RARE DISEASE
Bilirubin encephalopathy
Bilirubin encephalopathy
Bilirubin encephalopathy
Synonyms: Kernicterus
Synonyms: Kernicterus
Synonyms: Kernicterus
Drug discovery
988
papers
On emerging therapies
Overview
Bilirubin encephalopathy is a neurological disorder caused by severe unconjugated hyperbilirubinemia in newborns, leading to bilirubin deposition in brain tissue. Acute bilirubin encephalopathy (ABE) manifests with lethargy, poor feeding, hypertonia, seizures, and abnormal cry, progressing to kernicterus—a chronic condition marked by cerebral palsy, hearing loss, gaze abnormalities, and dental dysplasia. Timely intervention with phototherapy or exchange transfusion is critical to prevent irreversible damage [1][6][9].
Burden
Incidence ranges from 0.9–4.8 cases per 100,000 births in high-income countries, rising to 15% of neonatal deaths in low-resource settings [1][12][14].
Survivors face lifelong disabilities: 30–50% develop athetoid cerebral palsy, hearing loss, or intellectual deficits [3][6][19].
Preventable via TSB monitoring, yet delays in diagnosis/treatment persist globally [2][14][18].
Therapies
Phototherapy: First-line treatment to convert bilirubin into excretable isomers [3][8][16].
Exchange transfusion: Reserved for severe cases (TSB >25 mg/dL or signs of ABE) [3][8][16].
Adjuncts: Intravenous immunoglobulin for isoimmune hemolysis; emerging therapies like phenobarbital (enhances bilirubin conjugation) and metalloporphyrins (inhibit heme oxygenase) [5][8].
Categories: rare inborn errors of metabolism, rare neurological diseases
Research Papers
988 drug discovery papers about Bilirubin encephalopathy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
988 drug discovery papers about Bilirubin encephalopathy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-28 | TET1-mediated demethylation of UGT1A1 suppresses neuronal ferroptosis and brain injury in bilirubin encephalopathy.
Bilirubin encephalopathy (BE) is a severe neurological complication of neonatal hyperbilirubinemia, but the molecular mechanisms underlying bilirubin-induced brain injury remain unclear. We investigated whether UDP-glucuronosyltransferase 1A1 (UGT1A1) regulates neuronal ferroptosis in BE and whether this process is controlled by ten-eleven translocation methylcytosine dioxygenase 1 (TET1)-mediated demethylation. BE rat models were established by cisterna magna bilirubin injection, and bilirubin-treated PC12 cells were used for in vitro analysis. UGT1A1 and TET1 were overexpressed in vivo and in vitro, and UGT1A1 knockdown, Erastin, and 5-aza-2'-deoxycytidine were used for mechanistic studies. Brain injury, neurological function, ferroptosis-related oxidative stress, apoptosis, inflammatory factors, promoter methylation, and protein expression were evaluated by biochemical assays, Morris water maze, histology, TUNEL staining, qRT-PCR, western blotting, and chromatin immunoprecipitation (ChIP). UGT1A1 was downregulated in BE models. UGT1A1 overexpression reduced bilirubin accumulation, brain edema, neuronal injury, and cognitive impairment in BE rats, and suppressed ferroptosis by decreasing iron, malondialdehyde, acyl-CoA synthetase long-chain family member 4 (ACSL4), apoptosis, and inflammatory factors while restoring antioxidant indices and glutathione peroxidase 4 (GPX4). In bilirubin-treated PC12 cells, UGT1A1 also alleviated ferroptosis-related injury, whereas Erastin weakened these protective effects. UGT1A1 promoter methylation was increased in BE model cells, while TET1 expression was reduced in hippocampal tissue. TET1 bound the UGT1A1 promoter, reduced its methylation, restored UGT1A1 expression, and alleviated ferroptosis. UGT1A1 knockdown weakened the protective effects of TET1 in neuronal cells. TET1-mediated demethylation of UGT1A1 suppresses neuronal ferroptosis and brain injury in BE, identifying the TET1/UGT1A1 axis as a potential therapeutic target.
2026-06-30 | Efficacy of Bacillus clausii as an adjuvant therapy in pathological neonatal unconjugated hyperbilirubinemia in the Nile Delta region of Egypt: a randomized controlled trial.
Neonatal jaundice (NJ) is a common condition that may progress to serious complications such as kernicterus. Probiotics can also be used for treatment of jaundice by their effect on intestinal motility and microbial flora of the intestine. We aimed to evaluate the effect of probiotic supplementation as an adjuvant therapy in pathological neonatal unconjugated hyperbilirubinemia. A randomized, parallel-group comparative study was conducted on 44 neonates with confirmed pathological unconjugated hyperbilirubinemia admitted to the Neonatal Intensive Care Unit at Tanta University Hospital (Egypt) between May 2024 and April 2025. Participants were randomized (1:1) into two groups: phototherapy alone (control group n = 22) and phototherapy plus oral Bacillus clausii probiotic (probiotic group n = 22). Demographic data and bilirubin fractions were recorded. The primary outcome was the change in bilirubin levels; secondary outcomes included inflammatory biomarkers. Baseline characteristics were comparable between groups. Both groups exhibited significant declines in total serum bilirubin and indirect bilirubin, but only the probiotic group showed a significant reduction in direct bilirubin. By the end of treatment, the probiotic group showed a significantly greater reduction in lipopolysaccharide and tumor necrosis factor-α levels compared with the control group. Hospital stay was significantly shorter with probiotic therapy (3.8 ± 1.18 vs 6.3 ± 2.14 days; P < .001). Bacillus clausii supplementation alongside phototherapy significantly enhanced bilirubin reduction, decreased inflammatory markers, and shortened hospitalization, supporting its role as a beneficial adjunct therapy in neonatal hyperbilirubinemia.
2026-06-04 | NURSING CARE FOR NEWBORNS WITH HYPERBILIRUBINEMIA AND NEONATAL JAUNDICE PROBLEMS IN THE LAVALETTE HOSPITAL
Introduction: Hyperbilirubinemia is a common clinical problem in newborns, characterised by elevated bilirubin levels which lead to jaundice in neonates. If left untreated, this condition can lead to serious complications such as kernicterus and bilirubin encephalopathy. Methods: This study aims to analyse the nursing care provided to neonates with hyperbilirubinemia and jaundice, using a descriptive case study design at Lavalette Hospital. Participants were two neonates aged six and 17 days, both diagnosed with hyperbilirubinemia. Data were obtained through interviews with parents and nurses, direct observation of nursing actions and analysis of medical records. Data validation was performed using source triangulation. Results: The results of the three-day study showed a decrease in jaundice symptoms after two phototherapy sessions, as indicated by a reduction in the scores for yellow skin, yellow sclera and yellow mucous membranes. Conclusion: Phototherapy was effective in addressing the nursing issue of neonatal jaundice. The success of therapy was also supported by collaboration between medical personnel and family participation. Follow-up care focuses on increasing body weight and providing nutrition to prevent the recurrence of neonatal jaundice.
2026-05-10 | Clinical outcomes of the 2022 AAP hyperbilirubinemia guideline in term and late-preterm infants: a prospective study in Thailand.
Neonatal jaundice is a common condition, occurring in approximately 80% of term infants during the first week of life. Timely diagnosis and management are essential to prevent bilirubin-induced neurological damage. In 2022, the American Academy of Pediatrics (AAP) updated its guideline for managing hyperbilirubinemia in infants ≥ 35 weeks' gestation, raising treatment thresholds and recommending individualized follow-up based on gestational age, neurotoxicity risk factors, and the bilirubin-treatment threshold difference. Evidence from low- and middle-income countries on the clinical impact of these guideline is limited. We conducted a prospective observational study at Panyananthaphikkhu Chonprathan Medical Center, Thailand, from February 2024 to January 2025, including 1,104 neonates ≥ 35 weeks' gestation. All infants underwent total serum bilirubin (TSB) screening within 72 h of birth and were managed according to the 2022 AAP guideline. Phototherapy rates, follow-up recommendations, readmissions, exchange transfusions, and cases of acute bilirubin encephalopathy were recorded. In addition, the infants' TSB values were retrospectively applied to the 2004 AAP guideline to assess eligibility for phototherapy. Among infants who did not receive phototherapy, TSB values were retrospectively applied to the Bahr 2021 nomogram to determine follow-up recommendations for comparison with management based on the 2022 AAP guideline. Phototherapy was required in 221 infants (20.0%), representing a 38% relative reduction compared with the rate observed when the 2004 AAP guideline was retrospectively applied (32%; p < 0.001). Follow-up rates decreased from 56.9% under the Bahr 2021 nomogram to 52.7% under the 2022 guideline (absolute reduction, 4.3%; relative reduction, 7.5%; 95% CI, 5.91-9.03; p = 0.044). Readmission occurred in 127 infants (11.5%), most commonly due to suboptimal intake. No cases of acute bilirubin encephalopathy or exchange transfusion were reported. Implementation of the 2022 AAP guideline reduces phototherapy use and unnecessary follow-up visits without increasing adverse outcomes. With clearly structured follow-up schedules and close monitoring of infants at risk of developing severe jaundice, high-risk newborns can be managed effectively and safely. These findings support the applicability of the guideline in routine clinical practice, including in middle-income countries.
2026-04-27 | Yellow cerebrospinal fluid in an extremely preterm infant: a case report.
Although phototherapy has reduced the incidence of kernicterus in term infants, it remains a significant threat to extremely preterm infants due to their immature blood-brain barrier and frequent comorbidities such as sepsis. Current clinical practice relies on serum total bilirubin levels, which may not accurately reflect cerebral bilirubin exposure in this vulnerable population. This case report describes an extremely preterm infant (gestational age 28 1/7 weeks, birth weight 950 g) who developed visibly yellow cerebrospinal fluid (CSF) on the first day of life. Despite only minimal serum hyperbilirubinemia (4.4 mg/dL; ≈ 75.2 μmol/L), CSF bilirubin was markedly elevated at 10 mg/dL (≈ 171 μmol/L). The infant presented with respiratory distress syndrome and sepsis. Immediate intensive phototherapy was initiated, leading to the normalization of CSF bilirubin (3.6 mg/dL ≈ 61.5 μmol/L) within 4 days. Brain magnetic resonance imaging (MRI) and automated auditory brainstem response (AABR) performed at the corrected age of 4 months were both unremarkable. At the corrected age of 12 months, neurodevelopmental assessment using the Bayley Scales of Infant Development-III (BSID-III) showed scores within the normal range. This case illustrates that CSF bilirubin can serve as a sensitive early biomarker for identifying preterm infants at imminent risk for bilirubin neurotoxicity, particularly when serum bilirubin levels are misleadingly low. Targeted measurement of CSF bilirubin in selected high-risk infants, when a lumbar puncture is otherwise indicated, could enable more timely intervention and contribute to improved neurodevelopmental outcomes.
cell therapies
2026-09-01 | Case Report: Therapeutic plasma exchange for severe unconjugated hyperbilirubinemia with bilirubin-induced neurologic dysfunction in an adolescent with Crigler-Najjar syndrome type II.
