Iron-Deficiency Anemia Case File
Eugene C. Toy, MD, Gabriel M. Aisenberg, MD
Case 54
A healthy 52-year-old man presents to the office complaining of increasing fatigue for the past 4 to 5 months. He exercises every day, and lately he has noticed becoming short of breath while jogging. He denies orthopnea, paroxysmal nocturnal dyspnea, or swelling in his ankles. The patient reports occasional joint pain, for which he frequently uses over-the-counter ibuprofen. He denies bowel changes, melena, or bright red blood per rectum, but he reports vague left-sided abdominal pain for a few months off and on unrelated to food intake. The patient denies fever, chills, nausea, or vomiting. He has lost a few pounds intentionally with diet and exercise.
On examination, the patient weighs 205 lb and is afebrile. There is slight pallor of the conjunctiva, skin, and palms. No lymphadenopathy is noted. Chest is clear to auscultation bilaterally. Examination of the cardiovascular system reveals a regular rate and rhythm, with no rub or gallop. There is a systolic ejection murmur. His abdomen is soft and nontender, with no hepatosplenomegaly. Bowel sounds are present. He has no extremity edema, cyanosis, or clubbing. His peripheral pulses are palpable and symmetric. His hemoglobin level is 8.2 g/dL.
▶ What is the most likely diagnosis?
▶ What is your next diagnostic step?
▶ What are the risk factors for this condition?
ANSWERS TO CASE 54:
Iron-Deficiency Anemia
Summary: A 52-year-old man presents with
- A 4- to 5-month history of increasing exercise intolerance
- Regular nonsteroidal anti-inflammatory drug (NSAID) use
- Systolic ejection murmur and pallor on examination
- Hemoglobin of 8.2 g/dL
Most likely diagnosis: Chronic blood loss and iron-deficiency anemia, possibly due to regular NSAID use.
Next diagnostic step: Analyze the complete blood count (CBC), particularly the mean corpuscular volume (MCV), to determine if the anemia is microcytic, normocytic, or macrocytic; assess the leukocyte count and platelet count.
Risk factors: NSAID or anticoagulant use, iron-poor intake, gastrointestinal (GI) disorder (eg, celiac disease, autoimmune gastritis), or menses.
ANALYSIS
Objectives
- Recognize iron-deficiency anemia as the most common cause of anemia. (EPA 1, 2)
- Describe the diagnostic approach to anemia. (EPA 3)
- Identify the treatment of iron-deficiency anemia. (EPA 4)
Considerations
This 52-year-old man presents to the office with complaints of fatigue and dyspnea on exertion for the few months prior to the office visit. His physical examination is significant only for pallor. The serum hemoglobin level confirms anemia. The next step would be to characterize the anemia; if it is microcytic, which would be consistent with iron deficiency, confirmation should be performed with further testing for total iron-binding capacity (TIBC) and ferritin. In the postmenopausal female or adult male, iron-deficiency anemia indicates GI tract blood loss until proven otherwise, with colon cancer being the most serious possibility. This patient is using an NSAID, which may predispose to erosive gastritis. Once iron-deficiency anemia is confirmed, a thorough evaluation, including upper and lower endoscopy of the GI tract, is needed.
APPROACH TO:
Iron-Deficiency Anemia
DEFINITIONS
ANEMIA: Decreased red blood cell (RBC) mass, leading to less oxygen-carrying capacity. Anemia is defined as a hemoglobin level less than 13 g/dL in men and less than 12 g/dL in women.
IRON STUDIES: Ferritin is a marker of iron stores and is decreased in cases of iron deficiency. It is also an acute-phase reactant and therefore increases with inflammatory chronic diseases. The TIBC is an indirect measure of transferrin saturation levels and increases in iron deficiency.
MEAN CORPUSCULAR VOLUME: MCV is the average of RBC volume. Based on RBC size, anemia is categorized as microcytic (MCV < 80 fL), normocytic (MCV 80-100 fL), and macrocytic (MCV > 100 fL).
RETICULOCYTE: An immature RBC that usually is 1 to 1.5 days old.
RETICULOCYTE COUNT: A fraction of RBCs consisting of reticulocytes that indirectly indicates the bone marrow activity of the erythrocyte line. It is usually expressed as a percentage, with a normal value of 0.5% to 2% in nonanemic adults; the reticulocyte index adjusts the count for the level of anemia.
