case study for anemia

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Patient Case Presentation

Patient  Overview

M.J. is a 25-year-old, African American female presenting to her PCP with complaints of fatigue, weakness, and shortness of breath with minimal activity. Her friends and family have told her she appears pale, and combined with her recent symptoms she has decided to get checked out. She also states that she has noticed her hair and fingernails becoming extremely thin and brittle, causing even more concern. The patient first started noticing these symptoms a few months ago and they have been getting progressively worse. Upon initial assessment, her mucosal membranes and conjunctivae are pale. She denies pain at this time, but describes an intermittent dry, soreness of her tongue.

Vital Signs:

Temperature – 37 C (98.8 F)

HR – 95

BP – 110/70 (83)

Lab Values:

Hgb- 7 g/dL

Serum Iron – 40 mcg/dL

Transferrin Saturation – 15%

Medical History

• Diagnosed with peptic ulcer disease at age 21 – controlled with PPI pharmacotherapy
• IUD placement 3 months ago – reports an increase in menstrual bleeding since placement

Surgical History

• No past surgical history reported

Family History

• Diagnosis of iron deficiency anemia at 24 years old during pregnancy with patient – on daily supplement
• Otherwise healthy
• Diagnosis of hypertension – controlled with diet and exercise
• No siblings

Social History

• Vegetarian – patient states she has been having weird cravings for ice cubes lately
• Living alone in an apartment close to work in a lower-income community
• Works full time at a clothing department store

• Case report
• Open access
• Published: 13 September 2021

Critical iron deficiency anemia with record low hemoglobin: a case report

• Audrey L. Chai   ORCID: orcid.org/0000-0002-5009-0468 1 ,
• Owen Y. Huang 1 ,
• Rastko Rakočević 2 &
• Peter Chung 2  

Journal of Medical Case Reports volume  15 , Article number:  472 ( 2021 ) Cite this article

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Anemia is a serious global health problem that affects individuals of all ages but particularly women of reproductive age. Iron deficiency anemia is one of the most common causes of anemia seen in women, with menstruation being one of the leading causes. Excessive, prolonged, and irregular uterine bleeding, also known as menometrorrhagia, can lead to severe anemia. In this case report, we present a case of a premenopausal woman with menometrorrhagia leading to severe iron deficiency anemia with record low hemoglobin.

Case presentation

A 42-year-old Hispanic woman with no known past medical history presented with a chief complaint of increasing fatigue and dizziness for 2 weeks. Initial vitals revealed temperature of 36.1 °C, blood pressure 107/47 mmHg, heart rate 87 beats/minute, respiratory rate 17 breaths/minute, and oxygen saturation 100% on room air. She was fully alert and oriented without any neurological deficits. Physical examination was otherwise notable for findings typical of anemia, including: marked pallor with pale mucous membranes and conjunctiva, a systolic flow murmur, and koilonychia of her fingernails. Her initial laboratory results showed a critically low hemoglobin of 1.4 g/dL and severe iron deficiency. After further diagnostic workup, her profound anemia was likely attributed to a long history of menometrorrhagia, and her remarkably stable presentation was due to impressive, years-long compensation. Over the course of her hospital stay, she received blood transfusions and intravenous iron repletion. Her symptoms of fatigue and dizziness resolved by the end of her hospital course, and she returned to her baseline ambulatory and activity level upon discharge.

Conclusions

Critically low hemoglobin levels are typically associated with significant symptoms, physical examination findings, and hemodynamic instability. To our knowledge, this is the lowest recorded hemoglobin in a hemodynamically stable patient not requiring cardiac or supplemental oxygen support.

Peer Review reports

Anemia and menometrorrhagia are common and co-occurring conditions in women of premenopausal age [ 1 , 2 ]. Analysis of the global anemia burden from 1990 to 2010 revealed that the prevalence of iron deficiency anemia, although declining every year, remained significantly high, affecting almost one in every five women [ 1 ]. Menstruation is considered largely responsible for the depletion of body iron stores in premenopausal women, and it has been estimated that the proportion of menstruating women in the USA who have minimal-to-absent iron reserves ranges from 20% to 65% [ 3 ]. Studies have quantified that a premenopausal woman’s iron storage levels could be approximately two to three times lower than those in a woman 10 years post-menopause [ 4 ]. Excessive and prolonged uterine bleeding that occurs at irregular and frequent intervals (menometrorrhagia) can be seen in almost a quarter of women who are 40–50 years old [ 2 ]. Women with menometrorrhagia usually bleed more than 80 mL, or 3 ounces, during a menstrual cycle and are therefore at greater risk for developing iron deficiency and iron deficiency anemia. Here, we report an unusual case of a 42-year-old woman with a long history of menometrorrhagia who presented with severe anemia and was found to have a record low hemoglobin level.

A 42-year-old Hispanic woman with no known past medical history presented to our emergency department with the chief complaint of increasing fatigue and dizziness for 2 weeks and mechanical fall at home on day of presentation.

On physical examination, she was afebrile (36.1 °C), blood pressure was 107/47 mmHg with a mean arterial pressure of 69 mmHg, heart rate was 87 beats per minute (bpm), respiratory rate was 17 breaths per minute, and oxygen saturation was 100% on room air. Her height was 143 cm and weight was 45 kg (body mass index 22). She was fully alert and oriented to person, place, time, and situation without any neurological deficits and was speaking in clear, full sentences. She had marked pallor with pale mucous membranes and conjunctiva. She had no palpable lymphadenopathy. She was breathing comfortably on room air and displayed no signs of shortness of breath. Her cardiac examination was notable for a grade 2 systolic flow murmur. Her abdominal examination was unremarkable without palpable masses. On musculoskeletal examination, her extremities were thin, and her fingernails demonstrated koilonychia (Fig. 1 ). She had full strength in lower and upper extremities bilaterally, even though she required assistance with ambulation secondary to weakness and used a wheelchair for mobility for 2 weeks prior to admission. She declined a pelvic examination. No bleeding was noted in any part of her physical examination.

