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Nocturnal energy and BCAA supplementation in patients with liver cirrhosis
Hepatology Research 30S (2004) S63–S66
Nocturnal energy and BCAA supplementation in patients with liver cirrhosis Yoshiyuki Miwa∗ , Hisataka Moriwaki The First Department of Internal Medicine, Gifu University School of Medicine, Japan Accepted 9 August 2004
Abstract Patients with liver cirrhosis have protein-energy malnutrition (PEM) and run short of proteins and energy. Protein deficiency leads to hypoalbuminemia, which induces peritoneal effusion and edema. Energy deficiency decreases fat and muscle mass and causes muscle weakness, which decreases the QOL of these patients. A decrease in triceps skinfold thickness (TSF) and arm muscle circumference (AMC), which are indicators of hypoalbuminemia and energy deficiency, and a decrease in respiratory quotient (RQ) affect the prognosis of these patients. Therefore, appropriate nutritional assessment should be performed in order to detect PEM in these patients, and necessary proteins or energy should be supplied. TSF, AMC and RQ are improved by increasing the energy supply to correct its deficiency and by dividing daily food intake (in some cases, adding nocturnal supplementation). Serum albumin levels increase when branched-chain amino acids (BCAAs) are administered after every meal or at bedtime. Consequently, nutritional assessment on PEM, and nutritional therapy based on this assessment are essential for improving the QOL and prognosis of patients with liver cirrhosis. © 2004 Elsevier B.V. All rights reserved. Keywords: Protein-energy malnutrition; Nocturnal energy supplementation; Nocturnal BCAA supplementation
1. PEM and prognosis of patients with liver cirrhosis Patients with liver cirrhosis have protein-energy malnutrition (PEM) and run short of proteins and energy. Protein deficiency leads to a decrease in visceral proteins such as albumin and to decreased immunity. Decreased energy leads to decreased fat and muscle mass. Therefore, PEM affects the QOL and prognosis of patients with liver cirrhosis [1,2]. The occurrence frequency of PEM in patients with liver cirrhosis is very high (50%) [3]. For patients with liver cirrhosis, the serum albumin level and muscle mass are used as indicators of protein malnutrition, and body weight, fat mass, muscle mass and respiratory quotient measured with an indirect calorimeter are used as indicators of energy malnutrition. Decreases in these indicators deteriorate the prognosis of these patients. It has been ∗ Corresponding author. Present address: MIWA CLINIC, 3-3 NagaraHigashi, Gifu 502-0082, Japan. E-mail address: [email protected].
1386-6346/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.hepres.2004.08.012
reported that patients with a serum albumin level of 3.5 g/dl or more have a better prognosis than patients with a serum albumin level of less than 3.5 g/dl [4,5]. It has also been reported that the prognosis of patients with a triceps skinfold thickness (TSF) and arm muscle circumference (AMC) in or below the fifth percentile is worse than that of patients who have corresponding measurements above the fifth percentile [6]. An examination of energy metabolism in the early morning fasting state, using an indirect calorimeter, showed that the respiratory quotient (RQ) decreased in patients with liver cirrhosis, and that a decreased RQ worsened the prognosis [3]. In patients with liver cirrhosis, liver atrophy is observed, which decreases glycogen storage in the liver. Due to this, patients with liver cirrhosis in the early morning fasting state have a similar metabolic state to normal people who have fasted for 3 days. Sugar-burning decreases and fat-burning increases when patients with liver cirrhosis are in the early morning fasting state [7]. Moreover, patients with liver cirrhosis have an increased energy metabolism at rest [8]. This metabolic state of patients with liver cirrhosis decreases body
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fat and muscle mass, and ultimately leads to deterioration in the state of PEM.