CLINICAL APPROACH
Pathophysiology
Iron-deficiency anemia is the most common cause of anemia in the United States, affecting all ages and both genders. Iron is essential to the synthesis of hemoglobin. The normal daily intake of elemental iron is approximately 15 mg, of which only 1 to 2 mg are absorbed. The daily iron losses are about the same, and menstruation adds approximately 30 mg of iron lost each month.
When iron loss exceeds intake, iron deposits are gradually depleted. Hemoglobin and serum iron levels may remain normal in the initial stages, and decreasing serum ferritin (iron stores) levels can be one of the first changes seen. This leads to a progressive decrease in iron available for RBC formation. The liver tries to compensate for this change by increasing transferrin production and maximizing the use of available iron. Transferrin levels are indirectly measured by TIBC. Due to increased transferrin production, TIBC is high in patients with iron-deficiency anemia. As a result, transferrin saturation (serum iron divided by TIBC) is low. Initially anemia will have normal-appearing RBCs, but as anemia becomes more severe, microcytosis and hypochromia will develop. Later in the disease process, iron deficiency will affect other tissues, resulting in a variety of symptoms and signs.
Etiologies. The primary etiology for iron-deficiency anemia is blood loss (Table 54–1). In men, the most frequent cause is chronic GI tract occult bleeding; gastroenterology referral and endoscopic study of potential blood losses should be considered. In women, menstrual loss may be the main mechanism, but other causes must be considered. During pregnancy, iron transfer from the mother to the developing fetus makes supplemental iron especially important. Iron deficiency may also be a result of increased iron requirements, diminished iron absorption, or both. Iron deficiency can develop during the first 2 years of life if dietary iron is insufficient for the demands of rapid growth. Adolescent girls may become iron deficient from inadequate oral intake in addition to the loss from menstruation. The growth spurt in adolescent boys may also produce a significant increase in demands for iron. Less common than blood loss are other possible causes of anemia, such as decreased iron absorption after gastrectomy or malabsorption syndromes such as celiac disease.
Sideroblastic anemia is a disease in which the bone marrow produces abnormal RBCs, commonly microcytic and hypochromic. It can be both acquired and congenital, with X-lined sideroblastic anemia and isoniazid being some of the more common etiologies of microcytic sideroblastic anemia. The iron studies in sideroblastic anemia include increases in serum iron, serum ferritin concentration, and saturation of transferrin. Iron stain of the bone marrow (Prussian blue) reveals the pathognomonic feature of engorged mitochondria in the developing RBCs, called ringed sideroblasts (Figure 54–1). Another important clue to the presence of sideroblastic anemia is the presence of stippled RBCs in the peripheral blood smear (Figure 54–2); this is also seen in heavy lead exposure.
Figure 54–1. Ringed sideroblasts. (Reproduced with permission, from Jameson J, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. 2018. Copyright © McGraw Hill LLC. All rights reserved.)
Categorizing Anemias by MCV. A CBC with differential, platelets, and RBC indices is helpful in narrowing the differential diagnosis of anemia. The first step is to look at the MCV to categorize the anemia (Table 54–2). Iron deficiency usually leads to a microcytic anemia. The RBC distribution width (RDW) is a calculated index that quantitates the anisocytosis (variation in the RBC size) and helps to distinguish uncomplicated iron deficiencies from uncomplicated thalassemia. Microcytic anemia with an increased RDW is suggestive of iron-deficiency anemia because the bone marrow produces new erythrocytes of various sizes. A normal RDW in the presence of microcytic anemia is more suggestive of chronic disease, thalassemia, or even iron deficiency with concomitant anemia of chronic disease.
Figure 54–2. Basophilic stippling (arrow). (Reproduced with permission, from Litchman MA, Shafer MS, Felgar RE, et al, eds. Lichtman’s Atlas of Hematology. 2016. 2017. Copyright © McGraw Hill LLC. All rights reserved.)
A detailed history, physical examination, and further laboratory data may be necessary to achieve a final diagnosis.
Reticulocyte Count. The reticulocyte count is another important parameter to help in the differential diagnosis of anemia. A new RBC can be stained as a reticulocyte for 24 to 36 hours, after which the RBC circulates for approximately 120 days. The blood normally contains about 1 reticulocyte per 100 RBCs. The reticulocyte count is the percentage of reticulocytes per 100 RBCs, and it may be falsely elevated in the presence of anemia. Therefore, a corrected reticulocyte count (CRC) is calculated by multiplying the reported reticulocyte count by the patient’s hematocrit divided by 45 (normal hematocrit), or hemoglobin divided by 15.
