case study of iron deficiency anemia

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39-Year-Old Woman With an Obscure Case of Anemia

Shanique r palmer , mbbs, gita thanarajasingam , md, alexandra p wolanskyj , md.

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Individual reprints of this article are not available. Address correspondence to Alexandra P. Wolanskyj, MD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ( [email protected] ).

A 39-year-old woman was referred to our institution for evaluation of anemia. She was known to have multiple comorbidities and had a baseline hemoglobin concentration of approximately 10.5 g/dL. About 6 months before her referral, the patient began having recurrent episodes of severe anemia, with hemoglobin values as low as 3.5 g/dL. She had become transfusion-dependent and had received about 30 units of packed red blood cells (RBCs) in the preceding 3 months. The patient denied any history of easy bruisability, menorrhagia, or overt evidence of bleeding from any site. Additionally, she denied any change in the appearance or color of her urine and had no history of jaundice. There was no family history of anemia or any other hematologic disorder. As an outpatient, she had undergone an extensive evaluation at another institution, but results failed to provide an explanation for her anemia.

The patient's medical history was remarkable for severe asthma, thought to be due to Churg-Strauss syndrome. She had a tunneled central venous catheter for self-administration of intravenous corticosteroids at the earliest sign of an asthmatic exacerbation. Her other medications included bronchodilators, weekly erythropoietin injections, intravenous iron therapy, an antidepressant, and an anxiolytic.

At presentation, the patient's vital signs were normal. Physical examination was unremarkable except for mild generalized pallor. A complete blood count on the day of admission revealed the following (reference ranges shown parenthetically): hemoglobin, 4.9 g/dL (12.0-15.5 g/dL); mean corpuscular volume (MCV), 94.4 fL (81.6-98.3 fL); hematocrit, 13.4% (34.9%-44.5%); leukocyte count, 6.0 × 10 9 /L (3.5-10.5 × 10 9 /L); and platelet count, 203 × 10 9 /L (150-450 × 10 9 /L). The patient's partial thromboplastin time and prothrombin time (PT)/international normalized ratio were normal. These results were obtained within 24 hours of her last transfusion.

Which one of the following is the least likely in the differential diagnosis of this patient's anemia?

Chronic blood loss

Acute hemolysis

Chronic disease

Myelodysplastic syndrome

Acquired pure red cell aplasia

Anemia can be categorized as microcytic, normocytic, or macrocytic by examining the MCV. This patient clearly has a normocytic anemia, with her MCV of 94.4 fL, although this must be interpreted with some caution, given her history of multiple transfusions, which can normalize the MCV. Normocytic anemias are classically due to premature destruction or acute loss of RBCs or to decreased bone marrow production. With this in mind, we can approach the proposed list of differential diagnoses. Chronic blood loss usually leads to iron deficiency anemia, which is classically microcytic in nature; however, a normocytic anemia may also be seen. Hemolytic anemias usually result in a normocytic picture. Anemia of chronic disease is usually normocytic and is possible because of this patient's complicated medical history. The myelodysplastic syndromes refer to a heterogeneous group of stem cell disorders characterized by abnormal cellular maturation and, most commonly, chronic cytopenias. They result in macrocytosis, which is classically marked, with MCV sometimes greater than 110 fL. This is the only condition listed that classically results in a macrocytic anemia, rather than normocytic, and was therefore least likely to be the cause of the patient's anemia. Acquired pure red cell aplasia is a primary bone marrow disorder characterized by decreased reticulocytes and the virtual absence of erythroid precursors in the bone marrow. It is often idiopathic but may occur in association with various diseases, such as systemic lupus erythematosus and hematologic malignancies. Regardless of the underlying cause, the anemia is usually normocytic with absolute reticulocytopenia.

With the observation that the patient's anemia was normocytic with an MCV of 94.4 fL, the next task was to narrow the list of differential diagnoses and establish whether this was due to premature destruction or acute loss of RBCs vs decreased bone marrow production.

Which one of the following would be the next best test to narrow the list of differential diagnoses?

