Unconjugated Hyperbilirubinemia Research Articles

Use of fenofibrate as adjuvant to phototherapy in unconjugated neonatal hyperbilirubinemia: A systematic review and meta-analysis of randomized controlled trials.

Most neonates have neonatal jaundice, with 5-15% requiring phototherapy. Although phototherapy is beneficial, it can potentially extend hospital stays and cause harm. This study's purpose was to analyze the effects of fenofibrate and phototherapy on total serum bilirubin (TSB) levels at 24 and 48 hours (primary outcome) after intervention. Furthermore, the phototherapy duration and adverse events were also of interest (secondary outcome). The study protocol was registered in the PROSPERO database. Articles were searched on EMBASE, PubMed, Cochrane Library, and Google Scholar. Study selection was done following PRISMA and risk of bias studies were conducted. The Review Manager 5.4 was used for the meta-analysis. Nine studies, including 610 newborns, were identified and included in the meta-analysis. This meta-analysis discovered a significant change in TSB levels at 24 hours after intervention (mean difference (MD) -0.96 (95% CI -1.09, -0.83), p < 0.00001) with low heterogeneity and at 48 hours after intervention (MD -1.75 (95% CI -2.26, -1.24), p < 0.00001) with high heterogeneity. Significant shortening of phototherapy duration was observed in the interventional group (MD -15.28 (95% CI -20.65, -9.90), p < 0.00001) with high heterogeneities. One of the nine studies reported a non-significant occurrence of abdominal distension and diarrhea in the fenofibrate group. Fenofibrate might be applied as an adjuvant in unconjugated neonatal hyperbilirubinemia to reduce the average total serum bilirubin and shorten the length of phototherapy.

Therapeutic Options for Crigler–Najjar Syndrome: A Scoping Review

Crigler–Najjar Syndrome (CNS) is a rare genetic disorder caused by mutations in the UGT1A1 gene, leading to impaired bilirubin conjugation and severe unconjugated hyperbilirubinemia. CNS presents in the following forms: CNS type 1 (CNS1), the more severe form with the complete absence of UGT1A1 activity, and CNS type 2 (CNS2), with partial enzyme activity. This narrative review aims to provide a detailed overview of CNS, highlighting its clinical significance and the need for new, more effective treatments. By summarizing current knowledge and discussing future treatments, this article seeks to encourage further research and advancements that can improve outcomes for CNS patients. The literature analysis showed that CNS1 requires aggressive management, including phototherapy and plasmapheresis, but liver transplantation (LT) remains the only definitive cure. The timing of LT is critical, as it must be performed before the onset of irreversible brain damage (kernicterus), making early intervention essential. However, LT poses risks such as graft rejection and lifelong immunosuppression. CNS2 is milder, with patients responding well to phenobarbital and having a lower risk of kernicterus. Recent advancements in gene therapy and autologous hepatocyte transplantation offer promising alternatives to LT. Gene therapy using adeno-associated virus (AAV) vectors has shown potential in preclinical studies, though challenges remain in pediatric applications due to liver growth and pre-existing immunity. Autologous hepatocyte transplantation avoids the risk of rejection but requires further research. These emerging therapies provide hope for more effective and less invasive treatment options, aiming to improve the quality of life for CNS patients and reduce reliance on lifelong interventions.

Rate of glucose-6-phosphate dehydrogenase deficiency in neonatal indirect hyperbilirubinemia at a private tertiary centre.

