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Megaloblastic anemia is a type of macrocytic anemia that 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 often has a rather slow onset, and symptoms can range from asymptomatic to severe. The defect in red cell DNA synthesis is most often due to hypovitaminosis, specifically vitamin B12 deficiency or folate deficiency.

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. These hypersegmented neutrophils can be detected in the peripheral blood using a diagnostic smear of a blood sample.

Causes

 * Vitamin B12 deficiency:
 * Achlorhydria-induced malabsorption
 * Deficient intake
 * Deficient intrinsic factor, a molecule produced by cells in the stomach that is required for B12 absorption (pernicious anemia or gastrectomy)
 * Coeliac disease
 * Biological competition for vitamin B12 by diverticulosis, fistula, intestinal anastomosis, or infection by the marine parasite Diphyllobothrium latum (fish tapeworm)
 * Congenital vitamin B12 malabsorption (juvenile megaloblastic anemia 1 )
 * Chronic pancreatitis
 * Ileal resection and bypass
 * Nitrous oxide anesthesia (usually requires repeated instances).
 * Drugs that decrease Vitamin B12 absorption: Metformin, Proton Pump Inhibitors, Histamine receptor 2 antagonists
 * Chronic alcohol use
 * Folate deficiency:
 * Alcoholism
 * Deficient intake
 * Increased needs: pregnancy, infancy, rapid cellular proliferation, long term dialysis, inflammatory disorders, and cirrhosis
 * Malabsorption (congenital and drug-induced)
 * Intestinal and jejunal resection
 * (indirect) Deficient thiamine and factors (e.g., enzymes) responsible for abnormal folate metabolism.
 * Combined Deficiency: vitamin B12 & folate.
 * Inherited Pyrimidine Synthesis Disorders: Orotic aciduria
 * Inherited DNA Synthesis Disorders
 * Toxins and Drugs:
 * Folic acid antagonists (methotrexate)
 * Purine synthesis antagonists (6-mercaptopurine, azathioprine)
 * Pyrimidine antagonists (cytarabine)
 * Phenytoin
 * Acute myeloid leukemia
 * Inborn genetic mutations of the Methionine synthase gene
 * Congenital dyserythropoietic anemia
 * Copper deficiency resulting from an excess of zinc from unusually high oral consumption of zinc-containing denture-fixation creams has been found to be a cause.

Pathophysiology
Megaloblastic anemia occurs when there is a defect in DNA synthesis of the red blood cells while the RNA and cytoplasm is produced at a normal rate. For DNA synthesis to proceed as normal, deoxyuridine needs to be converted to thymidylate and this cannot be done without vitamin B12 and folate. Therefore, unbalanced cell proliferation and impaired cell division occur as a result of arrested nuclear maturation so the cells show nuclear-cytoplasmic asynchrony. The red blood cells will be large and immature as a result.

In the bone marrow, most megaloblasts are destroyed prior to entering the peripheral blood (intramedullary hemolysis), however some can escape to the peripheral blood.

Diagnosis
All megaloblastic anemias typically have a mean corpuscular volume (MCV) above 100fL. This may not always be the case if concurrent microcytic anemia is also present. The gold standard for the diagnosis of Vitamin B deficiency is a low blood level of Vitamin B which is characterized by cobalamin levels below 74 pmol/L. In the early stages of vitamin B12 deficiency, vitamin B12 levels may be within normal range, so a methylmalonic acid (MMA) test and a homocysteine test should be done for a better diagnosis. For all types of megaloblastic anemias, vitamin B12 levels are always completed and MMA levels are done to confirm the diagnosis. Hypovitaminosis B can result from a number of mechanisms, including those listed above. For determination of cause, further patient history, testing, and empirical therapy may be clinically indicated.

A measurement of serum methylmalonic acid (methylmalonate) can provide an indirect method for partially differentiating Vitamin B and folate deficiencies. The level of methylmalonic acid is not elevated in folic acid deficiency. Direct measurement of blood cobalamin remains the gold standard because the test for elevated methylmalonic acid is not specific enough. Vitamin B is one necessary prosthetic group to the enzyme methylmalonyl-coenzyme A mutase. This enzyme is responsible for the conversion of methylmalonyl-CoA to succinyl-CoA. In vitamin B deficiency, the dysfunction of this enzyme leads to a buildup of its substrate, methylmalonic acid. MMA levels can be elevated in other conditions, such as renal failure, so vitamin B12 deficency is not always definitive from MMA testing.

