Fructose, galactose and sorbitol metabolism

Fructose, galactose and sorbitol are monosaccharides or sugar alcohols that enter the body through diet or endogenous synthesis.

• Fructose is found in honey, fruit and many sweeteners; it is also produced in the brain via the polyol pathway.
• Galactose is a component of lactose and is metabolised to glucose in the liver.
• Sorbitol is a sugar alcohol that can be converted to fructose through the polyol pathway.

After ingestion, fructose is absorbed by GLUT‑5 and GLUT‑2 transporters in the small intestine. It is then phosphorylated by fructokinase and, in the liver, kidney and intestine, metabolised by aldolase B and triokinase. Galactose is first phosphorylated by galactokinase, then converted to glucose‑1‑phosphate by GALT, and finally enters glycolysis or gluconeogenesis. Sorbitol is oxidised by sorbitol dehydrogenase to fructose, which follows the same pathway as dietary fructose.

Essential fructosuria is an inherited, benign defect of fructokinase. The enzyme deficiency leads to an inability to phosphorylate fructose, causing its accumulation in the blood and urine. Patients are typically asymptomatic; the condition is usually discovered incidentally on newborn screening or during routine metabolic testing. No treatment is required, and dietary restriction of fructose is unnecessary. ^[1]

Hereditary fructose intolerance (HFI) is a rare autosomal recessive inherited disorder that occurs due to the mutation of enzyme aldolase B located on chromosome 9q22.3. A fructose load leads to the rapid accumulation of fructose 1‑phosphate and manifests with its downstream effects. Most commonly children are affected with gastrointestinal symptoms, feeding issues, aversion to sweets and hypoglycaemia. Liver manifestations include an asymptomatic increase of transaminases, steatohepatitis and rarely liver failure. Renal involvement usually occurs in the form of proximal renal tubular acidosis and may lead to chronic renal insufficiency. For confirmation, a genetic test is favoured over the measurement of aldolase B activity in the liver biopsy specimen. The crux of HFI management lies in the absolute avoidance of foods containing fructose, sucrose and sorbitol (FSS). ^[1]

When fructose‑1‑phosphate accumulates, it depletes inorganic phosphate, inhibiting glycogenolysis and gluconeogenesis. This leads to hypoglycaemia, lactic acidosis, hyperuricaemia and hyperalaninaemia. The excess fructose‑1‑phosphate also drives hepatic fat synthesis, causing steatohepatitis.

• Infants/children: vomiting, diarrhoea, failure to thrive, abdominal pain after introduction of fruit or honey.
• Older children/adults: hypoglycaemia, jaundice, hepatomegaly, elevated transaminases, chronic renal tubular acidosis.

• Biochemical: Elevated plasma fructose after a fructose challenge; increased urinary fructose‑1‑phosphate.
• Genetic: Sequencing of the ALDOB gene confirms pathogenic variants.

• Strict dietary restriction of all FSS.
• Education of family and caregivers about hidden sources of fructose and sorbitol.
• Monitoring of liver function, renal function and growth parameters.

A 4‑year‑old boy presents with recurrent vomiting after eating fruit. Blood tests show hypoglycaemia and elevated transaminases. A fructose tolerance test reveals a sharp rise in plasma fructose and a drop in phosphate. Genetic testing identifies a homozygous mutation in ALDOB. The diagnosis of HFI is confirmed. The family is instructed to eliminate all fructose, sucrose and sorbitol from the diet, and the child’s growth and liver enzymes improve over the next months.

Galactokinase (GALK1) is a cytosolic enzyme that phosphorylates galactose to galactose‑1‑phosphate, the first step in the Leloir pathway. The deficiency is inherited in an autosomal recessive manner and has a worldwide incidence, although the true figure is likely higher because many newborn screening programmes do not detect it. The condition was first described by Fanconi, who noted cataract formation after milk ingestion, and was later confirmed to be due to GALK1 deficiency. ^{[4] [3]}

The most consistent and well‑established feature is the development of cataracts in infancy. Cataract formation is typically the presenting symptom, prompting diagnosis. Beyond cataract, the phenotypic spectrum remains uncertain. Some patients develop neurological problems such as gait abnormalities and developmental delay, but these manifestations are not universal. A 6‑year‑old girl was diagnosed at 10 months after cataract surgery and later developed a gait abnormality at 4 years, illustrating the variable neurological involvement. Data from the Galactosemias Network registry are being collected to better characterise the phenotype, but current evidence suggests that cataract is the hallmark. ^[3]

Because the block occurs before the formation of galactose‑1‑phosphate, the downstream metabolites (galactose‑1‑phosphate, UDP‑galactose) are low, while free galactose accumulates. In vitro assays of erythrocyte galactokinase activity confirm the deficiency. However, whole‑body galactose handling can be surprisingly normal. In a case study, breath tests using ^13C‑labelled galactose at carbon‑1 and carbon‑2 positions showed oxidation rates within the normal range, despite deficient erythrocyte activity. A similar study using ^14C‑labelled galactose found normal oxidation, contrasting with earlier reports of reduced oxidation in other patients. These findings indicate that extra‑erythrocytic tissues may compensate for the enzymatic block, maintaining overall galactose oxidation.

The blockade reduces the conversion of galactose to galactose‑1‑phosphate, thereby limiting the generation of glucose‑1‑phosphate that feeds into glycolysis and glycogenesis. This can lead to a decreased production of CO₂ from galactose metabolism. In one patient, the reduced galactokinase activity in red blood cells was associated with normal activity in white blood cells, suggesting tissue‑specific expression differences. A Philadelphia variant of the GALK1 gene, more common in Black populations, shows normal activity in white blood cells but decreased activity in red blood cells, further illustrating the complexity of tissue‑specific enzyme expression.

