Prolonged Unconjugated Hyperbilirubinemia Research Articles

Should We Consider UGT1A1 Mutation Analysis in Evaluating the Prolonged Jaundice of Newborn Infants?

Purpose: Uridine diphosphate glucuronosyltransferase 1A isoform 1 (<i>UGT1A1</i>) is a crucial enzyme in bilirubin metabolism. Mutations in this gene cause prolonged unconjugated hyperbilirubinemia in infants. This study aimed to investigate the prevalence of <i>UGT1A1</i> mutations and their association with prolonged, unexplained, and unconjugated hyperbilirubinemia in infants.Methods: From July 2019 to March 2023, 74 infants with prolonged jaundice lasting >21 days were enrolled in this study. Diagnostic evaluations, including <i>UGT1A1</i> mutation analysis, were performed to identify the underlying causes of hyperbilirubinemia. This retrospective review evaluated the incidence and types of mutations in <i>UGT1A1</i>. The clinical and laboratory findings were compared based on the specific mutations detected.Results: Thirty-three infants agreed to <i>UGT1A1</i> mutation analysis, and 30 (90.9%) were positive for <i>UGT1A1</i> mutations. Single-nucleotide variants were detected in 20 (66. %) infants. The remaining 10 (33.3%) infants had multiple variants. No significant demographic differences were observed between the group that underwent <i>UGT1A1</i> mutation analysis and the group that did not. Among the identified genetic variants, c.211G>A (46.5%) and c.-3275T>G (30.2%) were the two most common variants. The other variants had the following percentages: c.1456T>G, c.-64G>C, and c.1091C>T (4.7% each); and c.-3152G>A, c.189C>T, and c.-41.-40 dup (2.3% each). Among the 20 infants with the c.211G>A variant, eight (40.0%) had a homozygous genotype and 12 (60.0%) had a heterozygous genotype. Infants harboring other variants exhibited heterozygous genotypes. When comparing the group with confirmed <i>UGT1A1</i> mutations to the group without detected mutations, breastfeeding was the only significant factor (<i>p</i>=0.027). No significant differences were found between the group with singlenucleotide variants and the group with multiple genetic variants or between the homozygous genotype group with c.211G>A and the heterozygous genotype group.Conclusion: Neonates with prolonged unconjugated hyperbilirubinemia may have a higher chance of <i>UGT1A1</i> mutation than expected. Analysis of <i>UGT1A1</i> mutations may be beneficial in infants with prolonged unexplained jaundice.

An evaluation of ursodeoxycholic acid treatment in prolonged unconjugated hyperbilirubinemia due to breast milk.

Prolonged jaundice is one of the most common problems during neonatal period. The aim of this study was to evaluate the efficiency of ursodeoxycholic acid (UDCA) treatment in newborn infants with prolonged unconjugated hyperbilirubinemia. The present study included 27 patients who were fed by breast milk and followed up in the outpatient clinic due to prolonged jaundice without any underlying etiological factor; 10 mg/kg/day UDCA was administrated in two doses for 7 days. Furthermore, 20 newborns diagnosed with prolonged jaundice with same characteristics were enrolled as the control group. The control group was also given a placebo; demographic characteristics, liver functions tests before and after the treatment, bilirubin decrease rates, and hemogram parameters of groups were compared. Total bilirubin levels in the study and control groups before the treatment were 16.02 ± 1.41 mg/dL and 15.93 ± 1.66 mg/dL, respectively (P = 0.84). Total bilirubin levels in the study and control groups at day 7 after UDCA treatment were detected 8.18 ± 2.31 mg/dL and 13.92 ± 2.66 mg/dL, respectively (P < 0.001), and at day 14 after the treatment were 5.45 ± 2.59 mg/dL and 11.91 ± 2.83 mg/dL, respectively (P < 0.001). Furthermore, serum aspartate aminotransferase (AST) was detected <21 U/L in the ROC analysis after UDCA treatment (P = 0.04). The study outcomes indicated that an efficient reduction in total bilirubin levels may be achieved, and outpatient clinic follow-up period may be reduced in patients whom UDCA was administrated. Moreover, it may be speculated that AST can be used to evaluate the efficacy after treatment. However, studies with larger sample sizes are needed for the routine use of UDCA in the treatment of prolonged jaundice.

