What is Megaloblastic Anemia?
Megaloblastic anemia, or MA, is a type of anemia where the bone marrow produces unusually large red blood cell precursors, known as megaloblasts. This happens because the DNA synthesis, responsible for cell division, is affected, leading to disturbed maturation between the nucleus and the rest of the cell. As a result, these precursors end up being larger than normal. This issue not only impacts the production of blood cells but also rapidly renewing tissues like the ones found in the gut.
Most often, this condition is caused by vitamin deficiencies, specifically in vitamin B12 and folate, both of which are important for making DNA. Other known triggers include copper deficiency, certain medications that interfere with DNA synthesis, and a rare genetic disorder called Thiamine-responsive megaloblastic anemia syndrome. The list of associated medications is long and often includes drugs for cancer, seizures, and HIV.
What Causes Megaloblastic Anemia?
Vitamin B12 and folic acid deficiencies are the main causes of megaloblastic anemia, a condition that affects your red blood cells. You can get folic acid from foods like green vegetables, fruits, meat, and liver. Adults need between 50 and 100 mcg per day, but during pregnancy, this increases to 600 mcg. Folic acid is mainly absorbed in a part of the small intestine called the jejunum. Your body stores around 5 mg of folic acid in the liver, which is enough for 3 to 4 months. You can become deficient in folic acid if you don’t eat enough of it, or if your body has an increased need for it (like in pregnancy or due to certain medical conditions), or if you take certain medications.
Similarly, vitamin B12, or cobalamin, can be found in meats, fish, eggs, and dairy products. People who follow a vegan diet can be low in this vitamin. Vitamin B12 is absorbed in your intestines when it binds to a protein called the intrinsic factor. Your body stores 2 to 3 mg of vitamin B12 in your liver, which is enough for 2 to 4 years. Certain conditions and surgeries can result in a shortage of vitamin B12 in your body.
Copper deficiency can also lead to anemia. Not having enough copper in your body can affect your blood cells and can also cause problems with your nervous system and bone marrow. Luckily, replacing the copper in your body can quickly reverse the effects on your blood, though nerve damage might take longer to heal.
There are also rare inherited conditions that can result in megaloblastic anemia. These include conditions like Thiamine-responsive megaloblastic anemia syndrome, which is associated with diabetes and hearing loss, and is caused by a defective gene for a thiamine transporter. Other examples include inherited deficiencies in a protein called intrinsic factor needed for Vitamin B12 absorption, and congenital folate malabsorption syndrome which is a condition present from birth in which the body is not able to absorb folic acid properly.
Megaloblastic anemia can also be caused by certain medications. These drugs either cause changes in the bone marrow or reduce the absorption or metabolism of folic acid or vitamin B12.
Risk Factors and Frequency for Megaloblastic Anemia
Megaloblastic anemia is a condition that isn’t uncommon, but scientists lack enough data about how many people have it. It’s occurrence varies among different groups and can be influenced by factors like general dietary habits, the prevalence of certain chronic conditions, such as pernicious anemia and H. pylori infections, and the regular consumption of folate-enriched food.
According to a 2016 study in the Netherlands that examined more than 3000 people with anemia, only 7.5% had a variant known as macrocytic anemia. Around 1.4% of all the cases were due to a shortage of vitamin B12, and 0.5% were due to a lack of folate.
Older individuals, particularly those over 60 years of age and living in retirement or eldercare facilities, appear to be more prone to megaloblastic anemia compared to those of the same age living independently. Pernicious anemia, which typically occurs in people over 40, is the most common cause of anemia stemming from a deficiency of cobalamin, another name for vitamin B12 and is more prevalent in the United Kingdom and Nordic countries.
Folate deficiency is less typical, especially in countries where food is consistently fortified with folate. A Canadian report from 2015 presents a folate deficiency prevalence of only 0.16% among hospitalized patients, generally due to reasons such as alcohol use disorder, malabsorption syndromes, and mental health issues leading to reduced food intake.
Signs and Symptoms of Megaloblastic Anemia
Megaloblastic anemia often goes unnoticed and is usually found during routine lab tests. When symptoms do appear, they generally include feeling weak, shortness of breath especially during activity, heart palpitations, and feeling faint. Physical signs can include paleness, fast heart rate, a heart murmur, a smooth glowing tongue condition known as Hunter glossitis, and an enlarged spleen. It can also cause yellow skin and eyes due to breakdown of blood cells within the bone marrow.
