Another Explanation for Breast Milk Jaundice
B
reast milk jaundice refers to an unconjugated hyperbiWas it a factor in the mother’s breast milk? Was there another lirubinemia associated with breastfeeding that deneonatal factor contributing to the observed jaundice? velops after 4-7 days of life in an otherwise-healthy Furthermore, not all infants with breast milk jaundice are neonate and has no other identifiable cause.1 It is distinfrom East Asia. Will infants with breast milk jaundice from other continents also be predominantly homozygous guished from breastfeeding jaundice, which occurs in the first UGT1A1*6? Obviously, similar investigaweek of life and is the result of insufficient See related article, p tions in breast milk jaundiced infants from intake or production of breast milk. The other areas should be undertaken to confirm or refute this ascause of breast milk jaundice has been the subject of sociation in other ethnic groups. numerous investigations based on the assumption that either The cause of breast milk jaundice in infancy appears to be a factor in the breast milk itself or in the neonate could multifactorial. No single cause to date explains this phenomcontribute to the observed clinical presentation. enon in all observed affected infants. Another issue that the Bilirubin conjugation and subsequent elimination is catainvestigators did not address in this study is the welllyzed by bilirubin uridine 50 -diphospho-glucuronosyltransferknown improvement in breast milk jaundice when breast ase 1 (UGT1A1).2 Defects in UGT1A1 cause hereditary milk feeding is temporarily suspended.8 Although there unconjugated hyperbilirubinemias—Crigler-Najjar syndrome type I (MIM #218800), in which there is complete deficiency of potentially could be a factor in the breast milk that inhibits the enzyme; Crigler-Najjar syndrome type II (MIM #606785), UGT1A1 enzyme activity, this unknown factor’s effect on howhere there is some limited activity of the enzyme; and Gilbert mozygous UGT1A1*6 or the fact that with the resumption of syndrome (MIM #43500), in which there is more enzyme acbreastfeeding the serum bilirubin concentration and jaundice tivity but less than in normal individuals.3 Polymorphic mutawill still decrease remain unexplained. Breast milk jaundice remains a fascinating occurrence in a tions of UGT1A1, specifically G71R in the coding region and subset of infants who are breast-fed. Mauro et al have found A(TA)7TAA with -3279T G in the regulatory region, are the yet another relationship for its incidence. What other causes most common mutations seen in Gilbert syndrome, and or relationships will be found that contribute to breast milk A(TA)7TAA, with -3279T G, is the sole cause of Gilbert synjaundice hopefully will be determined in the near future. n drome in white patients.4 Maruo et al5,6 have shown previously that G71R (but not A(TA)7TAA with -3279T G) is a cause of Philip Rosenthal, MD prolonged unconjugated hyperbilirubinemia in East Asian inProfessor of Pediatrics & Surgery fants and is also a risk factor for breast milk jaundice. 7 University of California, San Francisco In this issue of The Journal, Maruo et al describe the causal UCSF Benioff Children’s Hospital relationship between infants with breast milk jaundice and San Francisco, California homozygosity for UGT1A1*6. Using polymerase chain reaction–directed sequencing, they analyzed UGT1A1 gene allelic Reprint requests: Philip Rosenthal, MD, Pediatric Hepatology & Liver variation in 170 Japanese infants with breast milk jaundice, Transplant, 500 Parnassus Avenue, MU-416 East, Box 0136, San Francisco, CA 94143-0136. E-mail: [email protected] and these genotypes were compared with serum bilirubin concentrations. As a control group, UGT1A1 genotypes in 55 infants without breast milk jaundice also were analyzed. References The authors found that 52% of the infants with breast milk jaundice were homozygous UGT1A1*6. These infants had 1. Newman AJ, Gross S. Hyperbilirubinemia in breast-fed infants. Pediatrics serum bilirubin concentrations (21.8 3.65 mg/dL) that 1963;32:995-1001. 2. Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, were significantly greater than in infants with other genoChowdhury JR, et al. Bilirubin UDP-glucuronosyltransferase 1 is the types (P < .0001). Homozygous UGT1A1*6 was not detected only relevant bilirubin glucuronidating isoform in man. J Biol Chem in the control group of infants without breast milk jaundice. 1994;269:17960-4. The authors concluded that UGT1A1*6 is a major cause of 3. Kadakol A, Ghosh SS, Sappal BS, Sharma G, Chowdhury JR, Chowdhury NR. breast milk jaundice in infants in East Asia. Genetic lesions of bilirubin uridine-disphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: There are several additional points worthy of discussion as correlation of genotype to phenotype. Hum Mutat 2000;16:297-306. a result of this work. Although the majority (52%) of the Jap4. Maruo Y, D’Addario C, Mori A, Iwai M, Takahashi H, Sato H, et al. anese infants with breast milk jaundice were homozygous Two linked polymorphic mutations (A(TA)7TAA and T-3279G) of UGT1A1*6, a sizeable percentage (48%) did not have this genotype. What was the cause of their breast milk jaundice? The author declares no conflicts of interest.
