Curing Cholestatic Liver Disease After Cognitive Impairment

Cholestatic Bile flow can be hampered by liver conditions like primary biliary cholangitis (PBC), which can result in neurological problems.

There is presently no known cure for the ailment, and the causes of the onset of such neurological symptoms are mostly unclear. Newcastle University researchers have offered fresh explanations on how cholestatic liver illness affects cognition. The researchers also discovered that cognitive impairment can be reversed by obeticholic acid, a medication that is already used to safely treat PBC patients who do not respond well to first-line treatment.

The American Journal of Pathology has already published the complete report.

Recognizing the sources of the neurological problems Cholestatic liver disease causes

According to co-lead investigator Fiona Oakley of the Newcastle Fibrosis Research Group and Newcastle University, difficulty in intensity and a short attention span have long been linked with late stages of liver disease, but they now know these signs are a leading cause of impaired quality of life for patients at any disease stage.

Increasing the knowledge of the mechanisms behind these issues and using that knowledge to develop desperately needed therapy modalities were the driving forces behind the research, she added. The level of cognitive impairment of the kind reported in individuals with cholestatic liver disease was investigated using a well-established mouse model of bile duct ligation-induced cholestasis.

According to Dr. Oakley, the significance of analysing clinical qualities like short-term memory was meant to potentially tie the study to the real patient experience and how it can be enhanced by therapy. The researchers conducted the Y-maze test on the control mice to gauge their short-term and spatial memory. Compared to the controls, they showed short-term memory and cognitive abnormalities. After being exposed to cholestatic liver illness, the mice’s brains had considerable changes, as revealed by a pathology investigation. These alterations included the breakdown of the blood-brain barrier, aberrant hippocampus function, and the aging-related senescence or degeneration of neurons.

Locating a cognitive decline treatment

The researchers next looked at whether conventional PBC medications could reverse this cognitive deterioration in the animals. The two most popular PBC therapies, ursodeoxycholic and bezafibrate, did not significantly enhance short-term memory or stop neuronal ageing.

OCA, the most effective anti-cholestatic medication to date that has been licenced for treatment against PBC, did, however, reverse cognitive decline and restore blood-brain barrier integrity. OCA also restored normal hippocampus function and stopped the ageing of the liver and neurons.

In order to translate the results from in vivo animal models to human models, human brain cells were co-cultured with serum from both cholestatic mice and PBC patients. Similar to the mise, cholestatic serum-induced senescence in human cultured neurons could only be reversed by OCA.

The researchers claim that the mouse model was unable to discriminate between an indirect effect of OCA, in which it lessens cholestatic damage and hence lessens the variables that cause neurological symptoms, and an effect of OCA directly on the neurons. These findings imply the presence of a pro-senescent body in the serum of PBC patients and the ability of OCA to counteract this entity’s effects on neurons.

The researchers made a point of noting that neuronal ageing is a problem that affects many illnesses unconnected to cholestasis liver disease. According to Dr. Oakley, the findings indicate a clear path to treating a substantial symptom of cholestatic illness for which there is no present medication.

A tantalising subject that they are starting to investigate is whether the anti-senescent benefits of OCA extend to other circumstances as well, she said in her conclusion.