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THE ASSOCIATION BETWEEN MENTAL ILLNESS AND ALL-CAUSE MORTALITY IN PATIENTS WITH CIRRHOSIS: A VETERANS AFFAIRS RETROSPECTIVE COHORT STUDY
Methods: Female, C57BL6 mice aged 10-12 weeks received Lieber-deCarli diet with alcohol for 10 days followed by one binge (alcoholic hepatitis-AH-model) or calorie-matched control diet. Some mice received oral gavage of Evobrutinib, a BTK inhibitor (BTKi) or DMSO from day7 to day10. Liver damage was assessed by measuring serum ALT. Serum levels of proinflammatory cytokines were measured by ELISA. BTK phosphorylation (pBTK) was assessed in human or mouse livers by western blotting, and in bone marrow (BM) progenitors or liver neutrophils by flow cytometry. Circulating neutrophils from healthy controls (HC) and AH patients were analyzed for BTK expression by RNA-seq. Tandem mass spectrometry (LC-MS/MS) was performed in mouse liver lysates to identify BTK substrates.
Results: Our results from unbiased RNA-seq in circulating neutrophils showed a significant increase in BTK in AH patients compared to HC. Consistently, pBTK was significantly increased in neutrophils from AH patients compared to HC. We found that pBTK (Y223 and Y551) was upregulated in humans as well as in mouse livers with ALD. We further dissected that acute alcohol binge rather than chronic moderate alcohol use triggers pBTK in mice. In vitro, physiologically relevant doses of alcohol induced rapid pBTK induction in neutrophils that was partially TLR4-mediated. In a preclinical model of AH, administration of Evobrutinib, a small molecule BTK inhibitor, significantly decreased pro-inflammatory cytokines levels, and attenuated liver damage. Importantly, we discovered that alcohol-induced liver neutrophil infiltration correlated with the expansion of BM granulopoiesis, and that pBTK in BM progenitors was essential for alcohol-induced granulopoiesis. In vivo, BTK inhibition significantly reduced granulopoiesis, circulating neutrophils, and liver infiltration in the presence of alcohol administration. Mechanistically, using LC-MS/MS we discovered CD84 as a novel kinase target of BTK which is involved in granulopoiesis.
Conclusion: Our findings define a novel role of BTK in regulating CD84 phosphorylation and granulopoiesis that could be harnessed to address pressing therapeutic needs in AH.

There is a huge burden of undiagnosed but clinically significant liver disease in otherwise asymptomatic at risk individuals in community alcohol services. Early identification followed by effective behaviour change interventions are pivotal to change natural history of alcohol related liver disease. We aim to establish the feasibility of conducting a definitive RCT to test the effectiveness of transient elastography (TE) based advice and alcohol recovery video stories (ARVS) in changing high-risk drinking behaviour in community alcohol services.
Methods
RCT was conducted at three community alcohol services. Participants (≥18years) presenting to any of these services with a primary alcohol problem were recruited and randomised (1:1) to either control group and continued routine care, or to intervention group who in addition to routine care had TE, received advice based on results of the liver stiffness measure (LSM) and watched ARVS. Data were collected on demographics, self-reported alcohol intake, AUDIT, and severity of alcohol dependence questionnaire (SADQ) score. Follow up data was collected at six months. Our analysis assessed the feasibility of conducting a RCT, including identifying participant recruitment and retention rates, documenting intervention delivery and acceptability, and evaluating limited efficacy in changing drinking behaviour.
Results
382 participants were screened for eligibility, 184 were randomised (intervention n=93, control n=91), 128 (intervention n=71, control n=59) attended the post-randomisation baseline appointment and were included. Mean age was 43.9years (SD±11.9), majority were male (n=94, 73.4%), white (n=106, 82.8%), and heterosexual (n=115, 90.6%). Over a quarter were poly-drug users (n=25, 27.35), 22.8% (n=29) had co-existing disability, and 75.8% (n=97) had mental health issues. Baseline median daily self-reported alcohol intake was 26units (range 2-73), 92.8% (n=116) were alcohol dependent on AUDIT assessment, 54.3% (n=69) had severe alcohol dependence on SADQ. Six months follow-up was available in 75 (intervention n=47, control n=28). Intervention group compared to control reported greater reduction in daily self-reported alcohol intake (23.0 vs 19.5 units) (Figure 1), AUDIT category (57.8% vs 53.2%), were more likely to attend follow up, and complete the allocated treatment program. Of participants randomised to the intervention group 52 had transient elastography, of whom 21.2% (n=11) had raised LSM (≥8 kilopascal) (Figure 2). None of participants who received transient elastography reported increase in self-reported alcohol intake or AUDIT category.
Conclusion
Integration of transient elastography and ARVS in community alcohol services is feasible, it can stratify clinically significant liver disease, and supplement change in drinking behaviour. Normal LSM does not provide false reassurance.

Figure 1: Median reduction in daily self-reported alcohol intake (units) at 6 months

Figure 2: Results of transient elastography (kPa- Kilopascal, ≥15 kPa Advanced liver fibrosis, 8-14 kPa intermediate liver fibrosis, ≤7 kPa Normal/no significant liver fibrosis)
Methods: We conducted a retrospective cohort study of veterans with cirrhosis from 2008-2021. Simple linear regression was used to analyze trends in mental illness and engagement with outpatient care. We used inverse probability treatment weighting (IPTW)-adjusted Cox regression analysis to characterize the association between mental health-related diagnoses and all-cause mortality based on three distinct disease categories of any mental health diagnosis, alcohol use disorder (AUD)/substance use disorder (SUD), and non-AUD/SUD. Using these same methods, we examined the impact of regular outpatient mental health visits in subgroup analyses.
Results: We identified 115,409 patients, 81.7% of whom had any mental health diagnosis. There were statistically significant increases in the prevalence of all non-AUD/SUD diagnoses (p<0.001), but a slight decrease in prevalence of AUD and SUD (p<0.05; figure 1). However, the incidence proportions of all individual mental health diagnoses significantly increased since 2016 (p<0.05), with AUD and SUD representing the highest incidence proportions overall. There was also a significant increase in the number of mental health clinic visits per person-year (p<0.001), but a decrease in AUD/SUD clinic visits (p<0.001) during the study window. There was a 54% increased hazard in all-cause mortality for any mental health diagnosis, 11% for non-AUD/SUD, and 44% for AUD/SUD (each p<0.001). Regular mental health visits resulted in a 21% decreased risk in all-cause mortality for AUD/SUD diagnosis, compared to 3% and 9% for any mental health diagnosis and non-AUD/SUD diagnosis, respectively (each p<0.001; figure 2).
Conclusions: Mental illness is associated with an increased risk of all-cause mortality in veterans with cirrhosis. Regular outpatient mental healthcare is protective against all-cause mortality, particularly among patients with AUD/SUD. These findings suggest that greater attention should be paid to identifying mental health disease in patients with cirrhosis, and more resources should be allocated for mental health treatment, particularly in those with alcohol or substance use disorder. Future studies should focus on relevant clinical practice changes.

Figure 1 – Trends in Prevalence of MH Diagnoses, Utilization of Outpatient MH Care, and Incidence Proportion of MH Diagnoses

Figure 2 – IPTW Cox-Adjusted Survival Curves for Analyses of (A) Any Mental Health Comorbidity, (B) Non-AUD/SUD Mental Health Comorbidities, and (C) AUD/SUD Mental Health Comorbidities
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