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Flashcards in Megaloblastic Anemia Deck (17):

What is the definition of megaloblastosis?

Megaloblastosis (literally “very large blast”) refers to the abnormally large  precursor cells seen in the bone marrow, which are unable to complete cell division due to impaired DNA synthesis


What are the consequences of sustained abnormal DNA synthesis?

  • Bone marrow: Characteristically packed (hypercellular) with abnormally large precursor cells, often with destruction of blood elements within the marrow
    • Since mature cells are not released from the bone marrow into the blood, anemia, thrombocytopenia, and leucopenia result
    • This disparity between a hypercellular marrow and low peripheral blood counts is referred to as “ineffective erythropoiesis”
    • With destruction of bone marrow precursors, contents of the cytoplasm are released, and there is an increase in the serum bilirubin, LDH, and iron and a decrease in haptoglobin (markers of hemolysis)
  • Peripheral blood: Large, round (macrocytes) and oval shaped (macro-ovalocytes) red blood cells are observed
    • These cells account for an increase in the mean corpuscular volume (MCV)
    • The hypersegmented neutrophil (6 or more lobes in the nucleus) is another one of the hallmarks of megaloblastic anemia


What are the most common causes of megaloblastic anemia?

  • Vitamin B12 and Folic acid deficiency are the most common causes
  • Both are essential for normal DNA synthesis


What is the metabolism of Vitamin B12 and folic acid?

  • Folic acid is required for purine and pyrimidine synthesis as well as the production of thymidylate for DNA synthesis
  • Vitamin B12 accepts a methyl group from methyltetrahydrofolate (which is the 1st product of folic acid metabolism), allowing for the generation of tetrahydrofolate, which is necessary for synthesis of coenzymes needed for purine and glycine synthesis
  • Both vitamin B12 and folate participate in the methionine synthase reaction, converting the amino acid homocysteine to methionine
    • Therefore serum homocysteine levels will increase in patients with either vitamin B12 or folate deficiency
  • Vitamin B12 also participates in the conversion of methylmalonate to succinate
    • Therefore, serum levels of both homocysteine and methylmalonate will be increased in patients with vitamin B12 deficiency


Describe the process of vitamin B12 absorption and nutrition.

  • Vitamin B12 is only present in foods of animal origin (meat, eggs, dairy products), not vegetables
    • The usual daily dietary requirement of 3-5 µg is easily met by a Western diet, and only very strict vegetarians (vegans) are at risk for a true deficiency state
    • The total body stores offer a 2-4 year supply
  • The steps of absorption are as follows:
    • Vitamin B12 is initially bound to a salivary R-protein until it reaches the duodenum
    • In the duodenum, pancreatic proteases release vitamin B12 from the R-protein
    • B12 binds Intrinsic Factor (IF) which is released by gastric parietal cells.
    • The “IF-B12 complex” binds to receptors in the ileum
    • The complex is transported across the gut wall and the vitamin B12 is released from the IF
    • The vitamin B12 is then bound to transcobalamin II, a transport protein which circulates in plasma carrying vitamin B12 around the body


What are the common causes of vitamin B12 deficiency?

  • Congenital disorders
  • Poor intake (vegans)
  • Malabsorption
    • Intrinsic Factor Deficiency from Pernicious Anemia
      • Autoimmune illness with auto-antibodies that destroy gastric parietal cells (leading to deficient HCL production) and bind intrinsic factor
      • Subsequently, vitamin B12 absorption is impaired
      • Often occurs in older adults, can associate with other autoimmune disorders, and carries a small risk of gastric malignancy
    • Intrinsic Factor Deficiency from Gastrectomy
  • Pancreatic insufficiency
  • Small intestinal disorders
    • Bacterial overgrowth
    • Inflammatory Bowel Disease (Crohn’s) affecting ileum/ileal resection
    • Celiac sprue
    • Malignancy (lymphoma)


What are the clinical features of vitamin B12 deficiency?

  • Hematological consequences: Ineffective erythropoiesis
    • Anemia - Often leads to fatigue, exercise intolerance, and shortness of breath
    • Thrombocytopenia - can result in bruising or bleeding if severe
    • Leucopenia - can result in infections if severe
  • *Neurologic consequences: Sub-acute combined degeneration - demyelination of the neurons of the spinal column and cerebral cortex
    • Brain and cranial nerves - Dementia, personality changes, psychiatric disorders, disturbance in taste, smell
    • Neuropathy - Parasthesias (abnormal sensations) of the hands and feet, loss of vibratory and position sense, unsteadiness of gait
  • Oral manifestations: Soreness of the mouth and tongue, mucosal atrophy
  • Gastrointestinal symptoms: If due to malabsorption:  weight loss, pain, diarrhea


What are the methodologies involved in the laboratory diagnosis of vitamin B12 deficiency?

  • Low serum vitamin B12 level (normal range is 200-500 pg/mL)
    • Results can be misleading:  falsely low levels can be seen in those with:
      • folic acid deficiency
      • pregnancy
      • oral contraceptive use
      • aplastic anemia
      • multiple myeloma
  • Increased methylmalonate:
    • Because a deficiency impairs conversion of methylmalonate to succinate
  • Increased homocysteine:
    • Because a deficiency impairs conversion of homocysteine to methionine
  • *Pernicious Anemia:
    • Anti-parietal cell and/or intrinsic factor antibodies present
  • Schilling test 


What is the Schilling test? What are the steps involved?

