Amazoniac
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- Vitamin B12 among Vegetarians: Status, Assessment and Supplementation
- Treatment of vitamin B12 deficiency–Methylcobalamine? Cyancobalamine? Hydroxocobalamin?—clearing the confusion
- Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians | The American Journal of Clinical Nutrition | Oxford Academic
"A common mistake is to think that the presence of dairy products and eggs in the diet, as in LOV [Library of Virginia], can still ensure a proper intake of Cbl, despite excluding animal flesh. In reality, consumption of such foods, despite containing significant amounts of Cbl, would be sufficient neither on a daily basis nor in order to meet vitamin requirements [18].[*] A Dietary Reference Intake (DRI) of 2.4 μg/day for Cbl in adults is a common chosen value [19,20]. Such an amount is apparently exceeded by American adults, with a mean intake ranging from 4.6 to 6.3 μg/day [21]. However, it is not uncommon to see a moderate deficiency among omnivores in Western countries [22,23]. A recent report by the European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies established an Adequate Intake (AI) of 4 μg/day for adults, with a mean intake in European countries ranging between 4.2 and 8.6 μg/day [24]."
In the vegetarian diet, there are few sources of Cbl, whilst supplement use is frequently resisted.
Although some plant foods seem to represent a significant source of Cbl [30,31], data in the literature are still insufficient to determine whether Cbl is found in the active form, and whether regular consumption of these foods can be sustainable when the variability in the production processes is taken into account."
"In the cell, the Cbl isoforms are metabolized inside the peroxisome by the reactions of dealkylation, decyanation and reduction, and then released in the specific cell compartment as coenzyme Me-Cbl and Ado-Cbl, according to their cytosolic or mitochondrial fate, respectively [46]. This step is crucial in the activation of the provitamin forms. Other corrinoid compounds do not fulfill the vitamin functions, in all probability due to the binding power of the lower ligand with the cobalt, which does not allow peroxisome activation [45]. It seems that all isoforms, provitamins and coenzymes should follow a mandatory route before being assigned to the appropriate cell district. However, the H-Cbl form may be more reactive, and its use can be facilitated by a number of enzymatic processes through non-specific cellular reactions [47]. If this mechanism were confirmed, the use of already active Cbl cofactors would not represent any provitamin advantage [45]. In 1982, Gimsing et al. analyzed Cbl in tissues from patients with pernicious anemia. After administration of H-Cbl or Cn-Cbl, they found that detected plasma Cbl was dependent on the form administered, dominant in the blood pattern. Results from erythrocytes and liver biopsies showed no differences, irrespective of the Cbl form used, indicating that administered Cbl preparations are converted in vivo to the necessary coenzymes [48]. Although current studies have many limitations and altogether there are no significant differences, the retention percentage after oral ingestion may change between different forms [49]. Following the ingestion of 1 μg of Cbl, the retention of Ado-Cbl and H-Cbl is 34% and 56%, respectively. Following the ingestion of 5 μg of Cbl, the retention of Ado-Cbl and Cn-Cbl is 13% and 20%, respectively. Following the ingestion of 25 μg of Cbl, the retention of Cn-Cbl and Ado-Cbl is 6% and 8%, respectively [50]. Updated data are not currently available."
"Supplementation is often avoided due to preconceptions and aversion to products which are thought to be artificial, or due to the myth that the shortage will manifest itself only in rare cases after many years of ceased intake, an idea also supported by some researchers [115]. Although the shortage is documented in the macrobiotic community, many feel reluctant to use supplements, fortified foods, and more generally, processed foodstuffs [116]."
"The concomitant use of more specific markers enables a more detailed diagnosis. In adult German vegetarians, Cbl deficiency was present in 58%–66% or 61%–72% of participants if both criteria HTCII/MMA or HTCII alone were adopted, respectively [84,91,93,95]."
"Although in the past it was thought that only [vegans] were at risk of vitamin deficiencies, recent studies indicate that even the [lacto and ovo and vegetarians] are at risk [125,126,127]. Herrmann et al. found that deficiency rates among LOV/LV and VN were 32% and 43%, respectively [85]. Supplementation in LOV/LV was effective in reducing deficiency rates from 68% to 31%, but the amounts were still insufficient [18]. Also the increase of MCV and RDW, associated with the lack of Cbl, leads to the increased cardiovascular risk [128,129]. Neurological manifestations of vitamin deficiency can also occur in the absence of anemia [130]."
