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Normal serum γ-glutamyl-transpeptidase activity identifies groups of infants with idiopathic cholestasis with poor prognosis
CLINICAL AND LABORATORY OBSERVATIONS
Normal serum -y-glutamyl-transpeptidase activity identifies groups of infants with idiopathic cholestasis with poor prognosis G i u s e p p e Maggiore, M.D., Olivier Bernard, M.D., Caroline A. Riely, M.D., Michelle Hadchouel, M.D., Alain Lemonnier, Pharm.D, a n d Daniel Alagille, M.D. From the D~partement de P~diatrie, Unit~de Recherche d'H~patologie P~diatrique (INSERM U 56), and Laboratoire de Biochimie, H6pital de Bic~tre, France
It has become clear in the past few years that intrahepatic cholestasis can be categorized according to various causes and outcome. ',2 To plan for liver transplantation before onset of severe liver disease, early identification of those children at risk is necessary. We report that a simple assay for serum 3,-glutamyl-transPeptidase is a useful adjunct in defining a group of infants with cholestasis with poor prognosis. METHODS AND RESULTS From July 1, 1981, to January 1, 1985, serum 3,GT activity was assayed at the time of diagnostic investigation at Bic&re Hospital in 186 infants with cholestatic iaundice and normal prothrombin time, age d 12 months or younger, who were observed for at least 1 year or until death. In 157 infants, cholestasis could be classified into one of the known categories (Table 1), and serum 3,GT activity was elevated in all of them except one neonate with posthem0lytic conjugated hyperbilirubinemia, in whom jaundice cleared within a few months. In the 29 others, with cholestasis of unknown or!gin, the results of serum -yGT studies allowed separation into two groups (Table II): In group 1, 17 infants had high serum 3,GT activity; in all but one child in this group, the jaundice resolved and the results of clinical and laboratory investigations (including serum bilirubin, "rGT, alkaline phosphatase, and transaminase activity) were normal at the last examination, 12 to 42 months later. Fol!ow-up liver bioPsY tissue from one child at age 16 months showed moderate portal fibrosis and disappearance of previous lobular and ductal lesions. In only one child did jaundice progress, with pruritus, hard hepatomegaly, and progression of lobular and portal fibrosis on a repeat biopsy sPecimen at age 3 years. Submitted for publication Oct. 29, 1986;accepted March 10, 1987. Reprint requests: G. Maggiore, M.D. Clinica Pediatrica, IRCC S Policlinico, San Matteo, 27100 Pavia, Italy.
T a b l e I. Serum 3,-glutamyl-transpeptidase activity in 157 infants with idiopathic cholestasis
Diagnosis Biliary atresia Other extrahepatic obstructionst Syndromic paucity of interlobular bile ducts arAntitrypsin deficiency Other known intrahepatic causes:~
Serum "yGT' (IU/L)
No. of patients
Mean
113 10
660 665
l 18-2000 108-2700
14
772
207-1830
6 14
658 366
120-1410 17-1020
Range
*Normal range 5 to 35 1U/L. tBile ductlithiasis,four;choledochalcyst,three;spontaneousperforationof bile ducts, choledochalstenosis,gallbladderhydropsrelated to septicemia, one each. ~:Neonatalhepatitis,caused by cytomegalovirus,four; parenteralnutrition, three;sclerosingcholangitis,two;hypopituitarism,liverhemangioma,cystic fibrosis, nonsyndromicpaucity of interlobularbile ducts, posthemolytic conjugatedhyperbilirubinemia,one each.
