Hereditary Tyrosinemia Type 1: Clinical Guidelines

List of Abbreviations

AFP — Alpha-fetoprotein

aPTT – Activated partial thromboplastin time

ALT — Alanine aminotransferase

AST — Aspartate aminotransferase

GGT — Gamma-glutamyl transferase

HCC — Hepatocellular carcinoma

HT - Hereditary tyrosinemia

HT 1A - Acute hereditary tyrosinemia

HT 1B - Chronic hereditary tyrosinemia

CT - Computed tomography

ABG - Acid-base balance

MRI - Magnetic resonance imaging

MRCP - Magnetic resonance cholangiopancreatography

PTI - Prothrombin index

RP - Radiopharmaceutical

MS/MS - Tandem mass spectrometry

ALP - Alkaline phosphatase

FAH - Fumarylacetoacetate hydrolase

NTBC - 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (nitisinone**)

TORCH infections - An acronym for a group of infections transmitted vertically from mother to fetus: T - Toxoplasmosis, O - Others (syphilis, hepatitis B, varicella-zoster virus, other viruses and bacteria), R - Rubella, C - Cytomegalovirus, H - Herpes simplex virus

US – ultrasound examination

Terms and Definitions

Fanconi syndrome is a generalized dysfunction of the proximal renal tubules manifested by glucosuria, aminoaciduria, phosphaturia, and renal tubular acidosis.

Hypertrophic cardiomyopathy is characterized by thickening of the ventricular walls (predominantly the left ventricle), impairment of its diastolic function, and is frequently accompanied by the development of left ventricular outflow tract obstruction.

Tyrosinemic crises are conditions triggered by protein intake and accompanied by fever, vomiting, intoxication, and cardiomyopathy.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hereditary tyrosinemia type 1 (HT1), or hepatorenal tyrosinemia, is a rare (orphan) autosomal recessive disease caused by mutations in the FAH gene encoding the enzyme fumarylacetoacetate hydrolase. Synonyms: fumarylacetoacetase deficiency, fumarylacetoacetate hydrolase deficiency.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Pathogenic variants of the FAH gene lead to reduced activity of fumarylacetoacetate hydrolase (FAH, EC 3.7.1.2), which normally catalyzes the final step of tyrosine degradation into non-toxic fumarate and acetoacetate. As a result, tyrosine breakdown proceeds via an alternative pathological pathway, producing highly toxic and carcinogenic succinylacetone, maleylacetoacetate, and fumarylacetoacetate (Appendix A3.1).

The FAH gene is localized on the long arm of chromosome 15 (15q23-q25) and consists of 14 exons. To date, about 100 mutations have been described in the gene, common ones being: c.554-1G>T, c.1062+5G>A, c.1025C>T (Pro342Leu), and c.1090G>C (Glu364Gln) [13]. The pathogenesis of HT1 involves the toxic effects of fumarylacetoacetate, maleylacetoacetate, and their end metabolites—succinylacetone and succinylacetoacetate—which inhibit oxidative phosphorylation and block the Krebs cycle. The accumulation of these substances leads to progressive liver disease with the development of liver failure, cirrhosis, tubulopathy with the formation of renal tubulopathy, hypophosphatemic rickets, and Fanconi syndrome [14].

Additionally, succinylacetone inhibits $\delta$-aminolevulinic acid dehydratase, an intermediate mediator of porphobilinogen, leading to impaired heme biosynthesis, which may clinically manifest with symptoms of acute intermittent porphyria, such as abdominal pain, arterial hypertension, and peripheral polyneuropathy.

The majority (up to 90%) of patients without specific treatment (dietary therapy, pathogenetic drugs) and liver transplantation died before the age of 10. Survival depends on the timing of symptom onset [15].

1.3 Epidemiology of the Disease or Condition

The prevalence of HT1 in various populations ranges from 1:100,000 to 1:120,000 live newborns. No clear genotype-phenotype correlations have been established; different clinical variants may occur in members of the same family with identical mutations [1, 4, 10]. The highest prevalence of HT1 has been found in the Saguenay-Lac-St-Jean region (Quebec, Canada), where it reaches 1:1846, with 1 in 22 being a carrier [13–15]. In this population, the splicing site mutation c.1062+5G>A (IVS12+5G→A) is the most common (~90%) [12, 14, 15]. A high prevalence of HT1 is observed in the Chechen Republic—1:16,020, with the c.1025C>T (p.Pro342Leu) mutation being the most frequent [16].

1.4 Features of Coding the Disease or Condition

E70.2 - Disorders of tyrosine metabolism

1.5 Classification of the disease or condition

The classification of HT1 is based on the clinical variants of the disease course: acute (HT 1A) and chronic (HT 1B).

1.6 Clinical presentation of the disease or condition

In HT1, pregnancy and the perinatal period are usually uneventful, and the child appears healthy at birth. Family history may be burdened, with potential cases of early childhood death from cerebral hemorrhage or acute bleeding misdiagnosed as sepsis, intrauterine infections, or disseminated intravascular coagulation syndrome.

Acute hereditary tyrosinemia type 1 (HT1A) presents in the first 2–3 months of life and is characterized primarily by severe liver failure, hepatosplenomegaly, coagulopathy, and hypoglycemia, leading to death in the first months of life. Renal tubular dysfunction is accompanied by Fanconi syndrome and rickets [2, 8]. Patients are quite frequently misdiagnosed with sepsis, cytomegalovirus hepatitis, or fetal hepatitis. Children with HT1A exhibit pronounced intoxication, hypoglycemia, leukocytosis, and possible ascites, dynamic intestinal obstruction, or bowel paresis. At the same time, there are elevated levels of succinylacetone ($\geq$ 10–100-fold) and alpha-fetoprotein (AFP) ($\geq$ 100–1,000-fold). Cytolysis typically does not exceed 3 to 4 times the upper limit of normal, with moderate hyperbilirubinemia within 100–150 $\mu$mol/L, evenly distributed between direct and indirect bilirubin. The cause of death in the natural course of HT1A is usually acute liver failure accompanied by catastrophic hemorrhage. Diagnosis is complicated by concurrent conditions such as intrauterine infection, neonatal hepatitis, and sepsis.

In the acute form of HT1, the clinical picture is dominated by symptoms of intoxication (high fever, hyperexcitability, progressive impairment of consciousness ranging to coma), signs of liver damage (hepatomegaly, potentially combined with splenomegaly, ascites, jaundice—rarely), gastrointestinal syndrome (regurgitation after every feeding), severe hemorrhagic syndrome (melena, hematemesis, hematuria, ecchymoses, petechiae, epistaxis), and a specific urine odor (the smell of "boiled cabbage"). Starting from 3 weeks of age, if there is frequent regurgitation and vomiting, failure to thrive, marked muscle hypotonia, lethargy, nonspecific symptoms of intoxication, grayish skin, abdominal distension due to ascites and hepatosplenomegaly, dynamic intestinal obstruction (bowel paresis) with loose stools (with or without blood), possible edema or pedal pastosity; laboratory findings show hypoglucosemia, hypocoagulation, leukocytosis, cytolysis typically not exceeding 3 times the upper limit of normal, elevated gamma-glutamyl transferase (GGT), while bilirubin metabolism is usually undisturbed (i.e., cholestasis without jaundice), and AFP is significantly elevated (normal being up to 60 ng/mL in infants under 5 months) reaching up to 1,000,000 ng/mL, the child should undergo selective screening for inborn errors of metabolism, including HT1.

In the chronic form (HT1B), a different clinical picture is observed; the disease develops after one year of age, most commonly at 3–4 years. HT1B is initially less aggressive, but the disease progresses steadily and may be accompanied by episodes of acute metabolic decompensation. This form features varying degrees of liver damage, renal tubular dysfunctions, rickets-like skeletal changes due to hypophosphatemia and hyperphosphaturia, cardiomyopathy, and neurological crises resembling porphyric attacks (painful paresthesias, arterial hypertension, tachycardia, paralytic ileus, occasionally progressive paralysis), as well as hypoglycemia associated with pancreatic $\beta$-cell hyperplasia and hyperinsulinism. Neurological crises typically last 1–7 days, followed by a recovery period.

Patients exhibit impaired renal tubular reabsorption, leading to Fanconi syndrome, acidosis, generalized aminoaciduria, vitamin D-resistant hypophosphatemic rickets, and growth retardation. In some cases, children present with rickets and limb deformities so severe that they stop walking. Cirrhosis, hepatosplenomegaly, epistaxis, and hypoproteinemic edema may also be diagnosed at this age. HT1B is characterized by progressive liver changes leading to cirrhosis and the development of hepatocellular carcinoma. In fact, the risk of developing hepatocellular carcinoma in this disease is considered the highest among all inherited metabolic disorders [17, 18]. It was previously reported that hepatocellular carcinoma develops in 37% of patients with hereditary HT1 older than 2 years [19], but subsequent studies in Scandinavia [20] and Quebec [17] showed a lower incidence of hepatocellular carcinoma (~15%), likely due to liver transplantation and improved treatment modalities. Hepatocellular carcinoma in patients with hereditary tyrosinemia type 1 develops at an earlier age than in other inherited metabolic disorders (often before 5 years of age) [18]. Cytolysis is minimal (within three times the upper limit of normal). AFP levels are elevated up to 1000 ng/dL, and succinylacetone levels are no more than 20-fold elevated [9].

