THERAPEUTIC CONTROVERSIES Editedby Dennis F. Thompson and Marsha A. Raebel
TAURINE: AN ESSENTIAL AMINO ACID TO PREVENT CHOLESTASIS IN NEONATES? Denise Howard and Dennis F. Thompson
OBJECTIVE: To review the evidence that taurine can prevent cholestasis in neonates.
MEDLINE and EMBASE searches were conducted to identify both animal and human data regarding taurine's role in bile acid conjugation and liver disease (key terms: taurine, children less than two years old).
DATASOURCES:
Emphasis was placed on human data supplemented by relevant animal data.
STUDYSELECTION:
DATASYNTHESIS: Taurine appears to more effectively conjugate bile acids than glycine, and the end-products of conjugation are more soluble. Taurine deficiency may increase glyco-conjugates of bile acids and result in cholestasis. Although the cause of neonatal cholestasis probably is multifactorial, there are data indicating that adequate taurine may prevent cholestasis in neonates. CONCLUSIONS: Taurine
should be considered an essential amino acid for neonates and should be included in total parenteral nutrition solutions for these patients.
AnnPharmacother 1992:26: 1390-2. UNTIL RECENTLY, TAURINE HAS BEEN CONSIDERED a nonessential amino acid. Various organs and tissues (e.g., brain, retina, heart, liver, platelets) have been shown to possess a specific active transport system for taurine uptake from extracellular fluid.":' Several studies have found correlation between taurine deficiency and such abnormalities as retinal degeneration." growth retardation," congestive heart failure, and osmotic disorders.' The most well-documented function of taurine is its role in bile acid conjugation. Because taurine deficiency has been recognized in premature infants, many investigators now consider taurine an essential amino acid in neonates.v" Taurine, which is an end-product of sulfur amino acid metabolism, is one of the most abundant free amino acids
DENISE HOWARD, is a Doctor of Pharmacy Student. College of Pharmacy, University of Oklahoma Health Sciences Center. Oklahoma City, OK 73117: and DENNIS F. THOMPSON, Phann.D.. is the Assistant Dean for Clinical Programs. an Associate Professor. and the Head. Department of Pharmacy Practice. School of Pharmacy, Southwestern Oklahoma State University. Weatherford. OK 73096. Reprints: Dennis F. Thompson. Pharm.D.. Pharmacy Education. Saint Anthony Hospital. 1000 North Lee. Oklahoma City. OK 73101. MARSHA A. RAEBEL. Phann.D.. is the Coordinator of Drug Information and Clinical Pharmacy, Scott and White Memorial Hospital. a Clinical Associate Professor. College of Pharmacy, University of Texas at Austin. and an Assistant Professor of Medicine. Texas A&M University. College of Medicine. Temple. TX 76508.
1390 •
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in the body and is derived from methionine and cysteine." Its synthesis is governed primarily by the activity of cystine sulfinic acid decarboxylase, which initiates the conversion of cystine sulfinic acid to taurine.P':" The only welldefined metabolic function of taurine is its involvement in bile acid conjugation.'>" Galeano et aI. suggested that conjugation of bile acids is catalyzed by N-acetyl transferase, which has a greater affinity for taurine than for glycine. The proportion of tauro-conjugates is influenced by the body's hepatic pool of taurine," Other studies, using chromatographic analysis of neonatal duodenal fluid, showed that with adequate body pools, taurine conjugates three to five times more bile acid than glycine.P-" Theoretical advantages of tauro-conjugates over glyco-conjugates have been postulated. Because bile acids are preferentially conjugated with taurine, the implication is that bile flow can be improved with adequate taurine pools. Further, tauroconjugates, having a lower pK. may be more soluble than glyco-conjugates in premature infants," Cholestasis results from impairment of bile flow, which ultimately disrupts the function of bile salts in absorbing dietary lipids."