w wz «y Kor. J. Clin. Pharm., Vol., No.. 00 w wstpepyzdipjdbdje z w ½ Á Á Á»y Á Á y Á û Á w Á k w w w w w m w Ursodeoxycholic Acid in the Prevention of Pediatric Parenteral Nutrition-associated Cholestasis Ji Hee Kim X, yung Sook in X, Yong Won In X, Kie Ho Shon X, Kyung Eob Choi X, Yon Ho Choe, Nam Sun Beck, Suk Hyang Lee and Tae Sung Park a Division of Pharmaceutical Services, Samsung edical Center, Seoul, Korea b Department of Pediatrics, Samsung edical Center, Seoul, Korea c Graduate School of Clinical Pharmacy, Sookmyung Women's University, Seoul, Korea d Department of Statistics, Seoul National University, Seoul, Korea Cholestatic liver disease is a frequent complication of prolonged parenteral nutrition, especially in premature infants. Numerous factors have been cited as contributing to TPN associated cholestasis. However the exact etiology remains obscure. Ursodeoxycholic acid (UDCA) has been reported to be beneficial for children and adults with various chronic cholestatic liver disease. The aim of this prospective, randomized, double-blind, placebo-controlled study was to determine the preventive effects of UDCA administration during TPN. Seventeen pediatric patients ( boys and girls) undergoing TPN were assigned randomly to two groups, UDCA and placebo group. UDCA group (n=) received mg/kg/day UDCA and placebo group (n=) received mg/kg/day placebo enterally during the TPN period. Liver function tests (total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase) were performed before TPN and weekly or three times a week. The patients weights, complete blood count, composition of TPN, and the infusion rate of TPN and lipid were monitored everyday. Calcium and phosphate were monitored twice a week. Between the UDCA and placebo groups, there were no differences in weight at the onset of TPN, birth weight, duration of TPN, respiratory distress syndrome associated with prematurity, age at the onset of TPN, gestational age, the number of days the patients received antibiotics, the number of patients received enteral nutritions and the composition of TPN. In contrast, there was a significant difference between the UDCA and placebo groups in alanine aminotransferase levels during TPN. It doesn't seem that UDCA administration during TPN correlates directly with improvement of liver function. But the preventive administration of UDCA may be effective in reducing liver enzyme, alanine aminotransferase and has no adverse effects. Keywords total parenteral nutrition, cholestatic liver disease, ursodeoxycholic acid, preventive effect, liver function test, alanine aminotransferase» (Total Parenteral Nutrition, TPN) ), œ ƒ w y y w w e.» Correspondence to : w, Pharm. D. w w w p q ƒ - w w w 0y(0-) Tel: 0-0-, ax: 0-- E-mail: slee@sdic.sookmyung.ac.kr v ƒw w ù. w wù» ƒwš, w sw (direct bilirubin) e ƒƒ ùkù -). Peden ) n 000 g ƒ (cholestasis) y(biliary cirrhosis) w šw y w š. Beale ) 000 g
