ABSTRACTBackgroundFamilial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, associated with MEFV mutations. FMF patients can experience liver involvement, potentially leading to cirrhosis.ObjectivesThis study aimed to evaluate liver involvement in FMF patients at a French tertiary centre for adult FMF.MethodsWe conducted an observational study with FMF patients displaying 2 pathogenic MEFV mutations at the National Reference Center for Autoinflammatory Diseases and Inflammatory Amyloidosis (CEREMAIA) in Paris and included in the JIR cohort. MEFV heterozygous patients and those with other liver disease causes were excluded.ResultsAmong 533 FMF patients 12.4% had chronic liver abnormalities, with 30% who developed cirrhosis 54 years [36–57] in median after disease onset. Forty‐seven per cent were colchicine resistant, and 41% received interleukin‐1 inhibitors. Cirrhotic patients experienced delayed hepatopathy diagnosis, prolonged FMF diagnosis delay and late‐onset treatment initiation compared to those with only liver function test abnormalities. Colchicine resistance and interleukin‐1 inhibitor use were more common in cirrhotic patients. Body mass index and AA amyloidosis rates did not differ significantly between groups. Twenty‐one patients had undergone liver biopsies including 14 cirrhotic patients revealing steatohepatitis in 12 cases and probable steatohepatitis in 4. Other lesions, like iron overload and sinusoidal dilatation, were sporadically observed.ConclusionFMF patients are at risk of chronic liver disease. Regular liver function monitoring is crucial, particularly in case of persistent inflammation, due to the risk of progression to cirrhosis and its associated morbidity and mortality.

Background: When FMF patients with cirrhosis were compared with FMF patients without cirrhosis, those with cirrhosis had a significantly later diagnosis of hepatopathy: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease associated with a mutation in the MEFV gene. The liver may be involved in FMF, but data remain scarce; however, FMF patients may have cirrhosis [1]. The usual metabolic risk factors are not the only explanation, as they were not associated with persistent hepatic cytolysis in a previous work in FMF patients while studying a score of steatosis [2]. Objectives: Our aim was to evaluate liver involvement in FMF in a French tertiary centre for adult FMF. Methods: In this observational study, we included patients followed for FMF at the National Reference Centre for Adult Autoinflammatory Diseases and Inflammatory Amyloidosis (CEREMAIA) in Paris, France. Heterozygous patients and patients with other identified causes of hepatopathy were not included. Sociodemographic data, underlying characteristics of FMF, laboratory, imaging and pathological features, and complications of cirrhosis, if present, were recorded. Among FMF patients with hepatopathy, we compared patients with and without cirrhosis. Statistical analysis was performed using EasyMedStat. Results: Of the 533 adult FMF patients followed, 57 (10.7%) had chronic liver function abnormalities, including 17 (30%) with cirrhosis. Hepatic features developed 47 [24-58] years after FMF onset. All patients were receiving colchicine at a current median daily dose of 1.5 mg [1-2] mg, but 24 patients were colchicine-resistant (42%) and 23 (40%) were receiving interleukin-1 inhibitors, either anakinra (n=17) or canakinumab (n=8). Four patients also had AA amyloidosis. Thirty-five patients had active FMF with a CRP above 5 when liver abnormalities were detected. The median body mass index (BMI) was 26.3 [22.3-29.7] kg/m2. When FMF patients with cirrhosis were compared with FMF patients without cirrhosis, those with cirrhosis had a significantly later diagnosis of hepatopathy, a longer delay in diagnosis of FMF and in starting treatment for their FMF. Patients with colchicine resistance and on interleukin-1 inhibitors were significantly more common in the cirrhosis group. BMI and AA amyloidosis were not significantly different between groups. Liver ultrasound was performed in all but fifteen patients. FibroScan was performed in 32 patients with a median controlled attenuation parameter (CAP) score of 257 [226-303] dB/m and a median liver stiffness measurement (LSM) fibrosis stage score of 11.9 [6-17]. Nineteen patients underwent liver biopsy, including 14 with cirrhosis. The median SAF score was S1A3F4. Seventeen (90%) liver biopsies described inflammation with a variable infiltrate consisting of lymphocytes (n=8/13), neutrophils (n=3/13), monocytes and macrophages (n= 2/13), mononuclear cells (n=4/13) and fifteen had steatosis quantified as 15%, 11 patients had Mallory bodies and 11 patients had ballooning. Iron overload was found in 1 patient, vascular abnormalities in 4 patients and biliary abnormalities in 2 patients. Conclusion: FMF patients are at risk of chronic hepatopathy. This complication should be considered and sought because of its frequency in FMF patients, but also because of its morbidity with the risk of progression to cirrhosis and death. Liver function should be monitored in all FMF patients, especially those with uncontrolled inflammation. REFERENCES: [1] Fraisse T, Savey L, Hentgen V, Rossi-Semerano L, Koné-Paut I, Grateau G, et al. Non-amyloid liver involvement in familial Mediterranean fever: A systematic literature review. Liver Int. juin 2020;40(6):1269-77. [2] Deshayes S, Fraisse T, Fellahi S, Steichen O, Savey L, Turlin B, et al. Role of non-invasive methods in detecting liver impairment in familial Mediterranean fever adult patients with persistent hepatic cytolysis. Sci Rep. 5 oct 2022;12:16644. Acknowledgements: We wish to thank the following geneticians for performing MEFV sequencing at the diagnosis of FMF for French patients: Guilaine Boursier, Isabelle Touitou, Serge Amselem, Irina Giurgea, Isabelle Jeru, Laurence Cuisset. Disclosure of Interests: None declared.