-" Neonatal cholestasis can result from numerous mechanisms including congenital, viral, and druginduced etiologies. The association of total parenteral nutrition (TPN) and cholestasis in premature infants has largely been determined by histologic evidence obtained on biopsy. Liver biopsies, taken from infants administered TPN who developed cholestasis, consistently have revealed both intracellular and intracanalicular cholestasis with varying degrees of portal fibrosis, bile duct proliferation and inflammation, biliary cirrhosis, and bile plugging.P> This pathology results from the reduction of bile flow, suggesting that a disruption in bile salt formation may playa key role in neonatal TPN-associated cholestasis. Several theories have been proposed for the mechanism of bile flow disruption seen in neonates. The first is that neonates and preterm infants have immature metabolic pathways that may result in a decreased ability to synthesize the bile acids required for normal function.4. 12,23-25 This may be compounded by a process termed "physiologic cholestasis," which suggests that there may be perinatal delay in the maturation of processes necessary to ensure the efficient flow of bile. 26,27 The second theory is that with a decreased ability to synthesize taurine, exogenous sources may be
1992 November, Volume 26
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necessary. Human breast milk contains 25-35 umol/dl, of taurine." This maternal source probably supplies the infant with adequate taurine to prevent complications of impaired bile flow." However, for infants requiring TPN who do not receive taurine by any exogenous source, body stores may often be inadequate to prevent impaired bile flow. Results of clinical trials and animal studies suggest that taurine supplementation may reverse or protect against the development of cholestasis.v" In one study, Galeano et aI. randomized 24 low-birthweight infants into three groups. The first group received Enfamil Premature Formula without taurine. The second group received the same formulation as the first supplemented with 40 umol/dl, of taurine, an amount comparable to that found in preterm milk. The third group received their own mother's milk. There was no difference in the percent of calories absorbed or in fat intake among the three groups. A metabolic study revealed that the percent of fat absorbed was higher in the taurinesupplemented infants and was comparable to that of the group fed human milk. The coefficients of fat absorption were 87.5, 92.5, and 91.6 percent for groups 1,2, and 3, respectively. The authors suggested that taurine supplementation, by increasing fat absorption, increases the formation of bile acids and thus improves bile flow. It is important to note the improvement in fat absorption was more pronounced for saturated fatty acids," In an experimental model by Dorvil et al., guinea pigs were given 18 umol/l 00 g of body weight of lithocholic acid sulfate (S-LCA) by injection to induce cholestasis. Total bile acids were measured enzymatically and conjugates were identified by thin-layer chromatography. After SLCA injection, guinea pigs showed a 4: I predominance of glyco-conjugates. The total number and number of guinea pigs per treatment group were not reported. In one group, dietary supplementation with water containing 0.5% taurine was started after cholestasis developed. This group showed a reversal of the glycine-taurine ratio at the end of three days and a subsequent increase in bile flow, measured in 3D-minute intervals over three-hour periods. In another group, supplementation with taurine in the same manner was administered one, three, and five days in advance. Protective effects were exhibited with no pathologic liver changes on biopsy. In the final group, which had no taurine administered, bile flow was reduced to less than 20 percent within three hours of S-LCA injection and there was almost exclusive glycine conjugation." This study supports previous data suggesting that dietary supplementation of taurine appears to prevent the intrahepatic cholestasis induced by S-LCA conjugated with glycine.I3.28.29 This may be an important issue as neonates have a decreased ability to detoxify LCA because of immaturity of the sulfation pathway.I? There have been numerous reports of cholestasis in term and preterm infants administered long-term TPN without taurine supplementation. One of the most striking is by Beale et al., in which 62 premature infants received TPN because of respiratory complications. Infants with previous hepatic dysfunction or bilirubin abnormalities were excluded from the study. Of the 62 infants, 14 (23 percent) developed intrahepatic cholestasis indicated by a bilirubin greater than 1.6 mg/dL. The time to onset of cholestasis ranged from 5 to 83 days (mean 42). Infants weighing less than 1000 g at birth appeared to be at highest risk with the