Koilonychia, as seen in our patient above, is a nail disease commonly seen in hypochromic anemia, especially iron deficiency anemia, and refers to abnormally thin nails that have lost their convexity, becoming flat and sometimes concave in shape

She was admitted directly to the intensive care unit after her hemoglobin was found to be critically low at 1.4 g/dL on two consecutive measurements with an unclear etiology of blood loss at the time of presentation. Note that no intravenous fluids were administered prior to obtaining the hemoglobin levels. Upon collecting further history from the patient, she revealed that she has had a lifetime history of extremely heavy menstrual periods: Since menarche at the age of 10 years when her periods started, she has been having irregular menstruation, with periods occurring every 2–3 weeks, sometimes more often. She bled heavily for the entire 5–7 day duration of her periods; she quantified soaking at least seven heavy flow pads each day with bright red blood as well as large-sized blood clots. Since the age of 30 years, her periods had also become increasingly heavier, with intermittent bleeding in between cycles, stating that lately she bled for “half of the month.” She denied any other sources of bleeding.

Initial laboratory data are summarized in Table 1 . Her hemoglobin (Hgb) level was critically low at 1.4 g/dL on arrival, with a low mean corpuscular volume (MCV) of < 50.0 fL. Hematocrit was also critically low at 5.8%. Red blood cell distribution width (RDW) was elevated to 34.5%, and absolute reticulocyte count was elevated to 31 × 10 9 /L. Iron panel results were consistent with iron deficiency anemia, showing a low serum iron level of 9 μg/dL, elevated total iron-binding capacity (TIBC) of 441 μg/dL, low Fe Sat of 2%, and low ferritin of 4 ng/mL. Vitamin B12, folate, hemolysis labs [lactate dehydrogenase (LDH), haptoglobin, bilirubin], and disseminated intravascular coagulation (DIC) labs [prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, d -dimer] were all unremarkable. Platelet count was 232,000/mm 3 . Peripheral smear showed erythrocytes with marked microcytosis, anisocytosis, and hypochromia (Fig. 2 ). Of note, the patient did have a positive indirect antiglobulin test (IAT); however, she denied any history of pregnancy, prior transfusions, intravenous drug use, or intravenous immunoglobulin (IVIG). Her direct antiglobulin test (DAT) was negative.

A peripheral smear from the patient after receiving one packed red blood cell transfusion is shown. Small microcytic red blood cells are seen, many of which are hypochromic and have a large zone of pallor with a thin pink peripheral rim. A few characteristic poikilocytes (small elongated red cells also known as pencil cells) are also seen in addition to normal red blood cells (RBCs) likely from transfusion

A transvaginal ultrasound and endometrial biopsy were offered, but the patient declined. Instead, a computed tomography (CT) abdomen and pelvis with contrast was performed, which showed a 3.5-cm mass protruding into the endometrium, favored to represent an intracavitary submucosal leiomyoma (Fig. 3 ). Aside from her abnormal uterine bleeding (AUB), the patient was without any other significant personal history, family history, or lab abnormalities to explain her severe anemia.

Computed tomography (CT) of the abdomen and pelvis with contrast was obtained revealing an approximately 3.5 × 3.0 cm heterogeneously enhancing mass protruding into the endometrial canal favored to represent an intracavitary submucosal leiomyoma

The patient’s presenting symptoms of fatigue and dizziness are common and nonspecific symptoms with a wide range of etiologies. Based on her physical presentation—overall well-appearing nature with normal vital signs—as well as the duration of her symptoms, we focused our investigation on chronic subacute causes of fatigue and dizziness rather than acute medical causes. We initially considered a range of chronic medical conditions from cardiopulmonary to endocrinologic, metabolic, malignancy, rheumatologic, and neurological conditions, especially given her reported history of fall. However, once the patient’s lab work revealed a significantly abnormal complete blood count and iron panel, the direction of our workup shifted towards evaluating hematologic causes.

With such a critically low Hgb on presentation (1.4 g/dL), we evaluated for potential sources of blood loss and wanted to first rule out emergent, dangerous causes: the patient’s physical examination and reported history did not elicit any concern for traumatic hemorrhage or common gastrointestinal bleeding. She denied recent or current pregnancy. Her CT scan of abdomen and pelvis was unremarkable for any pathology other than a uterine fibroid. The microcytic nature of her anemia pointed away from nutritional deficiencies, and she lacked any other medical comorbidities such as alcohol use disorder, liver disease, or history of substance use. There was also no personal or family history of autoimmune disorders, and the patient denied any history of gastrointestinal or extraintestinal signs and/or symptoms concerning for absorptive disorders such as celiac disease. We also eliminated hemolytic causes of anemia as hemolysis labs were all normal. We considered the possibility of inherited or acquired bleeding disorders, but the patient denied any prior signs or symptoms of bleeding diatheses in her or her family. The patient’s reported history of menometrorrhagia led to the likely cause of her significant microcytic anemia as chronic blood loss from menstruation leading to iron deficiency.

