Relationship between serum bilirubin and coagulation test results in 1-month-old infants
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《美国医学杂志》
Baskent University, Faculty of Medicine, Department of Pediatrics, Turkey
Abstract
OBJECTIVE: Although the connection between cholestasis and conjugated hyperbilirubinemia is well known, mild hepatic dysfunction or cholestasis may also be associated with unconjugated hyperbilirubinemia in some infants with prolonged jaundice. The aim of this study was to investigate the relationship between serum bilirubin levels and alanine aminotransferase levels, aspartate aminotransferase levels, prothrombin time, activated partial thromboplastin time, and international normalization ratio findings in a group of infants. METHODS: The study included 77 healthy, term, breast-fed infants with jaundice and 56 age-matched, healthy, term, non-jaundiced controls. The 133 babies were divided into three subgroups according to their total bilirubin levels [group I (controls) <50 μmol/L, group II = 50-100 μmol/L, and group III >100 μmol/L, and the findings for the noted parameters were compared]. RESULTS: The mean conjugated bilirubin level was significantly higher, and the mean activated partial thromboplastin time significantly longer in group III than in group I. A significant positive correlation was found between bilirubin levels and PT and APTT results. CONCLUSION: Clinical vitamin K deficiency appeared unlikely to develop in this group of infants with prolonged unconjugated hyperbilirubinemia. However, a significant positive correlation between bilirubin levels and PT and APTT suggest that a higher bilirubin load to the liver may cause some degree of vitamin K deficiency due to mild cholestasis. The importance of this finding, and the possible benefits of vitamin K supplementation in 1-month-old breast-fed infants with bilirubin levels higher than 100 μmol/L require further investigation.
Keywords: Cholestasis; Coagulation; Vitamin K deficiency; Prolonged unconjugated hyperbilirubinemia
Prolonged jaundice is commonly described as hyperbilirubinemia persisting beyond the second week of life. This condition itself is not necessarily harmful; however, it can signify serious underlying pathologies such as hypothyroidism and several metabolic, hematologic, and liver diseases.[1] Although the connection between cholestasis and conjugated hyperbilirubinemia is well known, signs of mild hepatic dysfunction or cholestasis have also been observed in association with unconjugated hyperbilirubinemia in some infants with prolonged jaundice.[2],[3],[4] Mild cholestasis may impair gastrointestinal absorption of fat-soluble vitamin K, and vitamin K deficiency may develop in these cases. The aim of this study was to investigate the relationship between prolonged unconjugated hyperbilirubinemia and findings from liver function and coagulation testing in very young infants.
Materials and methods
This study included 77 (47 males and 30 females) healthy, term (gestational age 37 weeks), breast-fed Turkish infants who were admitted to our clinic at the age of 28-33 days with the complaint of jaundice. The mean birth weight of the infants was 3401.23±416.37 g. Fifty-six non-jaundiced, age-matched, healthy, term, breast-fed infants admitting to our well-baby nursery were examined as controls. All the infants had received 1 mg of vitamin K intramuscularly soon after birth. Informed consent was obtained from the subjects′ parents.
A pediatrician clinically examined all the jaundiced infants, and no other abnormalities were detected. Blood samples were obtained by venepuncture from all infants to determine serum levels of bilirubin (total and conjugated), alanine aminotransferase (ALT), aspartate aminotransferase (AST), as well as prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalization ratio (INR). Glucose-6-phosphate dehydrogenase (G6PD) level was also determined in the jaundiced infants and found normal. None of the infants had early hemolytic jaundice due to blood group incompatibility.
The infants were divided into three subgroups according to their total bilirubin levels: group I (controls) < 50 μmol/L, group II = 50-100 μmol/L, and group III> 100 μmol/L. Student′s t test, Post Hoc tests, and Pearson correlation tests were used for statistical analysis of the results. This study was approved by our hospital′s ethics committee.
Results
There were no significant differences among the groups regarding gestational age, birth weight and actual body weight. The laboratory data are shown in table1. None of the infants with prolonged jaundice had conjugated hyperbilirubinemia. The ALT, AST, PT, and INR results were similar in the three groups. The mean conjugated bilirubin level was significantly higher (p=0.017), and the mean APTT was significantly longer (p=0.048) in group III compared to group I. However, there were no statistical differences in conjugated bilirubin and APTT levels of group I when compared to the findings in group II. Similarly those levels did not differ between group II and III. A significant positive correlation was found between total bilirubin levels and PT results (p = 0.046). A similar correlation was also present between bilirubin levels and APTT (p = 0.009).
