Not all patients with megaloblastic anemia are symptomatic [5]. Patients with megaloblastosis may present with a history of the following features:

• Abdominal discomfort or bloating
• Anemia
• Anorexia
• Nausea
• Pale yellow skin 
• Sore tongue
• Weakness
• Lethargy
• Weight loss
• Constipation
• Bleeding per rectum may be suggestive of inflammatory bowel disease like Crohn disease
• Canker sores
• Consumption of raw fish may have led to infestation of tapeworm.
• Mental status changes (psychosis)
• Neurological deficits (paresthesia, numbness, pain, tingling, burning sensation, unsteady gait, loss of balance)
• Patients with other autoimmune disorders like type 1 diabetes or Graves disease should be suspected of having pernicious anemia.
• Prior abdominal surgery such as gastrectomy. A history of bowel resection may suggest blind loop syndrome.
• Strict vegetarian diet with no intake of dairy products or eggs.

Physical examination

• Tachycardia
• Dyspnea
• Tachypnea
• Yellowish skin discoloration (due to the anemia and jaundice) 
• Atrophic glossitis
• Neuropsychiatry evaluation may reveal paresthesias, numbness, weakness, loss of dexterity, impaired memory, and peripheral neuropathy 
• Loss of balance, abnormal gait, loss of proprioceptive senses, speech impairment, and absent vibratory senses may be caused by subacute combined degeneration of the cord due to vitamin B12 deficiency.
• Visual exam may reveal diminished or complete loss of vision due to optic atrophy
• Malabsorption features may include profuse diarrhea, abdominal distension, and steatorrhea

Patients with suspected megaloblastic anemia usually require a comprehensive workup that includes the following [6]:

• Blood smear usually shows macroovalocytes having an MCV >115 fl, anisocytosis, poikilocytosis, hypersegmented neutrophils, Howell-Jolly bodies and nucleated RBCs.
• Complete blood count that includes reticulocyte count, serum chemistry, lactate dehydrogenase (LDH) levels, indirect and direct bilirubin levels, levels of iron, ferritin, folate and cobalamin. Blood should usually be drawn prior to a meal or transfusion to avoid falsely elevated levels.
• Bone marrow aspiration is done to rule out a primary bone marrow disorder such as a myelodysplastic syndrome or leukemia and assess iron stores. 
• Levels of methylmalonic and homocysteine can differentiate between folate and cobalamin deficiency. Levels of both metabolites are increased in patients with cobalamin deficiency but in folate deficiency only homocysteine is elevated [7] [8].
• Patients with defects or absence of intrinsic factor need to undergo the Schilling test, when this test is available.
• Patients in whom the testing has been non-conclusive will need an empirical trial of folate and cobalamin. It is important not to give folate only in the presence of suspected cobalamin deficiency as this can worsen the neurological deficit.
• If a blind loop syndrome is suspected, imaging with barium swallow and follow-through series of the gastrointestinal tract is necessary. 
• If the above tests are not productive one may need to rule out autoimmune disorders, pancreatic insufficiency, tapeworm infestation, Crohn disease or Zollinger Ellison syndrome. Patients with folate deficiency may need to be worked up for malnutrition, celiac disease, alcoholism, exfoliative dermatitis and chronic hemolysis.

The treatment of megaloblastic anemia depends on the cause [9].

• Drug-induced megaloblastic anemia is treated by discontinuation of the offending agent.
• In patients in whom the cause is unknown, treatment involves administration of folate and cobalamin.
• Because megaloblastic anemia takes years to develop, most individuals are able to adjust to the low levels of hemoglobin. Blood transfusions are rarely required for treatment of megaloblastic anemia and are usually given to in patients who are symptomatic from severe life-threatening anemia that has failed to respond to folate and cobalamin.
• Even though several formulas of cobalamin exist, only the oral and IM formulas are recommended. The effectiveness of oral cobalamin for treatment of people with severe neurological deficit has not been proven and hence only the IM formula should be used. IV cobalamin is not recommended for clinical use as the majority of the supplement is rapidly excreted by the kidneys. In addition, the IV formula can also elevate blood pressure and it is prohibitively expensive. Cobalamin has also been associated with hypersensitive reactions which are felt to be due to other chemicals in the preparation. The dose of cobalamin depends on the severity of neurological or mental symptoms and the treatment is for life. Oral cobalamin is preferred in patients with bleeding disorders to avoid hematoma formation from the IM injection. Injections are preferred in patients with neurological symptoms and those who have difficulty absorbing (eg. after gastrectomy) the supplement. Overall, oral cobalamin is preferable and much cheaper than an IM injection.
• Folate like cobalamin can be administered orally or parenterally. Elderly people, patients with end stage renal disease and women who are pregnant or breast feeding should take folate orally on a regular basis. Folate supplements are also recommended in patients with psoriasis, exfoliative dermatitis, hyperhomocysteniemia and chronic hemolytic anemia.

