Magalloblastic Anemia: Epidemiology, Characteristics, Causes, Symptoms, Pathophysiology and Treatment

It refers to a group of anemias that have in common a selective reduction in the rate of synthesis of deoxyribonucleic acid (DNA).

However, transcription, translation, and protein synthesis normally proceed.

As a result, unbalanced cell growth occurs, and the dichotomy between cytoplasmic and nuclear maturation rates widens with each division during erythropoiesis.

Finally, the cell dies or omits the terminal division making it survive as giant end-stage cells ( macrocytes ) with a shortened life expectancy.

Therefore, the synthesis of delayed DNA leads to the accumulation of dead and dying megaloblasts in the medulla, creating a false appearance of medullar hyperplasia but with a gradual reduction in the number of mature cells expelled and eventually progress to pancytopenia.

Megaloblastic anemias are caused by vitamin B12 deficiency, folate deficiency, or related conditions that cause the alteration of DNA synthesis.


Epidemiological studies on megaloblastic anemia are scarce. However, megaloblastic is highest in countries where malnutrition is endemic, and routine vitamin supplements are unavailable for the elderly and pregnant women.


Inadequate food preparations and increased demand for folic acid during pregnancy are the most common causes of megaloblastic anemia.

Approximately 1 in 7500 people develop pernicious anemia in the US UU Per year, but this has been modified by the current fortification of foods and vitamin supplements in elderly patients in the USA. UU

International statistics showed that pernicious anemia and folate deficiency usually occurs in individuals older than 40 years, and the prevalence increases with older populations.

It is reported that the incidence of pernicious anemia is higher in Sweden, Denmark, and the United Kingdom than in other developed countries.

Physiology of cobalamin (B12) and folate

Vitamin B12 consists of a corrin ring with a cobalt atom at its center attached to a nucleotide moiety and is called cobalamins.

Biologically inactive pharmacological preparations of vitamin B12 include cyanocobalamin and hydroxocobalamin, while adenosylcobalamin and methylcobalamin generated by enzymatic synthesis are biologically active forms.

While adenosylcobalamin is the tissue form of vitamin B12, methylcobalamin circulates in the blood. Although a typical diet provides a significant excess of vitamin B12, the daily requirement is approximately 1-2 μg in adults.

In the digestion process, the R protein, whether of salivary or parietal origin, binds to the cobalamin released from complex dietary protein through the action of gastric secretion composed of pepsin and hydrochloric acid.

The cobalamin-R protein complex is degraded pancreatic secretions in the duodenum to release free cobalamin that binds to the intrinsic factor secreted in the stomach.

The cobalamin intrinsic factor complex is now transported to the terminal ileum, where absorption occurs. The failure of the physiological activity in any of these points produces megaloblastic anemia.

After absorption, the released vitamin binds to a transport protein called transcobalamin (TCII), transporting the vitamin to the enterohepatic circulation. Vitamin B12 is stored mainly in the liver in 2-3 mg, which is 1000 times higher than the daily requirement.

The physiological role of vitamin B12 includes:

  • Conversion of methyl-malonyl-coenzyme A (CoA) to succinyl CoA by adenosylcobalamin.
  • Conversion of homocysteine ​​into methionine.
  • Synthesis of S-adenosyl-methionine.

Physiology of folate

Folic acid is a compound molecule consisting of pteridine, p-aminobenzoic acid, and glutamic acid.

Folates are available as polyglutamates in many foods, such as leafy greens, yeast, and liver. However, overcooking easily destroys folic acid. Folate is absorbed as monoglutamates in the upper jejunum.

The daily folate requirement is 150 μg, and the folate body reserves are sufficient for six months.

The main intracellular compounds are the folate polyglutamates with other glutamates bound together. Folates are essential in many biochemical reactions, such as the synthesis of purines, thymine, and deoxyribonucleic acid (DNA).

Leading causes of deficiency of vitamin B12 or Cobalamin

Dietetics: the dietary cause of cobalamin deficiency is rare, except in strict vegetarians who avoid taking meat, eggs, and dairy products.

