A test system for minimal hepatic encephalopathy

Abstract

The application relates to a test system for minimal hepatic encephalopathy. The system comprises an input unit receiving information of cirrhosis type of a cirrhosis patient, a test unit for performing a Stroop test on the cirrhosis patient, and an analysis unit judging the disease condition of the patient based on detection information from the test unit, wherein the analysis unit is configured to judge the correlation between the cirrhosis patient and minimal hepatic encephalopathy based on the cirrhosis type of the cirrhosis patient transmitted by the input unit and the cut-off value of the Stroop test transmitted by the test unit. The application provides a test system that can be used on a patient terminal. The Stroop test is applied to the clinical detection of Chinese non-alcoholic cirrhosis. Patients can easily download and apply the APP carrying the Stroop test on mobile phones and complete the test by themselves. The whole process only takes a few minutes, and the patient does not need a third party to accompany throughout the process, greatly reducing the burden of clinicians.

Description

Technical Field

[0001] This invention relates to the field of early warning technology for cirrhosis, and in particular to a testing system for mild hepatic encephalopathy. Background Technology

[0002] Minimal hepatic encephalopathy (MHE) is an early stage of hepatic encephalopathy. Patients do not show any clinical signs of hepatic encephalopathy, their daily routines are generally no different from normal people, and routine physical examinations show no obvious abnormalities. However, when performing neurological intelligence tests (such as drawing or number connection tests), it can be found that their cognitive abilities are impaired to varying degrees, and their intelligence test results (especially operational abilities) are often positive.

[0003] Mild hepatic encephalopathy (MHE) is a neurocognitive disorder with a low diagnosis rate that can significantly impact a patient's quality of life and reduce their work capacity. Because early-stage hepatic encephalopathy is often asymptomatic, many patients lack awareness and neglect treatment, leading to the development of overt hepatic encephalopathy and even death. Mild hepatic encephalopathy is closely related to the progression of cirrhosis and its poor prognosis. Without effective treatment, it will gradually progress to overt hepatic encephalopathy. The one-year survival rate for severe hepatic encephalopathy is 50%, and the three-year survival rate is close to 25%. Severe hepatic encephalopathy has a poor prognosis, severely impacting patients' quality of life and even threatening their lives. Early diagnosis and treatment of mild hepatic encephalopathy are crucial for preventing the development of overt hepatic encephalopathy and the progression of cirrhosis. Minimal hepatic encephalopathy (HEE) has an insidious onset, and its cognitive function can only be screened, diagnosed, and assessed through sophisticated neurological intelligence testing. Currently, the most common method for diagnosing HEE is the traditional paper-and-pencil test, also known as the psychological hepatic encephalopathy score (PHES). However, paper-and-pencil tests are time-consuming and inconvenient, limiting their clinical application. In recent years, the Stroop test has been validated by large-scale, multicenter clinical trials as highly effective in diagnosing HEE, exhibiting excellent discrimination and identification capabilities. The Stroop test is simple and quick to perform, making it a suitable method for early diagnosis of HEE that patients can complete independently.

[0004] The prevalence of mesenchymal hepatic encephalopathy (MHE) is quite high in patients with cirrhosis. If intervention is not carried out early, it can further progress to overt hepatic encephalopathy, which seriously affects the patient's quality of life and increases the mortality rate. Therefore, research on early diagnosis and early treatment has extremely important clinical significance.

[0005] Currently, neuropsychological examinations are the preferred method for diagnosing MHE in China, and diagnosis primarily relies on neuropsychological tests. The PHES test results are influenced by age and education level, but its lengthy testing time and the need for researchers to participate in interpreting the five test methods throughout the process make it cumbersome and less commonly used clinically. The Stroop test primarily assesses a patient's alertness, responsiveness, sustained attention, and memory. The results can indirectly reflect the swelling of glial cells in the brain, the neural activity of the cerebral cortex, and the state of neural conduction function. Professor Jasmohan S. Bajaj of the McGuire Medical Center at Virginia Commonwealth University has conducted a multicenter, large-sample clinical study on the application of the Stroop test for diagnosing minimal hepatic encephalopathy. The results confirm that the Stroop test can diagnose minimal hepatic encephalopathy simply, quickly, and with high accuracy, and can also predict hepatic encephalopathy. Currently, an app for the Stroop test has been developed in the United States. The Stroop test for diagnosing minimal hepatic encephalopathy has also been validated in South Korea and Germany. The Stroop test is simple and easy to perform, less affected by the patient's education level, and can save clinicians a significant amount of time on neuropsychological testing. The Stroop test is highly operable and therefore has wide application value in the clinical treatment of liver diseases in my country.

[0006] Chinese patent application CN114767114A discloses a cognitive function assessment method based on the Stroop color-word test and near-infrared brain functional imaging. The cognitive function assessment method includes the following steps: obtaining light intensity data of the bilateral prefrontal cortex brain tissue and the Stroop color-word test results of the subject during the completion of the test using a functional near-infrared imaging system; converting the subject's light intensity data into brain physiological information data and calculating the intensity of the bilateral prefrontal cortex; testing subjects with cognitive decline or poor cognitive state who cannot cooperate well in completing traditional neuropsychological scale assessments using the above method; comparing the Stroop color-word test results and bilateral prefrontal cortex intensity of the above subjects with those of normal individuals to determine if there are significant differences, and analyzing their correlation with the MoCA score.

[0007] The "Guidelines for the Diagnosis and Treatment of Hepatic Encephalopathy" also affirms the diagnostic value of the Stroop test for mild hepatic encephalopathy and the therapeutic effect of traditional Chinese medicine. Recent clinical studies on the treatment of mild hepatic encephalopathy with traditional Chinese medicine have provided some clinical evidence, but randomized controlled trials using the Stroop test as a diagnostic and assessment standard are still very few.

[0008] Meanwhile, the application of the Stroop test in China is concentrated in patients with cirrhosis. However, this application group is not differentiated based on the cognitive abilities of different patients, especially those with alcoholic cirrhosis and those with non-alcoholic cirrhosis. Because the Stroop test is related to cognitive function, the impact of alcohol on cognitive function is not excluded during the test, leading to errors in the Stroop test for patients with alcoholic cirrhosis and increasing the risk of misdiagnosis.

