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Introduction
Anisocytosis is a laboratory finding where red blood cells (RBCs) show excessive variation in size. It is not a disease by itself but a sign of an underlying blood disorder, most commonly anemia.
In this article you will learn what anisocytosis means, how it is quantified by Red Cell Distribution Width (RDW), its three main types, common causes including iron deficiency and vitamin B12 deficiency, symptoms, complications, diagnosis by blood smear and complete blood count, and treatment and prevention based on the underlying cause.
What is Anisocytosis?
Definition and Etymology
Anisocytosis refers to excessive variation in the size of erythrocytes. The term comes from Greek: an meaning not, iso meaning equal, and cytosis meaning condition of cells. It is observed on peripheral blood film and by automated cell counters.
Anisocytosis indicates that the bone marrow is producing RBCs of unequal size due to defect in hemoglobin synthesis, DNA synthesis, or membrane formation.
RDW as a Quantitative Measure of Anisocytosis
Anisocytosis is quantified by Red Cell Distribution Width (RDW). RDW is a measure of variability of erythrocyte volume and is routinely reported as part of the complete blood count.
It is calculated as coefficient of variation of RBC volumes divided by Mean Corpuscular Volume (MCV):
RDW-CV = (Standard deviation of RBC volume / MCV) x 100
- Normal RDW-CV is generally 11.5% to 14.5%.
- Normal MCV is 80 to 100 fL.
- High RDW indicates increased anisocytosis. RDW along with MCV helps classify anemia.
Types of Anisocytosis
Based on MCV and underlying cause, three patterns are observed.
|
Type |
MCV Finding |
RDW |
Common Associations |
|---|---|---|---|
|
Anisocytosis with macrocytosis |
MCV > 100 fL |
High |
Vitamin B12/folate deficiency, liver disease, myelodysplasia |
|
Anisocytosis with microcytosis |
MCV < 80 fL |
High |
Iron deficiency, thalassemia, sideroblastic anemia, lead poisoning |
|
Anisocytosis with normocytosis |
MCV 80-100 fL |
High |
Early iron/folate deficiency, mixed deficiency, normocytic anemia with anisocytosis |
a. Anisocytosis with Macrocytosis
When RBCs are larger than usual. Observed in megaloblastic anemia due to Vitamin B12 or folate deficiency, myelodysplasia, chronic liver disease. Also associated with antimetabolite drugs and androgen therapy. Milder degree is commonly seen in chronic alcohol use.
b. Anisocytosis with Microcytosis
When RBCs are smaller than usual. Commonly observed in iron deficiency anemia, sideroblastic anemia, certain thalassemias, lead poisoning, and certain hemoglobinopathies like Hemoglobin H disease.
c. Anisocytosis with Normocytosis
When MCV is within normal range (80-100 fL) but RDW is high, indicating co-existence of normal-sized cells with microcytes and/or macrocytes. Early stage of deficiency, dimorphic anemia, or normocytic anemia with early anisocytosis. It does not mean low RBC number alone; it means normal average size with increased variation.
Causes of Anisocytosis
As anisocytosis is not a condition in itself, it is associated with other blood-related disorders.
Primary Cause: Anemia
Anemia is the primary cause. Different types result in different patterns of anisocytosis.
a. Iron Deficiency Anemia
Most common type of anemia. Results due to lack of iron in the body, not iodine, usually from chronic blood loss or dietary deficiency. Iron is essential for hemoglobin synthesis that carries oxygen. When iron is reduced, hemoglobinization is impaired and RBC size fluctuates. Usually results in anisocytosis with microcytosis. Common during pregnancy due to increased iron demand.
Correction: Original text mentioned iodine and RBCs storing iodine. Scientifically, RBCs store iron as part of hemoglobin, not iodine.
b. Sickle-Cell Anemia
Genetic autosomal recessive condition resulting in formation of sickle-shaped or crescent-shaped RBCs due to abnormal hemoglobin S. Can be inherited. Produces marked anisocytosis and poikilocytosis.
c. Thalassemia
Genetic disorder where body produces abnormal amounts or types of hemoglobin chains. Can be inherited. Results in anisocytosis with microcytosis, hypochromia, and target cells.
d. Hemolytic Anemia
Group of disorders where body destroys RBCs prematurely via autoimmune mechanisms, infections, or genetic defects. Causes reduction in RBC number and compensatory reticulocytosis, leading to anisocytosis.
e. Megaloblastic Anemia
Occurs when DNA synthesis is impaired due to lack of Vitamin B12 or folate. RBCs are large with nuclear-cytoplasmic asynchrony. Remaining RBCs are larger than normal. Shows anisocytosis with macrocytosis and hypersegmented neutrophils.
f. Aplastic Anemia
Bone marrow failure disorder when body does not produce enough blood cells. Caused by viral infections, drugs, exposure to toxic chemicals, or autoimmune destruction of stem cells. Pancytopenia may show anisocytosis.
g. Pernicious Anemia
Autoimmune disorder where body becomes incapable of absorbing vitamin B12 due to lack of intrinsic factor and anti-parietal cell antibodies. Leads to megaloblastic pattern with macrocytic anisocytosis.
