Hereditary fructose intolerance (HFI) is an inborn error of

fructose Fructose (), or fruit sugar, is a Ketose, ketonic monosaccharide, simple sugar found in many plants, where it is often bonded to glucose to form the disaccharide sucrose. It is one of the three dietary monosaccharides, along with glucose and gal ...

metabolism caused by a deficiency of the enzyme aldolase B. Individuals affected with HFI are asymptomatic until they ingest fructose, sucrose, or

sorbitol Sorbitol (), less commonly known as glucitol (), is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, which changes the converted aldehyde group (−CHO) to a primary alco ...

. If fructose is ingested, the enzymatic block at aldolase B causes an accumulation of fructose-1-phosphate which, over time, results in the death of liver cells. This accumulation has downstream effects on

gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...

and regeneration of

adenosine triphosphate Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...

(ATP). Symptoms of HFI include vomiting, convulsions, irritability, poor feeding as a baby,

hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...

, jaundice,

hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, ...

, hepatomegaly, hyperuricemia and potentially kidney failure. There are reported deaths in infants and children as a result of the metabolic consequences of HFI. Death in HFI is always associated with problems in diagnosis. HFI is an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

condition caused by mutations in the ''ALDOB'' gene, located at 9q31.1. HFI is typically suspected based on dietary history, especially in infants who become symptomatic after breast feeding. This suspicion is typically confirmed by molecular analysis Treatment of HFI involves strict avoidance of fructose in the diet. Older patients with HFI typically self-select a diet low in fructose, even before being diagnosed.

Presentation

The key identifying feature of HFI is the appearance of symptoms with the introduction of

to the diet. Affected individuals are asymptomatic and healthy, provided they do not ingest foods containing fructose or any of its common precursors,

sucrose Sucrose, a disaccharide, is a sugar composed of glucose and fructose subunits. It is produced naturally in plants and is the main constituent of white sugar. It has the molecular formula . For human consumption, sucrose is extracted and refined ...

and

. In the past, infants often became symptomatic when they were introduced to formulas that were sweetened with fructose or sucrose. These sweeteners are not common in formulas used today. Symptoms such as vomiting, nausea, restlessness, pallor, sweating, trembling and lethargy can also first present in infants when they are introduced to fruits and vegetables. These can progress to apathy, coma and convulsions if the source is not recognized early. When patients are diagnosed with HFI, a dietary history will often reveal an aversion to fruit and other foods that contain large amounts of fructose. Most adult patients do not have any dental caries.

Fructose metabolism

After ingestion, fructose is converted to fructose-1-phosphate in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

by fructokinase. Deficiencies of fructokinase cause essential fructosuria, a clinically benign condition characterized by the excretion of unmetabolized fructose in the urine. Fructose-1-phosphate is metabolized by aldolase B into dihydroxyacetone phosphate and glyceraldehyde. HFI is caused by a deficiency of aldolase B. A deficiency of aldolase B results in an accumulation of fructose-1-phosphate, and trapping of phosphate (fructokinase requires

(ATP)). The downstream effects of this enzyme block are the inhibition of glucose production and reduced regeneration of ATP.

Diagnosis

Because of the ease of therapy (dietary exclusion of fructose), HFI can be effectively managed if properly diagnosed. In HFI, the diagnosis of homozygotes is difficult, requiring a genomic DNA screening with

allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...

-specific probes or an enzyme assay from a liver biopsy. Once identified, parents of infants who carry mutant aldolase B alleles leading to HFI, or older individuals who have clinical histories compatible with HFI can be identified and counselled with regard to preventive therapy: dietary exclusion of foods containing fructose, sucrose, or sorbitol. If possible, individuals who suspect they might have HFI should avoid testing via fructose challenge as the results are non-conclusive for individuals with HFI, and even if the diagnostic administration of fructose is properly controlled, profound

and its sequelae can threaten the patient's well-being.

Treatment

Treatment of HFI depends on the stage of the disease, and the severity of the symptoms. Stable patients without acute intoxication events are treated by careful dietary planning that avoids fructose and its metabolic precursors. Fructose is replaced in the diet by

glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...

, maltose or other sugars. Management of patients with HFI often involves dietitians who have a thorough knowledge of what foods are acceptable.

References

External links