Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas

https://doi.org/10.1016/j.ymgme.2018.02.016Get rights and content

Highlights

  • HFI should be in the differential diagnosis of neonate/infantile acute liver failure due to possible fructose exposure.

  • Healthcare professionals must know that many common infant formulas contain fructose, even if not clearly labeled.

  • Early recognition of HFI and the implementation of fructose-free diet can be life-saving.

Abstract

Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by aldolase B (ALDOB) deficiency resulting in an inability to metabolize fructose. The toxic accumulation of intermediate fructose-1-phosphate causes multiple metabolic disturbances, including postprandial hypoglycemia, lactic acidosis, electrolyte disturbance, and liver/kidney dysfunction. The clinical presentation varies depending on the age of exposure and the load of fructose. Some common infant formulas contain fructose in various forms, such as sucrose, a disaccharide of fructose and glucose. Exposure to formula containing fructogenic compounds is an important, but often overlooked trigger for severe metabolic disturbances in HFI. Here we report four neonates with undiagnosed HFI, all caused by the common, homozygous mutation c.448G>C (p.A150P) in ALDOB, who developed life-threatening acute liver failure due to fructose-containing formulas. These cases underscore the importance of dietary history and consideration of HFI in cases of neonatal or infantile acute liver failure for prompt diagnosis and treatment of HFI.

Introduction

Hereditary fructose intolerance (HFI) (MIM 229600) is an autosomal recessive disorder caused by biallelic mutations in ALDOB, resulting in aldolase B deficiency. Individuals with HFI are unable to metabolize fructose, which leads to a toxic accumulation of fructose-1-phosphate (F-1-P) [1]. Excess F-1-P inhibits gluconeogenesis, glycogenolysis, and glycolysis, with resultant hypoglycemia, lactic acidosis, electrolyte disturbances, and cell toxicity to liver and kidney [1,2]. Clinical symptoms include nausea, vomiting, abdominal pain, and failure to thrive. If not recognized early, untreated HFI can lead to severe hepatic and renal dysfunction, seizures, coma and death [3].

Fructose is a naturally-occurring monosaccharide in fruits, honey and many vegetables. The classic presentation of HFI as an infant who presents around 6-months of life when fructose-containing foods, such as fruit, are first introduced into the diet [1]. However, any fructose source can precipitate symptoms. Sucrose and sorbitol are metabolized to fructose by hydrolysis and hepatic sorbitol dehydrogenase respectively [4,5]. Sucrose, sorbitol and many other fructogenic sweeteners are added to many processed foods for sweetness, including infant formula and over-the-counter (OTC) liquid medications [6,7], including widely available liquid preparations of acetaminophen, ibuprofen, and common cough syrups.

HFI is estimated to occur in 1 in 20,000 live births. Variable age of onset and severity of symptoms depends on when and how much fructose is introduced [1,2]. The relatively recent introduction of fructose and its antecedents to widely available commercial infant formulas has resulted in an alteration to the natural history of HFI and likely under-recognition of untreated HFI in neonates, with acute liver failure and potentially catastrophic consequences [3,8]. Yet, to our knowledge, this case series of four neonates is the largest report of HFI presenting with acute liver failure (ALF) after exposure to common infant formulas and emphasizes that HFI must be included on the differential diagnosis for acute neonatal or infantile hepatic failure.

Section snippets

Clinical summary

Here we present four cases of neonatal and early infantile acute liver failure (ALF) associated with multi-organ failure induced by sucrose-containing common infant formula in patients with undiagnosed HFI. All patients were appropriately grown, born at term after uncomplicated pregnancies and deliveries, and discharged within the first week of life. There was no known consanguinity. One patient had a family history of an older brother who died at day of life (DOL) 28 after a similar illness,

Discussion

The clinical presentation of HFI varies widely depending on the patient's age and the quantity and duration of fructose exposure. If the exposure is particularly large or prolonged, especially in neonates and infants, severe liver dysfunction and multi-organ failure can develop [[1], [2], [3],[8], [9], [10]]. ALF in neonates and young infants is a rare and devastating condition with multiple etiologies. Several treatable inborn errors of metabolism can present with neonatal and infant liver

Financial disclosure

The authors have no conflicts of interest to disclose.

Conflict of interest

The authors have no conflicts of interest to disclose.

This manuscript has not been published. It will not be submitted elsewhere while under consideration and, should it be published in Molecular Genetics and Metabolism, it will not be published elsewhere – either in similar form or verbatim – without permission of the editors.

References (18)

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