Original Article

Prevalence of minimal hepatic encephalopathy and qualityof life in patients with decompensated cirrhosis

Aline Mina,1 Segundo Moran,1 Nayeli Ortiz-Olvera,1 Robertino Mera3 and Misael Uribe2

1Laboratory of Gastro-hepatology Research, Hospital de Pediatría and Gastroenterology Department, CMN SigloXXI, Mexican Institute of Social Security, 2Médica Sur Clinic and Foundation, Mexico City, Mexico; and3Vanderbilt University Medical Center, Nashville, Tennessee, USA

Aim: Minimal hepatic encephalopathy (MHE) affects morethan 30% of patients with cirrhosis, and it has been suggestedthat despite no recognizable clinical symptoms of neurologi-cal abnormalities, it may affect health-related quality of life(HRQL); however, this fact remains controversial. The aim ofour study was to evaluate the prevalence of MHE and HRQL inpatients diagnosed with decompensated cirrhosis.

Methods: Patients with liver cirrhosis were selected inde-pendent of the etiology of the disease. All patients underwenta complete clinical history, and only patients with decompen-sated hepatic cirrhosis were included. Psychometric testswere applied to evaluate the presence of MHE along with theChronic Liver Disease Questionnaire. Appetite was measuredby verbal and visual analog scales.

Results: One hundred and twenty-five patients were in-cluded with a median age of 56.0 years. They were classified

according to the Child–Pugh index as A, (n = 56), B, (n = 51)and C (n = 18). Prevalence of MHE was 44.0% (n = 55). Inpatients with MHE, a significant reduction was observed indomains of activity (3.3 [2.0] vs 4.8 [2.8]), fatigue (3.2 [2.0] vs3.9 [2.3]), systemic symptoms (3.8 [2.0] vs 4.8 [1.7]), emotionalfunction (3.6 [1.9] vs 4.0 [1.9]) and global scoring (3.7 [1.7] vs4.3 [1.8]) when compared with non-MHE patients (n = 70).Twenty-two percent of the patients with MHE reported littleappetite compared with 11% in the non-MHE group.

Conclusion: The results suggest that MHE and a reduction inappetite are associated with deterioration in HRQL in patientswith decompensated cirrhosis.

Key words: appetite, decompensated cirrhosis,health-related quality of life, minimal hepaticencephalopathy.

INTRODUCTION

MINIMAL HEPATIC ENCEPHALOPATHY (MHE) isa complication of liver cirrhosis that is character-

ized by the presence of cognitive alterations undiag-nosed during routine clinical examination and identifiedsolely through psychometric or neurological tests.1–6

The prevalence of MHE in patients with cirrhosisvaries between 30% and 84%5,6 likely due to differencein criteria used to diagnosis MHE and due to the popu-lation selected.7

It has been suggested that MHE can affect patients’daily activities, work performance and health-relatedquality of life (HRQL), as well as increase the risk of falls

and causing and/or suffering traffic accidents. MHE mayalso predict the development of overt hepatic encepha-lopathy (OHE).5,8

Factors associated with impaired HRQL in patientswith cirrhosis include decompensation due to compli-cations caused by the disease such as OHE, ascites andloss of appetite.9–12 Nevertheless, there is no consistencyin the effect of MHE on the HRQL of patients withcirrhosis, and appetite has not yet been explored inpatients with MHE.5,7,8,13,14

For the aforementioned reasons, the objectives of thepresent study were to estimate the prevalence of MHEand to evaluate HRQL in a group of patients withdecompensated liver disease.

METHODS

Subjects

PATIENTS BETWEEN 18 and 75 years of age diag-nosed with decompensated cirrhosis of any etiology

attending the Gastroenterology Research Laboratory at

Correspondence: Mr Segundo Morán, Laboratory of Gastro-hepatologyResearch, Hospital de Pediatría, CMN, Siglo XXI, IMSS. AvCuauhtémoc 330, Colonia Doctores, Delegación Cuauhtémoc, 06720Mexico, DF, Mexico. Email: segundomoran@hotmail.comReceived 15 May 2013; revision 11 August 2013; accepted 12 August2013.

