Model of reticuloendothelial iron metabolism in humans: abnormal behavior in idiopathic hemochromatosis and in inflammation

Abstract Iron transport in the reticuloendothelial (RE) system plays a central role in iron metabolism, but its regulation has not been characterized physiologically in vivo in humans. In particular, why serum iron is elevated and RE cells are much less iron-loaded than parenchymal cells in idiopathic hemochromatosis is not known. The processing of erythrocyte iron by the RE system was studied after intravenous (IV) injection of 59Fe heat-damaged RBCs (HDRBCs) and 55Fe transferrin in normal subjects and in patients with iron deficiency, idiopathic hemochromatosis, inflammation, marrow aplasia, or hyperplastic erythropoiesis. Early release of 59Fe by the RE system was calculated from the plasma iron turnover and the 59Fe plasma reappearance curve. Late release was calculated from the ratio of 59Fe/55Fe RBC utilization in 2 weeks. The partitioning of iron between the early (release from heme catabolism) and late (release from RE stores) phases depended on the size of RE iron stores, as illustrated by the inverse relationship observed between early release and plasma ferritin (P less than .001). There was a strong correlation between early release and the rate of change of serum iron levels during the first three hours in normal subjects (r = .85, P less than .001). Inflammation produced a blockade of the early release phase, whereas in idiopathic hemochromatosis early release was considerably increased as compared with subjects with similar iron stores. Based on these results, we describe a model of RE iron metabolism in humans. We conclude that the RE system appears to determine the diurnal fluctuations in serum iron levels through variations in the immediate output of heme iron. In idiopathic hemochromatosis, a defect of the RE cell in withholding iron freed from hemoglobin could be responsible for the high serum iron levels and low RE iron stores.

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Model of reticuloendothelial iron metabolism in humans: abnormal behavior in idiopathic hemochromatosis and in inflammation

Blood ◽

10.1182/blood.v74.2.844.bloodjournal742844 ◽

1989 ◽

Vol 74 (2) ◽

pp. 844-851 ◽

Cited By ~ 1

Author(s):

G Fillet ◽

Y Beguin ◽

L Baldelli

Keyword(s):

Iron Metabolism ◽

Serum Iron ◽

Normal Subjects ◽

Heme Iron ◽

Rate Of Change ◽

Abnormal Behavior ◽

Early Release ◽

Iron Stores ◽

Idiopathic Hemochromatosis

Iron transport in the reticuloendothelial (RE) system plays a central role in iron metabolism, but its regulation has not been characterized physiologically in vivo in humans. In particular, why serum iron is elevated and RE cells are much less iron-loaded than parenchymal cells in idiopathic hemochromatosis is not known. The processing of erythrocyte iron by the RE system was studied after intravenous (IV) injection of 59Fe heat-damaged RBCs (HDRBCs) and 55Fe transferrin in normal subjects and in patients with iron deficiency, idiopathic hemochromatosis, inflammation, marrow aplasia, or hyperplastic erythropoiesis. Early release of 59Fe by the RE system was calculated from the plasma iron turnover and the 59Fe plasma reappearance curve. Late release was calculated from the ratio of 59Fe/55Fe RBC utilization in 2 weeks. The partitioning of iron between the early (release from heme catabolism) and late (release from RE stores) phases depended on the size of RE iron stores, as illustrated by the inverse relationship observed between early release and plasma ferritin (P less than .001). There was a strong correlation between early release and the rate of change of serum iron levels during the first three hours in normal subjects (r = .85, P less than .001). Inflammation produced a blockade of the early release phase, whereas in idiopathic hemochromatosis early release was considerably increased as compared with subjects with similar iron stores. Based on these results, we describe a model of RE iron metabolism in humans. We conclude that the RE system appears to determine the diurnal fluctuations in serum iron levels through variations in the immediate output of heme iron. In idiopathic hemochromatosis, a defect of the RE cell in withholding iron freed from hemoglobin could be responsible for the high serum iron levels and low RE iron stores.