- Feeling weak
- Shortness of breath during activity
- Heart palpitations
- Feeling faint
- Pale skin
- Fast heart rate
- Smooth glowing tongue (Hunter glossitis)
- Enlarged spleen
- Yellow skin and eyes
In cases of vitamin B12 deficiency, there can be some additional symptoms including unusual sensations like tingling, balance problems, sharp pains due to damage to the peripheral nerves, particularly in the legs. Sometimes, it can also lead to vision problems due to damage to the optic nerve. During a clinical examination, loss of a sense of body movement and position could be observed, along with a positive Romberg test, which checks for difficulty in maintaining upright posture. Other signs like Babinski reflex, reduced reflexes, and repetitive muscle spasms might also occur but are less common. Additionally, some psychological issues like a type of dementia might appear. However, these nerve-related disorders may not always fully improve even after treatment.
Pernicious anemia, a type of megaloblastic anemia, frequently occurs alongside other autoimmune conditions such as autoimmune thyroid disease, type 1 diabetes, and vitiligo, a disease that causes loss of skin color in patches.
Testing for Megaloblastic Anemia
If you have symptoms like unexplained large red blood cells (known as macrocytic anemia) or unusually formed white blood cells, your doctor might think you could have a health issue called megaloblastic anemia. In these cases, they’ll check for things like the size of your red blood cells or how many young red blood cells you have (referred to as a reticulocyte count).
They’ll also do a blood test to check your levels of two essential nutrients: vitamin B12 and folate. In some cases, if you have a balanced diet, they might only check your B12 level.
A normal B12 level tends to be above 300 pg/mL (above 221 pmol/L). If it’s between 200 to 300 pg/mL (148 to 221 pmol/L) it’s on the borderline and you may need more tests to figure out what’s causing it. Anything below 200 pg/mL (below 148 pmol/L) is usually seen as a deficiency – or lack of B12.
It’s worth noting, however, that certain conditions and medications could affect the accuracy of the B12 test result and either get a falsely low or high level.
In the case of folate, 2 to 4 ng/mL (from 4.5 to 9.1 nmol/L) is considered borderline. Anything below 2 ng/mL (below 4.5 nmol/L) usually points to deficiency in folate as well.
More specialized tests to check the levels of Methylmalonic acid and homocysteine might be needed if your results from the usual tests are borderline. They’re also useful in verifying a B12 deficiency. In particular, a significant level of Methylmalonic acid can pinpoint a B12 deficiency and differentiate it from a folate deficiency.
If B12 deficiency is determined, your doctor might run a test to check for specific immune system proteins (autoantibodies) that can cause a condition known as pernicious anemia.
It’s crucial to remember that tests for vitamin B12 and folate deficiencies should be performed simultaneously to ensure accurate diagnosis.
Additionally, the 2014 Guidelines from the British Committee for Standards in Hematology emphasized the importance of these and other tests in case of unexplained symptoms consistent with B12 deficiency.
Looking ahead, there’s a specialized test that measures ‘active’ B12 called Holotranscobalamin (HoloTC), which might become a routine diagnostic procedure in the future since it’s more specific than assessing total B12 levels.
Treatment Options for Megaloblastic Anemia
Vitamin B12 and folic acid are supplements that can be taken orally (by mouth) or parenterally (by injection). For patients who can effectively absorb these vitamins normally, oral supplementation (taking tablets or capsules by mouth) is usually the preferred method. But this approach isn’t quick, so if the situation demands fast supplementation, it’ll not be a suitable option.
If a patient isn’t showing any symptoms, taking these supplements orally should be enough, but for patients with neurological symptoms, or for those such as pregnant women or infants who need more of these vitamins, injections are typically recommended. If a patient is anemic with symptoms, they might need a blood transfusion to relieve symptoms since taking vitamin B12 and folic acid doesn’t rapidly correct anemia. A formulation of vitamin B12 that can be placed under the tongue is also available and may be suitable for patients who have a hard time absorbing nutrients in their intestines.
For children, doctors typically recommend a vitamin B12 injection of 50 to 100 micrograms once a week until the deficiency has been corrected. After that, they might need further injections every month or every other month, depending on the type of B12 used. Adults usually require a bigger dose of 1000 micrograms per injection on the same schedule. Alternatively, adults could take an oral dose of 1000 micrograms of vitamin B12 daily, provided they can absorb it normally. Studies have shown that both methods are equally effective in raising B12 levels in the blood. The length of treatment depends on what’s causing the deficiency. If the cause can be reversed, then the patient can stop taking the supplements once their B12 levels are normal. But in situations where a patient will always have a deficiency, they should continue to take the supplements indefinitely.
As for folic acid, a daily oral dose of 1 milligram is often recommended until deficiency has been corrected. Like with B12, if the cause of deficiency can be fixed, the patient can stop taking folic acid once their levels are back to normal. But if the cause cannot be reversed, they’ll likely need to take folic acid supplements long term.