Peripheral blood smear

Absolute reticulocyte count

Serum ferritin

Erythropoietin

Bone marrow biopsy and aspiration

The peripheral blood smear provides useful information that cannot be obtained with the usual complete blood count and can provide clues to a variety of bone marrow disorders, as well as systemic disorders that can have hematologic manifestations. However, it would not be the single best test to provide the necessary information at this point. We needed to establish whether there was an adequate or inadequate (ie, hypoproliferative) bone marrow response. An adequate response is usually due to hemolysis or acute loss of RBCs. The reticulocyte count is a good indicator of this and is the only test listed that could have directly provided this necessary piece of information. Anemia with an absolute reticulocyte count of less than 75 × 10 9 /L provides strong evidence of deficient production of RBCs, whereas a count of greater than 100 × 10 9 /L indicates a brisk and efficient response to hemolysis or blood loss. The region between these 2 limits remains a gray zone, and other clinical and laboratory parameters should be used to interpret the overall picture. The plasma ferritin level generally reflects overall iron storage and is typically used as a part of the panel to evaluate for iron deficiency anemia in a patient with microcytosis. Therefore, it would not be most useful in this patient with a normocytic anemia. Erythropoietin is a growth factor that is the primary stimulus for erythropoiesis. It would not be useful at this juncture in revealing whether the anemia is due to decreased production or increased loss of blood cells or premature destruction. A bone marrow biopsy would show erythroid hyperplasia, a nonspecific finding, if erythropoiesis is increased in response to the anemia. If there is a hypoproliferative state, the marrow may reveal a variety of findings, depending on the underlying diagnosis. Therefore, a bone marrow biopsy would be premature at this point. However, a bone marrow biopsy would be indicated if there was pancytopenia or if the peripheral smear showed abnormal cells, such as blast forms or dysplastic changes.

Our patient had a reticulocytosis of 13.3% (0.60%-1.83%), with an absolute reticulocyte count of 238.8 × 10 9 /L (29.5-87.3 × 10 9 /L).

At this time, which one of the following series of tests would be most helpful in further narrowing the differential diagnosis?

Total and indirect bilirubin levels, haptoglobin, lactate dehydrogenase (LDH)

Direct Coombs test

Indirect Coombs test

Activated partial thromboplastin time (aPTT), PT, fibrinogen, soluble fibrin monomer complex, and D-dimers

In this patient with an absolute reticulocytosis, ie, an adequate bone marrow response, the next step would be in differentiating between hemolysis and acute blood loss. Hemolysis is usually characterized by elevated indirect bilirubin concentrations, decreased serum haptoglobin concentrations (with intravascular hemolysis in particular), and increased serum LDH levels, and this series of tests would be most useful in narrowing the differential diagnoses at this point. The peripheral blood smear is less specific, but in the presence of hemolysis, it may reveal abnormally shaped RBCs, including fragmented RBCs (schistocytes, helmet cells), spherocytes, elliptocytes, or RBC inclusions, which may be seen in certain hemolysis-producing infections, such as malaria, babesiosis, and Bartonella . Hemolytic anemias may be acquired and immune, in which case there is immunologic destruction of RBCs mediated by autoantibodies directed against antigens on the patient's RBCs. The direct and indirect Coombs tests detect antibodies on the surface of the patient's RBCs and in the patient's serum, respectively. However, the presence of hemolysis must first be established, especially since a patient may have a mildly positive Coombs test that is clinically insignificant if not associated with ongoing hemolysis. The laboratory findings in disseminated intravascular coagulation and intravascular coagulation and fibrinolysis (DIC/ICF) include elevated D-dimer and soluble fibrin monomer complex levels, low fibrinogen levels, and prolonged PT and aPTT. Therefore, these investigations should be performed when a diagnosis of DIC/ICF is suspected. However, this patient's clinical scenario and laboratory findings to date, ie, lack of thrombocytopenia and normal PT and aPTT, do not suggest underlying DIC/ICF.

