Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: A randomized 12-month trial


  • Potential conflict of interest: Dr. Gane advises and is on the speakers' bureau of Novartis. He is also on the speakers' bureau of GlaxoSmithKline.


Patients with liver cirrhosis exhibit early onset of gluconeogenesis after short-term fasting. This accelerated metabolic reaction to starvation may underlie their increased protein requirements and muscle depletion. A randomized controlled trial was conducted to test the hypothesis that provision of a late-evening nutritional supplement over a 12-month period would improve body protein stores in patients with cirrhosis. A total of 103 patients (68 male, 35 female; median age 51, range 28–74; Child-Pugh grading: 52A, 31B, 20C) were randomized to receive either daytime (between 0900 and 1900 hours) or nighttime (between 2100 and 0700 hours) supplementary nutrition (710 kcal/day). Primary etiology of liver disease was chronic viral hepatitis (67), alcohol (15), cholestatic (6), and other (15). Total body protein (TBP) was measured by neutron activation analysis at baseline, 3, 6, and 12 months. Total daily energy and protein intakes were assessed at baseline and at 3 months by comprehensive dietary recall. As a percentage of values predicted when well, TBP at baseline was similar for the daytime (85 ± 2[standard error of the mean]%) and nighttime (84 ± 2%) groups. For the nighttime group, significant increases in TBP were measured at 3 (0.38 ± 0.10 kg, P = 0.0004), 6 (0.48 ± 0.13 kg, P = 0.0007), and 12 months (0.53 ± 0.17 kg, P = 0.003) compared to baseline. For the daytime group, no significant changes in TBP were seen. Daily energy and protein intakes at 3 months were higher than at baseline in both groups (P < 0.0001), and these changes did not differ between the groups. Conclusion: Provision of a nighttime feed to patients with cirrhosis results in body protein accretion equivalent to about 2 kg of lean tissue sustained over 12 months. This improved nutritional status may have important implications for the clinical course of these patients. (HEPATOLOGY 2008.)

Protein-energy malnutrition is a common finding in patients with liver cirrhosis and is associated with reduced survival.1, 2 Abnormal fuel metabolism that is characteristic of these patients may contribute to the progressive decline in nutritional status with worsening disease. In particular, after overnight fasting, patients with cirrhosis exhibit increased rates of fat oxidation and gluconeogenesis while glucose utilization and glycogenolysis are reduced compared to normal controls.3 This metabolic profile is similar to that seen in healthy volunteers after 2–3 days starvation and is consistent with reduced glycogen storage capacity of the cirrhotic liver.

Provision of a late evening meal may ameliorate this accelerated progression to a catabolic state with resulting improvement in nitrogen balance. A short-term (5-day) study by Swart et al.4 showed that an extra meal at bedtime could indeed improve nitrogen balance compared with isocaloric and isonitrogenous diets without an evening meal. Nitrogen balance measured after longer-term (3-month) supplementation with a late-evening snack enriched in branched-chain amino acids in an outpatient setting was also shown to be significantly improved compared with baseline.5 The results of these studies, and others that have investigated the effects of nocturnal feeding on aspects of energy and substrate metabolism in patients with cirrhosis,6–14 do not allow us to conclude whether the improved nitrogen economy brought about by nocturnal feeding translates to improved nutritional status over the long term.

The primary aim of the current study was to compare the effects of nighttime and daytime nutritional supplementation over a 12-month period on nutritional status of patients with cirrhosis as assessed by direct measurement of body protein stores. We also compared changes in quality of life, complication rates, and changes in plasma concentrations of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and one of its major binding proteins between the nighttime and daytime groups over this period.


CI, confidence interval; FFM, fat-free mass; FFMc, normally hydrated fat-free mass; GH, growth hormone; HRQOL, health-related quality of life; IGFBP-3, insulin-like growth factor binding protein-3; IGF-I, insulin-like growth factor-I; SEM, standard error of the mean; TBP, total body protein; TBW, total body water.

