Hereditary Fructose Intolerance

Etiology

HFI is an autosomal recessive disease caused by pathogenic variants in the ALDOB gene, which encodes aldolase B on chromosome 9q22.3. Aldolase B is required for the breakdown of fructose-1-phosphate into glyceraldehyde and dihydroxyacetone phosphate. The absence of functional aldolase B leads to an accumulation of fructose-1-phosphate.[3]

Epidemiology

Due to the relative rarity of HFI, pinpointing the exact prevalence in the population is difficult. Estimates have ranged from 1 in 20,000 to 1 in 60,000.[4] Other estimates state that HFI is more prevalent at 1 in 10,000 of the population.[5] HFI follows autosomal recessive inheritance, and no sex predilection has been identified. HFI can be caused by various mutations, ranging from simple missense mutations to deletions, frameshift mutations, and splicing-site mutations.

HFI is usually diagnosed a few months after birth. Symptoms are usually first noted after the introduction of fructose-containing foods into the diet. In untreated individuals, liver and kidney disease may cause significant morbidity. However, if proper dietary measures are taken, life expectancy is normal. Patients who are heterozygous do not show any symptoms. However, reports exist of hyperuricemia in heterozygote carriers of the disease, predisposing them to gout.[6]

Pathophysiology

In HFI, aldolase B deficiency causes accumulation of fructose-1-phosphate, which is toxic to the liver. Fructokinase converts fructose to fructose-1-phosphate using phosphate, and the resulting intracellular phosphate depletion inhibits phosphorylase A, thereby impairing glycogenolysis. Aldolase B deficiency also disrupts glycolysis and gluconeogenesis because dihydroxyacetone phosphate and glyceraldehyde-3-phosphate cannot be further metabolized normally. Hyperuricemia results from increased adenosine turnover and degradation. Other metabolic abnormalities reported in HFI include hypermagnesemia, lactic acidosis, and hyperalaninemia.

After ingestion of fructose, sucrose, or sorbitol, patients with HFI develop a cascade of biochemical abnormalities that underlies both acute symptoms and long-term complications. Fructose-1-phosphate accumulation traps phosphate intracellularly and depletes adenosine triphosphate (ATP), increasing the adenosine monophosphate (AMP) to ATP ratio and promoting AMP degradation, which contributes to hyperuricemia. Fructose-1-phosphate is also a potent inhibitor of phosphomannose isomerase.[7]

Phosphomannose isomerase is involved in the N-glycosylation pathway, which explains the N-glycosylation abnormalities observed in HFI. Untreated or inadequately treated disease can lead to hepatic disease, with asymptomatic elevated transaminase levels, and may progress to clinical manifestations of steatohepatitis, liver fibrosis, and ultimately liver failure.[7] Renal dysfunction may progress to chronic renal insufficiency, beginning as proximal renal tubular acidosis, Fanconi syndrome (causing aminoaciduria, phosphaturia, and bicarbonate loss), and nephrocalcinosis.[8]

Histopathology

HFI causes macrovesicular fatty change in the liver. Steatosis may progress to steatohepatitis, hepatocyte degeneration, fibrosis, and regenerative nodules.[9]

History and Physical

Classic descriptions of HFI usually describe an otherwise healthy infant who presents with nausea, vomiting, poor feeding, lethargy, and jaundice following the introduction of weaning foods into the diet,[10] but the presentation of affected patients is variable. Some may develop a strong aversion to sugar-containing foods.[11] While the classic form presents with the dramatic symptoms described above, following the introduction of fructose-containing foods, the clinical presentation may differ in cases where the defective gene product still retains some enzymatic activity. These patients may develop symptoms only when introduced to large quantities of fructose.[10]

Lethargy, diaphoresis, dehydration, shock, and abdominal pain may be present when the condition manifests later in life, and seizures, coma, or death may occur in individuals who do not receive treatment and develop severe hepatic and renal dysfunction.[12][13] When HFI is not diagnosed in infancy, the condition is usually discovered in older children. Less frequently, the diagnosis may not be apparent in childhood and may be made in adulthood.

Given the temporal relationship between symptoms and fructose intake, obtaining a thorough dietary history is essential. HFI should be suspected in any patient with these clinical features.[14] The physical examination may be normal or may reveal right upper-quadrant abdominal tenderness, hepatomegaly, and chronic growth restriction.

