Laboratory diagnosis of Megaloblastic Anaemia

Anemia is a blood disorder in which the number of red blood cells (RBCs) is lower than usual. RBCs transport oxygen through the body. When your body doesn’t have enough RBCs, your tissues and organs don’t get enough oxygen.

There are many types of anemia with different causes and characteristics. Megaloblastic anemia is characterized by RBCs that are larger than normal. There also aren’t enough of them.

When RBCs aren’t produced properly, it results in megaloblastic anemia. Because the blood cells are too large, they may not be able to exit the bone marrow to enter the bloodstream and deliver oxygen.

Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen^. Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis (M) stage. This leads to continuing cell growth without division, which presents as macrocytosis. Megaloblastic anemia has a rather slow onset, especially when compared to that of other anemias. The defect in red cell DNA synthesis is most often due to hypovitaminosis, specifically vitamin B12 deficiency or folate deficiency. Loss of micronutrients may also be a cause.

Megaloblastic anemia not due to hypovitaminosis may be caused by antimetabolites that poison DNA production directly, such as some chemotherapeutic or antimicrobial agents (for example azathioprine or trimethoprim).

The pathological state of megaloblastosis is characterized by many large immature and dysfunctional red blood cells (megaloblasts) in the bone marrow and also by hypersegmented neutrophils (defined as the presence of neutrophils with six or more lobes or the presence of more than 3% of neutrophils with at least five lobes). These hypersegmented neutrophils can be detected in the peripheral blood (using a diagnostic smear of a blood sample).

Megaloblastic anemia is a type of anemia characterized by very large red blood cells. In addition to the cells being large, the inner contents of each cell are not completely developed. This malformation causes the bone marrow to produce fewer cells, and sometimes the cells die earlier than the 120-day life expectancy. Instead of being round or disc-shaped, the red blood cells can be oval.

Etiology/Causes

There are many causes of megaloblastic anemia, but the most common source in children occurs from a vitamin deficiency of vitamin B12 and folate/folic acid.

These two nutrients are necessary for producing healthy RBCs. When you don’t get enough of them, it affects the makeup of your RBCs. This leads to cells that don’t divide and reproduce the way they should.

Vitamin B12 deficiency

Vitamin B12 is a nutrient found in foods and drinks such as:

• lamb liver, beef, and other types of meat
• sardines, tuna, and other types of fish
• eggs
• milk
• fortified nutritional yeast

Some people can’t absorb enough vitamin B12 from their diet, leading to megaloblastic anemia. Megaloblastic anemia caused by vitamin B12 deficiency is known as vitamin B12 deficiency anemia.

One rare type of vitamin B12 deficiency anemia is pernicious anemia. Pernicious anemia is an autoimmune condition and is due to the lack of a protein in the stomach called intrinsic factor. Without intrinsic factor, vitamin B12 can’t be absorbed, regardless of how much is consumed.

It’s possible to develop vitamin B12 deficiency anemia because there simply isn’t enough vitamin B12 in your diet. Since B12 isn’t naturally found in any plant-based products, vitamin B12 deficiency is common in people following a vegetarian or vegan diet.

You can also develop vitamin B12 deficiency anemia if you take medications that deplete vitamin B12, such as proton pump inhibitors and metformin (Fortamet, Glumetza). Having certain types of surgery, including bariatric surgery, can also result in an inability to absorb vitamin B12.

Folate deficiency

Folate is another nutrient that’s important for the development of healthy RBCs. Folate is found in foods such as:

• beef liver
• spinach
• Brussels sprouts
• avocados
• oranges

Folate is often mixed up with folic acid. Technically, folic acid is the artificial form of folate. You can find folic acid in supplements as well as fortified cereals and foods.

Your diet is an important factor in whether you have enough folate. Folate deficiency can also be caused by alcohol misuse, since alcohol interferes with the body’s ability to absorb folate and folic acid.