"Supplements have been demonstrated as efficient in the restoration of Cbl blood concentration [97,138]. Currently, the official position of associations and government agencies is categorical and unequivocal: in the case of a vegetarian diet, including LOV, LV and OV, supplementation of Cbl is required [11,13]. Cbl concentration per 100 g of cow’s milk, dairy products and chicken eggs ranged from 0.5 to 0.4 μg, from 4.2 to 3.6 μg, and from 2.5 to 1.1 μg, respectively [139,140]. Taking into account the losses during cooking and the specific absorption rate, these quantities are not sufficient to ensure the daily intake in a balanced diet [141]."
"Its safety has been demonstrated through the use of an ultra-high parenteral dose of 25 mg daily for 10 days followed by 25 mg monthly for five months [150]."
"The therapeutic administration of oral Cbl has proven to be as effective as intramuscular administration [152]. This is very useful, as intramuscular administration is far more expensive and rather painful for the patient, as well as not being free from complications [153]."
"Since the crystalline form of Cbl is not bound to food proteins, the bioavailability in supplements is equal, if not superior."
"The vegetarian diet is very high in fiber, which may reduce the ability to absorb some nutrients efficiently [156]. An excess of fiber in the diet could disrupt the re-absorption of the Cbl mechanism through enterohepatic circulation, although there is no evidence to confirm that this happens in humans [157]."
"The consumption of oral doses of 1 μg, 10 μg, 50 μg, 500 μg, 1000 μg, are absorbed with an efficiency of 56%, 16%, 3%, 2%, 1.3%, respectively [151]."
"Using multivitamins can be inefficient and counterproductive for the supplementation of Cbl. The Cbl can be degraded in the presence of vitamin C and copper with the formation of inactive by-products. These compounds can inhibit the transport system interacting with transporter proteins [172,173]. Nutritional yeast fortified with Cbl is available in the USA, though its use may be less effective than supplements, in the case of deficiency [97]."
"[..]an Italian study has shown that selected types of oyster mushrooms grown in the southern areas of Italy show a wide range of concentrations of Cbl from 0.44 to 1.93 μg/100 g, as detected by ELISA immunoassay. The highest concentration was found in the species Pleurotus nebrodalis, typical of the mountain areas in central Sicily [176]. Less common mushrooms such as Craterellus cornucopioides or Cantharellus cibarius may contain 1.09–2.65 μg/100 g [177]. Shiitake mushrooms, popular among vegetarians, can contain up to 5.61 ± 3.9 μg of Cbl per 100 g of dry weight (mostly in active form), although with great variability [178]. Even in this case, although a portion of 50 g of dried shiitake could be adequate to achieve the daily requirement, it is unlikely that this will happen daily. Among the most widely used edible seaweeds, Enteromorpha sp. and Porphyra sp. (also known as nori) contain relevant amounts of Cbl ranging from 32.3 to 63.6 μg/100 g [179]. In vitro tests are promising, but there are not enough human clinical trials to consider the use of seaweed as favorable in vitamin provision [180,181]. In a clinical trial of six vegan children, the daily use of nori seaweed seemed to prevent Cbl deficiency, measured via serum Cbl [182]. In disagreement with these data, Dagnelie et al. found no positive effects in using nori seaweed and spirulina on Cbl-deficient children [183]. The Cbl content of other edible macroalgae is negligible and approximately zero [184]."
"Some fermented vegetable foods, such as sauerkraut, natto and tempeh, can have significant amounts of Cbl. It is unlikely that their daily use in Western countries represents a stable source of Cbl. The presence of Cbl in these foods depends on environmental bacteria randomly present in the fermentative microorganism pool [194]. It is very difficult to standardize the content from one product to another as they are subject to wide variation. Tempeh, for example, during the fermentation of soy beans can develop Cbl in a range between 0.7 to 8 μg per 100 g [195]. Other fermented soy foodstuff has only trace amounts of Cbl [196,197]. In sauerkraut production, the addition of Proprionibacteria sp. to cabbage may boost Cbl concentration up to 7.2 μg/100 g [198]. The use of organic fertilizer can increase the content of Cbl in spinach leaves up to 0.14 μg/100 g. However, the quantity of spinach that needs to be ingested in order to satisfy the daily requirement would be prohibitive [199]."
"According to Carmel, a single oral dose of 50 μg, 500 μg or 1000 μg will be absorbed at an amount of 1.5 μg, 9.7 μg or 13 μg, respectively [151]."
