Hereditary fructose intolerance is a hereditary fermentopathy, which is based on a violation of the metabolism of fructose and the accumulation of its metabolic products, which are toxic to many organs and systems. This pathology begins to manifest itself from the very first years of life when eating products containing fructose. Symptoms include vomiting, abdominal pain, flatulence, diarrhea, increased excitability, tearfulness, sweating, convulsions, weight loss, liver enlargement. The diagnosis is based on the data of genetic research, instrumental and laboratory tests. The only treatment is diet therapy with the exclusion of fructose–containing foods from the diet.
E74.1 Disorders of fructose metabolism
Hereditary fructose intolerance (fructosemia) is a disease caused by the genetic inferiority of an enzyme that participates in the breakdown of fructose. This syndrome was first described in 1956, and a year later its hereditary nature was proved. Fructose (fruit sugar) is a widespread carbohydrate, in food products it is contained in three forms: monosaccharides – in fruits, berries, honey; disaccharides – in white and brown table sugar; fructans – in wheat and vegetables. The prevalence in different countries ranges from 1:23,000 to 1:40,000. The frequency of development of this condition among boys and girls is the same.
The immediate cause is a genetic defect of the enzyme fructose-1-phosphataldolase (aldolase B). There are more than 30 types of mutations of ALDOB-the aldolase B gene located at the q22.3 locus of the 9th chromosome, the most frequent of them are A149P, A150P, A175D and N335K. Hereditary fructose intolerance is a pathology with an autosomal recessive type of inheritance. If both parents are carriers of a pathological gene, then the probability of having a child with hereditary fructose intolerance is 25%. The trigger factor for the development of the disease clinic is the consumption of food containing fruit sugar. When ingested into the human body, fructose is metabolized in several ways, its cleavage by aldolase B is predominant.
As a result of the inferiority of aldolase B, the accumulation of fructose-1-phosphate (a product of intermediate fructose metabolism) occurs, triggering a very complex cascade of pathological reactions. Fructose-1-phosphate suppresses the activity of enzymes that catalyze the release of glucose from glycogen (glycogenolysis), resulting in a decrease in blood glucose levels. With hypoglycemia, cells begin to be in a state of energy deficiency. To replenish it, the mobilization of lipids from fat depots (lipolysis) is accelerated. Fatty acids enter the liver for the oxidation and synthesis of triglycerides and lipoproteins. However, in conditions of their massive intake, the liver does not cope with this function, as a result of which fatty acids condense and form ketone bodies, which are acids. Metabolic acidosis develops, in which vascular tone decreases, which leads to impaired blood circulation of organs and tissues.
Phosphorus metabolism is also disrupted, hypophosphatemia occurs. To replenish the lack of phosphates, the decay of adenylic nucleotides begins, the end product of which is uric acid. A decrease in urate excretion under acidosis conditions leads to hyperuricemia (secondary gout). In order to compensate for acidosis, calcium begins to be displaced from the bone tissue in exchange for hydrogen ions, which is then excreted in the urine. Osteopenia develops.
The disease begins to manifest itself in the first years of a child’s life, when he stops eating breast milk and starts eating fruit and vegetable purees, drinking fruit juices or sweet tea. Symptoms occur about 30 minutes after eating a fructose-containing food. There is belching of air, vomiting, abdominal pain, bloating, unstable stools or diarrhea. A little later, signs of hypoglycemia are added – the child first becomes tearful, excited, then sluggish and drowsy, sweating increases, tremors appear, muscle cramps may occur. The severity of symptoms depends on the degree of enzyme deficiency and the amount of fructose consumed.
If disease is not diagnosed, and the intake of fructose-containing products continues, there is an increase in the liver, jaundice staining of the skin and mucous membranes, pain, redness and swelling of the joints due to the deposition of uric acid in them. Due to massive lipolysis and impaired absorption of nutrients, the child begins to lose weight.
Consuming large amounts of fructose can lead to hypoglycemic coma, as the central nervous system of young children is very sensitive to hypoglycemia. With acidosis, potassium leaves the cells and enters the blood. Hyperkalemia occurs, which, by changing cellular excitability, causes various disorders of cardiac activity. The most formidable of them are ventricular fibrillation and cardiac arrest. Hypoglycemic coma and hyperkalemia without urgent medical intervention can be fatal. With long-term use of fructose in patients with hereditary fructose intolerance, hepatic and renal functions are disrupted, without treatment, cirrhosis of the liver and renal failure may occur.
