Introduction: Hyperbilirubinemia in newborns can lead to kernicterus, a severe form of neonatal encephalopathy caused by bilirubin toxicity. Despite timely interventions such as exchange transfusion, kernicterus can still develop, especially in high-risk infants. MRI is crucial for detecting early and evolving signs of bilirubin-induced brain damage. Case Report: We report a term newborn who developed severe hyperbilirubinemia and kernicterus despite receiving exchange transfusion. The infant presented on day 3 of life with jaundice, hypotonia, and feeding difficulties and had a bilirubin level of 51 mg/dL. After exchange transfusion, bilirubin levels normalized, but neurotoxicity persisted. Initial MRI at one month showed mild T1 hyperintensity in the hippocampi with no changes in the basal ganglia. At two months, T1 hyperintensities in the hippocampi partially resolved. By six months, MRI revealed T2 hyperintensities in the globus pallidus and hippocampal atrophy, consistent with kernicterus. Magnetic resonance spectroscopy (MRS) showed reduced N-acetylaspartate (NAA) levels, indicating neuronal loss. Discussion: MRI is essential in monitoring bilirubin-induced brain injury. In this case, early MRI findings showed mild hippocampal T1 hyperintensity, which resolved partially. At six months, T2 hyperintensities in the globus pallidus confirmed chronic bilirubin encephalopathy. MRS demonstrated a reduction in N-acetylaspartate, indicative of neuronal loss. Susceptibility-Weighted Imaging (SWI) showed no abnormalities, likely due to the myelination process in neonates. Conclusions: This case highlights the importance of repeated MRI in detecting bilirubin-induced brain damage. Early neuroimaging enables timely interventions and improves long-term neurodevelopmental outcomes in infants with severe hyperbilirubinemia.

The majority of newborns is affected by jaundice after birth. While most jaundice is physiologic, severe hyperbilirubinemia can lead to serious complications, such as chronic bilirubin encephalopathy. Hyperbilirubinemia typically results from increased bilirubin production, impaired clearance, excessive reabsorption, or a combination of these factors. Systematic risk assessment and screening are recommended for all infants to prevent neurologic injury from hyperbilirubinemia. Infants born prematurely and those with risk factors for bilirubin neurotoxicity warrant closer monitoring. Phototherapy is usually effective in lowering bilirubin levels, and exchange transfusion is rarely performed.