"There were no apparent substantial differences between the absorption of sublingual and oral forms [152,206]. However, oral dissolution could be critical in the secretion of the salivary R-binder and its subsequent bond. Since the Cbl would not be dissolved, about 88% could be not absorbed [54]. Since the development of a Cbl deficiency can also be observed among the LOV, the use of a supplement is necessary, regardless of the type of vegetarian diet [110]."
"If rare genetic defects of cellular trafficking and processing proteins exist, the choice of alternative forms of Cbl, such as Me-Cbl or H-Cbl could improve the effectiveness of supplementation [154,208,209,210]."
"The current data do not support the theory that vitamin deficiency needs 20–30 years to be manifested [125]."
"[..]cobalamin displays other functions, not strictly metabolic, that could be lacking when deficient. A vitamin B12 deficiency could be related to oxidative stress markers like plasma glutathione, malondialdehyde and serum total antioxidant capacity, which could contribute to a neurophysiological disturbance [220]. Furthermore, Cbl, particularly H-Cbl, can act as a detoxifying agent, removing potentially dangerous cyanid molecules from the body [212]."
.*This doesn't seem too unlikely given that milk is meant to be ingested as a sole food throughout the day in small amounts at a time.
"The main source of consumption in the general population comes from animal foods with a significant contribution from milk and dairy products [25]. Losses of up to 50% can occur through food processing which involves cooking, pasteurization and exposure to fluorescent light. This limits its availability, together with a drop in absorption capacity and an increase in Cbl concentration in food [26]. Some researchers claim that the currently recommended intake levels may not be sufficient for an adequate daily intake, with particular regard to aging and the physiological reduction in absorptive capacity [27]. With senescence, the epithelial cells of the stomach reduce their ability to biosynthesize the transporter proteins of Cbl. The gastric secretion ability is necessary both for the dissociation of Cbl from foods and for the binding to the carriers [28]. For these reasons, the American Institute of Medicine recommends a supplementation of Cbl for people of 50 years of age and older [19]. The development of blood and cognitive disorders are rather common aspects found among the elderly population [29].In the vegetarian diet, there are few sources of Cbl, whilst supplement use is frequently resisted.
Although some plant foods seem to represent a significant source of Cbl [30,31], data in the literature are still insufficient to determine whether Cbl is found in the active form, and whether regular consumption of these foods can be sustainable when the variability in the production processes is taken into account."
"In the cell, the Cbl isoforms are metabolized inside the peroxisome by the reactions of dealkylation, decyanation and reduction, and then released in the specific cell compartment as coenzyme Me-Cbl and Ado-Cbl, according to their cytosolic or mitochondrial fate, respectively [46]. This step is crucial in the activation of the provitamin forms. Other corrinoid compounds do not fulfill the vitamin functions, in all probability due to the binding power of the lower ligand with the cobalt, which does not allow peroxisome activation [45]. It seems that all isoforms, provitamins and coenzymes should follow a mandatory route before being assigned to the appropriate cell district. However, the H-Cbl form may be more reactive, and its use can be facilitated by a number of enzymatic processes through non-specific cellular reactions [47]. If this mechanism were confirmed, the use of already active Cbl cofactors would not represent any provitamin advantage [45]. In 1982, Gimsing et al. analyzed Cbl in tissues from patients with pernicious anemia. After administration of H-Cbl or Cn-Cbl, they found that detected plasma Cbl was dependent on the form administered, dominant in the blood pattern. Results from erythrocytes and liver biopsies showed no differences, irrespective of the Cbl form used, indicating that administered Cbl preparations are converted in vivo to the necessary coenzymes [48]. Although current studies have many limitations and altogether there are no significant differences, the retention percentage after oral ingestion may change between different forms [49]. Following the ingestion of 1 μg of Cbl, the retention of Ado-Cbl and H-Cbl is 34% and 56%, respectively. Following the ingestion of 5 μg of Cbl, the retention of Ado-Cbl and Cn-Cbl is 13% and 20%, respectively. Following the ingestion of 25 μg of Cbl, the retention of Cn-Cbl and Ado-Cbl is 6% and 8%, respectively [50]. Updated data are not currently available."
"Supplementation is often avoided due to preconceptions and aversion to products which are thought to be artificial, or due to the myth that the shortage will manifest itself only in rare cases after many years of ceased intake, an idea also supported by some researchers [115]. Although the shortage is documented in the macrobiotic community, many feel reluctant to use supplements, fortified foods, and more generally, processed foodstuffs [116]."