The mainstay of treatment is a galactose‑restricted diet, typically initiated after cataract diagnosis. In the reported case, dairy products were reintroduced at 15 months of age after cataract removal, and the patient remained asymptomatic apart from later neurological signs. The long‑term benefit of dietary restriction on cataract progression or neurological outcomes remains unclear, and further studies are needed. Because many newborn screening programmes do not detect GALK1 deficiency, clinicians should maintain a high index of suspicion in infants presenting with early cataract.

Classic galactosaemia (type I) is characterised by a complete or near‑complete loss of GALT activity. The enzyme normally catalyses the conversion of galactose‑1‑phosphate and UDP‑glucose to glucose‑1‑phosphate and UDP‑galactose. Without this step, galactose‑1‑phosphate accumulates, causing cellular toxicity and a spectrum of clinical manifestations.

Infants with classic galactosaemia typically present within the first weeks of life after the introduction of milk containing galactose. Common features include:

• Lethargy and poor feeding
• Vomiting
• Failure to thrive
• Hepatomegaly
• Osteomalacia
• Seizures
• Erythroderma

If untreated, the condition can be fatal within the first year of life. Early diagnosis and dietary restriction of galactose are essential for survival and long‑term outcomes.

In vivo studies using ^14C‑labelled galactose have quantified the impaired oxidation in classic galactosaemia. Individuals with GALT deficiency oxidise only about 8 % of ingested galactose in 5 hours, whereas controls oxidise 30 % to 35 %. Further studies with ^13C‑labelled galactose found an average oxidation of 4 % in 5 hours, compared with around 40 % in controls. In a 24‑hour period, classic galactosaemia patients eliminated approximately 17 % to 50 % of a 7 mg kg⁻¹ bolus dose, far below the 70 %–80 % elimination seen in healthy individuals. These data demonstrate a profound defect in galactose utilisation and clearance. ^[3]

The accumulation of galactose‑1‑phosphate is toxic to cells, particularly in the liver, kidneys, and brain. The excess galactose can also be converted to galactitol by aldose reductase, leading to osmotic damage in the lens of the eye and contributing to cataract formation. The persistent presence of galactose‑1‑phosphate interferes with normal carbohydrate metabolism, reducing the availability of glucose‑1‑phosphate for glycolysis and glycogenesis, and thereby impairing energy production.

The cornerstone of treatment is a strict galactose‑restricted diet, eliminating lactose and galactose from the infant’s nutrition. This dietary intervention reduces the accumulation of toxic metabolites and prevents the acute metabolic crisis. Long‑term complications, such as infertility, osteopenia, and neurocognitive deficits, may still occur despite dietary control, underscoring the need for early detection and lifelong monitoring.

Aldose reductase (AKR1B1) is a cytosolic enzyme that catalyses the NADPH‑dependent reduction of aldoses to their corresponding sorbitols. In the eye, it converts excess galactose to galactitol, a polyol that accumulates in lens epithelial cells and causes osmotic swelling, leading to cataract formation. The enzyme is highly expressed in the anterior lens epithelium, and its activity correlates with cataract severity in galactosemia models. In mice lacking aldose reductase, galactose feeding does not produce cataract, whereas re‑introduction of human aldose reductase restores the phenotype within days of life. Dietary restriction of galactose before two months of age can reverse cataract in humans, but delayed intervention requires surgical correction. Inhibition of aldose reductase has been proposed as a therapeutic strategy to prevent polyol accumulation and its sequelae, although it may not address all manifestations of the disease.

Lactase deficiency is classified into primary, secondary, and congenital forms. Primary lactase non‑persistence is the most common, characterised by a progressive decline in lactase activity after weaning. The prevalence of adult‑type lactase deficiency follows a north–south gradient: 5 %–15 % in Northern Central Europe and North American countries, 40 % in Mediterranean countries, and 65 %–90 % in African, Asian, and South American populations. In Europe, two single‑nucleotide polymorphisms (C/T‑13910 and G/A‑22018) are associated with lactase down‑regulation after infancy. Secondary lactase deficiency results from intestinal pathology (e.g., celiac disease, Crohn’s disease) or surgical interventions that damage the small‑bowel mucosa. Congenital lactase deficiency is rare, presenting at birth with almost complete absence of lactase; diagnosis relies on intestinal biopsy, while the hydrogen breath test (HBT) is a common non‑invasive alternative. Bacterial fermentation of undigested lactose in the colon increases exhaled hydrogen, which is measured in the HBT.

• Assuming that a normal breath test rules out all forms of lactase deficiency; congenital cases may still have minimal enzyme activity that is below the detection threshold of the test.
• Overlooking secondary causes: patients with celiac disease or inflammatory bowel disease may develop lactase deficiency that resolves with treatment of the underlying condition.
• Misinterpreting the prevalence data: the north–south gradient reflects genetic variation rather than environmental factors alone.
• Ignoring the role of aldose reductase in galactose‑induced cataract; dietary restriction alone may be insufficient if the enzyme remains active.

• Screening for lactase deficiency: The hydrogen breath test is routinely employed in patients with chronic diarrhoea, bloating, or abdominal pain after dairy ingestion.
• Management of galactosemia: Early dietary restriction of galactose, sucrose, and sorbitol is the cornerstone of treatment; monitoring for cataract development guides the timing of ophthalmic intervention.
• Pharmacological research: Aldose reductase inhibitors are investigated in clinical trials for diabetic complications and galactosemia, aiming to reduce polyol accumulation.
• Genetic counselling: Identification of SNPs associated with lactase non‑persistence informs dietary recommendations for at‑risk populations.