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Hereditary fructose intolerance
This condition occurs when the body lacks a specific enzyme, aldolase B, necessary for fructose metabolism. It can lead to serious health problems if fructose-containing foods are consumed, typically affecting infants and children, but can be diagnosed at any age.
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Overview
Hereditary fructose intolerance (HFI) is a rare inherited metabolic condition. It means that the body cannot properly process fructose, a type of sugar found naturally in many fruits, vegetables, and honey, and also used as a sweetener in many processed foods. Individuals with HFI lack a functional enzyme called aldolase B, which is crucial for breaking down fructose in the liver, kidneys, and small intestine [PMID:31536259].
When someone with HFI consumes fructose, the sugar cannot be metabolised correctly. This leads to a build-up of toxic by-products in the body, which can damage organs, particularly the liver and kidneys. Although often identified in infancy or early childhood when fructose is introduced into the diet, diagnosis can sometimes occur later in life if fructose intake has been limited or symptoms are mild.
Symptoms & clinical features
Symptoms of hereditary fructose intolerance can vary depending on the amount of fructose consumed and the age of the individual. In infants, when fructose is first introduced (e.g., through fruit purees, sweetened formulas, or some medications), symptoms can include vomiting, nausea, abdominal pain, poor feeding, irritability, and unexplained jaundice [PMID:33678033].
Older children and adults may experience similar symptoms, such as abdominal discomfort, bloating, diarrhoea, or low blood sugar (hypoglycaemia) after consuming fructose. A strong aversion to sweet foods or fruits might also develop naturally due to the body's negative reaction to fructose. If fructose intake continues, more severe issues can arise, including liver and kidney damage, growth failure in children, and bleeding disorders.
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Affected organs
The primary organs affected by hereditary fructose intolerance are the liver, kidneys, and gastrointestinal tract. The liver is particularly vulnerable because it is the main site where fructose is metabolised. Continuous exposure to fructose can cause liver enlargement, jaundice (yellowing of the skin and eyes), and potentially severe liver damage, including fibrosis or cirrhosis.
Kidneys can also be impacted, leading to issues with their normal filtering function. The gastrointestinal tract, including the small intestine, can experience symptoms like abdominal pain, nausea, and vomiting due to the initial processing of fructose. Over time, poor nutrient absorption may also occur, contributing to poor growth in children.
Risks & severity
The severity of hereditary fructose intolerance can vary significantly, depending on the individual's genetic changes and their dietary fructose intake. Undiagnosed and untreated HFI can lead to serious health complications, particularly severe liver damage, kidney problems, and growth impairment in children. In acute cases following high fructose ingestion, dangerously low blood sugar (hypoglycaemia) and metabolic acidosis can occur, which may require urgent medical attention [PMID:31536259].
The lifetime risks are largely determined by dietary management. With strict avoidance of fructose, individuals with HFI can generally lead healthy lives with minimal complications. The condition is often identified in infancy or early childhood, typically when dietary fructose is introduced. However, some individuals with milder forms or those who naturally avoid fructose may not be diagnosed until later in life.
Genetic causes
Hereditary fructose intolerance is caused by pathogenic variants in the ALDOB gene. The ALDOB gene provides instructions for making an enzyme called aldolase B. This enzyme plays a vital role in the breakdown of dietary fructose in the body, primarily in the liver, kidneys, and cells lining the small intestine.
When there are pathogenic variants in the ALDOB gene, the aldolase B enzyme is either deficient or completely non-functional. This prevents the normal metabolism of fructose. As a result, fructose-1-phosphate, a toxic by-product, accumulates within cells, particularly in the liver. This build-up interferes with other critical metabolic processes, leading to the symptoms and organ damage observed in HFI.
- ALDOB aldolase, fructose-bisphosphate BThe ALDOB gene provides instructions for producing aldolase B, an enzyme primarily active in the liver and essential for processing dietary fructose.
Inheritance pattern
Hereditary fructose intolerance follows an autosomal recessive inheritance pattern. This means that an individual must inherit two copies of a pathogenic ALDOB gene variant - one from each parent - to develop the condition. People who have only one copy of a pathogenic variant are called carriers; they typically do not show symptoms of HFI themselves but can pass the variant on to their children.
