J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.252 on 1 October 1989. Downloaded from Macrocytosis As An Indicator Of Human Disease

William F. Keenan, Jr., M.D.

Abstract: Adult patients with macrocytosis, defined as a mean corpuscular volume (MeV) greater than toO femtoliters, were studied to assess the importance of an elevated Mev. Mter eliminating pregnant and postpartum patients and patients receiving medications known to cause macrocytosis (e.g., phenytoin, zidovudine, and chemotherapeutic agents), 80 patients were identified and studied. Sixty-seven diagnoses were made in 56 patients. These diagnoses were, in descending order: alcoholism, hematological disorders, habitual drinking, B12 deficiency, chronic liver disease, folic acid deficiency, hypothyroidism, anorexia nervosa, and reticulocytosis. While an elevated Mev is neither sensitive nor specific for anyone disease state, an elevated Mev should raise suspicions of underlying pathology. (J Am Bd Fam Pract 1989; 2:252-6.)

With the advent of the automatic cell counter, appear as target cells. Hypothyroidism, too, physicians have had available to them a number may cause macrocytosis, sometimes with ane­ of red-cell indices, including the mean corpus­ mia, although the mechanism is poorly under­ cular volume (MCV). An elevated MCV (mac­ stood. Macrocytosis has been observed in popu­ rocytosis) can be seen in a variety of medi­ lations of patients with chronic obstructive cal conditions and can be caused by several pulmonary disease (COPD), but it is not known I 5 types of drugs. - Failure to attend t(; elevated whether the lung disease itself or some related l'v1CV, even when anemia is not present, might problem causes the MCV to rise.(\,7 be detrimental to the patient. This study was For a variety of reasons, alcohol abuse and undertaken to see whether investigating unex­ macrocytosis are linked. Alcohol can act as a di­ pected macrocytosis IS clinically useful and rect bone marrow toxin and produce macrocytes rewarding. that are often "thin" and have a reduced mean cell hemoglobin (MCH). Alcoholics may also de­ velop folic acid deficiency from an improper diet. http://www.jabfm.org/ Causes of Macrocytosis A lack of pyridoxine may result in pyridoxine­ Macrocytosis can be seen when normal matura­ responsive sideroblastic anemia, which can be tion of the red-cell nucleus is inhibited as in seen in as many as one-third of hospitalized alco­ folic acid or cobalamin (B I2 ) deficiency Crable holics. Finally, alcohol can interfere with cobala- I). Medications that interfere with folic acid mll1. a1 )SOrptlOn. .' H' <) utilization (e.g., phenytoin and methotrexate An elevated MCV occurs in hematological dis­

[commonly] and the sulfa derivatives and phe­ orders, particularly myelodysplastic, preleuke­ on 30 September 2021 by guest. Protected copyright. nobarbital [less commonly!) can also result in mic, and leukemic syndromes. Myelodysplasia, a macrocytosis.' Direct inhibition of nuclear heterogeneous group of disorders often observed maturation by anticancer chemotherapeutic in the elderly, results in disordered bone marrow agents and zidovudine (AZT) can produce an production with an anemia refractory to most elevated MCV. A variety of congenital dis­ treatments. Pyridoxine-resistant sideroblastic orders also show inhibited nuclear maturation. anemia is one type of myelodysplasia. These dis­ Chronic liver disease, presumably by interfer­ orders may be associated with macrocytosis, al­ ing with the synthesis of the red-cell mem­ though the red cells can be normal, or even re­ brane, can give rise to macrocytes that often duced, in size. lo Because reticulocytes are larger than mature red cells, any process that increases the relative proportion of reticulocytes to mature red cells Address reprint requests ro William F. Keenan, Jr., i\l.D., South Mountain Family Practice, 15-+5 Broadway Street, Bethle­ (e.g., hemolytic anemia) can cause a rise in the hem, PA IHOI5. MCV, although the effect is usually transient.

