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doi: 10.1111/ped.12609
Pediatrics International (2015) 57, 677–681
Original Article
Parenteral nutrition-associated liver disease in extremely low-birthweight infants with intestinal disease Katsuhisa Hirano,1 Akio Kubota,1 Masahiro Nakayama,2 Hisayoshi Kawahara,1 Akihiro Yoneda,1 Yuko Tazuke,1 Gakuto Tani,1 Tomohiro Ishii,1 Taro Goda,1 Satoshi Umeda,1 Shinya Hirno,3 Jun Shiraishi3 and Hirnoyuki Kitajima3 1 Pediatric Surgery, 2Clinical Laboratory Medicine and Anatomic Pathology and 3Neonatal Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan Abstract
Background: The aim of this study was to investigate factors associated with the development of parenteral nutritionassociated liver disease (PNALD) and to examine the clinicopathological relationship of PNALD in extremely lowbirthweight infants (ELBWI). Methods: The subjects were 13 ELBWI who had received PN because of intestinal perforation or functional ileus between 2000 and 2013. We measured the serum levels of biochemical parameters, including aspartate aminotransferase, alanine aminotransferase, and direct bilirubin. Liver histopathology was examined in relation to outcome. The subjects were categorized into two groups on liver histopathology: F(+), development of hepatic fibrosis and necrosis with/ without cholestasis; and F(−), no hepatic fibrosis. Results: Of 13 ELBWI, five died of hepatic failure, five died of sepsis, and the other three were alive at the time of the study. Of the five infants who died of hepatic failure, two developed fulminant hepatitis without cholestasis, and the other three developed chronic cholestasis and finally hepatic failure. Postmortem histopathology in F(+) indicated not only massive hepatic necrosis, but also massive hepatic fibrosis. These histopathological findings explained the clinical presentation of portal hypertension. There were significant differences in the fasting period after intestinal disease onset between the two groups. Conclusion: The prolonged fasting with PN is responsible for severe hepatocellular necrosis with fibrosis and consequent lethal portal hypertension.
Key words extremely low-birthweight infant, functional intestinal obstruction, hepatic failure, hepatic fibrosis, intestinal perforation, parenteral nutrition-associated liver disease.
Although parenteral nutrition (PN) has contributed enormously to improving the clinical outcome of infants who are unable to be fed because of various medical or surgical conditions of the intestine, in the early days PN was often associated with complications including catheter-related bloodstream infection or liver dysfunction,1,2 which have been responsible for deaths of infants with intestinal disease. PN-associated liver disease (PNALD) in neonates or infants mainly presents as cholestasis, which usually resolves with the resumption of enteral nutrition (EN), but in intractable cases it may lead to irreversible hepatic fibrosis and cirrhosis.3,4 Extremely low-birthweight infants (ELBWI) with gastrointestinal disease, including necrotizing enterocolitis (NEC), focal intestinal perforation (FIP)5–9 and meconiumrelated ileus (MRI),10–12 require PN with long-term fasting, which may cause intractable PNALD. The influence of PN on the premature liver has remained unclear, especially in ELBWI. The aim of this study was to investigate factors in the development of Correspondence: Katsuhisa Hirano, MD, 840, Murodocho, Izumi, Osaka 594-1101, Japan. Email: [email protected] Received 15 May 2014; revised 3 January 2015; accepted 4 February 2015.
© 2015 Japan Pediatric Society
PNALD and to elucidate the clinicopathological relationship of PNALD in ELBWI who received PN because of surgical or medical conditions.