The patient had a mildly reduced haptoglobin level at 14 mg/dL (30-200 mg/dL), likely secondary to her multiple transfusions. However, her LDH level was normal at 205 U/L (122-222 U/L), as were her total and direct bilirubin levels at 0.4 mg/dL (0.1-1.0 mg/dL) and 0.1 mg/dL (0.0-0.3 mg/dL), respectively. A peripheral blood smear showed no abnormally shaped RBCs. The overall picture was not in keeping with hemolysis. On the first day of her evaluation, the patient's hemoglobin concentration was 11.1 g/dL. By day 2 of her outpatient work-up, it had decreased to 5.6 g/dL, and she received 4 units of packed RBCs. Despite the transfusions, her hemoglobin concentration decreased further within 24 hours to 4.9 g/dL. At this point, the patient was admitted and received 3 more units of packed RBCs. During this time, she was asymptomatic, and her vital signs remained stable.

At this point, which one of the following would be the best step in the management of this patient?

Esophagogastroduodenoscopy

Colonoscopy

Computed tomography (CT) of the abdomen and pelvis

Transfer to the intensive care unit

Angiography of the gastrointestinal (GI) tract

The patient had no overt signs or symptoms of bleeding, and it would be unlikely for her to have occult GI bleeding that resulted in such dramatic decreases in her hemoglobin concentration. Also, results of fecal occult blood testing were negative. Therefore, neither upper nor lower GI endoscopy would be expected to reveal any useful information. However, the patient could have occult intra-abdominal bleeding, and noncontrast CT of her abdomen and pelvis would be crucial in ruling this out. The patient's mental status remained normal, and she was exhibiting no overt evidence of decreased perfusion or hemodynamic instability other than mild tachycardia. Therefore, she could be deemed clinically stable, and transferring her to the intensive care unit would be unnecessary at this time. She was well compensated despite the severity and acuteness of the anemia, no doubt in part due to her age and lack of other cardiac comorbidities. In this patient who is exhibiting no overt evidence of GI bleeding, angiography would not be the next best step.

Noncontrast CT of her abdomen and pelvis revealed normal findings. During the night of hospital day 2, an astute nurse noticed what appeared to be bloodstains on the patient's gown. The patient reported that she had spilled cranberry juice on the gown. Closer inspection of her room revealed several blood-soaked tissues and Styrofoam cups filled with fresh blood in her wastebasket. The patient was also found to have dried, crusted blood all over her fingernails, and a blood-stained 10-mL syringe, most of its labeling worn away by overuse, was found in her gown pocket ( Figure ).

Which one of the following is the most likely cause of this patient's anemia?

Factitious disorder

Munchausen by proxy

Malingering

Somatization disorder

Hypochondriasis

With the discovery made in the patient's room, in particular the syringe, the patient's self-phlebotomy became evident, leading to a diagnosis of factitious anemia. The most chronic and extreme form of factitious illness, Munchausen syndrome, typically includes travel from hospital to hospital combined with the willingness to submit to multiple procedures for self-fabricated signs of illness, as occurred with our patient before her presentation at our institution. In Munchausen by proxy, caregivers (usually mothers) induce illness in their children to obtain care and support for themselves. In malingering, illness is feigned to gain such external incentives as money or drugs or to avoid such consequences as military service or criminal prosecution. Factitious disorder, in contrast, has no incentive other than being a patient in the sick role. Since we identified no incentive other than obtaining our care, our patient could not be said to be malingering. Somatization refers to the tendency to experience psychological distress in the form of somatic symptoms not intentionally produced, thus differentiating this disorder from factitious illness or malingering. Hypochondriasis refers to a preoccupation with believing one is ill as a result of misconstruing physical symptoms that are not self-generated. By her self-phlebotomizing activity, our patient could not be considered hypochondriacal.

The patient was seen by the psychiatry service, and although she was obviously at risk of purposeful self-harm, she denied suicidal or homicidal ideation. It became evident that she had a history of severe depression, borderline personality disorder, chemical dependency, and a history of repeated episodes of parasuicide by means of wrist cutting. She gave consent for her central line to be removed, and this was done before her dismissal. There was direct communication with her primary care physicians and primary psychiatrist, and she was then dismissed from the hospital with a plan for close and consistent medical attention.

10-mL syringe allegedly used by the patient for self-phlebotomy.

