567716

research-article2015

NCPXXX10.1177/0884533614567716Nutrition in Clinical PracticeNey et al

Clinical Research

Insufficient Protein Intake Is Associated With Increased Mortality in 630 Patients With Cirrhosis Awaiting Liver Transplantation

Nutrition in Clinical Practice Volume XX Number X Month 201X 1­–7 © 2015 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533614567716 ncp.sagepub.com hosted at online.sagepub.com

Michael Ney, MD1; Juan G. Abraldes, MD1,2; Mang Ma, MD1,2; Dawn Belland, BSc2; Andrea Harvey, BSc2; Sarah Robbins, MD3; Vanessa Den Heyer, BSc1,2; and Puneeta Tandon, MD1,2

Abstract Background: For patients awaiting liver transplantation, we aimed to determine the prevalence and predictors of insufficient protein intake as well as to determine whether very low protein intake was an independent predictor of malnutrition and mortality. Materials and Methods: Adults with cirrhosis who were activated on our local liver transplant waiting list between January 2000 and October 2009 were included. Estimated protein intake was derived from dietary records. Patients with incomplete dietary records were excluded. Multivariable logistic regression and competing risk analysis were used. Results: Of 742 potential patients, 112 were excluded due to insufficient data, leaving 630 patients for evaluation. Mean protein intake was 1.0 ± 0.36 g/kg/d and only 24% of patients met the expert consensus recommended threshold of > 1.2 g/kg of protein per day. Very low protein intake (< 0.8 g/kg/d) was associated with worse liver disease severity (as measured by Child-Pugh or MELD). Protein intake below 0.8 g/kg/d was an independent predictor both of malnutrition as measured by the subjective global assessment (adjusted odds ratio [95% confidence interval (CI)]: 2.0 [1.3–3.0]) and of transplant waiting list mortality (adjusted hazard ratio [95% CI]: 1.8 [1.2–2.7]). Conclusion: In this large cohort of liver transplant waitlisted patients, very low protein intake was prevalent and independently associated with malnutrition and mortality. Unlike many other prognostic factors, protein intake is potentially modifiable. Prospective studies are warranted to evaluate the effect of targeted protein repletion on clinically relevant outcomes such as muscle mass, muscle function, immune function, and mortality. (Nutr Clin Pract. XXXX;xx:xx-xx)

Keywords liver cirrhosis; liver transplantation; nutrition assessment; mortality; malnutrition; dietary intake

Introduction Cirrhosis is the final common pathway of a wide range of hepatic insults.1 As cirrhosis progresses, patients experience both a decline in liver function as well as clinically significant losses in skeletal muscle mass, muscle function, and exercise capacity. These impairments in muscle mass and physical function are being increasingly recognized as strong independent predictors of morbidity and mortality both pre- and post-transplantation.2-7 As adequate protein intake is an essential building block to provide the amino acids required for the maintenance of muscle mass and function, protein intake warrants further exploration in this population. The target protein recommendations in cirrhosis have evolved since the 1970s and 1980s where it was common to restrict dietary protein to reduce the risk of hepatic encephalopathy. In 2004, a study by Cordoba and colleagues8 demonstrated that the amount of protein consumed did not influence the course of hepatic encephalopathy and, importantly, that even short-term protein restriction to 0.5 grams per kilogram of body weight per day (g/kg/d) resulted in increased muscle tissue breakdown. By expert consensus, the most recent

guidelines from the European Society for Parenteral and Enteral Nutrition (ESPEN) have set a target protein intake of 1.2–1.5 g/kg/d in cirrhosis.9 This target is higher than the recommended daily allowance (RDA) set for the general population of 0.8 g/kg/d10 as a result of the increased energy expenditure and predisposition for proteolysis and muscle breakdown that occur in cirrhosis.11 In noncirrhotic, predominantly elderly populations, increased dietary protein is associated with increased muscle mass,12-15 increased muscle strength,16,17 reduced frailty,18 reduced hospital readmissions, and, in a subgroup of malnourished elderly From 1Cirrhosis Care Clinic, Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; 2Liver Transplant Unit, University of Alberta, Edmonton, Alberta, Canada; and 3 Division of Gastroenterology, Royal Alexandra Hospital, Edmonton, Alberta, Canada. Financial disclosure: None declared. Corresponding Author: Puneeta Tandon, MD, University of Alberta, 130 University Campus, Zeidler Ledcor Center, Edmonton, Alberta, T6G2X8, Canada. Email: [email protected]