Crigler-Najjar syndrome type II (CNS-II) is a rare inherited disorder of bilirubin conjugation that typically responds to phenobarbital and is less frequently complicated by bilirubin neurotoxicity than CNS-I. During physiologic stress, unconjugated bilirubin may acutely rise, potentially increasing unbound bilirubin and neurologic risk. A 15-year-old male with a known history of CNS-II presented with two weeks of progressive abnormal movements and worsening jaundice, followed by decreased consciousness and incoherent speech. Initial testing demonstrated severe isolated hyperbilirubinemia with minimal direct bilirubin fraction and no laboratory evidence of hepatocellular injury or synthetic dysfunction. He was transferred to the medical Intensive Care Unit with suspected bilirubin-induced neurologic dysfunction. Given ongoing neurologic deterioration and severe hyperbilirubinemia despite supportive management, therapeutic plasma exchange (TPE) was initiated on the day of ICU admission and performed daily for seven sessions via central venous access with fresh frozen plasma used as the replacement fluid. Total bilirubin declined from 35.0 mg/dL on admission (16-Feb-2025) to 28.8 mg/dL by session 2 (17-Feb-2025),to 27.4 mg/dL by session 3 (18-Feb-2025), to 24 mg/dL by sessions 4-5 (19-20-Feb-2025),to 19.5 mg/dL by sessions 6-7(21-22-Feb-2025) and approximately 18.8 mg/dL after seven sessions (23-Feb-2025), accompanied by clinical improvement in alertness and abnormal movements. Brain MRI obtained after TPE sessions demonstrate no Acute Bilirubin Encephalopathy-pattern or basal ganglia involvement. This case supports consideration of TPE as a rescue strategy for severe unconjugated hyperbilirubinemia with neurologic dysfunction in older children with CNS-II when conventional measures are insufficient or impractical, while underscoring the need for standardized reporting of TPE protocols and longer-term neurodevelopmental outcomes.
2026-05-21 | Case Report: Retransplantation for Adult-Onset Bilirubin Encephalopathy After Auxiliary Partial Liver Transplant for Crigler-Najjar Syndrome Type 1 in Childhood.
Crigler-Najjar syndrome (CNS) type 1 is a genetic disorder that leads to severe unconjugated hyperbilirubinemia. Auxiliary partial orthotopic liver transplantation (APOLT) is preferred for metabolic liver diseases as a portion of the native liver is retained. Reported here are details of a 32-year-old male who developed bilirubin encephalopathy due to graft failure 27 years after APOLT performed at 5-year-old for CNS type 1. Initially, the bilirubin level was low, which then gradually increased to 7.3 mg/dL at age 12. At the age of 31, the bilirubin level began to rise rapidly and we submitted a request for deceased donor liver transplantation (DDLT) to the Committee for the Evaluation of Indications for DDLT in Japan. However, that was deemed as not indicated, because unconjugated bilirubin-dominant hyperbilirubinemia alone is generally not considered to cause encephalopathy in adults. Despite the high bilirubin level, the patient remained neurologically asymptomatic until occurrence of acute decompensation. At 32 years old, he was admitted on an emergency basis to our hospital with severe hyperbilirubinemia and neurological symptoms. After managing his general condition with intensive care, DDLT was finally performed, resulting in a drastic resolution of various symptoms. The findings in this case show that bilirubin-induced neurotoxicity in adults may be reversible and indicate that the current liver transplantation criteria used in Japan, which limit eligibility for CNS to pediatric patients, may have contributed to delayed transplantation. Re-evaluation of the transplant eligibility criteria is necessary to allow for a more inclusive approach that encompasses adult patients.
2026-04-30 | Liver Transplantation Outcomes in Crigler-Najjar Syndrome in Iran: A Single-Center Retrospective Cohort Study Over 20 Years.
Crigler-Najjar Syndrome (CNS) is a rare autosomal recessive disorder caused by uridine diphosphate glucuronosyltransferase (UGT1A1) deficiency, leading to unconjugated hyperbilirubinemia. Without treatment, patients are at high risk of kernicterus and irreversible neurological damage. Liver transplantation (LT) is the only curative option. This study aims to evaluate long-term outcomes of LT in CNS patients over a 20-year period in Iran. In this retrospective cohort study, we analyzed 69 patients with CNS who underwent LT between 2000 and 2023 at Namazi Hospital and Abu Ali Sina Transplant Center in Shiraz, Iran. Long-term follow-up data, graft function, patient survival, and pre- and post-LT outcomes were evaluated. Posttransplantation, bilirubin metabolism and liver function normalized rapidly. Within the first year, the overall mortality rate was 14.5%, mainly due to graft failure and sepsis. Late mortality (2.9%) was predominantly linked to chronic rejection and infections. LT remains a definitive curative option for patients with CNS. However, postoperative complications, particularly hematologic and renal dysfunction, remain significant concerns. These findings underscore the importance of ongoing monitoring and optimization of post-LT care. Furthermore, the lack of consensus regarding ideal timing for LT highlights the need for future prospective studies to better inform clinical decision-making.
2024-07-01 | Effectiveness of Double-volume Exchange Transfusion in Neonates with Hyperbilirubinemia: A Single-center Experience
A BSTRACT Background and Objectives: Double-volume exchange transfusion (DVET) is a life-saving procedure that replaces a neonate’s blood volume twice over with adult donor blood to treat neonatal hyperbilirubinemia and prevent kernicterus. This study assessed DVET’s effectiveness in reducing total serum bilirubin (TSB) concentration in neonates at risk of kernicterus and examined the disease conditions that necessitate DVET. Methods: This observational study assessed the effectiveness of DVET in 104 neonates at risk of kernicterus. Neonates meeting the American Academy of Pediatrics guidelines were selected. Blood samples were collected before and 24 h after DVET for TSB estimation and complete blood count analysis. Blood components were selected based on ABO, Rh, and other minor blood group incompatibility. DVET was performed using the push–pull method. Results: This study of DVET in 104 neonates with hyperbilirubinemia found that DVET is an effective treatment, reducing TSB levels by 61.72% on average. The most common cause of hyperbilirubinemia was idiopathic (25.6%), followed by ABO incompatibility (22.12%) and anti-D alloimmunization (17.31%). In hypothyroid, preterm, and sepsis cases, hemoglobin levels decreased by an average of 17.7%, 12.9%, and 13.9%, respectively, after DVET. However, in cases of minor alloimmunization and anti-D alloimmunization, hemoglobin levels increased by an average of 29% and 40.5%, respectively, after DVET. The maximum decrease in TSB level was observed in cases of ABO incompatibility with sepsis (82%), while the minimum decrease was seen in neonates undergoing DVET due to sepsis (50%). The percentage reduction of TSB level after DVET was similar for different etiologies, ranging from 50.2% to 65.4%. Conclusion: DVET is a rarely used procedure in the age of phototherapy and intravenous immunoglobulin for neonatal hyperbilirubinemia. However, it is the only effective treatment for very high bilirubin levels to prevent kernicterus or bilirubin encephalopathy.
2024-04-01 | Behavioral and neurocognitive phenotypes in Crigler-Najjar syndrome in Tunisia
Introduction Crigler-Najjar 1 (CN1) due to exon 3 mutations of the UGT1A1 gene is a not rare genetic disease in Tunisia with a founder effect. CN1 syndrome is very severe, and most of CN1 Tunisian patients die soon after birth, within a maximum of one year, due to kernicterus. Liver transplantation, which is the only available therapeutic method for CN1, remains unreachable. Objectives The aim of this study was to report behavioral and neurocognitive phenotypes in CN1 patients who survived to school enrollment. Methods We have selected all patients evaluated from 2004 to 2010, both clinically and molecularly, for a deficiency of bilirubin-UGT enzyme activity leading to a pathological elevation of unconjugated bilirubin with a suspicion of CN1 syndrome. Direct sequencing of targeted PCR amplification products was performed for molecular analysis of UGT1A1. Behavioral and mental features of patients were studied through our genetic counselling. Results We identified 15 patients with the homozygous c.1070 A>G Tunisian mutation. Their age at diagnosis ranged from one week to 9 months for 13 patients. Six of them died within a month of molecular investigation. Only two boys were of school age, i.e. 6 and 9 years. The first had been hospitalized at 3 months year-old for a prolonged jaundice treated with phenobarbital and phototherapy. His psychomotor and neurological development was normal, with school attendance at the age of six. The second patient presented with an unexplored jaundice at the age of 3 days, which was later complicated by seizures and treated with phenobarbital. Despite neurological and motor sequelae associated to language impairments with slurred speech, he attended school at the age of six. Conclusions The neurological and behavioral profile of CN1 patients depends on familial and medical management. Quick diagnosis, close follow up and early liver transplantation can improve prognosis. Disclosure of Interest None Declared
proteins
2026-08-24 | Albumin priming prior to an exchange transfusion: Is it time to prime for neuroprotection?
Albumin is the crux of the exchangeable (i.e., miscible) bilirubin pool, controlling via its high affinity binding the distribution of bilirubin within and across the intravascular and extravascular spaces. It follows that clinicians should leverage the administration of bilirubin free albumin in the management of hazardous hyperbilirubinemia to avoid or reverse bilirubin neurotoxicity. A standard double volume exchange transfusion does exactly that via the albumin laden fresh frozen plasma used to reconstitute the blood infused during the procedure. Albumin priming - the infusion of bilirubin-free albumin prior to a double volume exchange transfusion - augments the infant's pre-exchange albumin mass and albumin bilirubin binding capacity. As such, albumin priming can enhance bilirubin clearance over the course of the subsequent exchange transfusion and provide an immediate stepwise gain in neuroprotection during the pre-exchange period. The potential for neuroprotection against worsening bilirubin-induced neurological dysfunction is the principal reason to albumin prime and prime early when caring for a neonate with signs of intermediate to advanced stage acute bilirubin encephalopathy. Albumin priming should also be considered in asymptomatic infants whose bilirubin - albumin molar ratios approach or exceed albumin's saturable binding limits, as a preventive measure to attenuate bilirubin neurotoxicity risk.