Several cases of factitious anemia have been reported in the literature. 1 , 2 The patient is seldom caught in the act and usually denies the behavior, making the diagnosis difficult to establish incontrovertibly. Patients with this condition often have underlying psychiatric issues and constantly need to assume the sick role. Once the diagnosis is suspected, the patient should be confronted, and removal of any contributing medical device is essential. Early diagnosis is usually difficult but may prevent repeated hospitalizations and the risks associated with invasive diagnostic procedures. 2 Management is usually extremely difficult but should be centered around long-term psychotherapy. 2 A multidisciplinary approach is of utmost importance because patients usually become very uncooperative when they are discovered and may make attempts to break off relations with the current medical staff and seek medical attention elsewhere. Providing optimal management to an uncooperative patient may be difficult without violating the patient's autonomy. Therefore, a psychiatric consultation should be arranged as soon as possible, and seeking assistance from the institution's ethics and legal committees may be prudent.

The current case provides an opportunity to highlight an approach to the patient presenting with anemia. Anemia can be classified according to measurement of RBC size, as seen on the peripheral blood smear and as indicated by the MCV. This morphological approach categorizes the anemias as microcytic, normocytic, or macrocytic, providing a useful starting point to narrow the list of differential diagnoses. By definition, the MCV is normal (80-100 fL) in patients with normocytic anemia, low (<80 fL) in patients with microcytic anemia, and high (>100 fL) in patients with macrocytic anemia. 3

The presence of a microcytic anemia usually indicates a pathologic process involving hemoglobin synthesis. The most common cause is iron deficiency, but other classic causes include the thalassemias and other hemoglobinopathies, lead poisoning, sideroblastic anemia, and, less commonly, anemia of chronic disease. If microcytosis is identified, the next step would be to differentiate among these common causes, and this can be done by assessing serum iron studies, which include serum ferritin, iron, total iron-binding capacity, and transferrin saturation. In iron deficiency, the classic findings are a low serum ferritin value, which is diagnostic, elevated total iron-binding capacity, and low saturation. Other findings include a peripheral blood smear showing anisocytosis and poikilocytosis. If the serum ferritin level and other iron studies are normal, then thalassemia should be considered, and hemoglobin electrophoresis should be performed for the definitive diagnosis. Caution must be taken in interpreting the iron studies in anemia of chronic disease because findings are often inconsistent. The entire clinical scenario must be taken into account. 3 Sideroblastic anemias may be hereditary or acquired, and the latter is characterized by increased RBC distribution width, dimorphic RBCs, and bone marrow ringed sideroblasts.

If the anemia is found to be normocytic, the next step would be to differentiate between RBC destruction/loss and a hypoproliferative state. The presence of an increased reticulocyte response (>100 × 10 9 /L) suggests either loss or destruction of RBCs; thus, differentiation of these 2 conditions must be made. Hemolysis is characterized by elevated indirect bilirubin levels, decreased serum haptoglobin levels, and increased serum LDH levels. Also, the peripheral smear may reveal several abnormalities, such as fragmented RBCs and other abnormally shaped RBCs. If laboratory parameters or the peripheral smear is not suggestive of hemolysis, then a bleeding source should be sought. A normocytic anemia without reticulocytosis indicates an aplastic anemia; myelophthisis in which the bone marrow is replaced by fibrosis, tumor, or other abnormal cells; or lack of erythropoietin, which can be seen classically in renal failure.

The first step in evaluating a macrocytic anemia should be ruling out a marked reticulocytosis (polychromasia). Polychromasia may cause a regenerative macrocytosis. If this is found, evaluation for hemolysis or blood loss should be performed as outlined previously. Macrocytic anemias may be due to defects in DNA synthesis, resulting in oval macrocytes, or increase in the cholesterol/phospholipid ratio in membranes, resulting in round macrocytes.

Oval macrocytosis is classically due to vitamin B 12 or folate deficiency. If neither is present, then a bone marrow biopsy is warranted to look for the presence of a myelodysplastic syndrome. Round macrocytes may be due to severe alcoholism, liver disease, or hypothyroidism. Also, tobacco use and advanced age may result in round macrocytosis without anemia.

