Innovations in liver transplantation in 2020, position of the Belgian Liver Intestine Advisory Committee (BeLIAC).

Liver transplantation (LT) remains the only curative option for patients suffering from end-stage liver disease, acute liver failure and selected hepatocellular carcinomas and access to the LT-waiting list is limited to certain strict indications. However, LT has shown survival advantages for patients in certain indications such as acute alcoholic hepatitis, hepatocellular carcinoma outside Milan criteria and colorectal cancer metastases. These newer indications increase the pressure in an already difficult context of organ shortage. Strategies to increase the transplantable organ pool are therefore needed. We will discuss here the use of HCV positive grafts as the use of normothermic isolated liver perfusion. Belgian Liver Intestine Advisory Committee (BeLIAC) from the Belgian Transplant Society (BTS) aims to guarantee the balance between the new indications and the available resources.

Risk of hepatocellular carcinoma and fibrosis evolution in hepatitis C patients with severe fibrosis or cirrhosis treated with direct acting antiviral agents.

Background and study aims: Cirrhosis associated to chronic hepatitis C virus (HCV) is one of the leading cause of hepatocellular carcinoma (HCC). The goal of our study was to evaluate first the risk and determinants of HCC and second the evolution of fibrosis in patients treated for HCV with advanced fibrosis stages who achieved sustained virological response (SVR) after direct-acting antivirals (DAA) treatment. Patients and methods: We conducted a prospective study on HCV patients with F3 or F4 Metavir fibrosis scores treated with DAA between October 2014 and February 2017. The annual incidence rate for HCC was calculated. We used Cox regression model in order to identify factors associated with HCC. Transient elastography (TE) was performed 12 and 24 months after the end of DAA treatment and non-invasive liver fibrosis biomarkers were performed twice a year during follow-up. Results: 143 patients with severe fibrosis or cirrhosis were enrolled in the study. 6 patients developed HCC. The annual incidence rate of HCC in our cohort was 2.7 per 100 patients. Risk factors associated with HCC after DAA were genotype 2 and steatosis. Overall TE values significantly decreased after DAA treatment with a median value prior to treatment of 16.9 kPa to a median of 10.8 kPa 24 months after the end of the treatment. Biological fibrosis scores also significantly decreased following viral eradication. Conclusions: DAA treatment does not seem to be associated with HCC promotion after HCV eradication in patients with severe fibrosis stages. DAA-induced SVR is associated with a reduced estimation of fibrosis.

Targeting the gut microbiota to treat alcoholic liver diseases: evidence and promises.

The human intestine is colonized by a variety of microbes that influence the metabolic responses, the immune system and the nervous system. Dietary patterns are important factors that shape the composition of the gut microbiota. Many animal models of alcohol exposure have highlighted the key role of the alcohol-induced gut microbiota alterations, leaky gut and translocation of microbial products in the development of alcoholic liver disease (ALD). However, in humans, there is no clear picture defining an "alcoholic microbiome", and the link between intestinal dysbiosis and ALD development is far from being understood. Although we do not comprehend all the mechanistic insights, clinical studies aiming at modulating the gut microbiota of alcoholic patients have shown some beneficial effects. Here we review the potential therapeutic effects of probiotics in ALD and give some clinical perspectives on the role of prebiotics and the use of fecal microbiota transplantation.

[What is the role of the gut microbiota in the development of alcohol use disorders?] / Troubles liés à l'usage d'alcool : et si l'addiction trouvait son origine dans l'intestin ?

Alcohol addiction is a complex and multifactorial disease influenced by social, psychological and biological aspects. The current pharmacological drugs used in the management of alcohol dependence have shown only a modest efficacy and the relapse rate remains high in this disease. Recently, the gut microbiota, a huge and dynamic ecosystem made up of billions of microorganisms living in our intestine, has been shown to regulate many important functions for human health. Indeed, the gut microbiota is known to influence our metabolism, our immune system as well as our nervous system with consequences for brain functions, mood and behaviour. We have shown that heavy and chronic alcohol consumption induced important changes in the composition of the gut microbiota. Furthermore, the microbial changes are associated with the severity of depression, anxiety and alcohol craving that are important factors predicting the risk of relapse. This suggests the existence of a gut-brain axis in alcohol dependence and supports the development of new therapeutic alternatives, targeting the gut microbiota, in the management of alcohol dependence.