To investigate the rate of hospitalized neonates with glucose-6-phosphate dehydrogenase (G6PD) deficiency presented with indirect hyperbilirubinemia at a private tertiary center in Al-Ahsa, Saudi Arabia, over 4 years and to compare the characteristics of G6PD-deficient and normal neonates admitted for indirect hyperbilirubinemia. The retrospective case control study was carried out at Almoosa Specialist Hospital, Al-Ahsa, Saudi Arabia. Data were collected from Yassasi Medical System from 2018-2021 and finalized in 2024. The study included 2 groups: G6PD-normal and G6PD-deficient neonates with indirect hyperbilirubinemia not having recognizable triggers of hemolysis. The analysis focused on serum bilirubin levels, direct bilirubin levels, hematocrit levels, hemoglobin levels, reticulocyte percentage, G6PD levels, duration of phototherapy, and the need for exchange transfusion. The study enrolled 3200 neonates with hyperbilirubinemia, of whom 274 met inclusion criteria. A total of 103 (37.6%) neonates were G6PD-deficient, with 77 (74.8%) being male and 26 (25.2%) female. Glucose-6-phosphate dehydrogenase-deficient neonates exhibited significantly higher initial total bilirubin levels and earlier sampling times. There was no significant correlation between G6PD deficiency and hematocrit or hemoglobin levels in hyperbilirubinemic neonates, but 4 neonates required exchange transfusion, demonstrating statistical significance (p=0.009). High rate of G6PD deficiency in neonates with indirect hyperbilirubinemia, requiring close monitoring to prevent exchange transfusions, with no significant differences in hematocrit or hemoglobin levels.

Evaluation of phototherapy effects on platelet numbers and volumes in neonates with unconjugated hyperbilirubinemia in Sulaimani city/Kurdistan region/Iraq

Abstract: BACKGROUND: Unconjugated hyperbilirubinemia is a rather common disease that affects 60% of term and 80% of preterm infants within their 1st week of life. Phototherapy is considered the safest method for the treatment of unconjugated hyperbilirubinemia in neonates, which is the most common problem in the neonatal period. OBJECTIVES: To identify the effect of phototherapy on platelet numbers and volumes, and if the duration of treatment, gestational age, birth weight and other factors have some influences on this effect. PATIENTS, MATERIALS AND METHODS: A prospective cohort study was conducted from November 1, 2023, to April 1, 2024. Seventy-four neonates were enrolled in this study including males and females (1.39:1), with different gestational ages and birth weights. Neonates were selected according to the specific inclusion and exclusion criteria. Thorough history and physical examination performed with several laboratory investigations sent. Total serum bilirubin measured before starting phototherapy, after 24 hours, 48 h, 72 hours, and 4 days later. SPSS program was used to code, enter, and process the gathered data. RESULTS: Platelet number in general decreased with increasing duration of phototherapy regardless of other parameters (P = 0.045). In correlation to the duration of phototherapy and time of jaundice appearance, it was statistically significant for only neonates who required phototherapy for more than 4 days and time of jaundice appearance between 1 and 3 days (P = 0.042). Platelets number decreased with increasing duration of phototherapy especially in low birth weight and very low birth weight neonates, P value 0.028 and 0.047 respectively. There were statistically significant values (P = 0.002 and P = 0.001) in the correlation of decreasing platelet numbers to gestational age and duration of phototherapy, especially more evident with gestational age below 37 weeks (preterm) and in periods after 24 h and 72 h. There were no statistically significant values in platelet volumes in correlation to any of the previous parameters. CONCLUSIONS: Platelets number decreased with phototherapy management, and it is more evident with longer phototherapy duration, low birth weight and early onset, while platelet volume not affected. Hence, it is recommended to avoid unnecessary prolongation of phototherapy.