2. Nocturnal energy supplementation Eating the proper quantity of food three times a day is sometimes effective for improving energy deficiency in patients with liver cirrhosis. When patients with alcoholic liver cirrhosis were given three meals per day for 1 month, which contained an energy intake of 40 kcal/kg/day and a protein intake of 1.4 g/kg/day, the RQ improved, the muscle and fat mass increased, and the serum albumin level also increased [9]. However, nocturnal energy supplementation is effective when the total caloric intake from the three regular meals is insufficient, or when it is necessary to prevent the early morning fasting state. Dividing daily food intake into more than three meals is effective when patients need to be prevented from early morning fasting, even though their daily energy intake is sufficient. Swart et al. fixed the daily energy and protein intake and gave patients with liver cirrhosis three meals per day, four meals per day (including late evening snack (LES)) or six meals per day (including LES). They reported that the patients who had four or six meals showed significantly greater improvements in nitrogen balance than the patients who had three meals [10]. In patients with liver cirrhosis, dividing the daily food intake and using LES considerably improved the RQ, considerably increased sugar-burning and considerably decreased fat-burning (Table 1) [11,12]. Additionally, a study on normal people showed that the daily average serum insulin concentration was lower in people who had three meals per day than in people whose daily food intake was divided into a greater number of meals. Therefore, dividing daily food intake may be effective in improving glucose intolerance in patients with liver cirrhosis, although attention must be paid to nighttime hyperglycemia [13]. When we have to compensate for deficiencies in energy intake and prevent early morning fasting, nocturnal energy supplementation is added to regular meals. Chang et al. gave Table 1 The effect of nocturnal energy supplementation on metabolic parameters in cirrhosis [12] Controls
Cirrhosis Before NES
RQ REE/BMR %CHO %FAT %PRO
0.88 0.98 55.4 30.4 14.2
± ± ± ± ±
0.01 0.03 2.83 2.5 1.3
0.81 1.10 33.2 54.7 12.0
± ± ± ± ±
0.01* 0.04 4.2* 4.2* 1.4
After NES 0.86 1.04 47.6 38.7 13.7
± ± ± ± ±
0.01** 0.04 4.6** 4.7** 1.5
Values are expressed as mean ± S.E.M. RQ, respiratory quotient; REE, resting energy expenditure; BMR, basal metabolic rate; %CHO, %FAT, and %PRO, substrate oxidation rates for glucose, fat, and protein, respectively; NES, nocturnal energy supplementation. ∗ P < 0.001 compared with conrtrols. ∗∗ P < 0.05 compared with cirrhosis before NES.
patients 200 kcal of carbohydrates (two pieces of bread with strawberry jam) in addition to their three regular meals and reported that the RQ improved in the early morning, sugarburning increased, and fat- and protein-burning decreased [14]. It has been reported that giving patients with liver cirrhosis glucose at bedtime corrects increased protein metabolism and decreases ketone body levels [15]. Therefore, nocturnal energy supplementation may prevent the progression of PEM by inhibiting gluconeogenesis, which requires fat-burning and consumes endogenous proteins. Before nocturnal energy supplementation is given to patients, nutritionists should investigate their diet and should set the calories of the nocturnal energy supplement so that the necessary daily calories are not exceeded. It is important to pay attention to this because excessive energy intake may deteriorate glucose intolerance and cause fatty liver which leads to liver fibrosis [16].
3. Nocturnal BCAA supplementation As previously mentioned, patients with liver cirrhosis have hypoalbuminemia, which affects their QOL and prognosis. These patients run short of branched-chain amino acids (BCAAs), and there is a positive correlation between the Fischer’s ratio and the serum albumin level [17]. BCAA supplementation increases serum albumin levels and improves the prognosis of patients with liver cirrhosis [18,19]. Consequently, BCAA therapy is useful in improving the QOL and prognosis of patients with liver cirrhosis. However, in some patients, BCAA administration cannot increase the serum albumin levels. One of the reasons for this is that BCAA administration cannot increase the levels of BCAAs in the blood to a level high enough to induce albumin synthesis. When albumin synthesis in hepatocytes was examined by changing the Fischer’s ratio in the culture solution, the greatest amount of albumin was synthesized when the Fischer’s ratio was between three and six, which is the same as the physiological ratio. When the Fischer’s ratio was higher or lower than this range, albumin synthesis decreased [20]. Therefore, to increase the serum albumin level, the BCAA concentration should be kept as close to its physiological concentration as possible. The Fischer’s ratio in the early morning fasting state is significantly lower in patients with liver cirrhosis than in normal people. When these patients were given BCAA granules after every meal (BCAA: 12 g/day), their Fischer’s ratio was still low. However, when they were given 4 g of BCAA after breakfast and 8 g at bedtime, an increased Fischer’s ratio and a significantly improved nitrogen balance were observed in the early morning fasting state. Additionally, long-term nocturnal BCAA administration significantly improved the serum albumin levels (Fig. 1) [21]. Considering the circadian change of the Fischer’s ratio in patients with liver cirrhosis, nocturnal BCAA administration keeps the Fischer’s ratio high during the nighttime, and this may increase liver albumin synthesis.
