European Journal of

Europ. J. Pediat. 125, 97--102 (1977)

Pediatrics 9 by Springer-Verlag 1977

Hepatic Enzymes, Their Induction and Usefulness in Predicting Maximal Serum Bilirubin Levels in Premature Newborn Infants H. Bartels I, A. Fenner 2., W. van der Merwe 3, S. Barbalatt 3, and J. Wolfsdorf 3 1Department of Pediatrics, University of Kiel, Fr6belstr. 15, D-2300 Kiel, Federal Republic of Germany 2Division of Neonatology, Medical School, Kronsforder Allee 71--73, D-2400 Ltibeck, Federal Republic of Germany 3Department of Pediatrics and Child Health, Godfrey Huggins School of Medicine, University of Rhodesia, Salisbury, Rhodesia

Abstract. Sixty-seven babies were utilized to (a) document the serum bilirubin

lowering effect and safety of a phenobarbitone and nikethamide combination in neonatal hyperbilirubinaemia of non-hemolytic origin; (b) determine whether birthweight a n d / o r SGOT, S G P T or S G G T activity on day one of life correlated with the maximum serum bilirubin level achieved; and (c) investigate the pattern of hepatic enzyme levels in serum under normal conditions and following drug induction. Results indicate a significantly lower serum bilirubin level in the treated group of babies. Birthweight and day one S G G T levels, and SGGT/birthweight ratio correlated well with the maximum serum bilirubin reached, the latter ratio being particularly useful in predicting the degree of hyperbilirubinaemia. Key words: Gamma-glutamyl transferase - Enzyme induction - Neonatal jaundice Combined phenobarbitone-nikethamide prophylaxis.

Introduction

Phenobarbitone lowers the serum bilirubin level of newborn infants by inducing hepatic microsomal enzymes (review: Ballowitz, 1973/74; Maisels, 1972). Nikethamide may have a similar action (La Cauza et al., 1965; Sereni et al., 1967) or, when combined with phenobarbitone, produce a considerable augmentation of this effect (Ertel et al., 1969; Gmyrek et al., 1972; Kintzel, 1973; Patriarca et al., ! 975). As hepatic enzyme activity is related to the ability of the liver to excrete bilirubin, the present study was designed (a) to document again the efficacy and safety of phenobarbitone plus nikethamide in the reduction of neonatal hyperbilirubinaemia; (b) to determine whether serum enzymes, estimated soon after *

Corresponding author

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birth, could be of value in predicting the s u b s e q u e n t m a x i m u m serum b i l i r u b i n level in low birth weight babies, there being no m e t h o d at present of achieving this; a n d (c) to investigate the p a t t e r n of hepatic enzyme serum levels u n d e r n o r m a l c o n d i t i o n s a n d 'following drug i n d u c t i o n . I n the S o u t h of Africa, where the study was carried out, there is a high rate of low-birthweight i n f a n t s (up to 1 5 - - 2 0 % in a Negro M a t e r n i t y H o s p i t a l population). T h u s the necessity to search for m e t h o d s to prevent, in a large n u m b e r of infants, d a n g e r o u s degrees of h y p e r b i l i r u b i n a e m i a is greater t h a n in E u r o p e a n or A m e r i c a n N e o n a t a l Services.

Methods Sixty-seven babies (fifteen were products of multiple pregnancies), birthweight K2500 g, were randomly selected at birth for study in two groupsl: A (control) and B (experimental). Those infants who were selected at birth, but at six hours of age were too ilt, or who had evidence of AB0 incompatibility, or who subsequently died during the study period, or whose therapy did not conform exactly to that of the study protocol, were excluded from the total data analysis. Forty-four babies were available for complete analysis; however, whenever possible, depending on the information required, all information available was utilized. All infants and their mothers were initially blood-group typed, infants were weighed, their total serum bilirubin (TSB) estimated (Bilirubinometer, American Optical Co.) on days 3--7 inclusive, and their serum glutamic oxalacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and serum gamma-glutamyl transferase (SGGT) estimated on days 1 (prior to commencement of therapy), 4 and 7. Group B (experimental) babies were given nikethamide 100 mg/kg/day orally in 6 divided doses from the age of 6 hours, for 4 days, plus phenobarbitone 10 mg/kg/day orally, in 2 divided doses, for 3 days. Group A (control) babies received no therapy. All babies were managed by the usual nursery routine. All infants were carefully observed clinically: the two physicians caring for the patients were asked to report aII babies who appeared ill to an experienced neonatologist (A. F.) while being unaware as to which patients were actually enrolled in the study. These patients were then reexamined and note was taken if symptoms such as vomiting, jitteriness or any other evidence of cerebral disorders were present. In addition, members of the research team (W. v. d. M., S.B. and A.F.) drew capillary or venous blood for the necessary laboratory tests daily from day 1--7 inclusive, day 2 being the only exception. This again afforded an opportunity for close clinical assessment. In order to try to obtain a way of predicting the maximum serum bilirubin (MSB) level which might be reached by an infant, correlations between the following were sought in the control group: (1) birth weight (BW) and MSB level (2) SGOT, SGPT and SGGT activity on day 1 and MSB level (3) the ratio of SGOT, SGPT or SGGT activity on day 1 over BW and MSB level.

