Macrocytic Anemia: Types, Causes, Investigations and Treatment

Macrocytic anemia is a type of anemia in which the red blood cells are larger than their normal volume.

The term ‘macrocytic’ is a Greek word meaning ‘large cell’.

Macrocytic anemia comes under the morphological classification of anemia; in which anemia is classified according to the size of red blood cells. The size is reflected in the mean corpuscular volume (MCV).

The normal mean RBC volume or MCV is 80 to 100 femtoliters (fL= 10⁻¹⁵ L). The condition in which RBCs are larger than normal is called macrocytic anemia. In contrast, in microcytic anemia, the RBCs are smaller than normal.

Morphological classification of anemia

Types of Macrocytic Anemia

Macrocytic anemia is not a single disease entity. It is a condition caused due to different causes having different underlying pathologies; all of which result in abnormally large RBCs.

It is of two types

• Megaloblastic macrocytic anemia
• Non-megaloblastic macrocytic anemia

Causes of Macrocytic Anemia

Megaloblastic macrocytic anemia

It occurs due to deficiency of folate or vitamin B₁₂ or both.

Vitamin B12 Deficiency

• Nutritional deficiency
• Impaired absorption
  • Pernicious anemia
  • Gastrectomy (total or partial)
  • Lesions of the small intestine (diverticulosis, fistula, intestinal anastomosis)
  • Coeliac disease
  • Tropical sprue
  • Fish tapeworm (Diphyllobothrium latum) infestation
• Drugs
• Chronic pancreatic disease

Folate Deficiency

• Nutritional deficiency
• Impaired absorption
  • Alcoholism
  • Coeliac disease
  • Tropical sprue
• Increased demand
  • Pregnancy, infancy,etc
• Inability to utilize folate due to the action of folate antagonists (eg. methotrexate)

Combined Deficiency: Vitamin B12 & Folate

Miscellaneous Causes

• Inherited DNA synthesis disorders
• Toxins and Drugs
  • Nitrous Oxide

Non-megaloblastic macrocytic anemia

It occurs due to a variety of reasons and different settings.

• Increased erythropoiesis (high reticulocyte count)
  • Hemolytic anemia
  • Post-hemorrhagic anemia
• Alcoholism
• Chronic obstructive airways disease
• Hypothyroidism
• Cytotoxic drugs
• Increased RBC membrane surface area
  • Obstructive jaundice
  • Hepatic disease
  • Post-splenectomy
• Bone marrow disorders
  • Myelophthisic anemia
  • Myelodysplastic syndrome
  • Aplastic anemia
  • Acquired sideroblastic anemia

Pathophysiology of Macrocytic Anemia

Megaloblastic macrocytic anemia

Conditions causing megaloblastic anemia result in a failure of DNA synthesis and resultant impaired cell division. The end result is abnormal and immature large cells with an arrest in nuclear maturation. These cells are called megaloblasts.  Megaloblastic changes are most apparent in rapidly dividing cells such as blood cells and gastrointestinal cells. They can be seen in bone marrow aspirates and in peripheral smears.

Non-megaloblastic macrocytic anemia

Macrocytosis occurs due to the following reasons

• Presence of reticulocytes.

Reticulocytes are immature RBCs and are slightly larger than mature RBCs. When present in increased numbers, reticulocytes cause a mild to moderate degree of macrocytosis. Conditions like hemolytic anemia and hemorrhage which stimulate the bone marrow to increase erythropoiesis result in macrocytosis due to increased reticulocyte count.

• Presence of mature red cells of increased size

Certain conditions result in macro-normoblastic response ie, the erythroid precursor cells are larger than usual but their nuclear structure and maturation is normal (in contrast to megaloblastic response in which the cell size is large and the nucleus is immature due to block in DNA synthesis).

RBCs produced by macro-normoblastic bone marrow are macrocytic. Macro-normoblastic response occurs due to either abnormality of bone marrow function or due to extrinsic causes.

It is important to note that many conditions causing non-megaloblastic macrocytosis do not result in anemia or any other specific finding apart from large sized RBCs.

Causes of Spurious (False positive) Macrocytosis 

• Cold agglutinins
  • Presence of cold agglutinins causes RBCs to clump and appear larger.
• Hyperglycemia
  • Red cells from hemoconcentrated blood swell when diluted for testing resulting in fictitious macrocytosis.
• Significant leukocytosis
  • Increased sample turbidity due to large number of white blood cells results in an overestimation of red cell size.

Signs and Symptoms

Usual features are those common to anemia due to any cause. These include

• fatigue
• general malaise
• poor concentration
• shortness of breath
• paleness of the skin (pallor)
• lightheadedness
• dizziness

In very severe anemia, the body may compensate for the lack of oxygen-carrying capability of the blood by increasing cardiac output. The patient may then have symptoms such as palpitations, irregular heartbeat, angina, and heart failure.

Mild enlargement of the liver (hepatomegaly) and slight yellowing of the skin or eyes (jaundice) may also occur.

Megaloblastic anemia usually develops slowly and affected individuals may remain asymptomatic for many years.

