Hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism caused by a deficiency of the enzyme aldolase B. Individuals affected with HFI are asymptomatic until they ingest fructose, sucrose, or sorbitol. 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 and regeneration of

adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms o ...

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

hypoglycemia Hypoglycemia, also 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 triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

, 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, v ...

hepatomegaly Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdo ...

hyperuricemia Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7&nbs ...

and potentially

kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

. While HFI is not clinically a devastating condition, 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 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 fructose to the diet. Affected individuals are asymptomatic and healthy, provided they do not ingest foods containing fructose or any of its common precursors, sucrose and sorbitol. In the past, infants often became symptomatic when they were introduced to

formulas In science, a formula is a concise way of expressing information symbolically, as in a mathematical formula or a ''chemical formula''. The informal use of the term ''formula'' in science refers to the general construct of a relationship betwe ...

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 Tooth decay, also known as cavities or caries, is the breakdown of teeth due to acids produced by bacteria. The cavities may be a number of different colors from yellow to black. Symptoms may include pain and difficulty with eating. Complicatio ...

Fructose metabolism

After ingestion, fructose is converted to

fructose-1-phosphate Fructose-1-phosphate is a derivative of fructose. It is generated mainly by hepatic fructokinase but is also generated in smaller amounts in the small intestinal mucosa and proximal epithelium of the renal tubule. It is an important intermediate o ...

in the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

fructokinase Fructokinase (/fruc•to•ki•nase/ ki´nas, also known as D-fructokinase or D-fructose (D-mannose) kinase,essential fructosuria, a clinically

benign Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

condition characterized by the excretion of unmetabolized fructose in the urine. Fructose-1-phosphate is metabolized by aldolase B into dihydroxyacetone phosphate and

glyceraldehyde Glyceraldehyde (glyceral) is a triose monosaccharide with chemical formula C3 H6 O3. It is the simplest of all common aldoses. It is a sweet, colorless, crystalline solid that is an intermediate compound in carbohydrate metabolism. The word comes ...

. 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

homozygote Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

s is difficult, requiring a

genomic DNA Genomic deoxyribonucleic acid (abbreviated as gDNA) is chromosomal DNA, in contrast to extra-chromosomal DNAs like plasmids. Most organisms have the same genomic DNA in every cell; however, only certain genes are active in each cell to allow for ...

screening with

allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...

-specific probes or an

enzyme assay Enzyme assays are laboratory methods for measuring enzymatic activity. They are vital for the study of enzyme kinetics and enzyme inhibition. Enzyme units The quantity or concentration of an enzyme can be expressed in molar amounts, as with a ...

from a

liver biopsy Liver biopsy is the biopsy (removal of a small sample of tissue) from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment. Medica ...

. 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 simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

, maltose or other sugars. Management of patients with HFI often involves

dietitian A dietitian, medical dietitian, or dietician is an expert in identifying and treating disease-related malnutrition and in conducting medical nutrition therapy, for example designing an enteral tube feeding regimen or mitigating the effects of ca ...

s who have a thorough knowledge of what foods are acceptable.

References

External links