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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.)

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).)

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.)

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).)

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.

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.

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.

Background: Hyperbilirubinemia is one of the common complications after cardiac surgery and is associated with increased mortality. However, to the best of our knowledge, the reports on clinical significance of postoperative severe hyperbilirubinemia in Stanford type A aortic dissection (AAD) patients were limited., Methods: Patients who underwent surgical treatment for AAD in our center between January 2015 and December 2018 were retrospectively screened. In-hospital mortality, long-term mortality, acute kidney injury (AKI), and the requirement of continuous renal replacement therapy (CRRT) were assessed as endpoints. Univariate and multivariate regression models were employed to identify the risk factors of these endpoints., Results: After screening, 271 patients were included in our present study. Of the included patients, 222 (81.9%) experienced postoperative AKI, and 50 (18.5%) received CRRT. The in-hospital mortality was 30.3%. The 1-year, 2-year, and 3-year cumulative mortality were 32.9, 33.9, and 35.3%, respectively. Multivariate Logistic regression analysis indicated that age (P < 0.033), AKI stage 3 (P < 0.001), the amount of blood transfusion after surgery (P = 0.019), mean arterial pressure (MAP) in the first postoperative day (P = 0.012), the use of extracorporeal membrane oxygenation (ECMO) (P = 0.02), and the peak total bilirubin (TB) concentration (P = 0.023) were independent risk factors of in-hospital mortality. The optimal cut-off value of peak TB on predicting in-hospital mortality was 121.2 μmol/L. Patients with post-operation TB ≥ 121 μmol/L was associated with worse long-term survival as well., Conclusions: Severe post-operation hyperbilirubinemia is a common clinical situation in patients had AAD repair. In AAD patients with severe post-operation hyperbilirubinemia, older age, lower MAP, increased blood transfusion, stage 3 AKI, the use of ECMO, and the increased peak TB lead to increase in-hospital mortality.

Background: Untreated neonatal cholestasis can progress to liver cirrhosis and end stage liver disease in infancy due to prolonged hepatocyte and biliary tree injury and may require liver transplantation. Therefore, non-invasive evaluation of hepatic fibrosis is important in infants with cholestasis., Aim: To investigate the usefulness of periportal thickening (PT) measured on liver magnetic resonance imaging (MRI) for the assessment of hepatic fibrosis in infants with cholestasis including biliary atresia (BA)., Methods: This retrospective study included infants less than 6 mo who underwent liver MRI and biopsy for the evaluation of infantile cholestasis. PT and spleen size were measured on MRI. Serologic assessment was based on aspartate transaminase to platelet ratio index (APRI). The grade of histopathologic fibrosis was assessed by the METAVIR grading system. Correlation and diagnostic performance of PT, normalized spleen size ratio (SR, using the upper normal size limit), and APRI for diagnosing hepatic fibrosis were obtained by receiver-operating characteristic (ROC) curve analysis., Results: A total of 155 patients were included, 110 of which were diagnosed with BA. Mean age at the time of MRI was 57.6 ± 34.4 d. There were positive correlations between fibrosis grade and PT and SR, even after adjusting age (all, P < 0.001). For the diagnosis of significant fibrosis (METAVIR grade F2-F4), the area under the ROC curve was 0.899 (95%CI: 0.840-0.941) for PT (cutoff, 4.2 mm), which was higher than 0.741 (95%CI: 0.664-0.808) for SR and 0.712 (95%CI: 0.634-0.782) for APRI (both, P < 0.001). For the diagnosis of cirrhosis (F4), the area under the ROC curve was the highest with SR as 0.790 (95%CI: 0.718-0.852)., Conclusion: Liver MRI findings of PT and SR are useful to assess clinically significant hepatic fibrosis (F2 and higher) in infants with cholestasis including BA., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts-of-interest related to this article., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Mild hemolysis is difficult to determinate by traditional methods, and its role in Gilbert's syndrome (GS) is unclear. The main aims were to inspect the erythrocyte (RBC) survival in GS by using Levitt's carbon monoxide (CO) breath test and to assess its contribution to unconjugated hyperbilirubinemia., Methods: Fifty subjects with GS and 1 with type-II Crigler-Najjar syndrome (CN2) received RBC lifespan measurement with Levitt's CO breath test. Mean RBC lifespan was compared with normal referral value. Correlations of serum total bilirubin (TB) with RBC lifespan, blood panel data, demographic factors, and uridine diphosphate glucuronosyltransferase (UGT1A1) mutation load were calculated by Spearman analysis. Susceptibility factors for mild hemolysis were analyzed by multivariate regression analysis., Results: The mean RBC lifespan of the GS subjects was significantly shorter than the normal reference value (95.4 ± 28.9 days vs 126 days; t = -7.504, P < .01), with 30.0% below the lower limit of the normal reference range (75 days). The RBC lifespan of the participant with CN2 was 82 days. Serum TB correlated positively with UGT1A1 mutation load (γ = 0.281, P = .048), hemoglobin (γ = .359, P = .010) and hematocrit (γ = 0.365, P = .010), but negatively with RBC lifespan (γ = -0.336, P = .017). No significant susceptibility factors for mild hemolysis were found., Conclusions: The results indicate that mild hemolysis indeed, exists in a portion of patients with GS and might serve as an important contributor to unconjugated hyperbilirubinemia in addition to UGT1A1 polymorphism. Further studies on the mechanism and the potential risks in various medical treatments might be wanted.

