Patients With Aldolase B Deficiency Are Characterized by Increased Intrahepatic Triglyceride Content

Abstract

Context There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B−/−), the enzyme that converts fructose-1-phosphate to triose phosphates. Objective To translate these experimental findings to the human situation. Design Case-control study. Setting Outpatient clinic for inborn errors of metabolism. Patients or Other Participants Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15). Main Outcome Measure IHTG content, assessed by proton magnetic resonance spectroscopy. Results IHTG content was higher in aldo B−/− patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m2, respectively). Glucose excursions during an oral glucose load were higher in aldo B−/− patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B−/− patients than in controls (P < 0.001). Finally, plasma β-hydroxybutyrate, a biomarker of hepatic β-oxidation, was lower in aldo B−/− patients than controls (P = 0.009). Conclusions This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of β-oxidation are involved in the pathogenesis.

Hereditary Fructose Intolerance Diagnosed in Adulthood

“…Recently, higher intrahepatic triglyceride content was reported in HFI patients than healthy control groups, even with a fructose-restricted diet. 22 Nonalcoholic fatty liver disease is also a potential threat in HFI; regular follow-up is needed. Prognosis is excellent if patients maintain a strict exclusion diet.…”

Chronic systemic exposure to IL6 leads to deregulation of glycolysis and fat accumulation in the zebrafish liver

“…Our studies show that chronic systemic IL6 expression leads to a repression of aldob in the liver and accumulation of hexose monophosphates. ALDOB deficient individuals have been reported to have high intrahepatic triglyceride content (41). We hypothesized that ALDOB levels and the resulting metabolic changes would have a correlation with fat accumulation in patients.…”

Transferrin Isoforms, Old but New Biomarkers in Hereditary Fructose Intolerance

“…Based on the carrier frequency of the most common mutations in neonates, it has been estimated that the prevalence of HFI is around 1 in 26,000 live births in Europe [5] and 1 in 20,000 births in the US [6], yet many authors agree that it may be significantly underdiagnosed. Symptoms in HFI patients are usually initiated five or six months after birth due to the introduction of complementary feeding in the infant, who reacts with a variety of clinical signs such as failure to thrive, accompanied by vomiting, abdominal pain and acute liver failure [7]. HFI is also characterised by a set of metabolic alterations that include hypoglycaemia, metabolic acidosis, hypophosphatemia, hyperuricemia, hypermagnesemia and hyperalaninaemia after fructose loading [1].…”

“…There is a growing use of fructose, as it is widely used as a food additive, and small amounts of this sugar are hidden in many foods. Thus, it is not surprising that HFI patients develop previously unreported complications, such as liver steatosis [7,9] or signs of proximal tubular dysfunction [10,11].…”