Patients and Methods


Clinically stable patients with liver cirrhosis, aged 16 years and older, referred for nutritional support were eligible for inclusion in this study. The diagnosis of cirrhosis was based on either histologic analysis, clinical features of decompensated cirrhosis (jaundice, ascites, encephalopathy), laboratory evidence of liver synthetic failure (hyperbilirubinemia, hypoalbuminemia, prolonged prothrombin time), or radiologic findings of either nodular liver contour, or features of portal hypertension (ascites, varices, splenomegaly) in the absence of extrahepatic portal hypertension. Patients were excluded if they were on the waiting list for liver transplantation at the time of referral, were currently taking a nutritional supplement, or did not require nutritional supplementation because they were adequately nourished from their current intake. The latter determination was based on whether macronutrient intake, as assessed by a dietary history taken by one of two research dietitians (L.G. or K.M.), met the recommended requirements for patients with liver disease.15 The study was approved by the Auckland Ethics Committee, and written informed consent was obtained from each patient.

Study Protocol.

Consenting patients were randomized to receive 12 months of oral nutritional supplementation either late at night (after 2100 and before 0700 hours) or during the day (after 0900 and before 1900 hours). The randomization was stratified according to whether patients had recently (within the previous month) suffered a significant clinical event which required hospitalization, including spontaneous bacterial peritonitis, variceal bleeding, intractable encephalopathy, and an acute flare of their underlying liver disease. This ensured that these patients, who may avidly accrete body protein to replace the acute losses following hospitalization, were equally distributed across the two groups. The randomization schedule was held by an independent party who was not associated with the study, and the treatment allocation was provided to each patient in a sealed envelope. Each patient was provided with a diary to record time and amount of daily nutritional supplementation. Clinicians associated with the study and all investigators were blinded to the randomization allocation. Measurements of body composition, health-related quality of life (HRQOL), and plasma concentrations of GH, IGF-I, and IGF binding protein-3 (IGFBP-3) were obtained at baseline, prior to commencement of the nutritional supplementation. These measurements were repeated at 3, 6, and 12 months (Fig. 1). All patients underwent dietary assessment and received dietary advice from a study dietitian at baseline. Dietary assessment was repeated at 3 months. Patients were reviewed clinically at 3-month intervals, or more frequently if clinically indicated. Presence or absence of significant clinical events was recorded and patients were examined for ascites, encephalopathy, or other signs of decompensation. Renal and liver function tests were also obtained at each visit. Severity of liver disease was assessed according to the Child-Pugh score.

Figure 1.

Study design. Abbreviations: HRQOL, health-related quality of life; GH, growth hormone; IGF-I, insulin-like growth factor-1; IGFBP-3, insulin-like growth factor binding protein-3.

Nutritional Supplementation.

Each patient was prescribed two cans of Ensure Plus (Abbott Laboratories) to be taken daily, providing 710 kcal in 474 mL with caloric distribution as 15% (26 g) protein, 53% carbohydrate, and 32% fat. Diabetic Resource (Novartis) providing 500 kcal (24% [30 g] protein, 36% carbohydrate, and 40% fat) was prescribed for patients for whom satisfactory glycemic control could not be achieved on Ensure Plus despite adjustment of insulin dose and optimal medication. A compliance check was carried out by telephone approximately 1 month after randomization by a research nurse not otherwise associated with the study. Final compliance was assessed by returned diary and by exit interview conducted by the same research nurse.

Body Composition.

Body weight, total body nitrogen, total body fat, and bone mineral content were measured on each study day. Body weight was recorded to the nearest 0.1 kg using a beam balance. Adjustment was made for estimated weight of clothing.

Total Body Nitrogen.

