Continuing Education Activity

Hereditary fructose intolerance is an autosomal recessive disorder where patients lack the enzyme to break down fructose-1-phosphate. This disease usually presents during the weaning period with nausea, vomiting, jaundice, and hypoglycemia. Early recognition and prompt institution of dietary measures to restrict fructose are essential. This activity outlines the evaluation and management of patients with hereditary fructose intolerance and highlights the role of an interdisciplinary team in the management of patients with this condition.

Objectives:

• Identify the etiology of hereditary fructose intolerance.

• Review the appropriate evaluation of hereditary fructose intolerance.

• Outline the management options available for hereditary fructose intolerance.

• Describe interprofessional team strategies for improving care coordination and communication to advance the care of patients with hereditary fructose intolerance and improve outcomes.

Introduction

Fructose is a 6 carbon ketonic sugar that is commonly found in a wide variety of foods. Hereditary fructose intolerance is characterized by severe metabolic disturbances that include hypoglycemia, lactic acidosis, and hypophosphatemia. Hereditary fructose intolerance was originally characterized as an "idiosyncratic reaction to fructose" in a patient that developed violent nausea, abdominal pain, and faintness after consuming sucrose and fructose by Chambers and Fratt in 1956. The hepatic enzyme defect was discovered over the next 4 to 5 years, and the pathophysiology was delineated.

Etiology

Hereditary fructose intolerance is an autosomal recessive disease characterized by the absence of the enzyme aldolase B. Aldolase B is an essential enzyme that is responsible for the breakdown of fructose-1-phosphate into glyceraldehyde and dihydroxyacetone phosphate. In the absence of this enzyme, a buildup of fructose-1-phosphate occurs, which is toxic to the liver. Phosphate is utilized in the synthesis of fructose-1-phosphate by the enzyme fructokinase. As fructose-1-phosphate accumulates, intracellular phosphate stores are depleted. The combined effect of this change inhibits phosphorylase A, leading to the cessation of glycogenolysis. Aldolase B deficiency also causes impaired gluconeogenesis since DHAP and G3P cannot be condensed to form fructose 1,6- bisphosphate. Hyperuricemia is a common finding and is due to the increased turnover and breakdown of adenosine. Other metabolic abnormalities commonly seen are hypermagnesemia, lactic acidosis, and hyperalaninemia.

Epidemiology

Due to the relative rarity of the disease, it is difficult to pinpoint the exact prevalence in the population. Estimates have ranged from 1 in 20,000 to 1 in 60,000.[1] The inheritance is autosomal recessive, and there is no sex prediction. Hereditary fructose intolerance can be caused by various mutations, ranging from simple missense mutations to deletions, frameshift mutations, and mutations at splicing sites.

The disease is usually diagnosed a few months after birth. Symptoms are usually first noted after the introduction of fructose-containing foods in the diet. In untreated patients, liver and kidney disease may cause significant morbidity. However, if proper dietary measures are taken, the life expectancy is normal. 

Heterozygotes do not show any symptoms; however, there are reports of hyperuricemia in heterozygote carriers of the disease, predisposing them to gout.[2]

Pathophysiology

In patients with aldolase B deficiency, the ingestion of fructose, sucrose or sorbitol initiates a cascade of biochemical abnormalities that lead to the short term and long term complications of the disease. The intracellular trapping of phosphate and accumulation of fructose-1-phosphate is responsible for many of the manifestations of the disease. The depletion of ATP alters the AMP: ATP ratio, leading to an increased breakdown of AMP, leading to hyperuricemia seen in patients. Fructose-1-phosphate is a strong inhibitor of phosphomannose isomerase.[3] This enzyme is involved in the N-glycosylation pathway, explaining the abnormalities in N-glycosylation seen in HFI.

Untreated disease can lead to hepatic and renal dysfunction. Hepatomegaly and hepatic fibrosis may be observed. Renal manifestations include Fanconi-like syndrome and nephrocalcinosis. The mechanism behind renal dysfunction is not well characterized.

Histopathology

Hereditary Fructose Intolerance causes a macrovesicular fatty change in the liver.[4] Microscopy shows the degeneration of hepatocytes, fatty changes, fibrosis, and regenerative nodules.

History and Physical

Clinical vignettes on hereditary fructose intolerance usually describe an otherwise healthy infant that presents with nausea, vomiting, poor feeding, lethargy, and jaundice following the introduction of weaning foods into the diet.[5] Given the temporal relationship of the symptoms with fructose intake, the importance of a thorough dietary history cannot be understated. The presence of hereditary fructose intolerance should be suspected in any patient with the above clinical features in addition to hypoglycemia, hypophosphatemia, hyperuricemia, lactic acidosis, and hypermagnesemia.[6] The physical examination can reveal abdominal pain, hepatomegaly, and chronic growth restriction.