0 Kor. J. Clin. Pharm., Vol., No., 00 n z 000 g 0% w š šw 000 g % w w š w. w w w w» (total bile salt pool), ü, z sw ù» ). (biopsy)w Ÿwx w ) w y (portal fibrosis) ƒ ) (bile duct proliferation),0). w,)» ùkü. s ü s (endoplasmic reticulum) y š s (canaliculi) ü g. w š y (osmophilic) s s. w w y ) s (extrahepatic biliary atresia) w y, ù ƒ ¾ w w. 0,) Cohen ) w w (.%)ƒ (steatosis) ùkþ, (.%), x (extramedullary hematopoiesis) (.%), ü y (eosinophils in portal tracts) (.%) ùkû š šw. ùkù 0 z, z ùkû. 0 n. w» -% n z %ƒ šsw x (direct hyperbilirubinemia) ùkþ s³ z %ƒ aspartate aminotransferase (AST) w,). ƒ ù š ù w ƒ ƒ ƒ w, ³,, v. w ƒ», š,,). w w ƒ w wš ƒ w w œ, (necrotizing enterocolitis) s (aspiration pneumonia) x y w n, ƒw y (respiratory distress) š k w» ). w x w w w» w v w. y ü w k w š w w y ursodeoxycholic acid (UDCA) n w ü ü jš w š. UDCA n w w w w ƒ (total bile salt pool), ü, z sw y j» x n wš,-). t t (DA) UDCA xƒ y(biliary cirrhosis), m(biliary colic), ûs (cystic fibrosis), (esophageal varices), w(gallstone dissolution), (gallstone prevention) xƒ w ). w UDCA y (primary sclerosing cholangitis) y e ). Spagnuolo w ) x(pilot study)» w y 0 mg/kg/day UDCA n w y y - ü yw t γ-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), conjugated bilirubin, alanine aminotransferase (ALT)ƒ y.» UDCA n w GGT, ALP, ALT ƒƒ ù UDCA n y. Lindor) š ƒ (home) n û UDCA 00 mg/d n w» w ü total bilirubin e. mg/dl. mg/dl w z mg/dl š mg/dl ü. p w UDCA w w e z mw ù,,-) z w w.» w w, p sww y w ùkù w w UDCA z š w. w w y p š w. ü, n w
w w Ursodeoxycholic acid z w x z ü w Institutional Review Board(IRB) m sƒ z w. y w y v w, y ƒ w. ƒ w,» m,,, Á, y. ù w y ƒ» y ƒ š, UDCA ƒ, y ƒ y ƒ w ƒ š ƒw, s ƒ y, w y. w w w ùkù, w k ù w ¼, y ù y y ƒ e w, ƒ x w š w š q w wš y k g. n w w,, y w n UDCA n Placebo n ù. UDCA n UDCA, Placebo n Placebo n, UDCA t, x tablet ursodeoxycholic acid 00 mg, x mg, w ƒ e e. mg, w t v. mg, y ³. mg, yk l. mg, w. n mg/kg/day ww ww» n w e w š kg mg w w n w. ƒ w wì xk xk n. y w ƒ, y n w w» n w. n ù w w» n w. w»» mw wš, ùkû x n w. Placebo n y ùkù» e UDCA n w. w y w w w. «w x (complete blood count), total protein, albumin, cholesterol,» w ww e w v ww. Calcium, phosphate w» ww, w ww. ù x e y k ww. w x Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), total bilirubin, direct bilirubin, Alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT) wù w w. sƒü w x (White Blood Cell, WBC), C-Reactive Protein (CRP), Total Protein (TP), Albumin (Alb), Total Bilirubin (TB), Direct Bilirubin (DB), AST, ALT, ALP, Cholesterol, Calcium, Phosphate, GGTƒ w,», (, s,, ), n, n,» w. n y z (respiratory distress syndrome) (gastrointestinal disturbance) ù w. w w š ƒ TB, AST, ALT, ALP» n w w w. w w z TB, AST, ALT, ALP y» ùkü w»» UDCA n Placebo n y w sƒw. m UDCA n Placebo n p w» w t-test, Wilcoxon's rank sum test w s³ t r (mean±sd) ùkü (source),, û isher's exact test w. n» n TB, AST, ALT, ALP y w n» TB, AST, ALT, ALP w SAS(Statistical Analysis System, Ver.) mixed procedure w mixed model ww. m p-value <0.0 m w w sƒw.
