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Nutritional effects of alanyl-glutamine after liver transplantation in pigs
Nutritional Effects of Alanyl-Glutamine After Liver Transplantation in Pigs T. Azuma, W. Gu, A. Mizoe, J. Yamaguchi, H. Fujioka, and T. Kanematsu
P
ARENTERAL nutritional support in the early period after liver transplantation was reported to enhance muscle strength and shorten the period of stay in the intensive care unit.1 On the other hand, in patients with total parenteral nutrition (TPN), bacterial translocation into the portal vein through the atrophic intestinal mucosa is a problem.2 Although glutamine has beneficial effects on the morphology of the intestinal mucosa,2,3 commercially available amino acid solutions do not contain this amino acid because it is unstable in aqueous solutions. Recently, alanyl-glutamine (Ala-Gln) proved to be a soluble and stable form of glutamine in solutions.4 We reported that Ala-Gln prevented atrophy of the intestinal mucosa and reduced endotoxin levels in the portal vein after liver transplantation in pigs.5 We evaluated the difference between Ala-Gln and standard amino acids as a supplement to conventional TPN in an experimental liver transplantation model.
MATERIALS AND METHODS Fifteen pairs of female piglets weighing between 20 and 25 kg were used for orthotopic liver transplantation using standard procedures.5 The recipients were assigned to three groups according to the postoperative nutritional regimen: Group I had conventional TPN (total energy 41.0 kcal/kg per day, glucose 8.8 g/kg per day, total nitrogen 0.24 g/kg per day, n 5 4), Group II had Ala-Glnsupplemented conventional TPN (total energy 45.0 kcal/kg per day, glucose 8.8 g/kg per day, total nitrogen 0.43 g/kg per day, n 5 7). Group III had standard amino acids-enriched conventional TPN (total energy 45.0 kcal/kg per day, glucose 8.8 g/kg per day, total nitrogen 0.43 g/kg per day, n 5 4). The dosage of Ala-Gln was 1000 mg/kg body weight per day and the concentration in total amino acids solution was 26% in group II. The compositions of groups II and III had the same calorie and nitrogens. In all the groups, TPN solutions were half strength on postoperative day 1 and full strength after day 2. To assess the nutritional status, serum levels of albumin and urinary levels of 3-methylhistidine were monitored. Serum levels of glutamic oxaloacetic transaminase (GOT) as a grafted liver function and endotoxin levels in portal blood were also examined for up to 7 days. The animals were sacrificed on the postoperative day 7. The thickness of ileal mucosa was microscopically measured.
Fig 1. Serum levels of glutamic oxaloacetic transaminase in group III were significantly elevated compared to groups I and II on postoperative day 7.
RESULTS AND DISCUSSION
There was no significant difference in serum levels of albumin among the three groups. On the other hand, urinary levels of 3-methylhistidine in group III were significantly higher than the other two groups after postoperative day 5. Serum GOT levels after liver transplantation had a peak value over 700IU/L on the postoperative day 1 in all the groups. Although GOT levels decreased after day 3 in groups I and II, respectively, the levels in group III increased again (Fig 1). The mean thickness of the ileal mucosae taken from 12 donors, as control, was 60.0 6 7.9 mm. Seven days after liver transplantation, the thickness of the ileal mucosa was 44.7 6 0.8 mm in group I, 51.1 6 5.5 mm in group II, and 49.5 6 0.7 mm in group III. The thickness of ileal mucosa in groups I and III were significantly shortened compared to that of control, while there was no significant difference between group II and control. After liver transplantation, the mean endotoxin levels in the portal vein increased to more than 200 pg/mL on postoperative day 3 in all the
From the Department of Surgery II, Nagasaki University School of Medicine, Nagasaki, Japan. Address reprint requests to Takashi Azuma, Department of Surgery II, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852, Japan.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)01203-2
Transplantation Proceedings, 30, 3705–3706 (1998)
3705
3706
AZUMA, GU, MIZOE ET AL
of the ileal mucosa and reduced endotoxin level in the portal vein after liver transplantation.5 In this study, addition of standard amino acids, the same nitrogen volume of Ala-Gln, deteriorated nutritional parameter and liver function test after liver transplantation. These results suggest that grafted liver was intolerant of excess standard amino acids in the early period after the operation, and Ala-Gln proved to be a beneficial nutrient after liver transplantation in pigs.
