Hepcidin and anaemia

doi:10.1016/S0268-960X(03)00066-3

Blood Reviews

Volume 18, Issue 4, December 2004, Pages 219-225

https://doi.org/10.1016/S0268-960X(03)00066-3 Get rights and content

Abstract

The anaemia of chronic disease (ACD) is a common haematologic syndrome characterized by hypoferraemia with adequate reticuloendothelial iron stores. Frequently, serum ferritin concentration in these patients is elevated. The pathogenesis of ACD involves abnormalities in red cell survival, the erythropoietic response to anaemia, and in iron metabolism. Hepcidin is an antibacterial protein produced in the liver which can be found in blood or urine, and which participates in host defense. Recent studies have demonstrated that hepcidin is a key regulator of iron balance in the intestinal mucosa, and that abnormalities in hepcidin gene expression are associated with clinical abnormalities in iron parameters and, in some cases, with anaemia. Hepcidin is an acute-phase reacting protein, and it has been suggested that hepcidin is the key mediator of ACD. Investigation of hepcidin production in either serum or urine demonstrates a strong correlation with serum ferritin concentration. Differences between the hepcidin concentrations observed in ACD (or syndromes resembling ACD) and those observed in iron deficiency may depend on the definition used for the anaemia syndrome. It seems very likely that hepcidin is a major contributor to iron abnormalities characteristic of ACD; whether it contributes to the pathogenesis of the syndrome in a broader sense remains to be determined by further investigation.

Introduction

The anaemia of chronic disease (ACD) is one of the most common clinical syndromes encountered in the practice of medicine. It is likely that only blood loss with consequent iron deficiency is a more frequent etiology of anaemia.¹ This disorder typically manifests itself as a hypoproliferative anaemia accompanied by a low serum iron concentration despite adequate reticuloendothelial iron stores. ACD is traditionally associated with chronic infectious, inflammatory, and neoplastic diseases; but progress over the last 15 years in understanding its pathogenesis has led to the recognition of a broader range of associations.[2], [3] Syndromes similar or identical to ACD are also observed in critically ill patients in intensive care units,⁴ in the post-surgical setting,⁵ and following severe trauma.⁶

The diagnostic importance of altered iron metabolism in ACD has led many investigators to consider that these features indicate the dominant pathophysiologic process involved in this syndrome. The specific iron regulatory functions of the acute phase protein hepcidin, as well as the iron dysregulation syndromes observed in patients and transgenic animals with abnormalities of hepcidin gene expression (discussed below), have led many to consider that hepcidin is the key to unlocking the mysteries of ACD.⁷

In this review, the literature supporting the contributions of hepcidin to ACD will be summarized and related to other studies of the pathogenesis of this common yet incompletely understood disorder.

Section snippets

Overview

For many years, it has been recognized that the severity of ACD is correlated with the activity of the associated disease.[8], [9] This observation prompted a search for a common pathophysiologic mechanism which could apply to disorders of microbial, autoimmune, and malignant origins, and thus led investigators to consider mediators of the immune and inflammatory response, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and the interferons (IFN) as factors potentially involved in the

Hepcidin and iron metabolism

In 2000, Krause et al.³³ isolated a novel peptide from plasma. Since this peptide was produced in the liver and had antimicrobial effects, it was named liver-expressed antimicrobial peptide-1 (LEAP-1). Independently, Park et al.³⁴ isolated a 25 amino acid liver-derived peptide with antimicrobial effects from human urine, and named it hepcidin. The two peptides were shown to be identical, and the shorter name subsequently has attained more common usage and become standard nomenclature. As

Murine studies

Nicolas et al.⁴² evaluated the regulation of hepcidin mRNA in mouse liver in response to a number of factors relevant to various erythropoietic syndromes. Anaemia, whether due to acute haemolysis or to iatrogenic blood loss, was associated with decrease in hepatic hepcidin gene expression. Hypoxia, which is also associated with an increased demand for red cell production, had a similar effect. The investigators employed the turpentine abscess technique (a traditional method for inducing ACD in

Research agenda

•
Can hepcidin concentration (either in serum or in urine) distinguish ACD from iron deficiency anaemia more effectively than can the serum ferritin concentration?
•
What are the effects of hepcidin on erythroid progenitor colony formation, the erythropoietin response to anemia, and red cell survival (the non-iron processes involved in the pathogenesis of ACD)?
•
What are the performance characteristics of the serum and urine assays for hepcidin concentration, and does one or the other more accurately

Acknowledgements

Supported by funds from the Medical Research Service, US Department of Veterans Affairs and by grant HL-69418 from the US National Institutes of Health.

