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ContextLiver function abnormalities (LFAs) have been described in patients with Turner syndrome (TS). Although a high risk of cirrhosis has been reported, there is a need to assess the severity of liver damage in a large cohort of adult patients with TS.ObjectiveEvaluate the types of LFAs and their respective prevalence, search for their risk factors, and evaluate the severity of liver impairment by using a noninvasive fibrosis marker.MethodsThis was a monocentric retrospective cross-sectional study. Data were collected during a day hospital visit. The main outcome measures were liver enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase), FIB-4 score, liver ultrasound imaging, elastography, and liver biopsies, when available.Results264 patients with TS were evaluated at a mean age of 31.15 ± 11.48 years. The overall prevalence of LFAs was 42.8%. The risk factors were age, body mass index, insulin resistance, and an X isochromosome (Xq). The mean FIB-4 sore of the entire cohort was 0.67 ± 0.41. Less than 10% of patients were at risk of developing fibrosis. Cirrhosis was observed in 2/19 liver biopsies. There was no significant difference in the prevalence of LFAs between premenopausal patients with natural cycles and those receiving hormone replacement therapy (P = .063). A multivariate analysis adjusted for age showed no statistically significant correlation between hormone replacement therapy and abnormal gamma-glutamyl transferase levels (P = .12).ConclusionPatients with TS have a high prevalence of LFA. However, 10% are at high risk of developing fibrosis. The FIB-4 score is useful and should be part of the routine screening strategy. Longitudinal studies and better interactions with hepatologists should improve our knowledge of liver disease in patients with TS.

Objectif Etablir la prevalence des anomalies du bilan hepatique (ABH), les facteurs de risque associes et evaluer l’interet du score de fibrose Fib-4, chez les patientes adultes avec un syndrome de Turner (ST). Methodes Analyse transversale des donnees auxiologiques, du caryotype et du bilan hepatique dans une cohorte de patientes ST recueillies lors d’une hospitalisation de jour en centre de reference (CMERC) entre 2011 et 2020 et calcul du Fib4 (âge x ASAT/plaquettes x ALAT) Resultats 254 patientes ST, âgees de 32,6 ± 11 ans, avec un IMC de 25,3 ± 5 ont ete recrutees. 118 patientes (46,46 %) avaient une ABH, definie par des transaminases et/ou GGT > 1,5 N. Parmi elles, 31 etaient suivies en hepatologie. Les ABH etaient significativement correlees a une augmentation du IMC (p = 0,023), de l’âge (p Discussion Les complications hepatiques du ST sont peu etudiees [1] . Notre etude, comportant un nombre important de patientes ST adultes, montre une prevalence d’ABH proche de 50 %. L’atteinte hepatique est predominante en cas d’isochromosome Xq. Dans cette cohorte, un seuil de Fib-4 > 0,6 semble identifier les patientes avec un risque de complications hepatiques a type de fibrose. L’impact des traitements hormonaux sur les ABH est en cours d’evaluation.

Cancer is a leading cause of morbidity and deaths in solid organ transplant recipients. In immunocompetent patients, cancer prognosis has been dramatically improved with the development of immune checkpoint inhibitors (ICI), as programmed cell death protein 1/programmed death-ligand 1 and cytotoxic T lymphocyte-associated antigen 4 inhibitors, that increase antitumor immune responses. ICI has been developed outside of the scope of transplantation because of the theoretical risk of graft rejection, which has later been confirmed by the publication of several cases and small series. The use of ICI became unavoidable for treating advanced cancers including in organ transplant patients, but their management in this setting remains highly challenging, as to date no strategy to adapt the immunosuppression and to prevent graft rejection has been defined. In this article, we report a monocentric series of 5 solid organ transplant recipients treated with ICI and provide a comprehensive review of current knowledge of ICI management in the setting of solid organ transplantation. Strategies warranted to increase knowledge through collecting more exhaustive data are also discussed.

