Macrocytosis in the Elderly


Mary E. Sehl, MD, Arash Naeim, MD, PhD, and Susan L. Charette, MD


Pages 1 - 2

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Release Date: February 15, 2008
Expiration Date: February 15, 2009

Internists, family practitioners, geriatricians, cardiologists, and others who care for older patients.

Read the article, complete the evaluation and post-test, and return both to: NACCME via fax at (610) 560-0502. You will receive your certificate in 6-8 weeks. If you would like to print your certificate immediately, go to, register as a NACCME user and access the activity test and evaluation online.

Successful completion entails participants obtaining a score of at least 70% on the post-test. A certificate of completion will be mailed to the address listed on your post-test/evaluation form within 6-8 weeks of receipt of the documents.

This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NACCME designates this educational activity for a maximum of 1 AMA
PRA Category 1 Credit
™. Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.

This activity is sponsored by The North American Center for Continuing Medical Education.
Upon completion of this educational activity, participants should be able to:
1. Identify common causes of macrocytosis and macrocytic anemia.
2. Evaluate and diagnose macrocytic anemia.
3. Recommend appropriate management for vitamin B12 and folate deficiency.
4. Recognize important strategies to evaluate for myelodysplastic syndrome.

All those with control over the content of continuing education programs sponsored by NACCME are expected to disclose whether they do or do not have any real or apparent conflict(s) of interest or other relationships related to the content of their presentation(s). It is not assumed that these relationships will have an adverse impact on presentations; they are simply noted here to fully inform participants.

Dr. Charette has disclosed that she has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of her article.

Dr. Naeim has disclosed that he has received grant/research support from Amgen, Genentech, Pfizer, Bayer, and Onyx. He is a member of the speaker’s bureau for Amgen and Pfizer.

Dr. Sehl has disclosed that she has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of her article.

Reviewer: Dr. Miller has disclosed no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of this article.

Editor: M. Edwards has disclosed no significant financial relationship.

All NACCME employees involved in the planning and editing of this educational activity have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of this educational activity.

In compliance with ACCME Standards for Commercial Support and NACCME’s policy and procedure for resolving conflicts of interest, this continuing medical education activity was reviewed by a member of the Advisory Board in January, 2008 for clinical content validity, to ensure that the activity’s materials are fair, balanced, and free of bias, and that the activity materials represent a standard of practice within the profession in the U.S. and that any studies cited in the materials upon which recommendations are made are scientifically objective and conform to research principles generally accepted by the scientific community.

Clinical Vignette
Ms. N, an 88-year-old woman, presents for her first appointment to establish primary care with symptoms of generalized weakness, gradual functional decline, and a five-pound weight loss over the last year. Her past medical history includes hypertension, osteoarthritis, and gastroesophageal reflux disease. Ms. N takes medications daily including atenolol and omeprazole, and acetaminophen as needed for pain. She denies any abdominal pain, black tarry stools, or hematochezia, and states that her mood has been good. Ms. N remains fairly active working as a visual artist, though she notes that she now spends fewer hours painting than in past years. She also reports that previously she walked two miles a day, and currently walks only a few blocks a day because of her decreased energy level.

Ms. N’s physical exam is notable for a blood pressure of 150/90 mm Hg and a heart rate of 70 bpm. Her conjunctivae are slightly pale, her lungs demonstrate good air movement and are clear to auscultation, and her heart has regular rate and rhythm. Her abdomen is soft with no masses or organomegaly, although there is mild epigastric tenderness to deep palpation without rebound or guarding. Ms. N’s neurological exam reveals normal and symmetric deep tendon reflexes, and her strength is 5/5 throughout the upper and lower extremities. Her standing balance is steady from sitting to standing, and she is able to maintain her stance after a moderate push, although she has difficulty maintaining semi-tandem balance without use of her cane for support. Ms. N’s laboratory values are notable for normal creatinine, glucose, electrolytes, transaminases, and bilirubin levels. Her albumin is 3.1 g/dL, hemoglobin 10.1 g/dL, mean corpuscular volume (MCV) 101 femtoliters (fL), red cell distribution width (RDW) 16%, and reticulocyte count 1.1%. The patient is diagnosed with macrocytic anemia. Further work-up of Ms. N’s anemia reveals serum vitamin B12 and red blood cell (RBC) folate levels falling within the normal range. What further work-up for this patient’s macrocytic anemia is warranted?