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patients, reduced mortality.19 Although protein intake may also be a modifiable prognostic factor in patients with cirrhosis, in this population both the prevalence of insufficient protein intake and the effect of low intake on clinical outcomes remain unclear. Given the success of protein supplementation in nonliver patients, as well as the significant implications of muscle mass/ muscle function loss and impaired immunity in patients with cirrhosis, interventional studies are needed to clarify the role of protein supplementation in cirrhosis. Prior to designing such trials, in a retrospective series of patients with cirrhosis awaiting liver transplantation, we aimed to determine (a) the baseline level of daily protein consumption in this group and, therefore, the room available for an intervention to modify this variable, (b) predictors of low protein intake, and (c) whether protein intake was an independent risk factor for clinically relevant outcomes including malnutrition and liver transplant (LT) waiting list mortality.

Methods Study Population This retrospective study made use of our local LT database. This database includes adult patients (≥ 18 years) activated on the LT waiting list between January 2000 and October 2009 without acute liver failure, prior LT, or listing for multivisceral transplantation. All patients were assessed at the time of their LT evaluation and all had cirrhosis based on compatible histological or radiological findings. For the purposes of this study, patients were excluded if they did not have sufficient protein intake data recorded in the database. Local ethics approval was obtained prior to study initiation. The LT database was searched for data on patient demographics, liver disease severity (as measured by Child-Pugh status and the model for end-stage liver disease [MELD] score), laboratory data, etiology of cirrhosis, height and weight (including estimated dry weight), daily protein intake, transplant status, and mortality on the LT waiting list. Follow-up was recorded until death, liver transplantation, removal from the waiting list, or the end of the study period (January 27, 2011), whichever came first.

Definitions The estimated dry weight is a subjective estimation of a patient’s weight without ascites or pedal edema. At our center, dietitians almost always estimate this using the post-paracentesis body weight. Only if this is unavailable is the dry weight estimated by subtracting 5% of the patient’s weight in the presence of mild ascites, 10% in the presence of moderate ascites, and 15% in the presence of severe ascites. An additional 5% is subtracted if bilateral pedal edema is present. The dry weight body mass index (BMI) is calculated by dividing the estimated dry weight in kilograms by the height in meters squared.

The subjective global assessment (SGA) is a nutrition assessment tool developed by Detsky et al.20 It divides patients into 3 categories based on the bedside history and physical examination parameters: (A) well nourished, (B) moderately or suspected of being malnourished, and (C) severely malnourished.

Protein Intake Assessment As part of the LT assessment at our center, all patients undergo a 1-hour nutrition evaluation by a dietitian. Protein intake is estimated using a combination of a 2-day diet record, a food frequency questionnaire, and probing questions to clarify intake. The estimated protein intake is recorded in grams per day. To determine the goal protein intake for the individual patient, the protein intake in grams is divided by estimated dry weight in kilograms to obtain the intake in grams per kilogram per day. As per the ESPEN guidelines, a patient was considered to have met goal protein intake if his or her intake was > 1.2 g/kg/d.9 Low protein intake was defined as intake between 0.8 and 1.2 g/kg/d. In keeping with the RDA for the general population, very low protein intake was defined as < 0.8 g/kg/d.10 To avoid setting the goal protein intake too high for overweight patients, as per our institutional standard, if the estimated dry weight BMI was ≥ 30, target protein was dosed based on an ideal body weight (BMI of 24.9 × height in meters2).

Statistical Analyses Statistical analyses were performed with SPSS 21 statistical software (SPSS, Inc, Chicago, IL, USA) and R (http://www.rproject.org). Variables were described using means and standard deviations. Univariable and multivariable logistic regression was used to determine the predictors of protein intake and the predictors of a clinical diagnosis of malnutrition (defined as SGA class B or C). The risk of death was described with the cumulative incidence function taking into account liver transplantation as a competing risk. This provides a more accurate estimation of death rates than censoring patients at the time of liver transplantation in a Kaplan-Meier analysis.21 Comparisons between patients with different degrees of protein intake were performed with the Gray test.22 Factors associated with mortality were analyzed in a multivariable analysis with the modification of the Cox proportional hazards model proposed by Fine and Gray,23 again accounting for liver transplantation as a competing risk. Patients removed from the waiting list because they were considered too sick to undergo transplantation were counted as deaths. Patients removed because they were deemed too well to undergo transplantation were censored. For all analyses, 2-sided P values < .05 were considered statistically significant. All competing risks analyses were performed with the R package cmprsk.