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National Medical Center Siglo XXI were selected.Patients were excluded for the following reasons: ahistory of OHE, chronic renal disease, heart failureand/or chronic obstructive pulmonary disease, a recenthistory of alcohol abuse and/or drugs (<6 weeks), use ofpsychotropic drugs (benzodiazepines, anti-epileptics),treatment of OHE with lactulose, lactitol, rifaximin,neomycin and metronidazole; presence of gastrointesti-nal bleeding, neurological, psychiatric or ophthalmo-logical disorders that affect the ability to performpsychometric tests; and diagnosis of hepatocellularcarcinoma.

Diagnosis of cirrhosisCirrhosis was diagnosed by clinical and biochemicalfindings,15 methacetin oxidation lower than 14.6‰(sensitivity 92.6%, specificity 94.1% for prediction ofcirrhosis),16,17 or liver biopsy. Decompensated cirrhosiswas established according to the classification proposedby D’Amico et al.18

Neurological assessmentAll subjects completed a standardized battery composedof five psychometric tests: number connection tests Aand B; the digit symbol test; the line tracing test; andthe serial dotting test.19,20 To calculate the PsychometricHepatic Encephalopathy Score (PHES), the validatedequations for a Mexican population were used.21 Patientswere diagnosed with MHE when the PHES was less than−4 points.19–21 Psychometric evaluation was performedin a quiet room without distracting noises.

Laboratory parametersA fasting blood sample was drawn for those patientswith decompensated cirrhosis who agreed to participatein the study. Serum glucose, albumin, alanine amino-transferase (ALT), aspartate aminotransferase (AST),total bilirubin, creatinine, electrolytes, leukocytes, plate-lets, hematocrits and prothrombin time were analyzedby standard clinical laboratory methods (Dimension,RXL-Max analyzer; Dade Behring, Fort Lauderdale, FL,USA).

Nutritional assessmentTriceps skinfold thickness (TSF) and mid-arm circum-ference (MAC) were measured at the middle pointbetween the tip of the acromion and the olecranon ofthe non-dominant arm with the patient standing in arelaxed position. TSF measurements were taken using a

Lange caliper, while MAC measurements were madeusing a measuring tape. The anthropometric measure-ments were made by the same trained observer to reduceerror.22

Mid-upper arm muscle circumference (MAMC)was calculated using the following formula: ([MAC-π × TSF]2 / 4 π) − 10 for men and ([MAC-π × TSF]2 /4 π) − 6.5 for women. The percentiles of MAMC wereestablished from standard tables for healthy popula-tions based on age and sex.23,24 Severe malnutrition wasestablished when MAMC was below the fifth percentilewhile malnutrition was considered moderate whenMAMC was below the 10th percentile.25

Quality of lifeTo assess HRQL the Spanish version of Chronic LiverDisease Questionnaire (CLDQ) adapted for the Mexicanpopulation in our laboratory was used. It contained 29items grouped into six domains: abdominal symptoms;fatigue; systemic symptoms; activity; emotional func-tion; and worry. The score of the six domains and theoverall CLDQ was calculated with answers presented ona 7-point Likert scale, where number 1 referred to themaximum frequency (“always”) and 7 to the lowestfrequency (“never”).26,27 A change of 0.5 on the 1–7 scaleapproximates the important difference in questionnairescore.26

AppetiteAppetite was assessed using a visual and verbal analogscale. The visual analog scale (ViAS) had a line length of100 mm with words anchored at each end, one express-ing the most negative and the opposite expressing themost positive ratings.28 Patients marked with an “X” thepoint where participants rated their appetite.

