Cognitive function in patients with liver cirrhosis without overt hepatic encephalopathy: Assessment using an automated neuropsychological test battery

Arab Journal of Gastroenterology 13 (2012) 4–8

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Original Article

Cognitive function in patients with liver cirrhosis without overt hepatic encephalopathy: Assessment using an automated neuropsychological test battery Taofiki A. Sunmonu a,⇑, Olusegun Adekanle b, Morenikeji A. Komolafe c, Dennis A. Ndububa b a

Neurology Unit, Department of Medicine, Federal Medical Centre, Owo, Ondo State, Nigeria Gastroenterology Unit, Department of Medicine, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State, Nigeria c Neurology Unit, Department of Medicine, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State, Nigeria b

a r t i c l e

i n f o

Article history: Received 5 August 2011 Accepted 15 February 2012

Keywords: Cognition Cognitive functions Liver cirrhosis Hepatic encephalopathy Nigerians

a b s t r a c t Background and study aims: A wide range of neuropsychiatric disorders occur in patients with liver cirrhosis without overt hepatic encephalopathy. Cognitive dysfunctions do occur and these tend to impair patients’ vocational and social life as well as activities of daily living. The aim of this study is to evaluate cognitive functions in patients with liver cirrhosis without overt HE in Nigeria. Patients and methods: Thirty-four patients with liver cirrhosis and 41 normal subjects as control were studied. Medical history and general physical/neurological examinations were carried out on all the subjects. Blood samples were obtained for viral serological markers and liver functions tests. The ‘Fepsy’ automated neuropsychological test battery was performed for the assessment of auditory reaction time (psychomotor speed). Recognition memory test (memory), binary choice reaction task (psychomotor speed/attention) and vigilance task were also administered. The data were analysed with the aid of Statistical Package for Social Sciences (SPSS) version 15.0 software. Results: The mean age of patients with liver cirrhosis was 45.00 ± 13.83 years, while that of control subjects was 41.88 ± 139.49 years. The visual/auditory reaction time, binary choice reaction time and computerised visual reaction time were prolonged in patients with liver cirrhosis when compared with control subjects. However, there were differences in the recognition memory test and vigilance performances between the two groups. The patients with liver cirrhosis who had hepatitis C virus infection had poor psychomotor speed when compared with patients who were hepatitis C virus negative, but there was no statistical significant correlation between other aspects of liver function tests and cognitive functions in patients with cirrhosis. Conclusion: Patients with liver cirrhosis had similar cognitive functions on measures of memory and vigilance when compared with normal control subjects. However, there were significant differences in other aspects of cognitive functions between the two groups. Ó 2012 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.

Introduction A wide range of neuropsychiatric abnormalities, such as personality disorders, inappropriate affective behavioural and sleep functions as well as cognitive and psychomotor impairment, can occur in patients with liver cirrhosis [1]; this is classified as hepatic encephalopathy (HE). HE is graded into four stages of severity on the basis of clinical examination but the absence of clinical signs does not exclude the diagnosis of HE. Sub-clinical hepatic encephalopathy (SHE) is a term used to described the constellation of cognitive dysfunction in the absence of overt psychiatric signs, which can be detected only by neuropsychological tests. SHE often precedes overt HE, the onset of which can lead to death [2]. ⇑ Corresponding author. Tel.: +234 8033919452. E-mail address: [email protected] (T.A. Sunmonu).

