Fernando Pons-Romero

Alcohol recidivism impairs long-term patient survival after orthotopic liver transplantation for alcoholic liver disease.

The aim of this study was to evaluate the rate of alcohol recidivism after orthotopic liver transplantation (OLT) for alcoholic liver disease (ALD) and its influence on the allograft and patient survival, as well as the development of comorbidities and de novo cancers. The study was performed on 54 subjects previously analyzed and transplanted in our center for ALD, whose follow‐up was prolonged to a mean of 99.2 (SD 31.7) months (range, 14–155). Medical records were reviewed, and data on alcohol consumption, therapeutic compliance, graft evolution, rejection, infections, comorbidities, rates of de novo malignancies and other clinical events, and survival were collected. Comparisons between groups were performed by the Fishers exact test, and survival was assessed by the Kaplan‐Meier method. Survival curves were compared using the Mantel‐Cox statistic. The risk of death resulting from alcohol recidivism was analyzed with a Cox proportional hazards model. Fourteen patients who underwent transplantation for ALD (25.9%) returned to alcohol use between 5.0 and 86.9 months after OLT (median, 47.5). There was no significant association between the presence or absence of alcohol recidivism and the occurrence of graft rejection, infections, associated comorbidities after OLT, or compliance. The 5‐ and 10‐year survival rates for patients with alcohol recidivism were 92.9% and 45.1%, respectively, compared with 92.4% and 85.5%, respectively, for patients without alcohol recidivism. These figures show significantly lower survival rates in recidivistic patients after 10 years (P < 0.01, Mantel‐Cox). The fact that patients who resumed alcohol consumption have a worse 10‐year survival rate might be attributed to a higher frequency of deaths, primarily from cancer and cardiovascular events. (Liver Transpl 2005;11:420–426.)

Variceal ligation compared with endoscopic sclerotherapy for variceal hemorrhage: prospective randomized trial.

BACKGROUND To evaluate the safety and efficiency of variceal ligation compared with endoscopic sclerotherapy, 88 patients with cirrhosis with recent variceal bleeding were randomized to undergo either treatment. METHODS Sclerotherapy was performed using ethanolamine and polidocanol injection at 1, 2, and 3 weeks and every 3 weeks thereafter. The Stiegmann-Goff device was used for variceal ligation at the same intervals. RESULTS The rate of variceal eradication was the same for both groups, but eradication was accomplished sooner in patients undergoing variceal ligation (5.3+/-1.6 vs. 6.6+/-2.4 endoscopic sessions, p < 0.05) and with fewer complications (19 vs. 6, p < 0.005). The rate of recurrent bleeding was lower in patients treated by ligation (31% vs. 50%, p < 0.05). After eradication, variceal recurrence was more frequent in patients treated by variceal ligation at 1 and 3 years (47% and 92% vs. 23% and 55%, p < 0.01). Portal hypertensive gastropathy was significantly worse in the patients who had variceal ligation (17 patients vs. 6, p < 0.01). Survival and treatment failure were similar in both groups. CONCLUSIONS Variceal ligation was superior to sclerotherapy in terms of the rate of recurrent bleeding and the occurrence of complications but worse with respect to recurrence of varices and the evolution of portal hypertensive gastropathy. Long-term follow-up studies are required to find out whether there are deleterious effects of variceal ligation.

Non-alcoholic Steatohepatitis (NASH) and Hepatocellular Carcinoma

Non-alcoholic fatty liver disease (NAFLD) is characterized by an excessive accumulation of fatty acids and triglycerides within the cytoplasm of the hepatocytes of non-alcohol users. The natural history varies according to the initial histological diagnosis. A current consideration is that cryptogenic cirrhosis may be representative of a late stage of non-alcoholic steatohepatitis (NASH), which has lost its features of necroinflammatory activity and steatosis in up to 80% of patients. Since NASH is able to progress to cirrhosis, hepatocellular carcinoma (HCC) development may be an end-stage of this disease. We report below two clinical cases of patients diagnosed with NASH who developed HCC. The relationship between NAFLD and HCC is reviewed.

