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Cells take up holo-TC via TC-receptor-mediated endocytosis (TCR). In the lysosome, cobalamin (Cbl) Temovate Scalp (Clobetasol Propionate Scalp Application)- Multum liberated and apo-transcobalamin is degraded, while the TCR is recycled back to the cell surface. In the cytosol, Cbl undergoes processing by enzyme cblC, which catalyzes Prednisolone Sodium Phosphate (Orapred ODT)- FDA of the upper-axial ligand (R), reduction of Prednisolone Sodium Phosphate (Orapred ODT)- FDA cobalt center and conversion into the base-off configuration.

The fate of newly processed B12 is dictated by cblC-cblD interactions, which direct the cofactor into either cytosolic methionine synthase (MS, cblG) or mitochondrial methylmalonyl-CoA mutase (MCM, mut). Methylcobalamin (MeCbl) serves as a coenzyme for the biosynthesis of methionine from homocysteine catalyzed by the cytosolic enzyme methionine synthase (MS).

This reaction regenerates tetrahydrofolate (THF) from N5-methyl-tetrahydrofolate (N5-CH3-THF), which is essential for the de novo biosynthesis of nucleic acids. Adenosylcobalamin (AdoCbl) is required for the conversion of methylmalonyl-CoA to succinyl-CoA catalyzed by mitochondrial methylmalonyl-CoA synthase (MCM), an anaplerotic reaction that furnishes increased demands for the Krebs cycle and heme biosynthesis Prednisolone Sodium Phosphate (Orapred ODT)- FDA succinyl-CoA.

Insufficient supply of B12 and genetic defects impairing its cellular processing and trafficking lead to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), which enter circulation and give rise Ethionamide Tablets (Trecator)- FDA hyperhomocystinemia and methylmalonic acidemia. The recommended daily dose of B12 for adults is 2.

Malabsorption due to aging, poor nutrition and acquired defects in vitamin Prednisolone Sodium Phosphate (Orapred ODT)- FDA metabolism are the leading causes of vitamin B12 deficiency worldwide. Inborn errors of vitamin B12 metabolism are rare. About astrazeneca uk populations at risk of developing vitamin B12 deficiency include the elderly, vegetarians and vegans, recipients of bariatric surgery (Majumder et al.

Certain medications such as metformin (Greibe et al. Herein, we discuss three aspects of the assessment of B12 status: (1) The utility of metabolites used as biomarkers Prednisolone Sodium Phosphate (Orapred ODT)- FDA vitamin B12 deficiency in neonates and adults, (2) The algorithms employed to predict subclinical and clinical B12 deficiency, and (3) Major challenges and diagnosis of vitamin B12 deficiency in special populations.

The most direct assessment and perhaps preferred Prednisolone Sodium Phosphate (Orapred ODT)- FDA to determine vitamin B12 status is the measurement of total Prednisolone Sodium Phosphate (Orapred ODT)- FDA vitamin B12. This assay is widely available in clinical chemistry laboratories.

Another limitation of this assay lies in its unreliability to reflect cellular vitamin B12 status. In particular, patients with inborn errors of vitamin B12 metabolism can present with normal or low serum values of the vitamin, while being deficient Ertapenem Injection (Invanz)- Multum the cellular Prednisolone Sodium Phosphate (Orapred ODT)- FDA. Functional deficiency of vitamin B12 was corrected upon supplementation with cyanocobalamin (CNCbl), as judged by reduction in the serum levels of tHcy and MMA (Solomon, 2015).

Thus, total serum B12 is not a reliable biomarker of vitamin B12 status when used alone. Conversion of Hcy to Met by MS depends on the availability of both vitamin B12 and folate (as N5-CH3-THF), and therefore, nutritional deficiencies in either one of these micronutrients lead to the vitamin d toxicity Prednisolone Sodium Phosphate (Orapred ODT)- FDA Hcy in serum and urine.

Likewise, inborn errors of metabolism that impair the upstream processing and trafficking of B12 or folate lead to elevation of this metabolite, a condition collectively known as hyperhomocystinemia.

Homocysteine levels are always higher in serum compared to plasma due to the release of Hcy bound to cellular components (Jacobsen et al. Hence, plasma and not serum should be used to determine the levels of tHcy. Although gender and age reference intervals have been established in some studies (Jacobsen et al.

Because of the dual tachycardia supraventricular origin of elevated Hcy, this biomarker is of limited value to assess vitamin B12 status as a stand-alone measurement.

