Why does my patient with alcoholic cirrhosis have macrocytic anemia?

Macrocytic anemia is commonly due to folate or vitamin B12 (cobalamin) deficiency.1 Deficiency in these vitamins can be related broadly to poor intake, poor absorption, or drug interference. In patients with chronic excess alcohol consumption, both intake and/or absorption of these vitamins may be affected.

Although folate deficiency is increasingly rare in many developed countries due to mandatory folate fortification of flour and uncooked-grain, alcohol use can be associated with malnourishment severe enough to causes folate deficiency. In addition, alcohol itself can alter folate metabolism and absorption.  More specifically, chronic alcohol consumption has been shown to be associated with decreased folate absorption by the small intestine, altered intrahepatic processing and distribution between the systemic and enterohepatic folate circulations as well as increased folate urinary excretion. 2 Though uncommon,3 alcohol can also be associated with a food B12 malabsorption process, whereby despite adequate intake, B12 is not released or absorbed from food. 4

But what if serum folate and B12 levels return as normal in our patient with macrocytosis? It turns out that alcohol consumption, independent of folate or B12 deficiency, may also cause macrocytosis. 5 Though the exact mechanism is unknown, it may be related to alcohol’s direct toxicity or that of its metabolites; alcohol is oxidized to acetaldehyde, which affects membranes of red blood cells (RBCs) and their precursors by forming adducts with erythroid proteins,6 and interfering with cell division.7 Interestingly, alcohol-related macrocytosis may appear before anemia is detected and can resolve within 2-4 months of abstinence.

In addition to alcohol, cirrhosis itself may be associated with macrocytic anemia caused by lipid deposition on RBC membranes.1

See also a related pearl at  https://pearls4peers.com/2019/07/26/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   


  1. Hoffbrand V, Provan D. ABC of clinical haematology: macrocytic anaemias. BMJ 2011;314(7078):430–430. https://www.ncbi.nlm.nih.gov/pubmed/9040391
  2. Medici V, Halsted CH. Folate, alcohol, and liver disease. Mol Nutr Food Res 2013;57(4):596–606. https://www.ncbi.nlm.nih.gov/pubmed/23136133
  3. Bode C, Bode CJ. Effect of alcohol consumption on the gut. Best Pract Res Clin Gastroenterol [Internet] 2003;17(4):575–92. https://www.sciencedirect.com/science/article/pii/S1521691803000349
  4. Dali-Youcef N, Andrès E. An update on cobalamin deficiency in adults. QJM 2009;102(1):17–28. https://academic.oup.com/qjmed/article/102/1/17/1502492
  5. Savage DG, Ogundipe A, Allen RH, Stabler SP, Lindenbaum J. Etiology and diagnostic Evaluation of macrocytosis. Am J Med Sci [Internet] 2000;319(6):343–52. http://dx.doi.org/10.1016/S0002-9629(15)40772-4 https://www.ncbi.nlm.nih.gov/pubmed/10875288
  6. Latvala J, Parkkila S, Melkko J, Niemelä O. Acetaldehyde adducts in blood and bone marrow of patients with ethanol-induced erythrocyte abnormalities. Mol Med 2001;7(6):401–5. https://www.ncbi.nlm.nih.gov/pubmed/11474133
  7. Wickramasinghe SN, Malik F. Acetaldehyde causes a prolongation of the doubling time and an increase in the modal volume of cells in culture. Alcohol Clin Exp Res 1986;10(3):350–4. https://www.ncbi.nlm.nih.gov/pubmed/3526962


Contributed by Kim Schaefer, Harvard medical student, Boston, MA

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Why does my patient with alcoholic cirrhosis have macrocytic anemia?

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. https://www.ncbi.nlm.nih.gov/pubmed/368738
  2. Green R, Dwyre DM. Evaluation of macrocytic anemias. Semin Hematol 2015; 52: 279-286. https://www.sciencedirect.com/science/article/abs/pii/S0037196315000554


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?

Can native valve infective endocarditis be associated with hemolytic anemia?

Yes, but it’s rare!  Hemolytic anemia (HA) in the setting of infective endocarditis (IE) has only been described in a few case reports (1-3).  Although diseased valves may cause shearing stress that fragments RBCs, similar to that associated with mechanical heart valves, an autoimmune hemolytic process has also been implicated. 

A 2018 case report describes a patient with hypertrophic obstructive cardiomyopathy (HOCM) with left ventricular outflow tract (LVOT) obstruction who had HA secondary to subacute IE due to Actinomyces israelii (1).   The anemia completely resolved after treating the IE (1). The cause was most likely mechanical shearing (schistocytes or fragmented RBCs present on peripheral smear) by the diseased valves; autoimmune hemolysis was considered unlikely in this case due to consistently negative Coombs tests and failure to respond to corticosteroids (1). 