Kor. J. Clin. Pharm., Vol., No., 00 000 l 00 ¾ y. UDCA n, Placebo n n y p Table. y z (respiratory distress syndrome) y r UDCA n w ƒ w,. Placebo n w ƒ w w. Placebo n UDCA n p (p=0.) (p=0.) w w. w n» w Placebo n ¼ ùkû w (p=0.). y z (respiratory distress syndrome) n UDCA n, Placebo n Placebo n ù w (p=0.). ù s³ w UDCA n ù ù w (p=0.0) k» s³ n w ƒ (p=0.).» ƒ w».» ww UDCA n (.%), Placebo n (.%) Placebo n ù w (p=0.). w UDCA n û ƒ, ƒ š Placebo n û ƒ, ƒ. n û w ƒ (p=0.)(table ). Table. Baseline characteristics of study population Patients Gender Age/GA(wks) Weight (kg) Clinical diagnosis Duration of TPN (days) UDCA group yr. yr. d. d./ d./ yr. yr. d. d...0.00. 0...0..0 Cyclic vomiting Cerebral palsy ilk allergy diarrhea Chronic diarrhea Acute pancreatitis Chronic diarrhea(autoimmune enteropathy) Nausea and vomiting Placebo group mo. d./ d./ d./ yr. yr. 0 yr. d./.0 0.. 0..00.0 0.0. Chronic diarrhea Pancreatitis Eating disorder(anorexia nervosa) Cerebral palsy GA, Gestational Age; TPN, Total Parenteral Nutrition; RDS, Respiratory Distress Syndrome 0 0 0 Table. Comparison of characteristics between UDCA and Placebo groups Characteristics UDCA group mean±sd (N=) Placebo group mean±sd (N=) p value Weight at the onset of TPN(kg) Birthweight(kg) Duration of TPN(days) Age at the onset of TPN(days) Gestational age(wks) Enteral nutrition Boys/Girls.±..±.0.±.0 (.%).±..±. (.%) /.±..±. 0.±.0 (0%).0±..±. (.%) / 0. 0. 0. 0. 0.0 0. 0. 0. TPN, Total Parenteral Nutrition; RDS, Respiratory Distress Syndrome
w w Ursodeoxycholic acid z w w Placebo n» w TB (p=0.00), AST (p=0.0), ALT (p=0.0), ALP (p=0.0) s³ eƒ UDCA n w ùkû TB, ALT w ƒ (Table -). Placebo n UDCA n s (p=0.), (p=0.), (p=0.) e (p=0.00) w w ƒ (Table ). % Aminosteril Ped(R) w y Placebo n, UDCA n w (p=.000). Placebo n UDCA n w n w» n w w UDCA n ¼ ùkû ù w (p=0.). UDCA n Placebo n TB s³» y r 0 ¾ y ƒ w ƒ 0 z l Placebo n UDCA n w ùkù (igure ). UDCA n Placebo n AST s³» y r 0 ¾ y ƒ w ƒ 0 z l Placebo n UDCA n w ùkù (igure ). UDCA n Placebo n ALT s³» y r 0 ¾ y ƒ w ƒ 0 z l Placebo n UDCA n w ùkù (igure ). UDCA n Placebo n ALP s³» y r 0 ¾ y ƒ w ƒ 0 z l Placebo n Table. Comparison of TB(mg/dL) between UDCA and Placebo groups Patients Baseline* mean±sd Range UDCA group Placebo group. 0... 0. 0. 0. 0. 0..... 0. 0.. *total bilirubine at the onset of TPN 0.0±0. 0.±0..00±0. 0.±..0±.0 0.±0.0 0.±0. 0.0±0.00 0.±0.0 0.0±0.00.0±..±..±. 0.±0. 0.±0. 0.0±0..0±.00 0.-. 0.-0. 0.-. -.0.-. 0.-0. 0.-. 0. 0.-0. 0..-..-..-. 0.-. 0.-0. 0.-0..-. Table. Comparison of AST(U/L) between UDCA and Placebo groups Patients Baseline* mean±sd Range UDCA group Placebo group 0 00 0 *AST at the onset of TPN.±..0±..±..±0.0.00±..±..±0..