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Background: Biliary obstruction before liver resection is a known risk factor for post-operative complications. The aim of this study was to determine the impact of persistent hyperbilirubinemia following preoperative biliary drainage before liver resection., Methods: The ACS-NSQIP (2016-2021) database was used to extract patients with cholangiocarcinoma who underwent anatomic liver resection with preoperative biliary drainage comparing those with persistent hyperbilirubinemia (> 1.2 mg/dL) to those with resolution. Patient characteristics and outcomes were compared with bivariate analysis. Multivariable modeling evaluated factors including persistent hyperbilirubinemia to evaluate their independent effect on serious complications, liver failure, and mortality., Results: We evaluated 463 patients with 217 (46.9%) having hyperbilirubinemia (HB) despite biliary stenting. Bivariate analysis demonstrated that patients with HB had a higher rate of serious complications than those with non-HB (80.7% vs 70.3%; P = 0.010) including bile leak (40.9% vs 31.8%; P = 0.045), liver failure (26.7% vs 17.9%; P = 0.022), and bleeding (48.4% vs 36.6%; P = 0.010). Multivariable analysis demonstrated that persistent HB was independently associated with serious complications (OR 1.88, P = 0.020) and mortality (OR 2.39, P = 0.049) but not post-operative liver failure (OR 1.65, P = 0.082)., Conclusions: Failed preoperative biliary decompression is a predictive factor for post-operative complications and mortality in patients undergoing hepatectomy and may be useful for preoperative risk stratification., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Competing Interests: Declaration of Competing Interest The authors have no potential, perceived, or real conflicts of interest to disclose.

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 2×10 12 vector genomes (vg) per kilogram of body weight, and three received 5×10 12 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.)., (Copyright © 2023 Massachusetts Medical Society.)

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.] .

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.

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.

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., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

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., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

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., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2022 by the American Academy of Pediatrics.)

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., (© 2022. The Author(s).)

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.

Objective: Extracorporeal membrane oxygenation (ECMO)-associated direct hyperbilirubinemia (DHB) is likely multifactorial. The objective of this study is to assess the frequency and risk factors for developing direct hyperbilirubinemia while on ECMO, and its implication on the mortality of children., Methods: We performed a retrospective study between January 2010 and January 2020. Using Mayo Clinic electronic health record, we identified children (<18 years) who required veno-arterial (VA) ECMO support. Demographics, ECMO indication, laboratory findings, and outcomes were abstracted. Illness acuity scores, including vasoactive-ionotropic score (VIS), were used to assess disease severity at time of admission. Study cohort was divided into two groups: children who developed direct hyperbilirubinemia (DHB) on ECMO and children who did not (control). DHB was defined as direct bilirubin (DB) of >1.0 mg/dL. Disease acuity and mortality rates were compared between the two groups. Logistic regression was used to analyze the risk of mortality independent of potential confounding variables., Results: We identified 106 children who required ECMO support during the study period. Of those, 36 (34%) children developed DHB on ECMO. Illness acuity scores were significantly higher in the DHB group on ECMO day 2 (P = 0.046) and day 7 (P = 0.01). Mortality rate was higher in the DHB group 72%, versus 29% in the control group (P < 0.001)., Conclusion: DHB was associated with a higher mortality rate than the control group., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objective: Severe hyperbilirubinemia after cardiac surgery increases in-hospital and 1-year mortality. Our present study aimed to analyze the safety and efficacy of bilirubin adsorption (BA) in patients with post-cardiac-surgery severe hyperbilirubinemia., Methods: We retrospectively included patients who underwent BA due to severe hyperbilirubinemia after cardiac surgery in our center between January 2015 and December 2018. The change of serum bilirubin, alanine aminotransferase, aspartate aminotransferase, and 30-day and 1-year mortality were assessed as endpoints. Univariate and multivariate analyses were employed to identify the risk factors of patient 30-day mortality., Result: A total of 25 patients with 44 BA treatments were included. One BA treatment reduced total bilirubin (TB) concentration from 431.65 ± 136.34 to 324.83 ± 129.44 µmol/L ( p  < 0.001), with a reduction rate of 24.8%. No clinically relevant thrombosis of the extracorporeal circuit occurred during the BA treatment. The 30-day and 1-year mortality rates were 68% ( n  = 18) and 84% ( n  = 21), respectively. Multivariate analysis identified that TB level before BA treatment (odds ratio [OR] 1.010, 95% confidence interval [CI] 1.000-1.019; p  = 0.043) was an independent risk factor of 30-day mortality., Conclusions: BA treatment should be considered as an effective and safe method for the reduction of serum bilirubin in patients with post-cardiac-surgery severe hyperbilirubinemia. Patients with higher TB level before BA treatment had a relatively increased risk of 30-day mortality. Further studies are needed to evaluate the timing of BA for severe hyperbilirubinemia after cardiac surgery.

