Prevalence, clinical significance and prognosis value of liver stiffness measurement anomalies in transthyretin cardiac amyloidosis.

Background - Laboratory liver anomalies are common in cardiac amyloidosis; however, their significance regarding liver stiffness is unknown. The aim of this study was to investigate the prevalence, clinical significance, and prognostic value of liver stiffness measurement (LSM) anomalies in transthyretin cardiac amyloidosis (ATTR-CA). Methods - Consecutive patients diagnosed with ATTR-CA who underwent liver stiffness assessment were included in the study. Demographic, clinical, laboratory, transthoracic echocardiography and liver stiffness data were retrospectively collected. LSM was obtained through either transient elastography or supersonic shear imaging. Patient cohort was divided in two groups according to a 10 kPa threshold. Follow up data were collected for the occurrence of hospitalization for heart failure and all-cause death. Results - Two hundred and eighty-four patients with ATTR-CA - 26 (9 %) hereditary variant ATTR, 258 (91 %) wild-type ATTR - were included. A LSM over 10 kPa was found in 4 (15 %) and 98 (38 %) patients with ATTRv and ATTRwt respectively (p = 0.02). Among patients with ATTRwt, high LSM was more frequent in advanced stages of ATTR-CA and was associated with increased risk of hospitalization for heart failure after multivariate analysis with a hazard ratio of 2.41 [1.05-5.55] (p = 0.04). Among patients with NYHA stage 1, 28 % presented high LSM associated with high NT-proBNP levels. Integration of high LSM with NT-proBNP and estimated glomerular filtration rate provided a better estimate of patient survival. Conclusion - LSM over 10 kPa is found in up to 36 % of patients with ATTR-CA and is associated with advanced stages of cardiomyopathy and increased risk of hospitalization for heart failure in ATTRwt patients.

Management of intrahepatic and perihilar cholangiocarcinomas: Guidelines of the French Association for the Study of the Liver (AFEF).

Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant primary liver cancer. iCCA may develop on an underlying chronic liver disease and its incidence is growing in relation with the epidemics of obesity and metabolic diseases. In contrast, perihilar cholangiocarcinoma (pCCA) may follow a history of chronic inflammatory diseases of the biliary tract. The initial management of CCAs is often complex and requires multidisciplinary expertise. The French Association for the Study of the Liver wished to organize guidelines in order to summarize the best evidence available about several key points in iCCA and pCCA. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe the epidemiology of CCA as well as how patients with iCCA or pCCA should be managed from diagnosis to treatment. The most recent developments of personalized medicine and use of targeted therapies are also highlighted.

Portal vein thrombosis: diagnosis, management, and endpoints for future clinical studies.

Portal vein thrombosis (PVT) refers to the development of a non-malignant obstruction of the portal vein, its branches, its radicles, or a combination. This Review first provides a comprehensive overview of all aspects of PVT, namely the specifics of the portal venous system, the risk factors for PVT, the pathophysiology of portal hypertension in PVT, the interest in non-invasive tests, as well as therapeutic approaches including the effect of treating risk factors for PVT or cause of cirrhosis, anticoagulation, portal vein recanalisation by interventional radiology, and prevention and management of variceal bleeding in patients with PVT. Specific issues are also addressed including portal cholangiopathy, mesenteric ischaemia and intestinal necrosis, quality of life, fertility, contraception and pregnancy, and PVT in children. This Review will then present endpoints for future clinical studies in PVT, both in patients with and without cirrhosis, agreed by a large panel of experts through a Delphi consensus process. These endpoints include classification of portal vein thrombus extension, classification of PVT evolution, timing of assessment of PVT, and global endpoints for studies on PVT including clinical outcomes. These endpoints will help homogenise studies on PVT and thus facilitate reporting, comparison between studies, and validation of future studies and trials on PVT.

Liver disease in germline mutations of telomere-related genes: Prevalence, clinical, radiological, pathological features, outcome, and risk factors.

BACKGROUND AND AIM: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases. APPROACH AND RESULTS: Retrospective multicenter analysis of liver disease (transaminases > 30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n = 1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological, and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease in 48% and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and HCC occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥ 3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group [80/396, (20%)], OR 12.9 (CI 95%: 7.8-21.3, p < 0.001). CONCLUSIONS: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild, they may be associated with severe disease. Porto-sinusoidal vascular disease and cirrhosis were the most frequent lesions, suggesting that the mechanism of action is multifactorial.