±..0±..±..00±.0.0±.0 0.±..0±..0±..±..0±.0-0- - - - - - - - - - - - - - 0- - Table. Comparison of liver function studies between UDCA and Placebo groups Liver function studies UDCA group mean±sd (N=) Placebo group mean±sd (N=) p value Total bilirubin(mg/dl) AST(U/L) ALT(U/L) ALP(U/L).±..±.0.±.0.0±.00.±.0 0.±0. 0.±..±.0 0.00 0.0 0.0 0.0 AST, Aspartate Aminotransferase; ALT, Alanine Aminotransferase; ALP, Alkaline phosphatase
Kor. J. Clin. Pharm., Vol., No., 00 Table. Comparison of ALT(U/L) between UDCA and Placebo groups Patients Baseline* mean±sd Range UDCA group Placebo group 0 *ALT at the onset of TPN.0±..0±..±..±..00±0.00.±..±..00±.0.0±..±..00±..0±..±..00±.0.±.0.±..0±. - - - - - - - - - - - - -0-0 - - Table. Comparison of ALP(U/L) between UDCA and Placebo groups Patients Baseline* mean±sd Range UDCA group Placebo group 0 0 0 0 *ALP at the onset of TPN.±..±. 0.±..±0..0±..±0..±..±. 0.0±0..0±..±..00±..±0..0±..±. 0.±..±.0 - - - - - - 0-0- - - 0-0 -0 - - 0- - 0- ig.. Changes of Total Bilirubin levels in the UDCA (solid line) and Placebo (dotted line) group. UDCA n w ùkù (igure ).» e w sƒ w š ƒ TB, AST, ALT, ALP WBC, CRP, TP, Alb, Cholesterol, Calcium, Phosphate,,», (, s,, ), ig.. Changes of Aspartate Aminotransferase levels in the UDCA (solid line) and Placebo (dotted line) group. n, n, w mixed model ww w š q û w n TB, AST, ALT, ALP mixed model ww.. Total billirubin (TB) TB w UDCA n Placebo n Table. Comparison of TPN composition between UDCA and Placebo groups TPN composition UDCA group mean±sd (N=) Placebo group mean±sd (N=) p value Dextrose (g/kg/day) Amino acid (g/kg/day) Lipid (g/kg/day) Calories (kcal/kg/day).0±..0±0..±.0.±..±..±0..±0..0±. 0. 0. 0. 0.00
w w Ursodeoxycholic acid z w ig.. Changes of Alanine Aminotransferase levels in the UDCA (solid line) and Placebo (dotted line) group. ig.. Changes of Alkaline Phosphatase levels in the UDCA (solid line) and Placebo (dotted line) group. Placebo n UDCA n w TB ù w (p=0.0). x ü total protein ƒ TB (p=0.00) tƒ CRP ƒ TB (p=0.0). ù TB (p=0.0) (volume) j TB (p= 0.0). n w y z w n ƒ TB (p<0.000). n ƒ w TB (p=0.00)(table ).. Aspartate Aminotransferase (AST) Table 0. actors contributing to increase of AST level Effects Girls (reference=boys) Albumin (g/dl) Dextrose (g/kg/d) Calcium (mg/dl) Phosphate (mg/dl) TPN Calories (kcal/kg/d) Placebo group (reference=udca group) TPN, Total Parenteral Nutrition AST w UDCA n Placebo n UDCA n Placebo n w AST ù w (p=0.). ƒ AST (p=0.00). x ü phosphate ƒ û AST (p=0.0) x ü calcium ƒ û AST (p=0.000). s ƒ AST š(p=0.00) x ü ƒ AST (p=0.000). û w ƒ AST (p=0.00)(table 0). Covariance Structure Spartial(power) 0.0 (p=0.00) 0. (p=0.000) 