RESUMEN
BACKGROUND & AIMS: In ACLF patients, an adequate risk stratification is essential, especially for liver transplant allocation, since ACLF is associated with high short-term mortality. The CLIF-C ACLF score is the best prognostic model to predict outcome in ACLF patients. While lung failure is generally regarded as signum malum in ICU care, this study aims to evaluate and quantify the role of pulmonary impairment on outcome in ACLF patients. METHODS: In this retrospective study, 498 patients with liver cirrhosis and admission to IMC/ICU were included. ACLF was defined according to EASL-CLIF criteria. Pulmonary impairment was classified into three groups: unimpaired ventilation, need for mechanical ventilation and defined pulmonary failure. These factors were analysed in different cohorts, including a propensity score-matched ACLF cohort. RESULTS: Mechanical ventilation and pulmonary failure were identified as independent risk factors for increased short-term mortality. In matched ACLF patients, the presence of pulmonary failure showed the highest 28-day mortality (83.7%), whereas mortality rates in ACLF with mechanical ventilation (67.3%) and ACLF without pulmonary impairment (38.8%) were considerably lower (p < .001). Especially in patients with pulmonary impairment, the CLIF-C ACLF score showed poor predictive accuracy. Adjusting the CLIF-C ACLF score for the grade of pulmonary impairment improved the prediction significantly. CONCLUSIONS: This study highlights that not only pulmonary failure but also mechanical ventilation is associated with worse prognosis in ACLF patients. The grade of pulmonary impairment should be considered in the risk assessment in ACLF patients. The new score may be useful in the selection of patients for liver transplantation.
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Insuficiencia Hepática Crónica Agudizada , Humanos , Estudios Retrospectivos , Enfermedad Crítica , Cirrosis Hepática/complicaciones , Pronóstico , PulmónRESUMEN
BACKGROUND & AIMS: It remains unclear whether rectal colonization with multidrug-resistant organisms (MDROs) is prevalent and predisposes to infections by the same pathogens in patients with cirrhosis. METHODS: Two series of critically ill patients were evaluated. In the Barcelona cohort, 486 consecutive patients were prospectively evaluated, 129 with and 357 without cirrhosis (2015-2016). Rectal swabs were performed at admission and weekly thereafter (until intensive care unit [ICU] discharge) to detect MDRO colonization. Risk factors for colonization and infection by MDROs were evaluated. A retrospective cohort from Frankfurt (421 patients with cirrhosis; 2010-2018) was investigated to evaluate MDRO rectal colonization in another epidemiological scenario. RESULTS: In the Barcelona cohort, 159 patients were colonized by MDROs (32.7%), 102 (64.2%) at admission and 57 (35.8%) during follow-up. Patients with cirrhosis showed higher rates of rectal colonization at admission than those without cirrhosis (28.7% vs. 18.2%, p = 0.01) but similar colonization rates during ICU stay. Extended-spectrum beta-lactamase-Enterobacterales were the most frequent MDROs isolated in both groups. Colonization by MDROs independently increased the risk of infection by MDROs at admission and during follow-up. Risk of new infection by the colonizing strain was also significantly increased in patients with (hazard ratio [HR] 7.41) and without (HR 5.65) cirrhosis. Rectal colonization by MDROs was also highly prevalent in Frankfurt (n = 198; 47%; 131 at admission [66.2%] and 67 [33.8%] during follow-up), with vancomycin-resistant enterococci being the most frequent colonizing organism. Rectal colonization by MDROs was also associated with an increased risk of infection by MDROs in this cohort. Infections occurring in MDR carriers were mainly caused by the colonizing strain. CONCLUSION: Rectal colonization by MDROs is extremely frequent in critically ill patients with cirrhosis. Colonization increases the risk of infection by the colonizing resistant strain. LAY SUMMARY: Rectal colonization by multidrug-resistant organisms (MDROs) is a prevalent problem in patients with cirrhosis requiring critical care. The pattern of colonizing bacteria is heterogeneous with relevant differences between centers. Colonization by MDROs is associated with increased risk of infection by the colonizing bacteria in the short term. This finding suggests that colonization data could be used to guide empirical antibiotic therapy and de-escalation policies in patients with cirrhosis.
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Enfermedad Crítica , Staphylococcus aureus Resistente a Meticilina , Antibacterianos/uso terapéutico , Bacterias , Farmacorresistencia Bacteriana Múltiple , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes. METHODS: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. RESULTS: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality. CONCLUSIONS: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis. LAY SUMMARY: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.
