VI documento de consenso de la sociedad española de trasplante hepático (SETH)

The goal of the Spanish Liver Transplantation Society (La Sociedad Española de Trasplante Hepático) is to promote and create consensus documents about current topics in liver transplantation with a multidisciplinary approach. To this end, on October 20, 2016, the 6 th Consensus Document Meeting was held, with the participation of experts from the 24 authorized Spanish liver transplantation programs. This Edition discusses the following subjects, whose summary is offered below: 1) limits of simultaneous liver-kidney transplantation; 2) limits of elective liver re-transplantation; and 3) liver transplantation after resection and hepatocellular carcinoma with factors for a poor prognosis. The consensus conclusions for each of these topics is provided below.     

Androgen receptors in hepatocellular carcinoma and surrounding liver: relationship with tumor size and recurrence rate after surgical resection

Background/Aims: This study aimed to evaluate the parameters associated with the presence of androgen receptors in hepatocellular carcinoma and surrounding non-tumoral liver. Furthermore, we have assessed whether androgen receptor positively influences disease recurrence after surgical resection.Methods: Androgen receptor concentration was calculated by receptor binding assay in tumoral and non-tumoral liver in 43 patients (40 of them with cirrhosis) with hepatocellular carcinoma who underwent surgical resection.Results: Androgen receptors were found in 28 of the tumoral and in 30 of the non-tumoral samples, at concentrations ranging between 5 and 211 fmol/mg protein. The presence of androgen receptors within the tumor was significantly related to a smaller tumor size. Thereby, 22 of the 29 nodules ≤3 cm contained androgen receptors, while this occurred in only six of the 14 tumors larger than 3 cm (p<0.05). In contrast, the only parameter associated with the presence of androgen receptors in the non-tumoral liver was a lower gamma-glutamyltranspeptidase concentration. Disease recurrence after surgical resection was not only related to some tumor characteristics (increased alfa-fetoprotein concentration, presence of satellites, differentiation degree), but also to the presence of androgen receptors in the surrounding liver. Thus, the probability of recurrence after 1- and 2-year follow up in patients with androgen-positive livers was 33% and 50%, respectively, while it was 0% and 20% in those with androgen-negative livers (p<0.05). In contrast, the presence of androgen receptors within the tumor was not associated with a higher recurrence rate.Conclusions: These results show that only two thirds of hepatocellular carcinomas contained androgen receptors and that this feature was more frequent in small tumors. In addition, our data indicate that the presence of androgen receptors within the tumor does not imply a different outcome after surgical resection. In contrast, the presence of these receptors in the surrounding non-tumoral liver may be considered a risk factor for a higher incidence of disease recurrence.     

Rat CCl4‐induced cirrhosis plus total portal vein ligation: a new model for the study of hyperammonaemia and brain oedema

Introduction: Animal models used to study hyperammonaemic disorders related to chronic liver disease are unsatisfactory. These animals only develop hyperammonaemia and brain oedema when fed with diets supplemented with amonium acetate. Aim: To develop a novel experimental model of hyperammonaemia and brain oedema in CCl₄‐induced cirrhosis in rats. Methods: Four groups were studied: rats with sham intervention (S), rats with total portal vein ligation (TPVL), cirrhotic rats (LC), and cirrhotic rats with TPVL (LC+TPVL). When ascites was diagnosed, oral glutamine challenge (OGC) test was performed. Blood, liver, lungs and brain samples were collected to quantify liver function parameters, plasmatic and cerebral ammonia, endotoxaemia, liver and brain histology, brain oedema and portosystemic shunting degree. Results: LC+TPVL rats showed a significant increase in portosystemic shunting when compared with LC group and a significant derangement in liver function when compared with TPVL group. These alterations resulted in a significant increase in plasmatic and brain ammonia concentrations and a higher plasmatic endotoxaemia as compared with others. Similarly, the area under OGC curve was significantly increased in LC+TPVL group as compared with the others, and correlates with portal shunting. Low‐grade brain oedema was only observed in LC+TPVL group. All cirrhotic groups showed liver regeneration nodules and type‐II Alzheimer astrocytes Conclusion: LC+TPVL reproduce the main alterations – portosystemic shunting, plasmatic and cerebral hyperammonaemia and low‐grade brain oedema – observed in cirrhotic patients with hepatic encephalopathy.     