SHE has been reported to occur in about 30–84% of patients with liver diseases [3–5]. A prevalence rate as low as 0% and up to 28% has been quoted for chronic hepatitis C virus (HCV) infection [6]. In North America alone, it has been estimated that between 1.5 and 2 million people may have cognitive impairment associated with liver disease [7]. The prevalence rate of SHE in patients with liver cirrhosis is not fully known. Cognitive changes in liver diseases could be associated with serious functional consequences for patients, including a decrease in the ability to perform normal daily tasks such as driving [8], operating machinery [9], disturbance of sleep–wake cycle [10] and poor overall quality of life [11]. Early detection of the cognitive manifestation of chronic liver disease is important for both patient monitoring and timing of treatment. Although several studies have been done on the cognitive function of patients with liver cirrhosis among Caucasians, there is paucity of literature on this important

1687-1979/$ - see front matter Ó 2012 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ajg.2012.02.002

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T.A. Sunmonu et al. / Arab Journal of Gastroenterology 13 (2012) 4–8

topic in tropical Africa and hence the need for this study. The aim of this study is to evaluate cognitive functions in patients with liver cirrhosis without overt HE in Nigeria. It is hoped that the outcome of this study would give an insight into the management needs of these patients, especially in the area of activities of daily living and health-making decisions.

Patients and methods This is a cross-sectional study conducted between June 2008 and August 2010 in which 34 patients with liver cirrhosis attending the gastroenterology clinic of the Federal Medical Centre, Owo, and the Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria, were studied along with 41 healthy control subjects. The control subjects were age, sex and educationally matched healthy members of staff of the hospitals and patients without risk of cognitive impairment attending the gastroenterology clinic of the hospitals. The controls were also serologically negative for hepatitis B (HBV) and HCV infections. The inclusion criteria were patients with liver cirrhosis diagnosed by clinical, ultrasonographic, biochemical or histological criteria or a combination of all or some of these criteria who were 16 years of age or above. The exclusion criteria in the patients were age less than 16 years or greater than 70 years, the presence of overt HE, the presence of other neurologic disorders, the use of psychotropic drugs or drug abuse and years of education of patients less than primary school (6 years of school) as the test requires the subject to be literate. Patients with cerebrovascular disease, epilepsy and other medical conditions that may affect cognition were also excluded. The same exclusion criteria were also applicable to the normal control subjects. A questionnaire was developed and applied to all subjects and patients; emphasis in the questionnaire was on socio-demographic data, history and symptoms including risk factors for liver cirrhosis. General physical and neurological examinations were performed on all subject and patients. Blood samples were collected from the patients for liver function tests, prothrombin time and screening for HBV and HCV virus using an enzyme linked immunosorbent assay (ELISA) method. Liver ultrasound scan was done for all patients. The patients’ liver disease severity was graded using the Child–Pugh scoring system for liver cirrhosis. ‘Fepsy’ neuropsychological test battery was done in all subject and patients. The administration test was done using the iron psychology ‘Fepsy’ test, an automated neuropsychological test battery which has been used extensively in Nigeria and other institutions worldwide. It takes an average of 1 h to do ‘Fepsy’ to a subject. This is the first time that the ‘Fepsy’ neuropsychological test battery would be used in the evaluation of cognitive function in patients with liver cirrhosis in Nigeria. The memory function was assessed using the recognition memory test (RMT). The test involves the use of a study item consisting of three or four figures for the visual (non-verbal) memory and four or six words for the verbal memory test, which are presented simultaneously. The stimulus (study items) duration of presentation equals the number of items presented times 1 s. Details are described elsewhere.[12,13] Mental or psychomotor speed was assessed using the simple reaction time test. The reaction times for simple auditory and visual stimuli were measured. The auditory version involves the presentation of a sound stimulus of 800 Hz generated by the computer, and the subject is asked to react as quickly as possible by pressing the space bar as quickly as possible. For the visual version, the subject reacts as quickly as possible on seeing a white square in the middle of the computer by pressing the space bar. Thirty stimuli each were presented for the auditory and visual version. The result shows accuracy and speed of respond in milliseconds. Attention and concentration were assessed using