3,GT
3~-Glutamyl-transpeptidase
]
In all 12 children in group 2, serum 3,GT values were normal (<35 IU/L); jaundice or pruritus, and hepatomegaly or hepatosplenomegaly were always present at followup. Six children in this group died of liver failure between 13 and 58 months of age; repeat liver biopsy tissue from five others showed progression of fibrosis; and one child with ascites and liver failure underwent successful liver transp!antation. This group of infants with cholestasis, normal serum TGT activity, and poor prognosis was further characterized by the parents being related in six instances, and six infants had a sibling with a similar disease (five with related parents). Initial histologic studies of the liver showed minimal or moderate portal and lobular 251
25Z
Clinical and laboratory observations
The Journal of Pediatrics August 1987
Table II. Biochemical data for 29 infants with idiopathic cholestatic jaundice
Age (too) Group 1 Mean Range Group 2 Mean Range
3,GT activity (• normal)
Total bllirubin (u,mol/L')
Alkaline phosphatase activity (• normal)
Alanine aminotransferase activity (SGPT) (• normal)
2 1-11
6.5 2.1-13.7
126 58-212
1.2 Normal-2
2 Normal 5.3
6 1-12
Normal
181 41-360
2.1 Normal-5t
7.2 1.6-15
Group 1 included17 childrenwithincreased3'GTactivity;at follow-up,prognosiswas goodfor 16. Group 2 included12 childrenwith normal3"GTactivity;at follow-up,prognosiswas poor for all. *ToConvertto mg/dL, dividedby I7.1 tlncluesthree patientswith rickets. fibrosis, most often giant cell transformation and pseudoacinar formation of the hepatocytes and the presence of normal interlobular bile ducts, whereas in group 1, giant cell transformation was also present but in several cases was associated with bile ducts lesions in the form of ductal proliferation or bile duct cell necrosis. In children in group 2, serum 7GT activity remained normal throughout the follow-up period in all except one, in whom a transitory rise was associated with intrahepatic lithiasis, which cleared spontaneously. DISCUSSION 7-Glutamyl-transpeptidase is an amino acid transport enzyme present in different fetal and adult tissues of rodents and humans. In neonatal rat liver, histologically demonstrable 7GT activity rapidly declines in the postpartum period, and by the seventh day is virtually restricted to bile duct epithelium2 Moreover, in experimental bile duct injury in the rat, increases in serum 7GT activity strongly correlate with histologic evidence of bile duct cell necrosis, supporting the use of serum "yGT as a specific marker of bile duct lesions in the rat) Since 1960, serum 3,GT assay has been used as a potential diagnostic aid for liver disorders, but the clinical relevance of increased activitY of the enzyme remains controversial. In adult patients, the serum 3'GT activity, because of its low specificity compared with that of other standard liver function tests, is considered of little value in the differential diagnosis of hepatobiliary disease2 Our results confirm the lack of specificity of raised values of 3,GT in infants with cholestasis, especially with respect to the diagnosis of biliary atresia.~ Intrahepatic cholestasis with normal "rGT activity is relatively rare in adults, and is mainly associated with pregnancy, and drug-induced7 and benign recurrent eho-
lestasis. Those conditions are self-limiting; the histologic lesions are mainly lobular, and bile duct epithelium is spared. In this population of infants with intrahepatie cholestasis of unknown origin, however, our results suggest that persistently normal serum 3,GT activity helps identify a group with severe progressive liver disease, which may correspond to a hereditary disorder akin to Byler disease? Such a finding might allow early identification of those patients requiring liver transplantation, before obvious signs of liver failure are present. The results further suggest that this group of diseases is not related to bile duct damage but to a hepatocytic or canalicular disorder. In infants with eholestatic jaundice of unknown origin, raised serum 3,GT activity is most often, but not always, associated with a good prognosis, whereas normal serum 3,GT activity may be considered a sign of a poor prognosis.
REFERENCES 1. Alagille D. Management of chronic cholestasis in childhood. Semin Liver dis 1985;5:254. 2. Balistreri WF. Neonatal cholestasis. J PEDIATR 1985;106:171. 3. Iannacone PM, Koizumi J. Pattern and rate of disappearance of gamma-glutamyl-transpeptidase activity in fetal and neonatal rat liver. J Histochem Cytochem 1983;31:1312. 4. Leonard TB, Neptun DA, Popp JA. Serum gamma-glutamyltransferase as a specific indicator of bile duct lesions in rat liver. Am J Pathol 1984;116:262. 5. Penn R, Worthington DJ. Is serum 3,-glutamyltransferasea misleading test? Br Med J 1983;286:531. 6. Wright K, Christie DL. Use of 7-glutamyltransferase in the diagnosis of biliary atresia. Am J Dis Child 1981;135:134. 7. Haber J, Hubens H. Cholestatic jaundice after triacetyloleandomyci!a.Acta Gastroenterol Belg 1980;43:475. 8. Clayton R J, lber FL, Ruebner BH, McKusick VA. Byler diseases: fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child 1969;117:112.
