Current iron therapy in the light of regulation, intestinal microbiome, and toxicity: are we prescribing too much iron?

Iron deficiency is a widespread global health concern with varying prevalence rates across different regions. In developing countries, scarcity of food and chronic infections contribute to iron deficiency, while in industrialized nations, reduced food intake and dietary preferences affect iron status. Other causes that can lead to iron deficiency are conditions and diseases that result in reduced intestinal iron absorption and blood loss. In addition, iron absorption and its bioavailability are influenced by the composition of the diet. Individuals with increased iron needs, including infants, adolescents, and athletes, are particularly vulnerable to deficiency. Severe iron deficiency can lead to anemia with performance intolerance or shortness of breath. In addition, even without anemia, iron deficiency leads to mental and physical fatigue, which points to the fundamental biological importance of iron, especially in mitochondrial function and the respiratory chain. Standard oral iron supplementation often results in gastrointestinal side effects and poor compliance. Low-dose iron therapy seems to be a valid and reasonable therapeutic option due to reduced hepatic hepcidin formation, facilitating efficient iron resorption, replenishment of iron storage, and causing significantly fewer side effects. Elevated iron levels influence gut microbiota composition, favoring pathogenic bacteria and potentially disrupting metabolic and immune functions. Protective bacteria, such as bifidobacteria and lactobacilli, are particularly susceptible to increased iron levels. Dysbiosis resulting from iron supplementation may contribute to gastrointestinal disorders, inflammatory bowel disease, and metabolic disturbances. Furthermore, gut microbiota alterations have been linked to mental health issues. Future iron therapy should consider low-dose supplementation to mitigate adverse effects and the impact on the gut microbiome. A comprehensive understanding of the interplay between iron intake, gut microbiota, and human health is crucial for optimizing therapeutic approaches and minimizing potential risks associated with iron supplementation.

Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency. The progressive accumulation of globotriaosylceramide results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. The pharmacological chaperone migalastat was recently approved as an alternative to enzyme replacement therapy in patients with amenable mutations. In this article, we investigate the proportion of amenable mutations, related to phenotype, in a population of adult patients with FD in Switzerland. This study included 170 adult patients (n = 64 males) from 46 independent pedigrees with 39 different identified mutations over the last 59 years. Overall, 68% had the classic phenotype and 48% fulfilled the current amenability criteria. Migalastat was stopped in 2/11 (18%) patients: the only male classic patient, because of lack of efficacy based on lyso-Gb3 levels, and one patient with a benign variant. In males, the achieved enzyme activities in peripheral leucocytes under migalastat treatment differed from the activities in HEK-cells after incubation with migalastat (eg, 33% in PL vs 41% HEK-cells for p.F113L; 43% in leucocytes vs 36% in HEK-cells for p.N215S, 24-30% in leucocytes vs 96% in HEK-cells for S238N). In this national cohort, we found a relatively high proportion of patients with amenable GLA mutations, which, however, had heterogeneous extent of amenability: the higher the residual α-Gal A activity, the higher the chaperone effect. Further studies are required to investigate the long-term benefits of migalastat therapy depending on the achieved enzyme activities in different amenable mutations.

G-protein receptor kinase 4 polymorphism and response to antihypertensive therapy.

BACKGROUND: G-protein receptor kinase 4 polymorphism influences blood pressure regulation via modulation of dopamine receptor D1 in renal proximal tubular cells. We investigated the role of G-protein receptor kinase 4 polymorphism in the response to hypertensive therapy in patients with essential hypertension. METHODS: In a prospective study, we assessed the G-protein receptor kinase 4 polymorphisms R65L, A142V, and A486V in 100 hypertensive patients. We analyzed the association of the 3 gene variants on blood pressure control and response to antihypertensive therapy with single-locus analysis, haplotype analysis, and regression analysis. RESULTS: Hypertensive individuals with a homozygous double variant of 65 L and 142 V needed significantly more antihypertensive treatment (number of antihypertensives 2.59 vs 1.95, P = 0.043) and especially diuretic therapy (0.82 vs 0.49, P = 0.029) to reach the same mean arterial blood pressure than did homozygous carriers of only 1 variant or heterozygous/wild-type carriers of R65L, A142V, and A486V alleles. CONCLUSIONS: G-protein receptor kinase 4 polymorphism is associated with antihypertensive treatment response in patients with essential hypertension. Determination of G-protein receptor kinase 4 polymorphism may improve individual antihypertensive blood pressure control in patients with essential hypertension.

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).

