For many years, hyperbilirubinemia has been known to occur in the newborn. This disease, with its resultant morbidity, is so important that many articles reviewing all aspects of the subject have been written.1-10
Jaundice appears in approximately 50 per cent of full-term infants and in about 80 per cent in those born before term. Studies show that values of bilirubin in jaundiced newborns reach a peak concentration on approximately the third day. It must be stressed that any "high" bilirubin in the first week of life may cause brain damage. The rising indirect bilirubin, if uncontrolled, may be deposited in various parts of the central nervous system, causing the symptoms of kernicterus.1
Pathologically, there is bilirubin staining of the basal ganglia in kernicterus. Clinically, kernicterus is characterized by deep jaundice, lethargy, disinclination to feed, vomiting, cyanosis, convulsions, and opisthotonos. AU these symptoms may occur at the same time." Up to 75 per cent of babies with kernicterus will die, and those who survive have one or more severe central nervous symptoms, including athetosis, mental retardation, and deafness.3,12,13 It was formerly believed that dangers of kernicterus did not exist unless the bilirubin levels approached or exceeded 20 mg./100 ml. However, a few full-term infants have been reported who have shown neurologic signs suggestive of kernicterus, as well as some small, low-birth-weight infants who at autopsy have shown kernicterus at concentrations of less than 10 mg./100 ml.14,15 Nevertheless, at the present time, the level of bilirubin is the most important indicator for the prevention of brain damage; but its height and the duration of its high level may be due to many factors, among which are the following:
1. Reduction in available albumin pool for bilirubin binding
2. Substances binding to albumin and displacing bilirubin
d. Sodium benzoate
e. Nonesterified fatty acids, which increase under the following conditions: (1) fasting, (2) hypoglycemia, (3) heparin administration, (4) adrenalin administration
f. Hematin, occurring in hemolysis
3. Increase in bilirubin-albumin binding
a. Respiratory acidosis
b. Metabolic acidosis
Lanzkowsky has listed causes of indirect hyperbilirubinemia in the first week of life15 (Table 1). Table 2 lists the causes of hyperbilirubinemia that are unrelated to a hemolytic process as listed by Oski.16
Bilirubin metabolism is complicated and has been reviewed in detail by many authors.5,6,10,17-20 In its simplest form, the following organ systems are involved in the production, uptake, and excretion of bilirubin:
1. The reticuloendothelial system, which destroys the red blood cells and forms unconjugated bilirubin. Approximately 90 per cent of bilirubin is obtained from hemoglobin destruction; no one knows for certain where the remaining bile pigment is produced. This free unconjugated bilirubin is lipid soluble and water insoluble. It is toxic and causes the bilirubin encephalopathy. It is usually reported by the laboratory as the "indirect" bilirubin.
2. The hepatic system, which is involved with:
a. Uptake of the unconjugated bilirubin via the splenic vein.
b. Conjugation with enzymes such as glucuronyl transferase, sulfate transferase, and others. This is known as the conjugated bilirubin; it is water soluble and readily excreted.
c. Excretion of conjugated bilirubin via the common bile duct.
CAUSES OF INDIRECT HYPERBILIRUBINEMIA
CAUSES OF HYPERBILIRUBINEMIA UNRELATED TO A HEMOLYTIC PROCESS
3. The gastrointestinal system, where the conjugated bilirubin is acted on by intestinal bacteria.
So-called physiologic jaundice, which is one of the main nonhemolytic causes of indirect hyperbilirubinemia, is thus really the jaundice of hepatic immaturity. It may be due to a deficiency in transfer of unconjugated bilirubin from the plasma into the liver cells or a deficiency in the conjugation of bilirubin. The immature liver of the newborn infant cannot take the unconjugated bilirubin at a high enough rate. There are two liver proteins,19 the Y and Z proteins, which are essential for the uptake of unconjugated bilirubin. The Z protein, the less important of the two, develops during fetal life. The Y protein does not reach its mature level until the infant is two to three weeks old; thus hyperbilirubinemia frequently exists in the newborn infant.
