Tired? Breathless? RLS? Iron Deficiency Might be the Cause
- Iron-deficiency accounts for more than half of all cases of anemia
- Low iron causes a long list of symptoms, including confusion, thinning hair, depression and many more.
- Insufficient iron as the cause is often missed because doctors usually don’t order the right test (or they interpret it wrong).
- Most iron replacment can cause painful side effects. Know which form of iron to take that avoids these issues.
by Dr. John Neustadt
Iron is essential for health and required for hundreds of biological functions. Your red blood cell’s ability to carry oxygen requires oxygen. Your ability to create hormones such as thyroid hormone, dopamine and epinephrine depend on having enough iron. Iron is required to create, protect and repair your genes, to produce energy and for your muscle to work properly.
Iron deficiency often develops gradually, so most people don’t even realize they have a problem. People may blame their shortness of breath, restless leg syndrome (RLS), low energy or feeling depressed on other things, not realizing that low iron could be the underlying cause.
Iron Deficiency Anemia
Anemia is a medical condition in which the blood has a decreased ability to delivery oxygen to tissues and cells throughout the body. While there are many different types of anemia, the most common is iron deficiency anemia.
According to the World Health Organization, more than 30% of the worldwide population has anemia. Anemia hits low-income countries hardest, affecting one of every 2 pregnant women and preschool children in developing countries. Although low-income countries have the highest rates of anemia, it is a growing problem even in the United States. Rates of anemia nearly doubled from the period of 2003-2004 to the period of 2011-2012 in the United States, reaching a rate just above 7% by 2012.
While there are many types of anemia, iron deficiency anemia is the most common. Globally, iron-deficiency anemia accounts for at least 50% of all anemia cases, and an estimated 1.62 billion people suffer with iron deficiency. Iron deficiency anemia affects at least twice as many women as men.
While there are many different types of anemia, all end up having the same effect—a decrease in the ability to deliver oxygen to the cells. Hemoglobin is a specialized protein inside red blood cells that carries oxygen from the lungs to the rest of the body. Hemoglobin also returns carbon dioxide from the body’s cells to the lungs so that it can be exhaled. In anemia, when the amount of hemoglobin or red blood cells is lower than normal, tissues such as muscles and the brain become deprived of oxygen.
Since red blood cells survive for about 3-4 months, the pool of red blood cells in the body is in constant flux. Approximately two million cells are released from the bone marrow into circulation every second, and that same number of cells are recycled and replaced. The constant turnover of red blood cells means the body must have a steady supply of nutrients to produce healthy cells.
Iron Deficiency Symptoms
Since iron is used for so many processes in the body, it’s not surprising that low iron can show up as many different symptoms. The most common symptom is fatigue. That’s because every cell in the body relies on oxygen to produce energy. When the number of red blood cells or amount of hemoglobin in your blood is lower than normal, oxygen can’t be carried effectively throughout your body. That causes your cells to produce less energy, and that makes you feel tired. In fact, some of the earliest symptoms of iron deficiency are simply feeling tired, lethargic or weak.
Iron deficiency can be an underlying cause for:
- Burning, tingling or discomfort in the legs—symptoms that are often diagnosed as restless leg syndrome
- Cloudy thinking
- Feeling cold
- Hair loss, especially pre-menopausal hair loss
- Rapid heart rate
- Shortness of breath
Because these symptoms have many other possible causes, anemia often goes unrecognized. Symptoms vary depending on the severity of iron deficiency and can develop slowly over time.
It’s possible to have iron deficiency or anemia without noticing any symptoms. Anemia often develops gradually, with only vague and subtle signs in the early stages. Many children with mild anemia experience no symptoms at all. Many adults experience fatigue or mild depression, which they might attribute to other causes.
Causes of Iron Deficiency
While iron deficiency can occur in women because of blood loss from their periods, it can also be caused by more subtle blood loss in women and men from bleeding ulcers or inflammatory bowel disease (IBD), such as Crohn’s Disease or Ulcerative Colitis. Poor iron absorption because of celiac disease or other digestive disorders.
Chronic disease dramatically increases a person’s risk for anemia. As many as 74% of people with inflammatory bowel disease (IBD) also have anemia and as many as 43% of patients with hypothyroid disease. Chronic viral infections (such as hepatitis C or human immunodeficiency virus) and autoimmune diseases (like rheumatoid arthritis) are also strongly associated with anemia.
Iron deficiency anemia can also occur when there is an increased demand for blood, which occurs during pregnancy or periods of rapid growth in children.
An often-overlooked cause of iron deficiency is low-stomach acid, also called hypochlorhydria. According the US Centers for Disease Control and Prevention (CDC), low stomach acid decreases a persons’ ability to absorb iron. Digestion involves the breakdown of large molecules into smaller, readily absorbed molecules. Stomach acid is required for this process. When there isn’t enough stomach acid, people can have a decreased ability to digest and absorb nutrients from food.