2026-03-19 | A Comparative Public Health Perspective from India and Kyrgyzstan
Background Neonatal jaundice, the yellow discoloration of skin and sclera from unconjugated bilirubin accumulation, affects more than half of term newborns globally. While typically physiological and self-limiting, severe hyperbilirubinemia can cause kernicterus—a permanent, devastating neurological injury. India and Kyrgyzstan represent contrasting epidemiological landscapes: India, a lower-middle-income tropical giant with high birth volume, diverse genetic profiles, and heterogeneous health system capacity; Kyrgyzstan, a post-Soviet upper-middle-income mountainous republic with universal health coverage, cold climate, and concentrated specialised care. Comparative analysis illuminates how geography, genetics, health system architecture, and phototherapy access shape the burden, recognition, and outcome of this ubiquitous neonatal condition
2024-02-21 | Nerve Growth Factor Protects Brain Tissue from Hyperbilirubinemia by Down Regulating Fas/Fas Ligand Expression
To examine the potential protective impact and underlying mechanism of nerve growth factor on brain tissue in hyperbilirubinemia rats through the downregulation of Fas/Fas ligand expression. Thirty six healthy Sprague-Dawley rats were selected as normal control group, and 0.5 ml saline was injected intraperitoneally. The remaining 24 rats were injected intraperitoneally with 50 μg/g bilirubin to establish the model of hyperbilirubinemia. After the model was established successfully, they were divided into hyperbilirubinemia group and nerve growth factor intervention group. The rats in the nerve growth factor intervention group were intraperitoneally injected with 50 μg/kg/d nerve growth factor once a day for 3 d. Rats in each group were killed and their brain tissues were taken to wait for detection. The changes of pathological morphology and the Fas and Fas ligand were compared between the normal control group at 72 h and the hyperbilirubinemia group at 6 h, 24 h, 72 h and the nerve growth factor intervention group. In hyperbilirubinemia group and nerve growth factor intervention group, the brain tissue of rats had different degrees of neurocyto edema. After 6 h, the brain tissue of both groups had degeneration. After 24 h, the neuron necrosis was obvious. After 72 h, the brain tissue of both groups had glial cell proliferation, nuclear pyknosis and fragmentation. However, the severity of brain tissue in nerve growth factor intervention group was less than that in hyperbilirubinemia group, while that in normal control group was not obvious change. At 6 h, 24 h and 72 h, the Fas in the hyperbilirubinemia group was raised than that of the normal control group; while this in the nerve growth factor intervention group was reduced than that of hyperbilirubinemia. At 6 h, 24 h and 72 h, the Fas ligand in hyperbilirubinemia group was raised than that of normal control group; and it in nerve growth factor intervention group was reduced than that of hyperbilirubinemia group. The expression of Fas/Fas ligand can be downregulated by nerve growth factor, thereby providing protection to the brain tissue of rats with hyperbilirubinemia.
2022-09-08 | Effect of Pre-exchange Transfusion Albumin Infusion on Neonatal Hyperbilirubinemia: A Meta-analysis of Randomized Clinical Trials
Background: This study was carried out to systematically evaluate the efficacy and safety of pre-exchange transfusion (pre-ET) albumin infusion on neonatal hyperbilirubinemia. Methods: A comprehensive search of relevant studies from EMBASE, Medline, Cochrane Register of Controlled Trials, ClinicalTrials.gov, China National Knowledge Infrastructure, Wei Pu Information, Wan Fang Data, and Chinese Biomedical Literature Database was conducted from inception to December 2021. Two different authors screened the titles, abstracts, and full texts of the articles. The quality of the included trials was assessed independently by two different authors according to the Cochrane Collaboration’s Risk of Bias. The data were analyzed and compiled using Review Manager software (RevMan version 5.3). Results: In total, four studies enrolling 195 neonates were included in this review. The quality of the included studies was deemed fair to good. The meta-analysis showed that pre-ET albumin infusion was superior to exchange transfusion (ET) alone for reducing the need for repeating ET (risk ratio (RR) = 0.25, 95% confidence interval (CI): 0.09 - 0.72, I-squared (I2) = 8%; fixed effects model) and shortening the duration of phototherapy (PT) (mean difference (MD) = -11.46 hours, 95% CI: -16.56 to -6.36, I2 = 93%; random effects model (REM)). No significant differences were detected between the two groups for post-ET total serum bilirubin (TSB) at 6 hours (MD = -3.51 mg/dL, 95% CI: -7.93 - 0.93, I2 = 97%; REM) and 12 hours (MD = -4.21 mg/dL, 95% CI: -9.08 - 0.65, I2 = 99%; REM). None of the patients developed acute bilirubin encephalopathy in any of the trials. No death prior to hospital discharge was reported in any trials, and no adverse effects were observed in intervention groups. Conclusions: Based on four studied trials, pre-ET albumin infusion appears to be safe and effective in reducing the need for repeating ET and shortening PT duration. These potential benefits, including the reduction of post-ET TSB, need to be revalidated in future trials using rigorous methodology.
2020-11-02 | A questionnaire survey on the efficacy of various treatments for dyskinetic cerebral palsy due to preterm bilirubin encephalopathy.
Preterm children with severe dyskinetic cerebral palsy due to bilirubin encephalopathy often suffer from marked generalised hypertonus as they age. We performed a questionnaire survey to investigate patient-reported outcomes of treatments for improving their activities of daily life. A mail questionnaire was administered to the caregivers of 67 children with preterm bilirubin encephalopathy aged >4 years. We asked about the type of treatments they received and their efficacy using a five-point subjective scale for the following five domains: motor function, postural stability, sleep, pain, and care burden. The names of oral drugs and their efficacies were also explored. The response rate of the questionnaires was 62.7% (42/67), and we analysed the results from 41 validated cases. All children underwent rehabilitation. A total of 30 children received oral drugs, 22 botulinum toxin, 12 orthopaedic surgery, and 3 intrathecal baclofen. Each of these treatments was subjectively reported to be effective in more than half of the recipients for each of the five domains, whereas 23 (56%) required more than two types of treatments other than rehabilitation. Chlordiazepoxide was the most commonly used oral drug, by 28 children (68%), and was discontinued in 7 patients (25%) only. In the sleep domain, the rate of a positive effect was significantly higher for oral drugs (92.7%) than the other treatments (p < 0.01). All treatments were partially effective, but their appropriate combination based on a multidisciplinary approach is essential for muscle tone management in children with preterm bilirubin encephalopathy.
gene therapies
2024-12-01 | Approaches to therapy of Crigler–Najjar syndrome type 1 in children
The review is focused on exploring the etiology, pathogenesis, clinical manifestations, and primarily the contemporary treatment methods for Crigler–Najjar syndrome type 1. It considers relevant data regarding the efficacy and safety of the currently existing therapeutic strategies. Effective management of this condition relies on early diagnosis and prompt initiation of treatment, which are crucial for preventing disabling neurological complications associated with bilirubin encephalopathy in patients with Crigler–Najjar syndrome type 1. Prolonged phototherapy is the key treatment method, while liver transplantation represents a radical approach. Recent advances in gene therapy and the use of mesenchymal multipotent stromal cells present novel opportunities for developing alternative, less invasive treatment modalities aimed at improving the quality of life in such patients and reducing their dependence on long-term phototherapy, along with post-transplantation risk.
2024-09-17 | Therapeutic Options for Crigler-Najjar Syndrome: a Scoping Review
Crigler-Najjar Syndrome (CNS) is a rare genetic disorder caused by mutations in the UGT1A1 gene, leading to impaired bilirubin conjugation and severe unconjugated hyperbilirubinemia. CNS presents in two forms: CNS type 1 (CNS1), the more severe form with a complete absence of UGT1A1 activity, and CNS type 2 (CNS2), with partial enzyme activity. CNS1 requires aggressive management, including phototherapy and plasmapheresis, but liver transplantation (LT) remains the only definitive cure. The timing of LT is critical, as it must be performed before the onset of irreversible brain damage (kernicterus), making early intervention essential. However, LT poses risks such as graft rejection and lifelong immunosuppression. CNS2 is milder, with patients re-sponding well to phenobarbital and having a lower risk of kernicterus. Recent advancements in gene therapy and autologous hepatocyte transplantation offer promising alternatives to LT. Gene therapy using adeno-associated virus (AAV) vectors has shown potential in preclinical studies, though challenges remain in pediatric applications due to liver growth and pre-existing immunity. Autologous hepatocyte transplantation avoids the risks of rejection but requires further research. These emerging therapies provide hope for more effective and less invasive treatment options, aiming to improve the quality of life for CNS patients and reduce reliance on lifelong interven-tions.
2022-03-31 | Neuroglobin expression and function in the temporal cortex of bilirubin encephalopathy rats.
Bilirubin encephalopathy (BE) is a neurological syndrome in newborns, mainly caused by neuronal injury due to excessive oxidative stress produced by unconjugated bilirubin (UCB). Neuroglobin (NGB) can protect the brain by removing oxidative stress species, but its expression and significance in BE are not clear. To address this question, the neonatal BE model was established by injecting UCB into the cerebellomedullary cistern of 7-day-old SD rats. Rats were divided into a sham and BE 6 hr group, BE 12 hr group, BE 24 hr group, and BE 7 d group according to UCB action times. Hematoxylin/eosin and Nissl staining, and electron microscopy were employed to observe the pathological and ultrastructural changes of nerve cells in each group. Immunofluorescence staining was used to detect NGB expression sites and cell types. Western blotting and quantitative PCR served to detect NGB expression and test the mitochondrial apoptosis signal pathway. The results confirm that UCB can lead to pathological damage and ultrastructural changes in rats' temporal cortex, increasing the expression of apoptosis-related proteins Bax, Bcl-2, Cyt c, Caspase-3, and neuronal NGB. UCB promotes NGB expression with an increase in action time and reach a peak at 12 hr. In summary, brain damage induced by UCB will cause an increase in NGB expression, the increasing NGB can inhibit neuron apoptosis in early BE phases. Therefore, promoting the expression of endogenous NGB, to act as a neuroprotective agent may be a potential treatment strategy for BE.