What is pathologic hyperbilirubinemia if so many infants are jaundiced? No one really knows. Some authors have defined it as a total serum bilirubin greater than 12 mg./100 ml.21 Others believe that the "magic number" might be lower7 or higher.2 It must be remembered, however, that Odell and co-workers7 have shown that the risk of neurologic impairment correlates better with the duration of serum bilirubin in excess of 15 mg./100 ml. than with peak serum bilirubin levels. With levels above 20 mg./100 ml.,2,13 the risk of kemicterus becomes increasingly great, although, as previously mentioned, kemicterus may at times occur at lower levels of bilirubin, especially in sick premature infants with acidosis.3·4 Enzymes such as glucuronyl transferase are necessary for the conjugation of bilirubin and often are decreased or may even be absent in normal-birth-weight infants at term.-2 Therefore one has to postulate that there is a relatively greater degree of functional immaturity in the more jaundiced term infant in whom no hemolysis is present. We agree with OskiIH that the term "physiologic jaundice" should be replaced by "hyperbilirubinemia secondary to _____. "
For many years we have known that bilirubin must move into tissues like the brain to cause damage. This occurs when free bilirubin is available. However, albumin binds the free bilirubin to sites in the plasma and thus will prevent the movement of bilirubin into tissues. If there is low albumin (as in premature infants) or if the albumin sites are saturated, the bilirubin moves into the tissue.-3 The test, known as bilirubin-albumin binding capacity, is based on this concept and therefore depends on the availability of albumin to keep bilirubin in the plasma and thus prevent its movement into tissues. If albumin is low or in order to keep more bilirubin in the plasma, albumin is sometimes given to infants especially before an exchange transfusion.
Lanzkowsky and Shende1 have outlined the investigations of jaundiced infants and the various forms of therapy of hyperbilirubinemia to reduce bilirubin or the toxicity of bilirubin. To prevent hyperbilirubinemia, early feedings, phénobarbital, phototherapy, and exchange transfusions are used today. Formerly, one waited 48 hours or longer before feedings were started in the neonatal period.24 We now start to feed babies by four hours of age. If the baby is ill and cannot tolerate oral feedings, the intravenous route is used. No one knows why jaundice is thus reduced; possibly there is increased motility, with more rapid elimination of meconium, and thus less bilirubin is absorbed.13
Such drugs as phénobarbital21,23,26 have been used by many investigators to prevent or treat hyperbilirubinemia. Various doses have been used. The recommended dose is 5 mg. every eight hours for babies weighing at least 2.5 kg. and 6 mg. /kg. every 24 hours for babies under 2.5 kg. It has been shown that this drug is safe and increases the conjugation of bilirubin by induction of microsomal enzymes. However, it has been demonstrated that phototherapy with blue fluorescent lights of 200-300 foot-candles produced bilirubins lower than those in infants receiving phénobarbital.27
Stern8 has discussed the control of hyperbilirubinemia in the newborn in the United States. He mentions phototherapy but states that the classic approach to hyperbilirubinemia in the newborn has been its control through the use of exchange transfusions. At the New York Hospital-Cornell Medical Center, the mortality related to exchange transfusions is less than 1 per cent; but at other hospitals it can be much higher,3·15,17 as many complications, problems, and hazards of exchange transfusions3 occur. These include cardiac arrhythmias, cooling of the baby, air embolus, umbilical sepsis, and technical difficulties.
Phototherapy has become very popular in many institutions today. Cremer28 was the first to propose this mode of therapy in England. Lucey29 has listed many other groups of English, South American, French, and Italian workers who have reported very favorable experiences with this method of treatment. The basis is the photo-oxidation of bilirubin to innocuous pigments. This reduces the bilirubin level and thus prevents kernicterus. In other words, the toxic bilirubin is altered.
At the present time, although there may be some difference, the general feeling concerning the use of phototherapy is as follows:13,30
1. Blue fluorescent light is the most effective source for lowering bilirubin levels.
2. Phototherapy is indicated for any newborn with an increased risk of developing jaundice or already jaundiced.
3. Repeated serum bilirubin levels should be obtained to monitor the infant's response to the therapy. The frequency of these determinations depends on the rise or fall of the levels.
4. Phototherapy of the neonate need not be continued more than a few days, since decomposition of the unconjugated bilirubin is rapid. Usually four days is adequate. A decline of 1 to 4 mg. in serum bilirubin can be expected in jaundiced nonhemolytic infants after eight to 12 hours of exposure to light.
5. The infant's temperature should be monitored regularly to avoid overheating.
6. The infant's eyes should be shielded with patches to protect the developing macula.
Gellis31 mentions the ocular hazards of phototherapy for hyperbilirubinemia. He points out that blindfolding of infants subjected to phototherapy is justified, although there are potential hazards of ocular occlusion. In kittens there is a critical period, but this has not been demonstrated in human beings. He again points out the need for eye patches, which ensure that corneal exposure or abrasion does not occur. There also has not been an increased infection rate when eye patches are used.
Gellis31,32 also mentions the possible occurrence of diarrhea, growth retardation, decreased neurologic response, and discoloration of the skin. Lucey33 feels that there is no higher incidence of anemia in infants who have received phototherapy.