Normal serum -y-glutamyl-transpeptidase activity identifies groups of infants with idiopathic cholestasis with poor prognosis G i u s e p p e Maggiore, M.D., Olivier Bernard, M.D., Caroline A. Riely, M.D., Michelle Hadchouel, M.D., Alain Lemonnier, Pharm.D, a n d Daniel Alagille, M.D. From the D~partement de P~diatrie, Unit~de Recherche d'H~patologie P~diatrique (INSERM U 56), and Laboratoire de Biochimie, H6pital de Bic~tre, France
It has become clear in the past few years that intrahepatic cholestasis can be categorized according to various causes and outcome. ',2 To plan for liver transplantation before onset of severe liver disease, early identification of those children at risk is necessary. We report that a simple assay for serum 3,-glutamyl-transPeptidase is a useful adjunct in defining a group of infants with cholestasis with poor prognosis. METHODS AND RESULTS From July 1, 1981, to January 1, 1985, serum 3,GT activity was assayed at the time of diagnostic investigation at Bic&re Hospital in 186 infants with cholestatic iaundice and normal prothrombin time, age d 12 months or younger, who were observed for at least 1 year or until death. In 157 infants, cholestasis could be classified into one of the known categories (Table 1), and serum 3,GT activity was elevated in all of them except one neonate with posthem0lytic conjugated hyperbilirubinemia, in whom jaundice cleared within a few months. In the 29 others, with cholestasis of unknown or!gin, the results of serum -yGT studies allowed separation into two groups (Table II): In group 1, 17 infants had high serum 3,GT activity; in all but one child in this group, the jaundice resolved and the results of clinical and laboratory investigations (including serum bilirubin, "rGT, alkaline phosphatase, and transaminase activity) were normal at the last examination, 12 to 42 months later. Fol!ow-up liver bioPsY tissue from one child at age 16 months showed moderate portal fibrosis and disappearance of previous lobular and ductal lesions. In only one child did jaundice progress, with pruritus, hard hepatomegaly, and progression of lobular and portal fibrosis on a repeat biopsy sPecimen at age 3 years. Submitted for publication Oct. 29, 1986;accepted March 10, 1987. Reprint requests: G. Maggiore, M.D. Clinica Pediatrica, IRCC S Policlinico, San Matteo, 27100 Pavia, Italy.
T a b l e I. Serum 3,-glutamyl-transpeptidase activity in 157 infants with idiopathic cholestasis
Diagnosis Biliary atresia Other extrahepatic obstructionst Syndromic paucity of interlobular bile ducts arAntitrypsin deficiency Other known intrahepatic causes:~
Serum "yGT' (IU/L)
No. of patients
Mean
113 10
660 665
l 18-2000 108-2700
14
772
207-1830
6 14
658 366
120-1410 17-1020
Range
*Normal range 5 to 35 1U/L. tBile ductlithiasis,four;choledochalcyst,three;spontaneousperforationof bile ducts, choledochalstenosis,gallbladderhydropsrelated to septicemia, one each. ~:Neonatalhepatitis,caused by cytomegalovirus,four; parenteralnutrition, three;sclerosingcholangitis,two;hypopituitarism,liverhemangioma,cystic fibrosis, nonsyndromicpaucity of interlobularbile ducts, posthemolytic conjugatedhyperbilirubinemia,one each.