Background: This prospective cohort study aimed to investigate the association of hyperbilirubinemia with perforated appendicitis in the pediatric population. Patients and Methods: A total of 284 children in whom the diagnosis of acute appendicitis was established were included in this study. The patients were allocated in study groups in regard to operative findings. The first study group included patients who had perforated appendicitis (n = 64; 22.5%) whereas the patients in the second group had simple appendicitis (n = 220; 77.5%). Blood samples for serum bilirubin levels and acute inflammatory markers were taken before the patients underwent surgery. The primary outcome of the study was to investigate whether the level of serum bilirubin should be used to distinguish between simple and perforated appendicitis. Results: The median level of serum bilirubin in children with perforated appendicitis was 27 mcmol/L whereas the patients with simple appendicitis had lower median levels of serum bilirubin (10 μmol/L; p < 0.001). An area under the receiver operating characteristic (ROC) curve for total serum bilirubin was 0.876 (95% confidence interval [CI], 0.820-0.929) in the patients who had a perforated appendicitis. An ROC analysis showed the best sensitivity (92%) and specificity (77.3%) for a cutoff value of 15.5 mcmol/L for total serum bilirubin (p < 0.001). Hyperbilirubinemia at admission was found in 35 patients (54.7%) with complicated appendicitis and in 14 patients (6.4%) with non-perforated appendicitis (p < 0.001). The modeling of collected data by multivariable logistic regression identified serum bilirubin concentration (odss ratio [OR] = 1.12; 95% CI, 1.07-1.18; p < 0.001), serum sodium concentration (OR = 0.64; 95% CI, 0.51-0.81; p < 0.001), body temperature (OR = 2.48; 95% CI, 1.05-0.84; p < 0.001), and duration of symptoms (OR = 1.06; 95% CI, 1.02-1.09; p < 0.001) as risk factors for perforated appendicitis. Conclusion: Elevateds level of total serum bilirubin may be useful as an indicator of perforated appendicitis in children. Levels of bilirubin in serum is an inexpensive, simple, and available laboratory marker and should therefore be recommended in the initial evaluation for acute appendicitis in pediatric patients.

Background: Hyperbilirubinemia is a common complication after off-pump coronary artery bypass grafting (OPCAB), but the incidence and the risk factors are unclear. This study aimed to analyze the incidence and risk factors of postoperative hyperbilirubinemia in patients undergoing OPCAB., Methods: From December 2016 to March 2019, a total of 416 consecutive patients undergoing OPCAB were enrolled in this single-center retrospective study. Patients were divided into the normal serum total bilirubin group and the hyperbilirubinemia group based on the serum total bilirubin levels. Perioperative variables between the two groups were compared by univariate logistic regression analysis. Then, multivariate binary logistic regression analysis was used to analyze the independent risk factors of developing hyperbilirubinemia in patients underwent OPCAB. P < 0.05 was considered as statistically significant., Results: Thirty two of 416 (7.7%) patients developed postoperative hyperbilirubinemia. Univariate regression analysis showed significant differences in gender (73.96% vs. 93.75%, P = 0.012), preoperative total bilirubin levels (11.92 ± 4.52 vs. 18.28 ± 7.57, P < 0.001), perioperative IABP implantation (22.66% vs. 43.75%, P = 0.008), perioperative blood transfusion (37.50% vs. 56.25%, P = 0.037) between the two groups. Multivariate logistic regression analysis revealed that elevated preoperative serum total bilirubin levels (OR = 1.225, 95% CI 1.145-1.310, P < 0.001), perioperative blood transfusion (OR = 4.488, 95% CI 1.876-10.737, P = 0.001) and perioperative IABP implantation (OR = 4.016, 95% CI 1.709-9.439, P = 0.001) were independent risk factors for hyperbilirubinemia after OPCAB., Conclusions: Hyperbilirubinemia is also a common complication after OPCAB. Elevated preoperative serum total bilirubin levels, perioperative blood transfusion, and perioperative IABP implantation were independent risk factors for patients developing hyperbilirubinemia after OPCAB. Further studies need to be conducted to confirm the risk factors of hyperbilirubinemia after OPCAB procedure., (© 2021. The Author(s).)

