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BACKGROUND AND AIMS: Hepatic Venous Portal Gradient (HVPG) measurement remains the gold standard for estimating portal pressure gradient (PPG). AIM: To evaluate the correlation between EUS-guided portal pressure gradient (EUS-PPG) and HVPG in patients with chronic portal hypertension. PATIENTS AND METHODS: Patients with chronic portal hypertension in whom HVPG assessment was clinically indicated were invited to undergo transjugular HVPG and EUS-PPG with a 22G needle in separate sessions for comparison. Intra-class correlation coefficient (ICC), and Bland-Altman method were used to evaluate the agreement between techniques. RESULTS: 33 patients were included. No significant differences in technical success were observed: EUS-PPG (31/33, 93.9%) vs. HVPG (31/33, 93.9%). Thirty patients who underwent successful EUS-PPG and HVPG were analysed. Correlation between the two techniques showed an ICC: 0.82(0.65-0.91). Four patients had major discrepancies (≥ 5 mmHg) between HVPG and EUS-PPG. No significant differences in adverse events were observed. CONCLUSIONS: The correlation between EUS-PPG and HVPG was almost perfect. EUS-PPG could be a safe and reliable method for direct PPG measurement in cirrhotic patients and a valid alternative to HVPG. NCT05689268.
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Short-chain fatty acids (SCFAs) are gut microbiota-derived products that participate in maintaining the gut barrier integrity and host's immune response. We hypothesize that reduced SCFA levels are associated with systemic inflammation, endotoxemia, and more severe hemodynamic alterations in cirrhosis. Patients with cirrhosis referred for a hepatic venous pressure gradient (HVPG) measurement (n = 62) or a transjugular intrahepatic portosystemic shunt placement (n = 12) were included. SCFAs were measured in portal (when available), hepatic, and peripheral blood samples by GC-MS. Serum endotoxins, proinflammatory cytokines, and NO levels were quantified. SCFA levels were significantly higher in portal vs. hepatic and peripheral blood. There were inverse relationships between SCFAs and the severity of disease. SCFAs (mainly butyric acid) inversely correlated with the model for end-stage liver disease score and were further reduced in patients with history of ascites, hepatic encephalopathy, and spontaneous bacterial peritonitis. There was an inverse relationship between butyric acid and HVPG values. SCFAs were directly related with systemic vascular resistance and inversely with cardiac index. Butyric acid inversely correlated with inflammatory markers and serum endotoxin. A global reduction in the blood levels of SCFA in patients with cirrhosis is associated with a more advanced liver disease, suggesting its contribution to disease progression.-Juanola, O., Ferrusquía-Acosta, J., García-Villalba, R., Zapater, P., Magaz, M., Marín, A., Olivas, P., Baiges, A., Bellot, P., Turon, F., Hernández-Gea, V., González-Navajas, J. M., Tomás-Barberán, F. A., García-Pagán, J. C., Francés, R. Circulating levels of butyrate are inversely related to portal hypertension, endotoxemia, and systemic inflammation in patients with cirrhosis.
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Butiratos/sangue , Endotoxemia/sangue , Hipertensão Portal/sangue , Inflamação/sangue , Cirrose Hepática/sangue , Biomarcadores/sangue , Ácidos Graxos Voláteis/sangue , Feminino , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Peritonite/sangue , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Estudos RetrospectivosRESUMO
BACKGROUND & AIMS: Low-grade systemic inflammation is a crucial landmark in NAFLD favouring disease progression and comorbidities. We evaluated the input of circulating bacterial antigens on systemic markers of inflammation in NAFLD patients. PATIENTS & METHODS: Multicenter cross-sectional study including consecutive patients with biopsy-proven NAFLD. Demographic, metabolic and fibrosis-related variables were collected. Circulating bacterial antigens were quantified in blood. Toll-like receptor SNPs were genotyped. Serum cytokine levels were evaluated. Peripheral blood mononuclear cell response to bacterial antigens was evaluated in vitro. RESULTS: Three hundred and fifteen patients from five Spanish hospitals were distributed by BMI. At least, one bacterial antigenic type was found in 66 patients with BMI < 30 (63.4%) and 163 patients with BMI > 30 (77.3%) (P = .014). HOMA-IR was significantly higher in the presence of circulating antigens among patients with BMI < 30. NASH and significant fibrosis in non-obese patients were more frequent in the presence of at least two circulating antigenic types. Allelic frequencies of TLR variants were similar to controls and did not affect clinical or laboratory parameters. Pro-inflammatory cytokines were significantly increased in patients with bacterial antigens, regardless of BMI. TLR gene and protein expression levels were significantly increased in PBMCs from patients with bacterial antigens. Antigen concentrations independently influenced TNF-α and IL-6, in both BMI subgroups of patients. Age independently influenced TNF-α and IL-6 in non-obese patients, and TNF-α in obese patients. CONCLUSION: Serum circulating bacterial antigens as well as age were BMI-independent factors related to increased systemic inflammation in NAFLD and provides insight on the multifaceted sources of inflammation in these patients.
