October 24, 2017 6:00 am
The EASL International Liver Foundation joined forces for the first time with the Saudi Association for the Study of Liver Diseases and Transplantation SASLT in a common educational initiative which took place in Jeddah, Kingdom Saudi Arabia on September 29th, 2017. The meeting produced lively interactive scientific discussions between experts from Saudi Arabia and Europe on a variety of liver diseases.
The Foundation’s delegation included Chairman Prof. Massimo Colombo, EASL Vice Secretary-General Prof. Frank Tacke, Prof. Graham Foster and Prof. Ulrich Beuers. The meeting came as a follow-up to an earlier consultative meeting organized by the Foundation in Paris earlier last year on addressing liver diseases in the Middle East North Africa region.
“The level of scientific exchange was excellent and we definitely expect to see the collaboration with experts from Saudi Arabia to increase over the coming years” said the Foundation’s Chairman Prof. Massimo Colombo.
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October 24, 2017 5:00 am
The EASL International Liver Foundation to hold its first international consultative meeting on elimination of viral hepatitis in patients with chronic kidney disease in New Orleans on November 1st 2017.
The meeting is the result of a strategic partnership between the Foundation and the European Renal Association – European Dialysis and Transplant Association and is led by Professor Stanislas Pol and Professor Michel Jadoul.
Over the course of the meeting, a number of leading nephrologists from Europe and beyond will be discussing the challenges and opportunities associated with viral hepatitis elimination within this population and set the stage for comprehensive action plan.
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October 24, 2017 4:00 am
A new collaboration between the EASL International Liver Foundation and the European Haemophilia Consortium is expected to take place over the coming months. The two organisations held a consultative meeting in Vilnius, Lithuania on Friday, October 6th, 2017.
Over the course of the meeting the leadership of the two organisations have identified a number of areas for potential collaboration.
“The European Haemophilia Consortium represents a very dynamic, resourceful and committed organization. I am confident they would represent an invaluable collaboration asset to the Foundation,” said Prof. Massimo Colombo.
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October 24, 2017 3:00 am
The Thalassemia International Federation and the EASL International Liver Foundation are set to hold the first consultative meeting in Thessaloniki, Greece on November 17th 2017 on viral hepatitis elimination. The Foundation will be represented by Professor Christophe Hézode.
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October 24, 2017 2:00 am
The First investigator meeting for the NAFLD Policy Review will take place in Rome on November 10th 2017. The purpose of the study is to:
- Evaluate the extent to which European Union member countries have key policies in place to address NAFLD/NASH;
- Raise awareness about NAFLD/NASH through the NASH-Policy review study process/meetings and dissemination of its results at national and international meetings and in journals and other public relations and media activities.
Initial Confirmed study group attendees include:
- Quentin Anstee
- Massimo Colombo
- Helena Cortez-Pinto
- Jeffrey Lazarus
- Vlad Ratziu
- Frank Tacke
The preliminary results of the study are to be presented at an invitation only meeting in Pairs in conjunction with the EASL International Liver Congress.
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October 24, 2017 1:00 am
The mission of the program is to support innovative scientific research that will advance knowledge in the field of liver disease and provide support for research career development. The program provides financial support to the institutions of 3 junior faculty researchers for a 2-year period. Each award is funded up to USD130,000, payable in two installments of up to USD65,000 per year.
CONGRATULATIONS TO THE 2017 AWARD RECIPIENTS
Salvador Augustin, MD, PhD
Hospital Universitari Vall d’Hebron – Institut de Recerca (VHIR)
Universitat Autònoma de Barcelona, Spain
Hannelie Korf, PhD
The Katholieke Universiteit Leuven, Belgium
Christoph Welsch, MD
J. W. Goethe University Hospital, Frankfurt, Germany
The 2018 program cycle will open on October 20, 2017. For complete program information and to apply for an award, please visit the website below:
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October 23, 2017 8:00 am
Fotis Sampaziotis, Ludovic Vallier
Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge Stem Cell Institute, Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge, UK.