Pregnant people are more likely to have folate deficiency because of the high amounts of folate needed by the developing fetus.

The two most common causes of megaloblastic anemia are deficiencies of vitamin B12 and folate. Other sources of megaloblastic anemia include the following:

• Digestive diseases — Certain diseases of the lower digestive tract can lead to megaloblastic anemia. These include celiac disease, chronic infectious enteritis, and enteroenteric fistulas. Pernicious anemia is a type of megaloblastic anemia caused by an inability to absorb Vitamin B-12 due to a lack of intrinsic factor in gastric (stomach) secretions. Intrinsic factor enables the absorption of Vitamin B-12.
• Malabsorption — Inherited congenital folate malabsorption, a genetic problem in which infants cannot absorb folic acid in their intestines, can lead to megaloblastic anemia. This requires early intensive treatment to prevent long-term problems such as intellectual disabilities.
• Medication-induced folic acid deficiency — Certain medications, specifically ones that prevent seizures, such as phenytoin, primidone and phenobarbital, can impair the absorption of folic acid. The deficiency can usually be treated with a dietary supplement.
• Folic acid deficiency — Folic acid is a B vitamin required for the production of normal red blood cells. Folic acid is present in foods such as green vegetables, liver and yeast. It is also produced synthetically and added to many food items.

 

OTHER NAMES FOR MEGALOBLASTIC ANEMIA

Depending on its cause, megaloblastic anemia may also be referred to as:

• macrocytic anemia, which occurs when RBCs are larger than normal
• folic acid deficiency anemia or folate deficiency anemia
• pernicious anemia
• vitamin B12 deficiency anemia

Symptoms of megaloblastic anemia (CLINICAL FEATURES)

The most common symptom of megaloblastic anemia is fatigue.

Children with megaloblastic anemia may experience different symptoms and symptoms may vary in severity.

 Symptoms can vary from person to person. Some of the most common symptoms of megaloblastic anemia include: 

• shortness of breath
• muscle weakness
• skin that is paler than usual
• glossitis, or a swollen tongue
• a smooth or tender tongue
• loss of appetite or weight loss
• diarrhea
• nausea
• fast heart rate
• tingling in the hands and feet
• numbness in the hands and feet

Diagnosing megaloblastic anemia

One test used to diagnose anemia is a complete blood count (CBC). This test measures the different parts of your blood. As part of the CBC, a healthcare professional can check the number and appearance of your RBCs. They’ll appear larger and underdeveloped if you have megaloblastic anemia.

Your doctor will also gather your medical history and perform a physical exam to rule out other causes of your symptoms.

Your doctor will need to order more blood tests to figure out if vitamin deficiency is causing your anemia. These tests will also help them find out whether a vitamin B12 or folate deficiency is causing your condition.

The blood film can point towards vitamin deficiency:

• Decreased red blood cell (RBC) count and hemoglobin levels^[7]
• Increased mean corpuscular volume (MCV, >100 fL) and mean corpuscular hemoglobin (MCH)
• Normal mean corpuscular hemoglobin concentration (MCHC, 32–36 g/dL)
• Decreased reticulocyte count due to destruction of fragile and abnormal megaloblastic erythroid precursor.
• The platelet count may be reduced.^[8]
• Neutrophil granulocytes may show multisegmented nuclei ("senile neutrophil"). This is thought to be due to decreased production and a compensatory prolonged lifespan for circulating neutrophils, which increase numbers of nuclear segments with age.^{[citation needed]}
• Anisocytosis (increased variation in RBC size) and poikilocytosis (abnormally shaped RBCs).
• Macrocytes (larger than normal RBCs) are present.
• Ovalocytes (oval-shaped RBCs) are present.
• Howell-Jolly bodies (chromosomal remnant) also present.

