Interaction of Microbiome, Diet, and Hospitalizations Between Brazilian and American Patients With Cirrhosis.

BACKGROUND & AIMS: Gut microbiota are affected by diet, country, and affect outcomes in cirrhosis. Western diets are associated with dysbiosis. Comparisons with other diets is needed. We aimed to compare cirrhosis patients from the United States with cirrhosis patients from Brazil with respect to diet, microbiota, and impact on hospitalizations. METHODS: Healthy controls and compensated/decompensated outpatients with cirrhosis from the United States and Brazil underwent dietary recall and stool for 16S ribosomal RNA sequencing. Demographics and medications/cirrhosis details were compared within and between countries. Patients with cirrhosis were followed up for 90-day hospitalizations. Regression for Shannon diversity was performed within cirrhosis. Regression for hospitalizations adjusting for clinical and microbial variables was performed. RESULTS: Model for end-stage liver disease (MELD), diabetes, ascites, and albumin were similar, but more Americans were men, had higher hepatic encephalopathy and alcohol/hepatitis C etiology, with lower nonalcoholic fatty liver disease than Brazilians. Brazilians had higher cereal, rice, and yogurt intake vs the United States. As disease progressed, cereals, rice/beans, coffee, and chocolate consumption was reduced. Microbial diversity was higher in Brazilians. Within cirrhosis, high diversity was related to Brazilian origin (P < .0001), age, and cereal intake (P = .05), while high MELD scores (P = .009) and ascites (P = .05) did the reverse. Regardless of stage, beneficial taxa and taxa associated with grant and yogurt intake were higher (Ruminococcaceae, Christensenellacae, and Prevotellaceae), while pathobionts (Porphyromonadaceae, Sutterellaceae, and Enterobacteriaceae) were lower in Brazilians. More Americans were hospitalized vs Brazilians (P = .002). On regression, MELD (P = .001) and ascites (P = .001) were associated with higher hospitalizations, while chocolate (P = .03) and Brazilian origin (P = .001) were associated with lower hospitalizations with/without microbiota inclusion. CONCLUSIONS: Brazilian cirrhotic patients follow a diet richer in cereals and yogurt, which is associated with higher microbial diversity and beneficial microbiota and could contribute toward lower hospitalizations compared with a Western-diet-consuming American cohort.

Preservation of thrombin generation in cirrhosis despite abnormal results of international normalized ratio: implications for invasive procedures.

Thrombin generation is normal or elevated in patients with cirrhosis when tested in the presence of thrombomodulin, the activator of the main natural anticoagulant protein C. However, the relationship between thrombin generation with bleeding has been little explored in literature. 97 Consecutive patients with cirrhosis were prospectively included (58 men; 54 ±â€Š10 years) and divided into two groups international normalized ratio (INR) less than 1.5 (n = 72) or INR at least 1.5 (n = 25). 46 Healthy individuals were tested as controls. Endogenous thrombin potential (ETP) was measured without and with the addition of thrombomodulin. ETP measured without thrombomodulin was reduced in patients with cirrhosis when compared with controls, but no significant difference was found between the INR less than 1.5 and INR at least 1.5 groups (1250 ±â€Š315.7 versus 1186 ±â€Š238 nmol/l × min; P = 0.3572). After the addition of thrombomodulin, both groups generated thrombin comparable with controls (INR ≥ 1.5: 965.9 ±â€Š232.3; INR < 1.5: 893.0 ±â€Š368.6; controls: 915.0 ±â€Š458 nmol/l × min). 80% of patients had high ETP without/with thrombomodulin ratio, demonstrating the resistance to the anticoagulant action of thrombomodulin for both groups. This was more marked in the INR at least 1.5 group (0.81 ±â€Š0.1 versus 0.69 ±â€Š0.2; P = 0.0042). Postligation of esophageal varices bleeding occurred in 5.2% of patients (INR < 1.5, n = 3; INR ≥ 1.5, n = 2), all of them with ETP without/with thrombomodulin ratio ranging from 0.72 to 0.90 (controls 0.57 ±â€Š0.21). This study confirms that thrombin generation in the presence of thrombomodulin was normal in most patients with cirrhosis, including those with high INR value, but did not correlate with postligation of esophageal varices bleeding.

ß-Blocker therapy for cirrhotic cardiomyopathy: a randomized-controlled trial.

