Repurposing ICG enables MR/PA imaging signal amplification and iron depletion for iron-overload disorders

AbstractNormoferritinemic women with functional hyperandrogenism show a mild iron overload. Iron excess, hyperandrogenism, and cardioautonomic dysfunction contribute to blood pressure (BP) abnormalities in these patients. Furthermore, combined oral contraceptives (COC) prescribed for hyperandrogenic symptoms may worse BP recordings. Iron depletion by phlebotomy appears to lower BP in other acquired iron overload conditions. We aimed to determine the effect of iron depletion on the office BP, ambulatory BP monitoring, and frequency of hypertension in patients with functional hyperandrogenism submitted to standard therapy with COC. We conducted a phase 2 randomized, controlled, parallel, open-label clinical trial (NCT02460445) in adult women with functional hyperandrogenism including hyperandrogenic polycystic ovary syndrome and idiopathic hyperandrogenism. After a 3-month run-in period of treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to three scheduled bloodlettings or observation for another 9 months. Main outcome measures were the changes in office BP, 24-h-ambulatory BP, and frequency of hypertension in both study arms. From June 2015 to June 2019, 33 women were included in the intention-to-treat analyses. We observed an increase in mean office systolic BP [mean of the differences (MD): 2.5 (0.3–4.8) mmHg] and night-time ambulatory systolic BP [MD 4.1 (1.4–6.8) mmHg] after 3 months on COC. The percentage of nocturnal BP non-dippers also increased, from 28.1 to 92.3% (P < 0.001). Office and ambulatory BP did not change throughout the experimental period of the trial, both when considering all women as a whole or as a function of the study arm. The frequency of the non-dipping pattern in BP decreased during the experimental period [OR 0.694 (0.577–0.835), P < 0.001], regardless of the study arm. Decreasing iron stores by scheduled bloodletting does not override the BP abnormalities caused by COC in women with functional hyperandrogenism.

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Iron Depletion: An Ameliorating Factor for Sickle Cell Disease?

ISRN Hematology ◽

10.5402/2011/473152 ◽

2011 ◽

Vol 2011 ◽

pp. 1-4 ◽

Cited By ~ 5

Author(s):

P. C. Giordano ◽

W. Huisman ◽

C. L. Harteveld

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Beneficial Effect ◽

Sickle Cell ◽

Chelation Therapy ◽

Cell Disease ◽

Laboratory Practice ◽

Iron Depletion ◽

Severity Of The Disease

We report some observations from our laboratory practice that might be important for the treatment of sickle cell disease (SCD). We describe data from two cases indicating that iron depletion might have a beneficial effect diminishing the formation of HbS in favor of HbF, possibly reducing the severity of the disease. We believe that it would be worthwhile to monitor the course of the disease comparing cases with identical genotypes with and without iron depletion, and we advise to consider chelation therapy to reduce iron overload in patients with SCD.

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Phlebotomy as an Effective Treatment for Iron Overload after Allogeneic Hematopoietic Cell Transplantation: Iron Depletion Kinetics Are Influenced by the Donor Hemochromatosis (HFE) Genotype.

Blood ◽

10.1182/blood.v106.11.3717.3717 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3717-3717

Author(s):

Ann-Kathrin Eisfeld ◽

Medical Student ◽

Ralph Burkhardt ◽

Sabine Schroeder ◽

Rainer Krahl ◽

...

Keyword(s):

