Effect of hyperbilirubinemia and phototherapy on apoptotic microparticle levels in neonates.

OBJECTIVE: We aimed to evaluate the effect of hyperbilirubinemia and phototherapy on total apoptotic, platelet-derived, endothelial-derived, and tissue factor (TF)-positive apoptotic microparticle (MP) levels in neonates with nonhemolytic pathologic hyperbilirubinemia. METHODS: Thirty-three term neonates with nonhemolytic pathologic hyperbilirubinemia and 25 healthy term neonates were included. MP levels were analyzed by flow cytometry using peripheral blood samples only once for the neonates in the control group and twice for the neonates in the study group (before and after phototherapy). Annexin V-positive MPs were defined as apoptotic MPs. Platelet-derived MPs were defined as those containing CD31. MPs containing CD144 were defined as endothelial-derived MPs, and MPs expressing TF were identified as those containing CD142. RESULTS: The rates of total apoptotic and endothelial-derived apoptotic MPs were significantly higher in the study group than the control group before phototherapy (P = 0.012 and P = 0.003, respectively) and after phototherapy (P = 0.046 and P = 0.001, respectively). Total apoptotic, platelet-derived, endothelial-derived, and TF-positive apoptotic MPs did not show any significant differences before and after phototherapy in the study group (P = 0.908, P = 0.823, P = 0.748, and P = 0.437, respectively). CONCLUSIONS: Our study demonstrated that total apoptotic and endothelial-derived apoptotic MPs are increased in cases of nonhemolytic pathologic hyperbilirubinemia. We showed that phototherapy does not have a significant effect on apoptotic MP levels. Further studies are needed to evaluate the risk of elevated apoptotic MPs on the development of thromboembolism in neonates with nonhemolytic pathologic hyperbilirubinemia.

Acute hyperbilirubinemia determines an early subclinical renal damage: Evaluation of tubular biomarkers in cholemic nephropathy.

BACKGROUND AND AIMS: Cholemic nephropathy is a cause of acute kidney injury occurring in patients with jaundice. The aim of this study was to evaluate early renal function impairment in patients with mild acute hyperbilirubinemia in the absence of alterations of the common parameters used in clinical practice (serum creatinine or urea) and with normal renal morphology. We studied urinary biomarkers of tubular damage urinary neutrophil gelatinase-associated lipocalin (u-NGAL), urinary beta-2-microglobulin (u-B2M), urinary osteopontin (u-OPN), urinary trefoil factor 3 (u-TFF3) and urinary Cystatin C (u-Cys). METHODS: This is a case-control study investigating the following urinary biomarkers of tubular damage: u-NGAL, u-B2M, u-OPN, u-TFF3 and u-Cys, in patients with mild acute hyperbilirubinemia. Seventy-four patients were included in this study: 36 patients with jaundice and 38 patients without jaundice. RESULTS: Subjects with jaundice (total bilirubin 12.4 ± 7.3 mg/dL) showed higher u-NGAL, u-B2M, u-OPN, u-TFF3 and u-Cys compared with controls. After logistic regression analyses, including the following independent variables: age, estimated Glomerular Filtration Rate (eGFR), haemoglobin, diabetes, hypertension and jaundice, we observed a higher risk of elevated u-NGAL values (OR = 3.8, 95% CI 1.07-13.5, p = .03) and u-B2M (OR = 9.4, 95% CI 2.3-38.9, p = .0018) in jaundiced subjects. Moreover, urinary biomarkers had a direct correlation with serum cholestasis indexes. CONCLUSIONS: This study demonstrated increased urinary biomarkers of tubular damage (u-NGAL, u-B2M, u-OPN, u-TFF3, and u-Cys) in patients with mild hyperbilirubinemia in comparison with a control group. These findings suggest early renal tubular damage in the absence of alterations of the normal parameters used in clinical practice (eGFR, serum urea and renal morphology).

The associations of psychopathology and metabolic parameters with serum bilirubin levels in patients with acute-episode and drug-free schizophrenia: a 5-year retrospective study using an electronic medical record system.