"The concomitant use of more specific markers enables a more detailed diagnosis. In adult German vegetarians, Cbl deficiency was present in 58%–66% or 61%–72% of participants if both criteria HTCII/MMA or HTCII alone were adopted, respectively [84,91,93,95]."
"Although in the past it was thought that only [vegans] were at risk of vitamin deficiencies, recent studies indicate that even the [lacto and ovo and vegetarians] are at risk [125,126,127]. Herrmann et al. found that deficiency rates among LOV/LV and VN were 32% and 43%, respectively [85]. Supplementation in LOV/LV was effective in reducing deficiency rates from 68% to 31%, but the amounts were still insufficient [18]. Also the increase of MCV and RDW, associated with the lack of Cbl, leads to the increased cardiovascular risk [128,129]. Neurological manifestations of vitamin deficiency can also occur in the absence of anemia [130]."
"Supplements have been demonstrated as efficient in the restoration of Cbl blood concentration [97,138]. Currently, the official position of associations and government agencies is categorical and unequivocal: in the case of a vegetarian diet, including LOV, LV and OV, supplementation of Cbl is required [11,13]. Cbl concentration per 100 g of cow’s milk, dairy products and chicken eggs ranged from 0.5 to 0.4 μg, from 4.2 to 3.6 μg, and from 2.5 to 1.1 μg, respectively [139,140]. Taking into account the losses during cooking and the specific absorption rate, these quantities are not sufficient to ensure the daily intake in a balanced diet [141]."
"Its safety has been demonstrated through the use of an ultra-high parenteral dose of 25 mg daily for 10 days followed by 25 mg monthly for five months [150]."
"The therapeutic administration of oral Cbl has proven to be as effective as intramuscular administration [152]. This is very useful, as intramuscular administration is far more expensive and rather painful for the patient, as well as not being free from complications [153]."
"Since the crystalline form of Cbl is not bound to food proteins, the bioavailability in supplements is equal, if not superior."
"The vegetarian diet is very high in fiber, which may reduce the ability to absorb some nutrients efficiently [156]. An excess of fiber in the diet could disrupt the re-absorption of the Cbl mechanism through enterohepatic circulation, although there is no evidence to confirm that this happens in humans [157]."
"The consumption of oral doses of 1 μg, 10 μg, 50 μg, 500 μg, 1000 μg, are absorbed with an efficiency of 56%, 16%, 3%, 2%, 1.3%, respectively [151]."
"Using multivitamins can be inefficient and counterproductive for the supplementation of Cbl. The Cbl can be degraded in the presence of vitamin C and copper with the formation of inactive by-products. These compounds can inhibit the transport system interacting with transporter proteins [172,173]. Nutritional yeast fortified with Cbl is available in the USA, though its use may be less effective than supplements, in the case of deficiency [97]."
"[..]an Italian study has shown that selected types of oyster mushrooms grown in the southern areas of Italy show a wide range of concentrations of Cbl from 0.44 to 1.93 μg/100 g, as detected by ELISA immunoassay. The highest concentration was found in the species Pleurotus nebrodalis, typical of the mountain areas in central Sicily [176]. Less common mushrooms such as Craterellus cornucopioides or Cantharellus cibarius may contain 1.09–2.65 μg/100 g [177]. Shiitake mushrooms, popular among vegetarians, can contain up to 5.61 ± 3.9 μg of Cbl per 100 g of dry weight (mostly in active form), although with great variability [178]. Even in this case, although a portion of 50 g of dried shiitake could be adequate to achieve the daily requirement, it is unlikely that this will happen daily. Among the most widely used edible seaweeds, Enteromorpha sp. and Porphyra sp. (also known as nori) contain relevant amounts of Cbl ranging from 32.3 to 63.6 μg/100 g [179]. In vitro tests are promising, but there are not enough human clinical trials to consider the use of seaweed as favorable in vitamin provision [180,181]. In a clinical trial of six vegan children, the daily use of nori seaweed seemed to prevent Cbl deficiency, measured via serum Cbl [182]. In disagreement with these data, Dagnelie et al. found no positive effects in using nori seaweed and spirulina on Cbl-deficient children [183]. The Cbl content of other edible macroalgae is negligible and approximately zero [184]."
