Hepatic EncephalopathyNCT05421351
Immune Profile, Neuronal Dysfunction, Metabolomics and Ammonia in Therapeutic Response of HE in ACLF
An observational study of Hepatic Encephalopathy and Acute-On-Chronic Liver Failure, run by Post Graduate Institute of Medical Education and Research, Chandigarh at 1 site in India.
Trial summary
There is very little data related to the natural history of disease from covert HE (MHE and grade 1 HE) to overt HE (grades II, III and IV) in ACLF, with implications on long-term neurological recovery after an episode of overt HE. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Hepatic Encephalopathy, Acute-On-Chronic Liver Failure, Decompensated Cirrhosis
- How many people
- 135 participants
- Where
- 1 siteIndia
- Study dates
- 2 Oct 2022to May 2025
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: Experimental group (A1) n=75 Disease Control Group (A2) [ACLF without HE (n=20)], [Decompensated Cirrhosis without HE (n=20)] Healthy Control group-20
Who may be able to join
- 1 . Age 18-65 years 2. Either gender 3. Patients with ACLF (CANONIC definition) of any etiology with HE ≥grade 2 as per West-Haven Criteria
Who cannot join
- Patients with structural brain lesions, stroke, diagnosed neurological disease or history of seizures and are on neuropsychiatric medications, like sedatives, antidepressants, or antiepileptic drugs.
- Severe preexisting cardiopulmonary disease.
- Patients with hepatocellular carcinoma or systemic malignancy.
- Post liver transplant patients.
- HIV/AIDS infection.
- Patients who are having active COVID-19 infection.
- Those who do not consent to participate in the study.
- Those who have TIPS or Porto systemic surgical shunt in situ.
Trial locations and contacts
1 site in 1 country.
India1 site, 1 recruiting
- Recruiting
Postgraduate Institute of Medical Education and Research
Chandigarh, 160012
Madhumita PREMKUMAR, DM, 01722756344, drmadhumitap@gmail.com
About this study
Official title: Dynamic Changes in Immune Profile, Neuronal Dysfunction, Metabolomics and Ammonia in Pathogenesis and Therapeutic Response of Hepatic Encephalopathy in Acute-on-Chronic Liver Failure: a Prospective Cohort Study
There is very little data related to the natural history of disease from covert HE (MHE and grade 1 HE) to overt HE (grades II, III and IV) in ACLF, with implications on long-term neurological recovery after an episode of overt HE. The evolution and pathogenesis of HE is well described in ALF and cirrhosis, but the dynamic changes in HE in ACLF in response to therapy such as ammonia reduction measures, antibiotics to target sepsis and inflammation, measures to alter dysbiosis such as probiotics or fecal microbiota transplant, and measures to target immune dysfunction such as steroids in alcohol-associated hepatitis. The central role of ammonia in the pathogenesis of HE in ACLF has been challenged by recent data. The approach to HE in ACLF has now refocused on systemic and neuro-inflammation, gut dysbiosis, immune dysregulation, and multi-omics approach. Most importantly, the modulation of the metabolome in response to therapy and interventions, and the use of sedatives, paralytic agents, antibiotics etc. in ACLF with HE in a real-world setting has not been reported.
Read the detailed description
Hepatic Encephalopathy (HE) is a neuropsychiatric disorder characterized by cerebral dysregulation due to hepatic metabolic dysfunction and/or porto-systemic shunting (PSS) resulting in bypass of portal blood flow to the systemic circulation without hepatic detoxification. Hepatic Encephalopathy manifests as a broad spectrum of neurological, cognitive or psychiatric abnormalities ranging from subclinical alterations of cerebral function to coma"(1). Subtle alterations in cerebral function are only detectable by neuropsychological or neurophysiological assessment in minimal hepatic encephalopathy. Weissenborn et al., define HE as a 'significant condition of severe chronic or acute liver insufficiency that is characterized mainly by modifications of motor function, cognition, consciousness, personality. HE was traditionally differentiated into 3 categories as Type A, Type B and Type C. Acute-on-chronic liver (ACLF) has emerged as an independent clinical entity in the field of chronic liver disease which is related to high short-term mortality. The pathogenesis of HE involves blood-derived precipitating factors that cause a neurological deficit in patients with cirrhosis. A major presumption of pathogenesis of HE was assumed to be the central role of ammonia. However, there is now a paradigm shift in our understanding of the etiology, pathogenesis, evolution, and clinical correlation of HE in critically ill patients with cirrhosis and ACLF, wherein systemic inflammation, neuronal dysfunction, cerebral edema, oxidative stress and immune dysregulation are key factors in the multifactorial pathogenesis of HE.
