ascorbic-acid and Hemochromatosis

Ascorbate is a cofactor in numerous metabolic reactions. Humans cannot synthesize ascorbate owing to inactivation of the gene encoding the enzyme l-gulono-γ-lactone oxidase, which is essential for ascorbate synthesis. Accumulating evidence strongly suggests that in addition to the known ability of dietary ascorbate to enhance nonheme iron absorption in the gut, ascorbate within mammalian systems can regulate cellular iron uptake and metabolism. Ascorbate modulates iron metabolism by stimulating ferritin synthesis, inhibiting lysosomal ferritin degradation, and decreasing cellular iron efflux. Furthermore, ascorbate cycling across the plasma membrane is responsible for ascorbate-stimulated iron uptake from low-molecular-weight iron-citrate complexes, which are prominent in the plasma of individuals with iron-overload disorders. Importantly, this iron-uptake pathway is of particular relevance to astrocyte brain iron metabolism and tissue iron loading in disorders such as hereditary hemochromatosis and β-thalassemia. Recent evidence also indicates that ascorbate is a novel modulator of the classical transferrin-iron uptake pathway, which provides almost all iron for cellular demands and erythropoiesis under physiological conditions. Ascorbate acts to stimulate transferrin-dependent iron uptake by an intracellular reductive mechanism, strongly suggesting that it may act to stimulate iron mobilization from the endosome. The ability of ascorbate to regulate transferrin iron uptake could help explain the metabolic defect that contributes to ascorbate-deficiency-induced anemia.

Topics: Anemia; Animals; Ascorbic Acid; Astrocytes; Basic Helix-Loop-Helix Transcription Factors; beta-Thalassemia; Biological Transport; Erythropoiesis; Ferritins; Hemochromatosis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Iron; Transferrin

Routinely measuring iron status is necessary because not only are about 6% of Americans in significant negative iron balance, but about 1% have iron overload. Serum ferritin is in equilibrium with body iron stores, and is the only blood test that measures them. Barring inflammation, each one ng (0.0179 pmol) ferritin/ml of serum indicates approximately 10 mg (0.179 mmol) of body iron stores. Very early Stage I positive balance is best recognized by measuring saturation of iron binding capacity. Conversely, serum ferritin best recognizes early (Stage I and II) negative balance. Deviations from normal are: 1. Both stages of iron depletion (i.e. low stores, no dysfunction). Negative iron balance Stage I is reduced iron absorption producing moderately depleted iron stores. Stage II is severely depleted stores, without dysfunction. These stages include over half of all cases of negative iron balance. Treated with iron, they never progress to dysfunction, i.e. to disease. 2. Both stages of iron deficiency. Deficiency is inadequate iron for normal function, i.e. dysfunction, disease. Negative balance Stage III is dysfunction without anemia; Stage IV is with anemia. 3. Positive iron balance: Stage I is a multi-year period without dysfunction. Supplements of iron and/or vitamin C promote progression to dysfunction (disease). Iron removal prevents progression. Stage II is iron overload disease, encompassing years of insidiously progressive damage to tissues and organs from iron overload. Iron removal arrests progression.

Topics: Adolescent; Adult; Anemia, Hypochromic; Ascorbic Acid; Child; Child, Preschool; Cost-Benefit Analysis; Female; Ferritins; Folic Acid Deficiency; Gene Frequency; Genetic Predisposition to Disease; Hemochromatosis; HLA-A3 Antigen; Humans; Incidence; Infant; Inflammation; Iron; Iron Deficiencies; Male; Middle Aged; Pregnancy