Evaluation of Anti-HBs Serum Levels and Pharmacokinetic Profile After Intravenous Administration of Niuliva, a New Hepatitis B Immunoglobulin, Following Liver Transplantation

Purpose

We assessed whether trough anti–hepatitis B surface antigen (HBs) serum levels considered to be protective (>100 IU/L) were maintained in liver transplanted patients after 6 months of uninterrupted treatment with Niuliva, a new intravenous HBIg.

Methods

Twenty patients, aged 18–70 years, who had undergone liver transplantation due to HBV-related liver disease at least 1 year before inclusion were enrolled in a prospective, open-label, uncontrolled, multicenter clinical study. A fixed monthly dose of 5,000 IU of study medication was administered intravenously for 6 months.

Results

After the second infusion, all mean values of anti-HBs and 95% CIs were above the limit of 100 IU/L considered to be protective. The percentages of success ranged between 95% (95% CI 75.1%–99.9%) and 100% (95% CI 86.1%–100%). Mean values and 95% CI of in vivo recovery of anti-HBs at 15–30 minutes after each infusion showed overlaps between all intervals, which indicated that significant differences were not present in the recovery of post infusion anti-HBs in vivo. There were no recurrences of HBV infection during the study. There were no seroconversions in patients previously negative to hepatitis C virus or HIV. No serious adverse events related to the study medication were observed.

Conclusions

Serum levels of anti-HBs after using Niuliva in patients who had undergone liver transplantation were protective in 95%–100% of cases after the study period. This new HBIg showed the expected pharmacokinetic profile and was well tolerated and safe.     

Efficacy of central nervous system stimulant treatment for cocaine dependence: a systematic review and meta-analysis of randomized controlled clinical trials

AIMS: To evaluate the efficacy of central nervous system (CNS) stimulants compared with placebo for the treatment of cocaine dependence. METHODS: A systematic review and meta-analysis was carried out. Bibliographic databases were searched, reference lists of retrieved studies were hand-searched and the first authors of each study were contacted. All randomized controlled clinical trials (RCCT) comparing the efficacy of any CNS stimulant with placebo in cocaine-dependent patients were included. Quantitative data synthesis was performed for each single CNS stimulant and for all CNS stimulants. RESULTS: Nine RCCT met the inclusion criteria. These RCCT included 640 patients and compared five CNS stimulants: mazindol, dextroamphetamine, methylphenidate, modafinil and bupropion with placebo. No CNS stimulant improved study retention [RR = 0.94 (0.81-1.09)] or cocaine use [RR = 0.90 (0.79-1.02)]. An exploratory analysis using indirect estimations of cocaine use showed that the proportion of cocaine-positive urine screens was lower with dexamphetamine than with placebo [RR = 0.73 (0.60-0.90)] and that all CNS stimulants pooled together also suggested a significant decrease of cocaine use [RR = 0.87 (0.77-0.99)]. Data on craving could not be meta-analysed due to heterogeneity, but no RCCT found differences in cocaine craving between active drug and placebo except one, whose outcome favoured dexamphetamine. No serious adverse event (AE) was reported. Average of AE-induced dropouts was low and was greater for CNS stimulants than placebo: 4.4% versus 1.3% (P = 0.03). CONCLUSION: The main outcomes of this study do not support the use of CNS stimulants for cocaine dependence. Nevertheless, secondary analyses provide some hopeful results that encourage further research with these drugs, mainly with dexamphetamine and modafinil.     