Background: The purpose of the present systematic review was to evaluate the incidence, risk factors, and outcome of hyperbilirubinemia after cardiac surgery., Methods: The Population, Interventions, Comparators, Outcomes, and Study design (PICOS) framework was employed to develop the search strategy, and the findings are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. PubMed, Embase, and the Cochrane Library were systematically searched for studies that provided data on the incidence, risk factors, and outcomes of hyperbilirubinemia in cardiac surgery patients from January 1960 to May 2020. Publication bias was graphically explored through funnel plots, and the Newcastle-Ottawa quality assessment scale (NOS) was used to evaluate the quality of the included studies., Results: Ten studies with 6,100 patients were included in our systematic review. The pooled incidence of hyperbilirubinemia was 23% [95% confidence interval (CI), 0.13-0.32]. Preoperative factors, including right atrial pressure [mean difference (MD), 4.65; 95% CI, 4.43-4.88], total bilirubin (TB) concentration (MD, 0.72; 95% CI, 0.65-0.79), alkaline phosphatase (MD, 27.38; 95% CI, 12.94-41.82), and alanine aminotransferase (MD, 12.02; 95% CI, 10.73-13.31), and intraoperative factors, including cardiopulmonary bypass (CPB) time (MD, 1.57; 95% CI, 0.52-2.63), aortic cross-clamping (ACC) time (MD, 11.82; 95% CI, 9.50-14.14), and the amount of blood transfused (MD, 3.77; 95% CI, 0.68-6.85), were the most robust risk factors for hyperbilirubinemia after cardiac surgery. Additionally, postoperative hyperbilirubinemia was associated with increased in-hospital mortality [odds ratio (OR), 9.9; 95% CI, 5.00-19.60, P<0.0001]., Discussion: Hyperbilirubinemia was common and was associated with increased in-hospital mortality. Preoperative high right atrial pressure, high TB concentration, prolonged CPB and ACC time, and a large amount of blood transfused were the commonly observed risk factors for postoperative hyperbilirubinemia in cardiac surgery patients. Addressing these risk factors may be helpful to lower the occurrence of postoperative hyperbilirubinemia.

Hyperbilirubinemia occurs frequently after allogeneic stem cell transplantation. Causes include primary liver damage and endothelial complications as major contributors. Here, we have investigated the impact of early bilirubinemia (EB) on posttransplant outcomes. Maximum total bilirubin levels (days 0-28) were categorized using maximally selected log rank statistics to identify a cut off for the endpoint non-relapse mortality (NRM) in a training cohort of 873 patients. EB above this cut off was correlated with NRM and overall survival (OS) and with pre- and posttransplant Angiopoietin-2, interleukin (IL)18, CXCL8 and suppressor of tumorigenicity-2 (ST2) serum levels, and the endothelial activation and stress index (EASIX). Clinical correlations were validated in a sample of 388 patients transplanted in an independent institution. The EB cut off was determined at 3.6 mg/dL (61.6 µM). EB predicted OS (HR 1.60, 95% CI 1.21-2.12, p < 0.001), and NRM (CSHR 2.14; 1.28-3.56, p = 0.004), also independent of typical endothelial complications such as veno-occlusive disease, refractory acute graft-versus-host disease, or transplant-associated microangiopathy. However, EB correlated with high Angiopoietin-2, EASIX-pre and EASIX-day 0, as well as increased levels of posttransplant CXCL8, IL18, and ST2. In summary, EB indicates a poor prognosis. The association of EB with endothelial biomarkers suggests an endothelial pathomechanism also for this posttransplant complication.