Gilbert or Crigler\u2013Najjar syndrome? Neonatal severe unconjugated hyperbilirubinemia with P364L UGT1A1 homozygosity

BackgroundSeveral mutations of bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) have been reported in patients with unconjugated hyperbilirubinemia. Few reports are available about the p.Pro364Leu mutation (P364L, c.1091C > T) in homozygous newborns. We describe the clinical, laboratory and therapeutic approach in two Chinese neonates with severe jaundice, homozygous for the P364L mutation.Case presentationTwo Chinese breastfed female infants presented prolonged unconjugated hyperbilirubinemia at the age of 1 month. Total bilirubin was higher than 15 mg/dl (D < 1). An exhaustive etiological work-up to detect possible causes of hyperbilirubinemia (notably hemolytic ones) was negative.The promoter and coding regions of UGT1A1 were amplified by polymerase chain reaction (PCR) from genomic DNA isolated from leukocytes. Both patients resulted homozygous for a variant site within the coding region of the gene in the 4 exon, c.1091C > T, p.Pro364Leu.In front of the persistently high level of unconjugated bilirubin, phototherapy was performed without persistent results. A treatment with phenobarbital was then begun and bilirubin level progressively decreased, with a complete and persistent normalization. The therapy was stopped.ConclusionUGT1A1 enzyme activity associated with the P364L mutation has been described as 35.6% of the wild-type enzyme activity. Photo-therapy and phenobarbital can be useful in front of persistently high level of unconjugated bilirubin.Our cases presented high bilirubin values, overlapping between Gilbert syndrome (GS) and Crigler-Najjar syndrome type II (CNS), but the complete normalization of bilirubin makes GS more likely. Homozygous P364L variant can be associated with severe neonatal unconjugated hyperbilirubinemia in Chinese infants, but jaundice can completely resolve in a few months, contrary to what happens in Crigler-Najjar syndrome type II.

THE CHARACTERISTICS OF PROLONGED NEONATAL JAUNDICE INVESTIGATED AT PRIMARY HEALTH CLINICS IN KOTA BHARU, KELANTAN

Introduction: Prolonged neonatal jaundice is affecting 15-40% of breastfed new-borns. Although breastmilk jaundice is the common aetiology, undetected pathological causes could lead to unfavourable sequelae. This study described the characteristics, aetiology and burden of prolonged neonatal jaundice investigated at the primary care level in Kota Bharu district. Methods: This crosssectional study was done from July till December 2019, involving 14 health clinics in Kota Bharu. Selection criteria involved term new-borns at day 14 of life or preterm at day 21 of life that had visible jaundice or serum bilirubin &gt;85?mol/l. Clinical details, investigations, and management were carried out based on normal practice at the clinics. A registry was established to capture the burden. Results: Prolonged jaundice were detected among 22.5% [95% CI 21.5, 23.6] of new-borns attending primary health clinics in Kota Bharu. A total of 291 cases were further analysed; 275 (94.5%) were term newborns and 243 (83.5%) were breastfed. Affected new-borns underwent blood and urine sampling with multiple follow-ups. On average, jaundice subsided within 12 days [SD=5.5, 95% CI:11.7, 13.1] after detection of this condition. Majority had prolonged unconjugated hyperbilirubinemia (98.6%) and main aetiology was breastmilk jaundice (84.5%). Minority had hypothyroidism (3.4%) and conjugated hyperbilirubinemia (1.7%). Out of 129 cases sent for urine culture, 12 (9.3%) had significant growth, mostly E.coli. Conclusion: The majority of neonates with prolonged jaundice were term and breastfed. While the main aetiology was breastmilk jaundice, other underlying pathologies were also identified. As the burden of this condition is high, multistage investigation is strongly recommended. Urinary tract infections screening should be routinely considered.

