AUTHOR INFORMATION

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Authored by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research

Edited by Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Karl S Roth, MD
Editor's Email:	Michael Fasullo, PhD

eMedicine Journal, July 25 2005, VOLUME 6, Number 7

INTRODUCTION

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Background: Clinical intolerance to fructose was initially described in 1956. The following year, a familial incidence of the disorder in several family members, together with the postulate that the defect was a deficiency of hepatic fructose 1-aldolase, was reported. 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 be because of the fairly dramatic symptoms associated with ingestion of fructose, which are difficult to miss. These 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. Based upon this, homozygous neonates remain clinically well until confronted with dietary sources of fructose. Although the carbohydrate base in most infant formulas is lactose, some (notably the soy formulas) contain sucrose, a fructose-glucose disaccharide that may cause symptoms. The biochemistry of HFI is rather 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).

Under normal cellular conditions, the primary enzymatic activity of aldolase B is to cleave fructose diphosphate (FDP), thus forming rather than condensing the triose phosphate compounds; in this role, 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. By virtue of the absence of the latter function, clinical hypoglycemia in HFI can easily be explained.

Reduced cleavage of F-1-P leads to its cellular accumulation and inhibition of fructokinase, causing accumulation of free fructose 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, which accounts for the hyperuricemia observed during an acute episode. Competition between urate and lactate for excretion by the renal tubule accounts for the lactic acidemia.

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

Frequency:

• In the US: True prevalence has not been established, but HFI is thought to be more common than originally believed because many asymptomatic affected people may simply avoid ingestion of most or all sweets. Some have estimated the prevalence as high as approximately 1:20,000 individuals.

• Internationally: The prevalence of hereditary fructose intolerance in central Europe has been reported recently to be 1:26,100.

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

Sex: An autosomal recessive trait, cases of HFI are equally distributed between the sexes.

Age: In many young infants, the age of onset of symptoms leads to the diagnosis. An accurate dietary history is important; it can indicate a coincidence of onset with introduction of fruits into the diet.

CLINICAL

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History:

• As in other autosomal recessive disorders, a pedigree is unlikely to reveal other affected family members. Obligate heterozygotes do not show symptoms of HFI.



• The importance of an extensive dietary history, especially in HFI, cannot be overemphasized, as the history may be diagnostic. Many soy formulas contain sucrose as a carbohydrate source that may supply adequate fructose to cause clinical symptoms.



• Some affected infants refuse all sweets after becoming ill in early life; thus, a history of food rejection is also important.

Physical:

• A clinically well patient shows no abnormal physical findings.



• Acutely ill children are often tachypneic because of acidosis, they have enlarged livers, and they are slightly to moderately icteric; accompanying hypoglycemia may cause tremors and/or seizures, as well as diaphoresis.



• A common feature among treated children is exceptionally good dental hygiene, presumably because of the diminished carbohydrate intake.

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

WORKUP

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Lab Studies:

• The most straightforward approach to diagnosis, based on a good dietary history in a sick child, is to demonstrate the presence of a non–glucose-reducing sugar in the urine. This is accomplished easily, first by Clinitest and, if results are positive, then by thin-layer chromatographic separation.



• Urine metabolic screen may also provide evidence of glucosuria, proteinuria, and aminoaciduria, which are all part of the renal Fanconi syndrome.



• Plasma electrolytes are important because the renal tubular acidosis component of HFI may significantly depress the total plasma bicarbonate.



• Obtain liver function studies to assess the degree of hepatocellular disease.

Other Tests:

• Elimination of dietary fructose is both a compulsory and a therapeutic step, and, in a sick patient, elimination can also serve as a diagnostic test because all symptoms should resolve completely.



• Intravenous fructose tolerance testing should be performed only in an asymptomatic patient and in a controlled setting; do not use oral fructose tolerance testing because the GI response may be violent.



• The combination of a therapeutic response to elimination of fructose and a positive response to the fructose tolerance test is sufficient to obviate biopsy. However, a molecular analysis in leucocytes of the gene on chromosome 9 can provide definitive evidence of a mutation at the q22.3 site.

TREATMENT

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Medical Care: Definitive treatment simply consists of eliminating fructose from the diet. By doing so early in the course, the affected child's health is restored totally within days, and no residua occur. Hepatomegaly may require a number of months to resolve, however. Any prolonged delay in diagnosis may result in cirrhotic changes in the liver 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. Many unsuspected sources of these sugars exist. For example, potatoes, when prepared a certain way, may provide a significant amount of fructose. For this reason, a highly trained nutritionist's input is mandatory to health maintenance in this disorder.

MEDICATION

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

FOLLOW-UP

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Further Outpatient Care:

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

Transfer:

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

Deterrence/Prevention:

• Prolonged, albeit minor, dietary indiscretion in growing children may result in sufficient degrees of acidosis to cause growth impairment.



• HFI is an autosomal recessive disorder, with a 25% recurrence risk for subsequent pregnancies. Genetic counseling is important for parents and other relatives.

Complications:

• Hypoglycemia, if sufficiently severe, may result in diminished intellectual capacity.