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Relationship between hepcidin and GDF15 in anemic patients with type 2 diabetes without overt renal impairment
2015, Diabetes Research and Clinical Practice
Despite the absence of overt renal impairment and decreased erythropoietin (EPO) levels, patients are usually anemic. Hepcidin, which is induced by inflammatory stimuli, plays an important role in anemia in chronic disease. Growth differentiation factor 15 (GDF15) is a putative anti-inflammatory cytokine that is elevated in type 2 diabetes (T2DM). Hence, we investigated the relationship between hepcidin and GDF15 in anemic T2DM patients without overt renal impairment.
Among 1150 patients who visited Kyungpook National University Hospital for T2DM between June 2006 and June 2014, we selected 55 anemic patients without overt renal impairment (serum creatinine <1.5 mg/dL or estimated glomerular filtration rate >60 mL/min/1.73 m²) and other co-morbid diseases, including malignancy, thyroid disease, rheumatic arthritis, liver disease, iron-deficiency anemia and other endocrine disease. We measured anthropometric and metabolic parameters, as well as measured the serum iron, ferritin, interleukin-6 (IL-6), erythropoietin, hepcidin-25 and GDF15 levels.
Anemic T2DM patients without overt renal impairment presented a greater inflammatory state, with increased serum hsCRP, ESR and IL-6 levels compared with non-anemic T2DM patients. Both hepcidin and GDF15 levels were increased and showed a positive correlation in anemic T2DM patients.
In the absence of overt renal impairment, anemia in T2DM is associated with chronic inflammation, inducing elevation of hepcidin and GDF15 levels independently of the erythropoietin level.
Iron metabolism in obesity: How interaction between homoeostatic mechanisms can interfere with their original purpose. Part I: Underlying homoeostatic mechanisms of energy storage and iron metabolisms and their interaction
2015, Journal of Trace Elements in Medicine and Biology
Adipose tissue plasticity mediated by inflammation is an important evolutionary achievement to survive seasonal climate changes. It permits to store excessive calories and to release them if required, using inflammatory cells to remove the debris. This process is regulated by a complex interaction of cytokines (TNF-α, IL-6), adipokines (adiponectin, apelin, liptin), adhesion molecules (ICAM-1, VCAM-1, E-selectin) and transcription factors (NF-κB, HIF-1α). Iron mediates electron transfer as an essential component of e.g. myeloperoxidase, hemoglobin, cytochrome C and ribonucleotide reductase. Conversely, unbound iron can catalyze oxidation of lipids, proteins, and DNA. To balance the essential with the potentially toxic function requires an efficient iron homoeostasis. This is mediated by hepcidin's interaction with the iron-exporter ferroportin, to adapt intestinal iron absorption and body iron-sequestration to changes in demand. In addition, the interaction of iron-responsive elements (IRE) and iron-responsive proteins (IRP), the IRE/IRP-mechanism, regulates cellular iron homoeostasis. Obesity-induced inflammation interacts with both these mechanisms and disturbs iron availability by impairing its absorption, and by sequestering it in the reticuloendothelial system. Both mechanisms lead to anemia and reduce physical fitness which, in a vicious cycle, can support the development of pathological obesity. Thus, interaction between these two sets of beneficial regulatory mechanisms can become detrimental in situations of ample calorie supply.
Glycogen storage disease type Ia: Linkage of glucose, glycogen, lactic acid, triglyceride, and uric acid metabolism
2012, Journal of Clinical Lipidology
Citation Excerpt :
Weinstein and colleagues12 have reported that patients with GSD type Ia and large hepatic adenomas have a microcytic anemia associated with low iron levels, which is refractory to iron therapy. This anemia is linked to the presence of hepatic adenomas, and adenoma resection or liver transplantation has been associated with a return to normal hemoglobin levels.12–14 The anemia that develops in these patients appears to be an effect of aberrant expression of hepcidin by the adenomas.
