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Concept: Iron deficiency anemia

173

Background Intravenous (i.v.) iron can improve anaemia of chronic disease and response to erythropoiesis-stimulating agents (ESAs), but data on its use in practice and without ESAs are limited. This study evaluated effectiveness and tolerability of ferric carboxymaltose (FCM) in routine treatment of anaemic cancer patients. Patients and methods Of 639 patients enrolled in 68 haematology/oncology practices in Germany, 619 received FCM at the oncologist’s discretion, 420 had eligible baseline haemoglobin (Hb) measurements, and 364 at least one follow-up Hb measurement. Data of transfused patients were censored from analysis before transfusion. Results The median total iron dose was 1000 mg per patient (interquartile range 600-1500 mg). The median Hb increase was comparable in patients receiving FCM alone (1.4 g/dl [0.2-2.3 g/dl; N = 233]) or FCM + ESA (1.6 g/dl [0.7-2.4 g/dl; N = 46]). Patients with baseline Hb up to 11.0 g/dl and serum ferritin up to 500 ng/ml benefited from FCM treatment (stable Hb ≥11.0 g/dl). Also patients with ferritin >500 ng/ml but low transferrin saturation benefited from FCM treatment. FCM was well tolerated, 2.3% of patients reported putative drug-related adverse events. Conclusions The substantial Hb increase and stabilisation at 11-12 g/dl in FCM-treated patients suggest a role for i.v. iron alone in anaemia correction in cancer patients.

Concepts: Hemoglobin, Oncology, Iron, Interquartile range, Anemia, Iron deficiency anemia, Transferrin, Ferritin

169

Several epidemiological studies have reported that high concentrations of circulating ferritin, a marker of iron stores, are related to insulin resistance (IR); however, questions remain regarding inconsistent data between Asian men and women and the inadequate consideration of potential confounding effects on the relationship between ferritin and IR. Our aim was to examine the relationship between serum ferritin concentrations and IR markers in the Japanese population.

Concepts: Japan, Iron deficiency anemia, Asia, Demographics of Japan

167

BACKGROUND Iron deficiency and iron deficiency anaemia are frequent problems in both the primary and the specialist health services. It is important to detect iron deficiency and to determine the causal relationship because iron deficiency may be secondary to a serious disease. The diagnosis of iron deficiency is largely based on biochemical and haematological laboratory findings, but there is no standardisation or consensus on the interpretation of these findings.METHOD Non-systematic search in the PubMed database with a discretionary selection of articles, based on the authors' knowledge of the field.RESULTS Ferritin measurement is the most important analysis in the study of iron deficiency, but there is no consensus on the diagnostic cut-off. It is usual in Norway today to use a ferritin level of < 12 - 20 μg/L, but at this low level the sensitivity for detecting iron deficiency is very low. A number of studies show that if the diagnostic cut-off is increased to the order of 30 μg/L the sensitivity is significantly higher for only a small reduction in specificity.INTERPRETATION When studying iron deficiency as a cause of anaemia, the diagnostic cut-off for detecting deficiency should be higher than that used today. The ferritin level increases with inflammation and ought in practice to be considered in conjunction with the CRP level. The level of transferrin receptor in plasma increases with iron deficiency without being influenced by inflammation and is therefore a good supplement to ferritin measurement. Measurement of iron, transferrin and transferrin saturation provides little information additional to that provided by ferritin in iron deficiency studies.

Concepts: Hemoglobin, Iron, Anemia, Hematology, Iron deficiency anemia, Transferrin, Serum iron, Iron metabolism

166

Dietary iron absorption is regulated by hepcidin, an iron regulatory protein produced by the liver. Hepcidin production is regulated by iron stores, erythropoiesis and inflammation, but its physiology has not been characterized when repeated blood loss occurs. Hepcidin was measured in plasma samples obtained from 114 first-time/reactivated (no blood donations in prior 2 years) female donors and 34 frequent (≥3 red blood cell donations in prior 12 months) male donors as they were phlebotomized ≥4 or more times over 18-24 months. Hepcidin was compared to ferritin and hemoglobin using multivariable repeated measures regression models. Hepcidin, ferritin and hemoglobin declined with increasing frequency of donation in the first-time/reactivated females. Hepcidin and ferritin correlated well with each other (Spearman correlation of 0.74), but on average hepcidin varied more between donations for a given donor relative to ferritin. In a multivariable repeated measures regression model the predicted inter-donation decline in hemoglobin varied as a function of hepcidin and ferritin; hemoglobin was 0.51 g/dL lower for subjects with low (≤45.7 ng/ml) or decreasing hepcidin and low ferritin (≤26 ng/ml), and was essentially zero for other subjects including those with high (>45.7 ng/ml) or increasing hepcidin and low ferritin (≤26 ng/ml) (p<0.001). Hepcidin rapidly changes in response to dietary iron needed for erythropoiesis. The dynamic regulation of hepcidin in the presence of low ferritin suggests that plasma hepcidin may provide clinically useful information about an individual's iron status (and hence capacity to tolerate repeated blood donations) beyond that of ferritin alone.