In addition to these general features, megaloblastic anemia resulting from B12 deficiency may also be associated with the following features:

• Neurological symptoms

These include tingling or numbness in hands or feet, balance or gait problems, vision loss due to degeneration (atrophy) of the optic nerve, mental confusion, memory loss, etc. Several psychiatric abnormalities including depression, insomnia, listlessness, and panic attacks may also occur.

In a few cases, neurological symptoms may occur before the characteristic findings of anemia Folate deficiency generally does not result in neurological symptoms.

• Glossitis

Some individuals may develop a sore and reddened tongue.

• Gastrointestinal abnormalities

These include diarrhea, nausea, and loss of appetite.

Specific disease entities causing non-megaloblastic macrocytic anemia may result in distinctive signs and symptoms.

Investigations

Lab diagnosis of macrocytic anemia involves the following steps.

• Recognition of anemia as megaloblastic or non-megaloblastic (normoblastic)
• Identification of the specific cause of anemia

Complete Blood Count

• Increased mean corpuscular volume (MCV >100 fl)

Macrocytosis of megaloblastic macrocytic anemias is usually much greater than that of non-megaloblastic macrocytic anemias. The higher the MCV, the greater is the incidence of megaloblastosis. MCV values above 125 fl are almost always associated with megaloblastic anemias.

• Decreased hemoglobin level and red blood cell (RBC) count

Many cases of non-megaloblastic anemia do not result in reduced  hemoglobin or RBC count and the only abnormality is increased MCV.

Megaloblastic anemias also show the following features

• Increased mean corpuscular hemoglobin (MCH).
• Mean corpuscular hemoglobin concentration (MCHC, 32–36 g/dL) is normal.
• Many cases of megaloblastic anemia present with pancytopenia, ie, reduced levels of all the three formed elements of blood.

Reticulocyte Count

It is decreased in megaloblastic anemias due to the destruction of fragile and abnormal megaloblastic erythroid precursors (intramedullary hemolysis) resulting in ineffective hematopoiesis.

It is increased in nonmegaloblastic macrocytic anemias which occur due to increased erythropiesis.

ESR

It is usually elevated.

Peripheral Blood Film

The common underlying feature in all macrocytic anemias is presence of macrocytes which are larger than normal in size.

Apart from macrocytic RBCs, megaloblastic anemia also shows certain specific features which can be used to distinguish it from non-megaloblastic macrocytic anemias. These include:

• Ovalocytes and macro-ovalocytes (in contrast with round macrocytes of non-megaloblastic macrocytic anemias)
• Hypersegmented neutrophils (more than 5 % of neutrophils have 5 lobes or at least one neutrophil is 6 lobed )
• Erythroid precursors showing megaloblastic features may be seen.
• Some of the RBCs may show inclusions within their cytoplasm-Howell-Jolly bodies and Cabot rings

Bone Marrow Examination

Bone marrow is hypercellular with erythroid hyperplasia.

In megaloblastic anemia, erythroid precursors have megaloblastic features. They are larger than normoblastic cells and nucleus is immature. The neutrophil precursors show giant forms. Megakaryocytes may be large and hyperlobulated.

Bone marrow examination is not routinely needed to make the diagnosis of megaloblastic anemia if the peripheral blood picture shows typical features. If required, it should be performed before the initiation of therapy as within 12 hours of treatment, the megaloblastic changes in bone marrow are reversed to normoblastic.

In nonmegaloblastic anemia, erythroid precursors are macro-normoblastic with increased size and normal nuclear maturation. Bone marrow examination is essential if aplastic anemia or myelodysplastic syndrome is suspected.

Identification of Cause of Anemia

Megaloblastic anemia

Once it is confirmed that the macrocytic anemia is megaloblastic in nature, further investigations are based on the following parameters

Whether the anemia is due to deficiency of vitamin B12 or folate or both?

This is confirmed by measuring the following parameters

• Serum vitamin B12
• Serum folate
• RBC folate
• Serum homocysteine and methylmalonic acid (MMA) levels:  In vitamin B12 deficiency, levels of both are increased. In folate deficiency, level of homocysteine is increased but those of MMA is not increased.

What is the cause of deficiency of vitamin B12 or folate?

A battery of tests may be required to find the exact cause of deficiency.

• Serum intrinsic Factor (IF) and parietal cell antibodies
• Serum gastrin
• Schilling test
• Tests for malabsorption

Non-megaloblastic macrocytic anemia

The cause of non-megaloblastic macrocytic anemia is suspected after taking the clinical and blood features into consideration. The following tests may be carried out:

• Liver function tests
• Thyroid function tests

Treatment

It depends upon the underlying cause.

Megaloblastic anemia is treated by administration of vitamin B12 or folate or both. Blood transfusion is reserved for very severe anemia. The patient is instructed to consume vitamin B12 and folate-rich foods.

Non megaloblastic macrocytic anemia is treated by treating the underlying disorder. Since alcoholism is one of the important and widespread cause, its consumption should be reduced or stop.