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VITAMIN B12 HISTORY In the 1850s the English physician Thomas Addison described a lethal (pernicious) form of anaemia that could be related to pathological gastric mucosa and associated with the absence of acid in the stomach.
Thomas Addison 1795 - 1860 As described by Addison, patients with pernicious anaemia had symptoms of macrocytic anaemia, glossitis, and neurological signs such as paraesthesias and abnormal gait. There was no treatment for this disease and it was invariably fatal. Patients were left exhausted, were hospitalised, and had no hope of cure. Georges Richard Minot, an MD from Harvard, had the idea that something in food might help patients. In 1923 Minot teamed up with William Parry Murphy basing their investigations on previous work by George Whipple at Johns Hopkins. Whipple had bled dogs to make them anaemic and then determined which foods restored red blood cells. Red meat and some vegetables were effective, but liver was best of all. In 1926, at a meeting in Atlantic City, Minot and Murphy reported the sensational finding that 45 patients with pernicious anaemia had been cured by ingestion of large quantities of raw liver and that "clinical improvement had been obvious, usually within 2 weeks" There was much scepticism at the time but for their research Minot, Murphy, and Whipple received the Nobel Prize for Medicine in 1934. Still however, the active ingredient in liver was not known. Three years later William Castle also at Harvard, discovered that something in the stomach must be related to the disease as people with removal of the stomach often died of pernicious anaemia, liver did not work as a cure. He postulated an "intrinsic factor", present in the gastric mucosa, was necessary for normal absorption of the "extrinsic factor" in the liver. The "intrinsic factor" was lacking in pernicious anaemia patients. In 1948 the "extrinsic factor" was isolated in crystalline form from liver by Karl Folkers and his co-workers at Merck and named vitamin B12 and in 1956, the British chemist, Dorothy Hodgkin, described the structure of this large molecule, for which she received the Nobel Prize for Chemistry in 1964. In 1971 the organic chemist Robert Woodward (himself a Nobel laureate in 1965) announced the successful synthesis of the vitamin after ten years of effort.
Vitamin B12 structure A disease that had been fatal could now easily be treated by injections of pure vitamin B12, and without side effects. The patients recovered completely. Vitamin B12 deficiency was firmly linked with the concept of anaemia. However the haematological symptoms in vitamin B12 deficiency were accompanied by many other symptoms (as described by Addison) particularly neurologic or neuropsychiatric changes. These symptoms were long believed to be secondary to the anaemia. The prevailing idea maintained that no vitamin B12 deficiency occurred without anaemia. Recently, It has become evident that anaemia is just one of many symptoms of B12 deficiency, and that symptoms can frequently not be accompanied by anaemia at all. The prevalence of vitamin B12 deficiency is more common than ever expected. True pernicious anaemia with a lack of intrinsic factor, constitutes only a small fraction of all cases. Far more common may be malabsorption due to mild or moderate atrophic gastritis arising from decreased secretion of gastric acid required for the cleavage of protein-bound vitamin B12 from food. Moreover, it has been demonstrated that lifestyle factors, such as smoking and high alcohol consumption, impair cobalamin status, as may many drugs. Common genetic polymorphisms affecting enzyme activity have been found to influence metabolism thereby affecting vitamin requirement. The diagnostic challenge concerns those patients that are vitamin B12 deficient, and who would benefit from treatment, without clear signs or symptoms and/or the presence of anaemia. It is difficult to diagnose these patients but important to do so since neurological impairment may be irreversible if treatment is initiated too late. VITAMIN B12 IS BOUND TO AND TRANSPORTED BY PROTEINS Dietary vitamin B12 enters the stomach bound to animal proteins and is released from them by the action of pepsin and hydrochloric acid. The free vitamin B12 is then captured by the binding protein haptocorrin (HC). In the small intestine haptocorrin is degraded by pancreatic enzymes and the released vitamin B12 is complexed with intrinsic factor (IF) a protein synthesised by gastric parietal cells. The IF-vitamin B12 complex is then internalised in the small intestine by a receptor mediated mechanism and thereafter IF is proteolysed. Subsequently only vitamin B12 enters the circulation. In the circulation vitamin B12 is bound to two proteins, transcobalamin (TC) and haptocorrin (HC). Vitamin B12 bound to transcobalamin is known as holotranscobalamin (holoTC). HoloTC (or Active-B12) is the biologically active fraction that is delivered to all tissues of the body whereas the function of haptocorrin is unknown. After cellular uptake of HoloTC or Active-B12 transcobalamin is degraded and vitamin B12 serves as a coenzyme for two enzymatic reactions; the conversion of methylmalonyl-CoA to Succinyl-CoA and the conversion of homocysteine (Hcy) to methionine.