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Hepatopatia Gordurosa não Alcoólica , Antígenos de Bactérias , Índice de Massa Corporal , Estudos Transversais , Humanos , Inflamação , Leucócitos MononuclearesRESUMO
BACKGROUND/OBJECTIVE: Psoriasis and nonalcoholic fatty liver disease (NAFLD) are inflammatory diseases associated with increased cardiovascular risk, but no studies have evaluated cardiovascular risk in patients with both. The objective was to assess cardiovascular risk in patients with psoriasis and NAFLD. MATERIAL AND METHODS: Cross-sectional, single-centre study in patients with moderate to severe psoriasis. Participants underwent liver ultrasound to determine the presence of NAFLD. Cardiovascular risk was evaluated using the calibrated Framingham function and Systematic Coronary Risk Evaluation (SCORE) charts. Statistical analyses included a descriptive analysis, chi-square tests for comparing independent samples and stepwise multiple logistic regression to identify associations with the two risk scores. RESULTS: Psoriatic patients with NAFLD had significantly higher odds of moderate to very high 10-year cardiovascular risk compared to those without NAFLD, according to SCORE (71.5% versus 29.2%; odds ratio [OR] 6.0, 95% confidence interval [CI] 3.3-11.1; P < 0.001). Using both the SCORE and Framingham assessment methods, moderate to very high cardiovascular risk was independently associated with metabolic syndrome (Framingham: adjusted odds ratio [ORa] 5.5, 95% CI 2.3-12.9, P < 0.001; SCORE: ORa 4.7, 95% CI 1.9-11.7, P = 0.001) and systemic treatment (Framingham: ORa 3.4, 95% CI 1.4-8.5, P = 0.009; SCORE: ORa 3.2, 95% CI 1.2-8.2, P = 0.021). Using SCORE, cardiovascular risk was also associated with NAFLD (ORa of 2.8, 95% CI 1.2-6.6, P = 0.014). CONCLUSION: Psoriasis plus NAFLD confers higher cardiovascular risk at 10 years than psoriasis alone. In comorbid patients, more intense diagnostic efforts and follow-up are justified.
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Doenças Cardiovasculares/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Psoríase/epidemiologia , Medição de Risco , Glicemia/análise , Estudos Transversais , Diabetes Mellitus/epidemiologia , Dislipidemias/epidemiologia , Feminino , Humanos , Hipertensão/epidemiologia , Resistência à Insulina , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Sobrepeso/epidemiologia , Fatores de Risco , Espanha/epidemiologia , Triglicerídeos/sangueRESUMO
BACKGROUND & AIMS: Norfloxacin administration is useful in preventing bacterial infections in cirrhosis but associated to the generation of resistant species. Rifaximin is known to reach high concentrations in the intestinal lumen without generating relevant resistance in the intestinal flora. Our aim was to compare the effect of Norfloxacin and Rifaximin on intestinal flora composition, bacterial translocation and survival in cirrhotic rats. METHODS: Cirrhosis was induced in rats by oral administration of CCl4 . Animals were divided into three groups: only CCl4 (group I, n = 10); CCl4 + Norfloxacin (group II, n = 17) and CCl4 + Rifaximin (group III, n = 14). Gut bacterial composition, bacterial translocation and cytokine levels were measured. RESULTS: Forty-one rats were finally included. The incidence of viable and non-viable bacterial translocation was significantly reduced in animals receiving Norfloxacin; Rifaximin also decreased the incidence of viable and non-viable bacterial translocation, but did not reach statistical significance. Serum TNF-α levels were significantly lower in antibiotic groups. Norfloxacin modified intestinal microbiota, depleting significantly more pathobionts than Rifaximin. CONCLUSION: Norfloxacin is more effective than Rifaximin in preventing bacterial translocation in rats with cirrhosis probably because of its capacity to reduce pathobionts from intestinal microbiota.
