Fructose metabolism disorder (fructosuria) in children: symptoms, diagnosis, treatment

ICD-10 code

• E74.1 Disorders of fructose metabolism.
• E74.4 Disorders of pyruvate metabolism and gluconeogenesis.

Epidemiology

Fructosuria: homozygous frequency is 1 in 130,000.

Hereditary fructose intolerance: the incidence of the disease is 1 in 18,000 live births in England and 1 in 29,600 live births in Germany.

Fructose 1,6-biphosphatase deficiency: a rare inherited metabolic disorder.

Classification

There are three known hereditary disorders of fructose metabolism in humans. Fructosuria (fructokinase deficiency) is an asymptomatic condition associated with elevated levels of fructose in the urine; hereditary fructose intolerance (aldolase B deficiency); and fructose-1,6-biphosphatase deficiency, which is also classified as a gluconeogenesis defect.

Causes of fructosuria

Fructosuria is inherited in an autosomal recessive manner. The ketohexokinase (KHK) gene is mapped to chromosome 2p23.3-23.2.

Hereditary fructose intolerance

An autosomal recessive disease caused by mutations in the aldolase B gene. The aldolase B gene (ALDOB) is mapped to chromosome 9q22.3. About 30 different mutations have been described, the most common being missense mutations A150P, A175D and N335K, which together account for about 80% of mutant alleles; among Russian patients - more than 90%.

Fructose-1,6-biphosphatase deficiency

An autosomal recessive disorder caused by mutations in the fructose-1,6-bisphosphatase gene. The fructose-1,6-bisphosphatase gene (FBP1) is mapped to chromosome 9q22.2-q22.3. More than 20 different mutations have been described. The c.961insG mutation occurs with high frequency in Japan (46% of mutant alleles).

Pathogenesis of fructosuria

Fructosuria

10-20% of unsplit fructose is excreted unchanged in the urine, most of which is converted to fructose-6-phosphate via an alternative metabolic pathway. This reaction is catalyzed by ketohexokinase (fructokinase).

Hereditary fructose intolerance

The disease is associated with a deficiency of the second enzyme involved in fructose metabolism, aldolase B. Its defect leads to the accumulation of fructose-1-phosphate, which inhibits glucose production (gluconeogenesis and glycogenolysis) and causes hypoglycemia. Fructose intake leads to an increase in lactate concentration, which inhibits renal tubular secretion of urates, leading to hyperuricemia, aggravated by depletion of intrahepatic phosphate and accelerated degradation of adenine nucleotides.

Fructose-1,6-biphosphatase deficiency

Deficiency of the key enzyme of gluconeogenesis disrupts the formation of glucose from precursors, including fructose, so the normal level of glucose in the blood plasma in this pathology depends on the direct intake of glucose, galactose and the breakdown of liver glycogen. Hypoglycemia in the neonatal period is associated with a high need for gluconeogenesis, since the level of glycogen in newborns is low. Secondary biochemical changes: increased concentration of lactate, pyruvate, alanine and glycerol in the blood.

Symptoms of fructosuria

Fructosuria has no clinical manifestations.

Hereditary fructose intolerance

The first symptoms of the disease are associated with the intake of large amounts of fructose, sucrose or sorbitol. The younger the child and the more fructose has been ingested, the more severe the clinical manifestations. The disease can begin with acute metabolic decompensation and lead to death due to acute liver and kidney failure. In a more benign course, the first signs of the disease are apathy, lethargy, drowsiness, nausea, vomiting, increased sweating, and sometimes hypoglycemic coma. During this period, laboratory tests indicate acute liver failure and generalized dysfunction of the renal tubular system. If the diagnosis is not established and a diet is not prescribed, chronic liver failure, hepatomegaly, jaundice, blood clotting disorders, and edema develop. Hypoglycemia is inconstant and is observed only immediately after ingestion of fructose. Mild forms of the disease are described, which are manifested by an increase in the size of the liver and growth retardation in school age and in adults. Due to the fact that patients do not tolerate sweet foods well, they limit their consumption on their own, so patients with fructosemia almost never develop caries.