[0009] Furthermore, on the one hand, there are differences in understanding among those skilled in the art; on the other hand, the applicant studied a large number of documents and patents when making this invention, but due to space limitations, not all details and contents were listed in detail. However, this does not mean that the present invention does not possess the features of these prior art. On the contrary, the present invention already possesses all the features of the prior art, and the applicant reserves the right to add relevant prior art to the background art. Summary of the Invention

[0010] Hepatic encephalopathy is one of the critical complications of decompensated cirrhosis. Therefore, early diagnosis and intervention of hepatic encephalopathy is a crucial measure to save patients' lives. Minimal hepatic encephalopathy is the mildest form of hepatic encephalopathy, but clinical practice has shown that patients with minimal hepatic encephalopathy often have a poor prognosis. Furthermore, these patients often face risks when engaging in high-altitude work, driving, or similar activities, which also impacts their quality of life. The clinical manifestations of minimal hepatic encephalopathy are often subtle, requiring sophisticated neurological intelligence testing for identification. Clinicians are busy, and classic paper-and-pencil tests and human-machine interface tests are time-consuming. The Stroop test, on the other hand, is convenient, quick, easy for patients to master, offers more accurate timing, and does not require full clinician involvement, making it highly clinically feasible.

[0011] Furthermore, the testing system can implement different Stroop test standards based on different types of cirrhosis.

[0012] To address the aforementioned technical problems, this invention proposes a testing system for mild hepatic encephalopathy. The system includes an input unit that receives information about the type of cirrhosis in patients with cirrhosis, a testing unit for performing a Stroop test on the patients with cirrhosis, and an analysis unit that determines the patient's condition based on the detection information issued by the testing unit. The analysis unit is configured as follows:

[0013] The association between cirrhosis patients and mild hepatic encephalopathy was determined based on the cirrhosis type transmitted by the input unit and the cut-off value of the Stroop test transmitted by the test unit.

[0014] The beneficial effects of this technical solution are:

[0015] Hepatic encephalopathy is the most common cause of death in cirrhosis. Severe liver disease or portosystemic shunting can cause a syndrome based on metabolic disturbances and central nervous system dysfunction. Patients with mild clinical symptoms may only experience mild intellectual impairment, while those with severe symptoms may present with altered consciousness, behavioral abnormalities, and coma.

[0016] When patients are in the procoagulant phase of hepatic encephalopathy, they may only exhibit subtle personality and behavioral abnormalities. For example, some patients may be silent, while others may be talkative. Some patients may show slurred speech or slow movements. However, patients in this stage generally have no neurological signs, or only mild symptoms, which cannot be detected by medical equipment such as scanners. Because the onset of hepatic encephalopathy is not obvious, patients often miss the optimal window for treatment. This application provides a testing system that can be used on a patient's terminal (e.g., a mobile phone).

[0017] The Stroop test has been applied to the clinical treatment of non-alcoholic cirrhosis in China. The Stroop test APP can be easily downloaded and used on mobile phones. Patients can complete the test on their own, and the whole process only takes a few minutes. Moreover, the subject does not need to be accompanied throughout the process, which greatly reduces the burden on clinicians.

[0018] Patients can complete the test at home, making the process convenient and quick. This system also supports the early diagnosis of mild hepatic encephalopathy in clinical practice, demonstrating significant clinical application value.

[0019] According to a preferred embodiment, the types of cirrhosis include alcoholic cirrhosis and non-alcoholic cirrhosis.

[0020] According to a preferred embodiment, the analysis unit is configured as follows:

[0021] When the total on-phase time plus the total off-phase time of the Stroop test based on the test unit transmission is greater than 186.63 seconds, the patient with cirrhosis is confirmed to have mild hepatic encephalopathy. The cut-off value is the cut-off value of the total on-phase time plus the total off-phase time.

[0022] According to a preferred embodiment, the analysis unit is configured as follows:

[0023] When the liver cirrhosis type transmitted by the input unit is non-alcoholic cirrhosis,

[0024] When the total on-phase time plus the total off-phase time of the Stroop test based on the test unit transmission is greater than 205.86 seconds, the patient with cirrhosis is confirmed to have mild hepatic encephalopathy. The cut-off value is the cut-off value of the total on-phase time plus the total off-phase time.

[0025] The beneficial effects of this technical solution are:

[0026] This invention applies the Stroop test to and validates it in the Chinese population with non-alcoholic cirrhosis.

[0027] In Example 3, a prospective cohort of 66 cases was used to validate the diagnostic value of the Stroop test. It was found that the total on phase time plus the total off phase time in normal individuals was less than 205.86 seconds, while the total on phase time plus the total off phase time in patients with non-alcoholic cirrhosis was greater than 205.86 seconds. Therefore, this application proposes that the cut-off value for the total on phase time plus the total off phase time in patients with non-alcoholic cirrhosis should be 205.86 seconds.

[0028] According to a preferred embodiment, the system performs a Stroop test periodically. For example, the system can prompt the patient to perform a Stroop test once a day.

[0029] When a patient's Stroop test value decreases beyond a set value, the medication recommendation unit adjusts the recommended medication combination. Preferably, the adjustment refers to reducing the dosage of the medication combination, reducing the frequency of medication administration, or changing the medication formulation.

[0030] When a patient's Stroop test value rises above a set value, the medication recommendation unit stops recommending medications to the patient and prompts the patient to seek medical attention.

[0031] As long as the patient's Stroop test value does not rise or fall beyond the set value, the system maintains its current state, and the patient continues their current medication plan. However, if this situation occurs more frequently than the set value, or if only the test value rises during the above process, the medication recommendation unit stops recommending medication to the patient and prompts the patient to seek medical attention.

[0032] Specifically, the system can prompt patients to perform the Stroop test weekly.

[0033] When a patient's Stroop test cut-off value is above the value that confirms mild hepatic encephalopathy in a cirrhotic patient, and the patient's Stroop test cut-off value decreases for more than 10 seconds or decreases for four consecutive weeks, the drug recommendation unit reduces the dosage of traditional Chinese medicine by 20%.

[0034] When a patient's Stroop test cut-off value is above the value that confirms mild hepatic encephalopathy in a cirrhotic patient, and the Stroop test cut-off value increases for more than 10 seconds, the medication recommendation unit stops recommending medication to the patient and prompts the patient to seek medical attention.