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Insuficiencia Hepática Crónica Agudizada , Infecciones Bacterianas , Hepatitis Alcohólica , Cirrosis Hepática , Servicios Preventivos de Salud/métodos , Insuficiencia Hepática Crónica Agudizada/sangre , Insuficiencia Hepática Crónica Agudizada/diagnóstico , Insuficiencia Hepática Crónica Agudizada/etiología , Insuficiencia Hepática Crónica Agudizada/prevención & control , Infecciones Bacterianas/complicaciones , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/tratamiento farmacológico , Progresión de la Enfermedad , Europa (Continente)/epidemiología , Femenino , Hepatitis Alcohólica/complicaciones , Hepatitis Alcohólica/diagnóstico , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Cirrosis Hepática/epidemiología , Cirrosis Hepática/fisiopatología , Masculino , Anamnesis/estadística & datos numéricos , Persona de Mediana Edad , Evaluación de Necesidades , Puntuaciones en la Disfunción de Órganos , Factores Desencadenantes , PronósticoRESUMEN
BACKGROUND AND AIM: Acute-on-chronic liver failure (ACLF) is a sinister prognosis, and there is a need for accurate biomarkers and scoring systems to better characterize ACLF patients and predict prognosis. Systemic inflammation and renal failure are hallmarks in ACLF disease development and progression. We hypothesized that the combination of specific inflammatory markers in combination with clinical scores are better predictors of survival than the originally developed CLIF-C acute decompensation (AD) and CLIF-C ACLF scores. METHODS: We reevaluated all previously measured inflammatory markers in 522 patients from the CANONIC study, 342 without and 180 with ACLF. We used the Harrell's C-index to determine the best marker alone or in combination with the original scores and calculated new scores for prediction of mortality in the original CANONIC cohort. RESULTS: The best markers to predict 90-day mortality in patients without ACLF were the plasma macrophage activation markers soluble (s)CD163 and mannose receptor (sMR). Urinary neutrophil gelatinase associated lipocalin (UNGAL) and sCD163 were predictors for 28-day mortality in patients with ACLF. The newly developed CLIF-C AD + sMR score in patients without ACLF improved 90-day mortality prediction compared with the original CLIF-C AD score (C-index 0.82 [0.78-0.86] vs 0.74 [0.70-0.78, P = 0.004]). Further, the new CLIF-C ACLF + sCD163 + UNGAL improved the original CLIF-C ACLF score for 28-day mortality (0.85 [0.79-0.91] vs 0.75 [0.70-0.80], P = 0.039). CONCLUSIONS: The capability of these inflammatory markers to improve the original prognostic scores in cirrhosis patients without and with ACLF points to a key role of macrophage activation and inflammation in the development and progression of AD and ACLF.
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Insuficiencia Hepática Crónica Agudizada/diagnóstico , Insuficiencia Hepática Crónica Agudizada/mortalidad , Mediadores de Inflamación/sangre , Puntuaciones en la Disfunción de Órganos , Adulto , Anciano , Antígenos CD/sangre , Antígenos de Diferenciación Mielomonocítica/sangre , Biomarcadores/sangre , Biomarcadores/orina , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Lectinas Tipo C/sangre , Lipocalina 2/orina , Activación de Macrófagos , Masculino , Receptor de Manosa , Lectinas de Unión a Manosa/sangre , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Receptores de Superficie Celular/sangre , Factores de TiempoRESUMEN
BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a newly described syndrome, which develops in patients with acute decompensation of cirrhosis, and is characterized by intense systemic inflammation, multiple organ failures and high short-term mortality. The profile of circulating lipid mediators, which are endogenous signaling molecules that play a major role in inflammation and immunity, is poorly characterized in ACLF. METHODS: In the current study, we assessed the profile of lipid mediators by liquid chromatography coupled to tandem mass spectrometry in plasma from patients with acute decompensation of cirrhosis, with (n = 119) and without (n = 127) ACLF, and from healthy controls (n = 18). Measurements were prospectively repeated in 191 patients with acute decompensation of cirrhosis during a 28-day follow-up period. RESULTS: Fifty-nine lipid mediators (out of 100) were detected in plasma from cirrhotic patients, of which 16 were significantly associated with disease status. Among these, 11 lipid mediators distinguished patients at any stage from healthy controls, whereas 2 lipid mediators (LTE4 and 12-HHT, both derived from arachidonic acid) shaped a minimal plasma fingerprint that discriminated patients with ACLF from those without. Levels of LTE4 distinguished ACLF grade 3 from ACLF grades 1 and 2, followed the clinical course of the disease (increased with worsening and decreased with improvement) and positively correlated with markers of inflammation and non-apoptotic cell death. Moreover, LTE4 together with LXA5 (derived from eicosapentaenoic acid) and EKODE (derived from linoleic acid) were associated with short-term mortality. LXA5 and EKODE formed a signature associated with coagulation and liver failures. CONCLUSION: Taken together, these findings uncover specific lipid mediator profiles associated with disease severity and prognosis in patients with acute decompensation of cirrhosis. LAY SUMMARY: Acute-on-chronic liver failure (ACLF) is characterized by intense systemic inflammation, multiple organ failures and high short-term mortality. In the current study, we assessed the plasma lipid profile of 100 bioactive lipid mediators in healthy controls, patients with decompensated cirrhosis, and those who had developed ACLF. We identified lipid mediator signatures associated with inflammation and non-apoptotic cell death that discriminate disease severity and evolution, short-term mortality and organ failures.