CLINICAL CHARACTERISTICS OF INFANTS WITH PROLONGED JAUNDICE

OBJECTIVE: Prolonged unconjugated hyperbilirubinemia is a type of neonatal jaundice, which occurs in newborns with high bilirubin levels (&amp;gt; 8 mg/dl) persisting beyond 14-21 postnatal days. This study was carried out to evaluate and determine the clinical and laboratory characteristics of infants with prolonged jaundice and underling causes.MATERIAL AND METHODS: This prospective study was conducted on newborn infants diagnosed with prolonged unconjugated hyperbilirubinemia during January 2018 and December 2018 at our pediatric outpatient clinic. The demographic, clinical and laboratory characteristics of these patients were recorded and then analyzed.RESULTS: In total, 91 infants diagnosed with prolonged jaundice and 65 healthy newborn infants as control group were enrolled in this study. Of the infants with prolonged jaundice, mean birth-weight was 3152 ± 504 g (1800-4300 g), mean gestational age was 38.2 ± 1.6 weeks (35-41 weeks), and mean total bilirubin level at the time of diagnosis was 10.98 ± 2.3 mg/dL (8-18.7 mg/dL). There was male sex dominance in prolonged jaundice group (61.5%) Time to reach birth-weight was longer in infants with prolonged jaundice than control group (p = 0.02). The underlying etiologies of prolonged jaundice were as follows: breast milk (45%), congenital hypothyroidism (9.9%) and urinary tract infection (4.4%).CONCLUSIONS: Determining the main causes of prolonged jaundice in neonates is of paramount importance. In the majority of cases, neonatal hyperbilirubinemia is associated with physiological factors like breastfeeding

The Role of Oral Phenobarbital Therapy in the Management of Neonates with Prolonged Unconjugated Hyperbilirubinemia

Background: Prolonged jaundice is a type of neonatal jaundice, which occurs in infants with high bilirubin levels (&gt;10 mg/dl) persisting beyond day 14 of life in term neonates, and beyond day 21 in preterm neonates. Prolonged jaundice may be caused by predominantly conjugated or unconjugated hyperbilirubinemia. Distinguishing between these types of jaundice helps to determine the risk for pathological causes of prolonged jaundice.&#x0D; Phenobarbital has been used to treat neonatal jaundice since the 1960s. Numerous clinical trials have shown that both administration of phenobarbital to pregnant mothers before delivery and phenobarbital administration to neonates after delivery limit the severity of unconjugated hyperbilirubinemia, reduce the peak serum total bilirubin concentrations caused by physiologic jaundice by 50%, and the need for exchange transfusion.&#x0D; Objective: The aim of this study was to evaluate the role of phenobarbital in reducing the total serum bilirubin(TSB) in neonates with prolonged unconjugated hyperbilirubinemia.  &#x0D; Methods: This is a prospective clinical trial study that was performed in Karbala teaching hospital for children from 18th of December 2017 to the end of December 2018. A total of 101 neonate with prolonged unconjugated hyperbilirubinemia were included in this study. All neonates who included in this study received phenobarbital tablet (5 mg /kg/day) twice a day for 10 days and some of them need phototherapy according to American Academy Of Pediatrics Guidelines  for phototherapy,&#x0D; Results: There was a highly statistically significant decrease in TSB for the patients who were treated with phenobarbital compared to the baseline level, mean baseline TSB 14.57± 2.31 mg/dl versus TSB after phenobarbital 6.79±1.62 mg/dl (P value &lt;0.001). There was a highly statistically significant decrease in TSB for the patients who were treated with phototherapy in addition to phenobarbital compared to the baseline level, mean baseline TSB 19.94±1.36 mg/dl versus TSB after phototherapy and phenobarbital 6.33±1.37 mg/dl (P value &lt;0.001).&#x0D; Conclusions:  &#x0D; &#x0D; Oral phenobarbital supplementation in the neonates with prolonged unconjugated hyperbilirubinemia can significantly accelerate reduction in serum bilirubin levels.&#x0D; Phenobarbital was safe, tolerable and no obvious adverse effects had been reported.&#x0D; No need for cessation of breast feeding in cases of presumed breast milk jaundice.&#x0D;

TO STUDY THE INCIDENCE OF CONGENITAL HYPOTHYROIDISM IN BABIES WITH EXAGGERATED PHYSIOLOGICAL JAUNDICE

Background: Congenital hypothyroidism is well known cause of prolonged unconjugated hyperbilirubinemia and appears to be associated with the delayed maturation of hepatic uridine diphosphate glucoronyl transferase enzyme activity.&#x0D; Methods: This is a prospective, longitudinal and randomized study 100 babies are taken consisting of all newborn, age less than 28 days, admitted to hospital with exaggerated physiological jaundice.&#x0D; Results: One case of congenital hypothyroidism in exaggerated jaundice based on raised TSH levels. Rest of the cases (99%) having normal TSH levels. One case (1%) having TSH level of 48µu/ml on D7 of life indicating congenital hypothyroidism. TSB of this baby is 21.3 mg%.  One baby is having TSH level of 30.4µu/ml on D3 of life which subsequently decreased to normal physiological limits on D7 of life.&#x0D; Conclusion: Though the present study is unable to make significant correlation between cause and effect relationship of neonatal exaggerated jaundice and congenital hypothyroidism, but as one case has diagnosed to be suffering from congenital hypothyroidism, TSH should be considered as a screening test for all babies suffering from exaggerated physiological jaundice besides the other predisposing factors responsible for causation of hypothyroidism.&#x0D; Keywords: Neonatal hyperbilirubinemia, Preterm, Congenital hypothyroidism

