Neonatal jaundice is the most common condition requiring medical attention in the newborn period. It has been classically attributed to a number of more or less common causes. The causes are classically divided in two main groups. The first group is comprising of conditions

associated with an increase in break down of red blood cells such as Rhesus incompatibility, ABO blood group incompatibility, G6PD deficiency, birth trauma and polycythaemia. A second group consists of conditions in which the excretion of bilirubin is diminished such as

breast feeding jaundice, breast milk jaundice, Gilbert syndrome or the more severe Crigler Najjar syndrome.

Many babies however get jaundice

H., Nishio

H., Van Rostenberghe

M., Matsuo

R., Noraida

W.I., Wan Pauzi

English

Repository@USM

Lessons from the Molecular Biology ofNeonatal HyperbilirubinaemiaH. Van Rostenberghel,~(jj~H.Nishio, M. Matsuo,R. Noraida and W.I. Wan Pauzi/Medical School, Universiti Sains Malaysia,Kubang Kerian, Kelantan, MalaysiaSummaryCompared to Caucasians, South East Asian babies have more fre-quently jaundice, requiring phototherapy. This is partly due to the highprevalence of· G6PD deficiency and other genetically determinedhaematological abnormalities. If no underlying cause is found, thesebabies tend to be labelled as having 'excessive' physiological jaundiceor alternatively idiopathic pathological jaundice.It is likely however that jaundice in newborns is a complex interplaybetween multiple genetic and environmental risk factors. Often morethan one risk factor may be present such as in G6PD deficiency whererecently it was discovered that neonatal jaundice is often only not ac-companied by haemolysis. An association was found with Gilbert syn-dromeOne relatively recently described risk factor in the South East Asianpopulation is the presence of point mutations in the coding regions forthe gene of the uridine diphosphate glucuronyl transferase enzyme. Thesepoint mutations may decrease the activity of the enzyme responsible forglucuronidation of the indirect bilirubin just slightly. This can causejaundice that is really excessive in babies with other risk fact'ors.Neonatal jaundice is most likely a real multifactorial pathologicalevent based on many genetic and environmental factors. In future wewill look more at a combination of risk factors for jaundice, rather thanjust attributing the jaundice to one risk factor alone. The number ofbabies labelled as 'excessive physiologic jaundice' or idiopathic jaun-dice might decrease significantly in the near future.©2004 b)' MEDIMOND S.r.l. E414R9050 8990 13th Congress of the Federation ofAsia and Oceania Perinatal SocietiesIntroductionNeonatal jaundice is the most common condition requiring medicalattention in the newborn period. It has been classically attributed to anumber of more or less common causes. The causes are classicallydivided in two main groups. The first group is comprising of conditionsassociated with an increase in break down of red blood cells such asRhesus incompatibility, ABO blood group incompatibility, G6PD defi-ciency, birth trauma and polycythaemia. A second group consists ofconditions in which the excretion of bilirubin is diminished such asbreast feeding jaundice, breast milk jaundice, Gilbert syndrome or themore severe Crigler Najjar syndrome.Many babies however get jaundice without any of the above causesbeing identified. In these babies the term physiological jaundice is oftenapplied. Even if bilirubin levels go up in the phototherapy range it hasbeen called 'excessive physiological jaundice' and ifit approaches exchangetransfusion level it tends to. be called idiopathic pathological jaundice.In the latest decade and especially since the advent of genomicsthere have been some remarkable discoveries that may change our per-ception of the pathophysiology of neonatal jaundice thoroughly.' In-stead of attributing neonatal jaundice to a single condition as is classi-cally, done, we may realise in the near future that the presence of onerisk factor for NNJ is often not enough to cause severe or even mod-erately severe NNJ. New nsk factors have been identified and an asso-ciation of several risk factors may be often present 2. J so that it maybecome more appropriate to count the number of risk factors for thedevelopment of neonatal jaundice in a particular child rather than attrib-uting the jaundice to· one or another risk factor.G6PD DeficiencyG6PD deficiency is among the most common causes of neonataljaundice in many populations. G6PD deficiency can lead to severehaemolytic crises in older children and adults after exposure to oxidantstresses (favism). That is why it was classically believed that the neonataljaundice, associated with G6PD deficiency, is due to haemolysis aswell. There are indeed very occasionally babies with G6PD deficiencyhaving real favism-like presentations:~ In these babies