Effect of Prophylactic Antibiotics on Mortality in Severe Alcohol-Related Hepatitis: A Randomized Clinical Trial.

Importance: The benefits of prophylactic antibiotics for hospitalized patients with severe alcohol-related hepatitis are unclear. Objective: To determine the efficacy of amoxicillin-clavulanate, compared with placebo, on mortality in patients hospitalized with severe alcohol-related hepatitis and treated with prednisolone. Design, Setting, and Participants: Multicenter, randomized, double-blind clinical trial among patients with biopsy-proven severe alcohol-related hepatitis (Maddrey function score ≥32 and Model for End-stage Liver Disease [MELD] score ≥21) from June 13, 2015, to May 24, 2019, in 25 centers in France and Belgium. All patients were followed up for 180 days. Final follow-up occurred on November 19, 2019. Intervention: Patients were randomly assigned (1:1 allocation) to receive prednisolone combined with amoxicillin-clavulanate (n = 145) or prednisolone combined with placebo (n = 147). Main Outcome and Measures: The primary outcome was all-cause mortality at 60 days. Secondary outcomes were all-cause mortality at 90 and 180 days; incidence of infection, incidence of hepatorenal syndrome, and proportion of participants with a MELD score less than 17 at 60 days; and proportion of patients with a Lille score less than 0.45 at 7 days. Results: Among 292 randomized patients (mean age, 52.8 [SD, 9.2] years; 80 [27.4%] women) 284 (97%) were analyzed. There was no significant difference in 60-day mortality between participants randomized to amoxicillin-clavulanate and those randomized to placebo (17.3% in the amoxicillin-clavulanate group and 21.3% in the placebo group [P = .33]; between-group difference, -4.7% [95% CI, -14.0% to 4.7%]; hazard ratio, 0.77 [95% CI, 0.45-1.31]). Infection rates at 60 days were significantly lower in the amoxicillin-clavulanate group (29.7% vs 41.5%; mean difference, -11.8% [95% CI, -23.0% to -0.7%]; subhazard ratio, 0.62; [95% CI, 0.41-0.91]; P = .02). There were no significant differences in any of the remaining 3 secondary outcomes. The most common serious adverse events were related to liver failure (25 in the amoxicillin-clavulanate group and 20 in the placebo group), infections (23 in the amoxicillin-clavulanate group and 46 in the placebo group), and gastrointestinal disorders (15 in the amoxicillin-clavulanate group and 21 in the placebo group). Conclusion and Relevance: In patients hospitalized with severe alcohol-related hepatitis, amoxicillin-clavulanate combined with prednisolone did not improve 2-month survival compared with prednisolone alone. These results do not support prophylactic antibiotics to improve survival in patients hospitalized with severe alcohol-related hepatitis. Trial Registration: ClinicalTrials.gov Identifier: NCT02281929.

Individual and population screening of varices needing treatment by a simple, safe and accurate test.

BACKGROUND: Several tests have been developed to screen varices needing treatment (VNT) in different screening settings. We aimed to develop simple estimators to quantify VNT risk and spare endoscopy while missing <5% of VNT, adapted to different screenings in the main etiologies. METHODS: 2,368 patients with chronic liver disease were included. The main VNT predictors were platelets, prothrombin index (PI) and LSM. Their interactions led to score construction, LIP: (LSM*45)/(PI*platelets), and BLIP: BMI-adjusted LIP in NAFLD. Scores were categorized either for population (VNT sensitivity ≥95%) or individual (negative predictive value ≥95%) VNT screening. RESULTS: 1) Scores diagnosing VNT. AUROCs were, PLER: 0.767 Anticipate: 0.773 (p=0.059 vs previous), LIP: 0.779 (p=0.136), PLEASE: 0.789 (p=0.196). 2) Population screening performance was in increasing order (with missed VNT rate), Baveno6 criteria: 23.9% (2.5%), Anticipate: 24.5%, p=0.367 vs previous (3.3%), PLER: 27.3%, p<0.001 (3.6%), LIP: 33.4%, p<0.001 (4.2%), PLEASE: 35.2%, p=0.006 (3.6%). In NAFLD, LIP: 38.6%, BLIP: 40.8%, p=0.038. 3) Individual screening performance was, expanded Baveno6 criteria: 42.7%, LIP: 54.1%, p<0.001. In NAFLD, performance was, NAFLD-cirrhosis criteria: 66.7%, BLIP: 74.6%, p<0.001. CONCLUSION: LIP combined simplicity, performance and safety in each etiology. In NAFLD, BMI-adjusted LIP outperformed other tests.