Over the course of her 4-day hospital stay, she was transfused 5 units of packed red blood cells and received 2 g of intravenous iron dextran. Hematology and Gynecology were consulted, and the patient was administered a medroxyprogesterone (150 mg) intramuscular injection on hospital day 2. On hospital day 4, she was discharged home with follow-up plans. Her hemoglobin and hematocrit on discharge were 8.1 g/dL and 24.3%, respectively. Her symptoms of fatigue and dizziness had resolved, and she was back to her normal baseline ambulatory and activity level.

Discussion and conclusions

This patient presented with all the classic signs and symptoms of iron deficiency: anemia, fatigue, pallor, koilonychia, and labs revealing marked iron deficiency, microcytosis, elevated RDW, and low hemoglobin. To the best of our knowledge, this is the lowest recorded hemoglobin in an awake and alert patient breathing ambient air. There have been previous reports describing patients with critically low Hgb levels of < 2 g/dL: A case of a 21-year old woman with a history of long-lasting menorrhagia who presented with a Hgb of 1.7 g/dL was reported in 2013 [ 5 ]. This woman, although younger than our patient, was more hemodynamically unstable with a heart rate (HR) of 125 beats per minute. Her menorrhagia was also shorter lasting and presumably of larger volume, leading to this hemoglobin level. It is likely that her physiological regulatory mechanisms did not have a chance to fully compensate. A 29-year-old woman with celiac disease and bulimia nervosa was found to have a Hgb of 1.7 g/dL: she presented more dramatically with severe fatigue, abdominal pain and inability to stand or ambulate. She had a body mass index (BMI) of 15 along with other vitamin and micronutrient deficiencies, leading to a mixed picture of iron deficiency and non-iron deficiency anemia [ 6 ]. Both of these cases were of reproductive-age females; however, our patient was notably older (age difference of > 20 years) and had a longer period for physiologic adjustment and compensation.

Lower hemoglobin, though in the intraoperative setting, has also been reported in two cases—a patient undergoing cadaveric liver transplantation who suffered massive bleeding with associated hemodilution leading to a Hgb of 0.6 g/dL [ 7 ] and a patient with hemorrhagic shock and extreme hemodilution secondary to multiple stab wounds leading to a Hgb of 0.7 g/dL [ 8 ]. Both patients were hemodynamically unstable requiring inotropic and vasopressor support, had higher preoperative hemoglobin, and were resuscitated with large volumes of colloids and crystalloids leading to significant hemodilution. Both were intubated and received 100% supplemental oxygen, increasing both hemoglobin-bound and dissolved oxygen. Furthermore, it should be emphasized that the deep anesthesia and decreased body temperature in both these patients minimized oxygen consumption and increased the available oxygen in arterial blood [ 9 ].

Our case is remarkably unique with the lowest recorded hemoglobin not requiring cardiac or supplemental oxygen support. The patient was hemodynamically stable with a critically low hemoglobin likely due to chronic, decades-long iron deficiency anemia of blood loss. Confirmatory workup in the outpatient setting is ongoing. The degree of compensation our patient had undergone is impressive as she reported living a very active lifestyle prior to the onset of her symptoms (2 weeks prior to presentation), she routinely biked to work every day, and maintained a high level of daily physical activity without issue.

In addition, while the first priority during our patient’s hospital stay was treating her severe anemia, her education became an equally important component of her treatment plan. Our institution is the county hospital for the most populous county in the USA and serves as a safety-net hospital for many vulnerable populations, most of whom have low health literacy and a lack of awareness of when to seek care. This patient had been experiencing irregular menstrual periods for more than three decades and never sought care for her heavy bleeding. She, in fact, had not seen a primary care doctor for many years nor visited a gynecologist before. We emphasized the importance of close follow-up, self-monitoring of her symptoms, and risks with continued heavy bleeding. It is important to note that, despite the compensatory mechanisms, complications of chronic anemia left untreated are not minor and can negatively impact cardiovascular function, cause worsening of chronic conditions, and eventually lead to the development of multiorgan failure and even death [ 10 , 11 ].

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

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Department of Medicine, University of Southern California, Los Angeles, CA, USA

Audrey L. Chai & Owen Y. Huang

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles, CA, USA

Rastko Rakočević & Peter Chung

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AC, OH, RR, and PC managed the presented case. AC performed the literature search. AC, OH, and RR collected all data and images. AC and OH drafted the article. RR and PC provided critical revision of the article. All authors read and approved the final manuscript.

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Correspondence to Audrey L. Chai .

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Chai, A.L., Huang, O.Y., Rakočević, R. et al. Critical iron deficiency anemia with record low hemoglobin: a case report. J Med Case Reports 15 , 472 (2021). https://doi.org/10.1186/s13256-021-03024-9

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Published : 13 September 2021

DOI : https://doi.org/10.1186/s13256-021-03024-9

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• Menometrorrhagia
• Iron deficiency
• Critical care
• Transfusion

Journal of Medical Case Reports

ISSN: 1752-1947

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• History of Present Illness

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• Past Medical History
• Physical Examination
• Differential Diagnosis
• Relevant Next Steps
• Test Results
• Interim Differential Diagnoses
• Relevant Next Steps 2
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• About the Case

Anemia in a 42-year-old woman

• General : Patient says she felt fine until about 2 months ago when she had "the flu," which she describes as a low-grade fever, diffuse joint pain, malaise, and a non-pruritic rash primarily over her extremities. She took acetaminophen and her symptoms resolved after 4 days. Except for her fatigue and dyspnea, she has since felt well with normal appetite and no fever or chills.
• Skin : No rash or lesions noted.
• HEENT : Denies pain or swelling in her neck, no nasal discharge or bleeding.
• Pulmonary : Dyspnea climbing stairs, worsening over the past 3 weeks to the point that she cannot climb a flight of steps without pausing to rest. No cough or wheezing.
• Cardiovascular : No exertional chest pain, palpitations, orthopnea, or paroxysmal nocturnal dyspnea.
• Gastrointestinal : No nausea, vomiting, diarrhea or abdominal pain.
• Genitourinary : Menses normal, last period 2 weeks prior, normal amount of bleeding for her. No other vaginal bleeding. Urination normal, no visible blood.
• Musculoskeletal : No swelling or pain in joints or extremities.
• Neurologic : Unremarkable
• Psychiatric : Unremarkable

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.

