Clinical nutrition, enteral and parenteral nutrition

Effect of a carbohydrate-containing late-evening snack on energy metabolism and fasting substrate utilization in adults with acute-on-chronic liver failure due to Hepatitis B



This study investigates the effects of a carbohydrate (CHO; lotus-root starch) predominant, late-evening snack (LES), containing 200 kcal (50 g CHO) on fasting resting energy expenditure (REE) and nutrient oxidation in hospitalized adults with acute-on-chronic liver failure (ACLF).


Adults with ACLF were randomized to receive daily LES (treatment; n=35) or standard care (n=35; non-supplemented control) for 14 days. REE and respiratory quotient (RQ) were measured by indirect calorimetry, nutrient oxidation (CHO, protein and fat), intake and biochemical parameters were measured in both groups at baseline and after 14 days using validated techniques. Disease severity was measured using the model for end-stage liver disease (MELD).


No significant differences in macronutrient intake, anthropometric, demographic characteristics or MELD scores were observed between groups at baseline (P>0.05). Fasting RQ was significantly higher in the LES supplemented verses the control group after 2 weeks (P=0.02). CHO oxidation was significantly higher (P=0.001) and fat oxidation (P=0.02) was lower in the LES-supplemented group when compared with controls after 2 weeks. Fasting RQ and REE in the LES-supplemented group increased significantly (0.83 verses 0.88; P=0.007/1301±409 vs 1687±718 kcal/day; P=0.02) in patients with MELD scores 30 when compared with patients with MELD scores >30 (0.82 verses 0.84; P=0.27/ 1361±405 vs 1437±429 kcal/day; P=0.67) after supplementation.


A carbohydrate-predominant LES is associated with increases in fasting carbohydrate oxidation, REE and reductions in fat oxidation in adults with ACLF. Therapeutic strategies utilizing LES may promote improved nutritional status in adults with ACLF.


Acute-on-chronic liver failure (ACLF) is a sudden, severe and life-threatening deterioration of liver function in patients with chronic and pre-existing liver diseases such as chronic hepatitis and liver cirrhosis.1 China has a very high prevalence of Hepatitis B (7.18%).2 ACLF is an important cause of death in adults with Hepatitis B, with a fatality rate approximating 70%.3 One of the important comorbidities associated with ACLF in adults with Hepatitis B is the high rate of protein-energy malnutrition, which has been associated with alterations in nutrient utilization (increased fat and protein utilization and decreased carbohydrate utilization) in the fasted state.4, 5, 6 These changes in nutrient utilization often parallel changes in clinical signs and symptoms of worsening liver failure and contribute to increased morbidity and mortality and reduced quality of life in this patient population.5, 6, 7, 8, 9

Nocturnal supplementation is recommended by both the American Society for Parenteral and Enteral Nutrition10 and the European Society for Clinical Nutrition and Metabolism guidelines11 to avoid increased utilization of lean body stores to meet energy needs in patients with liver cirrhosis in the fasted state. Late-night snacks (LES) with varying nutritional content (high in branched chain amino acids (BCAA) and/or carbohydrates) have been shown to ameliorate the extent to which fat and nitrogen are utilized in the fasted state in patients with liver cirrhosis and to improve over all nitrogen balance and quality of life.7, 12, 13, 14, 15, 16, 17, 18, 19 Most of these studies have been shorter-term studies (<less than 3 months) and focused in populations with mild-to-moderate liver disease, rather than in patients with more severe liver disease.7 Few studies have examined the impact of an LES on fasting nutrient oxidation and related these to patient outcomes, particularly in patients with ACLF.7 Nakaya et al.12 reported long-term oral supplementation with a BCAA mixture in a LES was related to significant improvements in serum albumin level, energy balance and increased carbohydrate utilization in patients with liver cirrhosis, but some issues with patient adherence to supplementation related to adverse gastrointestinal symptomology made it difficult to fully examine the potential benefits of BCAA supplementation.7, 12 Little is known regarding the effects of LES on resting energy expenditure (REE) and how this may influence fasting nutrient utilization in adult patients with ACLF due to Hepatitis B infection. The study objective was to investigate the effect of a low-energy carbohydrate, low glycemic index predominant LES snack on fasting REE, respiratory quotient (RQ) and nutrient oxidation in hospitalized patients with ACLF due to Hepatitis B infection.