Problems with the absorption of cobalamin: atrophic gastritis and achlorhydria, which commonly occur in the elderly, are the two conditions that are responsible for the altered release of cobalamins linked to food. Therefore, cobalamin is not released from food for the absorption process.

In addition, the autoimmune destruction of the gastric parietal cells can lead to the failure to produce intrinsic factors.

This condition is called pernicious anemia. Pernicious anemia is recognized as the most well-known cause of cobalamin deficiency. It is diagnosed in 1% of people older than 60 years, and the incidence is slightly higher in women than in men.

H2 antagonists can also cause inhibition of intrinsic factor production.

The release of cobalamin from the R proteins can also be inhibited by the alkaline environment in the small intestine emanating from pancreatic insufficiency.

In contrast, the acid environment seen in conditions such as Zollinger Ellison syndrome also prevents cobalamin binding to intrinsic factors, which leads to a decrease in binding to inherent characteristics and the final interference with the absorption of cobalamin.

Disorders of the terminal ileum, the site of uptake of the cobalamin intrinsic factor complex, can cause cobalamin deficiency.

Disorders that may affect the terminal ileum include tropical sprue, inflammatory bowel disease, lymphoma, and ileal resection.

The autoimmune destruction of the ileal receptor, cubilin, as found in the syndrome of Imerslund Grasbeck, likewise dissociates the uptake of cobalamin linked to intrinsic factors.

In addition, bacterial colonization can occur in intestines deformed by stenosis, blind surgical loops, scleroderma, inflammatory bowel disease, or blind loop syndrome of amyloidosis resulting in cobalamin deficiency.

In this condition, the bacteria compete with the host for cobalamin to absorb cobalamin bound to the intrinsic factor.

The fish tapeworm, such as the Diphyllobothrium latum infestation, which is common in places like Canada, Alaska, and the Baltic Sea, feeds on cobalamin in the intestine, which reduces the amount of cobalamin available for ingestion by the host.

Exposure to nitrous oxide

The various causes of cobalamin deficiency include exposure to nitrous oxide, which through the oxidative inactivation of cobalamin, causes megaloblastic.

Prolonged exposure to nitrous oxide can cause severe mental and neurological disorders.

Several medications such as purine analogs (six mercaptopurine, six thioguanine), pyrimidine analogs (five fluorouracil and five azacitidine), and drugs that affect the metabolism of cobalamins such as P-aminosalicylic acid, phenformin, and metformin that can cause deficiency cobalamin.

Folate deficiency and causes

The leading cause of food folate loss is poor food preparation due to excessive dilution of food in the water, excessive heating, and subsequent inactivation of folate since folate is thermolabile.

However, fortifying foods with folate and other vitamins bypass this problem in developed countries. This must be aggressively promoted in many developing countries.

Folate storage lasts for approximately four weeks, after which a folate deficiency occurs if the folate intake is stopped. The daily requirement for adults is about 0.4 mg/day.

Folate deficiency occurs in situations in which there is an alteration in absorption due to certain intestinal disorders such as tropical sprue, non-tropical sprue (celiac disease), amyloidosis, and inflammatory bowel disease.

Folate deficiency occurs when there is an increase in the physiological demand for folic acids, such as chronic hemolytic conditions such as sickle cell anemia, hereditary spherocytosis, elliptocytosis, pregnancy, lactation, rapid growth, hyperalimentation.

Also, renal dialysis, where there is an escalating loss of rapidly dividing cells such as psoriasis and exfoliative dermatitis.

In addition, medications such as phenytoin, metformin, phenobarbitone, dihydrofolate reductase, folate inhibitors such as trimethoprim and pyrimethamine, methotrexate and sulfonamides can cause folate deficiency.

The megaloblastic changes in human immunodeficiency virus ( HIV ) infection and myelodysplastic disorders are due to the direct effect on deoxyribonucleic acid (DNA) in hemopoietic cells, and others divide rapidly.

Pathophysiology of megaloblastic anemia

The two vitamins, folic acid and cobalamin, act synergistically in generating the thymidylic acid used to synthesize DNA. Therefore, in cobalamin deficiency, a megaloblastic arrest is caused by a deficit in the use of folate.