Methods Thirty-five ELBWI received PN because of intestinal perforation or functional ileus between 2000 and 2013. They were without other severe anomalies. In 16 of the 35 ELBWI, liver samples were obtained from liver biopsy (n = 5) and autopsy (n = 11). Institutional review board approval was obtained for enrollment in the study. Three infants were excluded from the study, because one had inadequate medical records, and two were diagnosed with mitochondrial respiratory chain disorder and neonatal hemochromatosis, which influenced the liver histopathology, leaving a total of 13 ELBWI enrolled in this retrospective study. All ELBWI received the same PN protocol, described as follows: amino acid formulation (AA) was started from 1 day of age at 1 g/kg/day. AA was increased from 1 to 3 g/kg/day until milk intake was >80 mL/kg/day. Fat emulsion (Intralipos injection 10%; Otsuka Pharmaceutical Co., LTD, Tokyo, Japan) was started from 6 days old at 0.5 g/kg/day and increased until 2 g/kg/day. This protocol was adjusted according to patient
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Table 1 Outcome and maximum serum liver enzyme concentration in ELBWI Maximum AST (IU/L) ALT (IU/L) D-bil (mg/dL)
Alive 184 (74–254) 69 (10–223) 4.0 (3.6–10.2)
Died of sepsis 139 (49–623) 15 (7–65) 10.6 (0.4–16.4)
Died of hepatic failure 367 (76–2062) 147 (16–203) 15.7 (3–41.6)
P-value 0.153 0.102 0.401
Cholestasis is defined as d-bil > 2.0 mg/dL. ALT, alanine aminotransferase; AST, aspartate aminotransferase; d-bil, direct bilirubin; ELBWI, extremely low-birthweight infant.
condition (e.g. serum blood urea nitrogen level and infection etc.). PN was continued until EN dose was >100 g/kg/day. PN-associated cholestasis was defined as serum direct bilirubin (d-bil) >2.0 mg/dL.12–14 Laboratory data, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and d-bil, were compared among infant groups classified based on clinical outcome: death due to hepatic failure; death due to sepsis; or survival. Portal hypertension was identified on abdominal ultrasound. The ELBWI were categorized into two groups based on hepatic histopathology: those who developed fibrosis and necrosis (F(+)) and those who did not develop fibrosis (F(−)). Histopathology was analyzed in relation to clinical outcome, and the factors most responsible for necrosis and fibrosis were investigated. The factors included gestational age, birthweight, age at start of EN, age at onset of pathological condition (PC), absence or presence of surgical treatment, EN before PC onset, total duration of PN, duration of PN before PC onset, and fasting period with PN after PN onset. Statistical analysis
Data are given as median and range. Statistical analysis was performed with Mann–Whitney U-test, Wilcoxon signed-rank test, Kruskal–Wallis H-test, and chi-squared test. P < 0.05 was deemed statistically significant. Statistical calculations were performed using JMP (SAS Institute Inc, Cary, NC, USA).
Results Pathological condition included MRI (n = 6), NEC (n = 5), FIP (n = 1) and strangulation ileus with internal hernia (n = 1). Of the 13 infants, three survived and 10 eventually died. Five infants died
of hepatic failure and the remaining five died of sepsis. All infants who died of sepsis were not found to have pneumonia. The sepsis occurred due to catheter-related bloodstream infection or enteritis. In infants who died of sepsis, two died by the age of 8 days. Maximum serum AST, ALT, and d-bil concentration are given in Table 1. Serum AST, ALT, and d-bil concentration tended to be higher in infants who died of hepatic failure than in those in the other two groups, but there was no significant difference among the three groups. In the two infants who died of sepsis by 8 days of age, serum d-bil concentration was 2.0 mg/dL. ALT, alanine aminotransferase; AST, aspartate aminotransferase; d-bil, direct bilirubin; ELBWI, extremely low-birthweight infant.
nificant difference between the two groups. Serum ALT concentration in F(+) was significantly higher than that in F(−) (P < 0.05; Table 4), suggesting that diffuse hepatic necrosis was more severe in F(+) than in F(−). Suspected risk factors for hepatic fibrosis are listed in Table 5. There was no significant difference in age at the onset of PC, incidence of EN before PC onset (%), age at first EN, duration of PN before onset, and age of developing cholestasis between F(−) and F(+). Duration of PN was longer in F(+) than in F(−), but was not significantly different between the two groups (P > 0.05). The fasting period after PC onset was significantly longer in F(+) than in F(−) (P < 0.01). On ultrasonography, portal vein reflux, or hepatofugal flow was identified in four of five infants who died of hepatic failure. This explains the clinical presentation of portal hypertension.
b
Discussion
Fig. 1 Liver histopathology in two extremely low-birthweight infants with hepatic fibrosis (F(+)): one (a) survived and one (b) died of hepatic failure. (a) Normal hepatic lobules and portal-to-portal fibrosis are observed. (b) There are no normal hepatic cells, whereas extensive hepatic necrosis, diffuse fibrosis and pseudo-glandular proliferation are seen.