Low stomach acid is surprisingly common. Many people produce less stomach acid as they age, and it’s been estimated that 10–21% of people sixty to sixty-nine years old, 31% of those seventy to seventy-nine years old, and 37% of those above the age of eighty have low stomach acid, and this may be even higher in people with autoimmune conditions.
Risks for iron deficiency include:
- Celiac disease
- Chronic kidney disease
- Crohn’s Disease
- Gastric bypass surgery
- Hypochlorhydria (low stomach acid)
- Infections such as pylori
- Menses (periods)
- Ulcerative Colitis
- Vegetarian diet
Make Sure to Order the Right Test
The complete blood count (CBC) is a routine blood test that healthcare providers order on annual exams and as a general screening test for anemia. Along with reporting white blood cell and platelet counts, the results of the CBC show the number of immature red blood cells, the number of mature red blood cells, hemoglobin concentration and the size and shape of the red blood cells.
While a CBC is an excellent screening tool for anemia, it doesn’t test the most sensitive indicator of iron status—ferritin. Ferritin is the storage form of iron in the body, storing up to 80% of the total amount of iron. The largest concentrations of ferritin are in the liver, spleen, bone marrow and skeletal muscles. However, some ferritin circulates in the blood, which is why it can be detected on a blood test.
Since red blood cells last about 90 days, the amount the storage form of iron, ferritin, will be depleted about three months before evidence of low iron appear on a CBC test. And since iron is used for so many different processes in the body, people can experience symptoms of iron deficiency long before they appear on a CBC. A serum ferritin test is the most reliable screening test for iron status.
However, while it’s the most sensitive indicator for iron, the reference ranges on a serum ferritin test are so large that most clinicians don’t understand how to appropriately interpret them. Reference ranges on tests provide the “normal” values. Anything outside of that range is considered “abnormal.” Reference ranges are created by labs that take the results from a lot of test samples, apply some math to them and determine what normal is.
By definition, “normal” is a range in which 95% test results will fall. Since by definition 95% of people automatically fall within the normal range, there will always be 5% of people who are outside the normal range. What this math doesn’t tell healthcare providers or patients is what “optimal” results are. Your test result may be technically normal, but is it optimal for health? That would be a good question to ask your healthcare provider the next time you review labs.
Ferritin is a great example of this. Most data used to create standard laboratory reference ranges for serum ferritin are from studies conducted more than 30 years ago. These reference ranges do not reflect ethnic or geographic diversity, and were performed in an era for which laboratory methods no longer reflect present practice.
One consequence for using reference ranges based on decades-old studies is that the “normal” range for ferritin test results is so broad as to be clinically irrelevant. Normal reference ranges can vary by lab, but serum ferritin levels from 12 to 200 nanograms per milliliter are often considered “normal.” A ferritin level below 12 nanograms per milliliter is reported as iron deficiency. Many experts agree, however, that iron deficiency is likely when the ferritin level falls below 50 nanograms per milliliter.
In fact, a large study of nearly 200 women ages 18-53 years confirms that iron supplementation should begin long before a person’s serum ferritin drops below 12 nanograms per milliliter. Women were admitted into the study if they had normal CBC test results but levels of ferritin less than 50 and if they also complained of fatigue. In those women, taking iron supplementation for 12 weeks improved their energy by nearly 48%.
The standard reference range for ferritin also don’t apply well to the elderly or when inflammation is present. Low ferritin is an indicator of not having enough iron. But ferritin is released into the blood when the body reacts to inflammation. As people get older their risk for chronic inflammatory diseases increases. These include arthritis, heart disease, many cancers, glomerulonephritis, hepatitis, inflammatory bowel disease (IBD, which includes Crohn’s Disease and Ulcerative Colitis), asthma and autoimmune diseases such as Systemic Lupus Erythematosus (SLE, Lupus) and Sjogren’s Syndrome.
A study of nearly 250 elderly patients confirms this. Study volunteers were approximately 70 years old. The results showed that serum ferritin of less than 100 nanograms per milliliter predicted iron deficiency. The researchers concluded, “These findings indicate that in elderly subjects, iron deficiency anemia may develop with higher levels of serum ferritin. Hence, the conventional cutoff of serum ferritin for the diagnosis of iron deficiency anemia in young adults is not appropriate for the elderly population.”
What’s a person to do? Serum ferritin is the most sensitive indicator of iron status, yet the standard laboratory reference range for ferritin are so broad as to be not clinically relevant in for most people. And serum ferritin elevated in the elderly and people with inflammation even when the person doesn’t have iron deficient anemia.
When iron deficiency is detected, iron replacement is typically done using an iron dietary supplements combined with emphasizing more iron rich foods in the diet.
Oral iron is often prescribed in the form of iron salts, such as iron oxide, iron sulfate, iron gluconate or iron fumarate (these are also called ferrous oxide, sulfate, gluconate or fumarate). Unfortunately, taking iron in the form of iron salts presents 2 problems. The first is that only about 50% of the iron in these iron pills is absorbed through the intestinal lining. In some cases, the rate of absorption has been reported to be as low as 20%.