Discussion
The late form of vitamin K deficiency bleeding (VKDB) presents between 2 and 8 weeks of life. Due to the low vitamin K content of human milk, and to delayed colonization of the gut, this condition is seen almost exclusively in breast-fed infants.[5],[6] However, the majority of these infants exhibit no coagulation problems, and it is likely that other elements further decrease the vitamin K-dependent factors, causing bleeding.[7] Malabsorption of vitamin K due to underlying liver disease is the most common of these additional factors.[7],[8] In one study, 42% of 131 cases of late VKDB were associated with cholestatic liver disease.[9]
Prolonged jaundice with unconjugated hyperbilirubinemia is common in breast-fed infants. The question is whether prolonged unconjugated hyperbilirubinemia may produce some of the effects associated with cholestasis. In their investigation of breast-fed infants with prolonged unconjugated hyperbilirubinemia, Tazawa et al[4] found that ALT and AST values were normal, whereas alkaline phosphatase (ALP), gamma-glutamyltranspeptidase (GGT), and bile acid levels were elevated. These findings suggest that hepatic cell damage is unlikely, and that hepatic dysfunction related to mild cholestasis is probably what occurs in these cases. The authors also found a relationship between increased bile acid loading in the liver and elevated levels of serum unconjugated bilirubin in jaundiced breast-fed infants. It is known that bile acids and bilirubin compete with each other as they are being broken down in the liver, and that the level of biliary secretion of bilirubin is dependent on bile acid secretion.[2],[4] This reveals how cholestasis may be closely related to unconjugated hyperbilirubinemia.
In general, although few patients with prolonged unconjugated hyperbilirubinemia show apparent symptoms of cholestasis, some degree of vitamin K deficiency may occur due to malabsorption. Both the low vitamin K content of breast milk and mild cholestasis associated with prolonged unconjugated hyperbilirubinemia may predispose the infant to late VKDB. In the present the authors study, we investigated whether this mild cholestasis may affect coagulation parameters and cause some degree of vitamin K deficiency. The fact that there were no significant differences among the three groups′ AST and ALT levels indicate that elevated bilirubin levels do not imply hepatic cell damage. However, conjugated bilirubin levels were significantly higher in group III infants than in the controls, and this may suggest some degree of cholestasis in the former. The present study interpretation is limited by the fact that we did not evaluate ALP, GGT, and bile acid levels, all of which are important markers of cholestasis.
Clinically, a prolonged PT and INR results are important in the diagnosis of vitamin K deficiency.[5],[10] Although APTT was significantly longer in group III than in the controls, the three groups′ PT, APTT and INR findings were within the normal ranges. This finding suggests that clinical vitamin K deficiency is unlikely to develop in this group of infants with prolonged unconjugated hyperbilirubinemia. However, a significant positive correlation between bilirubin levels and PT and APTT suggest that a higher bilirubin load to the liver may cause some degree of vitamin K deficiency due to mild cholestasis. The importance of this finding, and the possible benefits of vitamin K supplementation in 1-month-old breast-fed infants with bilirubin levels higher than 100 mmol/L require further investigation. The levels of vitamin K, proteins induced by vitamin K antagonist, and vitamin K-dependent factors all of which are important markers of biochemical vitamin K deficiency need to be evaluated in a larger group of infants with higher unconjugated bilirubin levels in a further study.
References
1. Hannam S, McDonnell M, Rennie JM. Investigation of prolonged neonatal jaundice. Acta Pediatr 2000; 89: 694-697.
2. Tazawa Y, Yamada M, Nakagawa M, Konno T, Tada K. Serum bile acids and their conjugates in breast-fed infants with prolonged jaundice. Eur J Pediatr 1985; 144: 37-40.
3. Yamada M, Tazawa Y, Nakagawa M et al. Alterations of serum bile acid profile in breast-fed infants with prolonged jaundice. J Pediatr Gastroenterol Nutr 1985; 4: 741-745.
4. Tazawa Y, Abukawa D, Watabe M, Nakagawa M, Yamada M. Abnormal results of biochemical liver function tests in breast-fed infants with prolonged indirect hyperbilirubinemia. Eur J Pediatr 1991; 150 : 310-313.
5. Greer FR. Vitamin K status of lactating mothers and their infants. Acta Pediatr Suppl 1999; 430 : 95-103.
6. Motohara K, Matsukuro M, Matsuda I et al. Severe vitamin K deficiency in breast-fed infants. J Pediatr 1984; 105: 943-945.
7. Sutor AH, von Kries R, Cornelissen EAM, McNinch AW, Andrew M. Vitamin K deficiency bleeding (VKDB) in infancy. Thromb Haemost 1999; 81 : 456-461.
8. Zipursky A. Prevention of vitamin K deficiency bleeding in newborns. Br J Haematol 1999; 104: 430-437.
9. Loughnan PM, McDougall PN. Epidemiology of late onset haemorrhagic disease: a pooled data analysis. J Pediatr Child Health 1993; 29 : 177-181.
