Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare cholestatic liver disease. Such liver disease can get worse by female hormone disorder. Albumin dialysis or Molecular Adsorbent Recirculating Syst...Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare cholestatic liver disease. Such liver disease can get worse by female hormone disorder. Albumin dialysis or Molecular Adsorbent Recirculating System (MARS) has been reported to reverse severe cholestasis-linked pruritus. Here, we report the first use of MARS during a spontaneous pregnancy and its successful outcome in a patient with PFIC3 and intractable pruritus. Albumin dialysis could be considered as a pregnancy-saving procedure in pregnant women with severe cholestasis and refractory pruritus.展开更多
Importance:Liver transplantation(LT)is a life-saving therapy for patients with end-stage liver disease and with acute liver failure,and it is associated with excellent outcomes and survival rates at 1 and 5 years.The ...Importance:Liver transplantation(LT)is a life-saving therapy for patients with end-stage liver disease and with acute liver failure,and it is associated with excellent outcomes and survival rates at 1 and 5 years.The incidence of biliary complications(BCs)after LT is reported to range from 5%to 20%,most of them occurring in the first three months,although they can occur also several years after transplantation.Objective:The aim of this review is to summarize the available evidences on pathophysiology,risk factors,diagnosis and therapeutic management of BCs after LT.Evidence Review:a literature review was performed of papers on this topic focusing on risk factors,classifications,diagnosis and treatment Findings:Principal risk factors include surgical techniques and donor’s characteristics for biliary leakage and anastomotic biliary strictures and vascular alterations for non-anastomotic biliary strictures.MRCP is the gold standard both for intra-and extrahepatic BCs,while invasive cholangiography should be restricted for therapeutic uses or when MRCP is equivocal.About treatment,endoscopic techniques are the first line of treatment with success rates of 70-100%.The combined success rate of ERCP and PTBD overcome 90%of cases.Biliary leaks often resolve spontaneously,or with the positioning of a stent in ERCP for major bile leaks Conclusions and Relevance:BCs influence morbidity and mortality after LT,therefore further evidences are needed to identify novel possible risk factors,to understand if an immunological status that could lead to their development exists and to compare the effectiveness of innovative surgical and machine perfusion techniques.展开更多
AIM： To assess pre-orthotopic liver transplantation （OLT） factors that could be evaluated pre-operatively or controlled post-operatively associated with hepatocellular carcinoma （HCC） recurrence and disease-free ...AIM： To assess pre-orthotopic liver transplantation （OLT） factors that could be evaluated pre-operatively or controlled post-operatively associated with hepatocellular carcinoma （HCC） recurrence and disease-free survival after liver transplantation （LT）.METHODS： Four hundred and twelve patients transplanted for HCC between 1988 and 1998 in 14 French centers, who survived the postoperative period were studied. Kaplan Meier estimates were calculated for 24 variables potentially associated with recurrence of HCC. Uni- and multivariate analyses were conducted to identify independent predictors of recurrence. RESULTS： Overall 5-year disease-free survival was 57.1%. By univariate analysis, variables associated with disease-free survival were： presence of cirrhosis （P = 0.001）, etiology of liver disease （P = 0.03）, α fetoprotein level （〈 200, 200 to 2000, or 〉 2000; P 〈 0.0001）, y-GT activity （N, N to 2N or 〉 2N; P = 0.02）, the number of nodules （1, 2-3 or ≥ 4; P = 0.02）, maximal diameter of the largest nodule （〈 3 cm, 3 to 5 cm or 〉 5 cm; P 〈 0.0001）, the sum of the diameter of the nodules （〈 3 cm, 3 to 5 cm, 5 to 10 cm or 〉10 cm; P 〈 0.0001）, bilobar location （P = 0.01）, preoperative portal thrombosis （P 〈 0.0001）, peri-operative treatment of the tumor （P = 0.002） and chemoembolization （P = 0.03）, tumor differentiation （P = 0.01）, initial type of calcineurin inhibitor （P = 0.003）, the use of antilymphocyte antibodies （P = 0.02）, rejection episodes （P = 0.003） and period of LT （P 〈 0.0001）. By multivariate analysis, 6 variables were independently associated with HCC recurrence： maximal diameter of the largest nodule （P 〈 0.0001）, time of LT （P 〈 0.0001）, tumor differentiation （P 〈 0.0001）, use of anti-lymphocyte antibody （ATG） or anti-CD3 antibody （OKT3） （P = 0.005）, preoperative portal thrombosis （P = 0.06） and the number of nodules （P = 0.06）. CONCLUSION： This study 展开更多
Background/Aims: Whether primary biliary cirrhosis (PBC) autoimmune hepatitis (AIH) overlap syndrome requires immunosuppressive therapy in addition to ursodeoxycholic acid (UDCA) is a controversial issue. Methods: Sev...Background/Aims: Whether primary biliary cirrhosis (PBC) autoimmune hepatitis (AIH) overlap syndrome requires immunosuppressive therapy in addition to ursodeoxycholic acid (UDCA) is a controversial issue. Methods: Seventeen patients with simultaneous form of strictly defined overlap were followed for 7.5 years. First-line treatment was UDCA alone (UDCA) in 11 and combination of immunosuppressors and UDCA (UDCA+ IS) in 6. Results: Characteristics at presentation were not significantly different between the 2 groups. In the UDCA+ IS group (f-up 7.3 years), biochemical response in terms of AIH features (ALT< 2ULN and IgG< 16 g/L) was achieved in 4/6 and fibrosis did not progress. In the UDCA group, biochemical response was observed in three patients together with stable or decreased fibrosis (f-up 4.5 years) whereas the eight others were non-responders with increased fibrosis in four (f-up 1.6 years). Seven of these eight patients subsequently received combined therapy for 3 years. Biochemical response was obtained in 6/7 and no further increase of fibrosis was demonstrated. Overall, fibrosis progression in non-cirrhotic patients occurred more frequently under UDCA monotherapy (4/8) than under combined therapy (0/6) (P=0.04). Conclusions: Combination of UDCA and immunosuppressors appears to be the best therapeutic option for strictly defined PBC-AIH overlap syndrome.展开更多
