Transferrin;

How should I interpret serum ferritin and transferrin saturation in my patient with anemia?

FA Manian MD, MPH, , , , , Leave a comment

Let’s start with serum ferritin, an iron containing protein that’s considered the most sensitive and specific noninvasive diagnostic test for evaluating total body iron stores (vs. the gold standard—but invasive— iron staining of bone marrow). 1

Although the optimal ferritin threshold to diagnose iron deficiency (ID) varies, compared to bone marrow iron reserves, levels below 15 ug/L are considered 98% specific and 78% sensitive.2 At a higher cut off of less than 45 ug/L, its sensitivity is 85% with a specificity of 92%.3 So if your patient’s ferritin level is less than 45 ug/L—especially less than 15 ug/L—you can be quite confident that they have ID.  

Argument is often made that ferritin levels may be misleadingly high even in the presence of ID because it is an acute phase reactant and its synthesis is expected to increase in a variety of infectious and non-infectious inflammatory conditions. But this argument can only be taken so far, because ferritin synthesis still depends on the presence of cellular iron, such that even in the presence of inflammation, its levels are unlikely to be more 100 ug/L in patients with low iron stores or “absolute ID”.

Absolute ID should be distinguished from “functional” ID which is associated with adequate iron stores but inadequate iron availability to tissues due to cytokine-mediated hepcidin production and macrophage sequestration of iron. 4

This brings us to another key protein, serum transferrin which transports iron to vital tissues, including the bone marrow.  Transferrin saturation (TSat) is not only low (≤20%) in absolute ID but also in functional ID. 1 This is where a combination of serum ferritin and TSat is helpful. A low TSat combined with a normal or high serum ferritin suggests functional ID with the previously discussed caveat that serum ferritin levels may be normal or elevated—but usually less than 100 ug/L)— in patients with absolute ID and concurrent inflammation.

So in your patient with anemia, after reviewing their serum ferritin and TSat, you should have a good idea of whether they have ID and, if so, whether it’s related to an absolute or functional ID. In another post, I will discuss guidelines on the diagnosis and treatment of functional ID.

Bonus Pearl: Did you know that the commonly-cited difference in the threshold for anemia in males vs females (<13.0 g/dL and <12 g/dL, respectively) by WHO may at least in part be related to unrecognized and untreated ID in the female population studies over 50 years ago? 1

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References

  1. Martens KL, DeLoughery TG. Iron deficiency anemia. Ann Intern Med 2026; 179:1-16. Iron Deficiency Anemia | Annals of Internal Medicine
  2. Hallberg L, Bengtsson C, Lapidus L, et al. Screening for iron deficiency: an analysis based on bone marrow examinations and serum ferritin determinations in a population sample of women. Br. J Haematol 199385:787-798. Screening for iron deficiency: an analysis based on bone-marrow examinations and serum ferritin determinations in a population sample of women. – Abstract – Europe PMC
  3. Rockey DC, Altayar O, Falck-Ytter Y, et al. AGA technical review on gastrointestinal evaluation of iron deficiency. Gastroenterology 2020;159:1097-1119. AGA Technical Review on Gastrointestinal Evaluation of Iron Deficiency Anemia – Gastroenterology
  4. Camaschella C, Girelli D. The changing landscape of iron deficiency. Mol Aspects Med 2020;75:100861. The changing landscape of iron deficiency – PubMed

 

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

How should I interpret serum ferritin and transferrin saturation in my patient with anemia?

Should I routinely screen my patients with heart failure for iron deficiency?

FA Manian MD, MPH, , , , , , , Leave a comment

Even in the absence of anemia, screening for iron deficiency (ID) has been recommended in patients with heart failure (HF) with reduced ejection fraction (HFrEF) by some European and Australia-New Zealand cardiology societies. 1

In contrast, the 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines do not mention routine screening for ID in such patients but instead state (under “Anemia”) that in patients with NYHA class II and III HF and ID (ferritin < 100 ng/mL or 100 to 300 ng/mL plus transferrin saturation <20%), IV iron replacement “might be reasonable” to improve functional status and quality of life (IIb-weak recommendation).2

As these guidelines are primarily based on data derived from patients with HFrEF, whether patients with HF with preserved (eg, >45%) ejection fraction (HFpEF) should undergo routine screening for ID is even less clear due to conflicting data based on limited small studies 3,4

What is known is that up to 50% or more of patients with HF with or without anemia may have ID. 5 Although most studies involving ID and HF have involved patients with HFrEF, similarly high prevalence of ID in HFpEF has been reported. 6,7

A 2016 meta-analysis involving patients with HFrEF and ID found that IV iron therapy alleviates HF symptoms and improves outcomes, exercise capacity and quality of life irrespective of concomitant anemia; all-cause and cardiovascular mortality rates were not significantly impacted, however.8  

Fortunately, larger trials in the setting of acute and chronic systolic HF are underway (Affirm-AHF, 9 IRONMAN 10).  Stay tuned!