10. Andrew M. The relevance of developmental hemostasis to hemorrhagic disorders of newborns. Seminars Perinatol 1997; 21 : 70-85.(Tiker Filiz, Gurakan Berk)
Abstract
OBJECTIVE: Although the connection between cholestasis and conjugated hyperbilirubinemia is well known, mild hepatic dysfunction or cholestasis may also be associated with unconjugated hyperbilirubinemia in some infants with prolonged jaundice. The aim of this study was to investigate the relationship between serum bilirubin levels and alanine aminotransferase levels, aspartate aminotransferase levels, prothrombin time, activated partial thromboplastin time, and international normalization ratio findings in a group of infants. METHODS: The study included 77 healthy, term, breast-fed infants with jaundice and 56 age-matched, healthy, term, non-jaundiced controls. The 133 babies were divided into three subgroups according to their total bilirubin levels [group I (controls) <50 μmol/L, group II = 50-100 μmol/L, and group III >100 μmol/L, and the findings for the noted parameters were compared]. RESULTS: The mean conjugated bilirubin level was significantly higher, and the mean activated partial thromboplastin time significantly longer in group III than in group I. A significant positive correlation was found between bilirubin levels and PT and APTT results. CONCLUSION: Clinical vitamin K deficiency appeared unlikely to develop in this group of infants with prolonged unconjugated hyperbilirubinemia. However, a significant positive correlation between bilirubin levels and PT and APTT suggest that a higher bilirubin load to the liver may cause some degree of vitamin K deficiency due to mild cholestasis. The importance of this finding, and the possible benefits of vitamin K supplementation in 1-month-old breast-fed infants with bilirubin levels higher than 100 μmol/L require further investigation.
Keywords: Cholestasis; Coagulation; Vitamin K deficiency; Prolonged unconjugated hyperbilirubinemia
Prolonged jaundice is commonly described as hyperbilirubinemia persisting beyond the second week of life. This condition itself is not necessarily harmful; however, it can signify serious underlying pathologies such as hypothyroidism and several metabolic, hematologic, and liver diseases.[1] Although the connection between cholestasis and conjugated hyperbilirubinemia is well known, signs of mild hepatic dysfunction or cholestasis have also been observed in association with unconjugated hyperbilirubinemia in some infants with prolonged jaundice.[2],[3],[4] Mild cholestasis may impair gastrointestinal absorption of fat-soluble vitamin K, and vitamin K deficiency may develop in these cases. The aim of this study was to investigate the relationship between prolonged unconjugated hyperbilirubinemia and findings from liver function and coagulation testing in very young infants.
Materials and methods
This study included 77 (47 males and 30 females) healthy, term (gestational age 37 weeks), breast-fed Turkish infants who were admitted to our clinic at the age of 28-33 days with the complaint of jaundice. The mean birth weight of the infants was 3401.23±416.37 g. Fifty-six non-jaundiced, age-matched, healthy, term, breast-fed infants admitting to our well-baby nursery were examined as controls. All the infants had received 1 mg of vitamin K intramuscularly soon after birth. Informed consent was obtained from the subjects′ parents.
A pediatrician clinically examined all the jaundiced infants, and no other abnormalities were detected. Blood samples were obtained by venepuncture from all infants to determine serum levels of bilirubin (total and conjugated), alanine aminotransferase (ALT), aspartate aminotransferase (AST), as well as prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalization ratio (INR). Glucose-6-phosphate dehydrogenase (G6PD) level was also determined in the jaundiced infants and found normal. None of the infants had early hemolytic jaundice due to blood group incompatibility.
The infants were divided into three subgroups according to their total bilirubin levels: group I (controls) < 50 μmol/L, group II = 50-100 μmol/L, and group III> 100 μmol/L. Student′s t test, Post Hoc tests, and Pearson correlation tests were used for statistical analysis of the results. This study was approved by our hospital′s ethics committee.
Results
There were no significant differences among the groups regarding gestational age, birth weight and actual body weight. The laboratory data are shown in table1. None of the infants with prolonged jaundice had conjugated hyperbilirubinemia. The ALT, AST, PT, and INR results were similar in the three groups. The mean conjugated bilirubin level was significantly higher (p=0.017), and the mean APTT was significantly longer (p=0.048) in group III compared to group I. However, there were no statistical differences in conjugated bilirubin and APTT levels of group I when compared to the findings in group II. Similarly those levels did not differ between group II and III. A significant positive correlation was found between total bilirubin levels and PT results (p = 0.046). A similar correlation was also present between bilirubin levels and APTT (p = 0.009).
