Prognostic Nutritional Index Correlates with Liver Function and Prognosis in Chronic Liver Disease Patients

The Prognostic Nutritional Index (PNI) is widely recognized as a screening tool for nutrition. We retrospectively examined the impact of PNI in patients with chronic liver disease (CLD, n = 319, median age = 71 years, 153 hepatocellular carcinoma (HCC) patients) as an observational study. Factors associated with PNI < 40 were also examined. The PNI correlated well with the albumin–bilirubin (ALBI) score and ALBI grade. The 1-year cumulative overall survival rates in patients with PNI ≥ 40 (n = 225) and PNI < 40 (n = 94) were 93.2% and 65.5%, respectively (p < 0.0001). In patients with (p < 0.0001) and without (p < 0.0001) HCC, similar tendencies were found. In the multivariate analysis, hemoglobin (p = 0.00178), the presence of HCC (p = 0.0426), and ALBI score (p < 0.0001) were independent factors linked to PNI < 40. Receiver operating characteristic (ROC) curve analysis based on survival for the PNI yielded an area under the ROC curve of 0.79, with sensitivity of 0.80, specificity of 0.70, and an optimal cutoff point of 42.35. In conclusion, PNI can be a predictor of nutritional status in CLD patients. A PNI of <40 can be useful in predicting the prognosis of patients with CLD.


Introduction
Malnutrition is a condition in which the intake or absorption of nutrients essential for development and the prevention of disease is inadequate [1,2].Compared to healthy individuals, patients with gastrointestinal diseases often have altered nutrient metabolism [3][4][5][6][7].In particular, patients with chronic liver diseases (CLDs) frequently become malnourished [8].More than 844 million people worldwide currently suffer from CLDs, and approximately 2 million CLD patients die annually [8].The liver is an important organ in which the metabolism and biosynthesis of a multitude of proteins, carbohydrates, and fats take place.Thus, progressive liver disease often results in fat malabsorption, fat-soluble vitamin deficiencies, decreased levels of water-soluble vitamins, and altered micronutrient metabolism [9,10].In particular, cirrhotic patients have a high rate of proteinenergy malnutrition (PEM), sarcopenia, or decreased quality of life [9][10][11][12][13].Among a cohort of Child-Pugh class A patients, the 1-year mortality rate for those who were malnourished was approximately 20%, but none of the patients who received adequate amounts of nutrition died within 1 year [14].Malnutrition is known to have a significant impact on patient outcomes [14].Early detection and treatment of malnutrition may be necessary to improve patient outcomes.It is therefore important to accurately assess the nutritional status of CLD patients.
In this study, we conducted a nutritional evaluation of CLD patients using the Prognostic Nutritional Index (PNI).PNI was first suggested to be a predictor of nutritional

PNI and Our Analysis
PNI can be calculated as follows: 10 × serum albumin (g/L) + 0.005 × lymphocyte count in the peripheral blood (mm 3 ) [15,16].As mentioned earlier, PNI in each patient was calculated.First, we examined the relationship between PNI and the ALBI score [21] for all cases, hepatocellular carcinoma (HCC) cases, and non-HCC cases.Next, PNI and the percentage of patients with PNI < 40 were compared according to the albumin-bilirubin (ALBI) grade or modified ALBI (mALBI) grade [21,22] in all cases, HCC cases, and non-HCC cases.Next, factors associated with PNI < 40 were investigated in uni-and multivariate analyses.Next, we performed a receiver operating characteristic (ROC) curve analysis of independent factors in the multivariate analysis for PNI < 40.Next, the overall survival (OS) ratio was compared, stratified by the baseline PNI.Finally, we performed an ROC curve analysis for PNI based on the prognosis.

Statistical Considerations
For two-group comparisons of continuous parameters, Student's t test or the Mann-Whitney U test was applied as appropriate, and for multiple-group comparisons of continuous parameters, ANOVA or the Kruskal-Wallis test was applied as appropriate.For group comparisons of categorical parameters, the Pearson χ 2 test was applied.Pearson's correlation coefficient r was used for the correlation coefficient.For a comparison of survival, the Kaplan-Meier method was adopted and tested using the log-rank method.Details for continuous parameters are presented as the median (interquartile range, IQR) unless otherwise noted.Multivariate logistic regression analysis related to PNI < 40 was also performed to identify independent covariates.The significance level was set at 0.05 using JMP ver.17 (SAS Institute Inc., Cary, NC, USA).

The Relevance in PNI and the ALBI Score
PNI had a significant negative correlation with the ALBI score in all study subjects (r = −0.85,p < 0.0001) (Figure 1A).PNI also had a significant negative correlation with the ALBI score in HCC cases (r = −0.90,p < 0.0001) (Figure 1B) and in non-HCC cases (r = −0.82,p < 0.0001) (Figure 1C).PNI had a significant negative correlation with the ALBI score in all study subjects (r = −0.85,p < 0.0001) (Figure 1A).PNI also had a significant negative correlation with the ALBI score in HCC cases (r = −0.90,p < 0.0001) (Figure 1B) and in non-HCC cases (r = −0.82,p < 0.0001) (Figure 1C).

