Neonatal Hyperbilirubinemia.

Neonatal hyperbilirubinemia (NH) is a common phenomenon. In most cases, NH is benign and transient. However, in severe NH cases, neonates can develop encephalopathy and kernicterus. With appropriate screening and treatment, these adverse sequelae can be prevented. This article aims to provide the reader with an in-depth understanding of (1) bilirubin metabolism, (2) risk factors for severe NH, (3) NH screening and treatment, (4) various etiologies of severe NH, and (5) consequences of severe, untreated NH. [Pediatr Ann. 2022;51(6):e219-e227.].

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.

Rifampicin, not vitamin E, suppresses parenteral nutrition-associated liver disease development through the pregnane X receptor pathway in piglets.

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.

Maternal and Neonatal Metabolic Outcomes of Vitamin D Supplementation in Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis.

INTRODUCTION: Many scientists have revealed the association between vitamin D deficiency and gestational diabetes mellitus (GDM). The purpose of this review was to evaluate the impact of vitamin D supplementation on maternal and neonatal health measures in GDM. METHODS: A comprehensive systematic literature search in the electronic databases including Cochrane Central Register of Controlled Trials, MEDLINE (PubMed), Scopus, Web of Sciences, EMBASE, Google Scholar, Clininaltrial.gov, and ProQuest as well as SID, Magiran, Irandoc, and Iranmedex for Persian literature review carried out up to January 2018. All RCTs and quasi-experimental studies that compared vitamin D supplementation with placebo or without supplementation on GDM women were included in this review. RESULTS: Five randomized controlled trials involving 310 women were included in the meta-analysis. There were significant differences in fasting Plasma Glucose (FPG; mean difference [MD] -12.54, 95% CI -15.03 to -10.05; 3 trials, 223 participants); total cholesterol (TC; MD -24.77, 95% CI -32.57 to -16.98; 3 trials, 223 participants); low-density lipoprotein (LDL) cholesterol (MD -18.92, 95% CI -24.97 to -12.88; 3 trials, 223 participants); high-density lipoprotein (HDL) cholesterol (MD, 3.87, 95% CI 1.20-6.55; 3 trials, 223 participants); high sensitivity C-reactive protein -(hs-CRP; MD -1.35, 95% CI -2.41 to -0.28; 2 trials, 126 participants); and Newborns' hyperbilirubinemia (OR 0.33, 95% CI 0.13-0.80; 2 trials, 129 participants). CONCLUSIONS: Supplementation of GDM women with vitamin D may lead to an improvement in FPG, TC, LDL, HDL, hs-CRP serum levels as well as in newborns' hyperbilirubinemia.

Effect of Glyburide vs Subcutaneous Insulin on Perinatal Complications Among Women With Gestational Diabetes: A Randomized Clinical Trial.

Importance: Randomized trials have not focused on neonatal complications of glyburide for women with gestational diabetes. Objective: To compare oral glyburide vs subcutaneous insulin in prevention of perinatal complications in newborns of women with gestational diabetes. Design, Settings, and Participants: The Insulin Daonil trial (INDAO), a multicenter noninferiority randomized trial conducted between May 2012 and November 2016 (end of participant follow-up) in 13 tertiary care university hospitals in France including 914 women with singleton pregnancies and gestational diabetes diagnosed between 24 and 34 weeks of gestation. Interventions: Women who required pharmacologic treatment after 10 days of dietary intervention were randomly assigned to receive glyburide (n=460) or insulin (n=454). The starting dosage for glyburide was 2.5 mg orally once per day and could be increased if necessary 4 days later by 2.5 mg and thereafter by 5 mg every 4 days in 2 morning and evening doses, up to a maximum of 20 mg/d. The starting dosage for insulin was 4 IU to 20 IU given subcutaneously 1 to 4 times per day as necessary and increased according to self-measured blood glucose concentrations. Main Outcomes and Measures: The primary outcome was a composite criterion including macrosomia, neonatal hypoglycemia, and hyperbilirubinemia. The noninferiority margin was set at 7% based on a 1-sided 97.5% confidence interval. Results: Among the 914 patients who were randomized (mean age, 32.8 [SD, 5.2] years), 98% completed the trial. In a per-protocol analysis, 367 and 442 women and their neonates were analyzed in the glyburide and insulin groups, respectively. The frequency of the primary outcome was 27.6% in the glyburide group and 23.4% in the insulin group, a difference of 4.2% (1-sided 97.5% CI, -∞ to 10.5%; P=.19). Conclusion and Relevance: This study of women with gestational diabetes failed to show that use of glyburide compared with subcutaneous insulin does not result in a greater frequency of perinatal complications. These findings do not justify the use of glyburide as a first-line treatment. Trial Registration: clinicaltrials.gov Identifier: NCT01731431.