Detection of Major Mutations in CFTR, SERPINA1, HFE Genes in Benign Unconjugated Hyperbilirubinemia Phenotype

Detection of Major Mutations in CFTR, SERPINA1, HFE Genes in Benign Unconjugated Hyperbilirubinemia Phenotype

Etiological Evaluation of Term Neonates with Indirect Hyperbilirubinaemia

Aim: Indirect hyperbilirubinemia is a common disease in newborns with many risk factors. In our study, we aimed to investigate the effects of history, physical examination and investigations on treatment and follow-up of patients admitted to our neonatal intensive care unit with the diagnosis of indirect hyperbilirubinemia. Methods: In our cross-sectional and retrospective study, 226 patients who were born at term and hospitalized with the diagnosis of indirect hyperbilirubinemia were included. History, physical examination and examination data were evaluated from the patient files. Results: Of 226 patients included in the study, 126 (55.8%) were boys and 100 (44.2%) were girls. The mean gestational age was 38.3±0.4 weeks and the mean birth weight was 3146±32 grams. The mean postnatal days at the time of hospitalization were 4.1±0.1 days, hospitalization bilirubin was 17.1±0.2 mg/dl, duration of phototherapy was 38.2±1 hours, and weight loss during hospitalization was 3.7±0.3%. The most common diagnosis was ABO incompatibility (27.9%). Bilirubin levels were statistically significantly higher in patients with weight loss. When blood incompatibility and other diagnoses were compared, bilirubin and hemoglobin levels and postnatal age at the time of hospitalization were statistically significantly lower and length of hospitalization was statistically significantly higher in patients with blood incompatibility. Conclusion: Gender and mode of delivery were not significantly associated with hospitalization total bilirubin and duration of phototherapy. Patients with weight loss had statistically higher hospitalization total bilirubin than those without weight loss. In addition, the length of hospitalization of patients with ABO incompatibility was statistically significantly longer than patients hospitalized with other diagnoses.

Bilirubin measurements in neonates: uniform neonatal treatment can only be achieved by improved standardization.

Measurement of total bilirubin (TBil) concentration in serum is the gold standard approach for diagnosing neonatal unconjugated hyperbilirubinemia. It is of utmost importance that the measured TBil concentration is sufficiently accurate to prevent under treatment, unnecessary escalation of care, or overtreatment. However, it is widely recognized that TBil measurements urgently require improvement in neonatal clinical chemistry. External quality assessment (EQA) programs for TBil assess for differences between laboratories and provide supporting evidence of significant differences between various methods, manufacturers and measurement platforms. At the same time, many countries have adopted or only slightly adapted the neonatal hyperbilirubinemia management guidelines from the USA or UK, often without addressing differences in the methodology of TBil measurements. In this report, we provide an overview of the components of bilirubin that are measured by laboratory platforms, the availability of current reference measurement procedures and reference materials, and therole of EQA surveys in this context. Furthermore, the current status of agreement in neonatal bilirubin against clinical decision thresholds is reviewed. We advocate for enhancements in accuracy and comparability of neonatal TBil measurements, propose a path forward to accomplish this, and reflect on the position of the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Working Group Neonatal Bilirubin (WG-NB) in this matter.

Automated Auditory Brainstem Response in Neonates with Exchange Transfusion Indirect Hyperbilirubinemia Levels

Automated Auditory Brainstem Response in Neonates with Exchange Transfusion Indirect Hyperbilirubinemia Levels

Subcutaneous angiomyolipoma in a bichon frise dog. Clinical case

Angiomyolipoma located on the caudal part of the abdominal wall was reported in a 15–year–old femal bichon frise dog weighing 17 kg. A radiographic examination was performed followed by a histological examination of the mass, which revealed a benign encapsulated mesenchymal proliferation composed of three compartments: vascular, smooth muscle and adipose. The predominant adipose component is made of large lobules of mature adipocytes. A blood chemistry profile was performed revealing an increase in the activity of liver enzymes: Gammaglutamyl transferase (12.90 IU·l-1), Aspartate aminotransferase (70.1 IU·l-1), Alkaline phosphatase (403 IU·l-1); total, direct and indirect hyperbilirubinemia were also noted (6.71 mg·l-1, 1.54 mg·l-1, 5.17 mg·l-1 respectively). The management of angiomyolipoma requires surgery which consists of the removal of the neoplasia mass to prevent local progression. This clinical case is considered as the first case of angiomyolipoma reported in canine veterinary medicine in Algeria.