252 JABFP Ocrober-Decemher 1'lH'J Vol. 2 No. of J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.252 on 1 October 1989. Downloaded from Artifactual macrocytosis must be considered. tremely high values (more than 140 femtoliters) l l Osmotic forces can draw free water into erythro­ are often due to this process. . cytes; this happens when erythrocytes from pa­ Other miscellaneous conditions associated tients with longstanding hypernatremia or with macrocytosis are presented also in Table 1. hyperglycemia are mixed with the diluent used 11 12 in automatic cell counters. • In hemagglutina­ Methods tion, automatic cell counters read such clumps as Inpatient and outpatient laboratory work of a 4- single cells and report falsely high MCVs. Ex- physician family practice was periodically screened during a 45-month period for macrocytosis (de­ fined as an MCV > 100 fL). A single value greater than 100 fL was sufficient for inclusion in the Table 1. Causes of Macrocytosis. study. The charts of these patients were then re­ viewed. for problems that could be related to mac­ Increased number of reticulocytes Hemorrhage rocytosis. Patients on medications known to induce Hemolytic anemia macrocytosis, as well as pediatric and obstetrical Vitamin deficiency patients, were deleted from the study group. B12 deficiency Pernicious anemia When possible, patients were contacted and Postgastrectomy asked to have B12 and folic acid levels done. Be­ Malabsorption syndromes (e.g .• sprue) cause serum folate levels change rapidly with Fish tapeworm infestation Dietary insufficiency (strict vegetarians) short-term variations in dietary intake, red-cell Familial malabsorption folate levels were used when practical to indicate Isolated inability to absorb B12 from food the true deficiency more accurately. Folic acid deficiency Patients who admitted to alcohol consumption Increased demands (e.g .• pregnancy. exfoliative dermatitis) Dietary insufficiency were asked to fill out a questionnaire that incor­ Medications porated questions from the Mic~igan Alcohol Folic acid antagonism Screening Test (MAST). Patients were asked to Phenytoin and mephenytoin Methotrexate estimate their daily alcohol consumption, and on Pentamidine the basis of their answers, they were divided into Primidone one of three groups: social drinkers, habitual Pyrimethamine Triamterene drinkers who did not meet the criteria for alco­ T rimethoprim holism, and active alcoholics. They were consid­ http://www.jabfm.org/ Trimethoprim-sulfamethoxazole ered active alcoholics if they met the criteria of Trimetrexate the American Medical Association's task force on Chemo~herapeutic agents Zidovudine standardization of drug use terminology ("Alco­ Methyldopa (by induction of hemolytic anemia) hol abuse: use of ethyl alcohol in a quantity and Artifactual with a frequency that causes the individual sig­ Hypematremia Hyperglycemia nificant physiological, psychological or sociologi­ Cold agglutinin disease cal impairment") 14 or had MAST scores of five or on 30 September 2021 by guest. Protected copyright. Miscellaneous more and were currently drinking. Patients who Alcoholism Neonatal macrocytosis Hypothyroidism Chronic liver disease Table 2. Criteria for Habitual Drinking. Down syndrome Postsplenectomy Chronic obstructive pulmonary disease Sex Weight Criterion* Preleukemic and myelodysplastic syndromes Inherited disorders of DNA synthesis Women :S 100 pounds Hereditary orotic aciduria 2 drinks daily Women Lesch-Nyhan syndrome > 100 pounds > 2 drinks daily Men Methylmalonic aciduria :S 140 pounds 3 drinks daily Men 140 pounds F ormiminotransferase deficiency > > 3 drinks daily Dihydrofolate reductase deficiency Abnormal or deficient transcobalamin II "One drink consists of 12 ounces of regular beer. 1 ounce of liquor. 4 ounces of wine. or their equivalents.