Results T a b l e 1 d e m o n s t r a t e s the b i r t h weights, m e a n s a n d ranges, for each group. T h e r e is n o statistical difference b e t w e e n t h e m ( P > 0 . 3 ) . Initially four groups were contemplated with phototherapy being part of the therapeutic regimen in two of them. However, irradiance measurements of the phototherapy units, performed upon completion of the study, showed the lights to be totally ineffective due to their having been in constant use for several years (Wolfsdorf et al., 1975). Thus it appeared justified to consolidate the original four groups into two

Induction of Hepatic Enzymes and Bilirubin in Preterms

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Table 1. Birth weights (g) of untreated (Group A) and treated (Group B) infants a

n SD Range

Group A

Group B

22 1833 271 1300--2350

22 1924 394 1225--2475

a There is no statistically significant difference (P>0.3) between the two groups

E 16.

0 0

14

E 12 10 2

8

'~ E 2 m

6 4 2

o

II p~

3

4 5 days of life

6

7

.05

.001

.001

.001

.001

Fig. 1. Course of total serum bilirubin levels during the first week of life. Group A: hatched bars. Group B: open bars. Values are given as means (g) • 1 SD

F i g u r e 1 indicates s e r u m b i l i r u b i n levels f r o m d a y 3 and gives the statistical analyses between the groups. F o r g r o u p A (control) infants, m e a n m a x i m u m s e r u m b i l i r u b i n levels were achieved by d a y 5, while g r o u p B's ( e x p e r i m e n t a l ) levels s h o w e d a c o n s t a n t decline f r o m d a y 3 o n w a r d . M e a n b i l i r u b i n values b e t w e e n the g r o u p s were significantly different f r o m d a y 3 o n w a r d . F u r t h e r , in g r o u p A, 9 T S B values were f o u n d between 12 rag% a n d 18 mg%, while in g r o u p B, only one such level o c c u r e d (12.7 mg%). F r o m d a y 4 the difference b e t w e e n the m e a n s was 4 rag% or more. Clinical s y m p t o m a t o l o g y did n o t a p p e a r to differ f r o m t h a t o b s e r v e d in a n e o n a t a l nursery. P a r t i c u l a r a t t e n t i o n was p a i d to such s y m p t o m s as irritability, jitteriness, o r o t h e r m a n ifestation o f c e r e b r a l disorders. N o significant difference in the activities of S G O T , S G P T a n d S G G T c o u l d be e s t a b l i s h e d between g r o u p A a n d g r o u p B. In the c o n t r o l g r o u p , when B W was c o m p a r e d to M S B levels, a significant c o r r e l a t i o n was f o u n d (y = 2 . 3 5 - - 6 x ; n = 23; r = 0.4463; P < 0 . 0 5 ) . F i g u r e 2 depicts the significant c o r r e l a t i o n ( P < 0 . 0 5 ) f o u n d between d a y 1 S G G T a n d M S B levels, no such c o r r e l a t i o n h a v i n g been f o u n d for the o t h e r h e p a t i c enzymes estimated.

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E o o

a~ 20 E y= 6.86'10gx-1,66

.c_

15

n= 23

2

r =*0,/.18 p..:.05

E 10 l/1

E 5 E E 0

20

30

50

100

200 300

GGT activity day 1 (u/t) Fig. 2. Correlation between maximum bilirubin levels in Group A individuals (controls) and initial S G G T activities. Note log. scale on abscissa

E o o O3

20 y= 9,63x+ 1,25

c ..Q

n= 23 r =+0.526

2

o ~

p< ,01

x~ 10 E 2 E

5

x

E

0

r

0,5

110

1,5

[0g GGT activity day l(u/I )//birth weight (kg) Fig. 3. Correlation between maximum bilirubin levels of Group A individuals (controls) and the ratio of log. SGGT activity (day 1) to birth weight. Note that in all individuals whose log. S G G T / b i r t h Weight ratio was < 0 . 9 the maximum bilirubin remained under 12 mg/100 ml. In all but two infants with log. S G G T / B W r a t i o s > l . 1 the maximum bilirubin levels were in excess of 12 mg/100 ml

Induction of Hepatic Enzymes and Bilirubin in Preterms

101

E

0 (:3

O1

20

E y = 14,26x - 3,14

>

n:16

r

r = .-0,694

n

p~.01

25 E 2

10

E

5

X tg

E

0

0,5

1,0

1,5

log GGT activity day 1(u/[)/birth weight ( kg ) Fig. 4. Same plot as in Figure 3 with twins and triplets excluded. Note that correlation is closer: all infants with log. SGGT/BW ratios > 1.1 now fall into the high-bilirubin group (> 12 rag/ 100 ml)

Further, when the ratio of S G G T to BW against MSB levels was calculated (Fig. 3), the significance of the correlation increased ( P < 0.01), no infant with a S G G T / B W ratio of < 0.9 on the first day of life achieving a serum bilirubin level greater than 12 rag%. Conversely, all but two infants presenting with a S G G T / BW ratio greater than 1.1 on day 1, eventually reached MSB levels greater than 12rag%. If one excludes the seven products of multiple pregnancies, this correlation is further enhanced (Fig. 4).