An Evaluation of Infants Followed up With a Diagnosis of Indirect Hyperbilirubinemia

Amaç: İndirekt hiperbilirubinemi tanısıyla yatırılan yenidoğanların klinik ve demografik özellikleri, risk faktörleri ve tedavi yöntemlerinin araştırılması amaçlandı. Materyal ve Metod: Yenidoğan yoğun bakım ünitesine yatırılan 615 sarılıklı yenidoğan bebeğin demografik özellikleri, laboatuvar verileri ve yenidoğan sarılığı açısından risk faktörleri retrospektif olarak incelendi. Bulgular: Bebeklerin 340 (% 55,3)' ı kız, 275 (% 44, 7)' i erkek, 532 (% 86,50)' si matür, 80 (% 13)'i prematür ve 3 (% 0,50)'ü ise postmatür idi. Doğum ağırlıkları; 3185 gr ± 0, 50, 3200 (1300-5000) arasında idi. Olgularda en sık sarılık nedeni, Fizyolojik sarılık / Nedeni tespit edilemeyen sarılıklar iken, en az oranda tespit edilen sarılık nedeni ise intrakranial kanama ve konjenital santral sinir sistemi anomalileri idi. Tedavide, bebeklerin 406 (% 66,0)’sına sadece fototerapi, 35 (% 5,7)’ine ise kan değişimi de yapıldı. Diğer 174 olguya (% 28,3) fototerapi ile birlikte primer hastalığa bağlı olarak antibiyotik, sodium L-tiroksin ve/veya intravenöz sıvı tedavisi de verildi. Olguların 13 (% 2,1)'ünde rebound sarılık, 3 (% 0,5)'ünde geçici hipokalsemi, 1 (% 0,2)' inde anemi ve 1 (% 0,2)' inde ise ishal gelişti. 7 (% 1, 1) olgu altta yatan neden bağlı olarak ex oldu. 1 (% 0,2) bebekte kernikterus gelişirken, 607 (% 98,7) olgu şifa ile taburcu edildi. Sonuç: Hiperbilirubinemi, yenidoğan döneminde sık görülmektedir. Mortalite ve morbidite engellenmesinde hiperbilirubinemi tedavisinin zamanlaması son derece önemlidir.

Exploring a Case of Unconjugated Hyperbilirubinaemia Resulting from the Rare Coexistence of Inherited Disorders- A Case Report

Exploring a Case of Unconjugated Hyperbilirubinaemia Resulting from the Rare Coexistence of Inherited Disorders- A Case Report

Adrenal Hypoplasia Congenita Presenting as Adrenal Crisis, Unconjugated Hyperbilirubinemia, and Hyperpigmentation

Adrenal hypoplasia congenita is a relatively rare disorder characterized by atrophy or hypoplasia of the adrenal gland. It was first described by Sikl H in 1948 in 33-day-old infant. It is inherited as an autosomal recessive or X-linked disorder. It presents usually with adrenal insufficiency. In this article, we are presenting a case of congenital adrenal hypoplasia which presented with hypoglycemia, adrenal insufficiency, hyperbilirubinemia, and acquired hyperpigmentation in the neonatal period.

Mechanistic static modeling predicts low risk of unconjugated hyperbilirubinemia due to UGT1A1 inhibition by pirtobrutinib 200 mg once daily

Mechanistic static modeling predicts low risk of unconjugated hyperbilirubinemia due to UGT1A1 inhibition by pirtobrutinib 200 mg once daily

Forgoing Exchange Transfusion in Neonatal Hyperbilirubinemia: A Single-Center Retrospective Cohort Study.