Background Hepatic encephalopathy(HE)is highly prevalent in patients with liver diseases.The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation.However,some data suggest...Background Hepatic encephalopathy(HE)is highly prevalent in patients with liver diseases.The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation.However,some data suggest altered functioning of the blood–brain barrier(BBB).Assessing BBB function is challenging in clinical practice and at the bedside.Protein-S-100 Beta(PS100-Beta)could be a useful peripheral marker of BBB permeability in HE.This study aimed to assess plasmatic PS100-Beta levels in a prospective cohort of patients admitted to the intensive care unit(ICU)with decompensated cirrhosis with and without overt HE.Methods We retrospectively evaluated a prospective cohort of cirrhotic patients admitted to the ICU from October 2013 to September 2015 that had an available plasmatic PS100-Beta measurement.Patients with previous neurological impairment or limitation of intensive or resuscitative measures were excluded.Overt HE was defined as West-Haven grades 2 to 4.The patients were compared to a control cohort of outpatient clinic cirrhotic and non-cirrhotic patients explored for isolated elevation of liver enzymes.After ICU discharge,the patients were followed for at least 3 months for the occurrence of overt HE.Adverse outcomes(liver transplantation or death)were collected.The ability of PS100-Beta–in combination with other factors–to predict overt HE was evaluated in a multivariate analysis using logistic regression.Likelihood ratios were used to determine the effects and calculate odds ratios(OR).Survival analysis was performed by using the Kaplan–Meier method and survival between groups was compared using a Log-rank test.Results A total of 194 ICU patients and 207 outpatients were included in the study.Increased levels of plasmatic PS100-Beta were detected in the ICU decompensated cirrhotic patients compared with the outpatients([0.15±0.01]mg/L vs.[0.08±0]mg/L,P<0.001).ICU patients with overt HE had higher levels of PS100-Beta([0.19±0.03]mg/L)compared with the ICU patients without overt HE([0.13�展开更多
Hepatitis B and human immunodeficiency virus(HBV and HIV)infection share transmission patterns and risk factors,which explains high prevalence of chronic HBV infection in HIV infected patients.The natural course of HB...Hepatitis B and human immunodeficiency virus(HBV and HIV)infection share transmission patterns and risk factors,which explains high prevalence of chronic HBV infection in HIV infected patients.The natural course of HBV disease is altered by the HIV infection with less chance to clear acute HBV infection,faster progression to cirrhosis and higher risk of liver-related death in HIVHBV co-infected patients than in HBV mono-infected ones.HIV infected patients with chronic hepatitis B should be counseled for liver damage and surveillance of chronic hepatitis B should be performed to screen early hepatocellular carcinoma.Noninvasive tools are now available to evaluate liver fibrosis.Isolated hepatitis B core antibodies(anti-HBc)are a good predictive marker of occult HBV infection.Still the prevalence and significance of occult HBV infection is controversial,but its screening may be important in the management of antiretroviral therapy.Vaccination against HBV infection is recommended in non-immune HIV patients.The optimal treatment for almost all HIV-HBV co-infectedpatients should contain tenofovir plus lamivudine or emtricitabine and treatment should not be stopped to avoid HBV reactivation.Long term tenofovir therapy may lead to significant decline in hepatitis B surface Antigen.The emergence of resistant HBV strains may compromise the HBV therapy and vaccine therapy.展开更多
Metabolomics is defined as the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification.It is an"omics"technique that...Metabolomics is defined as the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification.It is an"omics"technique that is situated downstream of genomics,transcriptomics and proteomics.Metabolomics is recognized as a promising technique in the field of systems biology for the evaluation of global metabolic changes.During the last decade,metabolomics approaches have become widely used in the study of liver diseases for the detection of early biomarkers and altered metabolic pathways.It is a powerful technique to improve our pathophysiological knowledge of various liver diseases.It can be a useful tool to help clinicians in the diagnostic process especially to distinguish malignant and non-malignant liver disease as well as to determine the etiology or severity of the liver disease.It can also assess therapeutic response or predict drug induced liver injury.Nevertheless,the usefulness of metabolomics is often not understood by clinicians,especially the concept of metabolomics profiling or fingerprinting.In the present work,after a concise description of the different techniques and processes used in metabolomics,we will review the main research on this subject by focusing specifically on in vitro proton nuclear magnetic resonance spectroscopy based metabolomics approaches in human studies.We will first consider the clinical point of view enlighten physicians on this new approach and emphasis its future use in clinical"routine".展开更多
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 o...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 p = 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) ≥2,0.95 for F ≥3 and 0.96 for F = 4. Optimal stiffness cutoff values of 7.3, 9.8, and 17.3 kPa showed F ≥2, F ≥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.展开更多
AIMTo describe factors associated with treatment failure and frequency of resistance-associated substitutions （RAS）.METHODSHuman immunodefciency virus （HIV）/hepatitis C virus （HCV） coinfected patients starting a...AIMTo describe factors associated with treatment failure and frequency of resistance-associated substitutions （RAS）.METHODSHuman immunodefciency virus （HIV）/hepatitis C virus （HCV） coinfected patients starting a first direct-acting antiviral （DAA） regimen before February 2016 and included in the French ANRS CO13 HEPAVIH cohort were eligible. Failure was defned as： （1） non-response [HCV-RNA remained detectable during treatment, at end of treatment （EOT）]; and （2） relapse （HCV-RNA suppressed at EOT but detectable thereafter）. Sequencing analysis was performed to describe prevalence of drug class-specifc RAS. Factors associated with failure were determined using logistic regression models.RESULTSAmong 559 patients, 77% had suppressed plasmaHIV-RNA 〈 50 copies/mL at DAA treatment initiation41% were cirrhotic, and 68% were HCV treatmentexperienced. Virological treatment failures occurred in22 patients and were mainly relapses （17, 77%） thenundefined failures （3, 14%） and non-responses （29%）. Mean treatment duration was 16 wk overall. Posttreatment NS3, NS5A or NS5B RAS were detected in10/14 patients with samples available for sequencinganalysis. After adjustment for age, sex, ribavirin useHCV genotype and treatment duration, low platelecount was the only factor signifcantly associated with ahigher risk of failure （OR： 6.5; 95%CI： 1.8-22.6）. CONCLUSIONOnly 3.9% HIV-HCV coinfected patients failed DAAregimens and RAS were found in 70% of those failingLow platelet count was independently associated withvirological failure.展开更多