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Insuficiencia Hepática Crónica Agudizada/sangre , Metabolismo de los Lípidos , Lipidómica/métodos , Lípidos/sangre , Anciano , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
BACKGROUND & AIMS: High-density lipoprotein cholesterol (HDL-C) levels are reduced in patients with chronic liver disease and inversely correlate with disease severity. During acute conditions such as sepsis, HDL-C levels decrease rapidly and HDL particles undergo profound changes in their composition and function. We aimed to determine whether indices of HDL quantity and quality associate with progression and survival in patients with advanced liver disease. METHODS: HDL-related biomarkers were studied in 508 patients with compensated or decompensated cirrhosis (including acute-on-chronic liver failure [ACLF]) and 40 age- and gender-matched controls. Specifically, we studied levels of HDL-C, its subclasses HDL2-C and HDL3-C, and apolipoprotein A1 (apoA-I), as well as HDL cholesterol efflux capacity as a metric of HDL functionality. RESULTS: Baseline levels of HDL-C and apoA-I were significantly lower in patients with stable cirrhosis compared to controls and were further decreased in patients with acute decompensation (AD) and ACLF. In stable cirrhosis (n = 228), both HDL-C and apoA-I predicted the development of liver-related complications independently of model for end-stage liver disease (MELD) score. In patients with AD, with or without ACLF (n = 280), both HDL-C and apoA-I were MELD-independent predictors of 90-day mortality. On ROC analysis, both HDL-C and apoA-I had high diagnostic accuracy for 90-day mortality in patients with AD (AUROCs of 0.79 and 0.80, respectively, similar to that of MELD 0.81). On Kaplan-Meier analysis, HDL-C <17 mg/dl and apoA-I <50 mg/dl indicated poor short-term survival. The prognostic accuracy of HDL-C was validated in a large external validation cohort of 985 patients with portal hypertension due to advanced chronic liver disease (AUROCs HDL-C: 0.81 vs. MELD: 0.77). CONCLUSION: HDL-related biomarkers are robust predictors of disease progression and survival in chronic liver failure. LAY SUMMARY: People who suffer from cirrhosis (scarring of the liver) have low levels of cholesterol carried by high-density lipoproteins (HDL-C). These alterations are connected to inflammation, which is a problem in severe liver disease. Herein, we show that reduced levels of HDL-C and apolipoprotein A-I (apoA-I, the main protein carried by HDL) are closely linked to the severity of liver failure, its complications and survival. Both HDL-C and apoA-I can be easily measured in clinical laboratories and are as good as currently used prognostic scores calculated from several laboratory values by complex formulas.
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Insuficiencia Hepática Crónica Agudizada , Apolipoproteína A-I , HDL-Colesterol , Lipoproteínas HDL2 , Lipoproteínas HDL3 , Cirrosis Hepática , Insuficiencia Hepática Crónica Agudizada/sangre , Insuficiencia Hepática Crónica Agudizada/diagnóstico , Insuficiencia Hepática Crónica Agudizada/epidemiología , Insuficiencia Hepática Crónica Agudizada/metabolismo , Apolipoproteína A-I/sangre , Apolipoproteína A-I/metabolismo , Biomarcadores , HDL-Colesterol/sangre , HDL-Colesterol/metabolismo , Estudios Transversales , Progresión de la Enfermedad , Europa (Continente)/epidemiología , Femenino , Humanos , Lipoproteínas HDL2/sangre , Lipoproteínas HDL2/metabolismo , Lipoproteínas HDL3/sangre , Lipoproteínas HDL3/metabolismo , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/epidemiología , Masculino , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Valor Predictivo de las Pruebas , Pronóstico , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. METHODS: A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. RESULTS: Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). CONCLUSIONS: Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. CLINICALTRIALS. GOV NUMBER: NCT03056612. LAY SUMMARY: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk.
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Insuficiencia Hepática Crónica Agudizada/complicaciones , Hipertensión Portal/fisiopatología , Cirrosis Hepática/fisiopatología , Insuficiencia Hepática Crónica Agudizada/mortalidad , Insuficiencia Hepática Crónica Agudizada/fisiopatología , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Hipertensión Portal/etiología , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Tasa de Supervivencia/tendenciasRESUMEN
BACKGROUND & AIMS: We investigated the effect of albumin treatment (20% solution) on hypoalbuminemia, cardiocirculatory dysfunction, portal hypertension, and systemic inflammation in patients with decompensated cirrhosis with and without bacterial infections. METHODS: We performed a prospective study to assess the effects of long-term (12 weeks) treatment with low doses (1 g/kg body weight every 2 weeks) and high doses (1.5 g/kg every week) of albumin on serum albumin, plasma renin, cardiocirculatory function, portal pressure, and plasma levels of cytokines, collecting data from 18 patients without bacterial infections (the Pilot-PRECIOSA study). We also assessed the effect of short-term (1 week) treatment with antibiotics alone vs the combination of albumin plus antibiotics (1.5 g/kg on day 1 and 1 g/kg on day 3) on plasma levels of cytokines in biobanked samples from 78 patients with bacterial infections included in a randomized controlled trial (INFECIR-2 study). RESULTS: Circulatory dysfunction and systemic inflammation were extremely unstable in many patients included in the Pilot-PRECIOSA study; these patients had intense and reversible peaks in plasma levels of renin and interleukin 6. Long-term high-dose albumin, but not low-dose albumin, was associated with normalization of serum level of albumin, improved stability of the circulation and left ventricular function, and reduced plasma levels of cytokines (interleukin 6, granulocyte colony-stimulating factor, interleukin 1 receptor antagonist, and vascular endothelial growth factor) without significant changes in portal pressure. The immune-modulatory effects of albumin observed in the Pilot-PRECIOSA study were confirmed in the INFECIR-2 study. In this study, patients given albumin had significant reductions in plasma levels of cytokines. CONCLUSIONS: In an analysis of data from 2 trials (Pilot-PRECIOSA study and INFECIR-2 study), we found that albumin treatment reduced systemic inflammation and cardiocirculatory dysfunction in patients with decompensated cirrhosis. These effects might be responsible for the beneficial effects of albumin therapy on outcomes of patients with decompensated cirrhosis. ClinicalTrials.gov, Numbers: NCT00968695 and NCT03451292.
