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Questions and Answers
What are possible causes of vitamin B12 deficiency?
What are possible causes of vitamin B12 deficiency?
What is the main cause of folic acid deficiency?
What is the main cause of folic acid deficiency?
Clinical manifestations associated with folic acid deficiency prominently feature neuropathies.
Clinical manifestations associated with folic acid deficiency prominently feature neuropathies.
False
What laboratory tests are used for differential diagnosis of vitamin B12 and folate deficiencies?
What laboratory tests are used for differential diagnosis of vitamin B12 and folate deficiencies?
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What treatments are available for vitamin B12 and folate deficiencies?
What treatments are available for vitamin B12 and folate deficiencies?
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What is the initial response to therapy for deficiencies?
What is the initial response to therapy for deficiencies?
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Macrocytic nonmegaloblastic anemias are characterized by low MCV.
Macrocytic nonmegaloblastic anemias are characterized by low MCV.
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What are common causes of macrocytic anemia?
What are common causes of macrocytic anemia?
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What is the major cause of vitamin B12 deficiency?
What is the major cause of vitamin B12 deficiency?
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Pernicious anemia is characterized by atrophic gastritis and decreased gastric secretions.
Pernicious anemia is characterized by atrophic gastritis and decreased gastric secretions.
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What condition is associated with a weak association to pernicious anemia?
What condition is associated with a weak association to pernicious anemia?
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The classic symptoms of vitamin B12 deficiency include weakness, glossitis, and _____ in the limbs.
The classic symptoms of vitamin B12 deficiency include weakness, glossitis, and _____ in the limbs.
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Which of the following is a common symptom of vitamin B12 deficiency?
Which of the following is a common symptom of vitamin B12 deficiency?
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What is the recommended dietary intake of folic acid for adults?
What is the recommended dietary intake of folic acid for adults?
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Folic acid deficiency usually develops over several years.
Folic acid deficiency usually develops over several years.
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What is the initial sign of a positive response to vitamin B12 therapy?
What is the initial sign of a positive response to vitamin B12 therapy?
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Which test evaluates the pathophysiology of vitamin B12 malabsorption?
Which test evaluates the pathophysiology of vitamin B12 malabsorption?
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Match the following conditions with their associated deficiency:
Match the following conditions with their associated deficiency:
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What are the clinical signs of anemia?
What are the clinical signs of anemia?
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What is the mean corpuscular volume (MCV) level associated with macrocytic anemias?
What is the mean corpuscular volume (MCV) level associated with macrocytic anemias?
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Define anisocytosis.
Define anisocytosis.
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Define poikilocytosis.
Define poikilocytosis.
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What does it mean if red blood cells are described as normochromic?
What does it mean if red blood cells are described as normochromic?
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What does it mean if red blood cells are described as hypochromic?
What does it mean if red blood cells are described as hypochromic?
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What are megaloblasts?
What are megaloblasts?
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What deficiency is the primary cause of megaloblastic anemia?
What deficiency is the primary cause of megaloblastic anemia?
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Megaloblastic anemia is a type of microcytic anemia.
Megaloblastic anemia is a type of microcytic anemia.
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Hyper-segmented neutrophils have more than 5 lobes.
Hyper-segmented neutrophils have more than 5 lobes.
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What is the serum level of lactate dehydrogenase (LD) in megaloblastic anemia patients?
What is the serum level of lactate dehydrogenase (LD) in megaloblastic anemia patients?
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Which of the following vitamins are commonly deficient in megaloblastic anemia?
Which of the following vitamins are commonly deficient in megaloblastic anemia?
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Where is vitamin B12 absorbed in the body?
Where is vitamin B12 absorbed in the body?
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What are the expected red blood cell morphology findings in a peripheral smear of a patient with megaloblastic anemia?
What are the expected red blood cell morphology findings in a peripheral smear of a patient with megaloblastic anemia?
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What condition is indicated by the presence of Howell-Jolly bodies in red blood cells?
What condition is indicated by the presence of Howell-Jolly bodies in red blood cells?