the continuous performance test (CPT), which involves the display of a string of eight characters, either ‘XXXXXXXX’ or ‘XAXXXXXX’. The subject has to decide on the appearance of a character ‘A’ at a random position in the stimulus string that in half of the trails consists exclusively of the letter ‘X’. Responses were giving, by pushing, ‘Yes’ for appearance of ‘A’ and ‘No’ for the absence of ‘A’. The task is a continuous performance test that lasts for 10–20 min. The result yielded two parameters: (a) d values (perceptual; sensitivity – values of 2 and above point to a good discriminating ability) and (b) b values (response bias) – point to whether the testee is impulsively inclined to say ‘Yes’ or ‘No’ and a value <1 will reflect impulsive response while values >1 indicate a conservative way of responding. Binary choice task, which is a complex form of continuous performance test, was also used in the study. It assesses both attention/concentration and psychomotor speed. The task presents a more complex stimulus configuration, and latency times are longer than simple reaction tasks. The details of binary choice tasks assessment have been earlier described [12,13]. The ‘Fepsy’ instrument has been used previously for assessment of cognitive function in Nigerian patients with epilepsy [12,13] and renal impairment [14]. The mean scores on the various aspects of the ‘Fepsy’ were compared with control subjects using the Student’s t-test and the hepatitis serological status of the patients; the Child–Pugh class of the patients was analysed along with the scores on the subtest of the Fepsy using the Student’s t-test. The serum liver enzymes, serum albumin and prothrombin time were correlated with the various subtests of ‘Fepsy’ using Pearson’s moment of correlation. The p < 0.05 was taken as significant. Results Thirty-four patients with liver cirrhosis and 41 normal healthy controls were included in this study. The mean age of the patients with liver cirrhosis was 45.00 ± 13.82 years, while that of the control subjects was 41.88 ± 9.49 years. Other demographic details are as highlighted in Table 1. Laboratory parameters in patients with liver cirrhosis are shown in Table 2. The mean score of cognitive performances in the various subtests of the ‘Fepsy’ neuropsychological test batteries of patients with liver cirrhosis revealed prolonged auditory and visual reactions times when compared with control subjects (p < 0.05). The Computerized Visual Searching Task (CVST) was prolonged in the

Table 1 Demographic details of subjects. Variables

Liver cirrhosis

Controls

n

%

n

%

28 6 34

82.1 17.6 100.0

26 15 41

63.4 36.6 100.0

2. Level of education Primary 6 Secondary 16 Tertiary 12 Total 34

17.6 47.1 35.3 100.0

3 23 15 41

7.3 56.1 36.6 100.0

3. Age groups (years) 16–29 years 4 30–44 years 12 P45 years 18 Total 34

11.8 35.3 52.9 100.0

6 14 21 41

14.6 34.2 51.2 100.0

1. Sex Male Female Total

v2 – Chi-square value. P – level of significance. P < 0.05 – significant.

v2

P

3.307

0.069

1.953

0.377

0.132

0.936

Controls (n = 41) Mean ± SD

ART (ms) ART Dom ART Non-Dom

519.35 ± 221.81 482.41 ± 281.99

380.80 ± 142.68 324.51 ± 128.27

3.269 3.220

0.002 0.002

VRT (ms) VRT Dom VRT Non-Dom BCR mean (ms) BCR % correct CVST mean (s) RMTW % correct RMTF % correct

563.18 ± 305.95 563.94 ± 358.98 671.34 ± 180.03 83.08 23.62 ± 11.88 44.09 38.51

412.02 ± 130.17 382.29 ± 122.69 499.15 ± 90.35 93.36 18.00 ± 6.09 53.58 44.39

2.889 3.037 5.331 –3.276 2.635 –1.642 –1.541

0.005 0.003 0.000 0.002 0.010 0.105 0.128

Vigilance Vig d Vig b

1.25 0.88

0.71 1.08

–1.648 –2.142

0.104 0.036

ART – auditory reaction time. VRT – visual reaction time. BCR – binary choice reaction time. CVST – computerised visual searching task. RMTW – recognition memory test (words). RMTF – recognition memory test (figures). Vig d – perceptual sensitivity. Vig B – response bias. ms – milliseconds. s – seconds.

t

P

Vig b

0.92 0.84 0.163 0.850 1.42 1.15 0.077 0.926 40.03 37.85 0.079 0.780 40.09 48.36 1.152 0.292 23.32 ± 14.85 24.77 ± 8.48 0.109 0.744 80.74 86.01 0.690 0.413 724.69 ± 140.07 653.43 ± 191.86 1.374 0.251 622.38 ± 469.99 533.94 ± 225.32 0.461 0.503 617.44 ± 390.79 534.31 ± 206.03 0.566 0.458 F – F test value ANOVA. t – t-test value. P < 0.05 = significant.