Y. Miwa, H. Moriwaki / Hepatology Research 30S (2004) S63–S66
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Fig. 1. Changes in serum albumin level with nocturnal and daytime BCAA administration group for 3 months [21]. The level of serum albumin was significantly improved in the nocturnal group compared with daytime group (repeated measures ANOVA between groups; P < 0.01).
Table 2 PEM and nutrition therapy in liver cirrhosis Types of malnutrition
Symptoms
Recommended substrate
Energy malnutrition
Body weight loss >3 kg in 6 months TSF, AMC <5 percentile RQ < 0.85
Energy
Protein malnutrition
Serum albumin <3.5 g/dl
BCAA
Based on the previously described results, the indications for nutrition therapy in patients with liver cirrhosis are summarized in Table 2. Nutritional assessment is firstly performed. Thereafter, patients who run short of energy are given energy, patients who run short of proteins are given BCAAs, and patients who run short of both are given nutritional supplements or food which contain energy and BCAAs [22,23]. When normal administration is ineffective, dividing daily food intake should be considered, and in some cases, nocturnal supplementation should be added to this division. Data on the effect of LES on the QOL and prognosis of patients with liver cirrhosis should be obtained in the future.
References [1] Merli M, Riggio O, Dally L, et al. Does malnutrition affect survival in cirrhosis? Hepatology 1996;23:1041–6. [2] Anderson H, Borre M, Jakobsen J, et al. Decreased muscle strength in patients with alcoholic liver cirrhosis in relation to nutritional status, alcohol abstinence, liver function, and neuropathy. Hepatology 1998;27:1200–6. [3] Tajika M, Kato M, Mohri H, et al. Prognostic value of energy metabolism in patients with viral liver cirrhosis. Nutrition 2002;18:229–34. [4] Kuroki T, Nishiguchi S, Nakajima S, et al. Practical nutritional management for patients with liver cirrhosis: general diet therapy. Nihonrinsho 1994;52:197–202. [5] Moriwaki H, Miwa Y, Tajika M, et al. Branched-chain amino acids as a protein and energy source in liver cirrhosis. Biochem Biophys Res Commun 2004;313:405–9.
[6] Alberino F, Gatta A, Amodio P, et al. Nutrition and survival in patients with liver cirrhosis. Nutrition 2001;17:445–50. [7] Owen OE, Trapp VE, Reichard GA, et al. Nature and quality of fuels consumed in patients with alcoholic cirrhosis. J Clin Invest 1983;72:1821–32. [8] Greco AV, Mingrone G, Benedetti G, et al. Daily energy substrate metabolism in patients with cirrhosis. Hepatology 1998;27:346–50. [9] Campillo B, Bories PN, Leiuan M, et al. Short-term change in energy metabolism after 1 month of a regular oral diet in severely malnourished cirrhotic patients. Metabolism 1995;44:765–70. [10] Stwart GR, Zillikens MC, van Vuure JK, et al. Effect of a late evening meal on nitrogen balance in patients with cirrhosis of the liver. BMJ 1989;299:1202–10. [11] Verboeket-van de Venne WPHG, Westerterp KR, van Hock B, et al. Energy expenditure and substrate metabolism in patients with cirrhosis of the liver: effects of the pattern of food intake. Gut 1995;36:110–6. [12] Miwa Y, Shiraki M, Kato M, et al. Improvement of fuel metabolism by nocturnal energy supplementation in patients with liver cirrhosis. Hepatol Res 2000;18:184–9. [13] Jenkins DJA, Wolever TMS, Vuksan V, et al. Nibbling versus gorging: metabolic advantages of increased meal frequency. NEIM 1989;321:929–34. [14] Chang W-K, Chao Y-C, Tang H-S, et al. Effects of extracarbohydrate supplementation in the late evening on energy expenditure and substrate oxidation in patients with liver cirrhosis. JPEN 1997;21:96–9. [15] Zillikiens MC, van den Berg JWO, Wattimena JLD, et al. Nocturnal oral glucose supplementation: the effects on protein metabolism in cirrhotic patients and in healthy controls. J Hepatol 1983;17:377–83. [16] Hourigan LF, MacDonald GA, Purdie D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999;29:1215–9. [17] Muto