Unconjugated hyperbilirubinemia is part of the everyday life of the neonatal period as it reflects the adaptation of the metabolism of bilirubin. The neonatal hyperbilirubinemia usually resolves spontaneously, but it can also be the cause of an acute or chronic encephalopathy known as kernicterus. Regardless of the cause, the goal of therapy is to prevent this neurotoxicity while not causing undue harm. Phototherapy and, if it is unsuccessful, exchange transfusion (ECT)remain the primary treatment modalities used to keep the maximal total serum bilirubin (TSB) below pathologic levels. This is a descriptive retrospective cohort study of 69 live neonates hospitalized in the Department of Neonatology and Neonatal Resuscitation of Mohammed VI University Hospital with unconjugated hyperbilirubinemia requiring ECT and treated with intensive phototherapy instead, spanning five years from March 2016 to March 2021. We aim to demonstrate the effectiveness of phototherapy in achieving prolonged reduction of bilirubin levels and the prevention of neurological complications and to compare our results with those in the literature. The use of intensive phototherapy in the treatment of neonatal unconjugated hyperbilirubinemia is very effective in lowering total serum bilirubin when its level is in the range of exchange transfusion, and it has succeeded in preventing the neurological complications of severe hyperbilirubinemia. Through this study, it can be seen that phototherapy is an efficacious, simpler, and less hazardous alternative to exchange transfusion in achieving a sustained reduction of bilirubin levels and preventing neurological complications.

Why Infants with Some Inherited Metabolic Diseases do not Develop Neonatal Indirect Hyperbilirubinemia ? An Overlooked Detail

Why Infants with Some Inherited Metabolic Diseases do not Develop Neonatal Indirect Hyperbilirubinemia ? An Overlooked Detail

Case Report: Intrahepatic cholestasis: a diagnostic dilemma

Cholestasis is an impairment of bile formation or bile flow. The mechanisms of cholestasis can be broadly classified into intrahepatic and extrahepatic. Most of the time, etiology can be determined with proper history, physical examination, and diagnostic testing including laboratory and imaging tests. This is a case report of a patient with severe cholestasis who underwent extensive evaluation to determine the etiology of intrahepatic cholestasis. This Case Report details a 28-year-old male who presented with seven days’ history of yellowish discoloration of eyes, the passage of dark-colored urine, generalized body itching, and the passage of clay-colored stool. The patient had no similar episode in the past. Laboratory investigations showed unconjugated hyperbilirubinemia and increased alkaline phosphatase. Magnetic resonance cholangiopancreaticography was unremarkable and liver biopsy was suggestive of cholestatic pattern and negative for acute hepatitis. The bilirubin level started decreasing after a month. The etiology of intrahepatic cholestasis remained unknown. Genotyping could not be done due to limited available resources. It may have helped to diagnose familial hepatocellular cholestasis such as benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis. Gamma-glutamyl transferase is normal or mildly elevated in patients with BRIC. A similar picture was seen in our case as well. If the patient presents again with similar symptoms and findings, we can consider the diagnosis of BRIC.

Effectiveness of phototherapy with and without probiotics for the treatment of indirect hyperbilirubinaemia in preterm neonates: a randomised controlled trial

ABSTRACT Introduction Raised serum bilirubin levels can cause kernicterus, and premature infants are at increased risk owing to metabolic immaturity. The standard treatment for neonatal jaundice is phototherapy, but probiotics alone can reduce the duration of phototherapy and hospitalisation. Objectives To determine the effectiveness of phototherapy with and without probiotics for the treatment of indirect hyperbilirubinaemia in preterm neonates. Patients and methods The open-labelled randomised controlled trial was conducted from January 2022 to January 2023 in the neonatal unit of the University of Lahore Teaching Hospital, Pakistan. A total of 76 preterm neonates who fulfilled the selection criteria were included and divided into two groups. Both groups received standard phototherapy. In Group B, a probiotic (Saccharomyces boulardii) 125 mg, twice daily, orally (in 5 cc of whichever milk the infant was receiving) was given until discharge from hospital. The primary outcome measurements were the duration of phototherapy and the length of hospitalisation. Results The mean (SD) duration of phototherapy was 36.55 (14.25) hours in Group A and 24.61 (9.25) hours in Group B (p <0.05). The mean (SD) duration of hospital stay was 47.36 (16.51) hours in Group A and 33.13 (8.93) hours in Group B (p <0.05). Conclusion Oral probiotics (Saccharomyces boulardii) have a significant effect on the duration of phototherapy for neonatal hyperbilirubinaemia, and they decrease the chances of nosocomial infection. Exploration of clinical outcomes by investigating faecal flora and undertaking large randomised controlled trials of various probiotics are needed. Abbreviations ABE: acute bilirubin encephalopathy; CNS: central nervous system;GA: gestational age; IVIG: intravenous immunoglobulin; KSD: kernicterus;NNU: neonatal unit; RCT: randomised controlled trial; S. boulardii: Saccharomyces boulardii.