0. (p=0.00) -0. (p=0.000) -0. (p=0.0) -0.0 (p=0.00) -0.0 (p=0.). Alanine Aminotransferase (ALT) ALT w UDCA n Placebo n Placebo n UDCA n w ALT w (p=0.0). x ü calcium ƒ û ALT (p=0.0). s ƒ ALT š(p=0.000) n y z w w n ƒ ALT (p=0.00)(table ).. Alkaline phosphatase (ALP) Table. actors contributing to increase of TB level Covariance Structure Effects Compound Symmetry RDS a/w prematurity (reference= GI diseases).0 (p<.000) Volume of TPN (ml/kg/d) 0.00 (p=0.0) Infusion rate of TPN (ml/h) -0.0 (p=0.00) C-reactive protein (mg/dl) 0.0 (p=0.0) Total protein (g/dl) 0. (p=0.00) weight at the onset of TPN (kg) 0.0 (p=0.0) Placebo group (reference=udca group) 0. (p=0.0) RDS, Respiratory Distress Syndrome; a/w, associated with; GI, Gastrointestinal; TPN, Total Parenteral Nutrition
Kor. J. Clin. Pharm., Vol., No., 00 Table. actors contributing to increase of ALT level Effects RDS a/w prematurity (reference= GI diseases) Dextrose (g/kg/d) Calcium (mg/dl) Placebo group (reference=udca group) RDS, Respiratory Distress Syndrome; a/w, associated with; GI, Gastrointestinal Covariance Structure Compound Symmetry -0. (p=0.00) 0.0 (p=0.000) -0. (p=0.0) 0. (p=0.0) Table. actors contributing to increase of ALP level Effects RDS a/w prematurity (reference= GI diseases) Duration of TPN (days) Infusion rate of Lipid (ml/h) TPN Calories (kcal/kg/d) Placebo group (reference=udca group) RDS, Respiratory Distress Syndrome; a/w, associated with; GI, Gastrointestinal; TPN, Total Parenteral Nutrition Covariance Structure Compound Symmetry 0. (p=0.0) 0.00 (p=0.0) -0.0 (p=0.000) 0.00 (p=0.00) 0.0 (p=0.0) ALP w UDCA n Placebo n Placebo n UDCA n w ALP ù w (p=0.0). ALP š(p=0.00) ƒ w ALP (p=0.000). n» ƒw ALP (p=0.0). n w y z w n ƒ ALP (p= 0.0)(Table ). š Lindor UDCAƒ n ) y y š x k šw e. wì UDCA n w w w w UDCA z š w UDCA Placebo n w n y ALT w z ƒ.» w, x, e, w, e w»z y ). k halothane,, p s w ƒ DEHP [di(-ethyl-hexyl) phthalate]. w ƒ w y y» x» ³ w ³ e w w (ascending cholangitis) w. ³ ü (endotoxin) w ü ùký ). w w x» n (early exposure), w e,, k, z, w n»,,» -). UDCA n Placebo n w n w» s³ w w. Beale ) 000 g x» k» w w. n» ALP» ƒ š w.»» y x ù» n w š ). Vileisis w ) (. gm/kg/day) n š (. gm/kg/ day) n z y w ù š n y ùkû w sw (direct bilirubin) e ùkþ. w y w s n ƒ w. w w s
w w Ursodeoxycholic acid z w ü š ). n» TB, AST, ALT, ALP w ùkù. w UDCA n Placebo n n» s,,, w w ƒ. œ š) reamine œ š ƒ ƒw š x. reamine cystine sw š taurine sw. Cystine v p w ÿw cystine sw taurine š taurine k»,). Cystine cysteine e w, v w, û, û glutathione ùkú glutathione glutamic acid, cysteine, glycine. w taurine sw glycine s w ). t tyrosine, cysteine, branched chain amino acid v methionine, phenylalanine, glycine w»w x» n w ƒ w ). (source).