This chapter reviews the methodology for circulatory studies and then focus on the hemodynamic effects of pharmacological agonists and antagonists of the a- and ß-adrenergic and serotonergic systems as well as the effects of nitrates. Patients with liver disease are known to have alterations in sympathetic nervous system activity, so it is surprising that much clinical and experimental research has focused on the hemodynamic effects of sympathomimetic and sympatholytic agents and other vasoactive drugs. In humans, the systemic circulation is accessible to study by many methods. Cardiac output is measured readily by the Fick principle, using either thermodilution with a pulmonary artery catheter, or dye dilution with simultaneous arterial and venous catheterization. Hepatic blood flow can also be measured by hepatic dye clearance techniques. In patients with abnormal liver architecture, accurate measurement of hepatic extraction is essential; otherwise estimates of flow based on plasma clearance alone lead to large errors.

Background & Aims: Liver sinusoidal obstruction syndrome (SOS) is a well-established complication of myeloablative conditioning regimens used in hematopoietic stem cell transplantation. Hepatic venous pressure gradient (HVPG) >10 mmHg was described as an accurate diagnostic tool for SOS in the 1990s. However, epidemiology and presentation of SOS have dramatically changed. Moreover, elementary histological lesions influencing HVPG are unknown. Methods: We retrospectively analyzed the charts of all patients who underwent transjugular liver biopsy with HVPG measurement for a clinical suspicion of SOS at our center. Two expert pathologists unaware of the presence or absence of SOS reviewed all liver samples and graded elementary histological lesions according to a semi-quantitative scoring defined a priori. Results: Out of the 77 included patients, the 30 patients with SOS had higher HVPG than the 47 patients without SOS (median 14 mmHg [IQR 10-18], vs. 6 mmHg [3-9], respectively p <0.001). HVPG >10 mmHg had a specificity of 78% and a positive predictive value of 66% for the diagnosis of SOS. However, almost 40% of the patients with SOS had an HVPG ≤10 mmHg. HVPG correlated with sinusoidal congestion (r = 0.57; p = 0.001) and hepatocyte necrosis (r = 0.42; p = 0.02), but not with other lesions. Conclusion: Even though HVPG is higher in patients with SOS, low HVPG values do not rule out SOS. Thus, HVPG cannot be used alone, and should be combined with transjugular liver biopsy, for the diagnosis of SOS. Lay summary: Hepatic venous pressure gradient >10 mmHg has been described as an accurate tool for the diagnosis of liver sinusoidal obstruction syndrome after hematopoietic stem cell transplantation. This study shows that the sensitivity and specificity of hepatic venous pressure gradient measurement for sinusoidal obstruction syndrome are insufficient, so that liver pressure measurement should be combined with a liver biopsy in this setting.

BACKGROUND: Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect, defined by an increased alveolar-arterial oxygen gradient, induced by pulmonary vascular dilatations in the context of liver disease. The pathogenesis of HPS is poorly understood. Morphologic changes associated with HPS are unknown. This study aimed at describing imaging and pathology changes associated with HPS. METHODS: We performed a case-control study in candidates for transplant with suspicion of cirrhosis. Each patient with HPS (Pao(2 )<= 70 mm Hg) was matched to three control subjects for age, cause, and liver disease severity. Pretransplant thoracic and abdominal imaging and explanted livers were reviewed. RESULTS: CT scans and Doppler ultrasounds from 21 patients with HPS were compared with those from 63 control subjects. HPS was associated with a two- to threefold higher prevalence of obstructed intrahepatic portal branches, of slowed or hepatofugal portal blood flow, and of large abdominal portosystemic shunts. Hepatic artery diameter was also larger in patients with HPS. Explanted livers from 19 patients with HPS were compared with those from 57 control subjects. HPS was associated with a fourfold higher prevalence of portal venule thrombosis and a ninefold higher prevalence of extensive vascular proliferation within fibrous septa. Obstruction of centrilobular venules, sinusoidal dilatation, and liver parenchymal extinction were also more common in patients with HPS. CONCLUSIONS: HPS is associated with intrahepatic vascular changes and with features suggesting severe portal hypertension. These results raise the hypothesis that intrahepatic vascular changes precipitate the development of HPS, opening new therapeutic perspectives for HPS.