REFERENCES Fig 2. Levels of endotoxin in portal blood in group II were significantly decreased compared with group I on postoperative day 7.
groups. By day 7, levels in group II had reverted to preoperative values, whereas those in group I had increased again (Fig 2). We previously reported that Ala-Gln prevented atrophy
1. Reilly D, Mehta R, Teperman L, et al: J Parent Enter Nutr 14:386, 1990 2. Smith RJ, Wilmore DW: J Parent Enter Nutr 14:94S, 1990 3. Zhang W, Frankel WL, Singh A, et al: Transplantation 56:512, 1993 4. Scheppach W, Loges C, Bartram P, et al: Gastroenterology 107:429, 1994 5. Azuma T, Tanaka K, Gu W, et al: J Hepat Panc Surg 4:113, 1997
P
ARENTERAL nutritional support in the early period after liver transplantation was reported to enhance muscle strength and shorten the period of stay in the intensive care unit.1 On the other hand, in patients with total parenteral nutrition (TPN), bacterial translocation into the portal vein through the atrophic intestinal mucosa is a problem.2 Although glutamine has beneficial effects on the morphology of the intestinal mucosa,2,3 commercially available amino acid solutions do not contain this amino acid because it is unstable in aqueous solutions. Recently, alanyl-glutamine (Ala-Gln) proved to be a soluble and stable form of glutamine in solutions.4 We reported that Ala-Gln prevented atrophy of the intestinal mucosa and reduced endotoxin levels in the portal vein after liver transplantation in pigs.5 We evaluated the difference between Ala-Gln and standard amino acids as a supplement to conventional TPN in an experimental liver transplantation model.
MATERIALS AND METHODS Fifteen pairs of female piglets weighing between 20 and 25 kg were used for orthotopic liver transplantation using standard procedures.5 The recipients were assigned to three groups according to the postoperative nutritional regimen: Group I had conventional TPN (total energy 41.0 kcal/kg per day, glucose 8.8 g/kg per day, total nitrogen 0.24 g/kg per day, n 5 4), Group II had Ala-Glnsupplemented conventional TPN (total energy 45.0 kcal/kg per day, glucose 8.8 g/kg per day, total nitrogen 0.43 g/kg per day, n 5 7). Group III had standard amino acids-enriched conventional TPN (total energy 45.0 kcal/kg per day, glucose 8.8 g/kg per day, total nitrogen 0.43 g/kg per day, n 5 4). The dosage of Ala-Gln was 1000 mg/kg body weight per day and the concentration in total amino acids solution was 26% in group II. The compositions of groups II and III had the same calorie and nitrogens. In all the groups, TPN solutions were half strength on postoperative day 1 and full strength after day 2. To assess the nutritional status, serum levels of albumin and urinary levels of 3-methylhistidine were monitored. Serum levels of glutamic oxaloacetic transaminase (GOT) as a grafted liver function and endotoxin levels in portal blood were also examined for up to 7 days. The animals were sacrificed on the postoperative day 7. The thickness of ileal mucosa was microscopically measured.
Fig 1. Serum levels of glutamic oxaloacetic transaminase in group III were significantly elevated compared to groups I and II on postoperative day 7.
RESULTS AND DISCUSSION
There was no significant difference in serum levels of albumin among the three groups. On the other hand, urinary levels of 3-methylhistidine in group III were significantly higher than the other two groups after postoperative day 5. Serum GOT levels after liver transplantation had a peak value over 700IU/L on the postoperative day 1 in all the groups. Although GOT levels decreased after day 3 in groups I and II, respectively, the levels in group III increased again (Fig 1). The mean thickness of the ileal mucosae taken from 12 donors, as control, was 60.0 6 7.9 mm. Seven days after liver transplantation, the thickness of the ileal mucosa was 44.7 6 0.8 mm in group I, 51.1 6 5.5 mm in group II, and 49.5 6 0.7 mm in group III. The thickness of ileal mucosa in groups I and III were significantly shortened compared to that of control, while there was no significant difference between group II and control. After liver transplantation, the mean endotoxin levels in the portal vein increased to more than 200 pg/mL on postoperative day 3 in all the
From the Department of Surgery II, Nagasaki University School of Medicine, Nagasaki, Japan. Address reprint requests to Takashi Azuma, Department of Surgery II, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852, Japan.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)01203-2
Transplantation Proceedings, 30, 3705–3706 (1998)
3705
3706
AZUMA, GU, MIZOE ET AL
of the ileal mucosa and reduced endotoxin level in the portal vein after liver transplantation.5 In this study, addition of standard amino acids, the same nitrogen volume of Ala-Gln, deteriorated nutritional parameter and liver function test after liver transplantation. These results suggest that grafted liver was intolerant of excess standard amino acids in the early period after the operation, and Ala-Gln proved to be a beneficial nutrient after liver transplantation in pigs.
REFERENCES Fig 2. Levels of endotoxin in portal blood in group II were significantly decreased compared with group I on postoperative day 7.
groups. By day 7, levels in group II had reverted to preoperative values, whereas those in group I had increased again (Fig 2). We previously reported that Ala-Gln prevented atrophy
1. Reilly D, Mehta R, Teperman L, et al: J Parent Enter Nutr 14:386, 1990 2. Smith RJ, Wilmore DW: J Parent Enter Nutr 14:94S, 1990 3. Zhang W, Frankel WL, Singh A, et al: Transplantation 56:512, 1993 4. Scheppach W, Loges C, Bartram P, et al: Gastroenterology 107:429, 1994 5. Azuma T, Tanaka K, Gu W, et al: J Hepat Panc Surg 4:113, 1997