Megaloblastic Anemia /
Pernicious Anemia

Megaloblastic Anemia / Pernicious Anemia: Overview

Alternative names: Terms related to megaloblastic anemia include: pernicious anemia, megaloblastic anemia of pregnancy, folic acid deficiency anemia, folate deficiency anemia, vitamin B12 deficiency anemia, hypovitaminosis B12.

Megaloblastic anemias are somewhat rare blood disorders characterized by the presence of large, structurally and visually abnormal, immature red blood cells (megaloblasts).  Decreased numbers and immaturity of white blood cells (leukocytes) and blood platelets (thrombocytes) may also occur.  Megaloblastic anemias are usually caused by a deficiency or defective absorption of either vitamin B12 (cobalamin) or folic acid.  As a result, they are also known as the vitamin deficiency anemias.

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Folic acid was discovered in 1931 as a "cure" for the anemia of pregnancy.  Eating extra yeast also seemed to relieve the symptoms of pernicious anemia, but the neurological symptoms of this disease either were not resolved or appeared later on, confirming some doctors' feelings that there were two different problems involved.  In 1945, folic acid was isolated from spinach; we now know that B12 and folic acid produce two very similar deficiency problems.  B12 deficiency may lead to progressive and irreversible neurological damage, whereas a lack of folic acid will not.

Both vitamin B12 and folic acid are essential in the bone marrow for the production of healthy red blood cells in sufficient amounts.  If either is lacking in the diet, or if the absorption of either is impaired, megaloblastic anemia may result.  Other causes include leukemia, myelofibrosis, multiple myeloma, certain hereditary disorders, drugs that affect nucleic acid metabolism such as chemotherapy agents (methotrexate).

Incidence; Causes and Development; Contributing Risk Factors

Pernicious anemia is one of the megaloblastic anemias and can affect all racial groups, but the incidence is higher among people of Scandinavian or Northern European descent.  Pernicious anemia usually does not appear before the age of 30, although a juvenile form of the disease can occur in children and is evident before the child is 3 years old.

Folic acid deficiency anemia is more common in the Western world because many people there refuse to eat sufficient amounts of green, leafy vegetables.  Because the demand for folic acid increases among pregnant women and among patients on hemodialysis, risk becomes even higher for these people.

Pernicious anemia is caused by someone losing their ability to make intrinsic factor (IF), a substance that enables vitamin B12 to be absorbed from the intestine.  The result is vitamin B12 deficiency, which gradually affects sensory and motor nerves, causing neurological, gastrointestinal and cardiovascular problems.

Folic acid anemia occurs when folic-acid levels are low, usually due to inadequate dietary intake or faulty absorption.  In contrast to vitamin B12, the liver is able to store only a small amount of folic acid.  If the diet lacks folic acid, anemia will arise within a few months.

Folic acid deficiency is seen frequently among elderly women, especially those who have poor diets.  It usually results from a diet lacking in foods with high folic acid content, or from the body's inability to digest foods or absorb foods having high folic acid content.  Other factors that increase the risk of developing folic acid deficiency anemia are:

  • age
  • alcoholism
  • birth-control pills, anticonvulsant therapy, sulfa antibiotics, and certain other medications
  • illness
  • smoking
  • stress

Signs and Symptoms

Symptoms, which usually begin gradually, include loss of appetite, diarrhea, paleness, fatigue, and headache.  Tingling of the hands and feet, as well as the onset of spastic movements, may indicate that the nervous system has been affected.  Weight loss and lack of appetite (anorexia) may also occur, as well as jaundice, confusion and depression.

Lesions in the gastrointestinal tract may cause abnormal activity in the intestines and difficulties with the absorption of food.  Enlargement of liver and spleen (hepatosplenomegaly) may also occur, accompanied by yellow discoloration of the skin (jaundice) or pallor.  Weakness, heart palpitations, difficulty breathing, as well as pain in the limbs are other possible symptoms.  Mouth and tongue infection may also occur.  Neurological lesions, irritability, and abnormal feelings (e.g. of heat and cold) may also be present.

