Clinical Case Reports and Reviews Case Report ISSN: 2059-0393 Iron Deficiency Without Anemia – Common, Important, Neglected 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 very often associated with symptoms that severely impair the patient’s performance and quality of life and may even hinder the patient from Iron deficiency is the most common nutritional deficiency. Several overcoming the ordinary challenges of everyday life and may cause studies in Western countries have shown that 3–9% of children have permanent disability. iron deficiency before puberty. Some 11–33% of young women have iron deficiency after menarche, and 3.5–13% of males are iron deficient Evaluation of iron balance after having passed the growth spurt in adolescence. The prevalence The body contains about 3–4 grams of iron, most of which resides of iron deficiency is constantly high, at 9–22%, among menstruating in the iron stores of the body and bound to hemoglobin, muscle tissue women, but among adult males the prevalence settles to around 1–2%. and enzyme proteins of metabolism. After menopause, the prevalence of iron deficiency among females approaches the prevalence of males and is 1.4–4% [1-3]. It has been Males lose, on average, 1 mg and women 2 mg of iron daily as the estimated that 25–40% of females have iron deficiency anemia at some surface of the skin and mucous membranes of the gut are sloughed stage in their life [3,4]. Still, iron deficiency without anemia is much off; among women, menstrual bleedings account for the higher loss of more common than iron deficiency anemia. iron. These losses are compensated for by increased iron absorption from the small intestine. Of a daily intake of 10–14 mg of iron, 5–15% Excluding major blood loss, iron deficiency ensues as the end (or about 0.5–2.0 mg) is absorbed. This takes place regardless of the result of a long period of negative iron balance, i.e., when iron losses daily liberation and reuse of 20–25 mg of iron by the body. A regular exceed iron intake or there are increased demands [5,6]. First, iron occidental diet does not always provide a sufficient amount of iron. This stores are gradually and progressively depleted and only then anemia is the case especially at times of body growth, pregnancy, hemorrhage may develop. Clinical data is emerging and showing that many patients (e.g., heavy or prolonged menstrual bleeding) or high-level physical may remain in prelatent or latent stages of iron deficiency without training [3,7]. One milliliter of blood contains about 0.5 mg of iron. At progressing to anemia [2,3,7-9]. times of enhanced iron needs, the body may increase iron absorption, During my 30-year carrier as a consulting internist I have met provided that iron is available in the diet. The absorption of iron hundreds of patients, mainly menstruating females, who have sought from the gut into the body compartments is regulated by complicated medical advice for prolonged (1–35 years) fatigue, brain fog, muscle and physiological mechanisms [1,3,10]. joint pains, weight gain, headache, dyspnea, palpitations (sometimes Iron deficiency anemia:Anemia is defined as reduction of the associated with sleep disturbances), arrhythmia, lump in the throat or blood hemoglobin concentration to less than 120 g/L for women and difficulty in swallowing or restless legs. Over time, the patients have less than 130 g/L for men [11]. There are several forms of anemia and often received a spectrum of diagnoses and corresponding treatments: subclinical hypothyroidism, fibromyalgia, burnout, overtraining, asthma, somber mood extending from melancholy to severe therapy- resistant depression, chronic fatigue syndrome and chronic Lyme *Correspondence to: Esa Soppi, Depatrment of Internal medicine, Eira Hospital, disease. It is important to include iron deficiency without anemia as a Laivurinkatu 29, FI-00150 Helsinki, Finland, E-mail: [email protected] differential diagnostic possibility, because this type of iron deficiency is Received: May 30, 2019; Accepted: June 07, 2019; Published: June 10, 2019 Clin Case Rep Rev, 2019 doi: 10.15761/CCRR.1000456 Volume 5: 1-7 Soppi E (2019) Iron Deficiency Without Anemia – Common, Important, Neglected these cannot be differentiated from each other by the hemoglobin value Table 1. Different stages of iron deficiency (*A significant part of these patients may never alone. The most common form of anemia is, however, iron deficiency progress to overt anemia) anemia and iron deficiency must always be considered in the diagnosis Prelatent Latent* Preanemia* Anemia of anemia. Iron staining of a bone marrow aspiration sample is an Often reduced but Hemoglobin Normal Normal within the reference Reduced invaluable method to assess iron stores, but the procedure is often not range easily available (Table 1). Bone marrow iron Reduced Reduced Absent Absent Iron constitutes an essential cofactor of tens of enzymes in our Serum ferritin Reduced <50-70 μg/l <30 μg/l <15 μg/l Transferrin Normal, Normal, body, and the activity of these enzymes is reduced in iron deficiency. 15–20% <15% saturation >30% 20–30% Iron is required for these enzymes to work properly. These enzymes, Serum transferrin Normal Normal Often increased Increased e.g., cytochrome c, cytochrome oxidase, α-glycorophosphate oxidase, receptor succinic dehydrogenase, thyroid peroxidase and aconitase catalyze at Mean corpuscular Normal but least 180 biochemical reactions necessary for energy metabolism, brain volume/ close to Unequivocally Normal Slightly reduced function (e.g., dopamine metabolism, conduction of nerve impulses) hemoglobin lower limit of reduced and thyroid hormone synthesis [2,3,12,13]. This helps us to understand concentration reference Classical Common and may why the symptoms of iron deficiency are so extremely variable. Still, it Symptoms May exist Common symptoms of be debilitating is surprising that some more or less symptom-free patients with proven anemia iron deficiency of long duration experience dramatic exacerbation of the symptoms of iron deficiency in connection with an acute condition or stress. For the assessment of anemia, the blood count must always be reviewed, addition to the blood hemoglobin concentration [5,6]. A reduced erythrocyte size (E-MCV or median corpuscular volume) <80 fl and/or mean corpuscular hemoglobin (E-MCH) <27 pg indicate iron deficiency anemia. Iron deficiency anemia usually emerges gradually, and it is more important to follow the changes of the hemoglobin concentration and the other blood count values over time than just to evaluate a single blood count sample. Modern electronic patient charts make such an evaluation over time a rather simple endeavor. In a patient with symptoms, blood count changes in the direction of iron deficiency may imply the presence of iron deficiency even years before the stringent criteria of iron deficiency anemia are fulfilled. Because of Figure 1. The hemoglobin value of a young man, age 35, had been about 165 g/l in numerous blood samples taken over several years before the consultation the slow progression, especially young patients may have extremely low hemoglobin values – even as low as 40–60 g/L – at the time when iron for less than 4 months (arrow). By that time, the patient was clinically deficiency anemia is diagnosed. healthy, and his hemoglobin concentration reached the pretreatment Ferritin: Ferritin is the name of a family of complex molecules value within 2 years. He consumed a regular diet. Interestingly, the ferritin value continued to increase for 3 years, i.e., even long after the which bind iron [3]. One ferritin molecule may bind up to 4,500 hemoglobin had reached the normal value for him. This phenomenon iron atoms. The correlation between serum ferritin and body storage reflects how the iron stores were replenished over a period of time which iron levels is strong. Almost one third of the body iron is bound to exceeded the time to reach a normal hemoglobin value. This patient's ferritin, and thus changes in the body’s iron stores are reflected by the individual ferritin concentration exceeds 250 µg/L. Iron deficiency concentration of ferritin in the serum. The ferritin concentration rises may be corrected also if the patient follows a regular diet. Since iron also in inflammatory and infectious conditions. In this sense ferritin deficiency moves the iron balance in a positive direction, this facilitates acts like the erythrocyte sedimentation rate (ESR) or the concentration replenishment of iron stores, albeit very gradually.