Q. CAN YOU EXPLAIN TO US WHY IS BILE DUCT ENGINEERING SUCH AN IMPORTANT UNMET CLINICAL NEED?
Bile duct disease accounts for a third of adult and 70% of pediatric liver transplantations. Several of these disorders are widespread and affect the small branches of the intrahepatic bile ducts which are not amenable to surgical replacement or reconstruction. However, some of the most impactful cholangiopathies associated with liver transplantation can be limited to the large ducts of the extrahepatic biliary tree. These include Biliary Atresia, which constitutes the leading cause for pediatric liver transplantation and ischemic dominant strictures which represent one of the most common causes for graft failure following rejection. Surgical replacement of the affected bile ducts could address such challenges, but it is restricted by the lack of suitable healthy tissue. Portoenterostomy can be used as an alternative intervention; however, it is associated with complications such as reflux cholangitis. Furthermore, it is not therapeutic for the majority of the patients with biliary atresia who will proceed to have a liver transplantation later in life. The generation of bioengineered bile ducts could provide a viable alternative for the management of these disorders with a potential for reducing the need for transplantation.
Q. HOW FAR IS YOUR MOUSE MODEL FROM BEING UTILISED IN HUMANS?
Our mouse model demonstrated the capacity of our cells to survive and repair the biliary epithelium in vivo, while maintaining their functional properties. Furthermore, we illustrated their potential for generating bioengineered bile ducts in vitro, which then remodel and fully integrate to the mouse biliary tree following transplantation. However, several challenges remain prior to translation in humans. From an engineering perspective, we need to adapt our method to address challenges associated with the generation of human sized constructs and these new constructs would require additional in vivo testing in animals of appropriate size. Furthermore, there is a requirement to assess the immunogenicity of the constructs and the need for immunosuppression in the context of non-autologous and autologous transplantation studies. Finally, in terms of the cells, we would have to adapt our culture system to comply with Good Manufacturing Practice (GMP) guidelines which is a pre-requisite for any transplantation in patients. Only when these goals are met, we would be able to proceed to the first pilot safety studies in humans.
Q. WHAT ARE THE NEXT STEPS IN REGENERATIVE MEDICINE IN THE LAB?
Clinical translation of the bioengineered bile ducts technology requires up-scaling these constructs to near-human dimensions. Larger constructs with thicker wall will require incorporation of a vascular network to achieve adequate tissue oxygenation, long-term cholangiocyte survival and function. Once we address this challenge our goal is to integrate these constructs in a large animal model resembling human anatomy and assess the capacity of our constructs to integrate to the host vascular network, maintain their functional properties and sustain bile transport through a patent lumen. In parallel we are taking advantage of recent advances in organoid culture such as chemically defined hydrogels, to transfer our culture system to GMP-compliant conditions.
Importantly, cholangiopathies extend beyond disorders of the common bile duct. A significant proportion of biliary disease represents widespread disorders of the small or intermediate size intrahepatic bile ducts, which are not amenable to surgical replacement with bioengineered constructs. We have already illustrated the potential of our cholangiocyte organoids to remodel and spontaneously organize into ductular structures when transplanted in vivo. Therefore, is possible that these cells could also repopulate or regenerate damaged intrahepatic bile ducts when delivered to the biliary tree and we have already started exploring this approach in the context of diffuse cholangiopathies.
Q. TO WHAT EXTENT IS YOUR MODEL APPLICABLE TO A BIOARTIFICIAL LIVER?
In addition to the importance of bioengineered bile ducts for the management of cholangiopathies, our method represents the first step towards the generation of a bioartifical biliary tree which is a crucial component for the development of a bioartificial liver. Indeed, bile is constantly produced by hepatocytes and its toxicity is well established. The bile ducts play an essential role for the transfer of bile, the modification of its composition and act as a necessary barrier for the protection of the other parenchymal cells. Defective bile transport in cholangiopathies results in biliary cirrhosis and liver failure. Therefore, the incorporation of a bioengineered biliary system is pivotal for the success of a bioengineered liver and through this application bioengineered bile ducts could contribute to the management of any end-stage liver disease.
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October 23, 2017 7:00 am
Liver Unit, Clínica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain.