Iron is essential for life, but iron overload is toxic and potentially fatal. The liver is a major site of iron storage and is particularly susceptible to injury from iron overload, especially when (as in primary hemochromatosis) the iron accumulates in hepatocytes. Iron can be taken up by the liver in several forms and by several pathways including: (1) receptor-mediated endocytosis of diferric or monoferric transferrin or ferritin, (2) reduction and carrier-facilitated internalization of iron from transferrin without internalization of the protein moiety of transferrin, (3) electrogenic uptake of low molecular weight, non-protein bound forms of iron, and (4) uptake of heme from heme-albumin, heme-hemopexin, or hemoglobin-haptoglobin complexes. Normally, pathway 2 is probably the major one for uptake of iron by hepatocytes. Iron is stored in the liver in the cores of ferritin shells and as hemosiderin, an insoluble product derived from iron-rich ferritin. Iron in hepatocytes stimulates translation of ferritin mRNA and represses transcription of DNA for transferrin and transferrin receptors. The major pathologic effects of chronic hepatic iron overload are: (1) fibrosis and cirrhosis, (2) porphyria cutanea tarda, and (3) hepatocellular carcinoma. Although precise pathogenetic mechanisms remain unknown, iron probably produces these and other toxic effects by increasing oxidative stress and lysosomal lability. Vigorous efforts at diagnosis and treatment of iron overload are essential since the pathologic effects of iron are totally preventable by early vigorous iron removal and prevention of iron re-accumulation.

Topics: Ascorbic Acid; Carcinoma, Hepatocellular; Collagen; Free Radicals; Hemochromatosis; Humans; Iron; Liver; Liver Cirrhosis; Liver Neoplasms; Lysosomes; Membrane Potentials; Porphyrias; Potassium; Transferrin; Uroporphyrins; Vitamin E

Because of the catalytic action of iron in one-electron redox reactions, it has a key role in the formation of harmful oxygen derivatives and production of peroxidative damage to vital cellular structures. The clinical manifestations of iron overload may be prevented and even reversed by the effective administration of the iron-chelating drug deferoxamine (DF). Recent experimental evidence suggests that DF may also be useful in modifying disease conditions unrelated to iron overload by preventing the formation of free radicals, the powerful final effectors of tissue damage resulting from the respiratory burst of granulocytes and macrophages participating in the inflammatory response. Although much experimental work is still needed, this novel approach in iron-chelating therapy may have far-reaching implications in the management of autoimmune disease, adult respiratory distress syndrome, and organ transplantation. The poor intestinal absorption of DF, its almost prohibitive price, and short duration of action underline the need for new, orally effective iron chelators. A number of very promising orally effective drugs have been identified in recent years, such as the polyanionic amines, aryl hydrazones, and hydroxypyridones. Further development for clinical use of this new generation of iron-chelating drugs is a major challenge for future research.

Topics: Animals; Ascorbic Acid; Deferoxamine; Hemochromatosis; Humans; Iron; Iron Chelating Agents

Topics: Adult; Animals; Ascorbic Acid; Deferoxamine; Ferritins; Guinea Pigs; Haplorhini; Hemochromatosis; Hemosiderin; Humans; Iron; Iron Chelating Agents; Liver; Male; Rats; Scurvy; Spleen; Thalassemia

Topics: Ascorbic Acid; Blood Transfusion; Chelating Agents; Deferoxamine; Diet; Gentisates; Hemochromatosis; Hemosiderosis; Hydroxamic Acids; Hydroxybenzoates; Iron; Piperazines; Syndrome

Topics: Absorption; Anemia, Hypochromic; Ascorbic Acid; Cysteine; Erythropoiesis; Ferritins; Gastric Juice; Hemochromatosis; Humans; Inositol; Intestinal Mucosa; Iron; Pancreatic Juice; Succinates; Transferrin