[0035] If a patient's Stroop test cut-off value is above the value that confirms mild hepatic encephalopathy in patients with cirrhosis, and the patient has not experienced a reduction of more than 10 seconds for four consecutive weeks, medication should be discontinued and a clinical examination should be performed.

[0036] According to a preferred embodiment, the testing system further includes a drug recommendation unit, which is configured as follows:

[0037] If the analysis unit confirms that a patient with cirrhosis has mild hepatic encephalopathy, a recommended drug for the patient with cirrhosis will be generated.

[0038] According to a preferred embodiment, when a patient with non-alcoholic cirrhosis suffers from mild hepatic encephalopathy, the drug recommendation unit generates the following recommended drugs:

[0039] (1) Western medicines containing at least compound glycyrrhizin, compound coenzyme, and polyene phosphatidylcholine;

[0040] (2) The herbal formula shall contain at least 15g of Adenophora stricta, 15g of Ophiopogon japonicus, 15g of Rheum palmatum, 15g of Magnolia officinalis, 15g of Citrus aurantium, 15g of Paeonia lactiflora, and 15g of Acorus tatarinowii. The herbal formula shall be taken twice daily in 150ml.

[0041] According to a preferred embodiment, the input unit can also receive information on the patient's viral cirrhosis and non-viral cirrhosis, wherein when the patient has viral cirrhosis, the recommended drugs generated by the drug recommendation unit also include antiviral drugs.

[0042] According to a preferred embodiment, the input unit can also receive jaundice symptom information of patients with cirrhosis. When the analysis unit confirms that the patient with cirrhosis has mild hepatic encephalopathy, the traditional Chinese medicine prescription generated by the drug recommendation unit for the patient with jaundice also includes 30g of Lysimachia christinae and 30g of Artemisia capillaris.

[0043] According to a preferred embodiment, the jaundice symptom information includes jaundice levels reaching the diagnostic criteria and jaundice levels in patients with cirrhosis that continue to rise without receding.

[0044] According to a preferred embodiment, when the input unit also receives information on ascites symptoms in patients with cirrhosis, the drug recommendation unit is configured as follows:

[0045] In cases of ascites in patients with cirrhosis, the resulting traditional Chinese medicine formula also includes 30g of Imperata cylindrica root and 15g of Areca peel.

[0046] This invention provides a pharmaceutical composition for treating mild hepatic encephalopathy. The pharmaceutical composition comprises:

[0047] (1) Western medicines containing at least compound glycyrrhizin, compound coenzyme, and polyene phosphatidylcholine;

[0048] (2) A traditional Chinese medicine comprising at least 15 parts of Radix Adenophorae, 15 parts of Radix Ophiopogonis, 15 parts of Radix et Rhizoma Rhei, 15 parts of Cortex Magnoliae Officinalis, 15 parts of Fructus Aurantii Immaturus, 15 parts of Radix Paeoniae Rubra, and 15 parts of Rhizoma Acori Tatarinowii. Preferably, the pharmaceutical composition comprises Compound Glycyrrhizin, Compound Coenzyme Complex, Polyene Phosphatidylcholine, and the traditional Chinese medicine of 15g of Radix Adenophorae, 15g of Radix Ophiopogonis, 15g of Radix et Rhizoma Rhei, 15g of Cortex Magnoliae Officinalis, 15g of Fructus Aurantii Immaturus, 15g of Radix Paeoniae Rubra, and 15g of Rhizoma Acori Tatarinowii, wherein the traditional Chinese medicine formulation is administered 150 ml twice a day.

[0049] According to the previous research foundation of the research team, regarding the distribution pattern of traditional Chinese medicine syndromes of minimal hepatic encephalopathy, the syndrome of qi and yin deficiency with blood stasis is the most important traditional Chinese medicine syndrome type of minimal hepatic encephalopathy. The Yiqi Yangyin Jiedu Huayu formula is an empirical prescription for treating minimal hepatic encephalopathy summarized through repeated syndrome differentiation and treatment and many years of clinical practice, which can effectively cooperate with western medicine treatment to improve clinical efficacy.

[0050] The purpose of this study is to verify the clinical efficacy of the Yiqi Yangyin Jiedu Huayu formula in the treatment of minimal hepatic encephalopathy through the Stroop test. This study protocol has been reviewed and approved by the Ethics Committee of Beijing Ditan Hospital, Capital Medical University, with the ethical approval number Jing Di Lun Ke Zi (2020) No. (037)-02, and has been registered in the Chinese Clinical Trial Registry of the World Health Organization (ChiCTR2100055086).

[0051] According to the clinical experiment in Example 1, compared with the independent treatment with western medicine, the combined treatment of traditional Chinese medicine and western medicine can achieve better results, and at the same time, the combined treatment between the two will not increase the side effects during the treatment process.

[0052] According to a preferred embodiment, the traditional Chinese medicine further comprises 30 parts of Herba Lysimachiae and 30 parts of Herba Artemisiae Scopariae.

[0053] According to a preferred embodiment, the traditional Chinese medicine further comprises 30 parts of Rhizoma Imperatae and 15 parts of Pericarpium Arecae.

[0054] According to a preferred embodiment, the traditional Chinese medicine further comprises 60 parts of Radix et Rhizoma Rhei and 30 parts of Fructus Mume.

[0055] According to a preferred embodiment, the traditional Chinese medicine further comprises 30 parts of Fructus Trichosanthis and 15 parts of Semen Raphani.

[0056] According to a preferred embodiment, the present invention provides a traditional Chinese medicine composition capable of treating minimal hepatic encephalopathy in combination with western medicine. The traditional Chinese medicine composition comprises 15g of Radix Adenophorae, 15g of Radix Ophiopogonis, 15g of Radix et Rhizoma Rhei, 15g of Cortex Magnoliae Officinalis, 15g of Fructus Aurantii Immaturus, 15g of Radix Paeoniae Rubra, and 15g of Rhizoma Acori Tatarinowii.

