[Non-alcoholic steatohepatitis (NASH) : a model of metabolic inflammation («metaflammation¼)]. / Stéatohépatite non alcoolique (NASH) : un modèle d'inflammation métabolique («métaflammation¼).

Diseases related to fatty liver, independently of alcohol consumption («non-alcoholic fatty liver disease¼ or NAFLD), are increasing because of the epidemics of obesity and type 2 diabetes. These disorders reflect a continuum that comprises isolated steatosis, steatohepatitis (NASH) and fibrosis, with, at the end, an increased risk of cirrhosis and hepatocarcinoma. It has been recently proposed to replace the term NAFLD by MAFLD, i.e. «Metabolic (dysfunction) Associated Fatty Liver Disease¼, which better reflects the pathogenesis of the disease. Inflammation plays a crucial role in the aggravation of the disorder and profoundly influences the prognostic evolution. This article illustrates the natural history of this underestimated metabolic disorder, recall the diagnostic criteria used in clinical practice, emphasizes the deleterious role of inflammation and discusses some therapeutic perspectives.

: Les maladies liées à un «foie gras¼, indépendamment de la consommation d'alcool («non-alcoholic fatty liver disease¼ ou NAFLD), sont en augmentation en raison de l'«épidémie¼ d'obésité et de diabète de type 2. Il s'agit d'un continuum comprenant la stéatose isolée, la stéatohépatite (NASH) et la fibrose avec, in fine, un risque accru de cirrhose et d'hépatocarcinome. Il a été proposé récemment de remplacer le terme NAFLD par MAFLD pour «Metabolic (dysfunction) Associated Fatty Liver Disease¼, ce qui reflète mieux la pathogénie de la maladie. L'inflammation joue un rôle clé dans l'aggravation du trouble et conditionne l'évolution pronostique. Cet article retrace l'histoire naturelle de cette pathologie métabolique sous-estimée, rappelle les critères diagnostiques utilisés en clinique, précise le rôle délétère de l'inflammation et conclut par quelques perspectives thérapeutiques.

[Multidisciplinary management of the primary liver cancers]. / Prise en charge multidisciplinaire des tumeurs malignes primitives du foie.

In Belgium and around the world, the incidence of primary malignant liver tumours is increasing, both for hepatocarcinoma and cholangiocarcinoma. Their curative treatment is based on multidisciplinary and specialized care, of which surgery (including liver transplantation) remains the cornerstone, often associated with other logoregional treatments, as radioembolisation, radiofrequency ablation, and chemoembolisation. For advanced cases, the prognosis remains poor, in particular due to a certain chemoresistance of these tumours. New treatments include targeted therapies (including various tyrosine kinase inhibitors) and immunotherapy. A specialized multidisciplinary discussion is therefore necessary to define the best therapeutic management, individualized to each patient. In this article, the authors review the most recent data relating to the treatment of hepatocarcinoma and cholangiocarcinoma.

En Belgique et dans le monde, l'incidence des tumeurs malignes primitives du foie augmente, tant pour l'hépatocarcinome que le cholangiocarcinome. Leur traitement curatif repose sur une prise en charge multidisciplinaire et spécialisée, dont la chirurgie (incluant la transplantation hépatique) reste la pièce angulaire, souvent associée à d'autres traitements logo-régionaux (radioembolisation, radiofréquence, chimio-embolisation). Pour les cas avancés, le pronostic reste sombre, notamment en raison d'une certaine chimiorésistance de ces tumeurs. Les nouvelles prises en charge incluent des thérapies ciblées (notamment, divers inhibiteurs de tyrosine kinase) et de l'immunothérapie. Une discussion pluridisciplinaire spécialisée est donc nécessaire pour définir la meilleure prise en charge thérapeutique, individualisée pour chaque patient. Dans cet article, les auteurs revoient les données récentes relatives au traitement de l'hépatocarcinome et du cholangiocarcinome.

Selection criteria for liver transplantation in patients with hepatocellular carcinoma. Eastern and western experiences, and perspectives for the future.