A relationship may exist between body iron stores, endothelial dysfunction and overall cardiovascular risk.. To compare vascular compliance, biochemical endothelial function and antioxidant status between patients with homozygous hereditary haemochromatosis and healthy controls.. Haemochromatosis patients and healthy controls were recruited. Measures of vascular compliance were assessed by applanation tonometry. Serological markers of endothelial function (plasma lipid hydroperoxides, cell adhesion molecules), antioxidant levels (ascorbate, lipid soluble antioxidants) and high-sensitivity C-reactive protein (CRP) were also measured.. Thirty-five hereditary haemochromatosis patients (ten females, mean age 54.6) and 36 controls (27 female, mean age 54.0) were recruited. Haemochromatosis patients had significantly higher systolic and diastolic blood pressures. Pulse wave velocity (PWV) was significantly higher in male haemochromatosis patients (9.90 vs. 8.65 m/s, p = 0.048). Following adjustment for age and blood pressure, male haemochromatosis patients continued to have a trend for higher PWVs (+1.37 m/s, p = 0.058). Haemochromatosis patients had significantly lower levels of ascorbate (46.11 vs. 72.68 μmol/L, p = 0.011), retinol (1.17 vs. 1.81 μmol/L, p = 0.001) and g-tocopherol (2.51 vs. 3.14 μmol/L, p = 0.011). However, there was no difference in lipid hydroperoxides (0.46 vs. 0.47 nmol/L, p = 0.94), cell adhesion molecule levels (ICAM: 348.12 vs. 308.03 ng/mL, p = 0.32 and VCAM: 472.78 vs. 461.31 ng/mL, p = 0.79) or high-sensitivity CRP (225.01 vs. 207.13 mg/L, p = 0.32).. Haemochromatosis is associated with higher PWVs in males and diminished antioxidants across the sexes but no evidence of endothelial dysfunction or increased lipid peroxidation.

Topics: Adult; Aged; Ascorbic Acid; Biomarkers; Blood Pressure; C-Reactive Protein; Case-Control Studies; Cell Adhesion Molecules; Compliance; Endothelium, Vascular; Female; gamma-Tocopherol; Hemochromatosis; Homozygote; Humans; Lipid Peroxides; Male; Middle Aged; Pulse Wave Analysis; Risk Factors; Sex Factors; Vitamin A

The view of scurvy being exclusively a nutritional disorder needs to be updated. Genetic polymorphisms of HFE and haptoglobin (Hp) may explain the geographic variability of mortality caused by the European famine of the mid-19th century. In this period, potatoes had fallen victim to the potato blight and Ireland was more severely hit than continental Europe. Hereditary hemochromatosis is a genetic disorder with mutations in the HFE gene, characterized by iron overload (with a reduced vitamin C stability) and with a predominance of affected men. The Irish have the world's highest frequency of the C282Y mutation and the particular iron metabolism of the Irish helps to understand the size of the catastrophe and the observed overrepresentation of male skeletons showing scurvy. Hp is a plasma α2-glycoprotein characterized by 3 common phenotypes (Hp 1-1, Hp 2-1 and Hp 2-2). When the antioxidant capacity of Hp is insufficient, its role is taken over by hemopexin and vitamin C. The relative number of scurvy victims corresponds with the Hp 2-2 frequency, which is associated with iron conservation and has an impact on vitamin C stability. As iron is more abundant in males, males are overrepresented in the group of skeletons showing scurvy signs.

Topics: Ascorbic Acid; Europe; Genotype; Haptoglobins; Hemochromatosis; Hemochromatosis Protein; Histocompatibility Antigens Class I; History, 19th Century; Humans; Iron; Iron Overload; Male; Membrane Proteins; Phenotype; Polymorphism, Genetic; Scurvy; Starvation; White People

Research conducted before genotyping was possible suggested that subjects heterozygous for the genetic mutation associated with hemochromatosis absorbed nonheme iron more efficiently than did control subjects when tested with a fortified meal. Heme-iron absorption in these subjects has not been reported.. We compared the absorption of heme and nonheme iron from minimally or highly fortified test meals between HFE C282Y-heterozygous and wild-type control subjects.. After prospective genotyping of 256 healthy volunteers, 11 C282Y-heterozygous and 12 wild-type control subjects were recruited, and their iron absorption was compared by using a hamburger test meal with or without added iron and ascorbic acid. After retrospective genotyping of 103 participants in previous iron-absorption studies, 5 C282Y-heterozygous subjects were compared with 72 wild-type control subjects.. HFE C282Y-heterozygous subjects did not differ significantly from wild-type control subjects in their absorption of either heme or nonheme iron from minimally or highly fortified test meals. No differences were detected in blood indexes of iron status (including serum ferritin, transferrin saturation, and non-transferrin-bound iron) or in blood lipids or transaminases, but heterozygotes had significantly greater, although normal, fasting glucose concentrations than did wild-type control subjects. Compound heterozygotes (those who had both HFE C282Y and H63D mutations) absorbed more nonheme (but not heme) iron from meals with high (but not low) iron bioavailability.. HFE C282Y-heterozygous subjects did not absorb dietary iron more efficiently, even when foods were highly fortified with iron from ferrous sulfate and ascorbic acid, than did control subjects. Iron fortification of foods should not pose an additional health risk to HFE C282Y heterozygotes.

