Hereditary Fructose Intolerance

Hereditary fructose intolerance (HFI) is an autosomal recessive disorder due to deficiency of aldolase B (ALDOB, 9q31.1), which cleaves fructose-1-phosphate.

After fructose, sucrose or sorbitol ingestion, fructose-1-phosphate accumulates in the liver, kidney and intestine, trapping inorganic phosphate, depleting ATP, inhibiting glycogenolysis and gluconeogenesis, and causing hypoglycaemia, lactic acidosis, hyperuricaemia, hypophosphataemia, and liver and renal injury. Incidence is about 1 in 20,000 to 30,000 in Europe. Common variants are A149P, A174D and N334K (in Europeans). It must be distinguished from fructose malabsorption (a benign intestinal condition) and essential fructosuria.

• Asymptomatic until fructose, sucrose or sorbitol is introduced (weaning, fruit juices, sweetened formula, sucrose containing medicines)
• Acute exposure: nausea, vomiting, abdominal pain, sweating, pallor, tremor, hypoglycaemia (seizures, coma), lactic acidosis, hypophosphataemia, hypermagnesaemia, hyperuricaemia, and hypokalaemia
• Chronic exposure: failure to thrive, hepatomegaly with steatosis, jaundice, liver failure, proximal renal tubular acidosis (Fanconi like syndrome), coagulopathy, and cirrhosis
• Characteristic behavioural adaptation: spontaneous aversion to sweet foods, fruit and vegetables; excellent dental health (few caries)
• Intravenous fructose, sorbitol or invert sugar infusion can cause fatal reactions

1. Clinical suspicion from the history of symptoms after fructose or sucrose.
2. ALDOB genetic testing (sequencing and deletion analysis; detects over 95% with common variants; the diagnostic standard, replacing fructose tolerance tests and enzyme assay on liver biopsy, which are risky).
3. Biochemistry: during an attack, low glucose, high lactate, high uric acid, low phosphate; elevated transaminases; coagulopathy; urinary reducing substances, and carbohydrate deficient transferrin abnormalities.
4. Liver ultrasound and renal function tests.
5. Avoid intravenous fructose provocation testing.

• Acute hypoglycaemia: IV dextrose 10% 2 to 5 mL/kg, followed by continuous glucose infusion (6 to 10 mg/kg/min); correct acidosis and electrolytes, treat liver failure, and stop all fructose containing solutions, sorbitol and sucrose. Avoid glucagon (ineffective).
• Lifelong strict exclusion of fructose, sucrose, sorbitol and invert sugar.
• Tolerated intake is under 1 to 2 g/day in most patients (some tolerate up to 5 to 10 g/day, as individual thresholds vary).
• Read labels carefully and avoid fruit, many vegetables (sweet potatoes, carrots, onions in quantity), honey, sweeteners (sorbitol, xylitol, maltitol), and medications with sucrose or sorbitol excipients.
• Avoid IV infusions (fructose, sorbitol, invert sugar) and note alerts on medical bracelets.
• Supplements: vitamin C (to replace dietary loss; 100 mg/day), folic acid, and multivitamins; calcium and vitamin D.
• Monitoring: growth, liver and kidney function, and uric acid; dietitian follow up.
• Liver transplantation is rarely required for liver failure.
• Genetic counselling: 25% recurrence risk, carrier testing, and prenatal diagnosis.