Ever since the initial description of the Milan criteria, used for selecting patients with hepatocellular carcinoma (HCC) for liver transplantation (LT), there has been a clear need to go further than solely morphological criteria. Tumours exceeding the Milan criteria, but presenting favourable biological behaviour, might still allow for comparable overall- and disease-free survivals after LT. As it is well established that the presence of microvascular invasion is a major factor that influences HCC recurrence after LT, several serum and tissue biomarkers in addition to imaging studies are attracting wider attention as more refined tools for selecting HCC patients for LT. A thorough review of the recent literature on the subject was conducted. In the future a combination of systemic inflammation markers, biomarkers and morphological criteria may be key to more accurate prediction of HCC recurrence after LT. This may allow LT in patients whose HCC tumours exceed the Milan criteria but have favourable biological behaviour. Further prospective studies are required in order to improve patient selection for transplantation in HCC and these could help a move towards more transparent and improved management.

[Alcoholic hepatitis]. / L'hépatite alcoolique aiguë.

Alcoholic hepatitis is a syndrome defined primarily by the clinical onset of jaundice in patients with a concomitant heavy consumption of alcoholic beverages. This pathology is managed by alcohol withdrawal with a 30-day survival rate of 90 %. For patients with severe alcoholic hepatitis, with a Maddrey score greater than 32 (taking into account bilirubin and prothrombin time), treatment with corticosteroids is discussed provided that a possible infection can be sufficiently excluded or adequately managed. The administration of corticosteroids is continued for 28 days if the Lille score, calculated after 7 days of treatment, is favourable (inferior to 0.45), leading to a survival rate of 80-90 %. However, if the Lille score is unfavourable (superior to 0.45), the prognosis is bad, with a survival of only 25-30 % at 6 months. Special attention needs to be paid to assure a sufficient caloric intake during the treatment period for a successful management. Liver transplantation, previously prohibited for this indication, can be discussed under certain circumstances. However, the success of treatment is contingent upon the alcohol withdrawal. Innovative drugs are currently under investigation to improve the prognosis of this condition.

: L'hépatite alcoolique aiguë (HAA) se définit selon des paramètres essentiellement cliniques (ictère d'apparition récente chez un patient avec une consommation abusive d'alcool). L'HAA peu sévère est prise en charge par un sevrage éthylique, avec un espoir de survie de 90 % à un mois. Pour les patients atteints d'HAA sévère (évaluée par le score de Maddrey sup�rieur a 32, tenant compte de la bilirubine et du temps de prothrombine), un traitement par corticoïdes se discute, pour autant qu'une éventuelle infection ait pu être exclue ou jugulée. Le traitement par corticoïdes est poursuivi 28 jours si le score de Lille, calculé après 7 jours de corticoïdes, est favorable (inf�rieur a 0,45), avec un espoir de survie de 80-90 %. Par contre, si le score de Lille est défavorable (sup�rieur a 0,45), le pronostic est nettement plus péjoratif avec une survie de 25-30 % à 6 mois. Dans la prise en charge, on apportera une attention toute particulière à la nutrition avec un apport calorique suffisant. La transplantation hépatique, autrefois non autorisée dans cette indication, peut actuellement être discutée dans certaines circonstances particulières. La clé de la réussite résidera, de toute façon, dans le sevrage. Des médicaments novateurs sont actuellement en cours d'étude pour améliorer le pronostic de cette affection.

[Considerations on liver transplantation in the alcoholic patients]. / Problématique de la transplantation hépatique chez le patient alcoolique.

In Belgium as in many other countries, alcohol is one of the leading causes of adult liver transplantation. Liver transplantation for terminal liver failure due to excessive alcohol intake raises clear ethical issues concerning the use of grafts to save patients suffering from a self-inflecting affection. Alcoholic liver disease is one of the best indications for liver transplantation, with excellent results in terms of length of survival and post transplantation quality of life, if this transplantation is proposed by a multidisciplinary team in a patient able to and helped by a supporting family and social environment.