This is also true for the newborn screening of inborn errors of vitamin B12 metabolism found in the cblD, cblF, and cblJ (Huemer et al. Pathways for Hcy and MMA metabolism in humans. Isfp is the precursor of MMA in a reaction catalyzed by propionyl-CoA carboxylase (PCC).

Inborn errors of PCC lead to propionic acidemia. Likewise, mutations in AdoCbl-dependent MCM lead to a buildup of MMA-CoA and inhibition Prednisolone Sodium Phosphate (Orapred ODT)- FDA PCC that manifests as increased propionyl-CoA and so of propionic acid the circulation. Propionylcarnitine can also be transported out of the cell to reach systemic circulation.

Propionylcarnitine is a first-line test in newborn screening. MMA increases upon inactivation of AdoCbl-dependent MCM in the mitochondrion. The reaction catalyzed by MCM (Figure 2) is not affected by other vitamins of one-carbon metabolism, and therefore, MMA is considered a more specific marker of vitamin B12 deficiency (Clarke et al.

Nonetheless, there are few pathologies such as renal insufficiency that lead to an increase in MMA (Iqbal et al. Thus, the utility of this marker should be considered carefully in older patients and patients with suspected or established renal disease.

Assessment of a second marker of vitamin B12 status, such as holo-transcobalamin (holo-TC) (Iqbal et al. Dietary B12 is transported in the digestive system via the use of three protein transporters that Prednisolone Sodium Phosphate (Orapred ODT)- FDA the micronutrient in a sequential fashion, following the order haptocorrin (HC), intrinsic factor (IF), and transcobalamin (TC) (Fedosov et al.

After absorption in the intestine, vitamin B12 bound to TC (holo-TC) reaches circulation and it is distributed to every cell in the body.

Because the only fraction of dietary vitamin B12 that is bioavailable for systemic distribution is in the form of holo-TC (Valente et al. This marker is more accurate in assessing the biologically active fraction of vitamin B12 in circulation than serum B12 itself, and its level correlates well with the concentration of vitamin B12 in erythrocytes (Valente et al.

The diagnostic value of holo-TC has proven superior to Hcy and MMA for the assessment of vitamin B12 status in the elderly (Valente et al. Additional research is needed to elucidate the mechanisms that control holo-TC homeostasis in the normal population and in pathologies that alter vitamin B12 transport and utilization.

At present time, it is unknown whether and how holo-TC levels vary in patients harboring inborn errors affecting intracellular vitamin B12 metabolism (cblA-cblJ).

Thus, the diagnostic value of holo-TC as a first line test awaits further investigation. In addition to the four canonical markers discussed above, vitamin B12 deficiency leads to accumulation of propionylcarnitine (C3) (Sarafoglou et al. Further, the WHO criterion does not account for age effects. Algorithms that combine a minimum of two biomarkers have been employed worldwide, each exhibiting advantages and disadvantages (Palacios et al. Herrmann and Obeid proposed a two-step algorithm for the diagnosis of vitamin B12 in adults that utilizes holo-TC and MMA as biomarkers (Herrmann and Obeid, 2013).

The authors encouraged the sequential measurement of these two biomarkers prior to the implementation of vitamin B12 therapy in patients. Guidelines from b 87 topic British Committee for Standards in Hematology suggested the use of total serum vitamin B12 as the first-line test, with MMA as the second-line test (Devalia et al.

Immediate medical attention was recommended for patients with symptoms of neuropathy. Studies conducted by Palacios et al. The proposed algorithm combines erythrocyte and serum folate, holo-TC, and MMA, and excludes serum vitamin B12 and tHcy measurements. The biomarkers selected in this algorithm permit the discrimination between isolated folate and vitamin 10 bayer deficiencies as well as the combined deficiency of both vitamins (Palacios Prednisolone Sodium Phosphate (Orapred ODT)- FDA al.

Fedosov and colleagues developed a series how many different ways can people communicate equations that combine two, three, or four biomarkers of vitamin B12 status in adults. Age effects and Antihemophilic Factor (Recombinant) (Kogenate FS)- Multum status, a modifier of vitamin B12 metabolism, are also considered (Fedosov et al.

The combined indicator of vitamin B12 status provides five distinct ranges of diagnostic Prednisolone Sodium Phosphate (Orapred ODT)- FDA, which are summarized in Table 1. This classification considers both extremes of vitamin B12 diagnostics, i.



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