Johnson-Wimbley TD, Graham DY. Diagnosis and management of iron deficiency anemia in the 21st century. Therap Adv Gastroenterol. 2011;4(3):177-184.

WHO Global Database on Anaemia. Worldwide Prevalence of Anaemia 1993–2005 . Geneva, Switzerland: World Health Organization; 2008.

U. S. Preventive Services Task Force. Screening for iron deficiency anemia, including iron supplementations for children and pregnant women: recommendation statement. Am Fam Physician. 2006;74(3):461-464.

Van Vranken M. Evaluation of microcytosis. Am Fam Physician. 2010;82(9):1117-1122.

Ioannou GN, Spector J, Scott K, Rockey DC. Prospective evaluation of a clinical guideline for the diagnosis and management of iron deficiency anemia. Am J Med. 2002;113(4):281-287.

Goddard AF, James MW, McIntyre AS, Scott BB British Society of Gastroenterology. Guidelines for the management of iron deficiency anaemia. Gut. 2011;60(10):1309-1316.

Mast AE, Blinder MA, Gronowski AM, Chumley C, Scott MG. Clinical utility of the soluble transferrin receptor and comparison with serum ferritin in several populations. Clin Chem. 1998;44(1):45-51.

Knovich MA, Storey JA, Coffman LG, Torti SV, Torti FM. Ferritin for the clinician. Blood Rev. 2009;23(3):95-104.

Galloway MJ, Smellie WS. Investigating iron status in microcytic anaemia. BMJ. 2006;333(7572):791-793.

Assessing the iron status of populations: report of a joint World Health Organization/Centers for Disease Control and Prevention technical consultation on the assessment of iron status at the population level, Geneva, Switzerland, 6–8 April 2004. Geneva: World Health Organization, Centers for Disease Control and Prevention; 2005.

Skikne BS, Punnonen K, Caldron PH, et al. Improved differential diagnosis of anemia of chronic disease and iron deficiency anemia: a prospective multicenter evaluation of soluble transferrin receptor and the sTfR/log ferritin index. Am J Hematol. 2011;86(11):923-927.

Bermejo F, García-López S. A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases. World J Gastroenterol. 2009;15(37):4638-4643.

Centers for Disease Control and Prevention. Recommendations to prevent and control iron deficiency in the United States. MMWR Recomm Rep. 1998;47(RR-3):1-29.

American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 95: anemia in pregnancy. Obstet Gynecol. 2008;112(1):201-207.

Baker RD, Greer FR Committee on Nutrition, American Academy of Pediatrics. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0–3 years of age). Pediatrics. 2010;126(5):1040-1050.

Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials. JAMA. 2007;297(11):1241-1252.

Liu K, Kaffes AJ. Iron deficiency anaemia: a review of diagnosis, investigation and management. Eur J Gastroenterol Hepatol. 2012;24(2):109-116.

British Columbia Ministry of Health. Iron deficiency—investigation and management. http://www.bcguidelines.ca/guideline_iron_deficiency.html . Accessed November 13, 2012.

Carter D, Maor Y, Bar-Meir S, Avidan B. Prevalence and predictive signs for gastrointestinal lesions in premenopausal women with iron deficiency anemia. Dig Dis Sci. 2008;53(12):3138-3144.

American College of Obstetricians and Gynecologists Committee on Adolescent Health Care; American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG committee opinion no. 451: Von Willebrand disease in women. Obstet Gynecol. 2009;114(6):1439-1443.

Green BT, Rockey DC. Gastrointestinal endoscopic evaluation of pre-menopausal women with iron deficiency anemia. J Clin Gastroenterol. 2004;38(2):104-109.

Park DI, Ryu SH, Oh SJ, et al. Significance of endoscopy in asymptomatic premenopausal women with iron deficiency anemia. Dig Dis Sci. 2006;51(12):2372-2376.

Fraser IS, Langham S, Uhl-Hochgraeber K. Health-related quality of life and economic burden of abnormal uterine bleeding. Expert Rev Obstet Gynecol. 2009;4(2):179-189.

ACOG Committee on Practice Bulletins—Gynecology, American College of Obstetricians and Gynecologists. ACOG practice bulletin: management of anovulatory bleeding. Int J Gynaecol Obstet. 2001;72(3):263-271.

Hopper AD, Leeds JS, Hurlstone DP, Hadjivassiliou M, Drew K, Sanders DS. Are lower gastrointestinal investigations necessary in patients with coeliac disease?. Eur J Gastroenterol Hepatol. 2005;17(6):617-621.

Yates JM, Logan EC, Stewart RM. Iron deficiency anaemia in general practice: clinical outcomes over three years and factors influencing diagnostic investigations. Postgrad Med J. 2004;80(945):405-410.

Ioannou GN, Rockey DC, Bryson CL, Weiss NS. Iron deficiency and gastrointestinal malignancy: a population-based cohort study. Am J Med. 2002;113(4):276-280.

Lewis NR, Scott BB. Systematic review: the use of serology to exclude or diagnose coeliac disease (a comparison of the endomysial and tissue transglutaminase antibody tests). Aliment Pharmacol Ther. 2006;24(1):47-54.

