Hereditary Fructose Intolerance

Hereditary fructose intolerance (HFI) has been recognized as a genetic disorder in humans since 1956.1 It is quite different from fructose malabsorption (also known as dietary fructose intolerance).

What is HFI?

Scientific Definition

HFI is an autosomal recessive disorder of fructose metabolism due to a deficiency of fructose-1-phosphate aldolase (EC activity, which results in an accumulation of fructose-1-phosphate in the liver, kidney, and small intestine. The accumulated fructose-1-phosphate inhibits glycogen breakdown and glucose synthesis, thereby causing severe hypoglycemia following ingestion of fructose.

Understandable Definition

HFI is a condition people are born with, usually in families where there is no previous history. The condition makes it difficult for the body, chiefly the liver and kidney, to use fructose and fructose-containing foods. The sugar is taken up by the body, but in attempting to use the sugar, toxic substances are produced, which lead to serious illness.


These include severe abdominal pain, vomiting, and hypoglycemia following ingestion of fructose or other sugars metabolized through fructose-1-phosphate. Prolonged fructose ingestion in infants leads ultimately to hepatic and/or renal failure and death. Patients develop a strong distaste for sweet food, and can avoid a recurrence of symptoms chronic course of the disease by remaining on a fructose- and sucrose-free diet.

What HFI is NOT:

HFI symptoms are common to many other illness and disorders. However, HFI is most commonly confused with fructose malabsorption. This is a non-life threatening and much more common condition. This site contains a helpful comparison of the two conditions. The treatment for both is similar.

HFI Incidence Rate

The world-wide incidence rate of HFI remains unknown due to the difficulty of HFI diagnosis. The first report of an incidence rate was from Switzerland, where over a five year period that included 100,000 births, five cases of HFI were reported2. The degree of deviation in this estimate of 1 in 20,000 births is large and the incidence rate may range from 1 in 10,000 to 1 in 100,000. A more recent study in the UK using DNA testing indicated a more precise incidence rate of 1 in 22,000 where the range would be between 1 in 12,000 to 1 in 58,0003.

It is likely that the incidence rate varies quite widely among different ethnic groups. Until easier and more effective methods of diagnosis are available from research involving different ethnic groups, the incidence rate will remain unclear4. There have been numerous reports of self diagnosis in adulthood, inadvertent deaths to undiagnosed subjects, and homozygous-heterozygous marriages, all of which indicate that the incidence rate could be closer to 1 in 10,000567. If so, the carrier frequency would be 1 in 50. While the frequency of HFI in Switzerland is considered by many pediatricians to be higher than other parts of the world, the reports outlined above have occurred world-wide and the presumption that HFI is a rare disorder is clearly premature.


The only definitive way to ascertain if one is suffering from HFI is to have one of two tests:

  1. An enzymatic assay to determine aldolase activity. The aldolase is obtained from patient liver tissue in an invasive surgical procedure called a liver biopsy.
  2. A fructose tolerance test. Fructose is injected intravenously under controlled conditions where acute glucose, fructose, and phosphate levels are monitored.

HOWEVER, both tests represent considerable risk, especially in a newborn.

A newer, non-invasive DNA test is readily becoming more available. While the DNA test is not diagnostic because negative results do not guarantee that one does not have HFI, positive results, along with clinical symptoms, are strong indicators of disease. A presumptive diagnosis can be made.

H2 Breath Test

An unreliable method is the H2 breath test. The hydrogen breath test is a safe and noninvasive procedure that may diagnose fructose malabsorption. Following ingestion of fructose, the hydrogen concentration of the patient’s breath is measured at various time intervals. An increase above baseline hydrogen concentration suggests fructose malabsorption.

NOTE: This test has not been shown to be an effective means of diagnosing fructose intolerance.

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