Refractory ascites(RA)is a frequent and life-threatening complication of cirrhosis.In selected patients with RA,transjugular intrahepatic portosystemic shunt(TIPS)placement and liver transplantation(LT)are currently c...Refractory ascites(RA)is a frequent and life-threatening complication of cirrhosis.In selected patients with RA,transjugular intrahepatic portosystemic shunt(TIPS)placement and liver transplantation(LT)are currently considered the best therapeutic alternatives to repeated large volume paracentesis.In patients with a contraindication to TIPS or LT,the alfapump®system(Sequana Medical,Ghent,Belgium)has been developed to reduce the need for iterative paracentesis,and consequently to improve the quality of life and nutritional status.We report here recent data on technical progress made since the first implantation,the efficacy and tolerance of the device,the position of the pump in the therapeutic arsenal for refractory ascites,and the grey areas that remain to be clarified regarding the optimal selection of patients who are potential candidates for this treatment.展开更多
Determining the prognosis of cirrhotic patients is not an easy task. Prognostic scores, like Child-Pugh and Model of End-stage Liver Disease scores, are commonly used by hepatologists, but do not always reflect superi...Determining the prognosis of cirrhotic patients is not an easy task. Prognostic scores, like Child-Pugh and Model of End-stage Liver Disease scores, are commonly used by hepatologists, but do not always reflect superimposed events that may strongly influence the prognosis. Among them, bacterial intestinal translocation is a key phenomenon for the development of cirrhosis-related complications. Several biological variables(C-reactive protein, serum free cortisol, copeptin, von Willebrand factor antigen) are surrogates of "inflammatory stress" and have recently been identified as potential prognostic markers in cirrhotic patients. Most of these above mentioned markers were investigated in pilot studies with sometimes a modest sample size but allow us to catch a glimpse of the pathophysiological mechanisms leading to the worsening of cirrhosis. These new data should generate further well-designed studies to better assess the benefit for liver function of preventing intestinal bacterial translocation and microvascular thrombosis. The control of infection is vital and among all actors of immunity, vitamin D also appears to act as an anti-infective agent and therefore has probably a prognostic value.展开更多
Hepatocellular carcinoma is one of the leading causes of death by cancer worldwide.Prognosis of hepatocellular carcinoma is determined by characteristics of the tumor and the surrounding cirrhotic liver.Several molecu...Hepatocellular carcinoma is one of the leading causes of death by cancer worldwide.Prognosis of hepatocellular carcinoma is determined by characteristics of the tumor and the surrounding cirrhotic liver.Several molecular signatures reflecting tumor biology and derived from tumor analyses predict early tumor recurrence and survival.In contrast,molecular signatures from cirrhotic non-tumor samples are enriched in immunity/inflammation related genes and could predict late tumor recurrence.Moreover,combination of clinical,pathological,and molecular features may refine prognosis prediction in these patients.Finally,molecular signatures from both tumor and non-tumor tissues will be helpful in the future to guide treatments in different clinical settings.展开更多
BACKGROUND Liver fibrosis can result in end-stage liver failure and death.AIM To examine human liver fibrogenesis and anti-fibrotic therapies,we evaluated the three dimensional ex vivo liver slice(LS)model.METHODS Fib...BACKGROUND Liver fibrosis can result in end-stage liver failure and death.AIM To examine human liver fibrogenesis and anti-fibrotic therapies,we evaluated the three dimensional ex vivo liver slice(LS)model.METHODS Fibrotic liver samples(F0 to F4 fibrosis stage according to the METAVIR score)were collected from patients after liver resection.Human liver slices(HLS)were cultivated for up to 21 days.Hepatitis C virus(HCV)infection,alcohol(ethanol stimulation)and steatosis(palmitate stimulation)were examined in fibrotic(F2 to F4)liver slices infected(or not)with HCV.F0-F1 HLS were used as controls.At day 0,either ursodeoxycholic acid(choleretic and hepatoprotective properties)and/or α-tocopherol(antioxidant properties)were added to standard of care on HLS and fibrotic liver slices,infected(or not)with HCV.Expression of the biomarkers of fibrosis and the triglyceride production were checked by quantitative reverse transcription polymerase chain reaction and/or enzymelinked immunosorbent assay.RESULTS The cultures were viable in vitro for 21 days allowing to study fibrosis inducers and to estimate the effect of anti-fibrotic drugs.Expression of the biomarkers of fibrosis and the progression to steatosis(estimated by triglycerides production)was increased with the addition of HCV and/or ethanol or palmitate.From day 15 of the follow-up studies,a significant decrease of both transforming growth factorβ-1 and Procol1A1 expression and triglycerides production was observed when a combined anti-fibrotic treatment was applied on HCV infected F2-F4 LS cultures.CONCLUSION These results show that the human three dimensional ex vivo model effectively reflects the in vivo processes in damaged human liver(viral,alcoholic,nonalcoholic steatohepatitis liver diseases)and provides the proof of concept that the LS examined model permits a rapid evaluation of new anti-fibrotic therapies when used alone or in combination.展开更多