Infants receiving long-term parenteral nutrition (PN) develop PN-associated liver disease (PNALD). We previously (Ng K et al. JPEN J Parenter Enteral Nutr 40: 656-671, 2016. doi:10.1177/0148607114567900.) showed that PN containing soy-based lipid supplemented with vitamin E (α-tocopherol) prevents the development of PNALD. We hypothesize that this occurs via vitamin E activation of pregnane X receptor (PXR)-mediated pathways involved in bile acid metabolism. Neonatal piglets received PN for 14 days containing Intralipid (IL; soy-based lipid emulsion), IL supplemented with 12.6 mg·kg -1 ·day -1 vitamin E (VITE), or IL with 10 mg·kg -1 ·day -1 Rifadin IV (RIF), a PXR agonist. Pigs treated with IL and VITE, but not RIF, developed cholestasis and hyperbilirubinemia, markers of liver disease. The hepatic PXR target genes CYP3A29 and UGT1A6 increased during RIF treatment. RIF also modestly increased metabolism of chenodeoxycholic acid to the more hydrophilic bile acid hyocholic acid. Serum fibroblast growth factor (FGF)-19, a key regulator in suppressing hepatic bile acid synthesis, significantly increased in the RIF group. We conclude rifampicin modified markers of PNALD development by increased metabolism of bile acids and potentially suppressed bile acid synthesis. Vitamin E was ineffective at high lipid doses in preventing PNALD. NEW & NOTEWORTHY Intravenous vitamin E and rifampicin were administered to neonatal piglets receiving parenteral nutrition to determine their efficacy in reducing the progression of parenteral nutrition-associated liver disease (PNALD). Rifampicin increased serum FGF-19 concentrations and synthesis of the bile acid hyocholic acid which led to a reduction of PNALD parameters at 2 wk of administration. This result has potential clinical implications for the use of rifampicin as a safe and inexpensive treatment for short-term development of PNALD.

Background: Although the relationship between umbilical cord clamping time and various parameters such as hemoglobin (Hb) levels, iron deficiency, and risk of neonatal jaundice has previously been studied, to the best of our knowleadge there have been no studies investigating the relationship between cord clamping time and the risk of significant hyperbilirubinemia. We aimed to investigate the relationship between the time of umbilical cord clamping and transcutaneous bilirubin (TcB) measurements made on various postnatal hours, Hb and serum total bilirubin (STB) levels measured on postnatal 4th day, and the risk of development of significant hyperbilirubinemia requiring phototherapy treatment., Methods: Eligible newborns were divided into two groups on the basis of the time of cord clamping: those clamped late (60 seconds or more; Group I) and those clamped early (less than 60 seconds; Group II). Groups were compared with respect to the parameters of cord Hb, postnatal TcB measurements at 6th, 48th, 96th and 168th hours, and 96th hour Hb, STB and direct bilirubin levels., Results: TcB levels at the 96th and 168th hour were significantly higher in Group I when compared to Group II (p < 0.001 and p < 0.001, respectively). The 96th hour STB level was significantly higher in Group I when compared to Group II (p < 0.001). The need of phototherapy requirement was higher in Group I when compared to Group II (p=0.001). Increase in cord blood Hb for each 1 gr/dl caused a 3.94-fold increased risk in the requirement of phototherapy treatment. Cord clamping time showed statistically significant positive correlations with both cord blood and 96th hour venous Hb levels, with both 96th hour and 168th hour TcB levels, and with 96th hour STB levels., Conclusions: Newborns whose cords are clamped late should be followed up closely with respect to high postnatal bilirubin levels and other risks associated with significant hyperbilirubinemia requiring phototherapy treatment.

Background: Renal hypouricemia (RHUC) is an inherited heterogenous disorder caused by faulty urate reabsorption transporters in the renal proximal tubular cells. Anaerobic exercise may induce acute kidney injury in individuals with RHUC that is not caused by exertional rhabdomyolysis; it is called acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise (ALPE). RHUC is the most important risk factor for ALPE. However, the mechanism of onset of ALPE in patients with RHUC has not been elucidated. The currently known genes responsible for RHUC are SLC22A12 and SLC2A9., Case Presentation: A 37-year-old man presented with loin pain after exercising. Despite having a healthy constitution from birth, biochemical examination revealed hypouricemia, with a uric acid (UA) level of < 1 mg/dL consistently at every health check. We detected acute kidney injury, with a creatinine (Cr) level of 4.1 mg/dL, and elevated bilirubin; hence, the patient was hospitalized. Computed tomography revealed no renal calculi, but bilateral renal swelling was noted. Magnetic resonance imaging detected cuneiform lesions, indicating bilateral renal ischemia. Fractional excretion values of sodium and UA were 0.61 and 50.5%, respectively. Urinary microscopy showed lack of tubular injury. The patient's older sister had hypouricemia. The patient was diagnosed with ALPE. Treatment with bed rest, fluid replacement, and nutrition therapy improved renal function and bilirubin levels, and the patient was discharged on day 5. Approximately 1 month after onset of ALPE, his Cr, UA, and TB levels were 0.98, 0.8, and 0.9 mg/dL, respectively. We suspected familial RHUC due to the hypouricemia and family history and performed genetic testing but did not find the typical genes responsible for RHUC. A full genetic analysis was opposed by the family., Conclusions: To the best of our knowledge, this is the first report of ALPE with hyperbilirubinemia. Bilirubin levels may become elevated as a result of heme oxygenase-1 activation, occurring in exercise-induced acute kidney injury in patients with RHUC; this phenomenon suggests renal ischemia-reperfusion injury. A new causative gene coding for a urate transporter may exist, and its identification would be useful to clarify the urate transport mechanism.

