bubble_chart Overview

Megaloblastic anemia is a macrocytic anemia caused by a deficiency of folate or vitamin B₁₂, which affects the biosynthesis of deoxyribonucleic acid (DNA) and disrupts nuclear division. It is characterized by the presence of morphologically and functionally abnormal megaloblastic cells in the peripheral blood and bone marrow. In addition to anemia, patients may also exhibit symptoms and signs of the digestive and nervous systems.

bubble_chart Etiology

Folic Acid and Vitamin B₁₂ Metabolism

1. Metabolism of Folic Acid Folic acid is a water-soluble B vitamin that is abundant in leafy green vegetables and fruits, with moderate amounts found in animal organs and yeast. Folic acid is highly unstable and easily degraded by light and heat. Prolonged food storage or improper cooking can lead to significant loss of folic acid.
   In food, folic acid exists as pteroylpolyglutamate, which is broken down into pteroylmonoglutamate in the small intestine before absorption. The primary site of absorption is the proximal jejunum. After absorption, it circulates in the blood as N5-methyltetrahydrofolate. Under the action of vitamin B₁₂, it is demethylated to form tetrahydrofolate (THFA), which is then recombined into polyglutamates and stored in the liver and hemoglobin. Adults require approximately 50–200 μg of folic acid daily, with increased needs during childhood, pregnancy, lactation, infection, fever, and hemolysis. The total body store of folic acid is only 5–10 mg, and it is easily depleted. Therefore, in cases of nutritional deficiency, megaloblastic anemia due to folic acid deficiency is more likely to occur.
2. Metabolism of Vitamin B₁₂ Vitamin B₁₂, also known as cyanocobalamin, is a water-soluble B vitamin. It is primarily found in animal organs, such as the liver and kidneys, with higher concentrations in beef, while vegetables contain very little.

In food, vitamin B₁₂ first binds to R-binding protein in the stomach. In the duodenum, with the involvement of trypsin, it combines with intrinsic factor secreted by gastric parietal cells to form a vitamin B₁₂-intrinsic factor complex. Under conditions of pH 7.0 and the presence of calcium and magnesium ions, it is absorbed at the terminal ileum. Normally, about 70% of dietary vitamin B₁₂ can be absorbed, but absorption drops to less than 2% in the absence of intrinsic factor. The absorbed vitamin B₁₂ is transported via the bloodstream to the liver, bone marrow, and other proliferating cells. Some vitamin B₁₂ is excreted in bile, with two-thirds reabsorbed in the ileum under the action of intrinsic factor. Adults require only 2–5 μg of vitamin B12 daily, and the total body store of vitamin B12 is about 4–5 mg, sufficient for 3–5 years of use.

bubble_chart Pathogenesis

(1) Causes of Folic Acid and Vitamin B₁₂ Deficiency

1. Causes of Folic Acid Deficiency
   1. Inadequate Intake: Often due to malnutrition or insufficient folic acid content in food. Overcooking or pickling vegetables can lead to folic acid loss. Improper infant feeding and unreasonable complementary food introduction can also result in insufficient folic acid intake.
   2. Increased Demand: Children in growth periods, pregnancy, lactation, hemolytic anemia, sideroblastic anemia, certain skin diseases (e.g., psoriasis), malignancies, leukemia, lymphoma, hyperthyroidism, and patients undergoing long-term hemodialysis have increased folic acid requirements. Inadequate supplementation can lead to deficiency.
   3. Absorption Disorders: Small intestine inflammation, celiac disease, gastrectomy, small intestine resection, etc., can cause poor folic acid absorption.
   4. Drug Effects: Folic acid antagonists such as methotrexate, phenytoin sodium, isoniazid, and cycloserine can interfere with folic acid absorption.
2. Vitamin B₁₂ deficiency is rarely caused by dietary insufficiency. The reasons for vitamin B₁₂ deficiency include:
   1. Malabsorption
      1. Lack of Intrinsic Factor: Such as pernicious anemia, post-gastrectomy, extensive gastric injury;
      2. Intestinal Diseases: Such as regional ileitis, ileum resection, small intestine malignancies, celiac disease, etc.;
      3. Intestinal Parasites or Bacteria Competing for B
      4. 12: For example, diphyllobothriasis, blind loop syndrome after surgery, etc.
      5. Others: Certain drugs like para-aminosalicylic acid, colchicine, and neomycin can affect vitamin B12 absorption.
   2. Increased Demand: Such as pregnancy, hemolytic anemia, infections, hyperthyroidism, etc.
   3. Other rare causes include long-term vegetarianism or congenital transcobalamin deficiency.