Most of patients with hepatocellular carcinoma(HCC),are diagnosed at an advanced-stage explaining the poor prognosis of this cancer with a median survival without treatment around 8 months(1-3).Currently,two systemic ...Most of patients with hepatocellular carcinoma(HCC),are diagnosed at an advanced-stage explaining the poor prognosis of this cancer with a median survival without treatment around 8 months(1-3).Currently,two systemic multi-kinase inhibitors with anti-proliferative and antiangiogenic effects are available as first line treatments in advanced HCC.The first one,Sorafenib,was the only available systemic treatment available during one decade and was associated with an improvement of overall survival of around 3 months compared to placebo(4,5).The second one,lenvatinib,showed a similar median overall survival compared to Sorafenib in a non-inferiority phase-3 trial(6).No second line was available during several years due to toxicity or absence of efficacy of the different drugs tested in multicentric phase 3 randomized controlled trials.展开更多
Global prevalence of non-alcoholic fatty liver disease(NAFLD)and of NAFLD-hepatocellular carcinoma(HCC)is estimated to grow in the next years.The burden of NAFLD and the evidence that NAFLD-HCC arises also in noncirrh...Global prevalence of non-alcoholic fatty liver disease(NAFLD)and of NAFLD-hepatocellular carcinoma(HCC)is estimated to grow in the next years.The burden of NAFLD and the evidence that NAFLD-HCC arises also in noncirrhotic patients,explain the urgent need of a better characterization of the molecular mechanisms involved in NAFLD progression.Obesity and diabetes cause a chronic inflammatory state which favors changes in serum cytokines and adipokines,an increase in oxidative stress,DNA damage,and the activation of multiple signaling pathways involved in cell proliferation.Moreover,a role in promoting NAFLD-HCC has been highlighted in the innate and adaptive immune system,dysbiosis,and alterations in bile acids metabolism.Several dietary,genetic,or combined mouse models have been used to study nonalcoholic steatohepatitis(NASH)development and its progression to HCC,but models that fully recapitulate the biological and prognostic features of human NASH are still lacking.In humans,four single nucleotide polymorphisms(PNPLA3,TM6SF2,GCKR,and MBOAT7)have been linked to the development of both NASH and HCC in cirrhotic and non-cirrhotic patients,whereas HSD17B13 polymorphism has a protective effect.In addition,higher rates of somatic ACVR2A mutations and a novel mutational signature have been recently discovered in NASH-HCC patients.The knowledge of the molecular pathogenesis of NAFLD-HCC will be helpful to personalized screening programs and allow for primary and secondary chemopreventive treatments for NAFLD patients who are more likely to progress to HCC.展开更多
Porphyria cutanea tarda (PCT) is a metabolic disorder characterized by a reduced hepatic activity of uroporphynogen decarboxylase (URO-D), an enzyme of the heme synthesis. The clinical features of PCT may be brought i...Porphyria cutanea tarda (PCT) is a metabolic disorder characterized by a reduced hepatic activity of uroporphynogen decarboxylase (URO-D), an enzyme of the heme synthesis. The clinical features of PCT may be brought into light by hepatic injury induced by hepatitis C virus (HCV). A significant association between HCV and PCT is well recognized, although the role of HCV in the appearance of PCT is still debated because confounding factors often coexist, such as alcohol, other viruses, drugs or iron overload (Gisbert et al. J Hepatol 2003;39:620-627). HCV therapy may improve PCT although PCT was rarely reported as a de novo occurrence during an interferon/ribavirin therapy (Jessner et al. Hepatology 2002;36:1301-1302); here, we describe two such other cases.展开更多
AIM: To study the efficacy and factors associated with a sustained virological response (SVR) in chronic hepatitis C (CHC) relapsing patients. METHODS: Out of 1228 CHC patients treated with pegylated interferon (PEG-I...AIM: To study the efficacy and factors associated with a sustained virological response (SVR) in chronic hepatitis C (CHC) relapsing patients. METHODS: Out of 1228 CHC patients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV), 165 (13%) had a relapse. Among these, 62 patients were retreated with PEG-IFN-2a or-2b and RBV. Clinical, biological, virological and histological data were collected. Initial doses and treatment modifications were recorded. The efficacy of retreatment and predictive factors for SVR were analyzed. RESULTS: An SVR was achieved in 42% of patients. SVR was higher in young (< 50 years) (61%) than old patients (27%) (P = 0.007), and in genotype 2 or 3 (57%) than in genotype 1 or 4 (28%) patients (P = 0.023). Prolonging therapy for at least 24 wk more than the previous course was associated with higher SVR rates (53% vs 28%, P = 0.04). Also, a better SVR rate was observed with RBV dose/body weight > 15.2 mg/kg per day (70% vs 35%, P = 0.04). In logistic regression, predictors of a response were age (P = 0.018), genotype (P = 0.048) and initial RBV dose/body weight (P = 0.022). None of the patients without a complete early virological response achieved an SVR (negative predictive value = 100%). CONCLUSION: Retreatment with PEG-IFN/RBV is effective in genotype 2 or 3 relapsers, especially in young patients. A high dose of RBV seems to be important for the retreatment response.展开更多
The epidemiological features of hepatocellular carcinoma have changed significantly in the last decades.While for a long-time viral hepatitis and alcohol consumption have been the leading risk factors,the current spre...The epidemiological features of hepatocellular carcinoma have changed significantly in the last decades.While for a long-time viral hepatitis and alcohol consumption have been the leading risk factors,the current spread of obesity and type 2 diabetes has contributed to the emergence of non-alcoholic fatty liver disease(NAFLD)worldwide,which has become the leading chronic liver disease as well as one of the main etiologies of hepatocellular carcinoma(HCC),especially in western countries.In this review,we resume the latest data about the epidemiology of metabolic liver disease and HCC arising from NAFLD and discuss the main clinical and molecular features leading to the progression of liver disease and the development of HCC in NAFLD.The emerging concept of metabolic associated fatty liver disease and its association with the development of HCC are also introduced.展开更多