En Belgique, comme dans beaucoup d'autres pays, la maladie alcoolique constitue une des causes les plus fréquentes menant à la transplantation hépatique chez l'adulte. Or la transplantation hépatique chez des patients alcooliques pose de claires questions éthiques concernant l'utilisation de greffons pour soigner des patients souffrant d'une maladie trop souvent considérée comme étant auto-infligée. La maladie alcoolique du foie est une des meilleures indications de greffe hépatique, avec d'excellents résultats en termes de durée de survie et de qualité de vie après transplantation. Le pré-requis est que cette transplantation soit proposée par une équipe multidisciplinaire, chez un patient capable de se prendre en charge et soutenu par un environnement familial et social favorable.

[Membranous occlusion of the inferior vena cava a rare cause of Budd-Chiari syndrome]. / L'occlusion membraneuse de la veine cave inférieure : Une étiologie rare du syndrome de Budd-Chiari.

Rarely encountered in the Western countries, membranous occlusion of the inferior vena cava results from a fibrous thickening of the intima and is commonly located at the orifices of the hepatic veins. To date, two etiopathogenic hypotheses have been formulated: the first, dealing with the embryological aspect, the second, arguing for a thrombotic origin. Nevertheless, several studies are still underway to understand the exact physiopathological mechanism of this obstruction. Among these studies, some suspect the predisposing role of anatomical and infectious factors. On average, it takes 6 years between the beginning of the symptoms and the diagnosis. The later the diagnosis is settled, the higher is the risk of encountering a hepatocellular carcinoma. The most relevant additional examinations to visualize the membrane are the abdominal ultrasound and the cavography. Computed tomography allows to highlight the effects of obstruction on the hepatic parenchyma. Concerning the treatment, many studies showed that angioplasty has an excellent immediate and late efficacy. A few surgical techniques also exist but those are less exploited because of the non invasive aspect and lower morbidity-mortality of the endovascular treatment.

Rarement retrouvée en Occident, l'occlusion membraneuse de la veine cave inférieure résulte d'un épaississement fibreux de l'intima, préférentiellement situé en regard de l'abouchement des veines sus-hépatiques. Jusqu'à ce jour, deux hypothèses étiopathogéniques ont été formulées : l'une considérant plutôt le versant embryologique, l'autre plaidant pour une origine thrombotique. Néanmoins, plusieurs études sont toujours en cours afin de comprendre le mécanisme physiopathologique exact de cette obstruction. Certaines suspectent, notamment le rôle prédisposant de facteurs anatomiques et infectieux. La durée d'évolution des symptômes avant la pose du diagnostic est de 6 ans en moyenne. Plus ce dernier sera tardif, plus la probabilité de se retrouver face à un carcinome hépatocellulaire est importante. Les examens complémentaires de choix afin de visualiser la membrane sont l'échographie abdominale et la cavographie. La tomodensitométrie permet de mettre en évidence les répercussions de l'obstruction sur le parenchyme hépatique. D'un point de vue thérapeutique, plusieurs études ont démontré que l'angioplastie possédait une excellente efficacité immédiate et tardive. Certaines techniques chirurgicales existent également, mais sont peu exploitées en raison du caractère non invasif et de la moindre morbi-mortalité du traitement endovasculaire.

[Clinical case of the month. Extended portal vein thrombosis in patient on vitamin K antagonists]. / Thrombose portale étendue chez un patient sous anti-vitamine K.

There is a long-recognized association between cancer and venous thromboembolism. Venous thrombosis is the most common paraneoplastic complication. We describe a case of rupture of esophageal varices in a patient with a paraneoplastic portal thrombosis. We highlight the links between venous thromboembolism and cancer and also discuss treatment and prognostic factors.

Model simulation and experimental verification of a cation-exchange IgG capture step in batch and continuous chromatography.

The cation-exchange capture step of a monoclonal antibody (mAb) purification process using single column batch and multicolumn continuous chromatography (MCSGP) was modeled with a lumped kinetic model. Model parameters were experimentally determined under analytical and preparative conditions: porosities, retention factors and mass transfer parameters of purified mAb were obtained through a systematic procedure based on retention time measurements. The saturation capacity was determined through peak fitting assuming a Langmuir-type adsorption isotherm. The model was validated using linear batch gradient elutions. In addition, the model was used to simulate the start-up, cyclic steady state and shut down behavior of the continuous capture process (MCSGP) and to predict performance parameters. The obtained results were validated by comparison with suitable experiments using an industrial cell culture supernatant. Although the model was not capable of delivering quantitative information of the product purity, it proved high accuracy in the prediction of product concentrations and yield with an error of less than 6%, making it a very useful tool in process development.