Porto-Sinusoidal Vascular Disease: A Pediatric Study of 30 Patients.

OBJECTIVES: Porto-sinusoidal vascular disease (PSVD) refers to a broad spectrum of histological lesions and phenotypic expressions. There are only a few reported pediatric cases in the literature. The primary outcomes of this study were to describe the phenotype of children with PSVD, to specify their mode of presentation and their clinical, biological, histological, and radiological characteristics as well as to identify their underlying etiologies. METHODS: This is a descriptive, retrospective, and monocentric study of children followed at our reference center for rare vascular liver diseases. RESULTS: Our study included 30 children ages 2months to 17.4years at the time of diagnosis. in most cases, the diagnosis was made incidentally without manifestation of any clinical symptom but rather on the finding of splenomegaly on physical examination (n = 9) or biological abnormalities (n = 13). In the other cases, the main presenting symptom was an upper gastrointestinal bleeding (n = 6). At the first visit, liver laboratory values were either normal (37%) or slightly disturbed. Anemia and/or thrombocytopenia associated with hypersplenism were found in 60% of patients. Liver biopsy was necessary for diagnosis. A total of 80% of cases had no identified etiology. After a median follow-up of 4.5 years, 33% had not developed portal hypertension (PHT) and we reported the first pediatric case of hepatocellular carcinoma in PSVD children. CONCLUSIONS: PSVD is responsible for nonspecific symptomatology with variable evolution sometimes marked by serious complications requiring invasive treatments or even liver transplantation. Regular monitoring is essential to prevent, detect, and treat complications.

Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study.

BACKGROUND: Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence. METHODS: We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794. FINDINGS: Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% [95% CI -∞ to 21·1]; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% [95% CI 5·8-27·6]) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 [95% CI -0·07 to 0·55]), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 [95% CI 0·17-0·82]). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio [HR] 0·87 [95% CI 0·33-2·26]); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 [95% CI 0·16-0·47] and 0·21 [0·13-0·32]). INTERPRETATION: We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis. FUNDING: The present study has been granted by the French Ministry of Health-Programme Hospitalier de Recherche Clinique 2010.

Non-invasive diagnosis and follow-up of rare genetic liver diseases.

Rare genetic liver diseases can result in multi-systemic damage, which may compromise the patient's prognosis. Wilson's disease and alpha-1 antitrypsin deficiency must be investigated in any patient with unexplained liver disease. Cystic fibrosis screening of new-borns is now implemented in most high-prevalence countries. The diagnosis of these diseases can be strongly suggested with specific non-invasive tests. Molecular analysis gene for these diseases is long and tedious but is recommended to confirm the diagnosis and help for the family screening. Liver biopsy is not systematic and is discussed when it helps diagnosis. Currently, for these three diseases, non-invasive fibrosis markers could identify patients with risk of cirrhosis and complications. Rare genetic liver diseases can result in multi-systemic damage, which may compromise the patient's prognosis. Wilson's disease, must be investigated in any patient with unexplained liver disease and/or unexplained neurological or neuropsychiatric disorders. The diagnosis is based on a combination of clinical, biological features, including copper balance. The exchangeable copper/total copper ratio is a new sensible and specific biological marker, useful for the diagnosis of the disease. Timely diagnosis and treatment will prevent serious complications from the disease. Neurological evaluation and familial screening are essential in patients with Wilson's disease.

Non-invasive diagnosis and follow-up of portal hypertension.

