Cobalamin deficiency in pregnancy.
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ABSTRACT:
SUBMITTER: Konings H
PROVIDER: S-EPMC8222745 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Publications
Cobalamin deficiency in pregnancy.
Konings Heleen H Jacquemyn Yves Y
Clinical case reports 20210623 6
Hydroxycobolamine supplementation in hereditary cobolamine deficiency and serial biochemical follow-up allow uncomplicated pregnancy outcome. ...[more]
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Project description:Methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) are coenzymes for methionine synthase and methylmalonyl-CoA mutase, respectively. Hydroxylcobalamin (HOCbl) and cyanocobalamin (CNCbl) are frequently used for supplementation. MeCbl and AdoCbl have recently emerged as alternative forms in supplements. In the light of metabolic transformation of Cbl into its cofactor forms, this review discusses current evidence on efficacy and utility of different Cbl forms in preventing or treating Cbl deficiency. Cbl-transporting proteins bind and mediate the uptake of all aforementioned forms of Cbl. After internalization and lysosomal release, Cbl binds to the cytosolic chaperon MMACHC that is responsible for (i) flavin-dependent decyanation of [CN-Co(3+) Cbl to [Co(2+)]Cbl; (ii) glutathione-dependent dealkylation of MeCbl and AdoCbl to [Co(2+/1+)]Cbl; and (iii) glutathione-dependent decyanation of CNCbl or reduction of HOCbl under anaerobic conditions. MMACHC shows a broad specificity for Cbl forms and supplies the Cbl(2+) intermediate for synthesis of MeCbl and AdoCbl. Cobalamin chemistry, physiology, and biochemistry suggest that MeCbl and AdoCbl follow the same route of intracellular processing as CNCbl does. We conclude that supplementing MeCbl or AdoCbl is unlikely to be advantageous compared to CNCbl. On the other hand, there are obvious advantages of high parenteral doses (1-2 mg) of HOCbl in treating inborn errors of Cbl metabolism.
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Project description:BackgroundIron deficiency and cobalamin deficiency, as sequelae to chronic gastrointestinal (GI) disease, could result in anemia and increased morbidity in cats with chronic enteropathies.ObjectiveTo evaluate iron deficiency in cats with chronic GI disease and its relationship with hypocobalaminemia, anemia, and disease severity.AnimalsTwenty client-owned cats with primary GI disease.MethodsProspective, cross-sectional study. Cats were enrolled at the time of evaluation for chronic GI disease, after exclusion of comorbidities. CBC with reticulocyte indices, iron metabolism (serum iron and ferritin concentrations, total iron binding capacity [TIBC]), serum methylmalonic acid (MMA), cobalamin, and folate concentrations, pancreatic lipase and trypsin-like immunoreactivity, and disease severity were evaluated.ResultsAnemia (hematocrit <30%), iron deficiency, and cobalamin deficiency were diagnosed in 4/20, 7/20, and 8/20 cats, respectively. Hematocrit (rs = -.45; P < .05) and body condition score (rs = -.60; P < .01) negatively correlated with MMA. Median TIBC was lower in cats with increased vs normal MMA (218 μg/mL; range, 120-466 μg/mL vs 288 μg/mL; range, 195-369 μg/mL; P = .02). Hematocrit (rs = .51; P = .02), reticulocyte MCV (rs = .52; P = .02), reticulocyte hemoglobin content (rs = .71; P < .001), and percent transferrin saturation (rs = .79; P < .0001) positively correlated with serum iron concentration.Conclusions and clinical importanceFunctional iron deficiency was common in cats with chronic GI disease. Associations between hypocobalaminemia, iron parameters, and hematologic parameters warrant further investigation on the impact of iron deficiency on chronic GI disease morbidity in cats.