Total body nitrogen was measured by prompt gamma in vivo neutron activation analysis16 with a precision of 2.7%17 and an accuracy of within 4%18 (based on anthropomorphic phantoms). Briefly, the supine patient is scanned from the shoulders to the knees through two opposed neutron fields and the prompt gamma radiation resulting from thermal neutron reactions with hydrogen and nitrogen is monitored. The method assumes that the ratio of nitrogen to hydrogen counts over the region scanned is representative of the whole-body ratio. Total body nitrogen is calculated from this ratio, after correction for body habitus and background counts, using the known concentrations of hydrogen in the body compartments and the masses of fat, mineral, and the whole body. Total body protein (TBP) was calculated as 6.25 times total body nitrogen. For each patient, a preillness TBP was estimated based on height, sex, age, and preillness body weight using equations developed in our laboratory from measurements on 386 healthy volunteers (163 male, 223 female, age range 17–82).19 Preillness weight was that recalled by the patient and provides a more accurate estimate of weight when well than that predicted from published tables.20 For each patient, as a measure of body protein status, a protein index was calculated as the ratio of measured TBP to preillness TBP. For the healthy controls, protein index was 1.00 ± 0.09 (standard deviation) for both males and females.

Total Body Fat and Bone Mineral.

Total body fat and bone mineral content were measured by dual-energy X-ray absorptiometry (model DPX+, software version 3.6y, extended research analysis mode; GE-Lunar, Madison, WI). Using anthropomorphic phantoms of known fat content and with different levels of overhydration, the precision of the technique for total body fat was 1.3% and the accuracy better than 5%.18 Precision for bone mineral content based on repeated measurements of healthy individuals has been reported as 1% using the current software version.21

Hydration-Corrected Fat-Free Mass.

Fat-free mass (FFM) was calculated as the difference between body weight and total body fat. Total body water (TBW) was derived by a difference method that assumes a six-compartment model for the body and is described in detail elsewhere.22 Briefly, TBW equals the difference between body weight and the sum of TBP, total body fat, bone mineral content, nonbone minerals, and glycogen. The small nonbone mineral and glycogen compartments are estimated from TBP and total minerals, respectively, based on the sizes of these compartments in the Reference Man.23 Error propagation calculations suggest that precision close to 1% may be achieved for TBW derived by this method with accuracy better than 3%. The measured FFM was adjusted to represent normally-hydrated fat-free mass (FFMc) using the formula: FFMc = FFM (1 − TBW/FFM) / (1 − 0.73), as described in detail elsewhere.24

Health-Related Quality of Life.

HRQOL was assessed using the SF-36 questionnaire25 with modifications appropriate for patients with liver disease.26, 27 These modifications included four additional domains (health distress, positive well-being, limitations due to liver disease, and health distress due to liver disease) in addition to the four domains in the area of physical health and four in the area of mental health assessed by the standard SF-36 questionnaire. Raw scores were recoded, if necessary, aggregated, and transformed to a 0 to 100 scale with higher scores indicating better health.

Plasma GH, IGF-I, and IGFBP-3.

Fasted (greater than 4 hours) plasma samples were assayed (in batches) for GH by immunoradiometric assay, IGF-I by chemiluminescent immunoassay, and IGFBP-3 by radioimmunoassay.

Dietary Assessment.

Dietary energy and macronutrient intakes based on a comprehensive dietary recall28 were assessed for each patient by one of two research dietitians (L.G. or K.M.) in order to maintain low interobserver error. Nutrient analysis was performed using a software package (Foodworks; Xyris Software, Highgate Hill, Australia) based on the New Zealand Food Composition database.

Statistical Analysis.

This study was designed to test whether nighttime nutritional supplementation results in improved TBP stores compared to results of daytime supplementation over a 6-month period. At 90% power and α level of 5%, 42 patients in each group were required to experience a difference in protein retention of 1 kg over this period. This assumed a 1 g nitrogen/day retention rate as found in the short-term study of Swart et al.4 and preliminary measurements from our laboratory of the variability in changes in TBP with daytime supplementation. The target sample size was 106 patients, assuming a mortality rate of 10% and a further 10% undergoing liver transplantation over the study period.

