Anemia of Chronic Disorders: New Diagnostic Tools and New Treatment Strategies

doi:10.1053/j.seminhematol.2015.07.004

Seminars in Hematology

Volume 52, Issue 4, October 2015, Pages 313-320

https://doi.org/10.1053/j.seminhematol.2015.07.004 Get rights and content

Anemia in the setting of chronic inflammatory disorders is a very frequent clinical condition, which is, however, often neglected or not properly treated given the problems often caused by the diseases underlying the development of anemia. Mechanistically, anemia is mainly caused by inflammation-driven retention of iron in macrophages making the metal unavailable for heme synthesis in the course of erythropoiesis, and further by impaired biological activity of the red blood cell hormone erythropoietin and the reduced proliferative capacity of erythroid progenitor cells. Anemia can be aggravated by chronic blood loss, as found in subjects with gastrointestinal cancers, inflammatory or infectious bowel disease, or iatrogenic blood loss in the setting of dialysis, all resulting in true iron deficiency. The identification of such patients is a clinical necessity because these individuals need contrasting therapies in comparison to subjects suffering from only classical anemia of chronic disorders. The diagnosis is challenging because no state of the art laboratory test is currently available that can clearly separate patients with inflammatory anemia from those with additional true iron deficiency. However, based on our expanding knowledge on the pathophysiology of inflammatory anemia, new diagnostic markers, including the iron-regulatory hormone hepcidin, and hematologic parameters emerge. Apart from traditional anemia treatments such as blood transfusions, recombinant erythropoietin, and iron, including new high-molecular-weight formulations, new therapeutics are currently under preclinical and clinical evaluation. These novel compounds aim at correcting anemia by multiple pathways, including antagonizing the inflammation- and hepcidin-driven retention of iron in the monocyte–macrophage system and thereby promoting the supply of iron for erythropoiesis or by stimulating the endogenous formation of erythopoietin via stabilization of hypoxia-regulated factors.

Section snippets

Epidemiology

Anemia of chronic disorders (ACD) also termed as anemia of chronic disease or anemia of (chronic) inflammation is considered to be the second most frequent anemia in the world and is primarily found in subjects suffering from disorders that evolve from the activation of the immune system.¹ These diseases include mainly infections, cancer and chronic inflammatory auto-immune disorders but also extend to patients with chronic kidney disease specifically if they undergo regular dialysis or

Pathophysiology

Although the reasons for ACD are multifactorial, three immunity-driven pathophysiological pathways are central for its development.

First, inflammatory mediators significantly impact on iron homeostasis, which results in iron limitation for erythropoiesis and subsequent development of anemia. The inducers of these alterations of iron traffic are acute-phase proteins and cytokines. The mainly liver-derived peptide hepcidin, which can be induced by iron loading but also upon stimulation with

Diagnosis

ACD is diagnosed upon the presence of subnormal hemoglobin levels, increased concentration of markers of inflammation such as C-reactive protein or IL-6 and characteristic alterations of iron homeostasis (Table 1). The latter are low circulating iron levels and a reduced saturation of transferrin with the metal (TfS) along with normal or increased serum concentrations of the iron storage protein ferritin.1, 24 The latter feature distinguishes ACD from iron deficiency anemia (IDA) where ferritin

Treatment

The rational for the correction of anemia is to ameliorate the negative effects of anemia and iron deficiency on tissue oxygenation and cellular respiration40, 41 in order to increase cardiovascular⁴¹ and mental performance along with a gain in quality of life.⁴² Anemia improves or even disappears upon treatment and cure of the disease underlying ACD.¹ However, this goal can often not achieved, specifically in patients with cancer and auto-immune diseases, but also in subjects with end-stage

Conclusions

ACD is a frequent clinical condition in patients with inflammatory diseases, but often neglected by treating physicians as an entity that negatively impacts on the patients’ morbidity; it is therefore often insufficiently addressed. A specific challenge is to estimate the needs of iron in such patients as no gold standard diagnostic tests are currently available. Along this line we are still lacking information on how to best treat patients with ACD, what are the lower and upper therapeutic