Importance: The outcomes of newborn infants of women testing positive for SARS-CoV-2 in pregnancy is unclear., Objective: To evaluate neonatal outcomes in relation to maternal SARS-CoV-2 test positivity in pregnancy., Design, Setting, and Participants: Nationwide, prospective cohort study based on linkage of the Swedish Pregnancy Register, the Neonatal Quality Register, and the Register for Communicable Diseases. Ninety-two percent of all live births in Sweden between March 11, 2020, and January 31, 2021, were investigated for neonatal outcomes by March 8, 2021. Infants with malformations were excluded. Infants of women who tested positive for SARS-CoV-2 were matched, directly and using propensity scores, on maternal characteristics with up to 4 comparator infants., Exposures: Maternal test positivity for SARS-CoV-2 in pregnancy., Main Outcomes and Measures: In-hospital mortality; neonatal resuscitation; admission for neonatal care; respiratory, circulatory, neurologic, infectious, gastrointestinal, metabolic, and hematologic disorders and their treatments; length of hospital stay; breastfeeding; and infant test positivity for SARS-CoV-2., Results: Of 88 159 infants (49.0% girls), 2323 (1.6%) were delivered by mothers who tested positive for SARS-CoV-2. The mean gestational age of infants of SARS-CoV-2-positive mothers was 39.2 (SD, 2.2) weeks vs 39.6 (SD, 1.8) weeks for comparator infants, and the proportions of preterm infants (gestational age <37 weeks) were 205/2323 (8.8%) among infants of SARS-CoV-2-positive mothers and 4719/85 836 (5.5%) among comparator infants. After matching on maternal characteristics, maternal SARS-CoV-2 test positivity was significantly associated with admission for neonatal care (11.7% vs 8.4%; odds ratio [OR], 1.47; 95% CI, 1.26-1.70) and with neonatal morbidities such as respiratory distress syndrome (1.2% vs 0.5%; OR, 2.40; 95% CI, 1.50-3.84), any neonatal respiratory disorder (2.8% vs 2.0%; OR, 1.42; 95% CI, 1.07-1.90), and hyperbilirubinemia (3.6% vs 2.5%; OR, 1.47; 95% CI, 1.13-1.90). Mortality (0.30% vs 0.12%; OR, 2.55; 95% CI, 0.99-6.57), breastfeeding rates at discharge (94.4% vs 95.1%; OR, 0.84; 95% CI, 0.67-1.05), and length of stay in neonatal care (median, 6 days in both groups; difference, 0 days; 95% CI, -2 to 7 days) did not differ significantly between the groups. Twenty-one infants (0.90%) of SARS-CoV-2-positive mothers tested positive for SARS-CoV-2 in the neonatal period; 12 did not have neonatal morbidity, 9 had diagnoses with unclear relation to SARS-CoV-2, and none had congenital pneumonia., Conclusions and Relevance: In a nationwide cohort of infants in Sweden, maternal SARS-CoV-2 infection in pregnancy was significantly associated with small increases in some neonatal morbidities. Given the small numbers of events for many of the outcomes and the large number of statistical comparisons, the findings should be interpreted as exploratory.

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

From clinical practice, we noted that a subset of neonates with hyperinsulinism develop conjugated hyperbilirubinemia. A relationship between these two conditions has not been previously described. We aimed to assess the incidence of cholestasis in a cohort of neonates with hyperinsulinism and describe their clinical characteristics. In a retrospective cohort of 63 neonates with hyperinsulinism, 48% developed cholestasis (conjugated bilirubin > 17 μmol/L) with a median maximum conjugated bilirubin of 81 [21 to 191] μmol/L. A history of fetal distress (RR 2.3 [1.24-4.45], p < 0.01) and prematurity (RR 2.0 [1.23-3.26], p <0.01) was associated with the development of cholestasis, but not parental nutrition or other pharmacological treatments. An underlying etiology for the cholestasis was only found in 1 patient, and in all cases the cholestasis spontaneously improved.Conclusions: A significant percentage of infants with hyperinsulinism develop idiopathic, spontaneously resolving, conjugated hyperbilirubinemia. The association with a history of fetal distress potentially suggests that intrauterine factors leading to hyperinsulinism may also predispose towards conjugated hyperbilirubinemia. While the presence of neonatal cholestatic jaundice warrants timely investigations to exclude important underling etiologies, if validated, these findings may support a less invasive diagnostic workup of conjugated hyperbilirubinemia in infants with co-existent hyperinsulinism. What is Known: • Hyperinsulinism and conjugated hyperbilirubinemia are two common presentations in neonates. • A clinical association between the two conditions has not been described. What is New: • A significant proportion of infants with hyperinsulinism develop idiopathic, spontaneously resolving conjugated hyperbilirubinemia. • Increased risk for cholestasis in this patient population is associated with fetal distress and prematurity but not parental nutrition.