With a growing older patient population, chronic diseases will continue to increase in prevalence. As part of a comprehensive evaluation, laboratory studies are performed for a variety of reasons. Often, clinicians are faced with abnormal laboratory values in the setting of no symptoms, or in the setting of nonspecific symptoms that may be related to the laboratory abnormality. Furthermore, the laboratory value may be only slightly decreased or increased, or may be on the low or high end of a normal range. It may not always be clear how to proceed upon learning certain laboratory information. When does an abnormal laboratory value become significant? When is it a marker for disease or a source of functional decline? The preceding clinical vignette demonstrates such a scenario. What is the reason for the patient’s macrocytic anemia, and is it contributing to her physical and functional decline?

Macrocytosis is defined as the presence of erythrocytes that are larger than normal, usually reported when MCV is greater than 100 fL, with the precise upper limit varying between laboratories. Anemia is a marker for disease in the elderly population, and is associated with increased mortality, fatigue, functional dependence, falls, and hospitalization, as well as cardiovascular and neurological complications.1,2 Yet, it is uncertain whether an isolated elevation in MCV is an indicator of present or future disease.

Observation of an anemia with an elevated MCV will typically prompt an evaluation of serum vitamin B12 and folate levels, as well as a careful review of the patient’s medical history for previous gastrointestinal surgery and social history for alcohol abuse. However, the cause of the macrocytic anemia may remain elusive. A comprehensive approach to the evaluation and treatment of macrocytosis in the elderly will be discussed in this review.

Etiologies and Prevalence
The prevalence of anemia in general, defined as a hemoglobin level of < 13 g/dL for men and < 12 g/dL for women, is 11.0% in men and 10.2% in women age 65 years and older, and rises to 26.1% in men and 20.1% in women older than age 85 years.3-5 In the nursing home population, the prevalence of anemia climbs to 48%,6 with a large proportion of unexplained cases. Anemia is usually mild in the elderly population and is frequently overlooked. It has been estimated that only 3% of older patients have a moderate or severe anemia, with hemoglobin less than 11 g/dL.4

Proposed mechanisms for the increased prevalence of anemia with age include the aging of hematopoietic stem cells, age-dependent delay in maturation of bone marrow progenitors, limited proliferative capacity, disordered activation and humoral regulation, erythropoietin insufficiency, and androgen deficiency.7,8 Deficiencies of vitamin B12 or folate account for 14% of the cases of anemia in general, while 32% are attributed to anemia of chronic inflammation and chronic kidney disease, 20% are caused by iron deficiency (with or without vitamin B12 or folate deficiency), and 34% of cases are “unexplained.”2,4

The causes of macrocytic anemia and macrocytosis without anemia are summarized in Table I. The probability of a definitive diagnosis of macrocytic anemia rises with increasing MCV.9 The causes of vitamin B12 and folate deficiency are listed in Table II. While the lower limit of normal for serum vitamin B12 is variable, it is usually set at about 148 pmol/L (200 pg/mL).10 Vitamin B12 is stored in the liver, and variations in the methylenetetrahydrofolate reductase (MTHFR) enzyme determine how rapidly homocysteine will rise as vitamin B12 levels fall, accounting for the wide variance in the time until clinical deficiency develops, which may take months to years. In contrast to vitamin B12, folate levels drop quickly if dietary intake is decreased, and clinical deficiency can develop rapidly. The recommended daily intake of folate is 400 mcg a day. A significant drop in serum and RBC folate was observed in a study in which a folate-deficient diet (150-250 mcg of folate/day) was administered to healthy adult men living in a metabolic unit for 2-8 months.11 In a prospective study of institutionalized adults older than age 65 years, folate intake was shown to drop from day 1 to day 360 after admission, with RBC folate levels dropping concurrently.12

Causes of “unexplained” macrocytic anemia include hypothyroidism, neoplasia, chronic liver disease, alcohol, and medications.13-18 In addition, aplastic anemia, myelodysplastic syndrome (MDS), and sideroblastic anemia can present as a macrocytic anemia.9 Reticulocytosis, either in the setting of hemolytic anemia or following blood loss, can also lead to the observation of an increased MCV.19 A “malabsorption syndrome,” characterized by macrocytosis, folate, and iron deficiency, has been described in the elderly, in the setting of celiac disease, atrophic gastritis, or partial or total gastrectomy.20 Rare causes of macrocytic anemia have also been described, including familial macrocytosis and pregnancy in the absence of hypothyroidism.21

The causes of macrocytosis without anemia include many of the same causes as macrocytosis with anemia.21,22 Macrocytosis in the absence of anemia is usually the result of vitamin B12 or folate deficiency, alcohol abuse, or medications.23-27 Medications associated with macrocytosis include azathioprine, zidovudine, methotrexate and other chemotherapeutic agents, and several antiepileptic drugs (Table III).22 Other less common causes such as hemolytic anemia, chronic liver disease, malignancy, and myelodysplasia should also be considered.