UGT1A1
0
Uridine 5 -diphospho-glucuronosyltransferase 1
0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.03.038
1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
UGT1A1 as the principal cause of Gilbert syndrome. Hum Genet 2004; 115:525-6. 5. Maruo Y, Nishizawa K, Sato H, Doida Y, Shimada M. Association of neonatal hyperbilirubinemia with bilirubin UDPglucuronosyltransferase polymorphism. Pediatrics 1999;103:1224-7. 6. Maruo Y, Nishizawa K, Sato H, Takahashi H, Shimada M. Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations
2
Vol. -, No. of the bilirubin uridine diphosphate-glucuronosyltransferase gene. Pediatrics 2000;106:E59. 7. Maruo Y, Morioka Y, Fujito H, Nakahara S, Yanagi T, Matsui K, et al. Bilirubin UDP-glucuronosyltransferase variation is a genetic basis of breast milk jaundice. J Pediatr 2014;XX:XX-XXX. 8. Gartner LM. Breastfeeding and jaundice. J Perinatol 2001;21(Suppl 1): S25-9.
B
reast milk jaundice refers to an unconjugated hyperbiWas it a factor in the mother’s breast milk? Was there another lirubinemia associated with breastfeeding that deneonatal factor contributing to the observed jaundice? velops after 4-7 days of life in an otherwise-healthy Furthermore, not all infants with breast milk jaundice are neonate and has no other identifiable cause.1 It is distinfrom East Asia. Will infants with breast milk jaundice from other continents also be predominantly homozygous guished from breastfeeding jaundice, which occurs in the first UGT1A1*6? Obviously, similar investigaweek of life and is the result of insufficient See related article, p tions in breast milk jaundiced infants from intake or production of breast milk. The other areas should be undertaken to confirm or refute this ascause of breast milk jaundice has been the subject of sociation in other ethnic groups. numerous investigations based on the assumption that either The cause of breast milk jaundice in infancy appears to be a factor in the breast milk itself or in the neonate could multifactorial. No single cause to date explains this phenomcontribute to the observed clinical presentation. enon in all observed affected infants. Another issue that the Bilirubin conjugation and subsequent elimination is catainvestigators did not address in this study is the welllyzed by bilirubin uridine 50 -diphospho-glucuronosyltransferknown improvement in breast milk jaundice when breast ase 1 (UGT1A1).2 Defects in UGT1A1 cause hereditary milk feeding is temporarily suspended.8 Although there unconjugated hyperbilirubinemias—Crigler-Najjar syndrome type I (MIM #218800), in which there is complete deficiency of potentially could be a factor in the breast milk that inhibits the enzyme; Crigler-Najjar syndrome type II (MIM #606785), UGT1A1 enzyme activity, this unknown factor’s effect on howhere there is some limited activity of the enzyme; and Gilbert mozygous UGT1A1*6 or the fact that with the resumption of syndrome (MIM #43500), in which there is more enzyme acbreastfeeding the serum bilirubin concentration and jaundice tivity but less than in normal individuals.3 Polymorphic mutawill still decrease remain unexplained. Breast milk jaundice remains a fascinating occurrence in a tions of UGT1A1, specifically G71R in the coding region and subset of infants who are breast-fed. Mauro et al have found A(TA)7TAA with -3279T G in the regulatory region, are the yet another relationship for its incidence. What other causes most common mutations seen in Gilbert syndrome, and or relationships will be found that contribute to breast milk A(TA)7TAA, with -3279T G, is the sole cause of Gilbert synjaundice hopefully will be determined in the near future. n drome in white patients.4 Maruo et al5,6 have shown previously that G71R (but not A(TA)7TAA with -3279T G) is a cause of Philip Rosenthal, MD prolonged unconjugated hyperbilirubinemia in East Asian inProfessor of Pediatrics & Surgery fants and is also a risk factor for breast milk jaundice. 