Bone marrow nonneoplastic

Benign changes

Megaloblastic anemia

Topic Completed: 1 November 2013

Minor changes: 14 September 2021

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PubMed Search: Megaloblastic anemia [title] bone marrow

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Cite this page: Zhao X. Megaloblastic anemia. website. Accessed September 21st, 2021.
Definition / general
  • Heterogeneous group of disorders with common morphologic characteristics
  • The morphological hallmark of megaloblastosis is the megaloblast but megaloblastic changes are not limited to erythroid components
    • For example, hypersegmented neutrophils can be seen on peripheral blood smears and pancytopenia can occur
  • Megaloblastosis:
    • A generalized disorder, involving the most rapidly proliferating cells, e.g. gastrointestinal and uterine cervical mucosal cells
  • Megaloblasts:
    • Large cells with an increased nuclear/cytoplasmic ratio with delayed nuclear maturation but more advanced cytoplasmic maturation
    • Megaloblasts are usually abundant in bone marrow aspirates and can also be seen on peripheral blood smear
  • Usually individuals older than 40 years; prevalence increases in older populations
  • Incidence is highest in countries where malnutrition is prevalent and routine vitamin supplementation for the elderly and pregnant is not available
  • In United States, most commonly due to suboptimal food preparation and folate deficiency during pregnancy
  • Pernicious anemia: less common, ~1 case per 7500 per year in U.S., higher incidence in Sweden, Denmark, United Kingdom
  • Primarily bone marrow and peripheral blood are affected
  • General principles:
    • The common feature in megaloblastosis is a defect in DNA synthesis in the rapidly dividing cells
    • To a lesser extent, RNA and protein synthesis are also impaired
    • Therefore, unbalanced cell proliferation and impaired cell division occur as a result of arrested nuclear maturation
    • In the bone marrow, the more mature erythroid precursors are destroyed prior to entering the peripheral blood ("intramedullary hemolysis")
  • The most common causes for megaloblastosis:
    • Cobalamin (Cbl) deficiency
      • Vitamin B12 is a cobalt containing vitamin and is primarily found in meat, fish and dairy products
      • 5'-Deoxyladenosyl-Clb, methyl-Clb and hydroxo-Clb are active forms and occur naturally
      • Cyano-Clb is not a natural form but an in vitro artifact
    • Folate (pterolylpolyglutamates [PteGlus]) deficiency
      • Folates are found in vegetables, fruits and animal proteins
      • Both monoglutamate and polyglutamate forms exist in nature
    • Medications may interfere with pathways
    • Direct interference of DNA synthesis, e.g. by HIV infections and myelodysplastic disorders
  • Cobalamin metabolism:
    • Uptake and metabolism:
      • Dietary cobalamin binds nonspecifically to proteins, later is released by gastric digestion at a low pH → released cobalamin binds to R proteins → the cobalamin-R-protein complexes enter the duodenum → R proteins are degraded by pancreatic enzymes → cobalamin is released and is free to bind to intrinsic factor (IF), which is produced in the gastric fundus and cardia → IF stabilizes cobalamin and transports it to the terminal ileum → cobalamin intrinsic factor complexes are processed by receptors in the terminal ileum → cobalamin is released and absorbed → the absorbed cobalamin is bound to transcobalamin II (TC II) → TC II transports cobalamin to cells that internalize and use cobalamin for DNA synthesis
    • Storage:
      • Transcobalamin I (TC I) may play a role in cobalamin storage
      • Cobalamin is the only water soluble vitamin stored in human body: approximately 3 mg of cobalamin are stored, of which 1 mg is stored in the liver
    • Functions:
      • Interactions between cobalamins (5'-deoxyladenosyl-Clb, methyl-Clb) and folates (pterolylpolyglutamates [PteGlus]) are important for the synthesis of methionine and thymidine and hence DNA synthesis