Today many foods including cereals are fortified with folic acid supplements to reduce risk of malignancies (eg. colon, pancreas). However, it is important to note that fortifying foods with folate can lead to cobalamin-induced neuropsychiatric disorders. It is vital that no patient be started on only folate therapy in a patient with megaloblastic anemia until cobalamin deficiency has been ruled out. Giving only folate to improve the anemia will not correct the neuropsychiatric symptoms of cobalamin deficiency and can in fact worsen them. If not sure, both folate and cobalamin should be administered if cobalamin deficiency cannot be ruled out.

Once treatment has started, all patients need follow up and monitoring to determine if improvements occurring in the blood tests and clinical exam.

• Continued elevation of LDH levels is indicative of therapy failure, continued development of iron deficiency anemia or an error in the primary diagnosis.
• Blood work will usually reveal elevation in reticulocytes within days after starting therapy. Levels of platelets and leukocytes will be normal within days but hypersegmented neutrophils may persist for 1 to 2 weeks.
• The level of hemoglobin usually increases gradually and if normal hemoglobin level is not restored within 6 to 8 weeks another cause of anemia should be considered.
• Hypokalemia is common during treatment with folate or cobalamin in patients with megaloblastic anemia and can lead to serious arrhythmias. Thus, potassium levels should be closely monitored and supplements administered.
• Because there is a sudden increase in synthesis of red blood cells, iron deficiency anemia can occur during treatment of megaloblastic anemia, thus some patients may also need iron supplementation if there is a drop in hemoglobin levels.
• The primary cause of cobalamin or folate deficiency should be addressed as recommended.

In individuals in whom the cause of megaloblastic anemia is temporary and is known, the prognosis is good. Patients with unknown diagnosis are at risk for developing anemia related complications and hypokalemia during treatment. If the cobalamin deficiency is missed or not appropriately treated, patients can develop permanent neuropsychiatric manifestations including subacute combined degeneration of the spinal cord. Pregnant women who do not take folate supplements are at risk for giving birth the infants with neural tube defects.

The most common causes of megaloblastic anemia open link are deficiencies of vitamin B12 and/or folic acid. Cobalamin deficiency may be caused by:

• Consuming a strict vegetarian diet that is restricted in dairy products, eggs and no meat products
• Atrophic gastritis 
• Achlorhydria 
• Absence or deficiency of intrinsic factor which is seen for example in pernicious anemia or congenital intrinsic factor deficiency
• Pancreatic insufficiency 
• Zollinger-Ellison syndrome
• Gastrointestinal tract disorders like inflammatory bowel disease
• Lymphoma 
• Celiac disease
• Tropical sprue
• Ileal resection
• Blind loop syndrome
• Scleroderma 
• Intestinal strictures
• Diverticulosis
• Ingestion of the fish tapeworm, Diphyllobothrium latum
• Prolonged exposure to nitrous oxide has been associated with megaloblastic anemia due to inactivation of cobalamin due to oxidative stress
• Medications associated with megaloblastic anemia include sulfonamides, methotrexate, metformin, acyclovir, zidovudine and phenformin [4]

Stores of folate are limited and deficiency can develop in a matter of weeks if there is complete cessation of folate intake. Folate deficiency causes include:

• Poor preparation of foods such as excessive heating can inactivate folate
• Deficient intake
• Increased need during for example pregnancy, lactation, rapid growth, parenteral nutrition and psoriasis
• Inflammatory bowel disease 
• Amyloidosis
• Chronic alcoholism
• Tobacco smoking
• Medications that can cause folate deficiency include metformin, phenytoin, phenobarbital, methotrexate, oral contraceptives, trimethoprim sulfamethoxazole, sulfonamides, and valproic acid

Globally the most common cause of megaloblastic anemia is ill preparation of foods containing folate. The incidence of megaloblastic anemia is most common in countries where there is malnutrition and in countries where routine administering of folate to pregnant women and elderly individuals is not common.