Verbal analog scale (VeAS) showed a list of words inorder of the most negative rating to the most positive,where the patient marked with an “X” the word thatbest described their feeling of hunger. ViAS and VeASwere previously validated by our laboratory (r = 0.747,P < 0.001; Spearman coefficient).29

Ethical considerationsThe study was approved by the ethics committees andinvestigation review board at National Medical CenterSiglo XXI. The nature, purpose and risks of this studywere explained to the patients and their relatives. Beforethe study, a written consent form was signed by eachpatient.

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Statistical analysisContinuous variables were expressed as median(interquartile range) and data compared with Mann–Whitney U-test. Categorical variables were expressed aspercentages and data compared using χ2-test. A P < 0.05was considered statistically significant.

Variables with a P-value of less than 0.20 in theunivariate analysis and with clinical relevance weresubsequently introduced to a multiple linear regressionmodel to modulate the behavior of the dependent vari-able (quality of life).

A multivariate analysis was performed to confirm thatthe relationship found between HRQL and associatedvariables (MHE and appetite) remains besides the dif-ferences observed among both groups of patients (withand without MHE) at baseline. Two models of multiplelinear regressions were performed. The first modelincluded the laboratory and clinical components of theChild–Pugh score, whereas the second model includedthe Child–Pugh score. The aim was to analyze if bothmodels had the same effect on HRQL.

The independent variables were eliminated andreconsidered from the analysis if the P-value was greaterthan 0.05. This procedure was developed step-by-stepuntil no variable could be included or removed accord-ing to the above criteria.

All data were analyzed using SPSS version 19 (SPSS,Chicago, IL, USA).

RESULTS

Baseline characteristics

ONE HUNDRED AND twenty-five patients with adiagnosis of decompensated hepatic cirrhosis were

selected, of whom 55 (44.0%) presented MHE. Themedian age of the patients with MHE and without MHEwas 59 and 53 years, respectively.

When comparing clinical and demographic character-istics of both groups, significant differences wereobserved in age, Child–Pugh index, leukocytes, plate-lets, creatinine, hematocrits, albumin and prothrombintime (Table 1). Forty-one patients (58.6%) withoutMHE had moderate malnutrition, similar to the groupwith MHE (n = 31, 56.4%).

When appetite was evaluated by VeAS (Table 2),21.8% of the patients with MHE endorsed having littleappetite and 23.6% endorsed having good appetite,compared with 11.4% and 37.1%, respectively, inpatients without MHE (P = 0.108). When comparingthe medians obtained with the ViAS, a reduction in

appetite was observed in patients with MHE, althoughthis difference was not statistically significant. Neverthe-less, upon stratifying the patients according to theChild–Pugh score, among those with MHE a reductionin appetite was observed as the degree of hepaticdamage increased (Child A 5.6 [5.1] vs Child B 4.5 [2.2]vs Child C 4.4 [3.2]; P = 0.074), a situation that was notpresent in patients without MHE (Child A 4.8 [1.5] vsChild B 4.6 [2.1] vs Child C 6.1 [3.3]). In the MHEgroup, a significant reduction was observed in appetite(P = 0.027) in patients with Child B compared withthose classified as Child A.

Health-related quality of lifeTable 3 shows the medians of the six domains and theoverall score of the CLDQ. HRQL was lower in thegroup with MHE compared to those without the com-plication, and this difference was significant in thedomains of fatigue, systemic symptoms, activity, emo-tional function, as well as the overall score.

Multivariate analysisBased on univariate analysis after comparing patientswith MHE versus non-MHE, significant differences ortendencies were observed in 12 variables: age; Child–Pugh score; etiology; platelets; leukocytes; hematocrits;albumin; difference in coagulation time; presence ofascites; serum creatinine; and appetite measured byVeAS.

In the first model, all the aforementioned variableswere included except the Child–Pugh score (Table 4).MHE was the only variable that explained the differ-ences observed in the domain of activity and was afactor associated with the variations observed in thedomain of emotional function, as well as in the overallscore. The results obtained in the second model weresimilar to the first model, except in the domain of sys-temic symptoms, where MHE was a significant factor(Table 5).