The subacute and chronic forms of the disease occur in approximately 20–25% of patients with onset at 4–12 months, and clinical manifestation is triggered by external factors. Such triggering factors include febrile states, infections, protein loading, starvation, and other hypercatabolic states. Patients present with progressive liver damage with hepatomegaly or hepatosplenomegaly (cirrhosis, liver failure), growth retardation, signs of rickets, muscle hypotonia, and coagulopathy. Lagging physical development parameters is characteristic. Neurological symptoms often include hydrocephalic skull configuration, Graefe's sign, and psychomotor retardation. Neurological crises may occur (limb weakness, limb and diaphragmatic paralysis, vomiting, self-harm, etc.), which in some cases lead to a misdiagnosis of myasthenia gravis. Neurological changes are inconstant. Skin hyperpigmentation is frequently described.

It should be noted that this classification is rather arbitrary, since some children with acute decompensation during the first year of life survive and their form becomes "chronic," while patients with the "chronic" form remain at risk for metabolic crises. At the same time, the age of onset is an important prognostic indicator. Prior to the advent of pathogenetic treatment, 60% of children with disease onset under 2 months of age died, compared to 23% with onset between 2 and 6 months, and only 4% of children with onset after 6 months [21]. In some regions of the Russian Federation, mass screening programs for HT1 are carried out. It should be noted that up to 4 days of life in full-term and up to 7 days of life in preterm newborns, neonatal screening will be ineffective, as high concentrations of succinylacetone do not yet accumulate in the blood of patients with HT1 [31, 36].

Hepatic manifestations of type I tyrosinemia

The main clinical manifestations of HT1 are associated with liver damage. Acute liver failure, liver cirrhosis, and hepatocellular carcinoma may occur [21]. According to international studies, 69% of deaths were associated with liver failure and hemorrhage, and 16% with hepatocellular carcinoma. Synthetic function is impaired in the majority of patients with HT1. Clotting factor levels are markedly reduced in HT1, and in some patients, coagulation disorders are the leading feature while other signs of liver damage are mild, prompting investigation for a primary hematological problem [22]. Prothrombin time and partial thromboplastin time can be extremely prolonged even in clinically healthy children with HT1 detected by screening. Administration of vitamin K can only temporarily improve the coagulation profile. Serum transaminase levels vary and may be normal or slightly elevated, although in some crisis situations levels exceeding 1000 IU/L may be observed, indicating a more significant degree of hepatocyte injury and generally prompting steps toward emergency liver transplantation. Jaundice is rare in the early stages of hepatorenal tyrosinemia. Meanwhile, gamma-glutamyl transferase is usually elevated more than 2-fold, corresponding to dissociated cholestasis.

Hepatic crises can be triggered by infections and other catabolic stresses in both infants and older children. The child is irritable, weak, and frequently febrile. Ascites, jaundice, and gastrointestinal bleeding are common. A "boiled cabbage" odor may be perceived, but the odor is infrequent—present in approximately 15% of cases. Hepatomegaly of varying degrees is present. The crisis is accompanied by marked sweating; hyperhidrosis is often attributed to acute rickets, which does not exclude but rather confirms HT1. Tremor, hyperhidrosis, and severe weakness as manifestations of hypoglycemia during a crisis are more frequent than outside of it. During crises, elevated plasma levels of tyrosine, methionine, proline, and often other amino acids may be observed. Liver transaminases can rise sharply, and hyperbilirubinemia may develop, corresponding to hepatocyte breakdown. Renal tubular dysfunction may worsen during this period. Although many crises resolve spontaneously with a reduction in protein intake, adequate parenteral nutrition, and detoxification therapy, some progress to complete liver failure and hepatic encephalopathy.

Between crises, most patients exhibit mild to moderate hepatomegaly. Some patients with developing cirrhosis or hepatomegaly with impaired hemodynamics and increased parenchymal resistance (based on hepatic vessel Doppler ultrasound) present with splenomegaly. Liver transaminases are normal or slightly elevated, and bilirubin levels are normal. Alpha-fetoprotein is elevated (10–1,000,000 ng/mL; normal <10). Clinically, serum α-fetoprotein levels roughly reflect the aggressiveness of the disease, as do plasma methionine levels. Hyperbilirubinemia and hyperammonemia are late signs of liver failure.

Cirrhosis likely eventually develops in all patients with HT1, and the risk of hepatocellular carcinoma is extremely high [19]. Each year without treatment increases the risk of HCC from 14% to 75%. Early initiation of pathogenetic therapy, prior to one month of age, reduces the risk of HCC to 1% and decreases the need for liver transplantation from 71% to 26% [15, 23]. Importantly, far from every case of HCC occurs against the background of cirrhosis. Thus, in a review by R. Khanna (2018) encompassing 15 studies, the average incidence of HCC was 0.41 per million in children and 0.8 per million in the adult population [24]. The incidence of HCC in HT1 exceeds by 40 times its incidence in other metabolic and infectious liver diseases. The risk of developing HCC in HT1 arises in the absence of nitisinone therapy and when therapy is initiated later than 1 month of age [25]. Nevertheless, even after a prolonged untreated period, some children respond favorably to therapy—liver architecture is restored, tubulopathy resolves, bone mineral density and electrolyte balance are restored. Cases have been noted where patients were referred for transplantation with preliminary preparation using NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (nitisinone)) for 3 months to improve metabolic processes, and after this period, the indications for transplantation disappeared. Some children continued conservative therapy with stabilization and/or regression of cirrhosis.

Most imaging techniques (CT, ultrasound, angiography) do not reliably differentiate benign from malignant nodular lesions. For CT detection, it is important to perform scans with and without contrast, because contrast enhancement may obscure some nodules while revealing others. The sensitivity of ultrasound is at least equal to that of CT, but it largely depends on the operator's experience. It should be noted that since barbiturate premedication can precipitate porphyria-like crises, it is best to avoid its use in patients who have not received NTBC [26].

Neurological crises of type I tyrosinemia

Neurological crises in hepatorenal tyrosinemia are acute episodes of peripheral neuropathy. Clinically, the crises are divided into two phases: (1) an active period dominated by painful paresthesias, autonomic signs (e.g., hypertension, tachycardia, intestinal obstruction), and sometimes progressive paralysis, and (2) a recovery period following the paralytic crisis. Of 48 patients of French-Canadian descent, 20 (42 percent) were reported to have experienced neurological crises [27]. Peripheral hyperparesthesia manifests at an early age—the infant refuses to be held in the mother's arms, becomes distressed by touch or stroking, and prefers to remain in the crib. Painful crises are the most frequent neurological variant [28]. During the prodrome, which often occurs after a minor infection accompanied by anorexia and vomiting, the child is irritable and less active than usual. The child then develops severe pain, frequently in the legs. Patients often assume a position of extreme hyperextension of the trunk and neck, which can be mistaken for opisthotonos or meningismus. The hypertonia can be mistaken for tonic seizures, but the patients are actually conscious. True seizures may also occur, often in combination with severe hyponatremia [27]. The crises can be so agonizing that they are accompanied by self-injurious behavior [27]. Importantly, the intellectual development of children with HT1 is normal, and their level of consciousness does not decrease during crises.

The active phase usually lasts from 1 to 7 days. In very rare cases, mechanical ventilation was required during crises due to respiratory weakness, in one case for a period of more than 3 months [27]. Vomiting and intestinal obstruction frequently occur and can complicate the feeding regimen. Arterial hypertension and persistent tachycardia are characteristic of the early stage of a neurological crisis. Marked hyponatremia, hypophosphatemia, and hypokalemia may also occur [27].

It should be noted that such acute and severe symptoms were not observed in 30 Russian patients. Neurological crises are the main cause of morbidity in patients who have not received NTBC. According to an international survey, 10% of deaths in HT1 occurred during neurological crises. Children with HT1 and signs pointing to an impending neurological crisis should be hospitalized for continuous monitoring of respiratory function during the acute phase.

Renal Pathology in Type I Tyrosinemia

Patients with HT1 almost always exhibit renal involvement of varying degrees, ranging from mild tubular dysfunction to overt renal failure. The renal impairment corresponds to Fanconi syndrome, complete or incomplete: decreased blood calcium levels; decreased blood phosphorus levels; increased alkaline phosphatase levels; development of metabolic acidosis, impaired bicarbonate reabsorption in the proximal tubules; normal urinary calcium excretion may be present in the setting of hypocalcemia; increased urinary phosphate clearance, with intestinal phosphate absorption remaining unaffected; glucosuria (20–30 g/L and higher); development of generalized hyperaminoaciduria; impaired ammoniagenesis—decreased titratable acidity, increased urine pH above 6.0; development of hypokalemia.

The severity of proximal tubular dysfunction varies and can sharply worsen during periods of decompensation. Hypophosphatemic rickets is the main clinical sign of renal tubular dysfunction in HT1. Some children with HT1 exhibit renal tubular acidosis. Generalized aminoaciduria is more common than glucosuria. Urinary phosphate wasting is likely the primary mechanism of rickets in these patients, as evidenced by frequent manifestations of hypophosphatemia and the absence of hypocalcemia or dental enamel hypoplasia, which might otherwise suggest a vitamin D-related pathogenesis [29].

