Disease mechanisms and potential therapeutic approaches in alcohol-related liver disease

Background: Chronic alcohol-related liver disease (ALD) affects over 26 million people worldwide, progressing silently from simple steatosis to fibrosis and cirrhosis, often remaining asymptomatic until end-stage liver disease. Early diagnosis and sustained alcohol abstinence are critical but challenging due to high relapse rates. The gut-liver axis plays a pivotal role in fibrosis progression, with impaired gut barrier function exacerbating liver damage. Understanding ALD’s molecular mechanisms is essential for improving risk assessment and treatment. Emerging therapies, such as the postbiotic ReFerm®, show promise in restoring gut health, reducing fibrosis, and enhancing outcomes.

Aims: This thesis aimed to 1) characterise multi-omics dynamics across the full spectrum of liver disease, 2) investigate the efficacy, safety, and mechanism of a 24-week ReFerm® treatment on liver fibrosis in advanced compensated ALD, and 3) explore the cost-effectiveness of potential treatments for early ALD.

Methods: Study 1 included 859 individuals from seven clinical cohorts, representing a full spectrum of liver disease severity. Participants were categorised into six disease severity groups and we included 10 omics profiles from blood, plasma, stool, liver and urine. To identify omics features associated with disease severity we performed linear regression adjusted for age, sex, and medication. We clustered omics features with similar trajectory across disease severity and explored associations within each cluster using network analysis. Study 2 was a 24-week, open-label, randomised phase 2 trial comparing ReFerm® with standard nutritional support (Fresubin®) in patients with advanced ALD. Participants were randomly assigned 1:1 to receive either treatment. Liver biopsies, plasma, and stool were collected before and after intervention. Multiomics analyses of plasma and stool samples explored mode of action. In Study 3, we used a mathematical model to simulate the lifetime progression of ALD patients with advanced fibrosis and ongoing alcohol use. We compared two treatment scenarios: standard care and a theoretical treatment that halts fibrosis progression. The simulation calculated cost-effectiveness ratios for various treatment efficacy and cost combinations, comparing them to current management strategies.

Results: We identified 3,939 omics features associated with disease severity and six clusters of trajectory across disease severity. Disease severity was associated with increased inflammation, decreased lipid metabolism, and gut dysbiosis. ReFerm® reduced alpha-smooth muscle actin (α-SMA) expression by 8.3%, and improved markers for gut barrier function and liver regeneration. A cost-effectiveness model for ALD treatments showed ratios between treatment costs and efficacy in order to balance cost-effectiveness. 

Conclusion: This thesis examines the dynamic pathophysiology of liver disease, highlighting early molecular and microbial changes across its spectrum. Our research suggests that 24 weeks of ReFerm® treatment in advanced ALD may reduce activated hepatic stellate cells by improving gut barrier function. Our findings emphasize the importance of early intervention in ALD to lower mortality rates and reduce healthcare costs.