Disorders of Fructose Metabolism

Overview

Definition

Fructose metabolism is an enzymatic cascade, which causes a breakdown of fructose, a monosaccharide, for energy production. The complex process relies upon a series of enzymes (absent in some individuals) and may cause 3 distinct disorders: essential fructosuria, hereditary fructose intolerance, and intestinal fructose intolerance.

Normal fructolysis

Fructolysis is the 1st portion of fructose metabolism:

• Glucose transporter 2 (GLUT2) and glucose transporter 5 (GLUT5) absorb fructose (as a monosaccharide or disaccharide) from the lumen of the small intestine.
• GLUT2 brings fructose into hepatocytes.
• Fructose is converted into fructose-1-phosphate by fructokinase (also known as ketohexokinase). 
• Fructose-1-phosphate cannot be transported out of the cell.
• Fructose-1-phosphate is split by aldolase B (also known as fructoaldolase) into dihydroxyacetone phosphate (DHAP) and glyceraldehyde.
• DHAP and glyceraldehyde continue along the metabolic cascade to glycolysis.

Epidemiology

• Essential fructosuria: 
  • Incidence: 1 per 130,000 live births 
  • Difficult to report because asymptomatic
• Hereditary fructose intolerance:
  • Incidence: 1 per 20,000 live births
• Intestinal fructose intolerance:
  • Incidence: 1 per 10 live births
  • Common

Pathophysiology

Essential fructosuria (fructokinase deficiency):

• Autosomal recessive 
• Inability to convert fructose into fructose-1-phosphate
• Fructose is excreted in the urine.

Hereditary fructose intolerance (aldolase B/fructoaldolase deficiency):

• Autosomal recessive (heterozygotes are often asymptomatic)
• Fructose-1-phosphate cannot be split into DHAP and glyceraldehyde.
• Fructose-1-phosphate accumulation inhibits glycolytic and gluconeogenic pathways.

Intestinal fructose intolerance (deficiency/reduced activity of fructose carriers of the small intestine (GLUT5)):

• Fructose cannot be absorbed into enterocytes and remains in the small bowel lumen.
• Normal GI bacterial flora breaks down fructose.
• Byproducts of bacterial metabolism include methane and hydrogen.

Clinical Presentation

Essential fructosuria

Essential fructosuria is asymptomatic.

Hereditary fructose intolerance

Symptoms appear when fructose is introduced into the diet.

• Systemic: 
  • Failure to thrive
  • Lethargy
• GI:
  • Nausea
  • Vomiting
  • Jaundice
  • Hepatomegaly
• Neurologic:
  • Convulsions, seizures
  • Coma
• Endocrine: hypoglycemia

Intestinal fructose intolerance

Symptoms are most evident after ingestion of a fructose load (e.g., juice, fruit).

• GI:
  • Bloating
  • Nausea
  • Vomiting
  • Abdominal distention

Diagnosis

Essential fructosuria

• Incidental diagnosis: usually during another investigation
• Urine: reducing sugars present
• Genetic testing: mutation in KHK gene

Hereditary fructose intolerance

• Genetic testing:
  • Molecular genetic tests for the 3 most common aldolase B mutations:
    • A149P
    • A174D
    • N334K
  • 1 of the 3 mutations present in 90% of affected patients
  • Not detected on standard newborn screening
• Blood chemistry:
  • Hypoglycemia
  • Elevated uric acid
• A liver biopsy is required if blood testing is inconclusive or not available.

Intestinal fructose intolerance

Hydrogen breath testing detects hydrogen produced by GI bacteria.

Management

Essential fructosuria

• Benign condition 
• Does not require treatment

Hereditary fructose intolerance

• Acute management of symptoms, especially if life-threatening (e.g., seizures, hypoglycemia, decreased level of consciousness)
• Immediate initiation of fructose- and sucrose-free diet:
  • Exercise particular caution in the case of sorbitol infusion.
  • Sorbitol and fructose are metabolized by a similar process and can result in the same symptomatology.
• For young children, supplement vitamins in fruits and vegetables.

Intestinal fructose intolerance

• Dietary changes: 
  • Avoid fructose.
  • Avoid sorbitol.
  • Avoid disaccharides and oligosaccharides (e.g., mannitol, xylitol).
• Xylose isomerase, which converts fructose into glucose, may be supplemented. 
• Because GLUT2 transports glucose and fructose into the enterocytes independent of GLUT5, patients can tolerate sucrose.

Prognosis

Only patients with hereditary fructose intolerance have clinically significant complications:

• Liver and renal disease are common in patients unable to adhere to restrictions.
• If individuals do not adhere to a strict diet, death may result.

Clinical Relevance

• Inflammatory bowel disease (IBD): a general term describing disorders involving chronic inflammation of the digestive tract, including both Crohn’s disease and ulcerative colitis. The etiology of IBD is multifactorial; environmental, genetic, and immune factors are implicated. Symptomatology includes diarrhea, vomiting, GI pain, and weight loss. A definitive cure for IBD is not available. The goal of management is to control symptoms and induce remission. Surgical intervention to remove severely damaged segments of the bowel is sometimes necessary.
• Hepatomegaly: an abnormal enlargement of the liver found on physical examination or imaging. The etiology is varied, but many cases are attributed to infection, malignancy, or metabolic disorders such as hereditary fructose intolerance. Accurate diagnosis is important and work-up should include both blood work and imaging to find the underlying cause of the enlarged liver. Treatment is aimed at the underlying cause of the disease. 
• Splenomegaly: abnormal enlargement of the spleen. Splenomegaly can be attributed to numerous causes such as infections, infiltrative processes (e.g., acute leukemia/lymphoma), and various outflow obstructions of portal vein drainage. Aside from risks associated with the underlying pathology, enlargement of the spleen puts individuals at increased risk for splenic rupture. A splenic rupture is a significant medical emergency and may require surgical intervention.