Liver Graft-versus-host disease (GVHD) is common in patients with post-transplant liver dysfunction following allogeneic hematopoietic stem cell transplantation (AHSCT). Oftentimes, the diagnosis is made clinically, and liver biopsy is deferred. Our objective was to evaluate the risk factors and clinical outcomes of liver GVHD among patients who developed post-transplant liver dysfunction. Additionally, we evaluated the feasibility of liver biopsy in this population. We compared outcomes between liver GVHD and a "non-liver GVHD" group, which consisted of other etiologies of post-transplant liver dysfunction. Between January 2003 and December 2010, 249 patients developed post-transplant liver dysfunction following AHSCT: 124 patients developed liver GVHD and 125 were in the "non-liver GVHD" group. The incidence of acute and chronic liver GVHD at one year was 15.7% and 31.0%, respectively. The competing risk analysis revealed full intensity conditioning regimen (Hazard ratio [HR], 1.76; P = .008) and related donor (HR, 1.68; P = .004) as independent risk factors for liver GVHD. The time-varying covariate Cox regression analysis with competing risk event, demonstrated that liver GVHD was independently associated with higher non-relapse mortality, and adverse relapse-free and overall survival. A total of 112 liver biopsies were performed in 100 patients. No major complications were observed. Liver biopsy confirmed prebiopsy hypotheses in 49% of cases, and led to treatment modification in 49% of patients. Our study shows that liver GVHD is associated with adverse survival. Liver biopsy is safe and often helps directing care in this setting., (© 2019 Wiley Periodicals, Inc.)

Background: Hyperbilirubinemia, which is a sign of hemolytic disease of the newborn (HDN), can irreversibly damage the central nervous system., Objectives: To determine the etiology of HDN in affected patients and characterize the changing pattern of bilirubin using direct antiglobulin testing (DAT)., Methods: We collected clinical data from newborns who underwent perinatal DAT and from their mothers, between August 2008 and July 2017., Results: Among 303 neonates, 37 (12.2%) showed positive DAT results. The positive predictive values (PPVs) and negative predictive values (NPVs) based on DAT results were 75.7% and 28.9%, respectively, for starting phototherapy. Bilirubin levels increased more rapidly in the DAT-positive group, compared with the DAT-negative group. The initial bilirubin level differed significantly according to the etiology of hyperbilirubinemia. Further, neonates with anti-D showed higher delta bilirubin per day than neonates with other antibodies., Conclusion: Our results may help to determine the measurement period for bilirubin according to DAT results and etiology., (© American Society for Clinical Pathology 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cholecystoduodenostomy is a surgical procedure that bypasses the extrahepatic biliary tree and connects the gallbladder directly to the duodenum. This case describes the successful use of this procedure in a novel situation., Case Presentation: A premature (34 weeks gestation) female infant with cystic fibrosis required a laparotomy on day 1 of life due to an intrauterine small bowel perforation. Resection of small bowel and ileostomy formation resulted in short gut syndrome, with 82 cm residual small bowel and intact ileocaecal valve. Post-ileostomy reversal at 2 months old, she developed conjugated hyperbilirubinaemia. Despite conservative management including increased enteral feeding, ursodeoxycholic acid, cholecystostomy drain insertion and flushes, her cholestatic jaundice persisted. A liver biopsy revealed an "obstructive/cholestatic" picture with fibrosis. To avoid further shortening her gut with an hepatoportoenterostomy, cholecystoduodenostomy was performed at 3 months of age with subsequent post-operative improvement and eventual normalisation of her clinical jaundice and liver biochemistry., Conclusions: This is the first reported case of a cholecystoduodenostomy being used successfully to treat an infant with persistent conjugated hyperbilirubinemia, cystic fibrosis and short gut syndrome. Cholecystoduodenostomy is a treatment option that with further study, may be considered for obstruction of the common bile duct in patients with short gut and/or where a shorter operating time with minimal intervention is preferred.