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What is the recommended dietary intake of vitamin B12 for adults?
What is the recommended dietary intake of vitamin B12 for adults?
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What role does intrinsic factor play in the absorption of vitamin B12?
What role does intrinsic factor play in the absorption of vitamin B12?
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Study Notes
Anemia
- A low hemoglobin or hematocrit level in a patient.
- Macrocytic anemias have an increased mean corpuscular volume (MCV) greater than 100 fL.
Megaloblastic Anemia
- A common anemia worldwide
- A macrocytic anemia (MCV >100 fL) characterized by defective nuclear maturation due to impaired DNA synthesis
- Often caused by dietary deficiencies of vitamin B12 and/or folate
- Hyper-segmented Neutrophils: Neutrophils with more than 5 lobes, meaning there are more than 5 pieces of the nucleus
- Megaloblasts: Large and abnormal red cell precursors in the bone marrow
- Macro-ovalocytes: Large, oval-shaped red blood cells in the peripheral blood
Megaloblastic Anemia Causes
- Impaired DNA Synthesis: The primary cause of megaloblastic anemia is defective DNA synthesis.
- Nuclear-to-Cytoplasm Asynchrony: The nucleus lags behind the cytoplasm in development, resulting in fewer cell divisions.
- Howell-Jolly Bodies: Chromosomes may become separated during cell division, forming Howell-Jolly bodies (nuclear remnants).
Megaloblastic Anemia Effects on other cell lines
- Hyper-segmented Neutrophils: Increased numbers of neutrophils with more than 5 lobes.
- Giant Metamyelocytes: Granulocyte precursors are larger than normal.
- Abnormal Megakaryocytes: In severe anemia, an abnormal nuclear pattern in megakaryocytes may be seen.
Biochemical Aspects of Megaloblastic Anemia
- Thymidine Triphosphate (TTP) Deficiency: A decrease in TTP synthesis, a key component of DNA.
- Vitamin B12 and Folic Acid Deficiency: These vitamins act as cofactors in key reactions involved in DNA synthesis.
- Drug Interference: Drugs that interfere with the metabolism of vitamin B12 and/or folic acid can also cause DNA impairment.
Clinical Manifestations of Megaloblastic Anemia
- Severity of Symptoms: Can range from mild to severe, with symptoms such as weakness, fatigue, shortness of breath, and lightheadedness.
- Congestive Heart Failure: May or may not be present, depending on the severity of anemia.
- Lemon-Yellow Skin Tint: Mild jaundice and pallor may cause a lemon-yellow skin tint in severe cases.
- Increased Bilirubin: Increased bilirubin is reported in about 30% of patients due to intramedullary hemolysis caused by ineffective erythropoiesis.
Hematologic Features of Megaloblastic Anemia: Ineffective Hematopoiesis
- Increased MCV: MCV values are usually greater than 130 fL, reflecting the megaloblastic picture of the bone marrow.
- Decreased Reticulocytes: Reduced reticulocyte count indicates ineffective erythropoiesis.
- Shortened Life Span of Progenitors: Megaloblastic erythrocyte progenitors are fragile and die prematurely in the marrow.
- Intramedullary Hemolysis: Evidence of intramedullary hemolysis includes decreased haptoglobin, increased levels of serum bilirubin, serum lactate dehydrogenase (LD), and increased serum iron.
- Decreased Erythrocyte Production: Cell death occurs primarily in later stages of erythropoiesis, resulting in decreased production and release of mature erythrocytes.
Hematologic Features of Megaloblastic Anemia Continued: Ineffective Granulopoiesis and Thrombopoiesis
- Increased Bone Marrow White Cell Precursors: Immature white blood cell precursors accumulate in the bone marrow.
- Giant Bands and Giant Metamyelocytes: Larger-than-normal bands and metamyelocytes found in the bone marrow.
- Increased Abnormal Megakaryocytes: Increased abnormal megakaryocytes in the bone marrow and thrombocytopenia in the peripheral blood.
