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Table of Contents
ORIGINAL ARTICLES
Year : 2022  |  Volume : 14  |  Issue : 1  |  Page : 24-28

The efficacy of the EncephalApp in diagnosing minimal hepatic encephalopathy (MHE) among patients with liver cirrhosis in Jos Nigeria


1 Department of Internal Medicine, Jos University Teaching Hospital, Jos, Abuja, Nigeria
2 Department of Internal Medicine, University of Abuja Teaching Hospital, Gwagwalada, FCT, Abuja, Nigeria
3 Department of Radiology, Echolab Radiology and Laboratory Services, FCT, Abuja, Nigeria

Date of Submission16-May-2022
Date of Acceptance30-May-2022
Date of Web Publication21-Jul-2022

Correspondence Address:
Nyam Paul David
Department of Internal Medicine, Jos University Teaching Hospital, PMB 2076 Jos
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njgh.njgh_9_22

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  Abstract 

Background and Objectives: Minimal hepatic encephalopathy is a condition in which patients with liver cirrhosis with normal mental and neurological status on clinical examination show cognitive dysfunction detectable on psychometric or neurophysiologic tests. Routine detection of this condition is not commonly carried out despite the high prevalence among patients with liver cirrhosis and a high risk of progression to overt hepatic encephalopathy. We compared the smartphone based EncephalApp with the standard psychometric hepatic encephalopathy score (PHES) in diagnosing MHE in patients with liver cirrhosis in Jos University Teaching Hospital. Materials and Methods: Fifty healthy subjects and 42 patients with liver cirrhosis who did not have overt hepatic encephalopathy and who fulfilled other study criteria were recruited in this cross-sectional analytical study. Both healthy subjects and patients were tested with the EncephalApp, and with the paper-pencil PHES test. Data analysis was done using Statistical Package for the Social Sciences (SPSS) 23.0. A value of P < 0.05 was considered statistically significant. Results: The mean age of the control group was 35.9 ± 8.7 years, whereas that of the patient group was 38.9 ± 8.7, P = 0.099. The mean number of years in school for the control group was 16.5 ± 3.4 years, whereas that of the patients was 16.1 ± 3.1, P = 0.471. The prevalence of MHE by PHES was 40.5%. The prevalence of MHE by EncephalApp was 51.4% based on the cutoff of 241.8 s, sensitivity = 54.1% and specificity = 90.0%, AUROC = 0.77. Conclusion: The prevalence of MHE in patients with liver cirrhosis in Jos, Nigeria, is about the same with values documented in other parts of the world. The EncephalApp was shown to be a reliable screening tool with good sensitivity, specificity and AUROC in our patients with liver cirrhosis.

Keywords: Cirrhosis, EncephalApp, encephalopathy, hepatic, minimal


How to cite this article:
David NP, Duguru MJ, Davwar PM, Omaiye PO, Okeke EN, Ojonugwa Alufiya A, Umejiaku CC, Kenis SF, Makpu JD, Bitrus Sekat N. The efficacy of the EncephalApp in diagnosing minimal hepatic encephalopathy (MHE) among patients with liver cirrhosis in Jos Nigeria. Niger J Gastroenterol Hepatol 2022;14:24-8

How to cite this URL:
David NP, Duguru MJ, Davwar PM, Omaiye PO, Okeke EN, Ojonugwa Alufiya A, Umejiaku CC, Kenis SF, Makpu JD, Bitrus Sekat N. The efficacy of the EncephalApp in diagnosing minimal hepatic encephalopathy (MHE) among patients with liver cirrhosis in Jos Nigeria. Niger J Gastroenterol Hepatol [serial online] 2022 [cited 2022 Nov 26];14:24-8. Available from: https://www.njghonweb.org/text.asp?2022/14/1/24/351557




  Introduction Top


Hepatic encephalopathy (HE) is a term used to describe a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction, after exclusion of other known brain diseases.[1] It may be either overt HE or covert (i.e., minimal) HE).[1] Minimal hepatic encephalopathy (MHE) refers to the subtle changes in cognitive function that can be detected by psychometric tests in patients with cirrhosis who have no clinical evidence of HE.[2]

Psychometric HE tests have been used to diagnose MHE in research studies.[3] However, they have not been routinely used in clinical practice because they require permission from the copyrighted owners, and also, a long duration of time is required to complete a test.[3] Therefore, a point-of-care screening tool, that takes a shorter time, readily accessible and can be easily administered, or even self-administered, is required, as this may increase testing and detection of MHE. Studies have shown that MHE treatment generally improves cognitive outcomes.[4],[5] However, treating every patient with liver cirrhosis for MHE without testing may not be cost-effective.[4]

The EncephalApp is easy to administer and takes a shorter time (approximately 5 min, compared to 25 min for PHES).[6] It can be administered by a nurse, a clinic assistant, or even self-administered.[6]

The aim of this study is to determine the prevalence of MHE in patients with liver cirrhosis using both psychometric hepatic encephalopathy score (PHES) and EncephalApp and to show the non-inferiority of the smartphone-based EncephalApp to the standard, PHES.