Compensated advanced chronic liver disease (cACLD) describes the spectrum of advanced fibrosis/cirrhosis in asymptomatic patients at risk of developing clinically significant portal hypertension (CSPH, defined by a hepatic venous pressure gradient (HVPG) ≥10 mmHg). Patients with cACLD are at high risk of liver-related morbidity and mortality. In patients at risk of chronic liver disease, cACLD is strongly suggested by a liver stiffness (LSM) value >15 kPa or clinical/biological/radiological signs of portal hypertension, and ruled out by LSM <10 kPa, or Fibrotest® ≤0.58, or Fibrometer® ≤0.786. Patients with chronic liver disease (excluding vascular diseases) with a LSM <10 kPa are at low risk of developing portal hypertension complications. The presence of CSPH can be strongly suspected when LSM is ≥20 kPa. In a patient without clinical, endoscopic or radiological features of portal hypertension, measurement of the HVPG is recommended before major liver or intra-abdominal surgery, before extra-hepatic transplantation and in patients with unexplained ascites. Endoscopic screening for oesophageal varices can be avoided in patients with LSM <20 kPa and a platelet count >150 G/L (favourable Baveno VI criteria) at the time of diagnosis. There is no non-invasive method alternative for oeso-gastroduodenal endoscopy in patients with unfavourable Baveno criteria (liver stiffness ≥20 kPa or platelet count ≤50 G/l). Platelet count and liver stiffness measurements must be performed once a year in patients with cACLD with favourable Baveno VI criteria at the time of diagnosis. A screening oeso-gastroduodenal endoscopy is recommended if Baveno VI criteria become unfavourable.

Non-invasive diagnosis and follow-up of chronic infection with Hepatitis C Virus.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Clinical care for patients with HCV-related liver disease has advanced considerably with developments in screening, diagnostic procedures to evaluate liver fibrosis and improvements in therapy with pangenotypic direct antivirals and prevention. These AFEF guidelines on the non-invasive diagnosis and follow up of chronic infection with HCV describe the optimal management of HCV positive patients with non-invasive methods in screening, in assessing viral disease and liver fibrosis and the follow-up of these patients according to the value of FibroScan®, Fibrotest® or Fibrometer®. Hepatocellular carcinoma screening must continue in patients with liver stiffness by FibroScan® ≥10 kPa or Fibrotest® >0.58 or Fibrometer® >0.78 prior to treatment initiation. After reaching sustained virologic response, patients with a measurement of liver stiffness by FibroScan®<10 kPa or Fibrotest®≤0.58 or Fibrometer®≤0.78 before treatment initiation and without liver comorbidity (alcohol consumption, metabolic syndrome, HBV co-infection etc.) no longer require specific monitoring. The role of liver biopsy is discussed in some rare situations.

Non-invasive diagnosis and follow-up of vascular liver diseases.

Vascular disorders of the liver are rare diseases, some of which are diagnosed mainly with non-invasive tests and others by liver biopsy. Non-invasive methods can be used to diagnose and monitor these diseases. However, their evaluation needs to be performed by expert centers. Liver biopsy is needed each time there is an unexplained abnormality.

Non-invasive diagnosis and follow-up in liver transplantation.

The field of liver transplantation directly or indirectly embodies all liver diseases, in addition to specific ones related to organ rejection (cellular and humoral). The recommended non-invasive methods for determining the indication for liver transplantation are the Model for End-stage Liver Disease score, and the alpha-foetoprotein score in case of hepatocellular carcinoma. Radiological methods are the cornerstones for the diagnosis of vascular and biliary complications after liver transplantation. The possible diseases of the liver graft after transplantation are multiple and often intertwined. Non-invasive diagnostic methods have been poorly evaluated in this context, apart from the recurrence of hepatitis C. Liver biopsy remains the gold standard for evaluating graft lesions in the majority of cases, especially graft rejection.

Non-invasive diagnosis and follow-up of non-alcoholic fatty liver disease.

NAFLD is a frequent disease that affects 25% of the worldwide population. There is no specific diagnostic test for NAFLD, and the diagnosis mainly relies on the elimination of the other causes of chronic liver diseases with liver biopsy kept for unsure diagnoses. Non-invasive tests are now available to assess NAFLD severity and therefore to help physicians decide on the patient management and follow-up. These non-invasive tests can also be used to define pathways that organize referrals from primary care and diabetology clinics to the liver specialist, with the ambition to improve the screening of asymptomatic patients with NAFLD and advanced liver disease. NAFLD being the liver expression of the metabolic syndrome, physicians need also take care to screen for diabetes and to evaluate the cardiovascular risk in those patients. These recommendations from the French Association for the Study of the Liver (AFEF) aim at providing guidance on the following questions: how to diagnose NAFLD; how non-invasive tests should be used to assess NAFLD severity; how to follow patients with NAFLD; when to perform liver biopsy in NAFLD; and how to decide referral to the liver specialist for a patient with NAFLD.

