Iron


Article Author:
Jonathan Barney


Article Editor:
Leila Moosavi


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
8/15/2019 9:34:53 PM

Indications

Iron is a mineral necessary for human life. It plays an important role in DNA synthesis and many other metabolic processes. It is also an essential component of heme, within hemoglobin, the protein responsible for transporting oxygen throughout the body. Hemoglobin is present within erythrocytes (red blood cells) which are produced by hematopoietic stem cells of the bone marrow. The stimulus for the production of red blood cells within the marrow is provided by the kidneys, via a hormone called erythropoietin. Erythropoietin travels from the kidneys to the bone marrow where it exerts its action. In addition to providing a basal amount of erythropoietin, the kidneys will increase synthesis and secretion in response to hypoxia. 

Individuals who have a deficiency of iron have a decrease in their body’s ability to transport and subsequently utilize oxygen from the air they breathe. Symptoms may manifest in a variety of ways including but not limited to fatigue, pallor, tachycardia, and exercise intolerance. Though iron deficiency can occur with or without anemia, it is, in fact, the most common cause of anemia worldwide, representing a significant public health challenge.[1] Those most at risk are patients with an increased physiologic demand for iron, e.g., young children, adolescents, and pregnant women; as well as those with impaired absorption, e.g. those with inflammatory bowel disease or who have undergone certain gastrointestinal surgical procedures.[2] 

Evaluation of iron status is best performed by assessing serum ferritin and transferrin saturation. Serum ferritin represents the level of iron stores in the body. Serum ferritin value less than 30 ng/mL is generally considered diagnostic of iron deficiency; less than 10 to 15 ng/mL is 99 percent specific for iron deficiency anemia; with the caveat or ferritin also being an acute phase reactant, and levels may be affected by inflammatory processes. Transferrin saturation is another metric used to assess iron status which represents the level of iron readily available for transport to tissues. Transferrin saturation of under 20% generally indicates iron deficiency. Iron deficiency may also manifest on a complete blood count (CBC) as a microcytic, hypochromic, anemia; however, iron status should not be based solely on red blood cell characteristics as hematopoiesis is often not affected in early stages of deficiency.

The implementation of iron therapy can be initiated on the basis of several different guidelines depending on etiology. The European consensus on the diagnosis and management of iron deficiency and anemia in inflammatory bowel disease (ECCO) suggests iron supplementation for patients with ferritin under 30 ng/mL or less than 100 ng/mL if transferrin saturation is below 20% for those with iron deficiency due to inflammatory bowel disease. Similarly, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines use serum ferritin below 100 ng/mL and transferrin saturation under 20% as an indication for therapy in patients with renal disease. The European Society of Cardiology uses ferritin less than 100 ng/mL or 100 to 299 ng/mL with transferrin saturation below 20%, in patients with heart failure.[1] 

Most oral iron formulations are considered to be dietary supplements, and as such are not subject to the same set of regulations used by the U.S. Food and Drug Administration (FDA) in the evaluation of traditional drug products. Parenteral, i.e. intravenous iron therapy is approved by the FDA for treatment of iron deficiency anemia for patients who are intolerant to oral iron or have demonstrated an inadequate response, as well as for patients with chronic kidney disease. It should be noted that further guidelines and restrictions vary by individual brand of parenteral iron.

Mechanism of Action

Intravenous iron – Iron therapy in intravenous form consists of an iron-hydroxide core encased in a carbohydrate ligand. After administration, these complexes are taken up by macrophages via endocytosis. Once inside macrophages they can either be expelled into the serum as ferrous iron (Fe2+) or incorporated into ferritin for storage. The iron expelled from the macrophage is quickly oxidized to ferric iron (Fe3+) and bound to transferrin for transport to target sites, which include the bone marrow for production of hemoglobin and the liver for storage.[3]

