Rationale: Severe alcohol-associated hepatitis (SAH) is the most critical, acute, inflammatory phenotype within the alcohol-associated liver disease (ALD) spectrum, characterized by high 30- and 90-day mortality. Since several decades, corticosteroids (CS) are the only approved pharmacotherapy offering highly limited survival benefits. Contextually, there is an evident demand for 3PM innovation in the area meeting patients’ needs and improving individual outcomes. Fecal microbiota transplantation (FMT) has emerged as one of the new potential therapeutic options. In this study, we aimed to address the crucial 3PM domains in order to assess (i) the impact of FMT on mortality in SAH patients beyond CS, (ii) to identify factors associated with the outcome to be improved (iii) the prediction of futility, (iv) prevention of suboptimal individual outcomes linked to increased mortality, and (v) personalized allocation of therapy. Methods: We conducted a prospective study (NCT04758806) in adult patients with SAH who were non-responders (NR) to or non-eligible (NE) for CS between January 2018 and August 2022. The intervention consisted of five 100 ml of FMT, prepared from 30 g stool from an unrelated healthy donor and frozen at − 80 °C, administered daily to the upper gastrointestinal (GI) tract. We evaluated the impact of FMT on 30- and 90-day mortality which we compared to the control group selected by the propensity score matching and treated by the standard of care; the control group was derived from the RH7 registry of patients hospitalized at the liver unit (NCT04767945). We have also scrutinized the FMT outcome against established and potential prognostic factors for SAH — such as the model for end-stage liver disease (MELD), Maddrey Discriminant Function (MDF), acute-on-chronic liver failure (ACLF), Liver Frailty Index (LFI), hepatic venous-portal pressure gradient (HVPG) and Alcoholic Hepatitis Histologic Score (AHHS) — to see if the 3PM method assigns them a new dimension in predicting response to therapy, prevention of suboptimal individual outcomes, and personalized patient management. Results: We enrolled 44 patients with SAH (NR or NE) on an intention-to-treat basis; we analyzed 33 patients per protocol for associated factors (after an additional 11 being excluded for receiving less than 5 doses of FMT), and 31 patients by propensity score matching for corresponding individual outcomes, respectively. The mean age was 49.6 years, 11 patients (33.3%) were females. The median MELD score was 29, and ACLF of any degree had 27 patients (81.8%). FMT improved 30-day mortality (p = 0.0204) and non-significantly improved 90-day mortality (p = 0.4386). Univariate analysis identified MELD ≥ 30, MDF ≥ 90, and ACLF grade > 1 as significant predictors of 30-day mortality, (p = 0.031; p = 0.014; p = 0.034). Survival was not associated with baseline LFI, HVPG, or AHHS. Conclusions and recommendations in the framework of 3PM: In the most difficult-to-treat sub-cohort of patients with SAH (i.e., NR/NE), FMT improved 30-day mortality. Factors associated with benefit included MELD ≤ 30, MDF ≤ 90, and ACLF < 2. These results support the potential of gut microbiome as a therapeutic target in the context of 3PM research and vice versa — to use 3PM methodology as the expedient unifying template for microbiome research. The results allow for immediate impact on the innovative concepts of (i) personalized phenotyping and stratification of the disease for the clinical research and practice, (ii) multilevel predictive diagnosis related to personalized/precise treatment allocation including evidence-based (ii) prevention of futile and sub-optimally effective therapy, as well as (iii) targeted prevention of poor individual outcomes in patients with SAH. Moreover, our results add to the existing evidence with the potential to generate new research along the SAH’s pathogenetic pathways such as diverse individual susceptibility to alcohol toxicity, host-specific mitochondrial function and systemic inflammation, and the role of gut dysbiosis thereof.