Sidhu R, Sanders DS, Morris AJ, McAlindon ME. Guidelines on small bowel enteroscopy and capsule endoscopy in adults. Gut. 2008;57(1):125-136.

Ajmera AV, Shastri GS, Gajera MJ, Judge TA. Suboptimal response to ferrous sulfate in iron-deficient patients taking omeprazole. Am J Ther. 2012;19(3):185-189.

Maslovsky I. Intravenous iron in a primary-care clinic. Am J Hematol. 2005;78(4):261-264.

Silverstein SB, Rodgers GM. Parenteral iron therapy options. Am J Hematol. 2004;76(1):74-78.

Eichbaum Q, Foran S, Dzik S. Is iron gluconate really safer than iron dextran?. Blood. 2003;101(9):3756-3757.

Murphy MF, Wallington TB, Kelsey P, et al.; British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the clinical use of red cell transfusions. Br J Haematol. 2001;113(1):24-31.

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Case Study: A 78-Year-Old Man With Elevated Leukocytes and Anemia

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The following case study focuses on finding the optimal treatment for a 78-year-old man. Test your knowledge by reading the question below and making the proper selection.

A 78-year-old man presents with a three-year history of an elevated leukocyte count with recent fatigue and anemia. He has received two red blood cell transfusions in the past two months. His past medical history includes coronary artery disease and hypertension. His physical examination is unremarkable. The patient’s white blood cell (WBC) count is 75,000/uL, hemoglobin is 9.3 g/dL, and platelet count is 71,000/uL with a WBC differential including 60 percent neutrophils, 19 percent lymphocytes, 15 percent monocytes, and 6 percent eosinophils. His bone marrow aspirate shows mild erythroid dysplasia, 1 percent blasts with an increase in monocytes (14 percent) and eosinophils (7 percent). Chromosomal analysis demonstrates 46XY, t(5;12)(q33;p13)[16]; 46,XY[4]. Fluorescence in situ hybridization (FISH) testing for the BCR-ABL translocation and quantitative RT-PCR for the BCR-ABL transcript were both negative. What is the optimal treatment for this patient?

• Decitabine (Dacogen) 20 mg/m 2 daily x five days per month for three months and then re-examine the bone marrow
• Continued observation until further disease progression
• Imatinib (Gleevec) 400 mg once daily
• Standard induction chemotherapy with daunorubicin (50 mg/m 2 daily x three days) and Ara-C (100 mg/m 2 continuous infusion x seven days)

Explanation

Chronic myelomonocytic leukemia (CMML) is considered to be a clonal myeloid stem cell disorder. 1-3 In 2001, the World Health Organization (WHO) classified CMML as a myelodysplastic-myeloproliferative disease with diagnostic criteria including: 1) persistent peripheral blood (PB) monocyte count &gt;1X109/L; 2) absence of the Philadelphia chromosome; 3) &lt; 20 percent blasts in the PB or bone marrow (BM); and 4) dysplasia in one or more hematopoietic cell lineages. 2,3 The subcategory of CMML with eosinophilia was also established and is characterized by a PB eosinophilia of &gt;1500 cells/uL.

Translocation (5;12)(q31-q33;p12-p13) is a recurring cytogenetic abnormality reported in patients with CMML, in particular those with eosinophilia. 4 The t(5;12) translocation results in the fusion of the transmembrane and tyrosine kinase domains of the platelet-derived growth factor receptor-B ( PDGFR-B ) gene on chromosome 5 with the amino-terminal domain of the TEL/ETV6 gene of chromosome 12, a member of the ETS family of transcription factors. 5,6 The resultant aberrant tyrosine kinase activity of this hybrid protein is potentially the transforming event in these cases of CMML. 7-9 The overall incidence of t(5;12) in CMML is unknown but is presumed to be relatively rare. A retrospective analysis by Gunby, et al. demonstrated the translocation in only 1/27 patients with CMML. 10 Others have indicated only 40 to 50 known cases of CMML involving t(5;12) or similar chromosomal abnormalities involving the PDGFR-B loci. 11

Imatinib is a tyrosine kinase inhibitor with potent activity against BCR-ABL in chronic myeloid leukemia. Imatinib also inhibits a number of additional tyrosine kinases including PDGFRA, PDGFRB, and c-kit, providing the basis for its use in CMML involving the t(5;12) translocation. 12-14 Recently, Han, et al. reviewed 13 cases from the literature of myeloproliferative diseases with evidence of PGDFR-B translocations treated with imatinib. 11 An impressive number of complete responses were noted, encouraging further study of this agent in this CMML subgroup.

Given this patient’s age and absence of blastic transformation, intensive induction chemotherapy regimens such as daunorubicin and cytarabine would not be optimal. Such therapies can lead to significant treatment-related mortality in the elderly. The alternative plan of observation alone, while always an option for patients, would not be preferable for this symptomatic patient who has transfusion dependency and fatigue. Finally, hypomethylating agents, including decitabine have recently been evaluated in patients with CMML. 15,16 Overall response rates of 25 percent to 70 percent have been reported, with complete response rates ranging from 12 percent to greater than 60 percent. Although this is a treatment option, given the identification of the t(5;12) translocation, oral imatinib, which is generally well tolerated even in the elderly, is a rational treatment option for this patient.

In summary, CMML associated with t(5;12) translocation is a relatively rare disorder. Responses to imatinib are variable, but this agent offers a unique treatment alternative in a disease with relatively few curative options in the elderly population. Therefore, identifying this translocation, especially in CMML patients presenting with eosinophilia, should be a priority.