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Table 1.  Baseline Characteristics of 630 Adults Awaiting Liver Transplantation. Variable

Mean ± SD

No. (%)

Age Male Ethnicity  Caucasian  Asian   Native American  Other Etiology of cirrhosis   Hepatitis C  PBC/PSC/AIH  Alcohol  NASH/cryptogenic  Othera Hepatocellular carcinoma MELD score Child Pugh score Child Pugh category (A/B/C) Height, cm Estimated dry weight, kg Estimated dry weight BMI, kg/m2 Subjective global assessment (A/B/C) Protein intake per day, g Protein intake per day corrected for body weight, g/kg estimated dry weight Protein intake, g/kg estimated dry weight   < 0.8 g/kg (very low protein intake)   0.8–1.2 g/kg (low protein intake)   > 1.2 g/kg (target protein intake)

52.2 ± 8.9

  428 (67.9)   552 (87.6) 51 (8.1) 20 (3.2) 7 (1.0)   249 (39.5) 134 (21.3) 132 (21.0) 61 (9.7) 54 (8.5) 140 (22.2)     12.6%/53.0%/34.4%       36.2%/53.8%/10%       162 (25.7) 317 (50.3) 151 (24.0)

14.8 ± 6.3 8.7 ± 1.9 170.0 ± 10.0 73.4 ± 16.1 25.3 ± 4.8 68.8 ± 23.3 1.0 ± 0.36

AIH, autoimmune hepatitis; BMI, body mass index; HCV, hepatitis C virus infection; NASH, nonalcoholic steatohepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SD, standard deviation. a Other etiologies: hepatitis B (n = 31), α-1-antitrypsin deficiency (n = 7), hemochromatosis (n = 5), sarcoidosis (n = 3), Wilson’s (n = 3), erythropoietic porphyria (n = 1), drug induced (n = 1), schistosomiasis (n = 1), Alagille’s (n = 1), Budd-Chiari (n = 1).

Results Patient Characteristics Of 742 potential patients in the LT database, 112 were excluded due to insufficient protein data, leaving 630 available patients for analysis. The baseline characteristics of these patients are presented in Table 1. Sixty-eight percent of patients were male with a mean age of 52 years ± a standard deviation (SD) of 8.9. Eighty-eight percent of patients were Caucasian. The most common etiology of cirrhosis was hepatitis C, seen in 39.5% of patients. The mean MELD score at activation was 14.8 ± 6.3 and 22.2% of patients had hepatocellular carcinoma (all within liver transplantation criteria). Mean baseline laboratory values were representative of a transplant waitlisted population with a serum sodium of 136.0 ± 4.9 mmol/L, INR of 1.4 ± 0.3, bilirubin of 77.3 ± 111.7 umol/L, serum albumin level of 31 ± 6.5 g/L, and creatinine of 97.4 ± 73.8 umol/L.

± 0.4 g/kg/d. For the data analysis, protein intake was categorized as < 0.8 g/kg/d, 0.8–1.2 g/kg/d, and > 1.2 g/kg/d. Twentysix percent (162/630), 50% (317/630), and 24% (151/630) of patients fit into these categories, respectively (Table 1). Very low protein intake was considered to be < 0.8 g/kg/d. This pre-hoc threshold was justified based on the RDA cutoff of 0.8 g/kg/d in the general population and supported by the fact that our subsequent analyses did not show significant differences in mortality in patients consuming 0.8–1.2 g/kg/d or > 1.2 g/kg/d. On multivariable analysis, the 2 independent predictors of very low protein intake were liver function (as measured by either the Child Pugh score or MELD score) and etiology of liver disease (Table 2). The group of autoimmune liver disorders (primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis) was associated with a lower risk of very low protein intake.

Protein Intake and Predictors of Intake

Association Between Protein Intake and Malnutrition

The mean protein intake per day was 69 ± 23 grams. Corrected for estimated dry weight, this represents a protein intake of 1.0

Malnutrition (defined as SGA B or C) was assessed on the same day as protein intake assessment. Thirty-six percent of

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Table 2.  Independent Predictors of Protein Intake < 0.8 g/kg/d—Models Using the MELD Score or the Child Pugh Score. Multivariable Analysis With MELD

Multivariable Analysis With CP Score

Variable

OR (95% CI)

P Value

OR (95% CI)

P Value

Age (per 10-y increase) Male Etiology of cirrhosis  HCV  Alcohol  PBC/PSC/AIH  NASH/cryptogenic  Other Hepatocellular carcinoma MELD score (per 5 point increase) CP score (per 1 point increase)

