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Q1: What diagnosis would account for her “sugar intolerance” and what diagnostic test would you recommend?
This patient has a typical history of hereditary fructose intolerance. The disease, first reported in an adult in 1956 by Chambers and Pratt,1 usually comes to the attention of medical professionals incidentally when a patient seeks help for a different reason. Patients with this disease generally complain of phobic symptoms, faintness, sweating, abdominal pain, nausea, and vomiting after taking sugar or fructose. They also do not enjoy sweet taste. Our patient and her brother survived infancy and early childhood, developed a self protective aversion to sweets, and remained almost symptom-free following their meat and cheese diet.
Hereditary fructose intolerance is a recessively transmitted metabolic condition caused by catalytic deficiency of aldolase B in liver, kidney, and intestine.2 Aldolase B deficiency leads to inability to metabolise fructose, sorbitol, as well as other carbohydrates containing these sugars such as sucrose. The most frequent allele causing the disease in populations of northern European descent is A149P accounting for over 85% of mutant aldolase B alleles that have been studied in the UK.3 Development of hypoglycaemia after fructose ingestion or infusion is the easiest confirmatory test, though it unfortunately carries some risk and discomfort to the patient. Our patient's family doctor actually had performed that test in the past and confirmed typical biochemical changes. The other possible confirmatory studies include direct assay of fructaldolase activity in tissue (usually intestinal) biopsy,31P nuclear magnetic resonance spectroscopy to show an increase in sugar phosphates and decrease in inorganic phosphates in the liver of a patient with hereditary fructose intolerance after a fructose load, and the polymerase chain reaction combined with restriction enzyme digestion or oligonucleotide hybridisation for the most prevalent previously identified aldolase B mutations A149P, A174D, and N334K. The latter test will miss patients with rare alleles but will identify most of the patients of northern European descent.
Q2: How would you treat hypoglycaemia in such patients?
The treatment of choice for hypoglycaemia in patients with hereditary fructose intolerance is intravenous infusion of glucose. Hypoglycaemia is thought to develop due to inhibition of both gluconeogenesis and glycogenolysis because of the accumulation of fructose-1-phosphate and depletion of inorganic phosphate due to aldolase B deficiency. The exact mode of inhibition of glycogenolysis is unknown. In vitro studies suggest that the block of glycogen breakdown occurs at the level of phosphorylase.2Fructose-1-phosphate also prevents the formation of gluconeogenic intermediates (fructose-1,6-biphosphate and glucose-6-phosphate) by competitive effects on aldolase A and glucose-6-phosphate isomerase, respectively.2 In the absence of a fructose challenge there is no such metabolic inhibition and patients with hereditary fructose intolerance can tolerate prolonged fasting.
Clinical symptoms and signs
After taking sugar or fructose: symptoms of hypoglycaemia (phobic symptoms, faintness, sweating, coma, death) and gastrointestinal symptoms (abdominal pain, nausea, vomiting)
Excellent dental health
Aversion to sweets
Hypoglycaemia after a fructose load
Fructaldolase activity in tissue biopsy
31P nuclear magnetic resonance spectroscopy
Polymerase chain reaction for the aldolase B mutations
Intravenous or oral glucose for hypoglycaemia
Exclusion of fructose, sucrose, sorbitol from diet and medications
Medic-Alert bracelets advising the prohibited sugars and treatment of hypoglycaemia
Q3: What needs to be done for the patient?
Fructose, a constituent of fruits, vegetables, honey, and the disaccharide sucrose (table sugar), is present at a level of 50 to 100 g in the average Western diet. If the undiagnosed infant survives the difficult initial period of weaning, the child usually develops a self protective aversion to most sweet tasting foods as did our patient and her brother. Following a voluntary diet, which is refined by trial and error over their life times, adults with the condition can do well and remain undiagnosed for many years. A particular hazard for them has been indiscriminate use of fructose infusion as a part of total parental nutrition program. More than 20 fatal or near fatal cases resulting from this cause have been and continue to be reported in these patients.4 Introduction of a strict exclusion diet brings rapid return of normal health and development. The patient should use a Medic-Alert bracelet advising the prohibited sugars and the appropriate treatment of hypoglycaemia. Sucrose and sorbitol are also favoured components of syrups, suspensions, and coatings for tablets. Review of all prescription and over-the-counter medications is very important for patient well being.