Y, Yoshida T, Yamafuji M. Nutritional therapy for chronic liver failure: branched-chain amino acid therapy. Nihon-iji-shinpo 1983;3101:3–9. [18] Yoshida T, Muto H, Moriwaki H, et al. Effect of long-term oral supplementation with branched-chain amino acid granules on the prognosis of liver cirrhosis. J Gastroenterol 1989;24:692–8. [19] Marchesini G, Bianchi G, Merli M, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a doubleblind, randomized trial. Gastroenterology 2003;124:1792–801. [20] Okuno M, Moriwaki H, Kato M, et al. Changes in the ratio of branched-chain to aromatic amino acids affect the secretion of albumin in rat hepatocytes. Biochem Biophys Res Commun 1995;214:1045–50.
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[21] Fukushima H, Miwa Y, Ida E, et al. Nocturnal branched-chain amino acid administration improves protein metabolism in patients with liver cirrhosis: comparison with daytime administration. JPEN 2002;27:315–22. [22] Yamauchi M, Takeda K, Sakamoto K, et al. Effect of oral branched chain amino acid supplementation in the late evening on
the nutritional state of patients with liver cirrhosis. Hepatol Res 2001;21:199–204. [23] Nakaya Y, Harada N, Kakui S, et al. Severe catabolic state after prolonged fasting in cirrhotic patients: effect of oral branched-chain amino-acid-enriched nutrient mixture. J Gastroenterol 2002;37:531–6.
Nocturnal energy and BCAA supplementation in patients with liver cirrhosis Yoshiyuki Miwa∗ , Hisataka Moriwaki The First Department of Internal Medicine, Gifu University School of Medicine, Japan Accepted 9 August 2004
Abstract Patients with liver cirrhosis have protein-energy malnutrition (PEM) and run short of proteins and energy. Protein deficiency leads to hypoalbuminemia, which induces peritoneal effusion and edema. Energy deficiency decreases fat and muscle mass and causes muscle weakness, which decreases the QOL of these patients. A decrease in triceps skinfold thickness (TSF) and arm muscle circumference (AMC), which are indicators of hypoalbuminemia and energy deficiency, and a decrease in respiratory quotient (RQ) affect the prognosis of these patients. Therefore, appropriate nutritional assessment should be performed in order to detect PEM in these patients, and necessary proteins or energy should be supplied. TSF, AMC and RQ are improved by increasing the energy supply to correct its deficiency and by dividing daily food intake (in some cases, adding nocturnal supplementation). Serum albumin levels increase when branched-chain amino acids (BCAAs) are administered after every meal or at bedtime. Consequently, nutritional assessment on PEM, and nutritional therapy based on this assessment are essential for improving the QOL and prognosis of patients with liver cirrhosis. © 2004 Elsevier B.V. All rights reserved. Keywords: Protein-energy malnutrition; Nocturnal energy supplementation; Nocturnal BCAA supplementation
1. PEM and prognosis of patients with liver cirrhosis Patients with liver cirrhosis have protein-energy malnutrition (PEM) and run short of proteins and energy. Protein deficiency leads to a decrease in visceral proteins such as albumin and to decreased immunity. Decreased energy leads to decreased fat and muscle mass. Therefore, PEM affects the QOL and prognosis of patients with liver cirrhosis [1,2]. The occurrence frequency of PEM in patients with liver cirrhosis is very high (50%) [3]. For patients with liver cirrhosis, the serum albumin level and muscle mass are used as indicators of protein malnutrition, and body weight, fat mass, muscle mass and respiratory quotient measured with an indirect calorimeter are used as indicators of energy malnutrition. Decreases in these indicators deteriorate the prognosis of these patients. It has been ∗ Corresponding author. Present address: MIWA CLINIC, 3-3 NagaraHigashi, Gifu 502-0082, Japan. E-mail address: [email protected].