We at Roosevelt Hospital use phototherapy routinely on all babies who develop "severe" jaundice (bilirubin levels over 15 mg./100 ml. of serum in full-term infants less than three days of age) in an effort to decrease the need for an exchange transfusion. Gellis34 recommends phototherapy only if the serum bilirubin reaches 20 mg. If a full-term infant is sick, Gellis would start phototherapy at 15 mg. /100 ml. If, in spite of phototherapy, the bilirubin level rises to 25 mg. /100 ml., he would perform an exchange transfusion. If the full-term infant is sick, he would exchange at 20 mg./100 ml.
Recently the management of idiopathic hyperbilirubinemia in the term infant was reviewed.9 Lewak believes that phototherapy is valuable in preventing unnecessary exchange transfusions. He thinks that each physician caring for newborns must develop a scheme similar to the one presented by Gellis.34 I again must emphasize that healthy term babies should be watched until the serum reaches a certain level (15 to 20 mg./100 ml.), and then phototherapy should be started. Lewak states9 that there has been unnecessary overexposure of many infants to light.
In a recent symposium, Dr. Gordon B. Avery,35 chairman of neonatology at the Children's Hospital National Medical Center in Washington, D.C., reviewed the potentially adverse effects of phototherapy and exchange transfusions as compared with the possible dangers of kernicterus. He concluded that the dangers of phototherapy were few and that many of the socalled potential dangers of phototherapy were unwarranted. Among these, the concern over albuminbilirubin binding and retarded head growth appears to be unwarranted, as does the concern over the toxicity of photodecomposition products. He did, however, state that real consideration must be given to loose stools, increased fluid requirements, and potential damage to the eyes, if not protected. He emphasized that hyperbilirubinemia is a symptom that always requires a differential diagnosis.
In Sweden, Bengtsson and Verneholt36 have compared 111 healthy full-term infants with no signs of isoimmunization who had neonatal hyperbilirubinemia with a maximum bilirubin value exceeding 20 mg./100 ml. and 115 infants who had no clinical jaundice. Follow-up examination was performed six and a half to 13 years after birth. Among the 111 hyperbilirubinemic children, two had athetosis, one of them with classic kernicterus. Four children had hearing loss. In the control group, only one had slight unilateral incoordination and no one had hearing loss. There was no difference in the two groups in IQ values or psychologic disturbances. The authors believe that the bilirubin value should not be allowed to go above 25 mg. /100 ml.
At New York Hospital, Dahms37 and his associates compared the bilirubin levels in 199 breast- and bottle-fed infants. They found no difference in total bilirubin concentration at 48, 72, and 96 hours of age. Also, the percentage of infants having serum bilirubin concentrations above 15 mg./100 ml. was the same in both breast- and bottle-fed infants. In spite of this, Gellis38 comments that many physicians continue to recommend discontinuation of breast feeding in cases of hyperbilirubinemia. Hyperbilirubinemia is attributed far too often to breast milk.
Brown and Boon39 have listed many references of hyperbilirubinemia in Chinese, Malayans, Greeks, Italians, African Negroes, Sephardic Jews, Indians, Bantus, and Thais. We at Roosevelt Hospital have reported that this increased incidence of hyperbilirubinemia also occurs not infrequently in infants of Japanese parents.40
We have confirmed the previous report suggesting that the incidence of clinical jaundice was statistically higher in a Japanese study group than in a control group.40 In both groups, only uncomplicated term infants were examined. As described in the previous report,40 the effects of the other known causes of hyperbilirubinemia - such as medication (including vitamin K), anesthesia, and blood incompatibilities - were excluded. The absence of a positive correlation between hyperbilirubinemia and serum glutamic pyruvic transaminase precludes hepatic parenchymal pathology as its cause. The influence of the type of feeding appears to be significant. After the exclusion of the influence of breast feeding, however, a significantly higher incidence of jaundice was noted in Japanese newborns than in the control group. G-6-P-D was not a major contributing factor as indicated in the case of hyperbilirubinemia in Chinese infants.39
Hyperbilirubinemia among Japanese infants does not appear to be limited to our own patients who reside in New York City. Yamauchi indicates that he and his associates have independently observed the same phenomenon among Japanese infants born in Japan.41 These findings may not exclude the possibility of external factors, such as geographic or dietary causes. This, however, appears unlikely.
In most cases, clinical jaundice was recognized on the third neonatal day (Figure 1).
