Hereditary Fructose Intolerance (HFI) (Fructose 1-Phosphate Aldolase Deficiency) 

Updated: Oct 15, 2019
Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD 

Overview

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, coma, renal Fanconi syndrome, and severe metabolic acidosis (in part due to lactic acidosis). See the image below.

Pathophysiologic classification of lactic acidosis Pathophysiologic classification of lactic acidosis.

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.[1] 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).[2, 3, 4]

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 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.[5] The development of a mouse knock-out model for HFI may provide additional information in this regard.[6] 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.

Epidemiology

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 case per 20,000 individuals.

International

The prevalence of hereditary fructose intolerance in central Europe has been reported to be 1 case per 26,100 individuals.[7, 8]

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.[9] Adult-onset disease has been reported,[10] although whether such patients avoided fructose ingestion, thus avoiding clinical symptoms, or the latter truly did not manifest until adulthood, is arguable.

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.

 

Presentation

History

As in other autosomal recessive disorders, a pedigree is unlikely to reveal other family members with fructose 1-phosphate aldolase deficiency. Individuals who are obligate heterozygotes do not demonstrate the symptoms of hereditary fructose intolerance (HFI).

Because the history may be vital to any 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 Examination

A clinically well patient demonstrates no abnormal physical findings.

Acutely ill children are often tachypneic because of acidosis. They have enlarged livers and are slightly-to-moderately icteric. Accompanying hypoglycemia may cause tremors or seizures, as well as diaphoresis.

Abdominal pain may be observed.[11]

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 2015, more than 60 mutations have been reported at this locus, most of them single-base substitutions.[12, 13]

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.

 

DDx

Diagnostic Considerations

The overlap of gastrointestinal symptoms, such as severe abdominal pain and diarrhea combined with poor growth in young children, has led to reports of a condition known as "fructose intolerance" in association with intestinal fructose malabsorption. This condition is important to distinguish clearly from genetic fructose 1-phosphate aldolase deficiency, although results of breath hydrogen testing are controversial in diagnosis.

It has been postulated that fructose malabsorption may be a consequence of abnormalities in the intestinal GLUT5 transporter, although the results of molecular investigations are inconsistent. However, the imperative to making a correct diagnosis distinction is the ongoing hepatic damage seen in hereditary fructose intolerance (HFI), even in the presence of trace amounts of dietary fructose.[14]

 

Workup

Laboratory Studies

Based on the thorough dietary history of an ill child, the most straightforward approach to diagnosis of fructose 1-phosphate aldolase deficiency 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 (HFI) may significantly depress the total plasma bicarbonate level.

Obtain liver function test results to assess the degree of hepatocellular disease.

Molecular genetic testing is recommended to establish the nature of the biallelic ALDOB mutations and to provide the basis for prenatal testing. There is debate about the need for the latter, but the difficulties encountered with attempts to completely eliminate dietary sources of fructose may warrant it.

Other Tests

Elimination of dietary fructose is both a compulsory and therapeutic step. In patients who are ill, 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; oral fructose tolerance testing should be avoided 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. Biopsy of the liver should not be undertaken as a diagnostic procedure, except in cases of demonstrable liver disease.

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

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 months to resolve. Prolonged delay in diagnosis may result in cirrhotic changes with subsequent degeneration of function.

Consultations

Consultation with a biochemical geneticist for molecular diagnosis and a nutritionist for appropriate nutritional counseling is of critical importance to a good outcome.

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. In addition, many childhood medications contain fructose or sorbitol, the dimer of fructose. For these reasons, a highly trained nutritionist's input is mandatory to properly maintain the health of individuals with this disorder.

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.

Long-Term Monitoring

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.

In conjunction with transferrin isoelectric focusing (TfIEF), monitoring of increased aspartylglucosaminidase activity (AGA) could be used in the follow up of patients with hereditary fructose intolerance (HFI).[15]

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.

 

Medication

Medication Summary

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