Abstract
Number connection test A (NCT-A) and digit symbol test (DST), the preferential neuropsychological tests to detect minimal hepatic encephalopathy (MHE) in China, haven’t been standardized in Chinese population. We aimed to establish the norms based on a multi-center cross-sectional study and to detect MHE in cirrhotic patients. NCT-A and DST were administered to 648 healthy controls and 1665 cirrhotic patients. The regression-based procedure was applied to develop demographically adjusted norms for NCT-A and DST based on healthy controls. Age, gender, education, and age by education interaction were all predictors of DST, while age, gender, and education by gender interaction were predictors of log10 NCT-A. The predictive equations for expected scores of NCT-A and DST were established, and Z-scores were calculated. The norm for NCT-A was set as Z ≤ 1.64, while the norm for DST was set as Z ≥ − 1.64. Cirrhotic patients with concurrent abnormal NCT-A and DST results were diagnosed with MHE. The prevalence of MHE was 8.89% in cirrhotic patients, and only worse Child–Pugh classification (P = 0.002, OR = 2.389) was demonstrated to be the risk factor for MHE. The regression-based normative data of NCT-A and DST have been developed to detect MHE in China. A significant proportion of Chinese cirrhotic patients suffered from MHE, especially those with worse Child–Pugh classification.
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Introduction
Hepatic encephalopathy (HE) is one of serious complications of liver cirrhosis, severely affecting the lives of patients. Patients with HE have a spectrum of neurologic and psychiatric manifestations, which can be classified into 1–5 categories by the West Haven Criteria1. In recent decades, minimal hepatic encephalopathy (MHE), which is the mildest phase of HE, has been added into the West Haven Criteria, attracting more and more attentions2. MHE is defined as alterations in psychomotor or neuropsychiatric function without clinical evidence of neurological abnormalities, which can only be identified by neuropsychological or neurophysiological alterations3,4. The occurrence of MHE is common in patients with liver cirrhosis and it may affect the quality of life and patients’ driving ability5,6,7. Previous studies also showed that patients with MHE were more likely to develop overt hepatic encephalopathy (OHE), which caused a significant burden to health systems and society overall8,9,10.
Currently, there is no gold standard for the diagnosis of MHE. In western countries, the recognition of MHE depends on Psychometric Hepatic Encephalopathy Score (PHES), Stroop EncephalApp, Animal Naming Test, Critical Flicker Frequency test, and Inhibitory Control Test, et al.3,4,11,12. In China, due to the different language and cultural characteristics, abnormal results of both digit symbol test (DST) and number connection test A (NCT-A) have been recommended for diagnosing MHE13,14,15. DST and NCT-A are two sub-tests of PHES, and the normative data based on Chinese population are still lacking3,4,11. While China is a country with a vast territory and a large population, previous attempts on norms for NCT-A and DST were mostly based on studies with a small simple size and a single center, lacking consideration for demographic variables, such as age, gender, and education level, et al.16,17,18,19. Therefore, it is necessary to develop new norms for NCT-A and DST in China, which should be adjusted by demographic variables and standardized based on a multi-center, large sample size study.
The present cross-sectional study aimed to establish the Chinses norms for NCT-A and DST based on a large sample size of healthy population from multiple centers. The prevalence of MHE in patients with liver cirrhosis was further investigated in accordance with the established norms.
Methods
Healthy controls
648 Chinese-speaking healthy individuals aged 18–75 from 12 centers of China (Bei**g University of Chinese Medicine Affiliated Dongzhimen Hospital (Bei**g), Bei**g Ditan Hospital (Bei**g), The Fifth Medical Center of the General Hospital of the People’s Liberation Army of China (Bei**g), Fuzhou Infectious Disease Hospital (Fuzhou, Fujian), Guangdong Provincial Hospital of Chinese Medicine (Guangzhou, Guangdong), Shenzhen Hospital of Traditional Chinese Medicine (Shenzhen, Guangdong), the First Affiliated Hospital of Guangxi University of Chinese Medicine (Nanning, Guangxi), the First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine (Shenyang, Liaoning), the Affiliated Hospital of Shandong University of Traditional Chinese Medicine (**an, Shandong), Shanxi Provincial Hospital of Traditional Chinese Medicine (** the normative data, the use of mean and standard deviation within each subgroup, and conversion of raw scores to metrics such as Z or T scores were the most commonly used, considering the influence of demographic variables (e.g. age, education, gender) on the performance of neuropsychological tests. The use of mean and standard deviation requires dividing the sample into subgroups according to the predictive variables, and as a result, the sample size within subgroups will be significantly reduced. We have tried to establish the norms for NCT-A and DST using the mean and standard deviation, and the sample of some subgroups stratified by age, gender, and education was too small to ensure the reliability of the norms27. Therefore, the present study developed the regression-based normative data by converting raw scores to Z-scores. Some other studies have tried to establish the norms for NCT-A and DST in China. However, they just included a small sample of healthy participants in one or two medical centers, and ignored the influence of some demographic variables16,17,18,19. Healthy controls from 12 medical centers in different parts of China were included in the present study, ensuring the representativeness of participants to Chinese population. The results of the multivariate linear regression model showed that age, gender, education, and age by education interaction were predictors of DST, while age, gender, and education by gender interaction were predictors of log10 NCT-A. Younger age and more education years were reported to be associated with better performance of NCT-A and DST in most previous normative studies28,29. The processing speed of healthy individuals tends to decline along with the growth of age30. Moreover, participants with more educational experience are more familiar with paper–pencil tests than those without. The association between the scores of NCT-A and DST, and gender was a controversial issue in previous studies. While no significant difference was reported in some studies31,32,33,34, females were shown to possess better visual processing speed than males in the others19,29,35,36,37. Our results also showed that females outperformed males in both NCT-A and DST. Based on the above results, the normative data of NCT-A and DST adjusted to age, gender, education and interactions were developed, and a user-friendly EXCEL sheet was created for clinicians and patients. Specifically, results of NCT-A and DST in elderly people will be analyzed in future, which will not be described in this paper.