Background: Total parenteral nutrition (TPN) and biliary atresia (BA) are common causes of cholestasis in infancy. The diagnosis of BA is time sensitive due to an inverse correlation between age at intervention (hepatic portoenterostomy - HPE) and survival without liver transplantation. Clinical, laboratory, and histologic features of BA and parenteral nutrition associated cholestasis (PNAC) are similar, creating a diagnostic dilemma for cholestatic infants on parenteral nutrition. There is limited published information about the natural history of PNAC including time to resolution, or diagnostic tests that distinguish BA from other etiologies of cholestasis., Case Presentation: We present a case of a child diagnosed with BA whose cholestasis began while receiving TPN. His clinical course was notable for transient resolution of his cholestasis after stopping parenteral nutrition and ultimate intraoperative diagnosis., Conclusions: Clinicians who care for patients who frequently receive TPN should be aware that clinical, laboratory, imaging, and biopsy findings can be similar between BA and PNAC.

Aim: Acute appendicitis is one of the most common pathology requiring emergency operations, and if perforated, can cause morbidity and mortality. The serum bilirubin levels were studied to see whether an elevation predicted perforation., Material and Methods: In a retrospective cohort study the medical files of 221 patients who were operated for acute appendicitis were reviewed., Results: Total and indirect bilirubin levels were significantly higher in patients with a perforated appendicitis compared with patients with simple appendicitis. Elevated serum bilirubin had a sensitivity of 50.00 (95% CI 29.93 to 70.07) and a specificity of 80.73 (95% CI 74.43 to 86.05) when predicting a perforated appendicitis., Conclusions: Appendiceal perforation may be accompanied with elevated serum bilirubin level. Assessment of bilirubin levels must be a part of the initial evaluation of a suspected appendicitis in the emergency room., Key Words: Acute appendicitis, Gangrenous appendicitis, Perforated appendicitis, Serum bilirubin, Total Hyperbilirubinemia.

Background: Delayed cord clamping is the standard of care in infants not requiring resuscitation; however effects of cord clamping strategies have not been evaluated systematically in small for gestational age (SGA) infants. The primary objective was to compare effects of delayed cord clamping (DCC) and early cord clamping (ECC) on serum ferritin at 3 months in SGA infants born at ≥35 weeks. The secondary objectives were to compare hematological parameters, clinical outcomes in neonatal period and growth at 3 months of age., Methods: All eligible infants with fetal growth restriction were randomized to two groups, DCC at 60 s or ECC group in which the cord was clamped immediately after birth., Results: Total of 142 infants underwent randomization and subsequently 113 infants underwent definite inclusion. At 3 months, the median (IQR) serum ferritin levels were higher in DCC group, compared to ECC; 86 ng/ml (43.35-134.75) vs 50.5 ng/ml (29.5-83.5), p = 0.01. Fewer infants had iron deficiency in DCC group compared to ECC group; 9 (23.6%) vs 21 (47.7%), p = 0.03 [NNT being 4; 95% CI (2-25)].The proportion of infants with polycythemia was significantly higher in DCC group; 23 (41.81) % vs 12 (20.6%), p = 0.01. There was no difference in proportion of infants with symptomatic polycythemia or those who underwent partial exchange transfusions. Clinical outcomes and mortality were similar., Conclusions: DCC improves iron stores in SGA infants ≥35 weeks at 3 months of age without increasing the risk of symptomatic polycythemia, need for partial exchange transfusions or morbidities associated with polycythemia., Trial Registration: Our trial was retrospectively registered on 29th May 2015 through Clinical trials registry India. Registration number: CTRI 2015/05/005828 .

Background: It is controversial to test for urinary tract infection (UTI) in patients with unexplained indirect hyperbilirubinemia in the first 2 weeks of life. We aimed to study the prevalence and significance of UTIs in such neonates who were requiring phototherapy., Methods: Subjects were 2- to 14-day-old neonates with indirect bilirubin levels above phototherapy limit with no other abnormality in their bilirubinaemia-related etiologic workup. UTI was diagnosed by 2 consecutive positive cultures obtained by catheterisation, documenting growth of >10,000 colonies of the same microorganism with consistent antibiograms. The UTI (+) patients were evaluated by renal ultrasonography (US), and some were followed up for possible recurrent UTI., Results: 262 neonates were included in the study. UTI prevalence was 12.2%, and bacteraemia was 6.2% among UTI (+) patients. The two most common pathogens (81.2%) were Escherichiacoli and Klebsiella. pneumonia. All UTI (+) patients had undergone US, revealing 12.5% pelvicaliectasis, other 12.5% increased renal parenchymal echogenicity, 3.1% concurrent pelvicaliectasis and increased renal parenchymal echogenicity. 53.1% of UTI (+) patients had undergone follow-up, after which 23.5% recurrent UTI were found at the end of a mean of 52 months., Conclusion: We suggest that the neonates with unexplained pathological jaundice should be tested for possible UTI. Consequently, all newborns with UTI shall be evaluated by the urinary US and followed up for recurrent UTI., (Copyright © 2017. Published by Elsevier B.V.)