In liver failure, changes in gut microbiota and their by-products like amino acid metabolites, ammonia, endotoxin, oxidative stress, result in neurological transmission alterations like changes in glutamine (Glx), GABA transmission and oxidative stress. Systemic inflammation causes the release of pro inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. They act synergistically with ammonia in developing cognitive dysfunction in patients with HE in and cirrhosis. Currently, there is evidence of the role of neuroinflammation in liver failure. Neuroinflammation is characterized by microglial activation and increased synthesis of the in situ pro-inflammatory cytokines IL-6, IL-1β and TNF-α. Additionally, there is increased gut-liver-brain axis signaling that includes effects of chemokines and cytokines, increased monocytes demand after microglial activation, and changed permeability of the blood-brain barrier(BBB).
However, the exact mechanism by which cerebral edema and HE in ACLF is caused by inflammation is not well known. Thus, identification of novel biomarkers using markers of inflammation, metabolomics, and cerebral imaging techniques to assess the severity of HE in ACLF is essential. The presence of HE is a significant negative predictor of survival in patients with ACLF; hence, studies are needed to fill the gap that is present in the monitoring and prognostication of HE in critically ill patients.
Lactulose is mainstay treatment for HE currently and acts beyond mere ammonia reduction. Lactulose therapy over three months causes a reduction in levels of serum endotoxin, arterial ammonia, inflammatory cytokines and magnetic resonance spectroscopy (MRS) abnormalities(decreased Glx and increased choline and Myo-inositol) (10). Increased cerebral ammonia causes astrocyte swelling and leads to brain edema (11) Hence, most of the drugs used in the HE treatment primarily target ammonia level reduction in the blood. The therapeutic response and progression of HE in ACLF is yet unclear.
- Keywords
- Hepatic Encephalopathy, Acute-On-Chronic Liver Failure, Neurological Dysfunction, Metabolomics, Immune Profiling
- Medical subject headings
- Hepatic Encephalopathy, Acute-On-Chronic Liver Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Experimental | All patients with overt HE in ACLF of any etiology. | |
| Disease Control Group | 1. Diseased Control patients with Acute-on-Chronic Liver Failure with no Hepatic Encephalopathy 2. Diseased Control patients with Decompensated Cirrhosis with no Hepatic Encephalopathy | |
| Control Group 2 | Healthy Control without any liver disease |
What is being measured
The primary outcome is the main question the study is designed to answer.
Baseline Assessment of dynamic markers of systemic inflammation (IL-1, IL-6, TNF alpha, CD163, CD10, etc) following HE specific management strategies in ACLF.
Systemic inflammation and Immune profiling will be accessed by Flow Cytometry
Measured: Day 0
Changes in markers of systemic inflammation (IL-1, IL-6, TNF alpha, CD163, CD10, etc) following HE specific management strategies in ACLF.
Systemic inflammation and Immune profiling will be accessed by Flow Cytometry
Measured: Day 7
MR Imaging of HE in ACLF
MRI-MRS
Measured: MRI-MRS (At time of Discharge from Hospital)
Assessment of markers of neuronal dysfunction in HE in ACLF
Neuronal dysfunction markers will be assessed by ELISA for GFAP, S110B, etc
Measured: Day 0
Change in markers of neuronal dysfunction in HE in ACLF
Neuronal dysfunction markers will be assessed by ELISA for GFAP, S110B, etc
Measured: Day 7
Assessment of conventional markers of HE and clinical outcomes using standard tests like arterial ammonia, WHC and CHESS scores and severity scores of ACLF like (CLIF-C-ACLF/MELD Na).