3,GT
3~-Glutamyl-transpeptidase
]
In all 12 children in group 2, serum 3,GT values were normal (<35 IU/L); jaundice or pruritus, and hepatomegaly or hepatosplenomegaly were always present at followup. Six children in this group died of liver failure between 13 and 58 months of age; repeat liver biopsy tissue from five others showed progression of fibrosis; and one child with ascites and liver failure underwent successful liver transp!antation. This group of infants with cholestasis, normal serum TGT activity, and poor prognosis was further characterized by the parents being related in six instances, and six infants had a sibling with a similar disease (five with related parents). Initial histologic studies of the liver showed minimal or moderate portal and lobular 251
25Z
Clinical and laboratory observations
The Journal of Pediatrics August 1987
Table II. Biochemical data for 29 infants with idiopathic cholestatic jaundice
Age (too) Group 1 Mean Range Group 2 Mean Range
3,GT activity (• normal)
Total bllirubin (u,mol/L')
Alkaline phosphatase activity (• normal)
Alanine aminotransferase activity (SGPT) (• normal)
2 1-11
6.5 2.1-13.7
126 58-212
1.2 Normal-2
2 Normal 5.3
6 1-12
Normal
181 41-360
2.1 Normal-5t
7.2 1.6-15
Group 1 included17 childrenwithincreased3'GTactivity;at follow-up,prognosiswas goodfor 16. Group 2 included12 childrenwith normal3"GTactivity;at follow-up,prognosiswas poor for all. *ToConvertto mg/dL, dividedby I7.1 tlncluesthree patientswith rickets. fibrosis, most often giant cell transformation and pseudoacinar formation of the hepatocytes and the presence of normal interlobular bile ducts, whereas in group 1, giant cell transformation was also present but in several cases was associated with bile ducts lesions in the form of ductal proliferation or bile duct cell necrosis. In children in group 2, serum 7GT activity remained normal throughout the follow-up period in all except one, in whom a transitory rise was associated with intrahepatic lithiasis, which cleared spontaneously. DISCUSSION 7-Glutamyl-transpeptidase is an amino acid transport enzyme present in different fetal and adult tissues of rodents and humans. In neonatal rat liver, histologically demonstrable 7GT activity rapidly declines in the postpartum period, and by the seventh day is virtually restricted to bile duct epithelium2 Moreover, in experimental bile duct injury in the rat, increases in serum 7GT activity strongly correlate with histologic evidence of bile duct cell necrosis, supporting the use of serum "yGT as a specific marker of bile duct lesions in the rat) Since 1960, serum 3,GT assay has been used as a potential diagnostic aid for liver disorders, but the clinical relevance of increased activitY of the enzyme remains controversial. In adult patients, the serum 3'GT activity, because of its low specificity compared with that of other standard liver function tests, is considered of little value in the differential diagnosis of hepatobiliary disease2 Our results confirm the lack of specificity of raised values of 3,GT in infants with cholestasis, especially with respect to the diagnosis of biliary atresia.~ Intrahepatic cholestasis with normal "rGT activity is relatively rare in adults, and is mainly associated with pregnancy, and drug-induced7 and benign recurrent eho-
lestasis. Those conditions are self-limiting; the histologic lesions are mainly lobular, and bile duct epithelium is spared. In this population of infants with intrahepatie cholestasis of unknown origin, however, our results suggest that persistently normal serum 3,GT activity helps identify a group with severe progressive liver disease, which may correspond to a hereditary disorder akin to Byler disease? Such a finding might allow early identification of those patients requiring liver transplantation, before obvious signs of liver failure are present. The results further suggest that this group of diseases is not related to bile duct damage but to a hepatocytic or canalicular disorder. In infants with eholestatic jaundice of unknown origin, raised serum 3,GT activity is most often, but not always, associated with a good prognosis, whereas normal serum 3,GT activity may be considered a sign of a poor prognosis.
REFERENCES 1. Alagille D. Management of chronic cholestasis in childhood. Semin Liver dis 1985;5:254. 2. Balistreri WF. Neonatal cholestasis. J PEDIATR 1985;106:171. 3. Iannacone PM, Koizumi J. Pattern and rate of disappearance of gamma-glutamyl-transpeptidase activity in fetal and neonatal rat liver. J Histochem Cytochem 1983;31:1312. 4. Leonard TB, Neptun DA, Popp JA. Serum gamma-glutamyltransferase as a specific indicator of bile duct lesions in rat liver. Am J Pathol 1984;116:262. 5. Penn R, Worthington DJ. Is serum 3,-glutamyltransferasea misleading test? Br Med J 1983;286:531. 6. Wright K, Christie DL. Use of 7-glutamyltransferase in the diagnosis of biliary atresia. Am J Dis Child 1981;135:134. 7. Haber J, Hubens H. Cholestatic jaundice after triacetyloleandomyci!a.Acta Gastroenterol Belg 1980;43:475. 8. Clayton R J, lber FL, Ruebner BH, McKusick VA. Byler diseases: fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child 1969;117:112.