Hyperbilirubinemia is one of the most common occurrence in newborns and is toxic to the brain, resulting in neurological sequelae such as auditory impairment, with potential to evolve to chronic bilirubin encephalopathy and long-term cognitive impairment in adults. In the early postnatal period, neurogenesis is rigorous and neuroinflammation is detrimental to the brain. What are the alterations in neurogenesis and the underlying mechanisms of bilirubin encephalopathy during the early postnatal period? This study found that, there were a reduction in the number of neuronal stem/progenitor cells, an increase in microglia in the dentate gyrus (DG) and an inflammatory state in the hippocampus, characterized by increased levels of IL-6, TNF-α, and IL-1β, as well as a decreased level of IL-10 in a rat model of bilirubin encephalopathy (BE). Furthermore, there was a significant decrease in the number of newborn neurons and the expression of neuronal differentiation-associated genes (NeuroD and Ascl1) in the BE group. Additionally, cognitive impairment was observed in this group. The administration of minocycline, an inhibitor of microglial activation, resulted in a reduction of inflammation in the hippocampus, an enhancement of neurogenesis, an increase in the expression of neuron-related genes (NeuroD and Ascl1), and an improvement in cognitive function in the BE group. These results demonstrate that microglia play a critical role in reduced neurogenesis and impaired brain function resulting from bilirubin encephalopathy model, which could inspire the development of novel pharmaceutical and therapeutic strategies. Neonatal jaundice is a clinical manifestation of elevated total serum bilirubin (TSB), termed neonatal hyperbilirubinemia, which results from bilirubin that is deposited into an infant's skin. The characteristic features of neonatal jaundice include yellowish skin, sclerae, and mucous membranes. Jaundice derives from the French word jaune, meaning yellow. Neonatal jaundice is the most frequently encountered medical condition in the first 2 weeks of life and a common cause of readmission to the hospital after birth. Approximately 60% of term and 80% of preterm newborns develop clinical jaundice in the first week after birth. Neonatal jaundice is usually a mild, transient, and self-limiting condition known as physiologic jaundice. However, this should be distinguished from the more severe pathologic jaundice. The two types of neonatal hyperbilirubinemia are unconjugated hyperbilirubinemia (UHB) and conjugated hyperbilirubinemia (CHB). When neonatal jaundice is clinically identified, the underlying etiology of neonatal hyperbilirubinemia must be determined. In most neonates, unconjugated hyperbilirubinemia is the cause of clinical jaundice. However, some infants have conjugated hyperbilirubinemia, which is always pathologic and signifies an underlying medical or surgical etiology. Failure to identify and treat pathologic jaundice may result in bilirubin encephalopathy and associated neurological sequelae. The causes of pathologic UHB and CHB are numerous and varied. Preterm infants and those with congenital enzyme deficiencies are particularly prone to the harmful effects of unconjugated bilirubin on the central nervous system. Unconjugated hyperbilirubinemia is diagnosed by assessing bilirubin levels with a transcutaneous measurement device or blood samples for total serum bilirubin. Conjugated hyperbilirubinemia is typically diagnosed through laboratory studies, including serum aminotransferase, prothrombin time, urine cultures, tests for inborn errors of metabolism, and, in some cases, imaging studies. Severe hyperbilirubinemia can cause bilirubin-induced neurological dysfunction (BIND) and, if not treated adequately, may lead to acute and chronic bilirubin encephalopathy. Phototherapy and exchange transfusions are the mainstays of treatment of UHB, and a subset of patients also respond to intravenous immunoglobulin (IVIG). Treatment of CHB is more complex and depends on the etiology of the jaundice. Despite advances in the care and management of hyperbilirubinemia, it remains a significant cause of neonatal morbidity and mortality.

Unresolved neonatal hyperbilirubinemia may lead to the accumulation of excess bilirubin in the body, and bilirubin in neural tissues may induce toxicity. Bilirubin-induced neurological damage (BIND) can result in acute or chronic bilirubin encephalopathy, causing temporary or lasting neurological dysfunction or severe damage resulting in infant death. Although serum bilirubin levels are used as an indication of severity, known and unknown individual differences affect the severity of the symptoms. The mechanisms of BIND are not yet fully understood. Here, a zebrafish newborn hyperbilirubinemia model is developed and characterized. Direct exposure to excess bilirubin induced dose- and time-dependent toxicity linked to the accumulation of bilirubin in the body and brain. Introduced bilirubin was processed by the liver, which increased the tolerance of larvae. BIND in larvae was demonstrated by morphometric measurements, histopathological analyses and functional tests. The larvae that survived hyperbilirubinemia displayed mild or severe morphologies associated with defects in eye movements, body posture and swimming problems. Interestingly, a plethora of mild to severe clinical symptoms were reproduced in the zebrafish model.

Bilirubin-induced neurological damage (BIND) has been a subject of studies for decades, yet the molecular mechanisms at the core of this damage remain largely unknown. Throughout the years, many in vivo chronic bilirubin encephalopathy models, such as the Gunn rat and transgenic mice, have further elucidated the molecular basis of bilirubin neurotoxicity as well as the correlations between high levels of unconjugated bilirubin (UCB) and brain damage. Regardless of being invaluable, these models cannot accurately recapitulate the human brain and liver system; therefore, establishing a physiologically recapitulating in vitro model has become a prerequisite to unveil the breadth of complexities that accompany the detrimental effects of UCB on the liver and developing human brain. Stem-cell-derived 3D brain organoid models offer a promising platform as they bear more resemblance to the human brain system compared to existing models. This review provides an explicit picture of the current state of the art, advancements, and challenges faced by the various models as well as the possibilities of using stem-cell-derived 3D organoids as an efficient tool to be included in research, drug screening, and therapeutic strategies for future clinical applications.