Subjects and methods


Seventy patients (51 males, 19 females, mean age: 40.8±14.1 years) with ACLF due to Hepatitis B infection admitted to the Department of Hepatology, Beijing You An Hospital, Capital Medical University in Beijing China were enrolled into the study (2007–2011 December). The diagnosis of Hepatitis B viral infection was based on serology results (COBAS AmpliPrep/COBAS TaqMan HBV test, Roche Molecular Systems Inc, Branchburg, NJ, USA). ACLF definitions were based upon the Asian Pacific Association for the Study of the Liver (APASL) criteria.20 Patients were excluded from the study if they had a known history of hepatitis C virus infection, alcoholic liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, diabetes mellitus, thyroid dysfunction, neoplasm or had clinical evidence of dehydration/over-hydration or ascites and/or were infected with human immunodeficiency virus. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Human Research Committee of the Capital Medical University. Informed consent was obtained from all study participants before study enrollment.

Study design

All the patients were randomly divided into two groups; a treatment group (LES supplemented; n=35) and a control group (n=35). All study participants were provided with a standard hospital diet that provided 25–30 kcal/kg/day containing 60% carbohydrate, 24% fat and 16% protein (standard of care). Once enrolled, the patients (n=35) in the treatment group were provided with three meals/day and the LES over the entire study period (2 weeks). Control subjects enrolled were supplied with the equivalent meals for 2 weeks but were not supplemented with the LES. To ensure consistency of energy and macronutrient intake at baseline between both groups, all participants were supplied with three meals/day for 3 days before the initiation of the study, and 3 days food intake records were collected to assess baseline intake. Subjects in the treatment group had equivalent reductions in energy and carbohydrate at each meal to account for the increase in carbohydrate/energy (16.7 g CHO reduced at each meal) provided in the LES.

Dietary intake

Dietary intake was recorded and analyzed over the entire 2 weeks by trained personnel and nutrient intake (energy, fat, protein and carbohydrate) calculated using standardized Chinese Food Composition Tables.21 Subjects and/or their responsible caregivers were instructed how to record portion sizes, food type (including brand names of foods) on standardized diet intake records, which were reviewed by research personnel at the time of data collection to ensure completeness.

LES snack

The treatment group was also provided with an LES in the form of lotus-root starch, a favorite traditional snack within China. Traditionally lotus-root starch is used as a thickening agent in sauces in mixed food dishes and/or served as pudding. The nutritional composition of the LES consisted of: total energy: 200 kcal; 50 g of carbohydrate; 0.1 g protein; and 0.05 g fiber with a GI of 30.21, 22 Measurement of fasting REE, RQ, relevant laboratory parameters and substrate oxidation was performed at the time of study entry and after 2 weeks in both groups.

Anthropometric variables

Body weight and height were measured according to standard methodologies using a height/weight scale (RGZ120, Wuxi Weight Factory, Wuxi, China) with a precision of 0.2 kg and 0.2 cm, respectively. Body mass index was calculated as kg/m2.

Fasting REE, RQ and carbohydrate, protein and fat oxidation

Patients were fasted overnight (10–12 h) before indirect calorimetry was performed. The REE was determined using the cardiorespiratory diagnostics nutrition metabolism investigation system (Medgraphics Company, Saint Paul, MN, USA). Subjects were instructed to remain at rest (in bed) on the morning of testing for at least 30 min before indirect calorimetry was measured. The room temperature was kept between 24 and 26 °C with a humidity of 45–60%. The volume and gas were calibrated for the Cardiorespiratory Diagnostics nutrition metabolism investigation system. REE was expressed as an absolute value upon measurement and on a per kg body weight basis to account for variations in energy expenditure due to body weight. The predicted REE value was calculated using the Harris–Benedict equation.23 The average O2 amount consumed and the CO2 amount produced per minute by the subjects were used to calculate the actual REE using the Weir formula REE (kcal)=5.50VO2+1.76VCO2−1.99TUN.24 Subsequently, the RQ, that is, the ratio of the average CO2 produced to the amount of O2 consumed by the subjects, was calculated.

Twenty-four-hour urine samples were collected from all subjects to determine the urea nitrogen level using the HITACHI7170 Automatic Biochemistry Analyzer (Tokyo, Japan). Urinary nitrogen production was calculated based on the urinary urea elimination.25 Nitrogen concentration was used to determine the non-protein RQ and protein oxidation. Fat and carbohydrate oxidation was calculated according to the method of Lusk.26

Laboratory variables

A chemistry analyzer (OLYMPUS 5421, Olympus, Tokyo, Japan) was used to measure serum biochemical profiles including the concentrations of white blood cells, red blood cells, hemoglobin, platelets, cholesterol (CHO), triglyceride, aspartate aminotransferase, alanine aminotransferase, total protein, albumin, total bilirubin, cholinesterase and blood glucose.