PNI According to ALBI Grade and mALBI Grade in All Cases
The

ROC Analysis
An ROC analysis of independent continuous covariates in the multivariate analysis for PNI < 40 was performed.The corresponding area under the ROC curve (AUC), sensitivity, specificity, and best reference point for Hb and ALBI score are demonstrated in Table 4. ALBI score involved the highest AUC for PNI < 40 (AUC = 0.96), followed by Hb (AUC = 0.76).

ROC Analysis Based on Death or Survival for PNI
In the ROC analysis based on death or survival for PNI, the AUC was 0.79 (Figure 4H).The sensitivity and specificity were 0.80 and 0.70, respectively, with an optimal cutoff point of 42.35.

Discussion
In this study, PNI was found to be a predictor of nutritional status in patients with CLD.A PNI value of <40 may be useful in predicting prognosis in patients with CLD.These results are important because PNI may allow for early intervention in nutritional therapy for CLD patients.Early nutritional therapy may contribute to a better prognosis.
Patients with advanced chronic disease are often malnourished and are not able to obtain necessary nutrients through oral intake alone.Inadequate intake and malabsorption in the gastrointestinal tract can lead to poor body composition and biological function [8,23].Liver disease is no exception, and nutritional status has been recognized as a predictor of prognosis for patients with advanced liver disease [8,[24][25][26].However, nutritional assessment is often neglected in the routine care of CLD patients [27].Unfortunately, the reality is that nutritional problems in CLD patients are often underestimated, and adequate nutritional assessment is not performed.As a result, nutritional therapy

ROC Analysis Based on Death or Survival for PNI
In the ROC analysis based on death or survival for PNI, the AUC was 0.79 (Figure 4H).The sensitivity and specificity were 0.80 and 0.70, respectively, with an optimal cutoff point of 42.35.

Discussion
In this study, PNI was found to be a predictor of nutritional status in patients with CLD.A PNI value of <40 may be useful in predicting prognosis in patients with CLD.These results are important because PNI may allow for early intervention in nutritional therapy for CLD patients.Early nutritional therapy may contribute to a better prognosis.
Patients with advanced chronic disease are often malnourished and are not able to obtain necessary nutrients through oral intake alone.Inadequate intake and malabsorption in the gastrointestinal tract can lead to poor body composition and biological function [8,23].Liver disease is no exception, and nutritional status has been recognized as a predictor of prognosis for patients with advanced liver disease [8,[24][25][26].However, nutritional assessment is often neglected in the routine care of CLD patients [27].Unfortunately, the reality is that nutritional problems in CLD patients are often underestimated, and adequate nutritional assessment is not performed.As a result, nutritional therapy interventions for patients with CLD are often underutilized [27].Based on this background, it is desirable to assess nutritional status in patients with CLD.
Metabolism 2006 guidelines recommend the use of subjective global assessment (SGA) to identify CLD patients at risk for malnutrition [28].SGA is a bedside assessment tool to collect information on food intake, weight changes, and gastrointestinal symptoms; it also includes tests for subcutaneous fat loss, muscle weakness, ascites, and edema [8,29].While SGA is appropriate as a stand-alone nutritional assessment tool, several studies have reported that SGA can underestimate the disease severity and frequency of malnutrition in patients with the early stages of the disease [8,30].In the dual-energy X-ray absorptiometry method, a living body is irradiated with X-rays of two different energies, and body composition components are determined using the attenuation rate of the irradiated radiation as it passes through the body [28].Although this provides accurate information, it is not widely used due to its technical complexity and higher cost [8,29].Currently, there are many challenges with tools used to assess the nutritional status of CLD patients.PNI is a simple, objective indicator of inflammation and nutritional status, calculated from only serum albumin and lymphocyte counts [15,16,31].In recent studies, PNI has also been significantly correlated with prognosis and nutritional status in a variety of diseases [31].PNI may be useful in the nutritional assessment of patients with CLD.In the current study, we examined the influence of PNI in patients with CLD.The results of our study presented that PNI correlated strongly with ALBI score (r = −0.85)for all study subjects.A similar strong correlation with ALBI score was observed in HCC patients (r = −0.90)and non-HCC patients (r = −0.82).A comparison of PNI by ALBI grade or mALBI grade in patients with CLD showed a trend of decreasing PNI with worsening liver function.Thus, lower PNI can be associated with liver function.In our data, the percentages of patients with PNI < 40 in groups of ALBI grade 1, grade 2, and grade 3 among all study subjects were 0% (0/122) in ALBI grade 1, 42.1% (74/176) in grade 2, and 95.2% (20/21) in grade 3 (overall p < 0.0001).Identical tendencies were observed among HCC and non-HCC patients.PNI thus appears to be robustly associated with hepatic reserve capacity, with or without HCC.In our multivariate analysis, Hb and the presence of HCC, in addition to ALBI score, were significant covariates related to PNI.These results indicate that Hb and the presence of HCC, besides ALBI score, can be reliable markers for malnutrition in CLD patients.First, in terms of Hb, malnutrition is actually a known common cause of anemia, especially in certain clinical conditions such as older age [32,33].Second, in terms of comorbid malignancies, previous studies have shown that impaired nutritional status frequently occurs in HCC patients.Impaired nutritional status may also be associated with unfavorable outcome in patients with HCC [34][35][36][37].In terms of survival, the 1-year cumulative OS rates for patients with PNI ≥ 40 and PNI < 40 were 93.2% and 65.5%, respectively (p < 0.0001).In HCC cases and non-HCC cases, similar tendencies were seen.ROC analysis based on death or survival for PNI yielded an AUC of 0.79; the corresponding sensitivity (%) and specificity (%) were 80% and 70%, respectively, and the most suitable reference value for PNI was 42.35, which is close to the consensus value of PNI 40 [16].Considering the favorable results in ROC analyses for PNI, PNI may be a useful prognostic factor even in patients with CLD.
It must be stated that this study has several limitations.First, causality can be neither confirmed nor negated due to the observational study design.Second, this study was conducted with a Japanese population at a single institution and was retrospective by its nature.We have not studied non-Japanese ethnic groups.Additionally, in terms of survival analysis, various interventions for background CLD were given during the course of the follow-up period, which may have affected the prognosis and introduced bias.Despite these study limitations, the results of the current study indicate that PNI correlates well with ALBI score, and a lower PNI value may be a prognostic factor in patients with CLD.