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Influence of Salicylate Administration on Iron Metabolism

Blood ◽

10.1182/blood.v19.5.601.601 ◽

1962 ◽

Vol 19 (5) ◽

pp. 601-611 ◽

Cited By ~ 5

Author(s):

G. IZAK ◽

K. GALEWSKY-STEIN ◽

J. MENCZEL ◽

J. J. GROEN

Keyword(s):

Blood Loss ◽

Gastrointestinal Bleeding ◽

Acetylsalicylic Acid ◽

Survival Time ◽

Iron Metabolism ◽

Serum Iron ◽

Normal Subjects ◽

Red Cells ◽

Unknown Mechanism ◽

Chemical Interference

Abstract In nine patients with various diseases and in two normal subjects, administration of acetylsalicylic acid (aspirin) in amounts of 3-4 Gm. per day produced a drop in serum iron. This drop could not be explained by chemical interference with the determination, by blood loss, impaired absorption or increased excretion of iron. In addition, it was shown that during administration of salicylates the survival time of the red cells was diminished. It is suggested that salicylates might produce anemia not only by gastrointestinal bleeding but also by interference with the metabolism of iron through some unknown mechanism.

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Food iron absorption in idiopathic hemochromatosis

Blood ◽

10.1182/blood.v74.6.2187.2187 ◽

1989 ◽

Vol 74 (6) ◽

pp. 2187-2193 ◽

Cited By ~ 3

Author(s):

SR Lynch ◽

BS Skikne ◽

JD Cook

Keyword(s):

Serum Ferritin ◽

Iron Absorption ◽

Iron Status ◽

Normal Subjects ◽

Heme Iron ◽

Nonheme Iron ◽

Ferritin Concentration ◽

Normal Volunteers ◽

Idiopathic Hemochromatosis ◽

The Relationship

Abstract The relationship between iron status and food iron absorption was evaluated in 75 normal volunteers, 15 patients with idiopathic hemochromatosis, and 22 heterozygotes by using double extrinsic radioiron tags to label independently the nonheme and heme iron components of a hamburger meal. In normal subjects, absorption from each of these pools was inversely correlated with storage iron, as measured by the serum ferritin concentration. In patients with hemochromatosis, absorption of both forms of iron was far greater than would be predicted from the relationship between absorption and serum ferritin observed in normal volunteers. Nevertheless, there was still a modest but statistically significant reduction in absorption of nonheme iron with increasing serum ferritin. This relationship could not be demonstrated in the case of heme iron absorption. In heterozygotes, nonheme iron absorption from a hamburger meal containing no supplementary iron did not differ significantly from that observed in normal volunteers. However, when this meal was both modified to promote bioavailability and supplemented with iron, absorption of nonheme iron was significantly elevated. These studies confirm the presence of excessive nonheme iron absorption even from unfortified meals in patients with idiopathic hemochromatosis and suggest in addition that they are particularly susceptible to iron loading from diets containing a high proportion of heme iron. Impaired regulation of nonheme iron absorption was also observed in heterozygous individuals, but a statistically significant abnormality was demonstrable only when the test meal contained a large highly bioavailable iron supplement.

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Effects of Pregnancy and Lactation on Iron Metabolism in Rats

BioMed Research International ◽

10.1155/2015/105325 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Guofen Gao ◽

Shang-Yuan Liu ◽

Hui-Jie Wang ◽

Tian-Wei Zhang ◽

Peng Yu ◽

...