BACKGROUND: Cirrhotic cardiomyopathy is characterized by an attenuated contractile response to stress. Long-term exposure of ß-adrenergic receptors to persistently high levels of catecholamines has been implicated in its pathogenesis. We hypothesized that ß-blockade with metoprolol could reverse the changes in heart function and morphology in cirrhotic cardiomyopathy. PATIENTS AND METHODS: In this prospective randomized trial, we included 78 patients aged between 18 and 60 years with abnormal cardiac output response under dobutamine stress echocardiography, without primary cardiac disease or a history of alcohol intake. Patients were assigned randomly to receive metoprolol or placebo for 6 months. The primary endpoint was the improvement in cardiac output response to stress, measured by an increase in the left ventricle stroke volume more than 30%. RESULTS: Three (7.3%) patients in the metoprolol group and nine (24.3%) patients in the placebo group showed improved stroke volume (P=0.057). Diastolic dysfunction was found in two (4.8%) patients before and in five (15.6%) patients after therapy in the metoprolol group, and in 10 (27%) patients before and nine (31%) patients after therapy in the placebo group (P=0.67). After treatment, no echocardiography parameter of morphology was significantly different between metoprolol or placebo groups. No significant differences were observed in noradrenaline, plasma renin activity, and troponin levels between groups. Cirrhosis-related clinical events, including hospitalizations and mortality, were not significantly different between the two groups. Six months of therapy with ß-blocker did not ameliorate heart function and morphology in patients with cirrhotic cardiomyopathy.

Early predictors of acute kidney injury in patients with cirrhosis and bacterial infection: urinary neutrophil gelatinase-associated lipocalin and cardiac output as reliable tools.

BACKGROUND: Hemodynamic abnormalities and acute kidney injury (AKI) are often present in infected cirrhotic patients. Hence, an early diagnosis of AKI is necessary, which might require the validation of new predictors as the determinations of urinary neutrophil gelatinase-associated lipocalin (uNGAL) and cardiac output. METHODS: We evaluated 18 infected cirrhotic patients subdivided into two groups at admission (0 hours). In Group I, we collected urine samples at 0 hours, 6 hours, 24 hours, and 48 hours for uNGAL and fractional excretion of sodium determinations. In Group II, we measured cardiac output using echocardiography. RESULTS: The age of patients was 55.0±1.9 years, and 11 patients were males. The Model for End-Stage Liver Disease score was 21±1, whereas the Child-Pugh score was C in 11 patients and B in 7 patients. Both patients in Group I and Group II showed similar baseline characteristics. In Group I, we diagnosed AKI in 5 of 9 patients, and the mean time to this diagnosis by measuring serum creatinine was 5.4 days. Patients with AKI showed higher uNGAL levels than those without AKI from 6 hours to 48 hours. The best accuracy using the cutoff values of 68 ng uNGAL/mg creatinine was achieved at 48 hours when we distinguished patients with and without AKI in all cases. In Group II, we diagnosed AKI in 4 of 9 patients, and cardiac output was significantly higher in patients who developed AKI at 0 hours. CONCLUSION: Both uNGAL and cardiac output determinations allow the prediction of AKI in infected cirrhotic patients earlier than increments in serum creatinine.

m-RECIST at 1 month and Child A are survival predictors after percutaneous ethanol injection of hepatocellular carcinoma.

BACKGROUND AND AIMS: Percutaneous ethanol injection (PEI) is a well-established therapeutic option in patients with cirrhosis and hepatocellular carcinoma (HCC). The modified-Response Evaluation Criteria in Solid Tumors (m-RECIST) are an important tool for the assessment of HCC response to therapy. The aim was to evaluate whether HCC response according to the m-RECIST criteria could be an effective predictor of long-term survival in Barcelona Clinic Liver Cancer (BCLC) stage 0 and A HCC patients undergoing PEI. MATERIAL AND METHODS: 79 patients were followed-up for median time of 26.8 months. HCC diagnosis was based on the current guidelines of the American Association for Study of the Liver Diseases (AASLD) and European Association for Study of the Liver (EASL). Patient survival was calculated from the first PEI session to the end of the follow-up. RESULTS: The 1-, 3-, and 5-year overall survival rates were 79, 48 and 37%, respectively. In the multivariate analysis, Child-Pugh-Turcotte (CPT) (p = 0.022) and the response to m-RECIST criteria (p = 0.016) were associated with patient survival. CPT A patients who achieved Complete Response (CR) 1 month after PEI presented a 5-year survival rate of 55%. By contrast, the worst scenario, the group with CPT B but without CR had a 5-year survival rate of 9%, while the group with either CPT A or CR as a survival predictor had a 5-year survival rate of 31%. In conclusion, in BCLC stage 0 and A HCC-patients, m-RECIST at 1 month and Child A may predict survival rates after PEI.

