Prevalence and risk factors for minimal hepatic encephalopathy in cirrhotic patients with different etiologies

Abstract

Aims

Minimal hepatic encephalopathy (MHE) significantly affects the prognosis of patients with cirrhosis. This study was performed to determine whether there is a difference in the prevalence of MHE among patients with cirrhosis of different etiologies and whether the etiology directly influences the occurrence of MHE.

Methods

This multicenter, cross‐sectional study enrolled 1879 patients with confirmed cirrhosis at 40 hospitals from October 25, 2021, to January 10, 2023 (Trial registration: https://clinicaltrials.gov/[NCT05140837]). The patients' demographics, etiologies of cirrhosis, and laboratory test results were collected. The psychometric hepatic encephalopathy score (PHES) was determined in all patients to screen for MHE. Multivariate logistic analyses were performed to identify the risk factors for MHE.

Results

In total, 736 patients with cirrhosis were analyzed. The prevalence of MHE was 42.0% (n = 309). The primary etiology among all patients was hepatitis B virus (HBV)‐related cirrhosis (71.9% [529/736]). The prevalence of MHE was significantly higher in patients with alcoholic cirrhosis (57.1% [40/70]) than in those with HBV‐related cirrhosis (40.6% [215/529], p = 0.009) or hepatitis C virus (HCV)‐related cirrhosis (38.2% [26/68], p = 0.026). Age (odds ratio [OR], 1.042; 95% confidence interval [CI], 1.024–1.059; p < 0.001), duration of education (OR, 0.935; 95% CI, 0.899–0.971; p = 0.001), etiology (OR, 1.740; 95% CI, 1.028–2.945; p = 0.039), and high MELD‐Na scores (OR, 1.038; 95% CI, 1.009–1.067; p = 0.009) were independent risk factors for MHE. When patients with cirrhosis of different etiologies were analyzed separately, the results showed that age (OR, 1.035; 95% CI, 1.014–1.057; p = 0.001) and duration of education (OR, 0.924; 95% CI, 0.883–0.966; p = 0.001) were risk factors for MHE among patients with HBV‐related cirrhosis, whereas age (OR, 1.138; 95% CI, 1.033–1.254; p = 0.009) and creatinine concentration (OR, 16.487; 95% CI, 1.113–244.160; p = 0.042) were risk factors for MHE in patients with HCV‐related cirrhosis. No risk factors for MHE were found in patients with autoimmune cirrhosis. For patients with alcoholic cirrhosis, the platelet count (OR, 1.014; 95% CI, 1.000–1.027; p = 0.045) was a risk factor for MHE. The PHES subtest results were inconsistent among patients who had MHE with cirrhosis of different etiologies. Patients with HBV‐related cirrhosis performed better on Number Connection Test B and the serial dotting test than those with alcoholic cirrhosis (p = 0.007 and p < 0.001), better on Number Connection Test B than those with HCV‐related cirrhosis (p = 0.020), and better on the line tracing test than those with autoimmune cirrhosis (p = 0.037).

Conclusion

The etiology of cirrhosis affected the prevalence of MHE and risk factors for MHE. The domains of major cognitive impairment varied among patients with cirrhosis of different etiologies. Further studies are required to verify these findings.

INTRODUCTION

Minimal hepatic encephalopathy (MHE) is the early stage of hepatic encephalopathy (HE). It is characterized by neuropsychological and cognitive impairments but no apparent clinical manifestations, and it is mainly diagnosed using a specific neuropsychological test: the psychometric hepatic encephalopathy score (PHES). Despite atypical clinical symptoms, MHE leads to impaired cognitive functions such as compromised visual perception and construction, spatial orientation, motor speed, accuracy, concentration, and attention. It may further lead to an increased incidence of HE, falls, traffic accidents, and even death, and it results in a poor quality of life and a worsened prognosis for patients with cirrhosis. According to the recent global guidelines, all patients with cirrhosis should be screened for MHE and retested every 6 months if MHE is not detected initially.

