Evaluation of nutritional indicators and body composition in patients with advanced liver disease enrolled for liver transplantation 1

PURPOSE: Malnutrition is prevalent in patients with advanced liver disease (LD) related to multifactorial causes. Fluid retention can underestimate the nutritional status based on anthropometric measures. We evaluated nutritional indicators and body composition (BC) in patients with liver cirrhosis and correlated them with LD severity. METHODS: Forty three patients with LD enrolled for liver transplantation were evaluated by Anthropometric measures, subjective evaluation (Global Assessment of Nutritional Status – SGA) and biochemical indicators. Single-frequency electrical bioimpedance (SFE-BIA) was used to evaluate body composition (BC). It measured resistance (R), reactance (Xc) and the phase angle (PA). LD severity was estimated by Child-Pugh and Meld criteria (Model for End-Stage Liver Disease). RESULTS: Child-Pugh index between patients was 7.11±1.70 and Meld was 12.23±4.22. Arm Circumference, Arm Muscle Circumference and Arm Muscle Area, SGA, hemoglobin, hematocrit and albumin showed better correlation with disease severity. Xc and PA showed correlation both with Meld and Child-Pugh score when BC were evaluated. PA was depleted in 55.8% of the patients. CONCLUSIONS: Diagnosis of malnutrition varied according to the method. Global assessment of nutritional status showed better correlation with disease severity than with objective methods. Single-frequency electrical bioimpedance for body composition analysis in cirrhotic patients must be cautiously used; however, primary vectors seems to be valid and promising in clinical practice.


Introduction
Hepatic cirrhosis (HC) is characterized by chronic and irreversible change in liver parenchyma, leading to alterations in both liver structure and in the functional capacity of hepatocytes.
Together, these changes result in progressive liver function loss, thus affecting nutritional status and body homeostasis in patients with HC to a varying degrees.
Protein caloric malnutrition (PCM) is highly prevalent in patients with terminal liver disease 1 .Roongpisunthinpong et al. 2 suggest that PCM prevalence in chronic hepatic disease is between 10% and 100%, it is dependent on its severity regardless of disease cause.However, Malnutrition is associated with high morbidity and mortality, influencing the short and long term patient survival.
Impairment of cellular and humoral immune response in patients with HC may contribute to increased risk for infections 3 , decreased quality of life and survival, increased length of hospitalizations and, therefore, increased hospital costs 4 .
The subjective global assessment proposed by Detsky et al. 5 has been considered a good approach for subjective assessment of patients with liver disease 6 , but water retention complicates its applicability since the estimated weight loss, which is part of this assessment, becomes impaired 7 .
In recent studies [8][9][10] , electrical bioimpedance (BIA) and its vectors in particular has been proposed for body composition analysis of patients with chronic liver disease 11 .
Electrical bioimpedance consists in the delivery of a lowintensity (below human perceptibility) electric current 12 which flows through the body by the ions movements 13 .The opposition offered by the body to the passage of an electric current is called electrical impedance 14,15 , and it is inversely related to electrical conductivity.
Given the high prevalence of malnutrition and its relationship with morbidity and mortality in patients with liver cirrhosis as well as the absence of a gold-standard method for nutritional evaluation of these patients, we conducted the present study with the purpose to evaluate prospectively the nutritional indicators and body composition in patients with liver cirrhosis enrolled for liver transplantation and correlate them with disease severity.All patients that were included in the liver transplant waiting list presented major complications related to liver disease, with higher Meld and Child score at the time of inclusion.

Forty
Patients under the age of 18 years or undergoing treatment for hepatitis C or with a history of alcohol intake in a period less than six months were not included.
It was a cross-sectional analytical investigation, and the patients participated in interviews for clinical nutritional assessment (anthropometric, subjective and biochemical) and body composition evaluation.