Selectins and platelet-derived growth factor (PDGF) in schistosomiasis-associated pulmonary hypertension.

PURPOSE: The aim of this study was to evaluate the expression profiles of the relevant selectins and PDGF in schistosomiasis-associated pulmonary hypertension. METHODOLOGY: Patients with three distinct clinical profiles were enrolled in the study: IPAH(n = 11), schistosomiasis-associated PH (Sch-PH))(n = 13), and schistosomiasis without PH (Sch) (n = 13). Healthy volunteers, were recruited as a control group(n = 13). Echocardiography was performed in all groups, and the PH patients underwent right heart catheterization. Plasma soluble adhesion molecules E- and P-Selectin, PDGF-AB, PDGF-BB were determined by ELISA. RESULTS: E-selectin was significantly increased in the IPAH group compared with the other groups [the control, Sch + PH and Sch groups) (p < 0.001) (Fig. 2)]. P-selectin was lower in Sch (20.2 + 8.9 × 103 pg/mL) as compared to the control, (43 16.8 × 103 pg/mL), IPAH (35.8 7.8 × 103 pg/mL), and Sch + PH (36.8 ± 15.7 × 103 pg/mL) (p = 0.005) groups. Serum PDGF-BB levels were higher in the control group (8.9 ± 4.8 × 103 pg/mL) compared with the IPAH (3.7 ± 2.17 × 103 pg/mL), Sch + PH (5.2 ± 3.7 × 103 pg/mL) and Sch (2.4 ± 1.7 × 103 pg/mL) groups (p < 0.05). PDGF-AB levels were also higher in the control group (25.6 ± 8.6 × 103 pg/mL), compared with the other three groups, being the Sch group the one with lower serum levels of this marker (11.4 ± 8.6 × 103 pg/mL) (p = 0.006). CONCLUSIONS: In conclusion, vascular inflammation in schistosomiasis, with or without PH, is different from IPAH suggesting distinct pathophysiological mechanisms associated with the development of pulmonary hypertension.

Epidemiology of HCC in Brazil: incidence and risk factors in a ten-year cohort.

BACKGROUND AND AIM: The lack of information about hepatocellular carcinoma (HCC) in Brazil weakens health policy in preventing deaths from the illness. The aim of this study was to establish the cumulative incidence and the risk factors for hepatocellular carcinoma development in patients under a surveillance program. MATERIAL AND METHODS: 884 patients with compensated cirrhosis were prospectively followed up for at least five years, from August 1998 until August 2008, with at least one annual ultrasonography liver examination and serum alpha fetoprotein (AFP) measurement. RESULTS: Among 884 patients, 72 (8.1%) developed a tumor with a median follow up of 21.4 months. In the hepatocellular carcinoma group, hepatitis C virus infection was the major etiological factor (65.3%), 56.9% (41/72) were male and the mean average age was 57 ± 10 years. The annual incidence of hepatocellular carcinoma was 2.9%. 79.2% (57/72) of HCCs were detected within Milan Criteria, and the mean survival time was 52.3 months, significantly higher than for those outside Milan, with a mean time of 40.6 months (p = 0.0003). CONCLUSION: The annual incidence of HCC among this large series of Brazilian cirrhotic patients was around 2.9% with a detection rate of 8.1%, or a cumulative incidence rate over five years of 14.3%. The three variables related to HCC risk were low serum albumin [HR: 0.518 (0.46-0.78)], high AFP > 20 ng/mL [HR: 3.16 (1.86-5.38)], and ethnicity (Brazilian-East Asian descendants vs. other mixed Brazilian ethnicities) [HR: 2.86 (1.48-5.53)].

Serum B-type natriuretic peptide in the initial workup of patients with new onset ascites: a diagnostic accuracy study.