incidence of cholestasis being 50 percent. Infants weighing between 1000 and 1499 g had an 18 percent incidence and infants between 1500 and 2000 g a 7 percent incidence of cholestasis." Studies performed by Touloukian and Seashore" and Vileisis et aPI also reported TPN-associated cholestasis. In both of these studies, infants received long-term TPN solutions with no taurine added. These studies differed from the one by Beale et aI.,30 because most of the infants studied had prior hepatic dysfunction. In all of the infants who developed cholestasis, there was a dramatic rise in alkaline phosphatase and a direct bilirubin was above 2 mg/dL. Touloukian and Seashore reported that 8 of 19 infants developed cholestasis and that 6 of the 8 infants were premature (birthweight below 2 kg) supporting the association of increased risk in low-birth weight infants." Vileisis et al. reported that 43 of 82 infants developed cholestasis with no significant difference in mean gestational age." This may be explained by the fact that, although study criteria did not exclude low-birthweight infants, none of the initial birthweights were less than 2 g. In case reports by Cooper et al., three newborn infants diagnosed with necrotizing enterocolitis underwent intestinal resection. All three had biopsies that showed evidence of severe cholestasis, diffuse fibrosis, and bile duct proliferation. Two of the infants died from hepatic disease; the third death was attributed to sepsis. Values from serial plasma aminograms obtained in all three infants showed undetectable taurine concentrations, which led the investigators to conclude that taurine deficiency may increase glycoconjugates of bile acids, thereby resulting in cholestasis. Taurine-containing amino acid solutions for TPN vary in the amount of taurine available and are more costly than amino acid solutions without taurine (Table 1).32 These solutions are more expensive; however, if the evidence suggests that taurine-containing TPN solutions decrease the incidence of cholestasis in neonates, the higher cost can be justified. Taurine should be considered an essential amino acid for term or preterm infants who will be administered longterm TPN. The cause of cholestasis in premature infants probably is multifactorial; underlying disease, delay of enteral feeding, duration of TPN, and taurine-deficient TPN formulations may playa role. Although it has not been demonstrated that taurine deficiency is the sole cause of cholestasis, taurine supplementation seems to provide a mechanism to prevent or reverse this condition.v" It is important to note that premature infants are at risk for developing sepsis, necrotizing enterocolitis, or heart failure, all of which can independently produce cholestasis.'? As in the case studies presented by Cooper et aI.,28 all of the infants had severe necrotizing enterocolitis in which taurine Table I. Cost of Amino Acid Solutions With and Without Taurine SOLUTION (500 ml.)
Aminosyn PF 7% Trophamine 6% Freamine III 8.5% TravasoI5.5%
TAURINE CONTENT (mglIOOmL)
cosr'
50
62.21 56.18 56.55 43.59
($)
15
o o
'Obtained from Reference 32.
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deficiency complicates the true determination of cholestatic etiology. Patient populations generally have been small with few studies being prospective, randomized, or double-blind, indicating the need for larger, comparative trials to be performed. It does appear that low-birthweight infants are at greater risk for developing cholestasis't-" and the use of taurine-containing TPN solutions is advocated in this population. The incidence of cholestasis in infants on taurine-supplemented TPN compared with those on TPN without taurine additives has yet to be determined. The ideal study would provide the clinical evidence necessary to determine if taurine deficiency is a causal factor in neonatal cholestasis. ~
25. 26. 27. 28.
29.
30.