Ammonia will be assessed by PocketChem BA Blood Ammonia meter. WHC, CHESS will be assessed for encephalopathy and severity score will be calculated using blood investigation.
Measured: Day 0
Assessment of conventional markers of HE and clinical outcomes using standard tests like arterial ammonia, WHC and CHESS scores and severity scores of ACLF like (CLIF-C-ACLF/MELD Na).
Ammonia will be assessed by PocketChem BA Blood Ammonia meter. WHC, CHESS will be assessed for encephalopathy and severity score will be calculated using blood investigation.
Measured: Day 4
Assessment of conventional markers of HE and clinical outcomes using standard tests like arterial ammonia, WHC and CHESS scores and severity scores of ACLF like (CLIF-C-ACLF/MELD Na).
Ammonia will be assessed by PocketChem BA Blood Ammonia meter. WHC, CHESS will be assessed for encephalopathy and severity score will be calculated using blood investigation.
Measured: Day 7
Baseline Metabolomics in patients with HE in ACLF
Metabolomics will be performed by LC/GC-MS to find putative metabolites associated with HE
Measured: Day 0
Change in Metabolomics following specific management strategies for HE in ACLF and standard medical management of ACLF.
Metabolomics will be performed by LC/GC-MS to find putative metabolites associated with HE
Measured: Day 7
Secondary outcomes (2)
Predictors of HE resolution in ACLF
Predictability for outcomes of HE resolution and survival will be compared between novel biomarker and conventional tests
Measured: Day 90
New hospitalization till 90 days after enrolment.
Patient will be followed for 90 days to assess re-hospitalization and recurrence of HE
Measured: Day 90
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jun 2022
- Study start2 Oct 2022
- Primary completionMay 2024 (estimated)
- Study completionMay 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hepatic EncephalopathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 135 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Post Graduate Institute of Medical Education and Research, Chandigarh
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Madhumita Premkumar, Post Graduate Institute of Medical Education and Research, Chandigarh
- Investigators
- Dr Madhumita Premkumar, DM, Principal investigator, Post Graduate Institute of Medical Education and Research, Chandigarh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05421351
- Sponsor's protocol ID
- IEC/04/2022-2356
- Status last verified
- Apr 2023
- First submitted
- 23 May 2022
- Last updated
- 3 May 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Dynamic Changes in Immune Profile, Neuronal Dysfunction, Metabolomics and Ammonia in Pathogenesis and Therapeutic Response of Hepatic Encephalopathy in Acute-on-Chronic Liver Failure: a Prospective Cohort Study
- ClinicalTrials.gov ID
- NCT05421351
- Acronym / sponsor ID
- IEC/04/2022-2356
- Keywords
- Hepatic Encephalopathy, Acute-On-Chronic Liver Failure, Neurological Dysfunction, Metabolomics, Immune Profiling
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 135 participants (estimated)
- Lead sponsor
- Post Graduate Institute of Medical Education and Research, ChandigarhUniversity, hospital or other
- Study start
- 2 Oct 2022 (actual)
- Primary completion
- May 2024 (estimated)
- Study completion
- May 2025 (estimated)
- First posted
- 16 Jun 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
There is very little data related to the natural history of disease from covert HE (MHE and grade 1 HE) to overt HE (grades II, III and IV) in ACLF, with implications on long-term neurological recovery after an episode of overt HE. The evolution and pathogenesis of HE is well described in ALF and cirrhosis, but the dynamic changes in HE in ACLF in response to therapy such as ammonia reduction measures, antibiotics to target sepsis and inflammation, measures to alter dysbiosis such as probiotics or fecal microbiota transplant, and measures to target immune dysfunction such as steroids in alcohol-associated hepatitis. The central role of ammonia in the pathogenesis of HE in ACLF has been challenged by recent data. The approach to HE in ACLF has now refocused on systemic and neuro-inflammation, gut dysbiosis, immune dysregulation, and multi-omics approach. Most importantly, the modulation of the metabolome in response to therapy and interventions, and the use of sedatives, paralytic agents, antibiotics etc. in ACLF with HE in a real-world setting has not been reported.