The prevalence of MHE in previous global studies ranged from 20% to 74%, with studies in China showing a prevalence of 36.6%–48.1%. Studies focusing on how different etiologies of cirrhosis affect the prevalence of MHE have yielded inconsistent results. Some studies showed no direct relationship between different etiologies of cirrhosis and the prevalence of MHE. In other studies, however, the prevalence of MHE in patients with alcoholic cirrhosis or hepatitis C virus (HCV)-related cirrhosis was higher than that in patients with cirrhosis of other etiologies. Additionally, several studies examining the risk factors for MHE have reached inconsistent conclusions on whether the etiology of cirrhosis is a risk factor for the occurrence of MHE. In summary, it remains unclear whether there is a difference in the prevalence of MHE among patients with cirrhosis of different etiologies and whether etiology directly influences the occurrence of MHE. More evidence is needed in this area, especially in China, where 0.5% of the population has cirrhosis, resulting in a significant disease burden.

We performed a cross-sectional multicenter study involving a large sample size of patients with cirrhosis to (1) determine whether the etiology of cirrhosis affects the prevalence of MHE and risk factors for MHE and (2) further explore whether essential aspects of cognitive impairment differ across etiologies of cirrhosis.

METHODS

Study design and population

This multicenter study was initiated by the Portal Hypertension Alliance in China (CHESS) and the National Clinical Research Center for Infectious Diseases (Trial registration: [NCT05140837]). Patients with cirrhosis aged ≥18 years with adequate knowledge of numbers and the Chinese alphabet were enrolled at 40 hospitals from October 25, 2021, to January 1, 2023. Cirrhosis was diagnosed based on liver biopsy or clinical findings (including clinical manifestations, laboratory tests, liver stiffness measurement, and imaging examination). The exclusion criteria were (1) the presence of neurological or psychiatric diseases (e.g., schizophrenia, bipolar disorder, depression, anxiety, cerebral infarction, or cerebral hemorrhage); (2) previous or present overt HE; (3) consumption of psychotropic drugs (e.g., sedatives, hypnotics, or antidepressants) or drugs that can be used to treat HE (e.g., lactulose or rifaximin); (4) alcohol abuse (>40 g/day for men and >20 g/day for women) within 3 months or alcohol intake within the last week before enrollment; (5) previous upper gastrointestinal bleeding or spontaneous bacterial peritonitis within 3 months before enrollment; (6) previous transjugular intrahepatic portosystemic stent-shunt or other shunt surgery; (7) current or previous malignancies; (8) heart, lung, or kidney failure or unstable vital signs; (9) incomplete demographic information or PHES results; (10) unclear etiology; and (11) inaccessible Child–Pugh or MELD-Na information. This study is reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology checklist and was approved by the ethical review board of the participating institutions. Written informed consent was obtained from each patient.

Data collections and definitions

The patients' demographics, etiologies of cirrhosis, laboratory test results, and PHES results were collected and recorded using a standardized data collection form. Only patients who had cirrhosis with chronic HBV infection, chronic HCV infection, autoimmune liver disease (ALD), or alcoholic liver disease were analyzed in this study. Alcoholic cirrhosis was diagnosed by chronic heavy drinking (>40 g/day for men and >20 g/day for women) or a history of heavy drinking (80 g/day) for >2 weeks, combined with imaging/pathology or clinical fulfillment of the diagnostic criteria for cirrhosis. The duration of education was defined as the number of years of schooling. The MELD score was calculated as MELD = 9.57 × log e(CR) + 3.78 × log e(TBIL) + 11.70 × log e(INR) + 6.43, where CR is the creatinine concentration, TBIL is the total bilirubin concentration, and INR is the international normalized ratio. The MELD-Na score was subsequently calculated as MELD-Na = MELD + [1.32 × (137 − Na)] − [0.033 × MELD × (137 − Na)], where Na is the sodium concentration.