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Albúminas/administración & dosificación , Infecciones Bacterianas/inmunología , Citocinas/inmunología , Hipertensión Portal/fisiopatología , Hipoalbuminemia/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Albúmina Sérica/metabolismo , Infecciones Bacterianas/complicaciones , Infecciones Bacterianas/fisiopatología , Estudios de Casos y Controles , Femenino , Hemodinámica , Humanos , Hipertensión Portal/etiología , Hipoalbuminemia/etiología , Hipoalbuminemia/inmunología , Hipoalbuminemia/fisiopatología , Inflamación , Circulación Hepática , Cirrosis Hepática/complicaciones , Cirrosis Hepática/inmunología , Cirrosis Hepática/fisiopatología , Masculino , Persona de Mediana Edad , Presión Portal , Sistema Porta , Estudios Prospectivos , Renina/sangreRESUMEN
BACKGROUND & AIMS: We performed a randomized trial to determine whether albumin should be administered to patients with infections unrelated to spontaneous bacterial peritonitis (SBP). METHODS: We performed a multicenter, open-label trial in which 118 patients with cirrhosis, non-SBP infections, and additional risk factors for poor outcome were randomly assigned to receive antibiotics plus albumin (study group; n = 61) or antibiotics alone (control group; n = 57). The primary outcome was in-hospital mortality; secondary outcomes were effect of albumin on disease course. RESULTS: There were no significant differences at baseline between groups in results from standard laboratory tests, serum markers of inflammation, circulatory dysfunction, or liver severity scores. However, the combined prevalence of acute on chronic liver failure (ACLF) and kidney dysfunction was significantly higher in the study group (44.3% vs 24.6% in the control group; P = .02), indicating greater baseline overall severity. There was no significant difference in the primary outcome between groups (13.1% in the study group vs 10.5% in the control group; P = .66). Circulatory and renal functions improved in only the study group. A significantly higher proportion of patients in the study group had resolution of ACLF (82.3% vs 33.3% in the control group; P = .03). A significantly lower proportion of patients in the study group developed nosocomial infections (6.6% vs 24.6% in the control group; P = .007). CONCLUSIONS: In a randomized trial of patients with advanced cirrhosis and non-SBP infections, in-hospital mortality was similar between those who received albumin plus antibiotics vs those who received only antibiotics (controls). However, patients given albumin were sicker at baseline and, during the follow-up period, a higher proportion had ACLF resolution and a lower proportion had nosocomial infections. ClinicalTrials.gov no: NCT02034279.
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Insuficiencia Hepática Crónica Agudizada , Infecciones Bacterianas , Peritonitis , Albúminas , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/epidemiología , Humanos , Cirrosis Hepática/complicaciones , Peritonitis/tratamiento farmacológico , Peritonitis/epidemiologíaRESUMEN
Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute-on-chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28-day follow-up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short-term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow-up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow-up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow-up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality.
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Insuficiencia Hepática Crónica Agudizada/etiología , Quinurenina/sangre , Cirrosis Hepática/complicaciones , Triptófano/sangre , Insuficiencia Hepática Crónica Agudizada/sangre , Anciano , Infecciones Bacterianas/sangre , Infecciones Bacterianas/complicaciones , Estudios de Casos y Controles , Europa (Continente)/epidemiología , Femenino , Encefalopatía Hepática/sangre , Encefalopatía Hepática/complicaciones , Humanos , Inflamación/sangre , Inflamación/complicaciones , Cirrosis Hepática/sangre , Cirrosis Hepática/mortalidad , Cirrosis Hepática/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Insuficiencia Renal/sangre , Insuficiencia Renal/complicacionesRESUMEN
BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation of cirrhosis (AD), organ failure(s) and high risk of short-term mortality with bacterial infection frequently as precipitating event. Innate immune pattern recognition receptors and members of the lectin pathway of complement activation are crucial to the innate immune response to pathogens. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) of innate immune components are associated with the occurrence of bacterial infections or mortality in patients with cirrhosis hospitalized for AD or ACLF. METHODS: Twenty-one innate immunity SNPs with known functional implications were genotyped in 826 AD/ACLF patients included in the CANONIC study. Associations between baseline characteristics of the patients, the occurrence of bacterial infections and survival rate at 90 days of follow-up in relation to the innate immunity genetic variants were analysed. RESULTS: The NOD2-G908R genetic variant was associated with mortality (HR 2.25, P = .004) independently of age and MELD Score. This association was also found in a predefined subgroup analysis in patients with bacterial infections (HR 2.78, P < .001) along with MBL_Yx (HR 1.72, P = .008) and MASP2_371 (HR 1.67, P = .012) genetic variants. None of the analysed SNPs were significantly associated with the occurrence of acute bacterial infections or spontaneous bacterial peritonitis in particular. CONCLUSIONS: Innate immune system-specific NOD2-G908R, MBL_Yx and MASP2_371 genetic variants were independently associated with increased risk of short-term mortality in AD/ACLF patients with bacterial infection.