BACKGROUND: The oxidative system plays an important role in the pathogenesis of schizophrenia. Inconsistent associations were found between hyperbilirubinemia and psychopathology as well as glycolipid metabolism in patients with schizophrenia at different episodes. This current study aimed to examine these associations in patients with acute-episode and drug-free (AEDF) schizophrenia. METHODS: This is a retrospective study using 5 years of data from May 2017 to May 2022 extracted from the electronic medical record system of Chaohu Hospital of Anhui Medical University. Healthy controls (HCs) from the local medical screening center during the same period were also included. Participants' data of the bilirubin levels [total bilirubin (TB), conjugated bilirubin (CB), unconjugated bilirubin (UCB)], glycolipid metabolic parameters and the score of the Brief Psychiatric Rating Scale (BPRS) were collected. RESULTS: A total of 1468 case records were identified through the initial search. After screening, 89 AEDF patients and 100 HCs were included. Compared with HCs, patients had a higher CB level, and lower levels of glycolipid metabolic parameters excluding high density lipoprotein-cholesterol (HDL-C) (all P < 0.001). Binary logistic regression analyses revealed that high bilirubin levels in the patients were independently associated with higher total and resistance subscale scores of BPRS, a higher HDL-C level, and lower total cholesterol and triglyceride levels (all P < 0.05). CONCLUSION: Bilirubin levels are elevated in patients with AEDF schizophrenia. Patients with high bilirubin levels have more severe psychopathology and relatively optimized glycolipid metabolism. In clinical practice, regular monitoring of bilirubin levels in this patient population should be carried out.

Gene Therapy in Patients with the Crigler-Najjar Syndrome.

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

A New Hour-Specific Serum Bilirubin Nomogram for Neonates ≥35 Weeks of Gestation.

OBJECTIVE: To develop a statistically rigorous, hour-specific bilirubin nomogram for newborns based on a very large data set; and use it prospectively as a replacement for the 1999 Bhutani nomogram. STUDY DESIGN: This was a retrospective analysis of first total serum bilirubin (TSB) measurements from 15 years of universal bilirubin screening during birth hospitalizations at 20 Intermountain Healthcare hospitals. Hour-specific TSB values were assembled into a nomogram by percentile, and subgroups were compared. RESULTS: The information obtained included robust data in the first 12 hours after birth (which was not included in the 1999 nomogram), general agreement with the 1999 nomogram for values in the first 60 hours, but higher 75th and 95th percentile TSB values thereafter in the new version, no difference in TSB between male and female infants, higher TSB values among earlier gestation neonates (350/7-366/7 weeks vs ≥37 weeks, P < .0001), and lower TSB values in neonates of Black race (P < .0001) and higher values in neonates of Asian race (P < .001). CONCLUSIONS: An updated and more informative Bhutani neonatal bilirubin nomogram, based on 140 times the number of subjects included the 1999 version, is now in place in our health care system.

Utility of icteric index in clinical laboratories: more than a preanalytical indicator.

INTRODUCTION: Total bilirubin tests are highly demanded in clinical laboratories. Since icteric index (I-index) has zero cost, we aimed to evaluate its clinical utility and cost-effectiveness to determine if total bilirubin is necessary to be tested. We took into account if haemolysis could interfere to icteric index determination. MATERIAL AND METHODS: Retrospectively we reviewed I-index results in two cohorts (43,372 and 8507 non-haemolysed and haemolysed samples, respectively). All determinations were done using Alinity c chemistry analysers (Abbott Diagnostics). Receiver operating characteristic (ROC) curve was used to determine the optimal index cut-off to discriminate between normal and abnormal bilirubin concentration (20.5 µmol/L). RESULTS: The ROC curve analysis suggested 21.4 µmol/L as the optimal I-index cut-off but differences in sensitivity and specificity were detected between patient derivation. For rejecting purpose, 15.4 µmol/L and 17.1 µmol/L I-index thresholds were selected based on patient derivation (inpatients and emergency room; and primary care and outpatients, respectively) with 97% sensitivity and 0.25% false negative results. Sensitivity was much lower in haemolysed samples. We selected 34.2 µmol/L I-index as threshold to detect hyperbilirubinemia with 99.7% specificity and 0.26% false positive results, independent of haemolysis. With the icteric index cut-offs proposed, we would save 66% of total bilirubin requested and analyse total bilirubin in around 2% of samples without total bilirubin requested. CONCLUSIONS: This study supports the use of I-index to avoid bilirubin determination and to identify patients with hyperbilirubinemia. This work considers that the economic and test savings could help to increase the efficiency in clinical laboratories.