Brain-derived neurotrophic factor and its intracellular signaling pathways in cocaine addiction

Cocaine addiction is one of the severest health problems faced by western countries, where there is an increasing prevalence of lifelong abuse. The most challenging aspects in the treatment of cocaine addiction are craving and relapse, especially in view of the fact that, at present, there is a lack of effective pharmacological treatment for the disorder. What is required are new pharmacological approaches based on our current understanding of the neurobiological bases of drug addiction. Within the context of the behavioral and neurochemical actions of cocaine, this paper considers the contribution of brain-derived neurotrophic factor (BDNF) and its main intracellular signaling mechanisms, including mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3K), in psychostimulant addiction. Repeated cocaine administration leads to an increase in BDNF levels and enhanced activity in the intracellular pathways (PI3K and MAPK/ERK) in the reward-related brain areas, which applies especially several days following withdrawal. It has been hypothesized that these neurochemical changes contribute to the enduring synaptic plasticity that underlies sensitized responses to psychostimulants and drug-conditioned memories leading to compulsive drug use and frequent relapse after withdrawal. Nevertheless, increased BDNF levels could also have a role as a protection factor in addiction. The inhibition of the intracellular pathways, ERK and PI3K, leads to a disruption in sensitized responses and conditioned memories associated with cocaine addiction and suggests new, potential therapeutic strategies to explore in the dependence on psychostimulants.     

Detection of Metachronous Neoplasms in Colorectal Cancer Patients: Identification of Risk Factors

Purpose Patients with colorectal cancer have a high risk of developing metachronous neoplasms. Identification of predictive factors associated with such conditions would allow individualized follow-up strategies in these patients. This study was designed to identify individual and familial factors associated with the development of metachronous colorectal neoplasms in patients with colorectal cancer. Methods In the context of a prospective, multicenter, general population-based study—the EPICOLON project—all patients with colorectal cancer attended in ten Spanish hospitals during a one-year period were included. Patients with familial adenomatous polyposis or inflammatory bowel disease were excluded. All patients were monitored by colonoscopy within two years of the diagnoses. Demographic, clinical, pathologic, molecular (microsatellite instability status and immunohistochemistry for MSH2 and MLH1), and familial characteristics (fulfillment of Amsterdam I or II criteria, and revised Bethesda guidelines) were analyzed. Results A total of 353 patients were included in the study. At two years of follow-up, colonoscopy revealed the presence of adenomas in 89 (25 percent) patients and colorectal cancer in 14 (3.9 percent) patients, in 7 cases restricted to anastomosis. Univariate analysis demonstrated that development of metachronous neoplasm (adenoma or colorectal cancer) was associated with personal history of previous colorectal cancer (odds ratio, 5.58; 95 percent confidence interval, 1.01–31.01), and presence of previous or synchronous adenomas (odds ratio, 1.77; 95 percent confidence interval, 1.21–3.17). Although nonstatistical significance was achieved, metachronisms were associated with gender (P < 0.09) and differentiation degree (P < 0.08). Multivariate analysis identified previous or synchronous adenomas (odds ratio, 1.98; 95 percent confidence interval, 1.16–3.38) as independent predictive factor. Neither presence of tumor DNA microsatellite instability nor family history correlated with the presence of metachronous neoplasms. Conclusions Patients with previous or synchronous colorectal adenoma have an increased risk of developing metachronous colorectal neoplasms. Accordingly, this subgroup of patients may benefit from specific surveillance strategies. Supported by grants from the Red Nacional de Investigación en Hepatología y Gastroenterología (Instituto de Salud Carlos III, C03/02) and from Fondo de Investigaciones Sanitarias (FIS PI061384). Xavier Llor is a recipient of a Ramon y Cajal grant form Ministerio de Ciencia y Tecnología of the Spanish government Presented at the meeting of the United European Gastroenterology, Copenhagen, Denmark, October 15 to 19, 2005.