The second problem is that salts like ferrous sulfate cause unwanted gastrointestinal side effects, like nausea, indigestion or constipation. A summary of 43 studies found that ferrous sulfate was more than twice as likely to cause gastrointestinal distress than placebo and more than 3 times as likely to cause these side effects than intravenous iron.
Oral iron supplements are also available in a chelated form, rather than a salt form. Chelated iron is bound to amino acids, which improves its absorption and decreases side effects. Iron absorption from iron bisglycinate chelate has been shown to be 4 times better than absorption from ferrous sulfate. A randomized controlled trial of school children in Mexico found that oral supplementation with iron bisglycinate chelate increased ferritin (the storage form of iron in the body) more effectively that iron sulfate after 6-months of supplementation.
Because of complaints from patients about iron supplements causing GI cramping, bloating and constipation, Dr. Neustadt began researching the most absorbable and tolerable forms of iron. Based on this research, he created FerroSolve, which contains the highest-dose, most absorbable form of iron that’s GI safe and doesn’t cause discomfort or constipation.
Allen RP. Restless Leg Syndrome/Willis-Ekbom Disease Pathophysiology. Sleep Med Clin. 2015;10(3):207-14. [Article]
Babaei M, Shafiei S, Bijani A, Heidari B, Hosseyni SR, Vakili Sadeghi M. Ability of serum ferritin to diagnose iron deficiency anemia in an elderly cohort. Rev Bras Hematol Hemoter. 2017;39(3):223-228. [Article]
Bovell-Benjamin AC, Viteri FE, Allen LH. Iron absorption from ferrous bisglycinate and ferric trisglycinate in whole maize is regulated by iron status. Am J Clin Nutr. 2000;71(6):1563-1569. [Article]
Daru J, Colman K, Stanworth SJ, De La Salle B, Wood EM, Pasricha SR. Serum ferritin as an indicator of iron status: what do we need to know? Am J Clin Nutr. 2017;106(Suppl 6):1634S-1639S. [Article]
Duque X, Martinez H, Vilchis-Gil J, et al. Effect of supplementation with ferrous sulfate or iron bis-glycinate chelate on ferritin concentration in Mexican schoolchildren: a randomized controlled trial. Nutr J. 2014;1371. [Article]
Erdogan M, Mehmet E, Kösenli A, et al. Characteristics of anemia in subclinical and overt hypothyroid patients. Endocr J. 2012;59(3):213-220. [Article]
Harrington M, Hotz C, Zeder C, et al. A comparison of the bioavailability of ferrous fumarate and ferrous sulfate in non-anemic Mexican women and children consuming a sweetened maize and milk drink. Eur J Clin Nutr. 2011;65(1):20-25. [Article]
Higgins JM. Red blood cell population dynamics. Clin Lab Med. 2015;35(1):43-57. [Article]
Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Laboratory reference values. N Engl J Med. 2004;351(15):1548-1563. [Article]
Le CH. The Prevalence of Anemia and Moderate-Severe Anemia in the US Population (NHANES 2003-2012). PLoS One. 2016. [Article]
Ludwig H, Evstatiev R, Kornek G, et al. Iron metabolism and iron supplementation in cancer patients. Wien Klin Wochenschr. 2015;127(23-24):907-919. [Article]
Mackie S, Winkelman JW. Normal ferritin in a patient with iron deficiency and RLS. J Clin Sleep Med. 2013;9(5):511-513. [Article]
Micronutrient Deficiencies. World Health Organization Website. http://www.who.int/nutrition/topics/ida/en/. Accessed November 10, 2017. [Article]
Morinet F, Leruez-Ville M, Pillet S, Fichelson S. Concise review: Anemia caused by viruses. Stem Cells. 2011;29(11):1656-1660. [Article]
Namaste SM, Rohner F, Huang J, et al. Adjusting ferritin concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. Am J Clin Nutr. 2017;106(Suppl 1):359S-371S. [Article]
Park SY, Na SY, Kim JH, Cho S, Lee JH. Iron plays a certain role in patterned hair loss. J Korean Med Sci. 2013;28(6):934-938. [Article]
Recommendations to Prevent and Control Iron Deficiency in the United States. MMWR 1998;47(No. RR-3). Atlanta, GA: Centers for Disease Control and Prevention;1998. [Article]
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;10(2):e0117383. [Article]
Vaucher P, Druais PL, Waldvogel S, Favrat B. Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial. CMAJ. 2012;184(11):1247-1254. [Article]
Wang M. Iron Deficiency and Other Types of Anemia in Infants and Children. Am Fam Physician. 2016;93(4):270-278. [Article]
Wang W, Knovich MA, Coffman LG, Torti FM, Torti SV. Serum ferritin: Past, present and future. Biochim Biophys Acta. 2010;1800(8):760-769. [Article]
Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anemia in inflammatory bowel disease: a systematic review of the literature. Am J Med. 2004;116 Suppl 7A44S-49S. [Article]
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