Statistical analysis

Data analysis was performed using the SAS 9.0 statistical software (SAS, version 9.2.1; SAS Institute, Cary, NC, USA). The differences between groups in baseline characteristics were analyzed by χ2 test or independent samples t-test. The effects of LES were analyzed by repeated measures analysis of variance. The model for end-stage liver disease (MELD) was used to stratify patient data by disease severity (above and below 30). MELD is a score that predicts the 3 months mortality risk related to chronic liver disease.27, 28 All data in the text and tables are presented as mean±s.d. A value of P<0.05 was considered statistically significant.


Baseline demographic, anthropometric and dietary intake variables

Demographic and anthropometric characteristics and dietary intake of study participants are shown in Table 1. No significant differences in anthropometric and demographic characteristics of participants were noted between the two groups (P>0.05). The study and control subjects consumed the same standard hospital diet containing 25–30 kcal/kg/day (60% carbohydrate, 24% fat and 16% protein) (standard of care); but the study group had each meal reduced by 16.7 g CHO to ensure that both groups had an equivalent 24-h intake of energy and CHO. The study groups also consumed an LES (200 kcal; lotus-root starch). There were no significant differences in energy and nutrient intake between the control and treatment groups (P>0.05) at baseline and after 2 weeks on the study protocol.

Table 1 Demographic and anthropometric characteristics and food intake at baseline and after 2 weeks in patients with ACLF

Fasting REE and RQ

REE and RQ at baseline and after 2 weeks for the two groups are summarized in Table 2. No significant differences in REE and RQ at baseline were observed between the two groups. However, there was a significant difference in REE between the groups (1573±609 (+LES) vs 1357±205 (−LES) kcal/day after 2 weeks (P=0.01). In addition, no significant differences in REE were observed after 2 weeks in the control group; although there was a significant increase in REE (absolute and kcal/kg) in the LES supplemented group over the 2 weeks (P=0.03). After LES supplementation, the fasting RQ was also significantly higher in the treatment group (0.86) vs the control group (0.84) (P=0.03). Within the treatment group (+LES), RQ significantly increased from 0.82 to 0.86 (P=0.02), indicating increased glucose utilization in patients who consumed the LES over 2 weeks.

Table 2 Fasting REE and RQ in patients with ACLF

Influence of LES supplementation on RQ by disease severity

To assess the potential impact of LES supplementation on patient outcomes, we stratified the treatment group (+LES) into two groups based on the MELD: group A with MELD score30 (n=19) and group B with MELD score 30 (n=16) (Figure 1). LES treatment resulted in a significantly higher increase in RQ (0.83 vs 0.88 P=0.007) in patients with a MELD score of30 vs those with a MELD score greater >30 (0.82 vs 0.84; P=0.27) after 2 weeks of supplementation (P<0.05). In addition, LES supplementation was associated with a significantly higher REE on an absolute per kcal (1301±409 (baseline) vs 1687±718 kcal/day (after 2 weeks); P=0.02) for those with MELD scores30, when compared with those with MELD scores greater than 30 (1361±405 (baseline) vs 1437±429 (after 2 weeks) kcal/day; P=0.67) only.

Figure 1

The impact of disease severity on fasting RQs in hospitalized patients with ACLF due to Hepatitis B infection supplemented with a late evening snack. Disease severity was assessed using the MELD scores30 (a) and MELD scores>30 (b). MELD predicts the 3-month risk for death/intensive care unit admission in adult patients with chronic liver disease.27, 28

Fasting carbohydrate, fat and protein oxidation rates: effect of LES supplementation

Fasting substrate oxidation rates of protein, fat and carbohydrate are presented in Tables 3A/3B. Although no major differences in rates of protein, fat and CHO oxidation were noted between groups at baseline, a significant increase in CHO oxidation (P=0.002) and a significant decrease in fat oxidation (P=0.02) were noted after 2 weeks of LES supplementation. In contrast, no differences in nutrient oxidation were noted in the control group over the 2-week study period (Table 3A). When stratifying the data by MELD score (Table 3B) above and below 30 within the LES supplemented group, no major differences in nutrient oxidation were observed between groups at baseline. However, after 2 weeks of LES supplementation, a significant increase in rates of CHO oxidation (P=0.001) and a decrease in fat oxidation (P=0.02) were observed in patients with a MELD score<30 (Table 3B).