PHES calculation

To obtain their PHES, all patients completed the following five neuropsychological tests: Number Connection Test A (NCT-A), Number Connection Test B (NCT-B), digit symbol test (DST), line tracing test (LTT), and serial dotting test (SDT). Because of cultural differences, the Chinese alphabet was used for the NCT-B in this study. All tests were consecutively completed in the above sequence in a quiet environment. The results of the NCT-A, NCT-B, and SDT were measured in seconds, and the result of the DST was measured in points. The results of the LTT were measured as both the time needed to complete the test (LTT-t, seconds) and the error score (LTT-e, points) and were integrated by w-LTT = (1 + LTT-e/100) × LTT-t. The final PHES was generated by summing the scores of the five tests and ranged from +5 to −15. According to a previous study, patients with a total PHES of <−4 were diagnosed with MHE.

Statistical analysis

Continuous variables are presented as mean ± standard deviation for normally distributed data and as median and range for nonnormally distributed data. Categorical variables are presented as number and frequency with corresponding percentage (n [%]). Categorical variables were compared using the χ² test or Fisher's exact test, and continuous variables were compared using Student's t-test or the Mann–Whitney U test. Pearson or Spearman analysis was used to explore the correlation between variables.

A p-value of <0.05 was considered statistically significant. Statistical analysis was performed using SPSS Version 25.0 (IBM Corp.) and GraphPad Prism Version 9.0 (GraphPad Software).

RESULTS

A total of 1879 patients with cirrhosis fulfilled the inclusion criterion. After the application of the exclusion criteria, 736 patients were analyzed in the current study. The detailed patient selection process is shown in Figure .

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Baseline characteristics of patients with cirrhosis

The median (range) age and duration of education of all 736 patients with cirrhosis was 52.0 years (46.0–58.0 years) and 9.0 years (6.0–12.0 years), respectively. Of all patients, 67.9% (n = 500) were men. The primary etiology among all patients was chronic HBV infection (n = 529, 71.9%), followed by alcohol consumption (n = 70, 9.5%), ALD (n = 69, 9.4%) and chronic HCV infection (n = 68, 9.2%). Age and sex showed significant differences among patients with different etiologies of cirrhosis (p < 0.001). The details of all patients and patients in different groups are shown in Table .

Table 1 Baseline characteristics of patients with cirrhosis.

Characteristics	Total (n = 736)	HBV (n = 529)	HCV (n = 68)	ALD (n = 69)	Alcoholic (n = 70)	p Value
Age (year)	52.0 (46.0, 58.0)	51.0 (45.0, 56.0)	57.5 (53.0, 60.5)	58.0 (51.0, 65.0)	55.5 (51.0, 60.0)	<0.001
Sex (male/female)	500/236	396/133	33/35	29/40	44/26	<0.001
Education (year)	9.0 (6.0, 12.0)	9.0 (6.0, 12.0)	9.0 (6.0, 12.0)	9.0 (6.0, 12.0)	11.5 (6.0, 12.0)	0.106
Child–Pugh A/B/C	371/256/109	272/182/75	29/25/15	46/19/3	24/30/16	0.002
MELD-Na score	11.00 (8.00, 15.00)	9.00 (7.00, 15.00)	10.00 (8.00, 15.00)	11.00 (8.00, 12.00)	13.00 (10.00, 18.00)	<0.001
Platelet (×109/L)	83.00 (53.00, 132.00)	85.00 (52.00, 135.00)	84.00 (54.00, 135.00)	84.00 (58.00, 129.00)	69.50 (50.50, 99.00)	0.173
Total bilirubin (mg/dL)	1.44 (0.91, 2.61)	1.48 (0.90, 2.61)	1.08 (0.78, 1.44)	1.40 (0.97, 2.33)	1.89 (1.21, 4.27)	0.001
Albumin (g/L)	35.00 (30.00, 40.20)	35.05 (30.00, 40.70)	37.40 (32.50, 42.40)	34.00 (29.00, 38.00)	32.65 (29.85, 36.35)	<0.001
Serum sodium (mmol/L)	139.90 (137.50, 141.40)	139.50 (137.50, 141.00)	139.20 (138.00, 141.00)	141.07 (139.00, 143.00)	140.14 (137.00, 142.95)	<0.001
INR	1.24 (1.09, 1.44)	1.26 (1.10, 1.45)	1.13 (1.05, 1.29)	1.15 (1.02, 1.37)	1.30 (1.19, 1.55)	<0.001
Creatinine (mg/dL)	0.72 (0.60, 086)	0.74 (0.62, 0.86)	0.68 (0.59, 0.80)	0.63 (0.54, 0.72)	0.73 (0.66, 0.98)	<0.001