A female presented in infancy with hypotonia, undetectable serum glucose, lactic acidosis, and triglycerides >5000 mg/dL. The diagnosis of type 1A glycogen storage disease was made via the result of a liver biopsy, which showed increased glycogen and absent glucose-6-phosphatase enzyme activity. The patient was treated with dextrose administered orally, which was replaced by frequent feedings of cornstarch, which resulted in an improvement of her metabolic parameters. At age 18 years of age, she had marked hypertriglyceridemia (3860 mg/dL) and eruptive xanthomas and was treated with fenofibrate, atorvastatin, and fish oil. At age 29 years she was noted to have multiple liver adenomas, severe anemia, and hyperuricemia. Aggressive cornstarch therapy was commenced with a goal of maintaining her blood glucose levels >75 mg/dL and lactate levels <2 mmol/L. After 15 months on this regimen, her lipids levels (measured in mg/dL) off all medications were as follows: total cholesterol 222, triglycerides 179, high-density lipoprotein cholesterol 32, and calculated low-density lipoprotein cholesterol 154. Her weight was stable with a body mass index of 24.8 kg/m². Her liver adenomas had decreased in size, and her anemia and hyperuricemia had improved. She was homozygous for the R83C missense mutation in G6PC. Our data indicate that optimized metabolic control to maintain blood glucose levels >75 mg/dL is critical in the management of this disease.
Rethinking Iron Regulation and Assessment in Iron Deficiency, Anemia of Chronic Disease, and Obesity: Introducing Hepcidin
2012, Journal of the Academy of Nutrition and Dietetics
Adequate iron availability is essential to human development and overall health. Iron is a key component of oxygen-carrying proteins, has a pivotal role in cellular metabolism, and is essential to cell growth and differentiation. Inadequate dietary iron intake, chronic and acute inflammatory conditions, and obesity are each associated with alterations in iron homeostasis. Tight regulation of iron is necessary because iron is highly toxic and human beings can only excrete small amounts through sweat, skin and enterocyte sloughing, and fecal and menstrual blood loss. Hepcidin, a small peptide hormone produced mainly by the liver, acts as the key regulator of systemic iron homeostasis. Hepcidin controls movement of iron into plasma by regulating the activity of the sole known iron exporter ferroportin-1. Downregulation of the ferroportin-1 exporter results in sequestration of iron within intestinal enterocytes, hepatocytes, and iron-storing macrophages reducing iron bioavailability. Hepcidin expression is increased by higher body iron levels and inflammation and decreased by anemia and hypoxia. Importantly, existing data illustrate that hepcidin may play a significant role in the development of several iron-related disorders, including the anemia of chronic disease and the iron dysregulation observed in obesity. Therefore, the purpose of this article is to discuss iron regulation, with specific emphasis on systemic regulation by hepcidin, and examine the role of hepcidin within several disease states, including iron deficiency, anemia of chronic disease, and obesity. The relationship between obesity and iron depletion and the clinical assessment of iron status will also be reviewed.
Oncology
2012, The Cat
Oncology
2011, The Cat: Clinical Medicine and Management

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Published by Elsevier Ltd.

Hepcidin and anaemia

Abstract

Introduction

Section snippets

Overview

Hepcidin and iron metabolism

Murine studies

Research agenda

Acknowledgements

J Crit Care

Blood

Semin Arthritis Rheum

Blood

Blood

Blood

Biochem. Mol. Med

Blood

J. Lab. Clin. Med

FEBS Lett

J. Biol. Chem

Blood

J. Biol. Chem

Blood

Blood

Blood

The anemia of chronic disease

Semin. Hematol

The spectrum of diseases associated with the anemia of chronic disease: a study of 90 cases

Am. J. Med

Recent developments in the anemia of chronic disease

Curr. Hematol. Rep

Iron metabolism and erythropoiesis after surgery

Br. J. Surg

Anemia and blood transfusion in critically ill patients

JAMA

Some observations on anemia in rheumatoid arthritis

Blood

Pathogenesis of the anemia of chronic disease: a cytokine-mediated anemia

Stem. Cells

Advances in the anemia of chronic disease

Int. J. Hematol