[0057] Beneficial effects of the present technical solution:

[0058] After 4 weeks of treatment, 27 patients in the integrated traditional Chinese and Western medicine treatment group showed significant improvement, while 10 patients in the Western medicine treatment group showed significant improvement. After 4 weeks of treatment, 20 patients in the integrated traditional Chinese and Western medicine treatment group showed improvement, while 26 patients in the Western medicine treatment group showed improvement. A total of 47 patients in the integrated traditional Chinese and Western medicine treatment group showed improvement, with an effective rate of 94%, while 36 patients in the Western medicine treatment group showed improvement, with an effective rate of 72%. The difference between the two groups was statistically significant (P < 0.01).

[0059] The experimental results disclosed in the examples demonstrate that the traditional Chinese medicine composition disclosed in this application, when combined with existing Western medicine treatments, effectively improves the cure rate of mild hepatic encephalopathy. Detailed Implementation

[0060] Example 1

[0061] This invention provides a method for verifying mild hepatic encephalopathy.

[0062] 1. Clinical Data

[0063] 1.1 Diagnostic criteria

[0064] The diagnostic criteria for cirrhosis, Child-Pugh classification, and MELD score are based on the guidelines for the diagnosis and treatment of cirrhosis issued by the Chinese Society of Hepatology.

[0065] 1.2 Exclusion Criteria

[0066] 1) Hepatic encephalopathy with clinical symptoms; 2) History of mental abnormalities (such as severe anxiety, depression, etc.) or neurological abnormalities (sequelae of stroke, Parkinson's disease, etc.); 3) Use of anesthetics, sedatives, or central nervous system depressants (others such as ammonia-lowering drugs or branched-chain amino acids, etc.) within one month; 4) Patients with pathologically slowed reactions (such as anemia, hemoglobin below 90g / L; electrolyte and acid-base imbalance; body temperature exceeding 37.5℃); 5) Complications of upper gastrointestinal bleeding within the past two weeks; 6) Individuals who cannot undergo psychological intelligence testing due to educational level or vision (red-green color blindness); 7) Patients with severe cardiopulmonary diseases, cerebrovascular accidents, and severe diabetic complications; 8) Patients with alcoholic cirrhosis and a history of heavy alcohol consumption within the past three months; 9) Pregnant or lactating women.

[0067] 1.3 Shedding Criteria

[0068] 1) Those who voluntarily withdrew or revoked their informed consent; 2) Those who were lost to follow-up; 3) Those who were allergic to this drug, experienced serious complications, or refused to continue treatment.

[0069] 1.4 Rejection Criteria

[0070] Cases that have been enrolled but meet one of the following criteria should be excluded: 1) those who were mistakenly enrolled; 2) those who refused to take traditional Chinese medicine; 3) those who have no testing records.

[0071] The reasons for excluding cases should be recorded, and no statistical analysis of treatment efficacy should be performed.

[0072] 1.5 Grouping and Sources

[0073] This study employed a randomized controlled trial design. All enrolled cases were patients with cirrhosis diagnosed at Beijing Ditan Hospital between January 2020 and December 2021, based on biochemical, imaging, and clinical symptoms. According to previous literature, the clinical efficacy rate of integrated traditional Chinese and Western medicine treatment for mild hepatic encephalopathy was 90%, while the clinical efficacy rate in the Western medicine treatment group was 66.7%. The clinical efficacy rate was then substituted into the formula... This represents the mean of p1 and p2. Zα represents the mean of 1-p1 and 1-p2. α is 0.05. β is 0.2. Zα is 1.96. Zβ is 0.84. p1 is 0.9. p2 is 0.667. It is 0.7835. Substituting the above data into the formula with a value of 0.2165, we get n = 48. Adding a 10% dropout rate, we calculated that 50 cases would be enrolled in each of the experimental and control groups. The final sample size for this study was determined to be 100 cases, namely, 50 cases in the integrated traditional Chinese and Western medicine treatment group and 50 cases in the Western medicine treatment group. SPSS 23 statistical software was used to generate random number tables, which were printed out by designated personnel and sealed in opaque envelopes. After patients completed the enrollment screening, the envelopes were opened in order to determine the group of the enrolled patients. Once the group was determined, it could not be changed.

[0074] 2. Methods

[0075] 2.1 Intervention measures and follow-up design

[0076] All enrolled patients with cirrhosis were treated in accordance with the "Guidelines for the Diagnosis and Treatment of Cirrhosis" issued by the Chinese Society of Hepatology.

[0077] Western medicine treatment group:

[0078] 1) Treatment of the underlying cause: Patients with hepatitis B (entecavir 1 tablet Qd or tenofovir alafenamide fumarate 1 tablet Qd) or hepatitis C (Epclusa 1 tablet Qd) should be given antiviral treatment in a timely manner.

[0079] 2) Symptomatic treatment: Instruct the patient to follow a low-protein diet and administer compound glycyrrhizin 120mg Qd, polyene phosphatidylcholine 15ml Qd, and reduced glutathione 1200mg intravenously for liver protection and anti-inflammation.

[0080] 3) Treatment with oral lactulose 30ml once daily combined with probiotics (Bacillus licheniformis 0.5g twice daily, Bacillus subtilis 0.25g twice daily).

[0081] The integrated traditional Chinese and Western medicine treatment group, based on the Western medicine treatment group, applied a basic prescription for invigorating qi, nourishing yin, detoxifying, and removing blood stasis. The herbal composition included 15g of Adenophora stricta, 15g of Ophiopogon japonicus, 15g of Rheum palmatum, 15g of Magnolia officinalis, 15g of Citrus aurantium, 15g of Paeonia lactiflora, and 15g of Acorus tatarinowii. 150ml of the herbal composition was decocted and taken twice daily, with adjustments made according to the symptoms. For persistently elevated jaundice levels, 30g of Lysimachia christinae and 30g of Artemisia capillaris were added. For ascites, 30g of Imperata cylindrica and 15g of Areca catechu were added. For constipation or elevated blood ammonia, an enema (60g of Rheum palmatum and 30g of Prunus mume) was administered. For abdominal distension, 30g of Trichosanthes kirilowii and 15g of Raphanus sativus were added.

[0082] Treatment duration was one month. Follow-up frequency: baseline, 1 week after treatment, 2 weeks after treatment, and 4 weeks after treatment, for a total of 4 times.

