The magnitude of the plasma hepcidin response to oral iron supplements depends on the iron dosage.

BACKGROUND: Iron deficiency without anaemia is a common health problem, especially in young menstruating women. The efficacy of the usually recommended oral iron supplementation is limited due to increased plasma hepcidin concentration, which reduces iron absorption and leads to side effects such as intestinal irritation. This observation raises the question of how low-dose iron therapy may affect plasma hepcidin levels and whether oral iron intake dose-dependently affects plasma hepcidin production. METHODS: Fifteen non-anaemic women with iron deficiency (serum ferritin ≤30 ng/ml) received a single dose of 0, 6, 30, or 60 mg of elemental oral iron as ferrous sulfate on different days. Plasma hepcidin was measured before and seven hours after each dose. RESULTS: Subjects had an average age of 23 (standard deviation = 3.0) years and serum ferritin of 24 ng/ml (interquartile range = 16-27). The highest mean change in plasma hepcidin levels was measured after ingesting 60 mg of iron, increasing from 2.1 ng/ml (interquartile range = 1.6-2.9) to 4.1 ng/ml (interquartile range = 2.5-6.9; p < 0.001). Iron had a significant dose-dependent effect on the absolute change in plasma hepcidin (p = 0.008), where lower iron dose supplementation resulted in lower plasma hepcidin levels. Serum ferritin levels were significantly correlated with fasting plasma hepcidin levels (R2 = 0.504, p = 0.003) and the change in plasma hepcidin concentration after iron intake (R2 = 0.529, p = 0.002). CONCLUSION: We found a dose-dependent effect of iron supplementation on plasma hepcidin levels. Lower iron dosage results in a smaller increase in hepcidin and might thus lead to more efficient intestinal iron absorption and fewer side effects. The effectiveness and side effects of low-dose iron treatment in women with iron deficiency should be further investigated. This study was registered at the Swiss National Clinical Trials Portal (2021-00312) and ClinicalTrials.gov (NCT04735848).

Fabry disease biomarkers in patients switched from enzyme-replacement therapy to migalastat oral chaperone therapy.

Background: A biomarker profile was evaluated longitudinally in patients with Fabry disease switched from enzyme-replacement therapy (ERT) to migalastat. Methods: 16 Gb3 isoforms and eight lyso-Gb3 analogues were analyzed in plasma and urine by LC-MS/MS at baseline and at three different time points in naive participants and participants switching from either agalsidase α or ß to migalastat. Results: 29 adult participants were recruited internationally (seven centers). The Mainz Severity Score Index and mean biomarker levels remained stable (p ≥ 0.05) over a minimum of 12 months compared with baseline following the treatment switch. Conclusion: In this cohort of patients with Fabry disease with amenable mutations, in the short term, a switch from ERT to migalastat did not have a marked effect on the average biomarker profile.

Endocrine disorders in patients with Fabry disease: insights from a reference centre prospective study.

CONTEXT: Fabry Disease (FD) is a rare X-linked storage disease characterised by a-galactosidase A deficiency and diffuse organ accumulation of glycosphingolipids. Enzyme replacement and chaperone therapies are only partially effective. It remains unclear if FD-related endocrine disorders contribute to the observed morbidity. OBJECTIVE: To investigate the function of the endocrine system in patients with FD. DESIGN: We conducted an observational prospective study from 2017 to 2020. SETTING AND PATIENTS: We included 77 patients with genetically confirmed FD (27 men, 20/27 Classic, 7/26 Late Onset phenotype, 50 women, 41/50 and 9/50 respectively), who are systematically followed by our reference centre. RESULTS: 36/77 (46.8%) patients had VitD deficiency (25(0H)VitD <20 µg/L) despite the fact that 19/36 (52.8%) were substituted with cholecalciferol. Only 21/77 (27.3%) patients had normal VitD levels without VitD substitution. 11/77 (14.3%) had significant hypophosphatemia (p < 0.80 mmol/L). Three new cases (3.9%) of subclinical, two (2.6%) of overt and six (7.8%) of known hypothyroidism were identified. Of note, men had significantly higher renin levels than women [61.4 (26.1-219.6) vs.25.4 (10.9-48.0) mU/L, p = 0.003]. There were no major abnormalities in adrenal, growth and sex-hormone axes. Patients of Classic phenotype had significantly higher High-Density Lipoprotein Cholesterol (HDL-C) levels (p = 0.002) and in men those levels were positively correlated with globotriaosylsphingosin (Lyso-Gb3) values. 10/77 (13%) of the patients were underweight. CONCLUSIONS: VitD supplementation should be considered for all patients with FD. Thyroid screening should be routinely performed. Malnutrition should be prevented or treated, particularly in Classic phenotype patients. Overall, our data suggest that FD specialists should actively seek and diagnose endocrine disorders in their patients.

