Hepcidin;

In my patient with iron deficiency anemia (IDA), should I prescribe daily or every other day oral iron supplementation?    

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

Oral iron supplementation dosed every 48 hours is preferred over a daily regimen for at least 2 reasons: higher absorption and better tolerability. Improved absorption is due to an increase in hepcidin after oral intake of iron that lasts up to 48 hours which, paradoxically, also results in blocking further iron absorption during that period. In fact, a study comparing consecutive-day versus alternate-day dosing of oral iron supplementation found the fractional iron absorption to be 40-50% higher in alternate-day dosing.1

As for tolerability, the most frequent side effect of oral iron is gastrointestinal in nature, including nausea, vomiting, diarrhea, and constipation which are related to: 1. Excess amounts of unabsorbed iron leading to inflammation in the gut; and 2. An increase in the production of free radicals and peroxidation in the gut.2 Not surprisingly, alternate-day dosing has been shown to result in less side effects due to higher fractional iron absorption – leading to reduced levels of unabsorbed iron in the gut.3

Understanding the importance of optimal dosing regimen for oral iron supplementation is more than an academic exercise. Iron deficiency is the number one nutritional deficiency globally, affecting 30% of the world’s population.4 The most common causes are gastrointestinal blood loss and menstrual cycle blood loss, followed by a decrease in dietary fiber intake and decreased iron absorption. Undoubtedly, many providers will encounter patients with iron deficiency in need of oral supplementation. To increase both efficacy and compliance of oral iron supplementation, providers should consider every other day (every 48 h) dosing of oral iron in preference to daily dosing. 

Bonus Pearl:  Did you know that heme sources of iron from animals (eg, red meat, liver or kidney) are usually more bioavailable than their non-heme counterparts (eg, from green leafy vegetables) except for blackstrap molasses which has high iron content as well as exceptionally high bioavailability?5,6 

Contributed by Morgan Walters, DO, Internal Medicine Resident, Mercy Hospital-St. Louis, St. Louis, Missouri 

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References: 

  1. Stoffel N, Zeder C, Brittenham G, et al. Iron absorption from supplements is greater with alternate day than with consecutive day dosing in iron-deficient anemic women. Haematologica. 2020 May;105(5):1232-1239. doi: 10.3324/haematol.2019.220830.  Epub 2019 Aug 14. https://pubmed.ncbi.nlm.nih.gov/32650997/
  2. DeLoughery T, Jackson C, Ko C, et al. AGA Clinical Practice Update on management of Iron Deficiency Anemia: Expert Review. Clinical Gastroenterology and Hepatology 2024;22:1575–1583. Doi:0.1016/j.cgh.2024.03.046.  https://pubmed.ncbi.nlm.nih.gov/38864796/
  3. Stoffel N, Zeder C, Brittenham G, et al. Iron absorption from supplements is greater with alternate day than with consecutive day dosing in iron-deficient anemic women Haematologica. 2020 May;105(5):1232-1239. doi: 10.3324/haematol.2019.220830.  Epub 2019 Aug 14. https://pubmed.ncbi.nlm.nih.gov/32650997/
  4. Kumar A, Sharma E, Marley A, et al. Iron deficiency anaemia: pathophysiology, assessment, practical management. BMJ Open Gastro 2022;9:e000759. doi:10.1136/bmjgast-2021-000759. https://pubmed.ncbi.nlm.nih.gov/34996762/
  5. Brittany Lubeck, MS. “Is Molasses Healthy? What to Know about This Sweetener.” Verywell Health, May 10, 2024. https://www.verywellhealth.com/molasses-8640108.
  6. Hamlett, C. (2024, March 22). Meet Blackstrap Molasses: The “best source” of plant-based Iron. Plant Based News. https://plantbasednews.org/lifestyle/health/blackstrap-molasses-is-an-iron-rich-nutritional-powerhouse/ 

 

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!

In my patient with iron deficiency anemia (IDA), should I prescribe daily or every other day oral iron supplementation?    

Can my patient develop “anemia of chronic disease” acutely while hospitalized?

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

“Anemia of chronic disease” is better termed anemia of inflammation (AI) which may occur in acute as well as chronic inflammatory states. 1 As such, the view that anemia in the critically ill patients is simply caused by excess phlebotomy is inaccurate. 2 The CRIT study demonstrated that AI in critically ill patients develops even within 30 days, often despite blood transfusions. 3

In addition to the usual causes of AI (eg autoimmune disorders), AI can occur during bacterial, viral or yeast infections and sepsis 4,5.

Recent studies implicate both iron sequestration and impaired erythropoiesis as causes of AI. 1 Inflammation stimulates hepatic production of iron-regulatory peptide, hepcidin, which decreases delivery of iron from macrophages to developing erythrocytes.  Inflammation also causes production of pro-inflammatory cytokine, IL-6, which suppresses erythropoiesis.

Couple of cool studies using injection of heat-killed Brucella abortus in mice as a model of AI, showed dramatic hemoglobin drop by 7 days.6,7. In addition, not only were iron restriction from increase in hepcidin and transient erythropoiesis demonstrated, erythrocyte lifespan was also shortened in these experiments. AI is truly a multifactorial process.

 

References 

  1. Frankel PG. Anemia of inflammation: A review. Med Clin N Ame 2017;101:285-96. https://www.ncbi.nlm.nih.gov/pubmed/28189171
  2. Corwin HL, Krantz SB. Anemia of the critically ill: “Acute” anemia of chronic disease. Crit Care Med 2000;28:3098-99. https://www.ncbi.nlm.nih.gov/pubmed/10966311
  3. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT study: anemia and blood transfusion in the critically ill-current clinical practice in the United states. Crit Care Med 2004;32:39-52. https://www.ncbi.nlm.nih.gov/pubmed/14707558
  4. Gabriel A, Kozek S, Chiari A, et al. High-dose recombinant human erythropoietin stimulates reticulocyte production in patients with multiple organ dysfunction syndrome. J Trauma:Injury, Infection, and Critical Care 1998;44:361-67. https://www.ncbi.nlm.nih.gov/pubmed/9498512
  5. Roy CN. Anemia of inflammation. Hematology Am Soc Hematol Educ Program. 2010;2010:276-80. doi: 10.1182/asheducation-2010.1.276. https://www.ncbi.nlm.nih.gov/pubmed/21239806
  6. Kim A, Fung E, Parikh SG, et al. A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin. Blood 2014;123:1129-36. https://www.ncbi.nlm.nih.gov/pubmed/24357728
  7. Gardenghi S, Renaud TM, Meloni A, et al. Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus. Blood 2014;123:1137-45. https://www.ncbi.nlm.nih.gov/pubmed/24357729

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Can my patient develop “anemia of chronic disease” acutely while hospitalized?

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?