Other Associated Disorders
In addition to anemia, other conditions may result in anisocytosis:
- Chronic liver disease
- Myelodysplastic syndrome (MDS)
- Thyroid disorders
- Hemoglobin H disease
- Protein deficiency
- Cardiovascular diseases associated with high RDW
- Cytotoxic chemotherapy and cancer drugs
- Mixed nutritional deficiencies
Symptoms of Anisocytosis
Anisocytosis itself does not cause specific symptoms. Symptoms are due to underlying anemia and reduced oxygen delivery to organs, similar to anemia and other blood disorders.
Common Symptoms
- Weakness and fatigue
- Shortness of breath even with minimal exertion
- Chest pain and palpitations
- Headache and dizziness
- Pale skin, conjunctiva, and nail beds
- Cold hands and feet
- Difficulty concentrating
Complications if Untreated
If underlying cause is left untreated, it may lead to:
- Reduction in white blood cells and platelets (pancytopenia)
- Peripheral neuropathy and damage to nervous system in B12 deficiency
- Tachycardia, heart failure due to compensatory high output
- Severe pregnancy complications, including neural tube defects in developing fetus due to folate deficiency
- Growth and developmental delays
Diagnosis of Anisocytosis
Blood Smear - Gold Standard for Morphology
A sample of venous blood is collected and thin layer smeared on sterile glass slide, stained with Leishman or Wright-Giemsa stain, dried, and observed under microscope.
Staining helps differentiate size and shape. Through smear, size, shape, number of RBCs, hemoglobin content in each cell, cell volume, and hemoglobin concentration are assessed. Presence of macrocytes, microcytes, dimorphic population, and poikilocytosis is noted.
Complete Blood Count and RDW
Automated hematology analyzer provides:
- RBC count, Hemoglobin, Hematocrit
- MCV, MCH, MCHC, RDW
- High RDW indicates anisocytosis. Combined interpretation of MCV and RDW narrows differential diagnosis.
Other Laboratory Tests
Depending on suspected cause:
- Serum ferritin, serum iron, TIBC, transferrin saturation for iron deficiency
- Folate and Vitamin B12 levels
- Reticulocyte count
- Liver and thyroid function tests
- Hemoglobin electrophoresis for thalassemia
- Bone marrow examination in aplastic anemia or MDS
Treatment of Anisocytosis
Treatment Based on Underlying Cause
Treatment targets the cause, not anisocytosis alone.
- Anisocytosis due to iron deficiency or vitamin B12/folate deficiency is treated with oral or parenteral supplements and proper diet rich in iron, green leafy vegetables, legumes, meat, and fortified foods.
- Megaloblastic anemia due to B12 deficiency may require lifelong B12 injections, especially in pernicious anemia.
- Sickle cell anemia and thalassemia may require folic acid supplementation, hydroxyurea, blood transfusions, and in severe cases, bone marrow transplant or gene therapy approaches.
- Aplastic anemia may need immunosuppressive therapy and bone marrow transplant.
- Manage associated chronic liver disease, thyroid disorders, and stop offending drugs where possible.
Prevention
Diet and Lifestyle for Prevention
A proper diet with necessary nutrients and vitamins is useful in preventing nutritional anisocytosis.
- Balanced diet rich in iron, vitamin B12, folate, and protein
- Antenatal iron and folic acid supplementation during pregnancy
- Regular screening of at-risk groups
- Avoiding excessive alcohol
- Early treatment of chronic blood loss, infections, and thyroid disorders
- Lifestyle changes including proper supplementation and regular exercise improve overall hematologic health
For genetic causes like sickle cell anemia and thalassemia, genetic counseling and prenatal screening are important preventive strategies.
3. Key Takeaways
- Anisocytosis is excessive variation in RBC size, quantified by Red Cell Distribution Width (RDW), normal RDW-CV 11.5-14.5% and MCV 80-100 fL.
- Formula is RDW-CV = (SD of RBC volume / MCV) x 100; high RDW indicates anisocytosis.