Factitious disorders are difficult to diagnose. However, our patient presented with several clues, including her previous psychiatric history and the recurrent dramatic decreases in her hemoglobin concentration, usually when she was unsupervised. Heightened suspicion is the first step in arriving at the correct diagnosis. Additionally, if anemia is approached in a logical stepwise manner, as outlined previously, multiple expensive, unnecessary, and invasive investigations can be avoided, and if due to a factitious disorder, necessary psychotherapy can be implemented in a more timely fashion.

Acknowledgments

We thank J. Michael Bostwick MD, Department of Psychiatry, Mayo Clinic, Rochester MN, for his expertise in the care of this patient and guidance in the preparation of the submitted manuscript.

See end of article for correct answers to questions.

Correct answers: 1. d , 2. b , 3. a , 4. c , 5. a

• 1. Abram HS. Hollender MH Factitious blood disease. South Med J 1974;67(6):691-696 [ DOI ] [ PubMed ] [ Google Scholar ]
• 2. Haddad SA, Winer KK, Gupta A, Chakrabarti S, Noel P, Klein HG. A puzzling case of anemia. Transfusion 2002;42(12):1610-1613 [ DOI ] [ PubMed ] [ Google Scholar ]
• 3. Tefferi A. Anemia in adults: a contemporary approach to diagnosis. Mayo Clin Proc 2003;78(10):1274-1280 [ DOI ] [ PubMed ] [ Google Scholar ]
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MATTHEW W. SHORT, LTC, MC, USA, AND JASON E. DOMAGALSKI, MAJ, MC, USA

Am Fam Physician. 2013;87(2):98-104

Patient information : See related handout on iron deficiency anemia , written by the authors of this article.

Author disclosure: No relevant financial affiliations to disclose.

Iron deficiency is the most common nutritional disorder worldwide and accounts for approximately one-half of anemia cases. The diagnosis of iron deficiency anemia is confirmed by the findings of low iron stores and a hemoglobin level two standard deviations below normal. Women should be screened during pregnancy, and children screened at one year of age. Supplemental iron may be given initially, followed by further workup if the patient is not responsive to therapy. Men and postmenopausal women should not be screened, but should be evaluated with gastrointestinal endoscopy if diagnosed with iron deficiency anemia. The underlying cause should be treated, and oral iron therapy can be initiated to replenish iron stores. Parenteral therapy may be used in patients who cannot tolerate or absorb oral preparations.

Iron deficiency anemia is diminished red blood cell production due to low iron stores in the body. It is the most common nutritional disorder worldwide and accounts for approximately one-half of anemia cases. 1 , 2 Iron deficiency anemia can result from inadequate iron intake, decreased iron absorption, increased iron demand, and increased iron loss. 3 Identifying the underlying etiology and administering the appropriate therapy are keys to the evaluation and management of this condition.

Diagnosis of iron deficiency anemia requires laboratory-confirmed evidence of anemia, as well as evidence of low iron stores. 4 Anemia is defined as a hemoglobin level two standard deviations below normal for age and sex ( Table 1 ) . 5

A complete blood count can be helpful to determine the mean corpuscular volume or red blood cell size. Although iron deficiency is the most common cause of microcytic anemia, up to 40 percent of patients with iron deficiency anemia will have normocytic erythrocytes. 2 As such, iron deficiency should still be considered in all cases of anemia unless the mean corpuscular volume is greater than 95 μm 3 (95 fL), because this cutoff has a sensitivity of 97.6 percent. 6 Other causes of microcytosis include chronic inflammatory states, lead poisoning, thalassemia, and sideroblastic anemia. 1

The following diagnostic approach is recommended in patients with anemia and is outlined in Figure 1 . 2 , 6 – 11 A serum ferritin level should be obtained in patients with anemia and a mean corpuscular volume less than 95 μm 3 . Ferritin reflects iron stores and is the most accurate test to diagnose iron deficiency anemia. 7 Although levels below 15 ng per mL (33.70 pmol per L) are consistent with a diagnosis of iron deficiency anemia, using a cutoff of 30 ng per mL (67.41 pmol per L) improves sensitivity from 25 to 92 percent, and specificity remains high at 98 percent. 8 , 12 Ferritin is also an acute phase reactant and can be elevated in patients with chronic inflammation or infection. In patients with chronic inflammation, iron deficiency anemia is likely when the ferritin level is less than 50 ng per mL (112.35 pmol per L). 7 Ferritin values greater than or equal to 100 ng per mL (224.70 pmol per L) generally exclude iron deficiency anemia. 9 , 10

