The short and long-term prognostic influences of liver grafts with high bilirubin levels at the time of organ recovery.

BACKGROUND: Donors with hyperbilirubinemia are often not utilized for liver transplantation (LT) due to concerns about potential liver dysfunction and graft survival. The potential to mitigate organ shortages using such donors remains unclear. METHODS: This study analyzed adult deceased donor data from the United Network for Organ Sharing database (2002-2022). Hyperbilirubinemia was categorized as high total bilirubin (3.0-5.0 mg/dL) and very high bilirubin (≥5.0 mg/dL) in brain-dead donors. We assessed the impact of donor hyperbilirubinemia on 3-month and 3-year graft survival, comparing these outcomes to donors after circulatory death (DCD). RESULTS: Of 138 622 donors, 3452 (2.5%) had high bilirubin and 1999 (1.4%) had very high bilirubin levels. Utilization rates for normal, high, and very high bilirubin groups were 73.5%, 56.4%, and 29.2%, respectively. No significant differences were found in 3-month and 3-year graft survival between groups. Donors with high bilirubin had superior 3-year graft survival compared to DCD (hazard ratio .83, p = .02). Factors associated with inferior short-term graft survival included recipient medical condition in intensive care unit (ICU) and longer cold ischemic time; factors associated with inferior long-term graft survival included older donor age, recipient medical condition in ICU, older recipient age, and longer cold ischemic time. Donors with ≥10% macrosteatosis in the very high bilirubin group were also associated with worse 3-year graft survival (p = .04). DISCUSSION: The study suggests that despite many grafts with hyperbilirubinemia being non-utilized, acceptable post-LT outcomes can be achieved using donors with hyperbilirubinemia. Careful selection may increase utilization and expand the donor pool without negatively affecting graft outcome.

Results of the Study of the Auditory Analyzer in Newborns with Hyperbilirubinemia.

According to statistics, hyperbilirubinemia is observed during the first week of life in approximately 60% of full-term and 80% of premature newborns. It is known that indirect bilirubin has a neurotoxic effect. Accumulation of unconjugated bilirubin in some brain structures may appear to be a temporary or unexpected impairment in auditory, motor, or cognitive function. The narrowing of the OAE spectrum and low amplitude of the response, the increase in the latent periods of III, IV, V peaks, as well as the prolongation of the time of the central sound conduction of the III-V and I-V waves in all newborns with hyperilirubinemia, indicates a pathology of hearing of central origin with impaired conduction along the auditory pathways at the level the lower and middle thirds of the pons of the brain (Р ≤ 0.05).

Hyperbilirubinemia and Choledocholithiasis in an Extremely Premature Neonate.

Cholestasis affects 2% of newborns admitted to the neonatal intensive care unit and 20% of premature infants and requires a thoughtful evaluation and diagnostic workup.There may be a single responsible etiology, or its development may be multifactorial. Premature neonates are especially predisposed because of their increased risk of infections and acute illness, need for parenteral nutrition, and exposure to certain medications. Clinically, an infant may present with jaundice, evidence of hepatic injury, or worsening hepatic function. Diagnosis may be made in consultation with various pediatric subspecialists including gastroenterology, genetics, and surgery. Treatment depends on the etiology but may include medications or surgical interventions. Timely recognition and intervention improve outcomes. [Pediatr Ann. 2023;52(8):e297-e302.].

Gene Therapy in Patients with the Crigler-Najjar Syndrome.

