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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-024-00381-5.
- Publikační typ
- časopisecké články MeSH
Úvod: Slovensko je krajinou s najvyššou prevalenciou cirhózy pečene na svete, spolu s najvyšším podielom rómskeho etnika. Existuje však len málo dôkazov o zastúpení rómskeho etnika v národných kohortách pacientov s cirhózou. Ciele: 1. určiť prevalenciu rómskej etnickej príslušnosti v našich registroch cirhózy pečene a transplantácií pečene (LT); porovnať ich 2. základné charakteristiky a 3. finálne výsledky s pacientmi z väčšinovej populácie. Metodika a pacienti: Retrospektívna štúdia; údaje sme získali z 1. Registra cirhóz RH7; 2. Registra transplantácií pečene: a) pacienti vedení ako aktívni na čakacej listine na LT; b) pacienti, ktorí podstúpili prvú LT. Prvý zdroj – Register cirhóz RH7 (NCT 04767945; RH7 zaznamenáva po sebe idúcich pacientov s cirhózou pečene prijatých do nemocnice od r. 2014). Etnická príslušnosť bola do roku 2021 zaznamenaná ako tzv. pripísané etnikum. Druhý zdroj – register LT (od r. 2008); spôsob určenia etnickej príslušnosti bol identický s RH7. Okrem etnicity boli u všetkých pacientov analyzované: demografia, klinické premenné charakterizujúce cirhózu pečene, ako je etiológia a MELD skóre, ako aj základné premenné pre LT, ako je dĺžka čakacej doby a mortalita. Výsledky: Prezentujeme výsledky rómskeho etnika z troch kohort z dvoch registrov, tj. zo 1 515 pacientov z RH7, 464 pacientov zaradených do zoznamu čakateľov z LT registra a 302 transplantovaných pacientov z LT registra. Zastúpenie rómskeho etnika v týchto kohortách bolo 2 %, 4 % a 4 %. U rómskeho etnika z registra cirhóz boli zistené signifikantné rozdiely vo veku a pohlaví: 46 oproti 55 rokom (p = 0,001) a ženskom pohlaví 25 % oproti 39 % (p = 0,042). Z kandidátov prvýkrát zaradených na čakaciu listinu na LT boli rómski pacienti rovnako mladší – 42,6 oproti 51,5 rokom; u Rómov bola v nižšom počte zastúpená etiológia alkoholovej choroby pečene (ALD) a vo vyššom počte bola zastúpená autoimunitná etiológia. Nakoniec, pacienti po prvej LT, kde Rómovia boli opäť mladší – 40,2 oproti 51,6 rokom, opäť s nižším podielom etiológie ALD – 15 % oproti 47 % a vyšším podielom autoimunitnej etiológie – 39 % oproti 23 %. Finálne výsledky rómskeho etnika zo všetkých kohort boli v rámci terciárnej starostlivosti porovnateľné. Záver: 1. zastúpenie rómskeho etnika v rámci terciárnej starostlivosti je nižšie, ako sme očakávali, z neznámych dôvodov; 2. vek Rómov pri vstupe do zariadenia terciárnej starostlivosti je približne o desať rokov nižší; 3. finálne výsledky Rómov odoslaných do zariadenia terciárnej starostlivosti sú porovnateľné.
Introduction: Slovakia is a country with the highest prevalence of liver cirrhosis in the world and a country with the highest proportion of Roma ethnicity at the same time. However, there is only little evidence of Roma representation in national cohorts with cirrhosis. Aims: 1. To determine the prevalence of Roma ethnicity in our cirrhosis and liver transplant registers; to compare their 2. fundamental characteristics and 3. final results with patients from the majority population. Patients and methods: A retrospective study; we acquired data from 1. Cirrhosis registry RH7; 2. Liver transplant registry: a) patients listed active on the liver-transplant waiting list; b) patients underwent first LT. The first source – the cirrhosis registry RH7 (NCT 04767945; since 2014, RH7 has been listing consecutive patients admitted to hospital with liver cirrhosis). Up to 2021, the mode of the ethnicity determination was so-called “ascribed ethnicity”. The second source – the Liver transplant registry (since 2008); the mode of ethnicity determination was identical to the one of RH7. Apart from the ethnicity, the following points were recorded and analyzed in all patients: demographics, elementary cirrhosis-relevant clinical variables such as etiology and MELD score, as well as an elementary LT-relevant variables, such as waiting time and mortality. Results: We present the results on Roma ethnic group in three cohorts from two datasets, i.e. on 1,515 patients from RH7, on 464 waitlisted patients from LT registry and on 302 transplanted patients from LT registry, respectively. The representation of Roma ethnicity in these cohorts were 2%, 4%, and 4%, respectively. Significant differences in age and gender were detected in Roma cirrhotic patients: 46 vs. 55 years (P = 0.001) and female gender 25% vs. 39% (P = 0.042). Of the first time waitlisted candidates for LT, Roma patients were also significantly younger – 42.6 vs. 51.5 years; in addition, Romas had a less prevalent alcohol-associated etiology (ALD) and a more prevalent autoimmune etiology. Finally, Roma patients after first LT were younger – 40.2 vs. 51.6 years, again with lower etiology of ALD – 15% vs. 47% and more autoimmune etiology – 39% vs. 23%. The results of Romas from all cohorts in tertiary care were comparable. Conclusion: 1. the admission of Romas to a tertiary liver care is lower than expected, for unknown reasons; 2. the age of Romas entering tertiary care is approximately ten years lower; 3. the results of Romas in tertiary care is comparable to the majority population.