The primary analysis was performed on an intent-to-treat basis, and therefore available data from all patients entered into the study were used. Within-group changes from baseline at 3, 6, and 12 months and differences between groups were assessed using Student t test for paired and unpaired data, respectively. Repeated-measures analysis of variance with asphericity correction was used to detect significant interaction between the effect of the treatment and the response over time for patients with complete data over the 12-month study period. Fisher's exact test was used for categorical data. Nonparametric statistics (Spearman rank correlation test, Wilcoxon matched pairs test, and Mann-Whitney U test) were used for examining GH:IGF axis data. Partial correlation analysis was used between IGF-I or IGFBP-3 and protein index, adjusting for Child-Pugh score. In all cases, a two-sided 5% level was chosen for statistical significance. Results are expressed as mean ± standard error of the mean (SEM) unless otherwise stated. Analysis was carried out using SAS, release 9.1 (SAS Institute, Cary, NC).


A total of 106 patients were randomized to daytime or nighttime nutritional supplementation between February 2000 and May 2003. Follow-up was completed in May 2004. Three patients were randomized inappropriately following inadequate screening of their clinical notes for diagnosis of cirrhosis and current use of nutritional supplements and were excluded from further participation. Baseline characteristics of the remaining 103 patients are shown in Table 1. The two groups were well-balanced for all variables (P > 0.5). Three patients in the daytime group and seven in the nighttime group took a lower calorie supplement (Diabetic Resource). At 3, 6, and 12 months, 82, 75, and 69 patients, respectively, were assessed. The reasons for this attrition during the 12-month study period are detailed in Fig. 2. Patients who died or underwent liver transplant were not more predominant in one group (P = 0.39). Median baseline Child-Pugh score for patients who withdrew for other reasons was seven in the daytime group and six in the nighttime group (P = 0.52), and none died or underwent transplantation during the study period. Of these patients, five in the daytime group and three in the nighttime group requested withdrawal from the study because of refusal to continue with the nutritional supplement; two in the daytime group cited intolerance to the feed, and the remaining patients considered they did not need the supplement. Seven patients in the daytime group and four in the nighttime group failed to meet follow-up appointments.

Table 1. Baseline Characteristics of Patient Groups Prescribed Daytime or Nighttime Supplemental Feed
CharacteristicDaytime (n = 52)Nighttime (n = 51)
  • There were no significant differences between groups. Data are median (range), number of patients, or mean ± SEM.

  • *

    Patients were designated “unstable” if hospitalized within the previous month for a significant clinical event (see text for definition).

Sex (M:F)37:1531:20
Age (years)52 (31-71)50 (28-74)
Primary etiology  
Child-Pugh grading28A/13B/11C24A/18B/9C
Body weight (kg)75.9 ± 2.375.5 ± 2.3
Total body protein (kg)9.22 ± 0.288.71 ± 0.30
Total body protein (% predicted when well)85 ± 284 ± 2
Energy Intake (kcal/day)1845 ± 761739 ± 71
Protein intake (g/day)82 ± 573 ± 4
Figure 2.

Disposition of study patients. Number of patients not completing follow-up (baseline to month 3 + month 3 to month 6 + month 6 to month 12).

Intent-to-Treat Analysis.

TBP changes from baseline at 3, 6, and 12 months are shown in Fig. 3. Over the first 3 months, TBP increased by 0.38 kg (95% confidence intervale [CI]: 0.18–0.57 kg, P = 0.0004) in the nighttime group whereas in the daytime group the 0.11 kg (95% CI: −0.08–0.30 kg) change was not statistically significant (P = 0.25). Similarly, at 6 months, a significant increase in TBP was observed in the nighttime group but not in the daytime group (0.48 kg, 95% CI: 0.22–0.75 kg, P = 0.0007 versus 0.04 kg, 95% CI: −0.20–0.27 kg, P = 0.74). At 12 months, the change in TBP for the nighttime group was 0.53 kg (95% CI: 0.19–0.86 kg, P = 0.003) and for the daytime group 0.20 kg (95% CI: −0.03–0.43, P = 0.081). For the 69 patients who completed all measurements to 12 months, the 3-month changes in TBP for the nighttime and daytime groups were, respectively, 0.41 kg (CI: 0.19–0.62 kg, P = 0.0004) and 0.08 kg (CI: −0.12–0.28 kg, P = 0.41) and the corresponding 6-month changes were 0.49 kg (CI: 0.22–0.77 kg, P = 0.0009) and −0.05 kg (CI: −0.25–0.16 kg, P = 0.65). For these 69 patients, the time profile of the changes in TBP differed significantly between the groups (P = 0.024 for time × treatment interaction).

