CARTs for clinical profiles associated with the time required for the NCT-B
Among the total of 172 patients with early-stage HE, the mean time required for the NCT-B (NCT-B time) was 108.0 ± 48.1 sec. Age was selected as the variable for the initial split, and NCT-B time was 87.1 ± 41.0 sec in patients aged ≤ 65 years (Figure 1). In 91 patients aged ≤ 65 years, serum albumin level was selected as the variable for the second split; the NCT-B time was 108.5 ± 46.0 sec in patients with serum albumin < 2.85 g/dL. Additionally, Child–Pugh classification and serum chloride level were selected as the third and fourth splits, respectively.
Based on these results, we adopted serum albumin level as a biomarker to predict the impairment of cognitive function, determined as the prolongation of time required for the NCT-B in cirrhotic patients aged ≤ 65 years.
Characteristic features of patients aged ≤ 65 years without PSS
The presence of PSS often causes encephalopathy irrespectively of functional hepatic reserve. Thus, to accurately validate the predictive performance for cirrhosis-related cognitive dysfunction, patients with PSS were excluded from the 91 cirrhotic patients aged ≤ 65 years. The demographic and clinical characteristics of the patients in the final analysis are presented in Table 1. Twenty-seven cirrhotic patients (16 men and 11 women; mean age, 56.7 ± 8.6 years) were included in the study. Among these subjects, 66.7% had an initial onset of HE, 33.3% had a recurrence of HE, 74.1% developed HE grade I, 25.9% developed HE grade II, and the mean PSE index was 0.34. The majority of patients (70.4%) were classified as Child–Pugh B. The mean NCT-B was 92.2 ± 45.2 sec, which was lower than that in cirrhotic patients aged > 66 years (133.1 ± 43.1 sec), in agreement with the results of CART analysis (Figure 2). The mean blood ammonia concentration was 142.2 μg/dL, and the mean BTR was 3.32.
Table 1. Characteristics of patients
|
|
Characteristics
|
|
N
|
27
|
Age (years old)
|
56.7(8.6)
|
Sex (male/female)
|
16 (59.3%)/11 (40.7%)
|
Body weight (kg)
|
64.6(11.6)
|
Onset of HE (new-onset/recurrent)
|
18 (66.7%)/9 (33.3%)
|
PSE index
|
0.34(0.12)
|
HE grade I/II
|
20 (74.1%)/7 (25.9%)
|
Child-Pugh classification (A/B/C)
|
3 (11.1%)/19 (70.4%)/5 (18.5%)
|
Blood ammonia concentration (μg/dL)
|
142.2(41.1)
|
Predictive performance of serum albumin level to identify cognitive dysfunction in cirrhotic patients
To validate the predictive performance of serum albumin level in identifying the impairment of NCT-B time, we performed ROC curve analysis. In cirrhotic patients aged ≤ 65 years without PSS, ROC curve analysis revealed that the optimal albumin level cutoff point was 3.05 g/dL (sensitivity, 73.3%; specificity, 91.7%; PPV, 91.7%; NPV, 73.3%; accuracy, 81.5%), and the area under the curve (AUC) value was 0.80 (95% CI, 0.60–0.98) (Figure 3) for prolongation of NCT-B time. Among all cirrhotic patients, the AUC value to predict prolongation of NCT-B time was 0.63 (95% CI, 0.54–0.71)(cutoff point, 3.15 g/dL; sensitivity, 61.2%; specificity, 62.5%), which was remarkably lower than that in patients aged ≤ 65 years without PSS (Figure 3). These findings suggest that serum albumin level effectively identifies cognitive dysfunction in cirrhotic patients aged ≤ 65 years without PSS.
Efficiency of serum albumin level compared with other parameters related to cirrhosis-based HE
Next, to evaluate the potential of other parameters related to the occurrence of cirrhosis-based HE to predict cognitive dysfunction, we performed similar analyses of BTR, serum ammonia level, PT-INR, and total bilirubin level. For detection of the prolongation of NCT-B time in cirrhotic patients aged ≤ 65 years without PSS, the cutoff point was 3.295 for BTR (sensitivity, 46.7%; specificity, 66.7%; PPV, 63.6%; NPV, 50.0%; accuracy, 55.6%), 121.8 μg/dL for serum ammonia level (sensitivity, 73.3%; specificity, 58.3%; PPV, 71.4%; NPV, 61.5%; accuracy, 66.7%), 1.215 for PT-INR (sensitivity, 66.7%; specificity, 66.7%; PPV, 71.4%; NPV, 61.5%; accuracy, 66.7%), and 0.850 for total bilirubin (sensitivity, 93.3%; specificity, 41.7%; PPV, 73.3%; NPV, 66.7%; accuracy, 70.4%) (Supplementary Figure 1). The AUC value of serum albumin level (0.80) was higher than the AUC values of BTR (0.46; 95% CI, 0.23–0.69), serum ammonia level (0.61; 95% CI, 0.38–0.83), PT-INR (0.68; 95% CI, 0.46–0.87), and total bilirubin (0.69; 95% CI, 0.46–0.89) (Figure 4), indicating that compared with other parameters, serum albumin level is distinctly capable of predicting impaired cognitive function in cirrhotic patients aged ≤ 65 years.