IF 7.286; International audience; BACKGROUND:The outcome of cholangiopathy developing in intensive care unit (ICU) is not known in patients surviving their ICU stay.AIM:To perform a survey in liver units, in order to clarify the course of cholangiopathy after surviving ICU stay.METHODS:The files of the liver units affiliated to the French network for vascular liver disease were screened for cases of ICU cholangiopathy developing in patients with normal liver function tests on ICU admission, and no prior history of liver disease.RESULTS:Between 2005 and 2015, 16 cases were retrieved. Extensive burns were the cause for admission to ICU in 11 patients. Serum alkaline phosphatase levels increased from day 11 (2-46) to a peak of 15 (4-32) × ULN on day 81 (12-511). Magnetic resonance cholangiography showed irregularities or frank stenosis of the intrahepatic ducts, and proximal extrahepatic ducts contrasting with a normal aspect of the distal common bile duct. Follow-up duration was 20.6 (4.7-71.8) months. Three patients were lost to follow-up; 2 patients died from liver failure and no patient was transplanted. One patient had worsening strictures of the intrahepatic bile ducts with jaundice. Nine patients had persistent but minor strictures of the intrahepatic bile ducts on MR cholangiography, and persistent cholestasis without jaundice. One patient had normal liver function tests.CONCLUSIONS:In patients surviving their ICU stay, ICU cholangiopathy is not uniformly fatal in the short term or clinically symptomatic in the medium term. Preservation of the distal common bile duct appears to be a finding differentiating ICU cholangiopathy from other diffuse cholangiopathies.

Introduction Adult onset Still’s disease is a rare affection classified among non-hereditary autoinflammatory diseases. We here report a case of AOSD revealed during pregnancy with a life-threatening presentation along with a review of 19 cases from literature. Case A 38-years old woman was treated in our department for diffuse systemic sclerosis and associated Sjogren syndrome. She was pregnant and presented with acute fever and arthralgias. Laboratory data revealed mild liver cytolysis but a large screening for infectious and auto-immune diseases was negative and hepato-biliar imaging was normal. Ferritin levels were at 41 000 ng/mL with glycosylated ferritin less than 5%. The diagnosis of AOSD was stated and because of persistent fever and polyarthralgias, after exclusion of active infection, steroids were started (prednisone 1 mg/kg) associated with colchicine, which allowed clinical remission and C-reactive protein significant decrease. Conclusion Pregnancy-revealed AOSD appears to be a specifical subset of the disease with a systemic course, flares on first and second trimester, obstetrical complications such as prematurity and IUGR sometimes leading to life-threatening situations requiring parenteral corticotherapy and intravenous immunoglobulins.