Keyword(s):

Iron Deficiency ◽

Iron Metabolism ◽

Serum Iron ◽

Late Pregnancy ◽

Deficiency Anemia ◽

Iron Level ◽

Lactation Period ◽

Divalent Metal Transporter 1 ◽

Iron Stores ◽

Pregnancy And Lactation

In female, inadequate iron supply is a highly prevalent problem that often leads to iron-deficiency anemia. This study aimed to understand the effects of pregnancy and lactation on iron metabolism. Rats with different days of gestation and lactation were used to determine the variations in iron stores and serum iron level and the changes in expression of iron metabolism-related proteins, including ferritin, ferroportin 1 (FPN1), ceruloplasmin (Cp), divalent metal transporter 1 (DMT1), transferrin receptor 1 (TfR1), and the major iron-regulatory molecule—hepcidin. We found that iron stores decline dramatically at late-pregnancy period, and the low iron store status persists throughout the lactation period. The significantly increased FPN1 level in small intestine facilitates digestive iron absorption, which maintains the serum iron concentration at a near-normal level to meet the increase of iron requirements. Moreover, a significant decrease of hepcidin expression is observed during late-pregnancy and early-lactation stages, suggesting the important regulatory role that hepcidin plays in iron metabolism during pregnancy and lactation. These results are fundamental to the understanding of iron homeostasis during pregnancy and lactation and may provide experimental bases for future studies to identify key molecules expressed during these special periods that regulate the expression of hepcidin, to eventually improve the iron-deficiency status.

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Food iron absorption in idiopathic hemochromatosis

Blood ◽

10.1182/blood.v74.6.2187.bloodjournal7462187 ◽

1989 ◽

Vol 74 (6) ◽

pp. 2187-2193 ◽

Cited By ~ 105

Author(s):

SR Lynch ◽

BS Skikne ◽

JD Cook

Keyword(s):

Serum Ferritin ◽

Iron Absorption ◽

Iron Status ◽

Normal Subjects ◽

Heme Iron ◽

Nonheme Iron ◽

Ferritin Concentration ◽

Normal Volunteers ◽

Idiopathic Hemochromatosis ◽

The Relationship

The relationship between iron status and food iron absorption was evaluated in 75 normal volunteers, 15 patients with idiopathic hemochromatosis, and 22 heterozygotes by using double extrinsic radioiron tags to label independently the nonheme and heme iron components of a hamburger meal. In normal subjects, absorption from each of these pools was inversely correlated with storage iron, as measured by the serum ferritin concentration. In patients with hemochromatosis, absorption of both forms of iron was far greater than would be predicted from the relationship between absorption and serum ferritin observed in normal volunteers. Nevertheless, there was still a modest but statistically significant reduction in absorption of nonheme iron with increasing serum ferritin. This relationship could not be demonstrated in the case of heme iron absorption. In heterozygotes, nonheme iron absorption from a hamburger meal containing no supplementary iron did not differ significantly from that observed in normal volunteers. However, when this meal was both modified to promote bioavailability and supplemented with iron, absorption of nonheme iron was significantly elevated. These studies confirm the presence of excessive nonheme iron absorption even from unfortified meals in patients with idiopathic hemochromatosis and suggest in addition that they are particularly susceptible to iron loading from diets containing a high proportion of heme iron. Impaired regulation of nonheme iron absorption was also observed in heterozygous individuals, but a statistically significant abnormality was demonstrable only when the test meal contained a large highly bioavailable iron supplement.

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Evaluation of 99mTc-Label led Vitamin K4 as an Agent for Testicular Imaging

Nuklearmedizin ◽

10.1055/s-0038-1629552 ◽

1991 ◽

Vol 30 (01) ◽

pp. 35-39 ◽

Cited By ~ 1

Author(s):

H. S. Durak ◽

M. Kitapgi ◽

B. E. Caner ◽

R. Senekowitsch ◽

M. T. Ercan

Keyword(s):