Liver Function ◽

Iron Overload ◽

Cell Transplantation ◽

Serum Ferritin ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Hfe Gene ◽

Blood Transfusions ◽

Iron Depletion ◽

Iron Stores

Abstract Introduction: Iron metabolism plays an important role in hematopoiesis and immune response. In the present project, body iron stores and factors affecting iron storage such as HFE genotype and the number of blood transfusions were evaluated in patients after allogeneic hematopoietic cell transplantation (HCT). In patients with iron overload, the effect of phlebotomy (PT) on iron stores was analysed in correlation to HFE mutations. Patients and methods: Serum ferritin was measured in 201 consecutive patients transplanted from January 2001 to December 2004 at the University of Leipzig. After excluding patients with normal body iron (serum ferritin levels between 30–400 ng/ml) and patients surviving less than 4 months after HCT, 61 patients (31 males/30 females; median age 48 y) treated with PT were evaluated. Diagnoses included acute leukemias (n=29; 48%), chronic leukemias (n=15; 24%), MDS (n=8; 13%) and others (n=9; 15%). 33 patients (54%) were conditioned with Cyclophosphamid 120 mg/kg and 12 Gy TBI. Patients with unrelated donors received ATG 15 mg/kg/day for 3 days. The remaining patients (n=28; 46%) were treated with Fludarabin 30 mg/m2/day for 3 days and TBI 2 Gy applied once. Donors were matched related in 21 (34%) and matched unrelated in 40 (66%) patients. HFE genotype of patients and donors were analysed by real time PCR using a LightCycler, Roche. The effectiveness of PT was assessed by serum ferritin and liver function test evaluation. Results: The majority of patients after HCT (n=172; 86%) had iron overload with a median ferritin of 1697 ng/ml. From these, 61 patients received PT. These patients received a median of 28 (range 2–102) units of blood transfusions. Acute GvHD ≥ grade II was present in 25 (41%) and chronic GvHD in 19 (31%) patients. Elevated SGPT/SGOT and AP were detected in 34 (56%) and 39 (64%) patients respectively. Mutations in the HFE gene were found in 14 (25%) prior to HCT: heterozygosity (het) for H63D (n=10), for C282Y (n=3) and homozygosity for H63D (n=1). Similarly, 22 donors (40%) showed het. for H63D (n=12), for C282Y (n=4) and for S65C (n=4). Two donors were homozygous for S65C. After HCT, all pts expressed donor HFE genotype. PT was performed every 2 weeks with a median of 200 ml blood removed in one session. Interestingly, median Hemoglobin (Hb) rose under PT (p<0.0001). PT resulted in a significant depletion of iron stores (p<0.0001), improvement in SGPT/SGOT (p=0.002), bilirubin (p<0.0001), and AP (p=0.01). In multivariate analysis, a slower rate of iron depletion significantly correlated with mutated donor HFE genotype (p=0.002). In such patients less iron/ml blood were removed per PT and more often PT were required compared to patients with wildtype HFE donors. Conclusions: Iron overload is a frequent complication after HCT. PT is highly effective in removing excess iron and improving Hb and liver function associated with iron overload after HCT. Patients transplanted from a donor with a mutant HFE gene showed slower iron depletion kinetics by PT compared to patients transplanted from donors with wildtype HFE. The role of donor HFE genotype is currently being analysed in patients after HCT.

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Iron Overload in Functional Hyperandrogenism: In a Randomized Trial, Bloodletting Does Not Improve Metabolic Outcomes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa978 ◽

2021 ◽

Author(s):

Andrés E Ortiz-Flores ◽

María Ángeles Martínez-García ◽

Lía Nattero-Chávez ◽

Francisco Álvarez-Blasco ◽

Elena Fernández-Durán ◽

...

Keyword(s):

Insulin Sensitivity ◽

Iron Overload ◽

Polycystic Ovary ◽

Sensitivity Index ◽

Adult Women ◽

Open Label ◽

Iron Depletion ◽

Intention To Treat ◽

Plasma Hemoglobin ◽

Functional Hyperandrogenism

Abstract Context Functional hyperandrogenism may be associated with a mild increase in body iron stores. Iron depletion exerts a beneficial effect on metabolic endpoints in other iron overload states. Objectives (i) To determine the effect of iron depletion on the insulin sensitivity and frequency of abnormal glucose tolerance in patients with functional hyperandrogenism submitted to standard therapy with combined oral contraceptives (COC). ii) To assess the overall safety of this intervention. Design Randomized, parallel, open-label, clinical trial. Setting Academic hospital. Patients Adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. Intervention After a 3-month run-in period of treatment with 35 μg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to 3 scheduled bloodlettings or observation for another 9 months. Main outcome measures Changes in insulin sensitivity index and frequency of prediabetes/diabetes, and percentage of women in whom bloodletting resulted in plasma hemoglobin <120 g/L and/or hematocrit <0.36. Results From 2015 to 2019, 33 women were included by intention-to-treat. During the follow-up, insulin sensitivity did not change in the whole group of women or between study arms [mean of the differences (MD): 0.0 (95%CI: −1.6 to 1.6)]. Women in the experimental arm showed a similar odds of having prediabetes/diabetes than women submitted to observation [odds ratio: 0.981 (95%CI: 0.712 to 1.351)]. After bloodletting, 4 (21.1%) and 2 women (10.5%) in the experimental arm had hemoglobin (Hb) levels <120 g/L and hematocrit (Hct) values <0.36, respectively, but none showed Hb <110 g/L or Hct <0.34. Conclusions Scheduled bloodletting does not improve insulin sensitivity in women with functional hyperandrogenism on COC.

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Iron Absorption in Chronic Renal Disease

Clinical Science ◽

10.1042/cs0380191 ◽

1970 ◽

Vol 38 (2) ◽

pp. 191-196 ◽

Cited By ~ 47

Author(s):

J. W. Eschbach ◽

J. D. Cook ◽

C. A. Finch

Keyword(s):

Renal Failure ◽

Chronic Renal Failure ◽

Renal Disease ◽

Iron Overload ◽

Iron Absorption ◽

Chronic Renal Disease ◽

Iron Depletion ◽

Isotope Technique ◽

Double Isotope

1. Absorption of inorganic iron was studied in thirty-four patients with chronic renal failure by a double isotope technique. 2. Eight patients with normal iron balance had a mean absorption of 3·5%, ten patients with iron overload had a mean absorption of 3·6%, and sixteen patients with iron depletion had a mean absorption of 58%. Thus, alterations in absorption appeared to be related to disturbances in iron balance. 3. The rate of erythropoiesis had no evident effect on iron absorption nor did the degree of anaemia. 4. The presence of renal disease and the degree of azotaemia likewise did not appear to affect absorption.