two groups are shown in Table 3. There was no significant difference in sex, gestational age, birthweight, or diagnosis between the two groups. Maximum serum AST and d-bil concentration tended to be higher in F(+) than in F(−), but there was no sig-
Parenteral nutrition-associated liver disease is a common complication in young infants who receive PN. The etiology of PNALD is multifactorial; most factors responsible for PNALD have not been determined, and they vary among individual cases. Previous studies indicated that risk factors for PNALD were prematurity, low birthweight,15–18 NEC,17,19–21 long duration of PN,15–17,22,23 and bacterial translocation.24,25 In most cases in term infants, PNALD is commonly thought to be alleviated by the initiation or resumption of EN, and to normalize after the establishment of full EN.26 Liver function, however, sometimes deteriorates with the initiation or resumption of EN after fasting with PN, and leads to portal hypertension in ELBWI with gastrointestinal diseases.27,28 In this series, the main causes of death were sepsis and hepatic failure, and the histology of the associated changes between these
Table 3 Characteristics of ELBWI
Sex (M/F) Gestational age (weeks), median (range) Birthweight (g), median (range) Pathological condition Necrotizing enterocolitis Focal intestinal perforation Meconium-related ileus Strangulation ileus Perforation of intestine Dead/Alive
F(−) (n = 6) 4/2 24.5 (22.5–25.3) 552 (374–924)
F(+) (n = 7) 7/0 26.0 (22.6–28.4) 486 (434–974)
P-value 0.900 0.197 0.567
2 0 3 1 2 4/2
3 1 3 0 3 6/1
0.992
0.731 0.416
ELBWI, extremely low-birthweight infant.
© 2015 Japan Pediatric Society
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Table 5 Risk factors for hepatic fibrosis in ELBWI
Surgical treatment Jejunostomy Ileostomy Anastomosis Gastrografin enema Onset of PC (days of age) Received EN before onset (%) Age at first EN (days) Days of PN before onset (days) Fasting period after onset (days) Development of cholestasis (days of age) Duration of PN (days)
F(−) (n = 6) n, % or median (range) 1 1 0 0 3 7.5 (1–49) 100 3.5 (0–7) 3.5 (1–77) 2.5 (1–11) 9 (2–51) 23.5 (4–106)
F(+) (n = 7) n, % or median (range) 5 2 3 0 2 8 (1–77) 85.7 3 (0–18) 3.0 (0–33) 15 (7–56) 12 (10–35) 77 (36–160)
P-value 0.156
0.775 0.300 0.532 0.583 0.0006 0.519 0.063
ELBWI, extremely low-birthweight infant; EN, enteral nutrition; PC, pathological condition; PN, parenteral nutrition.
two causes was different. The two infants who died of sepsis without cholestasis had no histopathological findings of intrahepatic cholestasis, and the other three infants did have intrahepatic cholestasis. One of five infants who died of sepsis had extensive hepatic fibrosis and pseudo-glandular proliferation without hepatic necrosis. These clinical courses and histopathological findings suggest that only early death prevents hepatic fibrosis. In contrast, the infants who died of hepatic failure had extensive hepatic fibrosis, disappearance of hepatic lobules, diffuse hepatic necrosis and pseudo-glandular proliferation. These hepatic changes are different from those of PN-associated cholestasis usually encountered in term infants, and these findings may be specific for ELBWI with intestinal disease. The lack of fatty degeneration in the liver also suggests that these hepatic disease are not simply caused by PN. The duration of fasting with PN after the onset of intestinal disease was significantly longer in ELBWI with hepatic fibrosis. It was reported that a prolonged period of fasting caused atrophy of intestinal mucosa and of gut-associated lymphoid tissue, and a reduction in secretary immunoglobulin-A.12,13 Bacterial translocation followed by small bowel bacterial overgrowth possibly causes hepatic injury and the development of PNALD. In order to prevent intestinal mucosal atrophy, trophic feeding has been strongly recommended.15 Although EN was initiated as soon as possible, trophic feeding is difficult in ELBWI with gastrointestinal disease. Other promising strategies to prevent PNALD and rescue ELBWI with gastrointestinal disease could be fish oilbased lipid emulsion. The use of fish oil-based emulsion is recommended in children with PNALD.4 The beneficial effects of fish oil-based lipid emulsion (Omegaven; Fresenius Kabi, Bad Homburg, Germany) are attributed to their anti-inflammatory properties. Raptis et al. reported that the mechanism of the hepatic protective effect of Omegaven was via an antiinflammatory signal through the GPR120 fatty acid receptor on Kupffer cells.14 Puder et al. reported that fish oil was safe and contributed to improved outcome in infants with PNALD with short bowel syndrome.29 In order to improve the survival rate of ELBWI with gastrointestinal disease, a new strategy such as fish oil-based lipid emulsion is needed. © 2015 Japan Pediatric Society
The number of ELBWI in the present study was too small to define the factors of PNALD, but the presence of massive hepatic necrosis and fibrosis with pseudo-glandular proliferation was confirmed in this study. The present results also suggest an association between the fasting period with PN and these hepatic changes. In order to identify the factors associated with this hepatic disease and prevent the development of hepatic failure, more research is necessary. Conclusion
Histological changes in the liver in ELBWI with intestinal disease with PNALD can be categorized into two types: in one, the main change is intrahepatic cholestasis, which is usually reversible with resumption of EN; and in the other, the characteristic changes include severe hepatocellular necrosis with fibrosis and consequent portal hypertension and eventual hepatic failure. The prolonged fasting with PN is responsible for the development of the latter changes, which result in intolerance of EN and dependence on PN, with a subsequent malignant cycle and extremely poor prognosis.