Acute human parvovirus B19 infection triggers immune-mediated transient bone marrow failure syndrome, extreme direct hyperbilirubinaemia and acute hepatitis in patients with hereditary haemolytic anaemias: multicentre prospective pathophysiological study.

A total of 244 patients with hereditary haemolytic anaemias (HHA) were screened for acute symptomatic human parvovirus B19 infection (HPV-B19) in a prospective study. To assess the risks associated with HPV-B19 infection, patients were classified into Group I and Group II according to presence or absence (symptoms, signs and specific serology) of acute HPV-B19 infection respectively. In all, 131 (53·7%) patients had ß-thalassaemia, 75 (30·7%) hereditary spherocytosis (HS), 27 (11·1%) sickle cell anaemia (SCA) and 11 (4·5%) glucose-6-phosphate dehydrogenase (G6PD) deficiency. Of 33 (13·5%) patients who presented with symptomatic HPV-B19 infection, 19 (57·5%) had HS, nine (27·3%) had ß-thalassaemia and five (15·2%) had SCA. In Group I, there were significant differences in the mean white blood cell, red blood cell and platelet counts, haemoglobin concentration, total bilirubin (TB), alanine aminotransferase, aspartate aminotransferase and serum creatinine (all P < 0·001) compared to Group II. In all, 27 (81·8%) patients had arthropathy and bone marrow failure (BMF); 13 (39·4%) had acute kidney injury (AKI), more in SCA (80%); and 12 (36·4%) patients had hepatitis, more in HS (66·8%). Five (15·2%) patients with HS had BMF, AKI, nervous system involvement and extreme hyperbilirubinaemia (TB range 26·3-84·7 mg/dl). Five (15·2%) patients had haemophagocytic syndrome. Two patients with HS combined with Type-I autoimmune hepatitis presented with transient BMF. Complete recovery or stabilisation was noted at 12 months in every patient except for one patient with SCA who died during the infection. HPV-B19 must be suspected and screened in patients with HHA with typical and atypical presentations with careful follow-up.

Effects of bilirubin configurational photoisomers on the measurement of direct bilirubin by the vanadate oxidation method.

BACKGROUND: Direct-reacting bilirubin concentrations measured using vanadate chemical oxidation method do not exactly match the conjugated bilirubin concentration. One of the causes is the effect of bilirubin photoisomers. However, the quantitative evaluation of the effects of these photoisomers has not been sufficiently conducted. In particular, the influence of bilirubin configurational isomers on direct bilirubin is the most critical factor. METHODS: Sixteen residual serum samples were used. For quantitative analysis based on the change in direct bilirubin and bilirubin configurational isomer, samples were irradiated via blue light-emitting diodes to suppress the production of bilirubin structural isomers. Total bilirubin and direct bilirubin concentrations were measured using the vanadate chemical oxidation method. Concentrations of 4Z,15Z-bilirubin IXα and its photoisomers were measured using high-performance liquid chromatography. The sum of 4Z,15E-bilirubin IXα and 4E,15Z-bilirubin IXα was notated as bilirubin configurational isomer, and the differences between the measured values of the irradiated and non-irradiated samples were calculated and notated as ΔDB and ΔBCI. RESULTS: In non-irradiated and irradiated samples, total bilirubin and direct bilirubin concentrations were 10.73 mg/dL with significant a decrease to 10.60 mg/dL and 0.69 mg/dL with a significant increase to 0.78 mg/dL, while bilirubin configurational isomer values were 1.00 mg/dL and 1.52 mg/dL, respectively. The linear regression equation revealed a significant positive correlation of Y = 0.187X-0.006 between ΔDB (Y) and ΔBCI (X). CONCLUSION: Applying the vanadate chemical oxidation method affected approximately 19% of the bilirubin configurational isomer concentration for direct bilirubin. Extreme caution is necessary when interpreting the measured values of samples indicative of unconjugated hyperbilirubinaemia.

Survey of newborn direct antiglobulin testing practice in United States and Canadian transfusion services.