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Antibacterianos/farmacologia , Infecções Bacterianas/prevenção & controle , Translocação Bacteriana/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Cirrose Hepática Experimental/tratamento farmacológico , Norfloxacino/farmacologia , Rifaximina/farmacologia , Animais , Infecções Bacterianas/sangue , Infecções Bacterianas/microbiologia , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/microbiologia , Citocinas/sangue , Microbioma Gastrointestinal/efeitos dos fármacos , Mediadores da Inflamação/sangue , Cirrose Hepática Experimental/sangue , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/microbiologia , Masculino , Viabilidade Microbiana/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
BACKGROUND & AIMS: Minimal hepatic encephalopathy is associated with poor prognosis and mortality in patients with cirrhosis. We aimed at investigating whether bacterial-DNA translocation affects hyperammonaemia and neurocognitive scores in patients with mHE according to the use of lactulose. METHODS: Observational study including 72 mHE cirrhotic patients, as defined by a psychometric hepatic encephalopathy score (PHES)<-4 and/or a critical flicker frequency (CFF)<39 Hz. Bacterial-DNA, serum ammonia, pro-inflammatory cytokines and nitric oxide levels were evaluated. A second cohort of 40 lactulose-untreated patients were evaluated before and 6-month after lactulose administration (30-60 mL/d). RESULTS: In the first cohort, bacterial-DNA rate was significantly higher in patients without lactulose (39% vs 23%, P=.03). Serum ammonia and inflammatory markers were significantly increased in patients with bacterial-DNA, regardless the use of lactulose, and correlated with the amount of amplified bacterial-DNA. Neurocognitive scores were significantly worse in bacterial-DNA positive vs negative patients (PHES -7.6±1.1 vs -5.5±1.0; CFF 32.5±2.6 vs 36.2±2.8, P=.01). Lactulose was associated with improved neurocognitive scores in patients without bacterial-DNA. Serum ammonia levels inversely correlated with neurocognitive scores in patients with bacterial-DNA (PHES r=-.84; CFF r=-.72, P=.001). In the second cohort, lactulose reduced bacterial-DNA translocation (36%-16%, P=.02). Neurocognitive scores were significantly improved in bacterial-DNA positive patients who cleared bacterial-DNA during the period on lactulose. Serum ammonia levels correlated with both neurocognitive scores in patients with bacterial-DNA, either before or after lactulose. CONCLUSION: Bacterial-DNA translocation worsens neurocognitive scores in mHE patients and it is reduced by lactulose, enhancing the relevance of controlling bacterial antigen translocation in these patients.
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Translocação Bacteriana/efeitos dos fármacos , Fármacos Gastrointestinais/administração & dosagem , Encefalopatia Hepática/diagnóstico , Lactulose/administração & dosagem , Cirrose Hepática/complicações , Idoso , Amônia/sangue , Biomarcadores/sangue , Cognição , DNA Bacteriano/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Psicometria , Índice de Gravidade de Doença , EspanhaRESUMO
BACKGROUND: To analyse the clinical, epidemiological, microbiological and prognostic differences of pyogenic liver abscess (PLA) in older (≥ 65 years of age) versus younger patients (< 65 years). METHODS: Multicentre, retrospective cohort study in all patients with PLA admitted to two Spanish hospitals from January 2000 to January 2014. Cases were divided into two age groups (< 65 years and ≥65 years) for comparison of clinical, epidemiological and microbiological characteristics as well as treatment. RESULTS: Of 98 patients analysed, 40 patients were younger than 65, and 58 were aged 65 or older. Significant associations in the older group were found with female sex (adjusted odds ratio [ORa] 9.0; 95% CI 1.4, 56), non-cryptogenic origin (ORa 14.5; 95% CI 1.6, 129), absence of chronic liver disease (ORa 14; 95% CI 1.3, 155), Escherichia coli infection (ORa 7.7; 95% CI 1.03, 58), and incidence of complications (ORa 2.3; 95% CI 1.04, 5.4). Mortality was 8.2% overall, although all deaths occurred in the older group (8/58; 13.8%) (p = 0.02). DISCUSSION: Our results are in consonance with other published studies. Older patients with PLA tend to present more anomalies in the biliary tract (Kai et. al, World J Gastroenterol 18: 2948-295, 2012, Rahimian et. al, Clin Infect Dis 39:1654-9, 2004, Seeto, Medicine (Baltimore) 75:99-113, 1996, Kao et.al, Aliment Pharmacol Ther 36:467-76, 2012, Lai et. al, Gastroenterology 146:129-37, 2014), while younger patients are more often male and present more commonly with previous liver disease (especially related to alcohol) and cryptogenic PLA. CONCLUSION: In patients aged 65 or older, PLA was more common in women and in those with a history of biliary disease, and E. coli was the most frequent bacterium. Mortality was also higher in the older group.
