Hereditary Fructose Intolerance

Hereditary fructose intolerance (HFI) is a rare genetic disorder where individuals lack aldolase B, an enzyme required for the metabolism of fructose-1-phosphate. When an individual with HFI is exposed to fructose, fructose 1-phosphate accumulates in the liver and kidney. Symptoms of acute toxicity may include nausea, vomiting, abdominal pain, and hypoglycaemia. Chronic symptoms can include failure to thrive, fatigue, persistent abdominal pain, jaundice, and severe liver and kidney damage.

Fructose is primarily derived from the diet. It is found in its free form in honey, fruits, and some vegetables. Fructose can also be derived from the ingestion of sucrose and sorbitol. Sucrose is a disaccharide containing one glucose and one fructose molecule joined together, while sorbitol is converted to fructose in the liver.

When exclusively breastfed, infants with HFI are asymptomatic with normal growth and development. Symptoms typically become apparent when solid foods are introduced. However, symptoms can occur earlier when infant formula containing these sugars is used.

If this condition is identified and managed before organ damage occurs, quality of life and life expectancy are normal. Management requires the dietary restriction of fructose, sucrose, and sorbitol.

Hereditary fructose intolerance should not be confused with fructose malabsorption. Fructose malabsorption is a common condition where individuals cannot absorb fructose properly. The ingestion of fructose can produce gastrointestinal issues such as diarrhoea and bloating in these individuals. In contrast, HFI is a metabolic disorder that can lead to serious and life-threatening reactions upon exposure to fructose.

Sugars in medicines

Many medications and nutritional supplements contain sugars that must be avoided in HFI. Sorbitol is found in many medicines for oral use, particularly oral liquid medicines (e.g. analgesics, antibiotics). However, some capsules and tablets also contain this sugar.

The risk of harm is significantly higher when fructose or sorbitol is administered parenterally, particularly when the intravenous route is used. Fatal outcomes have been reported in adults with HFI following the intravenous administration of 25g of sorbitol. These reactions involve hepatorenal failure associated with bleeding.

Sorbitol is used as an excipient in some products for parenteral use. It can be used to adjust tonicity or as a stabilising agent for proteins and peptides. Products containing sorbitol include some monoclonal antibodies, immunoglobulins, growth factors, and vaccines. However, the amount can vary significantly. For example, Flebogamma® (human normal immunoglobulin) contains sorbitol 50mg/ml, while Stamaril® (yellow fever vaccine) contains only 8mg/dose of sorbitol.

The ingestion of large quantities of fructose can be particularly problematic for infants. Life-threatening events can occur when young children with HFI receive medicines containing fructose intravenously. As young children with this condition may not yet be diagnosed, it recommended to avoid the use of intravenous medicines containing fructose in children under two years unless there is an overwhelming need and no appropriate alternative.

Some vaccines routinely recommended for use in children under two years do contain sorbitol or sucrose as excipients (e.g. MMR and varicella zoster vaccines). However, the amounts are low and absorption slower due to their administration via the subcutaneous or intramuscular routes. Severe events due to HFI have not been reported with these vaccines.

Some examples of medicines containing sugars of concern in HFI are shown in Table 1.

Table 1. Medications containing fructose, sucrose, or sorbitol.

The polysorbate content of medicines should also be considered as these agents are derived from sorbitol. Polysorbates may be used as a surfactant to improve the dissolution of poorly water-soluble drugs (e.g. docetaxel, amiodarone) or to stabilise protein-based medicines (e.g. some monoclonal antibodies).

Summary

There is currently no established and generally accepted safe dose of fructose for patients with HFI. Some reports consider amounts up to 40mg/kg/day (up to 1.5g) safe. However, evidence suggests that inadequate restriction of fructose can cause growth deficiency even in patients who are clinically asymptomatic.

Maintaining a low fructose diet can be challenging due to the widespread presence of fructose in foods. Support groups can assist with practical dietary strategies.

During hospitalisation, additional care is required to avoid the administration of medicines and fluids containing fructose, sucrose, or sorbitol to patients with HFI.