  Materials and methods Top


The study was carried out in the Jos University Teaching Hospital (JUTH). The Medical Out-Patient Department and the medical wards were used. JUTH is a 520-bedded tertiary health institution in Jos, Plateau State, Nigeria. This study was a cross sectional analytical study.

Fifty healthy subjects and 42 patients with liver cirrhosis, aged 18 years and above were enrolled consecutively.

Ethical approval was obtained from the research and ethics committee of the JUTH. Informed consent was obtained from all the subjects before they were recruited for the study.

Patients (with liver cirrhosis) ARM

Patients with liver cirrhosis were diagnosed by imaging techniques (fibroscan or abdominal ultrasound scan). The evidence of liver cirrhosis included shrunken liver with coarse heterogeneous echotexture, surface nodularity, irregular outline, elongated tortuous blood vessels on abdominal ultrasound scan[7] or fibroscan score of greater than 12.5 kPa.[8]

Patients with overt HE (based on the West Haven criteria),[3] who could not read, those with red-green colorblindness (using the ISHIHARA chart), those with mini-mental score of <25, those with ongoing alcohol or substance abuse and those with nodules in the liver on abdominal ultrasound scan were excluded from the study.

The bio-data and other relevant history were obtained using a structured questionnaire.

Physical examination was performed. Mini-mental state examination to rule out cognitive disorders (a score of >25 was considered as normal)[9] was done by administering the mini-mental state examination form. A color vision assessment was done using the ISHIHARA chart. All recruited subjects had an abdominal ultrasound and / or Fibroscan done. Serum albumin, total bilirubin and INR were assayed (in order to determined participants Child-Pugh score) using Cobas C 111 analyzer (Roche, Germany). Transient elastography (Fibroscan) was done using Fibroscan Echosens, Paris, E100m002, 13-version. These procedures were done according to the manufacturer’s manual. The abdominal ultrasound scan was done using the Logiq V5 GE ultrasound machine and 3.5 MHZ curvilinear probe with the patients lying supine.

Psychometric hepatic encephalopathy score

Forms for psychometric HE (English version) were obtained Hannover Medical School in Germany (see acknowledgement). The diagnosis for MHE was done using the 5 parameters of the PHES (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)). This was administered to the patients and the controls. The total score was calculated.

For the number connection test A, the subjects were asked to join numbers serially from 1 to 25. Subjects were guided to join numbers and alphabets, serially, in a timed fashion, for NCT B. The number of seconds required in each was the outcome.

In the digit symbol test (DST), subjects were required to pair numbers and special symbols. An individual score is the number of correct pairs achieved within a 120 s time frame.

In the LTT, subjects were required to trace a line between 2 parallel lines and the time required and line tracing (LTT) errors noted (LTT errors is the number of time the subject strayed outside the parallel lines).

In the SDT, the subjects were asked to dot the center of 100 blank circles and the time required was the outcome.

EncephalApp

The application was downloaded from android app store and used on an android phone. The android phone screens were used to administer the test to all the subjects. The test was done in two formats, the “ON” state and the “OFF” state.

Both components (“OFF” and “ON” states) were administered after two training runs in both states had been given.

The specific outcomes at the end of the EncephalApp test were: (1) total time for five correct runs in the “off” state (Off Time), (2) number of runs needed to complete the five correct runs in the “OFF” state, (3) total time for five correct runs in the “ON” state (Onetime), and (4) number of runs needed to complete the five correct runs in the “ON” state

Control arm (healthy subjects)

These were recruited from staff (of all cadre) and students who consented to participate in the study. An abdominal ultrasound scan was done to exclude liver disease. Other relevant information was obtained using a structured questionnaire. The EncephalApp and PHES test were administered as described above.

Statistical analysis

Data was analyzed using SPSS version 23. Uniformly distributed quantitative variables were summarized using means, whereas non-uniformly distributed quantitative variables were summarized using median and inter-quartile range. Categorical variables were expressed using proportions with percentages. The chi-square test was used to test the significance of association between categorical variables. Student t test was used to compare two groups’ means. Analysis of variance (ANOVA) was used to compare more than two group means. Receiver operating characteristic analysis of the cutoffs was performed to compare the EncephalApp values and the standard (PHES). In all cases, a value of P < 0.05 was considered statistically significant and confidence interval at 95%.


