megaloblastic, Vitamin B12, and folic acid biochem and physic Flashcards
Be familiar with the nomenclature and properties of cobalamin
i) Nucleotide connected to porphrin like corrin ring with central Cobalt
ii) B12-CN attached to cobalt
iii) Found naturally in the body
- Methylcobalamin-methyl attached
- Adenosylcobalamin
Be familiar with nomenclatures and properties of folate.
i) Generic term for compounds that have vitamin activity fimilar to folic acid-double ring attached to para aminobenzoic acid attached to glutamic acid
ii) There’s a reduced form-tetrahydrofolate-carrier of single C
What are the metabolic reactions involving cobalamin?
i) Homocysteine to methionine, methylcobalomin is cofactor
ii) Methyl malonyl-coA to succinyl coA, adenosylcobalamin is cofactor
What are the major functions of folic acid?
a) Coenzymes involved in transfer of single carbon atom units
b) Part of two reactions essential to DNA synthesis
How does cobalamin and folate participate in DNA synthesis?
a) Cobalamin is needed for N5-methyl FH4→ FH4 [→N5,N10methylene FH4], which donates carbon to deoxyuridlate to form thymidilate
i) Cobalamin→methylcobalamine
What are the causes of the causes of intracellular N5, N10 – Methylene Tetrahydrofolate deficiency?
a) Tissue folate deficiency, insufficient N5-methyl FH4 delivery to cells
b) Tissue Cobalamin deficiency: can’t act as cofactor that transfers methyl group from N5 methyl FH4 to homocysteine for its conversion to methionine
i) N5 methyl FH4 trap: N5, N10 methylene FH4 diverted from DNA synthesis since methionine is low, but can’t be converted to FH4 for recyling b/c no cobalamine. Folate accumulates in cell as N5-methyl FH4
ii) Diminishes synthesis of folate polyglutamates: needs N5-formyl FH4 and N10 formyl TH4 to convert folate from monoglutamate to polyglutamate form
c) Dihydrofolate reductase deficiency. Needed to convert FH2 to FH4 which then becomes N5,N10 methylene TH4
What are the food sources, body stores, and daily requirements of cobalamin?
i) Food sources: animal products including dairy products and eggs
ii) Body stores: large, 2-5mg
iii) Daily requirements: small, 1-2 mcg
What are the food sources, body stores, and daily requirements of folate?
i) Food sources: vegetables, fruits, eggs
ii) Body stores: 5-10 mg
iii) Daily requirements: 50-200 mcg folic acid, 100-400 mcg of food folate
What is the mechanism of GI absorption of cobalamin?
i) Stomach: Peptic digestion frees cobalamin from food and attaches to:
- R protein (favored by acidity of stomach), can’t be absorbed
ii) Small intestine:
- Trypsin in pancreatic juice degrades R proteins and cobalmin becomes freed and binds to intrinsic factor (IF)
iii) Terminal ileum: Cbl-IF is absorbed by endocytosis
iv) Blood: transported as Cbl-TCII to blood to go to tissue
What is the mechanism of GI absorption of folate?
i) Folate in foods are polyglutamate forms, must be hydrolyzed to monoglutamates before absorption
ii) Catalyzed by conjugases
iii) Absorbed in jejunum
iv) In intestinal mucosal cell: converted to N5-methyl FH4 monoglutamate
What is the clinical sequelae of cobalamin and folate deficiency?
a) Hematologic: pancytopenia due to megaloblastosis, mucosal megaloblastosis and cell death, primary gastric atrophy in PA, variety of primary GI diseases
b) Reproduction: infertility
c) Cardiopulmonary: secondary to severe anemia
d) Neutropsychiatric: usually only in B12
e) Neural tube defect: folic acid deficiency
What are the features of megaloblastic hematopoiesis?
a) Pancytopenia with decreased retic count
b) Increase MCV and RDW
c) Hyperplastic marrow with increased ineffective hematopoiesis, increased indirect bilirubin and LDH due to destruction of cells in marrow and blood
d) Histological features:
- Hyper segmented PMNs
- Giant metamyelocyte
- Lots of parachromatin-like you can look through it
What lab tests do you use to identify cobalamin and folate deficiency?
a) Tests for cobalamin and folate
- Folate <5% may have cobalamin def
- Both normal: can exclude Cobalamin and folate deficiency
Why are elevated levels of homocysteine and methylmalonic acid used to identify cobalamin and folate deficiency?
a) Methyl THF and Methyl-B12 is needed for homocysteine→methionine
b) B12 is needed for methylmalonyl CoA→succinyl CoA
What are the causes of cobalamin deficiency?
a) Inadequate intake of cobalamin –unlikely
- vegans
b) Inadequate absorption –most common
- Gastic abnormalities: Hereditary IF deficiency, Total gastrectomy, pernicious anemia, Gastritis
c) Pancreatic insufficiency- rare
- Small bowel disease: ilial resection, blind loop or strictures, tropical aprue, celiac disease, Inflammatory bowel disease, fish tape worm
d) Oxidation of cobalamin- laughing gas
e) Defective transport or metabolism-hereditary, rare
- Decreased TCII or enzymatic mutations