Non-invasive diagnosis and follow-up of hyperferritinaemia.

Increased serum ferritin is a very frequent cause of referral for which thorough evaluation is required to avoid unnecessary exploration and inaccurate diagnosis. Clinicians must thus know factors and tools that are relevant in this setting. Several biochemical and radiological tools drastically improved the diagnosis work-up of increased serum ferritin. Because serum ferritin value can be altered by many cofounding factors, scrutiny in the initial clinical evaluation is crucial. Alcohol consumption, and the metabolic syndrome are the most frequent causes of secondary increased ferritin. Serum transferrin saturation level is a pivotal test, and if increased prompt testing for HFE C282Y patients in Caucasian population. In most cases further tests are require to establish whether increased ferritin is associated or not to iron overload. Magnetic resonance imaging is the reference method allowing to accurately establish liver iron content which indirectly reflect body iron load. Second line genetic testing for rare forms of iron overload or increased serum ferritin are available in reference center and should be discussed if diagnosis is equivocal or remain uncertain after careful evaluation. Definite genetic diagnosis is worthwhile as it allows family screening and refining long term management of the patient. Liver biopsy remains seldom useful to assess liver fibrosis, mostly in patients with severe iron overload.

Non-invasive diagnosis and follow-up of chronic infection with hepatitis B virus.

Diagnosis of chronic hepatitis B virus (HBV) infection, initial staging of infection and monitoring of treated and untreated patients are mainly based on clinical, biological and imaging criteria allowing a complete non-invasive management for the majority of patients. Along to the conventional virological tools, rapid diagnostic tests and blotting paper tests for HBV DNA are validated alternatives. After diagnosis, the initial work-up should include HIV, HCV and HDV serologies, HBeAg status, and HBsAg and HBV DNA quantification. Assessment of severity (inflammation and fibrosis) is based on ALT serum levels and non-invasive evaluation of liver fibrosis by elastography or blood tests, which must be interpreted cautiously using specific cut-offs and taking into account ALT levels. Taken together, these parameters allow disease classification and treatment decision. Decision of hepatocellular carcinoma screening by ultra-sound every six months may be difficult in non-cirrhotic patients and the use of risk-scores such as PAGE-B is encouraged. Chronic HBV infection often has a dynamic and often unpredictable profile and regular monitoring is mandatory. In untreated patients, regular (3-12 months) follow-up should include ALT and HBV DNA serum levels. Periodical HBsAg quantification and non-invasive evaluation of liver fibrosis may refine disease outcome and prognosis. In treated patients, checking efficacy is mainly based on HBV DNA negativity. In patients with advanced fibrosis, evolution of liver stiffness can be useful for portal hypertension evaluation, but its improvement should not be considered to stop hepatocellular carcinoma screening. Finally, new parameters (HBV RNA, HBcrAg) are promising but their use is still restricted for research.

Non-invasive diagnosis and follow-up of primary malignant liver tumours.

Among a wide range of malignant liver tumours, hepatocellular carcinoma (HCC) developed on a background of cirrhosis represents the most frequent clinical situation. In this setting, HCC is one of the rare solid tumours for which histological confirmation is not mandatory. The convergence of multiple arguments obtained by non-invasive parameters using radiological findings allows to avoid liver biopsy in a large proportion of patients when a diagnosis of underlying cirrhosis is ascertained. Conversely, in case of atypical presentation or in order to exclude other rare malignant tumours mostly developed in the absence of cirrhosis, liver biopsy will then be essential. Based on typical radiological patterns described by contrast-enhanced imaging, numerous clinical guidelines have endorsed non-invasive diagnosis, staging and monitoring of HCC patients under treatment since 20 years. These algorithms have evolved over the years, taking into account progress in radiological technology and advances in curative or palliative procedures. Large cohort studies have also helped to refine diagnostic criteria and prognostication in the setting of complex therapeutic strategy. Unsupervised multi-analysis approaches both at the biological and radiological levels will in the future enrich the panel of non-invasive markers useful in clinical practice to manage HCC and other malignant tumours.