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An Inhibitor of Uroporphyrinogen Decarboxylase (URO-D) Causes Porphyria Cutanea Tarda (PCT).

Blood ◽

10.1182/blood.v108.11.270.270 ◽

2006 ◽

Vol 108 (11) ◽

pp. 270-270

Author(s):

James P. Kushner ◽

Michael R. Franklin ◽

Christopher P. Reilly ◽

Hector A. Bergonia ◽

John D. Phillips

Keyword(s):

Mass Spectrometry ◽

Iron Overload ◽

Inhibitory Activity ◽

Absorption Maximum ◽

Aminolevulinic Acid ◽

Solid Phase ◽

Porphyria Cutanea Tarda ◽

Western Blots ◽

Iron Depletion ◽

Iron Deficient

Abstract Hepatic iron content is increased in patients with PCT and phlebotomy-induced iron depletion corrects the clinical and biochemical phenotype. Approximately 20 percent of patients with PCT are homozygous for mutations of the hemochromatosis gene (HFE) but the cause of iron overload in most patients is unknown. Hepatic URO-D activity is markedly reduced when PCT is manifest and URO-D activity improves following iron depletion. Most patients with PCT have no mutations of the URO-D gene (sporadic PCT) but approximately 1/3 of cases are heterozygous for URO-D mutations (familial PCT) (BLOOD. 2000; 95:1565–71). To determine the mechanism by which iron overload causes PCT we created 3 murine models: Mice with one null allele of Uro-d (Uro-d+/−) and 2 null Hfe alleles (Hfe−/ −) (PNAS.2001; 98:259–64); Uro-d+/− mice treated with iron-dextran, aminolevulinic acid (ALA) and polychlorinated biphenyls (PCB) and; wild type mice treated with iron, ALA and PCB (J. Biochem. Mol. Toxicol.2001; 15:287–93). All models accumulate uroporphyrin in the liver and all have hepatic URO-D activity of 25% or less but Western blots revealed no change in URO-D protein. An iron deficient diet prevented the PCT phenotype in Uro-d+/−, Hfe−/ − animals and greatly attenuated the phenotype in animals treated with ALA and PCB (Env. Toxicol. Pharmacol.2005; 417–23). Liver homogenates from all porphyric models were heat denatured and clarified by centrifugation. The supernatants inhibited the activity of purified recombinant human URO-D (rhURO-D) by approximately 60%. The inhibitory activity was further purified by solid phase extraction and HPLC. The fraction containing the inhibitory activity did not fluoresce. Mass spectrometry of this fraction demonstrated a dominant peak with a mass of 835 Da and an absorption maximum of approximately 500 nM, the optical signature of a porphomethene. An inhibitor with identical properties was generated by partially oxidizing the uroporphyrinogen (837 Da) substrate of URO-D under UV light. Full oxidation of either the inhibitor purified from porphyric mouse liver or from partially oxidized, enzymatically generated uroporphyrinogen (either isomer I or III) yielded a compound with a mass of 831 Da and an absorption maximum of approximately 400 nM, indicating that the fully oxidized inhibitor was uroporphyrin. Tandem mass spectrometry of the 835 Da inhibitor indicated that the inhibitor was a tetrapyrrole. Collectively these data indicate that the inhibitor is a porphomethene derived form uroporphyrinogen through oxidation of a single bridge carbon between adjacent pyrrole rings. An inhibitor of rhURO-D was also identified in heat-denatured cytosol from liver biopsy samples obtained from four humans with PCT. We conclude that clinical expression of PCT requires an iron dependant oxidation reaction that generates a porphomethene inhibitor of URO-D.

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1129 IRON OVERLOAD INCREASES SYMPATHETIC NERVOUS ACTIVITY: STUDY IN HEMOCHROMATOSIS PATIENTS AT DIAGNOSIS AND IRON DEPLETION

Journal of Hepatology ◽

10.1016/s0168-8278(10)61130-0 ◽

2010 ◽

Vol 52 ◽

pp. S436

Author(s):

R. Mariani ◽

A. Piperno ◽

P. Trombini ◽

S. Coletti ◽

M. Pozzi ◽

...