References 1 Peden VH, Witzleben CL, Skelton MA. Total parenteral nutrition. J. Pediatr. 1971; 78: 180–81. 2 Kubota A, Yonekura T, Hoki M et al. Total parenteral nutritionassociated intrahepatic cholestasis in infants: 25 years’ experience. J. Pediatr. Surg. 2000; 35: 1049–51. 3 Stanko RT, Nathan G, Mendelow H et al. Development of hepatic cholestasis and fibrosis in patients with massive loss of intestine supported by prolonged parenteral nutrition. Gastroenterology 1987; 92: 197–202. 4 Buchman AL, Iyer K, Frer J. Parenteral nutrition-associated liver disease and the role for isolated intestine and intestine/liver transplantation. Hepatology 2006; 43: 9–19. 5 Tatekawa Y, Muraji T, Imai Y et al. The mechanism of focal intestinal perforation in neonates with low birth weight. Pediatr. Surg. Int. 1999; 15: 549–52. 6 Cass DL, Brandt ML, Patel DL et al. Peritoneal drainage as definitive treatment for neonates with isolated intestinal perforation. J. Pediatr. Surg. 2000; 35: 1531–6. 7 Okuyama H, Kubota A, Oue T et al. A comparison of the clinical presentation and outcome of focal intestinal perforation and
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necrotizing enterocolitis in very-low-birth-weight neonates. Pediatr. Surg. Int. 2002; 18: 704–6. Kubota A, Yamanaka H, Okuyama H et al. Focal intestinal perforation in extremely-low-birth-weight neonates: Etiological consideration from histological findings. Pediatr. Surg. Int. 2007; 23: 997–1000. Kubota A, Imura K, Kobayashi T et al. Meconium related ileus in a perinatal referring center. J. Jpn Soc. Neonatol. 1995; 31: 120– 27. Kubota A, Kawahara H, Okuyama H et al. Pathology and pathophysiology of meconium-related ileus. Jpn J. Pediatr. Surg. 2006; 38: 609–14. Kubota A, Shiraishi J, Kawahara H et al. Meconium-related ileus in extremely-low-birth-weight neonates: Etiological consideration from histological and radiological studies. Pediatr. Int. 2011; 53: 887–91. Kudsk KA, Wu Y, Fukatsu K et al. Glutamine-enriched total parenteral nutrition maintains intestinal interleukin-4 and mucosal immunoglobulin A levels. JPEN J. Parenter. Enteral Nutr. 2000; 24: 270–4. Genton L, Reese SR, Ikeda S et al. The C-terminal heptapeptide of bombein reduces the deleterious effect of total parenteral nutrition (TPN) on gut-associated lymphoid tissue (GALT) mass but not intestinal immunoglobulin A in vivo. JPEN J. Parenter. Enteral Nutr. 2004; 28: 431–4. Raptis DA, Limani P, Jang JH et al. GPR120 on Kupffer cells mediates hepatoprotective effects of ω-3 fatty acids. J. Hepatol. 2014; 60: 625–32. Rangel SJ, Calkins CM, Cowles RA et al. Parenteral nutritionassociated cholestasis: An American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review. J. Pediatr. Surg. 2012; 47: 225–40. Pereira GR, Sherman MS, DiGiacomo J et al. Hyperalimentationinduced cholestasis. Increased incidence and severity in premature infants. Am. J. Dis. Child. 1981; 135: 586–9. Beath SV, Davies P, Papadopoulou A et al. Parenteral nutritionrelated cholestasis in postsurgical neonates: Multivariate analysis of risk factors. J. Pediatr. Surg. 1996; 31: 604–6.