DISCUSSION

THE RESULTS OF this study confirm that MHE isfrequent and has a negative impact on the HRQL

and on appetite in patients with decompensated cirrho-sis, even though the cognitive abnormalities character-istic of MHE are not detected during routine medicalexamination.

The prevalence of MHE in patients with cirrhosis hasbeen estimated to be between 30% and 84%5,6 depend-ing on the criteria used to make the diagnosis and the

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population being studied. According to the results of thepresent study, the prevalence of MHE in patients withdecompensated cirrhosis was 44.0%, a value lower thanthat found by Maric et al., who reported a frequency of80% in the same type of patients30

The causes of these difference may be due to the factthat Maric et al. included four patients with a history ofOHE and only patients with Child B and C, while, basedon the results of the present study, the prevalence of

Table 1 Demographic and clinical characteristics of patients

Variable Non-MHE, n = 70 MHE, n = 55 P

Age, years† 53.0 (17.8) 59.0 (15.0) 0.003Sex, F/M, n 42/28 37/18 0.457Child–Pugh n (%) n (%) 0.006

A 40 (57.1) 16 (29.1)B 21 (30.0) 30 (54.5)C 9 (12.9) 9 (16.4)

Etiology n (%) n (%) 0.084Alcohol 6 (8.6) 10 (18.2)Chronic hepatitis C infection 20 (28.6) 22 (40.0)Cryptogenic 20 (28.6) 13 (23.6)Others 24 (34.3) 10 (18.2)

TSF, mm† 23.0 (11.5) 23.0 (14.0) 0.990MAMC, cm2† 24.6 (12.9) 25.5 (12.2) 0.807AST, IU/mL† 49.0 (29.5) 45.0 (40.0) 0.868ALT, IU/mL† 41.0 (29.5) 37.0 (37.0) 0.273Glucose, mg/dL† 98.0 (40.0) 102.5 (54.8) 0.377Creatinine, mg/dL† 0.71 (0.2) 0.76 (0.4) 0.035Total proteins, g/dL† 7.6 (0.8) 7.6 (1.6) 0.529Sodium, mEq/L† 140.0 (4.5) 139.0 (5.5) 0.985Potassium, mEq/L† 4.2 (0.6) 4.4 (0.7) 0.180Leukocytes, 10−3/μL† 5.2 (2.7) 4.5 (2.3) 0.009Hematocrit, %† 39.8 (8.2) 36.2 (6.6) 0.005Platelets, 10−3/μL 101.0 (97.3) 94.6 (68.0) 0.195Albumin, g/dL† 3.8 (0.7) 3.5 (0.6) 0.027Total bilirubin, mM† 1.3 (1.0) 1.5 (1.2) 0.731PT above control, s† 1.9 (2.7) 3.7 (2.6) <0.0001Ascites, n (%) 23 (32.9) 28 (50.9) 0.079ViAS, cm† 4.8 (2.0) 4.6 (2.6) 0.715

†Values expressed as median (interquartile range).ALT, alanine aminotransferase; AST, aspartate aminotransferase; MAMC, mid-upper arm circumference; MHE, minimal hepaticencephalopathy; PT, prothrombin time; TSF, triceps skinfold thickness; ViAS, visual analog scale.

Table 2 Appetite in patients with decompensated cirrhosisassess by verbal analog scale

Category Non-MHE,n = 70, n (%)

MHE, n = 55,n (%)

Not at all 2 (2.9) 0 (0)A little 8 (11.4) 12 (21.8)Quite a bit 32 (45.7) 25 (45.5)Good 26 (37.1) 13 (23.6)Very much 2 (2.9) 5 (9.1)

MHE, minimal hepatic encephalopathy.

Table 3 Quality of life in patients with decompensatedcirrhosis

Domains Non-MHE (n = 70) MHE (n = 55)

Abdominal symptoms 4.5 (2.8) 4.0 (2.3)Fatigue 3.9 (2.3) 3.2 (2.0)*Systemic symptoms 4.8 (1.7) 3.8 (2.0)*Activity 4.8 (2.8) 3.3 (2.0)*Emotional function 4.0 (1.9) 3.6 (1.9)*Worry 4.6 (3.1) 3.8 (3.0)Global 4.3 (1.8) 3.7 (1.7)*

Values expressed as median (interquartile range); *P < 0.05,compared with Mann–Whitney U-test.MHE, minimal hepatic encephalopathy.