BACKGROUND: Patients with the Crigler-Najjar syndrome lack the enzyme uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1), the absence of which leads to severe unconjugated hyperbilirubinemia that can cause irreversible neurologic injury and death. Prolonged, daily phototherapy partially controls the jaundice, but the only definitive cure is liver transplantation. METHODS: We report the results of the dose-escalation portion of a phase 1-2 study evaluating the safety and efficacy of a single intravenous infusion of an adeno-associated virus serotype 8 vector encoding UGT1A1 in patients with the Crigler-Najjar syndrome that was being treated with phototherapy. Five patients received a single infusion of the gene construct (GNT0003): two received 2×1012 vector genomes (vg) per kilogram of body weight, and three received 5×1012 vg per kilogram. The primary end points were measures of safety and efficacy; efficacy was defined as a serum bilirubin level of 300 µmol per liter or lower measured at 17 weeks, 1 week after discontinuation of phototherapy. RESULTS: No serious adverse events were reported. The most common adverse events were headache and alterations in liver-enzyme levels. Alanine aminotransferase increased to levels above the upper limit of the normal range in four patients, a finding potentially related to an immune response against the infused vector; these patients were treated with a course of glucocorticoids. By week 16, serum bilirubin levels in patients who received the lower dose of GNT0003 exceeded 300 µmol per liter. The patients who received the higher dose had bilirubin levels below 300 µmol per liter in the absence of phototherapy at the end of follow-up (mean [±SD] baseline bilirubin level, 351±56 µmol per liter; mean level at the final follow-up visit [week 78 in two patients and week 80 in the other], 149±33 µmol per liter). CONCLUSIONS: No serious adverse events were reported in patients treated with the gene-therapy vector GNT0003 in this small study. Patients who received the higher dose had a decrease in bilirubin levels and were not receiving phototherapy at least 78 weeks after vector administration. (Funded by Genethon and others; ClinicalTrials.gov number, NCT03466463.).

COVID-19-induced transaminitis and hyperbilirubinemia: Presentation and outcomes.

The risk of liver injury in patients with coronavirus disease 2019 (COVID-19) infection is quite evident. Furthermore, liver function test abnormalities are still detected in COVID-19 patients despite the development of antivirals and the availability of several types of vaccines. This editorial describes liver involvement during COVID-19 infection in patients with or without preexisting liver injury, such as chronic liver disease, to elucidate COVID-19-induced liver function abnormalities and their severity, pathophysiology, clinical manifestations, and clinical and laboratory outcomes. We also discuss the effect of vaccination against COVID-19 to better understand host factors, such as age, gender, and race, on the incidence and severity of liver dysfunction at initial presentation and during the illness. Finally, we summarize the results of relevant meta-analyses published to date and highlight the importance of adequate liver function monitoring in the current climate of the overwhelming COVID-19 pandemic.

The application of hemoadsorption for hyperbilirubinemia and its impact on bilirubin removal kinetics in critically ill children.

Extracorporeal blood purification (EBP) is increasingly applied for bilirubin removal in critical care setting. We retrospectively reviewed the clinical features of children aged 1 month to 18 years old who received EBP for hyperbilirubinemia and explored the bilirubin removal kinetics by hemoadsorption (HA) in the pediatric intensive care unit of Hong Kong Children's Hospital from 3/2019 to 7/2022. Among the 14 episodes of EBP from six patients with a median age (interquartile range [IQR]) of 9.3(5.5) years old, 57.1% of them received HA, 33.3% received single-pass albumin dialysis (SPAD), and 7.1% received combined SPAD and HA. All HA episodes employed the Cytosorb® column. The median (IQR) pre-HA peak total bilirubin level was 406 (254) µmol/L. The saturation duration per HA episode was significantly shorter than the corresponding total treatment duration (8 vs 24 h, p = 0.012), and the median total and effective HA doses were 9.8(6.8) L/kg and 300.0 (163.4) mL/kg/h respectively. The overall bilirubin removal ratio by HA was 44.6 (14.5)%. A higher HA effective dose and a higher pre-HA bilirubin level were both associated with better bilirubin removal. No major EBP-specific complication was encountered. The liver enzymes showed improvement in all children. No patients required liver transplantation. There was no EBP-related mortality, but the overall PICU mortality of the cohort was 50%. HA was a safe and effective modality for bilirubin removal among children. Future studies should investigate the impact of bilirubin removal on clinical outcomes and explore the factors responsible for better removal efficacy.

Evaluation of thiol-disulfide homeostasis and oxidative stress parameters in newborns receiving phototherapy.

The aim of our study was to evaluate oxidative stress and thiol-disulfide homeostasis in term newborns receiving phototherapy. The study was planned as a single-blind, intervention study in a single center with level 3 neonatal intensive care unit to investigate the effect of phototherapy on the oxidative system in term newborns with hyperbilirubinemia. Neonates with hyperbilirubinemia were treated with total body exposure phototherapy technique for 18 h using a Novos® device. Blood samples of 28 term newborns were taken before and after phototherapy. Total and native thiol, total antioxidant status (TAS) and total oxidant status (TOS), and oxidative stress index (OSI) levels were measured. The 28 newborn patients included 15 (54%) males and 13 (46%) females with a mean birthweight of 3080.1 ± 366.5 g. Native and total thiol levels were found to be decreased in patients receiving phototherapy (p = 0.021, p = 0.010). Besides, significantly lower TAS and TOS levels were found after phototherapy (p < 0.001, p < 0.001). We found that decreased thiol levels were related to increased oxidative stress. We also determined significantly the lower bilirubin levels after phototherapy (p < 0.001). In conclusion, we found that phototherapy treatment induced decreased oxidative stress associated with hyperbilirubinemia in neonates. Thiol-disulfide homeostasis can be used as a marker of oxidative stress due to hyperbilirubinemia in the early period.