  Results Top


Fifty healthy subjects and 42 patients with liver cirrhosis were recruited in this study. Seventy percent (70%) of the healthy subjects were females, whereas 83% of the patients with liver cirrhosis were males [Figure 1]. The mean age and number of years in school of the patients was matched with that of the control group (see [Table 1]). Majority of the patients (59.5%) had advanced liver disease (Child-Pugh class B and C).
Figure 1: Distribution of study subjects according to gender and age group

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Table 1: Comparing various parameters in patient and control groups

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All parameters of PHES (NCTA, NCTB, DST, SDT and LTT) were significantly different, as it would be expected, in the control group and patient group. The total PHES was also significantly different, between the patients and the control group [Table 1].

Fifty nine percent (59.5%) of the patients have PHES score at or better than -4, considered to be the cutoff between normal subjects and patients. This places the prevalence of MHE among the patient group as detected by PHES at 40.5%. Sixty percent and 53.3% of the cirrhotic subjects in Child-Pugh class C and B respectively had MHE as detected by PHES, whereas only 11.8% of those in class A had MHE, P = 0.014 [Table 1].

Both the Ontime and the Offtime were significantly higher, in the patient group compared with the control group. The total time (Offtime + Ontime) was also significantly higher in the patient group [Table 1]. Based on a cutoff of Ontime + Offtime above 241.8 s (Ontime + Offtime above 2 SD of the mean of the control group), only 47.6% of the patients have a normal score. The prevalence of MHE in patients with liver cirrhosis based on this cutoff was 52.4% (based on the cutoff of 241.8 s), sensitivity = 54.1% and specificity = 90.0%, Area Under the Receiver Operating Characteristics (AUROC) = 0.77 [Figure 2].
Figure 2: AUROC for EncephalApp comparing with PHES

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  Discussion Top


Age and education have been shown to affect both the EncephalApp testing and the PHES,[10],[11] hence, we ensured that the control group and the patient group were age and education (number of years in school) matched.

The prevalence of MHE using PHES and EncephalApp, among the patients, were 40.5% and 52.4% respectively. This is not different from what has been documented in other studies. For example, a prevalence of 48% was found in a study in the US using the EncephalApp.[6] However, a study done in Lagos found a prevalence of 35.4% using the NCT-A and NCT-B, and a prevalence of 43.1% when electroencephalography was added to NCT-A and NCT-B to diagnose MHE.[12] This slight variation in prevalence suggests that different testing tools for MHE may give different results.

In this study, we found that all parameters of PHES were able to distinguish, with statistical significance, the patients with liver cirrhosis from the normal subjects. The mean of the Total PHES was also clearly statistically significantly different between the control group and the patients’ group. This is consistent with findings from other studies.[10],[11]

The sensitivity of EncephalApp, based on the cutoff of >241.8 s was 54.1% and specificity was 90.0%, AUROC = 0.77 [Figure 2]. A higher sensitivity of 73% and specificity of 70% was achieved when the cutoff was adjusted to >200.5 s. In comparison, a study in the US[6] (from three sites: Arkansas, Virginia and Ohio) in which 437 patients with liver cirrhosis were recruited and assessed for MHE using PHES and EncephalApp showed a prevalence of 51% using EncephalApp and 37% using PHES, with EncephalApp having a sensitivity of 80% and a specificity of 61% (AUROC = 0.89) when compared to PHES. The cutoff for EncephalApp total time (Ontime+Offtime) used in the study, (derived from a matched-control, worse than 2SD) was 195.9 s. The specificity of EncephalApp in our study was much higher than this study, although, the sensitivity was lower. Both studies have significantly high AUROC, showing that the EncephalApp can efficaciously detect MHE, hence, can be reliably utilized instead of PHES in the detection of MHE in different populations. A major difference in these two studies that may explain some variations is the sample size. Although the study in the US utilized a large sample size, our study had a smaller sample size in comparison. Because of the increase in the usage of smartphones across all populations, the finding in our study, which suggest that the EncephalApp is an effective diagnostic tool for MHE in our environment is a relevant and an important finding, however, further studies may be required to corroborate this finding.

