Macrocytic Anemia

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Macrocytic seen in

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• New born
• Megaloblastic anemia

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Megaloblastic anemia

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macro+oval macro

• Vitamin B12 deficiency
• Folic acid deficiency

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Macrocytes seen in

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• Liver disease/Alcoholism
• Hemolysis (polychromatophilic macrocyte)

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Two classes of Macrocytic anemia

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• Megaloblastic- Vitamin B12, folic acid, malignant growth
• Non-megaloblastic- chronic liver disease/alcoholism

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Causes of Macrocytic anemia

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• Reticulocytosis
• Liver disease/alcoholism
• Myelodysplastic syndromes
• Erythroleukemias (FAB-M6)
• Megaloblastic anemia

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Impaired DNA metabolism causes

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systemic effects impairing production of all readily dividing cells of the body

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Impaired DNA metabolism primarily effects:

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• Skin
• Epithelium of the GI
• Hematopoietic tissue

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Megaloblastic amenia is the hallmark for what disease?

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Diseases effecting DNA metabolism

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The root cause of megaloblastic anemia is:

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Impaired DNA deficiency

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Folate deficiency

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• Dietary inadequacy
• Impaired due to drug use
• Excessive loss with renal disease

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Vitamin B12 deficiency

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Dietary deficiency

Impaired transport-transcobalmin II deficiency

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Vitamin B12 deficiency:

Dietary deficiency

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• Inadequate intake
• Increased need during growth
• Impaired absorption

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Vitamin B12 deficiency: Dietary deficiency: Impaired absorption

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• Failure to split from haptocorrin
• Lack on intrinsic factor: gasterctomy, pernicous anemia, malabsorption, competition for the vitamin, D. latum infestation, blind loop syndrome

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Macrocytic (Megaloblastic) anemia is named after

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very large cells of the bone marrow that develop a distinctive morphology due to reduced numbers of division

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Folic acid and vitamin B12 play roles in the _____ of DNA

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synthesis

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MCV in macrocytic anemia

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>100fL

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Classes of macrocytic anemia

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Megaloblastic anemia

Non-meagloblastic

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Pathophysiology of Megaloblastic anemia

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Nuclear maturation defect- impaired DNA synthesis, N/C asynchrony

Systemic effects- impairs production of all rapidly dividing cells

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Etiology of Megaloblastic anemia

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90% of cases due to vitamin B12 or folic acid deficiency of both

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Clinical Finding in Megaloblastic anemia:

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• Anemia-ineffect hematopoiesis, pancytopenia, generic anemia symptoms
• Skin-yellow
• Symptoms of Alimentary Tract
• Effects of B12 and folic acid deficiency

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Symptoms related to Alimentary Tract

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• Loss of epithelium on the tongue resulting in smooth surface and soreness (glossitis)
• Loss of epithelium along the GI tract results in gastritis, nausea or constipiation

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Effects of Vitamin B12 and folate deficiency

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B12

• Neurological symptoms: memory loss, numbness, tingling in toes and fingers, loss of balance, impairment of walking

Folate

• Low folate high homecysteine levels risk for cardiovascular diseaese
• In pregnancy can cause neural tube defects in fetus

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Ineffective hematopoiesis in Megaloblastic Anemia

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• Hypercellular bone marrow
• Pancytopenic peripheral blood
• Intramedullary and intravascular hemolysis

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Bone marrow findings in Megaloblastic anemia

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• Hypercellular
• Erythroid hyperplasia
• Low M:E ratio 1:1 to 1:3
• Megaloblastic picture in all cell lines
• Megaloblastic erythrocytes being the predominant feature

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What makes megaloblastic anemia different from macrocytic

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Morphological changes to RBC: causes a nuclear-cytoplasmic asynchrony; the nucleus will lag behind

Most striking at polychromatophilic normoblast

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CBC results of Megaloblastic anemia

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• Low hematocrit and hemoglobin
• High MCV (100-160fL)
• MCH elevated
• MCHC within reference range
• RDW elevated

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Peripheral blood film Megaloblastic anemia

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• Pancytopenia
• Macrocytes
• Macroovalocytes
• Hypersegs (5 or more lobes)
• Howell-Jolly bodies
• Basophilic stippling
• Cabot rings
• Tear drop cells, fragments, microspherocytes

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Other laboratory Findings in Megaloblastic anemia

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• Increased bilirubin (indicates hemolysis)
• Increased lactate dehydrogenase (LDH) (from increased hemolysis)
• Decreased haptoglobin (protein that binds Hgb and removes damaged cells)

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Causes of vitamin deficiency

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• May be absolute: dietary deficiency
• Impaired use
• excessive loss

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Vitamin B12 (Cobalamin)

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• Large
• Water soluble
• Metabolic active forms: Adenosylcobalamin, Methylcobalamin
• Therapeutic forms: hydroxycobalamin, cyanocobalamin

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Dietary deficiencies of vit. B12 results from

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• Inadequate intake
• increased need
• impaired absorption

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Inadequate intake of B12

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• Possible of strict vegetarian who does not eat, meat, eggs or diary
• Best sources: liver, milk, eggs

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Increase in B12 need during:

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• Pregnancy
• lactation
• growth

Rate of cell replication is vigorous

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Impaired absorption of B12

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• Failure to separate from Haptocorrin
• Lack intrinsic factor
• General malabsorption
• Competition for vitamin B12
• Hereditary transcobalamin deficiency

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Hereditary transcobalamin deficiency is

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• Recessive deficiency of transcobalamin resulting in megaloblastic anemia
• If unrecognized and not treated, permanent neurological damage may occur

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Vitamin B12 is bound by what protein in the saliva

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haptocorrin (transcobalmin I)

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Where and how is B12 released from haptocorrin

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Small intestines by trypsin

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What does B12 bind to in the small intestines?

