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Protein Intake (<1.0 g/kg) Is a Risk Factor for Malnutrition in Patients With Cirrhosis


 Background and aimsThe prevalence of malnutrition in patients with cirrhosis is considerably high. Protein intake is a well-known risk factor for malnutrition, but studies on adequate protein intake are very scarce. We investigated the prevalence of malnutrition and amount of adequate protein intake in patients with cirrhosis.MethodsIn total, 361 patients with cirrhosis were enrolled. Muscle quality and quantity were retrospectively assessed using the grip strength test and bioelectrical impedance analysis. Subjective global assessment (SGA) of malnutrition and dietary intake assessments were performed by a clinical dietician.ResultsThe prevalence rates of sarcopenia, malnutrition assessed by SGA, and inadequate energy intake were 22.7%, 13.6%, and 27.5% respectively. The prevalence of malnutrition evaluated using any of the assessment methods was 46.3%, and no significant difference was observed according to liver disease etiology. The prevalence of malnutrition increased with the increasing disease severity and decreasing BMI. The prevalence of malnutrition was 64.4% in patients with protein intake <1.0 g/kg. Low protein intake, Child–Pugh C grade, older age, and low BMI were independent risk factors for malnutrition in multivariate analysis.ConclusionProtein intake below 1.0 g/kg is an independent risk factor for malnutrition in patients with cirrhosis.


Introduction
Malnutrition is one of the most common complications of cirrhosis and is associated with high mortality, high prevalence of infection, and portal hypertension-related complications, such as hepatic encephalopathy and ascites. (1)(2)(3)(4) Nutritional assessments and monitoring are essential for patients with cirrhosis, and several tools for evaluating malnutrition have been proposed. (5,6) Several assessment tools are currently used to assess for malnutrition in patients with liver disease (7,8); previous studies have reported a wide range of variability in the prevalence rate of malnutrition, from 5-99%, depending on the assessment tools used. (3,(9)(10)(11) Recently, the European Association for the Study of the Liver proposed practice guidelines on nutrition in chronic liver disease. (8) Body mass index (BMI) and disease severity have been suggested as the most important risk factors for malnutrition, but the other risk factors are unknown. Decreased protein intake is also an important risk factor for malnutrition. (12) The recommended daily protein intake in normal people is 0.83 g/kg, (13) while that in chronic liver disease patients is 1.2-1.5 g/kg.(5) Patients with chronic liver disease are recommended to consume 1.5 times more protein than that consumed by normal individuals. Patients with chronic liver disease experience protein de ciency and have a high incidence of malnutrition due to the following reasons: reduced diet, indigestion, malabsorption (fat malabsorption, vitamin malabsorption, bacterial overgrowth, and portal hypertensive enteropathy), kidney-related diseases, and metabolic abnormalities. (14) The recommended protein intake is based on the minimum protein requirement to maintain the nitrogen balance. Therefore, patients with liver disease should consume 1.2-1.5 g/kg/day of protein. The protein intake should be 1.5 times higher than the usual intake to prevent sarcopenia, which can lead to worse clinical outcomes. (15) A cutoff protein value of 1.2-1.5 g/kg/day was reported in a previous study involving patients with cirrhosis who consumed a high-protein diet. The study also showed that patients with cirrhosis should consume up to 1.8 g/kg of protein. (16) However, a protein intake of 0.8 g/kg/day only is required to achieve nitrogen balance in patients with alcoholic liver cirrhosis (LC), (17) and there is a lack of accurate evidence to show that 1.5 times higher protein intake than the usual intake can achieve nitrogen balance. Moreover, studies on the status of protein intake and adequate protein intake in patients with chronic liver disease are limited. In previous studies, the protein intake in patients with chronic liver disease was 1.16-1.31 g/kg. (18)(19)(20) However, the number of studies targeting all patients with chronic liver disease is relatively small, and the number of studies reporting the appropriate protein intake according to the severity of liver disease and various causes is limited.
Hence, we aimed to investigate the prevalence of malnutrition using various methods. In addition, we aimed to compare the frequency of malnutrition according to SGA, sarcopenia, and dietary intake records and assess the agreement between these tools in the era of obesity.

Study design
This study retrospectively evaluated 361 patients with cirrhosis who visited Hanyang University Hospital liver clinic between April 2018 and January 2019. Of the 361 patients, 12 patients were excluded from the analysis due to communication di culties, and 29 patients were excluded because they had comorbid chronic conditions, including thyroid disease, chronic obstructive pulmonary disease, kidney disease, and cancer other than liver cancer. Additionally, 11 patients with inadequate food diary data were excluded ( Fig. 1) and a total of 309 patients were included as a result. The study was approved by the Institutional Review Board (IRB) of Hanyang University Hospital (IRB approval number: 2019-05-018-001), and the study was performed in accordance with the relevant guidelines. The requirement for obtaining an informed consent was waived by the IRB.