Plasma and platelet lipidome changes in Fabry disease.

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by the progressive accumulation of globotriaosylceramide (Gb3) leading to systemic manifestations such as chronic kidney disease, cardiomyopathy, and stroke. There is still a need for novel markers for improved FD screening and prognosis. Moreover, the pathological mechanisms in FD, which also include systemic inflammation and fibrosis, are not yet fully understood. METHODS: Plasma and platelets were obtained from 11 ERT (enzyme-replacement therapy)-treated symptomatic, 4 asymptomatic FD patients, and 13 healthy participants. A comprehensive targeted lipidomics analysis was conducted quantitating more than 550 lipid species. RESULTS: Sphingadiene (18:2;O2)-containing sphingolipid species, including Gb3 and galabiosylceramide (Ga2), were significantly increased in FD patients. Plasma levels of lyso-dihexosylceramides, sphingoid base 1-phosphates (S1P), and GM3 ganglioside were also altered in FD patients, as well as specific plasma ceramide ratios used in cardiovascular disease risk prediction. Gb3 did not increase in patients' platelets but displayed a high inter-individual variability in patients and healthy participants. Platelets accumulated, however, lyso-Gb3, acylcarnitines, C16:0-sphingolipids, and S1P. CONCLUSIONS: This study identified lipidome changes in plasma and platelets from FD patients, a possible involvement of platelets in FD, and potential new markers for screening and monitoring of this disease.

Intravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentration.

This is the first study to investigate the efficacy of intravenous iron in treating fatigue in nonanemic patients with low serum ferritin concentration. In a randomized, double-blinded, placebo-controlled study, 90 premenopausal women presenting with fatigue, serum ferritin ≤ 50 ng/mL, and hemoglobin ≥ 120 g/L were randomized to receive either 800 mg of intravenous iron (III)-hydroxide sucrose or intravenous placebo. Fatigue and serum iron status were assessed at baseline and after 6 and 12 weeks. Median fatigue at baseline was 4.5 (on a 0-10 scale). Fatigue decreased during the initial 6 weeks by 1.1 in the iron group compared with 0.7 in the placebo group (P = .07). Efficacy of iron was bound to depleted iron stores: In patients with baseline serum ferritin ≤ 15 ng/mL, fatigue decreased by 1.8 in the iron group compared with 0.4 in the placebo group (P = .005), and 82% of iron-treated compared with 47% of placebo-treated patients reported improved fatigue (P = .03). Drug-associated adverse events were observed in 21% of iron-treated patients and in 7% of placebo-treated patients (P = .05); none of these events was serious. Intravenous administration of iron improved fatigue in iron-deficient, nonanemic women with a good safety and tolerability profile. The efficacy of intravenous iron was bound to a serum ferritin concentration ≤ 15 ng/mL. This study was registered at the International Standard Randomized Controlled Trial Number Register (www.isrctn.org) as ISRCTN78430425.

Effectiveness of low-dose iron treatment in non-anaemic iron-deficient women: a prospective open-label single-arm trial.

BACKGROUND: Iron deficiency without anaemia is highly prevalent and is particularly associated with fatigue, cognitive impairment, or poor physical endurance. Standard oral iron therapy often results in intestinal irritation with associated side effects and premature discontinuation of therapy, therefore, optimal oral iron therapy with sufficient iron absorption and minimal side effects is desirable. METHODS: Thirty-six iron-deficient non-anaemic premenopausal women (serum ferritin ≤30 ng/ml, haemoglobin ≥117 g/l) with normal body mass index (BMI) and no hypermenorrhea received 6 mg of elemental oral iron (corresponding to 18.6 mg ferrous sulphate) twice daily for 8 weeks. RESULTS: Participants treated with low-dose iron had an average age of 28 years and a BMI of 21 kg/m2. Their serum ferritin and haemoglobin increased significantly from 18 ng/ml to 33 ng/ml (p <0.001) and from 135 g/l to 138 g/l (p = 0.014), respectively. Systolic blood pressure increased from 114 mmHg to 120 mmHg (p = 0.003). Self-reported health status improved after 8 weeks (p <0.001) and only one woman reported gastrointestinal side effects (3%). CONCLUSION: This prospective open-label single-arm trial shows that oral iron treatment of 6 mg of elemental iron twice daily over 8 weeks is effective in iron-deficient non-anaemic women. Due to the negligible side effects, low-dose iron treatment is a valuable therapeutic option for iron-deficient non-anaemic women with normal BMI and menstruation. Further placebo-controlled studies with a larger number of participants are needed to confirm these results. CLINICALTRIALS: gov NCT04636060.