Q. WHY SO MUCH HYPE ON THE IMMUNE THERAPIES IN THE FIELD OF LIVER CANCER?
The story of drug development for hepatocellular carcinoma (HCC) has been disappointing in the past eight years with many drugs failing in phase III trials. Very recently, an increased survival was shown in patients that tolerated sorafenib but eventually had radiological progression and were next treated with regorafenib 1. But no systemic therapy is effective in the adjuvant setting after resection or percutaneous ablation, or in combination with locoregional therapies such as TACE. On the other hand, immunotherapy has revolutionized the treatment of cancer. Over the last 5 years, immune-based therapies have shown that they can prolong patient survival in a wide variety of tumors and clinical scenarios. So-called immune checkpoint inhibitors are now approved for the treatment of refractory Hodgkin’s disease; metastatic non-small cell lung cancer or locally advanced urothelial cancer resistant to chemotherapy; metastatic melanoma naive to chemotherapy; recurrent squamous cell carcinoma of the head and neck; or for the adjuvant treatment of stage III melanoma. For a good reason, the American Society of Clinical Oncology has considered immunotherapy the Advance of the Year in 2015 and 2016.
Q. WHAT ARE THE IMMUNE CHECKPOINTS AND WHY ARE THEY IMPORTANT?
Immune checkpoints are a specific subtype of membrane-bound molecules that provide fine-tuning of the immune response. They are expressed in different cell types involved in the immune response, including B and T cells, natural killer (NK) cells, dendritic cells, tumor associated macrophages, monocytes, and myeloid-derived suppressor cells (MDSC). The physiological function of these complexes is to prevent continuous T cell effector function upon initial stimulation and engagement of antigen-specific T cells. Thus, most of these molecules display an immunosuppressive activity that prevents uncontrolled T cell responses against infection and limit collateral tissue damage. The immune checkpoints most studied in human cancer are cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) 2. CTLA-4 is essential for the activation of helper CD4+ T cells and the priming phase of the immune response. Upon binding of its ligands, CTLA-4 decreases T cell activation following antigen presentation. CTLA-4 also plays a major role in the function of regulatory T cells (Treg), a subset of CD4+ T cells that inhibit the immune response. On the other hand, PD-1 is a key factor in the effector phase of the immune response. It is expressed by activated T and B cells and other cell types. Upon binding to its ligands (PD-L1 and PD-L2), PD-1 inhibits T cell activation and proliferation.
Monoclonal antibodies that bind these molecules and block their signaling are called immune checkpoint inhibitors. They release the brake that puts the immune response on hold and allow cytotoxic T cells to strike tumor cells. Other monoclonal antibodies may target different checkpoint molecules that provide positive signals for T cell or NK cell activation and proliferation, but they are at much earlier phases of clinical development.
Q. WHAT IS THE EXPERIENCE WITH THE USE OF CHECKPOINT INHIBITORS IN HCC?
Tremelimumab (a CTLA-4 blocking monoclonal antibody) was first evaluated in a small phase II trial that targeted patients with HCC and chronic HCV infection 3. Twenty-one patients with advanced disease were enrolled, including a significant proportion (42.9%) of patients in Child-Pugh stage B. Despite receiving a suboptimal dose of tremelimumab, a notable disease control rate of 76.4% was observed among 17 evaluable patients, including 3 partial responses and 4 prolonged (>6 months) stabilizations. Tremelimumab was well tolerated, with few patients experiencing grade 3 disabling adverse events (AE), even in the presence of liver dysfunction. In a second small pilot trial, incomplete tumor ablation using percutaneous radiofrequency (RFA) or transarterial chemoembolization (TACE) was combined in an attempt to enhance the effects of tremelimumab by inducing immunogenic tumor cell death 4. In this study, liver function was preserved in the most patients, all etiologies were included and the dose of tremelimumab was the standard. Nineteen patients were evaluable for response because they had measurable lesions that were not targeted by RFA or TACE. A disease control rate of 89% was reported, including 5 partial responses (26%) and 5 prolonged stabilizations. The median overall survival of 12.3 months compares well with placebo-treated patients in the second-line setting.
