Cardiometabolic consequences of Hereditary Fructose Intolerance

Improved treatment strategies for inborn errors of metabolism (IEM) have
resulted in better survival of many patients. However, longer lifespan also
confronts patients and physicians with new complications of IEM that were not
known before, simply due to the fact that patients succumbed before these
complications could develop. This demands a thorough long-term follow-up of the
natural history of all patients with IEM.

Hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism
as a consequence of a defect in Aldolase B. Ingestion of fructose can result in
gastrointestinal discomfort, hypoglycaemia and liver/renal failure. These
adverse reactions can be avoided by the adherence to a complete fructose
restricted diet through which HFI patients can live a relatively normal life.
Long-term follow-up of HFI patients, however, strongly suggests that patients
with HFI develop nonalcoholic fatty liver disease (NAFLD) despite fructose
restriction.

NAFLD is a liver condition that is characterized by a histological spectrum
ranging from simple steatosis, to hepatitis, fibrosis and cirrhosis that can
eventually lead to end-stage liver failure and hepatocellular carcinoma.
Moreover, scientific evidence is accumulating that NAFLD is a cardiovascular
risk factor per se. Accumulation of fat in the liver (i.e. simple steatosis)
results from increased flux of free fatty acids from adipose tissue or de novo
lipogenesis, or decreased secretion of VLDL particles or beta-oxidation. NAFLD
is frequently observed in obese subjects, as a consequence of sedentary
lifestyle and unhealthy dietary habits, such as consumption of fructose
enriched food products, which induce hepatic de novo lipogenesis.

Why then do patients with HFI * whose diet is devoid of lipogenic fructose *
develop NAFLD as well? We postulate that the susceptibility to develop NAFLD in
patients with HFI is caused by a continuous activation of hepatic glucokinase
by fructose-1-phosphate.

There is always endogenous production of fructose from glucose through the
polyol pathway. The accumulated fructose-1-phosphate (as a consequence of
Aldolase B deficiency in HFI) acts as a strong disruptor of the binding between
glucokinase regulatory protein and glucokinase, which causes glucokinase to
facilitate the conversion of glucose to glucose-6-phosphate. Increased
glucose-6-phosphate can have different fates. In the postprandial state it is
mainly stored as glycogen or converted to fatty acids and stored as fat
accounting for NAFLD.

Of interest, genetic studies have shown that this complex is relevant in the
development of NAFLD, since carriers of a missense variant in GCKR (that
encodes for a GKRP protein that binds glucokinase less effectively) are prone
to develop NAFLD.

Thus, increased de novo lipogenesis appears to be responsible for the
development of NAFLD in HFI. However, to study this research
question/hypothesis, expensive complex stable isotope studies are required. We
believe that measurement of plasma hepatokines might provide an alternative.
Hepatokines are proteins that are released by the liver into the systemic
circulation and are known to affect metabolic processes. If hepatokines are
measured in patients with HFI and subsequently compared with patients with
NAFLD of which the metabolic pathway has been elucidated, such as glycogen
storage disease type 1a (de novo lipogenesis) and familial
hypobetalipoproteinemia (impaired VLDL secretion), then the patterns will
provide more information of the metabolic pathways in HFI.

Based on the gaps in our knowledge (as stated above), we have formulated the
following objectives:

- To quantify the degree of hepatic fat accumulation and fibrosis in patients
with HFI.
- To gain more insight in the mechanism leading to NAFLD in patients with HFI
- To study the cardiovascular risk profile of patients with HFI.

This will be an observational study with a cross-scetional design.

This study will focus on the long term consequences of HFI.

For this, the following measurements will take place:

- Magnetic resonance spectroscopy of the liver, to quantify the degree of
hepatic fat accumulation.
- Fibroscan of the liver, to quantify the degree of liver fibrosis.
- Oral glucose tolerance test, to gain more insight in the mechanism
responsible for the development of NAFLD.
- Peripheral applanation tonometry and laser doppler flowmetry (as measure for
endothelial function), and carotid-femoral pulse wave velocity (as measure for
arterial stiffness) to study the cardiovascular effects of NAFLD.
- Blood withdrawal (hepatokine level, to gain more insight in the mechanism
responsible for the development of NAFLD and biomarkers of inflammation and
endothelial function, to study the cardiovascular effects of NAFLD).

The risks of this study are minimal, since no interventions are imposed. The
only invasive test is blood withdrawal, which is associated with minimal health
risk.