Identification of second-generation P2X3 antagonists for treatment of pain.

A second-generation small molecule P2X3 receptor antagonist has been developed. The lead optimization strategy to address shortcomings of the first-generation preclinical lead compound is described herein. These studies were directed towards the identification and amelioration of preclinical hepatobiliary findings, reducing potential for drug-drug interactions, and decreasing the projected human dose of the first-generation lead.

[Guidelines for prevention, detection and management of hyperbilirubinaemia in newborns of 35 or more weeks of gestation]. / Recomendaciones para la prevención, la detección y el manejo de la hiperbilirrubinemia en los recién nacidos con 35 o más semanas de edad gestacional.

Hyperbilirubinaemia is one of the most frequent causes of hospital readmission during the first week of life. Its detection is still a big challenge, mainly due to the early discharge from the hospital that can be associated with a delay of the diagnosis. The identification of those newborns at risk of developing significant hyperbilirubinaemia is one of the main priorities in the public health care system. An approach to the management of newborn jaundice is presented in this article, following the recommendations based on the medical evidence and on the opinion of the Standards Committee of the Spanish Society of Neonatology.

Characteristics of the heme catabolic pathway in mild unconjugated hyperbilirubinemia and their associations with inflammation and disease prevention.

Heme catabolism exerts physiological functions that impact health through depressing inflammation. Upon reactive pathway progression, as in Gilbert's Syndrome (GS; UGT1A1*28 polymorphism), aggravated health effects have been determined. Based on lower inflammation and improved metabolic health reported for GS, inter-group differences in heme catabolism were explored. Therefore, a case-control study including 120 fasted, healthy, age- and gender matched subjects with/without GS, was conducted. Genetic expressions of HMOX-1 and BLVRA were measured. Additionally participants were genotyped for those polymorphisms that are known (UGT1A1*28) or likely (HMOX-1 microsatellites) to impact bilirubinemia. Intracellular interleukins (IL-6, IL-1ß, TNFα), circulatory C-reactive protein (CRP), serum amyloid A (SAA) and haptoglobin (Hpt) were analysed as inflammatory markers. To assess intracellular heme oxygenase 1 (HO-1) isolated PBMCs were used. In GS vs. C, inflammation markers were significantly decreased. This was supported by an altered heme catabolism, indirectly reflecting in elevated unconjugated bilirubin (UCB; main phenotypic feature of GS) and iron, decreased hemopexin (Hpx) and Hpt and in up-regulated biliverdin reductase (BLVRA) gene expressions. Moreover, HMOX (GT)n short alleles were non-significantly more prominent in female GS individuals. Herewith, we propose a concept to elucidate why GS individuals encounter lower inflammation, and are thus less prone to oxidative-stress mediated diseases.

Newborn Bilirubin Screening for Preventing Severe Hyperbilirubinemia and Bilirubin Encephalopathy: A Rapid Review.