1.2 (1.0–1.6) 0.7 (0.4–1.0)

.08 .05

1.3 (1.0–1.6) 0.7 (0.4–1.0)

.06 .07

1 0.7 (0.4–1.2) 0.4 (0.2–0.7) 0.9 (0.5–1.8) 0.8 (0.4–1.6) 0.8 (0.5–1.2) 1.2 (1.1–1.4)

Reference .16 .001 .89 .48 .26 .006

1 0.7 (0.4–1.1) 0.5 (0.3–0.8) 1.0 (0.5–1.9) 1.0 (0.5–1.9) 0.9 (0.5–1.4)

Reference .13 .009 .99 .92 .54   .001

1.2 (1.1–1.4)

AIH, autoimmune hepatitis; CI, confidence interval; CP, Child Pugh; OR, odds ratio.

Table 3.  Independent Predictors of Moderate to Severe Malnutrition as Estimated by a Subjective Global Assessment Rating of B or C—Models Using the MELD Score or the Child Pugh Score. Multivariable Analysis With MELD

Multivariable Analysis With CP Score

Variable

OR (95% CI)

P Value

OR (95% CI)

Age (per 10-y increase) Male Hepatocellular carcinoma Etiology of cirrhosis  HCV  Alcohol  PBC/PSC/AIH  NASH/cryptogenic  Other Protein intake < 0.8 g/kg estimated dry weight CP score (per 1 point increase) MELD score (per 5 point increase)

1.1 (0.9–1.3) 1.4 (0.9–2.0) 0.4 (0.2–0.6)

.6 .14 .001

1.1 (0.9–1.3) 1.4 (0.9–2.1) 0.5 (0.3–0.8)

1 1.6 (1.0–2.7) 0.9 (0.5–1.4) 1.4 (0.7–2.7) 0.4 (0.2–0.8) 2.0 (1.3–3.0)

Reference .06 .54 .34 .01 .002

1 1.5 (0.9–2.6) 1.1 (0.6–1.8) 1.5 (0.8–3.0) 0.5 (0.2–0.9) 1.8 (1.2–2.8) 1.4 (1.2–1.5)

1.2 (1.1–1.5)

.006

P Value .45 .11 .002 Reference .11 .74 .21 .03 .009 .001  

AIH, autoimmune hepatitis; CI, confidence interval; CP, Child Pugh; OR, odds ratio.

patients were SGA-A, 54% SGA-B, and 10% SGA-C. On multivariable analysis, the independent predictors of malnutrition were very low protein intake (< 0.8 g/kg/d), liver function as measured by either the Child Pugh score or MELD score, hepatocellular carcinoma (associated with a lower risk of malnutrition), and the etiology of liver disease (Table 3).

Association Between Protein Intake and Mortality In the study cohort, the 6-month mortality rate was 14.4% and the 12-month mortality 20.2%. When stratified by protein ingestion, the 12-month mortality in patients consuming < 0.8 g/kg/d was 27.8% as compared with 15.9% in the 0.8– 1.2 g/kg/d and 17.2% in the > 1.2 g/kg/d subcategories (Figure 1).

A multivariable competing risks model was used to evaluate the independent predictors of waiting list mortality (Table 4). For this analysis, 617 patients had complete data available for evaluation: by the 1-year follow-up period, 116 of these patients had died, 288 were transplanted, and 213 remained alive on the waiting list. Increasing age, hyponatremia, liver disease severity as measured by either the Child Pugh or MELD scores, and protein intake < 0.8 g/kg/d were independently associated with mortality on the waiting list. A very low protein intake was associated with a 70% increase in the relative risk of death (adjusted hazard ratio [95% CI]: 1.8 [1.2–2.7]).

Discussion In this analysis of 630 LT waitlisted patients, the key findings are 3-fold. First, a striking 76% of patients had protein intake

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0.2

0.4

0.6

0.8

less than 0.8 g/Kg between 0.8 1.2 g/Kg more than 1.2 g/Kg

0.0

Cumulative incidence of death

1.0

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Time to death (months)

Figure 1.  Cumulative incidence of death on the waiting list for liver transplantation according to protein intake. Patients consuming 0.8–1.2 g/kg protein per day (n = 317) or > 1.2 g/ kg/d (n = 151) had a comparable mortality, with the highest mortality seen in patients consuming < 0.8 g/kg/d (n = 162). Liver transplantation was considered a competing event for these calculations.

