Specifics of HFI and Its
Diagnosis
Hereditary fructose intolerance has been
recognized as a genetic disorder in humans since 1956 (1). The condition is widespread, however,
most cases have been reported in Europe and North
America. The underlying problem
in treating HFI, as well as for a more complete characterization of the
population genetics of the disorder, is the difficulty of diagnosis. As
mentioned above, diagnosis of HFI is most critical during the newborn period.
The condition is manifested usually during infancy at weaning, when the child
is introduced to fruits and vegetables, or when feeding is transferred from
breast milk to artificial nutrients (2). Complete exclusion of fructose results
in dramatic recovery, however, early diagnosis is crucial for prevention of
fatalities in the high-risk period of infancy (3). In many cases preliminary
diagnoses are made simply based on symptoms exhibited by infants when they are
weaned to fructose-containing foods or formula supplements containing fructose.
Further standard clinical work-up may often reveal nonspecific liver
dysfunction. Current diagnostic
methods include the measurement of clinical
symptoms upon intravenous fructose challenge or the direct assay of aldolase
activity in liver biopsy samples (4, 5). Both of these diagnostic methods are
relatively invasive and the clinical analyses of fructose loading tests or aldolase
assays are not routinely available. In addition, diagnosis by a fructose
tolerance test leads to the same acute symptoms that can be life threatening.
Diagnosis is a challenge, particularly for infants who are suffering the acute
symptoms of the disease and, therefore, are not ideal candidates for either
test. Often diagnosis is not made until adulthood when patients sometimes
report symptoms as a "food allergy". Even in undiagnosed adults HFI
remains a problem due to recurrent inadvertent fructose ingestion. Many deaths
have been documented in undiagnosed HFI individuals who have been challenged
unintentionally (6). These reasons underscore the need for early, reliable, and
non-invasive diagnosis of HFI. One method
commonly employed for diagnosis of fructose malabsorption is the hydrogen (H2) breath test. This test does not give a proper
diagnosis for HFI.
HFI results from a deficiency of aldolase B activity in the
liver, kidney, and intestine (7). The disease is inherited as an autosomal
recessive trait and most parents of HFI patients and siblings who are carriers are
unaffected and exhibit wild-type aldolase B activities (8). These repercussions
of fructose ingestion are most dire for the newborn infant whose parents are
unaware of the disorder and may coerce the persistent ingestion of fructose,
making weaning during infancy the period of greatest risk. Undoubtedly some of
the many cases of undiagnosed liver failure in infancy may be due to HFI. Those
individuals that survive develop a permanent and powerful protective aversion
to sweet-tasting foods (9). However, even later in life acute exposure of HFI
subjects to the noxious sugar can lead to liver failure and death (10-12).
Aldolase B is the major aldolase isozyme in the liver and functions in both
fructose metabolism, using fructose 1-phosphate as a substrate, and in
gluconeogenesis, producing fructose 1,6-bisphosphate from the two triose phosphates,
glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. In the absence of
appreciable aldolase B activity, as in HFI patients, fructose challenge results
in a rapid accumulation of fructose 1-phosphate in the liver, causing
sequestration of inorganic phosphate. This drop in the intracellular phosphate
pool activates AMP deaminase, leading to degradation of adenine nucleotides
(13). The concomitant hypoglycemia is brought on by competitive inhibition of
phosphorylase a by fructose 1-phosphate (14). These potentially serious
manifestations of HFI arise from the inability of the body to degrade fructose
and the subsequent impairment of glucose homeostasis (15). Click to see a body
diagram of fructose metabolism in the normal
and HFI patient.
The treatment for HFI is the exclusion
of fructose, sucrose, and sorbitol (less than 40 mg/kg per day) from the diet
(3) and results in complete alleviation of most symptoms and a normal life span
(1). Older HFI subjects who adhere to a self-imposed fructose-restricted diet
may continue to live undiagnosed and lead relatively normal lives. Complete
exclusion of fructose is often difficult, however, and many HFI patients
develop a syndrome of chronic fructose intoxication characterized by retarded
growth, chronic liver disease, and hepatomegaly (3, 9, 15, 16). Furthermore, if
not treated properly, these patients suffer episodes of hypoglycemia, general
ill health, and strained relationships with family members due to their
peculiar eating habits (17). Constant daily risk remains for HFI individuals
due to the increasingly widespread use of these sugars as nutrients and
sweeteners (18).