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Insuficiencia Hepática Crónica Agudizada , Infecciones Bacterianas , Peritonitis , Insuficiencia Hepática Crónica Agudizada/genética , Infecciones Bacterianas/genética , Humanos , Inmunidad Innata/genética , Cirrosis Hepática/genética , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Proteína Adaptadora de Señalización NOD2/genéticaRESUMEN
BACKGROUND & AIMS: Antibiotic resistance has been increasingly reported in patients with decompensated cirrhosis in single-center studies. Prospective investigations reporting broad epidemiological data are scarce. We aimed to analyze epidemiological changes in bacterial infections in patients with decompensated cirrhosis. METHODS: This was a prospective evaluation of 2 series of patients hospitalized with decompensated cirrhosis. The Canonic series included 1,146 patients from Northern, Southern and Western Europe in 2011. Data on epidemiology, clinical characteristics of bacterial infections, microbiology and empirical antibiotic schedules were assessed. A second series of 883 patients from Eastern, Southern and Western Europe was investigated between 2017-2018. RESULTS: A total of 455 patients developed 520 infections (39.7%) in the first series, with spontaneous bacterial peritonitis, urinary tract infections and pneumonia the most frequent infections. Nosocomial episodes predominated in this series. Nearly half of the infections were culture-positive, of which 29.2% were caused by multidrug-resistant organisms (MDROs). MDR strains were more frequently isolated in Northern and Western Europe. Extended-spectrum beta-lactamase-producing Enterobacteriaceae were the most frequent MDROs isolated in this series, although prevalence and type differed markedly among countries and centers. Antibiotic resistance was associated with poor prognosis and failure of antibiotic strategies, based on third-generation cephalosporins or quinolones. Nosocomial infection (odds ratio [OR] 2.74; pâ¯<â¯0.001), intensive care unit admission (OR 2.09; pâ¯=â¯0.02), and recent hospitalization (OR 1.93; pâ¯=â¯0.04) were identified as independent predictors of MDR infection. The prevalence of MDROs in the second series (392 infections/284 patients) was 23%; 38% in culture-positive infections. A mild increase in the rate of carbapenem-resistant Enterobacteriaceae was observed in this series. CONCLUSIONS: MDR bacterial infections constitute a prevalent, growing and complex healthcare problem in patients with decompensated cirrhosis and acute-on-chronic liver failure across Europe, negatively impacting on prognosis. Strategies aimed at preventing the spread of antibiotic resistance in cirrhosis should be urgently evaluated. LAY SUMMARY: Infections caused by bacteria resistant to the main antibiotic families are prevalent in patients with cirrhosis. This study demonstrates that this healthcare problem is increasing and extends through all European regions. Infections caused by these difficult to treat bacteria resolve less frequently and often cause the death of the patient. The type of resistant bacteria varies markedly among different hospitals.
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Insuficiencia Hepática Crónica Agudizada , Antibacterianos/farmacología , Bacterias , Infecciones Bacterianas , Farmacorresistencia Bacteriana Múltiple , Cirrosis Hepática , Insuficiencia Hepática Crónica Agudizada/epidemiología , Insuficiencia Hepática Crónica Agudizada/terapia , Bacterias/clasificación , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Infecciones Bacterianas/clasificación , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/epidemiología , Infecciones Bacterianas/microbiología , Infección Hospitalaria/epidemiología , Progresión de la Enfermedad , Europa (Continente)/epidemiología , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Cirrosis Hepática/fisiopatología , Cirrosis Hepática/terapia , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Prevalencia , Pronóstico , Estudios Prospectivos , Factores de RiesgoRESUMEN
Balanced hemostasis with hypocoagulable and hypercoagulable features may occur in acute-on-chronic liver failure (ACLF). The characteristics and prognostic impact of the coagulation profile in ACLF are unknown. Consecutive patients with ACLF (n = 36) and acute decompensation (AD; n = 24) were included. Blood samples for thromboelastometry (TE) were obtained at admission and 72 hours thereafter. The coagulation profile was evaluated in patients with and without ACLF and in those with and without systemic inflammatory response syndrome. The impact of the coagulation profile on transfusion requirements, bleeding events, and short-term survival was assessed. At admission, patients with ACLF showed more hypocoagulable characteristics compared to AD subjects, with prolonged time to initial fibrin formation and clot formation time and decreased maximum clot firmness and alpha-angle values. TE parameters worsened at 72 hours in ACLF but improved in patients with AD. Prevalence of a hypocoagulable profile (three or more TE parameters outside range) was significantly higher in patients with ACLF either at admission (61% versus 29% in AD; P = 0.03) or during follow-up. Hypocoagulability correlated with systemic inflammation and was associated with higher 28-day (45% versus 16%; P = 0.02) and 90-day (52% versus 19%; P = 0.01) mortality rates but not with transfusion requirements or bleeding. Prolonged time to initial fibrin formation (extrinsic TE assay >80 seconds) and Model for End-Stage Liver Disease score at baseline were independent predictors of 28-day mortality. Conclusion: Patients with ACLF frequently show hypocoagulable features with prolonged time to initial fibrin formation and clot formation time and reduced clot firmness; these alterations worsen after admission, correlate with systemic inflammation, and translate into higher short-term mortality; hypofibrinolysis could contribute to organ failure in ACLF.