(2) Pathogenesis

Both folic acid and vitamin B₁₂ are indispensable coenzymes in nucleic acid metabolism. Normally, during cell division, nuclear DNA must double. When folic acid or vitamin B₁₂ is deficient, the synthesis of DNA in young red blood cells slows down, while RNA synthesis in the cytoplasm remains unaffected. The cytoplasm continues to develop and mature, leading to an imbalance between nuclear and cytoplasmic development. The nucleus lags behind, with loose nuclear chromatin and increased cytoplasm, resulting in giant cell changes (megaloblastic cells). This change is most pronounced in the erythroid series, with corresponding alterations in white blood cells and platelets.Additionally, in the propionate catabolic pathway, the conversion of methylmalonyl-CoA to succinyl-CoA requires vitamin B₁₂. When vitamin B₁₂ is deficient, this process is impaired, leading to increased methylmalonic acid in the blood. This substance can directly damage the nervous system, causing related clinical manifestations.

bubble_chart Clinical Manifestations

The onset is mostly gradual, with the following main clinical manifestations.

1. General symptoms often include general anemia symptoms, such as gradually developing weakness, palpitation, pale skin and mucous membranes, etc. Some patients may be accompanied by grade I jaundice.
2. Digestive system symptoms include loss of appetite, abdominal distension and fullness, diarrhea, glossitis, tongue pain, atrophy of tongue papillae, smooth tongue surface, and a crimson tongue texture resembling lean meat.
3. Neurological symptoms appear with vitamin B₁₂ deficiency, manifesting as weakness, numbness of the hands and feet, sensory disturbances, difficulty walking in the lower limbs, and other peripheral neuritis symptoms. When the posterior columns of the spinal cord degenerate, varying degrees of lower limb weakness, ataxia, unsteady gait, positive Romberg's sign, decreased or absent tendon reflexes, and reduced muscle tone may occur. With degeneration of the lateral columns of the spinal cord, severe weakness in both lower limbs or even paralysis may occur, along with hyperactive tendon reflexes, increased muscle tone, and positive pyramidal tract signs. Some patients may exhibit mental abnormalities, such as drowsiness, depression, or confusion.
4. Other symptoms include petechiae or bleeding due to thrombocytopenia.

bubble_chart Auxiliary Examination

1. Blood picture: Macrocytic normochromic anemia. The mature red blood cells vary in size and shape, with a predominance of large, oval-shaped red cells. Giant red cells, polychromatic cells, and basophilic stippling are increased. Cabot rings and Howell-Jolly bodies are occasionally seen in red cells, and a few nucleated red blood cells may appear. The white blood cell count is often decreased, with hypersegmented neutrophils (up to 6-8 lobes). Occasionally, giant band neutrophils are observed. The platelet count may also be reduced, with abnormal morphology, including increased size and irregular shape.
2. Bone marrow findings: The bone marrow is hypercellular, predominantly with erythroid precursors, resulting in a decreased myeloid-to-erythroid ratio. Numerous megaloblasts are present, characterized by large nuclei, loose chromatin, and abundant cytoplasm. Giant erythroid cells exhibit "immature nuclei with mature cytoplasm." Granulocytic precursors show giant changes starting from the promyelocyte stage, but the most prominent abnormalities are seen in myelocytes, metamyelocytes, and band neutrophils. Megakaryocytes may exhibit increased size and hypersegmentation, with impaired platelet maturation.
3. Blood generation and transformation: Serum indirect bilirubin is mildly elevated (Grade I). Serum iron and transferrin saturation are increased, while serum folate and vitamin B₁₂ levels are reduced below the normal range.
4. Gastric analysis: Gastric juice volume is reduced, and free hydrochloric acid is mostly absent or significantly decreased. After histamine injection, a small amount of free hydrochloric acid may appear in some folate-deficient patients. In pernicious anemia, free hydrochloric acid is consistently absent, even after histamine stimulation.

bubble_chart Diagnosis

The causes and clinical features of megaloblastic anemia include: macrocytic anemia in the blood picture; hypersegmentation of neutrophils (more than 5 lobes); typical megaloblastic changes in bone marrow smears; and the exclusion of other causes such as chronic liver disease, hematologic malignancies, and drug-induced megaloblastoid changes in the erythroid system of the bone marrow, which can confirm the diagnosis. Once the diagnosis is established, it is essential to further determine whether it is caused by folic acid deficiency or vitamin B₁₂ deficiency, as this is related to treatment and prognosis. A comprehensive analysis can be made based on certain laboratory tests and the results of low-dose experimental treatment. If folic acid deficiency is suspected, serum and red blood cell folate levels can be measured. Red blood cell folate reflects the body's storage status and has greater diagnostic value for folic acid deficiency. If vitamin B₁₂ deficiency is suspected, serum vitamin B₁₂ levels should be measured. A level <74 pmol/L suggests B₁₂ deficiency, and a vitamin B₁₂ absorption test should be performed.