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Anemia in Pregnancy With CKD
2024, Kidney International Reports
Chronic kidney disease (CKD), anemia, and iron deficiency are global health issues affecting individuals in both high-income and low-income countries. In pregnancy, both CKD and iron deficiency anemia increase the risk of adverse maternal and neonatal outcomes, including increased maternal morbidity and mortality, stillbirth, perinatal death, preterm birth, and low birthweight. However, it is unknown to which extent iron deficiency anemia contributes to adverse outcomes in CKD pregnancy. Furthermore, little is known regarding the prevalence, pathophysiology, and treatment of iron deficiency and anemia in pregnant women with CKD. Therefore, there are many unanswered questions regarding optimal management with oral or i.v. iron and recombinant human erythropoietin (rhEPO) in these women. In this review, we present a short overview of the (patho)physiology of anemia in healthy pregnancy and in people living with CKD. We present an evaluation of the literature on iron deficiency, anemia, and nutritional deficits in pregnant women with CKD; and we evaluate current knowledge gaps. Finally, we propose research priorities regarding anemia in pregnant women with CKD.
The role of iron in chronic inflammatory diseases: from mechanisms to treatment options in anemia of inflammation
2022, Blood
Citation Excerpt :
In this review, we focus on the prevalent diseases associated with AI and outline the most important molecular mechanisms that contribute to inflammatory hypoferremia and iron-restricted erythropoiesis.3,4 Iron-restricted erythropoiesis is an integral part of the pathophysiology of both AI and IDA, rendering differential diagnosis difficult specifically when both diseases coexist.5,6 Especially in low-income countries, where the burden of infectious diseases is high and true iron deficiency emerges because of poor nutritional iron availability and/or chronic blood loss, for example, owing to helminth infestations, AI and IDA frequently coaffect the same individuals.
Anemia of inflammation (AI) is a highly prevalent comorbidity in patients affected by chronic inflammatory disorders, such as chronic kidney disease, inflammatory bowel disease, or cancer, that negatively affect disease outcome and quality of life. The pathophysiology of AI is multifactorial, with inflammatory hypoferremia and iron-restricted erythropoiesis playing a major role in the context of disease-specific factors. Here, we review the recent progress in our understanding of the molecular mechanisms contributing to iron dysregulation in AI, the impact of hypoferremia and anemia on the course of the underlying disease, and (novel) therapeutic strategies applied to treat AI.
Diagnosis and treatment of ferropenic anemia in primary care in Spain
2022, Medicina Clinica Practica
Antecedentes y objetivo: la anemia ferropénica es una causa frecuente de consulta en la práctica médica habitual. Conocer cómo se diagnostica y se trata en la atención primaria puede permitir detectar si existe alguna área de mejora.
Métodos: estudio multicéntrico descriptivo tipo encuesta con 12 preguntas para conocer los aspectos de mayor variabilidad en el manejo de la anemia ferropénica. La población objeto de estudio son los médicos de los Centros de Asistencia Primaria de todo el ámbito nacional que atienden a estos pacientes.
Resultados: 732 médicos contestaron el formulario. Un 51,8% consideran que la anemia ferropénica es una enfermedad grave. Para diagnosticarla, un 80,7% revisa la ferritina y solo el 27,2% revisa el índice de saturación de la transferrina (IST). El 71,6% realiza analíticas de control cada 3 meses. Un 57,9% receta hierro solo durante 3 meses. El 47% finaliza el tratamiento cuando la Hb se normaliza. Cuando deriva al paciente, la mayoría lo hace al servicio de digestivo, seguido de hematología, medicina interna y ginecología.
Conclusiones: a pesar de que casi el 52% de los encuestados consideran que la anemia ferropénica es una enfermedad grave y que la ferritina es la determinación bioquímica más útil para su diagnóstico, alrededor de un 20% no la utiliza. Por otra parte, el IST que muchas veces puede ayudar a distinguir una anemia ferropénica de una anemia inflamatoria, solo lo solicita algo más del 27%, lo que puede conducir a errores diagnósticos. Por otra parte, en algunas ocasiones el tratamiento resulta insuficiente, ya que la mayoría trata a los enfermos únicamente durante 3 meses y el 47% finaliza el tratamiento cuando la Hb se normaliza, sin tener en cuenta el resultado de ferritina. Aunque se ha mejorado en el diagnóstico y el tratamiento de la anemia ferropénica en la asistencia primaria, es probable que muchos de los pacientes se beneficiarían de un mayor uso de la ferritina, el IST y de tratamientos de mayor duración.
Background and objective: Iron deficiency anemia is a frequent cause of consultation in routine medical practice. Knowing how it is diagnosed and treated in Primary Care can allow us to detect if there is any area for improvement.