1386-6346/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.hepres.2004.08.012
reported that patients with a serum albumin level of 3.5 g/dl or more have a better prognosis than patients with a serum albumin level of less than 3.5 g/dl [4,5]. It has also been reported that the prognosis of patients with a triceps skinfold thickness (TSF) and arm muscle circumference (AMC) in or below the fifth percentile is worse than that of patients who have corresponding measurements above the fifth percentile [6]. An examination of energy metabolism in the early morning fasting state, using an indirect calorimeter, showed that the respiratory quotient (RQ) decreased in patients with liver cirrhosis, and that a decreased RQ worsened the prognosis [3]. In patients with liver cirrhosis, liver atrophy is observed, which decreases glycogen storage in the liver. Due to this, patients with liver cirrhosis in the early morning fasting state have a similar metabolic state to normal people who have fasted for 3 days. Sugar-burning decreases and fat-burning increases when patients with liver cirrhosis are in the early morning fasting state [7]. Moreover, patients with liver cirrhosis have an increased energy metabolism at rest [8]. This metabolic state of patients with liver cirrhosis decreases body
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fat and muscle mass, and ultimately leads to deterioration in the state of PEM.
2. Nocturnal energy supplementation Eating the proper quantity of food three times a day is sometimes effective for improving energy deficiency in patients with liver cirrhosis. When patients with alcoholic liver cirrhosis were given three meals per day for 1 month, which contained an energy intake of 40 kcal/kg/day and a protein intake of 1.4 g/kg/day, the RQ improved, the muscle and fat mass increased, and the serum albumin level also increased [9]. However, nocturnal energy supplementation is effective when the total caloric intake from the three regular meals is insufficient, or when it is necessary to prevent the early morning fasting state. Dividing daily food intake into more than three meals is effective when patients need to be prevented from early morning fasting, even though their daily energy intake is sufficient. Swart et al. fixed the daily energy and protein intake and gave patients with liver cirrhosis three meals per day, four meals per day (including late evening snack (LES)) or six meals per day (including LES). They reported that the patients who had four or six meals showed significantly greater improvements in nitrogen balance than the patients who had three meals [10]. In patients with liver cirrhosis, dividing the daily food intake and using LES considerably improved the RQ, considerably increased sugar-burning and considerably decreased fat-burning (Table 1) [11,12]. Additionally, a study on normal people showed that the daily average serum insulin concentration was lower in people who had three meals per day than in people whose daily food intake was divided into a greater number of meals. Therefore, dividing daily food intake may be effective in improving glucose intolerance in patients with liver cirrhosis, although attention must be paid to nighttime hyperglycemia [13]. When we have to compensate for deficiencies in energy intake and prevent early morning fasting, nocturnal energy supplementation is added to regular meals. Chang et al. gave Table 1 The effect of nocturnal energy supplementation on metabolic parameters in cirrhosis [12] Controls
Cirrhosis Before NES
RQ REE/BMR %CHO %FAT %PRO
0.88 0.98 55.4 30.4 14.2
± ± ± ± ±
0.01 0.03 2.83 2.5 1.3
0.81 1.10 33.2 54.7 12.0
± ± ± ± ±
0.01* 0.04 4.2* 4.2* 1.4
After NES 0.86 1.04 47.6 38.7 13.7
± ± ± ± ±
0.01** 0.04 4.6** 4.7** 1.5
Values are expressed as mean ± S.E.M. RQ, respiratory quotient; REE, resting energy expenditure; BMR, basal metabolic rate; %CHO, %FAT, and %PRO, substrate oxidation rates for glucose, fat, and protein, respectively; NES, nocturnal energy supplementation. ∗ P < 0.001 compared with conrtrols. ∗∗ P < 0.05 compared with cirrhosis before NES.