UGT1A1 genotypes and unconjugated hyperbilirubinemia phenotypes in post-neonatal Chinese children

To retrospectively analyze and quantitatively correlate UGT1A1 (bilirubin UDP- glucuronosyltransferase gene) genotypes and unconjugated hyperbilirubinemia (UCH) phenotypes among Chinese children.We retrospectively reviewed UCH patients, quantitatively analyzed genotype-phenotype correlation by comparing with healthy controls. Pfam database, SWISS-model, and Pymol were used for UGT1A1 protein domain analysis and protein modeling for assessing the effect of novel missense variants on protein structure.Seventy four cases, including 21 prolonged unconjugated hyperbilirubinemia (PUCH), 30 Gilbert syndrome (GS), 22 Crigler-Najjar syndrome type II (CNS-II), and 1 Crigler-Najjar syndrome type I (CNS-I) phenotypes were analyzed. Total of 21 variants, including 7 novel variants (c.764T>A/p.L255Q, c.1112C>T/p.T371I, c.1028C>A/p.S343X, c.1047delG/p.I350YfsX16, c.996 + 5G>C/g.6923G>C, c.287G>A/p.G96E, and c.1142G>A/p.S381N) were found. In the multiple regression model, heterozygous A(TA)7TAA, G71R/P364L, and Y486D/other mutations were significantly associated with increased risk of GS, PUCH, and CNS-II, respectively. Total allele number is significantly associated with GS and CNS-II, with each increase in total allele number, the odds ratio (OR) of having GS and CNS-II increased by 1.46 and 4.47 fold, respectively. Having only functional polymorphisms in UGT1A1 gene is associated with increased risk of PUCH, and GS with OR values of 5.67 (95% CI: 1.52-21.13), and 3.88 (95% CI: 1.02-14.78), respectively. Having only mutation is associated with significantly increased risk of having GS phenotype (OR: 34.00, 95% CI: 4.65-248.37), but not CNS-II. Polymorphism plus mutation had the strongest association with CNS-II with OR value of 64.80 (95% CI: 7.68-546.41), followed by GS (OR: 4.53, 95% CI: 1.08-19.08).We detected 7 novel variants, and quantitatively calculated risks of having specific phenotypes using genetic data. Among Chinese children, G71R and P364L is independently associated with PUCH, A(TA)7TAA is associated with GS, and Y486D or other disease-causing mutations were associated with CNS-II. Multiple alleles were associated with more severe phenotypes. Combined variant of G71R+Y486D is a common occurrence among Chinese children with UCH.

Bilirubin Uridine Diphosphate-glucuronosyltransferase Polymorphism as a Risk Factor for Prolonged Hyperbilirubinemia in Japanese Preterm Infants

To determine whether a variant of the bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1*6) is a risk factor for prolonged hyperbilirubinemia in preterm infants. UGT1A1 genotypes in 46 Japanese preterm infants (<37 weeks of gestation) were compared with UGT1A1 genotypes in 38 control infants, using polymerase chain reaction-direct sequencing. Prolonged unconjugated hyperbilirubinemia was defined as serum total bilirubin concentration of >150 µmol/L (8.77 mg/dL) beyond 14 days of life. In the case group, 41 of 46 infants (89.1%) had a polymorphic variant, c.211G>A, p.G71R (UGT1A1*6). In the control group, 7 of 38 (18.4%) had UGT1A1*6. The allele frequency of UGT1A1*6 was 0.641 in the prolonged hyperbilirubinemia group, which was significantly higher than in the control group (0.092; P < .001). In total, 39 of 46 infants in the case group were breast fed, and only 10 infants in the control group were breast fed. These data suggest that UGT1A1*6 is a risk factor for prolonged unconjugated hyperbilirubinemia in preterm infants in Japan. Given the different rate of breast feeding in this study, additional data are necessary for drawing a definitive conclusion.