BACKGROUND: We hypothesized that variability in practice exists for newborn immunohematology testing due to lack of consensus guidelines. We report the results of a survey assessing that variability at hospitals in the United States and Canada. STUDY DESIGN AND METHODS: An AABB Pediatric Subsection working party developed and validated a survey of newborn immunohematology testing practice. The survey was sent electronically to transfusion service leadership at teaching institutions. RESULTS: The response rate was 67% (61/91); 56 surveys meeting inclusion criteria were analyzed. Approximately 90% (50/56) were from birth hospitals and 16.1% (9/56) were from pediatric hospitals. Newborn immunohematology testing is ordered as a panel by 66.0% (33/50) of birth hospitals. ABO group and DAT is mandated before discharge in 14/56 (25.0%) and 13/56 (23.2%), respectively. About 76.8% (43/56) selectively perform a DAT according to blood blank or clinical parameters. The most common DAT practices include anti-IgG only testing by 73.2% (41/56) and use of umbilical cord specimen type by 67.9% (38/56). A positive DAT is a critical value for 26.8% (15/56) and followed with eluate testing when a maternal antibody screen is positive for 48.2% (27/56). In the setting of a non-ABO maternal red cell antibody, 55.4% (31/56), phenotype neonatal red cells when the DAT is positive. Group O RBC are transfused irrespective of the DAT result for 82.1%, (46/56). CONCLUSION: There is variability in newborn immunohematology testing and transfusion practice and potential overutilization of the DAT. Evidence-based consensus guidelines should be developed to standardize practice and to improve safety.

Time to peak bilirubin concentration and advanced AKI were associated with increased mortality in rheumatic heart valve replacement surgery patients with severe postoperative hyperbilirubinemia: a retrospective cohort study.

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.

Post-transfusion hemoglobin response in patients with cirrhosis: Can we expect a 1 g/dL rise per unit transfused?

BACKGROUND: A patient's hemoglobin is typically expected to rise by 1 g/dL/unit transfused PRBCs. However, it has been theorized that mechanisms such as hyperbilirubinemia and splenomegaly might lead to either a direct lysis or sequestration of red blood cells that could decrease this proportionate response. STUDY DESIGN AND METHODS: Patients with resolved GI bleeding but still requiring transfusion to correct anemia were compared in cirrhosis and control groups. A retrospective chart review between 2015 and 2020 was conducted at a single institution. Data collected included age, sex, BMI, GI bleed diagnosis, number of PRBCs transfused, presence of splenomegaly and spleen size, alcohol use history, type of cirrhosis, MELD-Na at admission, GFR, and pre-and post-transfusion labs: total bilirubin, ALT, hemoglobin, hematocrit. A logic regression was performed for each group looking at which factors were associated with a successful response (defined as >0.9 g/dL hemoglobin per unit transfused). RESULTS: Mean change in hemoglobin was 0.77 g/dL in patients with cirrhosis compared to 1.46 g/dL in patients without (P < .001, N = 103). Odds ratios for presence of splenomegaly (0.22, N = 78) and female sex (4.39, N = 102) in predicting adequate response (>0.9 g/dL/unit) were both significant (P = .002) as well as portal hypertensive bleed diagnosis (0.28, N = 85, P = .0015). Factors that did not contribute included: age, race, BMI, alcohol use, GFR, change in ALT, and change in total bilirubin. CONCLUSIONS: Patients with cirrhosis have an approximately 50% decreased response to transfusion with PRBCs after resolution of a gastrointestinal bleed in comparison to patients without cirrhosis. Risk factors included splenomegaly, portal hypertension, and male sex.

Effects of Umbilical Cord Milking on Term Infants Delivered by Cesarean Section.

OBJECTIVE: Umbilical cord milking (UCM) is an efficient way to achieve optimal placental transfusion in term infants born by cesarean section (CS). However, it is not frequently performed due to concern for short-term adverse effects of increased blood volume, such as polycythemia and hyperbilirubinemia. The aim of this study is to evaluate the short-term effects of UCM on term infants delivered by CS. STUDY DESIGN: We conducted a pre- and postimplementation cohort study comparing term infants delivered by CS who received UCM five times (141 infants, UCM group) during a 6-month period (August 1, 2017 to January 31, 2018) to those who received immediate cord clamping (ICC) during the same time period (105 infants, postimplementation ICC) and during a 3-month period (October1, 2016 to December 31, 2016) prior to the implementation of UCM (141 infants, preimplementation ICC). RESULTS: Mothers were older in UCM group compared with both ICC groups. There were no significant differences in other maternal or neonatal characteristics. Although this study was not powered to detect differences in outcomes, the occurrence of hyperbilirubinemia needing phototherapy, symptomatic polycythemia, NICU admissions, or readmissions for phototherapy was similar between the groups. CONCLUSION: UCM intervention was not associated with increased incidence of phototherapy or symptomatic polycythemia in term infants delivered by CS.