Blood chemistries will also show:

• An increased lactic acid dehydrogenase (LDH) level. The isozyme is LDH-2 which is typical of the serum and hematopoietic cells.
• Increased homocysteine and methylmalonic acid in Vitamin B₁₂ deficiency
• Increased homocysteine in folate deficiency

Normal levels of both methylmalonic acid and total homocysteine rule out clinically significant cobalamin deficiency with virtual certainty.

Bone marrow (not normally checked in a patient suspected of megaloblastic anemia) shows megaloblastic hyperplasia.

Schilling test

Another test that your doctor may use to help with diagnosis is the Schilling test. The Schilling test is a blood test that evaluates your ability to absorb vitamin B12.

After you take a small supplement of radioactive vitamin B12, you’ll:

• collect a urine sample for your doctor to analyze
• take the same radioactive supplement in combination with the intrinsic factor protein that your body needs to be able to absorb vitamin B12
• provide another urine sample for comparison with the first one

If the urine samples show that you only absorbed the B12 after consuming it along with the intrinsic factor, it’s a sign that you don’t produce intrinsic factor on your own. This means that you’re unable to absorb vitamin B12 naturally.

DID YOU KNOW?

Folate is also known as vitamin B9, while vitamin B12 is also known as cobalamin.

Treatment for megaloblastic anemia

How you and your doctor decide to treat megaloblastic anemia depends on what’s causing it. Your treatment plan can also depend on your age and overall health as well as your response to treatments and how severe your disease is.

Treatment to manage anemia is often ongoing.

Vitamin B12 deficiency

In the case of megaloblastic anemia caused by vitamin B12 deficiency, you may need monthly injections of vitamin B12. You may also be given oral supplements.

Adding more foods with vitamin B12 to your diet can help. Additional foods that have vitamin B12 in them include:

• chicken
• fortified cereals, especially bran
• red meat
• shellfish

Some individuals have a genetic mutation on the methylenetetrahydrofolate reductase (MTHFR) gene. This gene is responsible for the conversion of certain B vitamins, including B12 and folate, into their usable forms within the body.

Supplemental methylcobalamin is recommended for individuals with the MTHFR mutation.

Regular intake of vitamin B12-rich foods, vitamins, or fortified products isn’t likely to prevent deficiency or its health consequences in those with this genetic mutation.

Folate deficiency

Megaloblastic anemia caused by a lack of folate may be treated with oral or intravenous folic acid supplements. Dietary changes also help boost folate levels.

More foods to incorporate into your diet include:

• leafy green vegetables
• peanuts
• lentils
• enriched grains

As with vitamin B12, individuals with the MTHFR mutation are encouraged to take methylfolate to prevent a folate deficiency and its complications.

Outlook for people living with megaloblastic anemia

In the past, megaloblastic anemia was difficult to treat. Today, people with megaloblastic anemia due to either vitamin B12 or folate deficiency can manage their symptoms and feel better with ongoing treatment and dietary supplements.

Vitamin B12 deficiency can lead to other problems. These can include nerve damage, neurological problems, and digestive tract problems. These complications can be reversed with early diagnosis and treatment.

Genetic testing is available to determine if you have the MTHFR genetic mutation. People who have pernicious anemia may also be at higher risk of stomach cancer and reduced bone strength. For these reasons, it’s important to catch megaloblastic anemia early.

Talk with your doctor if you notice any symptoms of anemia. You and your doctor can come up with a treatment plan and help prevent any permanent damage.

 Key Points
- Megaloblasts are large nucleated red blood cell precursors with noncondensed chromatin.
- The most common causes of megaloblastic, macrocytic anemia are deficiency or defective utilization of vitamin B12 or folate.
-  Do complete blood count, red blood cell indices, reticulocyte count, and peripheral smear.
- Measure vitamin B12 and folate levels and consider methylmalonic acid and homocysteine testing.
- Treat the cause of B12 or folate deficiency.

 

 

 

 

 https://nios.ac.in/media/documents/dmlt/hbbt/Lesson-17.pdf

https://www.chop.edu/conditions-diseases/megaloblastic-anemia 

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