Skeletal Changes in Type I Tyrosinemia

Prior to the advent of disease-modifying treatment, patients with HT1 suffered from severe multiplanar skeletal deformities, pathologic fractures, exaggerated manifestations of rickets in the form of cartilage hyperplasia (rachitic rosary), craniotabes, hyperhidrosis, Chvostek's sign, irritability, sweating, brittle nails, and dental abnormalities. Radiography reveals decreased bone age and osteopenia, progressing to osteoporosis, widening of the distal epiphyses of tubular bones, deformation and thinning of the cortical layer of the metacarpals, metatarsals, forearms, lower legs, and femurs, as well as saber shin deformities of all weight-bearing bones—lower legs if the child walked, or both femurs, arms, and forearms if the child only crawled. Chest and clavicle deformities, prominent Harrison's grooves, and hip dysplasia and subluxation are also observed.

The diagnosis of hereditary HT1 should be suspected in the presence of valgus (most commonly) or varus limb deformities accompanied by hepatomegaly. Some patients walk independently until 2–3 years of age, although their exercise tolerance is low, and then stop walking, which frequently prompts them to seek medical attention. This is quite typical for patients from large, socially disadvantaged, or non-Russian-speaking families living in rural areas, mountain villages, and remote regions lacking specialists.

Other Clinical Manifestations and Differential Diagnosis of Type 1 Tyrosinemia

Clinically significant hypertrophic cardiomyopathy has been reported in three children with tyrosinemia and was the cause of death in one [30].

Hypoglycemia is a typical symptom in infants under one year of age with a severe disease course accompanied by liver failure. Therefore, differential diagnosis with glycogen storage diseases and fatty acid beta-oxidation disorders should be performed.

Elevated tyrosine levels can also be observed in other forms of hereditary tyrosinemia, which differ in their clinical spectra. Deficiency of tyrosine aminotransferase—the first enzyme in the tyrosine catabolic pathway—leads to hereditary tyrosinemia type 2 (OMIM 276600), also known as Richner–Hanhart syndrome. Tyrosinemia type 2 is accompanied by elevated tyrosine levels in the blood and urine. The clinical phenotype includes intellectual disability, painful corneal lesions, photophobia, keratitis, and painful palmoplantar hyperkeratosis [4]. Mutations leading to reduced activity of p-hydroxyphenylpyruvate dioxygenase—the second enzyme of tyrosine catabolism—can contribute to the development of hawkinsinuria (OMIM 140350) or hereditary tyrosinemia type 3 (OMIM 276710).

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of HT1 is established based on family history data, clinical symptoms, instrumental examination findings, as well as the results of biochemical and DNA diagnostics

2.1 Complaints and Anamnesis

When taking the medical history and assessing complaints, it is recommended to pay attention to the following complaints and historical events:

• positive family history (similar symptoms in siblings of the proband, consanguineous marriage);

• cases of sudden infant death;

• regurgitation, vomiting;

• weight loss, poor weight gain;

• jaundice;

• epistaxis, bleeding from injection sites;

• enlargement of the liver and spleen;

• specific "cabbage-like" body odor;

• various skeletal deformities (most frequently of the lower extremities);

• history of hypoglycemia episodes.

Complaints and medical history are also described in the "Clinical Presentation" section.

2.2 Physical Examination

A patient with suspected HT1 should undergo a comprehensive physical examination, paying special attention to palpatory and percussive examination of the liver and spleen.

Acute form of HT 1A:

- growth retardation;

- febrile temperature;

- vomiting, dehydration;

- diarrhea;

- hepato-/hepatosplenomegaly;

- ascites and dynamic intestinal obstruction;

- jaundice (at the acute hepatitis stage);

- acute gastrointestinal bleeding (melena and coffee-ground emesis are possible);

- non-protein edema, anasarca;

- bleeding due to impaired hepatic protein-synthesizing function;

- sometimes a specific "cabbage-like" body odor;

- hyperhidrosis, which is pronounced during crises, especially against the background of fever and hypoglycemia;

- hyperesthesia (the child prefers to stay in the crib rather than being held in the mother's arms) as a manifestation of polyneuropathy.

Chronic HT 1B:

- growth retardation, delayed physiological tooth eruption by 3–4 years, delayed bone age;

- hepato-/hepatosplenomegaly;

- ascites and dynamic intestinal obstruction;

- jaundice (at the acute hepatitis stage);

- acute gastrointestinal bleeding (melena and coffee-ground emesis are possible);

- non-protein edema, anasarca;

- bleeding due to impaired hepatic protein-synthesizing function;

- sometimes a specific "cabbage-like" body odor;

- hyperhidrosis, which is pronounced during crises, especially against the background of fever and hypoglycemia;

- hyperesthesia (the child prefers to stay in voids rather than being held in the mother's arms) as a manifestation of polyneuropathy;

- rickets-like disorder due to severe tubulopathy;

- peripheral neuropathy, acute abdominal crises, or so-called "tyrosinemic" crises, which are triggered by the intake of high-protein foods and accompanied by fever, vomiting, and intoxication;

- cardiomyopathy and arterial hypertension manifest both as a result of metabolic processes and secondarily against the background of kidney damage.

2.3 Laboratory Diagnostics

Comments: It is important to remember that biological material sampling for assays (urine for succinylacetone and blood for tandem mass spectrometry) should be performed prior to the initiation of infusion therapy, especially the administration of plasma-substituting solutions and blood components.

A pathognomonic sign of HT 1 is a high level of succinylacetone in urine and blood plasma (normal range 0–2 mmol/mol creatinine). A slight increase in succinylacetone in blood and urine can be observed with protein overfeeding leading to functional insufficiency of FAH. Testing for succinylacetone must be performed before starting detoxification therapy, plasma transfusions, and other blood components.

A high level of methionine leads to a "cabbage-like" odor, which is not as specific as previously described and rather reflects hepatocellular insufficiency. A tyrosine level above 200 µmol/L and an elevation of its precursor phenylalanine in tyrosinemia are observed only in children with normal nutritional status. In malnourished children with a prolonged history and clinical presentation of protein-energy malnutrition, the blood levels of tyrosine and phenylalanine may be normal. During specific therapy with nitisinone**, a low-protein diet, and detoxification therapy, the level of succinylacetone significantly decreases and reaches normal values within 24 hours. One should be cautious when interpreting amino acid assay results, as elevated levels of phenylalanine, tyrosine, and methionine are frequently observed in conditions accompanied by severe liver damage.

Comments: AFP is a marker of bile duct proliferation; in HT 1B it is elevated tens of times, and in children with HT 1A even thousands of times. AFP is a nonspecific but highly sensitive indicator; if its level is normal, the diagnosis of HT 1 is doubtful. Normally in children aged 0 to 3 months, the AFP concentration is <1000 ng/mL; from 3 months to 18 years, the AFP concentration is <12 ng/mL.

Another marker is an elevated concentration of δ-aminolevulinic acid, since succinylacetone inhibits δ-aminolevulinic acid dehydratase in the liver and erythrocytes. Normally, the content of δ-aminolevulinic acid in a single urine sample is <34 µmol/L (conversion formula <4.5 mg/L × 7.626), and in 24-hour urine, from 11.4 to 57.2 µmol/day (1.5–7.5 mg/day).

An elevated concentration of δ-aminolevulinic acid is also noted in acute porphyrias (acute intermittent, variegate, congenital coproporphyria), lead poisoning, and aminolevulinate dehydratase deficiency (homozygotes). A moderate elevation may be observed in diabetic ketoacidosis, pregnancy, porphyria cutanea tarda, and the intake of certain anticonvulsants.

Comments: frequent pathogenic variants include: c.554-1G>T, c.1062+5G>A, c.1025C>T (Pro342Leu), c.1090G>C (Glu364Gln).

Comments: The blood shows a moderately elevated level of transaminases (2–3 times or more), a high level of gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP), which are signs of intrahepatic cholestasis. In HT 1A, moderate intrahepatic cholestasis is observed; in HT 1B, cholestasis can be dissociated: with a normal bilirubin level, there is a high level of GGT as well as alkaline phosphatase (ALP), the elevation of which may be a manifestation of acute rickets.

In the presence of a rickets-like disorder, ALP activity exceeds the normal limit by 5 times or more. The severity of tubulopathy is determined by electrolyte imbalance and manifests as low levels of calcium and phosphorus in blood serum. Fanconi syndrome can be either complete or incomplete; it is optimally determined by the calcium/creatinine and phosphorus/creatinine ratios in a single (second) portion of urine, which may be false-negative when blood levels of these electrolytes are low. Signs of Fanconi syndrome include glucosuria, generalized aminoaciduria, renal tubular acidosis, and phosphaturia. Secondary hyperparathyroidism is associated with hypocalcemia, hypophosphatemia, and corresponding calcium and phosphaturia [1,4,7,9].

Comment: A coagulogram is necessary to detect vitamin K–dependent coagulopathy, which is characterized by a deficiency of all hepatic coagulation factors (II, V, VII, X, IX, XI, XII), prolongation of prothrombin time and activated partial thromboplastin time (aPTT), a decrease in the prothrombin index, fibrinogen, and antithrombin III. Coagulopathy is more common in acute tyrosinemia (HT 1A), proceeds significantly more severely than in other liver diseases, while transaminase activity and bilirubin changes may be moderate and not correspond to the severity of the child's condition [1,4,7,9,10].

Level of Evidence 5 (Grade of Recommendations – C)

Comments: diseases that require differential diagnosis include: type 1 galactosemia, fatty acid oxidation disorders, mitochondrial hepatopathies, urea cycle disorders, Wilson's disease, oncological liver diseases, and other conditions accompanied by cholestasis syndrome. The choice of tests is individual depending on the clinical situation.