Long-Term Monitoring of Cardiac Involvement under Migalastat Treatment Using Magnetic Resonance Tomography in Fabry Disease.

Background: Fabry cardiomyopathy is characterized by left ventricular hypertrophy, myocardial fibrosis, arrhythmia, and premature death. Treatment with migalastat, an oral pharmacological chaperone, was associated with a stabilization of cardiac biomarkers and a reduction in left ventricular mass index, as measured by echocardiography. A recent study, using cardiac magnetic resonance (CMR) as the gold standard, found a stable course of myocardial involvement after 18 months of treatment with migalastat. Our study aimed to provide long-term CMR data for the treatment with migalastat. Methods: A total of 11 females and four males with pathogenic amenable GLA mutations were treated with migalastat and underwent 1.5T CMR imaging for routine treatment effect monitoring. The main outcome was a long-term myocardial structural change, reflected by CMR. Results: After migalastat treatment initiation, left ventricular mass index, end diastolic volume, interventricular septal thickness, posterior wall thickness, estimated glomerular filtration rate, and plasma lyso-Gb3 remained stable during the median follow-up time of 34 months (min.: 25; max.: 47). The T1 relaxation times, reflecting glycosphingolipid accumulation and subsequent processes up to fibrosis, fluctuated over the time without a clear trend. No new onset of late gadolinium enhancement (LGE) areas, reflecting local fibrosis or scar formation of the myocardium, could be detected. However, patients with initially present LGE showed an increase in LGE as a percentage of left ventricular mass. The median α-galactosidase A enzymatic activity increased from 37.3% (IQR 5.88-89.3) to 105% (IQR 37.2-177) of the lower limit of the respective reference level (p = 0.005). Conclusion: Our study confirms an overall stable course of LVMi in patients with FD, treated with migalastat. However, individual patients may experience disease progression, especially those who present with fibrosis of the myocardium already at the time of therapy initiation. Thus, a regular treatment re-evaluation including CMR is needed to provide the optimal management for each patient.

Mobilization of storage iron is reflected in the iron isotopic composition of blood in humans.

We recently showed in an animal model that iron isotopic composition varies substantially between different organs. For instance, iron in ferritin-rich organs--such as the major storage tissues liver, spleen, and bone marrow--contain a larger fraction of the heavy iron isotopes compared with other tissues, including blood. As a consequence, partitioning of body iron into red blood cells and storage compartments should be reflected in the isotopic pattern of blood iron. To confirm this hypothesis, we monitored blood iron isotope patterns in iron-overloaded subjects undergoing phlebotomy treatment by multicollector inductively coupled plasma mass spectrometry. We found that bloodletting and consequential replacement of lost blood iron by storage iron led to a substantial increase of the heavy isotope fraction in the blood. The progress of iron depletion therapy and blood loss was quantitatively traceable by isotopic shifts of as much as +1‰ in δ((56)Fe). These results show that--together with iron absorption efficiency--partitioning of iron between blood and iron storage tissues is an important determinant of blood iron isotopic patterns, which could make blood iron isotopic composition the first composite measure of iron metabolism in humans.

Iron overload associated symptoms and laboratory changes in the Swiss Haemochromatosis Cohort - when a clinician should become attentive.

AIMS OF THE STUDY: Hereditary haemochromatosis is a genetic disease characterised by progressive accumulation of iron in organs leading to many unspecific complaints, but even today diagnosis may be delayed. We aimed to identify symptoms associated with iron overload and parameters typical in patients with hereditary haemochromatosis which might help to facilitate detection and diagnosis in daily clinical routine. METHODS: We analysed the prospective Swiss Haemochromatosis Cohort (SHC), including 163 patients for whom serum ferritin levels at diagnosis were available. The cohort was stratified according to the degree of iron overload. Substantial iron overload was defined as serum ferritin concentrations ≥1000 µg/ml. RESULTS: Patients with substantial iron overload had significantly higher liver enzymes (p <0.001) and more often arthropathy of the metacarpophalangeal joints (p <0.001) and upper ankle joint (p = 0.003). Elevated liver enzymes, especially elevated alanine aminotransferase (ALT) levels, were associated with a 10.1-fold (95% confidence interval [CI] 4.8–21.2) increased the risk for serum ferritin levels ≥1000 µg/ml. Furthermore, metacarpophalangeal joint arthropathy emerged as an important predictor for iron overload with a 3.6-fold increased risk (95% CI 1.8–7.1; p <0.001). Only elevated ALT levels and metacarpophalangeal joint arthropathy remained significantly associated with elevated iron levels after adjustment for possible confounders in patients diagnosed with hereditary haemochromatosis. CONCLUSION: Elevated ALT levels and metacarpophalangeal arthropathy remained independently associated with elevated ferritin levels in patients with haemochromatosis and should prompt clinicians to consider iron overload in patients with hereditary haemochromatosis.    .