The main symptoms of pernicious anemia are tiredness, shortness of breath and fatigue.

Fatigue is often the first sign of folic acid deficiency anemia.  Other symptoms include:

Diagnosis and Tests

Between 50 and 75% of patients with pernicious anemia have antibodies to IF, and 93% have antibodies to parietal cells which means this is another autoimmune disorder.  Intrinsic factor and hydrochloric acid are produced by the parietal cells in the stomach; both are needed in order to release B12 from foods.

The megaloblastic anemias of whatever sort are usually diagnosed in the course of a regular blood examination.  The large, immature red blood cells are unmistakable.  Diagnosis is confirmed through blood tests to measure hemoglobin, an iron-containing compound that carries oxygen to cells throughout the body.  Symptoms may be reevaluated after the patient has taken prescription folic acid supplements.

Treatment and Prevention

Usually, injections of vitamin B12 are sufficient to overcome the deficiency.  Persons with this form of megaloblastic anemia usually have to take the supplemental B12 for the rest of their lives.  Persons with folic acid deficiency anemia usually take supplemental folic acid by mouth daily.  This treatment, too, may go on throughout a person's life.

Alternative therapies for folic acid deficiency anemia may include reflexology concentrated on areas that influence the liver and spleen.  Increasing consumption of foods high in folate is helpful.  Eating a mixture of yogurt (8 oz) and turmeric (1 tsp) also may help resolve symptoms.

Seek medical attention if...

A doctor should be seen if fever, chills, muscle aches, or new symptoms develop during treatment, or if symptoms do not improve after two weeks of treatment.

A physician should also be contacted if the tongue becomes slick or smooth or the patient:

  • bruises or tires easily
  • feels ill for more than five days
  • feels weak or out of breath
  • looks pale or jaundiced.

Signs, symptoms & indicators of Megaloblastic Anemia / Pernicious Anemia:

Lab Values - Cells

Lab Values - Chemistries

High serum iron

Elevated serum iron can occur as a result of pernicious anemia.

Lab Values - Nutrients


Symptoms - Cardiovascular


Symptoms - Head - Nose

Conditions that suggest Megaloblastic Anemia / Pernicious Anemia:



There is a particularly high incidence of vitiligo among individuals with pernicious anemia, and vice versa.  The reason for this is unknown.



Pernicious anemia is associated with other autoimmune conditions such as Hashimoto's disease, a form of hypothyroidism.



In one report, 47% of people with tinnitus and related disorders were found to have vitamin B12 deficiencies.  Supplementation may therefore be of benefit. [Vitamin B12 deficiency in patients with chronic-tinnitus and noise-induced hearing loss. Am J Otolaryngol 1993;14: pp.94-9]


700 women over 65 (most in their mid-70s) in the Women's Health and Aging Study were interviewed and had blood samples taken for analysis.  Overall, 14% were mildly depressed and 17% were severely depressed.  Blood tests revealed that a deficiency in vitamin B12 was relatively common.  Of the severely depressed women, 27% were deficient in the vitamin, compared with only 17% of the mildly depressed women and 15% of their happier counterparts. [American Journal of Psychiatry 2000;157: pp.715-72]

Risk factors for Megaloblastic Anemia / Pernicious Anemia:


Chronic Thyroiditis

Pernicious anemia is more common in people who have other autoimmune diseases such as thyroiditis.

Diabetes Type I

Relatives of people with Type 1 Diabetes, as well as the sufferers themselves, run a risk of developing celiac disease.  The resulting inflammation and tissue damage reduces vitamin B12 absorption and may lead to Pernicious anemia, which occurs in approximately 1 in 50 adults with Type 1 Diabetes.


Atrophic Gastritis

Gastric autoimmune disease has been classified into types A and B, based on the changes in different portions of the stomach.  Patients with antibodies to parietal cells (PCA) or intrinsic factor, or both, have atrophy of the fundal mucosa (Type A) and a very high rate of pernicious anemia, often associated with other autoimmune endocrine disorders.  In cases of Type B gastritis, PCA are lacking and there is no association with pernicious anemia or other autoimmune endocrine disorders.