2.4 Instrumental Diagnostics

Level of Evidence 5 (Grade of Recommendations – C)

Comments: Visualization of the liver parenchyma usually begins with an ultrasound examination, which is the primary imaging method, preferably supplemented by Doppler ultrasound and, if possible, elastometry. All patients with suspected HT1 should also undergo a renal ultrasound. Follow-up liver and kidney ultrasound scans should be performed every 6 months in the presence of steadily declining AFP levels. If nodules (both hyperechoic and hypoechoic) are detected in the liver, further imaging should be performed, preferably using MRI. However, there is no single ideal method. To some extent, the choice of method will depend on available resources and means.

The presence of a focal or multifocal parenchymal lesion in HT1 is already an indication for considering liver transplantation. There is no need for emergency surgery in cases of diffuse liver changes or cirrhosis without nodules, as treatment with nitisinone leads to the regression of cirrhosis and makes it possible to delay transplantation.

If the parenchyma shows diffuse hyperechogenicity and heterogeneity, but without mass lesions and with normal AFP levels, dynamic evaluation is indicated according to the monitoring schedule every 6 months [1,10-13]

If hypoechoic rounded formations (regenerative nodules) or other high-density formations suspicious for adenoma, carcinoma, or hemangioma appear, as well as upon additional imaging, the frequency of AFP testing increases to every 3 months. Discs or images of previous examinations should always be available for comparative evaluation with the current study. All patients must undergo an ultrasound examination of not only the liver, but also the kidneys. If nodules are present in the liver, further imaging should be performed, preferably using contrast-enhanced MRI.

Level of evidence — 5 (grade of recommendation C).

Comments: color Doppler can be used to assess liver vessels and portal hypertension. However, not all nodules may be detected, and the effectiveness of the method depends on the specialist's expertise. Multi-detector CT scanning is fast and provides multiplanar visualization with good spatial resolution of liver abnormalities. Contrast enhancement can improve detail from 66% to 82%, allowing the detection of malignant changes [14,17,18]. Nevertheless, a risk-benefit analysis is mandatory to avoid radiation exposure in children already at risk for malignancy, which requires reassessment. Sedation is sometimes required, which also limits the examination.

Level of evidence — 5 (grade of recommendation C).

Comments: Elastometry is an optimal non-invasive ultrasound method for the quantitative assessment of liver tissue density (computed tomography of the abdominal organs and/or magnetic resonance imaging of the abdominal organs serves as an alternative).

Level of evidence — 4 (grade of recommendation C).

Comments: These imaging methods are necessary to rule out malignancy, for example, when hepatocellular carcinoma is suspected, the risk of which is very high when AFP levels exceed the normal range by hundreds or even thousands of times. The choice is between CT or contrast-enhanced MRI. Affected hepatocytes do not accumulate the contrast agent. Pediatric age is not a direct contraindication to the study, but it limits its application. Time frames: arterial phase 10–20 sec, portal vein enhancement at 60–80 sec, and hepatic veins at 3–5 min. Following intravenous administration of the contrast agent, dynamic sequences allow for the analysis of nodule vascularization. Diffusion-weighted imaging can help differentiate well-differentiated hepatocellular carcinomas from benign nodules

Level of evidence — 4 (grade of recommendation C).

Comments: The method combines visualization with functional assessment. Impaired intracellular transport, excretion of the radiopharmaceutical (RP) with bile, pathways of its elimination from the body, including liver/spleen redistribution on static hepatoscintigraphy, and hyperfixation of the RP in the spleen exceeding 15% are signs of portal hypertension. Areas of decreased uptake represent fatty and connective tissue, cysts, adenoma (benign tumor), and regenerative nodules with decreased vascularization.

Renoscintigraphy allows for the differentiated evaluation of the function of the right and left kidneys.

Level of evidence — 5 (grade of recommendation C).

Comments: The diagnosis of HT1 is not morphologically verified because the changes are non-specific—fatty degeneration, bile duct proliferation, multinucleated hepatocytes, connective tissue proliferation, and the formation of pseudolobules.

Level of evidence — 4 (grade of recommendation C).

Comments: The study is performed in patients with signs of tubulopathy: altered laboratory parameters, rickets-like bone deformities. X-ray densitometry is generally prescribed for children older than 5 years.

Level of evidence — 5 (grade of recommendation C).

Comments: Including for the assessment of bone age. Radiographic determination of bone age is prescribed for children older than 2 years.

Level of evidence — 4 (grade of recommendation C).

Comments: These methods allow for the assessment of the morphofunctional state of the heart and are also necessary when examinations are performed under sedation.

2.5 Other Procedures

Comments: initial and follow-up consultations are indicated with a medical geneticist, ophthalmologist, neurologist, dietitian, gastroenterologist, pediatric surgeon, transplant surgeon, endocrinologist, cardiologist, pediatric cardiologist, trauma surgeon/orthopedist, nephrologist, pediatrician, general practitioner, as well as other specialists for patients with HT1 [1,4].

2.6. Differential Diagnosis

Level of Evidence 5 (Grade of Recommendations – C)

Comments: Acute HT1 should be differentiated from other inherited metabolic disorders, especially in the presence of a concomitant septic condition resistant to broad-spectrum antibiotic therapy. Virus-associated diseases (herpes viruses: cytomegalovirus, Epstein-Barr virus, human herpesvirus types 1, 2, and 6), and TORCH infections do not rule out the presence of type 1 HT1 [1,4,11].

Diagnostic evaluation for hepatomegaly and hepatitis must rule out galactosemia, fructosemia, fructose intolerance, Niemann-Pick disease, Wilson's disease, neonatal hemochromatosis, hemophagocytic lymphohistiocytosis, mitochondrial cytopathy, congenital disorders of glycosylation, transaldolase deficiency, acetaminophen (paracetamol) poisoning, infections (sepsis, salmonellosis, tuberculosis, herpes virus infection, including cytomegalovirus infection, viral hepatitis A and B), mushroom poisoning, and herbal medications. Generalized aminoacidemia is a frequent sign of liver failure and impaired assimilation function [1,4,6,7].

Renal involvement in HT1 should be differentiated from cystinosis, Lowe syndrome (oculocerebrorenal dystrophy), renal tubular acidosis, and Fanconi syndrome. In the presence of rickets-like skeletal changes, it is recommended to rule out hypophosphatasia (low serum alkaline phosphatase and phosphorus levels), vitamin D deficiency (nutritional and genetically determined), and Fanconi syndrome [1,4,9].

Neurological crises should be differentiated from manifestations of cerebral edema and hemorrhage, bacterial meningitis, hypernatremic dehydration, and acute intermittent porphyria [1,4,9].

In isolated hypertyrosinemia, dietary errors (excessive dietary protein intake) should be ruled out, as this is accompanied by transient tyrosinemia and functional deficiency of the FAH enzyme. Types II and III tyrosinemias, as well as other liver diseases with impaired synthetic and detoxifying functions, should also be ruled out [1,2,8].

Syndrome-based differential diagnosis is presented in Appendix A3.2.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

The mainstay of treatment is pathogenetic therapy combined with a low-protein diet and specialized amino acid-based formulas free of tyrosine and phenylalanine.

• For the treatment of HT1, lifelong pathogenetic therapy with nitisinone** (NTBC, 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione) is recommended for all patients [2,8,9,10, 31].

Level of evidence — 5 (grade of recommendation C).

Comments: For greater treatment efficacy, it is advisable to use nitisinone** at the stage preceding the development of hepatocellular carcinoma. The mechanism of action of the drug is that it blocks 4-hydroxyphenylpyruvate dioxygenase and prevents the formation of toxic end metabolites. Meanwhile, serum tyrosine levels increase, which is a strict indication for restricting natural dietary protein, and consequently phenylalanine (as a precursor of tyrosine) and tyrosine in the diet. Protein deficiency is compensated for by prescribing a specialized diet with restriction of these amino acids.

The dose of nitisinone** is selected individually depending on efficacy, which is assessed by the levels of succinylacetone in urine and blood, and serum tyrosine levels. The acute form of tyrosinemia (HT1A) requires nitisinone** at a dose of 2 mg/kg; as the child grows and body weight increases, the dose is reduced to 1 mg/kg [40].

The maintenance therapeutic dose for HT1A is 1 mg/kg/day; for HT1B, the starting dose is 1-1.5 mg/kg/day. If the tyrosine level is less than 600-800 µmol/L, the daily dose is administered orally in one or two doses. The half-life is 54 hours, which allows for a single daily dose. Dose adjustment of nitisinone** is carried out depending on biochemical parameters and the child's weight gain. About 10% of patients do not respond to nitisinone** therapy, as determined by the results of biochemical monitoring (urine succinylacetone, liver function tests, alpha-fetoprotein [AFP]). Such patients are potential candidates for liver transplantation.

If bilirubin levels are high (>100 µmol/L) and acute liver failure is combined with hyperammonemia (>100 µmol/L), the need for emergency liver transplantation cannot be ruled out.

A decrease in succinylacetone levels during nitisinone** therapy occurs within 24 hours, while amino acid concentrations (tyrosine and phenylalanine) increase depending on the amount of natural dietary protein. AFP decreases slowly depending on initial concentrations and does not always reach normal values.

