CE/CME Diagnosing and Classifying in Adult Primary Care Anemia affects more than 3 million people in the United States, making it a common problem in primary care practices. Once anemia is detected, clinicians must define the type and identify its underlying cause prior to initiating treatment. In most cases, the cause can be determined using information from the patient history, physical exam, and .

Jean O’Neil, DNP, RN, FNP-BC

Jean O’Neil is an nemia is commonly identified during Assistant Professor CE/CME INFORMATION routine physical exams and laboratory and Coordinator of Earn credit by reading this article and 1-3 the Adult Gerontol- A testing. However, treating anemia can successfully completing the posttest at ogy Acute Care present a challenge for the primary care pro- www.mdedge.com/clinicianreviews/ce/ Nurse Practitioner vider if the immediate cause is not apparent. Program in the cme/latest. Successful completion is Patricia A. Chin defined as a cumulative score of at least is a leading cause of anemia, but School of Nursing 70% correct. simply prescribing an iron supplement without at California State determining the type or the cause of the anemia University, Los This program has been reviewed and Angeles. is approved for a maximum of 1.0 hour of is not appropriate. Anemia that is misdiagnosed American Academy of Physician Assistants or goes untreated can be associated with a worse (AAPA) Category 1 CME credit by the prognosis, as well as increased health care costs.4 Physician Assistant Review Panel. [NPs: Primary care providers often manage pa- Both ANCC and the AANP Certification tients with common types of anemia and re- Program recognize AAPA as an approved fer patients with severe or complex anemia to provider of Category 1 credit.] Approval is specialists for further testing and treatment. valid through July 31, 2018. The most commonly used and cost-effective LEARNING OBJECTIVES diagnostic tool for anemia is the complete 2-6 • Discuss the importance of diagnosing blood count (CBC). The CBC provides de- the type of anemia in order to provide tails that can help the provider determine the appropriate treatment. type of anemia present, which in turn guides • Describe how the complete blood proper diagnostic testing and treatment. count and its indices are used to initially determine if an anemia is microcytic, EPIDEMIOLOGY normocytic, or macrocytic. Anemia involves a reduction in the number • List the more common causes of of circulating red blood cells, the blood he- microcytic, normocytic, and macrocytic moglobin content, or the , which anemia. leads to impaired delivery of oxygen to the • Discuss additional laboratory tests that may be used to body. Anemia affects more than 2 billion further assess the cause of people worldwide, with iron deficiency the 7 anemia. most common cause. Other leading nutri-

tional causes of anemia include vitamin B12 and deficiency.4,7 Approximately 3 to 4

28 Clinician Reviews • AUGUST 2017 clinicianreviews.com million Americans have anemia in some form, and it affects about 6.6% of men and 12.4% of women.5,8 The prevalence of ane- mia increases with age. Approximately 11% of men and 10% of women ages 65 or older have anemia, and in men ages 85 or older, prevalence of 20% to 44% has been report- ed.1,4 Anemia is present in about 3.5% of pa- tients with chronic disease, but only 15% of them receive treatment.4 lems, gastrointestinal , and active or recent history of blood loss.5,10 PATHOPHYSIOLOGY Blood is composed of water-based plasma CLINICAL PRESENTATION (54%), white blood cells and platelets (1%), There are several signs and symptoms that and red blood cells (45%).5 , should lead the primary care provider to the primary protein of the , suspect anemia (see Table 1).5,6 The sever- binds oxygen from the lungs and transports ity of these symptoms can vary from mild it to the rest of the body. Oxygen is then ex- to very serious. Severe anemia can lead to changed for carbon dioxide, which is car- organ failure and death. However, most pa- ried back to the lungs to be exhaled. tients with anemia are asymptomatic, and Hemoglobin is made up of four globin anemia is typically detected incidentally chains, each containing an iron ion held in during laboratory testing.1,2 a porphyrin ring known as a heme group.5 Once anemia is confirmed, the evalua- When the body detects low tissue oxygen, tion focuses on diagnosing its underlying the endothelial cells in the kidneys secrete cause. It should include a thorough patient the hormone erythropoietin (EPO), which history and review of systems to ascertain stimulates the to increase red whether the patient has symptoms such as cell production.5 This feedback loop can increased fatigue, palpitations, gastrointes- be interrupted by renal failure or chronic tinal distress, weakness, or dizziness. disease.4 In addition, bone marrow can- If the provider has access to past CBC re- not produce enough red blood cells if there sults, a comparison of the current and previ- are insufficient levels of iron, amino acids, ous results will help determine whether the protein, carbohydrates, lipids, folate, and anemia is acute or chronic. Anemia caused 5 vitamin B12. Toxins (eg, lead), some types of cancer (eg, lymphoma), or even common infections (eg, pneumonia) can suppress TABLE 1 the bone marrow, causing anemia. The Signs and Symptoms Associated more severe the anemia, the more likely With Anemia oxygen transport will be compromised and Abnormal uterine bleeding organ failure will ensue. Chest discomfort (angina) Mutations affecting the genes that en- Dyspnea code the globin chains within hemoglobin Fatigue can cause one of the more than 600 known Gastrointestinal distress with or without hematemesis (genetic defects of hemoglobin structure), such as sickle cell Jaundice disease and .5,9 While it is Melena important to identify and treat patients Orthostatic blood pressure changes with hemoglobinopathies, most Pallor have other causes, such as iron deficiency, Peripheral edema chronic disease, bone marrow defects, B12 Tachycardia (arrhythmias) deficiency, renal failure, medications, alco- Weakness holism, pregnancy, nutritional intake prob-

