Vitamin B12- Chemistry, functions and clinical significance - Comment
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Vitamin B12- Chemical structure, Forms of B12, Sources, absorption, storage, transportation, metabolic role, deficiency, megaloblastic anemia and neurological changes, laboratory diagnosis and treatment. What's covered in this presentation slides: 1. Vitamin B12 – Chemistry, functions and clinical significance Professor(Dr.) Namrata Chhabra Biochemistry for medics- Lecture notes www.namrata.co 1Namrata Chhabra 2. Synonyms • Cyanocobalamine • Anti Pernicious anemia factor • Extrinsic factor of Castle 2Namrata Chhabra 3. Structure • Cobalamin is analogous to heme in its structure having as its base a tetrapyrrole ring. • Instead of iron as a metal cofactor for heme, cobalamin has cobalt in a coordination state of six with o a benzimidazole group nitrogen coordinated to one axial position, o the four equatorial positions coordinated by the nitrogens of the four pyrrole groups and 3Namrata Chhabra 4. Structure of Vitamin B12 oThe sixth position occupied by either a deoxyadenosine group, a methyl group or a CN– group in the commercially available form in vitamin tablets. 4Namrata Chhabra 5. Forms of Cobalamin • Cobalamin (vitamin B12) exists in a number of different chemical forms. • All have a cobalt atom at the center of a corrin ring. • In nature, the vitamin is mainly in the 2-deoxyadenosyl (ado) form, which is located in mitochondria • The other major natural cobalamin is methylcobalamin, the form in human plasma and in cell cytoplasm. • There are also minor amounts of hydroxocobalamin to which methyl- and adenosyl cobalamin are rapidly converted by exposure to light. 5Namrata Chhabra 6. Dietary Sources • Cobalamin is synthesized solely by microorganisms. • Ruminants obtain cobalamin from the foregut, but the only source for humans is food of animal origin, e.g. meat, fish, and dairy products. • Vegetables, fruits, and other foods of non-animal origin are free from cobalamin unless they are contaminated by bacteria. • Strict vegetarians are at risk of developing B12 deficiency. 6Namrata Chhabra 7. Sources of vitamin B12 7Namrata Chhabra 8. Requirements of vitamin B12 • A normal Western diet contains between 5 and 30 μg of cobalamin daily. • Adult daily losses (mainly in the urine and feces) are between 1 and 3 μg (~0.1% of body stores) and, as the body does not have the ability to degrade cobalamin, daily requirements are also about 1 to 3 μg. • Body stores are of the order of 2 to 3 mg, sufficient for 3 to 4 years if supplies are completely cut off. 8Namrata Chhabra 9. Absorption • Two mechanisms exist for cobalamin absorption. • Passive absorption-occurring equally through buccal, duodenal and ileal mucosa; it is rapid but extremely inefficient, 240 pg/ml, • Most patients with overt vitamin B12 deficiency can have serum levels < 170 pg/ml, with symptomatic patients usually having levels < 100 pg/ml. • A level of 170 to 240 pg/ml is borderline. 36Namrata Chhabra 37. Laboratory Findings Estimation of serum methylmalonic acid levels • When the serum level of vitamin B12 is borderline, the diagnosis is best confirmed by finding an elevated level of serum methylmalonic acid (> 1000 nmol/L • However, elevated levels of serum methylmalonic acid can also be due to renal insufficiency. • The Schilling test is now rarely used. 37Namrata Chhabra 38. Essentials of diagnosis • Essentials of diagnosis are macrocytic anemia. • Macro-ovalocytes and hyper segmented neutrophils on peripheral blood smear, and • serum vitamin B12 level less than 100 pg/ml. 38Namrata Chhabra 39. Differential Diagnosis • Vitamin B12 deficiency should be differentiated from folic acid deficiency, the other common cause of megaloblastic anemia, in which red blood cell folate is low while vitamin B12 levels are normal. • The distinction between vitamin B12 deficiency and myelodysplasia (the other common cause of macrocytic anemia with abnormal morphology) is based on the characteristic morphology and the low vitamin B12 level 39Namrata Chhabra 40. Pernicious Anemia • Pernicious anemia is a chronic illness caused by impaired absorption of vitamin B12 because of a lack of intrinsic factor (IF) in gastric secretions. • The disease was named pernicious anemia because it was fatal before treatment became available • The term pernicious is no longer appropriate, but it is retained for historical reasons. 40Namrata Chhabra 41. Pernicious Anemia • Pernicious anemia occurs as a relatively common adult form of anemia that is associated with gastric atrophy and a loss of IF production and • as a rare congenital autosomal recessive form in which IF production is lacking without gastric atrophy. 41Namrata Chhabra 42. Clinical manifestations in Pernicious anemia • General findings: Weight loss of 10 to 15 pounds occurs in about 50 percent of patients and probably is due to anorexia, which is observed in most patients. • Anemia: The anemia often is well tolerated in pernicious anemia, and many patients are ambulatory with hematocrit levels in the mid teens. 