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A novel SLC40A1 p.Y333H mutation with gain of function of ferroportin: A recurrent cause of haemochromatosis in China.
Zhang, W, Xu, A, Li, Y, Zhao, S, Zhou, D, Wu, L, Zhang, B, Zhao, X, Wang, Y, Wang, X, et al
Liver international : official journal of the International Association for the Study of the Liver. 2019;(6):1120-1127
Abstract
BACKGROUND & AIMS Haemochromatosis type 4, also known as ferroportin disease, is an autosomal dominant genetic disorder caused by pathogenic mutations in the SLC40A1 gene, which encodes ferroportin 1 (FPN1). We have identified a novel SLC40A1 p.Y333H mutation in our previous study. In the present study, we tried to investigate the frequency and pathogenicity of the SLC40A1 p.Y333H mutation in haemochromatosis in China. METHODS Patients were analysed for SLC40A1 p.Y333H as well as mutations in the other classic haemochromatosis-related genes by Sanger sequencing. To analyse iron export capacity of the SLC40A1 p.Y333H mutant, the 293T cells were transfected with the SLC40A1 p.Y333H construct and then treated with hepcidin after exposure to ferric ammonium citrate. Cellular localization of mutant FPN1, expression of FPN1 and intracellular ferritin were analysed by immunofluorescence and Western blotting. RESULTS Of 22 unrelated cases with primary iron overload, three cases (3/22, 13.6%) harboured the SLC40A1 p.Y333H, with no missense mutations identified in any other classical haemochromatosis-related genes including HFE, HJV, HAMP and TFR2. Pedigree analysis showed that three probands and the son of one proband had haemochromatosis of stage 3, while the son of another proband with age of 16 showed elevated transferrin saturation but normal serum ferritin level. In vitro studies showed the mutant p.Y333H ferroportin was resistant to hepcidin, affecting the subsequent internalization and degradation of FPN1, and was associated with ferroportin gain of function. CONCLUSIONS The SLC40A1 p.Y333H mutation is associated with gain of function of ferroportin, representing one of the major aetiological factors of haemochromatosis in China.
2.
Intravenous Iron Replacement Improves Quality of Life in Hypoferritinemic Inflammatory Bowel Disease Patients with and without Anemia.
Eliadou, E, Kini, G, Huang, J, Champion, A, Inns, SJ
Digestive diseases (Basel, Switzerland). 2017;(5):444-448
Abstract
BACKGROUND No study has compared changes in quality of life (QoL) following iron therapy between anemic and non-anemic, hypoferritinemic patients. This study compares the impact of parenteral iron replacement on QoL in inflammatory bowel disease (IBD) patients with anemia, or in those with hypoferritinemia alone. METHODS Consecutive IBD patients diagnosed with anemia or hypoferritinemia were enrolled. IBD questionnaire (IBDQ) and 36-Item Short Form Survey (SF36) at diagnosis and 6 weeks post treatment were measured. RESULTS Ten patients with anemia and 13 with hypoferritinemia were treated with intravenous iron polymaltose. Across all patients, there was a significant improvement in median SF36 mental component score by 8.5 (p = 0.004) and median IBDQ by 12 (p = 0.02). There was a trend towards improved median SF36 physical component score by 3.2 (p = 0.6). These changes were not significantly different when comparing anemic with hypoferritinemic patients. In IBDQ, there was a trend toward greater improvement in hypoferritinemic vs. anemic patients (20 vs. 1.5, p = 0.31). CONCLUSIONS This is the first study to show that improvements in QoL in hypoferritinemic patients are similar to those with anemia. Based on these results, patients with IBD should be offered the option of iron therapy when they are found to be hypoferritinemic, even in the absence of anemia.
3.
Adjusting ferritin concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project.
Namaste, SM, Rohner, F, Huang, J, Bhushan, NL, Flores-Ayala, R, Kupka, R, Mei, Z, Rawat, R, Williams, AM, Raiten, DJ, et al
The American journal of clinical nutrition. 2017;(Suppl 1):359S-371S
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Abstract
Background: The accurate estimation of iron deficiency is important in planning and implementing interventions. Ferritin is recommended as the primary measure of iron status, but interpretability is challenging in settings with infection and inflammation.Objective: We assessed the relation between ferritin concentrations and inflammation and malaria in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y) and investigated adjustment algorithms to account for these effects.Design: Cross-sectional data from 15 surveys for PSC (n = 27,865) and 8 surveys for WRA (24,844), from the Biomarkers Reflecting the Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and combined with the use of a meta-analysis. Several approaches were explored to estimate depleted iron stores (ferritin concentration <12 μg/L in PSC and <15 μg/L in WRA) in inflammation and malaria settings as follows: 1) increase ferritin-concentration cutoff to <30 μg/L; 2) exclude individuals with C-reactive protein (CRP) concentrations >5 mg/L or α-1-acid glycoprotein (AGP) concentrations >1 g/L; 3) apply arithmetic correction factors; and 4) use a regression correction approach.Results: Depleted iron-store estimates incrementally increased as CRP and AGP deciles decreased (4% compared with 30%, and 6% compared with 29% from highest compared with lowest CRP deciles for pooled PSC and WRA, respectively, with similar results for AGP). Depending on the approach used to adjust for inflammation (CRP plus AGP), the estimated prevalence of depleted iron stores increased by 7-25 and 2-8 absolute median percentage points for PSC and WRA, respectively, compared with unadjusted values. Adjustment for malaria in addition to CRP and AGP did not substantially change the estimated prevalence of depleted iron stores.Conclusions: Our results lend support for the use of internal regression correction to estimate the prevalence of depleted iron stores in regions with inflammation. This approach appears to mathematically reflect the linear relation of ferritin concentrations with acute-phase proteins. More research is warranted to validate the proposed approaches, but this study contributes to the evidence base to guide decisions about how and when to adjust ferritin for inflammation.