According to the 2004 American Academy of Pediatrics guideline on the management of hyperbilirubinemia, every newborn should be assessed for the risk of developing severe hyperbilirubinemia with the help of predischarge total serum bilirubin or transcutaneous bilirubin measurements and/or assessments of clinical risk factors. The aim of this rapid review is 1) to review the evidence for 1) predicting and preventing severe hyperbilirubinemia and bilirubin encephalopathy, 2) determining the efficacy of home/community treatments (home phototherapy) in the prevention of severe hyperbilirubinemia, and 3) non-invasive/transcutaneous methods for estimating serum bilirubin level. METHODS: In this rapid review, studies were identified through the Medline database. The main outcomes of interest were severe hyperbilirubinemia and encephalopathy. A subset of articles was double screened and all articles were critically appraised using the SIGN and AMSTAR checklists. This review investigated if systems approach is likely to reduce the occurrence of severe hyperbilirubinemia. RESULTS: Fifty-two studies met the inclusion criteria. Included studies assessed the association between bilirubin measurement early in neonatal life and the subsequent development of severe hyperbilirubinemia and chronic bilirubin encephalopathy/kernicterus. It was observed that, highest priority should be given to (i) universal bilirubin screening programs; (ii) implementation of community and midwife practice; (iii) outreach to communities for education of prospective parents; and (iv) development of clinical pathways to monitor, evaluate and track infants with severe hyperbilirubinemia. CONCLUSIONS: We found substantial observational evidence that severe hyperbilirubinemia can be accurately predicted and prevented through universal bilirubin screening. So far, there is no evidence of any harm.

Neuroprotective Effect of Erythropoietin on Phenylhydrazine-Induced Hemolytic Hyperbilirubinemia in Neonatal Rats.

Neonatal unconjugated hyperbilirubinemia might cause severe bilirubin neurotoxicity in especially hemolytic conditions. The study aimed to elucidate the potential neuroprotective effects of erythropoietin (EPO) in hemolysis-induced hyperbilirubinemia. In newborn rats, hyperbilirubinemia secondary to hemolysis was induced by injecting with phenylhydrazine hydrochloride (PHZ) and rats were injected with either vehicle or EPO. At 54th hour of the PHZ injection, rats were decapitated. Serum levels of TNF-α, IL-1ß, IL-10, brain-derived neurotrophic factor (BDNF) and S100-B and brain malondialdehyde, glutathione levels and myeloperoxidase activities were measured. TUNEL staining and NF-κB expression were evaluated. As compared to control pups, in vehicle-treated PHZ group, TNF-α and IL-1ß levels, malondialdehyde level and myeloperoxidase activity were increased with concomitant decreases in IL-10 and glutathione. All EPO regimens reversed PHZ-induced alterations in IL-10, TNF-α, malondialdehyde and glutathione levels. Three-day-treatment abolished increases in myeloperoxidase activity and IL-1ß levels, while BDNF and S100-B were elevated. Increased TUNEL (+) cells and NF-κB expressions in the brain of PHZ group were reduced in the 3-day-treated group. EPO exerted anti-inflammatory effects on PHZ-induced neural damage in newborn rats, while the neuroprotection was more obvious when the treatments were repeated successively. The results suggest that EPO treatment may have a therapeutic potential in supporting neuroplasticity in the hyperbilirubinemic neonates.

Predictors of failure of fish-oil therapy for intestinal failure-associated liver disease in children.

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.

Thymoquinone, an active constituent of Nigella sativa seeds, binds with bilirubin and protects mice from hyperbilirubinemia and cyclophosphamide-induced hepatotoxicity.

Some reports indicate that thymoquinone (TQ), the main constituent of Nigella sativa seeds, is hepatoprotective. The aim of this study was to determine whether TQ is able to bind directly to bilirubin, and whether TQ or liposomal formulation of TQ (Lip-TQ) can reduce cyclophosphamide (CYP)-induced liver toxicity, serum bilirubin level in mice. The binding of TQ with bilirubin was studied by UV-VIS, fluorescence and Near-UV CD spectroscopy. Inhibition of binding of bilirubin to erythrocytes by TQ was also examined. To increase the in vivo efficacy, Lip-TQ was prepared and used against CYP-induced toxicity. The protective role of TQ or Lip-TQ against CYP-induced toxicity was assessed by determining the liver function parameters, the levels of superoxide dismutase (SOD) and catalase (CAT), and histological studies. It was found that TQ binds to bilirubin and significantly inhibits the binding of bilirubin to erythrocytes. Lip-TQ (10 mg/kg) significantly reduced the levels of aspartate transaminase (AST) from 254 ± 48 to 66 ± 18 IU/L (P < 0.001), alanine transaminase (ALT) from 142 ± 28 to 47.8 ± 16 IU/L (P < 0.05) and serum bilirubin from 2.8 ± 0.50 to 1.24 ± 0.30 mg/dl (P < 0.05). Treatment with Lip-TQ reduced the CYP-induced inflammation and hemorrhage in liver tissues. Moreover, treatment with free or Lip-TQ protected the activity of SOD and CAT in CYP-injected mice. Therefore, TQ can reduce the level of bilirubin in systemic circulation in disease conditions that lead to hyperbilirubinemia and liver toxicity and hence may be used as a supplement in the treatment of liver ailments.