References I. GhisoltiJ. Taurine and the premature. Bioi Neonate 1987;52:78-86. 2. Vinton NE, Laidlaw SA, Ament ME, Kopple JD. Taurineconcentra-
tions in plasmaand blood cells of patients undergoing long-termparenteralnutrition. Am J Clin Nutr 1986;44:398-404. 3. Vinton NE, Laidlaw SA, Ament ME, Kopple JD. Taurineconcentrationsin plasma, bloodcells,and urineof children undergoing long-term totalparenteral nutrition. PediatricRes 1987;21:399-403. 4. Vinton NE, Geggel HS, Ament ME, Heckenlively JR, Martin DA, Kopple JD. Taurinedeficiency in a child on total parenteral nutrition. Nutr Rev 1985;43:81-3. 5. Geggel HS, Ament ME, Heckenlively JR, Martin DA, Kopple JD. Nutritional requirement for taurinein patients receiving long-term parenteralnutrition. N Engl J Med 1985;312:142-6. 6. Hayes KC, Stephan ZF, Sturman JA. Growth depressionin taurinedepleted infantmonkeys. J Nutr 1980;110:2058-63. 7. Thurston JH, Hauhart RE, Dirgo JA. Taurine: a role in osmotic regulationof mammalianbrain and possibleclinical significance. Life Sci 1980;26:1561-8. 8. Galeano NF, Darling P, Lepage G, Leroy C, Collet S, Giguere R, et at. Taurine supplementation of a prematureformula improvesfat absorption in preterm infants. PediatricRes 1987;22:67-71. 9. Chipponi JX, Bleier JC, Santi MT, Rudman D. Deficiencies of essentialandconditionally essential nutrients. Am J Clin Nutr 1982;35: 1112-6. 10. Rassin DK, Gaull GE, Jarvenpaa AL, Raila CR. Feeding !he lowbir1h-weight infant. II. Effectsof taurineand cholesterol supplementationon aminoacidsand cholesterol. Pediatrics 1983;71:179-85. II. Kender BS. Taurine:an overview of its role in preventative medicine. PrevMed 1989;18:70-100. 12. Sturman JA, Rassin DK, Gaull GE. Taurine in developingrat brain: transferof [J6S]-taurine to pupsvia the milk. PediatricRes 1977;II :2833. 13. Dorvil NP, Yousef 1M, Tuchweber B, Roy CC. Taurine prevents cholestasis induced by lithocholic acidsulfatein guineapigs. Am J Clin Nutr 1983;37:221-32. 14. Challacombe DN, Edkins S, Brown GA. Duodenal bile acidsin infancy. Arch Dis Child 1975;50:837-43. 15. Okamoto E, Rassin DK, Zucker CL, Salen GS, Heird We. Role of taurinein feeding the low bir1h weightinfant. J Pediatr 1984;104:93641.
16. Encrantz JD, SjovolJ. On the bileacidsin duodenal contents of infants and children. Clin Chim Acta 1959;4:793-9. 17. Whitington PF. Cholestasis associated with total parenteral nutrition in infants. Hepatology 1986;5:693-6. 18. Sellinger M, Boyer JL. Physiology of bile secretion and cholestasis. Prog Liver Dis 1990;9:237-53. 19. Touloukian RJ, Seashore JH. Hepaticsecretoryobstruction with total parenteral nutrition in the infant. J PediatrSurg 1975;10:353-60. 20. Baker AL, Rosenberg IH. Hepatic complications of totalparenteral nutrition. Am J Med 1987;82:489-96. 21. Benjamin DR. Hepatobiliary dysfunction in infants and children associ-
ated with long-term total parenteral nutrition. A clinicopathologic study.AmJ Clin PathoI1981;76:276-83. 22. Dahms BB,Halpin TC Jr. Serial liverbiopsies in parenteral nutrition associated cholestasis of earlyinfancy. Gastroenterology 1981 ;81:136-44. 23. Watkins JB, Ingall D, Szczepanik P, Klein PD, Lester R. Bile-salt
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24.
31.
32.
metabolism in the newborn: measurement of poolsizeand synthesis by stableisotope technic. N Engl J Med 1973;288:431-4. Rigo J, Senterre J. Is taurineessentialfor the neonates? Bioi Neonate 1977;32:73-6. Sturman JA, Rassin DK, Gaull GE, Cote LJ. Taurine in developing rhesusmonkey brain. J Neurochem 1980;35:304-10. Boyer JL. New conceptsof mechanisms on hepatocyte bileformation. PhysiolRev 1980;60:303-26. Balistreri WF, Bove KE. Hepatobiliary consequences of parenteral alimentation. Prog Liver Dis 1990;9:567-98. Cooper A, Betts JM, Gilberto RP, Pereira GR, Ziegler MM. Taurine deficiency in the severe hepatic dysfunction complicating total parenteralnutrition. J PediatrSurg 1984;19:462-6. Fouin-Fortunet H, Lequernec L, Erlinger S, Lerebours E, Colin R. Hepatic alterations during total parenteral nutrition in patients with inflammatory boweldisease: a possible consequence of lithocholate toxicity. Gastroenterology 1982;82:932-7. Beale EF, Nelson RM, Bucciarelli RL, Donnelly WH, Eitzman DV. Intrahepatic cholestasisassociated with parenteralnutrition in premalUre infants. Pediatrics 1979;64:342-7. Vileisis RA, Inwood RJ, Hunt CEo Prospective controlled studyof parenteral nutrition-associated cholestaticjaundice: effect of protein intake. J Pediatr 1980;96:893-7. Sifton DW, ed. Drug topics red book. Montvale, NJ: Medical Economics Data. 1992.
