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Iron Deficiency Without Anemia – Common, Important, Neglected (2019)
Esa Soppi* Department of internal medicine, Eira Hospital, Laivurinkatu 29, FI-00150 Helsinki, Finland
Abstract
A serum ferritin concentration of <30 µg/L is the most sensitive and specific test for the identification of iron deficiency in patients with or without anemia. However, patients may be iron deficient at much higher concentrations of ferritin. Iron deficiency without anemia and with normal red blood count is a clinical challenge, and many patients have been diagnosed with a multitude of conditions ranging from hypothyroidism to depression to chronic fatigue syndrome over the years when they have sought help for their often debilitating symptoms. The keys to a correct diagnosis are assessment of the serum ferritin concentration and a meticulous medical history focusing on the possibility of life-long blood losses and diseases such as celiac disease. Differential diagnostic causes for the symptoms must be sought for. The mainstay of therapy is oral iron in sufficient doses for at least 6 to 9 moths together with serum ferritin monitoring. Some patients who do not respond to oral iron treatment may need intravenous iron. The longer the iron deficiency has lasted, the more challenging the therapy may be. Some iron deficient patients without anemia may have had the condition for over a decade, and may not fully recover. The amount of human suffering, the loss of quality of life and the indirect costs to society caused by iron deficiency are huge.
Introduction
Iron deficiency is the most common nutritional deficiency. Several studies in Western countries have shown that 3–9% of children have iron deficiency before puberty. Some 11–33% of young women have iron deficiency after menarche, and 3.5–13% of males are iron deficient after having passed the growth spurt in adolescence. The prevalence of iron deficiency is constantly high, at 9–22%, among menstruating women, but among adult males the prevalence settles to around 1–2%. After menopause, the prevalence of iron deficiency among females approaches the prevalence of males and is 1.4–4% [1-3]. It has been estimated that 25–40% of females have iron deficiency anemia at some stage in their life [3,4]. Still, iron deficiency without anemia is much more common than iron deficiency anemia.
Excluding major blood loss, iron deficiency ensues as the end result of a long period of negative iron balance, i.e., when iron losses exceed iron intake or there are increased demands [5,6]. First, iron stores are gradually and progressively depleted and only then anemia may develop. Clinical data is emerging and showing that many patients may remain in prelatent or latent stages of iron deficiency without progressing to anemia [2,3,7-9].
During my 30-year carrier as a consulting internist I have met hundreds of patients, mainly menstruating females, who have sought medical advice for prolonged (1–35 years) fatigue, brain fog, muscle and joint pains, weight gain, headache, dyspnea, palpitations (sometimes associated with sleep disturbances), arrhythmia, lump in the throat or difficulty in swallowing or restless legs. Over time, the patients have often received a spectrum of diagnoses and corresponding treatments: subclinical hypothyroidism, fibromyalgia, burnout, overtraining, asthma, somber mood extending from melancholy to severe therapyresistant depression, chronic fatigue syndrome and chronic Lyme disease. It is important to include iron deficiency without anemia as a differential diagnostic possibility, because this type of iron deficiency is very often associated with symptoms that severely impair the patient’s performance and quality of life and may even hinder the patient from overcoming the ordinary challenges of everyday life and may cause permanent disability.
Differential diagnosis
The symptoms experienced by persons with iron deficiency are not pathognomonic, although the saying that “usual diseases are common” fits very well. It is important that the physician considers the etiology: What causes the iron deficiency in the patient (Table 2)? Among the common causes for iron deficiency are heavy menstrual bleedings and hemorrhages in connection with pregnancy and delivery among females and multiple blood donations, celiac disease and ulcerative colitis in both genders.
