Profile of Gut Microbiota Associated With the Presence of Hepatocellular Cancer in Patients With Liver Cirrhosis.

BACKGROUND: Changes within the gut microbiota contribute to the progression of chronic liver diseases. According to the results of several studies performed in animal models, gut dysbiosis plays an important role in hepatocarcinogenesis. The aim of this study was to explore the characteristics of gut microbiota associated with the presence of hepatocellular cancer (HCC) in patients with cirrhosis of the liver undergoing liver transplantation. METHODS: A total of 15 patients with HCC and 15 non-HCC patients matched according to etiology of cirrhosis and Model for End-Stage Liver Disease (MELD) scores who underwent liver transplantations between 2012 and 2014 were included. Analysis of their gut microbial profile was based on prospectively collected stool samples from the pretransplant period. RESULTS: Patients with and without HCC were similar with respect to age (P = .506), sex (P = .700), hepatitis C virus (P > .999) and hepatitis B virus (P = .715) infection status, alcoholic liver disease (P > .999), and MELD score (P = .337). Notably, the presence of HCC was associated with significantly increased fecal counts of Escherichia coli (P = .025). Prediction of HCC presence based on E coli counts was associated with the area under the receiver-operating curve of 0.742 (95% confidence interval, 0.564-0.920), with the optimal cutoff on the level of 17.728 (natural logarithm of colony-forming units per 1 g of feces). Sensitivity and specificity rates for the established cutoff were 66.7% and 73.3%, respectively. CONCLUSIONS: The profile of gut microbiota associated with the presence of HCC in cirrhotic patients is characterized by increased fecal counts of E coli. Therefore, intestinal overgrowth of E coli may contribute to the process of hepatocarcinogenesis.

The relevance of intestinal dysbiosis in liver transplant candidates.

BACKGROUND: The gut microbial ecosystem plays an important role in the pathogenesis of liver diseases. However, the association of microbial community structure with the severity of liver dysfunction is not completely understood. METHODS: Fecal microflora was assessed in 40 patients with liver cirrhosis listed for primary liver transplantation (LT). Independent associations between fecal microbial counts and serum bilirubin, serum creatinine, international normalized ratio (INR), and the Model for End-stage Liver Disease (MELD) score were established in multiple linear regression models. RESULTS: Bifidobacterium (standardized regression coefficient [sß] = -0.549; P < 0.001), Enterococcus (sß = 0.369; P = 0.004), and yeast (sß = 0.315; P = 0.018) numbers were independently associated with serum bilirubin, while Escherichia coli counts (sß = 0.318; P = 0.046) correlated with INR, and Bifidobacterium counts (sß = 0.410; P = 0.009) with serum creatinine. Only Bifidobacterium (sß = -0.468; P = 0.003) and Enterococcus (sß = 0.331; P = 0.029) counts were independent predictors of the MELD score. Bifidobacterium/Enterococcus ratio, proposed as a measure of pre-LT gut dysbiosis, was significantly related to the MELD score following the adjustment for the absolute Bifidobacterium (sß = -0.333; P = 0.029) and Enterococcus (sß = -0.966; P = 0.003) numbers. This pre-transplant dysbiosis ratio (PTDR) was significantly correlated with Enterococcus (R = -0.897; P < 0.001) but not with Bifidobacterium (R = 0.098; P = 0.546) counts. Among the other components of gut microflora, only hydrogen peroxide (H2 O2 )-producing Lactobacillus strains significantly influenced Enterococcus counts (sß = 0.349; P = 0.028) and PTDR (sß = -0.318; P = 0.046). CONCLUSION: While the abundance of both Bifidobacterium and Enterococcus is related to liver dysfunction, the size of the Enterococcus population seems to be the most important determinant of pre-LT gut dysbiosis in cirrhotic patients. The H2 O2 -producing Lactobacillus strains potentially ameliorate this dysbiotic state.

Upper gastrointestinal endosonography in patients evaluated for liver transplantation.