[0083] 2.2 Observation

[0084] 2.2.1 Observation Indicators

[0085] Traditional Chinese medicine syndrome scores were recorded at baseline and at 4 weeks. MELD scores, Child-Pugh classification, blood ammonia (BA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total serum bilirubin (TBil), prothrombin activity (PTA), granulocyte-lymphocyte ratio (NLR), international normalized ratio (INR), MELD score, white blood cell count (WBC), hemoglobin (HGB), platelet count (PLT), potassium (K), sodium (Na), and creatinine (Cr) were recorded at baseline, 1 week, 2 weeks, and 4 weeks, respectively.

[0086] 2.2.2 Safety Evaluation Indicators

[0087] 1) Vital signs: body temperature, respiration, pulse, and blood pressure, monitored and recorded once a day; 2) Complete blood count: white blood cells (WBC), hemoglobin (HGB), and platelets (PLT); 3) Liver and kidney function: results were statistically analyzed at baseline, 1 week, 2 weeks, and 4 weeks; 4) Incidence of adverse events: the incidence of adverse events was statistically analyzed at 1 week, 2 weeks, and 4 weeks of treatment.

[0088] 2.3 Statistical Methods

[0089] Intention-to-treat (ITT) analysis was used to simultaneously record and statistically analyze eligible and dropout cases. For dropout cases, the reason for dropout was recorded, and the last test result was converted into the final result for statistical analysis.

[0090] Statistical analysis was performed using SPSS 23 (IBM Corp, NY): For normally distributed continuous data, the mean ± standard deviation was used. This indicates that a t-test was used for comparisons between the two groups. For non-normally distributed continuous data, an M(P) test was used. 25 P 75 This indicates that the rank-sum test was used for comparisons between groups. Count data were expressed as percentages, and the chi-square test was used for comparisons between groups. 2 All results were tested using a two-tailed test, and P < 0.05 was considered statistically significant.

[0091] 3 Experimental Results

[0092] 3.1 Comparison of general baseline data

[0093] From August 2021 to February 2022, 100 patients diagnosed with mild hepatic encephalopathy were obtained from Beijing Ditan Hospital affiliated to Capital Medical University. The 100 patients were randomly divided into a traditional Chinese and Western medicine treatment group and a Western medicine treatment group, with 50 patients in each group. There were 5 patients whose cases were dropped out, and the ITT analysis method was used for analysis.

[0094] Table 1 compares the baseline characteristics of the two groups of patients with mild hepatic encephalopathy. As shown in Table 1, there were no significant differences in gender, age, and education level between the integrated traditional Chinese and Western medicine treatment group and the Western medicine treatment group (P>0.05), and there were no statistically significant differences in baseline levels between the two groups (P>0.05), indicating that they were comparable.

[0095] Table 1

[0096]

[0097]

[0098] 3.2 Comparison of treatment efficacy rates between the two groups of patients with mild hepatic encephalopathy

[0099] After 4 weeks of treatment, 27 patients in the integrated traditional Chinese and Western medicine treatment group showed significant improvement, while 10 patients in the Western medicine treatment group showed significant improvement. After 4 weeks of treatment, 20 patients in the integrated traditional Chinese and Western medicine treatment group showed improvement, while 26 patients in the Western medicine treatment group showed improvement. A total of 47 patients in the integrated traditional Chinese and Western medicine treatment group showed improvement, with an effective rate of 94%, while 36 patients in the Western medicine treatment group showed improvement, with an effective rate of 72%. The difference between the two groups was statistically significant (P < 0.01).

[0100] 3.3 Comparison of liver function indicators before and after treatment in two groups of patients with mild hepatic encephalopathy

[0101] Table 2 shows a comparison of liver function indicators before and after treatment in two groups of patients with mild hepatic encephalopathy. As shown in Table 2, after 4 weeks of medication, the alanine aminotransferase and aspartate aminotransferase levels in the integrated traditional Chinese and Western medicine treatment group decreased significantly (P < 0.01). Compared with the Western medicine treatment group, the aspartate aminotransferase level in the integrated traditional Chinese and Western medicine treatment group began to decrease significantly in the 4th week of medication (P < 0.05).

[0102] The total bilirubin level in the integrated traditional Chinese and Western medicine treatment group began to decrease after one week of treatment with Chinese medicine (P<0.05), and the decrease was significant after four weeks (P<0.01). Compared with the Western medicine group, the total bilirubin level in the integrated traditional Chinese and Western medicine treatment group began to decrease significantly after two weeks of treatment with Chinese medicine (P<0.05), and the decrease was even more significant after four weeks of treatment with Chinese medicine (P<0.01).

[0103] The integrated traditional Chinese and Western medicine treatment group showed a significant increase in albumin levels after 4 weeks of Chinese medicine treatment (P<0.05). Compared with the Western medicine treatment group, the albumin levels were significantly higher after 2 weeks of Chinese medicine treatment (P<0.01).

[0104] After 1, 2 and 4 weeks of integrated traditional Chinese and Western medicine treatment and Western medicine treatment, the blood ammonia levels in both groups decreased significantly compared with the baseline level (P<0.01). In the 4th week of integrated traditional Chinese and Western medicine treatment, the blood ammonia level in the integrated traditional Chinese and Western medicine treatment group began to be significantly lower than that in the Western medicine treatment group (P<0.01).

[0105] In Table 2, a) represents the comparison with the same group before treatment, P < 0.05; b) represents the comparison with the same group before treatment, P < 0.01; c) represents the comparison between the two groups at the same time, P < 0.05; d) represents the comparison between the two groups at the same time, P < 0.01.

[0106] Table 2

[0107]

[0108] 3.4 Comparison of coagulation function indicators before and after treatment in two groups of patients with mild hepatic encephalopathy

[0109] Table 3 shows the comparison of coagulation function indicators before and after treatment in the two groups of patients with mild hepatic encephalopathy. As shown in Table 3, in the integrated traditional Chinese and Western medicine treatment group, prothrombin activity (PTA) began to improve after 1 week of traditional Chinese medicine treatment (P<0.05), and increased significantly after 2 weeks of traditional Chinese medicine treatment (P<0.01), while the international normalized ratio (INR) began to decrease after 1 week of traditional Chinese medicine treatment (P<0.05), and improved significantly after 4 weeks (P<0.01). Compared with the Western medicine treatment group, PTA increased significantly after 2 weeks of traditional Chinese medicine treatment (P<0.05), while PTA and INR improved significantly after 4 weeks of traditional Chinese medicine treatment (P<0.01).