In patients with no inflammatory states and in whom the ferritin level is indeterminate (31 to 99 ng per mL [69.66 to 222.45 pmol per L]), further tests can be performed to ascertain iron status. Values consistent with iron deficiency include a low serum iron level, low transferrin saturation, and a high total iron-binding capacity. 2

Soluble transferrin receptor and erythrocyte protoporphyrin testing, or bone marrow biopsy can be considered if the diagnosis remains unclear. 2 The soluble transferrin receptor level is an indirect measure of erythropoiesis and is increased in patients with iron deficiency anemia. 8 Another benefit of this test is that the soluble transferrin receptor level is unaffected by inflammatory states and can help identify concomitant iron deficiency anemia in patients with anemia of chronic disease. 12 Erythrocyte protoporphyrin is a heme precursor and accumulates in the absence of adequate iron stores. 11 If other tests are indeterminate and suspicion for iron deficiency anemia persists, the absence of stainable iron in a bone marrow biopsy is considered the diagnostic standard. 2

MEN AND POSTMENOPAUSAL WOMEN

Asymptomatic men and postmenopausal women should not be screened for iron deficiency anemia. Testing should be performed in patients with signs and symptoms of anemia, and a complete evaluation should be performed if iron deficiency is confirmed. 13

PREGNANT WOMEN

The American Academy of Family Physicians, U.S. Preventive Services Task Force, and Centers for Disease Control and Prevention recommend routine screening of asymptomatic pregnant women for iron deficiency anemia. 4 , 11 , 14 The American College of Obstetricians and Gynecologists recommends screening for anemia and implementing iron therapy if iron deficiency anemia is confirmed. 15 The defined values consistent with anemia in pregnancy are hemoglobin levels less than 11 g per dL (110 g per L) in the first or third trimester, or less than 10.5 g per dL (105 g per L) in the second trimester. 16 A maternal hemoglobin level of less than 6 g per dL (60 g per L) has been associated with poor fetal outcomes, including death. 15

The American Academy of Pediatrics recommends universal hemoglobin screening and evaluation of risk factors for iron deficiency anemia in all children at one year of age. 16 Risk factors include low birth weight, history of prematurity, exposure to lead, exclusive breastfeeding beyond four months of life, and weaning to whole milk and complementary foods without iron-fortified foods. 16 The Centers for Disease Control and Prevention recommends screening children from low-income or newly immigrated families at nine to 12 months of age, and consideration of screening for preterm and low-birth-weight infants before six months of age if they are not given iron-fortified formula. 14 The U.S. Preventive Services Task Force found insufficient evidence for screening in asymptomatic children six to 12 months of age and does not make recommendations for other ages. 4 A meta-analysis showed that infants in whom cord clamping was delayed for up to two minutes after birth had a reduced risk of low iron stores for up to six months. 17 Larger randomized studies that include maternal outcomes are needed before delayed cord clamping can be recommended for general practice.

Once iron deficiency anemia is identified, the goal is to determine the underlying etiology. Causes include inadequate iron intake, decreased iron absorption, increased iron demand, and increased iron loss ( Table 2 ) . 5 , 7 , 18 , 19

Iron Therapy

Premenopausal women with a negative evaluation for abnormal uterine bleeding can be given a trial of iron therapy. In children and pregnant women, iron therapy should be tried initially. Current guidelines recommend empiric treatment in children up to two years of age and in pregnant women with iron deficiency anemia; however, if the hemoglobin level does not increase by 1 g per dL (10 g per L) after one month of therapy in children or does not improve in pregnant women, further evaluation may be indicated. 4 , 15 , 16 In pregnant patients, poor compliance or intolerance should be considered, and parenteral iron may produce a better response. 15