The prevalence of the most common causes of macrocytic anemia in hospitalized patients was reported in a study of 300 patients admitted to a New York City teaching hospital.21 In this study, various medications accounted for 37% of cases, while alcohol abuse (defined as at least 80 g of alcohol consumption/day or a history of withdrawal seizures or delirium tremens) with liver disease accounted for 13%, alcohol abuse without liver disease accounted for another 13%, and reticulocytosis accounted for 8% of cases.21 Less prevalent causes included cobalamin and folate deficiency (6%), primary marrow disorders (6%), and nonalcoholic liver disease (6%).21 In 7% of cases the cause was not established.21 Major causes of macrocytic anemia in patients over age 70 years were bone marrow disorders, medications, alcohol abuse, and nonalcoholic liver disease.21 The predominant cause of reticulocytosis in this population was hemolytic anemia (95.8%), with 75% of these patients having sickle cell disease. It is significant to note that in one-third of cases of all patients with macrocytic anemia there was more than one cause of macrocytosis identified.21

In a separate study of 124 patients over age 75 years with an MCV above 95 fL, the prevalence of various causes of macrocytosis with or without anemia was examined.22 Using peripheral smears, serum vitamin B12 and RBC folate levels, thyroid function tests, and liver function tests, a cause of macrocytosis was identified in 75 of the 124 patients.22 Macrocytosis was found to be related to increased alcohol intake (17 patients), hypothyroidism (15 patients), vitamin B12 deficiency (15 patients), folate deficiency (15 patients), malignant disease (5 patients), antiepileptic drugs (3 patients), combined vitamin B12 and folate deficiency (3 patients), and chronic liver disease (2 patients).22 The 49 patients with “unexplained” macrocytosis underwent a bone marrow biopsy, and six patients were diagnosed with MDS (5 with refractory anemia and 1 with refractory anemia with ringed sideroblasts).22 Dysplastic features were found in 19 patients (8 with megaloblastic features and 11 with dyserythropoietic hypogranularity), consistent with a dysplastic process suggestive but not diagnostic for MDS, while 24 patients had no diagnostic features, and the etiology of their macrocytosis remained undiagnosed.22

Another study specifically examined the prevalence of MDS in a population of 3275 patients older than age 65 years hospitalized in an acute or subacute Geriatrics department.28 This study found that of the 245 patients who were found to have unexplained cytopenia, macrocytosis, or monocytosis, 15% (n = 37) had MDS, and of these, 34 patients had refractory anemia, two patients had refractory anemia with ringed sideroblasts, and one patient had refractory anemia with excess blasts.28

There are clearly many potential causes for macrocytosis among elderly patients. Etiologies and prevalence of anemia vary based on age (ie, young-old vs old-old population), number of coexisting illnesses, as well as several environmental and social variables. All of these factors are important to consider in the process of evaluating a patient with macrocytosis.

Evaluation of Macrocytosis
A careful medical, family, and social history should be obtained from the patient. The medical history should include questions about prior gastric or intestinal surgery, medications in the past and present, alcohol use, liver disease, and any history of bleeding or jaundice. Patients should be asked about weight loss and appetite, as well as their ability to do shopping, cooking, and meal preparation. All of these factors are essential to understanding nutritional status and functional ability. Furthermore, as poverty is associated with megaloblastic anemia in hospitalized patients,29 it is important to determine if the patient is having difficulty affording and obtaining food.

Laboratory evaluation should begin with a repeat complete blood count, along with a reticulocyte count and a peripheral smear. A peripheral smear should be examined for the presence of hypersegmentation of neutrophils, macro-ovalocytosis, anisocytosis, teardrops, nucleated red blood cells, or target cells, each of which is associated with various conditions (Table IV). Spurious macrocytosis, caused by laboratory error in the setting of cold or warm agglutinins,30 osmotic swelling from hyperglycemia,31,32 infectious mononucleosis,33 or machine-related error highlights the importance of examining the peripheral smear and erythrocyte volume histograms.