2018-12-01 | AAV8 Gene Therapy for Crigler-Najjar Syndrome in Macaques Elicited Transgene T Cell Responses That Are Resident to the Liver
Systemic delivery of adeno-associated viral (AAV) vectors has been evaluated for the treatment of several liver diseases, including homozygous familial hypercholesterolemia, ornithine transcarbamylase deficiency, and hemophilia. Here, we evaluated this approach for the treatment of Crigler-Najjar syndrome. We administered wild-type rhesus macaques with 1.0 × 1013 or 2.5 × 1013 genome copies/kg of an AAV serotype 8 vector expressing a codon-optimized version of human uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) from a liver-specific promoter. We extensively studied vector biodistribution, transgene expression, and immune responses following vector administration. All rhesus macaques survived until their scheduled necropsy at day 56 and showed no clinical abnormalities during the course of the study. Macaques administered with either vector dose developed a T cell response to the AAV capsid and/or transgene. We mapped the immunodominant epitope in the human UGT1A1 sequence, and we found no correlation between peripheral and tissue-resident lymphocyte responses. Upon further investigation, we characterized CD107a+, granzyme B+, CD4+, and CD8+ transgene-specific cellular responses that were restricted to tissue-resident T cells. This study highlights the importance of studying immune responses at the vector transduction site and the limited usefulness of blood as a surrogate to evaluate tissue-restricted T cell responses. Systemic delivery of adeno-associated viral (AAV) vectors has been evaluated for the treatment of several liver diseases, including homozygous familial hypercholesterolemia, ornithine transcarbamylase deficiency, and hemophilia. Here, we evaluated this approach for the treatment of Crigler-Najjar syndrome. We administered wild-type rhesus macaques with 1.0 × 1013 or 2.5 × 1013 genome copies/kg of an AAV serotype 8 vector expressing a codon-optimized version of human uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) from a liver-specific promoter. We extensively studied vector biodistribution, transgene expression, and immune responses following vector administration. All rhesus macaques survived until their scheduled necropsy at day 56 and showed no clinical abnormalities during the course of the study. Macaques administered with either vector dose developed a T cell response to the AAV capsid and/or transgene. We mapped the immunodominant epitope in the human UGT1A1 sequence, and we found no correlation between peripheral and tissue-resident lymphocyte responses. Upon further investigation, we characterized CD107a+, granzyme B+, CD4+, and CD8+ transgene-specific cellular responses that were restricted to tissue-resident T cells. This study highlights the importance of studying immune responses at the vector transduction site and the limited usefulness of blood as a surrogate to evaluate tissue-restricted T cell responses.
2018-07-03 | Advances in understanding disease mechanisms and potential treatments for Crigler–Najjar syndrome
Introduction: The Crigler–Najjar syndrome (CNS) is an ultra-rare recessive disorder of the liver. There is no effective cure, except for liver transplantation, a procedure with many risks and shortcomings. Thus, the development of novel therapeutic approaches is a clinical need.Areas covered: This review aims at describing potentialities and limitations of novel experimental treatments that can be applied to cure the CNS and other metabolic liver diseases. These include pharmacological and gene therapy approaches, some of them are now being applied in clinical trials of Crigler–Najjar patients. Brief descriptions of bilirubin metabolism, mechanisms of disease, and animal models are also included.Expert opinion: AAV-mediated gene therapy approaches to pediatric liver diseases are very challenging due to the potential loss of viral DNA consequent to liver growth. Novel immunomodulatory strategies are being developed that can allow re-administration of the therapeutic vector by blocking the generation of anti-AAV neutralizing antibodies. Another very promising approach is gene targeting of the therapeutic cDNA into a 'safe-harbor locus,' resulting in the permanent correction of the genetic defect. However, further experimentation is still required to increase safety and efficacy. The success of these approaches will result in alternative therapies to liver transplantation.
other
2026-07-16 | Efficacy and safety of different doses of intravenous immunoglobulin combined with phototherapy in neonatal hemolytic disease: a systematic review and meta-analysis.
Neonatal hemolytic disease is a major cause of neonatal hyperbilirubinemia and kernicterus. Intravenous immunoglobulin (IVIG) combined with phototherapy is a commonly used clinical intervention; however, the optimal dosing regimen remains controversial. This study aimed to systematically evaluate the efficacy and safety of different doses of IVIG combined with phototherapy in the treatment of neonatal hemolytic disease, and to provide evidence-based guidance for optimizing clinical dosing strategies. A comprehensive literature search was conducted in PubMed, Embase, the Cochrane Library, Web of Science, and Scopus, as well as Chinese databases including CNKI, Wanfang Data, VIP, and the Chinese Biomedical Literature Database, from inception to February 2026. Randomized controlled trials comparing high-dose versus low-dose IVIG combined with phototherapy in neonatal hemolytic disease were included. The primary outcomes included exchange transfusion rate, duration of phototherapy, length of hospital stay, serum bilirubin levels at 24 h, hemoglobin levels at 72 h, and incidence of adverse events. Meta-analysis was performed using RevMan 5.4.1, with fixed- or random-effects models applied according to heterogeneity. A total of 10 randomized controlled trials involving 690 neonates were included. Compared with the low-dose IVIG group, the high-dose IVIG group showed a significantly lower exchange transfusion rate (Peto OR = 0.24, 95% CI: 0.12-0.50, P = 0.0001), corresponding to an approximately 76% reduction in the odds of exchange transfusion. High-dose IVIG was also associated with a shorter duration of phototherapy (MD = - 9.11 h, P = 0.002), a shorter length of hospital stay (MD = - 1.83 days, P = 0.0008), and lower serum bilirubin levels at 24 h (MD = - 38.86, P < 0.00001). No statistically significant differences were observed between the two groups in hemoglobin levels at 72 h or adverse reaction rates (all P > 0.05). Compared with low-dose IVIG, high-dose IVIG combined with phototherapy was associated with lower exchange transfusion rates, shorter phototherapy duration and hospital stay, and lower serum bilirubin levels in neonates with hemolytic disease. No statistically significant differences were observed in hemoglobin levels at 72 h or adverse reaction rates between the two groups. Further large-scale, high-quality randomized controlled trials are warranted to confirm these findings and to clarify the potential impact of blood group subtype on treatment response. •Neonatal hemolytic disease remains a common cause of severe neonatal hyperbilirubinemia. •Intravenous immunoglobulin (IVIG) is frequently used as an adjunctive treatment, but the optimal dosage remains uncertain. • This meta-analysis compared different IVIG dosing regimens using randomized controlled trials only. • High-dose IVIG was associated with lower exchange transfusion rates and improved several short-term clinical outcomes.
2026-06-08 | Kernicterus and Bilirubin-Induced Neurologic Dysfunction (BIND): Pathophysiology, Clinical Management, and Strategies for Prevention of a Reversible Catastrophe
Kernicterus, or chronic bilirubin encephalopathy, represents a permanent, disabling neurologic condition resulting from the deposition of unconjugated bilirubin in the basal ganglia and brainstem nuclei of neonates. This review provides a comprehensive examination of the condition, beginning with its pathophysiological basis: the passage of lipid-soluble unconjugated bilirubin across an immature or compromised blood-brain barrier, followed by selective neuronal injury mediated by mitochondrial dysfunction, oxidative stress, and apoptosis. The etiological landscape is bifurcated into disorders of increased bilirubin production (hemolysis, polycythemia, birth trauma) and decreased excretion (hypoalbuminemia, UGT1A1 deficiency, breast milk jaundice), with a significant proportion of cases remaining idiopathic. Epidemiology reveals striking disparities by race, sex, and gestational age, with preterm and male infants at highest risk. The clinical progression follows a predictable three-phase acute course—from lethargy and poor feeding to hypertonia and opisthotonos, culminating in hypotonia and apnea—which, if untreated, evolves into chronic choreoathetoid cerebral palsy, auditory neuropathy, and oculomotor deficits. Diagnosis rests on serial bilirubin measurements, hematologic evaluation for hemolysis, and brainstem auditory evoked responses. Management is stratified by severity and includes intensive phototherapy, intravenous immunoglobulins for immune-mediated hemolysis, and exchange transfusion for emergent cases. Prevention remains the cornerstone: universal bilirubin screening, adherence to hour-specific nomograms, early follow-up, and parental education have drastically reduced the incidence in high-resource settings. The prognosis is excellent with early intervention but dismal with delayed recognition. Kernicterus is a largely preventable tragedy, and its continued occurrence—particularly in low- and middle-income countries—represents a failure of systems, not biology.
2026-06-01 | Neonatal Jaundice and the Developing Brain: Pathophysiology, Clinical Management, and Long-Term Neurological Outcome
Neonatal jaundice, characterized by elevated serum bilirubin levels, is a common condition affecting newborns globally. While mild jaundice is often benign, severe hyperbilirubinemia poses a significant risk to neurological development. If left untreated, it can lead to irreversible brain damage, with lifelong implications for affected children. This review aims to examine the impact of neonatal jaundice on pediatric neurological outcomes, focusing on the pathophysiology, risk factors, clinical manifestations, and long-term consequences. A comprehensive analysis of current literature was conducted, including clinical studies and systematic reviews. Emphasis was placed on understanding the neurological sequelae of neonatal jaundice and evaluating the effectiveness of therapeutic interventions. Findings indicate that severe neonatal jaundice is associated with neurological complications such as acute bilirubin encephalopathy and kernicterus. These conditions can result in motor impairments, hearing loss, speech delays, and cognitive dysfunction. Early diagnosis and interventions, such as phototherapy and exchange transfusion, have significantly reduced the incidence of severe outcomes. However, in low-resource settings, delayed diagnosis and inadequate treatment remain substantial challenges, increasing the risk of permanent disability. Neonatal jaundice, if improperly managed, poses serious risks to pediatric neurological health. Timely intervention and improved screening protocols are essential to prevent long-term neurological damage. Further research is needed to explore the subtle neurodevelopmental effects and to enhance care strategies, especially in under-resourced regions. A multidisciplinary approach is crucial to mitigate these risks and improve outcomes for affected children.
2026-03-18 | Predominance of Rh-mediated haemolytic disease driving exchange transfusions in rural north India: A five-year retrospective analysis revealing critical prevention gaps.
Exchange transfusion remains the definitive treatment for severe neonatal hyperbilirubinaemia; yet its aetiology and outcomes in rural tropical settings are poorly characterised. This five-year retrospective analysis of 58 neonates at a North Indian rural tertiary centre reveals that Rh incompatibility accounted for 76% of cases - a striking divergence from high income-country patterns where ABO incompatibility predominates - indicating critical gaps in antenatal Rh immuno-prophylaxis. The procedure achieved a mean bilirubin reduction of 50% (424 ± 106 to 212 ± 70&mu/L, p < 0.001) with no procedure-related mortality, though clinically significant adverse events occurred in 19% of neonates. Notably, 10.2% presented with acute bilirubin encephalopathy at the time of intervention, representing potentially preventable neurological injury. These findings make a compelling case for urgent, systematic improvements in antenatal screening, Rh immuno-prophylaxis access, and early jaundice recognition in tropical resource-limited settings.