Liver cirrhosis (n = 34) Mean ± SD

557.38 ± 352.81 424.31 ± 193.69 1.749 0.196

Test mean score

568.13 ± 271.77 486.69 ± 163.34 1.055 0.312

Table 3 Comparison of cognitive functions between patients with liver cirrhosis and normal controls using Fepsy.

16 16

AST – aspartate transaminase. ALT – alanine transaminase. PTR – prothrombin time. HBsAg – hepatitis B surface antigen. Anti-HCV – antibody to hepatitis C virus.

Child–Pugh class B C t P

73.5 20.6 5.9

0.89 1.37 4.55 0.10 1.33 0.28

25 7 2

Vig d

PTR (s) <1.7 1.7–2.2 P2.3

RMTF %Corr.

44.1 55.9

42.0 38.43 0.00 40.0 1.31 0.29

15 19

42.79 44.81 12.50 75.00 1.61 0.21

Child–Pugh class B C

RMTW % Corr.

20.6 20.6 26.5 32.3

CVST mean (s)

7 7 9 11

23.76 ± 11.16 24.78 ± 12.28 5.23 17.43 0.95 0.43

Total bilirubin (lmol L–1) <20 20–34 35–49 P50

89.1 80.7 48.3 100.0 2.63 0.07

52.9 35.3 11.8

BKG% Corr.

18 12 4

BKG mean (ms)

Serum albumin (g L–1) <30 30–39 P40

665.56 ± 193.74 660.32 ± 178.40 717.00 899.00 0.56 0.65

9.4 43.8 46.8

550.25 ± 240.81 497.95 ± 167.71 2778.00 334.00 26.28 0.000

3 14 15

VRT Non-Dom (ms)

64.7 35.3

547.92 ± 236.32 505.35 ± 144.10 1979.00 487.00 20.618 0.000

22 12

VRT Dom (ms)

47.1 50.0 2.9

ART Non-Dom (ms)

16 17 1

Liver enzymes AST (1 U L–1) <20 20.99 P100 AST (1 U L–1) <20 20–99 ALP – alkaline phosphatase (1 U L–1) <30 30–129 P130

ART Dom (ms)

35.2 58.8 3.0 3.0

12 20 1 1 1

12 20 1 1

N

%

HBAg ve + Anti-HCV ve HBsag +ve Anti-HCV +ve HbsAg +ve + Anti-HCV +ve F P

n Serological HBsAg ve + Anti-HCV ve HBsAg +ve 20 (58.8) Anti-HCV +ve HBsAg +ve and Anti-HCV +ve

465.00 ± 221.83 436.10 ± 175.16 1686.00 414.00 13.34 0.000

Frequency

Table 4 Impact of laboratory/clinical characteristics on cognitive functions in liver cirrhosis patients using Fepsy.

Variables

518.58 ± 198.84 482.80 ± 169.77 1302.00 477.00 6.53 0.002

Table 2 The distribution of laboratory and clinical variables in the patients with liver cirrhosis.

0.93 0.87 0.00 1.25 1.80 1.17

T.A. Sunmonu et al. / Arab Journal of Gastroenterology 13 (2012) 4–8

Variables

6

7

T.A. Sunmonu et al. / Arab Journal of Gastroenterology 13 (2012) 4–8 Table 5 Impact of laboratory/clinical variables on cognitive functions in liver cirrhosis patients using Fepsy. Variables

N

AST (I U L–1)

ART NonDom (ms)

VRT Dom (ms)

VRT NonDom (ms)

BCR mean (ms)

BCR % Corr.