Figure 3.

Total body protein (TBP) changes from baseline (mean ± SEM) at 3, 6, and 12 months of daytime (open bars) or nighttime (solid bars) nutritional supplementation in patients with cirrhosis. *P < 0.003 versus zero change. †P = 0.02 for comparison of groups.

The changes in FFM, corrected to normal hydration, from baseline to 3, 6, and 12 months are shown in Fig. 4. For the nighttime group, significant gains were observed at all three time points (P < 0.007) and for the daytime group, none of the changes was significant.

Figure 4.

Fat-free mass (FFM, corrected to normal hydration) changes from baseline (mean ± SEM) at 3, 6, and 12 months of daytime (open bars) or nighttime (solid bars) nutritional supplementation in patients with cirrhosis. *P < 0.007 versus zero change. †P < 0.03 for comparison of groups.

TBP changes from baseline at 3, 6, and 12 months are shown in Fig. 5 for patients grouped according to their Child-Pugh severity grade at baseline. At each severity level, the pattern of changes is similar to that seen for the groups as a whole with statistically significant increases in body protein seen in the nighttime group at 3 (P = 0.005), 6 (P = 0.015), and 12 months (P = 0.034) for Child A patients and at 6 months (P = 0.009) for Child C patients.

Figure 5.

Total body protein (TBP) changes from baseline (mean ± SEM) at 3, 6, and 12 months of daytime (open bars) or nighttime (solid bars) nutritional supplementation in patients grouped according to Child-Pugh severity grading. *P < 0.05 versus zero change.

Energy intake over the first 3 months increased from 1739 ± 71 to 2141 ± 61 kcal/day in the nighttime group (P < 0.0001) and from 1845 ± 76 to 2307 ± 79 kcal/day in the daytime group (P < 0.0001). The mean changes did not differ between the groups (401 ± 47 versus 462 ± 60 kcal/day, respectively, P = 0.42). Protein intake over this period increased from 73 ± 4 to 90 ± 3 g/day in the nighttime group (P < 0.0001) and from 82 ± 5 to 98 ± 4 g/day in the daytime group (P < 0.0001). The mean changes did not differ between the groups (16.3 ± 2.9 versus 15.6 ± 3.1 g/day, respectively, P = 0.86). The 3-month TBP changes for the nighttime and daytime groups were 26% and 8%, respectively, of the increased protein intake.

Death, transplantation, or a major complication requiring hospitalization were recorded in nine patients in the nighttime group and 14 in the daytime group (P = 0.34).

Per-Protocol Analysis.

A number of patients had difficulty consuming the full volume of supplement prescribed and 16 patients (eight in each group) of the 82 who completed 3 months of the study fell into this category. Of patients taking the full amount (34 in the nighttime group and 32 in the daytime group), 15 in the nighttime group and five in the daytime group took some or all of their supplement outside the prescribed times (P = 0.016). Of these 20 patients, eight (six of whom required English language interpreters) took half their supplement during the day and half at night. Forty-six (19 nighttime, 27 daytime) patients who completed at least 3 months of the study took their supplement as prescribed in regard to both amount and timing. Of these 46 patients, 41 remained in the study at 6 months and 40 at 12 months. The TBP changes over 3, 6, and 12 months for the daytime group were not statistically significant (0.02 ± 0.13, −0.05 ± 0.12, and 0.12 ± 0.13 kg, respectively). For the nighttime group, TBP increased from baseline at all three time points (0.38 ± 0.15 kg, P = 0.018; 0.53 ± 0.24 kg, P = 0.044; 0.61 ± 0.25 kg, P = 0.027; respectively). For patients completing the study, the time × treatment interaction effect did not reach statistical significance (P = 0.076).