Higher age at diagnosis of hemochromatosis is the strongest predictor of the occurrence of hepatocellular carcinoma in the Swiss hemochromatosis cohort: A prospective longitudinal observational study.

Hereditary hemochromatosis (HH) is the most common genetic disease in Caucasians which is characterized by an increased intestinal iron absorption, resulting into a progressive accumulation of iron in organs including liver, heart, and pancreas, leading to their progressive dysfunction. Hepatocellular carcinoma (HCC) is a long-term complication of HH, which contributes to increased mortality.We evaluated the risk factors of HCC in a prospective cohort of Swiss hemochromatosis patients with a long-term follow-up.We included 147 patients with the mean age at diagnosis of 48 years, in whom 70% were men. Overall, 9% of the patients developed HCC during the mean follow-up time of 14 years (range 1-40 years). Patients with HCC had higher age at diagnosis (61 ±â€Š11 vs 47 ±â€Š13 years, P = .003), more frequently liver cirrhosis on biopsy (90% vs 37.5%, P = .004), and higher serum ferritin levels [3704 (Q1:2025, Q3:4463) vs 1338 (Q1:691, Q3:2468) µg/L, P < .001], they needed more iron removed by phlebotomy until its depletion [8.9 (Q1:7.2, Q3:10.1) vs 3.8 (Q1:1.6, Q3:8.9) g, P = .029], compared to non-HCC patients. After adjustment for possible confounders, only higher age at diagnosis remained significantly associated with HCC development (odds ratio 1.19, 95% CI 0.056-0.397, P = .001, per year).Higher age at diagnosis showed the strongest association with the occurrence of HCC in Swiss hemochromatosis patients. Patients who were diagnosed at a higher age and with a high iron overload (serum ferritin levels >1000 µg/L) require regular screening even if they have no liver cirrhosis.

Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial.

BACKGROUND: Vitamin D deficiency is frequent and has been associated with fatigue in uncontrolled trials. METHODS: This is the first double-blind placebo-controlled clinical trial to investigate the efficacy of per os vitamin D3 (cholecalciferol) in treating fatigue among otherwise healthy persons with low serum 25-hydroxyvitamin D (25(OH)D) levels. We enrolled 120 individuals (mean age 29 ±â€Š6 years, 53% women) presenting with fatigue and vitamin D deficiency (serum 25(OH)D < 20 µg/L). Participants were randomized to a single oral dose of 100,000 units of vitamin D or placebo. The primary endpoint was intra-individual change in the fatigue assessment scale (FAS) at 4 weeks after treatment. RESULT: The mean age of the participants was 29 ±â€Š6 years, 53% were women. Mean FAS decreased significantly more in the vitamin D group (-3.3 ±â€Š5.3; 95% confidence interval [CI] for change -14.1 to 4.1) compared with placebo (-0.8 ±â€Š5.3; 95% CI for change -9.0 to 8.7); (P = 0.01). Amelioration of fatigue was reported more frequently in vitamin D than in placebo group (42 [72%] vs. 31 [50%]; P = 0.01; odds ratio [OR] 2.63, 95% CI for OR 1.23-5.62). Among all participants, improvement in fatigue score correlated with the rise in 25(OH)D level (R = -0.22, P = 0.02). CONCLUSION: Vitamin D treatment significantly improved fatigue in otherwise healthy persons with vitamin D deficiency.This study was registered at the www.ClinicalTrials.gov Protocol ID NCT02022475.

Progression of peripheral arterial occlusive disease is associated with Chlamydia pneumoniae seropositivity and can be inhibited by antibiotic treatment.