2026-03-15 | Neonatal hyperbilirubinemia: risk factors pathophysiology and complications
In newborns, elevated concentrations of unconjugated bilirubin can cross the blood-brain barrier and deposit in the basal ganglia or cerebellum, causing bilirubin-induced encephalopathy or kernicterus. Genetic polymorphisms in three bilirubin metabolism genes, including ABO/Rh incompatibility, glucose-6-phosphate dehydrogenase (G6PD) deficiency, uridine diphosphate gluconoryltransferase gene (UGT1A1), organ anion transporter genes (OATP1B1), and hemoxicase gene (HO-1), have been identified as causes of hyperbilirubinemia. Neonates with elevated hyperbilirubinemia are at risk for bilirubin-induced neurologic dysfunction (BIND).
small molecules
2026-09-28 | TET1-mediated demethylation of UGT1A1 suppresses neuronal ferroptosis and brain injury in bilirubin encephalopathy.
Bilirubin encephalopathy (BE) is a severe neurological complication of neonatal hyperbilirubinemia, but the molecular mechanisms underlying bilirubin-induced brain injury remain unclear. We investigated whether UDP-glucuronosyltransferase 1A1 (UGT1A1) regulates neuronal ferroptosis in BE and whether this process is controlled by ten-eleven translocation methylcytosine dioxygenase 1 (TET1)-mediated demethylation. BE rat models were established by cisterna magna bilirubin injection, and bilirubin-treated PC12 cells were used for in vitro analysis. UGT1A1 and TET1 were overexpressed in vivo and in vitro, and UGT1A1 knockdown, Erastin, and 5-aza-2'-deoxycytidine were used for mechanistic studies. Brain injury, neurological function, ferroptosis-related oxidative stress, apoptosis, inflammatory factors, promoter methylation, and protein expression were evaluated by biochemical assays, Morris water maze, histology, TUNEL staining, qRT-PCR, western blotting, and chromatin immunoprecipitation (ChIP). UGT1A1 was downregulated in BE models. UGT1A1 overexpression reduced bilirubin accumulation, brain edema, neuronal injury, and cognitive impairment in BE rats, and suppressed ferroptosis by decreasing iron, malondialdehyde, acyl-CoA synthetase long-chain family member 4 (ACSL4), apoptosis, and inflammatory factors while restoring antioxidant indices and glutathione peroxidase 4 (GPX4). In bilirubin-treated PC12 cells, UGT1A1 also alleviated ferroptosis-related injury, whereas Erastin weakened these protective effects. UGT1A1 promoter methylation was increased in BE model cells, while TET1 expression was reduced in hippocampal tissue. TET1 bound the UGT1A1 promoter, reduced its methylation, restored UGT1A1 expression, and alleviated ferroptosis. UGT1A1 knockdown weakened the protective effects of TET1 in neuronal cells. TET1-mediated demethylation of UGT1A1 suppresses neuronal ferroptosis and brain injury in BE, identifying the TET1/UGT1A1 axis as a potential therapeutic target.
2026-06-30 | Efficacy of Bacillus clausii as an adjuvant therapy in pathological neonatal unconjugated hyperbilirubinemia in the Nile Delta region of Egypt: a randomized controlled trial.
Neonatal jaundice (NJ) is a common condition that may progress to serious complications such as kernicterus. Probiotics can also be used for treatment of jaundice by their effect on intestinal motility and microbial flora of the intestine. We aimed to evaluate the effect of probiotic supplementation as an adjuvant therapy in pathological neonatal unconjugated hyperbilirubinemia. A randomized, parallel-group comparative study was conducted on 44 neonates with confirmed pathological unconjugated hyperbilirubinemia admitted to the Neonatal Intensive Care Unit at Tanta University Hospital (Egypt) between May 2024 and April 2025. Participants were randomized (1:1) into two groups: phototherapy alone (control group n = 22) and phototherapy plus oral Bacillus clausii probiotic (probiotic group n = 22). Demographic data and bilirubin fractions were recorded. The primary outcome was the change in bilirubin levels; secondary outcomes included inflammatory biomarkers. Baseline characteristics were comparable between groups. Both groups exhibited significant declines in total serum bilirubin and indirect bilirubin, but only the probiotic group showed a significant reduction in direct bilirubin. By the end of treatment, the probiotic group showed a significantly greater reduction in lipopolysaccharide and tumor necrosis factor-α levels compared with the control group. Hospital stay was significantly shorter with probiotic therapy (3.8 ± 1.18 vs 6.3 ± 2.14 days; P < .001). Bacillus clausii supplementation alongside phototherapy significantly enhanced bilirubin reduction, decreased inflammatory markers, and shortened hospitalization, supporting its role as a beneficial adjunct therapy in neonatal hyperbilirubinemia.
2026-06-04 | NURSING CARE FOR NEWBORNS WITH HYPERBILIRUBINEMIA AND NEONATAL JAUNDICE PROBLEMS IN THE LAVALETTE HOSPITAL
Introduction: Hyperbilirubinemia is a common clinical problem in newborns, characterised by elevated bilirubin levels which lead to jaundice in neonates. If left untreated, this condition can lead to serious complications such as kernicterus and bilirubin encephalopathy. Methods: This study aims to analyse the nursing care provided to neonates with hyperbilirubinemia and jaundice, using a descriptive case study design at Lavalette Hospital. Participants were two neonates aged six and 17 days, both diagnosed with hyperbilirubinemia. Data were obtained through interviews with parents and nurses, direct observation of nursing actions and analysis of medical records. Data validation was performed using source triangulation. Results: The results of the three-day study showed a decrease in jaundice symptoms after two phototherapy sessions, as indicated by a reduction in the scores for yellow skin, yellow sclera and yellow mucous membranes. Conclusion: Phototherapy was effective in addressing the nursing issue of neonatal jaundice. The success of therapy was also supported by collaboration between medical personnel and family participation. Follow-up care focuses on increasing body weight and providing nutrition to prevent the recurrence of neonatal jaundice.
2026-05-10 | Clinical outcomes of the 2022 AAP hyperbilirubinemia guideline in term and late-preterm infants: a prospective study in Thailand.
Neonatal jaundice is a common condition, occurring in approximately 80% of term infants during the first week of life. Timely diagnosis and management are essential to prevent bilirubin-induced neurological damage. In 2022, the American Academy of Pediatrics (AAP) updated its guideline for managing hyperbilirubinemia in infants ≥ 35 weeks' gestation, raising treatment thresholds and recommending individualized follow-up based on gestational age, neurotoxicity risk factors, and the bilirubin-treatment threshold difference. Evidence from low- and middle-income countries on the clinical impact of these guideline is limited. We conducted a prospective observational study at Panyananthaphikkhu Chonprathan Medical Center, Thailand, from February 2024 to January 2025, including 1,104 neonates ≥ 35 weeks' gestation. All infants underwent total serum bilirubin (TSB) screening within 72 h of birth and were managed according to the 2022 AAP guideline. Phototherapy rates, follow-up recommendations, readmissions, exchange transfusions, and cases of acute bilirubin encephalopathy were recorded. In addition, the infants' TSB values were retrospectively applied to the 2004 AAP guideline to assess eligibility for phototherapy. Among infants who did not receive phototherapy, TSB values were retrospectively applied to the Bahr 2021 nomogram to determine follow-up recommendations for comparison with management based on the 2022 AAP guideline. Phototherapy was required in 221 infants (20.0%), representing a 38% relative reduction compared with the rate observed when the 2004 AAP guideline was retrospectively applied (32%; p < 0.001). Follow-up rates decreased from 56.9% under the Bahr 2021 nomogram to 52.7% under the 2022 guideline (absolute reduction, 4.3%; relative reduction, 7.5%; 95% CI, 5.91-9.03; p = 0.044). Readmission occurred in 127 infants (11.5%), most commonly due to suboptimal intake. No cases of acute bilirubin encephalopathy or exchange transfusion were reported. Implementation of the 2022 AAP guideline reduces phototherapy use and unnecessary follow-up visits without increasing adverse outcomes. With clearly structured follow-up schedules and close monitoring of infants at risk of developing severe jaundice, high-risk newborns can be managed effectively and safely. These findings support the applicability of the guideline in routine clinical practice, including in middle-income countries.
2026-04-27 | Yellow cerebrospinal fluid in an extremely preterm infant: a case report.
Although phototherapy has reduced the incidence of kernicterus in term infants, it remains a significant threat to extremely preterm infants due to their immature blood-brain barrier and frequent comorbidities such as sepsis. Current clinical practice relies on serum total bilirubin levels, which may not accurately reflect cerebral bilirubin exposure in this vulnerable population. This case report describes an extremely preterm infant (gestational age 28 1/7 weeks, birth weight 950 g) who developed visibly yellow cerebrospinal fluid (CSF) on the first day of life. Despite only minimal serum hyperbilirubinemia (4.4 mg/dL; ≈ 75.2 μmol/L), CSF bilirubin was markedly elevated at 10 mg/dL (≈ 171 μmol/L). The infant presented with respiratory distress syndrome and sepsis. Immediate intensive phototherapy was initiated, leading to the normalization of CSF bilirubin (3.6 mg/dL ≈ 61.5 μmol/L) within 4 days. Brain magnetic resonance imaging (MRI) and automated auditory brainstem response (AABR) performed at the corrected age of 4 months were both unremarkable. At the corrected age of 12 months, neurodevelopmental assessment using the Bayley Scales of Infant Development-III (BSID-III) showed scores within the normal range. This case illustrates that CSF bilirubin can serve as a sensitive early biomarker for identifying preterm infants at imminent risk for bilirubin neurotoxicity, particularly when serum bilirubin levels are misleadingly low. Targeted measurement of CSF bilirubin in selected high-risk infants, when a lumbar puncture is otherwise indicated, could enable more timely intervention and contribute to improved neurodevelopmental outcomes.
cell therapies
2026-09-01 | Case Report: Therapeutic plasma exchange for severe unconjugated hyperbilirubinemia with bilirubin-induced neurologic dysfunction in an adolescent with Crigler-Najjar syndrome type II.