Owing to investigator oversight, a relatively small subgroup of patients were provided with and completed the HRQOL questionnaires. In the compliant patients, changes in HRQOL scores over 3, 6, and 12 months for the eight SF-36 domains and the four additional domains are shown in Fig. 6 for the daytime (n = 16, 12, and 15, respectively) and nighttime (n = 10, 10, and 9, respectively) groups. Significant increases in the scores for Role Physical, Social Functioning, Role Emotional, and Health Distress were seen in the nighttime group by 6 months, whereas none of the scores changed significantly in the daytime group. At 12 months, significant increases in these scores were also seen in the daytime group. For the subgroup of 18 patients (11 daytime and seven nighttime) who completed the study, the time × treatment interaction for each domain was not significant (P = 0.10–0.99).

Figure 6.

The 3-month, 6-month, and 12-month changes from baseline (mean ± SEM) in health-related quality of life (HRQOL, augmented SF-36) scores in patients with cirrhosis randomized to daytime (open bars) or nighttime (solid bars) nutritional supplementation. *P < 0.05 versus zero change. †P < 0.05 for comparison of groups. Abbreviations: BP, bodily pain; GH, general health; HD, health distress; HDLD, health distress due to liver disease; LLD, limitations due to liver disease; MH, mental health; PF, physical functioning; PWB, positive well-being; RE, role emotional; RP, role physical; SF, social functioning; VT, vitality.

Plasma GH, IGF-I, and IGFBP-3.

Baseline measurements of GH, IGF-I, and IGFBP-3 were carried out in 65 patients (40 in Child-Pugh Grade A, 19 in Child-Pugh B, and six in Child-Pugh C). Median plasma concentrations were, respectively, 2.4 (range 0.1–21.8) ng/mL, 52 (20–236) ng/mL, and 1.3 (0.2–2.8) mg/L. Plasma IGF-I concentration was weakly negatively correlated with GH concentration (r = −0.22, P = 0.08) and strongly correlated with IGFBP-3 concentration (r = 0.63, P < 0.0001). A significant positive correlation was seen between GH concentration and Child-Pugh score (r = 0.36, P = 0.003) and significant negative correlations were seen between IGF-I and IGFBP-3 concentrations and Child-Pugh score (r = −0.40, P = 0.001; r = −0.56, P < 0.0001; respectively). Concentrations of both IGF-I and IGFBP-3 were significantly correlated with protein depletion as measured by protein index (r = 0.27, P = 0.029; r = 0.29, P = 0.019; respectively). These correlations remained significant after controlling for Child-Pugh score (r = 0.28, P = 0.026; r = 0.32, P = 0.010; respectively).

Table 2 summarizes the baseline, 3-month, 6-month, and 12-month measurements of plasma GH, IGF-I, and IGFBP-3 concentrations in the daytime and nighttime groups for patients who completed the study (n = 42). At baseline, GH and IGFBP-3 concentrations did not differ significantly between the groups whereas IGF-I concentration was lower in the nighttime group. GH concentrations did not change in either group over the study period. A significant increase in IGF-I concentration was seen over the first 3 months in the nighttime group after which it decreased to baseline level. Parallel changes in IGFBP-3 were seen. In the daytime group, a small increase in IGF-I concentration was observed over the first 3 months after which no significant changes were seen. IGFBP-3 concentration also increased over the first 3 months. For these 42 patients, the TBP changes over 3, 6, and 12 months for the daytime group were not statistically significant (0.00 ± 0.11, −0.14 ± 0.11, and 0.15 ± 0.14 kg, respectively). For the nighttime group, TBP increased from baseline at all three time points (0.52 ± 0.12 kg, P = 0.0002; 0.58 ± 0.16 kg, P = 0.002; 0.57 ± 0.18 kg, P = 0.004; respectively).

