Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease

  • Amée M. Buziau
  • Casper G. Schalkwijk
  • Coen D.A. Stehouwer
  • Dean R. TolanEmail author
  • Martijn C.G.J. BrouwersEmail author


Hereditary fructose intolerance (HFI) is a rare inborn disease characterized by a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules. In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP, which are believed to cause symptoms, such as nausea, vomiting, hypoglycemia, and liver and kidney failure. These sequelae can be prevented by a fructose-restricted diet. Recent studies in aldolase B-deficient mice and HFI patients have provided more insight into the pathogenesis of HFI, in particular the liver phenotype. Both aldolase B-deficient mice (fed a very low fructose diet) and HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls. The liver phenotype in aldolase B-deficient mice was prevented by reduction in intrahepatic Fru 1P concentrations by crossing these mice with mice deficient for ketohexokinase, the enzyme that catalyzes the synthesis of Fru 1P. These new findings not only provide a potential novel treatment for HFI, but lend insight into the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD), which has raised to epidemic proportions in Western society. This narrative review summarizes the most recent advances in the pathogenesis of HFI and discusses the implications for the understanding and treatment of fructose-induced NAFLD.


Hereditary fructose intolerance Glucokinase regulatory protein Ketohexokinase Fructose De novo lipogenesis Non-alcoholic fatty liver disease 



The study in HFI patients was subsidized by the Netherlands Heart Foundation (#2015T042) and Stofwisselkracht. MB received a personal grant from the Diabetes Foundation (#2017.82.004). DT was supported by Colorado Research Partners LLC and National Institutes of Health (R01DK108859).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Endocrinology, Department of Internal MedicineMaastricht University Medical CenterMaastrichtThe Netherlands
  2. 2.Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal MedicineMaastricht University Medical CenterMaastrichtThe Netherlands
  3. 3.Cardiovascular Research Institute Maastricht (CARIM)MaastrichtThe Netherlands
  4. 4.Division of General Internal Medicine, Department of Internal MedicineMaastricht University Medical CenterMaastrichtThe Netherlands
  5. 5.Department of BiologyBoston UniversityBostonUSA

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