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Intrinsic factor

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Intrinsic factor is made by

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gastric parietal cells

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Vitamin B12 binding to intrinsic factor is required for absorption by:

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ileal cell

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What is the metabolically active transport protein associated with B12

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holotranscobalamin II

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haptocorrin is also known as

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R-protein

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HC counts for what percentage of B12 vitamin

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10-40%

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What is the primary mechanism of B12 vitamin

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intrinsic factor

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Absorption of B12 can be impaired by:

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• failure to separate haptocorrin-lack of gastric acidity or lack of trypsin
• lack of intrinsic factor-pernicious anemia
• general malabsorption- intestinal disease, surgical resection, irritable bowel disease
• competition for B12- D. latum

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Pernicious Anemia

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Primary cause of B12 deficiency:

• Lack of intrinsic factor: autoimmune, genetic

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Clinical manifestation of Pernicious Anemia

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• Neurological problems
• glossitis

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Impaired Absorption of B12

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• Lack of intrinsic factor
• gastrectomy
• chronic gastritis
• tropical/nontropical sprue
• inflammatory bowel disease

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Competition for B12

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D. latum

Bacteria blind loop syndrome

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B12 Transport Protein Defects

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• hereditary lack of transcobalamin II
• Abnormal transcobalamin II
• Abnormal vitamin B12-binding protein

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B12 dietary deficiency

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strict vegetarianism

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Folic acid deficiency

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• Dietary deficiency of folic acid results when there inadequate intake, increased need, or impaired absorption
• Folic acid: source and requirement
• Folic acid absorption and metabolism, metabolically active form

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Causes of folic acid deficiency

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• Dietary deficiency
• Malabsorption
• increased requirement
• drugs: methotrexate; hydroxyurea

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Diagnosis of Megaloblastic anemias

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• Physical examination
• Medical and family history
• Laboratory tests

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Diagnostic test for B12 Deficiency

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• Screening test: CBC, neutrophil lobe count, bilirubin, LDH
• Diagnostic test: serum B12, serum and urine methylmalonyl CoA: increased, serum and urine homocysteine: increased, Intrinsic factor antibody: present in the serum of 50-70% of patient with PA

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Assay for folate, vitamin B12, and methylmalonic acid

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• Assay for serum folate and vitamin B12: radioimmunoassay
• RBC folate assay may be performed
• Reflective assay for methylmalonyl CoA accumulates

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Reflective assays for methylmalonyl acid if vitamin B12 levels are low:

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• B12 is a cofactor in fatty acid oxidation; it is required for conversion of methylmalonyl CoA to succinyl CoA by the enzyme methlmalonyl mutase
• If B12 is deficient, methylmalonyl CoA accumulates
• Methylmalonic acid is assayed by mass spec

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Additional Diagnostic tests for B12 deficiency and Pernicious anemia

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• Active B12 (Transcobalamin-bound B12)
• Achlorhydria: not specified for PA
• Serum gastrin: 80-90%; not specific for PA
• Antibody to parietal cells: 80-90% of PA, specific for immune gastritis
• Schilling test for PA

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Shilling test

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• Distinguishes malabsorption of vit. B12 resulting from PA from other causes of malabsorption
• Evaluates absorption of vitamin B12
• Oral dose of radioactive B12 is given
• 24-hr urine collection tested for B12
• Presence of radioactive B12 indicates the patient is able to absorb vitamin B12
• If it does not appear in the urine there is an malabsorption problem
• To determine if it's PA,repeat the test in Part 2 intrinsic factor is given orally along with B12

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Algorithm for B12 deficiency

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• B12 <150 pmol/L: B12 deficient
• B12 150-250: additional testing
• B12 >-250pmol/L: unlikely deficiency

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Test for Folic acid deficiency

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• Screened test: CBC, neutrophil lobe count, bilirubin, LDH
• Serum and RBC folate: decreased
• Serum and urine homocysteine: increased

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Treatment for megaloblastic anemia

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appropriate vitamins

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Response to the treatment for megaloblastic anemia

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• High reticulocyte count
• resolution of moprhologic changes
• disappearance of anemia

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Vitamin independent megaloblastic anemia:

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• Inherited: congential dyserythropoiesis
• Acquired: myelodysplastic syndromes, erythroleukemia
• Drugs: methotrexate; hydroxyurea, others
• Toxic materials

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Macrocytic Anemia: Non-megaloblastic anemia

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• Liver Disease
• Alcoholism

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Alcoholism

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• MCV >100 fL, usually about 110fL
• Macrocystosis
• No macroovalocytes
• normal red cell precurcors
• no megaloblasts
• target cells in liver disease

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Macrocytic Anemia: Non-megaloblastic anemia

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• Acute blood loss
• Hemolytic anemia: macrocytosis, polychromasia, high reticulocyte count