Objective: Severe acute kidney injury (AKI) and hyperbilirubinemia increase the morbidity and mortality risk in patients undergoing emergency surgery for acute type A aortic dissection (AAAD). Our purpose was to investigate the risk factors of mortality in AAAD surgery patients who had severe postoperative hyperbilirubinemia and AKI receiving continuous renal replacement therapy (CRRT)., Methods: Patients who had severe hyperbilirubinemia and received CRRT after AAAD surgery in our center between January 2015 and December 2018 were retrospectively screened. Univariate and multivariate analyses were performed to identify the risk factors of in-hospital mortality. Kaplan-Meier curves were employed to evaluate the accumulated patient survival proportion., Results: After screening, 50 patients were included in our present study. The in-hospital mortality was 84%. The univariate logistic analysis showed that preoperative MAP (p = .017) and peak total bilirubin concentration (p < .001) were associated with in-hospital mortality in AAAD surgery patients who had severe postoperative hyperbilirubinemia and received CRRT. Multivariate logistic regression analysis revealed that the peak bilirubin concentration (odds ratio, 1.050; 95% confidence interval, 1.002-1.101; p = .041) after surgery was the only independent risk factor for in-hospital mortality. The optimal cutoff value of peak bilirubin for predicting in-hospital mortality was 134.4 μmol/L., Conclusions: AAAD surgery patients with severe hyperbilirubinemia and AKI requiring CRRT had a poor prognosis. Increased postoperative peak bilirubin concentration strongly increased the risk of patient in-hospital mortality. Therefore, these patients should be closely monitored and treated aggressively when possible., (© 2021 Wiley Periodicals LLC.)

Objective: To determine the possible risk factors associated with hepatic dysfunction during open-heart surgeries., Methods: After excluding 71 patients, 307 patients with possible low and moderate cardiac risk who underwent either coronary artery bypass graft surgery (CABG) (n=176) or valve repair surgery (mitral valve, mitral and aortic valves and/or tricuspid valve) (n=131) were investigated prospectively during a 6-month period. Hyperbilirubinemia is defined as an occurrence of a plasma total bilirubin concentration >34 µmol/L (2 mg/dL) in any measurement during the postoperative period; the patients were divided into groups with or without postoperative hyperbilirubinemia. The collected parameters were: alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin (TBil), gamma-glutamyl transpeptidase (GGT) and albumin. The parameters were collected preoperatively and postoperatively on days 1, 3 and 7. Preoperative, intraoperative, and postoperative risk factors were investigated. Logistic regression analysis was performed to identify the risk factors for postoperative hyperbilirubinemia., Results: Postoperative hyperbilirubinemia was observed in 7 of 176 patients (4%) who underwent CABG, and in 11 of 131 patients (8.4%) who underwent valve replacement surgeries. Independent risk factors for early postoperative hyperbilirubinemia were found as: ejection fraction (EF), aortic cross-clamp (ACC) time, intensive care unit stay and extubation time (P<0.001). In comparison to CABG procedures, postoperative hyperbilirubinemia was observed more frequently in patients undergoing valve surgeries (P=0.027)., Conclusion: Low EF and prolonged ACC time are significant independent risk factors for early postoperative hyperbilirubinemia during open-heart surgeries with cardiopulmonary bypass. Valve surgeries show a higher incidence of hyperbilirubinemia in comparison to CABG.

Hyperbilirubinemia in patients with sickle cell anemia (SCA) as a result of enhanced erythrocyte destruction, lead to cholelithiasis development in a subset of patients. Evidence suggests that hyperbilirubinemia may be related to genetic variations, such as the UGT1A1 gene promoter polymorphism, which causes Gilbert syndrome (GS). Here, we aimed to determine the frequencies of UGT1A1 promoter alleles, alpha thalassemia, and β S haplotypes and analyze their association with cholelithiasis and bilirubin levels. The UGT1A1 alleles, -3.7 kb alpha thalassemia deletion and β S haplotypes were determined using DNA sequencing and PCR-based assays in 913 patients with SCA. The mean of total and unconjugated bilirubin and the frequency of cholelithiasis in GS patients were higher when compared to those without this condition, regardless of age (P < 0.05). Cumulative analysis demonstrated an early age-at-onset for cholelithiasis in GS genotypes (P < 0.05). Low fetal hemoglobin (HbF) levels and normal alpha thalassemia genotype were related to cholelithiasis development (P > 0.05). However, not cholelithiasis but total and unconjugated bilirubin levels were associated with β S haplotype. These findings confirm in a large cohort that the UGT1A1 polymorphism influences cholelithiasis and hyperbilirubinemia in SCA. HbF and alpha thalassemia also appear as modulators for cholelithiasis risk.

