Transferrin Isoforms, Old but New Biomarkers in Hereditary Fructose Intolerance

Abstract

Hereditary Fructose Intolerance (HFI) is an autosomal recessive inborn error of metabolism characterised by the deficiency of the hepatic enzyme aldolase B. Its treatment consists in adopting a fructose-, sucrose-, and sorbitol (FSS)-restrictive diet for life. Untreated HFI patients present an abnormal transferrin (Tf) glycosylation pattern due to the inhibition of mannose-6-phosphate isomerase by fructose-1-phosphate. Hence, elevated serum carbohydrate-deficient Tf (CDT) may allow the prompt detection of HFI. The CDT values improve when an FSS-restrictive diet is followed; however, previous data on CDT and fructose intake correlation are inconsistent. Therefore, we examined the complete serum sialoTf profile and correlated it with FSS dietary intake and with hepatic parameters in a cohort of paediatric and adult fructosemic patients. To do so, the profiles of serum sialoTf from genetically diagnosed HFI patients on an FSS-restricted diet (n = 37) and their age-, sex- and body mass index-paired controls (n = 32) were analysed by capillary zone electrophoresis. We found that in HFI patients, asialoTf correlated with dietary intake of sucrose (R = 0.575, p < 0.001) and FSS (R = 0.475, p = 0.008), and that pentasialoTf+hexasialoTf negatively correlated with dietary intake of fructose (R = -0.386, p = 0.024) and FSS (R = -0.400, p = 0.019). In addition, the tetrasialoTf/disialoTf ratio truthfully differentiated treated HFI patients from healthy controls, with an area under the ROC curve (AUROC) of 0.97, 92% sensitivity, 94% specificity and 93% accuracy.

Keywords: aldolase B; biomarker; diet; fructose; hereditary fructose intolerance; sialotransferrin profile; sorbitol; sucrose.

Figure 1

The link between fructose metabolism and the profile of sialotransferrins in hereditary fructose intolerance. Dietary sorbitol and sucrose, i.e., a disaccharide formed by glucose and fructose, are precursors of fructose. The catabolic pathway of dietary fructose, sucrose and sorbitol is altered in patients with hereditary fructose intolerance (HFI). In aldolase B deficiency, the catabolism of fructose-1-P (F1P) is impaired (red bar), and this molecule is accumulated largely in the liver of HFI patients. Consequently, HFI patients have an abnormal transferrin (Tf) glycosylation pattern because of F1P-mediated competitive inhibition of mannose-6-phosphate isomerase (MPI). Tf exhibits different isoforms depending on the number of sialic acid residues present on its oligosaccharide chain; asialo-, monosialo-, disialo-, trisialo-, pentasialo-, and hexasialo-Tf. The sum of asialo-, monosialo-, and disialo-Tf is called carbohydrate-deficient Tf (CDT).

Figure 2

Sialotransferrin (sialoTf) isoform percentages in HFI patients (n = 37) and in their respective healthy controls (n = 32). Differences in continuous variables between HFI and their controls were calculated by using the Student’s t-test.

Figure 3

TetrasialoTf-to-disialoTf ratio and ROC curve in HFI patients (n = 37) and in their respective healthy controls (n = 32). AUROC = 0.97, 92% sensitivity, 94% specificity, 14.7 positive likelihood ratio, 0.09 negative likelihood ratio and 93% accuracy with a cut-off point of 93.