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Insuficiencia Hepática Crónica Agudizada/sangre , Trastornos de la Coagulación Sanguínea/etiología , Coagulación Sanguínea , Cirrosis Hepática/sangre , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Insuficiencia Hepática Crónica Agudizada/etiología , Insuficiencia Hepática Crónica Agudizada/mortalidad , Adulto , Anciano , Femenino , Humanos , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Estudios Prospectivos , España/epidemiología , Síndrome de Respuesta Inflamatoria Sistémica/etiología , TromboelastografíaRESUMEN
The aims of this study were to determine the role of cell death in patients with cirrhosis and acute decompensation (AD) and acute on chronic liver failure (ACLF) using plasma-based biomarkers. The patients studied were part of the CANONIC (CLIF Acute-on-Chronic Liver Failure in Cirrhosis) study (N = 337; AD, 258; ACLF, 79); additional cohorts included healthy volunteers, stable patients with cirrhosis, and a group of 16 AD patients for histological studies. Caspase-cleaved keratin 18 (cK18) and keratin 18 (K18), which reflect apoptotic and total cell death, respectively, and cK18:K18 ratio (apoptotic index) were measured in plasma by enzyme-linked immunosorbent assay. The concentrations of cK18 and K18 increased and the cK18:K18 ratio decreased with increasing severity of AD and ACLF (P < 0.001, respectively). Alcohol etiology, no previous decompensation, and alcohol abuse were associated with increased cell death markers whereas underlying infection was not. Close correlation was observed between the cell death markers and, markers of systemic inflammation, hepatic failure, alanine aminotransferase, and bilirubin, but not with markers of extrahepatic organ injury. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining confirmed evidence of greater hepatic cell death in patients with ACLF as opposed to AD. Inclusion of cK18 and K18 improved the performance of the CLIF-C AD score in prediction of progression from AD to ACLF (P < 0.05). CONCLUSION: Cell death, likely hepatic, is an important feature of AD and ACLF and its magnitude correlates with clinical severity. Nonapoptotic forms of cell death predominate with increasing severity of AD and ACLF. The data suggests that ACLF is a heterogeneous entity and shows that the importance of cell death in its pathophysiology is dependent on predisposing factors, precipitating illness, response to injury, and type of organ failure. (Hepatology 2018;67:989-1002).
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Insuficiencia Hepática Crónica Agudizada/fisiopatología , Biomarcadores/sangre , Muerte Celular , Queratina-18/sangre , Cirrosis Hepática/fisiopatología , Insuficiencia Hepática Crónica Agudizada/sangre , Insuficiencia Hepática Crónica Agudizada/complicaciones , Adulto , Anciano , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Hígado/patología , Cirrosis Hepática/sangre , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Análisis de SupervivenciaRESUMEN
Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival. PATIENTS: 407 patients with ACLF and 235 patients with acute decompensation (AD). RESULTS: 152 patients (37%) presented bacterial infections at ACLF diagnosis; 46%(n=117) of the remaining 255 patients with ACLF developed bacterial infections during follow-up (4 weeks). The corresponding figures in patients with AD were 25% and 18% (p<0.001). Severe infections (spontaneous bacterial peritonitis, pneumonia, severe sepsis/shock, nosocomial infections and infections caused by multiresistant organisms) were more prevalent in patients with ACLF. Patients with ACLF and bacterial infections (either at diagnosis or during follow-up) showed higher grade of systemic inflammation at diagnosis of the syndrome, worse clinical course (ACLF 2-3 at final assessment: 47% vs 26%; p<0.001) and lower 90-day probability of survival (49% vs 72.5%;p<0.001) than patients with ACLF without infection. Bacterial infections were independently associated with mortality in patients with ACLF-1 and ACLF-2. Fungal infections developed in 9 patients with ACLF (2%) and in none with AD, occurred mainly after ACLF diagnosis (78%) and had high 90-day mortality (71%). CONCLUSION: Bacterial infections are extremely frequent in ACLF. They are severe and associated with intense systemic inflammation, poor clinical course and high mortality. Patients with ACLF are highly predisposed to develop bacterial infections within a short follow-up period and could benefit from prophylactic strategies.