L'addiction à l'alcool est une maladie complexe, impliquant à la fois des facteurs sociaux, psychologiques et biologiques. La prise en charge des patients alcoolo-dépendants est difficile car les médicaments actuels ont une efficacité limitée dans le maintien de l'abstinence, et le taux de rechute reste très élevé. Récemment, le microbiote intestinal, un écosystème constitué de milliards de micro-organismes vivant dans notre intestin, est devenu un acteur clé de la santé humaine. Il est connu pour réguler notre métabolisme, notre système immunitaire, mais également notre système nerveux, et donc notre comportement et notre humeur. Nos études récentes ont montré que la consommation abusive d'alcool entraîne des modifications importantes de la composition du microbiote intestinal. Nous avons également montré que ces altérations microbiennes étaient associées à la sévérité des symptômes de dépression, d'anxiété et d'appétence à l'alcool, suggérant ainsi l'existence d'un dialogue entre l'intestin et le cerveau. Ces résultats encouragent la recherche de nouvelles pistes thérapeutiques, ciblant le microbiote intestinal, dans le traitement de la dépendance à l'alcool.

Stopping nucleos(t)ide analogue treatment in Caucasian hepatitis B patients after HBeAg seroconversion is associated with high relapse rates and fatal outcomes.

BACKGROUND: Stopping nucleos(t)ide analogues (NA) after hepatitis B e antigen (HBeAg) seroconversion is associated with high relapse rates in Asian patients, but data in Caucasian cohorts are scarce. Clinical course, outcomes and immunological aspects of chronic hepatitis B infections differ substantially between distinct ethnicities. AIM: The aim of this study was to determine relapse rates, factors predicting relapse and clinical outcomes after nucleos(t)ide analogue cessation in a large, predominantly Caucasian cohort of chronic hepatitis B patients with nucleos(t)ide analogue-induced HBeAg seroconversion. METHODS: This is a nationwide observational cohort study including HBeAg positive, mono-infected chronic hepatitis B patients with nucleos(t)ide analogue-induced HBeAg seroconversion from 18 centres in Belgium. RESULTS: A total of 98 patients with nucleo(s)tide analogue-induced HBeAg seroconversion were included in the study. Of the 62 patients who stopped treatment after a median consolidation treatment of 8 months, 30 relapsed. Higher gamma-glutamyl transferase levels at both treatment initiation (HR 1.004; P = 0.001 per unit increment) and HBeAg seroconversion (HR 1.006; P = 0.013 per unit increment) were associated with an increased risk of clinically significant relapse in a multivariate Cox regression model. Treatment cessation led to liver-related death in 2 patients, of whom one showed a severe flare. Of the patients who continued treatment after HBeAg seroconversion, none relapsed or developed severe hepatic outcomes. CONCLUSION: Treatment withdrawal in Caucasian chronic hepatitis B patients after nucleos(t)ide analogue-induced HBeAg seroconversion results in viral relapses in more than half of patients with potential fatal outcomes. These real-world data further lend support to preferentially continue NA treatment after HBeAg seroconversion until HBsAg loss.

The link between inflammation, bugs, the intestine and the brain in alcohol dependence.

In recent years, some new processes have been proposed to explain how alcohol may influence behavior, psychological symptoms and alcohol seeking in alcohol-dependent subjects. In addition to its important effect on brain and neurotransmitters equilibrium, alcohol abuse also affects peripheral organs including the gut. By yet incompletely understood mechanisms, chronic alcohol abuse increases intestinal permeability and alters the composition of the gut microbiota, allowing bacterial components from the gut lumen to reach the systemic circulation. These gut-derived bacterial products are recognized by immune cells circulating in the blood or residing in target organs, which consequently synthesize and release pro-inflammatory cytokines. Circulating cytokines are considered important mediators of the gut-brain communication, as they can reach the central nervous system and induce neuroinflammation that is associated with change in mood, cognition and drinking behavior. These observations support the possibility that targeting the gut microbiota, by the use of probiotics or prebiotics, could restore the gut barrier function, reduce systemic inflammation and may have beneficial effect in treating alcohol dependence and in reducing alcohol relapse.