Methionine is generated by transferring the methylene group of N5-methyltetrahydrofolate (FH4) to homocysteine ​​using the enzyme methyltransferase (methionine synthase).

In this biochemical process, methylcobalamin is the factor that helps the transfer of methyl as a coenzyme form of cobalamin. This is why the morphological abnormalities that emanate from the deficiency of cobalamin or folate seem precisely the same.


Megaloblastic anemias, regardless of the cause, share specific general characteristics. Anemia develops slowly with few or no symptoms until the hematocrit is severely depressed, and at this point, symptoms appear such as:

  • Weakness.
  • Palpitations
  • Fatigue.
  • Dizziness
  • Difficulty breathing.
  • Severe pallor and mild jaundice combine to produce a revealing lemon-yellow skin.

Folate or vitamin B12 deficiency

There are slight differences in clinical symptoms and the signs of megaloblastic anemia, depending on whether it is caused by folate deficiency or vitamin B12 deficiency.

In folate deficiency, the main clinical features include:

  • Anemic syndrome
  • Pallor.
  • Jaundice.
  • Hunter syndrome.
  • Pigmentation of the nails.
  • Change of hair color (gray hair early).
  • Splenomegaly in approximately 10-15% of patients.

In addition to the characteristics above, cobalamin deficiency manifests with neurological symptoms, which include:

  • Loss of sense of joint position in the toes.
  • Failure of the importance of vibration in fingers and fingers.
  • Paresthesia .
  • Hypoesthesia.
  • Tingling sensation.
  • Abnormalities in the march.
  • Loss of coordination.
  • Muscular weakness.
  • Spasticity
  • Optic neuropathy
  • Urinary and fecal incontinence.
  • Erectile dysfunction.
  • Dementia.
  • Memory loss.

These neuropathies are symmetrical and only affect the lower extremities. Demonstrable signs include positive Romberg sign, Babinsky reflex, termite sign, spasticity, hyporeflexia, and clonus.

Characteristics of the laboratory

The laboratory characteristics of megaloblastic anemia revolve around laboratory investigations and findings of deficiencies in vitamin B12 and folic acid.

Serum vitamin b12 y folate

It is known that these tests are limited by their low sensitivity and specificity, and it has been shown that the normal lower limits for vitamin B12 levels are not well defined. In addition, these tests are expensive and are not always available to the practicing clinician.

Serum levels b12

Previous studies showed that vitamin B12 levels were normal or elevated in myeloproliferative disorders, liver disease, congenital transcobalamin II deficiency, intestinal bacterial overgrowth, and prior administration of vitamin B12.

Serum folate levels

Folic acid deficiency is rare when food fortification is the order of the day, as in the USA. UU

Although tissue deposits may be regular, serum folate levels may decrease within a few days of folate restriction in the diet. Therefore, patients should fast before analyzing serum folate levels since serum folate levels increase with diet.

The mild degree of hemolysis may falsely show elevated serum folate levels due to the high concentration of folate within red blood cells (RBCs).

Celula bloody Rojas (RBC) folate

In RBC (for its acronym in English), the folate level is considered a more reliable source to determine the folate reserves in tissues.

Unlike serum folate, which is affected by dietary intake, folate levels remain constant throughout the cell’s life.

However, trials to measure folate levels in red blood cells have also been full of unreliability. It has been established that vitamin B12 deficiency is the cause of low levels of red cell folate.

It is estimated that approximately 60% of patients with pernicious anemia have low levels of folate in red blood cells, presumably because vitamin B12 is necessary for the regular transfer of methyltetrahydrofolate from plasma to red blood cells.

Bone marrow examination

The aspirated marrow is hypercellular with a marked imbalance in nuclear-cytoplasmic maturation, often called nuclear-cytoplasmic asynchrony.

This asynchrony occurs due to the progressive deficient synthesis of DNA and the nuclear disorders that accumulate with each cell division, slowing down nuclear replication and causing a cumulative delay in each step of the maturation division.

Therefore, imbalance in cell growth becomes more evident in mature hematopoietic cells.

The sideroblasts, precursors of red blood cells containing a more significant number of iron granules, increase in proportion.

In addition, due to erythroid hyperplasia, the ratio of myeloid to erythroid precursors (M / E ratio) is reversed and may fall to 1: 1 or even lower.