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18 Christensen RD, Henry E, Wiedmeier SE et al. Identifying patients, on the first day of life, at high-risk of developing parenteral nutrition associated liver disease. J. Perinatol. 2007; 27: 284–90. 19 Robinson DT, Ehrenkranz RA. Parenteral nutrition-associated cholestasis in small for gestational age infants. J. Pediatr. 2008; 152: 59–62. 20 Drongowski RA, Coran AG. An analysis of factors contributing to the development of total parenteral nutrition-induced cholestasis. JPEN J. Parenter. Enteral Nutr. 1989; 13: 586–9. 21 Spner AU, Yu S, Tracy TF et al. Parenteral nutrition-associated cholestasis in neonates: Multivariate analysis of the potential protective effect of taurine. JPEN J. Parenter. Enteral Nutr. 2005; 29: 337–43. 22 Beale EF, Nelson RM, Bucciarelli RL et al. Intrahepatic cholestasis associated with parenteral nutrition in premature infants. Pediatrics 1979; 64: 342–7. 23 Hoang V, Sills J, Chandler M et al. Percutaneously inserted central catheter for total parenteral nutrition in neonates: Complication rates related to upper versus lower extremity insertion. Pediatrics 2008; 121: 1152–9. 24 Sondheimer JM, Asturias E, Candnapaphornchai M. Infection and cholestasis in neonates with intestinal resection and long-term parenteral nutrition. J. Pediatr. Gastroenterol. Nutr. 1998; 27: 131–7. 25 Kubota A, Okada A, Imura K et al. The effect of metronidazole on TPN-associated liver dysfunction in neonates. J. Pediatr. Surg. 1990; 25: 618–21. 26 Kelly DA. Liver complications of pediatric parenteral nutrition – epidemiology. Nutrition 1998; 14: 153–7. 27 Javid PJ, Collier S, Richardson D et al. The role of enteral nutrition in the reversal of parenteral nutrition-associated liver dysfunction in infants. J. Pediatr. Surg. 2005; 40: 1015–18. 28 Kubota A, Mochizuki N, Shiraishi J et al. Parenteral-nutritionassociated liver disease after intestinal perforation in extremely low-birthweight infants: Consequent lethal portal hypertension. Pediatr. Int. 2013; 55: 39–43. 29 Puder M, Valim C, Meisel JA et al. Parenteral fish oil improves outcomes in patients with parenteral nutrition associated liver injury. Ann. Surg. 2009; 250: 395–402.
© 2015 Japan Pediatric Society
doi: 10.1111/ped.12609
Pediatrics International (2015) 57, 677–681
Original Article
Parenteral nutrition-associated liver disease in extremely low-birthweight infants with intestinal disease Katsuhisa Hirano,1 Akio Kubota,1 Masahiro Nakayama,2 Hisayoshi Kawahara,1 Akihiro Yoneda,1 Yuko Tazuke,1 Gakuto Tani,1 Tomohiro Ishii,1 Taro Goda,1 Satoshi Umeda,1 Shinya Hirno,3 Jun Shiraishi3 and Hirnoyuki Kitajima3 1 Pediatric Surgery, 2Clinical Laboratory Medicine and Anatomic Pathology and 3Neonatal Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan Abstract
Background: The aim of this study was to investigate factors associated with the development of parenteral nutritionassociated liver disease (PNALD) and to examine the clinicopathological relationship of PNALD in extremely lowbirthweight infants (ELBWI). Methods: The subjects were 13 ELBWI who had received PN because of intestinal perforation or functional ileus between 2000 and 2013. We measured the serum levels of biochemical parameters, including aspartate aminotransferase, alanine aminotransferase, and direct bilirubin. Liver histopathology was examined in relation to outcome. The subjects were categorized into two groups on liver histopathology: F(+), development of hepatic fibrosis and necrosis with/ without cholestasis; and F(−), no hepatic fibrosis. Results: Of 13 ELBWI, five died of hepatic failure, five died of sepsis, and the other three were alive at the time of the study. Of the five infants who died of hepatic failure, two developed fulminant hepatitis without cholestasis, and the other three developed chronic cholestasis and finally hepatic failure. Postmortem histopathology in F(+) indicated not only massive hepatic necrosis, but also massive hepatic fibrosis. These histopathological findings explained the clinical presentation of portal hypertension. There were significant differences in the fasting period after intestinal disease onset between the two groups. Conclusion: The prolonged fasting with PN is responsible for severe hepatocellular necrosis with fibrosis and consequent lethal portal hypertension.