A possible influence of Chlamydia pneumoniae seropositivity on the clinical course of peripheral arterial occlusive disease (PAOD) has not been investigated previously. Though roxithromycin therapy was found to inhibit progression of PAOD, the nature of this effect (antibiotic or anti-inflammatory) has remained elusive. The course of PAOD was prospectively assessed in elderly men during 4 years, comparing 51 C. pneumoniae seropositive (IgG>/=1:128) with 46 seronegative patients (IgG<1:64 and IgA<1:32). Twenty of the seropositive patients were treated with roxithromycin (400 mg daily) for 4 weeks. Limitation of the walking distance to 200 m or less was observed in 55% of the seropositive untreated patients as compared to 30% of both, seronegative and macrolide-treated patients. The number of invasive revascularizations per patient was 1.7 in the seropositive untreated group as compared to 0.5 in the seronegative and the macrolide-treated group. Considering possible confounding variables, such as classical vascular risk factors, ordinal regression analyses showed a significant association of C. pneumoniae seropositivity with limitation of the walking distance (p=0.027) and need for invasive revascularization (p=0.037). The effect of macrolide treatment on these outcome measures was marked (p<0.001 and p=0.040, respectively) during 2.7 years but decreased in the second part of the observation period. This study provides good evidence that C. pneumoniae are involved in the progression of PAOD and that antibiotic treatment directed against C. pneumoniae is effective in inhibiting this process.

Estimating iron overload in patients with suspected liver disease and elevated serum ferritin.

BACKGROUND: Iron status evaluation in patients with suspected liver disease and elevated serum ferritin is often challenging because hyperferritinemia does not always indicate iron overload. A reliable approach to estimate iron overload without exposing the patient to unnecessary investigations would help the clinician to identify patients who may take advantage of iron-removal therapy. METHODS: We analyzed all liver biopsies, including measurement of hepatic iron concentration, performed at the University Hospital Zurich from 1997 to 2010 to identify clinical and laboratory predictors of iron overload in patients with elevated serum ferritin (n = 147). RESULTS: Hyperferritinemia was predictive of iron overload only in patients with a high level of serum ferritin (>2000 µg/L). In patients with moderate hyperferritinemia, liver transaminases inversely correlated with hepatic iron concentration. A combination of both parameters expressed as ferritin/aspartate transaminase ratio was highly predictive of tissue iron overload (sensitivity 83.3%, specificity 78.6%). Receiver operating characteristic analysis resulted in an area under the curve of 0.83. CONCLUSIONS: We established a simple and reliable method to correctly estimate iron overload in patients with suspected liver disease and elevated serum ferritin.

Toll-like receptor 4 gene polymorphism modulates phenotypic expression in patients with hereditary hemochromatosis.

BACKGROUND: Clinical penetrance of hereditary hemochromatosis is highly variable. We hypothesized that it might be modified by factors involved in the cellular immune response, such as toll-like receptors (TLRs) or nucleotide oligomerization domain proteins (NODs). METHODS: Clinical expression of hemochromatosis was assessed as a function of TLR4, TLR9, and NOD2 polymorphisms in 99 homozygous carriers of the HFE C282Y mutation with mild-to-severe iron overload. RESULTS: Thirteen (13%) of the 99 hemochromatosis patients were heterozygous for a TLR4 Asp299Gly polymorphism and 86 (87%) were TLR4 wild-type-only carriers. Clinical expression of hemochromatosis was observed more frequently in carriers of the TLR4 polymorphism (100%) than in TLR4 wild-type carriers (56%, P = 0.002). This was based on higher prevalences of liver disease (92 vs. 45%, P = 0.002) and arthropathy of metacarpophalangeal joints (69 vs. 35%, P = 0.018) in TLR4 polymorphism carriers. The finding was strengthened by the strong association of TLR4 polymorphism with liver fibrosis in the subgroup of 52 patients who underwent a liver biopsy (P = 0.011). The TLR4 polymorphism did, however, not correlate with body iron overload. The study results remained significant in multiple regression analyses after excluding possible confounding effects, such as age, sex, alcohol, or meat intake, and in the subgroup of 84 patients presenting as the first members of their families. CONCLUSION: TLR4 Asp299Gly polymorphism modulates clinical expression in patients with hereditary hemochromatosis. The polymorphism does not correlate with iron overload suggesting that TLR4 plays a role in an inflammatory process arising from toxic effects of iron accumulation.

Growth hormone (GH) receptor isoform in acromegaly: lower concentrations of GH but not insulin-like growth factor-1 in patients with a genomic deletion of exon 3 in the GH receptor gene.

