#84: Anemia, Iron Deficiency, IV iron, and Tony Stark

February 26, 2018 | By Justin Berk

Abolish anemia, and iron deficiency w/tips on IV iron therapy from real life iron man, Michael Auerbach, MD, FACP, Clinical Professor of Medicine Georgetown University School of Medicine. Topics include oral versus IV iron therapy, safety of IV iron, ferritin cutoffs, and how to diagnosis/ treat iron deficiency in patients with chronic inflammation, chronic kidney disease, pregnancy, heart failure, and more! Take our Self Assessment Test Here.

Images by Beth Garbitelli; Written and produced by Justin Berk, MD and Matthew Watto, MD.

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Multiple Choice Questions

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 Clinical Pearls:

1. Giving IV iron is a chance to “make a patient all better the day you meet them” -Dr Auerbach.
2. IV iron relieves symptoms of anemia and non-anemic symptoms (e.g. pica, fatigue) of iron deficiency during the infusion! Mechanism unknown. -Dr Auerbach
3. Oral iron is effective, but poorly tolerated. Gastrointestinal side effects are reported by ~70% of patients. It should be dosed once every other day (Stoffel et al. Lancet Hematology 2017).
4. IV iron is safe and well tolerated. Serious reactions are rare, minor transfusion reactions occur in about 2%. Total dose of about 1000 mg will treat both actual (low total body iron) and functional iron deficiency (iron present, but unavailable for erythropoiesis).
5. Groups who should be given IV iron: Patients w/intolerance of oral iron, ongoing inflammation, heavy uterine bleeding, gastric bypass, hereditary hemorrhagic telangiectasia (Osler-Weber Rendu), inflammatory bowel disease, chronic kidney disease, or collagen vascular disease. -Dr Auerbach
6. Iron deficiency is common in pregnancy and leads to measurable neurologic outcomes in the child up to adulthood (Georgieff Nutr Rev 2011). Dr Auerbach recommends 1000 mg IV iron during 2nd or 3rd trimester if severe iron deficiency or oral iron intolerance (M Auerbach. Am J Hematol 2016).

History lesson on IV iron: High molecular weight iron dextran (HMWID) was the original IV iron, removed from the market in 1991 for rare, but serious and sometimes fatal anaphylaxis. Recombinant erythropoietin stimulating agents (ESAs) came out in 1988 for use in patients on dialysis, but didn’t work well until functional iron deficiency (iron restricted erythropoiesis) was discovered. When combined with IV iron, ESAs worked well for patients on dialysis and for chemotherapy induced anemia. Thus, interest in IV iron has grown (Auerbach et al. Haematologica. 2015 May; 100(5): e214–e215)  

Diagnosis of iron deficiency: Transferrin saturation (tsat) <19%, Ferritin <30 ng/mL (normal range is 40-200). Many sources use a ferritin cutoff of <15 ng/mL. Ferritin is an acute phase reactant that becomes elevated during inflammation. Soluble transferrin receptor (sTfR) is not an acute phase reactant. It is inversely proportional to tissue iron availability and thus, elevated in iron deficiency. For patients with chronic kidney disease (CKD) Tsat <19% or ferritin <100 suggest iron deficiency (Dr Auerbach). KDIGO recommends IV iron for anemic, nondialysis, CKD patients with tsat <30% and ferritin <500 (Visual summary KDIGO Anemia in CKD 2012).

Questions to ask patients with anemia, iron deficiency: Do you have restless legs at night? How much ice do you eat? Can you tolerate oral iron pills? Do you get nausea or constipation? Is your stool thick and difficult to pass?