Key words extremely low-birthweight infant, functional intestinal obstruction, hepatic failure, hepatic fibrosis, intestinal perforation, parenteral nutrition-associated liver disease.
Although parenteral nutrition (PN) has contributed enormously to improving the clinical outcome of infants who are unable to be fed because of various medical or surgical conditions of the intestine, in the early days PN was often associated with complications including catheter-related bloodstream infection or liver dysfunction,1,2 which have been responsible for deaths of infants with intestinal disease. PN-associated liver disease (PNALD) in neonates or infants mainly presents as cholestasis, which usually resolves with the resumption of enteral nutrition (EN), but in intractable cases it may lead to irreversible hepatic fibrosis and cirrhosis.3,4 Extremely low-birthweight infants (ELBWI) with gastrointestinal disease, including necrotizing enterocolitis (NEC), focal intestinal perforation (FIP)5–9 and meconiumrelated ileus (MRI),10–12 require PN with long-term fasting, which may cause intractable PNALD. The influence of PN on the premature liver has remained unclear, especially in ELBWI. The aim of this study was to investigate factors in the development of Correspondence: Katsuhisa Hirano, MD, 840, Murodocho, Izumi, Osaka 594-1101, Japan. Email: [email protected] Received 15 May 2014; revised 3 January 2015; accepted 4 February 2015.
© 2015 Japan Pediatric Society
PNALD and to elucidate the clinicopathological relationship of PNALD in ELBWI who received PN because of surgical or medical conditions.
Methods Thirty-five ELBWI received PN because of intestinal perforation or functional ileus between 2000 and 2013. They were without other severe anomalies. In 16 of the 35 ELBWI, liver samples were obtained from liver biopsy (n = 5) and autopsy (n = 11). Institutional review board approval was obtained for enrollment in the study. Three infants were excluded from the study, because one had inadequate medical records, and two were diagnosed with mitochondrial respiratory chain disorder and neonatal hemochromatosis, which influenced the liver histopathology, leaving a total of 13 ELBWI enrolled in this retrospective study. All ELBWI received the same PN protocol, described as follows: amino acid formulation (AA) was started from 1 day of age at 1 g/kg/day. AA was increased from 1 to 3 g/kg/day until milk intake was >80 mL/kg/day. Fat emulsion (Intralipos injection 10%; Otsuka Pharmaceutical Co., LTD, Tokyo, Japan) was started from 6 days old at 0.5 g/kg/day and increased until 2 g/kg/day. This protocol was adjusted according to patient
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Table 1 Outcome and maximum serum liver enzyme concentration in ELBWI Maximum AST (IU/L) ALT (IU/L) D-bil (mg/dL)
Alive 184 (74–254) 69 (10–223) 4.0 (3.6–10.2)
Died of sepsis 139 (49–623) 15 (7–65) 10.6 (0.4–16.4)
Died of hepatic failure 367 (76–2062) 147 (16–203) 15.7 (3–41.6)
P-value 0.153 0.102 0.401
Cholestasis is defined as d-bil > 2.0 mg/dL. ALT, alanine aminotransferase; AST, aspartate aminotransferase; d-bil, direct bilirubin; ELBWI, extremely low-birthweight infant.