You may find additional information in:
the National Institute of Health's "Online
Mendelian Inheritance in Man" HFI www site.
Or the following review articles:
References
1. Chambers, R.A. and Pratt, R.T.C. (1956) Idiosyncrasy to fructose Lancet
2, 340.
2. Baerlocher, K., Gitzelmann, R., Steinmann, B., and Gitzelmann-Cumarumsay,
N. (1978) Hereditary fructose intolerance in early childhood: a major
diagnostic challenge. Helv. Paediatr. Acta 33,465-487.
3. Cornblath, M. and Schwartz, R. (1991) Disorders of carbohydrate
metabolism in infancy: hereditary fructose intolerance. In Major Problems in
Clinical Pediatrics, 3rd edition, Blackwell Scientific Co., Cambridge,
Massachusetts.
4. Laméire, N., Mussche, M., Baele, G., Klint, J. and Ringoir, S.
(1978) Hereditary fructose intolerance: a difficult diagnosis in the
adult. Am. J. Med. 65, 416-423.
5. Steinmann, B. and Gitzelmann, R. (1981) The diagnosis of hereditary
fructose intolerance. Helv. Paediatr. Acta 36,297.
6. Cox, T.M. (1993) Iatrogenic deaths in hereditary fructose intolerance. Arch.
Dis. Childhood 69, 423-415.
7. Hers, H.G. and Joassin, G. (1961) Anomalie de l'aldolasehepatique dans
l'intolerance au fructose. Enzymol. Biol. Clin.1, 4-14.
8. Raivio, K., Perheentup, J. and Nikikila, E.A. (1967) Aldolase activities
in the liver in parents of patients with hereditary fructose intolerance. Clin.
Chim. Acta 17, 275-279.
9. Odiévre, M., Gentil, C., Gautier, M. and Alagille, D. (1978)
Hereditary fructose intolerance in childhood: diagnosis, management and course
in 55 patients. Am. J. Dis. Child.132, 605-608.
10. Schulte, M.J. and Lenz, W. (1977) Fatal sorbitol infusion in patient
with fructose-sorbitol intolerance. Lancet 2,188.
11. Heine, W., Schill, H., Tessman, D., Kupatz, H. (1969) Letale
Leberdystrophie bei drei Geschwistern mit hereditärer Fruktoseintoleranz
nach Dauertropfinfusionen mit sorbitolhaltigen Infusionslösungen. Dtsch
Gesundheitsw. 24, 2325-2329.
12. Hackl, J.M., Balogh, D., Kunz, F., Dworzak, E., Puschendorf, B.,
Decristoforo, A. and Maier, F. (1978) Postoperative Fruktoseintoleranz. Weiner.
Klin. Wschrift. 90, 237-240.
13. Van den Berghe, H., Bruntman, M., Vannestes, R. and Hers, H.G. (1977)
The mechanism of adenine triphosphate depletion in the liver after a load of
fructose. A kinetic study of liver adenylate deaminase. Biochem. J. 134,
637-645.
14. Kaufman, U., Froesch, E.R. (1973) Inhibition of phosphorylase-a by
fructose 1-phosphate, alpha-glycerolphosphate and fructose1,6-diphosphate;
explanation for fructose-induced hypoglycaemia in hereditary fructose
intolerance and fructose 1,6-diphosphatase deficiency. Eur. J. Clin. Invest.
3, 407-413.
15. Steinmann, B., Gitzelmann, R., and Van den Berghe, G. (2001) Disorders
of Fructose Metabolism, in The Metabolic and Molecular Basis of Inherited
Disease (Scriver, C., Beaudet, A., Sly, W., and Valle, D., Eds.) pp
1489-1520, McGraw-Hill, Inc, New York.
16. Mock, D., Perman, J., Thaler, M. and Morris, R.C. (1983) Chronic
fructose intoxication after infancy in children with hereditary fructose
intolerance. N. Engl. J. Med. 309, 764-770.
17. Cox, T.M. (1990) Fructose intolerance: heredity and the environment. In Genetics
and Human Nutrition (Randle, P.J., Bell,
J.I. and Scott, J., eds.) John Libbey, London, pp. 81-92.
18. Cox, T.M. (1994) Aldolase B and fructose intolerance. FASEB Journal.
8, 62-71.