Association between vitamin D level and community-acquired late-onset neonatal sepsis. / Asociación entre la concentración de vitamina D y la sepsis neonatal extrahospitalaria de aparición tardía.

INTRODUCTION: The objective was to determine the relationship between mother and infant vitamin D levels and late onset sepsis. POPULATION AND METHODS: Infants born > 37 weeks of gestational age who were hospitalized with the diagnosis of late-onset sepsis were enrolled to this prospective case control study. VitaminD levels of the infants and their mothers in the study and a control group were compared. RESULTS: Fourty six term patients with late-onset sepsis composed the study group, 46 patients with hyperbilirubinemia as the control group. Vitamin D supplementation during pregnancy was lower in mothers of study group compared to the control group (p = 0.001). Serum 25-hydroxyvitamin D levels of infants and mothers in the study group were significantly lower than the control group (p < 0.001). There was a positive correlation between 25-hydroxyvitamin D levels of mothers and infants in both groups (r: 0.38, p < 0.001). The best cut off value of 25-hydroxyvitamin D, which determines the risk of late-onset sepsis in neonates, was detected as 15.45 ng/ml (sensitivity: 91.3 %, specificity: 71.7 %, area under the curve: 0.824, p < 0.001). CONCLUSIONS: In this study, 25-hydroxyvitamin D levels were found to be lower in term infants with late-onset sepsis and among their mothers compared to the control group. Positive correlation was found between serum 25(OH)D levels of infants and their mothers.

Introducción. El objetivo fue determinar la relación entre la concentración materna e infantil de vitamina D y la sepsis de aparición tardía. Población y métodos. En este estudio se incluyó a los bebés nacidos con >37 semanas de gestación hospitalizados con diagnóstico de sepsis de aparición tardía. Se comparó la concentración de vitamina D de los niños y sus madres del grupo del estudio y del de referencia. Resultados. El grupo del estudio incluyó a 46 pacientes con sepsis de aparición tardía nacidos a término y el grupo de referencia, 46 pacientes con hiperbilirrubinemia. La suplementación con vitamina D durante el embarazo fue menor en las madres del grupo del estudio que en el de referencia (p = 0,001). La concentración sérica de 25-hidroxivitamina D [25(OH)D] de los niños y las madres del grupo del estudio fue significativamente menor que la del grupo de referencia (p < 0,001). Se observó una correlación positiva entre la 25(OH)D en las madres y los niños de ambos grupos (r: 0,38; p < 0,001). El valor de corte para la 25(OH)D, que determina el riesgo de sepsis neonatal de aparición tardía, se estableció en 15,45 ng/ml (sensibilidad: 91,3 %; especificidad: 71,7 %; área bajo la curva: 0,824; p < 0,001). Conclusiones. La concentración de 25(OH)D fue inferior en los bebés nacidos a término con sepsis de aparición tardía y sus madres en comparación con el grupo de referencia. La correlación entre la concentración sérica de 25(OH)D de los niños y sus madres fue positiva.

​False-positive paracetamol levels in a patient with hyperbilirubinaemia: clinical perspectives.