Gilbert's syndrome (GS) patients present with remittent unconjugated hyperbilirubinemia. In this study, we investigated the correlation between polymorphisms in the gene encoding UDP-glucuronosyltransferase, UGT1A1, and the development of unconjugated hyperbilirubinemia in clinical GS and post-hepatitis hyperbilirubinemia. Blood samples were collected from 285 patients, including 85 patients who were clinically diagnosed with GS, 70 patients who had indirect hyperbilirubinemia during the recovery period of chronic liver diseases, 109 patients with normal hepatic function and 21 chronic active hepatitis patients. All samples were tested for the presence of the *28/*6 UGT1A1 genotype by pyrosequencing. Compared with the GS-control group, a significant difference in variations of the UGT1A1*28/*6 allele gene was found in GS patients. The post-hepatitis group showed a significant difference in the UGT1A1*28/*6 allele gene frequency distribution relative to that in the hepatitis control group. There were no significant differences between the GS group and post-hepatitis group in the distribution of the UGT1A1*28/*6 allele gene frequency and UGT1A1 diplotypes. UGT1A1*28/*6 gene polymorphisms in patients who had indirect hyperbilirubinemia while recovering from chronic liver diseases presented similar patterns as those seen for GS patients. These findings suggest that a "Gilbert's-like" syndrome might be part of the spectrum of persistent unconjugated hyperbilirubinemia in post-chronic hepatitis patients.

Dubin-Johnson syndrome is a rare benign inherited disorder, caused by mutations in ABCC2 gen, and it is characterized by predominantly conjugated hyperbilirubinemia that can be increased by intercurrent infectious illnesses or surgical procedures. We report the case of a 10 year-old patient who showed, after a surgical procedure for peritonitis due to appendicitis, jaundice and predominantly conjugated hyperbilirubinemia, and he was diagnosed with Dubin-Johnson syndrome by genetic testing.

Background: Liver dysfunction in left ventricular assist device (LVAD) recipients is common both before and after implantation. Postoperative liver dysfunction (PLD) develops in some LVAD recipients without preoperative liver dysfunction. The aim of this study was to assess clinical outcomes in such patients., Methods: Records of all patients undergoing implantation of a HeartMate II (HM II, St. Jude Medical, Inc, Minneapolis, MN) LVAD at a single center at the University of Minnesota from January 2005 through June 2014 were analyzed. PLD was defined by hypertransaminasemia or hyperbilirubinemia, or both, during the hospitalization for LVAD implantation., Results: During the study period, 284 patients underwent HM II implantation. Excluded from analysis were 14 recipients with preoperative liver dysfunction. In the final cohort (n = 270), there were no major difference in preoperative characteristics among those patients with versus without PLD. PLD developed in 129 (47.8%) recipients: 16 (12.4%) had isolated hypertransaminasemia (group I), 76 (58.9%) had isolated hyperbilirubinemia (group II), and 37 (28.7%) had combined hypertransaminasemia and hyperbilirubinemia (group III). Group III LVAD recipients had significantly greater rates of 30-day, 90-day, and 1-year mortality, along with significantly higher transfusion requirements and higher rates of renal replacement therapy, prolonged ventilation, and vasopressor use. Moreover, their mortality risk was significantly higher than that of PLD-free LVAD recipients (hazard ratio, 4.6; 95% confidence interval, 2.1 to 10.1; p < 0.001)., Conclusions: Isolated hyperbilirubinemia is common after LVAD implantation. In this study, it was not associated with an increase in early or midterm postoperative mortality. However, postoperative combined transaminasemia and hyperbilirubinemia was associated with a significant increase in early and midterm morbidity and mortality. Further research into the pathogenesis of post-LVAD PLD is necessary., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background/aims: Metronomic chemotherapy (MET) is frequently administered in comparatively low doses as a continuous chemotherapeutic agent. The aim of this study was to evaluate the feasibility and overall survival (OS) of MET compared to sorafenib for advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT)., Methods: A total of 54 patients with advanced HCC and PVTT who had undergone MET were analyzed between 2005 and 2013. A total of 53 patients who had undergone sorafenib therapy were analyzed as the control group. The primary endpoint of this study was OS., Results: The median number of MET cycles was two (1-15). The OS values for the MET group and sorafenib group were 158 days (132-184) and 117 days (92-142), respectively ( P =0.029). The Cox proportional-hazard model showed that a higher risk of death was correlated with higher serum alpha fetoprotein level (≥400 mg/dL, hazard ratio [HR]=1.680, P =0.014) and Child-Pugh class B (HR=1.856, P =0.008)., Conclusions: MET was associated with more favorable outcomes in terms of overall survival than was sorafenib in patients with advanced HCC with PVTT, especially in patients with poor liver function. Therefore, MET can be considered as a treatment option in patients with advanced HCC with PVTT and poor liver function.

Jaundice in adults can be an indicator of significant underlying disease. It is caused by elevated serum bilirubin levels in the unconjugated or conjugated form. The evaluation of jaundice relies on the history and physical examination. The initial laboratory evaluation should include fractionated bilirubin, a complete blood count, alanine transaminase, aspartate transaminase, alkaline phosphatase, ?-glutamyltransferase, prothrombin time and/or international normalized ratio, albumin, and protein. Imaging with ultrasonography or computed tomography can differentiate between extrahepatic obstructive and intrahepatic parenchymal disorders. Ultrasonography is the least invasive and least expensive imaging method. A more extensive evaluation may include additional cancer screening, biliary imaging, autoimmune antibody assays, and liver biopsy. Unconjugated hyperbilirubinemia occurs with increased bilirubin production caused by red blood cell destruction, such as hemolytic disorders, and disorders of impaired bilirubin conjugation, such as Gilbert syndrome. Conjugated hyperbilirubinemia occurs in disorders of hepatocellular damage, such as viral and alcoholic hepatitis, and cholestatic disorders, such as choledocholithiasis and neoplastic obstruction of the biliary tree.