There is limited literature on Gilbert's syndrome (GS) in children with persistent unconjugated hyperbilirubinemia from Indian subcontinent. All patients (< 18 y of age) with genetically confirmed GS were included, and their profile was analysed. A total of 170 subjects were confirmed as having GS as per genetic analysis (133 with homozygous and 37 with heterozygous status). Majority were diagnosed in the adolescent age group (mean age 13.6 y). The median serum total bilirubin (TB) levels were around 3.3 mg/dl with maximum levels reaching upto 18 mg/dl. Around 15% subjects had an associated condition including hematological or hepatobiliary disease amongst others. GS is an important but under-recognised cause of unexplained unconjugated hyperbilirubinemia in Indian pediatric subjects. It may co-exist with other hematological and hepatobiliary disorders, and complicate the clinical/laboratory picture. Extent of hyperbilirubinemia may fluctuate to levels much higher than what is usually described in current world literature.

Background: In appendicitis, elevated intra-luminal pressure and ischemic necrosis of mucosa causes tissue gangrene or perforation. This leads to cytotoxin facilitated progressive bacterial invasion or translocation into the hepatic parenchyma through portal system. This phenomenon interferes with the bilirubin excretion into the bile canaliculi. In the present study, establishment of a possible role of hyperbilirubinemia as a marker of gangrenous/perforated appendicitis has been studied., Methods: After matching the inclusion and exclusion criteria, all cases of clinically diagnosed acute appendicitis were taken for this prospective, single center, observational study. Per-operative diagnosis was confirmed by histopathological examination., Results: Out of 110 subjects of acute appendicitis 41 subjects (37.27%) had hyperbilirubinemia. Out of 35 subjects diagnosed as complicated appendicitis 32 subjects (91.42%) had raised total bilirubin levels, while the remaining 03 (8.58%) had normal levels. Among 75 subjects diagnosed as acute simple appendicitis 09 subjects (12%) had raised total bilirubin level, while the remaining 66 subjects (88%) had normal levels. It was Mixed Type of Hyperbilirubinemia in gangrenous/perforated appendicitis. The sensitivity of Total serum bilirubin in predicting complicated appendicitis was found 91.43% (76.942% to 98.196%), where as the specificity of this test was 88.00% (78.439% to 94.363%). positive predictive value and negative predictive value were 78.03% and 95.65% respectively. Positive likelihood ratio and negative likelihood ratio were found to be 7.619 and 0.097 respectively taking prevalence of complicated appendicitis be 31.80%. Receiver Operating Characteristic curve was obtained which shows optimal criterion at Total Bilirubin Level 1.06 mg/dl where sensitivity was 91.43% and specificity was 97.33% at 95% confidence interval with 31.8% disease prevalence., Conclusions: This is to conclude that Serum bilirubin level estimation, which is a simple, cheap and easily available laboratory test, can be added to the routine investigations in clinically suspected cases of acute appendicitis for early diagnosis of complications. Trial registration Registered with Clinical Trials Registry-India (ICMR-NIMS) with Registration number CTRI/2019/05/018879 Dated 01/05/2019. This was a prospective trial. Trial URL: http://ctri.nic.in/Clinicaltrials/pdf&#95;generate.php?trialid=33113&EncHid=99780.32960&modid=1&compid=19%27,%2733113det%27 .