CVST mean (s)

RMTW % Corr.

RMTF % Corr.

Vig d

0.021 0.908 –0.115 0.410 –0.135 0.494 0.025

0.079 0.657 –0.092 0.604 0.140 0.478 –0.041

–0.029 0.871 –0.147 0.406 0.006 0.978 –0.144

0.039 0.020a –0.064 0.718 0.062 0.753 –0.195

0.085 0.642 –0.214 0.239 0.202 0.321 0.053

–0.215 0.230 0.134 0.456 –0.107 0.596 0.338

0.043 0.810 –0.240 0.179 0.266 0.180 0.248

–0.319 0.071 –0.80 0.658 –0.133 0.507 0.217

–0.258 0.147 –0.006 0.974 –0.111 0.582 0.136

0.134 0.457 0.007 0.970 0.151 0.451 0.127

Vig b

ALT (I U L )

34

ALP (I U L–1)

28

Serum albumin (g L–1)

33

r P r P r P r

Total bilirubin (lmol L–1)

33

P r

0.888 0.017

0.822 –0.109

0.423 –0.112

0.277 –0.155

0.777 –0.166

0.059 0.131

0.171 0.311

0.234 0.047

0.460 0.126

0.490 –0.103

0.68 0.371

PTR

33

P r P

0.926 –0.156 0.387

0.544 –0.152 0.399

0.536 –0.066 0.714

0.389 –0.068 0.706

0.373 0.150 0.422

0.475 –0.150 0.422

0.083 –0.156 0.395

0.798 0.118 0.519

0.490 –0.118 0.521

0.576 –0.118 0.521

0.037a –0.339 0.058

–1

34

ART Dom (ms)

0.113 0.533 0.196 0.277 0.440 0.022a 0.076

Analysis done with Pearson’s moments of correlation. r = Pearson’s coefficient. P = level of significance. a P < 0.05 – significance.

liver cirrhosis group; all these were statistically significant (p < 0.05). However, there was no difference in verbal and non-verbal memory and vigilance scores between the patients with liver cirrhosis and controls (p > 0.05, Table 3). Tables 4 and 5 highlight the impact of laboratory/clinical variables on cognitive function in patients with liver cirrhosis using ‘Fepsy’. In these, each laboratory/clinical variable was categorised and analysed simultaneously along with the mean scores of the various subtest of ‘Fepsy’ neuropsychological test batteries using the Student’s t-test, one-way analysis of variance (ANOVA) and Pearson’s moment of correlation, as appropriate. The patient with HCV infection had marked prolongation of auditory and visual reaction times when compared with other liver cirrhosis patients. There was no statistical difference in the performances on ‘Fepsy’ subtests between the Child–Pugh classes B and C liver cirrhosis patients (p > 0.05). There was negative correlation between the serum aspartate aminotransferase (AST) level and the visual reaction times in the non-dominant hand (p < 0.05) while there was no correlation between the serum AST level and the other ‘Fepsy’ subtests. There was negative correlation between the serum alanine aminotransferase (ALT) levels and the response bias scores of the vigilance task (p < 0.05) while there was no correlation between the serum ALT level and other ‘Fepsy’ subtest scores (p > 0.05). There was negative correlation between the response bias score of the vigilance task and the serum alkaline phosphatase (ALP) level in patients with liver cirrhosis (p < 0.05); however, there was no correlation between the serum ALP level and the scores on the other ‘Fepsy’ subtests (p > 0.05). Serum albumin, serum total bilirubin and prothrombin time (PTR) showed no correlation with scores on the ‘Fepsy’ subtests.