BACKGROUND: Endosonography (EUS), which merges endoscopic and ultrasound examinations, is a useful modality to display abnormal vessels that develop in the intrinsic circulation, frequently called "deep" varices. If these pathological veins exceed of 5 mm diameter, they significantly increase the risk of bleeding among patients with cirrhosis. In the most recent pilot study EUS proved useful to assess children for orthotopic liver transplantation (OLT). AIM: We performed a cross-sectional study of EUS on 33 (22 males and 11 females) adult cirrhotic subjects being assessed for OLT. MATERIALS/METHODS: We used an echoendoscope at 7.5 MHz/12 MHz/20 MHz to evaluate the esophagus and stomach, including "deep" periesophageal/perigastric varices (adjacent to the muscularis propria) and paraesophageal/paragastric varices (outside the muscularis propria). "Deep" varices were considered to be large if >5 mm. RESULTS: On endoscopy, 26 (79%) patients showed esophageal varices (EV), including 11 (33%) with large (>5 mm) varices. Gastric varices (GV) were observed in 13 (39%) subjects, with 3 patients displaying large (>5 mm) varices. On EUS large "deep" EV (both para and periesophageal) were observed in 12 (36%) subjects, among whom 5 (42%) did not have large varices on endoscopy. Large "deep" GV were found on EUS in 12 (36%) subjects. On endoscopy 4 of them (33%) showed no varices and 3 (25%) had small GV. CONCLUSIONS: EUS offers a precise evaluation of portal hypertension in OLT candidates. "Deep" potentially dangerous varices, which are undetected with routine endoscopy, were noted in a significant proportion of patients. The role of EUS in prioritizing subjects for OLT must be evaluated in a prospective study.

Administration of a recombinant factor Vlla in patients undergoing liver transplantation for fulminant hepatic failure.

BACKGROUND: Fulminant hepatic failure (FHF) is associated with profound clotting disturbances leading to the risk of a major blood loss during orthotopic liver transplantation (OLT). Application of a recombinant factor VIIa (rVIIa) that promptly corrects clotting abnormalities remains controversial in the OLT setting. We conducted a retrospective analysis of the effect of rVIIa on the prothrombin time (PT) and other perioperative parameters in patients transplanted for FHF in our center. MATERIALS AND METHODS: Nineteen consecutive patients (9 males/10 females) of overall mean age of 33 +/- 13 years underwent the procedure due to: Wilson's (n = 8), non-A-non-B hepatitis (n = 6) or Amanita phalloides toxicity (n = 5). All subjects received rVIIa at a mean dose of 54 +/- 16 microg/kg body weight at 10 minutes before the skin incision. The PT was measured at 15 minutes and 12 hours after injection. Data were analyzed with StatView program with P < .05 considered significant. RESULTS: Rapid correction of PT was observed in all patients: the mean PT before injection was 37 +/- 14 versus 14 +/- 3 after 15 minutes (P < .0001). Twelve hours after the injection the PT was 19 +/- 5 (P < .0001 vs before injection and P < .0007 vs 15 minutes after injection). Two patients died at 1 and 4 days after OLT. Mean red blood cell requirement was 5 +/- 4 U and fresh frozen plasma was 11 +/- 5 U. The mean operative time was 527 +/- 126 minutes and intensive care unit stay 8 +/- 9 days. None of the patients developed thromboembolic complications. CONCLUSION: Administration of rVIIa caused a rapid improvement in the PT shortly after injection. It was safe and not associated with any thromboembolic events in our series.

Immunosuppression with low-dose daclizumab in liver transplant recipients with impaired kidney function: a single-center experience.