Cadmium and arsenic override NF-κB developmental regulation of the intestinal UGT1A1 gene and control of hyperbilirubinemia.

Humanized UDP-glucuronosyltransferase (UGT)-1 (hUGT1) mice encode the UGT1 locus including the UGT1A1 gene. During neonatal development, delayed expression of the UGT1A1 gene leads to hyperbilirubinemia as determined by elevated levels of total serum bilirubin (TSB). We show in this report that the redox-sensitive NF-κB pathway is crucial for intestinal expression of the UGT1A1 gene and control of TSB levels. Targeted deletion of IKKß in intestinal epithelial cells (hUGT1/Ikkß(ΔIEC) mice) leads to greater neonatal accumulation of TSB than observed in control hUGT1/Ikkß(F/F) mice. The elevation in TSB levels in hUGT1/Ikkß(ΔIEC) mice correlates with a reduction in intestinal UGT1A1 expression. As TSB levels accumulate in hUGT1/Ikkß(ΔIEC) mice during the neonatal period, the increase over that observed in hUGT1/Ikkß(F/F) mice leads to weight loss, seizures and eventually death. Bilirubin accumulates in brain tissue from hUGT1/Ikkß(ΔIEC) mice inducing an inflammatory state as shown by elevated TNFα, IL-1ß and IL-6, all of which can be prevented by neonatal induction of hepatic or intestinal UGT1A1 and lowering of TSB levels. Altering the redox state of the intestines by oral administration of cadmium or arsenic to neonatal hUGT1/Ikkß(F/F) and hUGT1/Ikkß(ΔIEC) mice leads to induction of UGT1A1 and a dramatic reduction in TSB levels. Microarray analysis following arsenic treatment confirms upregulation of oxidation-reduction processes and lipid metabolism, indicative of membrane repair or synthesis. Our findings indicate that the redox state in intestinal epithelial cells during development is important in maintaining UGT1A1 gene expression and control of TSB levels.

Calcium plus vitamin D supplementation affects pregnancy outcomes in gestational diabetes: randomized, double-blind, placebo-controlled trial.

OBJECTIVE: The present study was designed to assess the effects of Ca+vitamin D supplementation on pregnancy outcomes in women with gestational diabetes mellitus (GDM). DESIGN: A randomized, double-blind, placebo-controlled trial was conducted among sixty women with GDM. Participants were divided into two groups to receive Ca+vitamin D supplements or placebo. Individuals in the Ca+vitamin D group (n 30) received 1000 mg Ca/d and two pearls containing 1250 µg (50 000 IU) of cholecalciferol (vitamin D(3)) during the intervention (one at study baseline and another at day 21 of the intervention); those in the placebo group (n 30) received two placebos of vitamin D at the mentioned times and placebos of Ca every day for 6 weeks. Pregnancy outcomes were determined. SETTING: A urban community setting in Arak, Iran. SUBJECTS: Sixty women with GDM and their newborns, living in Arak, Iran were enrolled. RESULTS: Women treated with Ca+vitamin D had a significant decrease in caesarean section rate (23·3 % v. 63·3 %, P=0·002) and maternal hospitalization (0 v. 13·3 %, P=0·03) compared with those receiving placebo. In addition, newborns of GDM women randomized to Ca+vitamin D had no case of macrosomia, while the prevalence of macrosomia among those randomized to placebo was 13·3 % (P=0·03). Lower rates of hyperbilirubinaemia (20·0 % v. 56·7 %, P=0·03) and hospitalization (20·0 % v. 56·7 %, P=0·03) were also seen in the supplemented group of newborns than in the placebo group. CONCLUSIONS: Ca+vitamin D supplementation for 6 weeks among pregnant women with GDM led to decreased caesarean section rate and maternal hospitalization, and decreased macrosomia, hyperbilirubinaemia and hospitalization in newborns.