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MHE was greater as the degree of hepatic damageincreased (Child A 28.6% vs Child B 58.8% vs Child C50%), results also observed in the study by Groeneweget al.31 and Román et al.32 Likewise, the diagnosis ofMHE was made only using two of the neuropsychologi-cal tests of reference – the numeric connection test Aand the symbols and numbers test – without makingan adjustment according to age or education levelof patients, also including the encephalogram whichshowed low correlation with neuropsychological tests(Cohen’s κ = 0.32).33

The encephalogram may be a diagnostic tool forpatients with liver disease because it is associated withthe severity of liver disease (Child–Pugh score) as well asthe presence of OHE.34 Nevertheless, currently its use asa diagnostic method for MHE is not very feasible due toits high cost and the need for specialized personnel forinterpretation.35–39

Compensated and decompensated cirrhosis are twoentities that present distinct causes of death, survivaland prognosis.18,40,41 To date, the present study and thatperformed by Maric et al. are the only reports that haveevaluated the prevalence of MHE in patients with

decompensated hepatic cirrhosis. Previous studies haveneither classified nor considered as part of the selectioncriteria the degree of decompensation, so it is unknownif the frequency of MHE is lower in patients with com-pensated cirrhosis.

Health-related quality of life in patients with MHE hasbeen evaluated with various questionnaires and invarious populations.5,7,8,13,14,32,42,43 To date, results are notconsistent in regards to the effect of this complicationon the daily life of patients with cirrhosis. Based on theresults of this study, MHE is a factor that deterioratesHRQL in patients with decompensated cirrhosis,showing significant difference in the domains of fatigue,systemic symptoms, emotional function, activity andoverall score, independent of the scoring obtained in theChild–Pugh index. The multivariate analysis confirmsthat MHE is a complication that impaired the domainsof activity, emotional function and global scoring on theCLDQ questionnaire.

Perhaps one of the main causes of inconsistent resultsin patients with MHE is the inclusion in the analysis ofheterogeneous groups of patients. Up to now, this is thefirst article that includes only patients with decompen-

Table 4 Multiple linear regression including the domains of CLDQ questionnaire and components of Child–Pugh index

Domains Variable Coefficient 95% CI Error P

Fatigue Alcoholic cirrhosis −1.301 −2.0 to −0.6 0.372 0.001Systemic symptoms Little appetite −0.730 −1.3 to 0.18 0.280 0.01

Leukocytes 0.100 0.0 to 0.2 0.049 0.043Hematocrit 0.050 0.0 to 0.8 0.016 0.002Platelets −0.004 −0.0 to 0.0 0.002 0.036Ascites −0.504 −0.9 to −0.1 0.205 0.015

Activity MHE −0.836 −1.4 to −0.3 0.295 0.005Emotional function Alcoholic cirrhosis −0.753 −1.4 to −0.1 0.344 0.030

MHE −0.476 −0.9 to −0.0 0.232 0.042Global MHE −0.425 −0.8 to 0.0 0.193 0.030

Alcoholic cirrhosis −0.702 −1.3 to −0.1 0.287 0.016

Model adjusted for age, etiology, creatinine, appetite measured by verbal analog scale, leukocytes, albumin, platelets, prothrombin time,ascites, diagnosis of MHE and hematocrit.CI, confidence interval; CLDQ, Chronic Liver Disease Questionnaire; MHE, minimal hepatic encephalopathy.