a known oxidantstress or infection can often be identified. Most babies however withG6PD deficiency and neonatal jaundice present quite differently andhave a gradual onset of jaundice, often only becoming visible on day3 of life. In this latest kind of presentation, usually no obvious signs ofhaemolysis can be found.Multiple studies have been undertaken looking at the presence ofhaemolysi,s in G6PD deficient neonates with jaundice. Measurement ofKuala Lumpur, Malaysia, April 14-18, 2004 91CO-haemoglobin (COBb) is a good way to assess bilirubin productionand haemolysis since in the production of bilirubin, protoheme is split,releasing CO which is produced in equimolar quantities with bilirubin.5Except for one study6 done in a Nigerian population, most studies measuringCO production in G6PD deficient neonates 7,8.9 showed only a veryslight increase in CO production compared to G6PD normal controlsbut CO production was found to be. completely similar in those G6PDdeficient neonates with and those without jaundice.Furthennore Kaplan 10 has shown quite conclusively that the levels ofdirect bilirubin were lower in G6PD deficient neonates with jaundicethan in G6PD normal neonates with jaundice, indirectly indicating thatthere may be also a decrease in glucuronidation of bilirubin in thoseG6PD deficient neonates with jaundice. Further genetic analysis2 of thesame study population showed indeed a high prevalence of polymor-phism of the promotor region of the UGTIAI gene. (Gilbert Syndrome).The currently available data suggest that the majority of babies withG6PD deficiency and neonatal jaundice do not have severe haemolysis.They have rather a very mild haemolysis that by itself may be notsevere enough to cause jaundice but a combination of G6PD deficiencyand other risk factors may be necessary to make the infants jaundicedThe molecular basis of G6PD deficiency has been studied in theMalaysian population and it was discovered that the genotype is hetero-geneous in Malays as well as in the Chinese race I1 - 1J •ABO IncompatibilityABO incompatibility is another major cause ofjaundice in the neonatalperiod. Often the babies get jaundice on day one of life. The directCoombs test is 'falsely' negative in up to 70 % of the cases. This meansthat in up to 70 % of cases of ABO incompatibility with early onsetjaundice we fail to show the presence of maternal antibodies against theblood group of the baby. This may be due to low titers of antibodies orto the immature expression on the red blood cells of the babies. Oftenwe fail to show a drop in haemoglobin levels and if the expression ofthe blood group is so immature in many red blood cells, othec factorsthan haemolysis alone may playa role in the pathophysiology of ABOincompatibility associated neonatal jaundice. Kaplan found that in aJewish population, Gilbert syndrome was a determining factor for jaun-dice related to ABO incompatibility 3Other 'VeIl Known Causes of JaundiceA similar reasoning may be made for most of the other. well knowncauses of jaundice. Some children with mild birth trauma develop se-vere jaundice while others with sever.e subaponeurotic haemorrhage do92 13th Congress of the Federation ofAsia and Oceania Perinatal Societiesnot develop jaundice. Similar observations can be made for polycythae-mia, breastfeeding jaundice and others. The subsequent discussion willcover some of such additional risk factors.Gilbert DiseaseThis is an autosomal dominant condition in which a polymorphismof the promotor region of the UGTIAI gene is observed. This diseaseoccurs with a high frequency in some Caucasian populations. It canpresent in the neonatal period with jaundice and patients may get mildjaundice in episodes of stress. The babies with only this genetic variantand no other risk factors for jaundice may not get jaundice but thosewith other risk factors may be the ones who get jaundice. 14Other Mutations in the UGTIAI GeneA large variety of other mutations have been described in populationsof different ethnic origin. However in the Southeast Asian populationwhere jaundice has a very high incidence, only recently some attentionhas been given to the molecular analysis of the UGTIAI gene. A firstmutation has been described in the Thai population 15 and has subse-quently been found in a relatively high proportion of Malay babies withjaundiceJ6 • .Two other novel mutations in the same gene have been recentlydescribed in Malaysian babies 17 • These could be either real mutations orpolymorphisms. In either case, it could be predisposing the neonates todevelop jaundice if other risk factors are present. By itself it mightdisturb the bilirubin metabolism rather mildly and not cause severejaundiceOther Potential Molecular Explanations of the NNJThere are numerous other enzymes or transport proteins involved inthe metabolism of bilirubin. There is the transport protein of bilirubinacross the liver