Achieving WHO recommendations for Hepatitis C Virus Elimination in Belgium.

BACKGROUD: The World Health Organization (WHO) released updated guidelines for the screening, care and treatment of patients with chronic hepatitis C virus (HCV) infection. METHODS: A previously described HCV disease burden model was used to develop a "WHO scenario" to achieve the WHO recommendations of a 90% reduction in incidence and 65% reduction in liver-related deaths. After determining the steps necessary to achieve this goal, the impact of realistic constraints was modeled. RESULTS: In 2015, there were 66.200 viremic infections, with 43% diagnosed and 1.350 treated. In order to reduce new infections, treatment must be extended to ≥ F0 patients, including people who inject drugs and other individuals at risk of transmitting HCV. -Additionally, diagnosis and treatment of 3.030 and 4.060 patients, respectively, would be required. The largest attenuation of the WHO scenario would occur if no new cases were diagnosed after 2018 (300% more viremic infections by 2030). Limiting treatment to ≥ F2 patients or treating fewer patients (3.000) would result in 220% or 140% more viremic cases, respectively, compared with the WHO scenario. CONCLUSION: Achieving the WHO guidelines in Belgium requires a coordinated effort to scale up treatment and prevention efforts and to allow treatment access to patients of all fibrosis stages. A scale-up of treatment, however, requires patients to be both diagnosed and linked to care, suggesting a need for increased awareness and expanded screening efforts. Finally, prevention of new HCV infections requires a comprehensive understanding of the population at risk of transmitting HCV.

The Disease Burden of Hepatitis C in Belgium : An update of a realistic disease control strategy.

BACKGROUND: This manuscript serves as an update to position papers published in 2014 based on the available Belgian hepatitis C virus (HCV) epidemiological data. METHODS: Building on the current standard of care (2015 : 900 ≥ F3 patients treated with 70-85% SVR), four new scenarios were developed to achieve the goals of near viral elimination and prevention of HCV associated morbidity and mortality by 2026 and 2031. Increases in treatment efficacy were assumed in 2016 (90% SVR) and 2017 (95% SVR). RESULTS: Scenario 1: Treating 6,670 patients annually by 2018 (≥ F0 beginning in 2017) and diagnosing 3,790 patients annually by 2020, a 90% reduction in viremic cases and advanced outcomes was observed by 2026. Scenario 2: Treating 4,300 patients annually by 2018 (≥ F0 beginning in 2020) without increasing the number diagnosed, a 90% reduction in viremic cases and 85%-95% reduction in advanced outcomes was observed by 2031. Scenario 3: Treating 5,000 ≥ F2 patients annually by 2018, and diagnosing 3,620 patients annually by 2020, a 90% reduction in advanced outcomes and 50% reduction in viremic cases was observed by 2026. Scenario 4: Treating 3,100 ≥ F2 patients annually by 2018 without increasing the number diagnosed, a 90%-95% reduction in advanced outcomes and 55% reduction in viremic cases was observed by 2031. CONCLUSIONS: Scenario 2 would provide the most favorable balance of outcomes (90% reduction in viremic prevalence and advanced outcomes) and realistic requirements for implementation (gradual increase in treatment, delayed incorporation of patients with no/mild fibrosis).

Alcohol-induced hypertension: an important healthcare target in Belgium.

Excessive alcohol intake is one of the leading causes of premature death in Europe and particularly in Belgium. Belgian people are consuming more alcohol per year than the European average. It is well established that excessive alcohol consumption is a significant predictor of the development of hypertension (HTN). Two million adults in Belgium suffer from HTN and this number will increase to three million by 2025. Less than 50% of Belgian people treated for HTN are well-controlled. Alcohol reduction in patients with HTN can significantly lower systolic and diastolic blood pressure. After reviewing the epidemiology of HTN and alcohol disorders in Belgium, this paper will focus on the rationale for alcohol screening and brief intervention in primary care. It will also describe the barriers to alcohol screening, and what could be the benefits of alcohol screening for our healthcare system. The authors believe that early identification through alcohol screening and brief intervention in general practice can help to improve the management of patients with HTN, to reach the targets of the WHO Global Action Plan, i.e., a 25% relative reduction in the risk of premature mortality from cardiovascular diseases, cancer, diabetes or chronic respiratory diseases. They are also convinced that this would allow achieving major healthcare savings.