An autoimmune mechanism was invoked by a 1999 report reviewing 6 cases of HA associated with IE (3).  All patients had fragmented erythrocytes, but several also demonstrated an immune-mediated mechanism for their HA, supported by the presence of spherocytes, splenomegaly, and + Coombs test (2,3).  The production of anti-erythrocyte antibodies, modification of antigenicity of erythrocyte antigens, or unmasking of antigens in IE may play a role (1,3). Additional evidence in support of an immune-mediated mechanism of HA in IE has been provided by an experimental study demonstrating significantly shorter RBC half-life in rabbits with intact spleen compared to that of splenectomized animals (4).



1. Toom S, Xu Y. Hemolytic anemia due to native valve subacute endocarditis with Actinomyces israellii infection. Clin Case Rep 2018;6: 376-79. https://onlinelibrary.wiley.com/doi/epdf/10.1002/ccr3.1333 

2. Hsu CM, Lee PI, Chen JM, et al. Fatal Fusarium endocarditis complicated by hemolytic anemia and thrombocytopenia in an infant. Pediatr Infect Dis 1994;13:1146-48. https://www.ncbi.nlm.nih.gov/pubmed/7892087 

3. Huang HL, Lin FC, Hung KC, et al. Hemolytic anemia in native valve infective endocarditis. Jpn Circ J 1999;63:400-403. https://www.ncbi.nlm.nih.gov/pubmed/10943622 

4. Joyce RA, Sand MA. Mechanism of anaemia in experimental bacterial endocarditis. Scand J Haematol 1975;15:306-11. https://www.ncbi.nlm.nih.gov/pubmed/1198067 


Contributed by Scott Goodwin, Medical Student, Harvard Medical School, Boston, MA. 


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Can native valve infective endocarditis be associated with hemolytic anemia?

Can my patient develop “anemia of chronic disease” acutely while hospitalized?

“Anemia of chronic disease” is better termed anemia of inflammation (AI) which may occur in acute as well as chronic inflammatory states. 1 As such, the view that anemia in the critically ill patients is simply caused by excess phlebotomy is inaccurate. 2 The CRIT study demonstrated that AI in critically ill patients develops even within 30 days, often despite blood transfusions. 3

In addition to the usual causes of AI (eg autoimmune disorders), AI can occur during bacterial, viral or yeast infections and sepsis 4,5.

Recent studies implicate both iron sequestration and impaired erythropoiesis as causes of AI. 1 Inflammation stimulates hepatic production of iron-regulatory peptide, hepcidin, which decreases delivery of iron from macrophages to developing erythrocytes.  Inflammation also causes production of pro-inflammatory cytokine, IL-6, which suppresses erythropoiesis.

Couple of cool studies using injection of heat-killed Brucella abortus in mice as a model of AI, showed dramatic hemoglobin drop by 7 days.6,7. In addition, not only were iron restriction from increase in hepcidin and transient erythropoiesis demonstrated, erythrocyte lifespan was also shortened in these experiments. AI is truly a multifactorial process.



  1. Frankel PG. Anemia of inflammation: A review. Med Clin N Ame 2017;101:285-96. https://www.ncbi.nlm.nih.gov/pubmed/28189171
  2. Corwin HL, Krantz SB. Anemia of the critically ill: “Acute” anemia of chronic disease. Crit Care Med 2000;28:3098-99. https://www.ncbi.nlm.nih.gov/pubmed/10966311
  3. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT study: anemia and blood transfusion in the critically ill-current clinical practice in the United states. Crit Care Med 2004;32:39-52. https://www.ncbi.nlm.nih.gov/pubmed/14707558
  4. Gabriel A, Kozek S, Chiari A, et al. High-dose recombinant human erythropoietin stimulates reticulocyte production in patients with multiple organ dysfunction syndrome. J Trauma:Injury, Infection, and Critical Care 1998;44:361-67. https://www.ncbi.nlm.nih.gov/pubmed/9498512
  5. Roy CN. Anemia of inflammation. Hematology Am Soc Hematol Educ Program. 2010;2010:276-80. doi: 10.1182/asheducation-2010.1.276. https://www.ncbi.nlm.nih.gov/pubmed/21239806
  6. Kim A, Fung E, Parikh SG, et al. A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin. Blood 2014;123:1129-36. https://www.ncbi.nlm.nih.gov/pubmed/24357728
  7. Gardenghi S, Renaud TM, Meloni A, et al. Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus. Blood 2014;123:1137-45. https://www.ncbi.nlm.nih.gov/pubmed/24357729

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Can my patient develop “anemia of chronic disease” acutely while hospitalized?

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. http://jn.nutrition.org/content/144/2/170.abstract
  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. https://www.ncbi.nlm.nih.gov/pubmed/17921401
  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. http://ajcn.nutrition.org/content/77/6/1474.full.pdf+html
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?

My elderly patient with aortic stenosis has iron deficiency in the setting of Heyde’s syndrome. Can surgical or transcatheter aortic valve replacement (SAVR, TAVR) reduce her risk of future gastrointestinal bleeding?

Yes! Heyde’s syndrome, characterized by aortic stenosis and GI angiodysplasia1, appears to respond to SAVR or TAVR by reducing future risk of GI bleed.

