Hereditary fructose intolerance
Hereditary fructose intolerance (HFI) is a rare autosomal recessive disorder caused by mutations in the ALDOB gene on chromosome 9q22.3, resulting in deficiency of the enzyme aldolase B, which is crucial for fructose metabolism in the liver, kidney, and small intestine.[1] This enzymatic defect leads to the accumulation of fructose-1-phosphate when fructose, sucrose, or sorbitol is ingested, depleting inorganic phosphate and ATP, and thereby disrupting gluconeogenesis, glycogenolysis, and other metabolic pathways, which can cause acute hypoglycemia, lactic acidosis, hypophosphatemia, and hyperuricemia.[2] Untreated, HFI can progress to severe complications such as hepatic failure, renal tubular dysfunction, and growth failure, but with early diagnosis and strict dietary management, affected individuals can achieve a normal life expectancy.[3] The disorder has an estimated prevalence of 1 in 20,000 to 1 in 60,000 individuals worldwide, with higher rates reported in some populations, such as Europeans (up to 1 in 26,100).[1] Symptoms typically emerge in infancy shortly after the introduction of fructose-containing foods like fruits, juices, or formulas with sucrose, manifesting as gastrointestinal distress (nausea, vomiting, abdominal pain), hypoglycemia-induced seizures, jaundice, and hepatomegaly.[2] Infants often exhibit an innate aversion to sweet-tasting foods as a protective mechanism, and chronic exposure without intervention may lead to failure to thrive, rickets, or chronic liver disease resembling non-alcoholic fatty liver disease (NAFLD).[3] Diagnosis is confirmed through molecular genetic testing for biallelic pathogenic variants in ALDOB (with over 68 variants identified, including the common p.Ala150Pro mutation accounting for about 53% of alleles), or by demonstrating reduced aldolase B activity in liver biopsy, though genetic testing is preferred for its non-invasiveness.[1] Supportive tests include elevated urine reducing substances (positive Benedict's test) after fructose challenge—though challenges are avoided due to risk—and abnormal carbohydrate-deficient transferrin (CDT) levels as a monitoring tool for dietary compliance.[2] Differential diagnoses include other inborn errors of metabolism such as glycogen storage diseases or galactosemia.[3] Management centers on lifelong strict avoidance of fructose, sucrose, sorbitol, and related compounds (collectively termed FSS), limiting intake to less than 1.5 g/day to prevent symptoms, with nutritional support via fructose-free formulas in infancy and education on hidden sources in processed foods.[1] Acute episodes require immediate intravenous glucose administration to correct hypoglycemia and metabolic derangements, often with hospitalization; long-term care includes monitoring for nutritional deficiencies and supplementation with multivitamins lacking FSS.[3] Recent research highlights persistent hepatic steatosis in many patients despite compliance, suggesting potential roles for ketohexokinase (KHK) inhibitors in future therapies; a 2025 clinical study demonstrated the safety and efficacy of pharmacological KHK inhibition in HFI patients, allowing limited fructose intake without symptoms, with ongoing trials (e.g., NCT06089265) further evaluating this approach.[1][4][5]Introduction
Definition and Overview
Hereditary fructose intolerance (HFI) is an autosomal recessive inborn error of metabolism characterized by a deficiency in the enzyme aldolase B, which impairs the breakdown of fructose-1-phosphate and leads to its toxic accumulation in affected tissues.[6] This enzyme deficiency prevents the normal metabolism of fructose, resulting in severe metabolic disturbances upon ingestion of fructose-containing compounds.[7] Ingestion of fructose, sucrose (which contains fructose), or sorbitol (a fructose precursor) triggers rapid accumulation of fructose-1-phosphate in the liver, kidney, and small intestine, depleting inorganic phosphate and ATP, which in turn causes hypoglycemia, liver dysfunction, and renal tubular damage.[8] These effects manifest primarily after dietary exposure, often beginning in infancy during weaning to solid foods.[6] The condition was first described in 1956 by Chambers and Pratt, who reported a case of fructose idiosyncrasy in a 24-year-old woman experiencing nausea, abdominal pain, and hypoglycemia after fructose intake.[9] The underlying enzyme defect was identified in 1963 by Froesch et al., linking it to aldolase B deficiency in the liver.[9] HFI is classified as a disorder of carbohydrate metabolism within the broader category of inborn errors of metabolism, specifically affecting the fructose metabolic pathway.[10] It is distinct from other aldolase deficiencies, such as those involving aldolase A (muscle-specific) or aldolase C (brain-specific), as aldolase B is uniquely expressed in the liver, kidney, and intestine.[6]Epidemiology
Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by biallelic mutations in the ALDOB gene, requiring inheritance of two mutated alleles for manifestation.[2] The carrier frequency in general populations is estimated at approximately 1 in 70 to 1 in 122, varying by region.[8][3] Global prevalence is estimated at 1 in 20,000 to 1 in 30,000 live births, though some studies report wider ranges up to 1 in 100,000 due to underreporting.[7] In European populations, rates are higher, with estimates of 1 in 20,000 overall; specific studies indicate 1 in 20,000 in Switzerland and 1 in 26,100 in Germany.[8][11][12] HFI is more common among individuals of European descent, with most documented cases originating from Europe and North America, reflecting both genetic distribution and diagnostic awareness in these areas.[13] There is no significant sex bias in HFI occurrence.[2] Consanguinity represents a key risk factor, as it elevates the chance of inheriting two mutated alleles in recessive disorders like HFI.[2] As of 2025, enhanced genetic testing and expanded newborn screening programs in parts of Europe and North America have facilitated earlier detection, though HFI remains excluded from routine newborn screening panels in most jurisdictions due to challenges in postnatal fructose exposure.[14]Pathophysiology
Normal Fructose Metabolism
Fructose, a monosaccharide abundant in fruits, honey, and processed foods, is primarily absorbed in the small intestine. It enters enterocytes via the fructose-specific transporter GLUT5 (SLC2A5), which has a high affinity for fructose (Km ≈ 6 mM), and is then transported across the basolateral membrane into the bloodstream by the facilitative transporter GLUT2 (SLC2A2).[15] This process allows efficient uptake of dietary fructose, with absorption capacity increasing post-weaning and in response to high-fructose diets through upregulation of GLUT5 expression via the transcription factor ChREBP.[15] Once in circulation, fructose reaches the liver, kidney, and other tissues for metabolism, though the liver handles the majority due to its high expression of relevant enzymes.[16] In the liver, fructose metabolism begins with rapid phosphorylation by fructokinase (ketohexokinase, KHK), primarily the C isoform (KHK-C), to form fructose-1-phosphate (F1P), consuming ATP in the process: \text{Fructose} + \text{ATP} \xrightarrow{\text{fructokinase}} \text{Fructose-1-phosphate} + \text{ADP} This step occurs without allosteric regulation, leading to quick depletion of inorganic phosphate and ATP if fructose intake is excessive.[15] F1P is then cleaved by aldolase B (fructose-1-phosphate aldolase) into dihydroxyacetone phosphate (DHAP) and glyceraldehyde: \text{Fructose-1-phosphate} \xrightarrow{\text{aldolase B}} \text{DHAP} + \text{Glyceraldehyde} DHAP directly enters the glycolytic pathway or can be converted to glycerol-3-phosphate for lipid synthesis, while glyceraldehyde is phosphorylated by triose kinase to glyceraldehyde-3-phosphate (G3P), which feeds into glycolysis or gluconeogenesis.[16] This pathway allows fructose to bypass the rate-limiting phosphofructokinase-1 (PFK-1) step in glycolysis, enabling unregulated flux into hepatic energy production, glycogen synthesis, or lipogenesis depending on nutritional state.[15] Extrahepatic metabolism of fructose occurs to a lesser extent in the kidney and intestine, following a similar pathway but with lower enzyme activities, particularly of KHK and aldolase B.[16] In the kidney, fructose is reabsorbed via GLUT5 and GLUT2 and metabolized locally to support renal energy needs, while intestinal enterocytes process a portion (up to 30%) of absorbed fructose before it reaches systemic circulation.[15] These sites contribute minimally to overall fructose clearance compared to the liver. Regulation of fructose metabolism is influenced indirectly by hormones such as insulin and glucagon, which modulate hepatic glucose-fructose interactions and overall substrate disposition.[16] For instance, F1P allosterically activates glucokinase, promoting glycogen synthesis in the fed state, while glucagon can enhance gluconeogenic flux from fructose-derived intermediates during fasting.[15] The bypass of PFK-1 ensures fructose metabolism remains relatively independent of glycolytic feedback, prioritizing rapid processing over tight hormonal control.[16]Genetic and Enzymatic Defects
