Background/Objectives: Hereditary fructose intolerance (HFI) is an inherited metabolic disorder caused by a deficiency of the enzyme fructose-1,6-bisphosphate aldolase. Treatment consists of a lifelong diet restricted in fructose, sucrose, and sorbitol (FSS). The aim of this study was to determine dietary intake of FSS and to analyze the consumption patterns of vegetables, fruit, legumes, pulses, and dried fruit in a nationwide cohort of HFI patients. Methods: Overall, 36 HFI patients and 28 age-, sex- and BMI-matched healthy control subjects participated in this study. A self-administered three-day dietary record and an adapted quantitative food frequency questionnaire (FFQ) including frequency and portion sizes were collected. FSS intake was calculated using the DIAL Nutritional Calculation Program (ALCE INGENIERÍA). Total fructose intake was calculated as the sum of free fructose, 50% of sucrose, and sorbitol. Results: Protein intake was significantly higher in HFI patients compared to the controls (92.43 g/day [65.1-165.03] vs. 70.39 g/day [35.21-133.83]; p = 0.001). In most patients, total fructose intake was within the recommended limits (9.79 mg/kg bw/day [0.29-59.09]), with no significant differences between children and adults (p = 0.325). Although the established dietary recommendations did not always match the actual intake observed in a real-life setting, in general, foods with higher fructose content were consumed less frequently and in smaller quantities. Conclusions: Further research on the fructose content of various foods, particularly fruits and vegetables, and updated dietary recommendations for HFI patients are warranted to provide the best tools for the nutritional management of the disease.

Hereditary Fructose Intolerance (HFI), a rare autosomal recessive metabolic disorder, has historically been considered benign when treated with a lifelong fructose-, sucrose and sorbitol-restricted diet. However, adverse metabolic manifestations have recently been reported in treated HFI patients. As serum metabolomics offers a valuable tool for assessing metabolic manifestations underlying inherited metabolic disorders, we aim to compare the serum lipidomic profile of HFI-treated patients with age-, gender-, and body mass index-matched healthy controls. Long-term dietary-treated HFI patients (n = 32) were compared to age-, sex-, and BMI-matched healthy controls (n = 28) using serum lipidomic analysis by tandem mass spectrometry, followed by pathway enrichment analysis. Furthermore, liver magnetic resonance imaging/spectroscopy (MRI/MRS), plasma lipoprotein and glycoprotein profiling using the LiposcaleⓇ, a two-dimensional proton nuclear magnetic resonance (2D-1H NMR) spectroscopy test, sialotransferrin analysis, and serum multiplex analysis of cytokines/chemokines were performed. The HFI patients exhibited a distinct serum lipidomic profile showing separate clusters in the multivariate analysis between these patients and the healthy controls. Top-interacting network analysis revealed abnormalities in lipid metabolism and inflammation as hallmarks of HFI. Indeed, significant liver steatosis, assessed by MRS proton density fat fraction (MRS-PDFF), was present in 75 % of HFI patients compared to 7 % in the control group. Moreover, low-grade systemic inflammation was highly prevalent in HFI patients, exhibiting elevated serum cytokines, C-reactive protein, acute phase proteins such as fibrinogen and ferritin, and increased low-grade inflammation score. Additionally, circulating glycoprotein acetyls (GlycA), a novel serum marker for low-grade inflammation, was significantly elevated in the HFI patients and associated with their lipidomic profile and markers of altered intestinal permeability, such as serum lipopolysaccharide binding protein. Furthermore, increased GlycA concentration in the HFI patients was associated with elevation of blood pressure and an altered serum lipoprotein profile, early factors of cardiovascular risk. Serum lipidomic study revealed previously unknown metabolic complications of HFI-treated patients. Notably, we have found that low-grade systemic inflammation is highly prevalent in the cohort of HFI patients and correlates with early factors of cardiovascular risk. Expanding our current understanding of the metabolic consequences in HFI-treated patients will provide the best care for patients.

