• Cobalamin was not discovered until 1948;its structure became known in 1955.Chemically, cobalamin is a corrin ringsystem consisting of pyrrole rings that holdin their centre a Co atom, to whichvariable ligands (R) are attached.
Absorption & excretionThe presence of sufficient gastric juice isessential to facilitate its absorption inintestine.Storage – liver.Excretion –feces and urine & breast milk
10• Known as the "red" vitamin because it existsas a dark red crystalline compound, VitaminB12 is unique in that it is the only vitamin tocontain cobalt (Co3+) metal ion, which, gives itthe red color.• The vitamin must be hydrolyzed from protein inorder to be active.• Intrinsic factor, a protein secreted byparietal cells of the stomach, carries it to theileum where it is absorbed.• It is transported to the liver and other tissues inthe blood bound to transcobalamin II.• It is stored in the liver attached totranscobalamin I.– It is released into the cell asHydroxocobalamin• In the cytosol it is converted tomethylcobalamin.• Or it can enter mitochondria and be convertedto 5’-deoxyadenosyl cobalamin.Dorothy Crowfoot Hodgkin(1910-1994)Dr. Stadtman in her lab
B12R + B12B12B12IF + B12IF . B12TCII . B12IFIFIFIFIFRRPancreatic proteases(degradation of R protein)Acid pHIleal receptorStomachVitamin B12 absorption
• Metabolism• hepatic• Half-life• Approximately 6 days(400 days in the liver)• Excretion• renal
FUNCTION: Required with folic acid for development of RBCs. Stimulates appetite and required for normalhealth. Cures neurological symptoms of perniciousanaemia.
15FUNCTIONRed Blood Cells – it is essential for productionof RBCsNervous – It improves concentration, memory,& balance.It is important for metabolism of fat,carbohydrate ,proteins, folic acid.It promotes growth and increases apatite.
BIOCHEMICAL FUNCTIONS OF B121. Methylmalonyl-CoA-isomerase: Itcatalyzes the reaction using B12 as acoenzymeMethylmalonyl-CoA → succinyl-CoA2. Methionine synthase or homocysteinemethyl transferase requires B12 ascoenzyme:
3. Conversion of Ribonucleotide todeoxyribonucleotide also needs B12. It isimportant in the synthesis of DNA hencedeficiency of B12 leads to the defectivesynthesis of DNA.4. Role as Hemopoietic Factor: Like folic acid,vitamin B12 is also concerned withhemopoiesis and is needed for maturationof RBCs.
5. Abnormal Homocysteine Level: Invitamin B12 deficiency, HomocysteineConversion to methionine a block so thathomocysteine is accumulated, leading tohomocystienuria. Homocysteine level inblood is related with myocardialinfarction. So1, B12 is protective againstcardiac disease.
Demyelination and Neurological Deficits: InB12 deficiency, methylation ofphosphatidyl ethanolamine to phosphatidylcholine is not adequate. This leads todeficient formation of myelin sheaths ofnerves, demyelination and neurologicallesions.
20Daily requirementMen – women – 1 mcgChildren –.2-1 mcg.Infant – 0.2 mcg
CAUSES OF B12 DEFICIENCY:1. Nutritional B12 deficiency.2. Decrease in absorption due to non-availability of absorptive sufface causedby gastrectomy, resection of ileum, blindloop syndrome.3. Elderly people are unable to absorb B12
4. Addisonian anemia is pernicious [fatal] withoutany remedy. It is manifested in persons 40years of age. It is an autoimmune disease andantibodies are formed against IF. Thedeficiency of IF leads to defective absorption ofB12.5. Atrophy of gastric epithelium: It leads todecreased IF and decreased absorption ofB12.
6. Drugs: Some drugs interfere withabsorption of B12. These are phenphormin,cholchicine, neomycine, ethanol and KCl.7. Increased requirement of B12 in pregnancyis common cause for vitamin B12deficiency.
24DEFICIENCYANEMIA it leads to Megaloblastic orpernicious anemiaDemyelination & irreversible nerve cell death.ORALThere is sore painful tongue, glossitis andglossodynia.
Tongue is inflamed & beefy red in coloursmall shallow ulcers resembling Apthousulcers on the tongue with atrophy of papillaewith a loss of normal muscle tone is calledhunters glossitis
Vitamin B12 (Cobalamin)Vitamin B12 (Cobalamin)Common initial sign of B12deficiency:The red sore tongue, withatrophy of the papillae isoften present in perniciousanemia and, in the caseillustrated,angularstomatitis is also present.
Vitamin B12 (Cobalamin)Vitamin B12 (Cobalamin)Pallor of perniciousanemia:There is a pronounced lemon-yellowish tint to the skintogether with faint icterus ofthe sclerae due tohyperbilirubinanemia. The skinis often velvety smooth, yetinelastic. It is remarkable howfrequently patients haveblonde or prematurely greyhair and light-colored irises.
Toxicity• Allergies to this vitamin are rare, and reactions (thesymptoms for which include acne, eczema, and aswelling or crusting of skin around the lips) usuallyoccur with injections, rather than tablets.• Rare side effects consist of itchy skin, wheezing,and diarrhea.• Life-threatening symptoms, usually resulting fromoverdose, consist of faintness (from anaphylaxis),,itching, and rash.
31MANAGEMENToral – in a dose from 6 to 150mcg. takenin these doses it helps in the treatment oflack of concentration, depression, poormemoryparental – 1000mcg of vitamin given twiceweekly in cases of anemia
BIOCHEMISTRY PEARLSVitamin B12 (cobalamin) plays a criticalrole in DNA synthesis and neurologicfunction.Cobalmin deficiency can lead to a widespectrum of hematologic,neuropsychiatric, and cardiovasculardisorders that can often be reversed byearly diagnosis and prompt treatment.
Cobalamin absorption from thegastrointestinal tract requires thepresence of a protein (the intrinsic factor,IF) secreted from the parietal cells thestomach to bind cobalamin and aid in itsabsorption in ileum.
• A 38-year old vegetarian (vegan)Caucasian female presents to her primarycare doctor with fatigue and tingling/numbness in her extremities (bilateral).The symptoms have been graduallygetting worse over the last year. Uponfurther questioning she reports frequentepisodes of diarrhea and weight loss.
• On exam, she is pale and tachycardic. Hertongue is beefy red and a neurologicexam reveals numbness in all extremitieswith decreased vibration senses. A CBCdemonstrates megaloblastic anemia.
What is the most likely diagnosis?What is the most likely underlying problemfor this patient?What are the two most common causes ofmegaloblastic anemia and how would thispatient’s history and examinationdifferentiate the two?