Macrocytosis 253 -

were not actively drinking at the time of the The level of macrocytosis was only somewhat J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.252 on 1 October 1989. Downloaded from study were believed not to have alcohol-induced related to the likelihood of finding pathology. macrocytosis and were not included among the Fifty-nine patients had an MCV of 10 1-\05 fL, active alcoholics. Habitual drinking was defined and 41 of these had some disease process that could on the basis of weight and sex Cfable 2). account for the macrocytosis. In the 11 patients Because smokers often have other behaviors whose MCVs were between 106 and 110, 7 were that are detrimental to their health, a smoking diagnosed, and in the 10 patients whose MCV history was obtained to see if alcohol abuse was was greater than 110, is had at least one disease more frequent in those patients who had macro­ present. cytosis and were actively smoking. Alcoholism and habitual drinking together ac­ Additional laboratory studies were done (e.g., counted for 29 of the diagnoses. Drinking behav­ thyroid testing, bone marrow biopsies) as indi­ ior of 15 patients was unknown to the primary cated to assist in diagnosis. Bone marrow biopsies care doctor. Ten percent of the nonsmokers had were not performed on patients who felt well and an alcohol-related problem compared with 63 did not have a significant anemia. percent of the smokers. BI2 and folic acid levels were measured in 74 Results patients, and vitamin deficiencies were found in Unexpected macrocytosis occurred fairly fre­ 13. Eight had low BI2 levels, and 5 had low folic quently during the course of the study. Eighty acid levels. Three more patients had borderline patients met the study's criteria. Forty-five were levels of B12 , and one had a borderline red-cell men (aged 28-86 years, median = 61); 35 were folate level. Six patients with a low BI2 level had women (aged 18-95 years, median == 67.5). The pernicious anemia, one had malabsorption sec­ majority were white; 3 were Hispanic, and 1 was ondary to a jejunal-colic fistula, and one refused black. The study group mirrored the demograph­ further work-up. Only 2 patients with BI2 defi­ ics of the practice. ciency were anemic when diagnosed. In the 80 patients, a relevant diagnosis was Of the patients with folic acid deficiency, one made in 56 (Table 3). These patients had a total had anorexia nervosa that was quite unexpected of 67 conditions that could cause an elevated until work-up disclosed the low folate level and MCV. Of the 67 diagnoses made, 38 were discov­ further investigation was done. A second patient ered in the course of evaluating the macrocytosis. with anorexia nervosa most likely had folic acid deficiency but had to be transported to an inpa­ tient psychiatric facility before testing could be http://www.jabfm.org/ Table 3. Diagnoses of 80 Patients with Unexpected Macrocytosis done. Another patient with unexpected folate de­ (Note: Several Patients Had More Than One Diagnosis). ficiency had achalsia when studied further. Nine patients had hematological diseases, in­ Unknown-22 cluding 3 with leukemia, one with preleukemic Alcohol related - 29 Alcoholics (20) changes, 2 with myelodysplastic syndrome, one

llabitual drinkers (9) with polycythemia vera, one with thrombocyto­ on 30 September 2021 by guest. Protected copyright. Hematological-9 penic purpura, and one with idiopathic pancyto­ Leukemia (3) Myelodysplasia (2) penia. The last 2 patients were also alcoholics. Idiopathic pancytopenia (J) Seven patients had chronic liver disease, but Prclc'Ikemia (I) these were not new diagnoses. Hypothyroidism Polycythemia vera (J) was found in 5 patients, although thyroid testing Thrombocytopenic pU'1mra (J) Chronic liver disease - 7 was done only when clinically indicated. Three B 12 deficiency - H of the 5 diagnoses were unexpected because the Pernicious anemia (6) patients were clinically euthyroid. In fact, one ,\hlabsorption (1) Unknown (I) patient had thyroid studies done because of diffi­ Folic acid deficiency - 5 culty in controlling hypertension, and another Hypothyroidism - 5 because of difficulties controlling cardiac ar­ Anorexia nervosa - 2 Elevated reticulocytosis - 2 rhythmias. Two of the 5 patients with hypothy­ roidism had mild anemia; both macrocytosis and