% ravasol(r) % Aminosteril Ped (R). % Aminosteril Ped(R).% ravasol(r) sw aspartic acid cysteine w š tyrosine w.% ravasol(r) w 0..% ravasol(r) % Aminosteril Ped(R) w glycine w. x û ƒ ƒw š0)ƒ ù n» x AST w. y gastrin cholecystokinin z ùkü y g ü k,).» ww UDCA n (.%), Placebo n (.%) Placebo n ù w. w x š s e x z,, s y (hepatocyte ballooning) e glycogen s w ùkù s n y g s z ƒ f w,). n» AST ALT s ƒ w ù TB, ALP s ƒ w. w ƒ AST š ƒƒ ALP (volume) j TB. UDCA w» yw x. UDCA Chinese black bear y e» ). 0 UDCA y e k w y (pill) xk ). UDCA %¾ wš ù w» chenodeoxycholic acid bacterial epimerization w. UDCA dihydroxy chenodeoxycholic acid (CDCA) deoxycholic acid e yw α, βdihydroxy-β-cholan--oic (C H 0 O ). UDCA n 0-0%ƒ 0 % ƒ, 0% ƒ. y 0%ƒ (hepatic extraction). UDCA glycine, taurine sww š z y (enterohepatic circulation) w. ƒ ³ w -dehydroxylation lithocholic acidƒ. CDCA -dehydroxylation lithocholic acid UDCA lithocholic acid y. lithocholic acid yy(sulfation) sw z. lithocholic acid yy sw ƒ wù yy sw ƒ w lithocholic acid g w. UDCA cholesterol 0-0%¾ j cholesterol jš y ƒ g UDCA -0 mg/kg/day n ü 0%¾ ƒ š. x s x x UDCA sw cholic acid, CDCA, deoxycholic acid, lithocholic acid sww sw w w,-). UDCA y e (hydrophilic bile acid pool) y, z (choleretic effect), ü w s y, wapoptosis. y(primary biliary cirrhosis) UDCA z yw š x y (primary sclerosing cholangitis), ü (intrahepatic cholestasis of pregnancy), ûs (cystic fibrosis), w ƒ ü (progressive
Kor. J. Clin. Pharm., Vol., No., 00 familial intrahepatic cholestasis), y(graft versus host disease) e ù ƒ v w k ). CDCA cholic acid 0-0% w deoxycholic acid cholic acid ³ -dehydroxylation CDCA cholic acid, deoxycholic acid ƒ w 0% w ). n z ¾ - ¾ w ƒ ) w n w ƒ w z ù y š p w n y sww w e w» sw g. y x e» ƒ y w ) n mg/kg/min mg/kg/min w» šx w w ƒ. n» n w ƒ» w TB n ƒ TB ƒ w.» n y w x) UDCA(0 mg/kg/d) yw t z ƒ. m UDCA š w ù. UDCA m0) ù UDCA n. UDCA n y ƒ UDCA n w y y z w. Heubi w w ) w tauroursodeoxycholic acid (TUDCA) ƒ 00 t. UDCA w z k w ù w TUDCA z w w. ³ s z ƒ lithocholic qx (sepsis) acid w ƒ j ) w ƒ w x ). n» TB t CRP w ùkû. ü e ). ü n y w ù n ü calcium x ƒ AST, ALT w. ALT p s ) TB, AST, ALT, ALP» UDCA n Placebo n w ALT. ¾ w w UDCA e z w ù z w š.. w» e y» w n»» y w UDCA z w. w yw z w w, ƒ. y ƒ. y n UDCA n Placebo n š y y vx w Placebo n ƒ vx 0% w ³x. w y ƒ» UDCA n Placebo n k ƒ.» w sw (direct bilirubin) p z GGT y w w. y UDCA Placebo n n z sw GGT ƒ». Duerksen k ù ö ) z xw w ü UDCA n w. w x UDCA n ƒ w. ) n ƒ ƒ w y w ù UDCA ƒ w ƒ n n ƒ ƒ w n y w». w y gastrin cholecystokinin g ƒ ú š ). n w ƒ ¼ w ù yw mixed model ww w. n w w w w UDCA n w yw z w w ù n ƒ w š UDCA n w.
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