Total Serum/plasma Bilirubin Research Articles

The biology of bilirubin production: overview of detection and inhibition

: Newborn jaundice is a benign condition commonly seen in the first postnatal week of life (or the transitional period). It is primarily due to an imbalance between the rate of production of the yellow-orange pigment bilirubin and its elimination by the liver. Infants with high bilirubin production rates (such as those who are undergoing hemolysis) or with insufficient hepatic bilirubin conjugating ability [such as those with uridine 5'-diphosho-glucuronosyltransferase (UGT1A1) deficiencies] can subsequently develop excessive circulating total serum/plasma bilirubin (TB) levels or hyperbilirubinemia. Bilirubin is formed during the degradation of heme, derived from the turnover of red blood cells (RBCs). In this reaction, which is catalyzed by the rate-limiting enzyme heme oxygenase (HO), carbon monoxide (CO), iron (Fe2+), and bilirubin are produced in equimolar quantities. As a result, measurements of total body CO production rates can be used as indices of bilirubin production. Standard treatment strategies for hyperbilirubinemia involves the use of phototherapy (specifically narrow-band blue wavelength light) and/or exchange transfusion. However, if infants with excessive hyperbilirubinemia are not identified or treated in a timely manner, they are at risk for developing bilirubin neurotoxicity, which can manifest as bilirubin-induced neurologic dysfunction (BIND) and result in neurologic sequelae (such as acute or chronic bilirubin encephalopathy. Here, we review the biology of bilirubin production and current technologies and approaches to identify and treat these high-risk infants.

Treatment criteria for infants with hyperbilirubinemia in Japan

With the availability of blue light-emitting diode phototherapy devices capable of delivering high-intensity irradiance, neonatologists in Japan are requesting revisions of the 1992 Kobe University treatment criteria for hyperbilirubinemia using total serum/plasma bilirubin (TB) and serum unbound bilirubin (UB) threshold values, especially for indications for exchange transfusion (ET). Retrospective data analysis of 1,184 infants born between January 2012 and November 2014 when the 1992 criteria were followed, we applied revised criteria proposed in 2017 to these infants to assess consequent changes in treatment recommendations. We found that the estimated number of infants with ET indications decreases from 48 to 20, with intensive phototherapy recommended for the remaining 28. Also, the estimated number of infants with phototherapy indications decreases from 446 to 195. We conclude that use of the revised criteria will lead to judicious use and reduction of phototherapy and ET in infants with hyperbilirubinemia.

Noninvasive methods for bilirubin measurements in newborns: A report

New technologies have become available for noninvasive assessments of neonatal hyperbilirubinemia. Our objective is to review the noninvasive methods for measuring bilirubin in the newborn. We searched relevant literature from 1966 to January 1, 2020, which included cross-sectional studies to define the accuracy of any noninvasive methods for measuring or estimating total serum/plasma bilirubin (TB) levels in newborns. We identified and included 83 relevant studies of direct visual assessment, icterometry, mobile phone applications, and transcutaneous bilirubinometry (TcB). Compared with laboratory TB measurements, visual assessment was the least accurate and least reliable (r: 0.37 to 074), while TcB was the most accurate, but not always near-equivalent (r: 0.45 to 0.99). The sensitivity and specificity of TcB cut-off values to detect significant hyperbilirubinemia (TB>95th percentile for age in hours) ranged from 74% to 100% and 18% to 89%, respectively.

Acute bilirubin encephalopathy: Some lessons learned

Acute bilirubin encephalopathy (ABE) is still an insufficiently addressed cause of mortality and long-term morbidity in low- and middle-income countries (LMICs). This article highlights that delayed or incorrect medical advice, inaccurate bilirubin measurements as well as ineffective phototherapy are some of the relevant causes predisposing jaundiced newborns to develop extreme hyperbilirubinemia [EHB, total serum/plasma bilirubin (TB) ≥ 25 mg/dL (428 µmol/L)] and subsequent ABE. Obstacles preventing state of the art management of such infants are also discussed. Prevention of ABE cannot occur without a system-based approach tailored to suit the needs and available resources of each community. Clear set protocols, rigorous training, monitoring, and accurate documentation together with simple innovative affordable technologies that can be locally produced, are essential to observe the change desired.

Identification of risk for neonatal haemolysis.