Reticulocyte Production Index. Another calculated measure to assess anemia is to look at the bone marrow response using the reticulocyte production index (RPI). The RPI accounts for prematurely released reticulocytes, or shift cells, as they have a longer life span and can lead to overestimation of daily RBC production. RPI can be calculated by dividing the CRC by 2.
For example, if the patient’s reticulocyte count is 6% and hematocrit 18, then
Iron Studies. Iron studies are very helpful to confirm a diagnosis of iron-deficiency anemia and to help in the differential diagnosis of other types of anemia, such as anemia of chronic disease and sideroblastic anemia (Table 54–3). These studies include serum iron levels, serum TIBC, and calculation of percentage saturation of transferrin. Low serum ferritin concentration is a reliable indication of iron deficiency. Serum ferritin values are increased with chronic inflammatory disease, malignancy, or liver injury; therefore, serum ferritin concentration may be above normal when iron deficiency exists with chronic diseases, such as rheumatoid arthritis, Hodgkin disease, or hepatitis, among many other disorders.
Abbreviations: SI, serum iron; TIBC, total iron-binding capacity.
Reproduced with permission,from Jameson J, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. 2018. Copyright © McGraw Hill LLC. All rights reserved.
Peripheral Blood Smear. Evaluating the peripheral blood smear for specific abnormalities in RBC morphology may be very useful for determining the etiology of anemia. In iron-deficiency anemia, the peripheral blood smear shows RBCs smaller than normal (microcytes) and hypochromia (Figure 54–3).
Figure 54–3. Hypochromic, microcytic RBCs (right side) are smaller than normal (left panel). (Reproduced with permission, from Jameson J, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. 2018. Copyright © McGraw Hill LLC. All rights reserved.)
Clinical Presentation
Anemia is most commonly diagnosed by a routine laboratory test, and patients are often asymptomatic. The lack of symptoms reflects the very slow development of iron deficiency and the ability of the body to adapt to lower iron reserves and anemia. More severe anemia may produce symptoms such as fatigue, shortness of breath, dizziness, headache, palpitations, and impaired concentration. Additionally, patients with chronic severe iron deficiency may develop pica, which involves cravings for nonfood objects such as dirt, paint, and ice. It is also linked to restless legs syndrome. Glossitis, cheilosis, or koilonychia may develop, and in rare cases, dysphagia associated with a postcricoid esophageal web (also known as Plummer-Vinson syndrome) may occur.
Treatment
Although the treatment of iron deficiency is straightforward, finding the underlying etiology is paramount. Treatment of iron-deficiency anemia consists of iron replacement therapy, typically with oral ferrous sulfate 325 mg two or three times daily, which provides 130 to 195 mg of elemental iron. Other iron preparations, such as ferrous fumarate or ferrous gluconate, can also be used and are equally effective. Correction of anemia usually occurs within 6 weeks, but therapy should continue for at least 6 months to replenish the iron stores. Oral iron therapy may cause GI side effects, such as constipation, nausea, and abdominal cramping. Taking the iron with meals may help with tolerance but can reduce absorption. Failure of iron-deficiency anemia to improve with oral iron supplementation suggests nonadherence to therapy, possible coexisting disease interfering with marrow response (eg, coexisting folate or B12 deficiency), or malabsorption of iron (eg, celiac sprue, atrophic gastritis). Parenteral iron therapy is indicated in patients with a poor absorption state (occurs in celiac disease, chronic kidney disease) or with excessive intolerance to oral therapy. Caution must be taken with parenteral high-molecular-weight iron dextran because anaphylaxis may occur. Newer parenteral iron compounds are now available with lower rates of adverse events.
It should be emphasized once again that after the diagnosis of iron deficiency is established, the cause of the iron loss should be identified. Except in menstruating women, the most common site of blood loss is the GI tract, and most patients will require endoscopic evaluation. Gastritis, peptic ulcers, and angiodysplasia are all common sources of blood loss, but the most serious diagnosis to exclude would be the possibility of an occult GI malignancy. Fecal occult blood testing (FOBT), such as a stool guaiac test, should not be used as a substitute for endoscopic evaluation, as even high-sensitivity FOBT has only 50% to 80% sensitivity for colorectal cancer.