The journal wishes to pass along the sad news that Dr. Reinhold W. Stockbrugger, the Editor of this Journal, died Friday 31 January 2018. He was 77 years old. We are deeply saddened by the sudden passing of Reinhold. He will be greatly missed. He was an enthusiastic and a reliable co-editor and working with him was a great pleasure. He was very involved in the Journal and was always willing to participate in efforts to improve the quality of the European Journal of Gastroenterology and Hepatology, with suggestions and new ideas such as giving a greater support to publications from young investigators. Reinhold possessed the spirit of a true European citizen and having lived in at least five European countries he was fluent in Italian, German, Swedish, Dutch, English, and French. He is best known for his activities on the European stage, one of which was the editorship of the European Journal of Gastroenterology and Hepatology, a position that he held from April 2008 until his untimely death in 2018. Reinhold was born on 22 August 1941 in Bunde, Germany. He studied medicine in Münster, Germany and Uppsala, Sweden, and graduated from Munster in 1969. He then went to Sweden (Sahlgrenska Hospital, Gothenburg, Sweden) to be trained in Internal Medicine and Gastroenterology. Joost met with Reinhold in 1989 in Maastricht as a student member part of the committee that was to select the first professor of Gastroenterology at Maastricht University, the Netherlands. He brought an impressive resume with experience as postgraduate clinical fellow with Dr. Peter B. Cotton at the Middlesex Hospital in London and as a consultant at the University of Gothenburg. At that time he was the Acting Medical Director of rehabilitation clinic ‘Marbachtal’ in Bad Kissingen (Germany). He was convincing, energetic and enthusiastic, and simply the best candidate. He started in Maastricht in 1990 as the Professor of Internal Medicine and Gastroenterology and did so until retirement in 2006. He was a great networker and one of his early achievements was the development of a population-based study on inflammatory bowel disease in South-Limburg, the Netherlands. This is an ongoing study that has included more than 2500 incident patients with Crohn’s disease or ulcerative colitis and has resulted in numerous papers. In Maastricht, Reinhold became acquainted with problem-based learning (PBL). Here, medical students use previous information and their experience as well as their ability to think rationally to assess a clinical problem with the aim to learn. Reinhold became a great proponent of PBL. He initiated exchange programmes between Maastricht and Ferrara and supported the introduction of a PBL program in the Ferrara Medical School (Italy). Reinhold accessed the European stage in 2001 when he became the councilor of the board of the Association des Sociétés National European et Mediterranean de Gastroenterologie (ASNEMGE). He immediately took the initiative to organize a 1-day ‘research corner’ at the United European Gastroenterology (UEG) week 2001 in Amsterdam and since then that has been a part of the UEG program. He designed this Young Investigator Meeting course to provide young physicians with the tools to do clinical research. His passion for research and education led to the UEG summer school that has become one of the educational crown jewels of the UEG. The Young Investigator Meeting channelled Reinhold’s passion for research and education. He was witty and during one of his talks on data storage he captivated the audience with his story that he had lost his PhD thesis just before it was to be printed. He had put the stack of papers on the top of his car, got in the car, and then drove off. As there was no copy (no computers in 1976), he was at a loss and 4 years of work gone. Fortunately, the next day a lady walked into the clinic with his lost thesis, thankfully complete, and he was able to publish his PhD thesis on ‘Aspects of chronic atrophic gastritis – with special reference to serum gastrin and antral gastrin cells’ in 1976. In 2009, he left ASNEMGE with the ‘ASNEMGE Distinguished Service Award’ and was elected chair of the public affairs committee of the UEG. There he campaigned for a screening program for colorectal cancer in all European countries. In Maastricht, he had designed a colonoscopy screening program for hospital employees and witnessed the benefits firsthand. As a UEG ‘Public Affairs Committee’ chair, he traveled around Europe, meeting with clinicians, patients, and politicians. His campaign efforts paid off and many European countries introduced a formal colorecral cancer screening screening program. Reinhold worked continuously for the greater good of European Gastroenterology. In one of the interviews he gave, he confided that his unfulfilled ambition was to keep working until the age of 85 years. It is unfortunate that we have to miss such a unique physician, a scientist, a teacher, and editor. Our thoughts are with Graziana his wife, and his children Stephanie and Philip. He will be greatly missed. Joost P.H. Drenth Didier LebrecDepartment of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The NetherlandsService d’hepatologieHôpital Beaujon, Clichy, France