Bone Marrow Morphology in Megaloblastic Anemia
- Hypercellular Bone Marrow: High number of cells in the bone marrow.
- Decreased Myeloid-to-Erythroid (M:E) Ratio: Increased erythroid precursors.
- Degree of Cellularity: The degree of increased cellularity depends on the severity of anemia.
- Megaloblasts: Large cells with increased amounts of RNA and loose nuclear chromatin, demonstrating nuclear-to-cytoplasm asynchrony.
Peripheral Blood Morphology in Megaloblastic Anemia
- Macrocytic, Normochromic Anemia: Increased MCV and normal mean corpuscular hemoglobin concentration (MCHC).
- Severity of Macrocytosis: The MCV is elevated, often ranging from 100 fL to 160 fL, depending on the severity of anemia.
- Decreased Red Cell Count: Generally decreased erythrocyte count.
- Shortened Survival Time of Macrocytes: Macrocytes have a shorter survival time (27 to 75 days) compared to normal red blood cells.
- Decreased Leukocyte Count: Leukocyte count may be normal initially but may decline over time.
- Thrombocytopenia: Platelet counts below 100 × 109/L have been reported in patients with severe anemia.
Peripheral Blood Morphology Continued
- Macrocytes and Macro-ovalocytes: Macrocytes and macro-ovalocytes are often present in the peripheral blood smear.
- Anisocytosis and Poikilocytosis: The degree of variation in red blood cell size and shape (anisocytosis and poikilocytosis) varies with the severity of anemia.
- Other Poikilocytes: Other abnormal red blood cell shapes, such as schistocytes, teardrop-shaped cells, spherocytes, and target cells may be observed.
- Elevated RDW: Increased red cell distribution width (RDW) due to increased anisocytosis.
- Dimorphic Red Cell Morphology: May be present in patients with iron-deficiency anemia, thalassemia, anemia of chronic disease, or hyperthyroidism in addition to megaloblastic anemia.
Peripheral Blood Morphology Continued
- Red Cell Inclusions: Howell–Jolly bodies, basophilic stippling, Cabot rings, and megaloblastic nucleated red blood cells may be seen.
- Decreased Reticulocyte Count and RPI: Decreased absolute reticulocyte count with a reticulocyte production index (RPI) of less than 2, indicating ineffective erythropoiesis.
- Hypersegmented Neutrophils: Neutrophils with 5 or more lobes, often seen in the peripheral blood smear.
Laboratory Tests for Megaloblastic Anemia
- Bone Marrow Examination: Not generally required for diagnosis.
- Elevated Lactate Dehydrogenase (LD): Increased LD levels due to hemolysis.
- Increased Indirect Bilirubin and Urobilinogen: Increased bilirubin and urobilinogen.
- Decreased Haptoglobin: Decreased haptoglobin levels indicate hemolysis.
- Increased Serum Iron and Ferritin: Increased serum iron and ferritin levels.
- Increased Erythropoietin (EPO): Increased EPO levels due to low erythrocyte count.
Vitamin B12 (Cobalamin)
- Structure and Absorption: A large, water-soluble molecule absorbed in the terminal ileum.
- Role of Intrinsic Factor (IF): Parietal cells in the stomach release intrinsic factor (IF) which binds to vitamin B12 and facilitates its absorption in the terminal ileum.
- Sources: Found in foods of animal origin such as liver, fish, poultry, meat, eggs, and dairy products.
- Requirements: Recommended dietary intake for adults is 5 µg/day.
- Storage: Body stores approximately 1 to 5 mg, with 1 to 2 mg stored in the liver.
- Time to Develop Deficiency: Due to significant liver storage and a low daily requirement, it takes several years for a deficiency to develop due to malabsorption.
Vitamin B12 Transport and Metabolism
- Intrinsic Factor (IF): A glycoprotein produced by parietal cells in the stomach that binds to vitamin B12.
- Transcobalamin II (TC II): The main transport protein for vitamin B12 in the plasma, delivering it to tissues for storage and DNA synthesis.
