Tyrosinemia is a rare hereditary disease from the group of amino acid metabolism disorders that occurs due to the lack of enzymes necessary for the biochemical transformations of tyrosine. Pathology is manifested by severe liver damage, blood clotting disorders, neurological complications and developmental delay. Diagnostics includes specific biochemical analyses, genetic tests, instrumental imaging (ultrasound of the abdominal cavity, bone radiography, radioisotope scanning of the liver). For the treatment of tyrosinemia, the drug nitizinone is used, a diet with tyrosine restriction is prescribed, liver transplantation is performed according to indications.
E70.2 Disorders of tyrosine metabolism
Tyrosinemia, first described by the British physician Margaret Baber in 1956, belongs to orphan diseases. The prevalence of type I disease is 1 case per 100-120 thousand newborns, type II is 1:250,000, type III occurs 1 time per million population. No sex differences were found among the patients. The urgency of the problem in pediatric practice lies in the fact that tyrosinemia does not have pathognomonic symptoms, often proceeds under different “masks”, which makes it difficult to diagnose and timely selection of treatment.
Tyrosinemia refers to hereditary diseases with an autosomal recessive type of transmission. It is caused by mutations of genes that encode certain enzymes involved in the biochemical transformations of amino acids. In modern genetics, there are 3 variants of gene defects that are accompanied by disorders of tyrosine metabolism. These include the following:
- FAN mutation. The structure of the protein encoding the enzyme fumarylacetoacetase, which is necessary at the final stage of tyrosine conversion, changes. At the same time, type 1 tyrosinemia develops.
- TAT mutation. The formation of the enzyme tyrosine aminotransferase involved in the first stage of the biochemical reaction is disrupted. The gene anomaly causes type II tyrosinemia (Richner-Hanhard syndrome).
- PHD mutation. The production of the enzyme hydroxyphenylpyruvate dioxygenase, which catalyzes the second stage of amino acid transformations, decreases. Such a gene defect provokes type 3 tyrosinemia.
Tyrosine metabolism in the human body is a complex cascade of biochemical reactions, as a result of which homotentizic acid, maleylacetoacetate, fumarylacetoacetate are successively formed from amino acids. Normally, this pathway ends with the decomposition of the substance into fumarate and acetoacetate. With tyrosinemia, different stages of transformations are disrupted, resulting in the accumulation of toxic metabolites succinylacetone, succinylacetoacetate.
Substances belong to the category of mitochondrial toxins: they disrupt the cycle of tricarboxylic acids in mitochondria, reduce energy production. They also accumulate in the liver parenchyma, leading to functional organ failure, affect the kidneys and myocardium, disrupt the formation of red blood cells. Succinylacetone has a powerful neurotoxic effect, causes a clinical picture similar to porphyria.
Tyrosinemia type I
About 75% of cases of type I tyrosinemia manifest in children in the first 2-7 months of life and are acute. The disease is manifested by febrile fever, gastrointestinal disorders (vomiting, diarrhea, refusal to eat), dehydration and slow weight gain. A typical sign of pathology is considered to be prolonged jaundice, later an increase and asymmetry of the abdomen due to hepatomegaly is added. In some children, a specific “cabbage” smell of skin is noticeable.
The remaining 25% of cases of the disease are chronic, which occurs after 1 year of life, often manifesting in adolescents. It is characterized by skeletal deformities, liver lesions, which increase against the background of taking protein food. Usually children suffer from hypersensitivity of the skin, paresthesia, prolonged constipation due to paralytic intestinal obstruction — all these symptoms indicate a neurological crisis.
Tyrosinemia type II
Tyrosinemia type II is characterized by skin and eye lesions that occur in the first year of a child’s life. Dermatological disorders include painful plaques on the palms and soles, ulcerative defects, foci of hyperkeratosis. Photophobia, lacrimation, keratitis are observed. Later, various neurological symptoms are added, as in type I pathology.
Tyrosinemia type III
The disease manifests itself in infancy with neurological signs: disorders of muscle tone, disorders of coordination of movements, convulsive seizures. Then patients develop mental retardation of varying severity. The medical literature also describes cases of asymptomatic course of this form of the disease.
Tyrosinemia causes liver failure, hemorrhagic syndrome, renal tubulopathy, which are the main causes of death in the first years of a patient’s life if he does not receive adequate therapy. The disease is often complicated by cirrhosis of the liver, hypertrophic cardiomyopathy, hypophosphatemic rickets. Up to 40% of cases of pathology result in the development of hepatocellular carcinoma.
