RESUMO
Acute-on-chronic liver failure (ACLF) is a syndrome marked by sudden liver function decline and multiorgan failure, predominantly acute kidney injury (AKY), in patients with chronic liver disease. Unregulated inflammation is a hallmark of ACLF; however, the key drivers of ACLF are not fully understood. This study explores the therapeutic properties of human mesenchymal stem cell (MSC) secretome, particularly focusing on its enhanced anti-inflammatory and pro-regenerative properties after the in vitro preconditioning of the cells. We evaluated the efficacy of the systemic administration of MSC secretome in preventing liver failure and AKI in a rat ACLF model where chronic liver disease was induced using by the administration of porcine serum, followed by D-galN/LPS administration to induce acute failure. After ACLF induction, animals were treated with saline (ACLF group) or MSC-derived secretome (ACLF-secretome group). The study revealed that MSC-secretome administration strongly reduced liver histological damage in the ACLF group, which was correlated with higher hepatocyte proliferation, increased hepatic and systemic anti-inflammatory molecule levels, and reduced neutrophil and macrophage infiltration. Additionally, renal examination revealed that MSC-secretome treatment mitigated tubular injuries, reduced apoptosis, and downregulated injury markers. These improvements were linked to increased survival rates in the ACLF-secretome group, endorsing MSC secretomes as a promising therapy for multiorgan failure in ACLF.
Assuntos
Insuficiência Hepática Crônica Agudizada , Humanos , Ratos , Animais , Suínos , Insuficiência Hepática Crônica Agudizada/terapia , Secretoma , Células-Tronco , Anti-InflamatóriosRESUMO
Liver transplantation is the only effective therapy to reduce the high mortality associated with acute liver failure and acute on chronic liver failure (ACLF). Single-pass albumin dialysis (SPAD) is an extracorporeal supportive therapy used as a bridge to liver transplantation or regeneration. We report a 44-year-old man with alcoholic cirrhosis admitted for critical COVID-19 pneumonia that evolves with ACLF. SPAD technique was performed completing six sessions, with a reduction of bilirubin and ammonia levels. He evolved with severe respiratory failure and refractory septic shock, dying. SPAD is a safe and efficient technique aimed to eliminate liver toxins, preventing multiorgan damage interrupting the process known as the "autointoxication hypothesis". It is easy to implement in any critical patient unit and has lower costs than other extracorporeal liver support therapies.
Assuntos
Humanos , Masculino , Adulto , Transplante de Fígado , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/terapia , COVID-19/complicações , Diálise Renal/métodos , Albuminas/uso terapêuticoRESUMO
Liver transplantation is the only effective therapy to reduce the high mortality associated with acute liver failure and acute on chronic liver failure (ACLF). Single-pass albumin dialysis (SPAD) is an extracorporeal supportive therapy used as a bridge to liver transplantation or regeneration. We report a 44-year-old man with alcoholic cirrhosis admitted for critical COVID-19 pneumonia that evolves with ACLF. SPAD technique was performed completing six sessions, with a reduction of bilirubin and ammonia levels. He evolved with severe respiratory failure and refractory septic shock, dying. SPAD is a safe and efficient technique aimed to eliminate liver toxins, preventing multiorgan damage interrupting the process known as the "autointoxication hypothesis". It is easy to implement in any critical patient unit and has lower costs than other extracorporeal liver support therapies.