[0110] In Table 3, a) represents the comparison with the same group before treatment, P<0.05; b) represents the comparison with the same group before treatment, P<0.01; c) represents the comparison between the two groups at the same time, P<0.05; d) represents the comparison between the two groups at the same time, P<0.01.

[0111] Table 3

[0112]

[0113] 3.5 Comparison of MELD scores and granulocyte-lymphocyte ratio (NLR) before and after treatment in two groups of patients with mild hepatic encephalopathy.

[0114] Table 4 shows the comparison of MELD scores and granulocyte-lymphocyte ratios before and after treatment in the two groups of patients with mild hepatic encephalopathy. As shown in Table 4, in the integrated traditional Chinese and Western medicine treatment group, after one week of treatment with traditional Chinese medicine, the MELD score and NLR significantly decreased (P < 0.05). Specifically, the NLR decreased significantly after two weeks of treatment with traditional Chinese medicine (P < 0.01), while the MELD score began to show a significant decrease after four weeks of treatment (P < 0.01). Compared with the Western medicine treatment group, the NLR began to decrease significantly after two weeks of treatment with traditional Chinese medicine (P < 0.05), and showed a significant decrease after four weeks (P < 0.01). After one week of treatment with traditional Chinese medicine, the MELD score in the integrated traditional Chinese and Western medicine treatment group was significantly lower than that in the Western medicine treatment group (P < 0.05), and after four weeks, the MELD score was significantly lower in the integrated traditional Chinese and Western medicine treatment group (P < 0.01).

[0115] In Table 4, a) represents the comparison with the same group before treatment, P<0.05; b) represents the comparison with the same group before treatment, P<0.01; c) represents the comparison between the two groups at the same time, P<0.05; d) represents the comparison between the two groups at the same time, P<0.01.

[0116] Table 4

[0117]

[0118]

[0119] 3.6 Comparison of TCM syndrome scores between two groups of patients with mild hepatic encephalopathy after treatment

[0120] The TCM syndrome score of the integrated TCM and Western medicine treatment group after treatment (6.3±1.6) was significantly higher than that before treatment (19±5.1) (P<0.01). The TCM syndrome score of the Western medicine treatment group after treatment (9.3±2.4) was also significantly improved compared with that before treatment (18.8±5.4) (P<0.01). The improvement of the TCM syndrome score of the integrated TCM and Western medicine treatment group after treatment was more significant compared with that of the Western medicine treatment group (P<0.01).

[0121] 3.7 Comparison of safety indicators before and after treatment in two groups of patients with mild hepatic encephalopathy

[0122] Table 5 shows a comparison of safety indicators before and after treatment in the two groups of patients with mild hepatic encephalopathy. As shown in Table 5, one patient in the integrated traditional Chinese and Western medicine treatment group experienced diarrhea in the second week of medication, which resolved after the prescription was adjusted. All patients had stable vital signs, and routine blood, urine, and stool examinations showed no abnormalities. Serum potassium, serum sodium, and serum creatinine were all within the normal range. There were no significant differences in white blood cell count, hemoglobin, and platelet count in the integrated traditional Chinese and Western medicine treatment group after treatment compared with those at admission (P>0.05). Therefore, it can be seen that the traditional Chinese medicine treatment did not cause any adverse effects.

[0123] The incidence of adverse events was 0% in the first week of integrated traditional Chinese and Western medicine treatment, 2% in the second week, and 2% in the fourth week.

[0124] In Table 5, a) represents the comparison with the same group before treatment, P<0.05; b) represents the comparison with the same group before treatment, P<0.01; c) represents the comparison between the two groups at the same time, P<0.05; d) represents the comparison between the two groups at the same time, P<0.01.

[0125] Table 5

[0126]

[0127]

[0128] 3.8 Analysis of Dropout and Exclusion Cases

[0129] A total of 5 cases were dropped out, with no cases excluded. In the integrated traditional Chinese and Western medicine treatment group, 3 patients failed to complete the required follow-up visit in week 4; in the Western medicine treatment group, 2 patients failed to complete the required follow-up visit in week 4. Intention-to-treat (ITT) analysis was used for all dropped out cases.

[0130] The test results showed that the combined Chinese and Western medicine treatment group reduced blood ammonia levels significantly better than the Western medicine treatment alone after 4 weeks of treatment.

[0131] Previous studies have shown that traditional Chinese medicines such as Rehmannia Decoction and enema formulas can lower blood ammonia levels. Although guidelines for hepatic encephalopathy do not recommend blood ammonia as an indicator for evaluating the efficacy of treatment, studies have demonstrated a close relationship between blood ammonia and patients' cognitive function. Currently, the mechanistic theory of hepatic encephalopathy is not unified, but blood ammonia remains one of the important pathogenic mechanisms. Compared with the Western medicine treatment group, the integrated traditional Chinese and Western medicine treatment group showed more significant clinical effects in improving patients' liver function and coagulation function. The granulocyte-lymphocyte ratio (GFR), which is the ratio of granulocytes to lymphocytes, mainly reflects the balance between inflammation and immunity in the body. In recent years, the GFR has been shown to be closely related to poor prognosis in liver disease patients; the higher the GFR, the worse the prognosis. Many studies have shown that the MELD score is closely related to the readmission time and survival of patients with end-stage liver disease; the higher the MELD score, the worse the prognosis. In this clinical trial, the integrated traditional Chinese and Western medicine treatment group showed a more significant decrease in both the GFR and MELD score compared to the Western medicine treatment group, suggesting that integrated traditional Chinese and Western medicine treatment significantly prolongs patients' survival time and improves the prognosis of patients with cirrhosis. The group treated with both traditional Chinese and Western medicine experienced fewer adverse reactions and stable laboratory indicators after treatment, suggesting that the combined treatment approach is safe and has strong clinical applicability.

[0132] Example 2

[0133] This invention relates to a testing system for mild hepatic encephalopathy.

[0134] This application uses the patients involved in Example 1 as samples to conduct Stroop test.

[0135] 1.1 Stroop Test Diagnostic Method

[0136] Download the Stroop app (Encephal App Stroop) from the Apple App Store. The 2013-2022 Jasmohan Bajaj test consists of two parts: an off phase and an on phase. Two practice tests are required before starting each phase.