If both parents are carriers of an ALDOB gene variant, there is a 25% chance with each pregnancy that their child will inherit two copies of the variant and therefore develop HFI. There is a 50% chance the child will be a carrier, and a 25% chance the child will inherit two unaffected copies of the gene and will not have the condition or be a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
A diagnosis of hereditary fructose intolerance is typically suspected based on an individual's symptoms, particularly if they occur after consuming fructose-containing foods. Initial investigations may include blood tests to check liver and kidney function, as well as blood sugar levels following a fructose challenge (which must be done under strict medical supervision due to potential risks).
Confirmation of HFI primarily involves genetic testing for variants in the ALDOB gene. This can be accessed via the NHS Genomic Medicine Service (GMS), often through referral from a general practitioner (GP) or specialist paediatrician or gastroenterologist to a clinical genetics service. Genetic testing for HFI falls under various NHS R-codes, which healthcare professionals use to order appropriate tests. An alternative, though less common, diagnostic method is a liver biopsy to measure aldolase B enzyme activity.
Management & lifestyle
Management for hereditary fructose intolerance centres on strict and lifelong dietary avoidance of all sources of fructose, sucrose (table sugar, which breaks down into fructose and glucose), and sorbitol (a sugar alcohol that the body can convert to fructose). This typically requires careful attention to food labels and choosing appropriate food substitutes. Dietitians specialising in metabolic disorders are crucial in providing guidance and support for this dietary management.
Regular monitoring of liver and kidney function is important, especially during childhood, to detect any potential complications early. Individuals with HFI should also be aware of hidden sources of fructose in medications, toothpaste, and other products. With vigilant dietary adherence, most individuals with HFI can lead healthy, symptom-free lives. Genetic counsellors can provide further information and support regarding the condition and its inheritance.
UK care pathway
In the UK, individuals suspected of having hereditary fructose intolerance would typically enter the NHS Genomic Medicine Service pathway. Referral from a GP or specialist to a clinical genetics service or specialist metabolic clinic would be the usual route. Genetic testing for ALDOB gene variants is available through the NHS GMS, often covered by specific R-codes for inherited metabolic disorders. Genetic counsellors play a vital role in explaining the condition, inheritance patterns, and supporting families through diagnosis and management.
Frequently asked questions
What foods contain fructose that I need to avoid?
Fructose is found naturally in many fruits (like apples, pears, grapes) and vegetables. It's also in honey, agave nectar, high-fructose corn syrup, and table sugar (sucrose). Careful label reading is essential to avoid these ingredients.
Can my child with HFI still eat any fruit or vegetables?
Some fruits and vegetables have very low fructose content and might be tolerated in small amounts, but this must be discussed with a specialist metabolic dietitian. Complete avoidance is often recommended initially, with gradual, supervised introduction of very low-fructose options if appropriate.
Is hereditary fructose intolerance the same as lactose intolerance?
No, they are different conditions. Hereditary fructose intolerance involves the inability to break down fructose, while lactose intolerance is the inability to digest lactose, a sugar found in milk and dairy products. They are caused by different enzyme deficiencies.
If I have HFI, will my children have it too?
HFI is autosomal recessive. If you have HFI, you will pass one copy of the pathogenic ALDOB gene variant to all your children. Whether your children also have HFI depends on the genetic status of your partner. If your partner is also a carrier, there is a 50% chance with each child that they will also have HFI.
What happens if someone with HFI accidentally eats fructose?
Accidental consumption can lead to symptoms like vomiting, abdominal pain, and low blood sugar. In severe cases, particularly with large amounts, it could lead to metabolic acidosis or liver damage. Seek medical attention if symptoms are severe or persistent after accidental ingestion.
References
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- Singh SK, Sarma MS. Hereditary fructose intolerance: A comprehensive review. World journal of clinical pediatrics. 2022. PMID: 36052111
- Adam MP, Bick S, Mirzaa GM. Hereditary Fructose Intolerance. 1993. PMID: 26677512
- Febbraio MA, Karin M. "Sweet death": Fructose as a metabolic toxin that targets the gut-liver axis. Cell metabolism. 2021. PMID: 34619076
- Ali M, Rellos P, Cox TM. Hereditary fructose intolerance. Journal of medical genetics. 1998. PMID: 9610797
- Cross NC, Cox TM. Hereditary fructose intolerance. The International journal of biochemistry. 1990. PMID: 2205519
- Goosenberg E, Hegde VS. Hereditary Fructose Intolerance. 2026. PMID: 32644528
- Albuquerque ALB, Dos Santos Borges R, Conegundes AF. Inherited Fanconi syndrome. World journal of pediatrics : WJP. 2023. PMID: 36729281