below the 1.2 g/kg/d intake recommended for patients with cirrhosis. Second, the major predictor of very low protein intake was increased liver disease severity (as measured by either the MELD or the Child Pugh score). Third, very low protein intake (< 0.8 g/kg/d) at study baseline was associated with worse clinical outcomes. After correcting for relevant variables such as age and liver disease severity, very low protein intake remained independently associated with a diagnosis of malnutrition (SGA B or C) made at study baseline and mortality on longitudinal follow-up. In our series, only 24% of patients met the cirrhosis-specific target intake of 1.2 g/kg/d. It is notable that 26% consumed even less than the 0.8 g/kg/d RDA set for the general population. Protein intake under the RDA is uncommon. Data from the National Health and Nutrition Examination Survey of adults in the United States estimated that in the age category of 50–70 years, only 7% of women and < 3% of men consumed less than the RDA.24 This is consistent with a second series of elderly patients (ages 65–75) from France where only 6% consumed < 0.8 g/kg/d.25 The causes of insufficient protein intake are likely to be multifactorial, ranging from a lack of knowledge about the importance of protein, challenges with food access, and low intake related to the symptoms of advanced liver disease. The major predictor of very low protein intake (< 0.8 g/kg/d) in our series was increasing liver disease severity as measured by the Child Pugh and MELD scores. This is consistent with data showing that as compared with Child Pugh A patients, those with Child Pugh B or C disease are more likely to have anorexia, impaired taste, and early satiety with intake limited by symptoms including pain, fatigue, nausea, and ascites.26 The second independent predictor associated with very low

protein intake in the current series was disease etiology, showing a less impaired protein intake in the subgroup of PBC, PSC, and autoimmune hepatitis patients. The reason for this association is unclear. Although not specifically evaluated as part of this study, it is possible that this protection may be on the basis of more stable socioeconomic factors in the PBC, PSC, and autoimmune hepatitis subgroup.27 Increasing age and female sex have been identified as predictors of reduced protein intake in the general population,24 and in our series, both trended to significance. The clinical implications of low protein intake in cirrhosis have not been well evaluated. In the current study, it is not surprising that very low protein intake was associated with a 2-fold increase in the diagnosis of moderate or severe malnutrition (SGA B or C). It is interesting that very low protein intake was also an independent predictor of mortality, associated with an almost 2-fold increase in the risk of death. This was despite adjustments for liver dysfunction, serum sodium level, patient age, and malnutrition as assessed by the SGA. Although causation cannot be determined based on a retrospective study, several factors make the association between very low protein intake and mortality plausible. Next to water, protein is the most abundant substance in the human body, essential for carrying out many vital body processes. Second, adequate protein intake is central to muscle synthesis. A growing number of studies have demonstrated that impairments in muscle mass and function are strong independent predictors of mortality in cirrhosis.6,7,28,29 Third, infection is a key cause of mortality in patients with cirrhosis.30 In both animal and human studies, a protein-restricted diet impairs both cell-mediated and humoral immunity.31,32 Moreover, dietary protein restriction produces a pro-inflammatory state (increase in IL-1, IL-6, and TNF-α) that is interestingly not seen with caloric restriction alone.33 As protein intake is a potentially modifiable prognostic factor, these findings support the performance of prospective randomized trials in the area. This is particularly relevant given the poor prognosis of patients with cirrhosis and because none of the other identified independent predictors of mortality (age, sodium, MELD, or Child Pugh) in Table 4 are easily modifiable. The optimal dose and timing of protein intake require further investigation in cirrhosis. The 0.8 g/kg/d RDA cutoff used for very low protein intake in the current study was originally derived in a series of predominantly healthy young men. It represents the minimal intake required to maintain body nitrogen equilibrium.10 Unlike healthy controls, however, patients with cirrhosis have altered macronutrient metabolism, becoming catabolic very quickly with stress and responding to even shortduration fasting with a switch from glycogenolysis to gluconeogenesis, proteolysis, and muscle breakdown.11 As a result of these alterations, nitrogen balance studies and ESPEN guidelines9 have suggested that closer to 1.2 g/kg/d is required to maintain nitrogen equilibrium in patients with cirrhosis.34,35 The current study would support the ESPEN guideline targets

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Table 4.  Predictors of Mortality—Competing Risks Models Using the MELD Score or the Child Pugh Score. Multivariable Analysis with MELD Variable

OR (95% CI)