Oral iron – Iron administered orally travels to the duodenum where it is taken up into enterocyte cells along the brush border by the divalent metal-ion transporter 1 (DMT1). From there, it can either be incorporated into ferritin for storage or expelled into the serum by the ferroportin 1 transporter on the basolateral membrane. This transporter is bound to multicopper oxidases that oxidize ferrous iron (Fe2+) into ferric iron (Fe3+) that can bind to transferrin for transport to the bone marrow for hemoglobin synthesis or to the liver for storage.[4]

Of note, these processes of active absorption can only absorb a set amount of iron at a given time. Iron consumed exceeding these limits is absorbed passively into the blood via the paracellular route.[4][5]

Administration

The administration of iron supplementation can be both orally and parenterally. Oral iron therapy is the preferred route as it tends to be both affordable and effective in mild to moderate cases of deficiency. For severe iron deficiency or when oral treatment fails (or is intolerable), or in patients with impaired intestinal absorption, intravenous therapy can be the administration option. Both oral and intravenous iron are available in a variety of formulations.[6]

Adverse Effects

Oral iron – the most common side effects of oral iron administration are gastrointestinal upset; including nausea, diarrhea, cramping, and more commonly constipation. More serious is gastrointestinal hemorrhage and ulceration, as well as hypersensitivity reactions.[7]

Intravenous iron – the most common side effect of intravenous iron administration is hypotension. Other side effects include minor infusion reactions, typically presenting as arthralgias/myalgias, as well as headache, nausea, and flushing.[8]

Contraindications

Hypersensitivity and hemochromatosis are the main contraindications. Contraindications to intravenous iron infusion include the first trimester of pregnancy. Use caution in patients with peptic ulcer disease, inflammatory bowel disease, and patients receiving regular blood transfusions.[9]

Monitoring

The hemoglobin level should increase by 2 g/dL within 4 to 8 weeks of initiating therapy. Ferritin should be rechecked 8 to 12 weeks after completion of treatment as normalization of ferritin levels and transferrin saturation is the target goal. For patients suffering from severe deficiency, it may take up to 3 months for hemoglobin to return to the normal range.[10]

Toxicity

Both oral and intravenous forms of iron have the potential for causing oxidative stress and damage. Iron-induced coagulopathy, liver damage, kidney failure, and cardiomyopathy may occur upon reaching toxic levels. The toxicity correlates with the amount of elemental iron within iron products ingested. Ingestion/administration of 20 mg/kg or more of elemental iron can result in symptoms of toxicity. Serum levels peak between 4 and 6 hours and can be used to assess the potential for toxicity. If a patient is symptomatic and hemodynamically unstable, they should be treated with IV fluids and potentially with deferoxamine – a chelating agent that can bind to iron and be excreted renally, removing it from the body. Vitamin K or fresh frozen plasma are therapy options in cases of iron-induced coagulopathy. A toxicologist should be consulted for guidance when iron toxicity is suspected.[11]

Enhancing Healthcare Team Outcomes

Healthcare teams are often made up of many members from different disciplines and can include, but are not limited to a physician, nurse practitioner or physician assistant, pharmacist, and nurse.

The physician (MD, DO, NP, PA) will evaluate and decide whether supplemental iron is needed. The pharmacist can consult with various dose formulations available and recommended doses, as well as performing medication reconciliation. Nursing can counsel on proper administration (e.g., avoid taking calcium of calcium-rich foods within 2 hours of supplemental iron, etc.) and verify patient compliance. A dietitian or nutritionist can also weigh in to educate the patient regarding improving their diet and iron-rich foods. All these providers on the interprofessional healthcare team must report back to the treating clinician should they encounter any concerns.

All such team members treating iron-deficient patients must be able to not only recognize indications for the administration of iron, but must also be familiar with contraindications, adverse effects, monitoring, and toxicity, and practice interprofessional communication to ensure all healthcare team members are in synch. Increasing the knowledge of iron therapy for each team member will improve implementation and by extension, improve patient outcomes. [Level V]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Iron - Questions

Take a quiz of the questions on this article.