Table 3a Fasting substrate oxidation in patients with ACLF in two groups
Table 3b Fasting substrate oxidation in patients with ACLF by disease severity in LES supplemented group only stratified by MELD

Laboratory variables

Laboratory data are shown in Table 4. There were no significant differences in alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, cholinesterase, white blood cell, hemoglobin, platelet, cholesterol, triglyceride, prothrombin, fasting blood sugar and MELD scores between control and study (+LES) groups at baseline (P>0.05). After 2 weeks, both groups experienced significant reductions in serum concentrations of alanine aminotransferase, total bilirubin and MELD scores, and significant increase in serum concentrations of %prothrombin. In addition, the study group (+LES) experienced significant increases in serum concentrations of cholinesterase, CHO and fasting blood sugar (P<0.05).

Table 4 Comparison of biomedical profile in two groups


This study aimed to investigate the effects of LES supplementation (lotus-root starch) for 2 weeks on fasting resting expenditure and nutrient oxidation in adults with ACLF due to Hepatitis B infection. The results show that daily consumption of a CHO-predominant LES for 14 days significantly increased carbohydrate oxidation and reduced fat oxidation in the fasted state in normo-metabolic adult patients with ACLF due to Hepatitis B infection. This was particularly evident in patients with MELD scores less than 30, indicating that LES supplementation using a CHO-based (lotus starch) LES may be an effective strategy to minimize the utilization of lean body stores for energy in the fasted state in patients with milder liver disease. This coincided with increases in fasting REE for patients with MELD scores less than 30, suggesting that alteration in substrate utilization with an CHO-predominant LES may have lead to improvements or stabilization in overall lean body mass in adults with ACLF.

Many studies have examined the efficacy of nutrient supplementation in patients with liver cirrhosis as the vehicle to improve overall nutritional status as the prevalence of protein-energy malnutrition is significantly high in this population.29 Most of these studies have focused on BCAA supplementation and the associated improvements in the quality of life and overall nitrogen balance7, 12, 14, 15, 16, 17, 18, 30, 31, 32, 33, 34, 35 that have been associated with the use of BCAA supplements in adults with liver disease. However, issues related to lack of long-term adherence to BCAA supplementation due to gastrointestinal upset have made long-term studies challenging.7, 33

More recently a stronger focus has been on the use of late-evening snacks (LES) as a method to minimize utilization of tissue stores for energy needs in the fasted state in patients with chronic liver disease.7, 14, 15, 16, 17, 18, 19, 36 Nocturnal energy supplementation could potentially be useful to correct abnormal fuel metabolism and to prevent malnutrition in patients with liver cirrhosis.17 Yamanaka-Okumura et al.13 showed that a carbohydrate-based LES with (rice ball) for 7 days resulted in significant increases in fasting RQs in adults with liver cirrhosis. Similar findings have also been shown with the use of BCAA-enriched LES in adults with chronic liver disease, but few of these studies have been done in patients with ACLF or have examined the effects of the BCAA in isolation of other macronutrients.7, 12, 14, 15 Hence, it is unclear the extent to which the actual BCAA by themselves contribute to improvements in overall nutrient utilization in the fasted state in patients with chronic liver or whether a combination of both carbohydrate and BCAA in an LES contributes to overall changes in fasting nutrient oxidation and energy metabolism.15 However, it is clear that offering an LES as an alternative to simply increasing total energy intake during the day has the greatest benefits.7, 12, 14, 34

Many studies have shown that cirrhotic patients have altered nutrient and energy metabolism, which can contribute to the increased risk for malnutrition and also seriously affect their prognosis.34, 35 Chun-Lei Fan9 showed that adults with chronic liver disease typically have significantly higher rates of fat oxidation and significantly lower rates of glucose oxidation resulting in increased utilization of body stores (lean body mass and fat mass). For patients with ACLF, acute decompensation in liver function can further exacerbate this issue, contributing to increased nutritional risk. The use of a carbohydrate-based nutritional module that is slowly digested and absorbed potentially may compensate for this deterioration in liver function and there by promoting increased utilization of this substrate for energy needs in the fasted state. The reason for this phenomenon may be related to the low glycemic index of the source of carbohydrate used within this study (33).21 Foods with low glycemic index are typically absorbed more slowly overnight, which may have resulted in increased carbohydrate utilization (higher fasting RQ) and a reduction in fat and protein mobilization from the adipocyte and lean tissue. Overall this could potentially minimize the extent to which protein-energy malnutrition occurs in patients with mild-moderate liver disease. Indeed, our data suggest that those with MELD scores less than 30 are more responsive to changes in nutrient oxidation with a CHO-predominant LES than those with MELD scores above 30, where little or no changes in fasting RQ/nutrient oxidation were observed. Therefore, it is possible that a CHO-predominant LES may prove less effective as a nutrition support approach to prevent protein-energy malnutrition in ACLF patients with more severe disease. This may be due in part to the potential for more severe lean body mass depletion in those with more severe disease.