The evaluation should begin with a thorough history and physical examination to help identify the cause of iron deficiency. The history should focus on potential etiologies and may include questions about diet, gastrointestinal (GI) symptoms, history of pica or pagophagia (i.e., compulsive consumption of ice), signs of blood loss (e.g., epistaxis, menorrhagia, melena, hematuria, hematemesis), surgical history (e.g., gastric bypass), and family history of GI malignancy. Patients with iron deficiency anemia are often asymptomatic and have limited findings on examination. Further evaluation should be based on risk factors ( Figure 2 ) . 10 , 15 , 17 – 21

PREMENOPAUSAL WOMEN

Excessive menstruation is a common cause of iron deficiency anemia in premenopausal women in developed countries; however, a GI source (particularly erosive lesions in the stomach or esophagus) is present in 6 to 30 percent of cases. 20 , 22 , 23 If the gynecologic workup is negative and the patient does not respond to iron therapy, endoscopy should be performed to exclude an occult GI source. 20 , 22 , 23

Excessive or irregular menstrual bleeding affects 9 to 14 percent of all women and can lead to varying degrees of iron deficiency anemia. 24 Etiologies include thyroid disease, uncontrolled diabetes mellitus, polycystic ovary syndrome, coagulopathies, uterine fibroids, endometrial hyperplasia, hyperprolactinemia, and use of antipsychotics or antiepileptics. Initial evaluation includes a history, physical examination, and pregnancy and thyroid-stimulating hormone tests. An endometrial biopsy should be considered in women 35 years and younger who have conditions that could lead to unopposed estrogen exposure, in women older than 35 years who have suspected anovulatory bleeding, and in women with abnormal uterine bleeding that does not respond to medical therapy. 25

In men and postmenopausal women, GI sources of bleeding should be excluded. Current recommendations support upper and lower endoscopy; however, there are no clear guidelines about which procedure should be performed first or if the second procedure is necessary if a source is found on the first study. 18 Lesions that occur simultaneously in the upper and lower tracts are rare, occurring in only 1 to 9 percent of patients. 18 However, one study showed that 12.2 percent of patients diagnosed with celiac disease and iron deficiency anemia had a secondary source of anemia, including three cases of colon cancer. 26 A study of patients with iron deficiency anemia of unknown etiology in the primary care setting found that 11 percent had newly diagnosed GI cancer. 27 Additionally, a cohort study found that 6 percent of patients older than 50 years and 9 percent of those older than 65 years will be diagnosed with a GI malignancy within two years of a diagnosis of iron deficiency anemia. 28 Celiac serology should also be considered for all adults presenting with iron deficiency anemia. 18 Upper endoscopy with duodenal biopsies should be performed to confirm the diagnosis after positive serologic testing and to evaluate for additional etiologies. 29

In patients in whom endoscopy may be contraindicated because of procedural risk, radiographic imaging may offer sufficient screening. The sensitivity of computed tomographic colonography for lesions larger than 1 cm is greater than 90 percent. 7 The use of barium enema is less reliable, but may be of use if colonoscopy or computed tomographic colonography is not available.

If initial endoscopy findings are negative and patients with iron deficiency anemia do not respond to iron therapy, repeat upper and lower endoscopy may be justified. In some instances, lesions may not be detected on initial examination (e.g., missed mucosal erosions in a large hiatal hernia, suboptimal preparation for colonoscopy, inadequate biopsy of a suspected lesion). 13 Colonoscopy can fail to diagnose up to 5 percent of colorectal tumors. 13

Additional evaluation of the small intestine is not necessary unless there is inadequate response to iron therapy, the patient is transfusion dependent, or fecal occult blood testing suggests that the patient has had obscure GI bleeding with the source undiscovered on initial or repeat endoscopy. 30 In these cases, further evaluation with capsule endoscopy should be considered. 30 Enteroscopy is an upper endoscopy procedure using a longer scope to visualize the proximal jejunum; it should be reserved to treat or biopsy lesions identified by capsule endoscopy. This test is a second-line technique for evaluating the small bowel because it is complicated by the level of sedation and duration of procedure. 13 Magnetic resonance imaging enteroclysis, computed tomographic enterography, or barium studies may also be considered, but have a limited ability to identify most small bowel lesions, which are mucosal and flat. 7

UNDERLYING CAUSE

Patients with an underlying condition that causes iron deficiency anemia should be treated or referred to a subspecialist (e.g., gynecologist, gastroenterologist) for definitive treatment.