Take Quiz
A man working for a company is relocated to a mountainside station to oversee the construction of a new corporate distribution center. When he first arrived there, he found that he was easily winded and tired, even when performing normal activities. After several weeks of living there, he feels like he is back to normal. Physiologic changes that led to the resolution of his symptoms include an increase in production of what protein?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Most ferrous salt products are orally administered. Which one of the following is a commercially available parenteral iron product?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 19-year-old female presents to the clinic complaining of dizziness, headache, and a racing heartbeat. She appears pale and tired. She denies having medical problems and is not taking any medication. When questioned about her about gynecologic history, she reports having very heavy menses over the past year. An initial laboratory workup is significant for a serum ferritin level of 20 ng/ml, transferrin saturation of 19%, and a hemoglobin of 10 g/dL. Which of the following best describes the patient's diagnosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 24-year-old female presents to the clinic with a chief complaint of exercise intolerance. She has also been feeling fatigued, slightly short of breath, and experiencing intermittent palpitations. Her past medical history is significant for inflammatory bowel disease. Which of the following is the best investigation to assess her iron status?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 16-year-old female presents to the emergency department with dizziness, fast heart rate, and fatigue. On evaluation, it is discovered that she lacks a metallic nutrient involved in the transport of oxygen in the blood. Which of the following is the most common side effect of the drug given to treat this condition?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 66-year-old female is admitted to the hospital for severe iron deficiency secondary to chronic kidney disease. After receiving her first two infusions of parenteral iron therapy, she begins to complain of muscle, and joint pain and her blood pressure drops to 92/65 mmHg. In addition to intravenous fluids, a drug with which of the following mechanism of action is most appropriate for this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 64-year-old female with a history of chronic kidney disease is started on dialysis. After two weeks, she begins having symptoms consistent with anemia. A complete blood count (CBC) obtained by her provider confirms anemia; however, her ferritin and transferrin saturation are within the normal range. Which of the following best explains these findings?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Iron - References

References

Muñoz M,Gómez-Ramírez S,Besser M,Pavía J,Gomollón F,Liumbruno GM,Bhandari S,Cladellas M,Shander A,Auerbach M, Current misconceptions in diagnosis and management of iron deficiency. Blood transfusion = Trasfusione del sangue. 2017 Sep;     [PubMed]
Girelli D,Ugolini S,Busti F,Marchi G,Castagna A, Modern iron replacement therapy: clinical and pathophysiological insights. International journal of hematology. 2018 Jan;     [PubMed]
Danielson BG, Structure, chemistry, and pharmacokinetics of intravenous iron agents. Journal of the American Society of Nephrology : JASN. 2004 Dec;     [PubMed]
Fuqua BK,Vulpe CD,Anderson GJ, Intestinal iron absorption. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2012 Jun;     [PubMed]
Geisser P,Burckhardt S, The pharmacokinetics and pharmacodynamics of iron preparations. Pharmaceutics. 2011 Jan 4;     [PubMed]
Crielaard BJ,Lammers T,Rivella S, Targeting iron metabolism in drug discovery and delivery. Nature reviews. Drug discovery. 2017 Jun;     [PubMed]
Tolkien Z,Stecher L,Mander AP,Pereira DI,Powell JJ, Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PloS one. 2015;     [PubMed]
Auerbach M,Macdougall IC, Safety of intravenous iron formulations: facts and folklore. Blood transfusion = Trasfusione del sangue. 2014 Jul;     [PubMed]
Rampton D,Folkersen J,Fishbane S,Hedenus M,Howaldt S,Locatelli F,Patni S,Szebeni J,Weiss G, Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica. 2014 Nov;     [PubMed]
Jimenez K,Kulnigg-Dabsch S,Gasche C, Management of Iron Deficiency Anemia. Gastroenterology     [PubMed]
Yuen HW,Becker W, Iron Toxicity 2019 Jan;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of PA-Hospital Medicine. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for PA-Hospital Medicine, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in PA-Hospital Medicine, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of PA-Hospital Medicine. When it is time for the PA-Hospital Medicine board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study PA-Hospital Medicine.