Noninvasive assessment of portal hypertension in cirrhosis:Liver stiffness and beyond

Liver stiffness measurement(LSM)is a good,but still limited tool to noninvasively assess complications and prognosis in patients with advanced liver disease.This review aims to consider the role of LSM for the diagnosis of portal hypertension-related complications and for assessment of prognosis in cirrhotic patients,and to highlight the drawbacks as well as some alternatives for improving the performance.Hence,this field is far from being closed,and deserves more attention.There is still a place for more carefully designed studies to find new,innovative and reliable approaches.

Diagnostic challenges in non-cirrhotic portal hypertension-porto sinusoidal vascular disease

Non-cirrhotic portal hypertension consists of a group of diseases characterized by signs and complications of portal hypertension,which differ from cirrhosis through histological alterations,hemodynamic characterization and,clinical outcome.Because of the similarities in clinical presentation and imaging signs,frequently these patients,and particularly those with porto-sinusoidal vascular disease(PSVD),are misdiagnosed as having liver cirrhosis and thus raising difficulties in their diagnosis.The most challenging differentiation to be considered is between PSVD and cirrhosis and,although not pathognomonic,liver biopsy is still the standard of diagnosis.Although they still require extended validation before being broadly used,new non-invasive methods for the diagnosis of porto-sinusoidal vascular disease,like transient elastography,contrast-enhanced ultrasound or metabolomic profiling,have shown promising results.Another issue is the differentiation between PSVD and chronic extrahepatic portal vein obstruction,especially now when it is known that 40%of patients suffering from PSVD develop portal vein thrombosis.In this particular case,once the portal vein thrombosis occurred,the diagnosis of PSVD is impossible according to the current guidelines.Moreover,so far,the differentiation between PSVD and sinusoidal obstruction syndrome has not been clear so far in particular circumstances.In this review we highlighted the diagnostic challenges regarding the PSVD,as well as the current techniques used in the evaluation of these patients.

Viscoelastic tests in liver disease: where do we stand now?

Hemostasis is a complex physiological process based on the balance between procoagulant and anticoagulant systems to avoid pathological bleeding or thrombosis.The changes in standard coagulation tests in liver disease were assumed to reflect an acquired bleeding disorder,and cirrhotic patients were considered naturally anticoagulated.In the light of the new evidence,the theory of rebalanced hemostasis replaced the old concept.According to this model,the hemostatic alteration leads to a unique balance between pro-coagulant,anticoagulant,and fibrinolytic systems.But the balance is fragile and may prone to bleeding or thrombosis depending on various risk factors.The standard coagulation tests[INR(international normalized ratio),platelet count and fibrinogen]only explore parts of the hemostasis,not offering an entire image of the process.Rotational thromboelastometry(ROTEM)and thromboelastography(TEG)are both point of care viscoelastic tests(VET)that provide real-time and dynamic information about the entire hemostasis process,including clot initiation(thrombin generation),clot kinetics,clot strength,and clot stability(lysis).Despite prolonged PT/INR(international normalized ratio of prothrombin time)and low platelet counts,VET is within the normal range in many patients with both acute and chronic liver disease.However,bleeding remains the dominant clinical issue in patients with liver diseases,especially when invasive interventions are required.VET has been shown to asses more appropriately the risk of bleeding than conventional laboratory tests,leading to decrial use of blood products transfusion.Inappropriate clotting is common but often subtle and may be challenging to predict even with the help of VET.Although VET has shown its benefit,more studies are needed to establish cut-off values for TEG and ROTEM in these populations and standardization of transfusion guidelines before invasive interventions in cirrhotic patients/orthotopic liver transplantation.

Metabolomics: From liver chiromancy to personalized precision medicine in advanced chronic liver disease

Currently there is a lack of accurate biomarkers for diagnosis and prognosis in advanced liver diseases. Either the occurrence of first decompensation, or diagnosis of acute on chronic liver failure, severe alcoholic hepatitis, or hepatocellular carcinoma(HCC), none of the available biomarkers are satisfactory. Metabolomics is the newest of omics, being much closer than the others to the actual phenotype and pathologic changes that characterizes a certain condition. It deals with a much wider spectrum of low molecular weight bio-compounds providing a powerful platform for discovering novel biomarkers and biochemical pathways to improve diagnostic, prognostication and therapy. Until now metabolomics was applied in a wide spectrum of liver conditions, but the findings were contradictory. This review proposes a synthesis of the existing evidences of metabolomics use in advanced chronic liver diseases, decompensated liver cirrhosis, severe alcoholic hepatitis and HCC.