These encouraging signs of antitumor activity and good safety profile provided a strong reason to test PD-1 inhibitors . Nivolumab (a PD-1 blocking monoclonal antibody) has been tested as first or second-line treatment in patients with advanced HCC across different etiologies (HCV infection, HBV infection, non-viral cirrhosis) 5. A dose-escalation cohort of 48 patients was followed by an expansion cohort of 214 patients treated with 3 mg/kg. Most patients had extrahepatic metastases (68%), and had received prior systemic therapy (76%), mainly Sorafenib. Treatment was by and large well tolerated with only 3% of patients discontinuing nivolumab due to treatment-related AE. Convincing signs of efficacy consisted in objective tumor responses in 15-20% of patients, which lasted for a median of 17 months. An additional 45% of patients had stable disease that was frequently durable too. These signs of efficacy were consistent with the most recently reported median overall survival of 28.6 months in the population naive to sorafenib, and 15.6 months in the population exposed to sorafenib (90% progressors) 6. This median survival compares well with any other phase 2 or 3 clinical trial of targeted agents including regorafenib, the first agent shown to prolong survival following sorafenib in a selected group of sorafenib-tolerant patients.
Q. WHAT ARE THE MAIN CHALLENGES FOR IMMUNOTHERAPY OF HCC?
Encouraging as they are, the results of the reported trials pose a number of challenges. First, checkpoint inhibitors should be tested in the first line setting. Indeed, a large phase III trial is comparing nivolumab and sorafenib as first line therapy in advanced HCC and the results will likely be reported in 2018. Second, their activity has to be tested in the intermediate stage (in combination with intraarterial therapies that are the standard of care) and in the early stage (as adjuvant therapy after resection or ablation). Third, 30% to 40% of patients do not respond to these agents. The mechanisms of primary resistance are largely unknown 7 but combination strategies may work in these patients as we have learned in melanoma. Indeed, several combinations of checkpoint inhibitors with other therapies are being tested. They may be based on the potential additive effect of a therapy with a proven treatment benefit (TACE or sorafenib) or is being investigated (ramucirumab, cabozantinib), but they can also be based on exploiting synergistic effects (radioembolization, oncolytic virotherapy) or avoiding primary resistance (anti-CTLA-4 plus anti-PD1/PD-L1, tumor vaccines). Finally, evaluation of tumor response and selection of the best candidates based on easily accessible biomarkers remain a true challenge.
- Bruix J, Qin S, Merle P, Granito A, Huang Y-H, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56–66. doi:10.1016/S0140-6736(16)32453-9.
- Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nature Reviews Gastroenterology & Hepatology 2015;12:681–700. doi:10.1038/nrgastro.2015.173.
- Sangro B, Gomez-Martin C, la Mata de M, Iñarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013;59:81–8. doi:10.1016/j.jhep.2013.02.022.
- Duffy AG, Ulahannan SV, Makorova-Rusher O, Rahma O, Wedemeyer H, Pratt D, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 2017;66:545–51. doi:10.1016/j.jhep.2016.10.029.
- El Khoueiry, Sangro…
- Crocenzi TS, El-Khoueiry AB, Yao T, Melero I, Sangro B, Kudo M, et al. Nivolumab in Sorafenib-Naive and -Experienced Patients With Advanced Hepatocellular Carcinoma: CheckMate 040 Study. Presented at the Annual Meeting of the American Society of Clinical Oncology 2017.
- O’Donnell JS, Long GV, Scolyer RA, Teng MWL, Smyth MJ. Resistance to PD1/PDL1 checkpoint inhibition. Cancer Treatment Reviews 2017;52:71–81. doi:10.1016/j.ctrv.2016.11.007.