A) Clinical evaluation
Disease severity was classified according to the criteria proposed by Child-Pugh et al. 16 and MELD -the Model for Endstage Liver Disease 17 .Due to the variation of the score of Child and Meld while on transplant waiting list, the values reported herein represent the values obtained in one given moment at the nutritional evaluation.

B) Nutritional evaluation
All subjects underwent anthropometric measurements of current weight (CW), height (H), arm circumference (AC) and triciptal skinfold (TSF).Body Mass Index for cirrhotic patients (BMI) as proposed by Campillo et al. 18 , arm muscle circumference (AMC) and corrected arm muscle area (cAMA) were estimated.AC, TSF and AMC classification was performed by using the percentage of adequacy through the method proposed by Blackburn and Harvey 19 , and patients with percentage of adequacy <90% were considered to be malnourished/depleted.cAMA was also evaluated by the method proposed by Blackburn and Harvey 19 ; however, those showing values below the 15th percentile were classified as malnourished /depleted.The subjective global nutritional assessment was performed by the method proposed by Detsky et al. 5 , which subjectively classifies individuals as well-nourished (A), moderately malnourished or suspected malnourished (B) or severely malnourished (C).
Total lymphocyte count was interpreted according to Blackburn et al. 20 , and values lower than 2000/mm 3 were classified as depletion.The cutoff value for albumin was <3.5 g/dl for depletion diagnosis.Additionally, a comparison was made according to tables of stratified values based on age and gender, as proposed by Barbosa-Silva et al. 14 .The values were considered to be reduced when the results were lower than the mean minus two standard deviations.

Statistical analysis
The nutritional indicators were dichotomized into malnutrition and without malnutrition or with depletion and without depletion.For analysis of qualitative variables, the Chi-   and Meld (r=-0.43,p = 0.004).The correlation was expected for Child-Pugh criteria, considering that albumin is one of the parameters in this classifi cation system.
The analyses of body composition demonstrated a reduced phase angle in 55.8% of the patients, according to gender and age.
The correlation of BIA parameters with liver disease severity is shown in Table 3 and illustrated in Figures 1 and 2.

Discussion
Malnutrition should be considered one of the most important prognostic factors in HC, and alert health professionals in the same extent as the presence of other common complications such as hepatic encephalopathy and ascites 21 .
For many years, malnutrition has been related to worse clinical outcomes and higher incidence of complications such as ascites, hepatic encephalopathy and infections 22 , hepatorenal syndrome and diabetes mellitus.It is considered a risk factor for morbidity and mortality in short and long term before and after transplantation 23,25 as well as in abdominal surgery 21 .A recent study by Sam and Nguyen 23 showed the association of PCM with longer hospitalization (8.7 days versus 5.7 days, p<0.0001), higher in-hospital mortality and a higher rate of readmissions.As reported in other study 10 malnutrition was also under diagnosed when Body Mass Index (BMI) was used, regardless of gender.However, malnutrition was more severe when AC and AMA were measured for females and males respectively.
One reason for the possible under diagnosed of malnutrition by BMI is related to the fluid and electrolyte retention in those patients, that may overestimate their measured weight 2 .
Even though the cutoff point used was specific for cirrhotic patient, as proposed by Campillo et al. 18 , malnutrition rates were far below those pointed out by other indicators.
Several studies have found changes in anthropometric indicators within the worsening of liver disease [1][2]8 .
Alberino et al. 1 also refer a negative correlation between AMA and the Child-Pugh criteria, but not with TSF.
In this study, nutritional indicators showed higher correlation with the Child-Pugh criteria than with Meld.It is noteworthy that, in the previous version of the Child-Pugh criteria, malnutrition level was considered as an indicator; however, the absence of an accurate tool for nutritional diagnosis has led to its exclusion.On the other hand, Meld estimation, so far, does not take nutritional status into account.Possibly, according to Stickel et al. 24 , this model fails in predicting survival in 15-20% of recipients of liver transplants for not considering the nutritional status.
SGA is a practical method for nutritional diagnosis.Its applicability to cirrhotic patients and to liver transplant candidates is valid, since liver disease changes the majority of objective indicators.
According to SGA, 46.5% of the patients showed a certain degree of malnutrition, and when weighed against the Child-Pugh criteria, for each unit of increase there is a 2.93 fold chance that the patient is malnourished.The other nutritional indicators did not show such strong association with the severity of liver disease.Roongpisunthinpong et al. 2 also reported that SGA correlates with liver disease severity, thus indicating the usefulness of SGA in patients with chronic liver disease.
An inverse correlation between disease severity and Hb, Ht and albumin was observed, regardless of the method used.The correlation of albumin levels and Child score was expected since it is used as a parameter for estimation.
Although hemoglobin and hematocrit count are independent of hepatic metabolism, they may be altered in patients with severe portal hypertension and hypersplenism as well as in the presence of gastrointestinal hemorrhages.It is noteworthy that laboratory parameters are affected by liver disease severity as well as by the etiological factors of the disease.Hence, they are more strongly correlated with disease severity than with malnutrition per se.BIA relationship with body composition is indirect and not completely understood.On the other hand, PA has been negatively correlated as a prognostic factor in many conditions such as neoplastic disease, hemodialysis, chronic obstructive pulmonary disease, HIV, including decompensate liver cirrhosis [27][28][29] .
The correlation of vectors with severity was better with Meld criteria, and Xc/H showed the greatest correlation.Since R is inversely proportional to the amount of water, it can be suggested that females present a smaller amount of body water than males, even in liver disease.
Based on the results, it seems appropriate to use brachial measures, such as AC, AMC, AMA and those of SGA in routine outpatient care for patients with chronic liver disease.Considering the Body Composition Analysis, the absolute values of vectors and PA can also be used either for a complementary nutritional assessment or primarily for monitoring patient's clinical outcomes.