Risks and benefits of prophylactic cyclic parenteral nutrition in surgical neonates.

BACKGROUND: Cyclic parenteral nutrition (PN) is used for both the treatment and prevention of parenteral nutrition-associated liver disease (PNALD). Early initiation of prophylactic cyclic PN may not be well tolerated in young neonates. Our objective was to test the hypothesis that prophylactic cyclic PN initiated prior to the onset of hyperbilirubinemia is associated with younger age at initiation, lower bilirubin levels, and similar rates of adverse events compared to therapeutic cyclic PN initiated after established cholestasis in surgical neonates. METHODS: A retrospective review of infants with gastrointestinal disorders requiring surgical intervention who received cyclic PN 2006-2011 was performed. RESULTS: Of the 43 infants eligible for analysis, 23 received prophylactic and 20 received therapeutic cyclic PN. Infants in both groups were comparable in demographics, surgical diagnoses, and illness severity. At initiation of cyclic PN, infants with prophylactic cyclic PN were significantly younger in chronologic (P = .003) and postmenstrual age (P = .029). Prophylactic cyclic PN was associated with a significantly lower incidence of hyperbilirubinemia (P = .001), lower maximum conjugated bilirubin (P < .0001), and lower last checked conjugated bilirubin (P = .032) compared to the therapeutic cyclic PN. The incidence of hypoglycemia, hyperglycemia, and hypertriglyceridemia was similar for the 2 groups. CONCLUSIONS: There may be a potential benefit to initiating cyclic PN prior to the development of hyperbilirubinemia in surgical neonates. Early initiation of prophylactic cyclic PN does not appear to increase the risk for adverse events.

Bodyweight loss in predicting neonatal hyperbilirubinemia 72 hours after birth in term newborn infants.

BACKGROUND: Severe dehydration is generally believed to be a cause of significant hyperbilirubinemia in newborn babies. This study aimed to analyze the weight loss of healthy term newborn infants at 24, 48 and 72 hours after birth to predict significant hyperbilirubinemia at 72 hours. METHODS: From January 2007 to December 2008, we conducted this retrospective chart review by measuring total bilirubin (transcutaneous and serum) in 343 healthy, term newborns with a birth body weight of more than 2500 g. We then analyzed the association between body weight loss (BWL) and significant hyperbilirubinemia (total bilirubin more than 15 mg/dL) 72 hours after birth. Receiver operating characteristic curves were used to evaluate the appropriate cutoff BWL percentages on the first three days after birth for the prediction of neonatal hyperbilirubinemia 72 hours after birth. RESULTS: A total of 115 (33.5%) neonates presented with significant hyperbilirubinemia 72 hours after birth, and the percentages of BWL on the first three days were all higher than those in the non-significant hyperbilirubinemia group (all p < 0.05). Breastfeeding was not statistically correlated with significant hyperbilirubinemia (p=0.86). To predict significant hyperbilirubinemia 72 hours after birth, receiver operating characteristic curve analysis showed that the optimum cutoff BWL percentages were 4.48% on the first day of life (sensitivity: 43%, specificity: 70%, positive likelihood ratio [LR+]: 1.43, and negative likelihood ratio [LR-]: 0.82), 7.60% on day 2 (sensitivity: 47%, specificity: 74%, LR+: 1.81, LR-: 0.72), and 8.15% on day 3 (sensitivity: 57%, specificity: 70%, LR+: 1.92, LR-: 0.61) (all p < 0.05). CONCLUSIONS: BWL on the first three days after birth may be a predisposing factor for neonatal hyperbilirubinemia, and may also serve as a helpful clinical factor to prevent significant hyperbilirubinemia 72 hours after birth. The optimal BWL cutoff percentages on the first three days after birth presented in this study may predict hyperbilirubinemia and indicate the need for supplementary feeding.