Method: Descriptive multicenter survey-type study with 12 questions to find out the aspects of greater variability in the management of iron deficiency anemia. The population under study are physicians from Primary Care Centers nationwide who treat these patients.
Results: 732 physicians answered the form. 51.8% consider iron deficiency anemia a serious disease. To make the diagnosis, 80.7% check the ferritin and only 27.2% the transferrin saturation index (IST). 71.6% performed control tests every 3 months. 57.9% prescribe iron only for 3 months. 47% end treatment when Hb normalizes. When the patient is referred, the majority do so to the digestive service, followed by hematology, internal medicine, and gynecology.
Conclusions: Despite the fact that almost 52% of those surveyed consider iron deficiency anemia a serious disease and that ferritin is the most useful biochemical determination for its diagnosis, around 20% do not use it. On the other hand, the IST, which can often help distinguish iron-deficiency anemia from inflammatory anemia, is only requested by slightly more than 27%, which can lead to diagnostic errors. On the other hand, on some occasions, the treatment is insufficient since the majority treat the patients for only 3 months and 47% finish the treatment when the Hb normalizes without taking into account the ferritin result. Although the diagnosis and treatment of iron-deficiency anemia in Primary Care has improved, it is likely that many patients would benefit from greater use of ferritin and IST and from longer-lasting treatments.
Clinical interpretation of serum hepcidin-25 in inflammation and renal dysfunction
2022, Journal of Mass Spectrometry and Advances in the Clinical Lab
Citation Excerpt :
Studies have identified promising applications of hepcidin-25 measurements in evaluations of iron deficiency anemia (IDA) [9,34,35], iron refractory iron deficiency anemia (IRIDA) [36,37] and iron overload disorders [38–43]. Additionally, hepcidin-25 has established its usefulness in differentiating iron deficiency from anemia of chronic disease (ACD), and in guiding appropriate routes of iron therapy [7,26,44–48]. It has been well recognized that hepcidin-25 quantification needs to be isoform specific, harmonization is required to ensure assay quality, and results should be interpreted in the light of the renal and inflammatory status.
Hepcidin is a hormone that regulates systemic iron homeostasis. Serum hepcidin levels are under the influence of various stimuli, particularly inflammation and renal dysfunction. The measurement of hepcidin in circulation is a potentially useful clinical tool in the diagnosis, monitoring and treatment of iron metabolism disorder, although clinical interpretation of hepcidin level remains difficult. We evaluated he diagnostic potential and limitations of hepcidin-25 by investigating its relationship with iron and hematological indices, inflammation, and renal dysfunction.
This retrospective study included 220 adult patients not requiring dialysis. Variations of biologically active hepcidin-25 were examined using a mass spectrometry-based assay in various inflammatory and renal states. The log[hepcidin]:log[ferritin] ratio was calculated as an hepcidin index.
In 220 adult patients not requiring dialysis, variation in hepcidin-25 level was significantly larger once CRP exceeded 10 mg/l (p < 0.001). Inflammation was not a determinant of hepcidin-25 in the setting of renal dysfunction. Hepcidin-25 median (7.37 nM) and variance were significantly higher (p < 0.001), once estimated glomerular filtration rate (eGFR) dropped below 30 ml/min/1.73 m². The log[hepcidin]:log[ferritin] index normalized hepcidin levels. Patients with iron deficiency have a notably lower index when compared to controls (-0.66 vs 0.3).
Severe renal dysfunction (eGFR < 30) affected hepcidin-25 expression and clearance to variable degree between individuals. Although, hepcidin-25 testing is not warranted in patients with infection, inflammatory autoimmune conditions (CRP > 10 mg/l) and/or severe renal dysfunction (eGFR < 30), the hepcidin index may serve as a potential biomarker for iron deficiency in complex cases.
Growing concerns about using hypoxia-inducible factor prolyl hydroxylase inhibitors for the treatment of renal anemia
2024, Clinical Kidney Journal
Serum Erythropoietin level in anemia of elderly with unclear etiology
2023, Scientific Reports

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^☆: Financial disclosure/conflicts of interest: G.W. received lecturing fees from Pharmacosmos and Vifor over the past 5 years.

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Anemia of Chronic Disorders: New Diagnostic Tools and New Treatment Strategies☆

Section snippets

Epidemiology

Pathophysiology

Diagnosis

Treatment

Conclusions

Blood

Biochim Biophys Acta

Blood

Cell

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Kidney Int

Blood

Blood

Biochim Biophys Acta

J Card Fail

Blood

Hematol Oncol Clin North Am

Kidney Int

Lancet

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Med Hypoth

Blood

Immunity

Blood

Immunobiology

Anemia of chronic disease

N Engl J Med

Beyond the cardiorenal anaemia syndrome: recognizing the role of iron deficiency

Eur J Heart Fail

Anemia: not just an innocent bystander?

Arch Intern Med