We described a 59-year-old male patient who underwent liver transplantation in 1989 for hepatocellular carcinoma （HCC） complicating hepatitis B virus （HBV） cirrhosis. In 2001 （12 years after liver transplantation...We described a 59-year-old male patient who underwent liver transplantation in 1989 for hepatocellular carcinoma （HCC） complicating hepatitis B virus （HBV） cirrhosis. In 2001 （12 years after liver transplantation）, he developed a lung metastasis of HCC without intrahepatic recurrence and the resection was done. In July 2003, he was symptom free without any recurrence. HCC metastasis can develop even after a very long time of liver transplantation. Many HCCs grow slowly, and the growth rate of recurrent tumors in patients receiving immunosuppressive therapy is significantly greater than that of those who do not receive immunosuppressive therapy.展开更多
Hepatocellular carcinoma（HCC）is one of the leading causes of cancer related death in Asia and Africa（1）.It reflects the high burden of hepatitis B virus（HBV）infection in these areas.Curative treatments of HCC as...Hepatocellular carcinoma（HCC）is one of the leading causes of cancer related death in Asia and Africa（1）.It reflects the high burden of hepatitis B virus（HBV）infection in these areas.Curative treatments of HCC as radiofrequency ablation and resection are impaired by a high rate of tumor recurrence.However,most of the time,HCC is frequently diagnosed at advanced stages where only展开更多
文摘Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare cholestatic liver disease. Such liver disease can get worse by female hormone disorder. Albumin dialysis or Molecular Adsorbent Recirculating System (MARS) has been reported to reverse severe cholestasis-linked pruritus. Here, we report the first use of MARS during a spontaneous pregnancy and its successful outcome in a patient with PFIC3 and intractable pruritus. Albumin dialysis could be considered as a pregnancy-saving procedure in pregnant women with severe cholestasis and refractory pruritus.
文摘Importance:Liver transplantation(LT)is a life-saving therapy for patients with end-stage liver disease and with acute liver failure,and it is associated with excellent outcomes and survival rates at 1 and 5 years.The incidence of biliary complications(BCs)after LT is reported to range from 5%to 20%,most of them occurring in the first three months,although they can occur also several years after transplantation.Objective:The aim of this review is to summarize the available evidences on pathophysiology,risk factors,diagnosis and therapeutic management of BCs after LT.Evidence Review:a literature review was performed of papers on this topic focusing on risk factors,classifications,diagnosis and treatment Findings:Principal risk factors include surgical techniques and donor’s characteristics for biliary leakage and anastomotic biliary strictures and vascular alterations for non-anastomotic biliary strictures.MRCP is the gold standard both for intra-and extrahepatic BCs,while invasive cholangiography should be restricted for therapeutic uses or when MRCP is equivocal.About treatment,endoscopic techniques are the first line of treatment with success rates of 70-100%.The combined success rate of ERCP and PTBD overcome 90%of cases.Biliary leaks often resolve spontaneously,or with the positioning of a stent in ERCP for major bile leaks Conclusions and Relevance:BCs influence morbidity and mortality after LT,therefore further evidences are needed to identify novel possible risk factors,to understand if an immunological status that could lead to their development exists and to compare the effectiveness of innovative surgical and machine perfusion techniques.
文摘AIM： To assess pre-orthotopic liver transplantation （OLT） factors that could be evaluated pre-operatively or controlled post-operatively associated with hepatocellular carcinoma （HCC） recurrence and disease-free survival after liver transplantation （LT）.METHODS： Four hundred and twelve patients transplanted for HCC between 1988 and 1998 in 14 French centers, who survived the postoperative period were studied. Kaplan Meier estimates were calculated for 24 variables potentially associated with recurrence of HCC. Uni- and multivariate analyses were conducted to identify independent predictors of recurrence. RESULTS： Overall 5-year disease-free survival was 57.1%. By univariate analysis, variables associated with disease-free survival were： presence of cirrhosis （P = 0.001）, etiology of liver disease （P = 0.03）, α fetoprotein level （〈 200, 200 to 2000, or 〉 2000; P 〈 0.0001）, y-GT activity （N, N to 2N or 〉 2N; P = 0.02）, the number of nodules （1, 2-3 or ≥ 4; P = 0.02）, maximal diameter of the largest nodule （〈 3 cm, 3 to 5 cm or 〉 5 cm; P 〈 0.0001）, the sum of the diameter of the nodules （〈 3 cm, 3 to 5 cm, 5 to 10 cm or 〉10 cm; P 〈 0.0001）, bilobar location （P = 0.01）, preoperative portal thrombosis （P 〈 0.0001）, peri-operative treatment of the tumor （P = 0.002） and chemoembolization （P = 0.03）, tumor differentiation （P = 0.01）, initial type of calcineurin inhibitor （P = 0.003）, the use of antilymphocyte antibodies （P = 0.02）, rejection episodes （P = 0.003） and period of LT （P 〈 0.0001）. By multivariate analysis, 6 variables were independently associated with HCC recurrence： maximal diameter of the largest nodule （P 〈 0.0001）, time of LT （P 〈 0.0001）, tumor differentiation （P 〈 0.0001）, use of anti-lymphocyte antibody （ATG） or anti-CD3 antibody （OKT3） （P = 0.005）, preoperative portal thrombosis （P = 0.06） and the number of nodules （P = 0.06）. CONCLUSION： This study
文摘Background/Aims: Whether primary biliary cirrhosis (PBC) autoimmune hepatitis (AIH) overlap syndrome requires immunosuppressive therapy in addition to ursodeoxycholic acid (UDCA) is a controversial issue. Methods: Seventeen patients with simultaneous form of strictly defined overlap were followed for 7.5 years. First-line treatment was UDCA alone (UDCA) in 11 and combination of immunosuppressors and UDCA (UDCA+ IS) in 6. Results: Characteristics at presentation were not significantly different between the 2 groups. In the UDCA+ IS group (f-up 7.3 years), biochemical response in terms of AIH features (ALT< 2ULN and IgG< 16 g/L) was achieved in 4/6 and fibrosis did not progress. In the UDCA group, biochemical response was observed in three patients together with stable or decreased fibrosis (f-up 4.5 years) whereas the eight others were non-responders with increased fibrosis in four (f-up 1.6 years). Seven of these eight patients subsequently received combined therapy for 3 years. Biochemical response was obtained in 6/7 and no further increase of fibrosis was demonstrated. Overall, fibrosis progression in non-cirrhotic patients occurred more frequently under UDCA monotherapy (4/8) than under combined therapy (0/6) (P=0.04). Conclusions: Combination of UDCA and immunosuppressors appears to be the best therapeutic option for strictly defined PBC-AIH overlap syndrome.