Introduction La maladie de Still est une pathologie rare classee parmi les maladies auto-inflammatoires non hereditaires. La presentation clinique peut aller d’une eruption pseudo-urticarienne avec arthralgies jusqu’a un tableau de syndrome d’activation macrophagique pouvant engager le pronostic vital. Les mecanismes physiopathologiques responsables restent indetermines mais semblent impliquer les interleukines 1b, 6 et 18. Plusieurs cas de maladie de Still revelee pendant la grossesse ont ete rapportes, sans que l’on sache s’il existe un sur-risque d’evenement obstetrical. Nous rapportons un cas de maladie de Still revele pendant la grossesse suivi d’une revue de 19 cas de la litterature. Observation Nous rapportons le cas d’une patiente de 38 ans, qui consulta dans le service en mai 2016 a 12 semaines de grossesse pour une fievre d’apparition recente sans autre symptome. Le bilan biologique realise revela une cytolyse hepatique moderee (ASAT et ALAT a 4xN), et un large bilan a la recherche d’une cause infectieuse ou auto-immune revient negatif. La fievre et la cytolyse regresserent spontanement en 3 jours. Deux mois plus tard, elle fut hospitalisee pour une fievre intense, une odynophagie et des douleurs abdominales. Le bilan retrouva une cytolyse hepatique plus marquee (ASAT et ALAT a 10xN) avec cholestase, elevation de la bilirubine conjuguee et syndrome inflammatoire avec CRP a 53 mg/L. Un dosage de la ferritine retrouva des valeurs moderement elevees a 657 ng/mL. Un bilan etiologique etendu a la recherche d’une cause infectieuse revint une nouvelle fois negative, les symptomes regresserent de nouveau sans traitement specifique. Un mois plus tard, a 28 semaines de grossesse, elle fut re-hospitalisee pour fievre et arthromyalgies, syndrome inflammatoire avec CRP a 163 mg/L, cytolyse hepatique a 2xN, avec une ferritinemie a 371 mg/L. Un scanner cervico-thoraco-abdomino-abdominal revela un epanchement pericardique modere non compressif ainsi qu’une hepatomegalie homogene. Devant la fievre persistante et les symptomes articulaires, apres exclusion d’une infection active, une corticotherapie d’epreuve fut debutee (Prednisone 1 mg/kg/jour) et permit une remission clinique et diminution du syndrome inflammatoire biologique. Au decours de la decroissance de la corticotherapie, a 12,5 mg/jour en association a la colchicine, les symptomes reapparurent et une immunotherapie a doses immunomodulatrices fut decidee. Juste avant la mise en route du traitement, la patiente developpa une agranulocytose attribuee a la colchicine, compliquee d’un sepsis severe a point de depart urinaire et une extraction fœtale fut decidee a 34 semaines de grossesse. La fievre et les arthralgies persisterent avec une cholestase et un syndrome inflammatoire majeurs (GGT 15xN, CRP a 320 mg/L), la ferritine s’eleva a 41,000 ng/mL et un dosage de la ferritine glycosylee revient inferieur a 5 %. Le diagnostic de maladie de Still put etre pose selon les criteres de Yamaguchi et de Fautrel, la corticotherapie reprise en association avec l’anakinra (100 mg/j) permettant une remission clinique et biologique rapide. La maladie de Still peut etre revelee par la grossesse comme rapporte pour la premiere fois en 1982. Nous avons rassemble 19 cas provenant de la litterature medicale. Les patientes avaient entre 19 et 38 ans (âge median 28,6). Parmi 18 grossesses, la premiere poussee de la maladie de Still survenait a 16,77 semaines de grossesse, et pour la majorite des patientes entre le premier et le deuxieme trimestre de grossesse. La presentation clinique associait arthromyalgies et arthrites, fievre irreguliere et pharyngite. Les taux de ferritinemie se situaient entre 1/311 et 41/424 ng/mL. La plupart des patientes recevaient une corticotherapie (n = 16/20), et deux furent traitees par immunoglobulines intraveineuses. Toutes les patientes avaient une forme systemique sans forme chronique articulaire. Il n’y avait pas de predominance particuliere entre les formes monocycliques et polycycliques. Les complications obstetricales etaient frequentes (n = 11/20) avec au premier plan des naissances prematurees (n = 10/20) parmi lesquelles 3 etaient dues a une rupture prematuree des membranes potentiellement imputable a la corticotherapie systemique. Trois naissances furent compliquees de retard de croissance intra-uterin, deux grossesses d’oligohydroamnios, et une de mort fœtale in utero. Conclusion La maladie de Still revelee par la grossesse semble etre une forme specifique associant une presentation systemique, des poussees aux premiers et deuxiemes trimestres de grossesse, des complications obstetricales comme la prematurite et des RCIU, engageant parfois le pronostic vital et necessitant corticotherapie systemique et immunoglobulines intraveineuses.

Noninvasive measurement of liver stiffness with transient elastography has been recently validated for the evaluation of hepatic fibrosis in chronic hepatitis C. The current study assessed the diagnostic performance of liver stiffness measurement (LSM) for the determination of fibrosis stage in chronic cholestatic diseases. One hundred one patients with primary biliary cirrhosis (PBC, n=73) or primary sclerosing cholangitis (PSC, n=28) were prospectively enrolled in a multicenter study. All patients underwent liver biopsy (LB) and LSM. Histological and fibrosis stages were assessed on LB by two pathologists. LSM was performed by transient elastography. Efficiency of LSM for the determination of histological and fibrosis stages were determined by a receiver operating characteristics (ROC) curve analysis. Analysis failed in six patients (5.9%) because of unsuitable LB (n=4) or LSM (n=2). Stiffness values ranged from 2.8 to 69.1 kPa (median, 7.8 kPa). LSM was correlated to both fibrosis (Spearman's rho= 0.84, P.0001) and histological (0.79, P.0001) stages. These correlations were still found when PBC and PSC patients were analyzed separately. Areas under ROC curves were 0.92 for fibrosis stage (F)or =2, 0.95 for For =3 and 0.96 for F=4. Optimal stiffness cutoff values of 7.3, 9.8, and 17.3 kPa showed For =2, For =3 and F=4, respectively. LSM and serum hyaluronic acid level were independent parameters associated with extensive fibrosis on LB. In conclusion, transient elastography is a simple and reliable noninvasive means for assessing biliary fibrosis. It should be a promising tool to assess antifibrotic therapies in PBC or PSC.

