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Megaloblastic Anemia

Megaloblastic Anemia

Article Author:
Anis Hariz
Article Editor:
Priyanka Bhattacharya
8/16/2020 3:05:03 AM
For CME on this topic:
Megaloblastic Anemia CME
PubMed Link:
Megaloblastic Anemia


Megaloblastic anemia (MA) encompasses a heterogeneous group of anemias characterized by the presence in the bone marrow of large red blood cell precursors called megaloblasts.[1] This condition is due to impaired DNA synthesis, which inhibits nuclear division. Cytoplasmic maturation, mainly dependent on RNA and protein synthesis, is less impaired; this leads to an asynchronous maturation between the nucleus and cytoplasm of erythroblasts, explaining the large size of the megaloblasts.[2] The process affects the entire hematopoiesis as well as rapidly renewing tissues such as gastrointestinal cells. Megaloblastic anemia is most often due to hypovitaminosis, specifically vitamin B12 (cobalamin) and folate, which are necessary for the synthesis of DNA.


Deficiencies of vitamin B12 and folic acid are the leading causes of megaloblastic anemia.

Folic acid is present in food such as green vegetables, fruits, meat, and liver. Daily adult needs range from 50 to 100 µg.  The recommended dietary allowance is 400 µg in adults and 600 µg in a pregnant woman.[3] Folic acid is meanly absorbed in the jejunum — the body stores around 5 mg of folate in the liver, enough for 3 to 4 months. Folic acid deficiency may be related to decreased intake in the case of alcoholism or malnutrition (elderly, institutions, poverty, special diets, etc.), increased demand particularly in case of pregnancy, hemolysis and hemodialysis and malabsorption (tropical sprue, celiac disease, jejunal resection, Crohn disease, etc.). In some cases, medications like anticonvulsants and anticancer agents cause megaloblastic anemia related to folate deficiency.

The primary dietary sources of cobalamin/vitamin B12 are meats, fish, eggs, and dairy products. Vegan diets are low in vitamin B12. However, not all vegans develop clinical evidence of deficiency.  Vitamin B12 is first bound within the duodenum and jejunum to intrinsic factor produced by gastric parietal cells and is then absorbed in the terminal ileum. Body stores 2 to 3 mg of vitamin B12 in the liver (sufficient for 2 to 4 years).

The most frequent cause of vitamin B12 deficiency is pernicious anemia caused by autoimmune gastric atrophy and leading to intrinsic factor production reduction.[4] Vitamin B12 deficiency may also develop following gastrectomy, ileal resection or ileitis of any cause. Other causes of impaired vitamin B12 absorption include Zollinger-Ellison syndrome, blind loop syndrome, fish tapeworm infestation, and pancreatic insufficiency.

In rare cases, MA is due to inherited problems:

  • Thiamine-responsive megaloblastic anemia syndrome: an autosomal recessive disease characterized by megaloblastic anemia associated with deafness and diabetes mellitus.[5]
  • Inherited deficiency of intrinsic factor or the receptor in the intestines: Imerslund-Grasbeck syndrome.
  • Some infants have congenital folate malabsorption.


Megaloblastic anemia is not rare, but data are insufficient regarding its prevalence. The condition is more prevalent in countries where malnutrition is a significant problem The prevalence increases in older people and during pregnancy. Nowadays, vitamin supplementation in elderly persons and folate administration during pregnancy has decreased the incidence of megaloblastic anemia. Pernicious anemia is the most frequent cause of anemia related to cobalamin deficiency worldwide and usually occur in individuals older than 40 years. The incidence of pernicious anemia is higher in the United Kingdom and Nordic countries than in other developed countries.[6]


The pathophysiology of this group of anemia is ineffective erythropoiesis secondary to intramedullary apoptosis of hematopoietic cell precursors, which results from DNA synthesis abnormalities. Both vitamin B12 and folate deficiencies may cause defective DNA synthesis. Subsequently, the nucleus and cytoplasm do not mature simultaneously. The cytoplasm (in which hemoglobin synthesis is unaltered) mature at the normal rate, and the nucleus (with DNA impairment) is not fully mature. 