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Project description:The challenges in medical management of cobalamin deficiency lie in attention to the unique pathophysiology that underlies cobalamin deficiency, more than in the mechanics of therapy. The central physiologic principles are that clinically important deficiency is more likely to occur (and progress) when intrinsic factor-driven absorption fails than when diet is poor and that most causes take years to produce clinically obvious deficiency. Transient defects have little clinical impact. The key management principle is the importance of follow-up, which also requires knowing how the deficiency arose. The virtues of these principles are not always fully appreciated. Recent developments have made diagnosis and management more difficult by diminishing the ability to determine cobalamin absorption status. Clinicians must also grapple with premature medicalization of isolated, mild biochemical changes that added many asymptomatic cases of still undetermined medical relevance to their caseload, often expanded by inflated cobalamin level criteria. The potential for misattribution of cobalamin-unrelated presentations to nongermane cobalamin and metabolite abnormalities has grown. Pathophysiologically based management requires systematic attention to each of its individual components: correctly diagnosing cobalamin deficiency, reversing it, defining its underlying cause, preventing relapse, managing the underlying disorder and its complications, and educating the patient.
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Project description:Background/Objective: Cobalamin (B12) deficiency is reported in 18% of adults with sickle cell disease (SCD) and only 10% without SCD; limited data are available on children. Diagnosing B12 deficiency is challenging given the lack of an established gold standard method of assessment and the unique renal features of SCD. B12 metabolism can be impacted by the clinical use of nitrous oxide gas (N2O), which is a standard therapy for SCD pain in some European countries. In response to emerging reports of neurologic sequalae in patients with SCD receiving N2O, we evaluated the prevalence of B12 deficiency in children with SCD pain. Methods: Secondary analysis of prospective blood and urine samples in children aged 3-21 hospitalized with SCD pain. B12 deficiency was defined as plasma methylmalonic acid (MMA) > 592 nmol/L or urine MMA/creatinine ≥ 2.2 mmol/mol. Results: Ninety-four children (13 ± 4 years, 54% female, 68% hemoglobin-SS, and 72% on hydroxyurea) were assessed. Further, 53% (50/94) had B12 deficiency diagnosed by either urine, plasma, or both; 27% (25/94) were deficient based on urine; 39% (37/94) were deficient by plasma; and 13% (12/94) were deficient by both plasma and urine. Plasma MMA and urine MMA/creatinine did not correlate with hemoglobin or mean corpuscular volume. Conclusions: B12 deficiency was common in children with SCD. The absence of a gold standard for diagnosing B12 deficiency compounded with the reliability issues of testing modalities make it impractical to determine whether this is an over- or under-estimation of the true prevalence. Future studies to better understand the dynamics of B12 metabolism during acute and steady states in SCD are warranted and could elucidate the influence of acute SCD pain on these biomarkers.
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Project description:Cobalamin (Cbl, B(12)) is an essential micronutrient required to fulfill the enzymatic reactions of cytosolic methylcobalamin-dependent methionine synthase and mitochondrial adenosylcobalamin-dependent methylmalonyl-CoA mutase. Mutations in the MMACHC gene (cblC complementation group) disrupt processing of the upper-axial ligand of newly internalized cobalamins, leading to functional deficiency of the vitamin. Patients with cblC disease present with both hyperhomocysteinemia and methylmalonic acidemia, cognitive dysfunction, and megaloblastic anemia. In the present study we show that cultured skin fibroblasts from cblC patients export increased levels of both homocysteine and methylmalonic acid compared to control skin fibroblasts, and that they also have decreased levels of total intracellular folates. This is consistent with the clinical phenotype of functional cobalamin deficiency in vivo. The protein changes that accompany human functional Cbl deficiency are unknown. The proteome of control and cblC fibroblasts was quantitatively examined by two dimensional difference in-gel electrophoresis (2D-DIGE) and liquid chromatography-electrospray ionization-mass spectrometry (LC/ESI/MS). Major changes were observed in the expression levels of proteins involved in cytoskeleton organization and assembly, the neurological system and cell signaling. Pathway analysis of the differentially expressed proteins demonstrated strong associations with neurological disorders, muscular and skeletal disorders, and cardiovascular diseases in the cblC mutant cell lines. Supplementation of the cell cultures with hydroxocobalamin did not restore the cblC proteome to the patterns of expression observed in control cells. These results concur with the observed phenotype of patients with the cblC disorder and their sometimes poor response to treatment with hydroxocobalamin. Our findings could be valuable for designing alternative therapies to alleviate the clinical manifestation of the cblC disorder, as some of the protein changes detected in our study are common hallmarks of known pathologies such as Alzheimer's and Parkinson's diseases as well as muscular dystrophies.
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