We have previously shown that the histological stage and severity of lymphocytic piecemeal necrosis (LPN) are independent predictive factors of cirrhosis development in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cirrhosis (PBC). Our aim during this study was to determine whether biochemical parameters classically used in PBC management and measured under UDCA could be considered as reliable surrogate markers for these histological prognostic indices in clinical practice.The study included 153 patients with PBC who had undergone a control liver biopsy after 2 years of UDCA therapy. The relationships between histological and biological features were assessed by variance analysis and logistic regression. The diagnostic value of independent markers was assessed in terms of their sensitivity, specificity, positive predictive value (PPV) and negative value (NPV) and receiver-operating characteristic curves.Two variables were independently associated with extensive fibrosis (i.e. advanced histological stages): serum levels of bilirubin and hyaluronic acid (HA). A fibrosis index ([bilirubin (micromol/l)/14]+[HA (microg/l)/143]) higher than 1.5 exhibited good PPV and specificity (74%) but rather poor NPV and sensitivity (64%) regarding a diagnosis of extensive fibrosis. The only independent marker of LPN was aspartate aminotransferase (AST) activity. AST activity of more than twice the upper limit of normal showed acceptable PPV (70%) but very low sensitivity (25%) for a diagnosis of LPN.Serum bilirubin and HA levels measured under UDCA therapy are of acceptable diagnostic value for extensive fibrosis, but none of the biochemical tests commonly employed in the management of PBC can be considered as surrogate markers of LPN. Taken together with our previous results, these findings suggest that liver biopsy may be necessary to screen UDCA-treated patients who might require additional therapies.

OBJECTIVES: During the progression of chronic liver disease towards cirrhosis, morphological studies have shown a close association between parenchymal remodeling and obliterative lesions of intrahepatic small portal and hepatic veins. These lesions are highly suggestive of intrahepatic thrombotic events, which may have a key role in the pathogenesis of hepatic fibrosis. The aim of the study was to investigate thrombotic risk factors in chronic hepatitis C patients with different extent of liver fibrosis. METHODS: The following thrombotic factors were evaluated in 68 hepatitis C patients with prothrombin activity >/= 80% (34 consecutive patients with extensive fibrosis and/or cirrhosis compared with 34 consecutive patients without extensive fibrosis and/or cirrhosis): factor V Leiden, G20210A prothrombin mutation, antithrombin, protein C and S deficiencies, hyperhomocysteinemia, elevated factor VIII level, and lupus anticoagulant. RESULTS: Three thrombotic risk factors were significantly more frequent in patients with extensive fibrosis and/or cirrhosis than in those without extensive fibrosis: protein C deficiency present in 14 patients (41%) as compared with three patients (9%), p= 0.004; elevated factor VIII level present in 19 patients (56%) as compared with six patients (18%), p= 0.002; and hyperhomocysteinemia present in 10 patients (29%) as compared with two patients (6%), p= 0.023. The association of two or three prothrombotic factors was present in 19 patients (56%) with extensive fibrosis and/or cirrhosis as compared with one patient (3%) without extensive fibrosis and/or cirrhosis, p < 0.001. CONCLUSION: Multiple thrombotic risk factors coexist frequently in patients with extensive fibrosis and early stage of cirrhosis. Their association with local inflammation could favor thrombotic events in the liver micro-circulatory bed.