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Insuficiencia Hepática Crónica Agudizada , Infecciones Bacterianas , Micosis , Insuficiencia Hepática Crónica Agudizada/diagnóstico , Insuficiencia Hepática Crónica Agudizada/microbiología , Insuficiencia Hepática Crónica Agudizada/mortalidad , Insuficiencia Hepática Crónica Agudizada/fisiopatología , Anciano , Infecciones Bacterianas/complicaciones , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/epidemiología , Progresión de la Enfermedad , Europa (Continente)/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Micosis/complicaciones , Micosis/diagnóstico , Micosis/epidemiología , Prevalencia , Pronóstico , Factores de Riesgo , Índice de Severidad de la Enfermedad , Análisis de SupervivenciaRESUMEN
BACKGROUND & AIMS: Type 1 hepatorenal syndrome (HRS) is the most high-risk type of renal failure in patients with cirrhosis. Terlipressin and albumin are effective treatments for type 1 HRS. However, the effects of acute on chronic liver failure (ACLF) grade on response to treatment are not clear. We aimed to identify factors associated with response to treatment with terlipressin and albumin in patients with type 1 HRS (reduction in serum level of creatinine to below 1.5 mg/dL at the end of treatment) and factors associated with death within 90 days of HRS diagnosis (90-day mortality). METHODS: We performed a retrospective analysis of 4 different cohorts of consecutive patients with HRS treated with terlipressin and albumin from February 2007 through January 2016 at medical centers in Europe (total, 298 patients). We analyzed demographic, clinical, and laboratory data collected before and during treatment; patients were followed until death, liver transplantation, or 90 days after HRS diagnosis. RESULTS: Response to treatment was observed in 53% of patients. Of patients with grade 1 ACLF, 60% responded to treatment; among those with grade 2 ACLF, 48% responded, and among those with grade 3 ACLF, 29% responded (P < .001 for comparison between grades). In multivariate analysis, baseline serum level of creatinine (odds ratio, 0.23; P = .001) and ACLF grade (odds ratio, 0.63; P = .01) were independently associated with response to treatment. Patient age (hazard ratio [HR], 1.05; P < .001), white blood cell count (HR, 1.51; P = .006), ACLF grade (HR, 2.06; P < .001), and no response to treatment (HR, 0.41; P < .001) associated with 90-day mortality. CONCLUSION: In a retrospective analysis of data from 4 cohorts of patients treated for type 1 HRS, we found ACLF grade to be the largest determinant of response to terlipressin and albumin. ACLF grade affects survival independently of response to treatment. New therapeutic strategies should be developed for patients with type 1 HRS and extrarenal organ failure.
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Insuficiencia Hepática Crónica Agudizada/patología , Antihipertensivos/administración & dosificación , Síndrome Hepatorrenal/complicaciones , Síndrome Hepatorrenal/tratamiento farmacológico , Albúmina Sérica Humana/administración & dosificación , Índice de Severidad de la Enfermedad , Terlipresina/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
UNLABELLED: Acute-on-chronic liver failure (ACLF) in cirrhosis is characterized by acute decompensation (AD), organ failure(s), and high short-term mortality. Recently, we have proposed (systemic inflammation [SI] hypothesis) that ACLF is the expression of an acute exacerbation of the SI already present in decompensated cirrhosis. This study was aimed at testing this hypothesis and included 522 patients with decompensated cirrhosis (237 with ACLF) and 40 healthy subjects. SI was assessed by measuring 29 cytokines and the redox state of circulating albumin (HNA2), a marker of systemic oxidative stress. Systemic circulatory dysfunction (SCD) was estimated by plasma renin (PRC) and copeptin (PCC) concentrations. Measurements were performed at enrollment (baseline) in all patients and sequentially during hospitalization in 255. The main findings of this study were: (1) Patients with AD without ACLF showed very high baseline levels of inflammatory cytokines, HNA2, PRC, and PCC. Patients with ACLF showed significantly higher levels of these markers than those without ACLF; (2) different cytokine profiles were identified according to the type of ACLF precipitating event (active alcoholism/acute alcoholic hepatitis, bacterial infection, and others); (3) severity of SI and frequency and severity of ACLF at enrollment were strongly associated. The course of SI and the course of ACLF (improvement, no change, or worsening) during hospitalization and short-term mortality were also strongly associated; and (4) the strength of association of ACLF with SI was higher than with SCD. CONCLUSION: These data support SI as the primary driver of ACLF in cirrhosis. (Hepatology 2016;64:1249-1264).