There was a significantly higher prevalence of MHE in patients who have advanced liver cirrhosis (Child-Pugh classes C and B) compared to those with early disease (Child-Pugh class A). The prevalence of MHE was 60.0% in Child-Pugh class C, 53.3% in Child-Pugh class B but only 11.8% in class A, P = 0.014). This is not different from what has been reported in other studies. A study in China, for example, showed a high prevalence of MHE (56.1%) among cirrhotic patients in Child-Pugh class C compared to 24.8% in class A.[13] Another study done in Romania using the PHES to diagnosed MHE, showed a significant correlation between PHES and Child-Pugh class (r= 0.525, P = 0.001).[14] These studies clearly indicate that the prevalence of MHE increases with increasing severity of liver disease. This is expected as patients who have liver cirrhosis and are in Child-Pugh class B or C are known to have several other complications including portal hypertension, ascites and spontaneous bacterial peritonitis which are known to predispose to HE[2]

The study is limited by its relatively small sample size and the use of a non-probability sampling technique.

The prevalence of MHE in patients with liver cirrhosis in Jos, North central Nigeria, is about the same with values documented in other parts of the world. In this study, the EncephalApp was shown to be an accurate, reliable yet a short screening tool for diagnosing MHE based on its high specificity and a good AUROC at a cutoff of >241.8 s (Offtime + Ontime) among our patients. We also showed that its sensitivity may be increased by reducing the cutoff to 200.5 s total time (Offtime + Ontime).

The prevalence of MHE among cirrhotics in our locality being high, hence, a protocol for routine screening of these patients will aid in the detection of this condition. We recommend a larger multicenter study on using EncephalApp to diagnose MHE in Nigeria in order to determine its nation-wide prevalence patterns, predisposing factors and important associations and also verify the reliability of this tool across various regions of our country.

Acknowledgement

We would like to express our profound gratitude to Jasmohan S. Bajaj, MD, a professor in the Department of Internal Medicine at the Richmond VA Medical Center, who is the pioneer of EncephalApp and who provided advice on how to get PHES forms. We also deeply appreciate Prof Karin Weissenborn of Hannover Medical School, Germany, through whom we were able to acquire the PHES forms.

Financial support and sponsorship

Not applicable.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT Hepatic encephalopathy–definition, nomenclature, diagnosis, and quantification: Final report of the working party at the 11th world congresses of gastroenterology, Vienna, 1998. Hepatology 2002;35:716-21.  Back to cited text no. 1
    
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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;61:642-59.  Back to cited text no. 2
    
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Mullen KD, Prakash RK Management of covert hepatic encephalopathy. Clin Liver Dis 2012;16:91-3.  Back to cited text no. 5
    
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Allampati S, Duarte-Rojo A, Thacker LR, Patidar KR, White MB, Klair JS, et al. Diagnosis of minimal hepatic encephalopathy using Stroop EncephalApp: A multicenter US-based, norm-based study. Am J Gastroenterol 2016;111:78-86.  Back to cited text no. 6
    
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Gaillard F, Niknejad M Cirrhosis. Reference article, Radiopaedia.org. Available from: https://doi.org/10.53347/rID-1131. [Last accessed on 2021 Jul 12].  Back to cited text no. 7
    
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Foucher J, Chanteloup E, Vergniol J, Castéra L, Le Bail B, Adhoute X, et al. Diagnosis of cirrhosis by transient elastography (fibroscan): A prospective study. Gut 2006;55:403-8.  Back to cited text no. 8
    
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Folstein M, Folsten S, McHugh P Mini-mental state: A practical method for grading the cognitive state of patients for the clinician. J Psychiatry Res. 1975;12:189-98.  Back to cited text no. 9
    
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Bajaj JS, Heuman DM, Sterling RK, Sanyal AJ, Siddiqui M, Matherly S, et al. Validation of EncephalApp, smartphone-based Stroop test, for the diagnosis of covert hepatic encephalopathy. Clin Gastroenterol Hepatol 2015;13:1828-35.e1.  Back to cited text no. 10
    
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Weissenborn K, Heidenreich S, Giewekemeyer K, Rückert N, Hecker H Memory function in early hepatic encephalopathy. J Hepatol 2003;39:320-5.  Back to cited text no. 11
    
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Nwabuaku OJ, Onyekwere CA, Ogun SA Minimal hepatic encephalopathy among chronic liver disease patients in a hospital. Niger J Gastroenterol Hepatol 2016;8:25-33.  Back to cited text no. 12
    
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Wang JY, Zhang NP, Chi BR, Mi YQ, Meng LN, Liu YD, et al. Prevalence of minimal hepatic encephalopathy and quality of life evaluations in hospitalized cirrhotic patients in China. World J Gastroenterol 2013;19:4984-91.  Back to cited text no. 13
    
14.
Badea MA, Drug VL, Dranga M, Gavrilescu O, Stefanescu G, Popa I, et al. Diagnosis of minimal hepatic encephalopathy in a tertiary care center from eastern Romania: Validation of the psychometric hepatic encephalopathy score (PHES). Metab Brain Dis 2016;31:1463-71.  Back to cited text no. 14
    


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