Soft Tissue ◽

Room Temperature ◽

Normal Subjects ◽

Left Testis ◽

Wide Range ◽

Activity Ratios ◽

The Right ◽

Radioactivity Levels

Vitamin K4 was labelled with 99mTc with an efficiency higher than 97%. The compound was stable up to 24 h at room temperature, and its biodistribution in NMRI mice indicated its in vivo stability. Blood radioactivity levels were high over a wide range. 10% of the injected activity remained in blood after 24 h. Excretion was mostly via kidneys. Only the liver and kidneys concentrated appreciable amounts of radioactivity. Testis/soft tissue ratios were 1.4 and 1.57 at 6 and 24 h, respectively. Testis/blood ratios were lower than 1. In vitro studies with mouse blood indicated that 33.9 ±9.6% of the radioactivity was associated with RBCs; it was washed out almost completely with saline. Protein binding was 28.7 ±6.3% as determined by TCA precipitation. Blood clearance of 99mTc-l<4 in normal subjects showed a slow decrease of radioactivity, reaching a plateau after 16 h at 20% of the injected activity. In scintigraphic images in men the testes could be well visualized. The right/left testis ratio was 1.08 ±0.13. Testis/soft tissue and testis/blood activity ratios were highest at 3 h. These ratios were higher than those obtained with pertechnetate at 20 min post injection.99mTc-l<4 appears to be a promising radiopharmaceutical for the scintigraphic visualization of testes.

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Evidence for an Increased Generation of Prostacyclin in the Microvasculature and an Impairment of the Platelet α-Granule Release in Chronic Renal Failure

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647030 ◽

1988 ◽

Vol 60 (02) ◽

pp. 205-208 ◽

Cited By ~ 21

Author(s):

Paul A Kyrle ◽

Felix Stockenhuber ◽

Brigitte Brenner ◽

Heinz Gössinger ◽

Christian Korninger ◽

...

Keyword(s):

Renal Failure ◽

Chronic Renal Failure ◽

Blood Clotting ◽

Normal Subjects ◽

Chronic Uraemia ◽

Wall Interaction ◽

End Stage ◽

Granule Release

SummaryThe formation of prostacyclin (PGI2) and thromboxane A2 and the release of beta-thromboglobulin (beta-TG) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the micro vasculature made to determine bleeding time, was studied in patients with end-stage chronic renal failure undergoing regular haemodialysis and in normal subjects. In the uraemic patients, levels of 6-keto-prostaglandin F1α (6-keto-PGF1α) were 1.3-fold to 6.3-fold higher than the corresponding values in the control subjects indicating an increased PGI2 formation in chronic uraemia. Formation of thromboxane B2 (TxB2) at the site of plug formation in vivo and during whole blood clotting in vitro was similar in the uraemic subjects and in the normals excluding a major defect in platelet prostaglandin metabolism in chronic renal failure. Significantly smaller amounts of beta-TG were found in blood obtained from the site of vascular injury as well as after in vitro blood clotting in patients with chronic renal failure indicating an impairment of the a-granule release in chronic uraemia. We therefore conclude that the haemorrhagic diathesis commonly seen in patients with chronic renal failure is - at least partially - due to an acquired defect of the platelet a-granule release and an increased generation of PGI2 in the micro vasculature.

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ÉTUDES IN VIVO SUR LE MÉTABOLISME DES ANDROGÉNES APRES ADMINISTRATION DE STÉROÏDES INHIBITEURS DE L'OVULATION

Acta Endocrinologica ◽

10.1530/acta.0.0500131 ◽

1965 ◽

Vol 50 (1) ◽

pp. 131-144 ◽

Cited By ~ 1

Author(s):

P. Mauvais-Jarvis ◽

M. F. Jayle ◽

J. Decourt ◽

J. Louchart ◽

J. Truffert

Keyword(s):

Luteinizing Hormone ◽

Urinary Excretion ◽

Normal Subjects ◽

Hormone Activity ◽

Testosterone Production ◽

Normal Men ◽

Ethinyl Oestradiol

ABSTRACT Normal subjects and hirsute women with micropolycystic ovaries were treated with ethinyl-oestrenol + 3-methoxy-ethinyl-oestradiol (Lyndiol®), in view of studying the action of this compound on the production of androgens and on the urinary excretion of their metabolites. In normal men, the production of testosterone and the excretion of androsterone and aetiocholanolone are suppressed, whereas the excretion of other 17-ketosteroids and the production of dehydroepiandrosterone sulphate are unchanged. Moreover, the luteinizing hormone activity (LH) in plasma is depressed. It seems that the preparation inhibits specifically the testicular androgen production, by suppressing the hypothalamo-hypophyseal control of LH. Testosterone production and urinary 17-ketosteroid excretion are modified in the same way in women with Stein-Leventhal's syndrome. Physiopathological and therapeutical implications which come from these results are discussed.