Objectives: Hepatitis-associated aplastic anemia (HAA) is a rare variant of aplastic anemia in which patients present with severe pancytopenia after an episode of acute hepatitis. The marrow failure is often rapid, severe, and usually fatal if untreated. The preceding hepatitis is largely under-studied., Methods: Retrospective study of the clinical and histopathologic features of hepatitis in pediatric patients who subsequently developed aplastic anemia and comparison with consecutive cases of acute liver failure and random cases of autoimmune hepatitis during the same time frame., Results: All 7 patients of HAA had significant elevations in aminotransferases and conjugated hyperbilirubinemia at initial presentation. Echoing liver function indices, cholestatic hepatitis with sinusoidal obstruction-type endothelial injury was seen histomorphologically. Autoimmune hepatitis serology such as anti-F-actin, anti-liver/kidney microsome, and hypergammaglobulinemia was negative in all patients. Five of 7 patients (71.4%) had, however, elevated antinuclear antibody, all with a speckled pattern. Hepatitis virus serology was negative in all patients. By immunohistochemical staining, the lobular CD8/CD4 lymphocyte ratio was markedly elevated in all of the initial samples with significant reduction in this ratio (P = 0.03) in 3 patients post treatment (ursodiol, antibiotics, and/or immunosuppressive therapy)., Conclusions: Hepatitis preceding HAA is characterized by marked elevation of aminotransferases, conjugated hyperbilirubinemia, elevated antinuclear antibody with a speckled pattern, cholestatic hepatitis with sinusoidal obstruction morphology, and CD8 dominant lobular infiltrates. The present study suggests HAA may result from cytotoxic T-cell-mediated sinusoidal endothelial and hepatocytic injury.

Cholestatic jaundice in infancy affects approximately 1 in every 2500 term infants and is infrequently recognized by primary providers in the setting of physiologic jaundice. Cholestatic jaundice is always pathologic and indicates hepatobiliary dysfunction. Early detection by the primary care physician and timely referrals to the pediatric gastroenterologist/hepatologist are important contributors to optimal treatment and prognosis. The most common causes of cholestatic jaundice in the first months of life are biliary atresia (25%-40%) followed by an expanding list of monogenic disorders (25%), along with many unknown or multifactorial (eg, parenteral nutrition-related) causes, each of which may have time-sensitive and distinct treatment plans. Thus, these guidelines can have an essential role for the evaluation of neonatal cholestasis to optimize care. The recommendations from this clinical practice guideline are based upon review and analysis of published literature and the combined experience of the authors. The committee recommends that any infant noted to be jaundiced after 2 weeks of age be evaluated for cholestasis with measurement of total and direct serum bilirubin, and that an elevated serum direct bilirubin level (direct bilirubin levels >1.0 mg/dL or >17 μmol/L) warrants timely consideration for evaluation and referral to a pediatric gastroenterologist or hepatologist. Of note, current differential diagnostic plans now incorporate consideration of modern broad-based next-generation DNA sequencing technologies in the proper clinical context. These recommendations are a general guideline and are not intended as a substitute for clinical judgment or as a protocol for the care of all infants with cholestasis. Broad implementation of these recommendations is expected to reduce the time to the diagnosis of pediatric liver diseases, including biliary atresia, leading to improved outcomes.

Background: Parenteral fish-oil (FO) therapy is a safe and effective treatment for intestinal failure-associated liver disease (IFALD). Patients whose cholestasis does not resolve with FO may progress to end-stage liver disease., Objective: We sought to identify factors associated with the failure of FO therapy in treating IFALD to guide prognostication and referral guidelines., Design: Prospectively collected data for patients treated with FO at Boston Children's Hospital from 2004 to 2014 were retrospectively reviewed. Resolution of cholestasis was defined as sustained direct bilirubin (DB) <2 mg/dL, and treatment failure as liver transplantation or death while DB was >2 mg/dL as of July 2015. Demographics, laboratory values, and medical history at FO therapy initiation were compared between patients who achieved resolution of cholestasis and those who failed therapy., Results: Among 182 patients treated with FO, 86% achieved resolution of cholestasis and 14% failed therapy. Patients who failed therapy had median (IQR) lower birth weight [1020 g (737, 1776 g) compared with 1608 g (815, 2438 g); P = 0.03] and were older at FO initiation [20.4 wk (9.9, 38.6 wk) compared with 11.7 wk (7.3, 21.4 wk); P = 0.02] than patients whose cholestasis resolved. Patients who failed therapy had more advanced liver disease at therapy initiation than patients whose cholestasis resolved, as evidenced by lower median (IQR) γ-glutamyltransferase [54 U/L (41, 103 U/L) compared with 112 U/L (76, 168 U/L); P < 0.001], higher DB [10.4 mg/dL (7.5, 14.1 mg/dL) compared with 4.4 mg/dL (3.1, 6.6 mg/dL); P < 0.001], and a higher pediatric end-stage liver disease (PELD) score [22 (14, 25) compared with 12 (7, 15); P < 0.001]. A PELD score of ≥15, history of gastrointestinal bleeding, age at FO initiation ≥16 wk, presence of nongastrointestinal comorbidities, and mechanical ventilation at FO initiation were independent predictors of treatment failure., Conclusions: Most infants with IFALD responded to FO therapy with resolution of cholestasis, and liver transplantation was rarely required. Early FO initiation once biochemical cholestasis is detected in parenteral nutrition-dependent patients is recommended. This trial was registered at clinicaltrials.gov as NCT00910104., (© 2016 American Society for Nutrition.)