Crigler-Najjar syndrome type II (CNS-II) is a rare inherited disorder of bilirubin conjugation that typically responds to phenobarbital and is less frequently complicated by bilirubin neurotoxicity than CNS-I. During physiologic stress, unconjugated bilirubin may acutely rise, potentially increasing unbound bilirubin and neurologic risk. A 15-year-old male with a known history of CNS-II presented with two weeks of progressive abnormal movements and worsening jaundice, followed by decreased consciousness and incoherent speech. Initial testing demonstrated severe isolated hyperbilirubinemia with minimal direct bilirubin fraction and no laboratory evidence of hepatocellular injury or synthetic dysfunction. He was transferred to the medical Intensive Care Unit with suspected bilirubin-induced neurologic dysfunction. Given ongoing neurologic deterioration and severe hyperbilirubinemia despite supportive management, therapeutic plasma exchange (TPE) was initiated on the day of ICU admission and performed daily for seven sessions via central venous access with fresh frozen plasma used as the replacement fluid. Total bilirubin declined from 35.0 mg/dL on admission (16-Feb-2025) to 28.8 mg/dL by session 2 (17-Feb-2025),to 27.4 mg/dL by session 3 (18-Feb-2025), to 24 mg/dL by sessions 4-5 (19-20-Feb-2025),to 19.5 mg/dL by sessions 6-7(21-22-Feb-2025) and approximately 18.8 mg/dL after seven sessions (23-Feb-2025), accompanied by clinical improvement in alertness and abnormal movements. Brain MRI obtained after TPE sessions demonstrate no Acute Bilirubin Encephalopathy-pattern or basal ganglia involvement. This case supports consideration of TPE as a rescue strategy for severe unconjugated hyperbilirubinemia with neurologic dysfunction in older children with CNS-II when conventional measures are insufficient or impractical, while underscoring the need for standardized reporting of TPE protocols and longer-term neurodevelopmental outcomes.
2026-05-21 | Case Report: Retransplantation for Adult-Onset Bilirubin Encephalopathy After Auxiliary Partial Liver Transplant for Crigler-Najjar Syndrome Type 1 in Childhood.
Crigler-Najjar syndrome (CNS) type 1 is a genetic disorder that leads to severe unconjugated hyperbilirubinemia. Auxiliary partial orthotopic liver transplantation (APOLT) is preferred for metabolic liver diseases as a portion of the native liver is retained. Reported here are details of a 32-year-old male who developed bilirubin encephalopathy due to graft failure 27 years after APOLT performed at 5-year-old for CNS type 1. Initially, the bilirubin level was low, which then gradually increased to 7.3 mg/dL at age 12. At the age of 31, the bilirubin level began to rise rapidly and we submitted a request for deceased donor liver transplantation (DDLT) to the Committee for the Evaluation of Indications for DDLT in Japan. However, that was deemed as not indicated, because unconjugated bilirubin-dominant hyperbilirubinemia alone is generally not considered to cause encephalopathy in adults. Despite the high bilirubin level, the patient remained neurologically asymptomatic until occurrence of acute decompensation. At 32 years old, he was admitted on an emergency basis to our hospital with severe hyperbilirubinemia and neurological symptoms. After managing his general condition with intensive care, DDLT was finally performed, resulting in a drastic resolution of various symptoms. The findings in this case show that bilirubin-induced neurotoxicity in adults may be reversible and indicate that the current liver transplantation criteria used in Japan, which limit eligibility for CNS to pediatric patients, may have contributed to delayed transplantation. Re-evaluation of the transplant eligibility criteria is necessary to allow for a more inclusive approach that encompasses adult patients.
2026-04-30 | Liver Transplantation Outcomes in Crigler-Najjar Syndrome in Iran: A Single-Center Retrospective Cohort Study Over 20 Years.
Crigler-Najjar Syndrome (CNS) is a rare autosomal recessive disorder caused by uridine diphosphate glucuronosyltransferase (UGT1A1) deficiency, leading to unconjugated hyperbilirubinemia. Without treatment, patients are at high risk of kernicterus and irreversible neurological damage. Liver transplantation (LT) is the only curative option. This study aims to evaluate long-term outcomes of LT in CNS patients over a 20-year period in Iran. In this retrospective cohort study, we analyzed 69 patients with CNS who underwent LT between 2000 and 2023 at Namazi Hospital and Abu Ali Sina Transplant Center in Shiraz, Iran. Long-term follow-up data, graft function, patient survival, and pre- and post-LT outcomes were evaluated. Posttransplantation, bilirubin metabolism and liver function normalized rapidly. Within the first year, the overall mortality rate was 14.5%, mainly due to graft failure and sepsis. Late mortality (2.9%) was predominantly linked to chronic rejection and infections. LT remains a definitive curative option for patients with CNS. However, postoperative complications, particularly hematologic and renal dysfunction, remain significant concerns. These findings underscore the importance of ongoing monitoring and optimization of post-LT care. Furthermore, the lack of consensus regarding ideal timing for LT highlights the need for future prospective studies to better inform clinical decision-making.
2024-07-01 | Effectiveness of Double-volume Exchange Transfusion in Neonates with Hyperbilirubinemia: A Single-center Experience
A BSTRACT Background and Objectives: Double-volume exchange transfusion (DVET) is a life-saving procedure that replaces a neonate’s blood volume twice over with adult donor blood to treat neonatal hyperbilirubinemia and prevent kernicterus. This study assessed DVET’s effectiveness in reducing total serum bilirubin (TSB) concentration in neonates at risk of kernicterus and examined the disease conditions that necessitate DVET. Methods: This observational study assessed the effectiveness of DVET in 104 neonates at risk of kernicterus. Neonates meeting the American Academy of Pediatrics guidelines were selected. Blood samples were collected before and 24 h after DVET for TSB estimation and complete blood count analysis. Blood components were selected based on ABO, Rh, and other minor blood group incompatibility. DVET was performed using the push–pull method. Results: This study of DVET in 104 neonates with hyperbilirubinemia found that DVET is an effective treatment, reducing TSB levels by 61.72% on average. The most common cause of hyperbilirubinemia was idiopathic (25.6%), followed by ABO incompatibility (22.12%) and anti-D alloimmunization (17.31%). In hypothyroid, preterm, and sepsis cases, hemoglobin levels decreased by an average of 17.7%, 12.9%, and 13.9%, respectively, after DVET. However, in cases of minor alloimmunization and anti-D alloimmunization, hemoglobin levels increased by an average of 29% and 40.5%, respectively, after DVET. The maximum decrease in TSB level was observed in cases of ABO incompatibility with sepsis (82%), while the minimum decrease was seen in neonates undergoing DVET due to sepsis (50%). The percentage reduction of TSB level after DVET was similar for different etiologies, ranging from 50.2% to 65.4%. Conclusion: DVET is a rarely used procedure in the age of phototherapy and intravenous immunoglobulin for neonatal hyperbilirubinemia. However, it is the only effective treatment for very high bilirubin levels to prevent kernicterus or bilirubin encephalopathy.
2024-04-01 | Behavioral and neurocognitive phenotypes in Crigler-Najjar syndrome in Tunisia
Introduction Crigler-Najjar 1 (CN1) due to exon 3 mutations of the UGT1A1 gene is a not rare genetic disease in Tunisia with a founder effect. CN1 syndrome is very severe, and most of CN1 Tunisian patients die soon after birth, within a maximum of one year, due to kernicterus. Liver transplantation, which is the only available therapeutic method for CN1, remains unreachable. Objectives The aim of this study was to report behavioral and neurocognitive phenotypes in CN1 patients who survived to school enrollment. Methods We have selected all patients evaluated from 2004 to 2010, both clinically and molecularly, for a deficiency of bilirubin-UGT enzyme activity leading to a pathological elevation of unconjugated bilirubin with a suspicion of CN1 syndrome. Direct sequencing of targeted PCR amplification products was performed for molecular analysis of UGT1A1. Behavioral and mental features of patients were studied through our genetic counselling. Results We identified 15 patients with the homozygous c.1070 A>G Tunisian mutation. Their age at diagnosis ranged from one week to 9 months for 13 patients. Six of them died within a month of molecular investigation. Only two boys were of school age, i.e. 6 and 9 years. The first had been hospitalized at 3 months year-old for a prolonged jaundice treated with phenobarbital and phototherapy. His psychomotor and neurological development was normal, with school attendance at the age of six. The second patient presented with an unexplored jaundice at the age of 3 days, which was later complicated by seizures and treated with phenobarbital. Despite neurological and motor sequelae associated to language impairments with slurred speech, he attended school at the age of six. Conclusions The neurological and behavioral profile of CN1 patients depends on familial and medical management. Quick diagnosis, close follow up and early liver transplantation can improve prognosis. Disclosure of Interest None Declared
proteins
2026-08-24 | Albumin priming prior to an exchange transfusion: Is it time to prime for neuroprotection?
Albumin is the crux of the exchangeable (i.e., miscible) bilirubin pool, controlling via its high affinity binding the distribution of bilirubin within and across the intravascular and extravascular spaces. It follows that clinicians should leverage the administration of bilirubin free albumin in the management of hazardous hyperbilirubinemia to avoid or reverse bilirubin neurotoxicity. A standard double volume exchange transfusion does exactly that via the albumin laden fresh frozen plasma used to reconstitute the blood infused during the procedure. Albumin priming - the infusion of bilirubin-free albumin prior to a double volume exchange transfusion - augments the infant's pre-exchange albumin mass and albumin bilirubin binding capacity. As such, albumin priming can enhance bilirubin clearance over the course of the subsequent exchange transfusion and provide an immediate stepwise gain in neuroprotection during the pre-exchange period. The potential for neuroprotection against worsening bilirubin-induced neurological dysfunction is the principal reason to albumin prime and prime early when caring for a neonate with signs of intermediate to advanced stage acute bilirubin encephalopathy. Albumin priming should also be considered in asymptomatic infants whose bilirubin - albumin molar ratios approach or exceed albumin's saturable binding limits, as a preventive measure to attenuate bilirubin neurotoxicity risk.