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Insulin Resistance and In Vivo Lipolytic Rate Are Positively Associated with Body Iron Stores in Obese Women

Diabetes ◽

10.2337/db18-2048-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 2048-P

Author(s):

BENJAMIN J. RYAN ◽

DOUGLAS W. VAN PELT ◽

LISA M. GUTH ◽

ALISON LUDZKI ◽

RACHEL A. GIOSCIA-RYAN ◽

...

Keyword(s):

Insulin Resistance ◽

Obese Women ◽

Body Iron ◽

Iron Stores

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Efficacy and safety of drospirenone-containing microdosage combined oral contraceptive use with starting contraception

GYNECOLOGY ◽

10.26442/2079-5696_2018.2.9-13 ◽

2018 ◽

Vol 20 (2) ◽

pp. 9-13

Author(s):

A R Khachaturian ◽

E V Misharina ◽

M I Yarmolinskaya

Keyword(s):

Blood Pressure ◽

Body Weight ◽

Oral Contraceptive ◽

Waist Circumference ◽

Young Women ◽

Iron Metabolism ◽

Serum Iron ◽

The Body ◽

Menstrual Bleeding ◽

Combined Oral Contraceptive

Androgen-dependent dermopathy, as well as premenstrual syndrome of varying severity in young women, can cause emotional depression, difficulties in social adaptation and even depressive disorders. The aim of the study was to study the safety and efficacy of using a combined oral contraceptive (COC) Dimia® containing 20 μg ethinyl estradiol and 3 mg drospirenone in young women, as well as its therapeutic effects in androgen-dependent dermopathy. Materials and methods. The study included 57 young women aged 23.1±2.2 years with signs of androgen-dependent dermopathy. The evaluation of the change in the character of menstrual bleeding, the anthropometric parameters (body weight, waist circumference and hips), the therapeutic effect of the drug on the symptoms of androgen-dependent dermopathy, as well as the dynamics of arterial pressure, hemoglobin level, serum iron have been studied. The psycho-emotional state was assessed using the SAN questionnaire (well-being-activity-mood). Results. During 6 months of observation, there was no significant change in the body mass index, waist circumference, and hips, and the drug did not affect the blood pressure numbers. Against the background of taking the drug, there was an increase in the parameters of iron metabolism (hemoglobin content, serum iron). After 3 months of taking the contraceptive with drospirenone, the number of patients with a complaint about the abundance of menstruation decreased more than twofold (from 22.8 to 10.5%), and after 6 months of taking the drug no patient noted the profuse nature of menstruation. Before the start of taking COC with drospirenone, 57.9% of women reported painful menstrual bleeding. Against the background of taking the contraceptive within 3 months, this complaint was stopped in all patients. Sufficient efficacy of treatment of androgen dependent dermopathy in young women with the help of a microdosed drospirenone-containing combined oral contraceptive is estimated from the dermatological acne index. The analysis of the SAN questionnaire made it possible to reveal the improvement in the psychoemotional state of patients on the background of taking the drug. The conclusion. The results obtained proved the effectiveness and safety of the microclinized COC Dimia®. The drug has no significant effect on body weight, blood pressure, provides reliable control of the cycle and a decrease in menstrual bleeding, which results in stabilization of iron metabolism in the body. Dimia® is effective in the treatment of androgen-dependent dermopathy and can be recommended to young women for starting contraception.

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