​Serum concentrations of paracetamol are measured to investigate the cause of acute hepatitis, monitor the clearance of paracetamol from the body and to determine if supratherapeutic levels warrant treatment with N-acetylcysteine (NAC). ​A 49-year-old man treated for ischaemic colitis developed worsening renal and liver function tests. As part of the investigation of hepatorenal failure, paracetamol levels were requested, which were elevated at 14 mg/L (normal <4 mg/L) resulting in treatment with NAC. Despite treatment, levels of paracetamol remained elevated and the link between hyperbilirubinemia and false-positive paracetamol levels was identified. ​Bilirubin and its by-products have intense absorbance in the ultraviolet and visible regions of the electromagnetic spectrum, causing interference in the enzymatic colorimetric assay most commonly used to measure paracetamol concentration, resulting in false-positive paracetamol levels. Laboratories correct for this interference above a predetermined bilirubin concentration, termed the Icteric Index; however, in our case this interference occurred at a lower level of hyperbilirubinaemia than previously identified as significant. This interaction was found to be more significant at lower bilirubin levels when low or no paracetamol levels were present in the serum, resulting in a change to laboratory practice and development of a 'Sliding Scale' approach to analysis. ​Concurrent bilirubin or Icteric Index measurement is recommended for all laboratories that use the enzymatic colorimetric assay for paracetamol measurement. Lower Icteric Index or bilirubin thresholds are required when low or no paracetamol levels are present in the serum to prevent false-positive paracetamol results. We describe a new 'Sliding Scale' approach to analysis, and highlight an important interaction for clinicians to be aware of.

Low Serum Levels of Fibroblast Growth Factor 2 in Gunn Rats: A Hyperbilirubinemia Animal Model of Schizophrenic Symptoms.

BACKGROUND: Fibroblast Growth Factor (FGF) 2 (also referred to as basic FGF) is a multifunctional growth factor that plays a pivotal role in the pro-survival, pro-migration and prodifferentiation of neurons. METHOD: Because alterations in FGF2 levels are suggested to contribute to the pathogenesis of schizophrenia, we investigated serum levels of FGF2 in the Gunn rat, a hyperbilirubinemia animal model of schizophrenic symptoms. RESULTS: The enzyme-linked immunosorbent assay showed that the serum levels of FGF2 in Gunn rats were 5.09 ± 0.236 pg/mL, while those in the normal strain Wistar rats, serum levels were 11.90 ± 2.142 pg/mL. The serum FGF2 levels in Gunn rats were significantly lower than those in Wistar rats. We also measured serum levels of Unconjugated Bilirubin (UCB) and found a significant negative correlation between UCB and FGF2 in terms of serum levels in all the rats studied. CONCLUSION: Since it is known that FGF2 regulates dopaminergic neurons and have antineuroinflammatory effects, our finding suggests that low FGF2 levels may contribute to the pathogenesis of schizophrenia, in which imbalanced dopamin-ergic signaling and neuroinflammation are supposed to play certain roles.

Periportal thickening on magnetic resonance imaging for hepatic fibrosis in infantile cholestasis.

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.

Risk factors and outcomes for hyperbilirubinaemia after heart surgery in children.

INTRODUCTION: Liver dysfunction, associated with morbidity and mortality, is common in patients with CHD. We investigate risk factors for and outcomes of hyperbilirubinaemia in neonates and infants after cardiac surgery. MATERIALS AND METHODS: In a retrospective analysis of neonates and infants undergoing cardiac surgery at our institution between January 2013 and December 2017, we identified those with post-operative conjugated hyperbilirubinaemia. We tested various demographic and surgical risk factors, and use of post-operative interventions, for an association with conjugated hyperbilirubinaemia. We also tested hyperbilirubinaemia for association with post-operative mortality and prolonged length of stay. RESULTS: We identified 242 post-operative admissions, of which 45 (19%) had conjugated hyperbilirubinaemia. The average conjugated bilirubin level in this group was 2.0 mg/dl versus 0.3 mg/dl for peers without hyperbilirubinaemia. The post-operative use of both extracorporeal membrane oxygenation (OR 4.97, 95% CI 1.89-13.5, p = 0.001) and total parenteral nutrition (OR 2.98, 95% CI 1.34-7.17, p = 0.010) was associated with conjugated hyperbilirubinaemia. No demographic variable analysed was found to be a risk factor. Hyperbilirubinaemia was associated with higher odds of mortality (OR 3.74, 95% CI 2.69-13.8, p = 0.005) and prolonged length of stay (OR 2.87, 95% CI 2.02-7.97, p = 0.005), which were independent of other risk factors. DISCUSSION: We identified the post-operative use of total parenteral nutrition and extracorporeal membrane oxygenation as risk factors for hyperbilirubinaemia. These patients were more likely to experience morbidity and mortality than control peers. As such, bilirubin may be marker for elevated risk of poor post-operative outcomes and should be more frequently measured after cardiac surgery.