基金supported by the Fondation pour le Recherche Médicale(grant number:EQU202003010517).
文摘Background Hepatic encephalopathy(HE)is highly prevalent in patients with liver diseases.The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation.However,some data suggest altered functioning of the blood–brain barrier(BBB).Assessing BBB function is challenging in clinical practice and at the bedside.Protein-S-100 Beta(PS100-Beta)could be a useful peripheral marker of BBB permeability in HE.This study aimed to assess plasmatic PS100-Beta levels in a prospective cohort of patients admitted to the intensive care unit(ICU)with decompensated cirrhosis with and without overt HE.Methods We retrospectively evaluated a prospective cohort of cirrhotic patients admitted to the ICU from October 2013 to September 2015 that had an available plasmatic PS100-Beta measurement.Patients with previous neurological impairment or limitation of intensive or resuscitative measures were excluded.Overt HE was defined as West-Haven grades 2 to 4.The patients were compared to a control cohort of outpatient clinic cirrhotic and non-cirrhotic patients explored for isolated elevation of liver enzymes.After ICU discharge,the patients were followed for at least 3 months for the occurrence of overt HE.Adverse outcomes(liver transplantation or death)were collected.The ability of PS100-Beta–in combination with other factors–to predict overt HE was evaluated in a multivariate analysis using logistic regression.Likelihood ratios were used to determine the effects and calculate odds ratios(OR).Survival analysis was performed by using the Kaplan–Meier method and survival between groups was compared using a Log-rank test.Results A total of 194 ICU patients and 207 outpatients were included in the study.Increased levels of plasmatic PS100-Beta were detected in the ICU decompensated cirrhotic patients compared with the outpatients([0.15±0.01]mg/L vs.[0.08±0]mg/L,P<0.001).ICU patients with overt HE had higher levels of PS100-Beta([0.19±0.03]mg/L)compared with the ICU patients without overt HE([0.13�
文摘Hepatitis B and human immunodeficiency virus(HBV and HIV)infection share transmission patterns and risk factors,which explains high prevalence of chronic HBV infection in HIV infected patients.The natural course of HBV disease is altered by the HIV infection with less chance to clear acute HBV infection,faster progression to cirrhosis and higher risk of liver-related death in HIVHBV co-infected patients than in HBV mono-infected ones.HIV infected patients with chronic hepatitis B should be counseled for liver damage and surveillance of chronic hepatitis B should be performed to screen early hepatocellular carcinoma.Noninvasive tools are now available to evaluate liver fibrosis.Isolated hepatitis B core antibodies(anti-HBc)are a good predictive marker of occult HBV infection.Still the prevalence and significance of occult HBV infection is controversial,but its screening may be important in the management of antiretroviral therapy.Vaccination against HBV infection is recommended in non-immune HIV patients.The optimal treatment for almost all HIV-HBV co-infectedpatients should contain tenofovir plus lamivudine or emtricitabine and treatment should not be stopped to avoid HBV reactivation.Long term tenofovir therapy may lead to significant decline in hepatitis B surface Antigen.The emergence of resistant HBV strains may compromise the HBV therapy and vaccine therapy.
文摘Metabolomics is defined as the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification.It is an"omics"technique that is situated downstream of genomics,transcriptomics and proteomics.Metabolomics is recognized as a promising technique in the field of systems biology for the evaluation of global metabolic changes.During the last decade,metabolomics approaches have become widely used in the study of liver diseases for the detection of early biomarkers and altered metabolic pathways.It is a powerful technique to improve our pathophysiological knowledge of various liver diseases.It can be a useful tool to help clinicians in the diagnostic process especially to distinguish malignant and non-malignant liver disease as well as to determine the etiology or severity of the liver disease.It can also assess therapeutic response or predict drug induced liver injury.Nevertheless,the usefulness of metabolomics is often not understood by clinicians,especially the concept of metabolomics profiling or fingerprinting.In the present work,after a concise description of the different techniques and processes used in metabolomics,we will review the main research on this subject by focusing specifically on in vitro proton nuclear magnetic resonance spectroscopy based metabolomics approaches in human studies.We will first consider the clinical point of view enlighten physicians on this new approach and emphasis its future use in clinical"routine".
文摘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 p = 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) ≥2,0.95 for F ≥3 and 0.96 for F = 4. Optimal stiffness cutoff values of 7.3, 9.8, and 17.3 kPa showed F ≥2, F ≥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.