Pulmonary complications of portal hypertension:The overlooked decompensation

The systemic nature of cirrhosis and portal hypertension has long been recognized,and the amount of data characterizing the interplay between each system is becoming ever so complex.Lung involvement was among the first described associated entities in cirrhosis,with reports dating back to the late nineteenth century.However,it appears that throughout the years,interest in the pulmonary complications of portal hypertension has generally faded,especially in contrast to other decompensating events,as expertise in this field has primarily been concentrated in highly experienced tertiary care facilities and liver transplantation centers.Despite affecting up to 10%-15%of patients with advanced liver disease and having a proven prognostic impact,hepato-pulmonary syndrome,porto-pulmonary hypertension,and hepatic hydrothorax are frequently misdiagnosed,mistreated,or misinterpreted.This lack of precision might adversely impact patient care,referral to expert centers,and,ultimately,liver disease-related mortality and successful transplantation odds.The present minireview aims to increase awareness of the pulmonary complications of chronic liver disease by providing a brief overview of each of the three entities.The paper focuses on the essential theoretical aspects,addressing the most critical knowledge gaps on the one hand and,on the other hand,critically discussing one key issue for each complication.

Malnutrition and non-compliance to nutritional recommendations in patients with cirrhosis are associated with a lower survival

BACKGROUND Malnutrition is frequently encountered in patients with cirrhosis and appears to significantly impact their prognosis.While evaluating the burden of malnutrition in cirrhosis is gathering momentum,as suggested by multiple recently published reports,there is still a persistent scarcity of solid data in the field,especially with regards to the role of nutritional interventions.AIM To assess the prevalence of malnutrition in patients with advanced cirrhosis and to evaluate its impact on survival.METHODS One hundred and one consecutive patients with advanced cirrhosis were screened for malnutrition using the Subjective Global Assessment(SGA)criteria and the mid-arm circumference(MAC).Malnutrition was defined as SGA class B and C and MAC<10th percentile.All patients were interviewed regarding their food intake using an adapted questionnaire.Subsequently,total energy intake was calculated and further subdivided in main nutrients.The data were then compared to the available recommendations at the time of analysis to assess adherence.RESULTS 54/79 patients(68.4%)in the decompensated group had malnutrition,while only 3/22 patients(13.6%)were malnourished in the compensated group.After a median follow-up time of 27 mo(0-53),the overall mortality was 70%.Survival was significantly lower among patients with malnutrition.The mortality rates were 50%at 1 year and 63%at 2 years for the patients with malnutrition,compared to 21%at 1 year and 30%at 2 years for patients without malnutrition(P=0.01).On multivariate analysis,the factors independently associated with mortality were age,creatinine level and adherence to the protein intake recommendations.The mortality was lower in patients with the appropriate protein intake:8%at 1 year and 28%at 2 years in the adherent group,compared to 47%at 1 year and 56%at 2 years in the non-adherent group.CONCLUSION The prevalence of malnutrition is high among patients with advanced cirrhosis and might be related in part to a low adherence to nutritional recommendations,especially with regards to protein intake.

Diagnosis of cirrhosis and portal hypertension:imaging,non-invasive markers of fibrosis and liver biopsy

The concept of‘cirrhosis’is evolving and it is now clear that compensated and decompensated cirrhosis are completely different in terms of prognosis.Furthermore,the term‘advanced chronic liver disease(ACLD)’better reflects the continuum of histological changes occurring in the liver,which continue to progress even after cirrhosis has developed,and might regress after removing the etiological factor causing the liver disease.In compensated ACLD,portal hypertension marks the progression to a stage with higher risk of clinical complication and requires an appropriate evaluation and treatment.Invasive tests to diagnose cirrhosis(liver biopsy)and portal hypertension(hepatic venous pressure gradient measurement and endoscopy)remain of crucial importance in several difficult clinical scenarios,but their need can be reduced by using different non-invasive tests in standard cases.Among non-invasive tests,the accepted use,major limitations and major benefits of serum markers of fibrosis,elastography and imaging methods are summarized in the present review.