Hereditary fructose intolerance (HFI), caused by Aldolase B deficiency, is a rare genetic disorder where fructose exposure leads to severe metabolic pathologies including Type-2 diabetes and liver steatosis. Despite adhering to fructose-free diets, some individuals still present with disease. Using a rat model of HFI we demonstrate that fructose independent pathologies exist and identify the molecular pathways driving disease. Aldob was deleted in Sprague Dawley rats using CRIPSR/Cas9 (AldoB-KO). Phenotypic, metabolomic and transcriptomic studies were conducted to identify mechanisms promoting fructose-independent pathologies. Potential molecular causes were tested using pharmacologic inhibitors and ASOs. Deletion of Aldob caused hepatic steatosis, fibrosis and stunted growth in rats weaned on low fructose chow recapitulating human HFI. On fructose-free chow, AldoB-KO rats were phenotypically normal. However, upon fasting, male and female AldoB-KO rats developed hepatic steatosis and hyperlipidemia due to impaired fatty acid oxidation (FAOx) and elevated de novo lipogenesis (DNL). Transcriptional and metabolomic profiling revealed increased hepatic Carbohydrate Response Element Binding Protein (ChREBP) activation in AldoB-KO rats due to glycolytic metabolite accumulation caused by impaired gluconeogenesis. Treatment with Acetyl-CoA Carboxylase (ACC) and Diacylglycerol Acyl Transferase 2 (DGAT2) inhibitors reduced hepatic lipids and plasma triglycerides in AldoB-KO rats. Finally, using electronic health records we observed increased metabolic dysfunction-associated steatohepatitis (MASH) diagnosis in individuals with HFI. Aldob deletion caused fructose-independent hyperlipidemia and steatosis upon fasting in rats. Individuals with HFI may have risk for hepatic disease and hyperlipidemia even upon fructose abstinence suggesting additional therapies may be needed to mitigate disease.

Hereditary fructose intolerance (HFI) is characterized by liver damage and a secondary defect in N-linked glycosylation due to impairment of mannose phosphate isomerase (MPI). Mannose treatment has been shown to be an effective treatment in a primary defect in MPI (i.e., MPI-CDG), which is also characterized by liver damage. Therefore, the aims of this study were to determine: (1) hepatic nucleotide sugar levels, and (2), the effect of mannose supplementation on hepatic nucleotide sugar levels and liver fat, in a mouse model for HFI. Aldolase B deficient mice (Aldob-/-) were treated for four weeks with 5% mannose via the drinking water and compared to Aldob-/- mice and wildtype mice treated with regular drinking water. We found that hepatic GDP-mannose and hepatic GDP-fucose were lower in water-treated Aldob-/- mice when compared to water-treated wildtype mice (p = 0.002 and p = 0.002, respectively), consistent with impaired N-linked glycosylation. Of interest, multiple other hepatic nucleotide sugars not involved in N-linked glycosylation, such as hepatic UDP-glucuronic acid, UDP-xylose, CMP-N-acetyl-beta-neuraminic acid, and CDP-ribitol (p = 0.002, p = 0.003, p = 0.002, p = 0.002), were found to have altered levels as well. However, mannose treatment did not correct the reduction in hepatic GDP-mannose levels, nor was liver fat affected. Aldob-/- mice are characterized by hepatic nucleotide sugar abnormalities, but these were not abrogated by mannose treatment. Future studies are needed to identify the underlying mechanisms responsible for the abnormal hepatic nucleotide sugar pattern and intrahepatic lipid accumulation in HFI. Trial Registration: PCT ID: PCTE0000340, this animal experiment is registered at (https://preclinicaltrials.eu/).

Early diagnosis of children with hereditary fructose intolerance, which can be achieved by proper history taking, thorough clinical examination, response to diet, and histopathological examination, followed by effective management with a lifelong fructose, sucrose, and sorbitol-free diet, ensures good prognosis and normal life.