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October 23, 2017 6:00 am
Raúl J. Andrade
Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). Madrid. Spain; firstname.lastname@example.org
Q. HOW FREQUENT IS DILI AMONG THE GENERAL POPULATION?
Idiosyncratic drug-induced liver injury (DILI) is a rare diagnosis in clinical practice by far less common than other liver diseases such as viral hepatitis. However, data on DILI incidence in the general population are very limited. A main barrier to undertake these studies is the lack of a standard for DILI diagnosis so suspected cases should undergo a formal causality assessment process, which always result in some degree of uncertainty. There have been 2 population-based studies published so far. In a prospective study of a population of 80,000 inhabitants of northern France, conducted during a 3 year-period, the incidence of DILI encountered was 13.9 cases per 100,000 inhabitants-years, a rate 16 times higher than that reported to the French National Agency of pharmacovigilance 1. More recently a population-based study in Iceland including all inhabitants (over 250.0000), reported an incidence of DILI of 19.1 cases per 10.000 inhabitants-years. Such as incidence for instance is higher than those of autoimmune hepatitis or primary biliary cholangitis and could be in the range of new cases of hepatitis C. The Icelandic study also reported cases of hepatotoxicity associated with herbal and dietary supplements and was able to evaluate the quantitative risk of DILI associated with hepatotoxic drugs, estimating the risk of amoxicillin-clavulanic acid hepatotoxicity in 1 per 2350 exposed individuals 2. Of note, a high proportion of cases in these studies went unnoticed and was detected by routine biochemistry. Hence, no question the true incidence of DILI is very likely underestimated in clinical practice.
Q. HOW ACCURATE IS THE CLINICAL DIAGNOSIS OF DILI AND WHO ARE THE RELEVANT PATIENTS AT RISKS?
Idiosyncratic hepatotoxicity can present with a broad a clinical spectrum, although most often does it as an acute viral hepatitis-like syndrome, symptoms not providing any particular clues for diagnosis unless eosinophilia or rash reinforces suspicion of drug allergy. New emerging biomarkers, which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122 are still under evaluation and are not available in routine clinical practice. Indeed, the absence of specific biomarkers makes DILI a diagnostic of exclusion so the causality assessment of a patient having a DILI suspicion case still relies on a temporal relationship between the initiation of a drug and the onset of liver damage along the judicious use and interpretation of serum liver biochemistry and other routine laboratory and imaging tests to careful rule-out alternative explanations of liver disease 3. A consensus group recently proposed strict criteria to define liver damage based on a threshold for liver enzyme elevation as a prerequisite to adjudicate a DILI case 4. At present time, there is a general consensus upon the use of these criteria in prospective Registry studies 5, 6. Besides, pathological findings in DILI are not specific resembling those of many other liver disorders, thus limiting the value of liver biopsy in DILI diagnosis, the exception being when worsening of a pre-existing liver disorder (i.e. alcoholic hepatitis, autoimmune hepatitis) is an alternative diagnosis to consider.
With regard to the relevant patients at DILI risk, we are just starting to identify the risk factors for hepatotoxicity. Genetic factors are important determinants in DILI as recently showed by genome-wide association studies (GWASs), which have discover a number of novel associations between hepatotoxicity with human leucocyte antigen (HLA) class I and II alleles. Interestingly, these associations, in contrast to GWASs focused on other complex traits, have substantially higher risk ratios for susceptibility to DILI 3. Interestingly, there is substantial overlap among the risk alleles associated with clinically varied phenotypes of toxicities due to structurally dissimilar compounds. Actually, a GWASs recently published from a joint international collaboration demonstrated HLA-A*33:01 as a risk factor for a cholestatic or mixed pattern of DILI when these are considered as a single phenotype irrespective of the causative drugs 7. Overall, the strength of association between HLA genotypes and DILI yet remarkable for some drugs (eg. HLA-B57*01 increases by 80 folds the risk of developing DILI when exposed to flucoxacilin) has raised controversy regarding the use of pre-prescription genotyping as the incidence of DILI is so low that this strategy is not cost-effective. In contrast, the majority of HLA alleles associated with DILI have a very high negative predictive value of >0.95. Therefore, genotyping can be used to rule out adverse hepatic reactions due to particular drugs so that alternative diagnoses are considered.
Other non-genetic risk factors of DILI such as age, gender or associated diseases are more elusive. Older patients and woman are generally believed to be more prone to DILI but this long-standing conception is not supported by evidence since these host factors have not yet been identified in large prospective Registries as a risk for all-cause DILI 5, 6. However, prescription patterns rather than a biological basis could account for the increase of risk reported in some studies. For instance, in the population based study from Iceland there was a trend of higher incidence of DILI with increasing ages that paralleled the number of prescription drugs 2. Nevertheless, age appears to have an influence on the DILI phenotype: cholestatic damage is more common in the elderly, whereas younger individuals more commonly exhibit hepatocellular injury 5.