Topics: Adult; Aged; Anemia, Iron-Deficiency; Ascorbic Acid; Case-Control Studies; Female; Ferritins; Food, Fortified; Genotype; Hemochromatosis; Hemochromatosis Protein; Heterozygote; Histocompatibility Antigens Class I; Homozygote; Humans; Intestinal Absorption; Ion Transport; Iron; Iron, Dietary; Male; Membrane Proteins; Middle Aged; Mutation; Prospective Studies; Retrospective Studies

We describe the case of a 36-year-old woman with hereditary hemochromatosis (HH) resulting in end-stage cardiomyopathy and treated successfully with orthotopic cardiac transplantation. Before and after transplantation, the patient underwent aggressive treatment with frequent phlebotomy. We used erythropoietin concomitantly to maintain adequate hematocrit to support continued phlebotomy. We believe that aggressive use of phlebotomy provided the patient hemodynamic benefit and hastened the return of endocrine function post-transplantation. We also believe that the patient's history of high-dose vitamin C usage may have accelerated iron deposition in the heart and other vital organs.

Topics: Adult; Ascorbic Acid; Cardiomyopathies; Combined Modality Therapy; Contraindications; Erythropoietin; Female; Heart Transplantation; Hemochromatosis; Humans; Phlebotomy

Topics: Ascorbic Acid; Chelating Agents; Deferoxamine; Dietary Supplements; Drug Therapy, Combination; Hemochromatosis; Humans

Hereditary haemochromatosis is characterised by iron overload that may lead to tissue damage. Free iron is a potent promoter of hydroxyl radical formation that can cause increased lipid peroxidation and depletion of chain-breaking antioxidants. We have therefore assessed lipid peroxidation and antioxidant status in 15 subjects with hereditary haemochromatosis and age/sex matched controls. Subjects with haemochromatosis had increased serum iron (24.8 (19.1-30.5) vs. 17.8 (16.1-19.5) mumol/l, p = 0.021) and % saturation (51.8 (42.0-61.6) vs. 38.1 (32.8-44.0), p = 0.025). Thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxidation, were increased in haemochromatosis (0.59 (0.48-0.70) vs. 0.46 (0.21-0.71) mumol/l, p = 0.045), and there were decreased levels of the chain-breaking antioxidants alpha-tocopherol (5.91 (5.17-6.60) vs. 7.24 (6.49-7.80) mumol/mmol cholesterol, p = 0.001), ascorbate (51.3 (33.7-69.0) vs. 89.1 (65.3-112.9), p = 0.013), and retinol (1.78 (1.46-2.10) vs. 2.46 (2.22-2.70) mumol/l, p = 0.001). Patients with hereditary haemochromatosis have reduced levels of antioxidant vitamins, and nutritional antioxidant supplementation may represent a novel approach to preventing tissue damage. However, the use of vitamin C may be deleterious in this setting as ascorbate can have prooxidant effects in the presence of iron overload.

Topics: Adult; Antioxidants; Ascorbic Acid; Female; Free Radicals; Hemochromatosis; Humans; Iron; Lipid Peroxidation; Male; Middle Aged; Thiobarbituric Acid Reactive Substances; Vitamin A; Vitamin E

In hemochromatosis and other disorders associated with iron overload, a significant fraction of the total iron in plasma circulates in the form of low molecular weight complexes not bound to transferrin. Efficient and unregulated clearance of this form of iron by the liver may account for the hepatic iron loading and toxicity that characterize these diseases. We tested this possibility by examining the hepatic removal process for representative iron complexes in the single-pass perfused rat liver. Hepatic uptake of both ferrous and ferric 55Fe from ultrafiltered human serum was found to be highly efficient and effectively irreversible (single-pass extraction of 1 microM iron, 58-75%). Similar high efficiencies were seen for iron complexed to specific physiologic and nonphysiologic coordinators, including histidine, citrate, fructose, oxalate and glutamate, and tricine. Because of lower plasma flow rates, single-pass extraction of these iron complexes in vivo should be even greater. Autoradiography confirmed that most iron had been removed by parenchymal cells. Hepatic removal from Krebs-tricine buffer was saturable with similar kinetic parameters for ferrous and ferric iron (apparent Km, 14-22 microM; V max, 24-38 nmol min-1 g liver-1). These findings suggest that high levels of non-transferrin-bound iron in plasma may be an important cause of hepatic iron loading in iron overload states.