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TABLE 2 DIAGNOSIS AND CLASSIFICATION Normal Ranges for Laboratory Tests Anemia in adults is defined as hemoglobin Used to Diagnose and Classify Anemia less than 13 g/dL in males and 12 g/dL in fe- males.6 The hemoglobin is part of the com- White blood cells 5,000-10,000/mm3 plete blood cell report, which also includes the white blood cell count (WBC), red blood Red blood cells Male: 4.7-6.1 x 1012/L cell count (RBC), hematocrit, platelet count, Female: 4.2-5.4 x 1012/L and indices. When investigating the underlying cause Hematocrit Male: 42%-52% of anemia, the most useful parts of the CBC Female: 37%-47% are the hemoglobin and the mean corpus- cular volume (MCV; see Table 2).6,10 The Hemoglobin Male: 13-17.4 g/dL MCV is the average volume of red cells in Female: 12-16 g/dL a specimen. This parameter is used to clas- sify the anemia as microcytic (MCV < 80 fL), Mean corpuscular volume 80-100 fL normocytic (MCV 80-100 fL), or macrocytic (MCV > 100 fL), which helps to narrow the count 0.5%-1.5% differential diagnosis and guide any further 5,6,10 Red cell distribution width 11%-14.5% testing (see Figure). It is important to note that the normal Iron Male: 80-180 mcg/dL ranges of the CBC parameters differ based Female: 60-160 mcg/dL on race, with persons of African ancestry having lower normal hemoglobin levels 10 Total iron binding capacity 250-460 mcg/dL than persons of Caucasian ancestry. In addition, laboratories may have slightly Transferrin Male: 215-365 mg/dL different normal values for the CBC based Female: 250-380 mg/dL on the equipment they utilize. Therefore, providers must follow their laboratory’s pa- Ferritin Male: 12-300 ng/mL rameters, as well as adjust for the patient’s Female: 10-150 ng/mL gender, age, and ethnicity.10

Folic acid 5-25 ng/mL Iron deficiency

Vitamin B12 160-950 pg/Ml In microcytic anemia, the RBCs are smaller than average (MCV < 80 fL), as well as hy- Methylmalonic acid < 3.6 µgmol/mmol creatinine pochromic due to lack of hemoglobin.9 Iron deficiency is the most common cause of Note: Values may differ based on lab equipment utilized for testing, patient 11,12 age, and ethnicity. microcytic anemia worldwide. There- Sources: Platt A, Eckman J. Clinician Reviews. 20065; Kaferle J, Strzoda fore, when a patient has microcytic anemia, CE. Am Fam Physician. 200914; Pagana K, et al. Mosby’s Diagnostic and a serum ferritin needs to be ordered. Fur- Laboratory Test Reference. 2015.20 ther testing of total iron-binding capacity (TIBC), transferrin saturation, serum iron, and serum receptor levels may be helpful by acute conditions, such as a suspicion of if the ferritin level is between 46-99 ng/mL blood loss or bone marrow suppression, and anemia due to iron deficiency is not must be attended to immediately. A pa- confirmed (see Table 2).12 tient with chronic anemia should be care- In iron deficiency anemia, serum ferritin fully monitored and may need follow-up and serum iron levels are low due to lack of for ongoing treatment. While a provider has iron, but serum TIBC is high.6 The elevated more time to work up a patient with chronic TIBC reflects increased synthesis of trans- anemia, the causes may not be as straight­ ferrin by the liver as it attempts to compen- forward. sate for the patient’s low serum iron level.9

