Methylmalonic Acid and Homocysteine as Indicators of Vitamin B-12 Deficiency in Cancer

Vashi, Pankaj G.; Edwin, Persis; Popiel, Brenten; Lammersfeld, C. A.; Gupta, Digant

doi:10.1371/journal.pone.0147843

Cited by 62 publications

(39 citation statements)

References 29 publications

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“…MMA methylmalonic acid, holoTC holotranscobalamin. Limit values for MMA and holoTC specified here are in accordance with those of other authors [7, 24, 29, 32]. For follow-up we recommend the measurement of homocysteine (normal: 5.0–15.0 µmol/l; pathological threshold: >25 µmol/l) [28] …”

Section: Introductionsupporting

confidence: 74%

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Rapid healing of a patient with dramatic subacute combined degeneration of spinal cord: a case report

Roessler

Wolff

2017

BMC Res Notes

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BackgroundPrevalence of cobalamin deficiency is high especially in older patients and an immediate therapy start is necessary to prevent irreversible neurological damages. Unfortunately, the diagnosis of cobalamin deficiency is difficult and at present, there is no consensus for diagnosis of this deficiency. Therefore, we aim to elucidate a meaningful diagnostic pathway by a case report with an initially misleading medical history.Case presentationA 57 year-old Caucasian man suffering from dramatic myelosis of the cervical posterior columns. Apart from associated neurological symptoms (tactile hypaesthesia, reduced vibration sensation, loss of stereognosis and of two-point-discrimination) there were no further complaints; especially no gastrointestinal, haematological or psychiatric disorders were provable. Cobalamin (vitamin B12) serum level was normal. The diagnosis of subacute combined degeneration of spinal cord was confirmed by an elevated methylmalonic acid, and hyperhomocysteinemia. Cobalamin deficiency was caused by asymptomatic chronic atrophic inflammation of the stomach with a lack of intrinsic factor producing gland cells. This was revealed by increased gastrin and parietal cell antibodies and finally confirmed by gastroscopy. Parenteral substitution of cobalamin rapidly initiated regeneration.ConclusionsThis case demonstrates that normal cobalamin serum levels do not rule out a cobalamin deficiency. In contrast, path-breaking results can be achieved by determining homocysteine, holotranscobalamin, and methylmalonic acid.

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Section: Introductionsupporting

confidence: 74%

“…The patient had a cobalamin level in the lower normal range. Several publications described the determination of serum cobalamin to be unreliable [2, 3, 5, 18, 23, 24, 28, 29]. Therefore, other diagnostic markers are needed:…”

Section: Discussionmentioning

confidence: 99%

Rapid healing of a patient with dramatic subacute combined degeneration of spinal cord: a case report

Roessler

Wolff

2017

BMC Res Notes

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“…Diagnosis of vitamin B 12 deficiency can, however, be difficult. Reports indicate that high serum vitamin B 12 levels can be accompanied by signs of deficiency, and functional deficiency from tissue uptake defects and action of vitamin B 12 at the cellular level have been implicated in this association [16,17]. Thus, functional vitamin B 12 deficiency can occur regardless elevated serum B 12 levels [17].…”

Section: Introductionmentioning

confidence: 99%

Vitamin B₁₂ deficiency in type 2 diabetic patients on metformin: a cross-sectional study from South-Western part of Ghana

Yakubu

Laing

Nsiah

et al. 2019

Alexandria Journal of Medicine

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Introduction: Metformin is the most widely administered anti-diabetic medication among type 2 diabetes mellitus (T2DM) patients. However, metformin induces vitamin B12 malabsorption which may increase the risk of vitamin B12 deficiency among T2DM patients. We determined the prevalence of vitamin B12 deficiency and related risk factors among Ghanaian T2DM patients on metformin therapy. Methods: This cross-sectional study recruited 196 T2DM patients attending the outpatient diabetic clinic at the Effia Nkwanta Regional Hospital, Ghana. Fasting venous blood was collected for biochemical analysis. Vitamin B12 deficiency was defined as serum B12 <100 pg/ml and methylmalonic acid (MMA) ≥ 0.4µmol/L. Results: The prevalence of vitamin B12 deficiency based on serum vitamin B12, MMA, and the combination of both methods were 32.1%, 14.8%, and 14.3%, respectively. Longer duration of metformin use [5-9 years; aOR= 2.83, 95% CI (1.03-7.81), p=0.045 and ≥10 years; aOR= 4.17, 95% CI (1.41-12.33), p=0.010], higher daily dose of metformin [1000-2000 mg/day; aOR= 1.34, 95% CI (0.25-2.74), p=0.038 and >2000 mg/day; aOR= 1.13, 95% CI (0.39-2.97), p=0.047], and very high body fat [aOR= 2.98, 95% CI (1.47-6.05), p=0.020] were significantly associated with increased odds of vitamin B12 deficiency. For daily dose of metformin, a cutoff value of 1500 mg/day presented with a sensitivity, specificity, and AUC of 71.4%, 40.1%, and 0.54 (95% CI, 0.53-0.54), respectively, in predicting vitamin B12 deficiency. A ≥ six (6) years duration of metformin therapy presented with a sensitivity, specificity, and AUC of 70.4%, 62.9%, and 0.66 (95% CI, 0.57-0.75), respectively, in predicting vitamin B12 deficiency. Conclusion: Vitamin B12 deficiency is high among T2DM patients on metformin therapy in Ghana. There is the need for regular monitoring of vitamin B12 levels especially in T2DM patients on metformin daily dose of ≥ 1500 mg for duration of therapy ≥ 6 years.