Topics: Anaerobiosis; Animals; Ascorbic Acid; Citrates; Ferrous Compounds; Hemochromatosis; Iron; Liver; Male; Metabolic Clearance Rate; Oxidation-Reduction; Perfusion; Rats; Rats, Inbred Strains

The effect on urinary iron excretion (UIE) of vitamin C administered orally 2 h after the start of an 8-hour desferrioxamine (DF) i.v. infusion was studied in 12 patients with untreated idiopathic hemochromatosis (IH). Mean +/- SEM basal UIE of 324.6 +/- 84.6 micrograms/24 h increased after a 1-gram i.v. DF infusion to 8,778.5 +/- 1,191.4 micrograms/24 h; when vitamin C 1 or 2 g were added to DF i.v. infusion, there were further increases to 11,241.5 +/- 1,486.1 (p less than 0.01) and 13,531.2 +/- 1,697.2 micrograms/24 h (p less than 0.05 versus the last value), respectively. Basal UIE did not significantly increase after oral vitamin C administration alone. No side effects were observed.

Topics: Adult; Ascorbic Acid; Deferoxamine; Female; Hemochromatosis; Humans; Iron; Male; Middle Aged; Time Factors

Topics: Anemia; Ascorbic Acid; Deferoxamine; Genes, Recessive; Hemochromatosis; Humans; Intestinal Absorption; Iron; Transfusion Reaction

Iron overload is an uncommon complication of untransfused chronic hemolytic anemias. This paper describes only the fourth reported case of erythrocyte pyruvate kinase deficiency and iron overload. Important aspects of this case are the presence of the HLA genotype commonly associated with genetic (idiopathic) hemochromatosis and a history of ingestion of large doses of ascorbic acid. Their roles in the development of iron loading and toxicity are discussed. A beneficial response to treatment with desferrioxamine was observed before significant iron removal. A mechanism for this action of desferrioxamine is proposed.

Topics: Ascorbic Acid; Erythrocytes; Hemochromatosis; HLA Antigens; Humans; Intestinal Absorption; Iron; Male; Middle Aged; Pyruvate Kinase; Spherocytosis, Hereditary

We describe rapidly fatal cardiomyopathy in a young man. He had for twelve months ingested large amounts of ascorbic acid and was admitted with severe heart failure having been symptomatic for two months. He died after eight days. Idiopathic haemochromatosis was diagnosed at autopsy. The clinical and laboratory features are discussed and the possible implications of ascorbic acid ingestion are explored.

Topics: Adult; Ascorbic Acid; Cardiomyopathies; Heart Failure; Hemochromatosis; Humans; Male; Myocardium

Adult patients with chronic iron overload were given oral ascorbic acid and continuous intravenous infusions of deferoxamine mesylate. The dosage of deferoxamine mesylate was altered every 48 hours from 1 g/sq m/24 hr to 2 or 4 g/sq m/24 hr. The average iron mobilization was 55.6 mg per day at the 1 g/sq m/24 hr dosage level, 78.6 mg every 24 hours at the 2 g/sq m/24 hr dosage level, and 90.1 mg every 24 hours at the 4 g/sq m/24 hr dosage level. Iron mobilization was undiminished when successive 14-day courses of deferoxamine separated by six-week intervals were administered.