30 Clinician Reviews • AUGUST 2017 clinicianreviews.com ANEMIA

FIGURE Classification of Anemia

Anemia Male: Hgb < 13 g/dL Female: Hgb < 12 g/dL

Microcytic Normocytic Macrocytic MCV < 80 fL MCV = 80-100 fL MCV > 100 fL

Test blood levels Test blood levels

Serum iron and Iron ETIOLOGY ferritin low deficiency • Acute blood Serum B low 12 Serum B12 and TIBC elevated anemia loss HC elevated folate normal • Chronic Serum folate low ETIOLOGY disease Serum iron • Thalassemias •  normal or • Bone marrow elevated • Infection disorders • Inflammation Serum ferritin Test MMA levels • normal or • Malignancy • Liver disease elevated • Renal • Medication insufficiency Elevated Normal TIBC normal (chemotherapy, • Sickle cell antivirals) Hgb disease electrophoresis Vitamin B12 Folate Normal in α deficiency deficiency Abnormal in β

Serum iron normal or decreased Chronic Serum ferritin normal or elevated disease TIBC normal or decreased Abbreviations: HC, homocysteine; Hgb, hemoglobin; MCV, ; Hgb electrophoresis normal MMA, methylmalonic acid; TIBC, total iron- binding capacity.

Since iron levels are controlled by absorp- mal (eg, gastrointestinal) bleeding or non- tion rather than excretion, iron is essentially physiologic (eg, poor dietary intake of iron) only depleted from the body through blood causes.11,12 Additional clinical findings asso- loss.12 Therefore, an adult patient who is ciated with chronic iron deficiency include iron deficient has lost more iron through glossitis, angular stomatitis, and koilonych­ blood loss than was replaced through nu- ias (spoon-shaped nails).12 tritional intake and gastrointestinal absorp- If the nutritional problem is corrected or tion. In children, increased growth-related the source of bleeding is controlled, treat- iron requirements combined with poor nu- ment with oral or intravenous iron supple- tritional intake of iron-rich foods is an addi- ments should result in improved serum tional mechanism for iron deficiency.11 hemoglobin and reticulocyte counts.13 In Iron defciency in all men and nonmen- the primary care setting, ferrous sulfate 325 struating women should always be worked mg, which provides 65 mg of elemental iron up for possible blood loss due to abnor- per tablet, orally three times daily is recom-

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TABLE 3 Causes of Abnormal Reticulocyte Count ally diagnosed in childhood.9 Patients with one of the minor forms of typi- Decreased reticulocyte count Increased reticulocyte count cally need minimal to no treatment.5 A pa- tient with significant anemia suspicious for Bone marrow failure Hemolysis thalassemia should undergo hemoglobin Chronic disease Hemorrhage electrophoresis testing to confirm the di- Folate deficiency Leukemia agnosis and to determine the type of thal- Infection Pregnancy assemia.2 Typically, hemoglobin electro-

Iron deficiency Recovery from vitamin B12, phoresis is normal in α thalassemia and is Liver disease folate, or iron deficiency abnormal in ß thalassemia, as well as other Malignancy Sickle cell anemia forms of thalassemia. Referral to a hematol- Pernicious anemia ogist for interpretation of these results and for further evaluation is appropriate.10 Vitamin B12 deficiency