The question of whether we should treat this type of hyperbilirubinemia in full-term infants is undetermined at present. However, Ose et al.42 reported that 30.6 per cent of their Japanese infants who required exchange transfusions had no known blood incompatibilities. Of these, 14 per cent showed evidence of brain damage. Other studies have reported a high incidence of kernicterus among blood-compatible Japanese infants after autopsy.43 In view of these reports, as well as two infants in our present group who underwent exchange transfusions for hyperbilirubinemia exceeding a total bilirubin concentration of 25 mg./100 ml. of serum, we have used phototherapy for all cases in which total bilirubin concentration exceeded 16 mg./100 ml. of serum before the third postnatal day without immediately detectable complications. The response of hyperbilirubinemia to phototherapy, measured by the reduction of serum total bilirubin concentration, has been prompt and satisfactory.
Figure 1. Serum bilirubin levels in untreated babies with moderate hyperbilirubinemia at Roosevelt Hospital.
In view of the current trend for early discharge of the obstetric patient and probable time of the peak concentration of serum bilirubin, it would seem important that the pediatrician take extra precautions if jaundice in offsprings of Japanese parents is present and pay special attention to the type of jaundice in any patient of Oriental origin. We suggest treating all of these infants with jaundice so as to prevent morbidity associated with brain damage.
1 . Lanzkowsky, P., and Shende, A. Physiologic and clinical considerations of blood disorders in low birth weight infants. Pediatric Annals 1: 1 (1972), 28.
2. Lanzkowsky, P. Hematologic disorders of infancy and childhood. I: Neonatal hematology. Pediatric Annals 3:2 (1974).
3. Grauaug, A. The management of jaundice in the newborn. Med. J. Aust. 2 (1972), 374.
4. Ackerman, B. P., Dyer, G. Y., and Leydorf. M. Hyperbilirubinemia in small premature infants. Pediatrics 45 (1970). 917.
5. Schmid, R. Hyperbilirubinemia. In Stanbury, J. B., Wyngarden, J. B., and Fredrickson, D. S. (eds). The Metabolic Basis of Inherited Disease, Second Edition. New York, Toronto, Sidney, London: McGraw-Hill, 1966, ch. 37.
6. Arias, I. M. The pathogenesis of physiologic jaundice of the newborn. A re-evaluation, bilirubin metabolism of the newborn. Bergsmo, D. (ed.). National Foundation Birth Defects, original article series, Volume 6. Baltimore: The Williams & Wilkins Company, 1970. p. 55.
7. Odell, G. P., Stavey, G. N. P., and Rosenberg, L A. Studies in kemicterus. 3: The saturation of serum protein with bilirubin during neonatal life and its relationship to brain damage at five years. J. Pediatr. 76 (1970), 12.
8. Stern, L. The control of hyperbilirubinemia in the newborn. Clin. Obstet. Gynecol. 14 (1971), 855
9. Lewak. N. Management of idiopathic hyperbilirubinemia in term infants: Community practices. Ped/africs 53 (1974), 471.
10. Thaler, M. N. Perinatal bilirubin metabolism. In Schulman, I. (ed.). Advances in Pediatrics, Volume 19. Chicago: Year Book Medical Publishers, 1972.
11. Van Praagh, R. Diagnosis of kemicterus in the neonatal period. Pediatrics 28 (1961), 870.
12. Culley, P.. et al. Sequelae of neonatal jaundice. Br. Med. J. 3 (1970), 383.
13. Harris, R. Jaundice. In Behrman, R. E. (ed.). Neonatahgy. St. Louis: C. V. Mosby Company. 1973, ch. 10.
14. Gartner, L, et al. Kemicterus: High incidence in premature infants with low serum bilirubin concentrations. Pediatrics 45 (1970). 906.
15. Lanzkowsky. P. Erythroblastosis fetalis. Pediatric Annals 3:2 (1974), 7.
16. Oski, F. S. Oxytocin and neonatal hyperbilirubinemia. Am. J. Dis. Child. 129 (1975), 1137.
17. Bauer, C. H.. and Miller. D. Bilirubin metabolism. Lecture to Allied Chemical Corporation, New York, NY., 1970.
18. Arias, I. M. Hepatic aspects of bilirubin metabolism. Ann. Rev. Med. 17 (1966), 257,
19. Levi. A. J., Gatmaitan, Z., and Arias, IM. Two hepatic cytoplasmic protein fractions, Y and Z, and their possible role in the hepatic uptake of bilirubin, sulfobromophthalein, and other anions. J. Clin. Invest. 48 (1969). 2156.
20. Arias, I. M.. et al. Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronyl transferase deficiency. Am. J. Med. 47 (1969), 365.
21. Halprin, T. F., et al. Prophylaxis of neonatal hyperbilirubinemia with phénobarbital. Obstet. Gynecol. 40 (1972), 85.