[0137] 1) Off-phase test: A # symbol appears each time in one of three colors: red, green, or blue. The patient is instructed to quickly press the corresponding color button at the bottom of the screen. The buttons are randomly arranged each time. Each round consists of 10 button presses. If the wrong color is pressed, the test must be repeated. A total of 5 rounds must be completed correctly. The system will automatically record the total test time and the total number of errors made.

[0138] 2) Open (on) phase test: The color of the words does not correspond to their meaning. Patients need to press the button with the correct color. A total of 5 rounds must be completed correctly after the test begins. After the test, the software will automatically record the time of all tests and the total number of times the test is completed.

[0139] Final results of the Stroop test:

[0140] 1) Total off phase time: The time required to complete 5 rounds of off phases;

[0141] 2) Correctly complete the required number of rounds for the 5-round "off" phase;

[0142] 3) Total On-Phase Time: The time required to complete 5 rounds of on-phase opening;

[0143] 4) Correctly complete the required number of rounds for the 5-round open phase;

[0144] 5) Total on phase time + total off phase time.

[0145] 1.2 Observation

[0146] Stroop test results were recorded at baseline and at 4 weeks: 1) total off phase time; 2) number of times the off phase was completed correctly; 3) total on phase time; 4) number of times the on phase was completed correctly; 5) total on phase time + total off phase time.

[0147] 1.3 Efficacy Evaluation Criteria

[0148] It was developed with reference to the "Guidelines for the Diagnosis and Treatment of Hepatic Encephalopathy in Liver Cirrhosis".

[0149] Significant effect: The patient's intelligence test results returned to normal (total on phase time + total off phase time of the Stroop test < 186.63s).

[0150] Effective: Improved patient intelligence test results (the total on phase time + total off phase time of the Stroop test is reduced by more than 20 seconds but more than 186.63 seconds compared with the time before treatment).

[0151] Invalid: Patient's intelligence test results show no change or worsen (the total on phase time of the Stroop test plus the total off phase time remains unchanged or is prolonged).

[0152] The effective rate of treatment = (number of cases with significant effect + number of cases with effect) / total number of cases.

[0153] 1.4 Results

[0154] 1.4.1 Comparison of Stroop test results before and after treatment in two groups of patients with mild hepatic encephalopathy

[0155] Table 6 shows a comparison of Stroop test results before and after treatment in two groups of patients with mild hepatic encephalopathy [M(P 25 P 75 As shown in Table 6, there was no significant difference in Stroop test results between the integrated traditional Chinese and Western medicine treatment group and the Western medicine treatment group before treatment (P>0.05). Neither group of patients with mild hepatic encephalopathy progressed to overt hepatic encephalopathy after 4 weeks of treatment.

[0156] After 4 weeks of treatment, the total off-phase time, total on-phase time, and total on-phase time + total off-phase time in the Stroop test of the integrated traditional Chinese and Western medicine treatment group were significantly lower than before treatment (P < 0.01), and the number of times the on-phase was correctly completed was also significantly lower (P < 0.05). After treatment, the total off-phase time, total on-phase time, total on-phase time + total off-phase time, and the number of times the on-phase was correctly completed in the Western medicine treatment group were also significantly lower than before treatment (P < 0.05).

[0157] The total off-phase time, total on-phase time, and total on-phase time plus total off-phase time in the integrated traditional Chinese and Western medicine treatment group were significantly lower than those in the Western medicine treatment group after 4 weeks of treatment (P < 0.01).

[0158] In Table 6, a) represents the comparison with the same group before treatment, P<0.05; b) represents the comparison with the same group before treatment, P<0.01; c) represents the comparison between the two groups at the same time, P<0.05; d) represents the comparison between the two groups at the same time, P<0.01.

[0159] Table 6

[0160]

[0161] Neurological intelligence testing is the most important diagnostic and monitoring method for mild hepatic encephalopathy. This clinical trial used the Stroop test for assessment. After treatment, the Stroop test results in both groups showed significant improvement compared to before treatment. Compared with the Western medicine treatment group, the Stroop test results in the integrated traditional Chinese and Western medicine treatment group showed a greater decrease and a more significant effect. Therefore, the Stroop test results demonstrate that the integrated traditional Chinese and Western medicine treatment is effective, and its efficacy is significantly better than that of the Western medicine treatment group. This result is consistent with the conclusions obtained in Example 1 through the detection of other indicators.

[0162] Example 3

[0163] This embodiment explores the diagnostic cutoff value for mild hepatic encephalopathy in non-alcoholic cirrhosis. A prospective cohort of 66 cases was used to validate the diagnostic value of the Stroop test.

[0164] This embodiment uses a prospective cohort of 66 patients to validate the diagnostic value of the Stroop test. To fully validate the reproducibility of the Stroop test, this embodiment repeats the Stroop test on an additional 66 patients with non-alcoholic cirrhosis. Table 7 shows the initial health status of the healthy individuals and non-alcoholic cirrhotic patients used in this application. The mean age of the 66 patients was (55.8 ± 11.0) years, their education level was 9.0 (9.0, 12.5) years, 15 patients (22.7%) had a history of hepatic encephalopathy, 57 patients had hepatitis B, 3 had hepatitis C, 3 had autoimmune diseases, and 3 had other causes. In Table 7, the cut-off value of the total on-phase time + total off-phase time for healthy individuals was less than 205.86 s, while the cut-off value of the total on-phase time + total off-phase time for non-alcoholic cirrhotic patients was greater than 205.86 s.

[0165] Forty patients with mild hepatic encephalopathy were screened using PHES as the gold standard. Forty-four more patients with mild hepatic encephalopathy were screened using the cut-off value of 205.86 s (total on-phase time + total off-phase time). The prospective validation cohort showed a sensitivity of 89%, specificity of 69%, positive predictive value of 0.81, and negative predictive value of 0.82. Prospective cohort studies are a fundamental form of cohort research. The grouping of study subjects is based on their current exposure status; the results are not yet available and require a prospective observation period. The above results demonstrate that the proposed cut-off values ​​for total on-phase time and total off-phase time have good diagnostic efficacy and clinical application value.