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Infecções por Escherichia coli/diagnóstico por imagem , Infecções por Escherichia coli/epidemiologia , Escherichia coli , Abscesso Hepático Piogênico/diagnóstico por imagem , Abscesso Hepático Piogênico/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND & AIMS: Patients with cirrhosis show recurrent access of bacterial products into the bloodstream inducing a multi-altered immunological status leading to relevant complications. We aimed at evaluating Bifidobacterium pseudocatenulatum CECT7765 effect on the host's macrophage function. PATIENTS & METHODS: Patients with cirrhosis and ascites were included. Granulocyte-macrophage colony-stimulating factor (GM-CSF) monocyte-derived and ascitic fluid (AF) macrophages were cultured with M-CSF, lipopolysaccharide (LPS) and/or the bifidobacterial strain. Pellets and supernatants were evaluated for gene expression of M1 and M2-related genes and cytokine secretion. Cell surface expression molecules were evaluated by flow cytometry. Kupffer cells from bile duct ligated and CCl4 rats were also evaluated. RESULTS: Experiments were run on GM-CSF blood-derived and AF macrophages from 10 patients with cirrhosis and 10 healthy donors. Different macrophage morphology was observed by optical microscopy in cells stimulated with bifidobacteria vs. LPS. M2-like expression of CD206, CD163 and CD16 was significantly increased in macrophages after stimulation with the bifidobacterial strain vs. LPS. B. pseudocatenulatum CECT7765 was able to significantly change the cytokine secretion pattern of blood-derived and AF macrophages and Kupffer cells from bile duct ligated and CCl4 cirrhotic rats compared to that induced by LPS. B. pseudocatenulatum CECT7765 was also effective in inducing a phenotype transition and a functional change from an M1- to an M2-related gene expression and cytokine secretion pattern in AF macrophages even after LPS-pretreatment. B. pseudocatenulatum CECT7765 did not reduce AF macrophage bacterial killing capacity. CONCLUSION: B. pseudocatenulatum CECT7765 induces a morphologic, phenotypic and functional transition towards an anti-inflammatory profile in GM-CSF monocyte-derived and AF macrophages from patients with cirrhosis that may help in controlling sustained inflammation in decompensated cirrhosis.
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Anti-Inflamatórios/farmacologia , Bifidobacterium , Cirrose Hepática/imunologia , Macrófagos/imunologia , Idoso , Polaridade Celular , Citocinas/biossíntese , Feminino , Humanos , Células de Kupffer/imunologia , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND & AIMS: Patients with decompensated cirrhosis show a marked innate immune response that shows a wide variability. The reasons for this fact have not been previously evaluated. This investigation was undertaken to study factors influencing the immune response intensity in both serum and ascitic fluid in patients with cirrhosis and ascites with presence of bactDNA. METHODS: 77 patients with cirrhosis and presence of bactDNA fragments in blood and ascitic fluid were included. Identification of bactDNA was evaluated by 16SrRNA gene PCR followed by nucleotide sequencing and by species-specific PCR. Concentration of amplified bacterial-DNA, bacteria identification, LPS, TNF-alpha, IFN-gamma, Interleukin 12 and nitric oxide in serum and ascitic fluid were evaluated as factors related to intensity of the immune response. RESULTS: Serum and AF levels of bactDNA, TNF-α, IFN-γ and nitric oxide concentration were higher in patients with presence of bactDNA from gram negative bacteria. Serum TNF-α levels showed a significant correlation with concentrations of bactDNA (r = 0.88; P = 0.001) and LPS (r = 0.28; P = 0.016). Serum nitric oxide levels were also significantly correlated with concentrations of bactDNA (r = 0.761; P = 0.001) but not with LPS levels. Levels of INF-γ and IL-12 were not significantly correlated with either bactDNA nor LPS levels. Plasmatic concentration of bactDNA was the most accurately correlated factor with the inflammatory response (ancova model included only levels of bactDNA (r(2) = 0.87, P = 0.047 for TNF-α; r(2) = 0.45, P = 0.03 for NOx). CONCLUSIONS: Bacterial-DNA concentration is the most influencing variable associated with serum TNF-α and nitric oxide response.
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Translocação Bacteriana , DNA Bacteriano/sangue , Cirrose Hepática/complicações , Cirrose Hepática/imunologia , Óxido Nítrico/sangue , Fator de Necrose Tumoral alfa/sangue , Idoso , Ascite/imunologia , Ascite/microbiologia , Líquido Ascítico/microbiologia , Feminino , Humanos , Imunidade Inata , Interferon gama/sangue , Interleucina-12/sangue , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Prospectivos , EspanhaRESUMO
BACKGROUND & AIMS: Inflammation is a common event in the pathogenesis of liver cirrhosis. The inflammasome pathway has acquired significant relevance in the pathogenesis of inflammation, but its role in the inflammatory response in patients with decompensated cirrhosis remains unexplored. METHODS: We performed a prospective study in which 44 patients with decompensated cirrhosis and 12 healthy volunteers were included. We isolated macrophages from blood and ascitic fluid and assessed the expression and activation of the inflammasome, its response to priming by bacterial products, and its association with the degree of liver disease. RESULTS: Macrophages from sterile ascitic fluids showed constitutive activation of caspase-1 and a marked increase in the expression of IL-1ß, IL-18, and absent in melanoma 2 (AIM2) when compared to blood macrophages. Pre-stimulation of blood-derived macrophages from cirrhotic patients with bacterial DNA increased the expression of AIM2 and induced a higher AIM2-mediated inflammasome response than priming with other bacterial products such as lipopolysaccharide. By contrast, activation of the AIM2 inflammasome did not require a priming signal in ascitic fluid-derived macrophages, demonstrating the preactivated state of the inflammasome in these cells. Last, higher IL-1ß and IL-18 production by ascitic fluid macrophages correlated with a more advanced Child-Pugh score. CONCLUSIONS: The inflammasome is highly activated in the ascitic fluid of cirrhotic patients, which may explain the exacerbated inflammatory response observed in these patients under non-infected conditions. Clinically, activation of the inflammasome is associated with a higher degree of liver disease.