It is necessary to increase the nitisinone** dose to 2 mg/kg/day if there is no positive trend in coagulogram parameters and urine succinylacetone levels within 2 weeks, while blood tyrosine levels remain high (above 800 µmol/L). Nitisinone** treatment must be continuous. During therapy with the drug, tyrosine concentration increases, and treatment interruptions threaten the development of tyrosinemic crises (porphyria-like neurological crises, malignancy). The recommended plasma NTBC concentration is 30-50 µmol. Obese children require maintaining a slightly lower drug concentration per 1 kg of weight, on average 35 mg/m²/day. Treatment efficacy depends on the timing of diagnosis and timely initiation of treatment. In 90% of patients receiving nitisinone**, liver failure becomes controllable, and extrahepatic manifestations are generally resolved. Global experience with nitisinone** (NTBC) in children who started treatment before 2 months of age has shown that the risk of developing hepatocellular carcinoma decreases from 40 to 5% [1,4,9, 40].

Level of evidence — 4 (grade of recommendation C).

Comments: The requirement for other essential amino acids is met by prescribing specialized formulas free of tyrosine and phenylalanine, which allows for an increased protein intake quota, achieving normal growth and development of the child, as well as lowering serum tyrosine concentration and reducing the frequency and severity of potential side effects.

Therapeutic nutrition calculations (in the presence of nitisinone therapy) for infants in the first year of life are based on a protein requirement close to the physiological level (2.2 – 2.3 g/kg of body weight per day); data are given in Table 2, Appendix A3.3. At least 50%-60% of the daily protein requirement is met by a specialized amino acid formula (Table 1, Appendix A3.3), and the remaining part (40-50%) is compensated by protein from expressed breast milk or a low-protein infant formula (1.2-1.3 g of protein per 100 ml of reconstituted formula), and after 4 months also by low-protein complementary foods (vegetable and fruit purees, milk-free porridges with a protein content of no more than 0.5 g per 100 ml of prepared porridge, specialized starch-based low-protein products such as sago, etc.). When prescribing a low-tyrosine and low-phenylalanine diet, minimum requirements for these amino acids are targeted (Table 3, Appendix A3.3). Caloric deficiency of the therapeutic diet is compensated by adding fats (vegetable oil, but no more than 3.5-4 g of total fat per kg of body weight per day) and increasing the carbohydrate quota by adding the aforementioned low-protein products, as well as 5% glucose. The therapeutic diet for patients older than one year is structured similarly, with total protein calculated based on safe protein requirements (no more than 1.5-1.8 g/kg of body weight per day).

If immediate initiation of nitisinone** therapy is not possible, the principles of diet therapy organization remain the same, but protein restrictions are stricter. Calculations are based on the minimum protein requirements per kg of body weight per day (in the first year of life – 1.5 mg/kg of body weight; in children over one year – from 1.5 to 1.2 g/kg of body weight). To balance the daily diet, natural low-protein and specialized starch-based products, as well as vegetable oils, are used; it is advisable to take into account the content of pathogenetically significant amino acids in these products. Lifelong adherence to a diet low in phenylalanine and tyrosine is necessary; in the acute period, the amount of total protein is reduced to 1.2-1.5 g/kg of body weight until the succinylacetone content in urine and/or blood normalizes. An example of nutrition calculation and daily food set are presented in Tables 3-4. The basic principles of therapeutic nutrition organization, calculation examples, and background materials are presented in Appendix A3.3.

• When treating HT1 patients, it is not recommended to use protein supplements in order to prevent the formation of toxic metabolites [1, 2, 3, 4, 10].

Level of evidence — 4 (grade of recommendation C).

Comments: Blood products are used strictly for vital indications during extracorporeal detoxification methods and plasma exchange; amino acid-based preparations (including hepatoprotectors based on ademetionine, ornithine, etc.) are excluded. Serums may be used in extreme necessity and after the administration of nitisinone**.

Level of evidence — 4 (grade of recommendation C).

Comments: Paracetamol** is excreted via the cytochrome P450 system. Diazepam**, valproic acid preparations, and other drugs with a hepatic route of metabolism can cause overdose and deterioration of the functional state of the liver.

For the pediatric population – Strength of recommendation C (Level of evidence - 5)

For the adult population – Strength of recommendation C (Level of evidence – 4)Comments: crises are caused by the discontinuation of nitisinone** therapy or in untreated patients (see section 1.6).

Patients require careful monitoring; in addition to the mandatory administration of nitisinone**, intravenous correction of electrolyte disorders (hyponatremia), arterial hypertension, and pain, as well as respiratory support up to mechanical ventilation, are carried out

Intravenous administration of 10% dextrose**/sodium chloride** 0.9% solution at doses 1.5–2 times exceeding the normal maintenance rate for the given age may be used as initial therapy, usually in combination with fast-acting antihypertensive agents and pain relief therapy. Sometimes intravenous boluses of 2% sodium chloride are required to treat recurrent hyponatremia.

With regular nitisinone** therapy, crises do not develop. Neurological crises in both infants and older children have been observed after short-term discontinuation of nitisinone** (>1 month) without other overt signs of HT-1 disease (changes in AFP, liver function tests including PT/aPTT, phosphates, acidosis). This once again emphasizes the importance of continuous compliance and laboratory monitoring of plasma NTBC levels [31].

Similarly to acute porphyria, #hemin 3 mg/kg for 3 days may also be used, among other treatments [43].

The patient should start receiving a standard diet with restriction of phenylalanine and tyrosine within 24 to 48 hours from the onset of the crisis [42].

3.2 Surgical Treatment

• In case of a progressive course of the pathological process in the liver, liver transplantation is recommended for patients with HT1 for the purpose of radical treatment of the disease [4, 7, 8, 31].

Level of evidence — 5 (grade of recommendation C).

Comments: In a state of acute liver failure, liver transplantation is performed provided that the coagulation profile does not improve after 1 week of treatment. In a state of chronic liver failure, the indication for liver transplantation is hepatocellular carcinoma, specifically a relapse of elevated alpha-fetoprotein levels and/or decompensation of liver cirrhosis, where various visualization methods (MRI, CT) are predominant, along with the appearance of nodes greater than 10 mm in diameter and an increase in their number. Biopsy of the nodes should be avoided due to the risk of metastasis. The decision on liver transplantation is made by a medical board.

Liver transplantation is an effective method of treating hereditary tyrosinemia when conservative therapy is impossible and when malignant formations develop in the liver [13,17,19].

Indications for liver transplantation in HT1 are:

1. Diagnosed HCC.

2. Appearance of focal lesions on MRI or CT and a relapse of AFP increase during nitisinone treatment in the chronic course of HT1.

3. Lack of effect from NTBC therapy in acute tyrosinemia, consisting of persistent hypocoagulation despite vitamin K therapy.

4. Decompensated cirrhosis complicated by ascites, hypocoagulation, patient dependence on albumin infusions, signs of encephalopathy, hyperammonemia, when there is no time to wait for the effect of NTBC.

Unlike patients with HCC without concomitant metabolic disease, patients with HT1 combined with HCC must be moved to the priority waiting list for transplantation; a wait-and-see strategy is not permitted.

In addition, it must be emphasized that even a technically resectable tumor (HCC, adenoma, hemangioma, cholangiocarcinoma) in a patient with HT1 requires liver transplantation, the urgency of which is determined by the malignancy of the neoplasm.

Patient survival after transplantation does not depend on the origin of the graft; a living related donor organ and a cadaveric organ are practically equivalent in 3-year survival, which is 75.5% and 78.9% respectively (according to an analysis from 2002 to 2012 of 2,103 living and 46,674 cadaveric transplantations) [15,16]. In recent years, split-liver transplantation has been gaining popularity, allowing one donor organ to be used for two recipients.

Level of evidence — 4 (grade of recommendation C).

• During any surgical interventions in patients not receiving NTBC, it is recommended to avoid the use of barbiturate premedication because these drugs can provoke porphyria-like crises [26, 27].

Level of evidence – 4 (strength of recommendation C).

3.3 Other Treatment

Not used

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Level of evidence — 5 (grade of recommendation C).

5. Prevention and Dispensary Observation

5.1. Prevention

• Families having a child with HT1 are recommended a consultation with a geneticist to determine genetic risks for the family and the prognosis for offspring [31].

Level of evidence — 5 (grade of recommendation C).

Comments: As with other autosomal recessive diseases, in HT1 the risk of having a child with the condition is 25% for each pregnancy. In families with a child with tyrosinemia, prenatal and preimplantation diagnostics are available. Prenatal diagnosis of HT1 is possible using direct or indirect DNA diagnostics on DNA samples extracted from chorionic villus sampling at 9-11 weeks of pregnancy and/or amniotic fluid cells at 20-22 weeks of pregnancy

Level of evidence — 5 (grade of recommendation C).

Comments: it is advisable to carry out vaccination with the participation of specialists experienced in working with patients with metabolic diseases, or under their supervision.

5.2. Dispensary follow-up

Level of evidence — 5 (grade of recommendation C).

Comment: the monitoring plan aims both to prevent complications of HT1 and to control side effects and ensure early diagnosis of HT1 complications, primarily HCC.

Comments: study of blood amino acid concentrations: at the start of therapy, then frequency in the first 6 months is 1 time per month, after the first 6 months and thereafter 1 time every 3 months; study of succinylacetone in urine: at the start of therapy, then frequency in the first 6 months is 1 time per month, after the first 6 months and thereafter 1 time every 6 months.

Comments: according to international guidelines, the optimal level is considered to be from 40 to 60 µM.

Performed at the start of therapy, then the frequency in the first 6 months is 1 time per month, after the first 6 months and thereafter 1 time every 6 months

Comments: Performed at the initiation of therapy, then at a frequency of once a month for the first 6 months, and every 6 months thereafter.