Concepts: Hemoglobin, Blood, Red blood cell, Spearman's rank correlation coefficient, Liver, Anemia, Hematology, Iron deficiency anemia

154

Abstract Background: Methylmalonic aciduria and homocystinuria type C (cblC), a disorder of vitamin B12 (cobalamin) metabolism caused by mutations in the MMACHC gene, presents with many systemic symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy are common in early onset form of the disease but are rare in adult onset forms. Materials and Methods: An adult Hispanic female presented with decreased central vision, bilateral pericentral ring scotomas and bull’s eye-appearing macular lesions at 28 years of age. Her medical history was otherwise unremarkable except for iron deficiency anemia and both urinary tract and kidney infections. Screening of the ABCA4 gene, mutations in which frequently cause bull’s eye maculopathy, was negative. Subsequently, analysis with whole exome sequencing was performed. Results: Whole exome sequencing discovered compound heterozygous mutations in MMACHC, c.G482A:p.Arg161Gln and c.270_271insA:p.Arg91Lysfs*14, which segregated with the disease in the family. The genetic diagnosis was confirmed by biochemical laboratory testing, showing highly elevated urine methylmalonic acid/creatinine and homocysteine levels, and suggesting disease management with hydroxycobalamin injections and carnitine supplementation. Conclusions: In summary, a unique case of an adult patient with bull’s eye macular lesions and no clinically relevant systemic symptoms was diagnosed with cblC by genetic screening and follow-up biochemical laboratory tests.

Concepts: Genetics, Anemia, Folic acid, Vitamin B12, Iron deficiency anemia, Genetic disorders, Methylmalonic acid, Methylmalonic acidemia

137

There has been no evidence for the necessity of endoscopy in asymptomatic young men with iron deficiency anemia (IDA). To determine whether endoscopy should be recommended in asymptomatic young men with IDA, we compared the prevalence of gastrointestinal (GI) lesions between young men (< 50 years) with IDA and those without IDA.

Concepts: Hemoglobin, Iron, Hematology, Iron deficiency anemia, Transferrin, Human iron metabolism, Iron deficiency, Serum iron

59

Tea interferes with iron absorption and can lead to iron deficiency anemia when consumed in large quantities. The rechallenge effect of green tea on anemia in a middle-aged man emphasizes the potential causal role of this beverage. Lifestyle and dietary habits are important diagnostic considerations in diseases of this type.

Concepts: Hemoglobin, Death, Iron, Iron deficiency anemia, Transferrin, Human iron metabolism

49

Iron deficiency causes long-term adverse consequences for children and is the most common nutritional deficiency worldwide. Observational studies suggest that iron deficiency anemia protects against Plasmodiumfalciparum malaria and several intervention trials have indicated that iron supplementation increases malaria risk through unknown mechanism(s). This poses a major challenge for health policy. We investigated how anemia inhibits blood stage malaria infection and how iron supplementation abrogates this protection.

Concepts: Immune system, Hemoglobin, Malaria, Plasmodium falciparum, Red blood cell, Iron deficiency anemia, Sickle-cell disease, Transferrin

34

The unified global efforts to mitigate the high burden of vitamin and mineral deficiency, known as hidden hunger, in populations around the world are crucial to the achievement of most of the Millennium Development Goals (MDGs). We developed indices and maps of global hidden hunger to help prioritize program assistance, and to serve as an evidence-based global advocacy tool. Two types of hidden hunger indices and maps were created based on i) national prevalence data on stunting, anemia due to iron deficiency, and low serum retinol levels among preschool-aged children in 149 countries; and ii) estimates of Disability Adjusted Life Years (DALYs) attributed to micronutrient deficiencies in 136 countries. A number of countries in sub-Saharan Africa, as well as India and Afghanistan, had an alarmingly high level of hidden hunger, with stunting, iron deficiency anemia, and vitamin A deficiency all being highly prevalent. The total DALY rates per 100,000 population, attributed to micronutrient deficiencies, were generally the highest in sub-Saharan African countries. In 36 countries, home to 90% of the world’s stunted children, deficiencies of micronutrients were responsible for 1.5-12% of the total DALYs. The pattern and magnitude of iodine deficiency did not conform to that of other micronutrients. The greatest proportions of children with iodine deficiency were in the Eastern Mediterranean (46.6%), European (44.2%), and African (40.4%) regions. The current indices and maps provide crucial data to optimize the prioritization of program assistance addressing global multiple micronutrient deficiencies. Moreover, the indices and maps serve as a useful advocacy tool in the call for increased commitments to scale up effective nutrition interventions.

Concepts: Malaria, Africa, Sub-Saharan Africa, North Africa, Iron deficiency anemia, Malnutrition, Vitamin A, Millennium Development Goals

28

The iron regulatory hormone hepcidin responds to both oral and parenteral iron. Here, we hypothesized that the diverse iron trafficking routes may affect the dynamics and kinetics of the hepcidin activation pathway. To address this, C57BL/6 mice were administered an iron-enriched diet or injected i.p. with iron dextran and analyzed over time. After 1 week of dietary loading with carbonyl iron, mice exhibited significant increases in serum iron and transferrin saturation, as well as in hepatic iron, Smad1/5/8 phosphorylation and bone morphogenetic protein 6 (BMP6), and hepcidin mRNAs. Nevertheless, hepcidin expression reached a plateau afterward, possibly due to upregulation of inhibitory Smad7, Id1, and matriptase-2 mRNAs, while hepatic and splenic iron continued to accumulate over 9 weeks. One day following parenteral administration of iron dextran, mice manifested elevated serum and hepatic iron levels and Smad1/5/8 phosphorylation, but no increases in transferrin saturation or BMP6 mRNA. Surprisingly, hepcidin failed to appropriately respond to acute overload with iron dextran, and a delayed (after 5-7 days) hepcidin upregulation correlated with increased transferrin saturation, partial relocation of iron from macrophages to hepatocytes, and induction of BMP6 mRNA. Our data suggest that the physiological hepcidin response is saturable and are consistent with the idea that hepcidin senses exclusively iron compartmentalized within circulating transferrin and/or hepatocytes.

Concepts: Protein, Iron, Iron deficiency anemia, Transferrin, Human iron metabolism, Iron deficiency, Serum iron, Iron metabolism