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Líquido Ascítico/citologia , Proteínas de Ligação a DNA/genética , DNA/genética , Regulação da Expressão Gênica , Inflamassomos/metabolismo , Cirrose Hepática/genética , Macrófagos/patologia , Adulto , Idoso , Western Blotting , Células Cultivadas , Citocinas/metabolismo , Proteínas de Ligação a DNA/biossíntese , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are commonly used antisecretory drugs and have been linked to an increased risk of bacterial infections in cirrhosis. We investigated whether the treatment with PPIs in cirrhosis affects the oxidative burst activity of granulocytes and monocytes and its possible interference with serum norfloxacin (Nflx) levels in these patients. METHODS: 70 patients with cirrhosis and ascitic fluid and 24 healthy controls were included in the study and distributed into groups according to the regular use of PPIs and/or norfloxacin. The blood granulocyte and monocyte's phagocytic activity and oxidative burst were evaluated by flow cytometry. Blood levels of norfloxacin were measured by HPLC and bacterial translocation was evaluated by detection of bacterial DNA in blood. RESULTS: Use of PPIs was associated with a decreased granulocyte and monocyte oxidative burst, but not of phagocytic activity, as compared with patients not receiving PPIs. PPIs use did not affect serum norfloxacin levels in patients. A not significant trend to an increased bacterial DNA translocation was observed in patients receiving PPIs, including patients simultaneously receiving norfloxacin. CONCLUSIONS: PPIs significantly decrease cellular oxidative burst in cirrhosis. This fact may provide a pathogenic explanation to the reported high rates of bacterial infections in this setting, and strongly suggests that PPIs should only be used in patients with cirrhosis when clinically indicated.
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Cirrose Hepática/metabolismo , Inibidores da Bomba de Prótons/efeitos adversos , Explosão Respiratória/efeitos dos fármacos , Idoso , Infecções Bacterianas/etiologia , Translocação Bacteriana/efeitos dos fármacos , Depressão Química , Interações Medicamentosas , Feminino , Granulócitos/imunologia , Granulócitos/metabolismo , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Norfloxacino/sangue , Fagocitose/efeitos dos fármacosRESUMO
Background & aims: This study aims to assess the incidence and characteristics of all cancers, hepatocellular carcinoma (HCC), and extrahepatic cancers in patients with cirrhosis of various etiologies. Methods: Prospective cohort study in patients with cirrhosis but no cancer, followed every 6-9 months through the HCC early detection program. Cancer incidence was compared with Spanish population data to calculate standardized incidence ratios (SIR), and cumulative incidence was calculated separately for cancer and competing events. Longitudinal outcomes were assessed with multivariate Fine-Gray and Cox regression models. Results: A total of 215 patients (68.4% male, median age 61 years) were included. Cirrhotic etiology was alcohol (38%), hepatitis B or C virus infection (36%), alcohol plus hepatitis B or C virus infection (9%), and other causes (17%). Sixty percent were current or former smokers. Thirty-nine cancers were observed (56% liver cancer), while 3.3 were expected (SIR 11.7; 95% confidence interval [CI] 8.6-16.1). Ten (4.6%) patients were censored for liver transplantation and 34 (15.8%) for death, constituting relevant competing risks. Smoking was significantly associated with overall cancer incidence (smokers: subdistribution hazard ratio [SHR] 3.14, 95% CI 1.33-7.38; former smokers: SHR 2.54, 95% CI 1.08-5.98). In the multivariable regression analysis, viral etiology, Child-Pugh score (B or C versus A), and smoking were associated with liver cancer, and smoking with extrahepatic cancer. Conclusions: Patients with cirrhosis have an 11-fold risk of cancer compared to the general population. Risk is increased in liver and non-liver cancers. Active surveillance of any type of cancer and smoking cessation interventions are needed in these patients.
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BACKGROUND & AIMS: Refractory ascites (RA) affects 10% of patients with advanced cirrhosis and ascites. Usual therapy includes large volume paracentesis, and in selected patients, a transjugular portosystemic shunt (TIPS). These therapies may be associated with increased morbidity: paracentesis may induce circulatory dysfunction and impair quality of life and TIPS may induce encephalopathy and is associated with increased mortality in patients with severe liver dysfunction. We present the results of a multicenter, non-randomized trial to assess the safety and efficacy of a new automated pump system for treatment of RA. METHODS: Forty patients at 9 centers (February 2010-June 2011) received an implanted pump for the automated removal of ascites from the peritoneal cavity into the bladder, from where it was eliminated through normal urination. Patients were followed-up for 6months. The primary study outcome was safety. Secondary outcomes included recurrence of tense ascites and pump performance. RESULTS: Surgical complications occurred early in the study and became less frequent. The pump system removed 90% of the ascites and significantly reduced the median number of large volume paracentesis per month [3.4 (range 1-6) vs. 0.2 (range 0-4); p <0.01]. Cirrhosis-related adverse events decreased along follow-up. CONCLUSIONS: The automated pump seems an efficacious tool to move out ascites from the peritoneal cavity to the bladder. Its safety is still moderate, but a broad use in different countries will improve the surgical technique as well as the medical surveillance. A prospective randomized clinical trial vs. large volume paracentesis is underway to confirm these preliminary results.