A dangerous consequence of the disease are tyrosinemic crises that occur with fever, intoxication, cardiomyopathy. After the manifestation of tyrosinemia, there is a delay in growth and bone age, a violation of the timing of the change of teeth, a lag in psychomotor development. The earlier the first symptoms appear, the more severe the prognosis, since such patients have serious cognitive abnormalities.
The initial examination is carried out by a pediatrician, a pediatric gastroenterologist, a hematologist or other specialists, which depends on the main clinical manifestations in a particular patient. During physical examination, there are no specific signs of tyrosinemia, therefore, a comprehensive laboratory and instrumental diagnosis is prescribed:
- Abdominal ultrasound. Ultrasound scanning visualizes diffuse changes in the liver structure, manifestations of portal hypertension, splenomegaly. Pancreatic hyperplasia and an increase in the size of the kidneys are less often detected. For a more detailed examination, ultrasound is supplemented by CT or MRI of the abdominal organs.
- Hepatoscintigraphy. Radioisotope examination is necessary for differential diagnosis of benign and malignant liver tumors, confirmation of portal hypertension. To assess the functional activity of the kidneys, renoscintigraphy is performed.
- Radiography of the skeleton. The study is recommended for detecting signs of rickets, as well as in the period of preparation for surgical or orthopedic correction of particularly severe bone deformities. To determine the mineral density of bone tissue, a non-invasive method of densitometry is used.
- Special biochemical diagnostics. There is an increase in the level of tyrosine over 500 mmol / l, its intermediate metabolites (4-hydroxyphenyl-pyruvic, 4-hydroxyphenyl-lactic, 4-hydroxyphenylacetic acids). Type 1 tyrosinemia is characterized by a high concentration of succinylacetone.
- Coagulogram. The analysis shows a deficiency of all hepatic coagulation factors, coagulopathy with prolongation of prothrombin and activated partial thromboplastin time. Blood clotting disorders are more typical for the acute form of tyrosinemia type 1.
- Genetic testing. It is the most reliable diagnostic method by which it is possible to confirm the presence of tyrosinemia and clarify its type after identification of a pathognomonic mutation. The study is done by genome sequencing.
Women with children with tyrosinemia are recommended to conduct prenatal screening at 8-11 weeks of subsequent pregnancies by direct or indirect DNA diagnostics of biopsies of chorionic villi. A burdened family history serves as an indication for selective neonatal screening, which involves measuring the level of succinylacetone in the urine of a child after birth, at the age of 7 and 28 days.
There is only one specific drug for violations of tyrosine metabolism — orphadine (nitisinone), which blocks one of the enzymes of the amino acid cycle, prevents the formation of toxic metabolites. Treatment is carried out continuously, the dose is selected individually taking into account the concentration of tyrosine in the body, coagulogram parameters, biochemical parameters of blood.
Drug therapy is necessarily combined with diet therapy. For patients with tyrosinemia, a special diet is selected with a low content of the amino acids tyrosine, phenylalanine, and a reduced amount of protein (up to 0.8-1 g / kg of body weight per day). To make up for protein deficiency, therapeutic mixtures of amino acids or protein hydrolysates that do not contain tyrosine are prescribed. Symptomatic treatment includes the following drugs:
- Vitamin and mineral mixtures. They are used to prevent hypovitaminosis, prevent rickets, and increase energy production. They have a beneficial effect on growth, physical development.
- Hepatoprotectors. Medications reduce the toxic effects of tyrosine metabolites on the liver, protect hepatocytes, and support their functional ability.
- Blood clotting factors. In severe coagulopathies accompanied by constant bleeding, replacement therapy with protein concentrates is used.
In the absence of a response to conservative therapy, too rapid progression of the disease, a sharp increase in the content of succinylacetone, the option of liver transplantation is considered. In acute liver failure in combination with hyperammonemia, an emergency organ transplant is often required to save the patient’s life. Another indication for transplantation is the presence of nodes in the hepatic parenchyma more than 1 cm in diameter.
Prognosis and prevention
Thanks to the improvement of diet therapy and other methods of treatment, tyrosinemia can be successfully controlled. However, with late diagnosis and the absence of specific therapy, about 90% of patients die before the age of 10. Primary prevention includes prenatal screening of pregnant women. Secondary preventive measures consist in early diagnosis and comprehensive treatment of patients to prevent life-threatening complications.