patients 200 kcal of carbohydrates (two pieces of bread with strawberry jam) in addition to their three regular meals and reported that the RQ improved in the early morning, sugarburning increased, and fat- and protein-burning decreased [14]. It has been reported that giving patients with liver cirrhosis glucose at bedtime corrects increased protein metabolism and decreases ketone body levels [15]. Therefore, nocturnal energy supplementation may prevent the progression of PEM by inhibiting gluconeogenesis, which requires fat-burning and consumes endogenous proteins. Before nocturnal energy supplementation is given to patients, nutritionists should investigate their diet and should set the calories of the nocturnal energy supplement so that the necessary daily calories are not exceeded. It is important to pay attention to this because excessive energy intake may deteriorate glucose intolerance and cause fatty liver which leads to liver fibrosis [16].
3. Nocturnal BCAA supplementation As previously mentioned, patients with liver cirrhosis have hypoalbuminemia, which affects their QOL and prognosis. These patients run short of branched-chain amino acids (BCAAs), and there is a positive correlation between the Fischer’s ratio and the serum albumin level [17]. BCAA supplementation increases serum albumin levels and improves the prognosis of patients with liver cirrhosis [18,19]. Consequently, BCAA therapy is useful in improving the QOL and prognosis of patients with liver cirrhosis. However, in some patients, BCAA administration cannot increase the serum albumin levels. One of the reasons for this is that BCAA administration cannot increase the levels of BCAAs in the blood to a level high enough to induce albumin synthesis. When albumin synthesis in hepatocytes was examined by changing the Fischer’s ratio in the culture solution, the greatest amount of albumin was synthesized when the Fischer’s ratio was between three and six, which is the same as the physiological ratio. When the Fischer’s ratio was higher or lower than this range, albumin synthesis decreased [20]. Therefore, to increase the serum albumin level, the BCAA concentration should be kept as close to its physiological concentration as possible. The Fischer’s ratio in the early morning fasting state is significantly lower in patients with liver cirrhosis than in normal people. When these patients were given BCAA granules after every meal (BCAA: 12 g/day), their Fischer’s ratio was still low. However, when they were given 4 g of BCAA after breakfast and 8 g at bedtime, an increased Fischer’s ratio and a significantly improved nitrogen balance were observed in the early morning fasting state. Additionally, long-term nocturnal BCAA administration significantly improved the serum albumin levels (Fig. 1) [21]. Considering the circadian change of the Fischer’s ratio in patients with liver cirrhosis, nocturnal BCAA administration keeps the Fischer’s ratio high during the nighttime, and this may increase liver albumin synthesis.
Y. Miwa, H. Moriwaki / Hepatology Research 30S (2004) S63–S66
S65
Fig. 1. Changes in serum albumin level with nocturnal and daytime BCAA administration group for 3 months [21]. The level of serum albumin was significantly improved in the nocturnal group compared with daytime group (repeated measures ANOVA between groups; P < 0.01).
Table 2 PEM and nutrition therapy in liver cirrhosis Types of malnutrition
Symptoms
Recommended substrate
Energy malnutrition
Body weight loss >3 kg in 6 months TSF, AMC <5 percentile RQ < 0.85
Energy
Protein malnutrition
Serum albumin <3.5 g/dl
BCAA
Based on the previously described results, the indications for nutrition therapy in patients with liver cirrhosis are summarized in Table 2. Nutritional assessment is firstly performed. Thereafter, patients who run short of energy are given energy, patients who run short of proteins are given BCAAs, and patients who run short of both are given nutritional supplements or food which contain energy and BCAAs [22,23]. When normal administration is ineffective, dividing daily food intake should be considered, and in some cases, nocturnal supplementation should be added to this division. Data on the effect of LES on the QOL and prognosis of patients with liver cirrhosis should be obtained in the future.