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Ascite/epidemiologia , Ascite/terapia , Proteínas de Membrana Transportadoras/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Hemodinâmica/fisiologia , Humanos , Rim/irrigação sanguínea , Fígado/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Recidiva , Resultado do TratamentoRESUMO
Bacterial translocation (BT) is defined by the passage of viable indigenous bacteria from the intestinal lumen to mesenteric lymph nodes (MLNs) and other territories, and its diagnostic criteria rely on the isolation of viable bacteria in MLNs. Small intestinal overgrowth, increased intestinal permeability and immunological alterations are the main factors involved in its pathogenesis. BT is obviously difficult to identify in patients with cirrhosis, and alternative methods have been proposed instead. Bacterial DNA detection and species identification in serum or ascitic fluid has been proposed as a reliable marker of BT. Bacterial products, such as endotoxin, or bacterial DNA can translocate to extra-intestinal sites and promote an immunological response similar to that produced by viable bacteria. Therefore, pathological BT plays an important role in the pathogenesis of the complications of cirrhosis, not only in infections, but by exerting a profound inflammatory state and exacerbating the haemodynamic derangement. This may promote in turn the development of hepatorenal syndrome, hepatic encephalopathy and other portal hypertension-related complications. Therapeutic approaches for the prevention of BT in experimental and human cirrhosis are summarized. Finally, new investigations are needed to better understand the pathogenesis and consequences of translocation by viable bacteria (able to grow in culture), or non-viable BT (detection of bacterial fragments with negative culture) and open new therapeutic avenues in patients with cirrhosis.
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Bactérias , Translocação Bacteriana , Intestino Delgado/microbiologia , Cirrose Hepática/microbiologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bactérias/imunologia , Bactérias/metabolismo , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/imunologia , Infecções Bacterianas/fisiopatologia , Infecções Bacterianas/terapia , Técnicas de Tipagem Bacteriana , Biomarcadores/análise , DNA Bacteriano/isolamento & purificação , Progressão da Doença , Endotoxinas/isolamento & purificação , Varizes Esofágicas e Gástricas/microbiologia , Hemorragia Gastrointestinal/microbiologia , Humanos , Hipertensão Portal/microbiologia , Intestino Delgado/imunologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/imunologia , Cirrose Hepática/fisiopatologia , Cirrose Hepática/terapia , Valor Preditivo dos Testes , Prognóstico , Fatores de RiscoRESUMO
BACKGROUND: Treatment with non-selective beta-blockers (NSBB) has been associated with anti-inflammatory and anti-cancer effects in patients with cirrhosis. This study aims to analyze the impact of chronic NSBB treatment on immune activation and disease progression in stable outpatients with cirrhosis. METHODS: In this prospective follow-up of 150 patients with cirrhosis, 39 received treatment with NSBB. Blood samples were taken every 6-9 months, and immune and adrenergic variables were measured. Mixed linear models were used to assess the effect of NSBB on these variables over time. Multivariate Cox regression was used to study associations with adverse clinical events (hepatocellular carcinoma, death, or liver transplant). RESULTS: Median follow-up was 1635 days. NSBB treatment was associated with significantly lower levels of IL-6 (ß - 4.7; 95% confidence interval [CI] -6.9, -2.6) throughout the study. During follow-up, 11 patients developed hepatocellular carcinoma, 32 died, and 4 underwent liver transplant. Patients with higher concentrations of IL-10, IL-6 and IFN-γ developed more clinical events. Event-free survival was significantly better in patients treated with NSBB (hazard ratio 0.36, 95% CI 0.18, 0.71) in a multivariate Cox regression adjusted for Child-Pugh-Score, esophageal varices, and platelets. CONCLUSION: Chronic treatment with NSBB in patients with stable cirrhosis gives rise to a different state of immune activation, characterized by lower concentrations of IL-6 over time, and it is associated with a reduced risk of adverse event (death, hepatocellular carcinoma, or transplant), after controlling for disease severity.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Estudos Prospectivos , Estudos Longitudinais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/induzido quimicamente , Interleucina-6 , Antagonistas Adrenérgicos beta/uso terapêutico , Cirrose Hepática/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/induzido quimicamenteRESUMO