Non-invasive diagnosis and follow-up of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a rare and chronic cholestatic liver disease of unknown cause commonly associated with inflammatory bowel disease (IBD) and characterized by progressive obliterative fibro-inflammation of the biliary tree. Although the natural course is highly variable, PSC is often progressive, leading to biliary cirrhosis and its complications. In addition, PSC is a condition harbouring broad neoplastic potential with increased susceptibility for the development of both biliary and colon cancer. As in other chronic liver diseases, non-invasive methods play a major role in the diagnosis and monitoring of PSC. MR cholangiography is the key exam for the diagnosis and has replaced diagnostic endoscopic retrograde cholangiopancreatography (ERCP). A strict and standardised protocol for carrying out MR cholangiography is recommended. Liver stiffness measured by FibroScan® correlates with the degree of liver fibrosis, has a prognostic value and should be repeated during follow-up. Invasive methods still play an important role, especially ERCP which is indicated for therapeutic purposes or for endo-biliary sample collection in suspected cholangiocarcinoma (following discussion in a multidisciplinary team meeting) and total colonoscopy which is recommended at the initial diagnosis of any PSC and annually in patients with IBD.

Non-invasive diagnosis and follow-up of benign liver tumours.

Hepatocellular benign liver tumours are mainly developed on normal liver and include hepatic hemangioma, focal nodular hyperplasia and hepatocellular adenoma from the most frequent to the less frequent. The diagnosis of hepatic hemangioma and of simple hepatic biliary cysts can be performed using non-invasive criteria using liver ultrasonography or contrast enhanced MRI. Most of the time the diagnosis of focal nodular hyperplasia can be achieved using contrast-enhanced ultrasonography or contrast enhanced MRI with an additional value of hepatobiliary contrast-agent in this setting. Rarely, if a doubt persists, a tumour and non-tumour liver biopsy can be required in order to establish the diagnosis. As hepatic hemangioma, simple hepatic biliary cysts and focal nodular hyperplasia are not associated with complications, they don't require any treatments or follow-up. Hepatocellular adenomas are mainly diagnosed at histology on surgical samples or liver biopsy even if some radiological features are highly suggestive of several subtypes of hepatocellular adenomas. Finally, the management of hepatocellular adenomas should be guided according to the tumour size, gender but also to the molecular subtypes.

A simple clinical score to promote and enhance ferroportin disease screening.

BACKGROUND & AIMS: Ferroportin disease is a rare genetic iron overload disorder which may be underdiagnosed, with recent data suggesting it occurs at a higher prevalence than suspected. Costs and the lack of defined criteria to prompt genetic testing preclude large-scale molecular screening. Hence, we aimed to develop a readily available scoring system to promote and enhance ferroportin disease screening. METHODS: Our derivation cohort included probands tested for ferroportin disease from 2008 to 2016 in our rare disease network. Data were prospectively recorded. Univariate and multivariate logistic regression were used to determine significant criteria, and odds ratios were used to build a weighted score. A cut-off value was defined using a ROC curve with a predefined aim of 90% sensitivity. An independent cohort was used for cross validation. RESULTS: Our derivation cohort included 1,306 patients. Mean age was 55±14 years, ferritin 1,351±1,357 µg/L, and liver iron concentration (LIC) 166±77 µmol/g. Pathogenic variants (n = 32) were identified in 71 patients. In multivariate analysis: female sex, younger age, higher ferritin, higher LIC and the absence of hypertension or diabetes were significantly associated with the diagnosis of ferroportin disease (AUROC in whole derivation cohort 0.83 [0.78-0.88]). The weighted score was based on sex, age, the presence of hypertension or diabetes, ferritin level and LIC. An AUROC of 0.83 (0.77-0.88) was obtained in the derivation cohort without missing values. Using 9.5 as a cut-off, sensitivity was 93.6 (91.7-98.3) %, specificity 49.5 (45.5-53.6) %, positive likelihood ratio 1.8 (1.6-2.0) and negative likelihood ratio 0.17 (0.04-0.37). CONCLUSION: We describe a readily available score with simple criteria and good diagnostic performance that could be used to screen patients for ferroportin disease in routine clinical practice. LAY SUMMARY: Increased iron burden associated with metabolic syndrome is a very common condition. Ferroportin disease is a dominant genetic iron overload disorder whose prevalence is higher than initially thought. They can be difficult to distinguish from each other, but the limited availability of genetic testing and the lack of definitive guidelines prevent adequate screening. We herein describe a simple and definitive clinical score to help clinicians decide whether to perform genetic testing.