      • Of note, the mechanisms for patchy demyelination and other neurological consequences of cobalamin deficiency are independent and differ from those responsible for the development of megaloblastic anemia
  • Folate metabolism:
    • Uptake of folate occurs in the jejunum and throughout the small intestine
    • The physiological absorption and transport of folate is receptor mediated
    • In contrast to cobalamin, there is no equivalent of intrinsic factor to stabilize and transport ingested folate
  • The etiology of megaloblastosis is rather diverse, with a common basis of impaired DNA synthesis
  • In brief, the most common causes of megaloblastosis are cobalamin (vitamin B12) and folate deficiency
  • Major causes for cobalamin deficiency:
    • The daily requirement of cobalamin is about 5 - 7 μg
    • Large amounts of cobalamin are stored in liver and other sites, thus cobalamin deficiency only develops about 3 - 4 years after the cessation of cobalamin uptake
    • Accordingly, dietary cobalamin deficiency rarely causes megaloblastic anemia, except in vegans (no meat, eggs or dairy products)
    • Atrophic gastritis and achlorhydria: commonly occur in the elderly → impaired release of protein bound cobalamins
    • Pernicious anemia (the best known cause): autoimmune destruction of gastric parietal cells → failure in secretion of intrinsic factor (IF), in the absence of which cobalamin is not absorbed
      • Pernicious anemia is diagnosed in about 1% of people older than 60 years, with the incidence slightly higher in females
    • H2 antagonists: inhibit IF secretion
    • Pancreatic insufficiency: the release of cobalamins from R proteins is impaired, thus cobalamins are not well absorbed
      • Also, in Zollinger-Ellison syndrome, large amounts of acid inactivates pancreatic enzymes
    • Disorders of the terminal ileum (the site of uptake of cobalamin-IF complexes): tropical sprue, inflammatory bowel disease, lymphoma and ileal resection
    • Blind loop syndrome: bacterial colonization (in intestines deformed from strictures, surgical blind loops, scleroderma, inflammatory bowel disease or amyloidosis) → bacteria compete with the host for cobalamin
    • Diphyllobothrium latum (fish tapeworm, most often found in Canada, Alaska and the Baltic Sea): compete with the host for ingested cobalamin
    • Nitrous oxide exposure: oxidative inactivation of cobalamin
    • Certain hereditary disorders
    • Certain medications: purine analogs (6-mercaptopurine, 6-thioguanine, acyclovir), pyrimidine analogues (5-fluorouracil, 5-azacytidine, zidovudine), ribonucleotide reductase inhibitors (hydroxyurea, cytarabine arabinoside), drugs that affect cobalamin metabolism (p-aminosalicylic acid, phenformin, metformin)
  • Major causes for folate deficiency
    • The daily requirement for folates in adults is approximately 0.4 mg
    • Storage is limited and folate deficiency develops about 3 - 4 weeks after the cessation of folate intake
    • Dietary folate deficiency: in United States, most people obtain sufficient folate from fortified foods
    • Of note, folates are very thermolabile and improper food preparation (e.g. excessive heating) is a major cause for folate deficiency, especially in the elderly
    • Failure to increased folate supplementation in response to increased demand: hemolysis, pregnancy, lactation, rapid growth, hyperalimentation, renal dialysis, psoriasis and exfoliative dermatitis
    • Intestinal disorders: tropical sprue, celiac disease, amyloidosis and inflammatory bowel disease → impede folate absorption
    • Alcoholism: the bioavailability of folate and folate dependent biochemical reactions are impaired
    • Certain hereditary disorders
    • Certain medications: phenytoin, metformin, phenobarbital, dihydrofolate reductase inhibitors (trimethoprim, pyrimethamine), methotrexate and other antifolates, sulfonamides (competitive inhibitors of 4-aminobenzoic acid), valproic acid
  • Other causes for megaloblastosis:
    • HIV infection and myelodysplastic disorders → direct effect on DNA synthesis in hematopoietic and other cells
Diagrams / tables

