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

ICD-10 code

• E74.1 Violations of fructose metabolism.
• E74.4 Infringements of exchange of pyruvate and gluconeogenesis.

Epidemiology

Fructozuria: the frequency of homozygotes is 1 per 130 000.

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

Lack of fructose 1.6-bisphosphatase: a rare hereditary metabolic disorder.

Classification

Three hereditary disorders of fructose metabolism are known in humans. Fructozuria (fructoquinase deficiency) is an asymptomatic condition associated with increased fructose in the urine: hereditary fructose intolerance (aldolase B deficiency) and fructose-1,6-bisphosphatase deficiency, which is also attributed to gluconeogenesis defects.

Causes of fructosuria

Fructozuria is inherited by autosomal recessive type. The ketohexokinase gene (KNK) is mapped on chromosome 2p23.3-23.2.

Hereditary intolerance to fructose

Autosomal recessive disease due to mutations of the aldolase gene B. The aldolase B gene (ALDOB) is mapped on chromosome 9q22.3. About 30 different mutations are described, the most common are missense mutations A150P, A175D and N335K, which together constitute about 80% mutant alleles; among Russian patients - more than 90%.

Insufficiency of fructose-1.6-bisphosphatase

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

Pathogenesis of fructosuria

Fructozuria

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

Hereditary intolerance to fructose

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

Insufficiency of fructose-1,6-bisphosphatase

Insufficiency 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 for this pathology depends on the direct intake of glucose, galactose and cleavage 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 concentrations of lactate, pyruvate, alanine and glycerin in the blood.

Symptoms of fructosuria

Fructozuria has no clinical manifestations.

Hereditary intolerance to fructose

The first symptoms of the disease are associated with the intake of a large amount of fructose, sucrose or sorbitol. The younger the child and the more fructose that has been administered, the more severe the clinical manifestations. The disease can begin with acute metabolic decompensation and lead to a fatal outcome on the background of acute hepatic and renal insufficiency. In a more benign course, the first signs of the disease - apathy, lethargy, drowsiness, nausea, vomiting, excessive sweating, sometimes hypoglycemic coma. During this period, laboratory indicators 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, clotting disorders, edema develop. Hypoglycemia is unstable and is observed only immediately after taking fructose. Soft forms of the disease are described, which are manifested by an increase in liver size and growth retardation at school age and in adults. Due to the fact that patients do not tolerate sweet food, they limit their use by themselves, therefore, in patients with fructoseemia, caries practically never develop.

Insufficiency of fructose-1,6-bisphosphatase

Approximately half of the patients manifest the disease in the first 5 days of life with hyperventilation syndrome and severe metabolic acidosis as a result of increased lactate and hypoglycemia. Death can occur in the first days of life from apnea against a background of severe metabolic acidosis. Attacks of metabolic ketoacidosis can proceed as a Rhea-like syndrome, they are provoked by starvation, intercurrent infections or gastrointestinal disorders. They are accompanied by a refusal of food, vomiting, diarrhea, episodes of somnolence, violations of the rhythm of breathing, tachycardia and muscle hypotension, there is an increase in liver size. During the attacks of metabolic decompensation, the concentration of lactate (sometimes up to 15-25 mM) increases, the pH level decreases and the lactate / pirouate ratio and alanine content increase; observe hypoglycemia, sometimes hyperketonemia. As with hereditary intolerance to fructose, the administration of solutions of fructose is contraindicated and may lead to death. During the interictal period, patients do not complain, although metabolic acidosis may persist. Tolerance to starvation increases with age. With the correct diagnosis and timely treatment started, the prognosis is favorable.

Diagnostics 

Fructozuria

As a rule, the disorder is detected accidentally during routine urinary screening for the presence of sugars and for thin-layer chromatography of monosaccharides.

Hereditary intolerance to fructose

With standard biochemical studies, an increase in the level of liver transaminases and bilirubin in the blood, generalized aminoaciduria and metabolic acidosis is revealed. Load tests with fructose are not recommended, since they can lead to serious complications. The main method of confirming the diagnosis is DNA diagnostics.

Insufficiency of fructose-1,6-bisphosphatase

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

Differential diagnostics

Fructozuria: with hereditary intolerance to fructose.

Hereditary intolerance to fructose: differential diagnosis should be carried out with hereditary metabolic diseases accompanied by early gastrointestinal and / or liver damage: fructose-1,6-bisphosphatase deficiency, tyrosinemia, type I, glycogenoses, type la, lb, ctl-antitrypsin deficiency; with organic aciduria accompanied by lactic acidosis, as well as pyloric stenosis, gastroesophageal reflux, at an older age - with Wilson-Konovalov's disease.

Lack of fructose-1,6-bisphosphatase: differential diagnosis should be carried out with impaired metabolism of pyruvate, mitochondrial respiratory chain defects, hepatic forms of glycogenoses, defects in beta-oxidation of fatty acids that occur as Reye syndrome.

Treatment of fructosuria and prognosis

Fructozuria

The prognosis is favorable, treatment is not required.

Hereditary intolerance to fructose

If the disease is suspected, all products containing fructose, sucrose and sorbitol should be immediately ruled out. It must be remembered that sorbitol and fructose can be present in some medicinal preparations (antipyretic syrups, immunoglobulin solutions, etc.). Sucrose should be replaced with glucose, maltose or cornstarch. After transferring the child to a diet, all manifestations of the disease quickly disappear, except for hepatome aliya, which can persist for several months or years after the start of treatment. If you follow a diet, the forecast is favorable.

Insufficiency of fructose-1,6-bisphosphatase

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

Tolerance to starvation increases with age. Many patients in older age suffer from excessive body weight, since they are accustomed to a certain dietary regime since childhood. The forecast is favorable.

[1], [2], [3], [4], [5], [6], [7]