin saturation increased risk of liver disease, especially liver fibrosis or cirrhosis, and liver cancer. Progressive increases in serum levels are markers of increased iron absorption and are amongst the earliest signs of haemochromatosis [24]. Progressively increasing serum ferritin (hyperferritinemia) is also characteristic of haemochromatosis [24], reflecting increasing iron storage; although ferritin levels are raised in several conditions including acute inflammation, which may have resulted in the weaker association trends between higher PRS for ferritin (or total iron- binding capacity) and increase risk of liver disease or co-morbidities.…”

Section: Discussionmentioning

confidence: 99%

“…Progressive increases in serum levels are markers of increased iron absorption and are amongst the earliest signs of haemochromatosis [24]. Progressively increasing serum ferritin (hyperferritinemia) is also characteristic of haemochromatosis [24], reflecting increasing iron storage; although ferritin levels are raised in several conditions including acute inflammation, which may have resulted in the weaker association trends between higher PRS for ferritin (or total iron- binding capacity) and increase risk of liver disease or co-morbidities. Raised serum iron biomarkers are reported in other HFE genotype groups, especially in p.C282Y/p.H63D compound heterozygotes, compared to non-carriers [25], however evidence for the impact on clinical diagnosis and morbidity is variable [26].…”

Section: Discussionmentioning

confidence: 99%

Penetrance of HFE haemochromatosis variants to clinical disease: polygenic risk score associations in UK Biobank

Pilling

Atkins

Melzer

2022

Preprint

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BackgroundThe iron overload condition Hereditary Heamochromatosis (HH) can cause liver cirrhosis and cancer, diabetes and arthritis. In Europeans, most HH disease occurs in male HFE p.C282Y homozygotes, yet only a minority of homozygotes in the general population develop these conditions. We aimed to determine whether common genetic variants influencing iron levels or risks for liver, diabetes or arthritis diagnoses in the general population also modify clinical penetrance in HFE p.C282Y and p.H63D carriers.Methods1,294 male and 1,596 female UK Biobank European-ancestry HFE p.C282Y homozygous participants with electronic medical records up to 14 years after baseline assessment were studied. Polygenic risk scores (PRS) quantified genetic effects on blood iron biomarkers and relevant diseases (identified in the general population). Analyses were repeated in 10,699 p.C282Y/p.H63D compound heterozygotes.ResultsIn male p.C282Y homozygotes, higher iron PRS increased risk of liver fibrosis or cirrhosis diagnoses (top 20% of iron PRS had Odds Ratio 4.90: 95% Confidence Intervals 1.63 to 14.73, p=0.005 versus bottom 20%), liver cancer, and osteoarthritis, but not diabetes. The liver cirrhosis PRS also associated with increased liver cancer diagnoses, and greater type-2 diabetes PRS increased risk of type-2 diabetes. In female p.C282Y homozygotes, osteoarthritis PRS was associated with increased osteoarthritis diagnoses, and type-2 diabetes PRS with type-2 diabetes. However, the iron PRS was not robustly associated with diagnoses in p.C282Y homozygote females, or in other p.C282Y/p.H63D genotypes.ConclusionsHFE p.C282Y homozygote penetrance to clinical disease in a large community cohort was partly explained by common genetic variants that influence iron and risks of related diagnoses in the general population. Including PRS in HH screening and diagnosis may help in estimating prognosis and treatment planning.Lay SummaryTwo or three sentences summarizing the main message of the article expressed in plain English to describe your findings to a non-medical audience.Hereditary Haemochromatosis, an iron overload condition, is the most common genetic disease in Northern Europeans; 1 in 150 people carry two copies of the highest risk mutation (called HFE p.C282Y).Only a minority of those with high risk HH variants actually develop iron overload diseases, such as liver cancer, cirrhosis, diabetes and arthritis. We tested whether known genetic variants with smaller effects on iron levels in the whole population modify risk of iron overload related disease in those with the HH high risk variants. We did similar tests for variants linked to each of the diseases caused by iron overload.Increased genetic risk for higher iron significantly raised the likelihood of liver fibrosis, cirrhosis and cancer in mutation carriers. In the future this information could help identify at-risk haemochromatosis patients early.

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HFE Genotype, Ferritin Levels and Transferrin Saturation in Patients with Suspected Hereditary Hemochromatosis

Cited by 7 publications

References 36 publications

Bloodlettings in Hemochromatosis Result in Increased Blood Lead (Pb) Concentrations

Bloodlettings in Hemochromatosis Result in Increased Blood Lead (Pb) Concentrations

Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: Associations in a large community cohort

Penetrance of HFE haemochromatosis variants to clinical disease: polygenic risk score associations in UK Biobank

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