Background: Hyperbilirubinemia after heart valve surgery (HVS) with cardiopulmonary bypass is frequently observed and associated with worse outcomes. We investigated the characteristics and prognosis of patients with severe hyperbilirubinemia after HVS for rheumatic heart disease (RHD) to identify the clinical outcomes and potential risk factors., Methods: Between 2015 and 2018, patients who underwent HVS in the cardiac surgery intensive care unit of our hospital were retrospectively screened. Risk factors for acute kidney injury (AKI), the requirement for continuous renal replacement therapy (CRRT), and in-hospital and long-term mortality were identified by univariate and multivariate analyses. The patient survival proportion was graphically presented with the Kaplan-Meier method., Results: A total of 149 patients who underwent HVS for RHD and had severe postoperative hyperbilirubinemia were included. Of the included patients, 80.5% developed postoperative AKI, and 18.1% required CRRT. The in-hospital mortality was 30.2%. Backward logistic regression analysis showed that the time to peak TB concentration (odds ratio [OR] 1.557, 95% confidence interval [CI] 1.259-1.926; P < 0.001) and advanced AKI (stage 2 and 3 AKI) (OR 19.408, 95% CI 6.553-57.482; P < 0.001) were independent predictors for in-hospital mortality. The cutoff value of the time to peak TB levels for predicting in-hospital mortality was 5 postoperative days., Conclusions: Severe postoperative hyperbilirubinemia is a life-threatening complication in patients who undergo HVS for RHD. Patients whose bilirubin levels continued to increase past the 5th postoperative day and who had advanced AKI (stages 2 and 3) were associated with a higher risk of mortality.

Background: Prompt management of acute graft-versus-host disease (GVHD) may prevent its morbidity and mortality. Maculopapular (MP) eruption is a presenting sign of acute GVHD, but differentiation from other causes of MP rash is challenging., Methods: A retrospective study was conducted among patients developing MP eruptions after allogeneic hematopoietic stem cell transplantation. We compared the clinical and histopathological differences between an acute cutaneous GVHD (group 1) and other MP eruptions (group 2). We also determined the clinical prognostic indicators linked to acute GVHD severity, morbidity, and mortality., Results: Of 95 patients identified, 75 met the classification criteria for acute GVHD, and 25 had other MP eruptions. Palm and/or sole involvement was more frequently found (51.4% vs. 12%, odds ratio [OR] [95% confidence interval] = 7 [2.1, 23.7], P < 0.01 and 41.4% vs. 0%, OR 37.2 [2.2, 635], P < 0.01, respectively) in group 1 than in group 2. Comparing the histological features between the two groups, necrotic keratinocytes in basal and spinous layers (92.9% vs. 22.2%, OR 27 [3.5, 594.7], P < 0.01) and (85.7% vs. 33.3%, OR 9.3 [1.4, 60.8], P = 0.02, respectively), diffuse basal vacuolization (42.9% vs. 0%, OR 14.5 [0.7, 298.2], P = 0.04), lymphocyte satellitosis (71.4% vs. 0%, OR 44.3 [2.1, 936.8], P < 0.01), and subepidermal clefts (42.9% vs. 0%, OR 14.5 [0.7, 298.2], P = 0.04) were significantly more apparent in group 1. Among extracutaneous presentations, diarrhea alone and/or accompanied by hyperbilirubinemia (47.1% vs. 16%, OR 4.3 [1.4, 13.1], P = 0.03 and 27.1% vs. 0%, OR 19.3 [1.1, 332.8], P < 0.01, respectively) and newly developed transaminitis (37.1% vs. 12%, OR 3.3 [1.1, 12.6], P = 0.02) suggested the diagnosis of acute GVHD. Mucosal involvement and/or blister formation correlated with severe acute GVHD (OR 26.6 [5.4, 130.4], P < 0.01). Skin and systemic GVHD severity correlated with time to rash resolution (P = 0.03 and P = 0.04, respectively), length of hospital stays (P < 0.01 and P < 0.01, respectively), and mortality (OR 4.87 [1.4, 17.4], P = 0.02 and OR 4.6 [1.3, 16.5], P = 0.02, respectively)., Conclusions: Our findings may be beneficial tools for establishing the diagnosis of acute GVHD., (© 2020 the International Society of Dermatology.)

We report a 73-year-old male with no relevant past medical history who presented with nephrotic syndrome and jaundice. Subsequent studies revealed immunoglobulinM (IgM) monoclonal gammopathy. Kidney biopsy revealed monoclonal Ig deposition disease and amyloidosis. Bone marrow biopsy demonstrated <10% infiltration by lymphoplasmacytic cells. However, rapidly progressive hypergammaglobulinemia of IgM and hyperbilirubinemia were noted. Despite aggressive treatment, the patient developed acute kidney injury and complications of hepatic failure. He eventually died of pneumonia, just two months after diagnosis.