Drug Side-Effect

Chemotherapy Side-Effects

Some chemotherapy agents are known inhibitors of folic acid enzymes and as such can induce a megaloblastic anemia.



Hyperthyroidism is one of the minor causes of B12 deficiency.


Vitamin B12 Requirement

The main indicator of vitamin B12 deficiency is pernicious anemia, which in turn is due to a deficiency of intrinsic factor.


Tapeworm Infection

Signs of infection with large tapeworms (especially with the broad fish tapeworm, Diphyllobothrium latum) include conditions associated with vitamin B12 deficiency such as megaloblastic anemia.

Tumors, Malignant

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Megaloblastic Anemia / Pernicious Anemia suggests the following may be present:




Bacterial Dysbiosis

Abnormal bacterial populations may consume cobalamin, contributing to B12 deficiency states and resulting in megaloblastic anemia.

Megaloblastic Anemia / Pernicious Anemia can lead to:

Dental / Oral

Canker Sores (Aphthous Ulcers)

Vitamin B12, folate, zinc and iron have been shown to be effective in up to 60% of patients with canker sores when such a vitamin or mineral deficiency has been documented. [Dermatologic Clinics 1996:14, pp.243-256, British Dental Journal 1985:159, pp.361-367]


Yeast / Candida Infection

Vitamin B12, B6, biotin and folate help maintain candida in its non-invasive form.  A B12 deficiency is one of several conditions that can stimulate candida growth.

Megaloblastic Anemia / Pernicious Anemia could instead be:


Alzheimer's Disease

Pernicious Anemia can be mistaken for Alzheimer's in older patients.



Additional mental disturbances resulting from pernicious anemia include: loss of alertness, drive, self-confidence, and independence, social withdrawal, nervous irritability, headaches, insomnia, moodiness, severe agitation, lack of coordination, anxiety, delusions of persecution, and mania.  Deficiency may also induce auditory hallucinations, psychosis, and paranoia.  80% of pernicious anemia patients show neurological changes and 60% exhibit personality changes.

Recommendations for Megaloblastic Anemia / Pernicious Anemia:

Laboratory Testing

Test for B12 Levels

A vitamin B12 deficiency is the most common cause of megaloblastic anemia.  When testing facilities are not available or cannot be afforded, intramuscular or sublingual B12, with or without folic acid, can be used to see if symptoms improve.

If vitamin B12 deficiency is suspected, tests to measure the blood level of B12 are routine.  Usually, the presence of the intrinsic factor (IF) is determined by testing for the presence of antibodies to the IF in the blood.  Gastric analysis may be required to confirm the presence or absence of IF.

Taking a lot of folic acid may cover up the B12 anemia and other symptoms until it is too late for effective treatment with vitamin B12.  Therefore, vitamin tablets of folic acid with over 400mcg have been taken off the market and are available by prescription only.  If megaloblastic anemia occurs, both folic acid and vitamin B12 levels should be checked to assure proper treatment and follow-up.

Test Folic Acid Levels

Prevention of folic acid deficiency anemia involves eating raw or lightly-cooked vegetables every day.  This will help maintain normal folic acid levels, as will taking a folic acid supplement containing at least 400mcg of this vitamin.  Because folic acid deficiency can cause birth defects, all women of childbearing age who can become pregnant should consume at least 400mcg of folic acid daily; a woman who is pregnant should have regular medical checkups, and take a good prenatal vitamin.

CAUTION: It is always important to discover the underlying deficiency that is causing a megaloblastic anemia.  Higher doses of folic acid (greater than 1mg per day) may improve or mask the anemia caused by a B12 insufficiency.  Unless the B12 deficiency is corrected, permanent nervous system damage may result.  In other words, don't treat a B12 deficiency with high doses of folic acid!

Physical Medicine


A person with folic acid deficiency anemia should rest as often as necessary until restored energy levels make it possible to resume regular activities.

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