The disease burden of hepatitis C in Belgium: development of a realistic disease control strategy.

BACKGROUND: Novel direct antiviral agents (DAAs) will become available soon with higher sustained viral response (SVR), fewer side-effects and higher compliance. Our aim was to evaluate different realistic strategies to control the projected increase in HCV-related disease burden in Belgium. METHODS: Based on literature review, expert opinions and historical assumptions, HCV-disease progression and mortality in Belgium was modeled to 2030. Strategies exploring the impact of increased treatment, treatment delay, and treatment restrictions were developed. RESULTS: Although the overall HCV prevalence is decreasing in Belgium, the burden of advanced stage HCV, including cirrhosis and hepatocellular carcinoma (HCC), is expected to increase under current treatment and cure rates. By increasing SVR to 90% from 2016 onward and the number of treated cases (from 710 to 2,050), in 2030 the cases with cirrhosis, decompensated cirrhosis and HCC would be significantly lower than in 2013. This strategy was found most efficient when applied to F2-F4 cases. To obtain comparable outcomes with F0-F4 cases, 3,490 patients should be treated. A two year delayed access to the DAAs increased HCV related morbidity and mortality by 15% relative to our strategy. CONCLUSIONS: Considering the evolving burden of HCV disease and the need for efficacious usage of healthcare resources, primary application of new DAAs in Belgium should focus on patients with significant and advanced fibrosis (F2-F4), providing these new drugs without delay upon availability and increasing access to therapy.

Hepatitis C epidemiology in Belgium.

BACKGROUND: The burden of hepatitis C virus (HCV) infection is significant and is increasing with the aging population. The results of a modeling study that included Belgium, along with many other countries, was published in April 2014. An in depth discussion surrounding the epidemiology of HCV in Belgium will be presented here. METHODS: A systematic literature review was conducted to assess the historical and current clinical burden of HCV in Belgium. Two expert panels were convened to discuss the strengths and limitations surrounding the available data and to generate consensus regarding the best estimates for total number of HCV cases, number of cases diagnosed, and the number of patients treated and cured, including potential HCV control strategies. RESULTS: Although no national studies exist, there were an estimated 70,000 (10,000-91,000) viremic HCV infections in 1994. By 2010 there were an estimated 22,900 individuals diagnosed with viremic HCV, and in 2011 approximately 710 patients were treated annually. An estimated 13% of liver transplants were attributable to HCV in 2011. Genotype 1 predominated (59%), followed by genotypes 3 (19%) and 4 (14%). CONCLUSIONS: Estimates of HCV prevalence, diagnosed cases and liver transplants due to HCV were available through published studies. However these publications were subject to bias and were occasionally outdated. Improved estimates of HCV prevalence would be useful for informing treatment, prevention and policy efforts in Belgium.

Current and future health and economic impact of hepatitis C in Belgium.

BACKGROUND AND STUDY AIMS: Chronic hepatitis C virus (HCV) infection is a serious global health problem affecting 150 million individuals worldwide. Although infection rates are decreasing, an aging population with progressing disease is expected to result in increased burden of advanced stage disease with high associated costs. This analysis describes the current and projected future economic impact of HCV sequelae in Belgium. METHODS: A previously described and validated model was populated with Belgian inputs and calibrated to project the current and future health and economic burden of HCV. Monte Carlo and sensitivity analyses were run to quantify uncertainty. All estimates exclude the cost of antiviral therapy. RESULTS: Costs associated with HCV were projected to peak in 2026 at Euro126M (Euro30M-Euro257M), while decompensated cirrhosis and hepatocellular carcinoma costs were projected to increase until 2031 and 2034. The projected 2014-2030 cumulative cost of HCV under current conditions was Euro1,850M. Scenarios to reduce the burden of HCV could result in Euro70M-Euro400M in cumulative cost savings. Starting treatment (1,000 patients) in 2015 could result in Euro150M cost savings. The lifetime cost of HCV increases with life expectancy, with highest future costs projected among young females with early stage disease. CONCLUSIONS: The economic burden of HCV and advanced stage disease were projected to further increase. Cost reductions are possible with timely interventions aimed at minimizing the health burden of advanced stage disease.

Salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis through DR5 and survivin-dependent mechanisms.

Ras activation is a frequent event in human hepatocarcinoma that may contribute to resistance towards apoptosis. Salirasib is a ras and mTOR inhibitor that induces a pro-apoptotic phenotype in human hepatocarcinoma cell lines. In this work, we evaluate whether salirasib sensitizes those cells to TRAIL-induced apoptosis. Cell viability, cell death and apoptosis were evaluated in vitro in HepG2, Hep3B and Huh7 cells treated with DMSO, salirasib and YM155 (a survivin inhibitor), alone or in combination with recombinant TRAIL. Our results show that pretreatment with salirasib sensitized human hepatocarcinoma cell lines, but not normal human hepatocytes, to TRAIL-induced apoptosis. Indeed, FACS analysis showed that 25 (Huh7) to 50 (HepG2 and Hep3B) percent of the cells treated with both drugs were apoptotic. This occurred through activation of the extrinsic and the intrinsic pathways, as evidenced by a marked increase in caspase 3/7 (five to ninefold), caspase 8 (four to sevenfold) and caspase 9 (eight to 12-fold) activities in cells treated with salirasib and TRAIL compared with control. Survivin inhibition had an important role in this process and was sufficient to sensitize hepatocarcinoma cells to apoptosis. Furthermore, TRAIL-induced apoptosis in HCC cells pretreated with salirasib was dependent on activation of death receptor (DR) 5. In conclusion, salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis by a mechanism involving the DR5 receptor and survivin inhibition. These results in human hepatocarcinoma cell lines and primary hepatocytes provide a rationale for testing the combination of salirasib and TRAIL agonists in human hepatocarcinoma.

The influence of laboratory-induced MELD score differences on liver allocation: more reality than myth.

BACKGROUND: Liver allocation in Eurotransplant (ET) is based on the MELD score. Interlaboratory MELD score differences in INR and creatinine determination have been reported. The clinical implication of this observation has not been demonstrated. METHODS: MELD scores were calculated in 66 patients with liver cirrhosis using bilirubin, creatinine, and INR analyzed in six liver transplant centers. Based on allocation results of ET, patients transplanted from December 2006 to June 2007 were divided according to MELD score in four groups. For each group, the influence of the match MELD on the probability of receiving a transplant was studied (Cox proportional hazards model). RESULTS: Laboratory-dependent significant differences in MELD score were demonstrated. Cox proportional hazards model showed a significant association between MELD score and the probability of organ allocation. The unadjusted hazard ratio for receiving a liver transplant was significantly different between group 2 and group 4 (group 2: MELD 19-24; group 4: MELD > 30). CONCLUSION: Laboratory-dependent significant differences in MELD score were observed between the six transplant centers. We demonstrated a significant association between the MELD score and the probability of organ allocation. The observed interlaboratory variation might yield a significant difference in organ allocation in patients with high MELD scores.

Chemoprevention of hepatocellular carcinoma. Proof of concept in animal models.