To identify neonates at risk of haemolytic hyperbilirubinaemia through near-concurrent measurements of total serum/plasma bilirubin (TB) or transcutaneous bilirubin (TcB) and end-tidal breath carbon monoxide (CO), corrected for ambient CO (ETCOc), an index of bilirubin production and haemolysis. Paired TB/TcB (mg/dL) and ETCOc (ppm) measurements were obtained in newborns (n = 283) at 20 to <60 hours of age in five nurseries. TB/TcB values were assigned TB/TcB percentile risk values using the Bhutani hour-specific nomogram. In infants having two serial TB/TcB measurements (n = 76), TB rate of rise (ROR, mg/dL/h) was calculated. For the entire cohort (n = 283), 67.1% and 32.9% had TB/TcB<75th and ≥75th percentile, respectively. TB/TcB (5.79 ± 1.84 vs 9.14 ± 2.25 mg/dL) and ETCOc (1.61 ± 0.45 vs 2.02 ± 1.35 ppm, p = 0.0002) were different between the groups. About 36.6% of infants with TB/TcB ≥75th percentile had ETCOc ≥ 2.0 ppm. In the subcohort of infants with serial TB/TcB measurements (n = 76), 44.7% and 55.3% had TB/TcB<75th and ≥75th percentile, respectively. TB/TcB (5.28 ± 1.97 vs 9.53 ± 2.78 mg/dL), ETCOc (1.72 ± 0.48 vs 2.38 ± 1.89 ppm, p = 0.05) and TB ROR (0.011 ± 0.440 vs 0.172 ± 0.471 mg/dL/h) were different between the groups. The combined use of TB/TcB percentile risk assessments and ETCOc measurements can identify infants with haemolytic hyperbilirubinaemia. The addition of TB ROR can identify those infants with elimination disorders.

International Perspectives: Clinical Kernicterus in Preterm Infants in Japan

In recent years, clinical kernicterus has been diagnosed in preterm infants on the basis of motor (kinetic) disorders such as choreoathetosis and dystonia, impairment in auditory neuropathy-type hearing, and abnormal pallidal signals on head magnetic resonance imaging. In Japan, it is currently estimated that at least 8 to 9 cases of kernicterus (approximately 2 per 1,000 cases) occur annually in preterm infants of less than 30 weeks’ gestation. Therefore, there is an urgent need to revise our jaundice management approach in preterm infants. Two major characteristics of Japanese preterm infants who develop clinical kernicterus are: (1) a peak total serum/plasma bilirubin (TB) level at 2 weeks of age or later; and (2) no markedly high total bilirubinemia. Some patients without high TB levels have high levels of unbound serum/plasma bilirubin (UB). Consequently, we propose that in Japanese preterm infants, continuous monitoring of bilirubin (using transcutaneous bilirubinometry or direct TB measurements) and/or binding status (UB levels or bilirubin-binding capacity) may be necessary.

Screening for Hyperbilirubinemia in Japanese Very Low Birthweight Infants Using Transcutaneous Bilirubinometry

To assess the accuracy of transcutaneous bilirubin (TcB) measurements at 5 different body sites in Japanese very low birthweight (VLBW) infants and to determine a cut-off value of TcB to detect total serum/plasma bilirubin (TB) levels ≥10mg/dL (171μM). In a prospective multicenter study, 85 Japanese VLBW infants were enrolled from 5 neonatal intensive care units during the study period. A total of 383 blood samples from infants not receiving phototherapy or ≥24hours postphototherapy were analyzed. TcB was measured at the forehead, sternum, upper back, lower abdomen, and waist within 1hour of blood collection. Linear regression analysis and Bland-Altman plots were used to compare TcB values at each site with TB levels. The TcB cut-off value for detecting TB ≥10mg/dL was determined by receiver operating characteristics curve analysis. TcB significantly correlated with TB, but the coefficient of determination varied among the sites (forehead: 0.5294, sternum: 0.6488, upper back: 0.6321, lower abdomen: 0.5430, waist: 0.7396). At a TcB value ≥8, the sensitivity was 100% at the sternum and upper back, 85% at the waist, 84% at the forehead, and 64% at the lower abdomen to detect TB ≥10mg/dL. In Japanese VLBW infants, the accuracy of TcB measurements varies according to body site. TcB ≥8 on the sternum or upper back is more reliable than that on the forehead, lower abdomen, or waist to detect TB levels ≥10mg/dL.