Conclusions
PNI may be a useful tool for assessing liver function for CLD patients.A PNI score of <40 is helpful for the prediction of prognosis in patients with CLD.
Author Contributions: Data collection, all authors; methodology, M.M., K.U. and H.N.; formal analysis, M.M. and H.N.; writing-original draft, M.M. and H.N.; writing-review and editing, all authors; supervision, H.N. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.

Institutional Review Board Statement:
We obtained ethical approval for the study from the ethics committee of OPMU Hospital (approval no.2021-109), and the protocol strictly observed all regulations of the Declaration of Helsinki.

Informed Consent Statement:
Due to the retrospective nature of this study, the requirement for informed consent from the patients was waived by the ethics committee of our hospital.

Data Availability Statement:
The data presented in this study are not publicly available due to privacy or ethical restrictions.

Diagnostics 2024 , 15 3. 2 .
13, x FOR PEER REVIEW 4 of The Relevance in PNI and the ALBI Score

Figure 1 .
Figure 1.The correlation between PNI and ALBI score for all cases (A), HCC cases (B), and non-HCC cases (C).

Figure 1 .
Figure 1.The correlation between PNI and ALBI score for all cases (A), HCC cases (B), and non-HCC cases (C).

Figure 1 .
Figure 1.The correlation between PNI and ALBI score for all cases (A), HCC cases (B), and non-HCC cases (C).

Figure 2 .
Figure 2. PNI according to ALBI grade (A) and modified ALBI grade (B) for all cases.PNI according to ALBI grade (C) and modified ALBI grade (D) for HCC cases.PNI according to ALBI grade (E) and modified ALBI grade (F) for non-HCC cases.

Figure 3 .
Figure 3. Percentage of patients with PNI < 40 according to ALBI grade (A) and modified ALBI grade (B) for all cases.Percentage of patients with PNI < 40 according to ALBI grade (C) and modified ALBI grade (D) for HCC cases.Percentage of patients with PNI < 40 according to ALBI grade (E) and modified ALBI grade (F) for non-HCC cases.

Figure 4 .
Figure 4.The cumulative OS rates among patients with PNI ≥ 40 and PNI < 40 in all cases (A), in HCC cases (B), in non-HCC cases (C), in alcoholic cases (D), in HBV cases (E), in HCV cases (F), and in MASLD cases (G).(H) ROC analysis based on the prognosis for PNI.

Figure 4 .
Figure 4.The cumulative OS rates among patients with PNI ≥ 40 and PNI < 40 in all cases (A), in HCC cases (B), in non-HCC cases (C), in alcoholic cases (D), in HBV cases (E), in HCV cases (F), and in MASLD cases (G).(H) ROC analysis based on the prognosis for PNI.

Table 4 .
Receiver operating characteristic curve analysis of independent parameters for PNI < 40.