EXTRACfO
Evaluar la evidencia de si taurina puede prevenir la colestasis en neonatos. OBJETIVO:
FUENTES DE INFORMACION: Biisqueda en MEDLINE y EMBASE se lIevaron a cabo para identificardatos en animales y humanos sobre el rol de taurina en la conjugaci6n de acido biliar y enfermedad del hfgado.
Se di6 enfasis a datos en humanos suplementados por datos relevantes en anirnales.
SELECCION DE FUENTES DE INFORMACION:
SINTESIS: Taurina aparenta conjugar acidos biliares mas efectivamente que glicina y los productos fmales de la conjugaci6n son mas solubles. Deficiencia de taurina puede aumentar los glico-conjugados de acidos biliares y resultar en colestasis. Aunque la causa de colestasis neonatal se debe probablemente a muchos factores, existen datos que indicanque taurina adecuada puede prevenir colestasis en neonatos.
CONCLUSIONES: Taurina debe considerarse como un aminoacido esencial en neonatos y debe incluirse en las soluciones de nutrici6n total parenteral para neonatos. GLENDA A. SOBRINO BURGOS
RESUME
Reviser les donnees demontrant une prevention possible de la cholestase chez Ie nouveau-ne par la taurine, un acide amine nonessentiel. OBJECI1F:
REVUE DE LITIERATURE: L'information provient d'une recherche de la litterarure basee sur les donnees anirnales et humaines ayant pour objet Ie role de la taurine dans la conjugaison des acides biliaires et la pathologie hepatique, La recherche fut executee par Ie biais du systeme MEDLINE et EMBASE. SELECflON DES ETUDES: Les etudes cliniques et animales pertinentesont ete selectionnees, RESUME: La taurine semble plus efficace 11 conjuguer les acides biliaires que la glycine. Les produits de conjugaisons formes sont aussi plus solubles. Une deficience en taurine peut augmenter la glyco-conjugaison des acides biliaires et produire une cholestase. Quoique la cholestase neonatale est probablement de causes multiples, il existe des donnees indiquant que la taurine peut prevenirla cholestase chez les nouveau-
nes. La taurine devrait eire consideree comme un acide amine essentiel pour les nouveau-nes et ainsi eire indue dans les solutions d'alirnentation parenterale totale. MICHELLE DEPOT CONCLUSIONS:
The AnnalsofPharmacotherapy • 1992 November, Volume 26 Downloaded from aop.sagepub.com at CORNELL UNIV on September 7, 2016
TAURINE: AN ESSENTIAL AMINO ACID TO PREVENT CHOLESTASIS IN NEONATES? Denise Howard and Dennis F. Thompson
OBJECTIVE: To review the evidence that taurine can prevent cholestasis in neonates.
MEDLINE and EMBASE searches were conducted to identify both animal and human data regarding taurine's role in bile acid conjugation and liver disease (key terms: taurine, children less than two years old).
DATASOURCES:
Emphasis was placed on human data supplemented by relevant animal data.
STUDYSELECTION:
DATASYNTHESIS: Taurine appears to more effectively conjugate bile acids than glycine, and the end-products of conjugation are more soluble. Taurine deficiency may increase glyco-conjugates of bile acids and result in cholestasis. Although the cause of neonatal cholestasis probably is multifactorial, there are data indicating that adequate taurine may prevent cholestasis in neonates. CONCLUSIONS: Taurine
should be considered an essential amino acid for neonates and should be included in total parenteral nutrition solutions for these patients.