Assuntos
Insuficiência Hepática Crônica Agudizada , COVID-19 , Transplante de Fígado , Masculino , Humanos , Adulto , Diálise Renal/métodos , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/terapia , COVID-19/complicações , Albuminas/uso terapêuticoRESUMO
Introduction: Acute-on-chronic liver failure (ACLF) is an acute liver decompensation in cirrhotic patients, which leads to organ failures and high short-term mortality. The treatment is based on the management of complications and, in severe cases, liver transplantation. Since specific treatment is unavailable, we aimed to evaluate the safety and initial efficacy of bone marrow mesenchymal stem cells (BM-MSC) in patients with ACLF Grades 2 and 3, a population excluded from previous clinical trials. Methods: This is a randomized placebo-controlled phase I-II single center study, which enrolled 9 cirrhotic patients from 2018 to 2020, regardless of the etiology. The control group (n = 5) was treated with standard medical therapy (SMT) and placebo infusion of saline. The intervention group (n = 4) received SMT plus 5 infusions of 1 × 106 cells/kg of BM-MSC for 3 weeks. Both groups were monitored for 90 days. A Chi-square test was used for qualitative variables, and the t-test and Mann-Whitney U test for quantitative variables. The Kaplan-Meier estimator was used to build survival curves. In this study, we followed the intention-to-treat analysis, with a significance of 5%. Results: Nine patients with a mean Child-Pugh (CP) of 12.3, MELD of 38.4, and CLIF-C score of 50.7 were recruited. Hepatitis C and alcohol were the main etiologies. The average infusion per patient was 2.9 and only 3 patients (2 in control and 1 in the BM-MSC group) received all the protocol infusions. There were no infusion-related side effects, although one patient in the intervention group presented hypernatremia and a gastric ulcer, after the third and fifth infusions, respectively. The survival rate after 90 days was 20% (1/5) for placebo versus 25% (1/4) for the BM-MSC. The patient who completed the entire MSC protocol showed a significant improvement in CP (C-14 to B-9), MELD (32 to 22), and ACLF (grade 3 to 0). Conclusion: BM-MSC infusion is safe and feasible in patients with ACLF Grades 2 and 3.
Assuntos
Insuficiência Hepática Crônica Agudizada , Células-Tronco Mesenquimais , Insuficiência Hepática Crônica Agudizada/terapia , Humanos , Prognóstico , Estatísticas não Paramétricas , Análise de Sobrevida , Taxa de SobrevidaRESUMO
INTRODUCTION AND OBJECTIVES: Acute on Chronic Liver Failure (ACLF) is characterized by organ failure and high 28-day mortality. Identifying clinical predictors associated with early mortality could have implications for the treatment of patients with ACLF. PATIENTS AND METHODS: Patients diagnosed with chronic liver failure that developed ACLF based on the EASL-CLIF Consortium definition admitted to the Intensive care unit of a tertiary hospital between 2012-2018 were included. Bivariate and multivariate Cox regression analyses were performed to identify factors associated with mortality. RESULTS: 148 patients (55% female) were diagnosed with ACLF of which 55% (nâ¯=â¯82) had ACLF grade 3, 28% (nâ¯=â¯41) grade 2 and 17% (nâ¯=â¯25) grade 1. The median age was 54 years (41-63). Hepatitis C virus (HCV) was the most frequent etiology in 29.8% (nâ¯=â¯44) of the patients with bacterial infection being the most predominant precipitant factor in 58.1% (nâ¯=â¯86). Ninety-day global cumulative survival was only 18%. When divided by grade, mortality reached to 10% in ACLF 3. Moreover, in the multivariate Cox regression analysis, renal failure (HR 3.26, 95% CI (2.13-4.99), brain failure (HR 1.37, 95% CI 1.09-2.04) and male sex (HR 1.62, 95% CI 1.10-2.40) were independent predictors of 28- and 90-day mortality. CONCLUSIONS: ACLF is a frequent syndrome among chronic liver disease patients. Brain and renal failure are significantly associated with higher mortality and are independent predictors of 28 and 90-day mortality.
