AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Clinical intolerance to fructose was initially described in 1956. The following year, researchers reported a familial incidence of the disorder in several family members, postulating that the defect was a deficiency of hepatic fructose 1-aldolase. Within the next 4-5 years, the enzyme defect in aldolase B isozyme in the liver was demonstrated, and hereditary fructose intolerance (HFI) became recognized as a distinct clinical entity. The rapid early progress in the understanding of this disorder may have occurred because of the fairly dramatic and difficult-to-miss symptoms associated with fructose ingestion. These symptoms include vomiting, hypoglycemia, failure to thrive, cachexia, hepatomegaly, jaundice, coagulopathy, severe metabolic acidosis (in part due to lactic acidosis), coma, and renal Fanconi syndrome.

Pathophysiology

Affected individuals are completely asymptomatic until they ingest fructose. Thus, homozygous neonates remain clinically well until confronted with dietary sources of fructose. Although lactose is the carbohydrate base in most infant formulas, some (eg, soy formulas) contain sucrose, a fructose-glucose disaccharide that may cause symptoms. The biochemistry of hereditary fructose intolerance  is complex for 2 reasons: (1) 3 isozymes of aldolase (A, B, C) exist, of which aldolase B is expressed exclusively in the liver, kidney, and intestine, and (2) aldolase B mediates 3 separate reactions (ie, cleavage of fructose 1-phosphate [F-1-P]; cleavage of fructose 1,6-diphosphate; and condensation of the triose phosphates, glyceraldehyde phosphate, and dihydroxyacetone phosphate to form fructose 1,6-diphosphate).

In normal cellular conditions, the primary enzymatic activity of aldolase B is to cleave fructose diphosphate (FDP), which forms rather than condenses the triose phosphate compounds. Here, the enzyme is central to the glycolytic pathway. Because the reaction is reversible, aldolase B is an essential enzyme in the process of gluconeogenesis (which is, in some respects, a reversal of glycolysis). The absence of the latter function readily explains the clinical hypoglycemia in individuals with hereditary fructose intolerance.

Reduced cleavage of F-1-P leads to its cellular accumulation and fructokinase inhibition, causing free fructose accumulation in the blood. A generally accepted consequence of this sequence is a dramatic change in the adenosine triphosphate (ATP)–adenosine monophosphate (AMP) cellular ratio, with a resultant acceleration in production of uric acid. This accounts for the hyperuricemia observed during an acute episode. Competition between urate and lactate for renal tubule excretion accounts for the lactic acidemia.

The cause of severe hepatic dysfunction remains unknown but may be a manifestation of focal cytoplasmic degeneration and cellular fructose toxicity. The cause of renal tubular dysfunction also remains unclear; patients with renal tubular dysfunction primarily present with a proximal tubular acidosis complicated by aminoaciduria, glucosuria, and phosphaturia. Thus, in an infant who is homozygous for fructose 1-aldolase deficiency, fructose ingestion triggers a cascade of biochemical events that result in severe clinical disease.  

Frequency

United States

Although the true prevalence has not been established, hereditary fructose intolerance may be more common than originally believed; many asymptomatic affected people may simply avoid the ingestion of most or all sweets. The prevalence has been estimated to be as high as 1 per 20,000 individuals.

International

Recently, the prevalence of hereditary fructose intolerance in central Europe has been reported to be 1 per 26,100 individuals.

Mortality/Morbidity

Morbidity is implicit in untreated patients. Hypoglycemia and acidosis may act together to cause organ shock or coma. Ongoing hepatocellular insult may result in cirrhosis and eventual hepatic failure. Failure to thrive progressing to cachexia is the rule. Mortality may result from any or all of the above conditions.

Sex

Hereditary fructose intolerance is an autosomal recessive trait that is equally distributed between the sexes.

Age

In many infants, the age at symptom onset leads to the diagnosis. An accurate dietary history can indicate a link between the introduction of fruits into the diet and symptom onset.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• As in other autosomal recessive disorders, a pedigree is unlikely to reveal other affected family members. Individuals who are obligate heterozygotes do not demonstrate the symptoms of hereditary fructose intolerance.
• Because the history may be vital to the diagnosis, the importance of taking an extensive dietary history, especially in individuals with hereditary fructose intolerance, cannot be overemphasized. Many soy formulas contain sucrose as a carbohydrate source that may supply enough fructose to cause clinical symptoms.
• Some affected infants refuse all sweets after becoming ill early in life; thus, a history of food rejection is also important.

Physical

• A clinically well patient demonstrates no abnormal physical findings.
• Acutely ill children are often tachypneic because of acidosis. They have enlarged liver and are slightly-to-moderately icteric. Accompanying hypoglycemia may cause tremors or seizures, as well as diaphoresis.
• Exceptionally good dental hygiene is a common feature among children with hereditary fructose intolerance, presumably because of diminished carbohydrate intake.

Causes

Hereditary fructose intolerance is inherited as an autosomal recessive trait. The gene has been mapped to one locus, band 9q22.3. As of 1995, 21 mutations had been reported at this locus, most of them single-base substitutions.

WORKUP

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Based on the thorough dietary history of a sick child, the most straightforward approach to diagnosis is to demonstrate the presence of a non–glucose-reducing sugar in the urine. This is readily accomplished with Clinitest. Then, if test results are positive, thin-layer chromatographic separation should be used for confirmation.
• Urine metabolic screening results may also provide evidence of glucosuria, proteinuria, and aminoaciduria, all of which are part of renal Fanconi syndrome.
• Plasma electrolyte levels are important to determine, because the renal tubular acidosis component of hereditary fructose intolerance may significantly depress the total plasma bicarbonate level.
• Obtain liver function test results to assess the degree of hepatocellular disease.