Detailed description
Hepatic Encephalopathy (HE) is a neuropsychiatric disorder characterized by cerebral dysregulation due to hepatic metabolic dysfunction and/or porto-systemic shunting (PSS) resulting in bypass of portal blood flow to the systemic circulation without hepatic detoxification. Hepatic Encephalopathy manifests as a broad spectrum of neurological, cognitive or psychiatric abnormalities ranging from subclinical alterations of cerebral function to coma"(1). Subtle alterations in cerebral function are only detectable by neuropsychological or neurophysiological assessment in minimal hepatic encephalopathy. Weissenborn et al., define HE as a 'significant condition of severe chronic or acute liver insufficiency that is characterized mainly by modifications of motor function, cognition, consciousness, personality. HE was traditionally differentiated into 3 categories as Type A, Type B and Type C. Acute-on-chronic liver (ACLF) has emerged as an independent clinical entity in the field of chronic liver disease which is related to high short-term mortality. The pathogenesis of HE involves blood-derived precipitating factors that cause a neurological deficit in patients with cirrhosis. A major presumption of pathogenesis of HE was assumed to be the central role of ammonia. However, there is now a paradigm shift in our understanding of the etiology, pathogenesis, evolution, and clinical correlation of HE in critically ill patients with cirrhosis and ACLF, wherein systemic inflammation, neuronal dysfunction, cerebral edema, oxidative stress and immune dysregulation are key factors in the multifactorial pathogenesis of HE.
In liver failure, changes in gut microbiota and their by-products like amino acid metabolites, ammonia, endotoxin, oxidative stress, result in neurological transmission alterations like changes in glutamine (Glx), GABA transmission and oxidative stress. Systemic inflammation causes the release of pro inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. They act synergistically with ammonia in developing cognitive dysfunction in patients with HE in and cirrhosis. Currently, there is evidence of the role of neuroinflammation in liver failure. Neuroinflammation is characterized by microglial activation and increased synthesis of the in situ pro-inflammatory cytokines IL-6, IL-1β and TNF-α. Additionally, there is increased gut-liver-brain axis signaling that includes effects of chemokines and cytokines, increased monocytes demand after microglial activation, and changed permeability of the blood-brain barrier(BBB).
However, the exact mechanism by which cerebral edema and HE in ACLF is caused by inflammation is not well known. Thus, identification of novel biomarkers using markers of inflammation, metabolomics, and cerebral imaging techniques to assess the severity of HE in ACLF is essential. The presence of HE is a significant negative predictor of survival in patients with ACLF; hence, studies are needed to fill the gap that is present in the monitoring and prognostication of HE in critically ill patients.
Lactulose is mainstay treatment for HE currently and acts beyond mere ammonia reduction. Lactulose therapy over three months causes a reduction in levels of serum endotoxin, arterial ammonia, inflammatory cytokines and magnetic resonance spectroscopy (MRS) abnormalities(decreased Glx and increased choline and Myo-inositol) (10). Increased cerebral ammonia causes astrocyte swelling and leads to brain edema (11) Hence, most of the drugs used in the HE treatment primarily target ammonia level reduction in the blood. The therapeutic response and progression of HE in ACLF is yet unclear.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Experimental | – | –All patients with overt HE in ACLF of any etiology. |
| Disease Control Group | – | –1. Diseased Control patients with Acute-on-Chronic Liver Failure with no Hepatic Encephalopathy 2. Diseased Control patients with Decompensated Cirrhosis with no Hepatic Encephalopathy |
| Control Group 2 | – | –Healthy Control without any liver disease |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- Experimental group (A1) n=75 Disease Control Group (A2) [ACLF without HE (n=20)], [Decompensated Cirrhosis without HE (n=20)] Healthy Control group-20
Key inclusion criteria (1 listed)
- 1 . Age 18-65 years 2. Either gender 3. Patients with ACLF (CANONIC definition) of any etiology with HE ≥grade 2 as per West-Haven Criteria
Key exclusion criteria (8 listed)
- Patients with structural brain lesions, stroke, diagnosed neurological disease or history of seizures and are on neuropsychiatric medications, like sedatives, antidepressants, or antiepileptic drugs.