Sources: Brill JR, Baumgardner D. Am Fam Physician. 20001; Pagana K, et Chronic disease al. Mosby’s Diagnostic and Laboratory Test Reference. 2015.20 If the patient has microcytic anemia and is not iron deficient or does not have thalas- semia, then anemia related to a chronic dis- mended for adults.13 This gives the patient ease should be considered.5 In such cases, the recommended dose of approximately the provider should order a reticulocyte 200 mg of elemental iron. Repeat hemoglo- count, which reveals how the bone marrow bin and iron studies should be conducted is responding to the anemia.5 again in three to six months.12,13 are immature red cells that have just been re- If the patient’s iron deficiency anemia leased from the bone marrow into the blood does not improve after oral iron therapy, stream. The bone marrow increases the re- there may be a source of blood loss the pro- lease of these cells in response to anemia.6 vider missed or a problem with malabsorp- Any condition that stimulates reticulo- tion of iron, which can be seen in those who cyte production or prevents the bone mar- have undergone gastric bypass surgery or row from producing reticulocytes will result who have inflammatory bowel disease.13 in abnormal values (see Table 3). A normal Such patients should be referred to a spe- reticulocyte count, expressed as the reticulo- cialist, such as a gastroenterologist, for fur- cyte production index, is between 0.5% and ther evaluation. 1.5%.5 The reticulocyte count is low in iron deficiency anemia and diseases that lead to Thalassemia decreased bone marrow production.5,6 Bone Microcytic anemia with normal or elevated marrow suppression can occur in the context serum iron and normal-to-increased serum of chronic disease, infection, or inflamma- ferritin can be seen in patients with a type tion. Malignancies are a less common cause of thalassemia (see Figure, page 31).2 Thal- for chronic disease microcytic anemia.6 assemias are inherited blood disorders that If the cause of the decreased reticulocyte reduce hemoglobin production, leading count is iron deficiency anemia, thentreat - to ; they are more common in ment with iron supplementation should re- those of Mediterranean, African, and South- sult in an increased reticulocyte count with- east Asian descent.2 Red cells in patients with in one week.13 The primary care provider a form of thalassemia are usually very small works in conjunction with the specialist to (microcytic) and have normal or elevated monitor the patient’s anemia when it is due red cell distribution width (RDW).10 to chronic disease or malignancy. Moderate and severe forms of thalas- semia can cause anemia. However, thal- assemia syndromes that can cause severe In macrocytic anemia, the RBCs are larger (transfusion-dependent) anemia are usu- than normal (MCV > 100 fL). This form of

32 Clinician Reviews • AUGUST 2017 clinicianreviews.com ANEMIA

anemia is usually caused by vitamin B12 and the B12 or folate level is only borderline folate deficiency, but it can also result from low, additional tests should be performed alcoholism, certain medications (eg, che- to help distinguish between B12 and folate motherapy, antivirals), bone marrow dis- deficiency. Both 12B and folate deficiencies orders (eg, leukemia), and liver disease (eg, can cause elevated homocysteine levels.13 5,14 ; see Figure, page 31). Common Clinically significant 12B deficiency causes medications that can cause elevation of methylmalonic acid (MMA), include the antiseizure drug , the whereas folate deficiency does not.13,14 El- antibiotics trimethoprim/sulfamethoxa- evation of MMA can be very sensitive for

zole and nitrofurantoin, the disease-mod- B12 deficiency but lacks specificity in certain ifying antirheumatic drug , situations, such as pregnancy, renal insuffi- and immunosuppressants such as azathio- ciency, and advanced age.13,14 14,15 prine. Antiviral agents, such as reverse Treatment of vitamin B12 and folate de- transcriptase inhibitors (eg, zidovudine) ficiencies with supplementation prevents used to treat HIV infection, can also cause progression of the disease, and has the macrocytosis with or without anemia.6,14 potential to relieve most of the symptoms.