Discussion
The late form of vitamin K deficiency bleeding (VKDB) presents between 2 and 8 weeks of life. Due to the low vitamin K content of human milk, and to delayed colonization of the gut, this condition is seen almost exclusively in breast-fed infants.[5],[6] However, the majority of these infants exhibit no coagulation problems, and it is likely that other elements further decrease the vitamin K-dependent factors, causing bleeding.[7] Malabsorption of vitamin K due to underlying liver disease is the most common of these additional factors.[7],[8] In one study, 42% of 131 cases of late VKDB were associated with cholestatic liver disease.[9]
Prolonged jaundice with unconjugated hyperbilirubinemia is common in breast-fed infants. The question is whether prolonged unconjugated hyperbilirubinemia may produce some of the effects associated with cholestasis. In their investigation of breast-fed infants with prolonged unconjugated hyperbilirubinemia, Tazawa et al[4] found that ALT and AST values were normal, whereas alkaline phosphatase (ALP), gamma-glutamyltranspeptidase (GGT), and bile acid levels were elevated. These findings suggest that hepatic cell damage is unlikely, and that hepatic dysfunction related to mild cholestasis is probably what occurs in these cases. The authors also found a relationship between increased bile acid loading in the liver and elevated levels of serum unconjugated bilirubin in jaundiced breast-fed infants. It is known that bile acids and bilirubin compete with each other as they are being broken down in the liver, and that the level of biliary secretion of bilirubin is dependent on bile acid secretion.[2],[4] This reveals how cholestasis may be closely related to unconjugated hyperbilirubinemia.
In general, although few patients with prolonged unconjugated hyperbilirubinemia show apparent symptoms of cholestasis, some degree of vitamin K deficiency may occur due to malabsorption. Both the low vitamin K content of breast milk and mild cholestasis associated with prolonged unconjugated hyperbilirubinemia may predispose the infant to late VKDB. In the present the authors study, we investigated whether this mild cholestasis may affect coagulation parameters and cause some degree of vitamin K deficiency. The fact that there were no significant differences among the three groups′ AST and ALT levels indicate that elevated bilirubin levels do not imply hepatic cell damage. However, conjugated bilirubin levels were significantly higher in group III infants than in the controls, and this may suggest some degree of cholestasis in the former. The present study interpretation is limited by the fact that we did not evaluate ALP, GGT, and bile acid levels, all of which are important markers of cholestasis.
Clinically, a prolonged PT and INR results are important in the diagnosis of vitamin K deficiency.[5],[10] Although APTT was significantly longer in group III than in the controls, the three groups′ PT, APTT and INR findings were within the normal ranges. This finding suggests that clinical vitamin K deficiency is unlikely to develop in this group of infants with prolonged unconjugated hyperbilirubinemia. However, a significant positive correlation between bilirubin levels and PT and APTT suggest that a higher bilirubin load to the liver may cause some degree of vitamin K deficiency due to mild cholestasis. The importance of this finding, and the possible benefits of vitamin K supplementation in 1-month-old breast-fed infants with bilirubin levels higher than 100 mmol/L require further investigation. The levels of vitamin K, proteins induced by vitamin K antagonist, and vitamin K-dependent factors all of which are important markers of biochemical vitamin K deficiency need to be evaluated in a larger group of infants with higher unconjugated bilirubin levels in a further study.
References
1. Hannam S, McDonnell M, Rennie JM. Investigation of prolonged neonatal jaundice. Acta Pediatr 2000; 89: 694-697.
2. Tazawa Y, Yamada M, Nakagawa M, Konno T, Tada K. Serum bile acids and their conjugates in breast-fed infants with prolonged jaundice. Eur J Pediatr 1985; 144: 37-40.
3. Yamada M, Tazawa Y, Nakagawa M et al. Alterations of serum bile acid profile in breast-fed infants with prolonged jaundice. J Pediatr Gastroenterol Nutr 1985; 4: 741-745.
4. Tazawa Y, Abukawa D, Watabe M, Nakagawa M, Yamada M. Abnormal results of biochemical liver function tests in breast-fed infants with prolonged indirect hyperbilirubinemia. Eur J Pediatr 1991; 150 : 310-313.
5. Greer FR. Vitamin K status of lactating mothers and their infants. Acta Pediatr Suppl 1999; 430 : 95-103.
6. Motohara K, Matsukuro M, Matsuda I et al. Severe vitamin K deficiency in breast-fed infants. J Pediatr 1984; 105: 943-945.
7. Sutor AH, von Kries R, Cornelissen EAM, McNinch AW, Andrew M. Vitamin K deficiency bleeding (VKDB) in infancy. Thromb Haemost 1999; 81 : 456-461.
8. Zipursky A. Prevention of vitamin K deficiency bleeding in newborns. Br J Haematol 1999; 104: 430-437.
9. Loughnan PM, McDougall PN. Epidemiology of late onset haemorrhagic disease: a pooled data analysis. J Pediatr Child Health 1993; 29 : 177-181.
10. Andrew M. The relevance of developmental hemostasis to hemorrhagic disorders of newborns. Seminars Perinatol 1997; 21 : 70-85.(Tiker Filiz, Gurakan Berk)