254 JABFP October-December 19H9 Vol. 2 No.4 J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.252 on 1 October 1989. Downloaded from anemia resolved after treatment with thyroid Vitamin deficiencies were found in a moderate hormone. number (16 percent) of the patients. One patient Six patients had clinically important lung dis­ with pernicious anemia had an elevated MeV ease. Each, however, had at least one other dis­ (120 fL), with mild anemia, when hospitalized 2 ease process that could explain the macrocytosis. years previously; work-up then would have pre­ Finally, two patients had reticulocytosis; one vented the profound anemia that developed and as a response to an acute hemorrhage (this patient obviated the need for a second hospitalization. was also folate deficient). The second, on lithium Apparently, ignoring an elevated MCV is not un­ therapy, refused further work-up. usual; several studies have been reported where an opportunity to make an early diagnosis of per­ Discussion nicious anemia was missed.l7,IH (In fact, abnor­ All told, an explanation for macrocytosis was mally low MCVs have also been frequently over­ 19 found in 70 percent of the study patients. Per­ looked. ,20) As in alcohol abuse, pernicious haps more important is the fact that 57 percent anemia may be present without macrocytosis be­ of the diagnoses were previously unknown to cause of conco'mitant medical problems. 21 the primary doctor, thus establishing the im­ Although prior studies have noted an associ­ portance of investigating an elevated MCV. ation between chronic obstructive pulmonary Even minimally elevated MCVs had a high like­ disease (COPD) and macrocytosis, this study did lihood of being associated with some disease not identify a single patient who had macrocy­ state. tosis based solely on the presence of COPD. In designing this study, a careful attempt was Instead, the macrocytosis was most likely ex­ made to identify problem drinkers. It was clear plained by a high alcohol intake or a vitamin defi­ that there were a number of patients with a fairly ciency. The association between smoking and high, regular alcohol intake who did not meet the macrocytosis as an indicator of greater than nor­ established criteria for alcohol abuse. A separate mal alcohol use has been noted elsewhere, at least category, habitual drinking, was used to describe in men. 16 them. Such a subset of patients may be important to identify because an elevated alcohol intake is Limitations thought to be a risk factor in such conditions as This study did not include patients who were hypertension, osteoporosis, diabetes mellitus, receiving drugs known to cause macrocytosis. and cerebrovascular disease. This does not mean that" these patients may not http://www.jabfm.org/ Alcoholism and habitual drinking together ac­ have other causes for their macrocytosis. For ex­ counted for 36 percent of the patients with mac­ ample, patients with the acquired immune defi­ rocytosis. This may actually represent an under­ ciency syndrome may be taking zidovudine, tri­ estimation, and, indeed, at least 3 patients who metrexate, or pyrimethamine, anyone of which did not admit to a high intake were strongly sus­ could cause macrocytosis. However, it is becom­ pected to be problem drinkers. Unfortunately, ing increasingly obvious that AIDS patients may macrocytosis is not a reliable screening tool for have significant deficiencies in both folic acid and on 30 September 2021 by guest. Protected copyright. alcohol abuse, because many alcoholics do not cobalamin. 22,23 have an elevated MCV, which may be due to By design, a single episode of macrocytosis was coexisting conditions such as iron deficiency or sufficient for inclusion in the study; whether per­ thalassemia minor. An elevated MCV is useful, sistent macrocytosis may be a better screen re­ though, for alerting the physician that alcohol mains to be investigated. Red-cell distribution 15 abuse may be a problem. ,16 widths (RDWs) were not available. Conceivably, For example, 2 patients who were initially patients with borderline elevations of their mean thought to have B\2 deficiency alone were found to corpuscular volumes who also have abnormal be very heavy drinkers when they were questioned RDWs may benefit from further revaluation. about their alcohol intake. Another, who initially admitted to only two drinks a day, when ques­ Summary tioned more closely, admitted to drinking two 8- An elevated MCV is neither sensitive nor spe­ ounce glasses of straight Scotch whisky daily. cific for anyone condition, but, like an elevated