- Three types: macrocytic anisocytosis (B12/folate deficiency, liver disease), microcytic anisocytosis (iron deficiency, thalassemia, lead poisoning), normocytic anisocytosis with high RDW (early or mixed deficiency).
- Iron deficiency is due to lack of iron for hemoglobin synthesis, not iodine; correction of iodine error is critical for scientific accuracy.
- Pernicious anemia is autoimmune loss of intrinsic factor causing B12 malabsorption leading to megaloblastic macrocytic anisocytosis with hypersegmented neutrophils.
- Symptoms reflect impaired oxygen delivery: fatigue, dyspnea on exertion, pallor, dizziness, palpitations; complications include pancytopenia, neuropathy, heart failure, and neural tube defects.
- Diagnosis by peripheral blood smear with Leishman stain is gold standard for morphology, plus CBC showing MCV and RDW, plus ferritin, iron studies, B12, folate, and hemoglobin electrophoresis.
- Treatment is cause-specific: iron, B12, folate supplementation, transfusion for severe thalassemia/sickle cell, bone marrow transplant for aplastic anemia and selected megaloblastic cases.
- Prevention includes balanced diet, antenatal supplementation, limiting alcohol, treating chronic disease, and genetic counseling for inherited anemias.
- Anisocytosis is distinct from poikilocytosis which is variation in shape; both often coexist in anemia.
4. Scientific References
- Hoffbrand AV, Moss PAH → Hoffbrand's Essential Haematology → 8th Edition → Wiley Blackwell → Chapter 2 Erythropoiesis and general aspects of anaemia; Chapter 3 Hypochromic anaemias; Chapter 8 Megaloblastic anaemias.
- Bain BJ → Blood Cells: A Practical Guide → 5th Edition → Wiley Blackwell → Chapter 2 Morphology of Blood Cells; Chapter 3 Red Cell Distribution Width and Blood Film Interpretation.
- Kumar V, Abbas AK, Aster JC → Robbins and Cotran Pathologic Basis of Disease → 10th Edition → Elsevier → Chapter 14 Red Blood Cell and Bleeding Disorders – Anemia, RDW.
- Firkin F, Chesterman C, Penington D, Rush B → de Gruchy's Clinical Haematology in Medical Practice → 5th Edition → Wiley Blackwell → Chapter 5 Anaemia – Classification by MCV and RDW.
- Rodak BF, Carr JH → Clinical Hematology Atlas → 5th Edition → Elsevier → Chapter 5 Red Blood Cell Morphology, Anisocytosis and Poikilocytosis.
- NCERT → Biology Textbook for Class XI → Reprint 2023-24 → National Council of Educational Research and Training, India → Chapter 18 Body Fluids and Circulation – Blood composition and functions.
- Constantino BT → Red cell distribution width, revisited → Laboratory Medicine → 2013 → Volume 44, Issue 2, Pages e2-e9 → DOI: 10.1309/LMWDAP4VBU6M3CIR
- Salvagno GL, Sanchis-Gomar F, Picanza A, Lippi G → Red blood cell distribution width: A simple parameter with multiple clinical applications → Critical Reviews in Clinical Laboratory Sciences → 2015 → Volume 52, Issue 2, Pages 86-105 → DOI: 10.3109/10408363.2014.992064
- Evans TC, Jehle D → The red blood cell distribution width → The Journal of Emergency Medicine → 1991 → Volume 9, Supplement 1, Pages 71-74 → DOI: 10.1016/0736-4679(91)90592-4
- Buttarello M, Plebani M → Automated blood cell counts: state of the art → American Journal of Clinical Pathology → 2008 → Volume 130, Issue 1, Pages 104-116 → DOI: 10.1309/EK3C7CTDKNVPXVTN
- Lippi G, Plebani M → Red blood cell distribution width (RDW) and human pathology. One size fits all → Clinical Chemistry and Laboratory Medicine → 2014 → Volume 52, Issue 9, Pages 1247-1249 → DOI: 10.1515/cclm-2014-0585
- National Library of Medicine → MedlinePlus Medical Encyclopedia → Anisocytosis – RDW Test → URL: https://medlineplus.gov/ency/article/003440.htm → Accessed 2025-2026
- National Center for Biotechnology Information → StatPearls – Red Cell Distribution Width → URL: https://www.ncbi.nlm.nih.gov/books/NBK542172/ → Accessed 2025-2026
- American Society of Hematology → Blood Education – Anemia and Red Cell Indices → URL: https://www.hematology.org/education/patients/anemia → Accessed 2025-2026
- World Health Organization → Anaemia – Key Facts and Laboratory Diagnosis → URL: https://www.who.int/news-room/fact-sheets/detail/anaemia → Accessed 2025-2026