Macrocytic anemias caused by low se- Oral, sublingual, or parenteral vitamin B12 rum levels of B12 and folate usually reflect or oral folate supplements can be started in problems with gastrointestinal malabsorp- the primary care setting once the provider

tion. For example, gastric bypass or Crohn has identified whether the patient is B12 de- disease can lead to malabsorption of vi- ficient, folate deficient, or both.

tamin B12 and increase a patient’s risk for The vitamin 12B dose used for deficiency- macrocytic anemia.13 induced macrocytic anemia depends on the

Vitamin B12 deficiency occurs in patients cause—for example, a temporary condition with pernicious anemia because they are such as pregnancy versus a lifelong disor- missing intrinsic factor, which is necessary der such as pernicious anemia.13 The usual 10 to facilitate B12 absorption in the ileum. oral dosing regimen is 2 mg/d; if intramus- Low vitamin B12 and folate levels also can cular injections are used, 50 to 100 mcg are result from inadequate dietary intake, al- given daily for a week, followed by weekly though this is rare in the United States due injections for a month, and then monthly to mandatory fortification of certain foods. injections of 1 mg for life, if necessary.13

A diet low in fresh vegetables is the lead- Bone marrow response to supplemental B12 ing cause of folate deficiency. While folate is very rapid, with increased reticulocyte deficiency related to poor nutritional in- counts seen within four or five days.13 take can be seen in all age groups, vitamin The usual dose for oral folic acid is 1 13 B12 deficiency more frequently affects the mg/d as needed. Folic acid can be given elderly or persons following a strict vegan for folate deficiency only if the vitamin 12B diet.14 level is normal. Giving folate to a patient

In addition to the fatigue and pallor as- with untreated vitamin B12 deficiency can sociated with macrocytic anemia, patients potentially worsen subacute combined de- 13,16 with vitamin B12 deficiency may also have generation of the spinal cord. a smooth tongue, peripheral neuropathy, 5,14 and edema. Severe vitamin B12 deficiency can lead to subacute combined degenera- In normocytic anemia, the hemoglobin is tion of the spinal cord, with demyelination low but the MCV is normal (see Figure, page of the dorsal and lateral columns most of- 31).1 The history and physical exam should ten occurring in the cervical and thoracic provide clues about whether the underlying regions.16,17 This spinal cord degeneration cause of the anemia requires emergent (eg, can cause paresthesia, muscle spasticity, active bleeding) or nonemergent (eg, ane- and ataxia.16 mia of chronic disease) management. Some When there is a macrocytic anemia, but of the causes of normocytic anemia are ac-

clinicianreviews.com AUGUST 2017 • Clinician Reviews 33 is suspected as the cause of the anemia, a consult is needed.1 Anemia caused by disseminated intravascular co- agulation or thrombotic thrombocytopenic purpura resulting in hemolysis are usually emergent conditions that require immedi- ate intervention, including hospitalization and management by a hematologist.1 tive bleeding, pregnancy, malnutrition, renal failure, chronic disease, hemolytic disorders, PATIENT EDUCATION hypersplenism, congenital disorders, endo- Patients and any accompanying fam- crine disorders, infection, and primary bone ily members should be educated about the marrow disorders.1,5 Expanded plasma vol- signs and symptoms of anemia, the diag- ume, as seen in pregnancy and overhydra- nostic testing and treatment regimens spe- tion, can also cause normocytic anemia.5 cific to their anemia, and medication com- If gastrointestinal bleeding is suspected or pliance issues. the patient reports dark, tarry stools consis- For instance, patients who abuse alco-

tent with melena, fecal occult blood testing hol often have both vitamin B12 and folate should be done. A positive result strongly deficiencies. If the macrocytosis is caused supports gastrointestinal bleeding as the by intake, then the provider should cause of the anemia.18 educate the patient on the importance of The reticulocyte count can also be help- alcohol abstention, as well as refer the pa- ful in identifying the cause of this type of tient for rehabilitation and psychologic anemia. A normocytic anemia with a nor- counseling, as needed. These patients can mal reticulocyte and normal RDW count sometimes recover from macrocytic ane- is usually related to chronic disease.1,10 For mia simply by stopping alcohol intake and example, chronic kidney disease (CKD) is improving their nutrition.19 Patients with associated with decreased EPO production microcytosis due to iron deficiency anemia due to impaired renal function, which leads should be advised about the importance of to reduced erythropoiesis. Decreased EPO good nutrition and compliance with iron prevents the bone marrow from making red supplementation. blood cells, resulting in anemia. However, a Repeat CBCs and a follow-up patient his- normocytic anemia with an elevated reticu- tory and physical exam will help the provider locyte count points to bleeding or hemoly- assess whether the anemia is resolving. Indi- sis, as the reticulosis shows that the bone vidualized plans that target the specific type marrow is increasing red cell production to of anemia identified, as well as its underlying make up for the lost red cells.5 cause, are key to successful treatment. Additional diagnostic laboratory testing for patients with normocytic anemia may CONCLUSION involve, for example, creatinine and blood When managing a patient with anemia, pro- urea nitrogen for patients with CKD, pro- viders must define the type of anemia pres- thrombin time with an INR and liver func- ent and identify its underlying cause before tion tests for patients with liver disease, and starting treatment. Clues from the patient’s urine human chorionic gonadotropin if history, physical exam, and CBC can help iso- pregnancy is suspected. late the cause of anemia. The MCV is the most For patients with an infection that is helpful of the because it causing severe hemolysis (eg, sepsis due allows the provider to classify the anemia as to a ß-hemolytic streptococcal infection), microcytic, macrocytic, or normocytic. blood cultures should be drawn.5 If red In cases in which the anemia is acute or blood cell destruction due to an artificial ­severe—or in which the patient remains cardiac valve or an autoimmune disorder anemic even after being treated by the pri-