基金Supported by Inserm-ANRS(French National Institute for Health and Medical Research-ANRS/France REcherche Nord and Sud Sida-hiv Hépatites)
文摘AIMTo describe factors associated with treatment failure and frequency of resistance-associated substitutions （RAS）.METHODSHuman immunodefciency virus （HIV）/hepatitis C virus （HCV） coinfected patients starting a first direct-acting antiviral （DAA） regimen before February 2016 and included in the French ANRS CO13 HEPAVIH cohort were eligible. Failure was defned as： （1） non-response [HCV-RNA remained detectable during treatment, at end of treatment （EOT）]; and （2） relapse （HCV-RNA suppressed at EOT but detectable thereafter）. Sequencing analysis was performed to describe prevalence of drug class-specifc RAS. Factors associated with failure were determined using logistic regression models.RESULTSAmong 559 patients, 77% had suppressed plasmaHIV-RNA 〈 50 copies/mL at DAA treatment initiation41% were cirrhotic, and 68% were HCV treatmentexperienced. Virological treatment failures occurred in22 patients and were mainly relapses （17, 77%） thenundefined failures （3, 14%） and non-responses （29%）. Mean treatment duration was 16 wk overall. Posttreatment NS3, NS5A or NS5B RAS were detected in10/14 patients with samples available for sequencinganalysis. After adjustment for age, sex, ribavirin useHCV genotype and treatment duration, low platelecount was the only factor signifcantly associated with ahigher risk of failure （OR： 6.5; 95%CI： 1.8-22.6）. CONCLUSIONOnly 3.9% HIV-HCV coinfected patients failed DAAregimens and RAS were found in 70% of those failingLow platelet count was independently associated withvirological failure.
文摘Refractory ascites(RA)is a frequent and life-threatening complication of cirrhosis.In selected patients with RA,transjugular intrahepatic portosystemic shunt(TIPS)placement and liver transplantation(LT)are currently considered the best therapeutic alternatives to repeated large volume paracentesis.In patients with a contraindication to TIPS or LT,the alfapump®system(Sequana Medical,Ghent,Belgium)has been developed to reduce the need for iterative paracentesis,and consequently to improve the quality of life and nutritional status.We report here recent data on technical progress made since the first implantation,the efficacy and tolerance of the device,the position of the pump in the therapeutic arsenal for refractory ascites,and the grey areas that remain to be clarified regarding the optimal selection of patients who are potential candidates for this treatment.
文摘Determining the prognosis of cirrhotic patients is not an easy task. Prognostic scores, like Child-Pugh and Model of End-stage Liver Disease scores, are commonly used by hepatologists, but do not always reflect superimposed events that may strongly influence the prognosis. Among them, bacterial intestinal translocation is a key phenomenon for the development of cirrhosis-related complications. Several biological variables(C-reactive protein, serum free cortisol, copeptin, von Willebrand factor antigen) are surrogates of "inflammatory stress" and have recently been identified as potential prognostic markers in cirrhotic patients. Most of these above mentioned markers were investigated in pilot studies with sometimes a modest sample size but allow us to catch a glimpse of the pathophysiological mechanisms leading to the worsening of cirrhosis. These new data should generate further well-designed studies to better assess the benefit for liver function of preventing intestinal bacterial translocation and microvascular thrombosis. The control of infection is vital and among all actors of immunity, vitamin D also appears to act as an anti-infective agent and therefore has probably a prognostic value.
文摘Hepatocellular carcinoma is one of the leading causes of death by cancer worldwide.Prognosis of hepatocellular carcinoma is determined by characteristics of the tumor and the surrounding cirrhotic liver.Several molecular signatures reflecting tumor biology and derived from tumor analyses predict early tumor recurrence and survival.In contrast,molecular signatures from cirrhotic non-tumor samples are enriched in immunity/inflammation related genes and could predict late tumor recurrence.Moreover,combination of clinical,pathological,and molecular features may refine prognosis prediction in these patients.Finally,molecular signatures from both tumor and non-tumor tissues will be helpful in the future to guide treatments in different clinical settings.
基金the Institut National de la Santéet de la Recherche Médicale(INSERM,France)and by Institut Pasteur(Paris,France)Daria Kartasheva-Ebertz received a PhD Fellowship from Assistance Publique-Hôpitaux de Paris(APHP,France).
文摘BACKGROUND Liver fibrosis can result in end-stage liver failure and death.AIM To examine human liver fibrogenesis and anti-fibrotic therapies,we evaluated the three dimensional ex vivo liver slice(LS)model.METHODS Fibrotic liver samples(F0 to F4 fibrosis stage according to the METAVIR score)were collected from patients after liver resection.Human liver slices(HLS)were cultivated for up to 21 days.Hepatitis C virus(HCV)infection,alcohol(ethanol stimulation)and steatosis(palmitate stimulation)were examined in fibrotic(F2 to F4)liver slices infected(or not)with HCV.F0-F1 HLS were used as controls.At day 0,either ursodeoxycholic acid(choleretic and hepatoprotective properties)and/or α-tocopherol(antioxidant properties)were added to standard of care on HLS and fibrotic liver slices,infected(or not)with HCV.Expression of the biomarkers of fibrosis and the triglyceride production were checked by quantitative reverse transcription polymerase chain reaction and/or enzymelinked immunosorbent assay.RESULTS The cultures were viable in vitro for 21 days allowing to study fibrosis inducers and to estimate the effect of anti-fibrotic drugs.Expression of the biomarkers of fibrosis and the progression to steatosis(estimated by triglycerides production)was increased with the addition of HCV and/or ethanol or palmitate.From day 15 of the follow-up studies,a significant decrease of both transforming growth factorβ-1 and Procol1A1 expression and triglycerides production was observed when a combined anti-fibrotic treatment was applied on HCV infected F2-F4 LS cultures.CONCLUSION These results show that the human three dimensional ex vivo model effectively reflects the in vivo processes in damaged human liver(viral,alcoholic,nonalcoholic steatohepatitis liver diseases)and provides the proof of concept that the LS examined model permits a rapid evaluation of new anti-fibrotic therapies when used alone or in combination.
文摘Most of patients with hepatocellular carcinoma(HCC),are diagnosed at an advanced-stage explaining the poor prognosis of this cancer with a median survival without treatment around 8 months(1-3).Currently,two systemic multi-kinase inhibitors with anti-proliferative and antiangiogenic effects are available as first line treatments in advanced HCC.The first one,Sorafenib,was the only available systemic treatment available during one decade and was associated with an improvement of overall survival of around 3 months compared to placebo(4,5).The second one,lenvatinib,showed a similar median overall survival compared to Sorafenib in a non-inferiority phase-3 trial(6).No second line was available during several years due to toxicity or absence of efficacy of the different drugs tested in multicentric phase 3 randomized controlled trials.