- TC I and TC III: Bind to vitamin B12, preventing loss in the urine.
Vitamin B12 Deficiency
- Dietary Deficiency: Nutritional vitamin B12 deficiency can occur in strict vegetarians.
- Malabsorption: The most common cause of vitamin B12 deficiency.
- Pernicious Anemia: The most common form of intestinal malabsorption, characterized by atrophic gastritis with a decrease in gastric intrinsic factor.
Pernicious Anemia
- Atrophic Gastritis: Atrophy of the gastric mucosa with decreased secretions and intrinsic factor production.
- Autoimmune Mechanism: The cause of gastric atrophy is likely autoimmune in nature with a genetic predisposition.
- Genetic Factors: A weak association between pernicious anemia and the human leukocyte antigen (HLA) has been reported.
- Association with Other Autoimmune Diseases: An association has been observed between pernicious anemia and other autoimmune disorders such as thyroid disease, diabetes mellitus, and rheumatoid arthritis.
- Helicobacter pylori: A major cause of gastritis and peptic ulcers contributes to the development of pernicious anemia.
- Immunologic Factors: Patients with pernicious anemia often have autoantibodies against parietal cells, gastric intrinsic factor, and thyroid tissue.
Vitamin B12 Deficiency
- Vitamin B12 deficiency usually has a gradual onset.
- Patients with pernicious anemia exhibit megaloblastic anemia symptoms, including fever and loss of appetite.
- Glossitis is prevalent in approximately half of patients with vitamin B12 deficiencies.
- Classic symptoms include weakness, glossitis, and paresthesias (tingling or numbness in limbs).
- Bone marrow morphology in vitamin B12 deficiency shows megaloblastic features with macro-ovalocytes in peripheral smears.
- Vitamin B12 deficiency is associated with complications in the gastrointestinal tract, thrombosis, and neurological system.
- Neurological complications are more common in pernicious anemia than other types of vitamin B12 deficiencies.
- Neurological abnormalities can range in severity and affect peripheral nerves and the spinal cord.
- In early stages, peripheral nerves are affected, causing symmetric tingling or numbness in the toes and later in all limbs.
- In later stages, the posterior spinal columns can be involved, leading to clumsiness, an incoordinate gait, severe weakness, stiffness in limbs, impaired memory, and depression.
- Severe psychiatric symptoms are less common but include hallucinations and severe depression.
- Neurological symptoms lasting less than 3 months are usually reversible.
- Left untreated, the neurological symptoms worsen over time, with severity directly proportional to the duration of symptoms.
Folic Acid Deficiency
- Folic acid is a water-soluble vitamin found in various foods, including green leafy vegetables, fruits, dairy products, cereals, and animal foods like liver and kidney.
- The average diet contains 400 to 600 µg of folate, but it is heat-labile and easily destroyed in overcooked vegetables.
- The recommended daily intake of folic acid for adults is 50 to 100 µg.
- The folic acid requirement significantly increases during infancy, pregnancy, and lactation.
- Folate deficiency during early pregnancy (first trimester) can cause neural tube defects in the fetus, leading to paralysis and brain damage.
- The body stores around 5 to 10 mg of folate, mostly in the liver.
- Folate is absorbed in the duodenum and jejunum, with about 80% of intake being absorbed.
- Folate is lost through body secretions like bile, urine, and sweat.
- Folate has a faster turnover and loss rate compared to Vitamin B12, resulting in deficiency developing within weeks or months.
- The primary cause of folic acid deficiency is inadequate dietary intake.
- Malabsorption, increased requirements (pregnancy/lactation), and drug-induced deficiencies (e.g., methotrexate) also contribute.
- Folic acid has been added to cereal grains, rice, and milled flour to increase intake.
- Women planning to become pregnant and in early pregnancy should focus on a folate-rich diet or take supplements to prevent its deficiency.
- Folate deficiency can cause severe birth defects in the spinal cord and brain of a developing fetus, known as neural tube defects (NTDs).