CASE CORRELATION
- See Case 55 (Symptomatic Anemia and Transfusion Medicine), Case 56 (Immune Thrombocytopenic Purpura/Abnormal Bleeding), and Case 58 (Sickle Cell Crisis).
COMPREHENSION QUESTIONS
54.1 A 25-year-old man with a history of a duodenal ulcer is being seen in the office for follow-up. He does not complain of abdominal pain and does not report any bloody stool or melena. His blood pressure (BP) is 120/80 mm Hg, heart rate (HR) is 80 beats per minute, and respiratory rate (RR) is 12 breaths/min. His hemoglobin level is 10 g/dL. Which of the following most likely will be seen on laboratory investigation?
A. Elevated TIBC
B. Mean corpuscular volume of 105 fL
C. Normal serum ferritin
D. Reticulocyte count of 4%
54.2 A 22-year-old woman is pregnant at 14 weeks’ gestation. She denies vaginal bleeding or prior medical problems. Her BP is 100/60 mm Hg, HR is 90 beats per minute, and RR is 14 breaths/min. Her hemoglobin level is 9 g/dL. She is counseled that the most likely cause of the low hemoglobin level is due to iron deficiency. She asks why she could have iron deficiency when she is no longer menstruating. Which of the following is the best explanation?
A. Expanded blood volume and transport to the fetus
B. Hemolysis
C. Iron losses as a result of relative alkalosis of pregnancy
D. Occult GI blood loss
54.3 A 35-year-old man who is mildly obese has undertaken a strict fad diet for 3 months. He previously had been healthy but now complains of fatigue. His hemoglobin level is 10 g/dL, and his MCV is 105 fL. Which of the following is the most likely etiology of his anemia?
A. Folate deficiency
B. Iron deficiency
C. Sideroblastic anemia
D. Thalassemia
E. Vitamin B12 deficiency
54.4 A 20-year-old woman is found to be anemic (10 g/dL) on routine laboratory tests. She is otherwise healthy, with review of systems notable only for heavy menses. Iron studies are as follows: decreased MCV, decreased ferritin, increased TIBC, and increased RDW. Which of the following is the best next step?
A. Transfuse one unit of packed RBCs
B. Start oral ferrous sulfate 325 mg twice daily
C. Refer for colonoscopy
D. Start oral folic acid 1 mg daily
E. Treat with intravenous iron dextran 100 mg
54.5 A 34-year-old woman of Mediterranean descent is found to have mild anemia on prenatal screening CBC. She denies any shortness of breath, fatigue, or blood in stool. Family history is notable for a brother who requires frequent blood transfusions. A CBC demonstrates microcytic, hypochromic anemia with high serum iron, normal RDW, normal ferritin, and low reticulocytes. Hemoglobin electrophoresis is normal. Which of the following is the best next diagnostic step?
A. Check lead levels
B. Repeat hemoglobin electrophoresis for improved sensitivity
C. Bone marrow biopsy
D. DNA testing
E. Start ferrous sulfate 325 mg daily and recheck CBC in 6 weeks
54.6 A 50-year-old man is being seen in the office for follow-up of severe rheumatoid arthritis. He declines taking medications except for a daily multivitamin with iron. His laboratory examination results include a hemoglobin level of 9.8 g/dL. The colonoscopy this year was normal. Which of the following lab findings would most likely to be seen on laboratory workup of his anemia?
ANSWERS
54.1 A. Chronic GI blood loss leads to low ferritin levels, reflecting diminished iron stores; elevated TIBC; and low iron saturation. There is a microcytic anemia (low MCV) with a low reticulocyte count. The reticulocyte count would be elevated (answer D) with acute blood loss, but the patient has not experienced this. An elevated MCV of 105 fL (answer B) would be indicative of macrocytic anemia such as folate or vitamin B12 deficiency, whereas iron deficiency is suggestive of microcytic anemia. Serum ferritin levels (answer C) would be decreased in iron deficiency.
54.2 A. Iron deficiency occurs in pregnancy as a result of the expanded blood volume and active transport of iron to the fetus. Hemolysis (answer B) and occult GI blood loss (answer D) would not be normal findings in pregnancy and would warrant further workup. Iron loss does not occur due to alkalosis (answer C).
54.3 A. Macrocytic anemia is usually a result of folate or vitamin B12 deficiency. Vitamin B12 stores last for nearly 10 years; therefore, a dietary change of several months would more likely cause folate deficiency. Folate is found in green leafy vegetables. Vitamin B12 deficiency (answer E) can also lead to neurologic symptoms. Iron deficiency (answer B), thalassemias (answer D), and sideroblastic anemias (answer C) will likely be microcytic with an MCV < 80 fL.