22. Hshia D. Y. Y. Inborn Errors of Metabolism. 1: Clinical Aspects, Second Edition. Chicago: Year Book Medical Publishers, 1966.
23. Odell. G. B. The dissociation of bilirubin from albumin and its clinical implications. J. Pediatr. 55 (1959). 268.
24. Wennberg, R P., Schwartz. R., and Sweet. A. Y Early versus delayed feedings of low birth weight infants: Effects on physiologic jaundice. J. Pediatr. 68 (1966), 860.
25. Yeung, C. Y., and Field. C. E. Phenobarbitone therapy in neonatal hyperbilirubinemia. Lancet 2 (1969), 135.
26. Sinniah. D., Tay, L K" and Dugdale. A. E. Phénobarbital i? neonatal jaundice. Arch. Dis. Child. 46(1971), 712.
27. Valdes. O. S., et al. Controlled clinical trial oi phénobarbital and/or light in reducing neonatal hyperbilirubinemia. J. Pediatr. 79 (1971). 1015.
28. Cremer, R. J., Perryman, P. W., and Richards, D. H. Influence of light on the hyperbilirubinaemia of infants. Lancet 2 (1958). 1094.
29. Lucey, J.. Ferreiro. M., and Hewitt, J. Prevention of hyperbilirubinemia of prematurity by phototherapy. Pediatrics 41 (1968), 1047.
30. Behrman. R. E., and Hsia, D. Y. Summary of a symposium on phototherapy for hyperbilirubinemia. J. Pediatr. 75 (1969). 718.
31. Gellis, S. S. Comments on phototherapy of jaundice in newborn infants. In Gellis, S. S. (ed.). Year Book of Pediatrics, 1973. Chicago: Year Book Medical Publishers, 1973.
32. Gellis. $. S. Comments on phototherapy and hyperbilirubinemia of the premature. In Gellis, S. S. (ed.). Year Book of Pediatrics, 1972. Chicago: Year Book Medical Publishers, 1972.
33. Gellis, S. S. Comments on the "bronze" body syndrome: Complication of phototherapy. In Gellis, S. S. (ed.). Year Book of Pediatrics, 1974. Chicago: Year Book Medical Publishers. 1974.
34. Gellis, S. S. Comments on management of idiopathic hyperbilirubinemia in term infants. In Gellis, S. S. (ed). Year Book of Pediatrics, 1975. Chicago: Year Book Medical Publishers. 1975, p. 32.
35. Avery, G. B. Potential harm of kemicterus said to offset risk of therapy. Pediatric News 9 (1975), 2.
36. Bengtsson, B.. and Vemeholt, J. A. Follow-up study of hyperbilirubinaemia in healthy, full-term infants without iso-immunization. Acta Pediatr. Scand. 63 (1974). 70.
37. Dahms, B. B., et al. Breast feeding and serum bilirubin values during the first 4 days of life. J. Pediatr. 83 (1973), 1049.
38. Gellis, S. S. Comments on breast feeding and serum bilirubin values during the first 4 days of life. In Gellis, S. S. (ed.). Year Book of Pediatrics, 1975. Chicago: Year Book Medical Publishers, 1975.
39. Brown, W. R.. and Boon, W. H. Hyperbilirubinemia and kemicterus in glucose-6-phosphate dehydrogenase deficient infants in Singapore. Pediatrics 41 (1968), 1055.
40. Horiguchi, T., and Bauer, C. H. Ethnic differences in neonatal jaundice: Comparison of Japanese and Caucasian newborn infants. Am. J. Obstet. Gynecol. 121 (1975). 71.
41. Yamauchi, Y., Okayama National Hospital, Japan. Personal communication.
42. Ose, T., et al. Follow-up study of exchange transfusion for hyperbilirubinemia in infants in Japan. Pediatrics 40 (1967), 196.
43. Sutow, W. W., Moloney. W. C. and Margóles. C. Kemicterus in Japanese infants. 1 : Clinical and serological data from 25 patients. Pediatrics 17 (1956). 349.
44. Maisels, M. J. Bilirubin: On understanding and influencing its metabolism in the newborn infant. Pediatr. Clin. North Am. 19 (1972). 447.
45. Odell, G. B., and Cohen. S. N. Albumin joining in the management of hyperbilirubinemia by exchange transfusion. Am. J. Dis. Child. 102 (1961). 699.
CAUSES OF INDIRECT HYPERBILIRUBINEMIA
CAUSES OF HYPERBILIRUBINEMIA UNRELATED TO A HEMOLYTIC PROCESS