• Bennett JM, Catovsky D, Daniel MT, et al. The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group . Br J Haematol. 1994;87:746-54.
• Elliott MA. Chronic neutrophilic leukemia and chronic myelomonocytic leukemia: WHO defined . Best Pract Res Clin Haematol. 2006;19:571-93.
• Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms . Blood. 2002;100:2292-302.
• Baranger L, Szapiro N, Gardais J, et al. Translocation t(5;12)(q31-q33;p12-p13): a non-random translocation associated with a myeloid disorder with eosinophilia . Br J Haematol. 1994;88:343-7.
• Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation . Cell. 1994;77:307-16.
• Wlodarska I, Mecucci C, Marynen P, et al. TEL gene is involved in myelodysplastic syndromes with either the typical t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13) . Blood. 1995;85:2848-52.
• Carroll M, Tomasson MH, Barker GF, et al. The TEL/platelet-derived growth factor beta receptor (PDGF beta R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF beta R kinase-dependent signaling pathways . Proc Natl Acad Sci USA. 1996;93:14845-50.
• Jousset C, Carron C, Boureux A, et al. A domain of TEL conserved in a subset of ETS proteins defines a specific oligomerization interface essential to the mitogenic properties of the TEL-PDGFR beta oncoprotein . Embo J. 1997;16:69-82.
• Ritchie KA, Aprikyan AA, Bowen-Pope DF, et al. The Tel-PDGFRbeta fusion gene produces a chronic myeloproliferative syndrome in transgenic mice . Leukemia. 1999;13:1790-803.
• Gunby RH, Cazzaniga G, Tassi E, et al. Sensitivity to imatinib but low frequency of the TEL/PDGFRbeta fusion protein in chronic myelomonocytic leukemia . Haematologica. 2003;88:408-15.
• Han X, Medeiros LJ, Abruzzo LV, et al. Chronic myeloproliferative diseases with the t(5;12)(q33;p13): clonal evolution is associated with blast crisis . Am J Clin Pathol. 2006;125:49-56.
• Magnusson MK, Meade KE, Nakamura R, Barrett J, Dunbar CE. Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor beta receptor fusion oncogene . Blood. 2002;100:1088-91.
• Carroll M, Ohno-Jones S, Tamura S, et al. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins . Blood. 1997;90:4947-52.
• Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative . Cancer Res. 1996;56:100-4.
• Aribi A, Borthakur G, Ravandi F, et al. Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia . Cancer. 2007;109:713-7.
• Wijermans PW, Rüter B, Baer MR, et al. Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML) . Leuk Res. 2008;32:587-91.

Additional Resources

• Han X, Medeiros J, et al. Chronic myeloproliferative diseases with the t(5;12)(q33;p13) . American Journal of Clinical Pathology. 2006;125(1):49-56.
• Elliot M. Chronic neutrophilic leukemia and chronic myelomonocytic leukemia: WHO defined . Best Practice &amp; Research Clinical Haematology. 2006;19(3):571-593.

Case study submitted by Dale Bixby, MD, PhD, of the University of Michigan.

American Society of Hematology. (1). Case Study: A 78-Year-Old Man With Elevated Leukocytes and Anemia. Retrieved from https://www.hematology.org/education/trainees/fellows/case-studies/male-elevated-leukocytes-and-anemia .

American Society of Hematology. "Case Study: A 78-Year-Old Man With Elevated Leukocytes and Anemia." Hematology.org. https://www.hematology.org/education/trainees/fellows/case-studies/male-elevated-leukocytes-and-anemia (label-accessed August 31, 2024).

"American Society of Hematology." Case Study: A 78-Year-Old Man With Elevated Leukocytes and Anemia, 31 Aug. 2024 , https://www.hematology.org/education/trainees/fellows/case-studies/male-elevated-leukocytes-and-anemia .

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Chapter 6-1:  Approach to the Patient with Anemia - Case 1

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Chief complaint, constructing a differential diagnosis.

• RANKING THE DIFFERENTIAL DIAGNOSIS
• MAKING A DIAGNOSIS
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Mrs. A is a 48-year-old white woman who has had fatigue for 2 months due to anemia.

Figure 6-1.

Diagnostic approach: anemia.

Anemia can occur in isolation, or as a consequence of a process causing pancytopenia, the reduction of all 3 cell lines (white blood cells [WBCs], platelets, and red blood cells [RBCs]). This chapter focuses on the approach to isolated anemia, although a brief list of causes of pancytopenia appears in Figure 6-1 . The first step in determining the cause of anemia is to identify the general mechanism of the anemia and organize the mechanisms using a pathophysiologic framework:

Acute blood loss: this is generally clinically obvious.

Underproduction of RBCs by the bone marrow; chronic blood loss is included in this category because it leads to iron deficiency, which ultimately results in underproduction.

Increased destruction of RBCs, called hemolysis.

Signs of acute blood loss

Hypotension

Tachycardia

Large ecchymoses

Symptoms of acute blood loss

Hematemesis

Rectal bleeding

Vaginal bleeding

After excluding acute blood loss, the next pivotal step is to distinguish underproduction from hemolysis by checking the reticulocyte count:

Low or normal reticulocyte counts are seen in underproduction anemias.

High reticulocyte counts occur when the bone marrow is responding normally to blood loss; hemolysis; or replacement of iron, vitamin B 12 , or folate.

Reticulocyte measures include:

The reticulocyte count: the percentage of circulating RBCs that are reticulocytes (normally 0.5–1.5%).