AnnPharmacother 1992:26: 1390-2. UNTIL RECENTLY, TAURINE HAS BEEN CONSIDERED a nonessential amino acid. Various organs and tissues (e.g., brain, retina, heart, liver, platelets) have been shown to possess a specific active transport system for taurine uptake from extracellular fluid.":' Several studies have found correlation between taurine deficiency and such abnormalities as retinal degeneration." growth retardation," congestive heart failure, and osmotic disorders.' The most well-documented function of taurine is its role in bile acid conjugation. Because taurine deficiency has been recognized in premature infants, many investigators now consider taurine an essential amino acid in neonates.v" Taurine, which is an end-product of sulfur amino acid metabolism, is one of the most abundant free amino acids
DENISE HOWARD, is a Doctor of Pharmacy Student. College of Pharmacy, University of Oklahoma Health Sciences Center. Oklahoma City, OK 73117: and DENNIS F. THOMPSON, Phann.D.. is the Assistant Dean for Clinical Programs. an Associate Professor. and the Head. Department of Pharmacy Practice. School of Pharmacy, Southwestern Oklahoma State University. Weatherford. OK 73096. Reprints: Dennis F. Thompson. Pharm.D.. Pharmacy Education. Saint Anthony Hospital. 1000 North Lee. Oklahoma City. OK 73101. MARSHA A. RAEBEL. Phann.D.. is the Coordinator of Drug Information and Clinical Pharmacy, Scott and White Memorial Hospital. a Clinical Associate Professor. College of Pharmacy, University of Texas at Austin. and an Assistant Professor of Medicine. Texas A&M University. College of Medicine. Temple. TX 76508.
1390 •
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in the body and is derived from methionine and cysteine." Its synthesis is governed primarily by the activity of cystine sulfinic acid decarboxylase, which initiates the conversion of cystine sulfinic acid to taurine.P':" The only welldefined metabolic function of taurine is its involvement in bile acid conjugation.'>" Galeano et aI. suggested that conjugation of bile acids is catalyzed by N-acetyl transferase, which has a greater affinity for taurine than for glycine. The proportion of tauro-conjugates is influenced by the body's hepatic pool of taurine," Other studies, using chromatographic analysis of neonatal duodenal fluid, showed that with adequate body pools, taurine conjugates three to five times more bile acid than glycine.P-" Theoretical advantages of tauro-conjugates over glyco-conjugates have been postulated. Because bile acids are preferentially conjugated with taurine, the implication is that bile flow can be improved with adequate taurine pools. Further, tauroconjugates, having a lower pK. may be more soluble than glyco-conjugates in premature infants," Cholestasis results from impairment of bile flow, which ultimately disrupts the function of bile salts in absorbing dietary lipids."-" Neonatal cholestasis can result from numerous mechanisms including congenital, viral, and druginduced etiologies. The association of total parenteral nutrition (TPN) and cholestasis in premature infants has largely been determined by histologic evidence obtained on biopsy. Liver biopsies, taken from infants administered TPN who developed cholestasis, consistently have revealed both intracellular and intracanalicular cholestasis with varying degrees of portal fibrosis, bile duct proliferation and inflammation, biliary cirrhosis, and bile plugging.P> This pathology results from the reduction of bile flow, suggesting that a disruption in bile salt formation may playa key role in neonatal TPN-associated cholestasis. Several theories have been proposed for the mechanism of bile flow disruption seen in neonates. The first is that neonates and preterm infants have immature metabolic pathways that may result in a decreased ability to synthesize the bile acids required for normal function.4. 12,23-25 This may be compounded by a process termed "physiologic cholestasis," which suggests that there may be perinatal delay in the maturation of processes necessary to ensure the efficient flow of bile. 26,27 The second theory is that with a decreased ability to synthesize taurine, exogenous sources may be
1992 November, Volume 26
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necessary. Human breast milk contains 25-35 umol/dl, of taurine." This maternal source probably supplies the infant with adequate taurine to prevent complications of impaired bile flow." However, for infants requiring TPN who do not receive taurine by any exogenous source, body stores may often be inadequate to prevent impaired bile flow. Results of clinical trials and animal studies suggest that taurine supplementation may reverse or protect against the development of cholestasis.v" In one study, Galeano et aI. randomized 24 low-birthweight infants into three groups. The first group received Enfamil Premature Formula without taurine. The second group received the same formulation as the first supplemented with 40 umol/dl, of taurine, an amount comparable to that found in preterm milk. The third group received their own mother's milk. There was no difference in the percent of calories absorbed or in fat intake among the three groups. A metabolic study revealed that the percent of fat absorbed was higher in the taurinesupplemented infants and was comparable to that of the group fed human milk. The