Q. IS THERE ANY LINK BETWEEN DILI AND AUTOIMMUNE LIVER DISEASES?
Yes, there is. For instance, recurrent DILI by a different drug tends to present with an AIH phenotype 8. Besides, DILI particularly induced for some drugs such as minocycline typically present with an autoimmune phenotype with antinuclear antibodies (ANAs), smooth muscle antibodies (SMAs) and elevated IgG levels as well as histological features of AIH. This situation is hard to differentiate from “idiopathic” AIH. AIH-induced by drugs typically resolves after stopping the causative drug. If treated with corticosteroids, a lack of recurrence following corticosteroid cessation supports a diagnosis of drug-induced AIH rather than idiopathic AIH. As yet there are no diagnostic tests to differentiate idiopathic from drug-related AIH, although histological findings can help in the differential diagnosis 9. The HLA-B*35:02 genotype, which is associated with minocycline-induced DILI, is a useful diagnostic test in the setting in distinguishing it from idiopathic AIH 3.
Q. CAN WE PREDICT PROGNOSIS OF DILI AND HOW DO WE TREAT IT?
Several studies have identified risk factors of severity in DILI. Hepatocellular injury, female sex and jaundice 5, as well as pre-existing liver disease 6 are associated with higher mortality, fulminant liver failure and liver transplantation. Nowadays, the large amount of information in liver biochemistry at DILI onset in order to predict a serious outcome. Thus, a marked increase of AST and an AST/ALT ratio >1.5 at DILI recognition predict a worse prognosis. In consequence, a new “Hys’law” meaning the use of AST or ALT, whichever was higher also showed a better balance between sensitivity and specificity as compared with the standard Hy´s law in predicting acute liver failure/liver transplantation 10.
Unfortunately, we do not have still specific therapy for DILI. Prompt withdrawal of any non-essential drug is paramount. Recent multicenter efforts could enable in a near future to undertake clinical trials in DILI.
- Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 2002;36:451-5.
- Bjornsson ES, Bergmann OM, Bjornsson HK, Kvaran RB, Olafsson S. Incidence, Presentation and Outcomes in Patients with Drug-Induced Liver Injury in the General Population of Iceland. Incidence, Presentation and Outcomes in Patients with Drug-Induced Liver Injury in the General Population of Iceland. Gastroenterology 2013; 144: 1419
- Kullak-Ublick GA, Andrade RJ, Merz M, End P, Benesic A, Gerbes AL, Aithal GP. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut 2017;66:1154-1164.
- Aithal GP, Watkins P B, Andrade RJ, Larrey D, Molokhia M, Takikawa H, Hunt CM, Wilke R A, Avigan M, Kaplowitz N, Bjornsson E, Daly AK. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther.: 2011 ; 89 : 806-815.
- Andrade RJ, Lucena MI, Fernandez MC, Pelaez G Pachkoria K, Garcia-Ruiz E, Garcia-Munoz B, Gonzalez-Grande R, Pizarro A, Duran JA, Jimenez M et al. Drug- induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129:512-521.
- Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J et al. Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. Gastroenterology 2015;148: 1340-52.
- Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, et al. Association of liver injury from specific drugs or group of drugs with polymorphism in HLA and in other genes in a genome wide association study. Gastroenterology. 2017;152:1078-1089.
- Lucena MI, Kaplowitz N, Hallal H, Castiella A, García-Bengoechea M, Otazua P, et al. Recurrent drug-induced liver injury (DILI with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis. J Hepatol 2011; 55:
- Foureau DM, Walling TL, Maddukuri V, et al. Comparative analysis of portal hepatic infiltrating leucocytes in acute drug-induced liver injury, idiopathic autoimmune and viral hepatitis. Clin Exp Immunol 2015; 180(1): 40-51.
- Robles-Diaz M, Lucena MI, Kaplowitz N, et al. Use of Hys law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. Gastroenterology 2014; 147: 109-118.
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