In the present work, we have evaluated the possibility of preventing liver carcinogenesis in rats at two stages of development. In the first series of experiments, we induced foci of altered hepatocytes, (FAH) which represent the first events in rodent liver carcinogenesis, using the chemical mutagens diethylnitrosamine (DEN) and acetylaminofluorene (AAF). In the second part of the work, we used repeated weekly injections of DEN only that gave rise to significant fibrosis at 11 weeks and the development of malignant tumours at 16 weeks. We chose to assess the chemopreventive effect of three different drugs: pioglitazone, lanreotide and S-trans-trans-farnesylthiosalicylic acid (FTS). Pioglitazone (PGZ) is an agonist of peroxisome proliferator-activated receptor gamma (PPARg), itself a member of the nuclear receptor superfamily, responsible for the modulation of a number of metabolic pathways, including cell differentiation, metabolism of lipids and inflammation. Lanreotide (LAN) is a somatostatin analogue that has an inhibitory effect on the release of several hormones, such as growth hormone and serotonine. FTS is a specific antagonist of the protoocogene Ras, tested here based on the rationale that Ras is activated in many hepatocellular carcinomas (HCC). We showed that both PGZ and LAN were efficient in the first, pre-neoplastic model, by reducing the size of FAH, decreasing proliferation specifically in FAH by interacting with proteins of the cell cycle. We could also demonstrate that LAN increased apoptosis. In the second model, LAN was able to diminish the number of established HCC by decreasing proliferation, in parallel with an anti-fibrotic action. Furthermore, enhanced apoptosis and antiangiogenic effects were observed when LAN was given from the start of the carcinogenic induction by DEN. The cellular mechanisms leading to its effects warrant further investigations. FTS also strongly inhibited the appearance of FAH and HCC in the second model, through a complete inhibition of Ras activation and the induction of pro-apoptotic pathways. On the contrary, PGZ did not prevent the appearance of neoplastic lesions. For these reasons, we did not analyse further its mechanism of action in the second model. Altogether, the results we obtained demonstrate an activity of both LAN and FTS, at the early onset of liver carcinogenesis, and later on when advanced fibrosis, cirrhosis and HCC are induced. These anti-tumoural effects could be complementary and will be tested in combination in the future.

The Ras inhibitor farnesylthiosalicyclic acid (FTS) prevents nodule formation and development of preneoplastic foci of altered hepatocytes in rats.

BACKGROUND: Aberrant activation of oncogenes, such as Ras, likely contributes to the development of hepatocarcinoma (HCC). AIMS/METHODS: We evaluated in vivo the effect of intraperitoneal injections of the Ras inhibitor S-trans, trans-farnesylthiosalicyclic acid (FTS) on Ras activation and the development of preneoplastic liver lesions in rats receiving weekly diethylnitrosamine (DEN) injections for 16weeks. Western blotting, quantitative PCR, immunohistochemistry, Tunel and caspase activity assays were used. RESULTS: FTS prevents liver nodule formation and reduces foci expressing the tumour marker GSTp. FTS abrogates DEN-induced Ras membrane activity, increases Tunel positive cells in transformed, GSTp-expressing hepatocytes, up-regulates caspase 3 and 8 activity, induces Fas, Fas ligand and JNK phosphorylation that occurs independently of TNFalpha and Trail. Cytochrome C release, Bax, Bcl2, Bcl-xl, Ki67 and nuclear cyclin D expression is not affected by FTS. CONCLUSIONS: FTS inhibits Ras activation and prevents preneoplastic liver nodule development by inducing apoptosis in transformed hepatocytes through activation of the Fas/Fas ligand system. FTS might be new molecule for HCC treatment.

Previous intravenous substance use and outcome of liver transplantation in patients with chronic hepatitis C infection.

BACKGROUND: End-stage liver disease due to hepatitis C viral (HCV) infection is the most common reason for liver transplantation. One of the major risk factors for infection with HCV is intravenous drug use (IVDU). The pretransplantation characteristics and outcome of liver transplantation in patients with chronic hepatitis C (CHC) infected after IVDU are poorly known. METHODS: We performed a retrospective cohort study in patients with CHC who underwent liver transplantation between 1998 and 2002 in Belgium. Seven patients with and 60 patients without a history of IVDU were compared. RESULTS: Patients with CHC infected after IVDU were primarily men, significantly younger, and affected more by genotype 2 or 3. There was no relapse in substance use. No patients required a second transplantation or developed surgical complications. Progression to fibrosis in the posttransplantation period seemed to be slower. Graft and patient survival, and compliance were similar in both groups. CONCLUSIONS: Compared with patients in the non-IVDU group, patients with CHC infected after IVDU in complete remission have the same compliance, and patient and graft survival after liver transplantation. Therefore, patients with IVDU should not be excluded for liver transplantation because of HCV-induced cirrhosis.