Discussion and Conclusions First, the above study confirms previous reports by G m y r e k et al. (1972), Kintzel (1973), and Patriarca et al. (1975), that a combination of phenobarbitone and nikethamide significantly reduces serum bilirubin levels in low birth weight babies from the fourth day of life without any obvious detrimental effects. Second, S G G T levels provide a general idea as to the expected degree of hyperbilirubinaemia. Possibly, the amount of S G G T activity at birth could be considered a parameter of the degree of "hepatic immaturity". This view receives support from two known facts: 1) S G G T levels during the neonatal period are significantly higher than in later life; 2) within the neonatal period, S G G T values are higher in preterm, as compared with term, infants (Barrels and v, Kleist, 1971; Sitzmann et al., 1971). When one combines BW and d a y - o n e - S G G T levels, the accuracy of predicting MSB is improved, even more so when singleton births

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are analysed on their own. This correlation between the M S B level achieved and d a y - o n e levels o f S G G T activity has not, as far as can be assessed, been reported previously. However, as the n u m b e r o f patients studied was fairly small, this requires further investigation. Hyperbilirubinaemia during the neonatal period remains a problem, particularly in premature infants. T h o u g h there are a variety of ways of dealing with the process once significant levels are reached, no data, other t h a n b r o a d generalisations, are available which will allow one to predict the level to which the serum bilirubin will rise in a given infant. If this information was available, it would obviously allow for the identification of an at-risk group and for early treatment to be instituted, particularly where early discharge policies are routine (Singer and Wolfsdorf, 1975). This study indicates the possibility that the S G G T / B W ratio m a y have a predictive value.

References Ballowitz, L.: Hyperbilirubingmie bei Neu- und Frtihgeborenen. Pgdiat. Prax. 13, 213--230 (1973/74) Bartels, H., v. Kleist, D.: Der diagnostische Wert der Aktivit~itsbestimmung der GammaGlutamyltranspeptidase im Serum. Mschr. Kinderheilk. 119, 334--336 (1971) Ertel, I. J., Newton, W. A., Jr.: Therapy in congenital hyperbilirubinemia: Phenobarbital and diethylnicotinamide. Pediatrics 44, 43~48 (1969) Gmyrek, D., Weh, L., Kalz, M., Bunke, H., Cario, W. R., Lindenau, E., Neumann, R., Pietsch, I., ScigaUa, P., Sima, K., Syllm-Rapoport, I.: Zur medikament6sen Prophylaxe der Neugeborenen-Hyperbilirubin~imie. 5. Mitteilung: Wirkungssteigerung durch Kombination der Induktoren Phenobarbital und Nikethamid. Dtsch. Ges.-Wesen. 27, 2221--2227 (1972) Kintzel, H.-W.: Prophylaxe des Morbus heamolyticus neonatorum und transitorischer Hyperbilirubin~imien von Neugeborenen durch eine Enzyminduktoren-Kombination. Blut 26, 297--302 (1973) La Cauza, C., Pinca, A., Varone, D.: Osservazioni cliniche sull, azione della dietilamide dell' acido nicotinico (Coramina) negli itteri neonatali. Minerva pediat. 17, 1966--1972 (1965) Maisels, M. J.: Bilirubin. On understanding and influencing its metabolism in the newborn infant. Pediat. Clin. N. Amer. 19, 447--501 (1972) Patriarca, P. L., Peracino, A., Mareovina, S., Zecca, G.: Profilassi dell' iperbilirubinemia neonatale con induttori enzimatici. Efficaeia dell' associazione farmacologiea fenobarbital + niketamide. Minerva pediat. 27, 865--873 (1975) Sereni, F., Perletti, L., Marini, A.: Influence of diethylnicotinamide on the concentration of serum bilirubin of newborn infants. Pediatrics 40, 446--449 (1967) Singer, B., Wolfsdorf, J.: Early discharge of infants of low birth weight: A prospective study. Brit. Med. J. 19751, 362--364 Sitzmann, F. C., Kellerer, K., Bierschenk, M.: Das Verhalten der Gamma-Glutamyl-Transpeptidase im Serum gesunder Kinder. Arch. Kinderheilk. 183, 276--284 (1971) Wolfsdorf, J., Fenner, A., Mann, M. D.: The importance of calibrating phototherapy units. S. Afr. Med. J. 49, 691--692 (1975) Received October 25, 1976