Different causes of prolonged unconjugated Jaundice in the newborns

Background: Prolonged unconjugated hyperbilirubinemia is a type of neonatal jaundice, which occurs in infants with high bilirubin levels (&gt;10 mg/dl) persisting beyond 14-21 days. Prolonged unconjugated hyperbilirubinemia is a common problem among newborns, and the prevalence rate has been estimated at 2-15%. According to the literature, breastfeeding is a major cause of prolonged jaundice, and about 40% of infants who are exclusively breastfed are diagnosed with this disorder. Among other pathological causes associated with prolonged hyperbilirubinemia are urinary tract infection (UTI), congenital hypothyroidism and hemolysis. So, this study was done to know the different causes of unconjugated jaundice in newborn.Methods: This Hospital based prospective descriptive study was carried out at outpatients and inpatients in the Department of pediatrics, SMS medical college Jaipur. Total 100 cases were taken and these neonates were evaluated to know different causes of unconjugated hyperbilirubenemia.Results: Most common cause of persistent jaundice in both term and preterm babies is breast milk jaundice (66%), other causes include isoimmunization (10%), cephalhematoma (7%), hypothyroidism (7%), sepsis (4%) and ABO incompatibility (3%). Etiology of persistent jaundice was not significantly different in term and preterm babies.Conclusions: Although breast milk jaundice is considered as a major cause of prolonged unconjugated hyperbilirubinemia in neonates, identification of other etiological factors, such as UTI, congenital hypothyroidism and hemolysis is also of paramount importance. Early diagnosis and treatment of these disorder could effectively prevent further complication in neonates. 

Etiologies of Prolonged Unconjugated Hyperbilirubinemia in Neonates Admitted to Neonatal Wards

Background: Jaundice is a common condition among neonates. Prolonged unconjugated hyperbilirubinemia occurs when jaundice persists beyond two weeks in term neonates and three weeks in preterm neonates. This study aimed to determine the etiologies of prolonged unconjugated hyperbilirubinemia in infants admitted to the neonatal ward of Besat Hospital in Hamadan, Iran. Methods: This study was conducted on all infants diagnosed with prolonged unconjugated hyperbilirubinemia during 2007-2012 in the neonatal ward of Besat Hospital in Hamadan, Iran. Demographic characteristics of infants, physical examination and laboratory findings were collected and analyzed to determine the etiologies of neonatal hyperbilirubinemia. Results: In total, 100 infants diagnosed with neonatal hyperbilirubinemia were enrolled in this study, including 49 male and 51 female neonates with mean age of 20±1 days and mean bilirubin level of 17.5±4.0 mg/dL. Main causes of hyperbilirubinemia were urinary tract infection, ABO incompatibility, hypothyroidism and glucose-6-phosphate dehydrogenase deficiency in 14%, 5%, 6% and 5% of neonates, respectively. Moreover, unknown etiologies, such as breastfeeding, were detected in 70% of the studied infants. Conclusion: According to the results of this study, determining the main causes of prolonged unconjugated hyperbilirubinemia in neonates is of paramount importance. In the majority of cases, neonatal hyperbilirubinemia is associated with physiological factors, such as breastfeeding.

Prolonged neonatal jaundice

Prolonged neonatal jaundice is defined as a jaundice lasting more than 14 days of life in the full-term infants [1,2]. Etiologically it is helpful to distinguish jaundice related to unconjugated (indirect) or conjugated (direct) hyperbilirubinemia. A prolonged unconjugated hyperbilirubinemia may be related to breastfeeding or to some pathological conditions as hemolytic diseases (due to Rh or AB0 incompatibility, or G6PD deficiency), congenital hypothyroidism, urinary infection, Crigler-Najjar or Gilbert syndromes [1,2]. Conjugated hyperbilirubinemia (cholestatic jaundice) is never physiologic. It affects 1/2500 live births and it should be suspected in all jaundiced infants with light stools and dark urine [3,4]. Delayed referral of cholestatic neonates is still a significant problem. To promote early diagnosis of cholestasis, it is recommended that any infant who remains jaundiced beyond age 2 to 3 weeks (for breastfed infants who can be monitored and who have an otherwise normal history and physical examination) should have the serum bilirubin level fractionated [5]. The differential diagnosis of cholestasis is extensive, and early recognition is essential to ensure timely treatment and optimal prognosis [6]. Developments in molecular genetic techniques have enabled the identification of causative genes, which has improved diagnostic accuracy for patients [7]. In case of neonatal cholestasis, the first step should be the assessment of coagulation and urgent parenteral vitamin K administration in case of coagulopathy and the exclusion of life-threatening conditions or disorders requiring urgent specific medical (eg. NTBC in tyrosinemia, elimination diet in galactosemia and ereditary fructose intolerance) and surgery treatment. Biliary atresia is the most frequent single cause of neonatal cholestasis and affected infants appear otherwise healthy and grow normally [8]. Early performance of a hepatoportoenterostomy in the first 45 days of life to restore bile flow and lessen further damage to the liver is thought to optimize outcome [9]. Infants admitted in NICUs have a rate of cholestasis higher than that reported in the general population of live births; in most cases, cholestasis is associated to multiple risk factors and shows a favorable outcome [10]. Long-term cholestasis determines malnutrition, psychomotor development delayed and immune deficiency. So that even when specific treatment is not available, infants who have cholestasis benefit from early medical management and nutritional support for malabsorption and vitamin deficiency [8].