UNLABELLED: Patients with cirrhosis receiving norfloxacin show a restored inflammatory balance that likely prevents clinical complications derived from an excessive proinflammatory response to bacterial product challenges. This study sought to investigate associated inflammatory control mechanisms established in patients with cirrhosis receiving norfloxacin. A total of 62 patients with cirrhosis and ascites in different clinical conditions were considered. Blood samples were collected and intracellular and serum norfloxacin were measured. Inflammatory mediators were evaluated at messenger RNA and protein levels. Neutrophils from all patients were cultured with lipopolysaccharide (LPS) and anti-interleukin-10 (anti-IL-10) monoclonal antibody in different conditions. IL-10 and heme oxygenase-1 (HO-1) were up-regulated in patients receiving norfloxacin and correlated with norfloxacin in a concentration-dependent manner, whereas proinflammatory inducible nitric oxide synthase, cyclooxygenase-2, and nuclear factor-κB behaved inversely. Higher IL-10 levels correlated with lower white blood cell count and higher mean arterial pressure. No correlations were found between IL-10 and disease clinical scores or liver function markers in blood. Neutrophilic in vitro assays showed that the effect of LPS on proinflammatory mediator levels in the presence of norfloxacin was abrogated by significantly increasing IL-10 and HO-1 expression. After stimulation with LPS plus anti-IL-10, proinflammatory mediators were dramatically increased in patients receiving norfloxacin, and increasing intracellular norfloxacin concentrations did not decrease the expression levels of these proinflammatory molecules. Unblocking IL-10 restored proinflammatory mediator and HO-1 expression to previously observed levels in response to LPS stimulation. CONCLUSION: Although the described association does not necessarily mean causality, an IL-10-mediated HO-1-induced anti-inflammatory mechanism is present in patients with cirrhosis receiving norfloxacin, that is directly associated with cell-modulating events in these patients.
Assuntos
Heme Oxigenase-1/fisiologia , Interleucina-10/fisiologia , Cirrose Hepática/tratamento farmacológico , Norfloxacino/uso terapêutico , Idoso , Anticorpos Monoclonais/farmacologia , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , DNA Bacteriano/sangue , Regulação para Baixo , Feminino , Heme Oxigenase-1/sangue , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-10/sangue , Interleucina-10/imunologia , Contagem de Leucócitos , Lipopolissacarídeos/farmacologia , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II , Norfloxacino/sangue , Peritonite/prevenção & controle , Estudos Prospectivos , Regulação para CimaRESUMO
BACKGROUND & AIMS: Ultrasonographic contrast agents allow the assessment of myocardial and renal perfusion through the analysis of refill kinetics after microbubbles rupture. This study evaluated the feasibility of contrast-enhanced ultrasonographic (CEUS) estimations of regional hepatic perfusion in patients with cirrhosis, and its correlation with clinical and hemodynamic parameters. METHODS: Fifty-five patients with cirrhosis undergoing hepatic vein catheterization were included. Hepatic perfusion was studied by CEUS (using Contrast Coherent Imaging) during a continuous i.v. infusion of microbubbles (SonoVue®); after their rupture (high insonation power), tissue refill was digitally recorded and time-intensity curves were electronically calculated on a region of interest of the right hepatic lobe. Regional hepatic perfusion (RHP) was calculated as microbubbles velocity×microbubble concentration. During hepatic vein catheterization, we measured hepatic blood flow by indocyanine green (ICG) infusion, hepatic venous pressure gradient (HVPG), and cardiac output (Swan-Ganz catheter). RESULTS: RHP was higher in patients than in healthy controls (5.1±3.7 vs. 3.4±0.7, p=0.003), and correlated with MELD (R=0.403, p=0.002), Child-Pugh score (R=0.348, p=0.009), and HVPG (R=0.279, p=0.041). RHP inversely correlated with ICG extraction (R=-0.346, p=0.039), ICG intrinsic clearance (R=-0.327, p=0.050), and ICG clearance (R=0.517, p=0.001), and directly correlated with hyperdynamic syndrome markers (cardiac index R=0.422, p=0.003; mean arterial pressure R=-0.405, p=0.004; systemic vascular resistance R=-0.496, p=0.001). CONCLUSIONS: RHP increases in patients with cirrhosis and correlates with the degree of liver failure and hyperdynamic syndrome. RHP increases along with liver functional reserve decrease, suggesting that RHP increase occurs mainly through anatomical/functional shunts. RHP by CEUS is a feasible novel, objective, quantitative, non-invasive tool, potentially useful for the estimation of hepatic perfusion in patients with cirrhosis.