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Insuficiencia Hepática Crónica Agudizada/complicaciones , Inflamación/etiología , Cirrosis Hepática/complicaciones , Insuficiencia Hepática Crónica Agudizada/sangre , Biomarcadores/sangre , Citocinas/sangre , Humanos , Inflamación/sangre , Cirrosis Hepática/sangreRESUMEN
BACKGROUND & AIMS: Cirrhotic patients with acute decompensation frequently develop acute-on-chronic liver failure (ACLF), which is associated with high mortality rates. Recently, a specific score for these patients has been developed using the CANONIC study database. The aims of this study were to develop and validate the CLIF-C AD score, a specific prognostic score for hospitalised cirrhotic patients with acute decompensation (AD), but without ACLF, and to compare this with the Child-Pugh, MELD, and MELD-Na scores. METHODS: The derivation set included 1016 CANONIC study patients without ACLF. Proportional hazards models considering liver transplantation as a competing risk were used to identify score parameters. Estimated coefficients were used as relative weights to compute the CLIF-C ADs. External validation was performed in 225 cirrhotic AD patients. CLIF-C ADs was also tested for sequential use. RESULTS: Age, serum sodium, white-cell count, creatinine and INR were selected as the best predictors of mortality. The C-index for prediction of mortality was better for CLIF-C ADs compared with Child-Pugh, MELD, and MELD-Nas at predicting 3- and 12-month mortality in the derivation, internal validation and the external dataset. CLIF-C ADs improved in its ability to predict 3-month mortality using data from days 2, 3-7, and 8-15 (C-index: 0.72, 0.75, and 0.77 respectively). CONCLUSIONS: The new CLIF-C ADs is more accurate than other liver scores in predicting prognosis in hospitalised cirrhotic patients without ACLF. CLIF-C ADs therefore may be used to identify a high-risk cohort for intensive management and a low-risk group that may be discharged early.
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Creatinina/sangre , Relación Normalizada Internacional , Recuento de Leucocitos , Cirrosis Hepática , Sodio/sangre , Insuficiencia Hepática Crónica Agudizada , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/mortalidad , Cirrosis Hepática/fisiopatología , Cirrosis Hepática/terapia , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Proyectos de Investigación/normas , Medición de Riesgo/métodos , Análisis de SupervivenciaRESUMEN
BACKGROUND & AIMS: In spite of the high incidence of hepatic encephalopathy (HE) in cirrhosis, there are few observational studies. METHODS: We performed an analysis to define the characteristics of HE and associated features using the database of the Canonic Study. Clinical, laboratory and survival data of 1348 consecutive cirrhotic patients admitted with an acute decompensation were compared according to the presence (n=406) or absence of HE and of acute-on-chronic liver failure (ACLF) (n=301). RESULTS: HE development was independently associated with previous HE episodes; survival probabilities worsen in relation to the presence and grade of HE. There were marked differences between HE associated (n=174) and not associated (n=286) to ACLF. HE not associated with ACLF occurred in older cirrhotics, inactive drinkers, without severe liver failure or systemic inflammatory reaction and in relation to diuretic use. In contrast, HE associated with ACLF occurred in younger cirrhotics, more frequently alcoholics, with severe liver failure and systemic inflammatory reaction, and in relation to bacterial infections, active alcoholism and/or dilutional hyponatremia. Prognosis was relatively preserved in the first and extremely poor in the second group. Independent risk factors of mortality in patients with HE were age, bilirubin, INR, creatinine, sodium, and HE grade. CONCLUSIONS: In cirrhosis, previous HE identifies a subgroup of patients that is especially vulnerable for developing new episodes of HE. The course of HE appears to be different according to the presence of ACLF.
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Encefalopatía Hepática/etiología , Encefalopatía Hepática/mortalidad , Cirrosis Hepática/complicaciones , Cirrosis Hepática/mortalidad , Fallo Hepático Agudo/complicaciones , Fallo Hepático Agudo/mortalidad , Anciano , Enfermedad Hepática en Estado Terminal/complicaciones , Enfermedad Hepática en Estado Terminal/mortalidad , Femenino , Humanos , Cirrosis Hepática Alcohólica/complicaciones , Cirrosis Hepática Alcohólica/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Factores de Riesgo , España/epidemiología , Factores de TiempoRESUMEN
BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a frequent syndrome (30% prevalence), characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality. This study develops and validates a specific prognostic score for ACLF patients. METHODS: Data from 1349 patients included in the CANONIC study were used. First, a simplified organ function scoring system (CLIF Consortium Organ Failure score, CLIF-C OFs) was developed to diagnose ACLF using data from all patients. Subsequently, in 275 patients with ACLF, CLIF-C OFs and two other independent predictors of mortality (age and white blood cell count) were combined to develop a specific prognostic score for ACLF (CLIF Consortium ACLF score [CLIF-C ACLFs]). A concordance index (C-index) was used to compare the discrimination abilities of CLIF-C ACLF, MELD, MELD-sodium (MELD-Na), and Child-Pugh (CPs) scores. The CLIF-C ACLFs was validated in an external cohort and assessed for sequential use. RESULTS: The CLIF-C ACLFs showed a significantly higher predictive accuracy than MELDs, MELD-Nas, and CPs, reducing (19-28%) the corresponding prediction error rates at all main time points after ACLF diagnosis (28, 90, 180, and 365 days) in both the CANONIC and the external validation cohort. CLIF-C ACLFs computed at 48 h, 3-7 days, and 8-15 days after ACLF diagnosis predicted the 28-day mortality significantly better than at diagnosis. CONCLUSIONS: The CLIF-C ACLFs at ACLF diagnosis is superior to the MELDs and MELD-Nas in predicting mortality. The CLIF-C ACLFs is a clinically relevant, validated scoring system that can be used sequentially to stratify the risk of mortality in ACLF patients.