Resume La mastocytose systemique est une maladie rare correspondant a une proliferation mastocytaire avec localisation tissulaire multiviscerale. Bien que l’atteinte hepatique soit frequente au cours des mastocytoses systemiques, elle n’est que tres exceptionnellement revelatrice. Nous rapportons ici deux observations de mastocytose systemique dont la symptomatologie hepatique d’installation tres rapide a ete revelatrice, insuffisance hepatocellulaire dans un cas et ictere dans l’autre. Ces deux observations montrent que la mastocytose systemique, comme d’autres pathologies tumorales, peut se reveler par une symptomatologie hepatique. Cette symptomatologie hepatique revelatrice est variable, de meme que les lesions anatomo-pathologiques hepatiques. La clef du diagnostic est la mise en evidence d’une infiltration tissulaire par des mastocytes tumoraux identifies a l’aide d’immunomarquages avec les anticorps anti-tryptase et/ou -CD117 (c-kit).

Summary Background and aims There is evidence for an association between thrombosis in the hepatic microcirculation and liver fibrosis. The aim of this study was to evaluate the role of daily low-dose aspirin (75 or 100 mg, given for prevention of hepatic artery thrombosis) in fibrosis progression to ≥ F2 fibrosis score in liver-transplant recipients with recurrent hepatitis C virus (HCV). Methods All HCV-positive patients who had undergone liver transplantation (LT) between 2000 and 2010 were included. Exclusion criteria were negative HCV RNA, previous LT or death within a year of LT. Liver fibrosis was assessed by histological evaluation. Data were censored at the date of the last histological evaluation before starting anti HCV therapy. Progression to fibrosis F ≥ 2 was analyzed with a multistate model with time-dependent covariables. Results One hundred and eighty-eight patients were included. In univariate analysis, older recipient and donor age, male donor gender, activity score ≥ A2 after LT, number of steroid boluses and aspirin intake (HR: 0.75 [0.57–0.97]; P = 0.03) influenced the risk of progression to fibrosis ≥ F2. In multivariate analysis, adjusted on site, older donor age, male donor gender, activity score ≥ A2 and number of steroids boluses, remained independent predictors of fibrosis progression, while younger recipient age and aspirin intake (HR: 0.65 [0.47–0.91]; P = 0.01) were associated with a slower fibrosis progression. Conclusion Low-dose aspirin treatment might be associated with a lower risk of liver fibrosis progression in patients with HCV recurrence after LT.

International audience

International audience; BACKGROUND & AIMS: Blood tests and transient elastography (Fibroscan™) have been developed as alternatives to liver biopsy. This ANRS HCEP-23 study compared the diagnostic accuracy of nine blood tests and transient elastography (Fibroscan™) to assess liver fibrosis, vs. liver biopsy, in untreated patients with chronic hepatitis C (CHC). METHODS: This was a multicentre prospective independent study in 19 French University hospitals of consecutive adult patients having simultaneous liver biopsy, biochemical blood tests (performed in a centralized laboratory) and Fibroscan™. Two experienced pathologists independently reviewed the liver biopsies (mean length=25±8.4 mm). Performance was assessed using ROC curves corrected by Obuchowski's method. RESULTS: Fibroscan™ was not interpretable in 113 (22%) patients. In the 382 patients having both blood tests and interpretable Fibroscan™, Fibroscan™ performed similarly to the best blood tests for the diagnosis of significant fibrosis and cirrhosis. Obuchowski's measure showed Fibrometer® (0.86), Fibrotest® (0.84), Hepascore® (0.84), and interpretable Fibroscan™ (0.84) to be the most accurate tests. The combination of Fibrotest®, Fibrometer®, or Hepascore® with Fibroscan™ or Apri increases the percentage of well classified patients from 70-73% to 80-83% for significant fibrosis, but for cirrhosis a combination offers no improvement. For the 436 patients having all the blood tests, AUROC's ranged from 0.82 (Fibrometer®) to 0.75 (Hyaluronate) for significant fibrosis, and from 0.89 (Fibrometer® and Hepascore®) to 0.83 (FIB-4) for cirrhosis. CONCLUSIONS: Contrarily to blood tests, performance of Fibroscan™ was reduced due to uninterpretable results. Fibrotest®, interpretable Fibroscan™, Fibrometer®, and Hepascore® perform best and similarly for diagnosis of significant fibrosis and cirrhosis.