Bilirubin Uridine Diphosphate-Glucuronosyltransferase Variation Is a Genetic Basis of Breast Milk Jaundice

To evaluate the role of bilirubin UDP-glucuronosyltransferase family 1, polypeptide A1 (UGT1A1) gene variations on prolonged unconjugated hyperbilirubinemia associated with breast milk feeding (breast milk jaundice [BMJ]). UGT1A1 gene allelic variation was analyzed in 170 Japanese infants with BMJ with polymerase chain reaction-direct sequencing, and their genotypes compared with serum bilirubin concentrations. In 62 of 170 infants, serum bilirubin concentration was followed after 4 months of life. Genotypes were examined in 55 infants without BMJ. Of 170 infants with BMJ, 88 (51.8%) were homozygous UGT1A1*6. Serum bilirubin concentrations (21.8 ± 3.65 mg/dL) were significantly greater than in infants with other genotypes (P < .0001). The Gilbert UGT1A1*28 allele was not detected in infants with BMJ, except in an infant who was compound heterozygous with UGT1A1*6. At 4 months of age, serum bilirubin concentration improved to >1 mg/dL, except in 2 infants who were homozygous UGT1A1*7. Homozygous UGT1A1*6 was not detected in the control group. One-half of the infants with BMJ were homozygous UGT1A1*6 and exhibited a serum bilirubin concentration significantly greater than other genotypes. This finding indicates that UGT1A1*6 is a major cause of BMJ in infants in East Asia. Previous finding have demonstrated that 5β-pregnane-3α,20β-diol present in breast milk inhibits p.G71R-UGT1A1 bilirubin glucuronidation activity. Thus, prolonged unconjugated hyperbilirubinemia may develop in infants with UGT1A1*6 who are fed breast milk.

Jaundice Due to Glucose-6-Phosphate Dehydrogenase Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency complicates the usually benign neonatal jaundice managed by existing prenatal and postnatal screening in the United States. Estimated at ∼3.4% incidence, the condition ranges by infant race/ethnicity (12.2% in African American male infants to nearly 0% in white female infants). Oxidant stressors, sepsis, and delay in bilirubin elimination (such as co-inheritance with Gilbert's disease or persistent enterohepatic recirculation) add to total plasma or serum bilirubin (TSB) rise, need for phototherapy, and risk for exchange transfusion. Biology of G6PD deficiency, in the context of gender, race, ethnicity, enzyme concentration, and interaction with postnatal environment, affects clinical presentations. Mutation of the X-linked G6PD gene results in varying enzyme activity. A combination of clinical patterns are suggested: (1) early-onset hyperbilirubinemia (ie, TSB &amp;gt;75th percentile and increased bilirubin production); (2) predischarge TSB &amp;lt;75th percentile track exacerbated by starvation, unrecognized sepsis or late prematurity; (3) slow postnatal rise with natural decline; (4) slow postnatal rise with persistent prolonged unconjugated hyperbilirubinemia, &amp;gt;2 weeks age; and (5) complicated by acute-onset, dramatic hyperbilirubinemia with TSB rise &amp;gt;1 mg/dL per hour (“favism”). Absent G6PD deficiency diagnosis, postdischarge management for phototherapy requires expert assessment and triage for probable risk of favism. Screening as well as clinician and parental awareness of G6PD enzyme deficiency has been shown to reduce adverse neonatal consequences in several communities worldwide.