Vitamin B12 is chiefly obtained from sea foods, meat and dairy products. Fruits and vegetables do not contain significant amounts of this vitamin. Vitamin B12 plays a vital role in numerous biochemical reactions in the body. It is critical for the process of myelination. Cobalamin deficiency can lead to abnormal myelination which can affect the spinal cord.

Unlike vitamin B12, folate is found in large amounts in fruits, vegetables and animal protein. Because most available dietary folate is in a conjugated form, it needs to be converted to dihydrofolic acid so that it can be absorbed; folate is readily absorbed from the small intestine and does not require the presence of intrinsic factor.

In megaloblastic anemia, there is decreased deoxythymidine triphosphate (dTTP) synthesis resulting in impairment in the synthesis of DNA, RNA and protein. The red blood cells (RBCs) that are produced show slowed nuclear maturation whereas cytoplasmic maturation is relatively unaffected. There is also rapid destruction of defective RBCs in the bone marrow. The impaired production and increased destruction of RBCs in the bone marrow results in anemia. Direct interference of DNA synthesis causing megaloblastic anemia may also occur due to HIV infections and myelodysplastic disorders. 

The uptake of cobalamin is from the intestine is a complex process. Ingested cobalamin initially binds in a nonspecific manner the protein molecules in food. In the presence of gastric acidity, the cobalamin is released and then binds to R-proteins that protect it from degradation by the intestinal enzymes and secretions. This cobalamin-R protein complex then reaches the terminal ileum where it requires the presence of intrinsic factor to be absorbed into the systemic circulation. The complex is then absorbed in the terminal ileum and then transported to the bone marrow [3]. Because cobalamin is stored in the body and very little cobalamin is required on a daily basis, deficiency of this vitamin can take several years to develop. On the other hand, folate is not stored and hence deficiency usually occurs in a matter of weeks after dietary intake is discontinued.

There are many causes of megaloblastic anemia and not all can be prevented. However, in patients with a strict vegetarian diet, supplements of folate and cobalamin should be recommended. In addition, these individuals should be educated on eating foods that are fortified with these supplements and also learn how to prepare foods. Examples of foods with high levels of folate include broccoli, asparagus, lettuce, spinach, bananas, liver, melons and mushrooms. To prevent loss of folate from foods, dilution in large amounts of water and excessive heating should be avoided. After discharge all patients must be monitored to ensure that the anemia is resolving. Periodic testing of hemoglobin, LDH, indirect bilirubin levels and blood smear is recommended.

Megaloblastic anemia is a hematological disorder where certain cells of the bone marrow have arrested during the phase of nuclear maturation. These large cells are referred to as megaloblasts and can be easily seen on a blood smear. Megaloblastic anemia can be associated with diverse clinical manifestation ranging from personality changes, neurological deficits, glossitis and pancytopenia. Asides from medications, folic acid deficiency and vitamin B12 deficiency are the most common causes of this anemia. Any process that interferes with absorption of cobalamin or folate from the intestine can potentially cause the disorder.

The condition is seen globally but most common in people with restricted diets and in presence of malnutrition. It is important to note that megaloblastic anemia that occurs with either folate or cobalamin deficiency can present with almost identical signs and symptoms, but the latter is also associated with subacute combined degeneration of the spinal cord. Adults usually require at least 5-7 microgram of cobalamin and about 0.4 mg of folate per day [1] [2].

Megaloblastic anemia is a type of blood disorder that results in abnormal cells in the blood circulation and bone marrow. Megaloblastic anemia can occur because of deficiency in folate or vitamin B12. Most people develop this type of anemia either because they have a deficient diet or they are unable to absorb the vitamin from the intestine.

Megaloblastic anemia can present with a variety of symptoms that include a red painful tongue, changes in personality, difficulty with balance and walking, burning or numbness in the legs, pale skin, weight loss and weakness.

The diagnosis of this anemia can be made by looking at a blood smear or performing other blood tests that can look at levels of the vitamins. Once diagnosed, treatment is required. If the treatment with folate and vitamin B12 is done promptly, the symptoms do reverse within a few months. To prevent megaloblastic anemia, people who eat a strict vegetarian diet should take supplements of folate and vitamin B12. Foods high in folate include broccoli, liver, melons and spinach. All women who get pregnant should take folate supplements to avoid developing spinal cord problems in the infant.

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