Plasma Leptin and TNF-α Levels in Chronic Hepatitis C Patients and Their Relationship to Hepatic Fibrosis

The aim of this study was to examine the possible relationship between the plasma levels of leptin and tumor necrosis factor (TNF)-α and the stage of hepatic fibrosis in a cohort of patients with chronic hepatitis C. Leptin and TNF levels were measured by RIA in 135 patients and in 75 age- and sex-matched controls. Liver disease was evaluated by the stage of fibrosis and the extent of inflammatory infiltrate in the liver biopsy. Leptin levels correlated with BMI values in healthy controls and in patients with chronic hepatitis C (men, r = 0.61, P = 0.0001; women, r = 0.68, P = 0.003). Leptin levels increased as hepatic fibrosis stage progressed both in male and in female patients (P < 0.001); also, TNF levels were higher in patients with an advanced stage of fibrosis (P = 0.006). In these patients, levels of leptin increased according to the progression of the stage of fibrosis; these data suggest that leptin may play a role in the regulation of hepatic fibrosis.

Are there Predictive Factors of Severe Liver Fibrosis in Morbidly Obese Patients with Non-alcoholic Steatohepatitis?

Background: Non-alcoholic steatohepatitis (NASH) is a clinicopathological entity characterized by the presence of steatosis and lobular and/or portal inflammation with or without fibrosis. Patients with non-alcoholic fatty liver and fibrosis on liver biopsy have increased liver-related deaths. Methods: 181 wedge liver biopsies, taken at the time of bariatric surgery from patients with a mean body mass index (BMI) of 47, were studied. In all cases, the liver biopsy was performed without knowledge of the patients clinical and biochemical data, which were then examined with univariate and multivariate analysis. Results: Diagnosis of NASH was established in 105 patients (91%); 74 patients (70%) showed mild steatosis, 20 (19%) had moderate inflammation and fibrosis, and 11 (10%) had steatosis with severe fibrosis. None of the liver biopsies showed cirrhosis. Age was the only independent predictor of moderate and severe fibrosis (p=0.001). Conclusions: Since only age was a predictor of moderate or severe fibrosis, and no clinical or biochemical abnormalities detected slowly progressive hepatic fibrosis, liver biopsy is the only means of detecting progression to more advanced liver disease in a NASH patient.

Changes in the Serum Levels of Interleukin-17/ Interleukin-23 During Acute Rejection in Liver Transplantation

Interleukin‐23 (IL‐23) and T helper 17 (Th17) cells have been cast as major players in autoimmunity, but their role in transplantation immunity remains to be specified. The aim of our study was to investigate the time course of serum levels of IL‐23 and IL‐17 during hepatic allograft rejection. Serum levels of IL‐23 and IL‐17 were determined in 20 healthy subjects and 50 hepatic transplant recipients. These patients were divided into 2 groups: group I was composed of 15 patients with acute rejection, and group II was composed of 35 patients without acute rejection. Samples were collected on days 1 and 7 after liver transplantation and on the day of liver biopsy. The concentrations of IL‐23 were similar for the rejection group and nonrejection group at early postoperative times. We observed a significant increase in serum IL‐23 levels in the rejection group when a diagnosis of acute rejection had been established. Similarly to IL‐23, at the diagnosis of acute rejection, the concentration of IL‐17 was significantly higher in the rejection group versus the nonrejection group. The whole transplant group, including those with stable graft function, had higher serum levels of IL‐23 and IL‐17 than the controls during the entire postoperative period. In conclusion, IL‐23 and IL‐17 are up‐regulated during acute hepatic rejection. These findings suggest a role for Th17 cells in human liver allograft rejection. Liver Transpl 15:629–633, 2009.

Viral replication in patients with concomitant hepatitis B and C virus infections.