If there is no elevation in reticulocyte count, serum B12 and RBC folate levels should be drawn. An RBC folate level is more reliable than a serum folate level as it reflects a time-averaged value because one meal can normalize the serum folate level in a patient who is actually deficient. When vitamin B12 levels are in the borderline range (200-400 pmol/L), vitamin B12 deficiency is still possible and responsive to replacement therapy. In this situation, further investigation of the serum methylmalonic acid (MMA) level and a homocysteine level is helpful, with elevated levels indicative of decreased metabolism, suggesting a diagnosis of B12 deficiency. Following the initiation of therapy, the peripheral smear and MCV can be followed to evaluate for a response to treatment. It is important to note that a diagnosis of B12 or folate deficiency can be a sign of many things, including underlying malabsorption, an autoimmune process, or poor nutrition. Careful investigation should be considered to differentiate between these causes, and may include a Schilling test and a comprehensive geriatric evaluation, with special attention to the patient’s functional history and nutritional status.

If the reticulocyte count is elevated, a hemolysis panel should be examined, including a lactate dehydrogenase level, a haptoglobin level, and a total bilirubin level, in addition to the peripheral smear mentioned above. If the reticulocyte count is on the high end of normal, or if there are any suggestive signs of hemolysis on the peripheral smear, careful consideration should be given to the possibility of a combined picture of marrow suppression and hemolytic anemia. If such a suspicion is raised, iron studies should be checked, including iron level, total iron-binding capacity (TIBC), ferritin, and transferrin saturation. Liver disease should be considered in each patient, and laboratory evaluation with coagulation tests, transaminases, and bilirubin should be performed, as well as a careful physical examination. If liver disease is suspected by any of the above, or target cells on the peripheral smear, a liver ultrasound is indicated. If the above work-up is inconclusive, careful consideration should be given to performing a bone marrow biopsy to evaluate for MDS or another process, such as viral infection.

Management of the Common Causes of Macrocytosis
The management of macrocytosis should be directed at the underlying etiology. As alcohol is commonly associated with macrocytosis and macrocytic anemia, it is important to address the hazards of alcohol use in older patients. Heavy drinking is defined as drinking more than two alcoholic drinks per day in men and more than one per day in women over age 65 years.34 Using this definition, heavy drinking is prevalent and accounts for approximately 15% of older men and women who drink alcohol.34 Determinants of alcohol abuse in older adults include social isolation, reduced mobility, and a history of alcohol use or abuse.35 It has been shown that smaller amounts of alcohol have larger effects on older individuals, and many people may not be aware of the risks of drinking the same amount of alcohol they have been accustomed to drinking for most of their lives. For patients with known or newly diagnosed liver disease, from any etiology, treatment should focus on their underlying condition, and they should be advised to avoid alcohol.

If B12 or folate deficiency is identified and replacement therapy is initiated, it is important to both carefully document a response to therapy and to identify an underlying cause of the deficiency. Nutritional and social factors need to be carefully addressed, and interventions such as increased social support, meal delivery programs, and nutritional counseling should be employed as indicated. A referral to a dietician may be helpful to make sure the patient has an adequate intake of vitamin B12 and folate from his or her diet. Folate replacement therapy is preferably initiated at 800-1000 mcg orally each day for 4 months.36 A much less common alternative, the parenteral route, in which 400 mcg of folate is delivered by daily intravenous or intramuscular delivery, is mainly used in situations in which the patient is not able to tolerate any oral intake. Recommended options for vitamin B12 replacement include oral or sublingual delivery of 500-1000 mcg daily, intranasal administration of 500 mcg in one nostril once weekly, and intramuscular or deep subcutaneous delivery of 30 mcg per day for 5-10 days, followed by a maintenance dose of 100-200 mcg per month; parenteral and oral options have been shown to be equivalent in efficacy.37-39 If pernicious anemia has been diagnosed, intramuscular doses should be started at 1000 mcg/day for 5 days, followed by 1000 mcg once a month.