The absolute reticulocyte count; the number of reticulocytes actually circulating, normally 25,000–75,000/mcL (multiply the percentage of reticulocytes by the total number of RBCs).

The reticulocyte production index (RPI)

Corrects the reticulocyte count for the degree of anemia and for the prolonged peripheral maturation of reticulocytes that occurs in anemia.

Normally, the first 3–3.5 days of reticulocyte maturation occurs in the bone marrow and the last 24 hours in the peripheral blood.

When the bone marrow is stimulated, reticulocytes are released prematurely, leading to longer maturation times in the periphery, and larger numbers of reticulocytes are present at any given time.

For an HCT of 25%, the peripheral blood maturation time is 2 days, and for an HCT of 15%, it is 2.5 days; the value of 2 is generally used in the RPI calculation.

The normal RPI is about 1.0.

However, in patients with anemia, RPI < 2.0 indicates underproduction; RPI > 2.0 indicates hemolysis or an adequate bone marrow response to acute blood loss or replacement of iron or vitamins.

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First Presentation of Sickle Cell Anemia in A 3.5-Year-Old Girl: A Case Report

1 Thalassemia and Hemoglobinopathy Research Center, Ahvaz Jondishapur University of Medical Sciences, Ahvaz, Iran

2 Department of Pediatrics Hematology/Oncology, Ahvaz Jondishapur University of Medical Sciences, Ahvaz, Iran

Dear Editor,

Sickle cell disease is an inherited disorder of hemoglobin synthesis, which affects many individuals worldwide. Vaso-occlusive, aplastic and sequestration crises are common in a sickle cell child.[ 1 ] One of the leading causes of death in children with sickle cell anemia is an acute splenic sequestration crisis.[ 2 ] Children with splenic sequestration disease who have not yet undergone autosplenectomy, as well as older patients with sickle cell disease or S-beta thalassemia, may have sudden, rapid, massive enlargement of the spleen with trapping of a considerable portion of the red cell mass. On physical examination, there may be profound hypotension with cardiac decompensation and massive splenomegaly. The hemoglobin concentration is at least 2 g/dL lower than baseline and is accompanied by a brisk reticulocytosis with increased nucleated red cells and moderate to severe thrombocytopenia.[ 2 ] ACS is an acute illness with lung injury characterized by any combination of chest pain, fever, or respiratory symptoms and accompanied by a new pulmonary infiltrate on a chest radiograph.[ 3 ] Elevated WBC count, dactylitis, and anemia predicted more severe later outcomes in children younger than 4 years.[ 4 ] Dactylitis, often referred to as hand-foot syndrome, is frequently the 1st manifestation of pain in children with sickle cell anemia, occurring in 50% of children by 2 years of age.[ 5 ]

A 3.5-year-old girl from race of Arab reffered to Shafa Hospital with severe anemia, thrombocytopenia, leucocytosis and elevated ESR and LDH. Her parents assigned fever, cough, pallor, weakness and tachypnea from six day ago ( Figure 1 ).

Chest x ray.

Past medical history and familial history of the patient was negative. On physical examination, she had fever with temperature of 39.5°C, severe pallor, pulse rate of 110 per minute, respiratory rate of 32 per minute and blood pressure of 90/60 mmHg. On abdominal examination, she had hepatosplenomegaly. Rales and rhonchi were in both lung fields on respiratory examination while the other systemic examination was essentially normal. Initial laboratory investigations demonstrated hemoglobin of 4.5 gm/dL, white cell count of 19,000/mm(3) (55% neutrophils, 45% lymphocyte), platelet count of 70,000/mm(3) and an erythrocyte sedimentation rate of 45 mm/hour. Renal function tests and urinalysis were normal. A chest radiograph revealed bilateral haziness. For decline of malignancy, bone marrow aspiration was done and discussed reactive bone marrow due to infection.

After one day a dactylitis was present in hands of the patient ( Figure 2 ).

Dactylitis.

In follow up of Hb electrophoresis, Hb s was 80%, Hb F: 18%, and Hb A2: 2%. Finally in peripheral blood smear, sickling of RBC was detected and the patient was diagnosed with sickle cell anemia and acute splenic sequestration crisis which was associated with acute chest syndrome treated with wide spectrum antibiotic (cefotaxim and erythromycin) and transfusion exchange ( Figure 3 ). The patient was discharged with stable clinical state after 8 days.

Prepheral blood smears with sickle cell.

The clinical presentation of our patient is rare and unusual for initial presentation of sickle cell anemia. Also association between acute chest syndrome and splenic sequestration is unusual.

Conflict of interest: None declared.

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• Case Study: Vitamin B12 Deficiency

Volume 35 Number 4 | August 2021

Minh kosfeld, phd, mlt(ascp) cm, patient physical examination on admission.

Our patient is a previously healthy 56-year-old white man who presents with progressive neuropathy and declining mental status over several months. The patient initially developed numbness of his fingertips and the balls of his feet and began to lose motor control of his hands, which manifested as dropping objects or flinging them as he tried to pick them up. As symptoms progressed, he had visual tracking problems that were severe enough to interfere with driving a car, and he developed short-term memory loss and slowing of cognitive function.

Laboratory Results

Diagnosis and Treatment

Based on the clinical presentation and laboratory findings, a diagnosis of psychomotor regression due to B12 deficiency was made. The patient was then treated with a series of B12 intramuscular injections, which resulted in rapid remission of associated neurological symptoms. In follow-up laboratory examinations, his B12 level was normalized in two months (606 pg/mL), and MMA in eight months (197 nmol/L).