Hyperbilirubinemia (HB) is sometimes encountered following bile-duct cannulation in rats. It possibly originates from the reduced functioning of multidrug resistance-associated protein 2 (Mrp2) and subsequent adaptive alterations in the expression of Mrp3 and the organic anion transporting polypeptides (Oatps). Our aim was to clarify the importance of excluding bile-duct-cannulated (BDC) rats with HB for proper conduct of drug excretion studies. We detected HB [serum total bilirubin concentration (TBIL) ≥0.20 mg/dl] in 16% of all BDC rats prepared. The serum activities of aspartate aminotransferase, alanine aminotransferase, leucine aminopeptidase, and alkaline phosphatase were within the respective normal ranges in the BDC rats with mild HB (TBIL, 0.20-0.79 mg/dl), indicating the absence of hepatic failure. In the pharmacokinetics of pravastatin, an Oatps/Mrp2 probe drug in the BDC rats, the apparent volume of distribution and the clearance were smaller in the mild HB group as compared with the normal group, suggesting the reduction of apparent hepatic uptake and hepatobiliary elimination. The biliary excretion (percentage of dose) was significantly reduced by 54%, suggesting that the biliary efflux activity via Mrp2 was reduced to a greater extent relative to metabolic activity in hepatocytes. The serum γ-glutamyltransferase (GGT) activity correlated with TBIL and inversely correlated with biliary excretion of pravastatin, a finding which could serve as a clue to uncover the regulatory system involving cooperation between GGT and Mrp2. In conclusion, BDC rats with HB, however mild, should be excluded from drug excretion studies to avoid the risk of underestimation of the biliary excretion of drugs., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Many different blood group systems, such as Rh, ABO, Kell, Kidd, Duffy, MNS, have been reported as causes of hemolytic disease of the newborn. Hemolysis due to minor blood group incompatibility in the fetus or newborn has been determined in isolated case reports. Here, we report a case of a patient who had received red cell transfusion due to severe Rh c and E incompatibility, leading to hemolytic anemia with heart failure. The mother and the baby were grouped B and B, respectively, both being positive for RhD antigen. The baby's blood group type was C+, c+, E+, e+, K-, while her mother's blood group type was C+, c-, E-, e+, K-. Our patient was diagnosed as Rh c and E incompatibility, leading to the hemolytic anemia. Minor blood group incompatibility should be considered in infants with prolonged jaundice and severe anemia, leading to heart failure.

Background: The etiologies of conjugated hyperbilirubinemia in infancy are diverse., Objective: Determine the prevalence rates of the specific etiologies of conjugated hyperbilirubinemia in infancy., Data Sources: EMBASE and Pubmed were searched electronically and the bibliographies of selected studies were search manually. The search was conducted independently by two authors., Study Selection: (1) prospective or retrospective case series or cohort study with 10 or more subjects; (2) consecutive infants who presented with conjugated hyperbilirubinemia; (3) subjects underwent appropriate diagnostic work-up for conjugated hyperbilirubinemia; (4) no specific diagnoses were excluded in the studied cohort., Data Extraction: Patient number, age range, country of origin, and categorical and specific etiologies., Results: From 237 studies identified, 17 studies encompassing 1692 infants were selected. Idiopathic neonatal hepatitis (INH) occurred in 26.0% of cases; the most common specific etiologies were extrahepatic biliary atresia (EHBA) (25.89%), infection (11.47%), TPN- associated cholestasis (6.44%), metabolic disease (4.37%), alpha-1 anti-trypsin deficiency (4.14%), and perinatal hypoxia/ischemia (3.66%). CMV was the most common infection identified (31.51%) and galactosemia (36.49%) was the most common metabolic disease identified., Limitations: Major limitations are: (1) inconsistencies in the diagnostic evaluations among the different studies and (2) variations among the sample populations., Conclusions: INH is the most common diagnosis for conjugated hyperbilirubinemia in infancy while EHBA and infection are the most commonly identified etiologies. The present review is intended to be a guide to the differential diagnosis and evaluation of the infant presenting with conjugated hyperbilirubinemia.

