Summary

Hereditary fructose intolerance (HFI) is a genetic disorder characterized by the body's inability to break down fructose, a sugar found in many fruits, vegetables, and honey. 

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Overview

Hereditary fructose intolerance (HFI) is a rare genetic disorder where the absence of an enzyme leads to fructose buildup, causing issues like hypoglycemia, digestive problems, and potential organ damage. Diagnosis involves symptoms, dietary assessment, lab, and genetic tests. Treatment requires a strict fructose-free diet and consuming glucose during low blood sugar episodes. Prevention isn't possible, but early diagnosis and adherence to a fructose-free diet can prevent complications in most cases.

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Prevalence & Risk factors

Hereditary fructose intolerance (HFI) is a rare genetic disorder, occurring due to the absence of the enzyme aldolase B. Estimates suggest its prevalence to range from 1 in 20,000 to 1 in 60,000 births.^[1] The condition is inherited in an autosomal recessive manner, meaning both parents must carry the abnormal gene for a child to inherit the disorder. Consanguineous relationships elevate the risk of inheriting HFI due to a higher chance of both parents carrying the same abnormal gene.

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Genetics

HFI stems from mutations within the ALDOB gene, encoding the Aldolase B enzyme. This enzyme is a key player in the hepatic breakdown of fructose. The diversity of mutations within ALDOB contributes to a spectrum of enzymatic deficiencies, influencing the ability to metabolize fructose effectively.^[2]

Affected individuals inherit two mutated copies of the ALDOB gene, one from each parent. Carriers, possessing one normal and one mutated copy, often remain asymptomatic but can pass the mutated gene to their offspring.^[1,5]

Genetic testing serves as a cornerstone for diagnosing HFI, enabling the identification of mutations in the ALDOB gene. Various DNA sequencing techniques allow for the detection of specific mutations associated with HFI.^[5,6]

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Pathophysiology

The absence of aldolase B, an enzyme crucial for breaking down fructose-1-phosphate into essential compounds, leads to a toxic accumulation of fructose-1-phosphate primarily in the liver. This accumulation disrupts the normal glycogen breakdown into glucose and depletes phosphate stores, hindering critical metabolic processes. As a consequence, metabolic abnormalities such as hyperuricemia, lactic acidosis, and hypermagnesemia are commonly observed in individuals with HFI. If left untreated, the disorder progresses and may result in hepatic and renal dysfunction, leading to severe complications.^[1]

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Signs & Symptoms 

Symptoms often manifest after the introduction of fructose-containing foods, especially in infants, underscoring the early onset of HFI. Symptoms may include:^[2-4]

• Digestive Problems. Symptoms often appear after the introduction of fruits, juices, or other foods containing fructose or sucrose. Digestive issues may include nausea, vomiting, abdominal pain, and bloating.
• Hypoglycemia (Low Blood Sugar). This can result in weakness, sweating, shakiness, irritability, and fatigue.
• Fructose accumulation can cause liver and kidney damage in severe cases. Symptoms might include jaundice (yellowing of the skin and eyes), enlarged liver, and potentially, kidney failure.
• Poor feeding, growth retardation, and inability to thrive. 
• Seizures.

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Diagnosis

Diagnosing hereditary fructose intolerance (HFI) involves:^[2,3]

• Clinical symptoms.
• Dietary assessment. Some individuals report symptoms after consuming fructose-rich foods, aiding diagnosis.
• Laboratory tests. Blood or urine tests can measure fructose-related substances.
• Liver biopsy. A liver biopsy can be required to measure the aldolase B activity.
• Genetic testing. Identifying mutations in the ALDOB gene confirms HFI.

A comprehensive approach combining these diagnostic methods ensures a thorough evaluation.

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Therapy 

The primary treatment for HFI is strict adherence to a fructose-free diet. Complete avoidance of fructose, sucrose, and sorbitol-containing foods is crucial to prevent further complications. This includes fruits, certain vegetables, honey, table sugar, and products with high-fructose corn syrup. During acute episodes of hypoglycemia, immediate glucose administration helps stabilize blood sugar levels and alleviate symptoms.^[3,4]

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Prevention 

Hereditary fructose intolerance is a genetic condition and therefore cannot be prevented. Genetic counseling is recommended for couples with a family history of HFI to understand the risk of passing on the defective gene to their children. Early diagnosis through genetic testing and prompt initiation of a fructose-free diet is important in preventing irreversible damage.

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Prognosis

With proper dietary management initiated early in life, most individuals with HFI can lead normal lives. However, severe cases with delayed diagnosis or poor compliance with dietary restrictions may lead to chronic complications involving growth retardation, as well as liver and kidney problems.^[1,3]  

Additionally, individuals with HFI may face challenges related to mental health and quality of life, given the constraints imposed by dietary restrictions and the need for constant management. Regular check-ups and monitoring are essential to address both physical and mental well-being.

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Recommendations

• Strictly follow a fructose-free diet, avoiding fructose, sucrose, and sorbitol-containing foods like fruits, honey, and high-fructose corn syrup products.
• Recognize symptoms like hypoglycemia or digestive issues after consuming fructose-rich foods and seek immediate glucose for hypoglycemic episodes.
• Regularly consult healthcare providers for check-ups and monitoring to catch complications early.
• Consider genetic counseling for family planning, especially if there's a family history of HFI.