What are the causes of non-megaloblastic (non-megaloblastic) macrocytic (large cell) normochromic (normal colored) anemia?

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From the Guidelines

Non-megaloblastic macrocytic normochromic anemia is a condition that requires a comprehensive evaluation to determine the underlying cause, which can include liver disease, alcoholism, myelodysplastic syndromes, and certain medications, and treatment should focus on addressing the primary condition. The most common causes of non-megaloblastic macrocytic normochromic anemia include liver disease, alcoholism, myelodysplastic syndromes, and certain medications 1. Initial evaluation should include:

  • Complete blood count
  • Peripheral blood smear
  • Reticulocyte count
  • Liver function tests
  • Thyroid function tests
  • Vitamin B12 and folate levels to rule out megaloblastic causes

Treatment depends on addressing the underlying cause:

  • Alcohol cessation for alcoholic patients
  • Discontinuation of offending medications
  • Management of liver or thyroid disease
  • In cases of myelodysplastic syndrome, referral to hematology is warranted for potential treatments like growth factors, lenalidomide, or hypomethylating agents 1. Lenalidomide is a recommended treatment for individuals with symptomatic anemia and del(5q) with or without other cytogenetic abnormalities. Erythropoietin may also be effective in patients with normal cytogenetics, less than 15% marrow ringed sideroblasts, and sEpo levels of 500 mU/mL or less 1. Prognosis varies widely depending on the underlying cause, with complete resolution possible when the primary condition is effectively treated.

From the Research

Definition and Classification of Macrocytic Anemia

  • Macrocytic anemia is defined as a red blood cell (RBC) mean corpuscular volume (MCV) >100 femtoliter (fL) 2, 3, 4, 5, 6.
  • Macrocytic anemias are generally classified into megaloblastic or nonmegaloblastic anemia 2, 3, 4, 5, 6.

Causes of Non Megaloblastic Macrocytic Anemia

  • Nonmegaloblastic macrocytic anemia is caused by various diseases such as myelodysplastic syndrome (MDS), liver dysfunction, alcoholism, hypothyroidism, certain drugs, and by less commonly inherited disorders of DNA synthesis 2.
  • Other causes of nonmegaloblastic macrocytic anemia include chronic liver dysfunction, hypothyroidism, alcohol use disorder, or myelodysplastic disorders 4.
  • Alcoholism is the most common form of nonmegaloblastic macrocytic anemia 3.

Diagnosis and Evaluation of Macrocytic Anemia

  • A blood smear should be performed to differentiate megaloblastic from nonmegaloblastic anemia 3.
  • Other testing should include vitamin B12 and red blood cell folate levels, reticulocyte count, and thyroid and liver function tests 3, 5, 6.
  • A carefully obtained history and examination with evaluation of a peripheral blood smear and reticulocyte count should be performed in most patients with macrocytosis 5.

Management of Macrocytic Anemia

  • Management of macrocytic anemia is specific to the etiology identified through testing and patient evaluation 4.
  • Macrocytic anemias are treated with cause-specific therapies, and it is crucial to differentiate nonmegaloblastic from megaloblastic anemia 2.

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Diagnosis and treatment of macrocytic anemias in adults.

Journal of general and family medicine, 2017

Research

Macrocytic anemia.

American family physician, 1996

Research

Anemia: Macrocytic Anemia.

FP essentials, 2023

Research

Evaluation of macrocytosis.

American family physician, 2009

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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