Two step capture and purification of IgG2 using multicolumn countercurrent solvent gradient purification (MCSGP).

A two-step chromatography process for monoclonal antibody (mAb) purification from clarified cell culture supernatant (cCCS) was developed using cation exchange Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) as a capture step. After an initial characterization of the cell culture supernatant the capture step was designed from a batch gradient elution chromatogram. A variety of chromatographic materials was screened for polishing of the MCSGP-captured material in batch mode. Using multi-modal anion exchange in bind-elute mode, mAb was produced consistently within the purity specification. The benchmark was a state-of-the-art 3-step chromatographic process based on protein A, anion and cation exchange stationary phases. The performance of the developed 2-step process was compared to this process in terms of purity, yield, productivity and buffer consumption. Finally, the potential of the MCSGP process was investigated by comparing its performance to that of a classical batch process that used the same stationary phase.

[Challenges to reduce mortality due to hepatitis C: improving accessibility to therapy and compliance]. / Défis pour réduire la mortalité liée a l'hepatite C: améliorer l'accessibilité au traitement et l'observance thérapeutique.

Current therapies with pegylated interferon and ribavirin are effective to eradicate the virus C. Improvements are foreseen in the near future with combination of the current treatment with antiviral therapies (antiproteases, antipolymerases). Eradication of the virus, when obtained, has a favorable impact on an individual basis. However, to reduce the mortality related to the virus C at a population level, an important point is the accessibility to therapy. It has been calculated that the impact of current management to reduce mortality is minimal, as compared to the absence of treatment, due to a poor accessibility to therapy. To obtain a significant additional reduction of mortality, a better screening, a better access to the threatment are crucial.

[Palliative management of hepatocarcinoma with sorafenib (Nexavar). Results of the SHARP study (sorafenib hepatocarcinoma assessment randomized protocol trial)]. / L'étude clinique du mois traitement de l'hépatocarcinome au stade palliatif par sorafénib (Nexavar). Résultats de l'étude SHARP (sorafenib hepatocarcinoma assessment randomized protocol).

Curative management of early-stage hepatocarcinoma may include partial hepatic resection, liver transplantation or tumoral necrosis using radiofrequency ablation or alcoholisation. Until recently, no efficient therapeutic mean was available for advanced hepatocarcinoma. Sorafenib (Nexavar, Bayer) is a multikinase inhibitor that decreases tumoral proliferation and angiogenesis, and increases apoptosis in many cancer models. The results of a phase 3 randomized, multicentric, study, entitled SHARP, have now demonstrated that sorafenib increases survival in patients with advanced hepatocarcinoma developed in Child A cirrhosis. Mean survival gain was a little less than 3 months, without any radiologic response or improvement in the delay before symptomatic progression of the disease. The monthly cost of sorafenib is a little more than 5,000 euros. It is now crucial to evaluate the potential role of sorafenib in adjuvant therapy after liver resection or radiofrequency ablation of hepatocarcinoma. The CHU of Liège is taking part to a randomized, multicentric study evaluating the use of sorafenib after liver resection or radiofrequency ablation for hepatocarcinoma. Another future evaluation could be the association of sorafenib with other antitumoral agents.

Liver transplant donation after cardiac death: experience at the University of Liege.