2026-03-19 | A Comparative Public Health Perspective from India and Kyrgyzstan
Background Neonatal jaundice, the yellow discoloration of skin and sclera from unconjugated bilirubin accumulation, affects more than half of term newborns globally. While typically physiological and self-limiting, severe hyperbilirubinemia can cause kernicterus—a permanent, devastating neurological injury. India and Kyrgyzstan represent contrasting epidemiological landscapes: India, a lower-middle-income tropical giant with high birth volume, diverse genetic profiles, and heterogeneous health system capacity; Kyrgyzstan, a post-Soviet upper-middle-income mountainous republic with universal health coverage, cold climate, and concentrated specialised care. Comparative analysis illuminates how geography, genetics, health system architecture, and phototherapy access shape the burden, recognition, and outcome of this ubiquitous neonatal condition
2024-02-21 | Nerve Growth Factor Protects Brain Tissue from Hyperbilirubinemia by Down Regulating Fas/Fas Ligand Expression
To examine the potential protective impact and underlying mechanism of nerve growth factor on brain tissue in hyperbilirubinemia rats through the downregulation of Fas/Fas ligand expression. Thirty six healthy Sprague-Dawley rats were selected as normal control group, and 0.5 ml saline was injected intraperitoneally. The remaining 24 rats were injected intraperitoneally with 50 μg/g bilirubin to establish the model of hyperbilirubinemia. After the model was established successfully, they were divided into hyperbilirubinemia group and nerve growth factor intervention group. The rats in the nerve growth factor intervention group were intraperitoneally injected with 50 μg/kg/d nerve growth factor once a day for 3 d. Rats in each group were killed and their brain tissues were taken to wait for detection. The changes of pathological morphology and the Fas and Fas ligand were compared between the normal control group at 72 h and the hyperbilirubinemia group at 6 h, 24 h, 72 h and the nerve growth factor intervention group. In hyperbilirubinemia group and nerve growth factor intervention group, the brain tissue of rats had different degrees of neurocyto edema. After 6 h, the brain tissue of both groups had degeneration. After 24 h, the neuron necrosis was obvious. After 72 h, the brain tissue of both groups had glial cell proliferation, nuclear pyknosis and fragmentation. However, the severity of brain tissue in nerve growth factor intervention group was less than that in hyperbilirubinemia group, while that in normal control group was not obvious change. At 6 h, 24 h and 72 h, the Fas in the hyperbilirubinemia group was raised than that of the normal control group; while this in the nerve growth factor intervention group was reduced than that of hyperbilirubinemia. At 6 h, 24 h and 72 h, the Fas ligand in hyperbilirubinemia group was raised than that of normal control group; and it in nerve growth factor intervention group was reduced than that of hyperbilirubinemia group. The expression of Fas/Fas ligand can be downregulated by nerve growth factor, thereby providing protection to the brain tissue of rats with hyperbilirubinemia.
2022-09-08 | Effect of Pre-exchange Transfusion Albumin Infusion on Neonatal Hyperbilirubinemia: A Meta-analysis of Randomized Clinical Trials
Background: This study was carried out to systematically evaluate the efficacy and safety of pre-exchange transfusion (pre-ET) albumin infusion on neonatal hyperbilirubinemia. Methods: A comprehensive search of relevant studies from EMBASE, Medline, Cochrane Register of Controlled Trials, ClinicalTrials.gov, China National Knowledge Infrastructure, Wei Pu Information, Wan Fang Data, and Chinese Biomedical Literature Database was conducted from inception to December 2021. Two different authors screened the titles, abstracts, and full texts of the articles. The quality of the included trials was assessed independently by two different authors according to the Cochrane Collaboration’s Risk of Bias. The data were analyzed and compiled using Review Manager software (RevMan version 5.3). Results: In total, four studies enrolling 195 neonates were included in this review. The quality of the included studies was deemed fair to good. The meta-analysis showed that pre-ET albumin infusion was superior to exchange transfusion (ET) alone for reducing the need for repeating ET (risk ratio (RR) = 0.25, 95% confidence interval (CI): 0.09 - 0.72, I-squared (I2) = 8%; fixed effects model) and shortening the duration of phototherapy (PT) (mean difference (MD) = -11.46 hours, 95% CI: -16.56 to -6.36, I2 = 93%; random effects model (REM)). No significant differences were detected between the two groups for post-ET total serum bilirubin (TSB) at 6 hours (MD = -3.51 mg/dL, 95% CI: -7.93 - 0.93, I2 = 97%; REM) and 12 hours (MD = -4.21 mg/dL, 95% CI: -9.08 - 0.65, I2 = 99%; REM). None of the patients developed acute bilirubin encephalopathy in any of the trials. No death prior to hospital discharge was reported in any trials, and no adverse effects were observed in intervention groups. Conclusions: Based on four studied trials, pre-ET albumin infusion appears to be safe and effective in reducing the need for repeating ET and shortening PT duration. These potential benefits, including the reduction of post-ET TSB, need to be revalidated in future trials using rigorous methodology.
2020-11-02 | A questionnaire survey on the efficacy of various treatments for dyskinetic cerebral palsy due to preterm bilirubin encephalopathy.
Preterm children with severe dyskinetic cerebral palsy due to bilirubin encephalopathy often suffer from marked generalised hypertonus as they age. We performed a questionnaire survey to investigate patient-reported outcomes of treatments for improving their activities of daily life. A mail questionnaire was administered to the caregivers of 67 children with preterm bilirubin encephalopathy aged >4 years. We asked about the type of treatments they received and their efficacy using a five-point subjective scale for the following five domains: motor function, postural stability, sleep, pain, and care burden. The names of oral drugs and their efficacies were also explored. The response rate of the questionnaires was 62.7% (42/67), and we analysed the results from 41 validated cases. All children underwent rehabilitation. A total of 30 children received oral drugs, 22 botulinum toxin, 12 orthopaedic surgery, and 3 intrathecal baclofen. Each of these treatments was subjectively reported to be effective in more than half of the recipients for each of the five domains, whereas 23 (56%) required more than two types of treatments other than rehabilitation. Chlordiazepoxide was the most commonly used oral drug, by 28 children (68%), and was discontinued in 7 patients (25%) only. In the sleep domain, the rate of a positive effect was significantly higher for oral drugs (92.7%) than the other treatments (p < 0.01). All treatments were partially effective, but their appropriate combination based on a multidisciplinary approach is essential for muscle tone management in children with preterm bilirubin encephalopathy.
gene therapies
2024-12-01 | Approaches to therapy of Crigler–Najjar syndrome type 1 in children
The review is focused on exploring the etiology, pathogenesis, clinical manifestations, and primarily the contemporary treatment methods for Crigler–Najjar syndrome type 1. It considers relevant data regarding the efficacy and safety of the currently existing therapeutic strategies. Effective management of this condition relies on early diagnosis and prompt initiation of treatment, which are crucial for preventing disabling neurological complications associated with bilirubin encephalopathy in patients with Crigler–Najjar syndrome type 1. Prolonged phototherapy is the key treatment method, while liver transplantation represents a radical approach. Recent advances in gene therapy and the use of mesenchymal multipotent stromal cells present novel opportunities for developing alternative, less invasive treatment modalities aimed at improving the quality of life in such patients and reducing their dependence on long-term phototherapy, along with post-transplantation risk.
2024-09-17 | Therapeutic Options for Crigler-Najjar Syndrome: a Scoping Review
Crigler-Najjar Syndrome (CNS) is a rare genetic disorder caused by mutations in the UGT1A1 gene, leading to impaired bilirubin conjugation and severe unconjugated hyperbilirubinemia. CNS presents in two forms: CNS type 1 (CNS1), the more severe form with a complete absence of UGT1A1 activity, and CNS type 2 (CNS2), with partial enzyme activity. CNS1 requires aggressive management, including phototherapy and plasmapheresis, but liver transplantation (LT) remains the only definitive cure. The timing of LT is critical, as it must be performed before the onset of irreversible brain damage (kernicterus), making early intervention essential. However, LT poses risks such as graft rejection and lifelong immunosuppression. CNS2 is milder, with patients re-sponding well to phenobarbital and having a lower risk of kernicterus. Recent advancements in gene therapy and autologous hepatocyte transplantation offer promising alternatives to LT. Gene therapy using adeno-associated virus (AAV) vectors has shown potential in preclinical studies, though challenges remain in pediatric applications due to liver growth and pre-existing immunity. Autologous hepatocyte transplantation avoids the risks of rejection but requires further research. These emerging therapies provide hope for more effective and less invasive treatment options, aiming to improve the quality of life for CNS patients and reduce reliance on lifelong interven-tions.
2022-03-31 | Neuroglobin expression and function in the temporal cortex of bilirubin encephalopathy rats.
Bilirubin encephalopathy (BE) is a neurological syndrome in newborns, mainly caused by neuronal injury due to excessive oxidative stress produced by unconjugated bilirubin (UCB). Neuroglobin (NGB) can protect the brain by removing oxidative stress species, but its expression and significance in BE are not clear. To address this question, the neonatal BE model was established by injecting UCB into the cerebellomedullary cistern of 7-day-old SD rats. Rats were divided into a sham and BE 6 hr group, BE 12 hr group, BE 24 hr group, and BE 7 d group according to UCB action times. Hematoxylin/eosin and Nissl staining, and electron microscopy were employed to observe the pathological and ultrastructural changes of nerve cells in each group. Immunofluorescence staining was used to detect NGB expression sites and cell types. Western blotting and quantitative PCR served to detect NGB expression and test the mitochondrial apoptosis signal pathway. The results confirm that UCB can lead to pathological damage and ultrastructural changes in rats' temporal cortex, increasing the expression of apoptosis-related proteins Bax, Bcl-2, Cyt c, Caspase-3, and neuronal NGB. UCB promotes NGB expression with an increase in action time and reach a peak at 12 hr. In summary, brain damage induced by UCB will cause an increase in NGB expression, the increasing NGB can inhibit neuron apoptosis in early BE phases. Therefore, promoting the expression of endogenous NGB, to act as a neuroprotective agent may be a potential treatment strategy for BE.
2018-12-01 | AAV8 Gene Therapy for Crigler-Najjar Syndrome in Macaques Elicited Transgene T Cell Responses That Are Resident to the Liver
Systemic delivery of adeno-associated viral (AAV) vectors has been evaluated for the treatment of several liver diseases, including homozygous familial hypercholesterolemia, ornithine transcarbamylase deficiency, and hemophilia. Here, we evaluated this approach for the treatment of Crigler-Najjar syndrome. We administered wild-type rhesus macaques with 1.0 × 1013 or 2.5 × 1013 genome copies/kg of an AAV serotype 8 vector expressing a codon-optimized version of human uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) from a liver-specific promoter. We extensively studied vector biodistribution, transgene expression, and immune responses following vector administration. All rhesus macaques survived until their scheduled necropsy at day 56 and showed no clinical abnormalities during the course of the study. Macaques administered with either vector dose developed a T cell response to the AAV capsid and/or transgene. We mapped the immunodominant epitope in the human UGT1A1 sequence, and we found no correlation between peripheral and tissue-resident lymphocyte responses. Upon further investigation, we characterized CD107a+, granzyme B+, CD4+, and CD8+ transgene-specific cellular responses that were restricted to tissue-resident T cells. This study highlights the importance of studying immune responses at the vector transduction site and the limited usefulness of blood as a surrogate to evaluate tissue-restricted T cell responses. Systemic delivery of adeno-associated viral (AAV) vectors has been evaluated for the treatment of several liver diseases, including homozygous familial hypercholesterolemia, ornithine transcarbamylase deficiency, and hemophilia. Here, we evaluated this approach for the treatment of Crigler-Najjar syndrome. We administered wild-type rhesus macaques with 1.0 × 1013 or 2.5 × 1013 genome copies/kg of an AAV serotype 8 vector expressing a codon-optimized version of human uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) from a liver-specific promoter. We extensively studied vector biodistribution, transgene expression, and immune responses following vector administration. All rhesus macaques survived until their scheduled necropsy at day 56 and showed no clinical abnormalities during the course of the study. Macaques administered with either vector dose developed a T cell response to the AAV capsid and/or transgene. We mapped the immunodominant epitope in the human UGT1A1 sequence, and we found no correlation between peripheral and tissue-resident lymphocyte responses. Upon further investigation, we characterized CD107a+, granzyme B+, CD4+, and CD8+ transgene-specific cellular responses that were restricted to tissue-resident T cells. This study highlights the importance of studying immune responses at the vector transduction site and the limited usefulness of blood as a surrogate to evaluate tissue-restricted T cell responses.