BACKGROUND: A genomic deletion of exon 3 (d3-GHR) of the growth hormone (GH) receptor (GHR) has been linked to the effectiveness of GH therapy in children with GH deficiency. Carriers of the d3-GHR genotype had higher GH-induced growth rates than children homozygous for the full-length (fl)-GHR. The aim of this study was to test whether the relationship between GH and insulin-like growth factor-1 (IGF-1) concentrations is influenced by the GHR genotype in patients with acromegaly. METHODS: Study participants were 44 adult patients with established diagnosis of acromegaly. The genotype of the GHR was determined in leukocyte DNA from peripheral blood. Clinical and biochemical findings at the time of diagnosis of acromegaly were obtained from the medical records of the patients. RESULTS: fl-GHR homozygosity was found in 22 (50%) of patients, and 22 (50%) of patients had at least 1 d3 allele (d3-GHR). Demographic and clinical characteristics (age, height, weight, estimated duration of disease, and mean tumor size) of the 2 groups were comparable. Median (range) serum IGF-1 concentrations at the time of diagnosis were 670 (447-1443) microg/L in the fl-GHR group and 840 (342-1494) microg/L in the d3-GHR group (P = not significant). Basal GH concentrations were higher in the fl-GHR group [29.7 (3.8-159) microg/L] than in the d3-GHR group [8.4 (2.6-74 microg/L), P = 0.002], and so were mean (30.4 vs 6.1 microg/L, P = 0.005) and nadir (20.5 vs 5.1 microg/L, P = 0.003) GH concentrations during an oral glucose tolerance test. CONCLUSIONS: The GHR fl/d3 genotype modulates the relationship between GH and IGF-1 concentrations in patients presenting with acromegaly.

Tumor necrosis factor-alpha -308G>A allelic variant modulates iron accumulation in patients with hereditary hemochromatosis.

BACKGROUND: In vitro and animal studies suggest that tumor necrosis factor alpha (TNF-alpha) modulates intestinal iron transport. We hypothesized that the effect of TNF-alpha might be particularly relevant if iron absorption is not effectively controlled by the HFE gene. METHODS: In patients with homozygous C282Y hemochromatosis, we investigated the influence of TNF-alpha -308G>A allelic variant on total body iron overload, determined in all patients by measuring iron removed during depletion therapy, and hepatic iron index and need for phlebotomy to prevent iron reaccumulation, measured in patient subgroups. RESULTS: Of 86 patients with hereditary hemochromatosis, 16 (19%) were heterozygous carriers and 1 (1%) was a homozygous carrier of the TNF-alpha promoter -308A allele. Mean (SD) total body iron overload was increased 2-fold in TNF-alpha -308A allele carriers [10.9 (7.6) g] compared with homozygous carriers of the G allele [5.6 (5.0) g, P<0.001]. Hepatic iron index differed markedly between TNF-alpha -308A allele carriers [5.6 (3.5) micromol/g/year] and homozygous G allele carriers [3.1 (2.2) micromol/g/year, P=0.040, n=30]. After iron depletion, the need for phlebotomy to prevent iron reaccumulation (maintenance therapy) was substantially higher in TNF-alpha -308A allele carriers than in homozygous G allele carriers (P=0.014, n=73). We used multiple regression analyses to exclude possible confounding effects of sex, age, family screening, body-mass index, and meat or alcohol intake. CONCLUSION: TNF-alpha -308G>A allelic variant modulates iron accumulation in patients with hereditary (homozygous C282Y) hemochromatosis, but the effect of the TNF-alpha -308A allele on clinical manifestations of hemochromatosis was less accentuated than expected from the increased iron load associated with this allele.

Hereditary hemochromatosis is reflected in the iron isotope composition of blood.

It has recently been shown that the iron isotopic composition of blood differs between individuals and sexes, which is supposed to reflect individual differences in iron metabolism. We hypothesized that patients suffering from hereditary hemochromatosis would demonstrate alterations in the iron isotopic composition of blood due to persistent up-regulation of intestinal iron absorption. Blood from 30 patients with homozygous C282Y hemochromatosis was analyzed for iron isotopic composition by a newly developed technique using multicollector inductively coupled plasma mass spectrometry (MC-ICP-MS). Blood of patients with hemochromatosis is characterized by a higher 56Fe/54Fe isotope ratio than blood of healthy individuals, which are either members of an age-matched control group (n = 10; P < .001) or young adults (n = 36; P < .001). In patients with hereditary hemochromatosis, the 56Fe/54Fe isotope ratio of blood significantly correlates with total-body iron accumulation, severity of clinical disease, and the need for regular phlebotomies to prevent iron reaccumulation. We conclude that blood of patients with hereditary hemochromatosis contains more of the heavier iron isotopes than blood of healthy individuals. The primary determinant of the iron isotopic composition of blood appears to be isotope-sensitive iron absorption in the intestine and the efficiency of this process.