Alessandra Pohlmann

Increase in liver stiffness after transjugular intrahepatic portosystemic shunt is associated with inflammation and predicts mortality

Transjugular intrahepatic portosystemic shunt (TIPS) efficiently treats complications of portal hypertension. Liver and spleen stiffness might predict clinically significant portal hypertension. This prospective study investigated liver stiffness in patients receiving TIPS regardless of indication. Of 83 included patients, 16 underwent transient elastography immediately before and 30 minutes after TIPS (acute group), while 67 received shear wave elastography of liver and spleen 1 day before and 7 days after TIPS (chronic group) and were followed further. In blood samples obtained before TIPS from cubital, portal, and hepatic veins, levels of several interleukins (IL1b, IL6, IL8, IL10, IL18) and interferon‐gamma were analyzed. In 27 patients (5 acute, 22 chronic), it resulted in an increase in liver stiffness of >10%. In 56 patients, liver stiffness decreased or remained unchanged (<10%). Importantly, spleen stiffness measured by shear wave elastography decreased in all patients (chronic group). None of the clinical or laboratory parameters differed between patients with increase in liver stiffness and those without. Of note, patients with increased liver stiffness showed higher overall and/or hepatic venous levels of proinflammatory cytokines at TIPS and higher incidence of organ failure and worse survival after TIPS. C‐reactive protein values and increase of >10% in liver stiffness after TIPS were the only independent predictors of mortality in these patients. Conclusion: This study demonstrates that the presence of systemic inflammation predisposes patients to develop increased liver stiffness after TIPS, a predictor of organ failure and death. (NCT03072615) (Hepatology 2018;67:1472‐1484).

Fat-free muscle mass in magnetic resonance imaging predicts acute-on-chronic liver failure and survival in decompensated cirrhosis

Muscle mass seems to be a prognostic marker in patients with liver cirrhosis. However, reported methods to quantify muscle mass are heterogeneous, consented cutoff values are missing, and most studies have used computed tomography. This study evaluated fat‐free muscle area (FFMA) as a marker of sarcopenia using magnetic resonance imaging (MRI) in patients with decompensated cirrhosis with transjugular intrahepatic portosystemic shunt (TIPS). The total erector spinae muscle area and the intramuscular fat tissue area were measured and subtracted to calculate the FFMA in 116 patients with cirrhosis by TIPS and MRI. The training cohort of 71 patients compared computed tomography–measured transversal psoas muscle thickness with FFMA. In 15 patients MRI was performed before and after TIPS, and in 12 patients follistatin serum measurements were carried out. The results on FFMA were confirmed in a validation cohort of 45 patients. FFMA correlated with follistatin and transversal psoas muscle thickness and showed slightly better association with survival than transversal psoas muscle thickness. Gender‐specific cutoff values for FFMA were determined for sarcopenia. Decompensation (ascites, overt hepatic encephalopathy) persisted after TIPS in the sarcopenia group but resolved in the nonsarcopenia group. Sarcopenic patients showed no clinical improvement after TIPS as well as higher mortality, mainly due to development of acute‐on‐chronic liver failure. FFMA was an independent predictor of survival in these patients. Conclusion: This study offers an easy‐to‐apply MRI‐based measurement of fat‐free muscle mass as a marker of sarcopenia in decompensated patients; while TIPS might improve sarcopenia and thereby survival, persistence of sarcopenia after TIPS is associated with a reduced response to TIPS and a higher risk of acute‐on‐chronic liver failure development and mortality. (Hepatology 2018;67:1014–1026)

Increased myocardial contractility identifies patients with decompensated cirrhosis requiring liver transplantation