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“…Therefore, our results of marker metabolites of vitamin B 12 status and holo-TC in this cell type can be directly compared to numerous studies of canonical inborn errors of vitamin B 12 metabolism, all of which have been performed in skin fibroblasts. The assessment of cobalamin status should include preferentially a combination of functional markers (tHcy, MMA) and systemic markers (plasma B 12 and holo-TC) [44][45][46][47]. Intracellular tHcy was slightly increased in GD cells, but the difference with respect to control did not hold statistical significance.…”

Section: Discussionmentioning

confidence: 92%

Assessment of cellular cobalamin metabolism in Gaucher disease

et al. 2020

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Background: Gaucher disease (GD) is a lysosomal disorder caused by biallelic pathogenic mutations in the GBA1 gene that encodes beta-glucosidase (GCase), and more rarely, by a deficiency in the GCase activator, saposin C. Clinically, GD manifests with heterogeneous multiorgan involvement mainly affecting hematological, hepatic and neurological axes. This disorder is divided into three types, based on the absence (type I) or presence and severity (types II and III) of involvement of the central nervous system. At the cellular level, deficiency of GBA1 disturbs lysosomal storage with buildup of glucocerebroside. The consequences of disturbed lysosomal metabolism on biochemical pathways that require lysosomal processing are unknown. Abnormal systemic markers of cobalamin (Cbl, B 12 ) metabolism have been reported in patients with GD, suggesting impairments in lysosomal handling of Cbl or in its downstream utilization events. Methods: Cultured skin fibroblasts from control humans (n = 3), from patients with GD types I (n = 1), II (n = 1) and III (n = 1) and an asymptomatic carrier of GD were examined for their GCase enzymatic activity and lysosomal compartment intactness. Control human and GD fibroblasts were cultured in growth medium with and without 500 nM hydroxocobalamin supplementation. Cellular cobalamin status was examined via determination of metabolomic markers in cell lysate (intracellular) and conditioned culture medium (extracellular). The presence of transcobalamin (TC) in whole cell lysates was examined by Western blot. Results: Cultured skin fibroblasts from GD patients exhibited reduced GCase activity compared to healthy individuals and an asymptomatic carrier of GD, demonstrating a preserved disease phenotype in this cell type. The concentrations of total homocysteine (tHcy), methylmalonic acid (MMA), cysteine (Cys) and methionine (Met) in GD cells were comparable to control levels, except in one patient with GD III. The response of these metabolomic markers to supplementation with hydroxocobalamin (HOCbl) yielded variable results. The content of transcobalamin in whole cell lysates was comparable in control human and GD patients. Conclusions: Our results indicate that cobalamin transport and cellular processing pathways are overall protected from lysosomal storage damage in GD fibroblasts. Extending these studies to hepatocytes, macrophages and plasma will shed light on cell-and compartment-specific vitamin B 12 metabolism in Gaucher disease.

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Methylmalonic Acid and Homocysteine as Indicators of Vitamin B-12 Deficiency in Cancer

Cited by 62 publications

References 29 publications

Rapid healing of a patient with dramatic subacute combined degeneration of spinal cord: a case report

Rapid healing of a patient with dramatic subacute combined degeneration of spinal cord: a case report

Vitamin B₁₂ deficiency in type 2 diabetic patients on metformin: a cross-sectional study from South-Western part of Ghana

Assessment of cellular cobalamin metabolism in Gaucher disease

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Methylmalonic Acid and Homocysteine as Indicators of Vitamin B-12 Deficiency in Cancer

Cited by 62 publications

References 29 publications

Rapid healing of a patient with dramatic subacute combined degeneration of spinal cord: a case report

Rapid healing of a patient with dramatic subacute combined degeneration of spinal cord: a case report

Vitamin B12 deficiency in type 2 diabetic patients on metformin: a cross-sectional study from South-Western part of Ghana

Assessment of cellular cobalamin metabolism in Gaucher disease

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Vitamin B₁₂ deficiency in type 2 diabetic patients on metformin: a cross-sectional study from South-Western part of Ghana