Hereditary fructose intolerance (HFI) is caused by pathogenic variants in the ALDOB gene, located on chromosome 9q22.3, which encodes the enzyme aldolase B, also known as fructose-1-phosphate aldolase.[17] This enzyme is primarily expressed in the liver, kidney, and small intestine, where it catalyzes the reversible cleavage of fructose-1-phosphate (F1P) into dihydroxyacetone phosphate (DHAP) and glyceraldehyde during fructose metabolism.[3] In individuals with HFI, biallelic loss-of-function variants in ALDOB result in deficient aldolase B activity.[9] More than 70 pathogenic variants in ALDOB have been identified in HFI patients, including missense, nonsense, frameshift, and splicing mutations that disrupt enzyme structure or expression.[18] Among Europeans, the most prevalent variant is c.448G>C (p.Ala150Pro; A150P), accounting for approximately 65% of disease alleles, followed by c.524C>A (p.Ala175Asp; A175D) at about 11%, and c.1005C>G (p.Asn335Lys; N335K) at around 8%.[12] These common missense mutations, particularly A150P, lead to thermolabile enzymes with reduced stability and catalytic efficiency.[19] The enzymatic defect manifests as severely reduced or absent aldolase B activity, typically less than 10% of normal levels in hepatic tissue, preventing the breakdown of F1P. This causes intracellular accumulation of F1P following fructose ingestion, which sequesters inorganic phosphate and depletes cellular ATP by stimulating futile cycling through fructokinase.[3] The resulting phosphate trapping inhibits glycogen phosphorylase and gluconeogenic enzymes, blocking glycogenolysis and gluconeogenesis, while ATP depletion impairs multiple metabolic pathways.[17] Pathophysiological effects include hypoglycemia due to depleted hepatic glucose production, lactic acidosis from impaired pyruvate metabolism and secondary DHAP imbalance, and hepatic cellular damage from energy failure.[9] HFI follows an autosomal recessive inheritance pattern, requiring biallelic pathogenic variants (homozygous or compound heterozygous) for disease manifestation, with full penetrance in affected individuals upon fructose exposure.[3] No significant environmental modifiers beyond dietary fructose intake have been identified that alter the penetrance.[17]Clinical Features
Acute Symptoms
Acute symptoms of hereditary fructose intolerance (HFI) typically manifest upon ingestion of fructose-containing foods, such as fruits, sucrose-sweetened products, high-fructose corn syrup, or sorbitol, most commonly after the age of 6 months when such foods are introduced during weaning.[3][8] These triggers lead to a rapid accumulation of fructose-1-phosphate due to aldolase B deficiency, the underlying metabolic block in HFI.[3] Core symptoms include severe hypoglycemia (often with blood glucose levels below 40 mg/dL), vomiting, abdominal pain, and lethargy, with onset typically occurring within 30-120 minutes after fructose ingestion; in severe cases, this can progress to seizures or coma.[3][17] Physiologically, these arise from rapid ATP depletion in the liver, which impairs glycogenolysis and gluconeogenesis, preventing adequate glucose production, alongside hyperuricemia resulting from purine nucleotide breakdown.[2][3] In infants, early manifestations often include poor feeding and refusal of sweet-tasting foods, often mimicking other gastrointestinal issues.[17] Older children and adults, if undiagnosed, may develop a learned aversion to sweet foods as a protective response, reducing the frequency of severe reactions but not eliminating risk upon accidental exposure.[8][17] A classic presentation, sometimes termed "fructose shock," involves sudden pallor, sweating, hypotonia, and profound lethargy following fructose intake, as observed in case reports of infants exposed via formula or early solids.[3][17]Chronic Manifestations
In untreated or poorly managed hereditary fructose intolerance (HFI), repeated fructose exposure leads to cumulative toxic effects from fructose-1-phosphate accumulation, resulting in progressive multisystem damage beyond acute episodes.[17] This chronic burden primarily affects growth, liver, kidneys, gastrointestinal tract, and neurological development in affected individuals, particularly children.[20] Growth disturbances are prominent in undiagnosed children, manifesting as failure to thrive with delayed weight gain and short stature due to caloric restriction from instinctive aversion to fructose-containing foods and associated malabsorption. Additionally, hypophosphatemia from renal tubular dysfunction can lead to rickets and bone deformities.[20][21] Hepatic involvement includes persistent fatty liver (steatosis), hepatomegaly, and jaundice, which can advance to steatohepatitis and cirrhosis with ongoing exposure, as fructose metabolites impair hepatocyte function and promote lipid accumulation.