Inclusion and exclusion criteria
Patients aged ≥ 19 years with cirrhosis were included in the study. LC was diagnosed based on clinical judgment or the results of imaging studies. Patients were classi ed as having alcoholic LC, non-alcoholic steatohepatitis (NASH-LC), or viral hepatitis (viral LC) according to the etiology of liver disease.
Patients with a history of medication usage and dietary interventions to control weight within the last 6 months, a comorbid chronic condition that may cause weight loss (thyroid disease, chronic obstructive pulmonary disease, or kidney disease), and malignancy other than liver cancer were excluded.

Quality and quantity of muscle mass
To diagnose sarcopenia, muscle mass was measured using bioelectrical impedance analysis (BIA) (Inbody 370; Inbody USA, Cerritos, CA, USA). Sarcopenia was de ned as the volume of appendicular  (23,24) and patients were screened for malnutrition if their total daily caloric consumption was lower than the estimated daily requirement.

De nition of malnutrition
Patients with malnutrition were assessed for undernutrition using one of the following screening methods: diagnosing sarcopenia, use of nutritional assessment tools, or use of dietary intake journals. (8) According to the European Society for Clinical Nutrition and Metabolism guidelines, malnutrition is de ned as BMI < 18.5 kg/m 2 ; unintentional weight loss exceeding 10% regardless of the time or weight loss of 5% within 3 months in addition to BMI < 20 kg/m 2 for individuals aged < 70 years and a BMI of 22 kg/m 2 for individuals aged ≥ 70 years; or FFMI < 15 for women and < 17 for men. (5) Statistical analysis Data analysis was performed using SPSS for Windows (Version 24; SPSS Inc., Chicago). All measurements are expressed as mean ± standard deviation. Analysis of variance, Student's t-tests, and chi-square tests were used to examine the differences among groups, and a P-value of < 0.05 was considered signi cant. Additionally, Cohen's kappa analysis was performed to examine the level of agreement of malnutrition determined using the different malnutrition assessment methods. This study was a descriptive study based on multiple patient charts and did not include calculation of the sample size. All patients with cirrhosis who visited the outpatient department during the study period were enrolled.

Basic characteristics and prevalence of malnutrition
A total of 309 patients with cirrhosis were included in the analyses. The mean patient age was 58.7 years, and 61.8% patients were men. In total, 88, 33, 172, 16 patients were categorized into the alcoholic LC, NASH-LC, viral LC, and other LC groups, respectively. The prevalence of sarcopenia was 22.7% (70/309).
The prevalence of malnutrition according to SGA was 11.7% (36/309), and the prevalence of inadequate dietary intake was 27.5% (85/309). Approximately 46.3% (n = 143) patients satis ed one of the three de nitions of malnutrition (Table 1).  Fig. 2). Although the prevalence of decompensated cirrhosis (Child-Pugh B and C grades) and the model for end-stage liver disease (MELD) scores were higher in the alcoholic LC group than in the viral LC and NASH-LC groups (P = 0.005 and P < 0.001, respectively), the prevalence of malnutrition was not signi cantly different among these groups (P = 0.962; Table 1). The prevalence of sarcopenia, inadequate dietary intake, and SGA malnutrition was not signi cantly different according to the etiology of cirrhosis. Although the total energy intake was similar across the etiologybased groups, the alcoholic LC group had the highest protein and fat consumption. Lipid intake was higher in the alcoholic LC and NASH-LC groups. None of the groups showed other between-group differences in dietary intake.

Prevalence of malnutrition according to disease severity
In total, 266 (88.1%) patients were classi ed as having Child-Pugh grade A, while 43 (13.9%) patients were classi ed as having Child-Pugh grade B or C. A total of 117 (44.0%) in the Child-Pugh A group, 15 (51.7%) in the Child-Pugh B group, and 11 (78.6%) in the Child-Pugh C group satis ed one of the three de nitions of malnutrition. The prevalence of malnutrition signi cantly increased with the increasing disease severity (P = 0.034; Table 2).  Table 2). The proportion of patients with sarcopenia and low SGA in the BMI < 18.5 kg/m 2 group was 80% and 50%, respectively. The prevalence of sarcopenia increased with the decreasing BMI (P for trend < 0.001).
Prevalence of malnutrition according to sarcopenia, SGA, and dietary intake A total of 36 (13.6%), 70 (22.7%), and 85 (27.5%) patients had abnormal SGA, sarcopenia, and inadequate dietary intake, respectively (Table 3 and Fig. 4). The prevalence of malnutrition by SGA signi cantly increased with the decreasing BMI and increasing Child-Pugh score. Malnutrition according to sarcopenia was signi cantly associated with BMI, but it was not statistically associated with the cause or severity of the disease. The prevalence of energy malnutrition (inadequate dietary intake) was not associated with the cause and severity of the disease or BMI.