Iron absorption and metabolism: Iron gets conjugated by acids in the stomach to vitamin C, amino acids, and sugars to protect it from the alkaline rush of the pancreas, which would turn it to ferric hydroxide (rust) and block absorption. Iron gets actively transported into cells in distal duodenum and proximal jejunum. Ferroportin exports iron from the cell into the plasma where it binds transferrin and is carried to the transferrin receptor for erythropoiesis. Excess iron gets picked up by macrophages and stored until needed. Hepcidin blocks ferroportin, which impairs iron absorption/release from gut epithelial cells and circulating macrophages (Wikipedia – Hepcidin diagram).

Iron restricted erythropoiesis: Also called functional iron deficiency, or anemia of chronic inflammation (disease). Diagnosed by normal or high serum ferritin and low transferrin saturation, generally <20%. These patients poorly absorb PO iron because of elevated hepcidin levels, but will respond to IV iron, which is directly available in the blood -Dr Auerbach.

Iron deficiency without anemia: Iron deficiency has neurologic, systemic symptoms even in absence of anemia. These patients should be treated with IV iron (Dr Auerbach’s expert opinion). Fatigue improved in patients with ferritin <15 ng/mL regardless whether or not anemia was present (Krayenbuel et al. Blood 2011)

Oral iron works, but is not well tolerated. There is not single best oral iron formulation at this time -Dr Auerbach.

Who should get IV iron? Patients w/ongoing inflammation, heavy uterine bleeding, gastric bypass, hereditary hemorrhagic telangiectasia (Osler-Weber Rendu), inflammatory bowel disease, chronic kidney disease, or collagen vascular disease. Insurance will pay for IV iron if these criteria are met -Dr Auerbach2.

Iron deficiency in pregnancy: Infants are not screened for iron deficiency despite increase in cognitive and behavior abnormalities up to age 19 years old (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1540447/,

Acute blood loss anemia and iron deficiency in patients admitted to the hospital should be given IV iron even if they are transfused blood because the iron in packed red blood cells is not available for erythropoiesis and other functions of iron until those cells are broken down -Dr Auerbach.  

Congestive heart failure (CHF): IV iron improves functional capacity, quality of life and CHF symptoms in patients with iron deficiency EVEN without anemia (Ankur et al IV iron for CHF NEJM 2009, Jankowska et al Eur J Heart Fail 2016)

Formulations of IV iron and Dr Auerbach’s recommend dosing
Choose from these options based on availability, cost, ease of dosing.

1. Iron sucrose: Downside = multiple infusions required. Given as 100-300 mg per dose on 3-10 occasions for total 1000 mg (Lexicomp). Easier to use in chemotherapy since patients already have multiple visits for infusions (Dr Auerbach).
2. Low molecular weight iron dextran: Take 60 minutes and cost $234/gm. *The label says to give it in 100 mg bolus, but Dr Auerbach gives it all in a single visit.
3. Ferumoxytol: Give 510 mg over 15 minutes x 2 doses. $318 per 510 mg.
4. Ferric carboxymaltose: 750 mg given in 10 minutes. Risk hypophosphatemia in 30-50% (rarely has clinical significance). Cost limits its use.

Minor transfusion reaction to IV iron: A syndrome occurs in approximately 1:200 patients, consisting of arthralgias, myalgias or flushing, without associated hypotension, tachycardia, tachypnea, wheezing, stridor or periorbital edema. It last 2-3 minutes. “The treatment is to chill” -Dr Auerbach.  After symptoms abate, re-challenge is appropriate (Auerbach et al. Haematologica. 2015 May; 100(5): e214–e215).

Disclosures: Dr Auerbach has consulted for all of the IV iron companies, but has no relevant financial interest in any of them. The Curbsiders report no relevant financial disclosures.

Goal: Listeners will develop an approach to iron deficiency anemia diagnosis and treatment.