Table 5 Multiple linear regression including various domains of CLDQ questionnaire and Child–Pugh score

Domain Variable Coefficient 95% CI Error P

Systemic symptoms Hematocrit 0.053 0.0 to 0.1 0.016 0.001MHE −0.520 −0.9 to −0.1 0.211 0.015

Model adjusted for age, etiology, creatinine, appetite measured by verbal analog scale, leukocytes, platelets, Child–Pugh score, diagnosisof MHE and hematocrit.CI, confidence interval; CLDQ, Chronic Liver Disease Questionnaire; MHE, minimal hepatic encephalopathy.

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sated cirrhosis, who have a greater risk of mortality andwho develop different complications than patients withcompensated cirrhosis.18,40,41 Therefore, it is importantto classify patients not only according to the Child–Pugh score, but also to the degree of decompensation.

Besides the inclusion of patients with alcoholic cir-rhosis in our study, the multivariate analysis shows thatMHE is an independent factor that deteriorates HRQL.However, to confirm that the relationship between thesetwo variables remains, we performed an analysis exclud-ing patients with alcoholic cirrhosis and HRQL was sig-nificantly lower in the domains of activity, emotionalfunction, worry and overall score in patients with MHEcompared with non-MHE patients (data no shown).

It is worth mentioning that not all previous studieshave excluded patients with a history of OHE, whichincreases the frequency of MHE because some patientshave persistent cognitive impairments after the treat-ment and resolution of OHE, which has a negativeimpact on HRQL of patients with liver cirrhosis.13,36

In addition, various questionnaires have been used toevaluate quality of life, both generic and specific, whichmakes results difficult to compare. The specific question-naire for hepatic failure approaches aspects of the socialenvironment, hepatic encephalopathy and fatiguewhich are not completely covered in general question-naires, including SF-36.44 Nonetheless, as has beenreported in patients with MHE, there is a greater risk ofcausing or suffering car accidents as well as falls.5,8,45–47

Likely, a more specific questionnaire including itemsthat explore functions related to these complications isneeded in order to increase the sensitivity. Also, addingan assessment of appetite in this population should beincluded.

The presence of malnutrition is another associatedfactor that can impair HRQL in patients with cirrho-sis.12 According to the results of this study, there wereno differences in nutritional status in patients withMHE or in those without MHE. Nevertheless, a signifi-cant reduction was noted in the appetite of patientswith MHE according to severity of the disease (Child–Pugh score). The Child–Pugh index has been consid-ered not only a risk factor for developing complicationssuch as MHE,30 it has also been associated with the lossof appetite and HRQL in patients with cirrhosis. Theresults of this study suggest that both MHE and appe-tite have a negative effect on HRQL in patients withdecompensated cirrhosis. Considering that the presentstudy is the first to explore appetite in patients withMHE, more studies are needed to prove the consistencyof this association.

Malnutrition is present in 20–84% of the patientswith liver disease.22 Changes in appetite are more fre-quent in patients with liver cirrhosis compared with thegeneral population, and have been associated withlower concentrations of zinc, vitamin A, magnesium, α-and β-carotene.48 Zinc deficiency has been associated asa risk factor for developing hepatic encephalopathy andits supplementation has been used in the treatment ofOHE;49 however, the results to date are inconclusive.

In a survey from Spain, 59% of hepatologists did notdiagnose MHE.37 In the USA, 26% of gastroenterologistssurveyed believed MHE should not be tested for.50 InMexico, testing is not done routinely during clinicalpractice. It appears that a timely diagnosis and treatmentof MHE would improve HRQL42,43 and reduce the risk ofdeveloping OHE.38 In addition, treatment with lactuloseis a cost-effective strategy, because in a period of 5 years,it would prevent an estimated 202 car accidents, gener-ating a saving of $US 8.5 million.39

The results of this study show that MHE and a reduc-tion in appetite are associated with deterioration inHRQL in patients with decompensated cirrhosis.

ACKNOWLEDGMENTS

THE AUTHORS THANK Montserrat Ferrer for allow-ing the adaptation of the validated Spanish version

of CLDQ for a Mexican population. This study was sup-ported by grants from the Mexican Institute of SocialSecurity (FIS/IMSS/PROT/G11/973).

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