Cessation of bleeding following SAVR or TAVR with gradual disappearance of angiodysplasia has been reported, in some cases despite long-term anticoagulant therapy2,3In fact, GI bleed may cease in 95% of cases following AVR vs 5% in cases controlled with laparotomy with or without bowel resection.  Further supporting the potential role of valve replacement is the observation that in patients who have undergone SAVR, aortic valve restenosis usually leads to the recurrence of GI bleeding which again resolves after redo surgery.

The pathophysiology of Heyde’s syndrome involves not only increased number of angiodysplasias but higher risk of bleeding from them.  Although its exact  physiological link is unclear, hypo-oxygenation of intestinal mucosa—possibly related to cholesterol emboli with resultant vasodilatation—has been hypothesized, among many others.4   Bleeding from angiodysplasias appears related to the high shear stress across the stenotic aortic valve, leading to acquired von Willebrand’s disease (Type 2AvWF disease) and coagulopathy.4

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    1. Heyde EC. Gastrointestinal bleeding in aortic stenosis. N Engl J Med 1958;259:196. https://www.nejm.org/doi/full/10.1056/NEJM200209123471122
    2. Abi-akar R, El-rassi I, Karam N et al. Treatment of Heyde’s syndrome by aortic valve replacement. Curr Cardiol Rev 2011;  7:47–49. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131716/
    3. Pyxaras, SA, Santangelo S. Perkan A et al. Reversal of angiodysplasia-derived anemia after transcatheter aortic valve implantation. J Cardiol Cases 2012; 5: e128–e131. https://www.sciencedirect.com/science/article/pii/S187854091100079X
    4. Kapila A, Chhabra L, Khanna A. Valvular aortic stenosis causing angiodysplasia and acquired von Willebrand’s disease: Heyde’s syndrome. BMJ Case Rep 2014 doi:10.1136/bcr-2013-201890. http://casereports.bmj.com/content/2014/bcr-2013-201890.full.pdf


Contributed by Biqi Zhang, Medical Student,  Harvard Medical School


My elderly patient with aortic stenosis has iron deficiency in the setting of Heyde’s syndrome. Can surgical or transcatheter aortic valve replacement (SAVR, TAVR) reduce her risk of future gastrointestinal bleeding?

What is the evidence for iron deficiency causing pica?

Pica refers to the compulsive craving and persistent consumption of substances not fit as food such as ice (pagophagia) and soil (geophagia). Several reports have implicated iron deficiency as a cause of pica, with resolution of symptoms following treatment of iron deficiency (1).

In a recent study involving blood donors , pica (particularly pagophagia) was nearly 3 times as likely among donors with iron deficiency  compared to iron-replete donors (11%  vs 4%, respectively, P<0.0001).  In the same study, donors with pica reported a marked reduction in their pica by day 5-8 of iron therapy. 

It has been suggested that cerebral tissue function may be adversely impacted by a deficiency in Fe-containing enzymes (e.g. cytochrome c reductase) resulting in behavioral disorders, such as hyperactivity and pica (2).  

Of interest, cats can be induced to swallow inedible objects when certain points in the hypothalamic area high in iron content are stimulated (3).


  1. Bryant BJ, Yau YY, Arceo SM, et al. Ascertainment of iron deficiency and depletion in blood donors through screening questions for pica and restless legs syndrome. Transfusion 2013;53:1637-1644. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691288
  2. Osman YM, Wali YA, Osman OM. Craving for ice and iron-deficiency anemia: a case series from Oman. Pediatric Hematol Oncol 2005; 22:127-131. https://www.ncbi.nlm.nih.gov/pubmed/15804997
  3. Von Bonsdorff B. Pica: a hypothesis.. British J Haematol 1977;35:476-477.  https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2141.1977.tb00611.x


Contributed by S.J. Lee,  Medical Student, Harvard Medical School, Boston, MA

What is the evidence for iron deficiency causing pica?

Can oral candidiasis be symptomatic without actual pseudomembranes or “thrush”?

Yes!  Although we often associate oral candidiasis with thrush or pseudomembranous white plaques, another common form of oral candidiasis seen in hospitalized patients is “acute atrophic candidiasis” (AAC), also referred to as “antibiotic sore mouth” because of its association with use of broad spectrum antibiotics (1,2). 

Despite the absence of thrush, patients with AAC often have erythematous patches on the palate, buccal mucosa and dorsum of the tongue. Common symptoms include burning sensation in the mouth (especially with carbonated drinks in my experience), dry mouth and taste buds “being off” (2).  

Aside from antibiotics, other predisposing factors for AAC include corticosteroids, HIV disease, uncontrolled diabetes mellitus, iron deficiency anemia, and vitamin B12 deficiency.

So next time you see a hospitalized patient with new onset sore, burning mouth that wasn’t present on admission, think of antibiotic sore mouth!

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1. Stoopler ET, Sollecito TP. Oral mucosal diseases. Med Clin N Am 2014;98:1323-1352. https://www.ncbi.nlm.nih.gov/pubmed/25443679

2. Millsop JW, Fazel N. Oral candidiasis. Clin Derm 2016;34:487-94. https://www.ncbi.nlm.nih.gov/pubmed/27343964

Can oral candidiasis be symptomatic without actual pseudomembranes or “thrush”?