Microvesicles (MVs) are extracellular vesicles released by cells following activation or apoptosis. Some MV subpopulations augment with cirrhosis severity and contribute to portal hypertension. This study aimed at determining if plasma MV levels can estimate the presence of hepatic venous pressure gradient (HVPG) ≥10 mm Hg and predict mortality in patients with advanced chronic liver disease. All patients with severe fibrosis or cirrhosis undergoing liver catheterization between 2013 and 2015 at two centers were prospectively included. We measured circulating levels of annexin V + , platelet, leukocyte, endothelial, and hepatocyte MVs. The test cohort included 139 patients. Hepatocyte MV levels were 4.0‐fold and 2.2‐fold higher in patients with Child‐Pugh C than in those with Child‐Pugh A or B liver disease, respectively. Levels of other MV subpopulations were not influenced by liver disease severity. Hepatocyte MV levels correlated with HVPG but could not identify patients with HVPG ≥10 mm Hg. Hepatocyte MV level >65 U/L predicted 6‐month mortality independently of Child‐Pugh score and of Model for End‐Stage Liver Disease (MELD). Patients with hepatocyte MV levels >65 U/L and MELD >15 had a higher 6‐month mortality than other patients (23% versus 3%; P = 0.001). These findings were confirmed in a validation cohort including 103 patients. Conclusion : Circulating MV levels cannot identify patients with HVPG ≥10 mm Hg; by contrast, hepatocyte MV levels strongly improve prediction of 6‐month mortality in patients with advanced chronic liver disease; therapies associated with decreased levels of circulating hepatocyte MV might be attractive strategies in patients with severe cirrhosis. (H epatology 2018).

BACKGROUND & AIMSThere is debate over the effects of long-term oral fluoroquinolone therapy in patients with advanced cirrhosis. We performed a randomized controlled trial to evaluate the effects of long-term treatment with the fluoroquinolone norfloxacin on survival of patients with cirrhosis.METHODSWe performed a double-blind trial of 291 patients with Child-Pugh class C cirrhosis who had not received recent fluoroquinolone therapy. The study was performed at 18 clinical sites in France from April 2010 through November 2014. Patients were randomly assigned to groups given 400 mg norfloxacin (n = 144) or placebo (n = 147) once daily for 6 months. Patients were evaluated monthly for the first 6 months and at 9 months and 12 months thereafter. The primary outcome was 6-month mortality, estimated by the Kaplan-Meier method, censoring spontaneous bacterial peritonitis, liver transplantation, or loss during follow-up.RESULTSThe Kaplan-Meier estimate for 6-month mortality was 14.8% for patients receiving norfloxacin and 19.7% for patients receiving placebo (P = .21). In competing risk analysis that took liver transplantation into account, the cumulative incidence of death at 6 months was significantly lower in the norfloxacin group than in the placebo group (subdistribution hazard ratio, 0.59; 95% confidence interval, 0.35-0.99). The subdistribution hazard ratio for death at 6 months with norfloxacin vs placebo was 0.35 (95% confidence interval, 0.13-0.93) in patients with ascites fluid protein concentrations <15 g/L and 1.39 (95% confidence interval, 0.42-4.57) in patients with ascites fluid protein concentrations ≥15 g/L. Norfloxacin significantly decreased the incidence of any and Gram-negative bacterial infections without increasing infections caused by Clostridium difficile or multiresistant bacteria.CONCLUSIONSIn a randomized controlled trial of patients with advanced cirrhosis without recent fluoroquinolone therapy, norfloxacin did not reduce 6-month mortality, estimated by the Kaplan-Meier method. Norfloxacin, however, appears to increase survival of patients with low ascites fluid protein concentrations. ClinicalTrials.gov ID: NCT01037959.