• Hepatocellular damage and fibrosis may result in hepatic cirrhosis.



• Severe metabolic acidosis may result in hypoperfusion and serious organ damage.

Prognosis:

• For the rapidly diagnosed and treated infant, the prognosis for a normal state of health is excellent.



• In the absence of substantial hepatic damage, life expectancy is normal.

Patient Education:

• Parents must receive genetic counseling as a 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

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Medical/Legal Pitfalls:

• Use of a diagnostic fructose hydrogen breath test for diagnostic purposes should always be preceded by a careful dietary history to exclude HFI.

Special Concerns:

• Carefully monitor the child's growth; minor and inadvertent dietary indiscretions may affect linear growth because of chronic systemic acidosis.

TEST QUESTIONS

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CME Question 1: Which of the following is not a part of the presentation of patients with hereditary fructose intolerance (HFI)?

A: Renal tubular acidosis
B: Lactic acidemia
C: Hyperuricemia
D: Hypoglycemia
E: Cataracts

The correct answer is E: Patients presenting with the rapid early signs of fructose intolerance usually have severe metabolic acidosis and hypoglycemia. The accumulation of free fructose in the blood changes the adenosine triphosphate (ATP)–adenosine monophosphate (AMP) cellular ratio, which results in accelerated production of uric acid and hyperuricemia. HFI also affects the kidney, causing severe proximal renal tubular acidosis. Cataracts are not a part of HFI presentation.

CME Question 2: Treatment of hereditary fructose intolerance (HFI) requires which of the following?

A: Hemodialysis
B: Elimination of all carbohydrate sources from the diet
C: Anticonvulsants
D: Elimination of fructose, sucrose, and sorbitol from the diet
E: Elimination of fructose only from the diet

The correct answer is D: Definitive treatment consists of eliminating fructose from the diet. By doing so early in the course, the affected child`s health is restored within days and no residua occur.

Pearl Question 1 (T/F): Patients with hereditary fructose intolerance (HFI) experience hypoglycemia with fructose ingestion.

The correct answer is True: The pathway resulting in synthesis of glucose from alternative substrates (gluconeogenesis) depends upon the aldolase B–mediated condensation of two 3-carbon fragments to produce the C-6 carbon skeleton of glucose. Gluconeogenesis is a vital pathway in glucose homeostasis and normally occurs mainly in liver and kidney tissues. Patients with HFI are usually aldolase B deficient in the liver and kidney tissues, which interrupts the glucogenesis pathway, causing hypoglycemia.

Pearl Question 2 (T/F): Lactic acidemia is observed during an acute episode of hereditary fructose intolerance (HFI).

The correct answer is True: Accumulation of phosphorylated compounds within the hepatocyte slows adenosine triphosphate (ATP) production and results in increased amounts of adenosine monophosphate (AMP) that the cell can catabolize to uric acid. Release of urate raises the blood concentration, causing competitive inhibition with lactic acid (normally present in low concentration) for excretion by the renal tubule.

Pearl Question 3 (T/F): A firm diagnosis of hereditary fructose intolerance (HFI) requires a biopsy.

The correct answer is False: First, a scrupulous dietary history that implicates fruits as the offending substances should lead to omission of all fructose sources from the diet. Eliminating fructose from the diet should produce a therapeutic response in days, thus establishing the diagnosis. Second, an intravenous fructose tolerance test that reveals hypoglycemia, decreased plasma phosphate, increased plasma magnesium, and uric acid also leads to a final diagnosis. Together, these 2 maneuvers provide firm grounds for clinical diagnosis; therefore, the combination of a therapeutic response to elimination of fructose and a positive response to the fructose tolerance test is sufficient to obviate a biopsy.

Pearl Question 4 (T/F): Hereditary fructose intolerance (HFI) has a clinical impact on the kidney.

The correct answer is True: The outstanding feature of fructose-induced renal abnormalities is severe proximal renal tubular acidosis with rapid onset following fructose ingestion. In addition, proximal tubular function is generally impaired, resulting in a renal Fanconi syndrome consisting of aminoaciduria, glucosuria, phosphaturia, and uricosuria. The entire complex is completely reversible with treatment.

BIBLIOGRAPHY

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• Ali M, Rellos P, Cox TM: Hereditary fructose intolerance. J Med Genet 1998 May; 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 1963; 34: 151-167.
• Levin B, Oberholzer VG, Snodgrass GJAI, Stimmler L, Wilmers MJ: Fructosaemia: an inborn error of fructose metabolism. Arch Dis Child 1963; 38: 220-230.
• Mass RE, Smith WR, Walsh JR: The association of hereditary fructose intolerance and renal tubular acidosis. Am J Med Sci 1966 May; 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 1967 Sep 9; 2(7515): 528-31[Medline].
• Santer R, Rischewski J, von Weihe M: The spectrum of aldolase B(ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe. Hum Mutat 2005; 25: 594.
• Steinmann B, Gitzelmann R: The diagnosis of hereditary fructose intolerance. Helv Paediatr Acta 1981 Sep; 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].

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