If hereditary fructose intolerance is suspected, anamnestic data are an important point. There is a clear link between the use of fructose-containing products and the occurrence of symptoms. It is mandatory to consult a geneticist and conduct a DNA study to identify a mutation in the aldolase B gene. The following research methods also help in the diagnosis of hereditary fructose intolerance:
- Blood test. In the biochemical analysis of blood, low levels of glucose and phosphates, an increase in potassium, uric acid and liver enzymes (ALT, AST), a pH shift to the acidic side are detected. With the development of cirrhosis of the liver, the coagulogram indicators change towards hypocoagulation – there is a decrease in the prothrombin index and fibrinogen, an elongation of the prothrombin time. With renal insufficiency, the concentration of urea and creatinine increases.
- General urinalysis. Calciuria, fructosuria, aminoaciduria (excretion of a large amount of amino acids in the urine) and oxalaturia (excretion of uric acid salts in the urine) are detected. In severe kidney pathology, proteinuria and cylindruria are detected – the presence of hyaline, granular and waxy cylinders in the urine (casts of renal tubules representing dead epithelial cells).
- Instrumental research. On the ECG, signs of hyperkalemia are detected – pointed T teeth, expansion of the QRS complex, ventricular tachycardia, ventricular fibrillation. Ultrasound of the abdominal cavity shows an increase in the size of the liver, its heterogeneous echogenicity, fat infiltration. With clinical and laboratory signs of liver cirrhosis, fibroelastography is performed on a Fibroscan device.
- Hydrogen breath test with fructose. The test is based on the fact that normally all fructose is absorbed in the small intestine. With fructosemia, part of the fructose enters the large intestine, where it is broken down into hydrogen, carbon dioxide and methane under the action of bacteria. Hydrogen will be released with intestinal gases and exhaled air. After taking fructose dissolved in water, patients with fructosemia have an increased hydrogen content in the exhaled air.
Differential diagnosis is carried out with irritable bowel syndrome, fructose malabsorption syndrome, diseases occurring with hypoglycemia and ketoacidosis (diabetes mellitus, insulinoma, nezidioblastosis), with hereditary metabolic disorders (tyrosinemia, glycogenoses). A geneticist, gastroenterologist, and endocrinologist take part in the differential diagnosis.
The only therapeutic method is the exclusion of fructose and sucrose from the diet. For children who are artificially fed, there are special mixtures without sugar content with lactose and dextrinmaltose. Due to insufficient weight, such children need to be fed meat, eggs and fish earlier. High amounts of fructose are found in apples, pears, grapes, cherries, watermelon, dates, mangoes, honey. All sugary drinks should be avoided, as they contain high-fructose syrup. It is recommended to limit foods rich in fructans – asparagus, onion, garlic, lentils, red beans, beets, wheat products (bread, pasta, flour pastries, cookies). It is also necessary to exclude sugar-substituting sweeteners (xylitol, mannitol, sorbitol, erythritol), because they are all derivatives of fructose. Sweeteners are found in diet drinks, chewing gum and lollipops.
It is forbidden to use medicines containing sorbitol and sugar as auxiliary substances. To do this, it is necessary to consult with a pediatrician to find alternative medicines. With relative insufficiency of aldolase B and mild symptoms, products with a moderate amount of fructose are allowed – apricots, plums, currants, lingonberries, citrus fruits, kiwi, carrots, rhubarb. It is recommended to read information about the amount of fructose on food packages – if its content is more than 80 mg per 100 g, their use should be limited.
Prognosis and prevention
With timely diagnosis and appointment of diet therapy without fructose and sugar, the prognosis is favorable. All laboratory abnormalities and clinical manifestations disappear quickly. The exception is hepatomegaly, which persists for several months. With prolonged use of fructose, kidney failure and cirrhosis of the liver develop. The only method of preventing fructosemia is genetic testing of parents to detect a mutation of the aldolase B gene if there was a patient with this pathology among their close relatives.