Evaluation

The evaluation of patients with suspected HFI includes:

• Laboratory testing in patients with HFI may show abnormalities, including hypoglycemia, hypophosphatemia, hyperuricemia, lactic acidosis, and hypermagnesemia.
• Clinical improvement after removal of fructose, sucrose, or sorbitol supports the diagnosis, but fructose loading tests are not used routinely because they may provoke severe hypoglycemia.
• The high sensitivity and noninvasive nature of aldolase B molecular genetic testing make it the preferred diagnostic test. Molecular testing can begin with single-gene sequencing of the ALDOB gene, which encodes the aldolase B enzyme, if the diagnosis has a very high pretest probability, and biallelic pathogenic variants in the gene are highly reliable diagnostic tests. Multigene panels and a genome-wide association testing approach broaden the diagnostic approach when the pretest likelihood of HFI is low.[15]
• A liver biopsy can be performed to assess aldolase B activity, but its high cost and invasiveness limit its use.[16]
• Transferrin isoelectric focusing can be used to diagnose and monitor patients with this condition. In HFI, the Ib pattern may be present, relating to the synthesis and assembly of glycans. An elevated carbohydrate-deficient transferrin level is an alternative and allows a more rapid means of detecting HFI.[17][18] Findings from another study showed that the greatest discriminative power for distinguishing patients with HFI from healthy controls was an elevated monoglycotransferrin-to-diglycotransferrin ratio (sensitivity of 93.3% and specificity of 92.9%).[19] These assays, however, have not yet become standard tests for diagnosing HFI.

Treatment / Management

Acute treatment is mostly supportive care, while other life-threatening differential diagnoses are ruled out. The cornerstone of treatment for HFI is strict avoidance of foods containing fructose, sucrose, and sorbitol. Enlisting the help of a dietitian is advisable because this diet must be followed strictly and lifelong to avoid liver or renal disease. Extensive lists of foods containing fructose are available, along with sample diets for patients with the condition. Complete exclusion of these sugars should be attempted in children, although fructose is present in many foods, with limited documentation.[18] Adults can generally tolerate up to 6 g of fructose per day, but the amount tolerated varies based on residual enzyme activity.[17]

Patients may be predisposed to nutritional deficiencies because the HFI diet requires a lower intake of fruits and vegetables. Supplementation with a multivitamin is recommended, particularly to address the risk of vitamin C deficiency with a fructose-free diet.[16] Ongoing monitoring of growth, renal, and hepatic function should be performed, especially when adherence to dietary fructose restriction is poor. Furthermore, fructose-containing formulas have caused life-threatening liver failure in neonates with undiagnosed HFI, which emphasizes the importance of early diagnosis.[12](B3)

Differential Diagnosis

The acute presentation of HFI can mimic the following diagnoses:

• Sepsis
• Disseminated intravascular coagulation
• Infectious hepatitis
• Toxin ingestion
• Genetic and metabolic diseases
  • Galactosemia
  • Urea cycle defects
  • Fatty acid oxidation disorders
  • Tyrosenemia
  • Organic acidemia [20]

Dietary Fructose Intolerance

Dietary fructose intolerance diagnosis shares clinical features with HFI, including nausea, diarrhea, and abdominal pain following fructose ingestion. Dysfunctional fructose transporters cause dietary fructose intolerance in the gastrointestinal tract. Dietary fructose intolerance is characterized by fructose in the stool, whereas HFI is characterized by fructose in the urine.

In children presenting with hepatomegaly, fatty liver, and elevated transaminases, the following conditions should be considered:

• Wilson disease
• α-1 Antitrypsin deficiency
• Glycogen storage disorder

In a presentation of hypoglycemia, acidosis, and hepatomegaly, the following should be considered:

• Fructose 1,6-bisphosphate deficiency
• Pyruvate carboxylase deficiency
• β-Ketothiolase deficiency
• Fatty acid oxidation defects
• Congenital disorder of glycosylation
• Mild variants of respiratory chain defects [20]

HFI is distinguished from this last group of diagnoses by intolerance of sugary foods and the predominance of gastrointestinal tract symptoms.

Prognosis

Patients who adhere to a fructose-free diet have an excellent prognosis. In cases where adherence to the diet is not absolute, morbidity and mortality are increased due to hepatic and renal disease.

Complications

Complications of HFI include:

• Chronic ingestion of fructose can lead to cirrhosis and liver failure. Even when patients are on fructose-restricted diets, they may have greater intrahepatic fat content, suggesting that trace amounts of fructose may contribute to liver pathology. The fatty infiltration of the liver has important implications for long-term monitoring.[3]
• Renal insufficiency or failure may occur.
• Growth restriction may occur in individuals who do not adhere to dietary restrictions.[21]
• The hypoglycemia during an acute episode may lead to central nervous system dysfunction and cognitive impairment.
• Coagulopathy and acidosis during an acute episode may lead to multiorgan dysfunction and failure.[22]
• Patients are at risk of fulminant sepsis, most often caused by Escherichia coli.[23]