Objective: We assessed the relative contributions of increased bilirubin production (indexed by end-tidal carbon monoxide (CO) concentrations, corrected for ambient CO (ETCOc)) to hour-specific total bilirubin (TB) levels in healthy late preterm and term newborns., Study Design: Post hoc analyses of concurrent ETCOc and TB (at 30±6 h of age) and follow-up TB levels at age 96±12 h and up to 168 h after birth were performed in a cohort of 641 term and late preterm infants., Results: Increased bilirubin production (hour-specific ETCOc ⩾1.7 p.p.m. at age 30±6 h) was noted in ~80%, 42% and 32% of infants in the high-, intermediate- and low-risk TB zones, respectively. One infant with TB <40th percentile and ETCOc <1.7 p.p.m. developed TB ⩾95th percentile at age 168 h, probably due to decreased bilirubin elimination., Conclusions: Infants in the high-risk quartile of the hour-specific bilirubin nomogram have a higher mean bilirubin production. Infants with TB levels ⩾95th percentile without increased bilirubin production have impaired bilirubin elimination.

Background and Aims: HLA class I alleles, in particular HLA-B*57, constitute the most consistent host factor determining outcomes in untreated HCV- and HIV-infection. In this prospective cohort study, we analysed the impact of HLA class I alleles on all-cause mortality in patients with HIV-, HCV- and HIV/HCV- co-infection receiving HAART., Methods: In 2003 HLA-A and B alleles were determined and patients were prospectively followed in 3-month intervals until 2013 or death. HLA-A and B alleles were determined by strand-specific oligonucleotide hybridisation and PCR in 468 Caucasian patients with HCV- (n=120), HIV- (n=186) and HIV/HCV-infection (n=162). All patients with HIV-infection were on HAART. In each patient group, HLA class I-associated survival was analysed by Kaplan-Meier method and Cox regression analysis., Results: At recruitment the proportion of patients carrying a HLA-B*57 allele differed between HIV- (12.9%) and HCV-infection (4.2%). Kaplan Meier analysis revealed significantly increased mortality in HLA-B*57-positive patients with HIV-infection (p=0.032) and HIV/HCV-co-infection (p=0.004), which was apparently linked to non-viral infections. Cox logistic regression analysis confirmed HLA-B*57 (p=0.001), serum gamma-glutamyltranspeptidase (p=0.003), serum bilirubin (p=0.022) and CD4 counts (p=0.041) as independent predictors of death in HIV-infected patients., Conclusion: Differences in the prevalence of HLA-B*57 at study entry between HIV- and HCV- infected patients may reflect immune selection in the absence of antiviral therapy. When patients were treated with HAART, however, HLA-B*57 was associated with increased mortality and risk to die from bacterial infections and sepsis, suggesting an ambiguous role of HLA-B*57 for survival in HIV/HCV infection depending on the circumstances.

A man in his late 40s with sickle cell anaemia (HbSS) presented to the emergency department with 2 weeks of diffuse oedema, increased abdominal girth and dyspnoea. His anasarca was thought to be indicative of an acute decompensation of his known liver cirrhosis with transfusion-induced haemosiderosis. While his anasarca improved with diuresis, his direct hyperbilirubinaemia suddenly worsened without any signs of haemolysis, biliary disease or obstruction. He also developed an acute worsening in serum creatinine (1.17-7.0 mg/dL in 7 days) despite subsequent treatment for presumed hepatorenal syndrome (HRS). Given his clinical decline, the patient's goals of care were transitioned to comfort measures only. His clinical presentation and rapid liver and renal deterioration were most typical of sickle cell intrahepatic cholestasis (SCIC). SCIC can lead to rapid deterioration in renal function and can be mistaken for HRS. When SCIC is suspected, consideration of exchange transfusions should be made early., (2015 BMJ Publishing Group Ltd.)

Objectives: Byler disease, originally described in Amish kindred, results from mutations in ATPase Class I Type 8b Member 1 (ATP8b1). Specific clinical reports of Amish Byler disease were last published 40 years ago. These investigations were directed at the present detailed clinical understanding of the early course of hepatic manifestations of Byler disease., Methods: This study analyzed routine clinical practice and outcomes of children with Byler disease (defined by homozygous c.923G>T mutation in ATP8b1), who initially presented to Children's Hospital of Pittsburgh of UPMC between January 2007 and October 2014. Data were analyzed to the earlier of 24 months of age or partial external biliary diversion., Results: Six children presented between 1 and 135 days of life: 2 presented with newborn direct hyperbilirubinemia, 2 had complications of coagulopathy, 1 had failure to thrive and rickets, and 1 sibling was identified by newborn genetic testing. Intensive fat-soluble vitamin supplementation was required to prevent insufficiencies in vitamins D, E, and K. Hyperbilirubinemia was variable both over time and between children. Serum bile acid levels were elevated, whereas γ-glutamyltranspeptidase levels were low normal. Scratching behavior (pruritus) was intractable in 4 of 6 children with onset between 6 and 12 months of age. Features of portal hypertension were not observed. Partial external biliary diversion was used during the second year of life in 4 children., Conclusions: Detailed analysis of Byler disease revealed varied disease presentation and course. Nutritional issues and pruritus dominated the clinical picture in the first 2 years of life.