Findings in percutaneous trans-hepatic cholecysto-cholangiography in neonates and infants presenting with conjugated hyperbilirubinemia: emphasis on differential diagnosis and cholangiographic patterns.

BACKGROUND: Biliary atresia (BA) is one of the causes of conjugated hyperbilirubinemia in infants which if untreated leads to end-stage liver disease and death. Percutaneous Trans-hepatic Cholecysto-Cholangiography (PTCC) is a minimally invasive study which can be utilized in the diagnostic work-up of these patients. This study's purpose is to describe the experience with PTCC in neonates, the imaging findings encountered, and the abnormal patterns which warrant further investigation. METHODS: A 16-year single-center retrospective study of patients with persistent neonatal cholestasis (suspected BA) undergoing PTCC. Patient demographics, laboratory values, PTCC images, pathology and surgical reports were reviewed. RESULTS: 73 patients underwent PTCC (68% male, mean age 8.7 weeks, mean weight 4.0 Kg). The majority of studies were normal (55%). Abnormal patterns were identified in 33 cases, 79% were diagnosed with BA and 12% with Alagille syndrome. Non-opacification of the common hepatic duct with a narrowed common bile duct (42%) and isolated small gallbladder (38%) were the most common patterns in BA. CONCLUSION: PTCC is a minimally invasive study in the diagnostic work-up of infants presenting with conjugated hyperbilirubinemia (suspected BA). Further invasive investigations or surgery can be avoided when results are normal.

Rolling stones: an instructive case of neonatal cholestasis.

BACKGROUND: Jaundice within the first 1-2 weeks of a neonate's life will generally self-resolve; however, if it lasts longer than this time frame it warrants further work up. Direct or conjugated hyperbilirubinemia can suggest neonatal cholestasis, which in turn reflects marked reduction in bile secretion and flow. The differential diagnosis for neonatal cholestasis is broad. Neonatal choledocholithiasis is a rare cause of neonatal cholestasis, but should be considered on the differential diagnosis for patients presenting with elevated conjugated bilirubin. CASE PRESENTATION: We describe an infant who presented with neonatal cholestasis. He subsequently underwent work up for biliary atresia, as this is one of the more time-sensitive diagnoses that must be made in neonates with conjugated hyperbilirubinemia. He was ultimately found to have choledocholithiasis on magnetic resonance cholangiopancreatography. He was managed conservatively with optimizing nutrition and ursodeoxycholic acid therapy. CONCLUSIONS: We found that conservative management, specifically optimizing nutrition and treating with ursodeoxycholic acid, can be a sufficient approach to facilitating resolution of the choledocholithiasis and conjugated hyperbilirubinemia.

Benign inheritable disorders of bilirubin metabolism manifested by conjugated hyperbilirubinemia-A narrative review.

Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. Hyperbilirubinemia is an important clinical sign that needs to be investigated under a stepwise evaluation. Inherited non-hemolytic conjugated hyperbilirubinemic conditions include Dubin-Johnson syndrome (caused by mutations affecting ABCC2 gene) and Rotor syndrome (caused by the simultaneous presence of mutations in SLCO1B1 and SLCO1B3 genes). Although classically viewed as benign conditions requiring no treatment, they lately gained an increased interest since recent studies suggested that mutations in the responsible genes leading to hyperbilirubinemia, as well as minor genetic variants, may result in an increased susceptibility to drug toxicity. This article provides a comprehensive review on the pathophysiology of Dubin-Johnson and Rotor syndromes, presenting the current knowledge concerning the molecular details and basis of these conditions.

A 12-Day-Old Female with Hypothermia, Hypoglycemia and Hyperbilirubinemia.