BACKGROUND: Nephrotoxicity of calcineurin inhibitors (CNI) may exert detrimental effects, particularly in orthotopic liver transplantation (OLT) patients with impaired kidney function. Immunosuppression with daclizumab permits delayed introduction of CNI, and may be preferred for patients with kidney dysfunction. This retrospective analysis of our experience using daclizumab was performed among patients who underwent transplantation with impaired kidney function. METHODS: We analyzed 168 patients. A serum creatinine (Cr) level >1.5 mg/dL was the indication for a protocol with low-dose daclizumab (50 mg intravenous [IV], day 0 and day 4), mycophenolate mofetil (MMF; 500 mg twice daily IV/orally), and tapering doses of prednisolone from day 0 after OLT. CNI were introduced at day 4-15 after OLT. Patients with a Cr level <1.5 mg/dL received immunosuppression with CNI+MMF+steroids or CNI+steroids. RESULTS: Fourteen patients fulfilled the criterion for daclizumab immunosupression. Their Cr and creatinine clearance (CrCl) values at OLT were 2.85 +/- 1.22 mg/dL and 19 +/- 11 mL/min, respectively. In the remaining 154 patients, Cr and CrCl results were 0.88 +/- 0.3 mg/dL and 107 +/- 82 mL/min, respectively. At discharge, the daclizumab group showed Cr and CrCl estimates of 0.97 +/- 0.45 mg/dL and 86 +/- 34 mL/min (P < .0001 for both, when compared with prior to OLT). Both Cr and CrCl levels at discharge were not different from those values of patients who underwent transplantation with normal kidney function. The incidence of acuterejection was 14% in the daclizumab group and 18% in the other recipients (P = not significant [NS]). CONCLUSIONS: Immunosuppression with low-dose daclizumab and delayed introduction of CNI was safe and did not increase the risk of an acute rejection episode, thus offerring an excellent therapeutic option for patients who undergo transplantation with impaired kidney function.

Assessment of a modified Child-Pugh-Turcotte score to predict early mortality after liver transplantation.

OBJECTIVE: The Model for End-Stage Liver Disease (MELD) predicts mortality on the transplant list; however, it has not been of much use to predict posttransplant outcomes. Several prognostic models have been tested among patients with cirrhosis; nevertheless, their predictive value has not been established in the posttransplant setting. We recently modified the Child-Pugh-Turcotte (CPT) score by adding creatinine levels (CPT + Cr), which has proven useful for patients with alcoholic cirrhosis. This retrospective analysis sought to predict early (1 month) mortality using CPT + Cr versus 5 other prognostic models in patients who underwent orthotopic liver transplantation (OLT) at our center. MATERIALS AND METHODS: We included 48 consecutive patients (30 males, 18 females, median age 51 years). The predictive values of CPT + Cr were compared with CPT scores without or with the Huo modification, CPT + Na, MELD, and MESO, which is the MELD to serum Na ratio. Pearson correlations and ROC curves as evidenced by the area under the curve (AUC) were determined for each index. P < .05 was considered to be significant. RESULTS: CPT + Cr showed the highest correlation with the risk of death (r = .368, P = .01); MELD and MESO were the lowest (r = .204, P = NS; and r = .254, P = NS, respectively). ROC analysis showed the best predictive value of CPT and CPT-Crea with AUC of 0.758 (P = .010) and 0.748 (P = .011) respectively, as compared to 0.689 for MESO and 0.659 for MELD (both NS). CONCLUSIONS: A modified CPT score with creatinine levels may be of value to predict early death after OLT. Its usefulness must be validated in a prospective study of a large patient cohort.

Modified Charlson Comorbidity Index in predicting early mortality after liver transplantation.

BACKGROUND: The Charlson Comorbidity Index for orthotopic liver transplantation (CCI-OLT) is a modified clinical score recently proposed to be useful for the assessment of long-term survival after OLT. It includes 9 associated conditions selected upon a multivariate analysis of a large cohort of transplant recipients. Its role in predicting early mortality after OLT has not yet been investigated. We sought to CCI-OLT as a potential predictor of 1-month mortality after OLT. MATERIALS/METHODS: One hundred ninety-seven OLT were performed in our center between March 2002 and February 2009. After exclusion of patients who underwent transplantation for fulminant hepatic failure or those who underwent regrafting, we included a group of 169 patients. Viral (39%) and alcohol-induced (23%) cirrhosis were the most common indications for OLT. The CCI-OLT index was assessed in all patients. RESULTS: In total, 146 (86%) subjects survived and 23 (14%) died within 1 month after LT. Fifty-one (30%) patients suffered at least 1 comorbidity that was included in the CCI-OLT. Direct comparison between survivor versus nonsurvivor groups showed no significant difference in terms of the total frequency of comorbidities (30.1% vs 30.4%; P > .99) or the number or the type of comorbidity. The most commonly associated condition in both groups was diabetes mellitus. CONCLUSION: Unlike the case of long-term survival, CCI-OLT did not seem to predict early (1-month) mortality after OLT.