[17] [7] Renal effects feature proximal tubular dysfunction akin to Fanconi syndrome, characterized by phosphaturia, aminoaciduria, and hypophosphatemia, stemming from enzyme deficiency in the renal cortex that disrupts reabsorption during fructose metabolism.[20] Gastrointestinal complications involve chronic diarrhea and nutritional imbalances, including vitamin deficiencies, driven by recurrent malabsorption and sustained aversion to sweets that limits dietary variety.[17] Neurologically, recurrent hypoglycemia from prior acute exposures contributes to developmental delays, while severe, prolonged cases may cause permanent brain injury through energy deficits and metabolic stress.[20]Diagnosis
Clinical Assessment
Clinical assessment of hereditary fructose intolerance (HFI) begins with a detailed history to identify patterns suggestive of the disorder. Key elements include inquiring about family history of metabolic or liver disorders, as HFI is inherited in an autosomal recessive manner.[22] Symptoms often emerge during weaning or introduction of sucrose-containing foods in infancy, with affected individuals typically developing an aversion to fruits, sweets, or other fructose-rich items due to associated discomfort.[2][17] In older children or adults, a lifelong pattern of avoiding sugary foods and episodic nausea following inadvertent exposure may be reported.[23] Physical examination may reveal hepatomegaly, jaundice, and signs of malnutrition or dehydration, particularly in acute presentations following fructose ingestion.[2][17] Chronic cases can show growth restriction or failure to thrive without dysmorphic features, helping to differentiate HFI from syndromic metabolic conditions.[2] Abdominal tenderness may be present, but other systemic signs like ascites or edema are less common unless liver involvement is advanced.[17] Red flags that raise suspicion for HFI include recurrent hypoglycemia unrelated to diabetes, postprandial vomiting or abdominal pain shortly after consuming fructose-containing meals, and incidentally elevated liver enzymes in otherwise asymptomatic children.[2][22] These features, combined with a history of symptom timing linked to dietary fructose exposure, warrant prompt evaluation to prevent complications.[17] Differential diagnosis considers overlaps with other inborn errors of metabolism, such as galactosemia or glycogen storage diseases, which may present with hypoglycemia, liver dysfunction, or failure to thrive; however, HFI is distinguished by its specific triggers tied to fructose, sucrose, or sorbitol intake rather than galactose or complex carbohydrates.[2][17] Initial laboratory investigations focus on basic metabolic screening, including blood glucose to detect hypoglycemia, liver function tests showing elevated transaminases (ALT and AST), and serum uric acid levels, which may be increased due to metabolic perturbations.[2][22] Urinalysis for reducing sugars, positive in the presence of fructose but negative on glucose dipstick, provides supportive evidence during acute episodes.[17]Confirmatory Tests
Confirmatory diagnosis of hereditary fructose intolerance (HFI) typically follows clinical suspicion and relies on direct assessment of aldolase B enzyme activity or identification of pathogenic variants in the ALDOB gene.[3] Enzyme assays provide definitive evidence of aldolase B deficiency by measuring its activity in tissue samples. The gold standard involves a liver biopsy, where aldolase B activity below 10% of normal levels confirms the diagnosis, as this enzyme is primarily expressed in the liver, kidney, and small intestine.[3] Less invasive alternatives include intestinal biopsies obtained via endoscopy, which can also demonstrate reduced activity, though liver samples are preferred for accuracy due to higher enzyme expression.[23] These assays are particularly useful when genetic testing is inconclusive or unavailable, but their invasive nature limits routine use.[2] Genetic testing has become the preferred confirmatory method owing to its high sensitivity and non-invasive approach. Sequencing of the ALDOB gene, often via next-generation sequencing panels, identifies biallelic pathogenic variants responsible for HFI, with detection rates exceeding 95% in affected individuals.[3] Common mutations, such as A149P, A174D, and N334K, account for a significant portion of cases in certain populations, enabling targeted testing.[24] Prenatal diagnosis is feasible through amniocentesis or chorionic villus sampling for at-risk pregnancies, allowing early intervention.