Inhibitory Effect of 5β-Pregnane-3α,20β-Diol on Transcriptional Activity and Enzyme Activity of Human Bilirubin UDP-Glucuronosyltransferase

Prolonged unconjugated hyperbilirubinemia in infants associated with breast milk feeding is a common pediatric problem known as breast milk jaundice (BMJ). A polymorphic mutation (G71R) of bilirubin UDP-glucuronosyltransferase (UGT1A1) is a known cause of BMJ on the infantile side, but the responsible components of breast milk are not currently known. We analyzed the inhibitory effect of 5β-pregnane-3α,20β-diol (pregnanediol) on transcriptional activity and enzyme activity of UGT1A1. To this end, we constructed two types of expression vectors. One type comprised vectors including the upstream enhancer-promoter sequence of UGT1A1 for WT and variant type (-3279T>G with A(TA)7TAA), used in studying transcriptional regulation. The other type comprised vectors including cDNA of UGT1A1 for WT and the G71R variant, used in studying enzyme activity. In an in vitro expression study, pregnanediol did not affect the transcriptional activity of UGT1A1 enhancer-promoter complex of WT and variant type, even with coexistence of transcriptional factors such as constitutive androstane receptor or pregnane X receptor. In contrast, in the presence of 100 μM pregnanediol, bilirubin glucuronidation of G71R-UGT1A1 was reduced to 51% of WT. We suggest that pregnanediol is a cause of breast milk jaundice in carriers of G71R.

Prolonged Unconjugated Hyperbiliriubinemia in Breast-fed Male Infants with a Mutation of Uridine Diphosphate-Glucuronosyl Transferase

To test the hypothesis that a mutation in uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) gene of breast-fed infants is a contributory factor to prolonged unconjugated hyperbilirubinemia. Of 125 breast-fed term infants, 35 infants had prolonged unconjugated hyperbilirubinemia; another 90 breast-fed neonates without prolonged jaundice were control infants. The polymerase chain reaction-restriction fragment length polymorphism method was used to detect the known variant sites (promoter area, nucleotides 211, 686, 1091, and 1456) of the UGT1A1 gene. Of 35 breast-fed infants with prolonged unconjugated hyperbilirubinemia, 29 had at least 1 mutation of the UGT1A1 gene. Variation at nucleotide 211 was most common. The percentages of the neonates carrying the variant nucleotide 211 were significantly different between the prolonged hyperbilirubinemia group and control neonates. Male breast-fed infants had a higher risk than female infants for prolonged hyperbilirubinemia. Male breast-fed neonates with a variant nucleotide 211 in UGT1A1 have a high risk for developing prolonged hyperbilirubinemia.

The relationship between Gly71Arg and TATA box polymorphism of UGT1A1 gene and prolonged hyperbilirubinemia of breast milk feeding infant in Korean

Purpose : It has been known that breast milk cause prolonged unconjugated hyperbilirubinemia. UGT1A1 is a important gene of uridine diphosphate glucuronosyltransferase (UGT) which has a major role of bilirubin metabolism. These findings suggest that there is a relationship between UGT1A1 gene mutation and prolonged jaundice of breast feeding infant. The aim of study was to investigate whether a polymorphism of the UGT1A1 gene exist in prolonged hyperbilirubinemia of breast milk feeding Korean infant. Methods : The genomic DNA was isolated from 50 full term Korean neonates, who had greater than a 10 mg/dL of serem bilirubin after 2 weeks of birth with no significant cause, and the other genomic DNA was isolated from 162 full term Korean neonates of the control population. Both group fed breast milk. We performed direct sequencing of TATA box and Gly71Arg polymorphism of the UGT1A1 gene. Results : Two of the 50 neonates with hyperbilirubinemia had AA polymorphism, and 40 had GA polymorphism. Five of the 129 neonates of the control group had AA polymorphism, and 4 had GA polymorphism. The allele frequency of G>A polymorphism in the hyperbilirubinemia group was 44.0%; it was significantly higher than 5.4% of the control group. TATA box polymorpism was not different both group significantly. Conclusion : Our result indicated that Gly71Arg polymorphism is associated with the prolonged hyperbilirubinemia of breast milk-feeding infant in Korean, while TATA box polymorphism is not associated with the prolonged hyperbilirubinemia of breast milk-feeding infant in Korean.