Two algorithms based on sequential measurements of liver and spleen stiffness using two-dimensional shearwave elastography (2D-SWE) have been recently proposed to estimate clinically significant portal hypertension (hepatic venous pressure gradient [HVPG] ≥10 mm Hg) in patients with cirrhosis, with excellent diagnostic accuracy.To validate externally these algorithms in a large cohort of patients with cirrhosis.One hundred and ninety-one patients with stable cirrhosis (Child-Pugh class A 39%, B 29% and C 31%) who underwent liver and spleen stiffness measurements using 2D-SWE at the time of HVPG measurement were included. Diagnostic accuracy of the 2 algorithms was assessed by calculating sensitivity, specificity, positive and negative predictive values.The first algorithm, using liver stiffness <16.0 kilopascals (kPa) and then spleen stiffness <26.6 kPa, was used to rule-out HVPG ≥10 mm Hg. In our population, its sensitivity and negative predictive value were 95% and 63% respectively. The second algorithm, using liver stiffness >38.0 kPa, or liver stiffness ≤38.0 kPa but spleen stiffness >27.9 kPa, was used to rule-in HVPG ≥10 mm Hg. In our population, its specificity and positive predictive value were 52% and 83% respectively. Restricting the analyses to the 74 patients without any history of decompensation of cirrhosis or to the 65 patients with highly reliable liver stiffness measurement did not improve the results.In our population, diagnostic accuracies of non-invasive algorithms based on sequential measurements of liver and spleen stiffness using 2D-SWE were acceptable, but not good enough to replace HVPG measurement or to base clinical decisions.

The diagnosis of alcoholic hepatitis (AH) often requires a transjugular liver biopsy (TJLB), a procedure that is not always readily accessible. We analyzed plasma biomarkers to estimate the presence of histological features of AH among patients with clinical suspicion of AH. Using enzyme‐linked immunosorbent assay, we tested M65 and M30 (circulating fragments of cytokeratin‐18) and their respective fraction carried by microvesicles (MVs), CCL20 and TREM1. Leukocyte, platelet, and endothelial‐derived MVs were quantified by way of flow cytometry. Test and validation cohorts prospectively included patients with clinical features of AH undergoing TJLB. In the test cohort, 46 of 83 (55%) patients showed histological features of AH. Age, bilirubin, INR, and creatinine (ABIC) score was B or C in 83%. Patients with histologically proven AH had higher levels of total and MV‐bound M65 and total and MV‐bound M30 and CCL20 than those without ( P < 0.001 for all tests). Levels of TREM‐1 and of subpopulations of MVs were not different between groups. M65 and M30 both had an area under the receiver operating characteristics curve of 0.84 to estimate the presence of AH. For M65, a cutoff of 2000 IU/L had a positive predictive value of 91%, whereas a cutoff of 641 IU/L had a negative predictive value of 88%. In the validation cohort, AH was histologically confirmed in 48 of 68 (71%) patients. ABIC score was B or C in 69% of patients. For M65, the above cutoffs had a diagnostic accuracy of 81%. Even better results were obtained in patients with suspicion of severe AH (ABIC B or C) in both cohorts. Conclusion : Plasma levels of cytokeratin‐18 fragments are reliable noninvasive markers of AH. Using the proposed cutoffs for M65, two thirds of TJLB can be avoided, which can be useful in centers where this technique is not readily available. (H epatology 2017;66:555–563).

Summary Background Beta‐blockers may have to be interrupted in patients with cirrhosis. The concept of a rebound after interruption of beta‐blockers is based on an animal study and on isolated case reports of variceal bleeding. Aim To determine if a rebound occurs in patients with cirrhosis following abrupt interruption of beta‐blockers. Methods We prospectively included all consecutive patients with cirrhosis undergoing right heart and hepatic vein catheterisation. Four groups were defined: ‘no beta‐blockers’ including patients not receiving beta‐blockers; ‘≤1 day’, ‘2–3 days’ and ‘≥4 days’ classified according to the time patients had interrupted beta‐blockers before catheterisation. Results were expressed as median (interquartile range). Results A total of 150 patients were included. Among the 25 patients in the groups ‘2–3 days’ and ‘≥4 days’, median duration of beta‐blockers interruption was 4 (3–6) days. No gastrointestinal bleeding occurred during that period, nor during the following month. Hepatic venous pressure gradient was not different among patients in usually treated with beta‐blockers. After adjustment, beta‐blockers interruption was not associated with hepatic venous pressure gradient. Cardiac index was higher in the ‘≥4 days’ group [4.6 L/min/m 2 (3.5–5.1)] than in the ‘≤1 day’ group [3.4 (2.6–4.0); P = 0.001] or in the ‘2–3 days’ group [3.1 (2.7–3.7); P = 0.007], but not different from the ‘no beta‐blockers’ group. Conclusions Abrupt interruption of beta‐blockers is associated neither with an apparent increase in the risk of variceal bleeding nor with a haemodynamic rebound. Thus, interruption of beta‐blockers in patients with cirrhosis may not require particular dosing or surveillance.