Elsevier

Journal of Hepatology

Volume 66, Issue 3, March 2017, Pages 528-536
Journal of Hepatology

Research Article
Minimal hepatic encephalopathy in children with chronic liver disease: Prevalence, pathogenesis and magnetic resonance-based diagnosis

https://doi.org/10.1016/j.jhep.2016.10.026Get rights and content

Background & Aims

Data on minimal hepatic encephalopathy (MHE) in children is scarce. We aimed to study MHE in children with chronic liver disease (CLD) and to validate non-invasive objective tests which can assist in its diagnosis.

Methods

We evaluated 67 children with CLD (38 boys; age 13 [7–18] years) and 37 healthy children to determine the prevalence of MHE. We also assessed the correlation of MHE with changes in brain metabolites by magnetic resonance spectroscopy (1HMRS), diffusion tensor imaging (DTI) derived metrics, blood ammonia and inflammatory cytokines (interleukin-6 [IL6], tumor necrosis factor alpha [TNF-α]). In addition, the accuracy of MR-based investigations for diagnosis of MHE in comparison to neuropsychological tests was analysed.

Results

Thirty-four (50.7%) children with CLD had MHE on neuropsychological tests. MHE patients had higher BA (30.5 [6–74] vs. 14 [6–66] μmol/L; p = 0.02), IL-6 (8.3 [4.7–28.7] vs. 7.6 [4.7–20.7] pg/ml; p = 0.4) and TNF-α (17.8 [7.8–65.5] vs. 12.8 [7.5–35] pg/ml; p = 0.06) than No-MHE. 1HMRS showed higher glutamine (2.6 [2.1–3.3] vs. 2.4 [2.0–3.1]; p = 0.02), and lower choline (0.20 [0.14–0.25] vs. 0.22 [0.17–0.28]; p = 0.1) and myo-inositol (0.25 [0.14–0.41] vs. 0.29 [0.21–0.66]; p = 0.2) in MHE patients than those without MHE. Mean diffusivity (MD) on DTI was significantly higher in 6/11 brain areas in patients with MHE vs. no MHE. Brain glutamine had a significant positive correlation with blood ammonia, IL-6, TNF-α and MD of various brain regions. Neuropsychological tests showed a negative correlation with blood ammonia, IL6, TNF-α, glutamine and MD. Frontal white matter MD had a sensitivity and specificity of 73.5% and 100% for diagnosing MHE.

Conclusions

In children with CLD, 50% have MHE. There is a significant positive correlation between markers of hyperammonemia, inflammation and brain edema and these correlate negatively with neuropsychological tests. MD on DTI is a reliable tool for diagnosing MHE.

Lay summary

Fifty percent of children with chronic liver disease develop minimal hepatic encephalopathy (MHE) and perform poorly on neuropsychological testing. These children have raised blood ammonia, inflammatory cytokines and mild cerebral edema on diffusion tensor imaging as compared to children without MHE. The higher the ammonia, inflammatory cytokines and cerebral edema levels the poorer the performance on neuropsychological assessment. The estimation of mean diffusivity on diffusion tensor imaging is an objective and reliable method for diagnosing MHE.

Introduction

Minimal hepatic encephalopathy (MHE) represents the mildest form of hepatic encephalopathy (HE) seen in patients with liver dysfunction and/or portosystemic shunting [1]. MHE is characterized by subtle motor and cognitive deficits, affecting attention, speed of information processing, motor abilities and co-ordination [1], [2]. The prevalence of MHE in adults with chronic liver disease (CLD) ranges from 30–84% [2], [3]. This variation is attributed to differences in severity of liver disease, extent of portosystemic shunting, and cut-offs for abnormal neuropsychological tests (NPT) for diagnosing MHE [2]. A single study in 30 CLD children found MHE in 57% cases [4].

MHE patients have no recognizable clinical symptoms of HE and thus cannot be diagnosed on standard neurological examination. NPT using a battery of tests is the current gold standard for diagnosis in adults [2]. However, NPT have their own limitation of being affected by patients’ age, education, anxiety, and interest in participation [5], [6]. These factors assume greater significance while testing children, especially the younger ages. Various advanced magnetic resonance imaging (MRI) methods (spectroscopy [1HMRS], diffusion tensor imaging [DTI], magnetization transfer ratio and voxel based imaging), have been used for the evaluation and characterization of MHE [7], [8], [9]. 1HMRS and DTI have been shown to be safe, non-invasive and reliable for evaluating MHE in children with extrahepatic portovenous obstruction (EHPVO) [10].

The diagnosis of MHE is essential for many reasons; it can impair the daily functioning and quality of life [11], increases risk of developing overt HE and reduces survival in adults with cirrhosis [12], [13]. In children, MHE leads to poor performance in educational and vocational areas [14]. Remarkably, it can be treated effectively and easily [2], [11]. Thus, there is a need to study MHE in children with CLD and to validate non-invasive objective tests which can assist in its diagnosis.

The objectives of our study were: a) to determine the prevalence of MHE in children with CLD; b) to evaluate the correlation of MHE with changes on brain metabolites on 1HMRS, DTI derived metrics, blood ammonia (BA) and inflammatory cytokines; and c) to determine the potential of 1HMRS and DTI derived metrics for diagnosis of MHE as an objective tool compared to NPT.

Section snippets

Material and methods

Stable children with CLD diagnosed on the basis of liver biopsy, and/or clinical, imaging and endoscopic findings (⩾grade II esophageal varices) were prospectively enrolled from the in-patients ward. A questionnaire regarding demography and history was filled and a physical examination including detailed neurological evaluation was done to exclude the presence of any illness that could affect the NPT. The West Haven criteria were used to differentiate between grade 0 and 1 HE [1], [15]. A

Results

Of the 247 CLD children evaluated, 67 (13 [7–18] years, 38 boys) were enrolled (Fig. 2). Autoimmune liver disease (AILD, 28; 41.8%) was the most common etiology followed by Budd-Chiari Syndrome (18; 26.9%), biliary cirrhosis (9; 13.4%), cryptogenic (9; 13.4%) and hepatitis B (3; 4.5%).

Discussion

In this study of 67 CLD children, 34 (50.7%) had MHE on NPT. MHE patients had a significantly higher BA, brain Glx and MD in various brain regions compared to patients with no MHE. The inflammatory cytokines (TNF-α and IL-6) were higher while choline and MI were lower on 1HMRS in MHE patients compared to patients with no MHE, but the difference was not significant. T1SI in the globus pallidus and FA values of various brain regions on DTI were similar in MHE and no MHE groups. There was a

Financial support

The study was funded by an extramural grant from Indian Council of Medical Research (ICMR), New Delhi, India (No 5/4/3-12/2011/NCD-II). Saurabh Chaturvedi also acknowledges the financial assistance from ICMR, India.

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Authors’ contribution

Anshu Srivastava – obtained funding, study concept and design, study supervision, analysis and interpretation of data, drafting of the manuscript, final approval of the version to be published

Saurabh Chaturvedi – acquisition of data, analysis and interpretation of data, drafting of the manuscript, final approval of the version to be published

RK Gupta – obtained funding, study concept and design, critical revision of the manuscript for important intellectual content, final approval of the

Acknowledgement

We thank Prof Vikas Agarwal (Department of Immunology) for helping in estimation of blood cytokines.

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