To detect folate deficiency, folate serum levels are usually tested. A folate serum level of below 4.5 nmol/L is considered folate deficient. Homocysteine and MMA levels are also taken to confirm folate deficiency and when folate levels are inconclusive. Due to the mechanism of action of methylmalonyl-coenzyme A mutase, MMA levels would be within normal range in folate deficiency. However, homocysteine levels are elevated in both folate and Vitamin B12 deficiency. Homocysteine is metabolized to methionine and this reaction requires both vitamin B12 and folate. So, if MMA levels are normal and homocysteine levels are elevated, then it is consistant with folate deficiency.

Due to the lack of available radioactive Vitamin B and better tests being available, the Schilling test is no longer available and is largely a historical artifact. The Schilling test used to be performed to determine whether one should start parenteral or oral therapy, but evidence now shows that both routes are effective.

Blood findings
The blood film can point towards vitamin deficiency:


 * Decreased red blood cell (RBC) count and hemoglobin levels
 * Increased mean corpuscular volume (MCV, >100 fL) and mean corpuscular hemoglobin (MCH)
 * Decreased reticulocyte count
 * Possibly low platelet count
 * Peripheral blood smear shows Neutrophil granulocytes that are presented as multisegmented nuclei. Over 5% of the neutrophils in the blood smear are multilobed (defined as 5 or more lobes on the nucleus)
 * Anisocytosis (increased variation in RBC size) and poikilocytosis (abnormally shaped RBCs).
 * Macrocytes (larger than normal RBCs) are present.
 * Ovalocytes (oval-shaped RBCs) are present.

Blood chemistries will also show:


 * An increased lactate dehydrogenase (LDH) level.
 * Increased homocysteine and methylmalonic acid in Vitamin B deficiency
 * Increased homocysteine in folate deficiency
 * Low serum vitamin B12 levels (<148 pmol/L) in vitamin B12 deficiency.
 * Low serum folate level. This can be variable depending on food eaten and blood transfusions, so it is not very indicative of 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.

Signs and Symptoms
The signs and symptoms of megaloblastic anemia can vary depending on age, concomitant medical conditions, severity of disease, and the specific type of megaloblastic anemia. The general symptoms patients may exhibit in all types of anemia include fatigue, dizziness, weakness, heart palpitations, shortness of breath, chest pain, and difficulty exercising as normal. Upon evaluation, non-specific signs a person may have are high heart rate, pale appearance, and mild cognitive impairment.

A classic presentation specifically in vitamin B12 deficiency is neurological and cognitive changes. Some of these changes can be seen in folate deficiency, but it is not very common. These changes commonly include abnormal sensation in the skin, abnormal gait, and muscle weakness. Some cognitive or psychological symptoms seen are memory impairment, insomnia, irritability, and mood changes. Other vitamin B12 specific symptoms include glossitis and rarely skin hyperpigmentation.

A clinical presentation specific to folate deficiency is oral ulcers. In pregnant women with folate deficiencies, especially if deficient in the first 12 weeks of pregnancy, there is a high risk of neural tube defects and cleft lip and palate in the fetus. Neurological abnormalities can be seen in folate deficiency, but it is not very common.

Treatment
The treatment of megaloblastic anemia should first acknowledge the underlying cause and treat or modify that if possible. Very severe anemia or deficiency may need initial blood transfusions to stabilize the patient.

For vitamin B12 deficiency, diet and replacement therapy is paramount for treatment. Some foods rich in vitamin B12 include fortified cereals, fish, meat products, dairy, and eggs. In those with deficiency, cyanocobalamin either parenterally or orally should be given. The parenteral option is often chosen if a patient has impaired absorption, if neurological symptoms are present, or initially if deficiency is severe. In adults, the normal cyanocobalamin dose given parenterally is 1000 mcg injected once a week until the deficiency is corrected. Then it will be given once a month. Another parenteral regimen is to inject 1000 mcg once a day for 1 week, then weekly for 1 month, then monthly afterwards. Oral cyanocobalamin has similar efficacy to the parenteral option, so it is also a good choice for those wanting to avoid injections. The dose given to correct the anemia is oral cyanocobalamin 1000-2000 mcg once daily. Whether choosing an oral therapy or parenteral therapy, the treatment should continue until the deficiency is resolved. Blood work should be taken after 1-2 months of treatment and we should expect hemoglobin levels to normalize at that point. The decision to stop vitamin B12 supplementation depends on whether the causative factor has been resolved.

In folate deficiency, diet and supplementation is important. Some foods rich in folate are beef liver, fortified cereals, green leafy vegetables, and lentils. Parenteral folic acid is not used often since synthetic oral folic acid is almost completely absorbed. It can however be used in cases of severe anemia that is symptomatic. Oral folic acid supplementation is more common, with deficiency being treated with a dose of 1-5 mg once daily. The treatment with oral folic acid should continue for 4 months if the cause for the deficiency is identified and corrected. Otherwise, long term therapy is warranted. Symptoms of the deficiency should start to improve early on with blood values being normal within the first 2 months.