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. 2026 Feb 27;40(2):1144–1152. doi: 10.21873/invivo.14269

Association of Liver Immune Status Index With the Nutritional Status and Prognosis in Patients With Cirrhosis

RYOTA YOSHIOKA 1, TAKASHI NISHIMURA 1, NAOTO IKEDA 1, NOBUHIRO AIZAWA 1, TOMOYUKI TAKASHIMA 1, YUKIHISA YURI 1, TARO KIMURA 1, NOBUHITO TOKURA 1, RYOTA NAKANO 1, HIDEYUKI SHIOMI 1, SHINICHIRO SHINZAKI 1, HIRAYUKI ENOMOTO 1
PMCID: PMC12949892  PMID: 41760292

Abstract

Background/Aim

In patients with cirrhosis, decreased immune function is observed and is considered to lead to various unfavorable clinical events. Although it is not easy to clinically evaluate the immune status of patients, the Liver Immune Status Index (LISI) was recently proposed as an indicator to estimate the immune status of patients after hepatectomy for hepatocellular carcinoma. We investigated the relationship between the LISI and liver function, nutritional status, and prognosis of patients with cirrhosis.

Patients and Methods

The present study analyzed 319 patients with cirrhosis who underwent nutritional assessment using indirect calorimetry at our institution. Associations between LISI values and liver functional parameters, nutritional status, and the prognosis of patients with cirrhosis were assessed.

Results

LISI values increased in line with disease severity and positively correlated with the Child-Pugh and albumin-bilirubin (ALBI) scores. The LISI was inversely associated with the geriatric nutritional risk index (GNRI) value, and the LISI values in patients with protein malnutrition were higher than in those without protein malnutrition. In addition, LISI values were higher in patients with energy malnutrition than in those without. When we classified the patients into two groups according to the median LISI, patients with a high LISI had a poorer prognosis than those with a low LISI.

Conclusion

The LISI was associated with the severity of liver fibrosis, decreased liver function, and malnutrition. In addition, the LISI value was related to a poor prognosis.

Keywords: Liver Immune Status Index, liver cirrhosis, malnutrition, prognosis

Introduction

In patients with cirrhosis, decreased immune function is observed (1, 2) and is considered to lead to various undesirable clinical events, including not only suffering from the infectious diseases but also developing hepatocellular carcinoma (HCC) (3-5). Although it is not easy to clinically evaluate the immune status of patients, the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the liver natural killer (NK) cells is suggested to reflect the antitumor function against HCC, and the Liver Immune Status Index (LISI) has been proposed as an indicator to estimate TRAIL expression in liver NK cells (6, 7). Elevated LISI values were associated with reduced liver functional parameters and were further related to recurrence and a poor prognosis in patients with HCC after hepatectomy (6, 7).

However, these reports analyzed patients who were able to undergo hepatic resection and the enrolled patients had well-maintained liver function. Therefore, the clinical significance of LISI in cases of decreased hepatic function has not yet been sufficiently evaluated. In addition, although elevated LISI has been reported to correlate with worsening liver function parameters, its association with nutritional status has not yet been investigated.

In patients with cirrhosis, protein-energy malnutrition (PEM) is a frequently observed complication, and the serum albumin value and non-protein respiratory quotient (NPRQ) measured by indirect calorimetry have been used for assessing protein malnutrition and energy malnutrition, respectively (8-11).

In the current research, we assessed the clinical significance of LSIS in patients with cirrhosis, including those with a reduced liver reserve capacity, by investigating the relationship between the LISI and liver function tests, nutritional status, and prognosis.

Patients and Methods

Patients. This study investigated 319 patients with cirrhosis who underwent nutritional assessment using indirect calorimetry between April 2006 and January 2012. According to the Japanese guidelines (12), liver cirrhosis was clinically diagnosed based on the combination of the results of various clinical assessments, including liver biopsy, blood tests, and imaging findings (13). The current research was performed with the approval of the ethics committee of our university (No. 3431-202504-153).

Laboratory data and liver-related biomarkers. All laboratory data were obtained on the day of the nutritional evaluation. For the evaluation of the liver function, the Child-Pugh and ALBI scores were calculated. The Child-Pugh score and grade were determined according to standard criteria (14). ALBI score and ALBI grade (15-17) were determined as follows: ALBI score=[Log10 bilirubin (μmol/l)×0.66]+[albumin (g/l)×(–0.0852)]. The patients were categorized according to the following grades: ALBI grade 1/2/3 (≤–2.60/>–2.60 to –1.39/>–1.39). Because ALBI grade 2 can include a wide range of patients with cirrhosis, the modified ALBI (mALBI) grade, which subclassifies ALBI grade 2 into grade 2a and 2b, was proposed, and the mALBI grade was determined according to the following categories: grade 1/2a/2b/3 (≤–2.60/>–2.60 to –2.27/>–2.27 to –1.39/>–1.39) (18).