There are several conditions and illnesses with symptoms mimicking iron deficiency. Examples are hypothyroidism, profound vitamin D deficiency, vitamin B12 deficiency, celiac disease, testosterone deficiency, abnormal calcium metabolism, sleep apnea, heavy smoking and even occult malignancy [3,17]. Adequate differential diagnostic consideration is, of course, needed. There are innumerable patients with iron deficiency who have been put on thyroid hormone medication despite normal thyroid function. This is due to the fact that the symptoms of hypothyroidism and iron deficiency are very similar, and the serum thyrotropin activity tends to increase in iron deficiency [22,25]. In this setting, increased TSH-values are due to the enzyme thyroid peroxidase, a hormone that contributes to thyroid hormone synthesis. Thyroid peroxidase contains an iron moiety and in iron deficiency the function of the enzyme is disturbed. The symptoms may abate transiently when the patient takes thyroid hormone, but the iron deficiency must be corrected as soon as possible, during which time the need of thyroxin often decreases. Patients with iron deficiency tend to tolerate thyroid hormones poorly. Once the iron stores have been replenished, it is best to discontinue thyroid medication, if possible. Since both hypothyroidism and iron deficiency are common, it is by no means rare for a patient to have both conditions simultaneously, possibly even complemented with other comorbidities which further accentuate symptoms.
*Iron inhibits the absorption of thyroid hormones, and hence it is best to take the thyroxin tablet in the morning and the first iron pill around noon. Iron absorption is reduced by milk, calcium and magnesium products and by proton pump inhibitors. Also, coffee, tea and cereal products affect negatively the uptake of iron. At higher doses of iron intake, these diet restrictions have less importance. The impact of vitamin C as an uptake enhancer diminishes also when the iron dose increases. The role of the diet as a treatment modality of iron deficiency is generally modest, but once iron deficiency has been corrected, dietary iron is a significant iron homeostasis-maintaining factor.
Conclusion
Iron deficiency is very common and may be ranked among the most common public health concerns today. Diagnosing iron deficiency, especially if there is no iron deficiency anemia, is a challenge for the clinician. Iron deficiency without anemia seems to be an autonomous clinical condition which needs special attention, as has been suggested earlier [9]. Clearly, we have yet much to learn about iron deficiency and iron metabolism and how they relate to the spectrum of symptoms experienced by the patient. Iron deficiency is a real and harsh disease which may lead to severe symptoms and work incapacity. The longer the duration of iron deficiency, the more difficult it is to treat. The treatment of iron deficiency is often carried out with too small doses of iron and for too short a time. The treatment response must be followed up with assessments of the blood count and the serum ferritin concentration. Follow-up must continue for at least one year after normalization of the hemoglobin and ferritin concentrations.
Esa Soppi* Department of internal medicine, Eira Hospital, Laivurinkatu 29, FI-00150 Helsinki, Finland
Abstract
A serum ferritin concentration of <30 µg/L is the most sensitive and specific test for the identification of iron deficiency in patients with or without anemia. However, patients may be iron deficient at much higher concentrations of ferritin. Iron deficiency without anemia and with normal red blood count is a clinical challenge, and many patients have been diagnosed with a multitude of conditions ranging from hypothyroidism to depression to chronic fatigue syndrome over the years when they have sought help for their often debilitating symptoms. The keys to a correct diagnosis are assessment of the serum ferritin concentration and a meticulous medical history focusing on the possibility of life-long blood losses and diseases such as celiac disease. Differential diagnostic causes for the symptoms must be sought for. The mainstay of therapy is oral iron in sufficient doses for at least 6 to 9 moths together with serum ferritin monitoring. Some patients who do not respond to oral iron treatment may need intravenous iron. The longer the iron deficiency has lasted, the more challenging the therapy may be. Some iron deficient patients without anemia may have had the condition for over a decade, and may not fully recover. The amount of human suffering, the loss of quality of life and the indirect costs to society caused by iron deficiency are huge.
Introduction
Iron deficiency is the most common nutritional deficiency. Several studies in Western countries have shown that 3–9% of children have iron deficiency before puberty. Some 11–33% of young women have iron deficiency after menarche, and 3.5–13% of males are iron deficient after having passed the growth spurt in adolescence. The prevalence of iron deficiency is constantly high, at 9–22%, among menstruating women, but among adult males the prevalence settles to around 1–2%. After menopause, the prevalence of iron deficiency among females approaches the prevalence of males and is 1.4–4% [1-3]. It has been estimated that 25–40% of females have iron deficiency anemia at some stage in their life [3,4]. Still, iron deficiency without anemia is much more common than iron deficiency anemia.
