{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T11:49:40Z","timestamp":1792496980086,"version":"4.5.0"},"reference-count":37,"publisher":"American Academy of Pediatrics (AAP)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2002,10,1]]},"abstract":"<jats:p>Objective. The objective of this study was to evaluate the roles of production and conjugation of bilirubin, individually and in combination, in the mechanism of neonatal jaundice.<\/jats:p><jats:p>Methods. A cohort of healthy, term male newborns was sampled on the third day of life, coincident with routine metabolic screening, for blood carboxyhemoglobin determination, a reflection of heme catabolism, and for serum unconjugated and conjugated bilirubin fractions, reflecting bilirubin conjugation. The former was determined by gas chromatography, corrected for inspired CO (COHbc), and expressed as percentage of total hemoglobin. Serum bilirubin fractions were quantified by alkaline methanolysis and reverse phase high performance liquid chromatography. The sum of all bilirubin fractions comprised serum total bilirubin (STB). Total conjugated bilirubin (TCB) was comprised of the sum of the conjugated fractions and was expressed as percentage of STB (TCB[%]). A \u201cbilirubin production\/conjugation index\u201d (COHbc\/[TCB(%)] represented the combined roles of these modalities in the mechanism of bilirubinemia. Relationships between STB concentrations on the one hand, and COHbc values, TCB(%) proportions, and the production\/conjugation index on the other, were determined by applying a best-fit regression analysis methodology.<\/jats:p><jats:p>Results. Mean (\u00b1 standard deviation) STB concentration at the time of sampling was 114 \u00b1 48 \u03bcmol\/L (range: 8\u2013263 \u03bcmol\/L). Mean COHbc value was 0.77 \u00b1 0.19%, and median (interquartile range) TCB(%) was 0.737 (0.465\u20131.260)%. COHbc values correlated directly with STB concentrations (r = 0.38; s = 46.1), and TCB(%) correlated inversely with STB (r = 0.40; s = 45.8). The production\/conjugation index correlated positively with STB values (r = 0.61; s = 45.8), the r value for the index being higher than that of either COHbc or TCB(%), individually. The bilirubin production\/conjugation index seemed to have a biphasic relationship to STB: STB values rose steeply in concert with increasing index values in the lower range of the index, and subsequently plateaued in the higher range of the index.<\/jats:p><jats:p>Conclusions. Within the range of STB concentrations encountered, both increasing bilirubin production and diminishing bilirubin conjugation contributed to STB. The production\/conjugation index confirmed that imbalance between production and conjugation of bilirubin plays an important role in the mechanism of neonatal bilirubinemia. alkaline methanolysis, bilirubin, bilirubin conjugation, carbon monoxide, carboxyhemoglobin, gas chromatography, hemolysis, high performance liquid chromatography, physiologic jaundice.<\/jats:p>","DOI":"10.1542\/peds.110.4.e47","type":"journal-article","created":{"date-parts":[[2004,8,14]],"date-time":"2004-08-14T00:17:55Z","timestamp":1092442675000},"page":"e47-e47","source":"Crossref","is-referenced-by-count":108,"title":["Imbalance Between Production and Conjugation of Bilirubin: A Fundamental Concept in the Mechanism of Neonatal Jaundice"],"prefix":"10.1542","volume":"110","author":[{"given":"Michael","family":"Kaplan","sequence":"first","affiliation":[{"name":"Department of Neonatology, Shaare Zedek Medical Center, Jerusalem, Israel"},{"name":"Faculty of Medicine of the Hebrew University, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Muraca","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Padua, Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Hammerman","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Shaare Zedek Medical Center, Jerusalem, Israel"},{"name":"Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firmino F.","family":"Rubaltelli","sequence":"additional","affiliation":[{"name":"Department of Neonatology, University of Florence, Florence; Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria T.","family":"Vilei","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Padua, Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik J.","family":"Vreman","sequence":"additional","affiliation":[{"name":"Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University Medical Center, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David K.","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University Medical Center, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"417","published-online":{"date-parts":[[2002,10,1]]},"reference":[{"key":"2021121006415157300_R1","unstructured":"Watchko JF. Indirect hyperbilirubinemia in the neonate. In: Maisels MJ, Watchko JF, eds. Neonatal Jaundice. Amsterdam, the Netherlands: Harwood Academic Publishers; 2000:51\u201372"},{"key":"2021121006415157300_R2","doi-asserted-by":"crossref","unstructured":"Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med.2001;344:581\u2013590","DOI":"10.1056\/NEJM200102223440807"},{"key":"2021121006415157300_R3","unstructured":"Stevenson DK, Vreman HJ, Benaron DA. Evaluation of neonatal jaundice: monitoring the transition in bilirubin metabolism. J Perinatol.1996;16:562\u2013567"},{"key":"2021121006415157300_R4","doi-asserted-by":"crossref","unstructured":"Stevenson DK, Vreman HJ. Carbon monoxide and bilirubin. Pediatrics.1997;100:252\u2013254","DOI":"10.1542\/peds.100.2.252"},{"key":"2021121006415157300_R5","doi-asserted-by":"crossref","unstructured":"Vreman HJ, Mahoney JJ, Stevenson DK. Carbon monoxide and carboxyhemoglobin. 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The prenatal and postnatal development of UDP-glucuronyltransferase activity towards bilirubin and the effect of premature birth on this activity in the human liver. Biochem J.1981;196:257\u2013260","DOI":"10.1042\/bj1960257"},{"key":"2021121006415157300_R10","doi-asserted-by":"crossref","unstructured":"Muraca M, Blanckaert N, Fevery JJ, Rubaltelli FF, Carnielli V, Pettena G. Serum bilirubin mono- and di-conjugates in human newborns. In: Rubaltelli FF, Jori G, eds. Neonatal Jaundice. New Trends in Phototherapy. New York, New York: Plenum Press; 1984:13\u201321","DOI":"10.1007\/978-1-4684-7517-3_2"},{"key":"2021121006415157300_R11","doi-asserted-by":"crossref","unstructured":"Fevery J, Blanckaert N. What can we learn from analysis of serum bilirubin?J Hepatol.1986;2:113\u2013121","DOI":"10.1016\/S0168-8278(86)80014-9"},{"key":"2021121006415157300_R12","doi-asserted-by":"crossref","unstructured":"Muraca M, Fevery J, Blanckaert N. 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