The prevalence of MHE among all 736 patients with cirrhosis was 42.0% (n = 309). However, among the patients grouped according to different etiologies, we found that the highest prevalence of MHE reached 57.1% (40/70) in the alcoholic cirrhosis group. The prevalence of MHE was 40.6% (215/529), 38.2% (26/68), and 40.6% (28/69) in the HBV, HCV, and ALD groups, respectively. The χ² test showed a significant difference in the prevalence of MHE among the groups (p = 0.001). Further comparison between groups showed that the prevalence of MHE was higher in patients with alcoholic cirrhosis than in those with HBV and HCV infection (p = 0.009 and 0.026) (Figure ). This tendency was also found between the alcoholic and ALD groups, although with no statistically significant differences (p = 0.051) (Figure ).

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Risk factors for the occurrence of MHE in patients with cirrhosis

Univariate and multivariate logistic analyses were performed to explore risk factors for MHE in patients with cirrhosis. As shown in Table , age (odds ratio [OR], 1.042; 95% confidence interval [CI], 1.024–1.059; p < 0.001), duration of education (OR, 0.935; 95% CI, 0.899–0.971; p = 0.001), etiology (OR, 1.740; 95% CI, 1.028–2.945; p = 0.039), and MELD-Na score (OR, 1.038; 95% CI, 1.009–1.067; p = 0.009) were independent risk factors for the occurrence of MHE in all patients with cirrhosis (Table ).

Table 2 Risk factors for the occurrence of MHE in patients with cirrhosis.

Items	Univariate	Multivariate
OR (95% CI)	p Value	OR (95% CI)	p Value
Age	1.043 (1.026–1.061)	<0.001	1.042 (1.024–1.059)	<0.001
Sex (male/female)	0.863 (0.631–1.180)	0.356
Duration of education	0.935 (0.901–0.970)	<0.001	0.935 (0.899–0.971)	0.001
Etiology	1.968 (1.196–3.238)	0.008	1.740 (1.028–2.945)	0.039
MELD-Na	1.038 (1.011–1.066)	0.006	1.038 (1.009–1.067)	0.009
Child–Pugh	1.303 (1.065–1.594)	0.010

Because the etiology was found to be an independent risk factor for the occurrence of MHE in the preliminary analysis, we then included age, sex, duration of education, platelet count, total bilirubin concentration, albumin concentration, serum sodium concentration, international normalized ratio, and creatinine concentration to further explore the risk factors for MHE in patients with different etiologies. The multivariate logistic regression results are shown in Tables  and .

Table 3 Risk factors for the occurrence of MHE in patients with cirrhosis of different etiologies.

Items	HBV	HCV
Univariate	Multivariate	Univariate	Multivariate
OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p
Age	1.040 (1.020–1.061)	<0.001	1.035 (1.014–1.057)	0.001	1.133 (1.033–1.243)	0.008	1.138 (1.033–1.254)	0.009
Sex (male/female)	0.751 (0.505–1.117)	0.751			1.100 (0.413–2.927)	0.849
Duration of education	0.920 (0.880–0.961)	<0.001	0.924 (0.883–0.966)	0.001	0.908 (0.804–1.026)	0.121
Platelet	0.997 (0.986–1.069)	0.026			0.994 (0.986–1.002)	0.166
Total bilirubin	1.027 (0.856–1.349)	0.197			0.970 (0.616–1.526)	0.895
Albumin	0.976 (0.952–1.001)	0.062			0.960 (0.897–1.026)	0.229
Serum sodium	0.971 (0.921–1.024)	0.275			0.873 (0.731–1.043)	0.873
INR	0.970 (0.823–1.142)	0.970			0.817 (0.097–6.886)	0.853
Creatinine	1.530 (0.850–2.754)	0.156			12.898 (1.019–163.213)	0.048	16.487 (1.113–244.160)	0.042

Table 4 Risk factors for the occurrence of MHE in patients with cirrhosis of different etiologies.