Keyword(s):

Iron Overload ◽

Nervous Activity ◽

Sympathetic Nervous Activity ◽

Iron Depletion ◽

Sympathetic Nervous

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Iron Depletion Improves Glycemic Control in Poorly Controlled Type 2 Diabetic Patients with Iron Overload and Negative Main HFE-Gene Mutations

Journal of Diabetes Mellitus ◽

10.4236/jdm.2015.53020 ◽

2015 ◽

Vol 05 (03) ◽

pp. 164-172 ◽

Cited By ~ 1

Author(s):

Adel A. Mahmoud ◽

Adel A. Elazab Elged ◽

Rasha A. Elgamal ◽

Abdelhady M. Hamada

Keyword(s):

Glycemic Control ◽

Iron Overload ◽

Gene Mutations ◽

Hfe Gene ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Iron Depletion ◽

Hfe Gene Mutations ◽

Type 2 Diabetic

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Quantification by Superconducting Quantum Interference Device (SQUID) of Iron Overload after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).

Blood ◽

10.1182/blood.v112.11.2134.2134 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2134-2134

Author(s):

Alessandro Busca ◽

Michele Falda ◽

Paola Manzini ◽

Sergio D’antico ◽

Franco Locatelli ◽

...

Keyword(s):

Risk Factor ◽

Iron Overload ◽

Median Time ◽

Serum Ferritin ◽

Fungal Infections ◽

Ferritin Level ◽

Unrelated Donor ◽

Iron Depletion ◽

Hematopoietic Stem ◽

The Impact

Abstract Introduction. Iron overload (IO) is an adverse prognostic factor in patients who undergo allogeneic HSCT for thalassemia and appears to play a similar role in patients with other hematological disorders. Estimation of IO is primarily based on serum ferritin, however many confounding factors particularly in HSCT recipients may result in frequent ferritin overestimation. Aim of the study was to quantify IO by SQUID after HSCT and evaluate the impact on hepatic function and infections. Additionally, the feasibility of iron-depletion has been investigated. Methods. Between December 2005 and December 2007, 102 consecutive pts who were admitted at our outpatient department have been analyzed. Patients received HSCT from a matched sibling (n=66), a partially matched relative (n=4) or a matched unrelated donor (n=32). Primary diagnosis included acute leukemia/MDS in 61% of cases. Assessment of IO after HSCT included serum ferritin and in those with hyperferritinemia (> 1000 ng/ml), liver iron concentration (LIC) was evaluated by SQUID magnetic susceptometry. Iron removal therapy was offered to patients with moderate (LIC 1000–2000 microg/gww) or severe (LIC >2000 microg/gww) IO. Results. Patients who were in complete remission underwent ferritin assessment at a median time of 578 days from transplantation. Fifty-seven had a ferritin level below the threshold of 1000 ng/ml; in this cohort the median time from HSCT to ferritin assessment was 1006 days, significantly different from the median time of 183 days of the 45 patients who had a ferritin level > 1000 ng/ml. LIC evaluated by SQUID was available for 42/45 patients with elevated ferritin values. Overall, 29 patients had moderate to severe IO: median LIC values were 1493 microg/gww (range 1030–3253 microg/gww). Thirteen patients had normal LIC values (LIC<400 microg/gww) despite high serum ferritin levels. Multivariate analysis showed a significant correlation between ferritin levels > 1000 ng/ml and the occurrence of liver dysfunction defined by the presence of at least one abnormal liver function test (LFT) on two or more occasions (OR 6.8; 95%CI 2.2–20.6); the correlation hold the statistical significance even including into the multivariate model the different time of ferritin assessment. In addition, the rate of proven/probable invasive fungal disease was significantly higher among patients with hyperferritinemia as compared to patients with normal ferritin levels (13% vs 0%; p=.006). Nineteen of the 23 patients considered eligible to iron depletion, underwent regular phlebotomy: 9 patients completed the program after a median time of 10 months (range 3–13 months), reaching the target of ferritin < 500 ng/ml; for 6 patients the program is still ongoing, while 4 patients discontinued the phlebotomy protocol (relapse n=2; hypotension, n=1; progressive anemia, n=1). In 8/9 patients who were revaluated by SQUID at the end of iron depletion program there was a significant decrease of LIC (median 1368 microg/gww to 606 microg/gww; p=.005) that parallels changes of serum ferritin; one patient did not show e remarkable reduction of LIC despite serum ferritin normalization.. Three of the 4 patients ineligible to phlebotomy were successfully treated with deferasirox and 1 patient was treated with deferoxamine. Conclusion. The measurement of LIC obtained by SQUID documented the presence of moderate/severe IO in 69% of the patients with high ferritin levels. Our preliminary data showed that in HSCT recipients, high ferritin level is an independent risk factor for the occurrence of abnormal LFTs and IO may be considered a potential risk factor for fungal infections. A phlebotomy program resulted feasible in 65% of the patients who might benefit from a procedure of iron depletion

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