In myelogram, megaloblastosis presents as large red blood cells (megaloblasts) and also by hypersegmented neutrophils which are detectable in a peripheral blood smear.  Poikilocytosis and anisocytosis are common due to ineffective erythropoiesis.  The bone marrow evaluation shows hypercellularity with abnormal maturation and proliferation of red cell precursors. Erythroblasts show a failure of nuclei maturation maintaining open or lax chromatin and normal mature cytoplasm.

History and Physical

Usually, anemia develops gradually, and symptoms are present only in severely anemic patients. Common symptoms include weakness, shortness of breath primarily during exercise, palpitation, and lightheadedness. Physical examination may found pallor, tachycardia, functional heart murmur, Hunter’s glossitis, and splenomegaly. Jaundice can occur from intramedullary hemolysis.

There are some minor differences between the clinical manifestations caused by cobalamin deficiency and folic acid deficiency; in vitamin B12 deficiency, neurological manifestations are observable. Main symptoms are paresthesia and balance disorders. Patients with vitamin B12 deficiency may present lancinating pains caused by peripheral neuropathy that mainly affects the lower extremities. Less frequently, there may be a development of visual disturbances caused by optic atrophy. The clinical exam usually shows loss of vibratory sense and proprioception with a positive Roberg’s test. Babinski reflex, hyporeflexia, and clonus are less frequent. Moreover, there are psychological disturbances that include a form of dementia. These neurological disorders may not be reversible after replacement therapy.

Pernicious anemia frequently has associations with other autoimmune conditions such as autoimmune thyroid disease, type 1 diabetes, and vitiligo.


All types of megaloblastic anemia present the same laboratory findings whether they are due to cobalamin or folic acid deficiency. In a complete blood count (apart from anemia) the most noteworthy finding is macrocytosis. Furthermore, varying degrees of leuko-neutropenia and thrombocytopenia can be present, especially in the case of chronic deficiencies. The reticulocyte count is low. In peripheral blood smear (PBS), megaloblasts, while not pathognomic, are highly suggestive of megaloblastic anemia. The changes are not limited to red blood cells and hypersegmented neutrophils, with six or more lobes, may be seen. Other findings include Howell-Jolly bodies, anisocytosis, and poikilocytosis.

If there are megaloblasts on PBS with a high reticulocyte count, the first-line of investigation includes an assay of vitamin B12 and folate red blood cells levels. Levels less than 200 pg/ml of vitamin B12 indicate deficiency. 

Treatment / Management

In cases of vitamin B12 deficiency, the treatment centers on intramuscular injections of hydroxocobalamin. Usually, patients receive 1000 ug of vitamin B12 daily in their first week of treatment. In the following month, they receive weekly and then monthly injections.  Usually, reticulocytosis occurs within 3 to 5 days. By the tenth day, hemoglobin starts to increase, and a total resolution of anemia normally occurs after 2 months of treatment.  Reversal of neurological changes typically takes a longer time, and some manifestations will not disappear even if treatment starts promptly. The treatment should be continued indefinitely at a dose of 1000 ug/month. In some cases, in particular, in patients with prior total gastrectomy or extensive ileal resection, preventive treatment with vitamin B12 is for life.

In the case of folate deficiency, it is essential to ascertain the absence of concomitant vitamin B12 deficiency before starting therapy. Indeed, neuropathy may worsen if large doses of folic acid are administered in the presence of a concomitant vitamin B12 deficiency.

Folic acid supplementation, 1 to 5 mg/day, is usually given orally. In patients with malabsorption, parenteral preparation is the recommendation.  To prevent relapse treatment should continue for a minimum of two years.   

Differential Diagnosis

The complete blood count may show macrocytosis in non-megaloblastic macrocytic anemias. Reticulocyte count will help distinguish between two primary conditions. If reticulocytosis is present, hemolytic anemia and acute hemorrhage are the two main conditions for which the clinician must look. If a reticulocytopenia is present, the underlying conditions may be evident in some cases such as hypothyroidism, alcoholism, liver dysfunction, and certain drugs. In the other cases, one should perform bone marrow aspiration provided that the investigations to exclude vitamin B12 or folate deficiency are carried out. Indeed, myelodysplastic disorders and sideroblastic anemia can manifest as refractory megaloblastic anemia.