condition (e.g. serum blood urea nitrogen level and infection etc.). PN was continued until EN dose was >100 g/kg/day. PN-associated cholestasis was defined as serum direct bilirubin (d-bil) >2.0 mg/dL.12–14 Laboratory data, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and d-bil, were compared among infant groups classified based on clinical outcome: death due to hepatic failure; death due to sepsis; or survival. Portal hypertension was identified on abdominal ultrasound. The ELBWI were categorized into two groups based on hepatic histopathology: those who developed fibrosis and necrosis (F(+)) and those who did not develop fibrosis (F(−)). Histopathology was analyzed in relation to clinical outcome, and the factors most responsible for necrosis and fibrosis were investigated. The factors included gestational age, birthweight, age at start of EN, age at onset of pathological condition (PC), absence or presence of surgical treatment, EN before PC onset, total duration of PN, duration of PN before PC onset, and fasting period with PN after PN onset. Statistical analysis
Data are given as median and range. Statistical analysis was performed with Mann–Whitney U-test, Wilcoxon signed-rank test, Kruskal–Wallis H-test, and chi-squared test. P < 0.05 was deemed statistically significant. Statistical calculations were performed using JMP (SAS Institute Inc, Cary, NC, USA).
Results Pathological condition included MRI (n = 6), NEC (n = 5), FIP (n = 1) and strangulation ileus with internal hernia (n = 1). Of the 13 infants, three survived and 10 eventually died. Five infants died
of hepatic failure and the remaining five died of sepsis. All infants who died of sepsis were not found to have pneumonia. The sepsis occurred due to catheter-related bloodstream infection or enteritis. In infants who died of sepsis, two died by the age of 8 days. Maximum serum AST, ALT, and d-bil concentration are given in Table 1. Serum AST, ALT, and d-bil concentration tended to be higher in infants who died of hepatic failure than in those in the other two groups, but there was no significant difference among the three groups. In the two infants who died of sepsis by 8 days of age, serum d-bil concentration was 2.0 mg/dL. ALT, alanine aminotransferase; AST, aspartate aminotransferase; d-bil, direct bilirubin; ELBWI, extremely low-birthweight infant.
nificant difference between the two groups. Serum ALT concentration in F(+) was significantly higher than that in F(−) (P < 0.05; Table 4), suggesting that diffuse hepatic necrosis was more severe in F(+) than in F(−). Suspected risk factors for hepatic fibrosis are listed in Table 5. There was no significant difference in age at the onset of PC, incidence of EN before PC onset (%), age at first EN, duration of PN before onset, and age of developing cholestasis between F(−) and F(+). Duration of PN was longer in F(+) than in F(−), but was not significantly different between the two groups (P > 0.05). The fasting period after PC onset was significantly longer in F(+) than in F(−) (P < 0.01). On ultrasonography, portal vein reflux, or hepatofugal flow was identified in four of five infants who died of hepatic failure. This explains the clinical presentation of portal hypertension.
b
Discussion
Fig. 1 Liver histopathology in two extremely low-birthweight infants with hepatic fibrosis (F(+)): one (a) survived and one (b) died of hepatic failure. (a) Normal hepatic lobules and portal-to-portal fibrosis are observed. (b) There are no normal hepatic cells, whereas extensive hepatic necrosis, diffuse fibrosis and pseudo-glandular proliferation are seen.
two groups are shown in Table 3. There was no significant difference in sex, gestational age, birthweight, or diagnosis between the two groups. Maximum serum AST and d-bil concentration tended to be higher in F(+) than in F(−), but there was no sig-
Parenteral nutrition-associated liver disease is a common complication in young infants who receive PN. The etiology of PNALD is multifactorial; most factors responsible for PNALD have not been determined, and they vary among individual cases. Previous studies indicated that risk factors for PNALD were prematurity, low birthweight,15–18 NEC,17,19–21 long duration of PN,15–17,22,23 and bacterial translocation.24,25 In most cases in term infants, PNALD is commonly thought to be alleviated by the initiation or resumption of EN, and to normalize after the establishment of full EN.26 Liver function, however, sometimes deteriorates with the initiation or resumption of EN after fasting with PN, and leads to portal hypertension in ELBWI with gastrointestinal diseases.27,28 In this series, the main causes of death were sepsis and hepatic failure, and the histology of the associated changes between these
Table 3 Characteristics of ELBWI
Sex (M/F) Gestational age (weeks), median (range) Birthweight (g), median (range) Pathological condition Necrotizing enterocolitis Focal intestinal perforation Meconium-related ileus Strangulation ileus Perforation of intestine Dead/Alive
F(−) (n = 6) 4/2 24.5 (22.5–25.3) 552 (374–924)
F(+) (n = 7) 7/0 26.0 (22.6–28.4) 486 (434–974)
P-value 0.900 0.197 0.567
2 0 3 1 2 4/2
3 1 3 0 3 6/1
0.992
0.731 0.416
ELBWI, extremely low-birthweight infant.