Background and aims: Intestinal inflammation assessed by fecal calprotectin (F‐CAL) in advanced chronic liver disease (ACLD) may represent an early sign of intestinal barrier dysfunction. We aimed to explore the usefulness of F‐CAL testing in ACLD in the prediction of adverse outcomes (AO, death, or LT) and refinement of prognostic stratification.Patients and methods: We explored the RH7 cirrhosis registry comprising consecutive hospitalized patients and a control group with data on disease phenotype, demographics, anthropometrics, prognostic indices, and medication. The F‐CAL was evaluated on admission and reported in multiples of the upper limit of normal or terciles. Predictive power was tested in the Cox model for AO over 180 days. Additional risk refinement by F‐CAL was tested for both groups.Results: We enrolled 263 cases in the study group with a median age of 57.2 years, M/F ratio 167/96, with alcohol, metabolic dysfunction‐associated steatotic liver disease, MetALD, and viral etiologies in 72.2%, 9.1, 8.0, 3.4%. The median F‐CAL was 3.92 × ULN. The control group comprised 108 cases. The adjusted Cox model confirmed F‐CAL (hazard ratio [HR] = 1.05, p < 0.001) and F‐CAL terciles (HR = 1.413, p = 0.009) as independent predictors of AO. F‐CAL terciles had higher predictive accuracy in CLIF‐C‐AD11 × ULN) could identify patients having 2–3 times higher risk of AO. This approach has been validated in the control group.Conclusion: Among hospitalized patients with ACLD, F‐CAL values were independently proportional to the risk of AO, particularly in early disease stages when high F‐CAL values could refine prognostic stratification.

Background and aims: Hepatic venous pressure gradient (HVPG) is a strong surrogate of severity and outcome but its relative prognostic value in metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) is yet to be clarified. We compared HVPG in MASLD with ALD and other etiologies according to cirrhosis complications. Patients and methods: In our cirrhosis registry RH7, we identified patients with data on HVPG and scrutinized them against the etiology of advanced chronic liver disease (ACLD) (MASLD, ALD, Other) and specific complications of ACLD such as variceal bleeding or ascites. We excluded patients with advanced malignancies and less than 6 months of follow-up. Results: We enrolled 220 patients with ALD, MASLD, and Other etiology in 128, 52, and 40 cases, respectively; te median age was 57, 60, and 52 years (P = 0.09); the proportion of females was 31, 67, and 55%, respectively (P < 0.01). Median MELD scores in ALD, MASLD, and Other etiologies were 16.0, 13.0, and 12.0 (P < 0.01), and the median HVPG was 18.0, 14.0, and 11.5 mmHg (P < 0.001). In 19, 30, and 25 compensated patients, the median HVPG was 10.0, 11.5, and 11.0 mmHg (P = 0.97). In 109, 22, and 15 decompensated patients, the median HVPG was 19.0, 15.5 and 14 mmHg (P = 0.01 for trend, difference ALD vs. other P < 0.01, ALD vs. MASLD, P = 0.295). Between decompensated MASLD and ALD patients, we observed no differences in the proportion of clinically significant portal hypertension (CSPH) (>10 mmHg). Conclusion: In our cirrhosis registry study of hospitalized patients with ACLD, baseline HVPG measured for accepted indications differed according to the etiology of dACLD: patients with ALD had the highest values followed by MASLD and Other etiologies. Importantly, when looked at from the point of view of complications, the treshold for clinically significant portal hypertension remained fixed at the level recommended by BAVENO Consensus - 10 mm Hg irrespective of etiology.

Background: It is assumed that the prevalence of hepatitis D in HBsAg-positive individuals reaches 4.5–13% in the world and on average about 3% in Europe. Data from several European countries, including Slovakia, are missing or are from an older period. Methods: We analyzed all available data on hepatitis D from Slovakia, including reports from the Slovak Public Health Authority and the results of one prospective study, and three smaller surveys. The determination of anti-HDV IgG and IgM antibodies and/or HDV RNA was used to detect hepatitis D. Results: In the years 2005–2022, no confirmed case of acute or chronic HDV infection was reported in Slovakia. The presented survey includes a total of 343 patients, of which 126 were asymptomatic HBsAg carriers, 33 acute hepatitis B, and 184 chronic hepatitis B cases. In a recent prospective study of 206 HBsAg-positive patients who were completely serologically and virologically examined for hepatitis B and D, only 1 anti-HDV IgG-positive and no anti-HDV IgM or HDV RNA-positive cases were detected. In other smaller surveys, two anti-HDV IgG-positive patients were found without the possibility of HDV RNA confirmation. In total, only 3 of 329 HBsAg-positive patients (0.91%) tested positive for anti-HDV IgG antibodies, and none of 220 tested positive for HDV RNA. Conclusion: The available data show that Slovakia is one of the countries with a very low prevalence of HDV infection, reaching less than 1% in HBsAg-positive patients. Routine testing for hepatitis D is lacking in Slovakia, and therefore it is necessary to implement testing of all HBsAg-positive individuals according to international recommendations.