Persons with genetic deficiency of, or non-functional, transcobalamin show characteristic haematologic and/or neurologic and/or metabolic pathologies of B12 deficiency at an early age. They, however, can often present with serum B12 concentrations well within the normal range. Absence or dysfunction of transcobalamin is serious and potentially fatal, whereas lack of haptocorrin seems benign and is usually discovered accidentally. Under normal circumstances, approximately 70% -90% of serum B12 is bound to haptocorrin, and 10-30% to transcobalamin. This fact, coupled with the shorter half-life of transcobalamin bound vitamin B12 compared to haptocorrin bound vitamin B12, makes a decrease in serum holotranscobalamin levels a likely early marker of B12 deficiency. THE METABOLIC ROLE OF VITAMIN B12 There are several different forms of vitamin B12, or cobalamins, but only two cobalamins are metabolically active: methyl- and adenosylcobalamin. The common feature for all cobalamin forms is a corrin ring with a central cobalt atom. The commercially available forms, used for treating deficiency: hydroxo- (OHCbl) and cyanocobalamin (CnCbl), are converted within the body into the active forms.
Adenosylcobalamin mediates the mitochondrial conversion of methylmalonyl-CoA to succinyl-CoA, which enters the tricarboxylic acid cycle. Adenosylcobalamin is therefore of importance for lipid and carbohydrate metabolism. Deficiency of adenosylcobalamin leads to accumulation of methylmalonic acid (MMA). Methylcobalamin is a co-factor for methionine synthase (MS) in the conversion of homocysteine to methionine in the methylation cycle. This reaction requires methyltetrahydrofolate (methylTHF) as a substrate, and constitutes a unique point of interaction between two vitamins, vitamin B12 and folate. A deficiency of methylcobalamin and/or methylTHF causes increased total levels of homocysteine (tHcy). Both folate and vitamin B12 deficiency can cause megaloblastic anaemia. The macrocytic anaemia seen in vitamin B12 deficiency is actually a secondary deficiency of active folate forms. The underlying mechanism is that vitamin B12 deficiency blocks the transformation of methylTHF to THF and to intracellular folate polyglutamates. The result is inadequate levels of the formyl and methylene derivatives needed for the synthesis of nucleic acid precursors. Both folate and vitamin B12 deficiency also result in decreased synthesis of S-adenosylmethionine (SAM). SAM is essential for over 100 identified essential methylation reactions, such as the methylation of nucleic acids (DNA and RNA), phospholipids (myelin), polysaccharides, and catecholamines, and many other molecules. Data generated from clinical observations of hereditary enzymatic defects, leading to inhibition of adenosylcobalamin or methylcobalamin synthesis, supports the view that methylation is crucial for normal neurological function. In animal models cobalamin neuropathy can be induced by inactivation of methylcobalamin, The close interaction between vitamin B12 and folate explains why the symptoms in B12 and folate deficiency may be identical. In summary, functional vitamin B12 deficiency, due to disturbed absorption or distribution, or a defect in some enzyme implicated in the methylation cycle, results in impairment of both cell division and of methylation of phospholipids, proteins, catecholamines and polysaccharides. WHAT ARE THE SYMPTOMS OF B12 DEFICIENCY?The initial symptoms of vitamin B12 deficiency are insidious and could easily be overlooked. The classical symptoms of anaemia are by no means obligatory. Early symptoms/findings of anaemia may also be masked by excess folic acid, or concurrent iron deficiency. Diffuse neuropsychiatric symptoms may often be the earliest symptoms. The commonest neurological symptoms in vitamin B12-deficiency are paraesthesia of the hands and feet, diminished perception of vibration and position, absence of reflexes, and unsteady gait and balance (ataxia), but the range of symptoms is broad. The psychiatric symptoms associated with vitamin B12 deficiency are also varied and fall into several different clinical categories. Confusion and memory disturbances are the most common. Depression, with or without psychotic components, and cognitive decline are frequent. Swings in mood and personality changes may be early signs of what may later be manifested as psychiatric disease. Such vague symptoms of vitamin B12 deficiency are easily overlooked, especially as the serum concentration of vitamin B12 can lie within the reference range. Many disorders in the gastrointestinal tract can give rise to a deficiency of vitamin B12. Symptoms from the gastrointestinal tract, more or less pronounced, may be present, as well as poor mucosal function with subsequent specific symptoms such as glossitis. Elderly persons are especially at risk of developing a vitamin B12 deficiency. Age-related, often asymptomatic atrophic gastritis is common and may be enough to cause a patient to slide slowly into a negative vitamin B12 balance with depleted stores of the vitamin, giving rise to vitamin B12 deficiency. Infants of vegetarian/vegan mothers are also in danger of developing vitamin B12 deficiency, even though their mothers may not suffer from disorders of B12 absorption and do not show any deficiency symptoms. This is due to the relatively high requirement in the rapidly growing child. Vitamin B12-deficiency concomitant with auto-immune diseases other than pernicious anaemia is often seen. |
NewsComing Soon ! The full video recording of the Euromedlab 2007 Active B12 workshop will be available in the next few weeks, register for your copy.
Live CME Web Conference on vitamin B12 deficiency, Prof. Ralph Green, Dec 13th 2007, register now. Meetings
8-11 December, 2007 |
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