In severe cases, numerous giant pronorblasts with a vast number of mitotic figures are present.

The iron content of macrophages is often increased. Even with the attempt to mask megaloblastic anemia by the coexistence of microcytic anemia, megaloblastic anemia will usually show hypersegmented neutrophils in the blood and giant metamyelocytes and bands in the medulla.

Substantial disintegration of the erythroblasts occurs within the sequelae of the medullary sinuses as a consequence of a prolonged undue arrest of erythroblasts with non-condensed nuclei in which the products of their disintegration are scaphraphragmatic by macrophages.

This process is known as ineffective erythropoiesis.

Dignity error

It should be noted that megaloblastic anemia can be misdiagnosed as acute leukemia when megaloblastic anemia is severe.

In this case, typical megaloblasts are absent, and most of the available cells are foreign megaloblastic pronomorblasts that dominate the medulla due to the lack of maturation of the erythroid series and, therefore, increase the possibility of erythroleukemia.

In contrast, a patient with only macrocytosis, without anemia, and any cellular abnormality in the peripheral blood film may not require a bone marrow examination.

Granulocytes and megakaryocytes are also affected by the imbalance of cell growth in megaloblastic anemia.

The myeloid cells are usually large, but it is the presence of giant metamyelocytes and giant junction forms that are pathognomonic of megaloblastic anemia.

There is also complex lobular hypersegmentation ( pseudo hyperdiploidy ) of megakaryocytes. There may be fragments of megakaryocytes and giant platelets in circulation.

Serum concentrations of methylmalonic acid (MMA) and homocysteine

Several critical metabolic pathways require the functions of cobalamin and folate as cofactors. The generation of methionine from homocysteine ​​requires vitamin B12 and folic acid cofactors.

However, the production of succinyl CoA from l-methylmalonyl CoA requires only vitamin B12. Succinyl CoA generated is involved in oxidative phosphorylation reactions within cells.

Therefore, these metabolites provide early information on the cellular status of vitamin B12 and folate.

Serum levels of these metabolites help distinguish folate from vitamin B12 deficiency. In contrast, most patients with folate deficiency only have normal levels of methylmalonic acid (MMA) or slightly elevated patients with vitamin B12 deficiency levels.

It is noteworthy that almost 50% of patients with elevated metabolites have regular serum vitamin B12 levels. Therefore, the low sensitivity of serum vitamin B12 levels is emphasized, especially when signs and symptoms implicate.

In general, measuring serum levels of MMA and homocysteine ​​is a well-established way of differentiating cobalamin deficiency from folate deficiency. In contrast, in cobalamin deficiency, both metabolites are elevated.

Patients with cobalamin nonanemic deficiency are best identified using MMA, which is much more sensitive than homocysteine. In contrast, in patients with folate deficiency, there is a marked elevation of homocysteine ​​levels, while serum levels of MMA are not elevated.

Therefore, measuring the serum level of these two metabolites provides a means to distinguish cobalamin from folate deficiency and provides a reliable degree of accuracy in diagnosing these deficiency states.

However, the sensitivity of identifying patients with cobalamin deficiency is masked by a renal dysfunction that leads to a falsely elevated serum MMA.

Also, hereditary hyperhomocysteinemia, where elevated homocysteine ​​can confuse when diagnosing folate deficiency. It is recommended that MMA be measured only if the initial vitamin B12 or homocysteine ​​levels are abnormal.


It will be determined by the doctor based on:

  • Age, general health, and medical history.
  • Extension of the condition.
  • Causes of anemia.
  • Tolerance of specific drugs.
  • The expectations of the treatment.
  • The opinion or preference of the patient or representative.

If the disorder is caused by digestive problems (absorption of nutrients), you may need treatment. Vitamin B12 supplements are better absorbed when injected.

Folate-rich foods include:

  • Lettuce.
  • Spinach.
  • Liver.
  • Rice.
  • Chickpeas.
  • Coles.
  • Wheat germ
  • Soybeans.
  • Beans.
  • Peanut.
  • Oranges
  • Asparagus.
  • Green peas.
  • Green leafy vegetables.