ORAL IRON THERAPY

The dosage of elemental iron required to treat iron deficiency anemia in adults is 120 mg per day for three months; the dosage for children is 3 mg per kg per day, up to 60 mg per day. 1 An increase in hemoglobin of 1 g per dL after one month of treatment shows an adequate response to treatment and confirms the diagnosis. 16 In adults, therapy should be continued for three months after the anemia is corrected to allow iron stores to become replenished 7 ( Figure 3 6 , 28 , 31 ) .

Adherence to oral iron therapy can be a barrier to treatment because of GI adverse effects such as epigastric discomfort, nausea, diarrhea, and constipation. These effects may be reduced when iron is taken with meals, but absorption may decrease by 40 percent. 1 Medications such as proton pump inhibitors and factors that induce gastric acid hyposecretion (e.g., chronic atrophic gastritis, recent gastrectomy or vagotomy) are associated with reduced absorption of dietary iron and iron tablets. 31

PARENTERAL IRON THERAPY

Parenteral therapy may be used in patients who cannot tolerate or absorb oral preparations, such as those who have undergone gastrectomy, gastrojejunostomy, bariatric surgery, or other small bowel surgeries. The most common indications for intravenous therapy include GI effects, worsening symptoms of inflammatory bowel disease, unresolved bleeding, renal failure–induced anemia treated with erythropoietin, and insufficient absorption in patients with celiac disease. 32

Parenteral treatment options are outlined in Table 3 . 2 , 16 Serious adverse effects have occurred in up to 0.7 percent of patients receiving iron dextran, with 31 recorded fatalities reported between 1976 and 1996. 32 , 33 Iron sucrose and sodium ferric gluconate (Ferrlecit) have greater bio-availability and a lower incidence of life-threatening anaphylaxis compared with iron dextran. 2 Approximately 35 percent of patients receiving iron sucrose have mild adverse effects (e.g., headache, nausea, diarrhea). 7 One small study cited similar adverse effect profiles between intravenous iron dextran and sodium ferric gluconate, with only one serious adverse effect reported in the iron dextran group. 34 If this finding is duplicated in larger studies, it could support the use of iron dextran over sodium ferric gluconate, because the total dose can be given in one sitting. A newer formulation, ferumoxytol, can be given over five minutes and supplies 510 mg of elemental iron per infusion, allowing for greater amounts of iron in fewer infusions compared with iron sucrose. 2

There are no standard recommendations for follow-up after initiating therapy for iron deficiency anemia; however, one suggested course is to recheck complete blood counts every three months for one year. If hemoglobin and red blood cell indices remain normal, one additional complete blood count should be obtained 12 months later. A more practical approach is to recheck the patient periodically; no further follow-up is necessary if the patient is asymptomatic and the hematocrit level remains normal. 7

BLOOD TRANSFUSION

There is no universally accepted threshold for transfusing packed red blood cells in patients with iron deficiency anemia. Guidelines often specify certain hemoglobin values as indications to transfuse, but the patient's clinical condition and symptoms are an essential part of deciding whether to transfuse. 35 Transfusion is recommended in pregnant women with hemoglobin levels of less than 6 g per dL because of potentially abnormal fetal oxygenation resulting in non-reassuring fetal heart tracings, low amniotic fluid volumes, fetal cerebral vasodilation, and fetal death. 15 If transfusion is performed, two units of packed red blood cells should be given, then the clinical situation should be reassessed to guide further treatment. 35

Data Sources: A PubMed search was completed in Clinical Queries using the key terms iron deficiency and anemia. The search included meta-analyses, randomized controlled trials, controlled trials, and reviews. Searches were also performed using Essential Evidence Plus, the Cochrane database, the National Guideline Clearinghouse database, the Trip Database, DynaMed, and the Agency for Healthcare Research and Quality evidence reports. Search date: January 10, 2012.

World Health Organization. Iron Deficiency Anaemia: Assessment, Prevention, and Control: A Guide for Programme Managers . Geneva, Switzerland: World Health Organization; 2001.

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