OBJECTIVE: Donation after cardiac death (DCD) has been proposed to overcome in part the organ donor shortage. In liver transplantation, the additional warm ischemia time associated with DCD procurement may promote higher rates of primary nonfunction and ischemic biliary lesions. We reviewed the results of liver transplantation from DCD. PATIENTS AND METHODS: From 2003 to 2007, we consecutively performed 13 controlled DCD liver transplantations. The medical records of all donors and recipients were retrospectively reviewed, evaluating in particular the outcome and occurrence of biliary complications. Mean follow-up was 25 months. RESULTS: Mean donor age was 51 years, and mean intensive care unit stay was 5.4 days. Mean time between ventilation arrest and cardiac arrest was 9.3 minutes. Mean time between cardiac arrest and arterial flushing was 7.7 minutes. No-touch period was 2 to 5 minutes. Mean graft cold ischemia time was 295 minutes, and mean suture warm ischemia time was 38 minutes. Postoperatively, there was no primary nonfunction. Mean peak transaminase level was 2546 UI/mL. Patient and graft survival was 100% at 1 year. Two of 13 patients (15%) developed main bile duct stenosis and underwent endoscopic management of the graft. No patient developed symptomatic intrahepatic bile duct strictures or needed a second transplantation. CONCLUSIONS: Our experience confirms that controlled DCD donors may be a valuable source of transplantable liver grafts in cases of short warm ischemia at procurement and minimal cold ischemia time.

[Recent advances in liver surgery and transplantation]. / Actualités en chirurgie et transplantation hépatique.

Over the last 20 years, significant improvements in hepatic surgery and transplantation have allowed better results. Better patients selection, new preoperative modalities aiming at modifying the volume of the liver or the tumour, new surgical techniques, and better postoperative management are the keys to improved outcome. These progresses are reviewed in this article. In hepatic surgery, the latest surgical improvements are the possibility of laparoscopic hepatic resection and of radiofrequency ablation. Modern neoadjuvant chemotherapy may in some cases allow a reduction of large liver colorectal metastases and render them resectable. Improved radiological techniques allow better planning of the surgical resections, reduction of the risks by calculation of the residual liver mass, and induction of liver hypertrophy by preoperative portal embolisation. In liver transplantation, the most significant changes were the use of living related liver donors and of non-heart beating donors to overcome the cadaveric organ donor shortage.

[The FibroScan: a new non invasive method of liver fibrosis evaluation]. / Le FibroScan: une nouvelle méthode d'évaluation non invasive de la fibrose hépatique.

The FibroScan is a device allowing a non invasive diagnosis and quantification of liver fibrosis. The procedure is based on transient elastography and allows to record liver stiffness by measuring the velocity of shear wave across liver parenchyma. The elasticity is directly correlated to velocity of the wave. In chronic hepatitis C, there is a good correlation between liver elasticity and stage of fibrosis. The FibroScan has also been studied in other chronic liver diseases, such as hepatitis B, primary biliary cirrhosis, sclerosing cholangitis, auto-immune hepatitis, alcohol, steatosis, hemachromatosis with reproductible results. In a cirrhotic patient, it also allows to assess the severity of cirrhosis and to evaluate the risk of complication. It is a painless procedure, with a good acceptability by the patients. Therefore, the FibroScan can be regularly performed, allowing the follow up of fibrosis evolution over time.

[Management of hyperferritinemia]. / Mise au point. D'une hyperferritinémie.

Hemochromatosis is the most common genetic disorder in persons of northern European descent, and the majority of cases are caused by a mutation in the gene HFE. Genetic testing for hemochromatosis is therefore indicated in all patients with increases in transferrine saturation and ferritin levels. When this genetic testing does not demonstrate a hemochromatosis, other diseases responsible for elevated ferritin levels have to be ruled out, mainly hemolytic anemia, chronic inflammatory disorders, liver diseases such as hepatitis B or C, alcohol abuse, and non alcoholic fatty liver disease. In demonstrated iron overload with absence of classic causes, second-line genetic testing should be considered.

[Gastro-esophageal reflux and asthma]. / Reflux gastro-oesophagien et asthme.

Gastro-oesophageal reflux (GER) is more frequent in asthmatic patients than in the community at large. A causative association between the two diseases is suspected. Twenty-four hour ambulatory intraoesophageal pH monitoring represents the golden standard for the diagnosis of GER. The medical and/or surgical treatment of reflux in asthmatic patients with GER can improve pulmonary symptoms and to a lesser extent pulmonary function. The selection of the patients who will benefit from a GER treatment is difficult. Some symptoms like intrinsic asthma, nocturnal crises, could predict a good response to GER treatment.

Prevalence of hepatitis G virus in a haemodialysis unit.