Coadministration of atazanavir-ritonavir and zinc sulfate: impact on hyperbilirubinemia and pharmacokinetics.

Atazanavir (ATV) causes an elevation of unconjugated hyperbilirubinemia (HBR) as a result of UDP glucuronyltransferase (UGT) 1A1 inhibition. Zinc sulfate (ZnSO4) reduces unconjugated hyperbilirubinemia in individuals with Gilbert's syndrome. We assessed the changes in total, conjugated, and unconjugated bilirubin and the effect on ATV pharmacokinetics (PK) after single and 14-day dosing of ZnSO(4). HIV patients, stable on ATV/ritonavir (ATV/r)-containing regimens with a total bilirubin level of >25 mmol/liter received 125 mg daily of ZnSO(4) as Solvazinc tablets for 14 days. ATV/r and bilirubin concentrations were measured pre-ATV/r dose and 2, 4, 6, 8, and 24 h post-ATV/r dose; before ZnSO4 initiation (phase 1), after a single dose (phase 2) and after 14 days (phase 3). Changes in bilirubin and ATV/r concentrations in the absence or presence of ZnSO4 were evaluated by geometric mean ratios (GMRs) and 90% confidence intervals (CIs; we used phase 1 as a reference). Sixteen male patients completed the study maintaining virologic suppression; ZnSO(4) was well tolerated. Statistically significant declines in total bilirubin C(max) and AUC(0-24) of 16 and 17% were seen in phase2 and 20% in phase 3. Although there were no significant changes in conjugated bilirubin, unconjugated bilirubin Cmax and AUC(0-24) of were lower (17 and 19%, phase 2; 20 and 23% during phase 3). The ATV GMRs (90% CI) for C(trough), C(max), and AUC(0-24) were 0.74 (0.62 to 0.89), 0.82 (0.70 to 0.97), and 0.78 (0.70 to 0.88). Intake of ZnSO(4) decreases total and unconjugated bilirubin and causes modest declines in ATV exposure. ZnSO(4) supplementation may be useful in management of ATV-related HBR in selected patients.

Hepatic fibrosis persists and progresses despite biochemical improvement in children treated with intravenous fish oil emulsion.

OBJECTIVES: Intestinal failure-associated liver disease (IFALD) is a multifactorial process, which can culminate in cirrhosis and need for transplantation. Fish oil-based lipid emulsions (FOE) reportedly reverse hyperbilirubinemia, but there are little data on their effect on the histopathology of IFALD. METHODS: We blindly examined sequential liver biopsy data on 6 children receiving FOE, with scoring of cholestasis, inflammation, fibrosis, and ductal proliferation based on standardized systems. This information was correlated with biochemical and clinical data to determine any possible relations between biologic and histologic improvement. RESULTS: The median gestational age was 35 weeks, median birth weight 2064 g, and common most reason for intestinal loss was gastroschisis (5/6 children). Median intestinal length was 26 cm beyond the ligament of Treitz and most children had roughly 2 of 3 of their colonic length. It was observed that although hyperbilirubinemia reversed and hepatic synthetic function was preserved across timepoints, fibrosis was persistent in 2 cases, progressive in 3 cases, and regressed in only 1. It remained severe (grade 2 or higher) in 5 of 6 children at last biopsy. Histologic findings of cholestasis improved in all patients and inflammation improved in 5 of 6 children. There were mixed effects on ductal proliferation and steatosis. CONCLUSIONS: In children treated with FOE, reversal of hyperbilirubinemia is not reflected by a similar histologic regression of fibrosis at the timepoints studied. Children with IFALD should have active ongoing treatment and be considered for early referral to an Intestinal Failure Program even with a normalized bilirubin.