42Namrata Chhabra 43. Clinical manifestations in Pernicious anemia Gastrointestinal findings: • Approximately 50 percent of patients have a smooth tongue with loss of papillae. The tongue may be painful and beefy red. These symptoms may be associated with changes in taste and loss of appetite. • Patients may report either constipation or having several semisolid bowel movements daily. This has been attributed to megaloblastic changes of the cells of the intestinal mucosa. • Nonspecific gastrointestinal symptoms include anorexia, nausea, vomiting, heartburn, flatulence, and a sense of fullness. • Rarely, patients present with severe abdominal pain associated with abdominal rigidity; this has been attributed to spinal cord pathology. 43Namrata Chhabra 44. Clinical manifestations in Pernicious anemia Nervous system: • Neurological symptoms can be elicited in most patients with pernicious anemia, and the most common symptoms are paresthesias, weakness, clumsiness, and an unsteady gait. • These neurological symptoms are due to myelin degeneration and loss of nerve fibers in the dorsal and lateral columns of the spinal cord and cerebral cortex. 44Namrata Chhabra 45. Clinical manifestations in Pernicious anemia Genitourinary system: • Urinary retention and • Impaired micturition may occur because of spinal cord damage. • This can predispose patients to urinary tract infections. 45Namrata Chhabra 46. Laboratory Studies • The peripheral smear shows oval macrocytes, hyper segmented granulocytes, and anisopoikilocytosis. • In severe anemia, red blood cell inclusions may include Howell-Jolly bodies, Cabot rings, and punctate basophilia. 46Namrata Chhabra 47. Laboratory Studies • Gastric secretions: Total gastric secretions are decreased to about 10 percent of the reference range. • Most patients with pernicious anemia are achlorhydric, even with histamine stimulation. • IF is either absent or markedly decreased. 47Namrata Chhabra 48. Laboratory Studies • Serum Cbl levels: The serum Cbl is low in patients with pernicious anemia; however, it may be within the reference range in certain patients with other forms of Cbl deficiency. 48Namrata Chhabra 49. Laboratory Studies • Schilling test: The Schilling test measures Cbl absorption by increasing urine radioactivity after an oral dose of radioactive Cbl. • The test is useful in demonstrating that the anemia is caused by an absence of IF and is not secondary to other causes of Cbl deficiency. • It is used to identify patients with classic pernicious anemia, even after they have been treated with vitamin B12 49Namrata Chhabra 50. Laboratory Studies • Serum: The indirect bilirubin may be elevated because pernicious anemia is a hemolytic disorder associated with increased turnover of bilirubin. • The serum lactic dehydrogenase usually is markedly increased 50Namrata Chhabra 51. Histological Findings • The bone marrow biopsy and aspirate usually are hyper cellular and show trilineage differentiation. • Erythroid precursors are large and often oval. 51Namrata Chhabra 52. Complications • If patients are not treated early in the disease, neurological complications can become permanent. • Severe anemia can cause congestive heart failure or precipitate coronary insufficiency. • The incidence of gastric adenocarcinoma is 2- to 3-fold greater in patients with pernicious anemia than in the general population of the same age. 52Namrata Chhabra 53. Prognosis • Early recognition and treatment of pernicious anemia provides a normal, and usually uncomplicated, lifespan. • Delayed treatment permits progression of the anemia and neurological complications. The mental and • neurological damage can become irreversible without therapy. 53Namrata Chhabra 54. Treatment of vitamin B12 deficiency • The indications for starting cobalamin therapy are : • A well-documented Megaloblastic anemia • or other hematological abnormalities • or neuropathy due to the deficiency. 54Namrata Chhabra 55. Treatment of vitamin B12 deficiency • Patients with pernicious anemia have historically been treated with parenteral therapy. • Intramuscular injections of 100 mcg of vitamin B12 are adequate for each dose. • Replacement is usually given daily for the first week, weekly for the first month, and then monthly for life. • It is a lifelong disorder, and if patients discontinue their monthly therapy the vitamin deficiency will recur. • Oral cobalamin may be used instead of parenteral therapy and can provide equivalent results. The dose is 1000 mcg/day and must be continued indefinitely. 55Namrata Chhabra 56. Further reading • A case oriented approach towards Biochemistry- By Namrata Chhabra http://www.jaypeedigital.com/(X(1)S(vclizd4r0zr y5eoz45exstdx))/Book/BookDetail?isbn=9789 350901885 56Namrata Chhabra |
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| Posted by : peter88 | Post date : 2019-11-07 01:48 | ||
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