Excluding major blood loss, iron deficiency ensues as the end result of a long period of negative iron balance, i.e., when iron losses exceed iron intake or there are increased demands [5,6]. First, iron stores are gradually and progressively depleted and only then anemia may develop. Clinical data is emerging and showing that many patients may remain in prelatent or latent stages of iron deficiency without progressing to anemia [2,3,7-9].
During my 30-year carrier as a consulting internist I have met hundreds of patients, mainly menstruating females, who have sought medical advice for prolonged (1–35 years) fatigue, brain fog, muscle and joint pains, weight gain, headache, dyspnea, palpitations (sometimes associated with sleep disturbances), arrhythmia, lump in the throat or difficulty in swallowing or restless legs. Over time, the patients have often received a spectrum of diagnoses and corresponding treatments: subclinical hypothyroidism, fibromyalgia, burnout, overtraining, asthma, somber mood extending from melancholy to severe therapyresistant depression, chronic fatigue syndrome and chronic Lyme disease. It is important to include iron deficiency without anemia as a differential diagnostic possibility, because this type of iron deficiency is very often associated with symptoms that severely impair the patient’s performance and quality of life and may even hinder the patient from overcoming the ordinary challenges of everyday life and may cause permanent disability.
Differential diagnosis
The symptoms experienced by persons with iron deficiency are not pathognomonic, although the saying that “usual diseases are common” fits very well. It is important that the physician considers the etiology: What causes the iron deficiency in the patient (Table 2)? Among the common causes for iron deficiency are heavy menstrual bleedings and hemorrhages in connection with pregnancy and delivery among females and multiple blood donations, celiac disease and ulcerative colitis in both genders.
There are several conditions and illnesses with symptoms mimicking iron deficiency. Examples are hypothyroidism, profound vitamin D deficiency, vitamin B12 deficiency, celiac disease, testosterone deficiency, abnormal calcium metabolism, sleep apnea, heavy smoking and even occult malignancy [3,17]. Adequate differential diagnostic consideration is, of course, needed. There are innumerable patients with iron deficiency who have been put on thyroid hormone medication despite normal thyroid function. This is due to the fact that the symptoms of hypothyroidism and iron deficiency are very similar, and the serum thyrotropin activity tends to increase in iron deficiency [22,25]. In this setting, increased TSH-values are due to the enzyme thyroid peroxidase, a hormone that contributes to thyroid hormone synthesis. Thyroid peroxidase contains an iron moiety and in iron deficiency the function of the enzyme is disturbed. The symptoms may abate transiently when the patient takes thyroid hormone, but the iron deficiency must be corrected as soon as possible, during which time the need of thyroxin often decreases. Patients with iron deficiency tend to tolerate thyroid hormones poorly. Once the iron stores have been replenished, it is best to discontinue thyroid medication, if possible. Since both hypothyroidism and iron deficiency are common, it is by no means rare for a patient to have both conditions simultaneously, possibly even complemented with other comorbidities which further accentuate symptoms.
*Iron inhibits the absorption of thyroid hormones, and hence it is best to take the thyroxin tablet in the morning and the first iron pill around noon. Iron absorption is reduced by milk, calcium and magnesium products and by proton pump inhibitors. Also, coffee, tea and cereal products affect negatively the uptake of iron. At higher doses of iron intake, these diet restrictions have less importance. The impact of vitamin C as an uptake enhancer diminishes also when the iron dose increases. The role of the diet as a treatment modality of iron deficiency is generally modest, but once iron deficiency has been corrected, dietary iron is a significant iron homeostasis-maintaining factor.
Conclusion
Iron deficiency is very common and may be ranked among the most common public health concerns today. Diagnosing iron deficiency, especially if there is no iron deficiency anemia, is a challenge for the clinician. Iron deficiency without anemia seems to be an autonomous clinical condition which needs special attention, as has been suggested earlier [9]. Clearly, we have yet much to learn about iron deficiency and iron metabolism and how they relate to the spectrum of symptoms experienced by the patient. Iron deficiency is a real and harsh disease which may lead to severe symptoms and work incapacity. The longer the duration of iron deficiency, the more difficult it is to treat. The treatment of iron deficiency is often carried out with too small doses of iron and for too short a time. The treatment response must be followed up with assessments of the blood count and the serum ferritin concentration. Follow-up must continue for at least one year after normalization of the hemoglobin and ferritin concentrations.
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