Neonatal Jaundice and Breastfeeding

Neonatal jaundice is related to breastfeeding in three primary clinical situations: exclusively breastfed healthy term newborns during the first postnatal week, newborns who receive inadequate breastfeeding and have high concentrations of indirect bilirubin during the first postnatal week (“nonfeeding” jaundice), and breastfed infants who experience prolonged unconjugated hyperbilirubinemia (breast milk jaundice). Nonfeeding jaundice has been suggested to be related to a significantly greater weight loss on the third postnatal day compared with the birthweight following delayed initiation of or inadequate breastfeeding. This can be a particular problem among neonates discharged from the hospital within 48 hours, often requiring readmission for treatment of hyperbilirubinemia. Several hypotheses have been proposed for the source of breast milk jaundice, including the presence of a UDP-glucuronosyltransferase inhibitor, beta-glucuronidase, or a yet-unidentified factor in human milk that could inhibit bilirubin excretion and result in hyperbilirubinemia. Careful education about breastfeeding and monitoring of mothers as well as assessment of newborns for the risk of developing severe hyperbilirubinemia can aid in preventing neonatal jaundice. Treatment of hyperbilirubinemia is based on total serum bilirubin concentrations and can range from administration of intravenous fluids and supplementation with milk formula to intensive phototherapy and exchange transfusion. Experimental treatments include the use of stannsoporfin and beta-glucuronidase inhibitors as chemoprevention therapies and minimal aliquots of L-aspartic acid and enzymatically hydrolyzed casein to inhibit beta-glucuronidase.

Arias icterus: Prolonged unconjugated hyperbilirubinemia caused by breast milk

Breast milk jaundice occurs in 1-2% of healthy breast-fed newborns and young infants. It develops as the result of liver immaturity and the inhibitory effect of mother's milk to the clearance of unconjugated bilirubin. The paper analyzes variations in the level and length of unconjugated hyperbilirubinemia in breast-fed infants. The study was conducted on a sample of 29 young infants (19 male) with breast milk jaundice. All infants were born on time, by natural delivery and without complications. All were on breast-feeding only and developed optimally. None of the infants had either haemolysis or any other disease associated with unconjugated hyperbilirubinemia. All infants had physiological jaundice in the first week after birth, with unconjugated bilirubin level of 166-260 micromol (201.50 +/- 36.37 micromol). In the postneonatal period the highest bilirubin level was recorded in the fifth week of life and was 87-273 micromol (166.82 +/- 45.06 micromol), which then spontaneously, without interruption of breast-feeding, gradually declined. The decrease of the unconjugated fraction of serum bilirubin between the fourth and fifth week was significant, and after that highly significant. The normalization of serum bilirubin occurred in the seventh and thirteenth week (10.41 +/- 1.68 micromol). Negative consequences of hyperbilirubinemia were not noted in any of the infants. Breast milk jaundice presents a harmless and transitory disorder of bilirubin metabolism. It occurs in healthy breast-fed neonates and young infants. Jaundice is most marked in early neonatal period, and then it gradually declines and disappears between the seventh and thirteenth week.

Relationship between serum bilirubin and coagulation test results in 1-month-old infants.

Although the connection between cholestasis and conjugated hyperbilirubinemia is well known, mild hepatic dysfunction or cholestasis may also be associated with unconjugated hyperbilirubinemia in some infants with prolonged jaundice. The aim of this study was to investigate the relationship between serum bilirubin levels and alanine aminotransferase levels, asparte aminotransferase levels, prothrombin time, activated partial thromboplastin time and international normalization ratio findings in a group of infants. The study included 77 healthy, term, breast-fed infants with jaundice and 56 age-matched, healthy, term, non-jaundiced controls. The 133 babies were divided into three subgroups according to their total bilirubin levels [group I (controls) <50 μmol/L, group II=50-100 μmol/L, and group III >100 μmol/L, and the findings for the noted parameters were compared]. The mean conjugated bilirubin level was significantly higher, and the mean activated partial thromboplastin time significantly longer in group III than in group I. A significant positive correlation was found between bilrubin levels and PT and APTT results. Clinical vitamin K deficiency appeared unlikely to develop in this group of infants with prolonged unconjugated hyperbilirubinemia. However, a significant positive correlation between bilirubin levels and PT and APTT suggest that a higher bilirubin load to the liver may cause some degree of vitamin K deficiency due to mild cholestasis. The importance of this finding, and the possible benefits of vitamin K supplementation in 1-month-old breast-fed infants with bilirubin levels higher than 100 μmol/L require further investigation.