coefficients of fat absorption were 87.5, 92.5, and 91.6 percent for groups 1,2, and 3, respectively. The authors suggested that taurine supplementation, by increasing fat absorption, increases the formation of bile acids and thus improves bile flow. It is important to note the improvement in fat absorption was more pronounced for saturated fatty acids," In an experimental model by Dorvil et al., guinea pigs were given 18 umol/l 00 g of body weight of lithocholic acid sulfate (S-LCA) by injection to induce cholestasis. Total bile acids were measured enzymatically and conjugates were identified by thin-layer chromatography. After SLCA injection, guinea pigs showed a 4: I predominance of glyco-conjugates. The total number and number of guinea pigs per treatment group were not reported. In one group, dietary supplementation with water containing 0.5% taurine was started after cholestasis developed. This group showed a reversal of the glycine-taurine ratio at the end of three days and a subsequent increase in bile flow, measured in 3D-minute intervals over three-hour periods. In another group, supplementation with taurine in the same manner was administered one, three, and five days in advance. Protective effects were exhibited with no pathologic liver changes on biopsy. In the final group, which had no taurine administered, bile flow was reduced to less than 20 percent within three hours of S-LCA injection and there was almost exclusive glycine conjugation." This study supports previous data suggesting that dietary supplementation of taurine appears to prevent the intrahepatic cholestasis induced by S-LCA conjugated with glycine.I3.28.29 This may be an important issue as neonates have a decreased ability to detoxify LCA because of immaturity of the sulfation pathway.I? There have been numerous reports of cholestasis in term and preterm infants administered long-term TPN without taurine supplementation. One of the most striking is by Beale et al., in which 62 premature infants received TPN because of respiratory complications. Infants with previous hepatic dysfunction or bilirubin abnormalities were excluded from the study. Of the 62 infants, 14 (23 percent) developed intrahepatic cholestasis indicated by a bilirubin greater than 1.6 mg/dL. The time to onset of cholestasis ranged from 5 to 83 days (mean 42). Infants weighing less than 1000 g at birth appeared to be at highest risk with the
incidence of cholestasis being 50 percent. Infants weighing between 1000 and 1499 g had an 18 percent incidence and infants between 1500 and 2000 g a 7 percent incidence of cholestasis." Studies performed by Touloukian and Seashore" and Vileisis et aPI also reported TPN-associated cholestasis. In both of these studies, infants received long-term TPN solutions with no taurine added. These studies differed from the one by Beale et aI.,30 because most of the infants studied had prior hepatic dysfunction. In all of the infants who developed cholestasis, there was a dramatic rise in alkaline phosphatase and a direct bilirubin was above 2 mg/dL. Touloukian and Seashore reported that 8 of 19 infants developed cholestasis and that 6 of the 8 infants were premature (birthweight below 2 kg) supporting the association of increased risk in low-birth weight infants." Vileisis et al. reported that 43 of 82 infants developed cholestasis with no significant difference in mean gestational age." This may be explained by the fact that, although study criteria did not exclude low-birthweight infants, none of the initial birthweights were less than 2 g. In case reports by Cooper et al., three newborn infants diagnosed with necrotizing enterocolitis underwent intestinal resection. All three had biopsies that showed evidence of severe cholestasis, diffuse fibrosis, and bile duct proliferation. Two of the infants died from hepatic disease; the third death was attributed to sepsis. Values from serial plasma aminograms obtained in all three infants showed undetectable taurine concentrations, which led the investigators to conclude that taurine deficiency may increase glycoconjugates of bile acids, thereby resulting in cholestasis. Taurine-containing amino acid solutions for TPN vary in the amount of taurine available and are more costly than amino acid solutions without taurine (Table 1).32 These solutions are more expensive; however, if the evidence suggests that taurine-containing TPN solutions decrease the incidence of cholestasis in neonates, the higher cost can be justified. Taurine should be considered an essential amino acid for term or preterm infants who will be administered longterm TPN. The cause of cholestasis in premature infants probably is multifactorial; underlying disease, delay of enteral feeding, duration of TPN, and taurine-deficient TPN formulations may playa role. Although it has not been demonstrated that taurine deficiency is the sole cause of cholestasis, taurine supplementation seems to provide a mechanism to prevent or reverse this condition.v" It is important to note that premature infants are at risk for developing sepsis, necrotizing enterocolitis, or heart failure, all of which can independently produce cholestasis.'? As in the case studies presented by Cooper et aI.,28 all of the infants had severe necrotizing enterocolitis in which taurine Table I. Cost of Amino Acid Solutions With and Without Taurine SOLUTION (500 ml.)