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mary care provider—referral to a specialist is mia.html#a. Accessed April 29, 2017. 9. DeLoughery TG. Microcytic anemia. N Engl J Med. 2014;371(14): ­appropriate. CR 1324-1331. 10. Tefferi A, Hanson CA, Inwards DJ. How to interpret and pur- sue an abnormal complete blood cell count in adults. Mayo Find the posttest for this activity at Clin Proc. 2005;80(7):923-936. www.mdedge.com/clinicianreviews/ 11. Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015; 372(19):1832-1843. ce/cme/latest 12. Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician. 2007;75(5):671-678. 13. Rodgers GP, Young N. The Bethesda Handbook of Clinical REFERENCES Hematology. 3rd ed. Baltimore: Lippincott Williams and 1. Brill JR, Baumgardner D. Normocytic anemia. Am Fam Physician. Wilkins; 2013:1-21. 2000;62(10):2255-2263. 14. Kaferle J, Strzoda CE. Evaluation of macrocytosis. Am Fam 2. Van Vranken M. Evaluation of microcytosis. Am Fam Physician. Physician. 2009;79(3):203-208. 2010;82(9):1117-1122. 15. Hesdorffer CS, Longo DL. Drug-induced megaloblastic ane- 3. National Institutes of Health/National Heart, Lung, and Blood mia. N Engl J Med. 2015;373(17):1649-1658. Institute. How is anemia diagnosed? www.nhlbi.nih.gov/ 16. Vasconcelos OM, Poehm EH, McCarter RJ, et al. Potential health/health-topics/topics/anemia/diagnosis. Accessed April outcome factors in subacute combined degeneration. J Gen 28, 2017. Intern Med. 2006;21(10):1063-1068. 4. Smith RE Jr. The clinical and economic burden of anemia. Am J 17. Vide AT, Marques AM, Costa JD. MRI findings in subacute Manag Care. 2010;16(3):S59-S66. combined degeneration of the spinal cord in a patient with 5. Platt A, Eckman J. Diagnosing anemia. Clinician Reviews. restricted diet. Neurol Sci. 2011;33(3):711-713. 2006;16(2):44-50. 18. Kessenich CR, Cronin K. Fecal occult blood testing in older 6. Karnath B. Anemia in the adult patient. Hosp Physician. adult patients with anemia. Nurse Pract. 2013;38(1):6-8. 2004;40(10):32-36. 19. Imashuku S, Kudo N, Kaneda S. Spontaneous resolution of 7. World Health Organization. Micronutrient deficiencies. www.who. macrocytic anemia: old disease revisited. J Blood Med. int/nutrition/topics/ida/en/#. Accessed April 29, 2017. 2012;3:45 -47. 8. US Department of Health and Human Services, Office of 20. Pagana K, Pagana T, Pagana T. Mosby’s Diagnostic and Women’s Health. Iron-deficiency anemia. www.women- Laboratory Test Reference. 12th ed. St. Louis, MO: Elsevier shealth.gov/publications/our-publications/fact-sheet/ane- Mosby; 2015: 497-501, 785-791, 805-806.

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