Inflammatory and Neuroimmune Guided Investigation of Underlying Fatigue in Patients With Cirrhosis

Fatigue is a common and debilitating symptom of cirrhosis, the advanced stage of chronic liver disease. Around two-thirds of people with cirrhosis experience fatigue, which can affect their ability to carry out everyday activities and substantially reduce their quality of life. Despite this, the biological causes of fatigue in cirrhosis are poorly understood and there are currently no effective treatments specifically targeting this symptom. Cirrhosis is associated with long-term changes in the immune system, including increased inflammation in the blood. Inflammation in the body can also affect the brain and may alter processes important for normal brain function. We therefore propose that increased inflammation in people with cirrhosis may contribute to the development of fatigue by affecting brain cells. This study will recruit 50 people with stable alcohol-related cirrhosis: 25 experiencing clinically significant fatigue and 25 without clinically significant fatigue. Participants will attend a single study visit, during which information about their fatigue, mood, thinking abilities and liver disease will be collected, alongside a blood sample. We will compare blood samples from participants with and without fatigue to identify differences in inflammation and immune function. We will then use the serum (the liquid component of blood) collected from participants to treat human brain cells grown in the laboratory. This will allow us to investigate whether blood from people experiencing fatigue affects the growth, development and survival of brain cells differently from blood from people without fatigue. By combining measurements in patients with laboratory experiments, we aim to identify biological mechanisms that may contribute to fatigue in cirrhosis. In the longer term, this could identify potential targets for new treatments and improve our understanding and management of this currently undertreated symptom.

Inclusion Criteria: * Alcohol related cirrhosis (based on clinical, biochemical, histological and/or radiological parameters) * Child Pugh class A-B (score 5-9) * Abstinence from alcohol for a minimum of 6-months * Capacity to consent Exclusion Criteria: * Pregnancy * Breastfeeding * Variceal bleeding, infection, overt hepatic encephalopathy, bacterial peritonitis or acute-on-chronic liver failure (ACLF) in previous 14 days * Current overt hepatic encephalopathy (West Haven grade ≥ 2) * Liver transplant * Active malignancy * BMI ≥ 35 * Diabetes mellitus (type 1 or type 2) * HIV, hepatitis B or hepatitis C (HBsAg negative and HCV RNA negative can be included) * Antibiotics in previous 7 days * Current rifaximin use * Current antidepressant use * Current immunosuppression * Current use of benozodiazepines or other GABAergic drugs * Current use of opioids * Diagnosis of concurrent primary medical disorder defined by fatigue as a key symptom including chronic fatigue syndrome, fibromyalgia, post-viral fatigue syndrome, long COVID and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. * Diagnosis of severe major depressive disorder or other major neuropsychiatric disorder * Patients who have a medical condition, or relevant psychological, familial, or social factor that may jeopardise their health, compliance, or influence the trial integrity