According to the regression-based normative data of NCT-A and DST, the prevalence of MHE in cirrhotic patients was 8.89% in China. It was lower than those in previous studies with similar diagnosis criteria. A positive correlation between the prevalence of MHE and patients’ CPC was shown, which was consistent with previous reports13,16,38. The low prevalence may be caused by following reasons. Firstly, our study did not include cirrhotic patients caused by alcoholic liver disease, as well as patients with a history of OHE. There is mounting evidence that alcohol may impair patients cognitive function39,40, which can bring cofounding factors to the diagnosis of MHE. Furthermore, the proportion of cirrhotic patients with CPC-B/C in our study was lower than that in previous studies, whom were reported to have a higher prevalence of MHE than patients with CPC-A. The different normative data of NCT-A and DST also accounted for the different prevalence.
Our study was not without limitations. Healthy controls included were not from community, but were mostly patients’ family members. Healthy controls’ average age was younger than the reported average age of Chinese41. Moreover, medical centers in our study were mostly located in key cities. This may affect the representativeness of healthy controls. However, patients and their family members in large hospitals usually come not only from local cities, but also from all over the country. The regression-based approach was also conducted to reduce bias. Lastly, although the demographic variables were considered in develo** the regression-based normative data, occupation and the urban–rural difference were not taken into account. Patients with some jobs were difficult to be classified as “white collars” or “blue collars” workers, and occupation was also closely related to the education level. With the rapid development of China in recent decades, it has been difficult to distinguish whether people come from urban or rural areas.
Conclusion
Our study firstly developed the regression-based normative data of NCT-A and DST based on a large sample from 12 medical centers all over the country, and a user-friendly calculator was offer. A considerable number of cirrhotic patients were diagnosed with MHE based on the normative data, and the prevalence was positively correlated with CPC. The standardization of NCT-A and DST will contribute to the clinical and research practice in China. The clinical screening of MHE needs to be paid attention in cirrhotic patients, especially those with CPC-B/C.
Data availability
The data used to support the findings of this study are available from the corresponding author upon request.
Abbreviations
- HE:
-
Hepatic encephalopathy
- MHE:
-
Minimal hepatic encephalopathy
- OHE:
-
Overt hepatic encephalopathy
- PHES:
-
Psychometric hepatic encephalopathy score
- DST:
-
Digit symbol test
- NCT-A:
-
Number connection test A
- SD:
-
Standard deviation
- CPC:
-
Child–Pugh classification
- HCV:
-
Hepatitis C virus
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Acknowledgements
We would like to thank all the patients, their families, and the investigators who participated in the study.
Funding
This study is funded by the Research Projects for the Business Construction of National Clinical Research Base of Traditional Chinese Medicine from the State Administration of Traditional Chinese Medicine (No. JDZX2015300) and the “111 Project” from Bei**g university of Chinese medicine and Dongzhimen hospital (No. 2016-DZM111-JC016).
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Study concept and design (Y.Y., D.G., P.Z.), acquisition of data (P.Z., X.C., D.M., Y.G., Y.L., D.Z., Q.L., M.Z., B.L., F.L., J.X., X.W., Y.L.), analysis and interpretation of data (P.Z.), drafting of the manuscript (P.Z.), critical revision of the manuscript for important intellectual content (YY), administrative, technical, or material support (H.D., D.G., Y.Y.), and study supervision (D.G., X.L., Y.Y.). All authors have made a significant contribution to this study and have approved the final manuscript.
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Zhang, P., Gan, D., Chi, X. et al. Regression-based Chinese norms of number connection test A and digit symbol test for diagnosing minimal hepatic encephalopathy. Sci Rep 14, 4005 (2024). https://doi.org/10.1038/s41598-024-54696-4
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DOI: https://doi.org/10.1038/s41598-024-54696-4
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