"Some fermented vegetable foods, such as sauerkraut, natto and tempeh, can have significant amounts of Cbl. It is unlikely that their daily use in Western countries represents a stable source of Cbl. The presence of Cbl in these foods depends on environmental bacteria randomly present in the fermentative microorganism pool [194]. It is very difficult to standardize the content from one product to another as they are subject to wide variation. Tempeh, for example, during the fermentation of soy beans can develop Cbl in a range between 0.7 to 8 μg per 100 g [195]. Other fermented soy foodstuff has only trace amounts of Cbl [196,197]. In sauerkraut production, the addition of Proprionibacteria sp. to cabbage may boost Cbl concentration up to 7.2 μg/100 g [198]. The use of organic fertilizer can increase the content of Cbl in spinach leaves up to 0.14 μg/100 g. However, the quantity of spinach that needs to be ingested in order to satisfy the daily requirement would be prohibitive [199]."
"According to Carmel, a single oral dose of 50 μg, 500 μg or 1000 μg will be absorbed at an amount of 1.5 μg, 9.7 μg or 13 μg, respectively [151]."
"There were no apparent substantial differences between the absorption of sublingual and oral forms [152,206]. However, oral dissolution could be critical in the secretion of the salivary R-binder and its subsequent bond. Since the Cbl would not be dissolved, about 88% could be not absorbed [54]. Since the development of a Cbl deficiency can also be observed among the LOV, the use of a supplement is necessary, regardless of the type of vegetarian diet [110]."
"If rare genetic defects of cellular trafficking and processing proteins exist, the choice of alternative forms of Cbl, such as Me-Cbl or H-Cbl could improve the effectiveness of supplementation [154,208,209,210]."
"The current data do not support the theory that vitamin deficiency needs 20–30 years to be manifested [125]."
"[..]cobalamin displays other functions, not strictly metabolic, that could be lacking when deficient. A vitamin B12 deficiency could be related to oxidative stress markers like plasma glutathione, malondialdehyde and serum total antioxidant capacity, which could contribute to a neurophysiological disturbance [220]. Furthermore, Cbl, particularly H-Cbl, can act as a detoxifying agent, removing potentially dangerous cyanid molecules from the body [212]."
- Treatment of vitamin B12 deficiency–Methylcobalamine? Cyancobalamine? Hydroxocobalamin?—clearing the confusion
"In vitamin B12 deficiency, decreased MeCbl leads to the ‘folate trap’, that is, a functional deficiency of folate.4"
"Vitamin B12 has two active forms, methylcobalamin and adenosylcobalamin (AdCbl), formed as a result of two distinct metabolic cascades.1,6,7 Their metabolic fates and thereby their functions are also distinct. AdCbl is the major form in cellular tissues stored in the mitochondria. MeCbl is found in the cytosol, and it predominates in blood and in other body fluids.8"
"In vitamin B12 deficiency, decreased AdCbl leads to a decrease in the conversion of methylmalonyl-CoA to succinyl-CoA with a resultant increase in methylmalonyl-CoA, which disturbs the carbohydrate, fat, aminoacid and urea metabolism and thereby affects the synthesis of neuronal myelin.10"
I'm quoting these again to include images this time:
.
"To summarize, the preferred formulation for vitamin B12 deficiency should be a combination of the active forms of vitamin B12, MeCbl and AdCbl, or HCbl[.]" "In case of the oral route, about 500–750 μg of each, MeCbl and AdCbl, would be required. A lower quantity may be required via the parenteral route. Only in the rare genetic disorders of conversion of vitamin B12 to its active coenzyme forms are the active forms to be used exclusively by the parenteral route."
."Vitamin B12 has two active forms, methylcobalamin and adenosylcobalamin (AdCbl), formed as a result of two distinct metabolic cascades.1,6,7 Their metabolic fates and thereby their functions are also distinct. AdCbl is the major form in cellular tissues stored in the mitochondria. MeCbl is found in the cytosol, and it predominates in blood and in other body fluids.8"
"In vitamin B12 deficiency, decreased AdCbl leads to a decrease in the conversion of methylmalonyl-CoA to succinyl-CoA with a resultant increase in methylmalonyl-CoA, which disturbs the carbohydrate, fat, aminoacid and urea metabolism and thereby affects the synthesis of neuronal myelin.10"
I'm quoting these again to include images this time:
"To summarize, the preferred formulation for vitamin B12 deficiency should be a combination of the active forms of vitamin B12, MeCbl and AdCbl, or HCbl[.]" "In case of the oral route, about 500–750 μg of each, MeCbl and AdCbl, would be required. A lower quantity may be required via the parenteral route. Only in the rare genetic disorders of conversion of vitamin B12 to its active coenzyme forms are the active forms to be used exclusively by the parenteral route."
- Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians | The American Journal of Clinical Nutrition | Oxford Academic