Other Tests

• Elimination of dietary fructose is both a compulsory and therapeutic step. In sick patients, elimination may also serve as a diagnostic test, because all symptoms should completely resolve.
• Only asymptomatic patients in a controlled setting should undergo intravenous fructose tolerance testing; do not use oral fructose tolerance testing because of the potentially violent GI response.
• The combination of a therapeutic response to fructose elimination and a positive response to the fructose tolerance test is sufficient to exclude obtaining a biopsy sample. However, a molecular analysis in leucocytes of the gene on chromosome 9 may provide definitive evidence of a mutation at the q22.3 band.

Histologic Findings

In a liver biopsy specimen from an untreated patient, evidence of hepatocellular involvement is clear, including areas of focal necrosis, fatty degeneration in peripheral lobules, bile duct proliferation, and late changes of portal and biliary cirrhosis. Histologic changes are much less striking in the kidney and intestine, the other tissues with aldolase-B deficiency. The kidney may demonstrate granulation of the proximal tubular epithelium with some tubule dilatation. The intestine may show small areas of hemorrhage in the submucosa or serosa. Except in untreated patients with cirrhosis late in the course of disease, all of the above changes are reversible. Of note, the availability of molecular analysis of the gene defect obviates the need for a corroborative biopsy sample.

TREATMENT

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Definitive treatment simply consists of eliminating fructose from the diet. Eliminating fructose early in the disease course totally restores the affected child's health within days, with no residua. However, hepatomegaly may require a number of months to resolve. Prolonged delay in diagnosis may result in cirrhotic changes with subsequent degeneration of function.

Consultations

When appropriate, consult a biochemical geneticist and a nutritionist.

Diet

Appropriate treatment consists of elimination of fructose, sorbitol, and sucrose sources, such as fruits and table sugar. Unsuspected sources of these sugars abound. For example, potatoes that are prepared a certain way provide a significant amount of fructose. For this reason, a highly trained nutritionist's input is mandatory to properly maintain the health of individuals with this disorder.

MEDICATION

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug therapy is not a component of the standard of care for this condition. See Treatment.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Close dietary monitoring is important for a good outcome and should include at least semiannual visits to a biochemical geneticist and monthly meetings with a nutritionist.

Transfer

• Infants, particularly young children, may be sufficiently ill to require transfer for supportive care, even after a proper diagnosis has been made. Severe acidosis and hepatocellular dysfunction carry their own rates of morbidity, independent of and despite the reversibility of hereditary fructose intolerance with treatment.

Deterrence/Prevention

• Prolonged, albeit minor, dietary indiscretions in growing children may result in acidosis that is severe enough to impair growth.
• Hereditary fructose intolerance is an autosomal recessive disorder.  Subsequent pregnancies carry a 25% risk of recurrence. Parents and other relatives must receive genetic counseling.

Complications

• Hypoglycemia, if sufficiently severe, may result in diminished intellectual capacity.
• Hepatocellular damage and fibrosis may result in cirrhosis.
• Severe metabolic acidosis may result in hypoperfusion and serious organ damage.

Prognosis

• The prognosis is excellent for infants who receive rapid diagnosis and treatment.
• In the absence of substantial hepatic damage, life expectancy is normal.

Patient Education

• Parents must receive genetic counseling as part of their education in the care of the child.
• Stress the importance of input from a nutritionist and the essential nature of a cooperative relationship in the long-term care of the child.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• A careful dietary history to exclude hereditary fructose intolerance should always be obtained before a fructose hydrogen breath test is used for diagnostic purposes.

Special Concerns

• Carefully monitor the child's growth; minor and inadvertent dietary indiscretions may lead to chronic systemic acidosis, which may affect linear growth.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Ali M, Rellos P, Cox TM. Hereditary fructose intolerance. J Med Genet. May 1998;35(5):353-65. [Medline].
• Chambers RA, Pratt RTC. Idiosyncrasy to fructose. Lancet. 1956;2:340.
• Froesch ER, Prader A, Labhart A, Stuber HW, Wolf HP. Die hereditare Fructoseintoleranz, eine bisher nicht bekannte kongenitale Stoffwechselstorung. Schweiz Med Wochenschr. 1957;87:1168-1171.
• Froesch ER, Wolf HP, Baitsch H, Prader A, Labhart A. Hereditary fructose intolerance. An inborn defect of hepatic fructose-1-phosphate splitting aldolase. Am J Med. Feb 1963;34:151-67. [Medline].
• Levin B, Oberholzer VG, Snodgrass GJAI, Stimmler L, Wilmers MJ. Fructosaemia. An inborn error of fructose metabolism. Arch Dis Child. Jun 1963;38:220-30. [Medline].
• Mass RE, Smith WR, Walsh JR. The association of hereditary fructose intolerance and renal tubular acidosis. Am J Med Sci. May 1966;251(5):516-23. [Medline].
• Muller P, Meier C, Bohme HJ. Fructose breath hydrogen test - is it really a harmless diagnostic procedure?. Dig Dis. 2003;21:276-278.
• Perheentupa J, Raivio K. Fructose-induced hyperuricaemia. Lancet. Sep 9 1967;2(7515):528-31. [Medline].
• Santer R, Rischewski J, von Weihe M, Niederhaus M, Schneppenheim S, Baerlocher K, et al. The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe. Hum Mutat. Jun 2005;25(6):594. [Medline].
• Steinmann B, Gitzelmann R. The diagnosis of hereditary fructose intolerance. Helv Paediatr Acta. Sep 1981;36(4):297-316. [Medline].
• Tolan DR. Molecular basis of hereditary fructose intolerance: mutations and polymorphisms in the human aldolase B gene. Hum Mutat. 1995;6(3):210-8. [Medline].

Article Last Updated: Aug 31, 2007