  • (Complex and time consuming and is currently not routinely performed)
  • Part one: Is malabsorption present?
    • An oral physiologic dose of radiolabeled vitamin B12 is administered (while the recipient is fasting) followed (in 1-2 hours) by an intramuscular injection of high dose of non-radioactive vitamin B12
    • The non-radioactive IM dose will saturate B12 binding sites in the liver
    • If the radio-labeled vitamin B12 is appropriately absorbed, it will be excreted into the urine
    • Urine is collected and radioactivity counted– individuals with normal capacity to absorb vitamin B12 will have a high urine radioactivity count
      • ​individuals with malabsorption will have a low radioactivity count
  • Part two (performed 1 week later): Is the malabsorption due to IF deficiency?
    • All the steps are the same as part one, except that intrinsic factor is given orally concurrently with the radioactive vitamin B12
    • In this case, individuals with pernicious anemia will excrete high levels of radioactivity since functional intrinsic factor has been supplied
    • Individuals with malabsorption due to other causes will still show low radioactivity counts in the urine since the radiolabeled vitamin is not absorbed


What is the treatment of vitamin B12 deficiency?

  • Vitamin B12 can be administered by an intramuscular (IM) or deep subcutaneous (SC) injection
    • Therapy initially is given daily for 2 weeks, and then monthly for life
  • Oral therapy can be considered for maintenance
    • Most recommend IM or SC to fully replete B12 stores first
  • The response to therapy can be measured as follows: reticulocytes (young red blood cells) are expected to appear in the blood by 2-3 days and maximum 5-8 days after initiating therapy
  • The hematocrit will start to rise at 5 to 7 days, but will take weeks to fully recover
    • Neurologic problems may recover slowly, and some may be irreversible


Describe the nutrition and absorption of folate deficiency.

  • Folic acid is often found in leafy vegetables, but is easily destroyed by cooking
  • An unfortified Western diet barely meets the minimal daily requirement, and therefore folic acid intake may be insufficient in those with poor nutrition or high demand
  • Also, in contrast to vitamin B12, body stores provide only a 3-4 month supply 
  • The absorption of folic acid is similar to that of vitamin B12:
    • Food folic acid is hydrolyzed, reduced and methylated to form methyltetrahydrofolate
    • Absorption occurs in the proximal small intestine
    • Methyltetrafolate is transported across tissues, where it donates the methyl group (to vitamin B12) and serves as a substrate for purine and pyrimidine metabolism and DNA synthesis
    • The liver absorbs folic acid and can contain several milligrams of stores, and recycles folic acid into bile for reabsorption by the gut (enterohepatic circulation)


What are the causes of folate deficiency?

  • Dietary deficiency (in contrast to vitamin B12 deficiency)
    • Alcoholism
    • Elderly
  • Increased requirements
    • Hemolytic anemia (sickle cell anemia)
    • Pregnancy
    • Exfoilative dermatitis/psoriasis
  • Malabsorption
    • Small bowel disorders (celiac disease, inflammatory bowel disease, and lymphoma)
  • Metabolic inhibition
    • Alcohol
    • Drugs
      • dehydrofolate reductase inhibitors - Methotrexate, Trimethoprim
      • Anticonvulsants
  • Loss
    • Hemodialysis


What are the clinical features of folate deficiency?

  • Evidence of malnutrition or alcoholism may be evident
  • The hematologic manifestations are similar to that of vitamin B12 deficiency
  • In contrast to vitamin B12 deficiency, neurologic manifestations are much less common with isolated folic acid deficiency
  • *In pregnancy, folic acid deficiency is associated with neural tube defects


How is folate deficiency diagnosed?

  • Decreased serum folate: (<2 ng/mL)
    • This measure is quite sensitive to diet, and may normalize after 1 hospital meal
    • An acute alcohol binge may impair enterohepatic circulation and result in low levels, even though liver stores are not depleted
    • This test is often done first, and if borderline (between 2-4), an RBC folate may be ordered.
  • Decreased Red blood cell folate: (<280 nm/L)
    • The RBC folate may better reflect tissue folate deficiency, but is low in 50% of patients with primary vitamin B12 deficiency
  • Increased Homocysteine: Decreased conversion of homocysteine to methionine


What is the treatment of folic acid deficiency?

  • *It is important to exclude vitamin B12 deficiency before treating, because folic acid supplementation will correct the anemia but not the neurologic manifestations
    • Treatment is with oral folic acid, 1-5mg daily for 4 months—easily absorbed even in patients with defects in small intestinal function
    • Prophylactic treatment is indicated in patients with high demand (hemolytic anemia and pregnancy)


What are some not so common causes of megaloblastic anemia and macrocytosis?

  • Other Causes of Megaloblastic Anemia (**FYI)
    • Hereditary disorders of DNA synthesis:
      • Orotic aciduria
      • Lesch-Nyhan syndrome
      • congenital dyserythropoietic anemia
      • Acquired disorders of DNA synthesis: Erythroleukemia, Drug-induced causes (anti-retrovirals, chemotherapy)
  • Other Causes of Macrocytosis (Mean Corpuscular Volume > 100):
    • Alcohol
    • Liver disease
    • Hypothyroidism
    • Bone marrow failure states
      • aplastic anemia
      • myelodysplastic syndrome
    • Reticulocytosis
    • Drugs (hydroxyurea, anti-retrovirals)
    • Artifact


Compare and contrast B12 deficiency and folic acid deficiency.

See Table in Learning Guide!