Level of Evidence 5 (Grade of Recommendations – C)

Comment: performed at the initiation of therapy, once a month (for the first 6 months), and subsequently once a year during long-term therapy.

Comments: Performed at the initiation of therapy, once a month (for the first 6 months), and subsequently at least once a year during long-term therapy.

Comments: Performed at the initiation of therapy, once a month (for the first 6 months), and subsequently, on average, once a year during long-term therapy.

Comments: Performed at the initiation of therapy, once every 3 months (for the first 6 months), and subsequently at least once a year during long-term therapy.

Comments: Patients with HT1 remain at high risk for malignancies, including during therapy and partially after liver transplantation. These risks can be significantly reduced to below 1% if NTBC treatment is initiated in early childhood and continued without interruption. Lifelong monitoring for these hepatic complications in HT1 is mandatory. It is performed at least once a year.

Level of evidence — 5 (grade of recommendation C).

Comments: Color Doppler can be used to assess hepatic vessels and portal hypertension. However, not all nodules can be detected, and the efficacy of the method depends on the operator's experience. Multi-detector CT scanning is fast and provides multiplanar visualization with good spatial resolution of liver anomalies. Contrast enhancement can improve detail from 66% to 82%, allowing the detection of malignant changes [14, 17, 18]. Nevertheless, a risk-benefit analysis is mandatory to avoid radiation exposure in children already at risk for malignancy, thus requiring reassessment. Sedation is sometimes required, which also limits the study.

Level of evidence — 5 (grade of recommendation C).

Comments: Fibroelastography is an optimal non-invasive ultrasound method for quantitative assessment of liver tissue stiffness and helps determine treatment efficacy. Frequency: annually (alternative options include abdominal computed tomography and/or abdominal magnetic resonance cholangiopancreatography [MRCP]).

Level of evidence — 5 (grade of recommendation C).

Comments: These imaging modalities are necessary to rule out malignancy, for example, when hepatocellular carcinoma is suspected—a risk that is extremely high when AFP levels are hundreds or even thousands of times above normal. The choice is between contrast-enhanced CT or MRI, with gadoxetic acid (trade name Primovist) being the agent of choice for MRI. Affected hepatocytes do not accumulate the contrast agent. Pediatric age is not an absolute contraindication to the scan, but it limits its use. Timing parameters: arterial phase at 10–20 seconds, portal venous enhancement at 60–80 seconds, and hepatic veins at 3–5 minutes. Following intravenous administration of gadoxetic acid, dynamic sequences allow for the analysis of nodular vascularity. Diffusion-weighted imaging can help differentiate differentiated hepatocellular carcinomas from benign nodules. Indicated at the start of therapy and subsequently once a year.

Level of evidence — 4 (grade of recommendation C).

Comments: This method combines imaging with functional assessment. Impaired intracellular transport and biliary excretion of the radiopharmaceutical, its elimination pathways from the body, as well as liver/spleen redistribution on static hepatoscintigraphy and radiopharmaceutical hyperfixation in the spleen exceeding 15%, are signs of portal hypertension. Areas of decreased uptake represent fatty and connective tissue, cysts, adenomas (benign tumors), or regenerative nodules with reduced vascularity.

Renoscintigraphy allows for the differential evaluation of the function of the right and left kidneys. The frequency is determined individually.

Level of evidence — 5 (grade of recommendation C).

Comments: The study is performed in patients with signs of tubulopathy: abnormal laboratory values and rickets-like bone deformities. Densitometry is generally prescribed for children older than 5 years. It is performed at the initiation of therapy and subsequently based on clinical indications, on average once a year.

Level of evidence — 5 (grade of recommendation C).

Comments: Including for the assessment of bone age. Radiographic determination of bone age is indicated for children older than 2 years.

Level of evidence — 5 (grade of recommendation C).

Comments: Indicated prior to planned orthopedic interventions. Targeted chest X-ray is indicated when procedures are performed under general anesthesia, or in the presence of clinical manifestations of respiratory failure or cardiomyopathy.

Level of evidence — 4 (grade of recommendation C).

Comments: These methods allow for the evaluation of the morphofunctional state of the heart and are also required when procedures are performed under general anesthesia. The frequency is determined individually.

Level of evidence — 4 (grade of recommendation C).

Comments: The following blood parameters must be monitored: acid-base balance, liver function tests (bilirubin, ALT, AST, GGT - gamma-glutamyl transpeptidase, alkaline phosphatase, albumin), coagulogram (PTI, APTT, fibrinogen), urea, electrolytes, creatinine, calcium, phosphorus, complete blood count, amino acid profile, AFP, succinylacetone, and if possible, NTBC concentration; in acute liver failure, additionally determine ammonium and glucose; as well as urine parameters: glucose, amino acids, phosphorus and calcium/creatinine ratios, albumin, protein, beta-2-microglobulin.

Subsequently, after normalization of the parameters, the interval between tests should be at least 6 months.

Level of evidence — 4 (grade of recommendation C).

Comments: Blood folates are monitored in case of blood coagulation disorders and for the differential diagnosis of coagulopathies.

Level of evidence — 4 (grade of recommendation C).

Comments: The examination should be performed before starting pharmacotherapy and monthly for half a year after initiating treatment, as nitisinone** may cause adverse effects such as conjunctivitis, corneal opacity, keratitis, photophobia, reversible leukopenia, granulocytopenia, and thrombocytopenia. Leukocytosis, blepharitis, pruritus, exfoliative dermatitis, and erythematous rash are less common. After the first 6 months, the frequency is based on clinical indications, on average once a year.

Comments: Dietary therapy is adjusted by medical geneticists or dietitians at a frequency of once a month during the 1st year of life, then once every 3 months and as clinically indicated up to 3 years of age; once every 6 months after 3 years of age

Comments: indicated are initial and follow-up consultations by a medical geneticist, ophthalmologist, neurologist, orthopedist, gastroenterologist, endocrinologist, cardiologist, pediatric cardiologist, nephrologist, pediatrician, general practitioner (therapist), transplantologist, as well as specialists in other fields for HT1 patients with impaired functions of the respective organs and systems

Comments: Parents of the child must always have an information sheet outlining emergency measures during the onset of a metabolic crisis.

6. Organization of Medical Care

HT1 patients may be provided with any type, setting, and form of medical care stipulated by the legislation of the Russian Federation, as clinically indicated.

Indications for hospital admission to a medical organization:

1. provision of diagnosis and treatment requiring prolonged medical observation and monitoring of clinical and laboratory parameters (day-care or inpatient setting), preparation for liver transplantation, and liver transplantation;

2. the need for various types of expert evaluations or medical examinations in a medical institution when they cannot be performed in an outpatient setting (including issuing a federal consilium or medical commission conclusion);

3. acute life-threatening conditions and conditions that may develop severe complications requiring emergency treatment, including intensive care, as well as 24-hour medical supervision and special diagnostic and therapeutic procedures.

Indications for discharging a patient from a medical organization:

1. absence of a threat to the patient's life and risk of complications requiring emergency treatment upon completion of diagnostic procedures.

2. stabilization of the patient's condition and main clinical and laboratory parameters of the pathological process, no need for prolonged medical supervision (day or inpatient care);

3. completion of the patient's diagnostic and treatment plan, with recommendations provided for further follow-up and management.

4. need to transfer the patient to another medical facility or social care institution.

The duration of hospitalization depends on the speed of diagnosis verification and the initiation of specific therapy. A response to nitisinone treatment is observed within the first few days. The duration of hospitalization also depends on the rate of recovery of coagulation parameters and is typically 30 days.

7. Additional Information

In children older than one year, prior to diagnosis, the most frequent reason for admission to a surgical department is suspected hepatitis or a liver mass; they are also referred to oncologists, infectious disease specialists, and pediatric gastroenterologists-hepatologists.

Carrying out differential diagnosis, establishing a diagnosis, and prescribing specific therapy shortens the hospital stay. With nitisinone therapy, the duration of inpatient treatment usually does not exceed 14 days. Patients with stable metabolic monitoring indicators and alpha-fetoprotein (AFP) levels can be managed in outpatient settings and day care units (with a hospital stay of at least 10 days).

Abdominal ultrasound should be performed every 6 months, and liver magnetic resonance imaging (MRI) annually; if suspicious nodular lesions are detected, contrast-enhanced imaging methods (CT, MRI, radioisotope scanning) are indicated to confirm hepatocellular carcinoma. Alpha-fetoprotein levels should be monitored every 3–6 months, and a secondary rise in AFP should prompt a comprehensive workup for HCC. Consultation with an oncologist is indicated.

Monitoring of nitisinone therapy includes determining blood phenylalanine and tyrosine levels. If phenylalanine levels are low (less than 20 µmol/L), dietary protein intake must be increased. Tyrosine levels should ideally be maintained in the range of 200–400 µmol/L to prevent adverse effects. Adverse effects such as photophobia and a sensation of "grit in the eyes" occur when serum tyrosine concentrations rise above 800 µmol/L and are caused not so much by the action of nitisinone as by dietary non-compliance and poor parental adherence.

Illness in children presenting with liver failure often has an extremely severe course with marked coagulopathy and ascites. The administration of nitisinone leads to clinical improvement within a few days, with 90% of patients responding to therapy. If the coagulogram does not improve within 1 week, the dose of nitisinone should be increased. With treatment, in the majority of children with clinical manifestations of cirrhosis and portal hypertension, therapy leads to compensation and even regression of cirrhotic changes.