Risk factors for malnutrition (multivariate analysis)
Logistic regression analysis was performed to identify the risk factors that affect the prevalence of malnutrition. The etiology of LC did not in uence the prevalence of malnutrition. However, low protein intake (< 1.0 g/kg), Child-Pugh C grade, older age, and low BMI were independent risk factors for malnutrition (Table 4). Among the patients with cirrhosis, 43.6% patients consumed < 1.0 g/kg of protein per day. The prevalence of malnutrition was 69.2% among patients with a protein intake of < 1.0 g/kg/day. Based on the receiver operating characteristic curve, protein intake showed the best performance in predicting malnutrition (Fig. 3). The areas under the curve for protein intake, BMI, and the MELD score were 0.788, 0.600, and 0.473, respectively. among patients with Child-Pugh grade C and those with protein intake < 1.0 g/kg/day, respectively.
A previous study reported a protein intake of 1.16-1.31 g/kg/day in patients with liver disease, which is not signi cantly different from the 1.29 g/kg/day protein intake indicated in this study. In a previous study, the average patient age with compensated viral liver cirrhosis was 68.3 years, (20) which was higher than that in this study (58.7 years). However, the mean patient age in this study was similar to that in other studies, and no signi cant difference was observed in terms of sex. Previous studies included non-cirrhotic Hepatitis C virus (HCV) patients,(18) non-LC and LC patients, (19) or viral LC patients. (20) This study included all patients with chronic liver disease and analyzed and compared the nutritional intake according to the LC status and cause and severity of the disease. A 24-hour recall method, a food intake frequency recall method, a meal diary method, and an actual measurement method were used to determine the study participants' nutrition intake. In most previous studies, protein intake was assessed using the 24-hour recall method. The recall method is used to estimate the nutrient intake from the surveyed data based on the type and amount of food consumed within 24 hours. It can be performed within a short period of time, and only slight changes in the dietary habits can occur; however, this method cannot be used to measure the food intake based on the 24-hour data, and a recall bias may potentially occur. The most accurate measurement method is the weighing method, which can accurately measure the food intake by weighing the food ingredients cooked before meals and subtracting the amount of food remaining after the meal. However, this method is di cult to apply in the clinical setting.
This study con rmed the nutrient intake in patients with chronic liver disease using the dietary diary method. The results of assessment using this method were not considered valid due to the limited food list. However, it had lesser recall bias and was a relatively accurate method as it was possible to record the type of food and food intake in a diary format while the participant was eating.
In this study, 13.6% patients with cirrhosis had malnutrition based on the SGA results. In previous studies, the prevalence of malnutrition varied from 5-99% according to the de nition of malnutrition. (3, 9-11, 19, 25) In a previous study involving 1,402 patients published in 1994, mid-arm muscle circumference and mid-arm fat circumference were measured, and malnutrition was de ned as a median value of < 5%. In this study, the prevalence of malnutrition was 30%. It is unclear whether there is a difference in the prevalence of malnutrition according to the etiology of cirrhosis. Some studies showed a higher prevalence of malnutrition in patients with alcoholic cirrhosis than in those with non-alcoholic cirrhosis. (26,27) However, a signi cant difference was found in the baseline severity of liver disease between the two patient groups and the assessment method used in these studies may not be optimal. For example, it might be inappropriate to measure the simple skin fold thickness and body fat mass of patients with NASH-associated cirrhosis to assess malnutrition. The total fat mass is relatively preserved in patients with NASH cirrhosis. In our study and previous studies, (3,28) the prevalence of low SGA and sarcopenia did not differ according to etiology of the disease.
The present study has several limitations. First, sarcopenia was diagnosed by measuring the ASM using BIA, and the results could be in uenced by excess body uid. Although the proportion of patients with generalized edema and/or ascites was small, the prevalence of sarcopenia can be overestimated in patients with decompensated diseases. Assessment of the psoas muscle area using abdominal computed tomography, the phase angle α, or body cell mass, which is not affected by uid accumulation, is more appropriate in patients with decompensated cirrhosis to evaluate the presence of sarcopenia. (29,30) Second, the study included outpatients, and the number of patients with decompensated cirrhosis was relatively small. Hence, future studies should be conducted in a larger sample of patients with cirrhosis to assess their nutritional status and evaluate the prevalence of malnutrition in terms of the severity of cirrhosis. Third, nutrient intake assessments were performed using an FFQ. The volume of food intake is more accurately evaluated using a 3-day dietary journal, which includes the food intake during the weekend. Although the FFQ allows the examination of dietary habits in patients with chronic disease, it is di cult to accurately assess the volume of food intake using this method.
In conclusion, the prevalence of malnutrition, assessed using various assessments, was 46.3%. The prevalence of malnutrition increased as the disease severity increased and protein consumption decreased. The prevalence of malnutrition was extremely high in patients with a protein intake of < 1.0 g/kg. Taken together, the study suggests that protein intake is a good indicator of adequate dietary intake, and 39.5% patients with cirrhosis consume < 1.0 g/kg of protein.

Declarations Data availability statement
The data that support the ndings of this study are available from the corresponding author upon reasonable request.