B12 is the largest and most complex of the water-soluble B vitamins. Since it contains cobalt, compounds with B12 activity are collectively called “cobalamins.” For humans, the only natural dietary sources of B12 are animal products (meat, dairy), in which it is bound to protein. The B12 absorption mechanism is complex, requiring several transporter proteins. First, it must be freed from the food matrix by gastric HCl and pepsin. Once liberated, it is transported to the duodenum by haptocorrin (transcobalamin I), a cobalamin-binding protein produced in the saliva. In the duodenum, pancreatic digestive enzymes free B12 from haptocorrin, allowing it to bind intrinsic factor (IF), a transporter protein synthesized by the parietal cells of the gastric mucosa. This B12-IF complex travels to the terminal ileum where it is absorbed and the B12 is separated from IF. B12 then is delivered to peripheral tissues and the liver by transcobalamin II and haptocorrin, respectively. 1,2

B12 is essential for DNA synthesis, hematopoiesis, and myelination. In different metabolically active forms, it functions as a cofactor for two different enzymes. As methylcobalamin, B12 activates cytoplasmic methionine synthase to convert homocysteine to the essential amino acid methionine. Methionine is required for the formation of S-adenosylmethionine, a universal methyl donor for almost 100 different substrates, including DNA, RNA, proteins, and lipids. As adenosylcobalamin, B12 activates the mitochondrial L-methylmalonyl-CoA mutase to convert L-methylmalonyl-CoA to succinyl-CoA in the metabolism of propionate, a short-chain fatty acid. 3,4 In B12 deficiency, these cofactors are unavailable, causing homocysteine and MMA to accumulate.

Despite our understanding of the metabolic disturbances resulting from B12 deficiency, its pathogenesis is not as well understood. Deficiency of B12 can lead to two major clinical syndromes, megaloblastic anemia and neuropathy. 1,3,4 It is thought that severe B12 deficiency interferes with the synthesis of DNA needed for hematopoiesis, leading to megaloblastic anemia, the appearance of hypersegmented neutrophils, and possible pancytopenia. 5 Regarding neuropathy, it is thought that long-term B12 deficiency may lead to impaired synthesis of ethanolamine, phospholipids, and sphingomyelin, resulting in altered myelin integrity. 6 An enigmatic feature of B12 deficiency is that its clinical presentations vary and may entail only hematologic or neurological abnormalities, or both. 1

Common diagnostic lab tests for B12 deficiency typically begin with serum B12 measurement and a complete blood count (CBC). Low B12 levels and evidence of megaloblastic anemia (decreased RBC, Hgb, Hct, WBC, platelet count, increased MCV, large oval RBCs and hypersegmented neutrophils) indicate B12 deficiency. For ambiguous results, MMA and homocysteine levels should also be measured to confirm. 2,4 Serum MMA is the most sensitive marker of B12 status where its increase indicates decreased tissue B12. However, it also rises with renal insufficiency and tends to be higher in older adults. Plasma homocysteine is a sensitive indicator for early B12 deficiency where it rises quickly as B12 status declines. However, it also rises in folate or B6 deficiency and especially with renal insufficiency, reducing its specificity. 3,4 Additional tests include serum or RBC folate to differentiate causes of macrocytic anemia, and Anti-IF or Anti-parietal cell antibodies to confirm pernicious anemia. 1,2

Caregivers should be aware of the different clinical presentations of B12 deficiency and screen for it in high-risk populations. Risk factors include insufficient dietary B12 intake (vegetarians), lack of intrinsic factor (autoimmune pernicious anemia), food-bound malabsorption (atrophic gastritis of aging or chronic H. pylori infection), gastrointestinal surgery (post gastrectomy or ileal resection), pancreatic or intestinal disorders (chronic pancreatitis, Crohn’s, or Celiac disease), genetic disorders (Transcobalamin II deficiency), and use of certain drugs (long-term use of metformin, H2 receptor antagonists or Proton-pump inhibitors). 1,2,3

Diagnosis of B12 deficiency can be complicated since symptoms may be vague and lab test results can be equivocal. Despite the low B12, high MMA, and significant neurologic symptoms, this patient’s homocysteine level was normal, and he was not anemic. With no known risk factor for B12 deficiency, assays were done for anti-IF antibodies to evaluate for pernicious anemia and AChR binding antibodies for Myasthenia Gravis. However, this patient’s positive symptomatic and serologic responses to B12 supplementation suggest that simple vitamin B12 deficiency was the etiology. Fortunately, B12 therapy reversed his most severe neurological symptoms, although that may not always be the case. Since the reason for the deficiency is unknown, he will continue to receive B12 supplementation indefinitely.

• Michael J Shipton and Jecko Thachil, Vitamin B12 deficiency–A 21st century perspective. Clin Med (Lond). 2015 Apr; 15(2): 145–150. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4953733/
• https://labtestsonline.org/conditions/vitamin-b12-and-folate-deficiencies
• Vitamin B12. https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/
• Bishnu Prasad Devkota. Methylmalonic Acid. https://emedicine.medscape.com/article/2108967-overview#showall
• Mark J Koury, Prem Ponka. New insights into erythropoiesis: the roles of folate, vitamin B12, and iron. Annu Rev Nutr. 2004;24:105-31. https://pubmed.ncbi.nlm.nih.gov/15189115/
• Brahim El Hasbaoui, Nadia Mebrouk, Salahiddine Saghir, Abdelhkim El Yajouri, Rachid Abilkassem, and Aomar Agadr. Vitamin B12 deficiency: case report and review of literature. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140678/

Minh Kosfeld is Director/Assistant Professor, Investigative and Medical Sciences Program, in the Department of Clinical Health Sciences at Saint Louis University in Missouri.