Renal tubular function normalizes, and urinary losses of calcium and phosphorus cease.

Nitisinone treatment during the first 3 months of life prevents the development of cardiomyopathy; when therapy is initiated later, its course improves regardless of the disease form.

The use of nitisinone ensures the complete resolution of porphyria-like neurological crises.

Nitisinone therapy shifts the HT-1 phenotype to the tyrosinemia type II phenotype (see Appendix A3.1). The natural course of type II tyrosinemia, which represents a genetic deficiency of 4-hydroxyphenylpyruvate dioxygenase, is extremely rare and poorly described in literature, but intellectual disability is a well-known component of this disease's clinical spectrum.

Treatment of tubulopathy (Fanconi syndrome) and vitamin D-resistant rickets is most effective at early stages and includes, in addition to NTBC, the administration of active vitamin D metabolites (calcitriol^**), calcium preparations, and dibasic phosphates. Evaluation includes determining acid-base status (blood pH, standard bicarbonates, base deficit).

The combination of aminoaciduria, glucosuria, phosphaturia, and renal tubular acidosis indicates complete Fanconi syndrome and leads to severe rickets, nephrocalcinosis, glomerulosclerosis, and chronic kidney disease.

Without nitisinone treatment, the vast majority of children die before the age of 15; the age of onset is the decisive prognostic factor, meaning that children with acute and subacute tyrosinemia (HT1A) die before 1 year of age. The use of nitisinone without pathogenetic dietary therapy also leads to the slow progression of liver and kidney dysfunction, as well as musculoskeletal changes.

Criteria for Evaluating the Quality of Medical Care

Table 1. Quality assessment criteria for primary health care provided to adults and children with hereditary tyrosinemia type 1 (ICD-10 codes: E70.2)

Table 2. Criteria for assessing the quality of specialized medical care for adults and children with hereditary tyrosinemia type 1 (ICD-10 codes: E70.2)

References

Appendix A1. Working Group Composition

1. Anisimova Inga Vadimovna, PhD in Medical Sciences, Head of the Medical Care Organization Department, Medical Geneticist at the Research Centre for Medical Genetics (Bochkov RSCMG), Member of the Association of Medical Geneticists

2. Bagaeva Madlena Enverovna, PhD in Medical Sciences, Senior Researcher at the Department of Pediatric Gastroenterology, Hepatology and Dietology of the Clinic at the Federal Research Centre of Nutrition and Biotechnology

3. Baydakova Galina Viktorovna, PhD in Biological Sciences, Leading Researcher at the Laboratory of Inherited Metabolic Diseases, Research Centre for Medical Genetics, member of the Russian Society of Medical Geneticists.

4. Baranov Alexander Alexandrovich, Academician of the RAS, Professor, Doctor of Medical Sciences; Honorary President of the Union of Pediatrists of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health of the National Medical Research Centre No. 2 (Petrovsky National Research Centre of Surgery), Professor at the Department of Pediatrics and Pediatric Rheumatology of the Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Chief freelance pediatric specialist of the Ministry of Health of Russia

5. Bushuyeva Tatiana Vladimirovna, Doctor of Medical Sciences, National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation,

6. Vashakmadze Nato Dzhemberovna, Doctor of Medical Sciences, Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University, Research Institute of Pediatrics and Child Health of the National Medical Research Centre No. 2 (Petrovsky National Research Centre of Surgery), Member of the Union of Pediatrists of Russia.

7. Gundobina Olga Stanislavovna, PhD in Medical Sciences, Leading Researcher, Gastroenterologist at the Research Institute of Pediatrics and Child Health of the National Medical Research Centre No. 2 (Petrovsky National Research Centre of Surgery), Member of the Union of Pediatrists of Russia

8. Degtyareva Anna Vladimirovna, Doctor of Medical Sciences, Professor, Highest Category Physician, Head of the Pediatrics Department, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

9. Zhurkova Nataliya Vyacheslavovna, PhD in Medical Sciences, Leading Researcher at the Research Institute of Pediatrics and Child Health of the National Medical Research Centre No. 2 (Petrovsky National Research Centre of Surgery), Member of the Union of Pediatrists of Russia, Member of the Association of Medical Geneticists (AMG) mailto:annadim@yahoo.com

10. Zakharova Ekaterina Yuryevna, Doctor of Medical Sciences, Head of the Laboratory of Hereditary Metabolic Diseases at the Research Centre for Medical Genetics (Bochkov RSCMG), Member of the Russian Society of Medical Genetics, Member of the Society for the Study of Inborn Errors of Metabolism (SSIEM).

11. Kondakova Olga Borisovna, PhD in Medical Sciences, Medical Geneticist at the National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation

12. Kutsev Sergey Ivanovich, Academician of the RAS, Doctor of Medical Sciences, Director of the Research Centre for Medical Genetics (Bochkov RSCMG), President of the Association of Medical Geneticists.

13. Lavrova Alla Evgenyevna, Doctor of Medical Sciences, Chief Researcher, Physician of the Highest Qualification Category in Pediatrics, Head of the 2nd Pediatric Department, Privolzhsky Research Medical University of the Ministry of Health of the Russian Federation

14. Mikhaylova Svetlana Vitalievna, Doctor of Medical Sciences, Head of Department at the Russian Children's Clinical Hospital of the Ministry of Health of the Russian Federation.

15. Movsisyan Goar Borisovna, PhD in Medical Sciences, Physician at the Gastroenterology Department of the National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation

16. Nazarenko Lyudmila Pavlovna, Professor, Doctor of Medical Sciences, Deputy Director for Research and Clinical Work, Head of the Laboratory of Hereditary Pathology at the Research Institute of Medical Genetics, Tomsk National Research Medical Center of the RAS, Member of the Association of Medical Geneticists (AMG).

17. Namazova-Baranova Leyla Seymurovna, Academician of the RAS, Professor, Doctor of Medical Sciences, President of the Union of Pediatrists of Russia; Past President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health of the National Medical Research Centre No. 2 (Petrovsky National Research Centre of Surgery), Head of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Chief freelance pediatric specialist in preventive medicine of the Ministry of Health of Russia

18. Nikolaeva Ekaterina Alexandrovna, Doctor of Medical Sciences, Professor, Member of the Russian Society of Medical Genetics

19. Pashkova Irina Evgenyevna, PhD in Medical Sciences, Head of the Pediatric Department at the Shumakov National Medical Research Center of Transplantology and Artificial Organs

20. Pervunina Tatiana Mikhailovna, PhD in Medical Sciences, Director of the Institute of Perinatology and Pediatrics, Almazov National Medical Research Centre of the Ministry of Health of the Russian Federation mailto:ptm.pervunina@yandex.ru

21. Pechatnikova Natalia Leonidovna, Neurologist, Head of Department, Morozovskaya Children's City Clinical Hospital of the Moscow Healthcare Department

22. Pogosyan Nelly Sergeevna, Representative of the All-Russian Orphan Disease Society

23. Polyakova Svetlana Igorevna, Doctor of Medical Sciences, Professor at the Department of Hospital Pediatrics named after Academician V.A. Tabolin, Pediatric Faculty, Pirogov Russian National Research Medical University (RNRMU), Moscow

24. Potapov Alexander Sergeevich, Doctor of Medical Sciences, Professor, Gastroenterology Department of the National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Department of Pediatrics and Pediatric Rheumatology of the Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University)

25. Pushkov Alexander Alekseevich, PhD in Biological Sciences, Leading Researcher at the Laboratory of Medical Genomics of the National Medical Research Center for Children's Health of the Ministry of Health of Russia, Member of the Association of Medical Geneticists

26. Repina Svetlana Afanasyevna, PhD in Medical Sciences, Medical Geneticist at the Medical Care Organization Department of the Research Centre for Medical Genetics (Bochkov RSCMG)

27. Savostyanov Kirill Viktorovich, Doctor of Biological Sciences, Head of the Medical Genetic Centre, Head of the Laboratory of Medical Genomics at the National Medical Research Center for Children's Health of the Ministry of Health of Russia, Professor at the Department of Pediatrics and Public Health at the National Medical Research Center for Children's Health of the Ministry of Health of Russia, Member of the Association of Medical Geneticists

28. Seitova Gulnara Narimanovna, PhD in Medical Sciences, Chief Physician of the Medical Genetic Centre (Genetic Clinic) of the Research Institute of Medical Genetics, Tomsk National Research Medical Center of the RAS

29. Sviridova Valeria Valerievna, Medical Geneticist at the Medical Care Organization Department of the Research Centre for Medical Genetics (Bochkov RSCMG), Junior Researcher at the Laboratory of Mutagenesis of the Research Centre for Medical Genetics (Bochkov RSCMG)

30. Selimzyanova Lilia Robertovna, PhD in Medical Sciences, Leading Researcher at the Research Institute of Pediatrics and Child Health of the National Medical Research Centre No. 2 (Petrovsky National Research Centre of Surgery), Associate Professor at the Department of Pediatrics and Pediatric Rheumatology of the Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University)

31. Smirnova Olga Yakovlevna, Medical Geneticist, Senior Researcher at the Department of Standardization and Study of Evidence-Based Medicine Foundations of the Research Institute of Pediatrics and Child Health of the National Medical Research Centre No. 2 (Petrovsky National Research Centre of Surgery), Member of the Union of Pediatrists of Russia, Member of the Association of Medical Geneticists

32. Strokova Tatiana Viktorovna, Doctor of Medical Sciences, Professor of the RAS, Head of the Department of Pediatric Gastroenterology, Hepatology and Dietology of the Clinic at the Federal Research Centre of Nutrition and Biotechnology

33. Subbotin Dmitry Mikhailovich, Medical Geneticist at the Research Centre for Medical Genetics (Bochkov RSCMG), Member of the Association of Medical Geneticists

34. Surkov Andrey Nikolaevich, Doctor of Medical Sciences, Head of the Pediatric Gastroenterology Department of the Pediatric Inpatient Facility, Head of the Department of Scientific Foundations of Pediatric Gastroenterology, Hepatology and Metabolic Disorders at the Research Institute of Pediatrics and Child Health of the National Medical Research Centre No. 2 (Petrovsky National Research Centre of Surgery), Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Member of the Union of Pediatrists of Russia

35. Tepayev Rustem Faridovich, Doctor of Medical Sciences, Head of Anesthesiology and Intensive Care at the National Medical Research Center for Children's Health of the Ministry of Health of Russia, Professor at the Department of Pediatrics and Pediatric Rheumatology of the Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University)

36. Fedoseenko Marina Vladislavovna, PhD in Medical Sciences, Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health Deviations and Chronic Diseases, Leading Researcher, Pediatrician at the Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Centre of Surgery; Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia.