Age (per 10-y increase) Serum sodium (mmol/L) Etiology of cirrhosis  HCV  Alcohol  PBC/PSC/AIH  NASH/cryptogenic  Other Protein intake < 0.8 g/kg estimated dry weight Subjective global assessment B/C CP score (per 1 point increase) MELD score (per 5 point increase)

Multivariable Analysis with CP Score

P Value

1.5 (1.1–1.9) 0.94 (0.90–0.98)

.004 .002

1 0.7 (0.4–1.2) 0.6 (0.4–1.1) 0.6 (0.3–1.4) 0.6 (0.3–1.4) 1.8 (1.2–2.7) 1.1 (0.7–1.6)

Reference .2 .08 .1 .3 .006 .8

1.4 (1.2–1.6)

< .00001

OR (95% CI)

P Value

1.4 (1.1–1.9) 0.94 (0.90–0.99)

.003 .01

1 0.7 (0.4–1.1) 0.7 (0.4–1.3) 0.7 (0.3–1.2) 0.7 (0.3–1.7) 1.7 (0.6–2.6) 1.0 (0.6–1.4) 1.4 (1.2–1.5)

Reference .1 .3 .2 .5 .007 .8 < .00001  

AIH, autoimmune hepatitis; CI, confidence interval; CP, Child Pugh; OR, odds ratio.

for stable outpatients. As occurs with noncirrhotic patients, protein targets are, however, likely to be dynamic; higher protein intake, for example, is suggested for patients with critical illness36 or sarcopenic obesity (characterized by low muscle mass with high fat mass).37–39 Cirrhosis-specific data in these areas are currently lacking and require evaluation. The optimal distribution of the daily protein dose to patients with cirrhosis also requires evaluation. It is clear that the late evening administration of calories is beneficial in these patients, as it reduces the length of overnight fasting, reduces gluconeogenesis, and thereby improves lean muscle mass.40 In noncirrhotic aging patients, experts have suggested that the intake of 25–30 grams of high quality protein per meal may maximize the muscle protein synthetic response.41 Others have suggested that the administration of 80% of the recommended protein intake taken at the lunch time meal (protein pulse feeding) may optimize lean muscle mass.42,43 The safety and efficacy of these approaches will need to be considered in patients with cirrhosis.8 There are several study limitations. First, as total caloric intake was not recorded and as we did not have access to the original 2-day diet records, we were unable to calculate and control for this variable. Since calorie and protein intake often run in parallel, however, this limitation is unlikely to change the article’s main conclusions. Moreover, as evidenced by the direct correlation of protein intake with outcomes in noncirrhotic populations and the key link between protein intake and muscle synthesis, protein intake is recognized as a particularly relevant subcomponent of total caloric intake. Second, although it was a detailed assessment, protein intake was estimated at only a single time point during the study. Therefore, we were unable to assess for differences in intake over time that may have occurred with disease progression and with nutrition counseling. Moreover, although the assessment was detailed

and often supplemented by information from family members, the estimation relied on accurate dietary recall. Third, the estimated dry weight has the inherent limitations of being a subjective estimation. Last, it is unfortunate that we did not have available to us measures of muscle mass, muscle function, or immune function that correlated with the timing of the nutrition intake data. This retrospective study sets the stage for prospective studies that can systematically evaluate these parameters as well as parameters related to infection and worsening ascites or hepatic encephalopathy, all of which are more accurately assessed prospectively. In conclusion, considering the above limitations, the main strengths of this study are that in a large sample of patients, very low protein intake is highlighted as being a prevalent factor associated with both malnutrition and mortality. Protein intake should therefore be routinely assessed and strongly encouraged. In addition, the data provide strong support for the performance of prospective protein intervention trials in cirrhosis. These trials can more definitively evaluate the practicality of achieving protein targets in these patients and the Child Pugh stratified effect of protein repletion on clinically relevant outcomes such as muscle mass, muscle function, immune function, and mortality.

References 1. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis. A systematic review of 118 studies. J Hepatol. 2006;44:217-231. 2. Lemyze M, Dharancy S, Wallaert B. Response to exercise in patients with liver cirrhosis: implications for liver transplantation. Dig Liver Dis. 2013;45(5):362-366. 3. Dharancy S, Lemyze M, Boleslawski E, et al. Impact of impaired aerobic capacity on liver transplant candidates. Transplantation. 2008;86(8): 1077-1083.

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Insufficient Protein Intake Is Associated With Increased Mortality in 630 Patients With Cirrhosis Awaiting Liver Transplantation.

For patients awaiting liver transplantation, we aimed to determine the prevalence and predictors of insufficient protein intake as well as to determin...
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