基金Nault JC received research grant from Bayer and Ipsen.
文摘Global prevalence of non-alcoholic fatty liver disease(NAFLD)and of NAFLD-hepatocellular carcinoma(HCC)is estimated to grow in the next years.The burden of NAFLD and the evidence that NAFLD-HCC arises also in noncirrhotic patients,explain the urgent need of a better characterization of the molecular mechanisms involved in NAFLD progression.Obesity and diabetes cause a chronic inflammatory state which favors changes in serum cytokines and adipokines,an increase in oxidative stress,DNA damage,and the activation of multiple signaling pathways involved in cell proliferation.Moreover,a role in promoting NAFLD-HCC has been highlighted in the innate and adaptive immune system,dysbiosis,and alterations in bile acids metabolism.Several dietary,genetic,or combined mouse models have been used to study nonalcoholic steatohepatitis(NASH)development and its progression to HCC,but models that fully recapitulate the biological and prognostic features of human NASH are still lacking.In humans,four single nucleotide polymorphisms(PNPLA3,TM6SF2,GCKR,and MBOAT7)have been linked to the development of both NASH and HCC in cirrhotic and non-cirrhotic patients,whereas HSD17B13 polymorphism has a protective effect.In addition,higher rates of somatic ACVR2A mutations and a novel mutational signature have been recently discovered in NASH-HCC patients.The knowledge of the molecular pathogenesis of NAFLD-HCC will be helpful to personalized screening programs and allow for primary and secondary chemopreventive treatments for NAFLD patients who are more likely to progress to HCC.
文摘Porphyria cutanea tarda (PCT) is a metabolic disorder characterized by a reduced hepatic activity of uroporphynogen decarboxylase (URO-D), an enzyme of the heme synthesis. The clinical features of PCT may be brought into light by hepatic injury induced by hepatitis C virus (HCV). A significant association between HCV and PCT is well recognized, although the role of HCV in the appearance of PCT is still debated because confounding factors often coexist, such as alcohol, other viruses, drugs or iron overload (Gisbert et al. J Hepatol 2003;39:620-627). HCV therapy may improve PCT although PCT was rarely reported as a de novo occurrence during an interferon/ribavirin therapy (Jessner et al. Hepatology 2002;36:1301-1302); here, we describe two such other cases.
基金Supported by Assistance publique-H pitaux de Paris, IN-SERM U773-CRB3 and University Paris-DiderotFees from Roche, Schering Plough, Novartis, Gilead Sciences, BMS,MSD, Vertex, Tibotec, Biolex, to Marcellin PZymmogenetics and grants from Gilead Sciences, Roche and Schering Plough
文摘AIM: To study the efficacy and factors associated with a sustained virological response (SVR) in chronic hepatitis C (CHC) relapsing patients. METHODS: Out of 1228 CHC patients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV), 165 (13%) had a relapse. Among these, 62 patients were retreated with PEG-IFN-2a or-2b and RBV. Clinical, biological, virological and histological data were collected. Initial doses and treatment modifications were recorded. The efficacy of retreatment and predictive factors for SVR were analyzed. RESULTS: An SVR was achieved in 42% of patients. SVR was higher in young (< 50 years) (61%) than old patients (27%) (P = 0.007), and in genotype 2 or 3 (57%) than in genotype 1 or 4 (28%) patients (P = 0.023). Prolonging therapy for at least 24 wk more than the previous course was associated with higher SVR rates (53% vs 28%, P = 0.04). Also, a better SVR rate was observed with RBV dose/body weight > 15.2 mg/kg per day (70% vs 35%, P = 0.04). In logistic regression, predictors of a response were age (P = 0.018), genotype (P = 0.048) and initial RBV dose/body weight (P = 0.022). None of the patients without a complete early virological response achieved an SVR (negative predictive value = 100%). CONCLUSION: Retreatment with PEG-IFN/RBV is effective in genotype 2 or 3 relapsers, especially in young patients. A high dose of RBV seems to be important for the retreatment response.
文摘The epidemiological features of hepatocellular carcinoma have changed significantly in the last decades.While for a long-time viral hepatitis and alcohol consumption have been the leading risk factors,the current spread of obesity and type 2 diabetes has contributed to the emergence of non-alcoholic fatty liver disease(NAFLD)worldwide,which has become the leading chronic liver disease as well as one of the main etiologies of hepatocellular carcinoma(HCC),especially in western countries.In this review,we resume the latest data about the epidemiology of metabolic liver disease and HCC arising from NAFLD and discuss the main clinical and molecular features leading to the progression of liver disease and the development of HCC in NAFLD.The emerging concept of metabolic associated fatty liver disease and its association with the development of HCC are also introduced.
文摘We described a 59-year-old male patient who underwent liver transplantation in 1989 for hepatocellular carcinoma （HCC） complicating hepatitis B virus （HBV） cirrhosis. In 2001 （12 years after liver transplantation）, he developed a lung metastasis of HCC without intrahepatic recurrence and the resection was done. In July 2003, he was symptom free without any recurrence. HCC metastasis can develop even after a very long time of liver transplantation. Many HCCs grow slowly, and the growth rate of recurrent tumors in patients receiving immunosuppressive therapy is significantly greater than that of those who do not receive immunosuppressive therapy.
基金supported by HECAM (BPI), EBCI, INCa (Wnt HCC project). J-C.N.supported by a fellowship from INCa
文摘Hepatocellular carcinoma（HCC）is one of the leading causes of cancer related death in Asia and Africa（1）.It reflects the high burden of hepatitis B virus（HBV）infection in these areas.Curative treatments of HCC as radiofrequency ablation and resection are impaired by a high rate of tumor recurrence.However,most of the time,HCC is frequently diagnosed at advanced stages where only