The aim of this study was to assess the implications of dual infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). The HBV and HCV status in 100 patients with chronic hepatitis was analysed. HBV DNA was studied using liquid hybridization and the polymerase chain reaction (PCR). HCV viremia was measured using qualitative and quantitative PCR. The HCV genotype was determined by PCR. Patients were divided into three groups according to their HCV-RNA and HBsAg status: group I consisted of 40 patients with chronic hepatitis caused by HBV; group II, 40 patients with chronic hepatitis caused by HCV; and group III, 20 patients infected with both viruses. The HBV-DNA level was higher in group I than in group III (66.4 vs. 11.5 pg/ml; p<0.05). Quantification of HCV viremia revealed mean values of 36.9 copies × 105/ml in group II and 5.5 copies/ml × 105 in group III (p<0.05). The mean aminotransferase level and histological activity were higher in group III. HCV genotype 1b was the predominant type. The data suggest that there is reciprocal inhibition of viral replication in patients with dual HBV and HCV infection. Liver disease appears to be more severe in patients with chronic hepatitis B and C.

Osteoprotegerin and RANKL in alcoholic liver cirrhosis.

Abstract: Background/aims: The mechanisms leading to osteoporosis in alcoholic liver disease remain poorly understood. Recently identified soluble circulating osteoprotegerin (OPG), is the osteoclastogenesis inhibitory factor. It acts as a decoy receptor for osteoclast activating factor, receptor activator of nuclear factor‐κB ligand (RANKL), and impairs osteoclast function. The aim of our study was to investigate the OPG/RANKL system in alcoholic cirrhotic patients and their correlation with biochemical marker of bone turnover.

Increased expression of Ob‐Rb and its relationship with the overexpression of TGF‐β1 and the stage of fibrosis in patients with nonalcoholic steatohepatitis

Abstract: Aims: The main aim of this study was to examine the relationship of the leptin system in steatosis and nonalcoholic steatohepatitis (NASH). The study also analysed the pathogenic role of the leptin system in the development of hepatic fibrosis and its relation with the TGF‐β1 system.

Involvement of the Fas system in liver allograft rejection

OBJECTIVE:Recent studies suggest that apoptosis is an important mechanism of cell death in the rejection of liver allografts and that this process is mediated via Fas. The aim of this study was to analyze the expression of the Fas system during the liver allograft rejection and its evolution after treatment.METHODS:We evaluated 14 patients with liver allograft rejection before and after treatment. Fas immunostaining was performed by the labeled streptavidin-biotin peroxidase method using a 200-fold dilution of a monoclonal antibody. Assessment of apoptosis was determined by the terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) technique on deparaffined liver samples. Serum levels of soluble Fas antigen (sFas) were detected by an enzyme immunoassay procedure. Twelve liver transplant patients without allograft rejection were analyzed as a control group.RESULTS:The number of hepatocytes expressing Fas antigen, the percentage of apoptotic hepatocytes, and the sFas levels were higher in patients with liver allograft rejection than in controls (27.9 ± 23.1% vs 1.4 ± 1.2%, p < 0.001; 2.2 ± 0.9% vs 1.0 ± 0.1%, p = 0.02; 24.2 ± 39.6 vs 2.8 ± 4.0 IU/ml, p = 0.03, respectively). There was a correlation between the levels of sFas, AST (r = 0.86, p < 0.001), ALT (r = 0.78, p = 0.02), and γ-globulin levels (r = 0.86, p < 0.001). After the rejection treatment we found a significant decrease in the Fas antigen expression (18.6 ± 13.3%, p < 0.05), TUNEL index (0.2 ± 0.4, p < 0.05), and levels of sFas (9.9 ± 30.25 IU/ml, p = 0.005).CONCLUSIONS:1) The demonstration of hepatocytes with Fas antigen expression and the labeling of the nuclei by the TUNEL assay suggest that apoptosis mediated by the Fas system plays a role in the pathogenesis of liver allograft rejection. 2) The Fas expression and the sFas levels decreased in patients with treatment response.