Discussion Cognitive dysfunction is known to occur in patients with liver cirrhosis but few studies have been done in Africa on this issue in patients with liver cirrhosis. Chronis liver disease patients exhibited poor cognitive functions when compared with control subjects [15–17]. The cognitive functions include poor psychomotor function, attention/concentration deficit and memory impairment. More recent studies also corroborated these findings [15–19]. Several publications [14,16–19] showed that memory impairment is common in patients with liver cirrhosis without

HE; however, a study [15] showed that memory function and general intellectual abilities may be preserved in patients with SHE. This finding is keeping with the outcome of this present study, which showed that there was no difference in memory and vigilance function in patients with liver cirrhosis when compared with normal control subjects. Collie [17] showed that some biochemical makers of disease severity in chronic liver disease such as serum albumin level and PTR negatively correlated with cognitive performance in patients with liver cirrhosis, and PTR did not influence the cognitive performance. This may probably be attributed to the small size of our study sample. Similarly, markers of liver injury such as serum AST, ALT and ALP were shown not to influence cognitive performance in patients with liver cirrhosis [17], and this in agreement with our study. Previous reports from studies of cirrhotic of mixed aetiologies [15–17] suggested that individuals with HCV infection have significantly impaired cognitive functions when compared with other aetiologies. In our work the patient with HCV infection showed marked impairment of psychomotor function among patients with HCV infection, although the effect of HCV infection did not significantly affect the domain of memory functions, vigilance and attention and concentration. However, it should be taken into consideration that the small sample size of the study as well as the small number with HCV infection in the cohort might have accounted for these findings. Previous reports also showed that an increased severity of liver disease (Child–Pugh class) was associated with poor cognitive performance. Li et al. [20] assessed 409 Chinese cirrhotic patients without overt clinical encephalopathy using the Number Connection Test – A and the Symbol Digit Test along with 358 healthy controls. SHE was diagnosed in 108 of the patients, and analysis of the findings based on liver cirrhosis severity using the Child–Pugh grading system showed that patients with more severe liver disease (Child–Pugh class C) performed poorly in the assessment of memory attention/concentration and psychomotor speed than those with mild to moderate liver disease (Child–Pugh classes A and B). Collie also demonstrated this in their study among Australian patients with liver cirrhosis [17]. Citro et al. documented an abnormal trail-making test in 77 Italian cirrhotic patients without overt encephalopathy (West Haven stage o); this abnormality was observed to increase from 22.2% in Child–Pugh A to 63.4% and 74% in Child–Pugh B and C, respectively [21]. Another study with a small sample size from Turkey [22] of memory impairment in patients with liver cirrhosis showed no influence of disease severity (using Child–Pugh grading) on

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memory function. This present study did not show any influence on the Child–Pugh grading system on psychomotor speed, attention/concentration and vigilance; this may probably be due to the small sample size of our study. In conclusion we were able to demonstrate that patients with liver cirrhosis without overt encephalopathy performed poorly when compared with control subjects on psychomotor functions and attention/concentration. However, there was no significant difference on memory and vigilance function in liver cirrhosis patients and normal healthy controls. In patients with liver cirrhosis, clinical and biochemical variables such as the serum liver enzymes level, serum albumin, PTR and Child–Pugh class did not influence their cognitive functions significantly. However, HCV infection was associated with poor psychomotor function in the patients. We are aware that the sample size is small, and this is due to the poor hospital attendance of patients with liver cirrhosis as many of them often seek spiritual/traditional care for their ailment. In addition, because of late presentation in the hospital many of the patients succumbed to early mortality before complete clinical and laboratory evaluation. Conflicts of interest The authors declared that there was no conflict of interest. References [1] Gerber T, Schomerus H. Hepatic encephalopathy in liver cirrhosis: pathogenesis, diagnosis and management. Drugs 2000;60(6):1353–70. [2] Bustamante J, Rimola A, Ventura PJ, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999;30(5):890–5. [3] Gitlin N, Lewis DC, Hinkley L. The diagnosis and prevalence of subclinical hepatic encephalopathy in apparently healthy, ambulant, non-shunted patients with cirrhosis. J Hepatol 1986;3(1):75–82. [4] Quero JC, Schalm SW. Subclinical hepatic encephalopathy. Semin Liver Dis 1996;16(3):321–8.

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