Table 2. Results of Serial Measurements of GH, IGF-I, and IGFBP-3 in 42 Patients Taking Daytime or Nighttime Nutritional Supplements
VariableGroup (n)Baseline (0)3 Months6 Months12 MonthsP value*
0 to 3 mo3 to 6 mo6 to 12 mo
  • Data are expressed as median (range).

  • *

    Wilcoxon matched pairs test.

  • Significant difference between groups (P = 0.024).

GH (ng/mL)Day (19)2.4 (0.1–21.8)1.2 (0.1–22.5)0.5 (0.1–8.8)0.9 (0.1–15.5)0.290.570.66
 Night (23)1.7 (0.2–13.0)2.8 (0.1–18.0)1.9 (0.1–18.9)2.4 (0.1–16.2)0.940.160.84
IGF-I (ng/mL)Day (19)70 (34–124)75 (38–145)73 (37–115)76 (20–132)0.0490.170.78
 Night (23)52 (20–109)61 (20–117)54 (20–101)50 (20–115)0.00090.0470.77
IGFBP-3 (mg/L)Day (19)1.4 (0.7–2.8)1.5 (0.8–2.8)1.4 (0.6–2.6)1.5 (0.6–2.9)0.00020.0070.31
 Night (23)1.3 (0.6–2.3)1.5 (0.6–2.5)1.4 (0.3–2.2)1.3 (0.3–2.2)0.0190.0520.86


This study shows that provision of a nutrient-dense nighttime feed to patients with liver cirrhosis results in significant accretion of total body protein over a 12-month period of supplementation. This gain of approximately 0.5 kg was achieved largely by 3 months and sustained over the subsequent 9 months. Patients who received nutritional supplementation during the day neither lost nor gained appreciable body protein. Energy and protein intake increased significantly in both groups of patients by similar amounts, so improved nitrogen retention in the nighttime group is not explained by increased protein intake in this group. Rather, the results can be interpreted to mean that by limiting the overnight fasting period with a late-evening “meal” the progression to early onset of nocturnal gluconeogenesis from amino acids is blunted with improvement in net nitrogen balance. About 25% of the increased protein intake in the nocturnal feeding group was retained. Protein accretion of 0.5 kg equates to 2–2.5 kg lean muscle and is confirmed by our independent measurement of FFM with appropriate correction for the overhydration commonly seen in these patients.24 Our results suggest that the benefits of nocturnal supplementation are not restricted to those patients with more severe disease but are seen also in patients with compensated, Child A, cirrhosis.

This study, which is the only long-term longitudinal study yet to be reported of nocturnal versus daytime nutritional supplementation, confirms the preliminary findings of Swart et al.4 The nitrogen retention observed by Swart et al.4 in their short-term study (1 g nitrogen/day or 6.25 g protein/day) equates to 0.5 kg over 90 days, consistent with the protein accretion measured in the present study. Others have also used nitrogen balance techniques to assess the benefits of late-evening nutritional supplements or snacks on nutritional status.5, 7, 8, 10 With the exception of Nakaya et al.5, all these published studies have been conducted over short periods (<1 week) in small groups of patients. Nakaya et al.5 showed that nitrogen balance measured after 3 months supplementation with a late-evening snack (210 kcal/day) enriched in branched-chain amino acids was significantly higher than at baseline. Interestingly, in their unblinded study, no improvement in nitrogen balance was observed with ordinary food (isocaloric but not isonitrogenous) as a late-evening snack. This study has addressed the need for a long-term controlled study in an outpatient population in which the effect of nocturnal feeding on nutritional status is quantified by direct measurement of changes in total protein stores rather than by inference from nitrogen balance measurements performed before and after the intervention.