2018-07-03 | Advances in understanding disease mechanisms and potential treatments for Crigler–Najjar syndrome
Introduction: The Crigler–Najjar syndrome (CNS) is an ultra-rare recessive disorder of the liver. There is no effective cure, except for liver transplantation, a procedure with many risks and shortcomings. Thus, the development of novel therapeutic approaches is a clinical need.Areas covered: This review aims at describing potentialities and limitations of novel experimental treatments that can be applied to cure the CNS and other metabolic liver diseases. These include pharmacological and gene therapy approaches, some of them are now being applied in clinical trials of Crigler–Najjar patients. Brief descriptions of bilirubin metabolism, mechanisms of disease, and animal models are also included.Expert opinion: AAV-mediated gene therapy approaches to pediatric liver diseases are very challenging due to the potential loss of viral DNA consequent to liver growth. Novel immunomodulatory strategies are being developed that can allow re-administration of the therapeutic vector by blocking the generation of anti-AAV neutralizing antibodies. Another very promising approach is gene targeting of the therapeutic cDNA into a 'safe-harbor locus,' resulting in the permanent correction of the genetic defect. However, further experimentation is still required to increase safety and efficacy. The success of these approaches will result in alternative therapies to liver transplantation.
other
2026-07-16 | Efficacy and safety of different doses of intravenous immunoglobulin combined with phototherapy in neonatal hemolytic disease: a systematic review and meta-analysis.
Neonatal hemolytic disease is a major cause of neonatal hyperbilirubinemia and kernicterus. Intravenous immunoglobulin (IVIG) combined with phototherapy is a commonly used clinical intervention; however, the optimal dosing regimen remains controversial. This study aimed to systematically evaluate the efficacy and safety of different doses of IVIG combined with phototherapy in the treatment of neonatal hemolytic disease, and to provide evidence-based guidance for optimizing clinical dosing strategies. A comprehensive literature search was conducted in PubMed, Embase, the Cochrane Library, Web of Science, and Scopus, as well as Chinese databases including CNKI, Wanfang Data, VIP, and the Chinese Biomedical Literature Database, from inception to February 2026. Randomized controlled trials comparing high-dose versus low-dose IVIG combined with phototherapy in neonatal hemolytic disease were included. The primary outcomes included exchange transfusion rate, duration of phototherapy, length of hospital stay, serum bilirubin levels at 24 h, hemoglobin levels at 72 h, and incidence of adverse events. Meta-analysis was performed using RevMan 5.4.1, with fixed- or random-effects models applied according to heterogeneity. A total of 10 randomized controlled trials involving 690 neonates were included. Compared with the low-dose IVIG group, the high-dose IVIG group showed a significantly lower exchange transfusion rate (Peto OR = 0.24, 95% CI: 0.12-0.50, P = 0.0001), corresponding to an approximately 76% reduction in the odds of exchange transfusion. High-dose IVIG was also associated with a shorter duration of phototherapy (MD = - 9.11 h, P = 0.002), a shorter length of hospital stay (MD = - 1.83 days, P = 0.0008), and lower serum bilirubin levels at 24 h (MD = - 38.86, P < 0.00001). No statistically significant differences were observed between the two groups in hemoglobin levels at 72 h or adverse reaction rates (all P > 0.05). Compared with low-dose IVIG, high-dose IVIG combined with phototherapy was associated with lower exchange transfusion rates, shorter phototherapy duration and hospital stay, and lower serum bilirubin levels in neonates with hemolytic disease. No statistically significant differences were observed in hemoglobin levels at 72 h or adverse reaction rates between the two groups. Further large-scale, high-quality randomized controlled trials are warranted to confirm these findings and to clarify the potential impact of blood group subtype on treatment response. •Neonatal hemolytic disease remains a common cause of severe neonatal hyperbilirubinemia. •Intravenous immunoglobulin (IVIG) is frequently used as an adjunctive treatment, but the optimal dosage remains uncertain. • This meta-analysis compared different IVIG dosing regimens using randomized controlled trials only. • High-dose IVIG was associated with lower exchange transfusion rates and improved several short-term clinical outcomes.
2026-06-08 | Kernicterus and Bilirubin-Induced Neurologic Dysfunction (BIND): Pathophysiology, Clinical Management, and Strategies for Prevention of a Reversible Catastrophe
Kernicterus, or chronic bilirubin encephalopathy, represents a permanent, disabling neurologic condition resulting from the deposition of unconjugated bilirubin in the basal ganglia and brainstem nuclei of neonates. This review provides a comprehensive examination of the condition, beginning with its pathophysiological basis: the passage of lipid-soluble unconjugated bilirubin across an immature or compromised blood-brain barrier, followed by selective neuronal injury mediated by mitochondrial dysfunction, oxidative stress, and apoptosis. The etiological landscape is bifurcated into disorders of increased bilirubin production (hemolysis, polycythemia, birth trauma) and decreased excretion (hypoalbuminemia, UGT1A1 deficiency, breast milk jaundice), with a significant proportion of cases remaining idiopathic. Epidemiology reveals striking disparities by race, sex, and gestational age, with preterm and male infants at highest risk. The clinical progression follows a predictable three-phase acute course—from lethargy and poor feeding to hypertonia and opisthotonos, culminating in hypotonia and apnea—which, if untreated, evolves into chronic choreoathetoid cerebral palsy, auditory neuropathy, and oculomotor deficits. Diagnosis rests on serial bilirubin measurements, hematologic evaluation for hemolysis, and brainstem auditory evoked responses. Management is stratified by severity and includes intensive phototherapy, intravenous immunoglobulins for immune-mediated hemolysis, and exchange transfusion for emergent cases. Prevention remains the cornerstone: universal bilirubin screening, adherence to hour-specific nomograms, early follow-up, and parental education have drastically reduced the incidence in high-resource settings. The prognosis is excellent with early intervention but dismal with delayed recognition. Kernicterus is a largely preventable tragedy, and its continued occurrence—particularly in low- and middle-income countries—represents a failure of systems, not biology.
2026-06-01 | Neonatal Jaundice and the Developing Brain: Pathophysiology, Clinical Management, and Long-Term Neurological Outcome
Neonatal jaundice, characterized by elevated serum bilirubin levels, is a common condition affecting newborns globally. While mild jaundice is often benign, severe hyperbilirubinemia poses a significant risk to neurological development. If left untreated, it can lead to irreversible brain damage, with lifelong implications for affected children. This review aims to examine the impact of neonatal jaundice on pediatric neurological outcomes, focusing on the pathophysiology, risk factors, clinical manifestations, and long-term consequences. A comprehensive analysis of current literature was conducted, including clinical studies and systematic reviews. Emphasis was placed on understanding the neurological sequelae of neonatal jaundice and evaluating the effectiveness of therapeutic interventions. Findings indicate that severe neonatal jaundice is associated with neurological complications such as acute bilirubin encephalopathy and kernicterus. These conditions can result in motor impairments, hearing loss, speech delays, and cognitive dysfunction. Early diagnosis and interventions, such as phototherapy and exchange transfusion, have significantly reduced the incidence of severe outcomes. However, in low-resource settings, delayed diagnosis and inadequate treatment remain substantial challenges, increasing the risk of permanent disability. Neonatal jaundice, if improperly managed, poses serious risks to pediatric neurological health. Timely intervention and improved screening protocols are essential to prevent long-term neurological damage. Further research is needed to explore the subtle neurodevelopmental effects and to enhance care strategies, especially in under-resourced regions. A multidisciplinary approach is crucial to mitigate these risks and improve outcomes for affected children.
2026-03-18 | Predominance of Rh-mediated haemolytic disease driving exchange transfusions in rural north India: A five-year retrospective analysis revealing critical prevention gaps.
Exchange transfusion remains the definitive treatment for severe neonatal hyperbilirubinaemia; yet its aetiology and outcomes in rural tropical settings are poorly characterised. This five-year retrospective analysis of 58 neonates at a North Indian rural tertiary centre reveals that Rh incompatibility accounted for 76% of cases - a striking divergence from high income-country patterns where ABO incompatibility predominates - indicating critical gaps in antenatal Rh immuno-prophylaxis. The procedure achieved a mean bilirubin reduction of 50% (424 ± 106 to 212 ± 70&mu/L, p < 0.001) with no procedure-related mortality, though clinically significant adverse events occurred in 19% of neonates. Notably, 10.2% presented with acute bilirubin encephalopathy at the time of intervention, representing potentially preventable neurological injury. These findings make a compelling case for urgent, systematic improvements in antenatal screening, Rh immuno-prophylaxis access, and early jaundice recognition in tropical resource-limited settings.
2026-03-15 | Neonatal hyperbilirubinemia: risk factors pathophysiology and complications
In newborns, elevated concentrations of unconjugated bilirubin can cross the blood-brain barrier and deposit in the basal ganglia or cerebellum, causing bilirubin-induced encephalopathy or kernicterus. Genetic polymorphisms in three bilirubin metabolism genes, including ABO/Rh incompatibility, glucose-6-phosphate dehydrogenase (G6PD) deficiency, uridine diphosphate gluconoryltransferase gene (UGT1A1), organ anion transporter genes (OATP1B1), and hemoxicase gene (HO-1), have been identified as causes of hyperbilirubinemia. Neonates with elevated hyperbilirubinemia are at risk for bilirubin-induced neurologic dysfunction (BIND).
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