Learning objectives:
After listening to this episode listeners will…

1. Define iron deficiency anemia
2. Interpret iron studies and ferritin measurement
3. Recall the limitations of oral iron supplementation
4. Differentiate between the available forms of IV iron supplementation
5. Recognize symptoms of iron deficiency aside from anemia
6. Identify patient groups who may benefit from IV iron supplementation

Time Stamps

• 00:00 Disclaimer
• 00:35 Intro
• 01:27 Listener feedback
• 02:35 Guest bio
• 04:49 Basics of diagnosing iron deficiency, ferritin, soluble transferrin receptor, a new definition
• 07:09 Getting to know our guest
• 08:27 Book recommendations
• 09:33 Brief history of iron deficiency and IV iron
• 15:20 Iron deficiency from menorrhagia
• 19:55 IV iron cures symptoms of iron deficiency, pica immediately
• 20:40 Iron and neurologic symptoms, restless leg syndrome
• 23:30 Iron restricted erythropoiesis, anemia of chronic inflammation
• 26:02 Overview of iron absorption
• 28:35 Iron deficiency without anemia, treatment
• 33:52 Time to improvement with iron therapy
• 34:45 Indications for IV iron
• 38:09 Comparing the oral iron formulations
• 40:05 Iron deficiency and pregnancy
• 42:54 Diagnosis of iron deficiency
• 46:20 Should IV iron be given to patients getting blood transfusion
• 48:40 Is iron safe during active infection?
• 49:17 Iron in congestive heart failure
• 51:50 Questions from social media
• 53:35 Minor infusion reaction from IV iron
• 54:35 Comparison of different IV iron formulations
• 57:35 Take home points
• 60:35 Outro

Links from the show:

1. Bellevue (book) by David OShinsky
2. Polio (book) by David OShinsky
3. Krayenbuel et al. IV iron or placebo for symptomatic non-anemic iron deficient anemia Blood 2011
4. Moretti et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood 2015
5. Editorial by Auerbach and Schrier. Treatment of iron deficiency is getting trendy. Lancet Haematology 2018.
6. What are some underrecognized symptoms of iron deficiency w/o anemia? http://www.bloodjournal.org/content/early/2011/06/24/blood-2011-04-346304?sso-checked=true
7. Association between Iron Deficiency and Pediatric psychiatric disorder → https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680022/
8. Improvements in iron status and cognitive function in young women consuming beef or non-beef lunches. https://www.ncbi.nlm.nih.gov/pubmed/24379009
9. RLS and response to IV Iron https://www.ncbi.nlm.nih.gov/pubmed/25441748
10. Wang, C et al. Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products. JAMA. 2015 Nov 17;314(19):2062-8. (Free Abstract)
11. Treatment of iron deficiency anemia in adults by Stanley Schrier and Michael Auerbach @UpToDate.com (Subscription required)
12. Approach to anemia in adults with heart failure by Wilson Colucci. @UpToDate.com (Subscription required)
13. British Society of GI Guidelines on workup for iron deficiency: http://gut.bmj.com/content/60/10/1309
14. Serum transferrin receptor/ferritin ratio (http://www.bloodjournal.org/content/89/3/1052?variant=long)
15. Review. Clara Camaschella. Iron Deficiency Anemia. N Engl J Med 2015; 372:1832-1843.
16. Tolkien et al. Ferrous Sulfate Supplementation Causes Significant Gastrointestinal Side-Effects in Adults: A Systematic Review and Meta-Analysis. PLOS One 2015
17. Consider iron supplementation in fatigued non-anemic iron deplete women 1) www.bmj.com/content/326/7399/1124 2) http://www.cmaj.ca/content/early/2012/07/09/cmaj.110950
18. Is there any reason to hold iron in the setting of infection? http://www.clevelandclinicmeded.com/medicalpubs/ccjm/iron-therapy-for-anemia-harmful-setting-infection-3-2011/
19. IV Iron and Heart failure: Anker et al 2009 NEJM = FAIR-HF trial: http://www.nejm.org/doi/full/10.1056/NEJMoa0908355 CONFIRM-HF trial:www.ncbi.nlm.nih.gov/pubmed/25176939; Recent review: https://www.ncbi.nlm.nih.gov/pubmed/26821594