Severe hyperbilirubinemia is associated with higher risk of contrast-related acute kidney injury following contrast-enhanced computed tomography.

INTRODUCTION: Contrast-induced acute kidney injury (CI-AKI) is associated with high risks of morbidity and mortality. Hyperbilirubinemia might have some renal protection but with no clear cutoff value for protection. Related studies are typically on limited numbers of patients and only in conditions of vascular intervention. METHODS: We performed this study to elucidate CI-AKI in patients after contrast-enhanced computed tomography (CCT). The outcomes were CI-AKI, dialysis and mortality. Patients were divided to three groups based on their serum levels of total bilirubin: ≤1.2 mg/dl, 1.3-2.0 mg/dl, and >2.0 mg/dl. RESULTS: We enrolled a total of 9,496 patients who had received CCT. Patients with serum total bilirubin >2.0 mg/dl were associated with CI-AKI. Those undergoing dialysis had the highest incidence of PC-AKI (p<0.001). No difference was found between the two groups of total bilirubin ≤1.2 and 1.3-2.0 mg/dl. Patients with total bilirubin >2mg/dl were associated with CI-AKI (OR = 1.89, 1.53-2.33 of 95% CI), dialysis (OR = 1.40, 1.01-1.95 of 95% CI) and mortality (OR = 1.63, 1.38-1.93 of 95% CI) after adjusting for laboratory data and all comorbidities (i.e., cerebrovascular disease, coronary artery disease, peripheral arterial disease, and acute myocardial infarction, diabetes mellitus, hypertension, gastrointestinal bleeding, cirrhosis, peritonitis, ascites, hepatoma, shock lung and colon cancer). We concluded that total bilirubin level >2 mg/dl is an independent risk factor for CI-AKI, dialysis and mortality after CCT. These patients also had high risks for cirrhosis or hepatoma. CONCLUSION: This is the first study providing evidence that hyperbilirubinemia (total bilirubin >2.0 mg/dl) being an independent risk factor for CI-AKI, dialysis and mortality after receiving CCT. Most patients with total bilirubin >2.0mg/dl had cirrhosis or hepatoma.

The prevalence and prognostic implications of pre-procedural hyperbilirubinemia in patients undergoing transcatheter aortic valve replacement.

Preoperative hyperbilirubinemia is associated with increased mortality and morbidity after cardiac surgery. However, this clinical significance is unclear with transcatheter aortic valve replacement (TAVR) procedures. The aims of this study were to determine the prevalence and prognostic implications of preoperative elevations of serum total bilirubin on TAVR outcomes. In 611 consecutive patients who underwent an elective TAVR procedure, 576 patients had recorded serum total bilirubin levels. Hyperbilirubinemia was defined as any value of serum total bilirubin ≥ 1.2 mg/dL obtained within 30-days prior to the TAVR procedure. The primary composite endpoint was post-TAVR all-cause in-hospital mortality or stroke. The overall prevalence of hyperbilirubinemia was 10% (n = 58). There were no patients with a prespecified diagnosis of liver cirrhosis. Pre-TAVR hyperbilirubinemia compared to normal bilirubin level was more common in younger (78 ± 10 vs. 82 ± 8 years old, p < 0.001) males (15 vs. 6%, p < 0.001), with history of pacemaker or ICD (33 vs. 18%, p = 0.005), congestive heart failure New York Heart Association class IV within 2 weeks from TAVR (35 vs. 14%, p < 0.001), severe tricuspid regurgitation (14 vs. 4%, p < 0.001), and atrial fibrillation or flutter (60 vs. 40%, p = 0.004, respectively). Pre-TAVR hyperbilirubinemia was independently associated with an increased post-TAVR in-hospital mortality (7 vs. 2% in normal bilirubin, p = 0.03), stroke (5 vs. 1%, p = 0.019, respectively), and a composite endpoint of death or stroke (12 vs. 3%, p < 0.001). Preoperative hyperbilirubinemia in patients undergoing TAVR is more prevalent than previously considered with multifactorial causes. Hyperbilirubinemia is independently associated with an increased post-TAVR in-hospital mortality and stroke.