Items	ALD	Alcoholic
Univariate	Multivariate	Univariate	Multivariate
OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p
Age	1.045 (0.995–1.098)	0.076			1.054 (0.993–1.119)	0.086
Sex (male/female)	1.733 (0.653–4.600)	0.269			0.750 (0.279–2.015)	0.568
Duration of education	1.012 (0.897–1.142)	0.845			0.942 (0.827–1.073)	0.370
Platelet	0.992 (0.982–1.002)	0.115			1.014 (1.000–1.027)	0.045	1.014 (1.000–1.027)	0.045
Total bilirubin	0.893 (0.749–1.065)	0.208			0.996 (0.894–1.111)	0.949
Albumin	0.997 (0.926–1.072)	0.932			0.923 (0.851–1.002)	0.055
Serum sodium	0.980 (0.863–1.112)	0.755			1.004 (0.916–1.101)	0.928
INR	0.839 (0.462–1.523)	0.564			5.320 (0.691–40.958)	0.109
Creatinine	1.601 (0.215–11.918)	0.646			0.606 (0.126–2.913)	0.532

For patients with HBV-related cirrhosis, age (OR, 1.035; 95% CI, 1.014–1.057; p = 0.001) and duration of education (OR, 0.924; 95% CI, 0.883–0.966; p = 0.001) were risk factors for MHE (Table ). For patients with HCV-related cirrhosis, age (OR, 1.138; 95% CI, 1.033–1.254; p = 0.009) and creatinine concentration (OR, 16.487; 95% CI, 1.113–244.160; p = 0.042) were risk factors for MHE (Table ). For patients with ALD-related cirrhosis, no significant risk factors were found (Table ). For patients with alcoholic cirrhosis, the platelet count (OR, 1.014; 95% CI, 1.000–1.027; p = 0.045) was a risk factor for MHE (Table ).

Comparison of PHES subtest results in patients with different etiologies of cirrhosis

The results of the five subtests of the PHES in all patients diagnosed with MHE were compared according to etiology to identify areas of potential differences despite the presence of cognitive dysfunction in all. Figure  shows that the NCT-B and SDT results of patients with MHE in the HBV group were better than those in the alcoholic cirrhosis group (p = 0.007 and p < 0.001) (Figure ). In addition, patients with MHE in the HCV group had worse NCT-B results than those in the HBV group, and patients with MHE in the ALD group had worse w-LTT results than those in the HBV group (p = 0.020 and p = 0.037) (Figure ). No significant differences were found in the comparison of the other subtest results between groups. In particular, the results of the NCT-A and DST were more stable and consistent in all four groups of patients (Figure ).

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DISCUSSION

Previous studies have shown that MHE impairs patients' quality of life and that early intervention for it can improve patients' cognitive impairment. However, previous studies have yielded inconsistent results regarding whether MHE is affected by the etiology of cirrhosis. Our results suggest that etiology is an independent risk factor for MHE in patients with cirrhosis and that the prevalence of MHE is highest in patients with alcoholic cirrhosis. To our knowledge, this is the first report to compare the prevalence of MHE and risk factors for MHE in patients with cirrhosis of four different etiologies.

Previous studies on MHE were mainly preliminary comparisons of the characteristics of patients with and without MHE, and some of these studies did not produce meaningful results in terms of etiology between the two groups of patients. By contrast, other studies have revealed differences in the prevalence of MHE in patients with cirrhosis of different etiologies, mainly showing a significant increase in the proportion of MHE in patients with alcoholic cirrhosis. However, either no further analysis was performed, or further investigation of risk factors for MHE in some studies subsequently ruled out the etiology. On the contrary, studies have also shown that the prevalence of MHE in patients with alcoholic cirrhosis is significantly higher than that in patients with other causes of cirrhosis at the time of the preliminary analysis; moreover, as an independent influencing factor, there is a synergistic effect with cirrhosis, exacerbating cognitive impairment in affected patients. Although HCV infection is associated with cognitive impairment, no significant difference has been found in multiple factors.