Background: It is assumed that the prevalence of hepatitis D in HBsAg-positive individuals reaches 4.5-13% in the world, and on average about 3% in Europe. Data from several European countries, including Slovakia, are missing or are from an older period. Methods: We analyzed all available data on hepatitis D from Slovakia, including reports from the Slovak Public Health Authority and the results of one prospective study, and three smaller surveys. The determination of anti-HDV IgG and IgM antibodies and/or HDV RNA was used to detect hepatitis D. Results: In the years 2005-2022, no confirmed case of acute or chronic HDV infection was reported in Slovakia. The presented survey includes a total of 343 patients, of which 126 were asymptomatic HBsAg carriers, 33 acute hepatitis B, and 184 chronic hepatitis B cases. In a recent prospective study of 206 HBsAg-positive patients who were completely serologically and virologically examined for hepatitis B and D, only 1 anti-HDV IgG positive and no anti-HDV IgM or HDV RNA positive cases were detected. In other smaller surveys, 2 anti-HDV IgG positive patients were found without the possibility of HDV RNA confirmation. In total, only 3 of 329 HBsAg-positive patients (0.91%) tested positive for anti-HDV IgG antibodies and none of 220 tested positive for HDV RNA. Conclusion: The available data show that Slovakia is one of the countries with a very low prevalence of HDV infection reaching less than 1% in HBsAg-positive patients. Routine testing for hepatitis D is lacking in Slovakia, and therefore it is necessary to implement testing of all HBsAg-positive individuals according to international recommendations.

Background and aims: Alcohol-associated hepatitis (AH) frequently triggers acute decompensation (AD) in cirrhosis, with severe AH linked to high short-term mortality, especially in acute-on-chronic liver failure. Current corticosteroid treatments have limited efficacy, highlighting the need for new therapies. We hypothesized that severe AH outcomes are influenced by early specialized care; thus, we examined the impact of time-to-tertiary care (TTTc). Methods: Adults with cirrhosis or advanced chronic liver disease were enrolled (RH7, NCT04767945). AH was diagnosed using National Institute on Alcohol Abuse and Alcoholism criteria. Primary admission site, TTTc, and adverse outcomes (death or liver transplantation) were analyzed. Patients admitted directly to tertiary care were assigned a TTTc of zero. Results: Of 221 AD-AH patients, 107 were transferred from secondary care to tertiary care (TTTc >0) and 114 were admitted directly (TTTc = 0). TTTc >0 patients were younger (48.3 vs. 52 years, P = .008) and had more severe disease, as shown by model for end-stage liver disease scores (25.5 vs. 20.8, P < .001) and Maddrey’s discriminant function (59.3 vs. 40.6, P < .001). Propensity-score matching yielded 49 case pairs. The Cox model showed that transfer from secondary care was not associated with increased risk, but delayed transfer (days, hazard ratio = 1.03, 95% confidence interval 1.01–1.05) independently predicted adverse outcomes. Conclusions: Delayed initiation of specialized care adversely impacts outcomes in AD-AH. If validated, timely care bundles could improve AH survival, similar to sepsis or vascular syndromes. Highlights: AD-AH is a common syndrome associated with high short-term mortality. There is an unmet need for new prognosis-modifying therapies for AH. Currently, in real-life hepatology, refining the existing bundle of care is the only practical option to improve the prognosis of AD-AH. Past experience with acute coronary syndromes, stroke, and sepsis, emphasizing symptoms-to-intervention duration, combined with the recent COVID-19 lockdown finding of increased mortality due to skewed access to specialized liver care indicates that focusing on timely specialized care might be key to improved outcome in certain liver conditions. In this line, we set out to track the number of days elapsing between admission to SC and referral to TC, coining this interval as “time-to-tertiary care” (TTTc). We examined TTTc as a potential compound surrogate that might influence the prognosis in AD-AH. After correcting for important baseline differences, we conclude that the delay of transfer to the tertiary care hospital was independently associated with a worse prognosis with each additional day in TTTc increasing adverse outcomes by nearly 3%.