The LISI and its classification. The LISI, which was proposed as an index associated with TRAIL activity, was calculated using the following formula: LISI=36.39 – [6.18×albumin (g/dl)] – [0.50×body mass index (BMI)]+[2.91×FIB-4 index]. The FIB-4 index, a widely used liver fibrosis marker, was calculated using the following formula: FIB-4 index=age [years]×AST [U/l] / (ALT [U/l])1/2 / (platelet count [109/l]) (19, 20).

Regarding the grouping of the LISI values, previous reports have defined three groups (low risk: <4.55, moderate risk: 4.55–15.33, and high risk: >15.33) (6, 7). However, these reports investigated cases after liver resection, and the patients had a well-maintained hepatic reserve. All cases in our study had liver cirrhosis, and 46% of them had decompensated cirrhosis (Child-Pugh B or C); only six cases were categorized into the low-risk group (LISI <4.55). Therefore, we classified the patients into two groups based on the median LISI (LISI cutoff value: 21.0) and compared the data between the high- and low-value groups (Table I).

Table I. Characteristics of the enrolled patients with chronic liver diseases (N=319).

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Quantitative variables are expressed as the median (interquartile range). HBV: Hepatitis B virus; HCV: hepatitis C virus; ALD: alcoholic-related liver disease; NASH: nonalcoholic steatohepatitis; AIH: autoimmune hepatitis; PBC: primary biliary cholangitis; ALBI: albumin-bilirubin; mALBI: modified ALBI; NPRQ: non-protein respiratory quotient; GNRI: geriatric nutritional risk index; LISI: liver immune status index.

The evaluation of the nutritious status. PEM was diagnosed based on the following criteria (8-11): i) Protein malnutrition: cases with low albumin values (≤3.5 g/dl) were regarded as having protein malnutrition. ii) Energy malnutrition: In patients with cirrhosis, abridged gluconeogenesis leads to increased fat burning and a decreased non-protein respiratory quotient (NPRQ). The NPRQ was determined using indirect calorimetry as described previously, and cases with a low NPRQ value (<0.85) were regarded as having energy malnutrition (11, 21, 22). Cases with both types of malnutrition were classified as the protein-energy malnutrition (PEM) group.

The GNRI, which was shown to relate to the nutritional status of patients having chronic liver diseases, was determined as follows (23, 24): GNRI=14.89×albumin (g/dl)+41.7×[actual weight/ideal weight]. The ideal weight (kg) was obtained as the calculated value of “[height (m)]2×22 (kg/m2)”.

Statistical analyses. Continuous data from the two groups were compared using the Mann-Whitney method. Regarding the correlation between continuous parameters, Pearson’s correlation coefficient was calculated and expressed as the r-value. Regarding the correlation between the Child-Pugh score and LISI, Spearman’s rank correlation coefficient was calculated and expressed as the ρ-value. All statistical results were obtained using the JMP® Student Edition software program (JMP Statistical Discovery LLC, Cary, NC, USA).

Results

Basic clinical data of the enrolled patients. As mentioned in the previous section, 319 patients with cirrhosis (196 male patients and 123 female patients) were analyzed (Table I). The median age of the analyzed patients was 65 years old, and HCV-infection was the most frequent cause of liver cirrhosis in this cohort. The numbers of cases classified into Child-Pugh grades A, B, and C were 172, 124, and 23, respectively. Among 319 patients, 171 had protein malnutrition (albumin ≤3.5 g/dl), and 173 had energy malnutrition (NPRQ <0.85). One hundred and three patients had both types of malnutrition and were diagnosed with PEM.

Association of the LISI with the liver functional parameters. LISI values were positively associated with the Child-Pugh score (Figure 1A) and were significntly higher in compensated patients (Child-Pugh A) than in those with decompensated cirrhosis (Child-Pugh B or C) (Figure 1B). In addition, LISI values were positively correlated with the ALBI score (Figure 2A) and increased with the severity of the mALBI grade (Figure 2B).

Figure 1.

Figure 1

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Association of the Liver Immune Status Index (LISI) with the liver functional parameters. (A) LISI values are positively associated with the Child-Pugh score. (B) The LISI values in patients having compensated cirrhosis (Child-Pugh A) are significantly higher than those in patients having decompensated cirrhosis (Child-Pugh B or C).

Figure 2.

Figure 2

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Association of the Liver Immune Status Index (LISI) values with the albumin-bilirubin (ALBI) score and the modified ALBI (mALBI) grade. LISI values are positively correlated with the ALBI score (A) and increase with the mALBI grade (B).

Association of the LISI with the nutrition-related parameters. We further investigated the relationship between LISI values and nutritional status in patients with cirrhosis. The LISI value was inversely correlated to the GNRI value (Figure 3A), and patients with low GNRI values had significantly higher LISI values than those with high GNRI values (Figure 3B). Additionally, the LISI values in patients with protein malnutrition were higher than those in patients without protein malnutrition (Figure 4A). In addition, the LISI values in patients with energy malnutrition were higher than those in patients without energy malnutrition (Figure 4B).

Figure 3.