A 12-day-old, full-term female, born small for gestational age, presented to the emergency department with a 1-week history of worsening hyperbilirubinemia, intermittent hypoglycemia, and episodic hypothermia. The baby's emergency department evaluation revealed transaminitis, pneumatosis intestinalis, indirect hyperbilirubinemia, and hypoglycemia. She was admitted to the ICU and received intravenous glucose, bowel rest, and phototherapy. Thyroid-stimulating hormone, thyroxine, and cortisol levels were low, and growth hormone was undetectable. The patient was hospitalized for a total of 19 days and was discharged from the hospital.

The prognostic significance of postoperative hyperbilirubinemia in cardiac surgery: systematic review and meta-analysis.

BACKGROUND: Hyperbilirubinemia following cardiac surgery is a common phenomenon and is of emerging interest in prognostic factor research. This systematic review and meta-analysis evaluated the association between post-operative hyperbilirubinemia (PH) and mortality and morbidity in cardiac surgery patients. METHODS: Ovid Medline and Ovid Embase were searched from inception to July 2020 for studies evaluating the prognostic significance of PH following cardiac surgery. Maximally adjusted odds ratios (OR) with associated confidence intervals were obtained from each study and pooled using random effects inverse variance modelling to assess in-hospital mortality. Standardised mean differences were pooled to assess Intensive Care Unit (ICU) and hospital length of stay (LOS). Qualitative analysis was performed to assess ventilation requirements and long-term mortality. Meta-regression was used to assess inter- and intra-study heterogeneity. RESULTS: 3251 studies satisfied the selection criteria, from which 12 studies incorporating 3876 participants were included. PH significantly predicted in-hospital mortality with a pooled OR of 7.29 (95% CI 3.53, 15.09). Multiple pre-defined covariates contributed to the prognostic significance of PH, however only aortic cross-clamp time (p < 0.0001) and number of transfusions (p = 0.0001) were significant effect modifiers. PH significantly predicted both ICU LOS (Mean difference 1.32 [95% CI 0.04-2.6]) and hospital LOS (Mean difference 1.79 [95% CI 0.36-3.21]). Qualitative analysis suggested PH is associated with increased post-operative ventilation requirements and reduced long-term survival rates. CONCLUSIONS: Hyperbilirubinemia is a cost-effective, widely available prognostic marker of adverse outcomes following cardiac surgery, albeit with residual sources of heterogeneity.

Post-Operative Severe Hyperbilirubinemia: A Case Report.

Hyperbilirubinemia is commonly seen in medical practice. But what could be the highest level of bilirubin in an individual that is still an unanswered question. We came across to a 37 years old lady in October 2018 with hepaticolithiasis who underwent extended choledocholithotomy. Her preoperative serum bilirubin was within normal range. Post-operatively she developed cholangitis and from 3rd post-operative day onwards she developed severe hyperbilirubinemia, which was high as 70.47 mg/dl on the 6th post-operative day. Other causes of post-operative hyperbilirubinemia were excluded. She was managed conservatively for this hyperbilirubinemia and bilirubin level gradually reduced.

Abdominal Complications During Treatment for Pediatric Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) accounts for 15% to 20% of childhood leukemias. Because of high-intensive therapy, up to 5% of patients suffer from treatment-related mortality (TRM). Abdominal complications are frequent, however, literature on this subject is sparse. We aimed to characterize severe abdominal pain (AP) and hyperbilirubinemia experienced by pediatric AML patients treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO)-AML 2004 protocol (n=313). Patients were censored at hematopoietic stem cell transplantation and relapse. Toxicity information was collected prospectively. Additional information was requested retrospectively from the treating centers. Sixteen episodes of hyperbilirubinemia and 107 episodes of AP were reported. The treating centers deemed infection (30%) and typhlitis (18%) as the most frequent causes of AP. Six patients developed appendicitis (2%). Patients experiencing concurrent AP and sepsis had a high risk of TRM (36%, n=4). Eighty percent of episodes with hyperbilirubinemia fulfilled the European Society for Bone and Marrow Transplantation criteria for sinusoidal obstruction syndrome. In conclusion, abdominal complications were frequent with infection considered the predominate cause. Most patients with hyperbilirubinemia fulfilled the criteria for sinusoidal obstruction syndrome. AML treatment might be associated with appendicitis. Patients suffering from concurrent AP and sepsis had a high risk of TRM indicating that high awareness of abdominal complications is essential to reduce mortality, especially during sepsis.