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Thymidine and methionine synthesis


Clinical features
  • History:
    • May range from asymptomatic to severe anemia and related symptoms (e.g. weakness, cardiopulmonary impairment)
    • Intramedullary hemolysis: lemon color complexion
    • Gastrointestinal symptoms: e.g. loss of appetite, weight loss, nausea, constipation
    • Mental changes, ranging from personality change to psychosis
    • Peripheral neuropathy: numbness, pain, tingling, burning in hands and feet, loss of sensation (e.g. feeling like wearing thin stocking or glove)
    • Unsteady gait and loss of balance: occur in subacute combined spinal cord degeneration
    • Patients with cobalamin deficiency may present primarily with neurological impairment with no anemia; neurologic symptoms range from mild to severe
  • Physical:
    • Findings in mild anemia, especially if gradual and compensated: pale, weak, otherwise asymptomatic
    • Findings in severe anemia: dyspnea, tachycardia and cardiopulmonary distress
    • Findings in anemia with intramedullary hemolysis: increased indirect bilirubin level → lemon yellow complexion
    • Glossitis: smooth tongue (loss of papillae) associated with cobalamin deficiency
    • Dermatologic signs: increased melanin synthesis → hyperpigmentation of the skin and abnormal pigmentation of hair
    • A broad spectrum of mental changes: from irritability to psychosis
    • Peripheral neuropathy: seen in both folate and cobalamin deficiencies
    • Subacute combined degeneration: abnormal gait, loss of balance, speech impairment and loss of proprioceptive and vibratory senses, even blindness due to optic atrophy seen in cobalamin deficiency
    • Abdominal scars: may suggest a blind loop syndrome due to gastric surgery or a lack of ileal absorption of cobalamin due to ileal resection
    • Signs of malabsorption: weight loss, abdominal distention, diarrhea and steatorrhea, often also metabolic bone disease or bleeding due to deficiencies in vitamin K dependent factors, seen in tropic sprue and celiac disease
Laboratory - recommended tests to order
  • Complete blood count (CBC) and peripheral blood smear; lactate dehydrogenase (LDH), indirect bilirubin, iron and ferritin assays
  • Tests for cobalamin deficiency (e.g. serum cobalamin, Schilling test, protein bound absorption test)
  • Tests for folate deficiency (e.g. red blood cell folate, better than serum folate)
  • Diagnostic imaging studies for possible blind loop syndrome
  • Bone marrow aspiration and biopsy
Prognostic factors
  • In general favorable, if the etiology is identified and appropriate treatment provided
  • Folate deficiency during pregnancy can lead to neural tube defects and other developmental disorders in the fetus
  • During therapy for cobalamin deficiency, patients are at risk for hypokalemia and anemia related cardiac complications
Case reports
  • Cobalamin (100 - 1000 μg)
    • Given parenterally daily for 2 weeks, then weekly until the hematocrit value is normal and then monthly for life
    • Cobalamin therapy for patients with mental and neurological impairment due to cobalamin deficiency should be treated with a more aggressive cobalamin protocol
    • Oral cobalamin (1000 - 2000 μg) also can be administered
  • Folate (3 - 5 mg)
    • Should be administered orally, or comparable doses can be administered parenterally
    • Folate should be administered prophylactically during pregnancy, lactation and the perinatal period
    • Fortification of foods and folic acid supplements have been recommended to reduce the risk of pancreatic, cervical and colon cancers
  • Serum ferritin and iron studies should be performed to establish baseline iron levels since iron is consumed when patients are treated with cobalamin and folate and iron supplementation may both be needed
Microscopic (histologic) description
  • Bone marrow core biopsy and aspirate show hypercellular marrow with erythroid hyperplasia:
    • Erythroid precursors show megaloblastic features: cells larger than normoblasts with immature nuclear development
    • Megaloblastic changes are most prominent in more mature erythroid precursors
    • Cytoplasmic maturation is normal but nuclear remnants, Howell-Jolly bodies may be present in the cytoplasm
    • Giant bands (neutrophils) can be present
    • Megakaryocytes may be large and hyperlobulated
  • Of note, bone marrow megaloblastic changes are reversible within 12 hours after treatment with cobalamin or folate and bone marrow morphology appears to be normal within 2 - 3 days → bone marrow aspiration should be performed as soon as possible and preferably before treatment
Microscopic (histologic) images

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Megaloblastic anemia - various images

Peripheral smear description
  • Usually demonstrate macro-ovalocytes, characteristic of megaloblastosis
    • Macro-ovalocytes should be distinguished from macrocytes (not oval, seen in liver disease, hemolytic anemia and in patients with increased red blood cell production)
  • May also reveal megaloblasts and hypersegmented neutrophils (containing 5 lobes in > 5% neutrophils or containing 6 or more lobes)
  • May show red blood cells with multiple Howell-Jolly bodies
  • Macrocytosis due to cobalamin or folate deficiencies may be masked in patients with iron deficiency but hypersegmentation of neutrophils can persist in iron deficiency
Peripheral smear images

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Round macrocytes in liver disease

Macrocytosis with a lymphocyte

Positive stains
Differential diagnosis
  • Critical to distinguish between cobalamin and folate deficiencies: the treatment of the former with folate but not cobalamin may lead to progression of neurological impairment
  • Critical to distinguish among the various causes of cobalamin and folate deficiencies as treatment differs
  • May be misinterpreted as acute leukemia or myelodysplasia when the morphologic changes in hematopoietic cells are very bizarre
  • Consider other potential causes of macrocytosis when clinically appropriate
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