My patient with anemia has an abnormally high mean red blood cell corpuscular volume (MCV). What conditions should I routinely consider as a cause of his macrocytic anemia?

Anemia with mean corpuscular volume (MCV) above the upper limit of normal (usually ≥ 100 fL) is considered macrocytic anemia. The numerous causes of macrocytic anemia can be divided into major categories (1,2) (Figure 1).

First, a reticulocyte production index should be calculated and if elevated the MCV can be above the normal range due to the large size of reticulocytes. Once high MCV is not thought to be related to reticulocytosis, the majority of macrocytic anemias can be categorized according to one of two major mechanisms: 1. Liver disease; and  2. Impairment of DNA synthesis, which includes nutritional deficiencies (folate, B12), drug effect (e.g co-trimoxazole, anti-neoplastic agents and certain anti-retroviral drugs) and “idiopathic” causes (myelodysplastic syndromes).

Mild macrocytosis can also be seen in hypothyroidism and hypoproliferative anemias such as aplastic anemia.  Macrocytosis without anemia or liver disease can also be a manifestation of heavy alcohol intake.

Macrocytic anemia in liver disease is due to excess lipid deposition in the red blood cell (RBC) membrane, not impairment of DNA synthesis. Enlarged RBCs are usually round and  often have a targeted appearance in liver disease; acanthocytes (spur cells) may also be present (Fig 2). In contrast, in disorders of impaired DNA synthesis, enlarged RBCs are often oval-shaped (macro-ovalocytes) (Fig 3).

Other common abnormalities seen with macrocytic anemia include hypersegmented neutrophils (eg, induced by B12 or folate deficiency), and in the case of myelodysplastic syndromes, hypogranulated neutrophils and Pelger-Huet neutrophil abnormalities.

Bonus pearl: Did you know that the MCV unit, fL, stands for femtoliters or 1/1,000,000,000,000,000 L? 


Figure 1. Major causes of macrocytic anemia. MDS: myelodysplastic syndrome.


Macrocytic_Anemia_Figure 1

Fig 2. Round macrocytes with targeting and abundant acanthocytes (spur cells) in a patient with hepatic cirrhosis.


Macrocytic_Anemia_Figure 2

Fig 3. Oval macrocytes in a patient with large granular cell leukemia and an MCV of 125 fL who received cyclophosphamide.


  1. Ward PC. Investigation of Macrocytic Anemia. Postgrad Med 1979; 65: 203-207.
  2. Green R, Dwyre DM. Evaluation of macrocytic anemias. Semin Hematol 2015; 52: 279-286.


Contributed by Tom Spitzer, MD, Director of Cellular Therapy and Transplantation Laboratory, Massachusetts General Hospital, Boston, MA.

My patient with anemia has an abnormally high mean red blood cell corpuscular volume (MCV). What conditions should I routinely consider as a cause of his macrocytic anemia?

Why is my hospitalized patient with alcohol withdrawal syndrome so thrombocytopenic?

Although thrombocytopenia associated with chronic alcoholism may be related to complications of cirrhosis (eg, platelet sequestration in spleen due to portal hypertension, poor platelet production, and increased platelet destruction) (1), it may also occur in the absence of cirrhosis due to the direct toxic effect of alcohol on platelet production and survival (2).

In a prospective study of patients ingesting the equivalent of a fifth or more daily of 86 proof whiskey admitted for treatment of alcohol withdrawal—without evidence of severe liver disease, infection or sepsis— 81% had initial platelet counts below 150,000/µl, with about one-third having platelet counts below 100,000 µl (as low as 24,000/ul) (3).

In most patients, 2-3 days elapsed before the platelet count began to rise significantly, peaking 5-18 days after admission. Others have also reported that platelet counts rise within 5-7 days and normalize in a few weeks after alcohol withdrawal (1); bleeding complications have been uncommon in this setting.

Perhaps even more intriguing is the report of the association between thrombocytopenia in early alcohol withdrawal and the development of delirium tremens or seizures (sensitivity and specificity ~ 70%, positive predictive value less than 10% but with a negative predictive value of 99%) (4)! In fact, the authors suggested that, if their findings are corroborated, a normal platelet count could potentially be used to identify patients at low risk of alcohol withdrawal syndrome and therefore outpatient therapy. 

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1. Mitchell O, Feldman D, Diakow M, et al. The pathophysiology of thrombocytopenia in chronic liver disease. Hepatic Medicine: Evidence and Research 2016;8 39-50.

2. Cowan DH. Effect of alcoholism on hemostasis. Semin Hematol 1980;17:137-47.

3. Cowan DH, Hines JD. Thrombocytopenia of severe alcoholism. Ann Intern Med 1971;74:37-43.

4. Berggren U, Falke C, Berglund KJ, et al. Thrombocytopenia in early alcohol withdrawal is associated with development of delirium tremens or seizures. Alcohol & Alcoholism 2009;44:382-86.


Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Why is my hospitalized patient with alcohol withdrawal syndrome so thrombocytopenic?

My 35 year old patient with Crohn’s disease has peripheral neuropathy but no anemia or macrocytosis. Could he still have vitamin B-12 deficiency?

Absolutely! A significant number of patients with B-12 deficiency are neither anemic nor have macrocytosis but may still have related neurological symptoms.

A large study involving a nationally representative sample of older U.S. adults (aged >50 y) sponsored by the CDC reported a prevalence of B-12 deficiency without anemia or without macrocytosis of about 4% each . 1 Interestingly, in this study,  there was no evidence that mandatory folic acid fortification of certain foods was associated with lower prevalence of B-12 deficiency without anemia or macrocytosis.

In another study, the proportion of subjects with low serum B-12 but without macrocytosis was 70% or higher, irrespective of pre- or post-fortification period.2 Interestingly, in the age group <65 y, the post-fortification was associated with significantly higher proportion of patients without macrocytosis (85% vs. 45% in the prefortification period) in this study.

Younger age groups seem to also be overrepresented among patients with B-12 deficiency but no anemia, with a prevalence of 50% in <60 y age group with B-12 deficiency compared to 38% and 31% among older age groups (60-74 y and >74 y, respectively).3

So, keep B-12 deficiency in mind in the presence of compatible neurological symptoms even in the absence anemia or macrocytosis!



  1. Qi YP, Do AN, Hamner HC, et al. The prevalence of low serum vitamin B-12 status in the absence of anemia or macrocytosis did not increase among older U.S. adults after mandatory folic acid fortification. J Nutr 2014;144:170-76.
  2. Wyckoff KF, Ganji V. Proportion of individuals with low serum vitamin B-12 concentrations without macrocytosis is higher in the post-folic acid fortification period than in the pre-folic acid fortification period. Am J Clin Nutr 2007;86:1187-92.
  3. Mills JL, Von Kohorn I, Conley MR, et al. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr 2003;77:1474-7.
My 35 year old patient with Crohn’s disease has peripheral neuropathy but no anemia or macrocytosis. Could he still have vitamin B-12 deficiency?