Assuntos
Meios de Contraste , Cirrose Hepática/diagnóstico por imagem , Microbolhas , Adulto , Velocidade do Fluxo Sanguíneo , Estudos de Casos e Controles , Cateterismo , Feminino , Veias Hepáticas/diagnóstico por imagem , Humanos , Circulação Hepática , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fosfolipídeos , Estudos Prospectivos , Reprodutibilidade dos Testes , Hexafluoreto de Enxofre , UltrassonografiaRESUMO
UNLABELLED: Presence of bacterial DNA in noninfected patients with cirrhosis and ascites is associated with a marked inflammatory response including activation of the inducible form of nitric oxide synthase and release of nitric oxide, similar to that observed in patients with spontaneous bacterial peritonitis. Although presence of bacterial DNA is associated with an impaired prognosis, no information is available regarding its hemodynamic consequences. Systemic and hepatic hemodynamics before and after a liquid test meal were assessed in a series of 75 noninfected patients with cirrhosis (55 with ascites). Bacterial DNA was measured by polymerase chain reaction. Bacterial DNA was detected only in patients with ascites. Clinical data and liver function were similar in ascitic patients with presence (n = 21) or absence of bacterial DNA (n = 34). Bacterial-DNA(+) patients had significantly lower mean arterial pressure (P = 0.002) and systemic vascular resistance (P = 0.03) than bacterial-DNA(-) patients. Cardiac output, cardiopulmonary pressures, hepatic venous pressure gradient (HVPG), and hepatic blood flow were similar in both groups. Thirty minutes after the test meal, in response to increased blood flow caused by postprandial hyperemia, there was a significantly greater increase in HVPG and impaired hepatic vasorelaxation in bacterial-DNA(+) as compared with bacterial-DNA(-) patients, which indicates hepatic endothelial dysfunction. Indeed, the increase in HVPG after the test meal significantly correlated with serum bacterial DNA concentration. CONCLUSION: Presence of bacterial DNA, a marker of bacterial translocation, is associated with aggravation of peripheral vasodilation and with worsening of intrahepatic endothelial dysfunction.
Assuntos
Infecções Bacterianas/fisiopatologia , Translocação Bacteriana , DNA Bacteriano/metabolismo , Hemodinâmica , Circulação Hepática/fisiologia , Cirrose Hepática/fisiopatologia , Fígado/fisiopatologia , Adulto , Idoso , Ascite/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Resistência VascularRESUMO
Insertion of a transjugular intrahepatic portosystemic shunt (TIPS) is an increasingly used treatment in the management of the complications of portal hypertension. However, one of the complications of this technique is refractory or recurrent hepatic encephalopathy, which poses a difficult clinical problem. We report the case of a patient who underwent TIPS insertion to control bleeding due to esophageal varices. The patient subsequently developed refractory hepatic encephalopathy, requiring reduction of the caliber of the shunt.
Assuntos
Procedimentos Endovasculares/métodos , Encefalopatia Hepática/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Complicações Pós-Operatórias/cirurgia , Ascite/tratamento farmacológico , Ascite/etiologia , Procedimentos Endovasculares/instrumentação , Desenho de Equipamento , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/cirurgia , Furosemida/uso terapêutico , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/cirurgia , Encefalopatia Hepática/etiologia , Humanos , Hipertensão Portal/complicações , Hipertensão Portal/cirurgia , Veias Jugulares , Circulação Hepática , Cirrose Hepática Alcoólica/complicações , Masculino , Pessoa de Meia-Idade , Politetrafluoretileno , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Derivação Portossistêmica Transjugular Intra-Hepática/instrumentação , Complicações Pós-Operatórias/etiologia , Propranolol/uso terapêutico , Reoperação , Espironolactona/uso terapêutico , StentsRESUMO
Psoriasis and non-alcoholic fatty liver disease (NAFLD) are both inflammatory diseases. The study objective was to estimate the risk of NAFLD, non-alcoholic steatohepatitis, and liver fibrosis (by liver stiffness and liver biopsy) in patients with psoriasis and to determine the epidemiological, clinical, immunological (TNF-α, IL-2, IL-6, IL-12, IL-17, IL-23, and TGF-ß) characteristics, and bacterial translocation. Of the 215 psoriatic patients included, 91 presented NAFLD (prevalence: 42.3%). Compared to patients with psoriasis alone, those with NAFLD were significantly more likely to have metabolic syndrome, diabetes, dyslipidemia, body mass index ≥ 30 kg/m2, homeostatic model assessment of insulin resistance ≥ 2.15, and greater psoriasis area severity index. NAFLD patients also had significantly higher levels of TNF-α (p = 0.002) and TGF-ß (p = 0.007) and a higher prevalence of bacterial translocation (29.7% vs. 13.7%; p = 0.004). Liver stiffness measurement was over 7.8 kPa in 17.2% (15/87) of NAFLD patients; 13 of these underwent liver biopsy, and 5.7% (5/87) had liver fibrosis, while 1.1% (1/87) had advanced fibrosis or non-alcoholic steatohepatitis. In conclusion the prevalence of NAFLD in patients with psoriasis is high and associated with a higher prevalence of metabolic syndrome features, bacterial translocation and a higher pro-inflammatory state. It is worth mentioning that liver fibrosis and non-alcoholic steatohepatitis are not frequent in this population of patients.