Clinical Trial Details
— Status: Recruiting
Administrative data
NCT number |
NCT05421351 |
Other study ID # |
IEC/04/2022-2356 |
Secondary ID |
|
Status |
Recruiting |
Phase |
|
First received |
|
Last updated |
|
Start date |
October 2, 2022 |
Est. completion date |
May 2025 |
Study information
Verified date |
April 2023 |
Source |
Postgraduate Institute of Medical Education and Research |
Contact |
Dr Madhumita Premkumar, DM |
Phone |
7087003409 |
Email |
drmadhumitap[@]gmail.com |
Is FDA regulated |
No |
Health authority |
|
Study type |
Observational
|
Clinical 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. 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.
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.