7 University of California, San Francisco In this issue of The Journal, Maruo et al describe the causal UCSF Benioff Children’s Hospital relationship between infants with breast milk jaundice and San Francisco, California homozygosity for UGT1A1*6. Using polymerase chain reaction–directed sequencing, they analyzed UGT1A1 gene allelic Reprint requests: Philip Rosenthal, MD, Pediatric Hepatology & Liver variation in 170 Japanese infants with breast milk jaundice, Transplant, 500 Parnassus Avenue, MU-416 East, Box 0136, San Francisco, CA 94143-0136. E-mail: [email protected] and these genotypes were compared with serum bilirubin concentrations. As a control group, UGT1A1 genotypes in 55 infants without breast milk jaundice also were analyzed. References The authors found that 52% of the infants with breast milk jaundice were homozygous UGT1A1*6. These infants had 1. Newman AJ, Gross S. Hyperbilirubinemia in breast-fed infants. Pediatrics serum bilirubin concentrations (21.8 3.65 mg/dL) that 1963;32:995-1001. 2. Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, were significantly greater than in infants with other genoChowdhury JR, et al. Bilirubin UDP-glucuronosyltransferase 1 is the types (P < .0001). Homozygous UGT1A1*6 was not detected only relevant bilirubin glucuronidating isoform in man. J Biol Chem in the control group of infants without breast milk jaundice. 1994;269:17960-4. The authors concluded that UGT1A1*6 is a major cause of 3. Kadakol A, Ghosh SS, Sappal BS, Sharma G, Chowdhury JR, Chowdhury NR. breast milk jaundice in infants in East Asia. Genetic lesions of bilirubin uridine-disphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: There are several additional points worthy of discussion as correlation of genotype to phenotype. Hum Mutat 2000;16:297-306. a result of this work. Although the majority (52%) of the Jap4. Maruo Y, D’Addario C, Mori A, Iwai M, Takahashi H, Sato H, et al. anese infants with breast milk jaundice were homozygous Two linked polymorphic mutations (A(TA)7TAA and T-3279G) of UGT1A1*6, a sizeable percentage (48%) did not have this genotype. What was the cause of their breast milk jaundice? The author declares no conflicts of interest.
UGT1A1
0
Uridine 5 -diphospho-glucuronosyltransferase 1
0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.03.038
1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
UGT1A1 as the principal cause of Gilbert syndrome. Hum Genet 2004; 115:525-6. 5. Maruo Y, Nishizawa K, Sato H, Doida Y, Shimada M. Association of neonatal hyperbilirubinemia with bilirubin UDPglucuronosyltransferase polymorphism. Pediatrics 1999;103:1224-7. 6. Maruo Y, Nishizawa K, Sato H, Takahashi H, Shimada M. Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations
2
Vol. -, No. of the bilirubin uridine diphosphate-glucuronosyltransferase gene. Pediatrics 2000;106:E59. 7. Maruo Y, Morioka Y, Fujito H, Nakahara S, Yanagi T, Matsui K, et al. Bilirubin UDP-glucuronosyltransferase variation is a genetic basis of breast milk jaundice. J Pediatr 2014;XX:XX-XXX. 8. Gartner LM. Breastfeeding and jaundice. J Perinatol 2001;21(Suppl 1): S25-9.