54.4 B. This patient has ongoing blood loss from heavy menses leading to iron-deficiency anemia, with characteristic laboratory test values (low MCV, low ferritin, high TIBC, high RDW). Treatment of choice is oral iron supplementation. Intravenous iron formulations (answer E) are indicated only in specific situations, such as inability to tolerate oral iron and malabsorption. Demonstration of a failure of oral therapy is often needed prior to intravenous iron treatment. Iron dextran is rarely used due to concern for anaphylaxis. In addition, the patient has a clear etiology for iron loss, so endoscopy (answer C) is not indicated. Transfusion (answer A) is reserved for patients with hemoglobin < 7 g/dL or hemoglobin < 8 g/dL if symptomatic. Oral folic acid supplementation (answer D) would not be contraindicated in this case but is not as important as iron supplementation. Typically, vitamin C is also provided in addition to the oral iron to enhance intestinal absorption.
54.5 D. Thalassemia usually leads to a microcytic anemia with uniform red cell size (normal RDW) and excess iron stores. The patient’s asymptomatic anemia, ethnicity, and family member with transfusion-dependent anemia are consistent with alpha-thalassemia minor. Alpha-thalassemia minor can have normal hemoglobin electrophoresis, and diagnosis requires DNA sequencing. Checking lead levels (answer A) would be indicated if there is suggestive history, such as occupational exposure or living in an old house with lead-based paint. Repeating hemoglobin electrophoresis (answer B) does not increase sensitivity for the diagnosis of thalassemia. A bone marrow biopsy (answer C) is indicated when there is suggestion of a bone marrow process such as compromise of more than one cell line (eg, anemia and/or leukopenia and/or thrombocytopenia). Iron sulfate supplementation (answer E) is not indicated since serum iron stores are in excess and supplementation may lead to iron toxicity.
54.6 C. The patient has an inflammatory condition (rheumatoid arthritis) that would cause an anemia of chronic disease. The typical parameters with chronic inflammation would be a normocytic (normal to slightly low MCV), normal to high serum ferritin level (due to inability to mobilize iron), and low serum iron levels (due to lack of iron in circulation). Although a microcytic anemia can be seen, normocytic anemia with elevated ferritin (acute-phase reactant) is more common in chronic disease. Answer A (high MCV, normal to elevated ferritin, normal TIBC, and normal serum iron levels) is consistent with a folate or vitamin B12 deficiency. Answer B (borderline low MCV, high/normal ferritin, TIBC normal, and normal serum iron level) is consistent with sideroblastic anemia. Answer D (low MCV, low ferritin, high TIBC, and low iron levels) is consistent with iron-deficiency anemia. Answer E (normal/high MCV, normal ferritin, low TIBC, normal serum iron) is consistent with hemochromatosis (iron overload).
CLINICAL PEARLS
▶ The values for MCV, RDW, and RPI are important parameters in the evaluation of anemia.
▶ Reticulocyte production index < 2 in an anemic patient is indicative of hypoproliferative bone marrow disorder.
▶ Think of iron deficiency in an anemic patient with low MCV, low ferritin, and low RPI.
▶ Iron-deficiency anemia in men or postmenopausal women is primarily a result of GI blood losses; therefore, iron-deficiency anemia in this patient population warrants a thorough GI workup.
▶ Iron-deficiency anemia in reproductive age women is most often caused by menstrual blood loss.
▶ Fecal occult blood testing is negative in approximately 20% to 50% of patients with colorectal cancer. Therefore, a negative fecal occult blood test in the presence of iron-deficiency anemia should not discourage you from pursuing a thorough GI workup if clinically indicated.
REFERENCES
Adamson JW. Iron deficiency and other hypoproliferative anemias. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018. http://accessmedicine.mhmedical.com/Content.aspx?bookid=1130& sectionid=79731112. Accessed June 18, 2019.
Adamson JW, Longo DL. Anemia and polycythemia. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018. http://accessmedicine.mhmedical.com/content.aspx?bookid=2129& sectionid=192014145. Accessed June 18, 2019.
Goddard AF, James MW, McIntyre AS, et al. Guidelines for the management of iron deficiency anaemia. Gut. 2011;60:1309-1316.
Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011-1023.
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