- MeSH
- epidemiologické studie MeSH
- jaterní cirhóza * epidemiologie MeSH
- lidé MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- Romové MeSH
- seznamy čekatelů MeSH
- transplantace jater * statistika a číselné údaje MeSH
- zdravotně rizikové chování MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Slovenská republika MeSH
Úvod: Nealkoholová tuková choroba pečene (NAFLD) je najrýchlejšie rastúcou príčinou ochorení pečene. Pri vzniku po transplantácii pečene (LT) pre iné indikácie nesie názov de novo NAFLD. Cieľ: Stanoviť incidenciu de novo NAFLD a jej asociáciu s BMI a fibrózou po LT v jednom transplantačnom centre. Metódy: Medzi januárom 2015 a decembrom 2020 sme realizovali propektívnu observačnú štúdiu u po sebe nasledujúcich pacientov po LT pre iné indikácie ako NAFLD. Sledovali sme demografické ukazovatele, etiológiu cirhózy pečene, MELD sklóre a Child Pugh skóre. Šesť, 12 a 24 mesiacov po LT sme hodnotili BMI, MR spektroskopiu (MRS, [≥ 5 % = NAFLD]) a MR elastografiu (MRE, [≥ 2,88 kPa = signifikantná fibróza, ≥ 3,54 kPa = pokročilá fibróza]). Výsledky: V sledovanom intervale sme do štúdie zaradili 164 pacientov po LT. Na základe vopred definovaných kritérií sme vylúčili 37 pacientov, do finálnej analýzy sme zaradili 104 pacientov s mediánom 53 rokov, 38 % žien, s mediánom MELD 15 bodov a BMI 25,4. Medián BMI – 6, 12 a 24 mes. po LT bol 25,5 vs. 27,3 (p = 0,032) a 26 vs. 27,8 (p = 0,062). MRS % – 6, 12 a 24 mes. po LT boli 4,5 oproti 5,1 (p = 0,2) a 4,4 oproti 7 (p = 0,012). Šesť, 12 a 24 mesiacov po LT sme signifikantnú fibrózu zistili u 27 %, 35 % a 46 % (p = 0,09) a pokročilú fibrózu u 4,7 %, 1,2 % a 15 % pacientov (p = 0,003). Závery: Počas dvoch rokov po LT pre iné indikácie ako NAFLD sme zaznamenali stúpajúci trend BMI, stúpajúci výskyt de novo NAFLD, signifikantnej a pokročilej fibrózy.
Background: Non-alcoholic fatty liver disease (NAFLD) is the fastest-growing cause of liver diseases; after liver transplantation (LT) for another indications bears the name de novo NAFLD. Aims: We set out to determine the incidence of de novo NAFLD and its associations with BMI and fibrosis in patients (pts) after LT at a single transplant centre. Methods: We organized an observational study of consecutive pts after LT for non-NAFLD causes between January 2015 and December 2020. At the baseline, we recorded the demographics, etiology of cirrhosis, MELD and Child-Pugh score; 6, 12 and 24 months after LT we recorded BMI, MR spectroscopy (MRS, [≥5% = NAFLD]) and MR Elastography (MRE, [≥2.88 kPa = significant fibrosis, ≥3.54 kPa = advanced fibrosis]). Results: We enrolled 164 pts after LT, excluded 37% for pre-defined criteria and analysed 104 pts with median age 53 years, 38% women, with median MELD 15 points and BMI 25.4. The median BMI – 6, 12 and 24 months after LT – were 25.5 vs 27.3 (P = 0.032) and 26 vs 27.8 (p = 0.062). MRS % – 6, 12, and 24 months after LT were 4.5 vs 5.1 (P = 0.2) and 4.4 vs 7 (P = 0.012). Significant fibrosis 6, 12 and 24 months after LT were found in 27%, 35% and 46%, respectively (P = 0.09), and advanced fibrosis in 4.7%, 1.2% and 15%, respectively (P = 0.003). Conclusions: Over 2 years after LT for various non-NAFLD indications, we identified rising BMI and rising incidence of de novo NAFLD and of significant and advanced fibrosis.