Conclusions
The diagnosis of nutritional status varied according to the method used.Body mass index was less suitable for malnutrition detection.The nutritional indicators that best correlated with the severity criteria proposed by Child-Pugh were arm circumference, arm muscle circumference, arm muscle area and global assessment of nutritional status.Single-frequency bioimpedance for body composition analysis in cirrhotic patients must be cautiously used; however, the use of primary vectors seems to be valid.
-three patients with liver cirrhosis of different etiologies treated in nutrition outpatient units were evaluated between March 2008 and March 2009, after approval by the Ethics Committee of the Sao Paulo State University (UNESP).Demographic included 13 (30.2%)females and 30 (69.8%) males patients, aged between 30 to 70 years and from different ethnic groups.
It was performed by single-frequency electrical bioimpedance (BIA), Biodynamics model 450 (TBW), by applying an 800mA current with a frequency of 50 KHz.The following primary measurements were used: resistance (R), reactance (Xc) and phase angle.Both R and Xc were normalized by height, leading to resistance/height (R/H) and reactance/height (Xc/H), expressed as Ω/m units.Normalization is necessary considering that the absolute values vary with body size.Height is considered a good normalization index as it is not affected by fluid retention or malnutrition.They were evaluated according to their absolute values and the phase angle.

Table 1 )
, suggesting that the lower the values for nutritional indicators, worse is the severity of liver disease.
square test and Fisher's exact test when appropriate (p<0.05), were utilized.Student's t test was used for quantitative variables for normal data.ResultsAlcoholic liver cirrhosis was more prevalent (32.6%), followed by the hepatitis C virus infection (25.6%).Alcoholic liver cirrhosis alone and mixed etiology (alcohol + virus C) was observed in 48.9% of the patients.

TABLE 1 -
Pearson's correlation between nutritional indicators and liver disease severity.

TABLE 2 -
Fitting of the logistic regression model for SGA and disease severity indicators.

TABLE 3 -
Pearson's Correlation Coeffi cients for Bioimpedance and disease severity indicators.