When a patient starts taking supplements, their bodies will start to respond within a week. Their hemoglobin (the protein in red blood cells that carries oxygen) and hematocrit (the proportion of red blood cells to the total blood volume) levels should fully return to normal within 1 to 2 months. But any neurological symptoms, such as changes in behavior or problems with nerves, might take anywhere from 3 to 12 months to improve and might even get worse before they get better. In some cases, neurological symptoms might not go away completely. This is why it’s so important to diagnose and treat vitamin deficiencies early, as people with long-lasting or severe neurological symptoms may continue to experience them even when getting treatment.
What else can Megaloblastic Anemia be?
A blood test can reveal if the size of red blood cells is larger than usual, a condition called macrocytosis. This can be seen in a type of blood disorder known as non-megaloblastic macrocytic anemias. By checking the number of newly produced blood cells called reticulocytes, a doctor can determine whether two main conditions are present: hemolytic anemia (blood cells getting destroyed) or acute bleeding.
If there’s a lower than normal reticulocyte count, it could point to conditions such as an underactive thyroid, frequent alcohol consumption, issues with the liver, or the impact of certain drugs. In cases where these can’t explain the anemia, the doctor may need to take a sample from the bone marrow for further analysis, but only after tests for vitamin B12 or folate deficiency have been done.
Some conditions, like myelodysplastic disorders (abnormal cells in the bone marrow) and sideroblastic anemia (iron buildup in the mitochondria of the blood cells), can show themselves as hard-to-treat megaloblastic anemia. The most common conditions that could cause this type of anemia, which also result in an increase in the size of red blood cells, include:
- Alcoholic hepatitis (liver inflammation due to alcohol)
- Atrophic gastritis (stomach lining inflammation)
- Gastric cancer (stomach cancer)
- Celiac sprue (gluten-induced small intestine damage)
- Tropical sprue (similar to celiac but due to infection in the tropics)
- Myelodysplastic syndrome (abnormal cells in the bone marrow)
- Aplastic anemia (bone marrow can’t produce sufficient new blood cells)
- Acquired sideroblastic anemia (red blood cells can’t use iron to generate hemoglobin)
- Homocystinuria (an inherited disorder that affects the breakdown of an amino acid called homocysteine)
What to expect with Megaloblastic Anemia
The outlook for individuals with megaloblastic anemia is generally promising when this blood disorder is accurately diagnosed and the specific cause is addressed. Although blood irregularities tend to improve with sufficient supplementation, improvements in neurological symptoms might take a bit longer.
Prompt detection and supplementation can enhance the outlook of megaloblastic anemia, which may have little or no associated health risks or fatality. However, certain complications can result in less favorable outcomes, such as stomach cancer in patients who have this type of anemia as a consequence of a condition known as pernicious anemia. Yet, these poor outcomes are more related to pernicious anemia than the megaloblastic disease. Further details on stomach cancer connected to pernicious anemia are discussed later.
Possible Complications When Diagnosed with Megaloblastic Anemia
Complications from a type of anemia known as megaloblastic anemia can vary based on the exact cause. The most serious complication seen in patients with this type of anemia, specifically brought on by a condition called pernicious anemia, is stomach cancer. The rate of stomach cancer in patients with this type of anemia was reported as a little over a quarter of a percent per patient per year. It was found that patients with pernicious anemia have seven times the normal risk for developing stomach cancer.
A recent study also found increased risks for stomach adenocarcinoma, a specific type of stomach cancer, and gastric carcinoid, a type of tumor, in patients with pernicious anemia. Another known complication associated with this type of anemia is linked to a deficiency in folate, a type of B vitamin. This deficiency can result in neural tube defects in unborn babies. However, this complication can be prevented with adequate supplementation during pregnancy.
A study from 2018 suggests that not getting enough folic acid, or having a folate deficiency, can increase the risk for certain types of cancers. These include cancers of the head and neck, oral cavity and voice box, esophagus, pancreas, bladder, and cervix.
Preventing Megaloblastic Anemia
When it comes to patient education, it’s important to focus on fixing possible dietary issues, discussing problems with nutrient absorption, and addressing other factors that can be changed like alcohol consumption and medication routines. Individuals who strictly follow a vegan or Mediterranean diet are at a higher risk of lacking vitamin B12, so they should regularly take supplements to fill this gap. Patients should also be guided to limit their alcohol usage and maintain a well-rounded diet to avoid anemia caused by malnutrition.
If anemia is due to changes or illnesses in the digestive system, patients should understand the cause of their condition and the significance of taking their medication as instructed. It is crucial to know about the possibly permanent neurological effects of a B12 deficiency. To avoid these, patients should keep to their treatment plan. Those diagnosed with a condition called pernicious anemia should keep an eye on any signs of stomach issues, as these could be early indicators of stomach cancer that needs immediate attention.
Finally, for those patients who are taking medications that could potentially cause anemia, it’s extremely important that they take vitamin supplements while on these drugs to prevent developing anemia.