[3] If sequence analysis is negative, deletion/duplication studies may be performed to detect larger structural variants.[25] Metabolic provocation tests, once used for confirmation, are now largely obsolete due to their risks. The intravenous fructose tolerance test, which monitors blood glucose, phosphate, and lactate levels after fructose administration, is deprecated because it can precipitate life-threatening hypoglycemia, lactic acidosis, or even death in undiagnosed individuals.[3] Similarly, oral fructose loading to measure urinary fructose-1-phosphate is restricted to research settings under strict supervision, as it replicates the metabolic crisis.[26] Supporting laboratory findings post-fructose exposure further corroborate the diagnosis by revealing characteristic metabolic derangements. These include profound hypoglycemia accompanied by hypophosphatemia and lactic acidosis, resulting from fructose-1-phosphate accumulation that sequesters phosphate and impairs gluconeogenesis.[2] In contrast, galactose metabolism remains normal, helping differentiate HFI from galactosemia or glycogen storage diseases.[3] Liver function tests may show elevated transaminases, but these are non-specific.[27]Management
Dietary Restrictions
The cornerstone of management for hereditary fructose intolerance (HFI) is a lifelong strict avoidance of fructose, sucrose (a disaccharide composed of glucose and fructose), and sorbitol to prevent metabolic crises and long-term organ damage.[3] This dietary restriction is essential because even small amounts of these compounds can overwhelm the deficient aldolase B enzyme, leading to toxic accumulation of fructose-1-phosphate in the liver and kidneys.[3] Safe daily intake is generally considered to be less than 40 mg/kg body weight or approximately 1.5 g total, though many guidelines recommend complete elimination to minimize risk, with tolerances potentially increasing to under 6 g per day in adulthood under close supervision.[21] Foods to avoid include all fruits and fruit juices due to their high fructose content, as well as vegetables such as tomatoes, sweet potatoes, and others not explicitly low in fructose; common sweeteners like high-fructose corn syrup (HFCS), honey, agave, molasses, and inverted sugar; and processed foods containing hidden sucrose or sorbitol, such as sweetened cereals, sauces, condiments, and sugar-free gums or candies.[28] Allowed foods focus on those providing energy from glucose or other non-fructose sources, including glucose-based starches like rice, potatoes, pasta, and unsweetened cereals; proteins such as plain meats, fish, poultry, eggs, and cheeses; fats like butter, oils, and sugar-free mayonnaise; and limited low-fructose vegetables including asparagus, cabbage, cauliflower, celery, green beans, lettuce, onions, peppers, spinach, and wax beans.[28][22] During illness or stress, when glycogen stores may deplete, supplementation with pure glucose or dextrose is recommended to maintain blood sugar levels without risking fructose exposure.[3] Practical strategies for adherence emphasize careful label reading to identify hidden sources of fructose, sucrose, sorbitol, or related additives in packaged goods, medications, and infant formulas, with exclusive breastfeeding or sucrose-free formulas advised for infants. Nutritional counseling by a registered dietitian specializing in metabolic disorders is crucial to ensure a balanced diet that meets caloric, protein, and micronutrient needs, potentially including "sugar-free" multivitamin supplements to compensate for restricted fruits and vegetables.[3] Ongoing monitoring involves regular follow-up with a dietitian to assess dietary compliance and nutritional status, using tools such as food diaries or mobile apps designed for low-fructose tracking (e.g., those aligned with metabolic society recommendations). According to updated 2024 clinical practice guidelines from metabolic experts, periodic biochemical tests like serum carbohydrate-deficient transferrin (CDT%) can help evaluate inadvertent fructose exposure.[21]| Food Category | Permitted Examples | Prohibited Examples |
|---|---|---|
| Dairy | Milk, cheese, eggs | Sweetened yogurt, fruit yogurt, chocolate milk |
| Proteins | Plain beef, fish, poultry, eggs | Processed meats with added sugar (e.g., ham, hot dogs) |
| Starches | Rice, potatoes, pasta, unsweetened cereals | Sugar-coated cereals |
| Vegetables | Asparagus, cabbage, lettuce, onions, potatoes | Tomatoes, sweet potatoes, most others |
| Sweeteners | Glucose, dextrose, maltose, zero-calorie options (e.g., aspartame) | Fructose, sucrose, HFCS, honey, sorbitol |
| Fats & Condiments | Butter, oil, sugar-free mayonnaise | Sugar-containing dressings, ketchup |