References [1] Merli M, Riggio O, Dally L, et al. Does malnutrition affect survival in cirrhosis? Hepatology 1996;23:1041–6. [2] Anderson H, Borre M, Jakobsen J, et al. Decreased muscle strength in patients with alcoholic liver cirrhosis in relation to nutritional status, alcohol abstinence, liver function, and neuropathy. Hepatology 1998;27:1200–6. [3] Tajika M, Kato M, Mohri H, et al. Prognostic value of energy metabolism in patients with viral liver cirrhosis. Nutrition 2002;18:229–34. [4] Kuroki T, Nishiguchi S, Nakajima S, et al. Practical nutritional management for patients with liver cirrhosis: general diet therapy. Nihonrinsho 1994;52:197–202. [5] Moriwaki H, Miwa Y, Tajika M, et al. Branched-chain amino acids as a protein and energy source in liver cirrhosis. Biochem Biophys Res Commun 2004;313:405–9.
[6] Alberino F, Gatta A, Amodio P, et al. Nutrition and survival in patients with liver cirrhosis. Nutrition 2001;17:445–50. [7] Owen OE, Trapp VE, Reichard GA, et al. Nature and quality of fuels consumed in patients with alcoholic cirrhosis. J Clin Invest 1983;72:1821–32. [8] Greco AV, Mingrone G, Benedetti G, et al. Daily energy substrate metabolism in patients with cirrhosis. Hepatology 1998;27:346–50. [9] Campillo B, Bories PN, Leiuan M, et al. Short-term change in energy metabolism after 1 month of a regular oral diet in severely malnourished cirrhotic patients. Metabolism 1995;44:765–70. [10] Stwart GR, Zillikens MC, van Vuure JK, et al. Effect of a late evening meal on nitrogen balance in patients with cirrhosis of the liver. BMJ 1989;299:1202–10. [11] Verboeket-van de Venne WPHG, Westerterp KR, van Hock B, et al. Energy expenditure and substrate metabolism in patients with cirrhosis of the liver: effects of the pattern of food intake. Gut 1995;36:110–6. [12] Miwa Y, Shiraki M, Kato M, et al. Improvement of fuel metabolism by nocturnal energy supplementation in patients with liver cirrhosis. Hepatol Res 2000;18:184–9. [13] Jenkins DJA, Wolever TMS, Vuksan V, et al. Nibbling versus gorging: metabolic advantages of increased meal frequency. NEIM 1989;321:929–34. [14] Chang W-K, Chao Y-C, Tang H-S, et al. Effects of extracarbohydrate supplementation in the late evening on energy expenditure and substrate oxidation in patients with liver cirrhosis. JPEN 1997;21:96–9. [15] Zillikiens MC, van den Berg JWO, Wattimena JLD, et al. Nocturnal oral glucose supplementation: the effects on protein metabolism in cirrhotic patients and in healthy controls. J Hepatol 1983;17:377–83. [16] Hourigan LF, MacDonald GA, Purdie D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999;29:1215–9. [17] Muto Y, Yoshida T, Yamafuji M. Nutritional therapy for chronic liver failure: branched-chain amino acid therapy. Nihon-iji-shinpo 1983;3101:3–9. [18] Yoshida T, Muto H, Moriwaki H, et al. Effect of long-term oral supplementation with branched-chain amino acid granules on the prognosis of liver cirrhosis. J Gastroenterol 1989;24:692–8. [19] Marchesini G, Bianchi G, Merli M, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a doubleblind, randomized trial. Gastroenterology 2003;124:1792–801. [20] Okuno M, Moriwaki H, Kato M, et al. Changes in the ratio of branched-chain to aromatic amino acids affect the secretion of albumin in rat hepatocytes. Biochem Biophys Res Commun 1995;214:1045–50.
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[21] Fukushima H, Miwa Y, Ida E, et al. Nocturnal branched-chain amino acid administration improves protein metabolism in patients with liver cirrhosis: comparison with daytime administration. JPEN 2002;27:315–22. [22] Yamauchi M, Takeda K, Sakamoto K, et al. Effect of oral branched chain amino acid supplementation in the late evening on
the nutritional state of patients with liver cirrhosis. Hepatol Res 2001;21:199–204. [23] Nakaya Y, Harada N, Kakui S, et al. Severe catabolic state after prolonged fasting in cirrhotic patients: effect of oral branched-chain amino-acid-enriched nutrient mixture. J Gastroenterol 2002;37:531–6.