Enhancing Healthcare Team Outcomes

Megaloblastic anemias are optimally managed through an interprofessional team approach:

  • Folic acid and vitamin B12 deficiencies are the leading causes of megaloblastic anemia.
  • The leading cause of vitamin B12 deficiency is pernicious anemia caused by autoimmune destruction of gastric parietal cells.
  • Excess cell turnover, increased demand, malabsorption or a poor diet may cause folate deficiency.
  • The onset of megaloblastic anemia is usually insidious. Apart from an anemic syndrome, patients with vitamin B12 deficiency may present neurologic symptoms.  
  • Treatment of folate deficiency is with folic acid supplements.
  • Treatment of vitamin B12 deficiency is usually with injections of hydroxocobalamin.
  • A pharmacist can verify the particular supplement and dosing tin conjunction with the prescriber.
  • Nursing will provide monitoring on subsequent visits, verifying treatment effectiveness compliance, and answering any patient questions, and informing the clinician of any concerns or changes.
  • A nutritional consult may also be in order, in coordination with the prescriber supplementation program.

The above-outlined interprofessional strategies will help drive outcomes positively. [Level 5]


[1] Wickramasinghe SN, Diagnosis of megaloblastic anaemias. Blood reviews. 2006 Nov;     [PubMed PMID: 16716475]
[2] Green R,Datta Mitra A, Megaloblastic Anemias: Nutritional and Other Causes. The Medical clinics of North America. 2017 Mar;     [PubMed PMID: 28189172]
[3] Stamm RA,Houghton LA, Nutrient intake values for folate during pregnancy and lactation vary widely around the world. Nutrients. 2013 Sep 30;     [PubMed PMID: 24084052]
[4] Toh BH, Diagnosis and classification of autoimmune gastritis. Autoimmunity reviews. 2014 Apr-May;     [PubMed PMID: 24424193]
[5] Khurshid A,Fatima S,Altaf C,Malik HS,Sajjad Z,Khadim MT, Thiamine Responsive Megaloblastic Anaemia, Diabetes Mellitus and Sensorineural Hearing Loss in a Child. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2018 Sep;     [PubMed PMID: 30173687]
[6] Bizzaro N,Antico A, Diagnosis and classification of pernicious anemia. Autoimmunity reviews. 2014 Apr-May;     [PubMed PMID: 24424200]
[7] Sayar EH,Orhaner BB,Sayar E,NesrinTuran F,Küçük M, The frequency of vitamin B12, iron, and folic acid deficiency in the neonatal period and infancy, and the relationship with maternal levels. Turk pediatri arsivi. 2020;     [PubMed PMID: 32684759]
[8] Oo TH, Diagnostic difficulties in pernicious anemia. Discovery medicine. 2019 Nov-Dec;     [PubMed PMID: 32053765]
[9] Sobczyńska-Malefora A,Harrington DJ, Laboratory assessment of folate (vitamin B{sub}9{/sub}) status. Journal of clinical pathology. 2018 Nov;     [PubMed PMID: 30228213]
[10] Rao S,Colon Hidalgo D,Doria Medina Sanchez JA,Navarrete D,Berg S, Et Tu, B12? Cobalamin Deficiency Masquerading As Pseudo-Thrombotic Microangiopathy. Cureus. 2020 Jul 9;     [PubMed PMID: 32670728]
[11] Rojas Hernandez CM,Oo TH, Advances in mechanisms, diagnosis, and treatment of pernicious anemia. Discovery medicine. 2015 Mar;     [PubMed PMID: 25828519]
[12] Mohamed M,Thio J,Thomas RS,Phillips J, Pernicious anaemia. BMJ (Clinical research ed.). 2020 Apr 24;     [PubMed PMID: 32332011]