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Differentiation of minimal and grade 1 hepatic encephalopathy using neurophysiological, neuropsychological, magnetic resonance spectroscopic, and systemic inflammatory parameters
Lalit C Kummetha, Shrey Bhatt, Venkatesh Vaithiyam, Barjesh C Sharma, Siddharth Srivastava, Bhawna Mahajan, Kalpana Bansal, Neera Chaudhry, Monica S Tandon, Sanjeev Sachdeva, Ajay Kumar, Ashok Dalal, Ujjwal Sonika
Lalit C Kummetha, Shrey Bhatt, Venkatesh Vaithiyam, Barjesh C Sharma, Siddharth Srivastava, Sanjeev Sachdeva, Ajay Kumar, Ashok Dalal, Ujjwal Sonika, Department of Gastroenterology, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, New Delhi 110002, Delhi, India
Bhawna Mahajan, Department of Biochemistry, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi 110002, India
Kalpana Bansal, Department of Radiology, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, New Delhi 110002, Delhi, India
Neera Chaudhry, Department of Neurology, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, New Delhi 110002, Delhi, India
Monica S Tandon, Department of Anesthesia and Intensive Care, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, New Delhi 110002, Delhi, India
Co-first authors: Lalit C Kummetha and Shrey Bhatt.
Co-corresponding authors: Venkatesh Vaithiyam and Barjesh C Sharma.
Author contributions: Kummetha LC and Bhatt S wrote the original draft and they contributed equally to this manuscript as co-first authors; Kummetha LC, Bhatt S, Sharma BC, Srivastava S, and Vaithiyam V contributed to writing, reviewing, and editing; Vaithiyam V and Sharma BC contributed equally to this manuscript as co-corresponding authors; Sharma BC, Srivastava S, and Vaithiyam V contributed to conceptualization; Mahajan B, Bansal K, Chaudhry N, and Tandon MS provided resources for the study; Srivastava S, Sachdeva S, Kumar A, Dalal A, and Sonika U performed the final review of the manuscript. All authors have read and approved the final version of the manuscript.
Institutional review board statement: This study was approved by the Institutional Ethics Committee of Maulana Azad Medical College, New Delhi (approval No. F.1/IEC/MAMC/DM/M.CH (100/06/2023/No.419).
Clinical trial registration statement: This study was registered with the Clinical Trials Registry of India (CTRI) (No. CTRI/2023/10/059338).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Data sharing statement: All data specific to this study are available with the corresponding author at the Department of Gastroenterology, GIPMER, Delhi, India, and can be provided upon request.
Corresponding author: Barjesh C Sharma, DM, MD, Director, Professor, Department of Gastroenterology, Govind Ballabh Pant Institute of Post Graduate Medical Education and Research, JLN Marg, Near Delhi Gate, New Delhi 110002, Delhi, India.
drbcsharma@hotmail.com
Received: December 23, 2025
Revised: January 21, 2026
Accepted: March 13, 2026
Published online: May 27, 2026
Processing time: 154 Days and 18 Hours
BACKGROUND
Hepatic encephalopathy (HE) is traditionally classified as overt and minimal HE (MHE). The International Society for HE and Nitrogen Metabolism clubbed MHE and grade 1 HE as “covert” HE. However, these appear to be distinct entities.
AIM
To compare inflammatory markers, magnetic resonance spectroscopy (MRS), Bispectral index (BIS), spectral electroencephalography (EEG), and natural history of MHE and grade 1 HE.
METHODS
In this prospective study, 150 patients with cirrhosis were categorized into three groups: No HE (n = 50), MHE (n = 50), and grade 1 HE (n = 50). Patients were assessed using the West Haven criteria, the psychometric HE score, critical flicker frequency, MRS, inflammatory markers (cytokines and endotoxins), BIS, and spectral EEG. All patients were followed up for HE progression, complications, hospitalizations, and mortality over 12 months.
RESULTS
Patients with grade 1 HE showed significantly higher levels of ammonia (164.08 ± 30.12 vs 123.42 ± 19.97, P < 0.001), endotoxins (0.60 ± 0.05 vs 0.47 ± 0.04, P < 0.001), and cytokines than those with MHE. MRS in grade 1 HE revealed reduced myoinositol (-0.2 vs -0.11, P < 0.001) and choline levels (0.38 ± 0.33 vs 0.42 ± 0.18, P < 0.001) and elevated glutamine levels (1.01 ± 0.38 vs 0.73 ± 0.23, P < 0.001) compared to MHE. BIS values were lower in grade 1 HE compared to MHE (72.9 ± 5.49 vs 81.48 ± 3.9, P < 0.001). Spectral EEG metrics effectively distinguished MHE from grade 1 HE with high diagnostic accuracies. Model for end-stage liver disease, interleukin-12, BIS, and spectral EEG changes were independent predictors of survival.
CONCLUSION
MHE and grade 1 HE exhibit distinct inflammatory, neuropsychological, and neurophysiological profiles, as well as differences in their survival.
Core Tip: Minimal hepatic encephalopathy (MHE) and grade 1 hepatic encephalopathy (HE) are often collectively referred to as covert HE. In this prospective study, we compared neuropsychological, neurophysiological, inflammatory, and magnetic resonance spectroscopic parameters in cirrhotic patients with no HE, MHE, and grade 1 HE. Grade 1 HE exhibited significantly higher inflammatory markers, greater cerebral metabolic changes, and more severe Bispectral index and electroencephalography abnormalities than MHE. Grade 1 HE was independently associated with an increased risk of progression to overt HE, hospitalization, and death. These findings support that MHE and grade 1 HE are distinct entities.