- Clinical features of folate deficiency overlap with those of Vitamin B12 deficiency, including insidious anemia characterized by megaloblastic anemia morphology in bone marrow and peripheral blood.
- While neuropathy is primarily associated with B12 deficiency, cases of neurological abnormalities, such as depression, dementia, and peripheral neuropathy, have been linked to folate deficiency.
Megaloblastic Anemia
- Megaloblastic anemia is categorized as a macrocytic anemia, characterized by defective nuclear maturation due to impaired DNA synthesis.
- The bone marrow of patients with megaloblastic anemia is hypercellular with a low M:E ratio (1:1 to 1:3), high numbers of megaloblasts, and giant bands and metamyelocytes.
- Peripheral blood shows pancytopenia, macrocytes, macro-ovalocytes, and hypersegmented neutrophils.
- Biochemical changes include increased levels of LDH, indirect bilirubin, serum iron and ferritin, and erythropoietin.
- The primary causes of megaloblastic anemia are vitamin B12 deficiency, folic acid deficiency, or a combination of both.
- The major cause of vitamin B12 deficiency is pernicious anemia, a condition characterized by the lack of gastric intrinsic factor.
- Clinical manifestations often associated with vitamin B12 deficiency include anemia, fever, glossitis, and neurological symptoms.
- Other causes of vitamin B12 deficiency involve dietary malabsorption due to various diseases and drug interactions.
Laboratory Diagnosis of Megaloblastic Anemia
- Patient's physical examination, medical history, drug history, family history, and laboratory tests are essential in differentiating megaloblastic anemias.
- The most common laboratory screening tests for megaloblastic anemias are:
- Low hemoglobin level or hematocrit
- High (elevated) MCV
- Peripheral blood smear morphology, including macro-ovalocytes and hypersegmented neutrophils.
Schilling Test
- The Schilling test is used to assess the pathophysiology of vitamin B12 malabsorption and is performed in two parts:
- Part 1: The patient receives 0.5 to 2.0 µg of labeled (57Co or 58Co) vitamin B12 orally. Two hours later, an intramuscular flushing dose (1000 µg) of unlabeled vitamin B12 is administered to saturate circulating cobalamin binders. The amount of labeled vitamin B12 is measured in a 24-hour urine collection.
- Part 2: The test is repeated with the addition of IF to the oral dose to determine if malabsorption is due to a lack of IF.
Treatment of Megaloblastic Anemia
- Most individuals with vitamin B12 deficiency require lifelong vitamin therapy.
- Cyanocobalamin and hydroxocobalamin are the two therapeutic forms of vitamin B12.
- Vitamin B12 can be administered orally to patients with dietary deficiency or those who cannot tolerate parenteral treatment.
- It is usually injected intramuscularly or subcutaneously.
- Vitamin B12 treatment protocols vary, but often involve an initial dose of 100 to 1000 µg/day for 2 weeks, followed by weekly injections until hematological values stabilize, and finally monthly injections for life.
Macrocytic Non-Megaloblastic Anemia
- Causes include liver disease, alcoholism, reticulocytosis, hypothyroidism, myelodysplastic syndrome, and chronic obstructive pulmonary disease.
Summary Points:
- Megaloblastic anemia is caused by defective DNA synthesis leading to ineffective erythropoiesis, granulopoiesis, and thrombopoiesis.
- The Schilling test is used to determine the cause of vitamin B12 malabsorption.
- The initial sign of positive response to therapy is an increase in reticulocyte counts.
- Macrocytic non-megaloblastic anemias have a high MCV, macrocytes in the peripheral blood, and normocellular or hypercellular bone marrow with erythroid hyperplasia.
- The most common causes of macrocytic anemia are liver disease and alcoholism.
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Description
This quiz explores the causes, clinical manifestations, and treatments of vitamin B12 and folate deficiencies. It includes questions on diagnostic laboratory tests and the types of anemia associated with these deficiencies. Test your knowledge on this essential topic in clinical practice.