© 2015 Japan Pediatric Society
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Table 5 Risk factors for hepatic fibrosis in ELBWI
Surgical treatment Jejunostomy Ileostomy Anastomosis Gastrografin enema Onset of PC (days of age) Received EN before onset (%) Age at first EN (days) Days of PN before onset (days) Fasting period after onset (days) Development of cholestasis (days of age) Duration of PN (days)
F(−) (n = 6) n, % or median (range) 1 1 0 0 3 7.5 (1–49) 100 3.5 (0–7) 3.5 (1–77) 2.5 (1–11) 9 (2–51) 23.5 (4–106)
F(+) (n = 7) n, % or median (range) 5 2 3 0 2 8 (1–77) 85.7 3 (0–18) 3.0 (0–33) 15 (7–56) 12 (10–35) 77 (36–160)
P-value 0.156
0.775 0.300 0.532 0.583 0.0006 0.519 0.063
ELBWI, extremely low-birthweight infant; EN, enteral nutrition; PC, pathological condition; PN, parenteral nutrition.
two causes was different. The two infants who died of sepsis without cholestasis had no histopathological findings of intrahepatic cholestasis, and the other three infants did have intrahepatic cholestasis. One of five infants who died of sepsis had extensive hepatic fibrosis and pseudo-glandular proliferation without hepatic necrosis. These clinical courses and histopathological findings suggest that only early death prevents hepatic fibrosis. In contrast, the infants who died of hepatic failure had extensive hepatic fibrosis, disappearance of hepatic lobules, diffuse hepatic necrosis and pseudo-glandular proliferation. These hepatic changes are different from those of PN-associated cholestasis usually encountered in term infants, and these findings may be specific for ELBWI with intestinal disease. The lack of fatty degeneration in the liver also suggests that these hepatic disease are not simply caused by PN. The duration of fasting with PN after the onset of intestinal disease was significantly longer in ELBWI with hepatic fibrosis. It was reported that a prolonged period of fasting caused atrophy of intestinal mucosa and of gut-associated lymphoid tissue, and a reduction in secretary immunoglobulin-A.12,13 Bacterial translocation followed by small bowel bacterial overgrowth possibly causes hepatic injury and the development of PNALD. In order to prevent intestinal mucosal atrophy, trophic feeding has been strongly recommended.15 Although EN was initiated as soon as possible, trophic feeding is difficult in ELBWI with gastrointestinal disease. Other promising strategies to prevent PNALD and rescue ELBWI with gastrointestinal disease could be fish oilbased lipid emulsion. The use of fish oil-based emulsion is recommended in children with PNALD.4 The beneficial effects of fish oil-based lipid emulsion (Omegaven; Fresenius Kabi, Bad Homburg, Germany) are attributed to their anti-inflammatory properties. Raptis et al. reported that the mechanism of the hepatic protective effect of Omegaven was via an antiinflammatory signal through the GPR120 fatty acid receptor on Kupffer cells.14 Puder et al. reported that fish oil was safe and contributed to improved outcome in infants with PNALD with short bowel syndrome.29 In order to improve the survival rate of ELBWI with gastrointestinal disease, a new strategy such as fish oil-based lipid emulsion is needed. © 2015 Japan Pediatric Society
The number of ELBWI in the present study was too small to define the factors of PNALD, but the presence of massive hepatic necrosis and fibrosis with pseudo-glandular proliferation was confirmed in this study. The present results also suggest an association between the fasting period with PN and these hepatic changes. In order to identify the factors associated with this hepatic disease and prevent the development of hepatic failure, more research is necessary. Conclusion
Histological changes in the liver in ELBWI with intestinal disease with PNALD can be categorized into two types: in one, the main change is intrahepatic cholestasis, which is usually reversible with resumption of EN; and in the other, the characteristic changes include severe hepatocellular necrosis with fibrosis and consequent portal hypertension and eventual hepatic failure. The prolonged fasting with PN is responsible for the development of the latter changes, which result in intolerance of EN and dependence on PN, with a subsequent malignant cycle and extremely poor prognosis.
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