Fructose-1,6-biphosphatase deficiency

In approximately half of the patients, the disease manifests itself in the first 5 days of life with hyperventilation syndrome and severe metabolic acidosis due to increased lactate levels and hypoglycemia. Death may occur in the first days of life from apnea against the background of severe metabolic acidosis. Attacks of metabolic ketoacidosis can occur as a Reye-like syndrome, they are provoked by starvation, intercurrent infections or gastrointestinal dysfunction. They are accompanied by refusal to eat, vomiting, diarrhea, episodes of somnolence, respiratory rhythm disturbances, tachycardia and muscle hypotension, and an increase in the liver size occurs. During attacks of metabolic decompensation, the lactate concentration increases (sometimes up to 15-25 mM), the pH level decreases and the lactate/pyruate ratio and alanine content increase; hypoglycemia and sometimes hyperketonemia are observed. As with hereditary fructose intolerance, the administration of fructose solutions is contraindicated and can be fatal. During the interictal period, patients do not complain, although metabolic acidosis may persist. Tolerance to fasting increases with age. With a correct diagnosis and timely treatment, the prognosis is favorable.

Diagnostics

Fructosuria

As a rule, the disorder is detected by chance during standard urine screening for the presence of sugars and thin-layer chromatography of monosaccharides.

Hereditary fructose intolerance

Standard biochemical studies reveal elevated levels of liver transaminases and bilirubin in the blood, generalized aminoaciduria, and metabolic acidosis. Fructose loading tests are not recommended, as they can lead to severe complications. The main method of confirming the diagnosis is DNA diagnostics.

Fructose-1,6-biphosphatase deficiency

The main method of confirming the diagnosis is DNA diagnostics. It is also possible to determine the enzyme activity in a liver biopsy.

Differential diagnostics

Fructosuria: with hereditary fructose intolerance.

Hereditary fructose intolerance: differential diagnosis should be carried out with hereditary metabolic diseases accompanied by early damage to the gastrointestinal tract and/or liver: fructose-1,6-biphosphatase deficiency, tyrosinemia, type I, glycogenoses, type Ia, Ib, ctl-antitrypsin deficiency; with organic acidurias accompanied by lactic acidosis, as well as pyloric stenosis, gastroesophageal reflux, in older age - with Wilson-Konovalov disease.

Fructose-1,6-biphosphatase deficiency: differential diagnosis should be carried out with pyruvate metabolism disorders, mitochondrial respiratory chain defects, hepatic forms of glycogenosis, and fatty acid beta-oxidation defects occurring as Reye's syndrome.

Treatment of fructosuria and prognosis

Fructosuria

The prognosis is favorable and no treatment is required.

Hereditary fructose intolerance

If this disease is suspected, all products containing fructose, sucrose and sorbitol should be immediately excluded. It should be remembered that sorbitol and fructose may be present in some medications (antipyretic syrups, immunoglobulin solutions, etc.). Sucrose should be replaced with glucose, maltose or corn starch. After the child is put on a diet, all manifestations of the disease quickly disappear, with the exception of hepatomealia, which may persist for several months or years after the start of treatment. If the diet is followed, the prognosis is favorable.

Fructose-1,6-biphosphatase deficiency

During acute metabolic decompensation, intravenous administration of 20% glucose and sodium bicarbonate is necessary to control metabolic acidosis and hypoglycemia. Outside of crises, it is recommended to avoid fasting and adhere to a diet with limited fructose/sucrose, replace part of dietary fats with carbohydrates and limit protein. During intercurrent infections, frequent feedings with slowly absorbed carbohydrates (raw starch) are recommended. In the absence of stress factors leading to metabolic decompensation, patients do not experience significant clinical disorders.

Fasting tolerance increases with age. Many older patients are overweight because they have been accustomed to a certain diet since childhood. The prognosis is favorable.

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