While MHE may not be diagnosed directly, past research has explored how underlying liver disease of different etiologies affects brain function. Increasing evidence suggests the presence and replication of HCV in the brain. Compared with HCV-negative controls, HCV-positive patients demonstrated significantly higher levels of proinflammatory cytokines within the brain. Most HCV-positive patients, regardless of the degree of liver fibrosis, show changes in language learning, attention, executive function, and memory when assessed by appropriate neuropsychological tests. In addition to the etiological differences, there is also a difference in the persistence of the viral response in patients with cirrhosis due to viral hepatitis. After treatment for HCV-related MHE, patients achieved a sustained virological response that resulted in the reversal of MHE symptoms. Further investigation is needed regarding the relationship between hepatitis C and cognitive impairment.

Patients with primary biliary cirrhosis and primary sclerosing cholangitis may experience fatigue, attention issues, and psychomotor dysfunction independent of the severity of the liver disease as well as poorer performance on objective cognitive tests. Research has also confirmed that patients with steatohepatitis or cirrhosis exhibit similar degrees of hippocampal neuroinflammation. Our findings showed that the indicators of the cirrhosis disease condition had no relationship with the occurrence of MHE in patients with ALD, which partially supports the above finding that the severity of cirrhosis does not affect neurologic microenvironmental inflammation in patients with ALD.

The effects of alcohol on brain function are well known and have also been found in healthy people. In addition to the higher prevalence of MHE in patients with alcoholic cirrhosis, impaired memory and frontal executive function and early development of overt HE are more common in patients with alcoholic cirrhosis than in other patients. Research has also demonstrated that reserve brain function was significantly lower in patients with alcoholic cirrhosis than in those with nonalcoholic cirrhosis and remained poorer during the follow-up period despite the patients' abstinence from alcohol.

Previous studies have been fairly consistent in showing that age, years of education, and MELD-Na scores are risk factors for MHE, and the results of our preliminary analysis were in agreement with this. In addition, because etiology was found to be an independent risk factor for the occurrence of MHE in our preliminary analysis, we considered it separately according to etiology. Except for studies that explicitly included patients with specific etiologies, few studies to date have explored risk factors separately according to etiology. In the present study, we compared the differences in risk factors for cirrhosis between different factors and obtained positive results, which will help guide clinical efforts to monitor specific populations.

The cognitive domains that are impaired in patients with MHE are related to attention, visuospatial functioning, processing speed, cognitive flexibility, and psychomotor speed. In the present study, we concluded that the prevalence of MHE and risk factors for MHE varied among patients with cirrhosis of different etiologies. Therefore, we hypothesized that the direction of the main impaired cognitive functions varies among etiologies. A comparison of the five subtests of the PHES in all patients diagnosed with MHE based on etiology showed that patients with alcoholic cirrhosis performed significantly worse on the NCT-B and SDT than patients with HBV-related cirrhosis. Meanwhile, patients with ALD performed worse on the w-LTT than patients with HBV-related cirrhosis. The PHES was initially constructed by selecting from more than two dozen tests the five that could best differentiate patients with MHE, among which the NCT-A\NCT-B assessed visuospatial orientation, motor speed, concentration, and attention; DST assessed visual retention and short memory, perceptual-motor speed, and visuomotor integrative ability; LTT assessed psychomotor retardation and visuomotor coordination function; and SDT assessed motor speed and coordination dexterity and perceptual discrimination ability. The above PHES subtest results in patients with different etiologies may suggest differences in the domains of cognitive functioning that are primarily impaired in these patients, such that patients with alcoholic cirrhosis are more severely impaired in terms of psychomotor speed/accuracy and coordination than patients with HBV-related cirrhosis. A previous study showed that an impaired cognitive status may be associated with abnormalities of regional brain function in patients with chronic liver disease (such as in the right and left posterior parts of the basal ganglia and right occipital lobe) together with reduced uptake in the right anterior cingulate region. It is also worth exploring whether the brain regions on imaging may behave differently in patients with different etiologies. Furthermore, our results showed that both the NCT-A and DST were more stable across etiologies, which is consistent with previous studies showing that the values of these two tests are more stable and valid in the overall PHES. Chinese guidelines on the management of HE in patients with cirrhosis recommend using a combination of the NCT-A and DST to diagnose MHE, and our results support and provide some evidence for this strategy as well.