The development of liver fibrosis markers in primary biliary cirrhosis (PBC) is needed to facilitate the assessment of its progression and the effectiveness of new therapies. Here, we investigated the potential usefulness of transient elastography (TE) in the noninvasive evaluation of liver fibrosis stage and disease progression in PBC. We performed, first, a prospective performance analysis of TE for the diagnosis of METAVIR fibrosis stages in a diagnostic cohort of 103 patients and, second, a retrospective longitudinal analysis of repeated examinations in a monitoring cohort of 150 patients followed-up for up to 5 years. All patients were treated with ursodeoxycholic acid. Diagnostic thresholds of liver stiffness in discriminating fibrosis stages ≥F1, ≥F2, ≥F3, and =F4 were 7.1, 8.8, 10.7, and 16.9 kPa, respectively. TE showed high performance and was significantly superior to biochemical markers (e.g., aspartate aminotransferase [AST]/platelet ratio, FIB-4, hyaluronic acid, AST/alanine aminotransferase ratio, and Mayo score) in diagnosing significant fibrosis, severe fibrosis, or cirrhosis. Analysis of the monitoring cohort data set using generalized linear models showed the following: (1) an overall progression rate of 0.48 ± 0.21 kPa/year (P = 0.02) and (2) no significant progression in patients with F0-F1, F2, or F3 stages, but a significant increase (4.06 ± 0.72 kPa/year; P < 0.0001) in cirrhotic patients. A cut-off value of 2.1 kPa/year was associated with an 8.4-fold increased risk of liver decompensations, liver transplantations, or deaths (P < 0.0001, Cox regression analysis). Conclusion: TE is one of the best current surrogate markers of liver fibrosis in PBC. Over a 5-year period, on-treatment liver stiffness appears stable in most noncirrhotic PBC patients, whereas it significantly increases in patients with cirrhosis. Progression of liver stiffness in PBC is predictive of poor outcome. (HEPATOLOGY 2012;56:198–208)

Liver biopsy is the gold standard for assessing fibrosis but has several limitations. We evaluated a noninvasive method, so-called diffusion-weighted magnetic resonance imaging (DWMRI), which measures the apparent diffusion coefficient (ADC) of water, for the diagnosis of liver fibrosis in patients with chronic hepatitis C virus (HCV). We analyzed 20 healthy volunteers and 54 patients with chronic HCV (METAVIR: F0, n = 1; F1, n = 30; F2, n = 8; F3, n = 5; and F4, n = 10) prospectively included. Patients with moderate-to-severe fibrosis (F2-F3-F4) had hepatic ADC values lower than those without or with mild fibrosis (F0-F1; mean: 1.10 +/- 0.11 versus 1.30 +/- 0.12 x 10(-3) mm2/s) and healthy volunteers (mean: 1.44 +/- 0.02 x 10(-3) mm2/s). In discriminating patients staged F3-F4, the areas under the receiving operating characteristic curves (AUCs) were 0.92 (+/-0.04) for magnetic resonance imaging (MRI), 0.92 (+/-0.05) for elastography, 0.79 (+/-0.08) for FibroTest, 0.87 (+/-0.06) for the aspartate aminotransferase to platelets ratio index (APRI), 0.86 (+/-0.06) for the Forns index, and 0.87 (+/-0.06) for hyaluronate. In these patients, the sensitivity, specificity, positive predictive value, and negative predictive value were 87%, 87%, 72%, and 94%, respectively, with an ADC cutoff level of 1.21 x 10(-3) mm2/s. In discriminating patients staged F2-F3-F4, the AUC values were 0.79 (+/-0.07) for MRI, 0.87 (+/-0.05) for elastography, 0.68 (+/-0.09) for FibroTest, 0.81 (+/-0.06) for APRI, 0.72 (+/-0.08) for the Forns index, and 0.77 (+/-0.06) for hyaluronate.This preliminary study suggests that DWMRI compares favorably with other noninvasive tests for the presence of significant liver fibrosis.