Improved testing for vitamin B₁₂ deficiency: correcting MMA for eGFR reduces the number of patients classified as vitamin B₁₂ deficient

Abstract

Background Methylmalonic acid (MMA) can detect functional vitamin B deficiencies as it accumulates early when intracellular deficits arise. However, impaired clearance of MMA from blood due to decreased glomerular filtration rate (eGFR) also results in elevated plasma MMA concentrations. Alternative to clinical trials, a data mining approach was chosen to quantify and compensate for the effect of decreased eGFR on MMA concentration. Methods Comprehensive data on patient's vitamin B, eGFR and MMA concentrations were collected ( n = 2906). The relationship between vitamin B, renal function (eGFR) and MMA was modelled using weighted multiple linear regression. The obtained model was used to estimate the influence of decreased eGFR on MMA. Clinical impact was examined by comparing the number of patients labelled vitamin B deficient with and without adjustment in MMA. Results Adjusting measured MMA concentrations for eGFR in the group of patients with low-normal vitamin B concentrations (90-300 pmol/L) showed that the use of unadjusted MMA concentrations overestimates vitamin B deficiency by 40%. Conclusions Through a data mining approach, the influence of eGFR on the relation between MMA and vitamin B can be quantified and used to correct the measured MMA concentration for decreased eGFR. Especially in the elderly, eGFR-based correction of MMA may prevent over-diagnosis of vitamin B deficiency and corresponding treatment.

Methylmalonic acid, vitamin B12, renal function, and risk of all-cause mortality in the general population: results from the prospective Lifelines-MINUTHE study

“…In this study, we investigated the cross-sectional association of vitamin B12 and eGFR with MMA. In line with previous studies [2][3][4], we found that MMA levels are associated with vitamin B12 and eGFR and that MMA levels are highest in subjects with a combination of low vitamin B12 levels and impaired renal function. However, we found that only 22% of variation in circulating MMA concentration was explained by vitamin B12, eGFR, age, sex, and SES.…”

“…However, concentrations of MMA are not only elevated in vitamin B12 deficiency, but are also known to increase during renal dysfunction [3,4]. Moreover, methylmalonyl-CoA is an intermediate in the metabolism of propionic acid (PA), which is produced as a result of beta-oxidation of odd-chain fatty acids and branchedchain amino acids, metabolism of cholesterol sidechains, and fermentation by colonic microbiota [5,6].…”

Diagnostic Performances of Urinary Methylmalonic Acid/Creatinine Ratio in Vitamin B12 Deficiency

“…Interestingly, these biomarkers increased at early stages of renal impairment with eGFR <100 mL/min/1.73 m 2 . Van Loon et al already reported similar results for plasma MMA at the early stage of renal impairment (≤90 mL/min/1.73 m 2 ) [18]. The impairment of renal function could affect the interpretation of the plasma HCyst and the plasma MMA.…”

“…Nevertheless, these biomarkers are not strictly specific for B12 deficiency: vitamin B2, B6, and folate deficiencies can raise the plasma HCyst levels [34][35][36], while dehydration and increased levels of propionic acid can also increase the plasma MMA levels [37]. However, the main impediment is renal impairment as it increases both plasma HCyst and plasma MMA values, leading to an important loss of specificity in this situation [15][16][17][18][38][39][40][41][42]. Fedosov et al proposed an interesting index calculation based on measurements of different biomarkers to suppress the "inherent noise" of each individual marker of B12-deficiency [43,44].…”

“…Indeed, different conditions may increase the plasma HCyst levels, like folate deficiency [12,13], advanced age [14], and renal failure [15,16]. Plasma MMA is more specific to the B12 status than plasma HCyst, but an increase of plasma MMA level is also observed at a decreased kidney function [17,18]. Thus, the diagnosis of B12 deficiency is difficult to establish in the case of renal impairment.…”