The main limitation of this study is that despite our standardized training for the calculation of the PHES, potential bias arising from the multicenter background could not be eliminated. Additionally, because of the multicenter study design and large-scale population, we were unable to obtain current virological laboratory results for all patients with viral hepatitis.

In summary, this study has clarified that the etiology of cirrhosis affects the incidence of MHE and has identified respective risk factors based on several different etiologies. These findings are of clinical significance. Moreover, the domains of major cognitive impairment varied among patients with different etiologies of cirrhosis, warranting further studies.

AUTHOR CONTRIBUTIONS

Qingge Zhang, Ying Guo, Hongmei Zu, Jing Wang, Jiaojian Lv, Xiaoning Zhang, Fanping Meng, Jiahuan Li, Jie Li, Yangzhen Bianba, Jia Shang, Guo Zhang, Fei Liu, Zhaowei Tong, Chuang Lei, Wei Ye, Qiaohua Yang, Ningning Wang, Ying Song, Wei Fu, Ziyue Li, Yanjing Gao, Yongping Zhang, Jiafang Chen, Caiyun Wu, Qi Zheng, Fang Wang, Jiali Yu, Lianjie Lin, Chuanlong Yang, Xiaoting Yang, Xiaomin Ye, Xiangmei Wang, and Xuelan Zhao enrolled the patients and analyzed and interpreted the patient data. Xiaolong Qi, Fusheng Wang, and Junliang Fu participated in the research design. Xiaoyan Li, Shanghao Liu, and Huiling Xiang contributed to writing the manuscript. All authors read and approved the final manuscript.

ACKNOWLEDGMENTS

We thank Gaiping Zhang, Zhaolan Yan, Huafang Gao, Ruixin Song, Shuangling Ni, Tong Dang, Xin Zheng, Jian Wang, Weihua Wu, Xiaosong Yan, Zhuoga Cidan, Huiming Jin, Wenjuan Wang, Yan Huang, Wei Zhang, Qinghai Wang, Rongyu Tang, Yong-zhong Li, Yiling Li, Lihui Sun, Caiyan Zhao, Yongshuai Liu, Lan Liu, Riwang Hu, Lingzhen Hou, Liyan Lin, Qiyuan Tang, Lei Zhu, Jiaying Xiao, Hui Lv, Lin Huang, Haibing Gao, and Zemin Tian for contributing to this work. This study was supported by grants from the Innovation Groups of the National Natural Science Foundation of China (81721002), the Capital Clinical Diagnosis and Treatment Technology Research and Transformation Application Project (Z201100005520046), Tianjin Key Medical Specialty Construction Project (TJYXZDXK-034A), and Tianjin Health Science and Technology Project (TJWJ2022XK029).

CONFLICT OF INTEREST STATEMENT

Xiaolong Qi is the Editor-in-Chief of Portal Hypertension & Cirrhosis. He is therefore excluded from the peer-review process and all editorial decisions related to the publication of this manuscript. The remaining authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT

The data of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT

The study was approved by the Ethics Review Group of the Fifth Medical Center of Chinese PLA General Hospital (KY-2022-4-30-1) and the Ethics Committee of the First Hospital of Lanzhou University (LDYYLL2021-361). Written informed consent was obtained from each patient.

References

American Association for the Study of Liver Diseases; European Association for the Study of the Liver. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol. 2014;61(3):642‐659. [DOI: https://dx.doi.org/10.1016/j.jhep.2014.05.042]