Assuntos
Insuficiência Hepática Crônica Agudizada/mortalidade , Encefalopatias/epidemiologia , Doença Hepática Terminal/complicações , Doença Hepática Terminal/mortalidade , Insuficiência Renal/epidemiologia , Insuficiência Hepática Crônica Agudizada/diagnóstico , Insuficiência Hepática Crônica Agudizada/terapia , Adulto , Cuidados Críticos , Doença Hepática Terminal/terapia , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
Acute on chronic liver failure is an increasingly recognized syndrome characterized by acute decompensation of chronic liver disease associated with organ failure and high short-term mortality. ACLF is frequent, affecting between 24 and 40% of patients admitted for complications of cirrhosis. Sepsis, active alcoholism, and relapse of chronic viral hepatitis are the most frequent precipitating factors. However, in up to 40%50% of the cases of ACLF have no identifiable trigger. The stage of severity of Acute on chronic liver failure is very important because it allows us to stratify patients according to their prognosis, evaluate therapeutic response, determine transplant urgency, deciding intensive care unit admission, and also have a basis on which to decide therapeutic futility. (AU)
Assuntos
Humanos , Insuficiência Hepática Crônica Agudizada/diagnóstico , Insuficiência Hepática Crônica Agudizada/fisiopatologia , Falência Hepática Aguda , Insuficiência Hepática Crônica Agudizada/terapiaRESUMO
The aim of this study was to propose a stem cell therapy for hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) based on plasma exchange (PE) for peripheral blood stem cell (PBSC) collection and examine its safety and efficacy. Sixty patients (n=20 in each group) were randomized to PE (PE alone), granulocyte colony-stimulating factor (G-CSF) (PE after G-CSF treatment), and PBSC transplantation (PBSCT) (G-CSF, PE, PBSC collection and hepatic artery injection) groups. Patients were followed-up for 24 weeks. Liver function and adverse events were recorded. Survival analysis was performed. PBSCT improved blood ammonia levels at 1 week (P<0.05). The level of total bilirubin, international normalized ratio, and creatinine showed significant differences in the 4th week of treatment (P<0.05). The survival rates of the PE, G-CSF, and PBSCT groups were 50, 65, and 85% at 90 days (P=0.034). There was a significant difference in 90-day survival between the PE and PBSCT groups (P=0.021). The preliminary results suggested that PBSCT was safe, with a possibility of improved 90-day survival in patients with HBV-ACLF.
Assuntos
Insuficiência Hepática Crônica Agudizada , Vírus da Hepatite B , Hepatite B/complicações , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/terapia , Adulto , Feminino , Fator Estimulador de Colônias de Granulócitos , Humanos , Masculino , Pessoa de Meia-Idade , Troca Plasmática , Transplante de Células-TroncoRESUMO
BACKGROUND: Cystatin C (CysC) is an early biomarker of renal dysfunction scarcely studied in patients awaiting liver transplantation (LT). Sarcopenia is frequent in cirrhosis and impacts prognosis. We aimed to assess the capability of these factors to predict survival and acute-on-chronic liver failure (ACLF) in patients awaiting LT, as well as early post-LT outcomes. METHODS: Single-center study that included all cirrhotic patients listed for LT between 2014 and 2017. Competing risk regression analysis was used to evaluate the capability of liver-, kidney-, and global status-related variables at waitlist (WL) inclusion to predict WL mortality and ACLF. Variables associated with post-LT outcomes were evaluated with logistic regression analysis. RESULTS: One-hundred-and-eighty patients were included. Fifty-six (31%) patients developed ACLF, 54 (30%) underwent LT and 35 (19%) died. In the adjusted competing risk regression analysis, CysC ≥ 1.5 mg/L, sarcopenia and MELD-Na were independent predictors of ACLF in the WL, while CysC ≥ 1.5 mg/L, sarcopenia and albumin were independent predictors of mortality. The cumulative incidence of ACLF and mortality at 12 months were 50% and 34% in patients with sarcopenia and CysC ≥1.5 mg/L. An estimated glomerular filtration rate by chronic kidney disease (CKD)-EPI-CysC-creatinine <60 mL/min/1.73 m at WL inclusion was an independent predictor of the need for renal replacement therapy (RRT) in the first month post-LT. CONCLUSIONS: Higher levels of CysC and sarcopenia are strongly associated with the ACLF and mortality in WL. The assessment of both risk factors may improve the prognostic evaluation and allow identifying a group of patients with a very high risk of poor outcomes while awaiting LT.