[0166] Table 8 shows the ROC curves for normal individuals without a history of overt hepatic encephalopathy (ROC curve results of the Stroop test for non-alcoholic cirrhosis). (The larger the area under the ROC curve, the higher the diagnostic accuracy. On the ROC curve, the point closest to the upper left of the graph represents the cut-off value, which indicates both high sensitivity and specificity). The sensitivity was 90%, the specificity was 71%, the positive predictive value was 0.72, and the negative predictive value was 0.89.

[0167] Diagnostic cutoff value for mild hepatic encephalopathy in non-alcoholic cirrhosis: A total of 160 patients with non-alcoholic cirrhosis were included, and the baselines of the two groups were comparable (P>0.05). As shown in Table 8, the cutoff value of 205.86s for the total on phase time and total off phase time was used as the diagnostic cutoff value for mild hepatic encephalopathy in non-alcoholic cirrhosis.

[0168] Sensitivity, specificity, positive predictive value, and negative predictive value are indicators used in medicine to assess the accuracy of diagnosis.

[0169] Sensitivity, also known as the true positive rate, refers to the proportion of people who actually have the disease but are correctly diagnosed by a certain diagnostic method. Higher sensitivity indicates a lower false negative rate, meaning it reduces missed diagnoses when used for disease screening. It is calculated as A / (A+C).

[0170] Specificity, also known as the true negative rate, refers to the proportion of people who are actually disease-free but are correctly diagnosed as disease-free by a certain diagnostic method. Higher specificity indicates a lower false diagnosis rate, meaning a lower false diagnosis rate when used for disease screening. It is calculated as D / (B+D).

[0171] The positive predictive value (PMR) is the proportion of people in a population who test positive by a certain diagnostic method but actually have the disease. A higher PMR indicates a more accurate diagnosis. It is calculated as A / (A+B).

[0172] The negative predictive value (NMR) is the proportion of people in a population who test negative by a diagnostic method but are actually disease-free. A higher NMR indicates a more accurate diagnosis. It is calculated as D / (C+D).

[0173] In this experiment, sensitivity is of great significance for evaluating the accuracy and reliability of diagnostic methods; therefore, 205.86s was selected as the gold standard for diagnosis.

[0174] Table 7

[0175]

[0176] Table 8

[0177]

[0178] This embodiment demonstrates that the Stroop test is simple, quick, and highly accurate in diagnosing mild hepatic encephalopathy. The Stroop test is easy to perform, less affected by the patient's education level, and can save clinicians a significant amount of time on neurological intelligence testing. It is highly operable and has wide application value in clinical liver disease treatment in my country.

[0179] It should be noted that the specific embodiments described above are exemplary. Those skilled in the art can devise various solutions inspired by the disclosure of this invention, and these solutions all fall within the scope of this invention and its protection. Those skilled in the art should understand that this specification is illustrative and does not constitute a limitation on the claims. The scope of protection of this invention is defined by the claims and their equivalents. This specification contains multiple inventive concepts; terms such as "preferredly," "according to a preferred embodiment," or "optionally" indicate that the corresponding paragraph discloses an independent concept. The applicant reserves the right to file divisional applications based on each inventive concept. Throughout the text, features introduced by "preferredly" are merely optional and should not be construed as mandatory. Therefore, the applicant reserves the right to abandon or delete relevant preferred features at any time.

Claims

1. A testing system for mild hepatic encephalopathy, characterized in that, The system includes an input unit for receiving information about the type of cirrhosis in patients with cirrhosis, a testing unit for performing a Stroop test on the patients with cirrhosis, and an analysis unit for determining the patient's condition based on the test information issued by the testing unit. The analysis unit is configured as follows: The association between the cirrhosis patient and mild hepatic encephalopathy is determined based on the cirrhosis type of the cirrhosis patient transmitted by the input unit and the cut-off value of the Stroop test transmitted by the test unit. The types of cirrhosis include alcoholic cirrhosis and non-alcoholic cirrhosis; The analysis unit is configured as follows: When the type of cirrhosis transmitted by the input unit is non-alcoholic cirrhosis, Furthermore, if the cut-off value of the Stroop test transmitted by the test unit is greater than 205.86 s, it is confirmed that the cirrhotic patient has mild hepatic encephalopathy.

2. The testing system for mild hepatic encephalopathy according to claim 1, characterized in that, The testing system also includes a drug recommendation unit, which is configured as follows: If the analysis unit confirms that the cirrhotic patient has mild hepatic encephalopathy, a recommended drug for the cirrhotic patient is generated.

3. The testing system for mild hepatic encephalopathy according to claim 2, characterized in that, When a patient with non-alcoholic cirrhosis (NAFLD) also has mild hepatic encephalopathy, the drug recommendation unit generates the following recommended drugs: (1) Western medicines containing at least compound glycyrrhizin, compound coenzyme, and polyene phosphatidylcholine; (2) The herbal medicines shall contain at least 15 g of Adenophora stricta, 15 g of Ophiopogon japonicus, 15 g of Rheum palmatum, 15 g of Magnolia officinalis, 15 g of Citrus aurantium, 15 g of Paeonia lactiflora, and 15 g of Acorus tatarinowii. The above herbal medicine formula shall be taken twice a day in 150 ml.

4. The testing system for mild hepatic encephalopathy according to claim 3, characterized in that, The input unit can also receive information about the patient's viral cirrhosis and non-viral cirrhosis. When the patient has viral cirrhosis, the recommended drugs generated by the drug recommendation unit also include antiviral drugs.

5. The testing system for mild hepatic encephalopathy according to claim 3, characterized in that, The input unit can also receive jaundice symptom information from patients with cirrhosis. When the analysis unit confirms that the patient with cirrhosis has mild hepatic encephalopathy, the traditional Chinese medicine prescription generated by the drug recommendation unit for the patient with jaundice also includes 30g of Lysimachia christinae and 30g of Artemisia capillaris.

6. The testing system for mild hepatic encephalopathy according to claim 5, characterized in that, The jaundice symptom information includes jaundice levels reaching the diagnostic criteria and jaundice levels in patients with cirrhosis that continue to rise without receding.

7. The testing system for mild hepatic encephalopathy according to claim 3, characterized in that, When the input unit also receives information about ascites symptoms in patients with cirrhosis, the drug recommendation unit is configured as follows: In the case of ascites in the patient with cirrhosis, the prepared traditional Chinese medicine formula also contains 30 g of Imperata cylindrica root and 15 g of Areca peel.

Images