cells. There are also the heme oxidase and the b[liverdinreductase. In each of these, there may be a genetic or environmentalfactor interfering enough with the metabolism of bilirubin to cause jaundiceor be at least a significant risk factor worsening jaundice in the presenceof other risk factors, Examples of these include the fact that some stresshormones such as corticoids or some endotoxins could increase theactivity of biliverdin reductase and stimulate as such the bilirubin pro-duction 1&. .There is a vast field for future research in order to elucidate fully thepathophysiology of neonatal jaundice .Kuala Lumpur, Malaysia, April 14-18, 2004 93ConclusionResults of recent studies and developments in molecular biology areleading to newer insights in the pathophysiology of neonatal jaundice.Often significant jaundice may not be attributable to just one cause butneonatal jaundice has most likely a truly multifactorial causality. As ourknowledge in the bilirubin metabolism on the molecular level advances,we may meet less and less 'excessive physiological jaundice' or idi-opathic pathological jaundice. A better knowledge of all risk factorsinvolved will lead to a more effective prevention of severe neonataljaundice through identification and early treatment of high-risk cases.References1. Watchko JF, Daood MJ, Biniwale M. Understanding neonatal hyperbilirubi-naemia in the era of genomics. Semin Neonatal, 7(2): 143-152,2002.2. Kaplan M, Renbau.Tll P, Levy-Lahad E, Hammerman C, et a1. Gilbert syn-drome and glucose-6-phosphate dehydrogenase deficiency: a dose-depend-ent genetic interaction crucial to neonatal hyperbilirubinemia. Proc NatlAcad Sci USA. 94(22):12128-12132,1997.3. Kaplan M, Hammerman C, Renbaum P, Klein G, et a1. Gilbert's syndromeand hyperbilirubinaernia in ABO-incompatible neonates. Lancet, 356(9230):652-653,2000. :4. Kaplan M, Hammerman C. Glucose-6-phosphate dehydrogenase deficiency:a potential source of severe neonatal hyperbilirubinaemia and kernicterus.Semin Neonatal, 7(2): 121-128,2002.5. Engel RR, Rodkey FL, Krill CE, Jr. Carboxyhemoglobin levels as an indexof hemolysis. Pediatrics, 47(4):723-730,1971.6. Slusher TM, Vretnan HJ, McLaren DW, Lewison LJ, et a1. Glucose-6-phosphate dehydrogenase deficiency and carboxyhemoglobin concentra-tions associated with bilirubin-related morbidity and death in Nigerian in-fants. J Pediatr, 126(1):102-108,]995.7. Kaplan M, Vreman HJ, Hammerman C, Leiter C, et al. Contribution ofhaemolysis to jaundice in Sephardic Jewish glucose-6-phosphate dehydro-genase deficient neonates. Br J Haemato!, 93(4):822-827,1996.8. Seidman DS, Shiloh M, Stevenson DK, Vreman HJ, et a1. Role of hemolysisin neonatal jaundice associated with glucose-6 phosphate dehydrogenasedeficiency. J Pediatr. 127(5):804-806,1995.9. Van Rostenberghe H, Selamah G, Nik Zainal A, Nishio H. Poor correlationbetween hemolysis and neonatal jaundice in Malaysian G6PD-deficicnt babies.Submitted for publication to Pediatr In!10. Kaplan M, Muraca M, Hammerman C, Vilei MT, et a1. Unconjugated andconjugated bilirubin pigments during perinatal development. V. Effect ofphototherapy on serum conjugated bilirubin in hyperbilirubinemic neonates.Bio! Neonate. 73(3): 155-160,1998.11. YusoffNM, Shirakawa T, Nishiyama K, Ghazali S, et al. Molecular hetero-geneity of glucose-6-phosphate dehydrogenase deficiency in Malays inMalaysia. Int J Hemato!, 76(2): 149-152,2002.94 13th Congress oj the Federation ojAsia and Oceania Perinatal Societies12. Ainoon 0, Joyce J, Boo NY, Cheong SK. et al. Glucose-6-phosphate de-hydrogenase (G6PD) variants in Malaysian Chinese. Hum Mutat, 14(4):352,1999.13. Ainoon 0, Yu YH, Amir Muhriz AL, Boo NY, et al. Glucose-6-phosphatedehydrogenase (G6PD) variants in Malaysian Malays. Hum Mutat,21(1): 101,2003.14. Ulgenalp A, Duman N, Schaefer FV, Whetsell L, et al. Analyses of poly-morphism for UGTI * 1 exon 1 promoter in neonates with pathologic andprolonged jaundice. Bioi Neonate, 83(4):258-262,2003.15. Sutomo R, Laosombat V, Sadewa AH, Yokoyama N, et al. Nove! missensemutation of the UGTIA1 gene in Thai siblings with Gilbert's syndrome.Pediatr Int, 44(4):427-432,2002.16. Sutomo R, Norlelawati A, Yusoff N, Van Rostenberghe H et al. Screeningfor G71R mutation of the UGT1A1 gene in the Javanese-Indonesian andMalay-Malaysian populations. Pediatr Int, 46(5), 200417. Norlelawati A, Van Rostenberghe H,,-Sutomo R, Matsuo M. et al. NovelMissense Mutations 964A-.7G and 1477G-.7C, in the UGT1Al Gene inMalay Babies with Early Onset of Severe Neonatal Jaundice. Submitted forpublication to Annals Med Gen18 Dennery PA. The biology ofheme oxygenase during development. Neoreviews,2: e67-e73, 2001

Lessons From The Molecular Biology Of Neonatal Hyperbilirubinaemia.

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Lessons From The Molecular Biology Of Neonatal Hyperbilirubinaemia.

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