Evaluation of the new restandardized Abbott Architect 25-OH Vitamin D assay in vitamin D-insufficient and vitamin D-supplemented individuals.

BACKGROUND: Recently, Abbott Diagnostics has restandardized the Architect 25(OH)D assay against the NIST SRM 2972. We have evaluated the analytical and clinical performance of the restandardized Architect 25(OH)D assay and compared its performance with a NIST-traceable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method and the Roche total 25(OH)D assay in vitamin D-insufficient individuals before and after vitamin D3 supplementation. METHODS: Frozen serum samples were obtained from 88 healthy subjects with self-perceived fatigue and vitamin D-insufficiency <50 nmol L-1 who were randomized to receive a single 100 000 IU dose of vitamin D3 (n = 48) or placebo (n = 40). Total 25(OH)D concentrations were measured before and 4 weeks after supplementation by the restandardized Architect 25(OH)D assay, LC-MS/MS, and Roche assay. RESULTS: The Architect 25(OH)D assay showed an intra- and inter-assay imprecision of <5%. Comparison of the Architect assay with the LC-MS/MS method showed a good correlation in both vitamin D-insufficient and vitamin D-supplemented subjects, however, with a negative mean bias of 17.4% and 8.9%, respectively. As compared to the Roche assay, the Abbott assay underestimated 25(OH)D results in insufficient subjects (<50 nmol L-1 ) with a mean negative bias of 17.1%, this negative bias turned into a positive bias in supplemented subjects. Overall there was a moderate agreement in classification of vitamin D-insufficient and -supplemented individuals into different vitamin D states between the Architect 25(OH)D method and LC-MS/MS. CONCLUSION: The routine use of the restandardized Architect 25(OH)D results in a slight underestimation of circulating total 25(OH)D levels at lower concentrations and thus potential misclassification of vitamin D status.

Impact of a single oral dose of 100,000 IU vitamin D3 on profiles of serum 25(OH)D3 and its metabolites 24,25(OH)2D3, 3-epi-25(OH)D3, and 1,25(OH)2D3 in adults with vitamin D insufficiency.

BACKGROUND: We investigate the effect of a high dose of vitamin D3 on circulating concentrations of 25(OH)D3 and its metabolites 24,25(OH)2D3, 3-epi-25(OH)D3, and 1,25(OH)2D3 in healthy individuals with self-perceived fatigue and vitamin D insufficiency [25(OH)D3<50 nmol/L]. METHODS: One hundred and seven study participants (age 20-50 years) were randomized to receive a single 100,000 IU dose of vitamin D3 (n=52) or placebo (n=55). Vitamin D metabolite concentrations in serum were measured before, and 4 weeks after, supplementation. RESULTS: Overall, 52% of participants receiving vitamin D3 attained a serum 25(OH)D3 level >75 nmol/L. Among individuals who received vitamin D3, there were significant increases in serum concentrations of 25(OH)D3 and its metabolites 24,25(OH)2D3, 3-epi-25(OH)D3, and 1,25(OH)2D3 at 4 weeks; however, inter-individual variability in these changes was substantial. Positive correlations between serum 25(OH)D3 and 24,25(OH)2D3 and 3-epi-25(OH)D3, and a significant negative correlation between serum 1,25(OH)2D3 and 3-epi-25(OH)D3, were found 4 weeks after supplementation. The 24,25(OH)2D3/25(OH)D3 and 24,25(OH)2D3/1,25(OH)2D3 ratios were significantly increased, compared with baseline, in participants receiving vitamin D3. Baseline 25(OH)D3 concentration was the only factor predictive of the change in 25(OH)D3 after supplementation. CONCLUSIONS: Administration of a single high dose of vitamin D3 leads to a significant increase in concentrations of 25(OH)D3, 24,25(OH)2D3, 3-epi-25(OH)D3 and 1,25(OH)2D3; induction of the catabolic pathway predominates over the production of 1,25(OH)2D3. Due to the high inter-individual variation in the 25(OH)D3 response to supplementation, any given dose of vitamin D is unlikely to achieve optimal vitamin D status in all treated individuals.