Macrocytosis 255 sedimentation rate, an elevated MeV is often in­ 12. Beautyman W, Bills T. Osmotic error in erythrocyte J Am Board Fam Pract: first published as 10.3122/jabfm.2.4.252 on 1 October 1989. Downloaded from dicative of an underlying problem. Because the volume determinatiolls. Am .I Ilcmatol 19H2; 12: MeV is a routine measurement on most auto­ 3H3-9. mated cell counters, it has the added advantage of I 3. Bessman .I D, Banks D. Spurious macrocytosis, a common clue to erythrocyte cold agglutinins. Am .I being extremely economical. Clin Pathol 19HO; N:797-HOO. I.J.. Rinaldi RC, Steindler EM, Wilford BB, Goodwin D. References Clarification and standardization of substance abuse I. Wintrobe MM, Lee GR, Boggs DR, et aI., cds., Clini­ terminology . .lAMA 19HH; 259:555-7. cal hematology. Hth cd. Philadelphia: I,ea & Febiger, 15. Chalmers DM, Rinsler MG, MacDermott S, Spicer 19H I. CC, Levi AJ. Biochemical and haematological indi­ 2. De Veber LL, Valentine GH. Nitrofurantoin and cators of cxcessive alcohol consumption. Gut 19H I ; megaloblastic anemia \letterl. Lancet 1964; 2:097 -H. 22:992-1l. 3. Akin K. Macrocytosis and leukopenia in Down's Ill. Papoz L, Warnet .1M, PC(luignot G, Eschwege E, syndrome lletterl. JAMA 19HH; 259:H42. Claude J R, Schwartz D. Alcohol eonsumptin in a -1-. Schmidt PJ. Lvlcan corpuscular volume and anemia healthy population. Relationship to gamma-gluta­ !letter] . .lAMA 19H I; 2-1-6: I H99. my I transferase activity and mean corpuscular vol­ Waxman S, Corcino JJ, Herbert V. Drugs, toxins ume. JAMA 19i1l; 245: INH-51. and dietary amino acids affecting vitamin BI2 or folic 17. Carmel R Macrocytosis, mild anemia, and delay in acid absorption or utilization. Am .I Med 1970; the diagnosis of pernicious anemia. /\rch Intern Med -1-H:599-WH. 1979; 139:47-50. 6. O'Neill BJ, Marlin GE, Streeter AM. Red-cell mac­ I H. Hall CA. Vitamin B 12 deficiency and early rise rocytosis in chronic obstructive airway disease. Med in mean corpuscular volume. JAMA 19H 1; 245: ./ Aust 1972; 1:2H3. I I 44-1l. 7. Thong KL, Hanley SA, McBrideJA. Clinical signifi­ 19. Hansen RM, Hanson G, Anderson T. Failure to sus­ cance of a high mean corpuscular volume in nonane­ pect and diagnose thalassemic syndromes. Interpre­ mic patients. Can Med Assoc./ 1977; 117 :90H-IO. tation of RBC indices by the non hematologist. Arch H. Wu A, Chanarin I, Levi AJ. Macrocytosis of chronic Intern Med 19H5; 145:93-4. alcoholism. Lancet 19N; I :H29-31. 20. Howe RB. Are "indexes" an index of physician per­ 9. Lindenbaum J, Lieber CS. Alcohol-induced malab­ formance? Arch Intern Med 19i15; 145:46. sorption of vitamin BI2 in man. Nature 1969; n-l-:H06. 21. Carmel R Pernicious anemia. The expected findings 10. Foucar K, Langdon RM 2nd, Armitage JO, Olson of very low serum cobalamin levels, anemia, and DB, Carroll '11 .II'. Myelodysplastic syndromes. macrocytosis are often lacking. Arch Intern Med

A clinical and pathological analysis of 109 cases. 19i1H; 14il:I712-4. http://www.jabfm.org/

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251l JABFP Octoher-December l'JH'J Vol. 2 No.4