UNLABELLED: Heart failure (HF) is, after cirrhosis, the second-most common cause of ascites. Serum B-type natriuretic peptide (BNP) plays an important role in the diagnosis of HF. Therefore, we hypothesized that BNP would be useful in the differential diagnosis of ascites. Consecutive patients with new onset ascites were prospectively enrolled in this cross-sectional study. All patients had measurements of serum-ascites albumin gradient (SAAG), total protein concentration in ascitic fluid, serum, and ascites BNP. We enrolled 218 consecutive patients with ascites resulting from HF (n = 44), cirrhosis (n = 162), peritoneal disease (n = 10), and constrictive pericarditis (n = 2). Compared to SAAG and/or total protein concentration in ascites, the test that best discriminated HF-related ascites from other causes of ascites was serum BNP. A cutoff of >364 pg/mL (sensitivity 98%, specificity 99%, and diagnostic accuracy 99%) had the highest positive likelihood ratio (168.1); that is, it was the best to rule in HF-related ascites. Conversely, a cutoff ≤ 182 pg/mL had the lowest negative likelihood ratio (0.0) and was the best to rule out HF-related ascites. These findings were confirmed in a 60-patient validation cohort. CONCLUSIONS: Serum BNP is more accurate than ascites analyses in the diagnosis of HF-related ascites. The workup of patients with new onset ascites could be streamlined by obtaining serum BNP as an initial test and could forego the need for diagnostic paracentesis, particularly in cases where the cause of ascites is uncertain and/or could be the result of HF.

Nodules less than 20 mm and vascular invasion are predictors of survival in small hepatocellular carcinoma.

BACKGROUND: The aims of this study were to analyze the overall survival of patients with cirrhosis and small hepatocellular carcinoma (HCC) and identify independent pretreatment predictors of survival in Brazil. METHODS: Between 1998 and 2003, 74 patients with cirrhosis and small HCC were evaluated. Predictors of survival were identified using the Kaplan-Meier survival curves and the Cox model. RESULTS: The overall survival rates were 80%, 41%, and 17% at 12, 36, and 60 months, respectively. The mean length of follow-up after HCC diagnosis was 23 months (median 22 mo, range: 1 to 86 mo) for the entire group. Univariate analysis showed that model for endstage liver disease (MELD) score (P=0.016), Child-Pugh classification (P=0.007), alpha-fetoprotein level (P=0.006), number of nodules (P=0.041), tumor diameter (P=0.009), and vascular invasion (P<0.0001) were significant predictors of survival. Cox regression analysis identified vascular invasion (relative risk=14.60, confidence interval 95%=3.3-64.56, P<0.001) and tumor size >20 mm (relative risk=2.14, confidence interval 95%=1.07-4.2, P=0.030) as independent predictors of decreased survival. Treatment of HCC was related to increased overall survival. CONCLUSIONS: Identification of HCC smaller than 20 mm is associated with longer survival. Presence of vascular invasion, even in small tumors, maybe associated with poor prognosis. Treatment of small tumors of up to 20 mm diameter is related to increased survival.

Bone disease in primary biliary cirrhosis: lack of association with distal renal tubular acidosis.

BACKGROUND AND AIMS: Primary biliary cirrhosis (PBC) might be complicated by osteoporosis, whose etiology remains unknown but seems to be multifactorial. Prevalence rates of 30% to 60% for distal renal tubular acidosis (DRTA) have been reported in PBC patients, generally as incomplete DRTA. Although it is undisputed that a reduced bone mineral density (BMD) is the expected outcome among patients who have been suffering from longstanding chronic metabolic acidosis, it is unclear if incomplete DRTA is also associated with metabolic bone disease in PBC patients. The present study was undertaken to compare the BMD of PBC patients with and without DRTA. METHODS: The BMD of 23 PBC patients (11 with DRTA and 12 without), all with normal clearance of creatinine, was assessed by dual energy radiograph absorptiometry. The diagnosis of DRTA was made if the urine pH was above 5.4 in all samples after the oral acid overload, showing tubular inability to acidify urine in the presence of test-induced systemic metabolic acidosis. RESULTS: Densitometric signs of osteoporosis were found in 82% of DRTA cases and in 83% of patients without DRTA (difference not significant). There were no significant differences in BMD measurement, T and Z scores of patients with and without DRTA. CONCLUSIONS: The present study could not support a correlation between the presence of DRTA and the bone loss observed in PBC patients.