Topics: Administration, Oral; Adult; Aged; Ascorbic Acid; Deferoxamine; Female; Hemochromatosis; Humans; Infusions, Parenteral; Iron; Male; Middle Aged; Time Factors

Topics: Adolescent; Adult; Aged; Ascorbic Acid; Deferoxamine; Drug Evaluation; Female; Hemochromatosis; Hemosiderosis; Humans; Iron; Male; Middle Aged; Thalassemia

Vitamin C status was studied, by means of leucocyte ascorbic acid concentrations, in 67 cases of idiopathic hemochromatosis subdivided into 44 untreated and 25 treated cases (2 patients belonging to both subgroups) and compared to 31 normal subjects and 37 alcoholic cirrhosis patients. The control groups exhibited the following mean levels (+/- SEM): 34.4 +/- 1.9 microgram/10(8) WBC in normals and 22.0 +/- 1.8 microgram/10(8) WBC in alcoholic cirrhosis. In idiopathic hemochromatosis the mean levels were: for the untreated group 19.5 +/- 1.7 microgram/10(8) WBC and for the treated group 34.3 +/- 2.3 microgram/10(8) WBC. These results (1) affirm an important vitamin C deficiency in the untreated disease; (2) suggest that iron overload is the main causal factor in view of the striking difference--to date unreported--between untreated and treated cases of idiopathic hemochromatosis. Besides its possible theoretical interests, this vitamin C deficiency is responsible in idiopathic hemochromatosis for a significant underestimation of the desferrioxamine-induced urinary iron excretion.

Topics: Adult; Aged; Ascorbic Acid; Ascorbic Acid Deficiency; Female; Hemochromatosis; Humans; Iron; Leukocytes; Liver Cirrhosis, Alcoholic; Liver Function Tests; Male; Middle Aged

Topics: Administration, Oral; Animals; Ascorbic Acid; Benzoates; Blood Transfusion; Body Weight; Calcium; Carboxylic Acids; Catechols; Chelating Agents; Copper; Deferoxamine; Disease Models, Animal; Feces; Hemochromatosis; Hydroxylation; Injections, Intraperitoneal; Iron; Iron Chelating Agents; Iron Radioisotopes; Lethal Dose 50; Magnesium; Mice; Mice, Inbred Strains; Rats; Zinc

Topics: Adult; Arthritis; Ascorbic Acid; Biopsy; Bloodletting; Deferoxamine; Female; Gastric Juice; Hemochromatosis; Humans; Intestinal Absorption; Iron; Liver; Male; Middle Aged

Topics: Animals; Ascorbic Acid; Cobalt; Copper; Cysteine; Dactinomycin; Deferoxamine; Dinitrophenols; Edetic Acid; Fatty Liver; Fluorides; Fructose; Glucose; Glutathione; Hemochromatosis; Inflammation; Iodoacetates; Iron; Lipotropic Agents; Liver Cirrhosis; Lung; Macrophages; Microscopy, Electron; Potassium Permanganate; Protein Biosynthesis; Puromycin; Rabbits; RNA; Saponins; Sucrose; Surface-Active Agents; Transferrin; Trypsin

Topics: Ascorbic Acid; Ascorbic Acid Deficiency; Deferoxamine; Hemochromatosis; Humans; Iron; Leukocytes; Male; Siderosis; Transfusion Reaction

Studies of the ascorbic acid status in two subjects with idiopathic haemochromatosis and in 12 with transfusional siderosis showed that all had decreased levels of white cell ascorbic acid. The urinary excretion of ascorbic acid was also diminished in those subjects in whom such measurements were made. The administration of ascorbic acid was followed by only a small rise in the urinary ascorbic acid output, while the oxalic acid levels (measured in two subjects) showed a significant rise. These findings resemble those described in siderotic Bantu, and support the thesis that increased iron stores lead to irreversible oxidation of some of the available ascorbic acid.

Topics: Adolescent; Adult; Ascorbic Acid; Blood Platelets; Blood Transfusion; Child; Diet; Hemochromatosis; Humans; Iron; Leukocytes; Middle Aged; Oxalates; Siderosis; Thalassemia

Topics: Ascorbic Acid; Carbohydrate Metabolism; Hemochromatosis; Humans; Iron; Scurvy; Skin Diseases; Vitamins

Topics: Anemia; Anemia, Sideroblastic; Ascorbic Acid; Hemochromatosis; Humans; Pyridoxine; Vitamin B 6; Vitamins

Topics: Ascorbic Acid; Hemochromatosis; Humans