bubble_chart Treatment Measures

The treatment principle for megaloblastic anemia is to eliminate the causes of folate or vitamin B₁₂ deficiency, actively treat the underlying disease, and supplement the deficient vitamins—folate or vitamin B₁₂

1. Treat the underlying disease to remove the disease cause, adjust the diet, and consume foods rich in folate and vitamin B₁₂, such as fresh green vegetables, meat, eggs, etc.
2. Supplement folate or vitamin B₁₂
   1. For folate deficiency, administer oral folate 5mg three times daily. For those unable to take oral medication, intramuscular injection of 15mg once daily may be given. After hemoglobin returns to normal, maintenance therapy is generally unnecessary. However, in certain conditions such as chronic hemolysis, chronic skin disease, or long-term hemodialysis for uremia, long-term maintenance therapy is required. Vitamin C stabilizes and enhances folate absorption, so it should be used concomitantly with folate. Patients with folate deficiency often also lack proteins, other vitamins, or iron, which should also be supplemented during treatment.
   2. For vitamin B₁₂ deficiency, administer vitamin B12 100μg intramuscularly once a month for two weeks, then twice a week for four weeks, or once a month after blood counts normalize. Patients with pernicious anemia or post-gastrectomy require long-term maintenance therapy with monthly injections of 100μg. For those with neurological symptoms, the dose should be doubled.
3. For cases with concurrent folate and vitamin B₁₂ deficiency, or when it is unclear whether the deficiency is due to vitamin B₁₂ or folate, both vitamin B₁₂ and folate should be administered simultaneously. In cases of vitamin B₁₂ deficiency treated with folate alone, while blood counts may improve, more vitamin B₁₂ is consumed, potentially triggering or worsening neurological symptoms.
   Generally, 8–12 hours after the above drug therapy, megaloblasts in the bone marrow begin to transform into normal erythroblasts. Within 48–72 hours, the morphology of megaloblasts largely normalizes, and reticulocytes start to rise after 3 days, peaking between 4–10 days, with concurrent recovery of white blood cells and platelets. Blood counts typically return to normal in about 1–2 months. In some cases, during the initial stage of treatment, reticulocytes increase rapidly, followed by a rise in hemoglobin, but if hemoglobin does not reach expected levels despite increasing doses of vitamin B₁₂ and folate, iron deficiency should be considered. After confirmation, iron supplements should be administered accordingly.
4. Prevent and treat infections, as infections are one of the complications leading to treatment failure, especially intestinal infections. Large numbers of bacteria can deplete significant amounts of vitamin B₁₂ and damage the intestinal mucosa, impairing vitamin B₁₂ absorption. Therefore, effective antibiotics should be administered promptly.
5. Other treatments: For chronic pancreatic disease, intrinsic factor may be ineffective. Administering pancreatic enzymes or trypsin can free vitamin B₁₂ from its R-protein and bind it to intrinsic factor. If treatment is ineffective, consider misdiagnosis, concurrent infection, or coexisting iron deficiency. In severe megaloblastic anemia, after drug therapy, large amounts of potassium enter cells, potentially causing a sudden drop in serum potassium. Combined with myocardial hypoxia and degeneration, this can lead to sudden death, so potassium supplementation should be monitored. Blood transfusion only temporarily improves anemia and does not address the damage caused by folate and vitamin B₁₂ deficiency, so it is reserved for severe anemia cases.

bubble_chart Prevention

In most cases of folate or B₁₂ deficiency, different measures can be taken for prevention based on the underlying causes.

Infants and young children should be fed appropriately, with timely introduction of complementary foods. During childhood development, a diversified diet should be maintained to prevent picky eating. Pregnant women should strengthen their nutrition appropriately and consume fresh vegetables and fruits in moderation. Those with a history of nutritional anemia should pay attention to folate supplementation, taking 5mg of oral folate daily. Nutrition education should be provided to correct picky eating and cooking habits, and dietary guidance should be given to vegetarians. Infections, especially intestinal infections, should be prevented and promptly controlled. For patients with chronic hemolytic anemia, chronic inflammation, myeloproliferative disorders, malignancies, hyperthyroidism, or those on long-term antiepileptic drugs, appropriate folate supplementation is recommended. Gastrectomy patients should receive adequate vitamin B₁₂ supplementation. Patients with idiopathic steatorrhea should avoid gluten-containing foods and ensure the simultaneous supplementation of other nutrients.

bubble_chart Differentiation

This disease needs to be differentiated from the following conditions:

1. Pancytopenia: requires differentiation from aplastic anemia;
2. Grade I jaundice: requires differentiation from hemolytic anemia;
3. Increased megaloblastic erythrocytes in the bone marrow: requires differentiation from erythremia and erythroleukemia. These conditions are often accompanied by sternal tenderness, hepatosplenomegaly, and leukemic changes in the bone marrow and blood picture.