Aminosyn PF 7% Trophamine 6% Freamine III 8.5% TravasoI5.5%
TAURINE CONTENT (mglIOOmL)
cosr'
50
62.21 56.18 56.55 43.59
($)
15
o o
'Obtained from Reference 32.
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deficiency complicates the true determination of cholestatic etiology. Patient populations generally have been small with few studies being prospective, randomized, or double-blind, indicating the need for larger, comparative trials to be performed. It does appear that low-birthweight infants are at greater risk for developing cholestasis't-" and the use of taurine-containing TPN solutions is advocated in this population. The incidence of cholestasis in infants on taurine-supplemented TPN compared with those on TPN without taurine additives has yet to be determined. The ideal study would provide the clinical evidence necessary to determine if taurine deficiency is a causal factor in neonatal cholestasis. ~
25. 26. 27. 28.
29.
30.
References I. GhisoltiJ. Taurine and the premature. Bioi Neonate 1987;52:78-86. 2. Vinton NE, Laidlaw SA, Ament ME, Kopple JD. Taurineconcentra-
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EXTRACfO
Evaluar la evidencia de si taurina puede prevenir la colestasis en neonatos. OBJETIVO:
FUENTES DE INFORMACION: Biisqueda en MEDLINE y EMBASE se lIevaron a cabo para identificardatos en animales y humanos sobre el rol de taurina en la conjugaci6n de acido biliar y enfermedad del hfgado.
Se di6 enfasis a datos en humanos suplementados por datos relevantes en anirnales.
SELECCION DE FUENTES DE INFORMACION:
SINTESIS: Taurina aparenta conjugar acidos biliares mas efectivamente que glicina y los productos fmales de la conjugaci6n son mas solubles. Deficiencia de taurina puede aumentar los glico-conjugados de acidos biliares y resultar en colestasis. Aunque la causa de colestasis neonatal se debe probablemente a muchos factores, existen datos que indicanque taurina adecuada puede prevenir colestasis en neonatos.
CONCLUSIONES: Taurina debe considerarse como un aminoacido esencial en neonatos y debe incluirse en las soluciones de nutrici6n total parenteral para neonatos. GLENDA A. SOBRINO BURGOS
RESUME
Reviser les donnees demontrant une prevention possible de la cholestase chez Ie nouveau-ne par la taurine, un acide amine nonessentiel. OBJECI1F:
REVUE DE LITIERATURE: L'information provient d'une recherche de la litterarure basee sur les donnees anirnales et humaines ayant pour objet Ie role de la taurine dans la conjugaison des acides biliaires et la pathologie hepatique, La recherche fut executee par Ie biais du systeme MEDLINE et EMBASE. SELECflON DES ETUDES: Les etudes cliniques et animales pertinentesont ete selectionnees, RESUME: La taurine semble plus efficace 11 conjuguer les acides biliaires que la glycine. Les produits de conjugaisons formes sont aussi plus solubles. Une deficience en taurine peut augmenter la glyco-conjugaison des acides biliaires et produire une cholestase. Quoique la cholestase neonatale est probablement de causes multiples, il existe des donnees indiquant que la taurine peut prevenirla cholestase chez les nouveau-
nes. La taurine devrait eire consideree comme un acide amine essentiel pour les nouveau-nes et ainsi eire indue dans les solutions d'alirnentation parenterale totale. MICHELLE DEPOT CONCLUSIONS:
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