The efficacy of a CHO-predominant LES vs a combined CHO-protein LES snack as a nutritional support approach to correct protein-energy malnutrition may also be related to the extent of lean body mass depletion experienced by ACLF patients, particularly in those with severe disease and/or those individuals with hypermetabolism. These factors may result in increased needs for both nocturnal sources of protein and CHO-predominant LES.5 In this study, only increases in REE (on an absolute kcal basis and on a per kg body weight basis) were observed in the patients with milder liver disease (MELD scores30) supplemented with the LES. This coincided with small gains in body weight in this group which may reflect increases in over all lean body mass and overall nutritional status, resulting in modest increases in REE (from 83.9 to 105% predicted). However, it is unclear whether changing the macronutrient composition or dose of the LES would confer greater changes in lean body mass, improvements in overall nutritional status, REE and/or substrate oxidation in ACLF patients with more severe disease. Two studies showed that higher energy intakes of an LES (700 kcal vs 200 kcal) resulted in significantly higher gains in lean body mass accumulation in adults with chronic liver disease over 1 year of supplementation.13, 37 Other studies have also shown that LES that contain both protein (in the form of BCAA) and varying levels of CHO and fat have also shown to be equally as effective at promoting positive changes in nutrient utilization, but inconsistent findings have been found in terms of the impact of this on overall REE.12, 14, 34 More work needs to be done to confirm the efficacy of varying energy and macronutrient composition of LES in ACLF patients on substrate utilization and REE over a spectrum of liver disease severity.

Limitations in this study design include the smaller sample size which made it difficult to determine the efficacy of LES supplementation on nocturnal CHO utilization based on liver disease severity (MELD scores above and below 30). A conferred strength is that the population studied was relatively homogeneous (Hepatitis B), was not hypermetabolic, and changes in substrate utilization were measured using validated methodologies, demonstrating that the addition of a relatively small CHO-based LES was associated with favorable improvements in fasting nutrient utilization. In addition, none of the patients experienced any adverse side effects. Lotus-root starch is a common traditional food in China, which is easily cooked and can be used for long-term daily consumption for patients without any socioeconomic constraints as it is inexpensive and an affordable alternative compared with other nutrient modules. Lotus-root starch has a significantly lower glycemic index than most other sources of wheat or rice starches, and hence offers the opportunity to prolong postprandial euglycemia.21 It also potentially avoids the adverse side effects of other modules like the BCAA: gastrointestinal upset and the potential for hypoglycemia.7, 38 This is particularly important in a population that can experience significant and rapid reductions in hepatic reserve and function. Similar benefits have been observed when LES have been combined with α-glucosidase inhibitors in patients with liver cirrhosis.39 Studying the postprandial glucose response to the LES using a glucose tolerance test) would have added conferred strength to understanding the contribution of the LES to overall postprandial carbohydrate utilization; but unfortunately this analysis was not performed.

One interesting finding was a significant increase in cholinesterase, a marker of hepatic reserve, significantly increased in the LES supplemented group. Although the use of an LES supplement may have been contributing factor in this, it is more likely that overall medical management (antiviral and anti-infective therapy) are more likely to have the major factor because we did not observe any major differences in overall liver function between the two groups after 2 weeks.

In conclusion, the ingestion of a LES carbohydrate module (lotus-root starch) in normo-metabolic ACLF patients with mild-moderate disease severity, was associated with increased carbohydrate utilization and reductions in fat utilization in the fasted stated. This may be due to the lower GI of the carbohydrate module resulting in prolonged postprandial delivery of CHO into the blood stream following nocturnal consumption, but further investigation is required to confirm this finding. Although these findings should be validated in larger prospective trials of longer study duration, these results advocate the necessity of nocturnal carbohydrate supplementation in the management of patients with ACLF.


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We acknowledge the participation of the patients in this study. Funding for this study was provided from the Foundation of Capital Medicine Development Committee (H020920020890). This work was supported by grants from the Foundation of Capital Medicine Development Committee (H020920020890).

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Correspondence to Q H Meng.

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Hou, W., Li, J., Lu, J. et al. Effect of a carbohydrate-containing late-evening snack on energy metabolism and fasting substrate utilization in adults with acute-on-chronic liver failure due to Hepatitis B. Eur J Clin Nutr 67, 1251–1256 (2013).

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  • acute-on-chronic liver failure
  • hepatitis b
  • energy expenditure
  • substrate oxidation
  • nutrition support

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