BACKGROUND: Recently, a novel blood-borne virus has been identified and named hepatitis G virus. Transfusion is the main route of transmission. It is known that patients on maintenance dialysis are more susceptible to infections with parenterally-transmitted viruses than the general population. The aim of the present study was to determine the prevalence of hepatitis G infection in a Belgian dialysis unit. METHODS: The entire population of our dialysis unit (82 patients) was tested for the presence of hepatitis G virus (HGV) by reverse transcriptase polymerase chain reaction. History of transfusion or renal transplantation, coinfections with hepatitis B and C viruses, and serum aminotransferase levels were also tested. RESULTS: Thirteen patients (16%) were found positive for HGV-RNA. Among these patients, 69.2% were infected by the G virus alone, 15.4% were coinfected with B virus, and 15.4% with C virus. All but one patient had a history of transfusion. Ten of the thirteen infected patients (77%) had normal aminotransferase (< 30 UI/l). Three patients had elevated aminotransferase levels (23%); one was coinfected with B virus, one with C virus, and the last one had a diabetes-induced fatty liver infiltration. No liver biopsies were performed. CONCLUSIONS: It is concluded that infection with G virus is common among dialyzed patients. This high rate of infection could be related to previous transfusions, but may as well be due to nosocomial transmission. In our series, at least one patient has been contaminated by another road than transplantation or transfusion. Finally, it does not appear clearly that chronic infection with hepatitis G virus induces liver disease, as defined by elevated aminotransferase level.

Bronchial eosinophilic infiltration in Crohn's disease in the absence of pulmonary disease.

BACKGROUND: Immunological and functional bronchopulmonary abnormalities may be present in up to two-thirds of patients with Crohn's disease. Having recently described a mild increase in methacholine airways responsiveness in these patients, we investigated whether this physiological abnormality is associated with bronchial inflammation since it has previously been described in asthma. METHODS: Eighteen patients with Crohn's disease and 15 healthy controls matched for age, atopy and smoking habit, were studied. All the subjects underwent a bronchial methacholine challenge (1, 4 and 16 mg/mL) and a sputum induction by inhalation of hypertonic saline (NaCl 4.5%). The sputum samples were analysed for their cellular composition as well as for the levels of several mediators and proteins in the fluid phase, including eosinophil cationic protein (ECP), myeloperoxydase, albumin, alpha2-macroglobulin, interleukin-8 (IL-8), IgA and IL-8/immunoglobulin A complexes. RESULTS: When compared to control subjects, patients with Crohn's disease had significantly higher sputum eosinophil counts (14.5% [0-79.9%] vs 0.2% [0-2.3%]; P < 0. 001) and ECP levels (26.2 microg/L [4-124.2 microg/L] vs 9.8 microg/L [0-94.2 microg/L]; P < 0.05). However, patients with Crohn's disease had no sign of increased plasma exudation as reflected by sputum levels of albumin and alpha2-macroglobulin similar to those seen in control subjects. Furthermore the sputum levels of IL-8, IgA and IL-8/IgA complexes were not significantly different between the two groups. The magnitude of the fall in forced expiratory volume in 1 s after methacholine inhalation was significantly increased in Crohn's disease patients although it did not correlate with the extent of sputum eosinophilia or with the sputum ECP levels. CONCLUSIONS: Crohn's disease patients without any clinical respiratory involvement have airway eosinophilia without local increased plasma exudation. However, bronchial eosinophilia in Crohn's disease per se is not sufficient to induce clinically significant airway hyperresponsiveness, suggesting that other factors than bronchial eosinophilic infiltration are required for the clinical expression of an airway instability.

[Pseudo-alcoholic hepatitis and cirrhosis caused by amiodarone (Cordarone)]. / Hépatite pseudo-alcoolique et cirrhose induite par l'amiodarone (Cordarone).

Amiodarone is an antiarrhythmic drug widely used to treat a variety of supraventricular and ventricular arrhythmias. However its drawback is a very slow elimination and very frequent adverse effects (thyroid, pulmonary, neurologic, ocular, dermatologic, hepatic disorders). We describe a patient who developed a pseudoalcoholic liver disease and a cirrhosis after use of Amiodarone for a long period of time.