Patients may develop strong aversions to sugar-containing foods.[7] There are anecdotal reports of patients having exceptional dental hygiene due to their peculiar eating habits.[8] The disease can present in different presentations. While the classical form presents with dramatic symptoms following the introduction of fructose-containing foods, the clinical presentation may differ in cases where the defective gene product still possesses some enzymatic activity. These patients may develop symptoms only when introduced to large quantities of fructose.

Evaluation

Evaluation for hereditary fructose intolerance usually begins with a test for reducing substances in a patient's urine with suggestive symptoms. The dipstick test for glucose is usually negative. Confirmatory testing can include genetic testing or measurement of aldolase activity in a liver biopsy sample. The high sensitivity and the non-invasive nature of aldolase B molecular genetic testing make it a favorable option. Molecular testing approaches exist and include single gene sequencing, multi-gene panels, and genomic testing.

Treatment / Management

Acute management is mostly supportive care, while other life-threatening differential diagnoses are ruled out.

The cornerstone of hereditary fructose intolerance management is the absolute avoidance of foods containing fructose, sucrose, and sorbitol-containing products. Enlisting the help of a nutritionist may be helpful. Extensive lists of foods containing fructose are available, along with sample diets for patients with the condition.

Patients may be predisposed to nutritional deficiency as their diets necessitate lower fruit and vegetable consumption. Supplementation with a multivitamin is recommended. Follow-up testing of growth, renal, and hepatic function may be useful, especially when compliance with dietary fructose restriction is poor.

Transferrin isoelectric focusing (TfIEF) and monitoring of increased aspartylglucosaminidase activity (AGA) could be used in the follow-up of patients with this condition.

Differential Diagnosis

The acute episode of hereditary fructose intolerance can present similarly to sepsis, disseminated intravascular coagulation, infectious hepatitis, toxin ingestion, and genetic and metabolic diseases.[9] Metabolic diseases such as galactosemia, urea cycle disorders, fatty acid oxidation disorders should be considered in the differential diagnosis. 

Dietary fructose intolerance is a distinct clinical entity from hereditary fructose intolerance. It shares the clinical features of nausea, diarrhea, and abdominal pain following the ingestion of fructose. The dysfunctional fructose transporters cause dietary fructose intolerance in the gut. It is characterized by the presence of fructose in the stool in contrast to the fructose that is seen in the urine in hereditary fructose intolerance.

Prognosis

Patients who adhere to a fructose-free diet have an excellent prognosis. In cases where compliance with the diet is not absolute, morbidity due to renal and kidney issues can be expected.

Complications

1. Chronic ingestion of fructose can lead to hepatic dysfunction and cirrhosis.
2. Renal dysfunction may be seen.
3. Growth restriction can be seen in individuals that are not compliant with dietary restrictions.[10]
4. The hypoglycemia during an acute episode may lead to central nervous system dysfunction and diminished intellectual capacity.
5. Coagulopathy and acidosis during an acute episode may lead to multiorgan dysfunction.[11]
6. Patients are usually at risk of fulminant sepsis with Escherichia coli.[12]

Consultations

After the diagnosis of hereditary fructose intolerance has been established, evaluation by the following consultants may be considered:

• Nutritionist with experience in treating metabolic disorders
• Clinical geneticist
• Hepatologist
• Nephrologist
• Biochemical geneticist

Deterrence and Patient Education

Patients need to be periodically counseled about the importance of fructose avoidance in their diet. Counseling should be ideally done by a nutritionist with experience in dealing with hereditary fructose intolerance. Patients should wear a medic alert bracelet at all times. Patients who are adherent to their diet have the most favorable outcomes.

Enhancing Healthcare Team Outcomes

Patients with hereditary fructose intolerance benefit greatly from the early diagnosis and treatment of the condition. Raising awareness about this potentially life-threatening condition can lead to early recognition. While a pediatrician will always be involved in caring for patients with this condition, it is important to involve an interprofessional team of a hepatologist, nephrologist, clinical geneticist, and genetic counselor. Nutritionists must periodically counsel patients about the importance of compliance with dietary restrictions. Nurses are vital in educating the family about the condition. Pharmacists play a vital role in ensuring that medications are free of fructose or substances that can be broken down into fructose. Involving an interprofessional team is essential for the successful management of patients with this disorder. [Level 5]