The diagnosis and treatment of an underlying myeloproliferative disorder, myelofibrosis, or MDS can be challenging in an elderly patient. The presence of neutropenia, monocytosis, circulating blasts, reticulocytopenia, and thrombocytopenia in a patient with macrocytosis suggests the presence of an underlying dysplastic process. Before an invasive procedure such as a bone marrow biopsy is performed, it is imperative to consider what would be done if abnormal results were uncovered, and whether the patient might tolerate any treatment should a diagnosis of bone marrow failure or malignancy be found. Typically, these treatments involve chemotherapeutic agents or newer, novel treatment modalities, some of which are currently being evaluated in clinical trials. It is important to discuss the potential results and possible treatment options along with their side effects with patients and their families prior to invasive testing. It may be worthwhile to consider less invasive cytogenetic testing prior to performing a bone marrow biopsy. For example, one option is peripheral blood fluorescence in situ hybridization (FISH) testing for the 5q-deletion, as this finding has been shown to be associated with a more favorable prognosis and better response to treatment in patients with MDS.40

Treatment options for MDS have traditionally been directed toward supportive care, with a goal of reducing the need for transfusions and decreasing the risk of infection and hospitalization. Administration of recombinant human erythropoietin has been shown to effectively reduce the rate of transfusion41 and increase quality of life.42 This treatment is safe and well-tolerated in a substantial proportion of patients with low and intermediate risk for MDS, and patients have been shown to maintain their response to this therapy over a 9-month follow-up interval.42

The decision to consider further therapy for patients with MDS depends on both the aggressiveness of the disease (transformation to leukemia, increased need for transfusion) and the general health and performance status of the patient. Azacitidine has been shown to increase the median time to leukemic transformation or death, and to significantly improve overall quality of life, with a reduction in fatigue, dyspnea, and psychological distress, and an improvement in physical functioning and positive affect, in a phase III Cancer and Leukemia Group B (CALGB) study of 191 patients, with a median age of 67.5 years.43 In a recent study of 170 patients age 62-76 years with MDS, decitabine was shown to provide durable responses with increased time to transformation to acute myelogenous leukemia (AML) and improved survival over best supportive care.44 Decitabine has been shown to be especially effective in elderly patients with high-risk features and poor prognoses.45 Arsenic trioxide has also recently been shown to have activity against MDS, in a phase II study in 76 patients with median age 68 and 70.1 years, with benefits shown with respect to transfusion independence.46

Allogeneic stem cell transplantation from an unrelated donor in patients age 60-74 years with AML has been associated with a two-year overall survival of 62.7% and comparable rates of acute and chronic graft versus host disease to younger patients.47 It is of note that not many patients in this study were older than age 65 years, with a median age of 63, suggesting that the results may not be applicable to a very old population. Furthermore, novel treatment modalities are being tested for the treatment of MDS, including anti-angiogenic therapies, receptor tyrosine kinase inhibitors, PKC inhibitors, P38-alpha MAPK inhibitors, DNA methylation inhibitors, matrix metalloproteinase inhibitors, farnesyl transferase inhibitors, and pharmacologic differentiators.48

Macrocytosis with or without anemia can be a concerning finding in an elderly patient, raising several questions surrounding the necessity and tolerability of several aspects of both the diagnostic work-up and therapeutic options available. Careful attention must be given to nutritional history, mobility and functional history, social history, alcohol history, environment and support network, in addition to past medical and surgical history. Treatment should be directed at the underlying cause or causes. With the development of more tolerable therapeutic strategies to treat myelodysplastic and myeloproliferative processes in older adults, discussions must be held regarding what to do with information potentially gathered from invasive procedures.

Follow-up from Clinical Vignette
Upon further review of Ms. N’s laboratory investigation, her serum vitamin B12 level was noted to be on the low end of the normal range (230 pg/mL), and her serum MMA level was found to be elevated. She was diagnosed with vitamin B12 deficiency. In addition, upon careful reviewing of alcohol history, she reported consuming one to two glasses of scotch per evening. Ms. N was counseled on the hazards of alcohol use and instructed to reduce her alcohol intake. She was initiated on replacement doses of vitamin B12, starting with 30 mcg vitamin B12 daily, followed by 100 mcg per month, administered subcutaneously. In addition, she was referred for nutritional counseling with attention to foods rich in B12 and folate. Two months following her initial visit, Ms. N reported better energy levels and her hemoglobin had risen to 11.7 g/dL.

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