The results for HRQOL in protocol-compliant patients are suggestive of a general improvement in this parameter with nocturnal feeding, at least over the first 6 months. By 12 months, some improvement was evident in both daytime and nighttime groups. However, the small number of patients contributing to these results and the possibility of bias toward patients experiencing some improvement make definitive conclusions difficult. Although the number of patients who suffered a major complication or underwent transplantation was 56% higher in the daytime group, this difference was not statistically significant. Larger studies with HRQOL and complication rates as endpoints are indicated to definitively assess the benefits of nocturnal feeding on these important clinical outcomes

In patients with cirrhosis, the GH:IGF axis is profoundly disturbed with characteristically high circulating GH and low IGF-I and IGFBP-3 levels, indicating a state of severe GH resistance which may be central to the severe protein catabolic state observed in this patient group.29, 30 Baseline measurements in a subgroup of patients in this study were similar to those published elsewhere29, 31–33 and confirm these derangements in levels of GH, IGF-I, and IGFBP-3. We have also confirmed the positive association between plasma IGF-I and IGFBP-3 concentrations.29 IGF-I and IGFBP-3 decreased with increasing disease severity, as assessed by Child-Pugh score, in agreement with the findings of others29, 32 and consistent with a dominant role of the liver cell mass in IGF-I and IGFBP-3 production. We also found that serum GH levels increased with worsening disease.

IGF-I has been reported to be a sensitive marker of acute changes in nutritional status in human volunteers34 and malnourished patients.35 In patients with alcoholic liver disease, IGF-I levels correlated significantly with a composite measure of nutritional status, independent of liver dysfunction, and improved with nutritional therapy.36 In contrast, Caregaro et al.32 did not find a significant association between circulating IGF-I and anthropometric markers of malnutrition in patients with alcoholic and viral-related cirrhosis. This study showed that plasma IGF-I was significantly associated with protein depletion measured directly and that this association was independent of disease severity.

We examined whether the improvement in nitrogen economy effected by nocturnal feeding was reflected in increased circulating IGF-I and IGFBP-3 concentrations. Our results suggest that the initial 3-month improvement in nutritional status in nocturnally fed patients is associated with an improvement in concentrations of IGF-I and its binding protein. As far as we are aware, increases in levels of these growth factors in association with improved nitrogen economy have not been reported previously in patients with cirrhosis.

Attrition of patients through the study may introduce bias in our results particularly if the reasons for drop-out were related to response to the intervention. It is difficult to prove that our analysis of the available data is representative of the complete data had it been obtainable. However, 14 of the 19 patients who dropped out for reasons other than death or transplant did so before the 3-month assessment and largely because of refusal to continue with the nutritional supplement. Compliance with the prescribed nutritional regimen was a problem in this study, with a significant number of patients who either did not take the full daily amount or took the supplemental nutrition outside of the designated times. Language difficulties for a number of patients who required an interpreter contributed to the latter. Of those who completed at least 3 months of the study, more patients in the nighttime group failed to take the supplement as prescribed (P = 0.049). Measures designed to optimize compliance, including follow-up calls and diary recording, were clearly not successful in a significant number of patients. Strengths of the study were the use of an objectively measured endpoint (total body protein) and blinding of the investigators to the group allocation for the purposes of intent-to-treat analysis.

In summary, this study has shown for the first time that a change of timing of a nutritional intervention results in significant improvement in body protein stores and hence nutritional status of patients with liver cirrhosis. This was an outpatient study, because our intention was to demonstrate whether an improvement in nutritional status could be achieved by implementing a simple nutritional regime, in an unsupervised ambulatory setting, which could be easily translated to clinical practice. It remains to be seen whether this improvement results in significant positive benefits for these patients in terms of either incidence of complications of cirrhosis, survival, or need for transplantation. A much larger study would be required to examine these clinical outcomes; nevertheless, the feasibility and rationale for such a study is supported by the present work. In the interim, we strongly suggest that dietary recommendations for patients with cirrhosis include a late-evening nutrient-dense “meal”.


We thank Abbott Laboratories (NZ) Ltd. for supplies of Ensure Plus and Elana Brokenshire for assistance.