- Severe preexisting cardiopulmonary disease.
- Patients with hepatocellular carcinoma or systemic malignancy.
- Post liver transplant patients.
- HIV/AIDS infection.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Baseline Assessment of dynamic markers of systemic inflammation (IL-1, IL-6, TNF alpha, CD163, CD10, etc) following HE specific management strategies in ACLF.
Time frame: Day 0
Systemic inflammation and Immune profiling will be accessed by Flow Cytometry
Changes in markers of systemic inflammation (IL-1, IL-6, TNF alpha, CD163, CD10, etc) following HE specific management strategies in ACLF.
Time frame: Day 7
Systemic inflammation and Immune profiling will be accessed by Flow Cytometry
MR Imaging of HE in ACLF
Time frame: MRI-MRS (At time of Discharge from Hospital)
MRI-MRS
Assessment of markers of neuronal dysfunction in HE in ACLF
Time frame: Day 0
Neuronal dysfunction markers will be assessed by ELISA for GFAP, S110B, etc
Change in markers of neuronal dysfunction in HE in ACLF
Time frame: Day 7
Neuronal dysfunction markers will be assessed by ELISA for GFAP, S110B, etc
Assessment of conventional markers of HE and clinical outcomes using standard tests like arterial ammonia, WHC and CHESS scores and severity scores of ACLF like (CLIF-C-ACLF/MELD Na).
Time frame: Day 0
Ammonia will be assessed by PocketChem BA Blood Ammonia meter. WHC, CHESS will be assessed for encephalopathy and severity score will be calculated using blood investigation.
Assessment of conventional markers of HE and clinical outcomes using standard tests like arterial ammonia, WHC and CHESS scores and severity scores of ACLF like (CLIF-C-ACLF/MELD Na).
Time frame: Day 4
Ammonia will be assessed by PocketChem BA Blood Ammonia meter. WHC, CHESS will be assessed for encephalopathy and severity score will be calculated using blood investigation.
Assessment of conventional markers of HE and clinical outcomes using standard tests like arterial ammonia, WHC and CHESS scores and severity scores of ACLF like (CLIF-C-ACLF/MELD Na).
Time frame: Day 7
Ammonia will be assessed by PocketChem BA Blood Ammonia meter. WHC, CHESS will be assessed for encephalopathy and severity score will be calculated using blood investigation.
Baseline Metabolomics in patients with HE in ACLF
Time frame: Day 0
Metabolomics will be performed by LC/GC-MS to find putative metabolites associated with HE
Change in Metabolomics following specific management strategies for HE in ACLF and standard medical management of ACLF.
Time frame: Day 7
Metabolomics will be performed by LC/GC-MS to find putative metabolites associated with HE
2 secondary outcomes
Predictors of HE resolution in ACLF
Time frame: Day 90
New hospitalization till 90 days after enrolment.
Time frame: Day 90
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 May 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dr Madhumita Premkumar, DM principal investigator
Post Graduate Institute of Medical Education and Research, Chandigarh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Hepatic Encephalopathy and Acute-On-Chronic Liver Failure, run by Post Graduate Institute of Medical Education and Research, Chandigarh at 1 site in India.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 3 May 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in India. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Dr Madhumita Premkumar, DM (7087003409, drmadhumitap@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Baseline Assessment of dynamic markers of systemic inflammation (IL-1, IL-6, TNF alpha, CD163, CD10, etc) following HE specific management strategies in ACLF. (time frame: Day 0). The study lists 10 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 May 2023; AzTrials last refreshed its copy on 6 Nov 2026.