Cognitive deficits have been recognized as symptoms of advanced liver disease for many years. As reported in Bioengineer, the American Journal of Pathology recently published a study providing insights into the relationship between cholestasis and cognitive impairment.
Although there is no cure for primary biliary cholangitis (PBC), the progression of the disease and its symptoms can be managed with certain medications. For example, investigators found that obeticholic acid (OCA), which is used as a treatment for PBC patients, reverses cognitive impairment.
OCA, approved by NICE, was the first new therapy to treat PBC in twenty years. OCA therapy reduces memory deficits and reverses age-related deterioration (liver senescence).
Co-leader Dr. Fiona Oakley of the Newcastle Fibrosis Research Group explained that the investigators are attempting to improve patients’ lives through an understanding of underlying mechanisms. They will use this new information to develop various treatment approaches.
PBC and Adverse Events
The blood-brain barrier’s integrity is compromised by bile flow from cholestasis. This event is defined as either a reduction or a stoppage of the bile flow into the intestine. The cause may be a stone disrupting the bile duct or it may originate from liver disease.
The researchers induced cholestasis in mouse models by performing ligation (tying) which causes injury to the liver. This enabled the researchers to examine cognitive impairment similar to that of humans.
The cholestatic mice were tested in a Y maze for visual thinking and short-term memory. Analysis of their brains identified brain changes, loss of integrity in the blood-brain barrier, and a neural deterioration related to aging (neuronal senescence).
The researchers then considered if first and second-line PBC treatments currently in use would improve short-term memory or reverse neural senescence and found neither effective.
However, OCA, considered second-line therapy for PBC, did reverse cognitive impairment and restored the integrity of the blood-brain barrier. OCA also normalized hippocampal function and reversed both neuronal and liver senescence.
In an effort to expand the animal model analyses to human PBC models, neural cells from humans were then co-cultured. The serum was obtained from both human PBC patients and cholestatic mice. The researchers reported that only OCA was effective.
The team recognized a pro-senescent factor in PBC patients’ serum and suggest that OCA works with neurons in reversing that effect.