COMPLEX CHARACTERISTICS OF ETIOLOGY AND PATHOGENESIS OF NEONATAL HYPERBILIRUBINEMIA STATES

Аннотация

Pathological hyperbilirubinemia develops due to exacerbation of physiological mechanisms or addition of pathogenetic factors, including: 1) hemolytic conditions (immune conflicts, erythrocyte membranopathies and enzymopathies); 2) polymorphism of genes encoding bilirubin metabolism enzymes; 3) obstructive processes in the biliary system; 4) metabolic and endocrine disorders; 5) infectious and inflammatory diseases with liver damage. Keywords. Neonatal jaundice, hyperbilirubinemia, bilirubin metabolism, UDP- glucuronosyltransferase, hemolysis, liver transport proteins, enterohepatic circulation, genetic polymorphism, bilirubin encephalopathy. Research objective. To study the molecular and cellular foundations of jaundice syndrome development in the neonatal period. Introduction. Jaundice syndrome in the neonatal period represents a unique clinical and biochemical phenomenon, reflecting a complex set of molecular and cellular processes characteristic of postnatal adaptation of the newborn infant. The prevalence of this condition reaches 60-80% among full-term and 80-90% among premature newborns, which determines the high medical and social significance of in-depth study of its formation mechanisms at subcellular and molecular levels. Modern achievements in molecular biology, proteomics, and genomics have significantly expanded our understanding of the fundamental principles of bilirubin metabolism and its regulation in the perinatal period. It has been established that the development of jaundice syndrome in newborns is determined by a cascade of interrelated molecular events, including processes of formation, transport, metabolic transformation, and excretion of bilirubin, each of which is characterized by pronounced age-specific features. Hemoglobin catabolism in the neonatal period has a number of fundamental differences, caused by both accelerated destruction of fetal hemoglobin and peculiarities of the heme oxygenase system functioning. It has been established that the activity of heme oxygenase-1 (HO-1) in monocytes and macrophages of newborns significantly exceeds that in adults, which, combined with increased erythrocyte mass (on average 34% more per kilogram of body weight), contributes to bilirubin production in the volume of 8-10 mg/kg/day compared to 3-4 mg/kg/day in adults. At the molecular level, the transport of unconjugated bilirubin into hepatocytes occurs through several mechanisms, including both passive diffusion and active transport involving 93 OATP (Organic Anion Transporting Polypeptides) carrier proteins, the expression of which in the perinatal period is characterized by ontogenetic regulation. Molecular genetic studies have shown that polymorphism of the SLCO1B1 and SLCO1B3 genes encoding the OATP1B1 and OATP1B3 transporters is associated with an increased risk of developing severe hyperbilirubinemia in newborns. The excretion of conjugated bilirubin into bile canaliculi occurs with the participation of ATP-dependent transporters MRP2 (Multidrug Resistance-associated Protein 2) and BSEP (Bile Salt Export Pump), the expression of which also has pronounced age-specific features. Molecular studies have shown that in the perinatal period, there is a switch from transcriptional regulation phenomena to post-translational mechanisms of canalicular transport control, mediated by phosphorylation processes and changes in the subcellular localization of transporter proteins. The molecular and cellular mechanisms of the neurotoxic effect of unconjugated bilirubin deserve special attention. It has been established that the damaging effect of bilirubin on nervous system cells is based on processes of mitochondrial respiration disruption, induction of oxidative stress, dysregulation of calcium homeostasis, and activation of pro-apoptotic signaling pathways. Molecular genetic studies have identified a number of candidate genes whose polymorphism may modify the susceptibility of neurons to the toxic effects of bilirubin, including genes for antioxidant enzymes, neurotrophic factors, and ABC family transporters. Despite significant progress in understanding the molecular and cellular fundamentals of neonatal jaundice development, a number of fundamental questions remain insufficiently studied. In particular, epigenetic mechanisms regulating the expression of key proteins in bilirubin metabolism, molecular foundations of individual variability in blood-brain barrier permeability to bilirubin, as well as signaling cascades determining the selective vulnerability of certain neuron populations to bilirubin-induced damage require in-depth research. Conclusions: Thus, a comprehensive study of the molecular and cellular foundations of jaundice syndrome development in the neonatal period represents an actual direction of modern neonatology and molecular medicine, capable of providing a fundamental basis for developing personalized approaches to the prevention and treatment of pathological hyperbilirubinemia