Glucose-6-phosphate dehydrogenase deficiency and neonatal indirect hyperbilirubinemia: a retrospective cohort study among 40,305 consecutively born babies

Background and objectiveGlucose-6-phosphate dehydrogenase deficiency (G6PDD) being highly prevalent in the Middle East, the primary objective was to estimate the incidence of neonatal jaundice among G6PD-deficient neonates and to explore its association with various risk factors.MethodsThis retrospective cohort study includes 7 years data of neonates diagnosed with G6PDD between 1st January 2015, and 30 September 2022, from Al Wakra Hospital, HMC Qatar.ResultsAmong the 40,305 total births, 1013 had G6PDD with an incidence of 2.51%. Of all the G6PDD babies, 24.6% (249/1013) received phototherapy and three babies required exchange transfusion. Statistically significant associations were noted between the need for phototherapy and gestational age, gestational age groups, birth weight, and birth weight groups, but logistic regression analysis showed significant association for phototherapy only with the gestational age group.ConclusionUniversal screening and proper follow-up is essential for G6PDD as it plays crucial role in neonatal jaundice.

Rare red cell enzymopathies in the Indian population: A comprehensive review

Red blood cell enzyme deficiencies are a rare category of hemolytic anaemia that typically present in children with varying degrees of hemolysis, indirect hyperbilirubinemia and splenomegaly. Glucose 6-phosphate dehydrogenase (G6PD) is the most common enzyme deficiency, followed by pyruvate kinase deficiency (PKD). This article aims to understand the pathophysiology of the rare enzymopathies due to deficiencies in the Embden-Meyerhoff pathway, glutathione metabolism, hexose monophosphate shunt and nucleotide metabolism pathway, and to study the incidence, clinical symptoms, diagnostic strategy, and management of enzyme deficiencies in the Indian patients. Most red blood cell (RBC) enzyme deficiencies are inherited in an autosomal recessive fashion except for G6PD, and phosphoglycerate kinase deficiency which has X-linked inheritance. Presentation depends on the representation of the enzyme on different tissues of the body, hence some enzyme deficiencies may present with neurological or muscular manifestations. In patients with suspected hemolytic anaemia, complete blood count and peripheral smear help in differentiating from hemoglobinopathies, etc. To clinch the diagnosis enzyme levels and genetic testing may be required. These tests guide antenatal diagnosis in subsequent pregnancies. Management of RBC enzymopathies depends on the predominant symptoms and severity of hemolysis. Patients with marked hemolysis require regular blood transfusions and hence appropriate chelation therapy. Hematopoeitic stem cell transplant is attempted in patients with severe spectrum with variable results. Newer drugs, including mitapivat have proven to be beneficial in adults with PKD and ongoing trials in children are showing promising results.

Risk factors for exchange transfusion in neonates with unconjugated hyperbilirubinemia: A tertiary care hospital study.

Risk factors for exchange transfusion in neonates with unconjugated hyperbilirubinemia: A tertiary care hospital study.