The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• pediatricians;

• general practitioners

• general practitioners (family medicine);

• gastroenterologists;

• medical geneticists;

• dietitians;

• neurologists;

• oncologists;

• pediatric oncologists;

• medical psychologists;

• medical students, interns, residents;

Table 3. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 4. Scale for assessing levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 5. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision — at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012 "On approval of the Procedure for providing pediatric care"

2. Order of the Russian Ministry of Health No. 274n dated April 21, 2022, "On Approval of the Procedure for Providing Medical Care to Patients with Congenital and (or) Hereditary Diseases"

3. State Register of Medicines: https://grls.rosminzdrav.ru

Main regulatory and legal acts governing the provision of

palliative medical care

1. Federal Law No. 18-FZ dated March 6, 2019, "On Amendments to the Federal Law 'On the Basics of Protecting the Health of Citizens in the Russian Federation' Regarding the Provision of Palliative Medical Care."

2. Order of the Russian Ministry of Health No. 345n, Russian Ministry of Labor No. 372n dated May 31, 2019, "On approval of the Regulations on the organization of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations, and other non-profit organizations operating in the field of health protection."

3. Order of the Russian Ministry of Health No. 348n dated May 31, 2019, "On approval of the list of medical devices intended to maintain human organs and body systems, provided for home use."

4. Order of the Russian Ministry of Health No. 505n dated July 10, 2019, "On approval of the Procedure for the transfer by a medical organization to a patient (their legal representative) of medical devices intended to maintain the functions of human organs and body systems for home use in the provision of palliative medical care."

5. Order of the Ministry of Health of the Russian Federation No. 831 dated October 3, 2019, "On Approval of the Departmental Target Program 'Development of the Palliative Medical Care Delivery System'."

Other regulatory and legal documents used in the development of the clinical guidelines:

1. Federal Law No. 323-FZ dated November 21, 2011, "On the Basics of Protecting the Health of Citizens in the Russian Federation" (Collected Legislation of the Russian Federation, 2011, No. 48, Art. 6724);

2. International Statistical Classification of Diseases and Related Health Problems (ICD-10);

3. Order of the Ministry of Health of the Russian Federation No. 205n dated May 2, 2023, On approval of the nomenclature of positions of medical workers and pharmaceutical workers.

4. Order of the Ministry of Health of the Russian Federation No. 541n dated July 23, 2010. "Unified Qualification Handbook of Positions of Managers, Specialists, and Employees, Section: Qualification Characteristics of Positions of Healthcare Workers."

5. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'On the Fundamentals of Public Health Protection in the Russian Federation' regarding Clinical Guidelines".

6. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard template of clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in the clinical guidelines."

7. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On approval of the nomenclature of medical services."

8. Order of the Ministry of Labor and Social Protection of the Russian Federation No. 585n dated August 27, 2019 "On Classifications and Criteria Used in Carrying Out Medical and Social Assessment of Citizens by Federal State Medical and Social Assessment Institutions";

9. Order of the Ministry of Health of the Russian Federation No. 1094n dated November 24, 2021 "On approval of the Procedure for prescribing medicinal products, prescription forms for medicinal products, the Procedure for issuing said forms, their accounting and storage, forms of prescriptions containing appointments of narcotic drugs or psychotropic substances, the Procedure for their manufacture, distribution, registration, accounting and storage, as well as the Rules for issuing prescription forms, including in the form of electronic documents"

10. Order of the Ministry of Health and Social Development of the Russian Federation "On the procedure for the use of medicinal products in patients for vital indications" No. 494 dated August 9, 2005

11. List of specialized medical nutrition products for disabled children for 2024, approved by Order of the Government of the Russian Federation No. 3551-r dated December 11, 2023

Examples of diagnosis formulation

• Hereditary tyrosinemia type 1A (acute course) complicated by acute liver failure, vitamin K-dependent coagulopathy, acute posthemorrhagic anemia secondary to catastrophic hemorrhage (overt bleeding from an acute gastric ulcer and intraventricular hemorrhage).

• Hereditary tyrosinemia type 1A (acute course) complicated by liver cirrhosis, vitamin D-resistant rickets, incomplete Fanconi syndrome. Dynamic large bowel obstruction. Sepsis.

• Hereditary tyrosinemia type 1B (chronic course) complicated by liver cirrhosis, portal hypertension, skeletal bone deformities secondary to complete Fanconi syndrome.

• Hereditary tyrosinemia type 1B (chronic course) complicated by hepatocellular carcinoma of the right lobe of the liver and liver fibrosis [1,4,10].

Note legend

** – a medicinal product included in the Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended on June 9, 2023) "On Approval of the List of Vital and Essential Drugs, as well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for the Provision of Medical Care"

# - The use of a medicinal product in accordance with indications (characteristics) not specified in its instructions for use (off-label) is carried out by decision of the medical commission subject to the signed informed voluntary consent (pursuant to Federal Law No. 323-FZ of November 21, 2011, as amended).

*** - a medical device implanted into the human body when providing medical care within the framework of the state guarantees program for free medical care to citizens;

**** - specialized medical nutrition product included in the list of specialized medical nutrition products for disabled children (List of specialized medical nutrition products for disabled children for 2024, approved by Order of the Government of the Russian Federation No. 3551-r dated December 11, 2023).

Appendix A3.1. Scheme of metabolic pathways in type I tyrosinemia.

Fig. 1. Tyrosine metabolic pathways (solid line – normal metabolic pathway, dashed lines – alternative pathway).

Appendix A3.2. Syndromic differential diagnosis of type I tyrosinemia.

Table 6. Differential diagnosis of type I tyrosinemia

Appendix A3.3. Principles of organizing medical nutrition in type I tyrosinemia.

Specialized domestic and foreign products based on amino acids free of phenylalanine and tyrosine, intended for patients of various ages, are registered in the Russian Federation (Table 7). The calculation of the required product quantity is based on the protein equivalent.

Table 7. Chemical composition of specialized medical nutrition products for patients with type I tyrosinemia (per 100 g of dry product)¹

¹-products are registered within the territories of the Customs Union member states and included in the List of specialized products for disabled children pursuant to Order of the Government of the Russian Federation No. 3551-r dated December 11, 2023

Table 8. Recommended protein intake norms for healthy children of various ages [2,3]

Table 9. Permissible amounts of essential amino acids in the diet of children with inherited amino acidopathies [8].

Table 10. Example of nutritional calculation for a 3-year-old child with type I tyrosinemia.

Body weight 14 kg [2].

Table 11. Approximate daily food set, its chemical composition and energy value for young children (1-3 years) with type I tyrosinemia [2].

Appendix A3.4. Blood parameter monitoring plan and frequency of instrumental examinations during combination therapy

Table 12. Laboratory and instrumental parameter monitoring plan during combination therapy

+ - as indicated;

1MRI with contrast is preferred when an adenoma is suspected, when nodules are detected, and to assess kidney size.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Tyrosinemia type I is a hereditary disorder characterized by impaired tyrosine amino acid metabolism, manifesting as intoxication by its metabolic products, liver, kidney, and central nervous system damage.

The acute form of type I tyrosinemia manifests in the first weeks/months of life with febrile fever, vomiting, diarrhea, dehydration, jaundice with hepatosplenomegaly, acute gastrointestinal bleeding, developmental delay, and a specific "cabbage-like" body odor. Chronic type I tyrosinemia proceeds with predominant liver damage (cirrhosis), kidney involvement, and tyrosinemic crises accompanied by fever, vomiting, intoxication, and cardiomyopathy, triggered by protein intake. Chronic tyrosinemia presents with growth retardation, a 3–4 year delay in physiological tooth eruption, and delayed bone age. In the absence of timely diagnosis and treatment, the prognosis is grave.

After diagnosis is established, treatment is prescribed using a drug, which prevents the formation of toxic tyrosine metabolites and diet therapy characterized by dietary protein restriction and the use of specialized amino acid formulas. Treatment is carried out under strict medical supervision. It is extremely critical to strictly follow all medical prescriptions regarding medication intake and diet.

Considering the autosomal recessive inheritance pattern and high risk of recurrence in families with a child with tyrosinemia, medical genetic counseling is indicated.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.