Figure 3

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Association of the Liver Immune Status Index (LISI) with the Geriatric Nutritional Risk Index (GNRI). The LISI is inversely associated with the GNRI (A), and patients with low GNRI values have significantly higher LISI values than those with high GNRI values (B).

Figure 4.

Figure 4

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Association of the Liver Immune Status Index (LISI) with protein and energy malnutrition. The presence of a high LISI is associated with protein malnutrition (A) and energy malnutrition (B), which are characterized by a low albumin level (≤3.5 g/dl) and low NPRQ value (<0.85), respectively.

Association between the LISI value and the prognosis of patients with cirrhosis. Finally, we studied the relationship between the LISI value and the prognosis of patients with cirrhosis. When we classified the patients into two groups according to the median LISI value, patients with a high LISI value showed a poorer prognosis than those with a low LISI value (Figure 5).

Figure 5.

Figure 5

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Association of the Liver Immune Status Index (LISI) with the prognosis of patients with cirrhosis. We investigated whether or not LISI values were associated with the prognosis of patients with cirrhosis. Categorization of patients into two groups according to the median LISI indicates that those with a high LISI have a poorer prognosis than those with a low LISI.

Discussion

Liver cirrhosis is the severe progression of various chronic liver diseases and can lead to various complications (25-29), In addition, patients with liver cirrhosis have a decreased immune status (1, 2). Although the immune function is considered to be associated with the anticancer function (30-32), it is not easy to estimate immunological status based on general clinical variables; however, the novel marker LISI was recently proposed as an index that can relate to the activity of TRAIL in patients with HCC after hepatectomy (6). The LISI was shown to be associated with liver function tests and liver fibrosis markers, and related to recurrence and a poor prognosis in patients with HCC after surgery. We therefore assessed the involvement of the LISI in the clinical conditions of patients with cirrhosis.

Our results showed that a high LISI value was related to the severity of the liver diseases, which was assessed by the Child-Pugh score/grade (Figure 1) and the ALBI score/grade (Figure 2), and the findings obtained from patients with cirrhosis were consistent with the previous reports that investigated patients with HCC after the curative surgery (6, 7). In addition, we showed that a high LISI was associated with a low nutritional status, which was suggested by the low GNRI (Figure 3) and the presence of protein malnutrition and/or energy malnutrition (Figure 4). Energy nutrition is ideally evaluated using indirect calorimetry but is not easy to perform routinely. Thus, our nutritious evaluations, which were conducted using a specific method, should provide unique results.

The LISI was originally generated using the clinical data of patients with HCC who had undergone surgical hepatic resection, and previous papers (6, 7) classified the patients into three groups (low-risk: <4.55, moderate-risk: 4.55-15.33, and high-risk: >15.33). However, the studies analyzed patients who underwent hepatectomy, and the liver function of the enrolled patients was relatively well maintained. In our cohort, all patients had liver cirrhosis, and only six cases were classified into the low-risk group. Thus, as mentioned above, our cohort was divided into two groups using the median LISI as the cutoff value (cutoff=21.0). Similarly, in a report that analyzed patients undergoing living-donor liver transplantation, the LISI values of the living donors (having a normal liver) were classified into two groups (high donor LISI, >–1.23; and low donor LISI, ≤–1.23), suggesting that the optimal cutoff value of LISI could vary depending on the cohort analyzed (33). Our findings showed that the LISI value could be a unique marker associated with the liver function, nutritional status, and prognosis in patients with cirrhosis. However, additional studies are required to determine the ideal cutoff value for risk stratification.

Study limitations. First, this study was retrospective with data from a single institution. In addition, the enrolled patients were restricted to those who received indirect calorimetry at our institution. Thus, the analyzed cohort may have included participants with specialized characteristics, potentially introducing bias. Second, we did not investigate whether or not the LISI was associated with TRAIL activity in our cohort. Third, as mentioned above, the appropriate LISI cutoff values might vary depending on the enrolled cohort, and each study adopted different cutoff values. Thus, further studies with various cohorts are required to precisely evaluate the clinical impact of the LISI.

In summary, we showed that LISI was associated with the severity of liver fibrosis, liver function, and nutritional status in patients with cirrhosis. We also showed that high LISI was associated with unfavorable prognosis in patients with cirrhosis.

Conflicts of Interest

The Authors have no conflicts of interest to declare in relation to the present study.

Authors’ Contributions

Study design: R.Y. and H.E. Data acquisition: R.Y., T.N., N.I., N.A, T. T., Y.Y., T.K., N.T., R.N., H.S. and H.E. Data analyses: R.Y., T.N., S.S. and H.E. Writing and editing the first draft of the manuscript: R.Y., S.S and H.E. The final version of the manuscript was approved by all the Authors.

Acknowledgements

The Authors thank Higuchi Y, Nagumo E, Fujii S, Kiriyama H, Kawai S, Kido H, Hiyashi M, and Shimoji Y (Hyogo Medical University) for technical and secretarial assistance.

Funding

No external funding was granted for this research.

Artificial Intelligence (AI) Disclosure

No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

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