Bonus Pearl: Did you know that iron deficiency directly affects human cardiomyocyte function by impairing mitochondrial respiration  and reducing its contractility and relaxation?11

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References

  1. Silverberg DS, Wexler D, Schwartz D. Is correction of iron deficiency a new addition to the treatment of the heart failure? Int J Mol Sci 2015;16:14056-74. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490538/
  2. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure. Circulation 2017;136:e137-e161. https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000509
  3. Kasner M, Aleksandrov AS, Westermann D, et al. Functional iron deficiency and diastolic function in heart failure with preserved ejection fraction. International J of Cardiol 2013;168:12:4652-57. https://www.ncbi.nlm.nih.gov/pubmed/23968714
  4. Enjuanes C, Klip IT, Bruguera J, et al. Iron deficiency and health-related quality of life in chronic heart failure: results from a multicenter European study. Int J Cardiol 2014;174:268-275. https://www.ncbi.nlm.nih.gov/pubmed/24768464
  5. Drodz M, Jankowska EA, Banasiak W, et al. Iron therapy in patients with heart failure and iron deficiency: review of iron preparations for practitioners. Am J Cardiovasc Drugs 2017;17:183-201. https://www.ncbi.nlm.nih.gov/pubmed/28039585
  6. Bekfani T, Pellicori P, Morris D, et al. Iron deficiency in patients with heart failure with preserved ejection fraction and its association with reduced exercise capacity, muscle strength and quality of life. Clin Res Cardiol 2018, July 26. Doi: 10. 1007/s00392-018-1344-x. https://www.ncbi.nlm.nih.gov/pubmed/30051186
  7. Nunez J, Dominguez E, Ramon JM, et al. Iron deficiency and functional capacity in patients with advanced heart failure with preserved ejection fraction. International J Cardiol 2016;207:365-67. https://www.internationaljournalofcardiology.com/article/S0167-5273(16)30185-1/abstract
  8. Jankowska EA, Tkaczynszyn M, Suchocki T, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Failure 2016;18:786-95. https://www.ncbi.nlm.nih.gov/pubmed/26821594
  9. https://clinicaltrials.gov/ct2/show/NCT02937454
  10. https://clinicaltrials.gov/ct2/show/NCT02642562
  11. Hoes MF, Beverborg NG, Kijlstra JD, et al. Iron deficiency impairs contractility of human cardiomyoctyes through decreased mitochondrial function. Eur J Heart Failure 2018;20:910-19. https://www.ncbi.nlm.nih.gov/pubmed/29484788  

 

Should I routinely screen my patients with heart failure for iron deficiency?

What is the mechanism of anemia of chronic disease in my patient with rheumatoid arthritis?

FA Manian MD, MPH, , , , , , Leave a comment

Anemia of chronic disease (ACD)—or more aptly “anemia of inflammation”— is the second most common cause of anemia after iron deficiency and is associated with numerous acute or chronic conditions (eg, infection, cancer, autoimmune diseases, chronic organ rejection, and chronic kidney disease)1.

The hallmark of ACD is disturbances in iron homeostasis which result in increased uptake and retention of iron within cells of the reticuloendothelial system, with its attendant diversion of iron from the circulation and reduced availability for erythropoiesis1. More specifically, pathogens, cancer cells, or even the body’s own immune system stimulate CD3+ T cells and macrophages to produce a variety of cytokines, (eg, interferon-ɤ, TNF-α, IL-1, IL-6, and IL-10) which in turn increase iron storage within macrophages through induction of expression of ferritin, transferrin and divalent metal transporter 1.

In addition to increased macrophage storage of iron, ACD is also associated with IL-6-induced synthesis of hepcidin, a peptide secreted by the liver that decreases iron absorption from the duodenum and its release from macrophages2. TNF-α and interferon-ɤ also contribute to ACD by inhibiting the production of erythropoietin by the kidney.  Finally, the life span of RBCs is adversely impacted in AKD due to their reduced deformability and increased adherence to the endothelium in inflammatory states3.

Of interest, it is often postulated that by limiting access to iron through inflammation, the body hinders the growth of pathogens by depriving them of this important mineral2.

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References

  1. Weiss, G and Goodnough, L. Anemia of chronic disease. N Engl J Med 2005; 352; 1011-23. http://www.med.unc.edu/medclerk/medselect/files/anemia2.pdf
  2. D’Angelo, G. Role of hepcidin in the pathophysiology and diagnosis of anemia. Blood Res 2013; 48(1): 10-15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624997/pdf/br-48-10.pdf                                                                                                                                  
  3. Straat M, van Bruggen R, de Korte D, et al. Red blood cell clearance in inflammation. Transfus Med Hemother 2012;39:353-60. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678279/pdf/tmh-0039-0353.pdf

 

Contributed by Amir Hossein Ameri, Medical Student, Harvard Medical School

                     

What is the mechanism of anemia of chronic disease in my patient with rheumatoid arthritis?