Late allocation of organs for transplant impairs post–liver transplantation (LT) survival. Cardiac dysfunction, especially diastolic and autonomic dysfunction, is frequent and plays an important role in the prognosis of patients with cirrhosis. However, the role of myocardial contractility is unexplored, and its prognostic value is controversially discussed. This study analyses the role of myocardial contractility assessed by speckle tracking echocardiography in LT allocation. In total, 168 patients with cirrhosis (training cohort, 111; validation cohort [VC], 57) awaiting LT in 2 centers were included in this retrospective study. Also, 51 patients from the training and all patients from the VC were transplanted, 36 patients of the training and 38 of the VC were alive at the end of follow‐up, and 21 nontransplanted patients died. Contractility of the left ventricle (LV) increased with severity of the Child‐Pugh score. Interestingly, higher LV contractility in the training cohort patients, especially in those with Child‐Pugh C, was an independent predictor of reduced transplant‐free survival. In male patients, the effects on survival of increased left and right ventricular myocardial contractility were more pronounced. Notably, competing risk analysis demonstrated that increased contractility is associated with earlier LT, which could be confirmed in the VC. Importantly, LV myocardial contractility had no impact on survival of patients not receiving LT or on post‐LT survival. In conclusion, this study demonstrates for the first time that increased myocardial contractility in decompensated patients identifies patients who require LT earlier, but without increased post‐LT mortality. Liver Transplantation 24 15–25 2018 AASLD.

Circulating microbiome in blood of different circulatory compartments

We read with interest the recent review by Tilg et al ,1 which summarised the role of microbiota in liver diseases and pointed out that a causal link with systemic inflammation has still not been established. This letter fills in this gap and provides an analysis of the circulating microbiota in portal vein as the link between gut and liver. The access to portal circulation is possible during the implantation of a transjugular intrahepatic portosystemic shunt (TIPS). Therefore, we characterised the circulating microbiome in portal vein (first venous outflow in gut–liver axis), liver outflow, central venous blood and peripheral venous blood from seven patients with decompensated liver cirrhosis receiving TIPS for either variceal bleeding (n=3) or refractory ascites (n=4) (mean Model for End-stage Liver Disease (MELD) 8.4 (range 6–13), Child-Pugh-Score (CHILD) A: n=4, CHILD B: n=3) (figure 1A). We performed 16S ribosomal RNA (rRNA) gene sequencing of buffy coat samples and identified 65 genera belonging to four phyla (predominantly Proteobacteria) in this cohort (online supplementary figure 1 and figure 1B). Blood microbiome phylum compositions identified in our …

Circulating CXCL10 in cirrhotic portal hypertension might reflect systemic inflammation and predict ACLF and mortality

CXCR% ligands play an important role in hepatic injury, inflammation and fibrosis. While CXCL9 and CXCL11 are associated with survival in patients receiving transjugular intrahepatic portosystemic shunt (TIPS), the role of CXCL10 in severe portal hypertension remains unknown.

Increased myocardial contractility identifies decompensated cirrhotic patients requiring liver transplantation

Late allocation of organs for transplant impairs post–liver transplantation (LT) survival. Cardiac dysfunction, especially diastolic and autonomic dysfunction, is frequent and plays an important role in the prognosis of patients with cirrhosis. However, the role of myocardial contractility is unexplored, and its prognostic value is controversially discussed. This study analyses the role of myocardial contractility assessed by speckle tracking echocardiography in LT allocation. In total, 168 patients with cirrhosis (training cohort, 111; validation cohort [VC], 57) awaiting LT in 2 centers were included in this retrospective study. Also, 51 patients from the training and all patients from the VC were transplanted, 36 patients of the training and 38 of the VC were alive at the end of follow‐up, and 21 nontransplanted patients died. Contractility of the left ventricle (LV) increased with severity of the Child‐Pugh score. Interestingly, higher LV contractility in the training cohort patients, especially in those with Child‐Pugh C, was an independent predictor of reduced transplant‐free survival. In male patients, the effects on survival of increased left and right ventricular myocardial contractility were more pronounced. Notably, competing risk analysis demonstrated that increased contractility is associated with earlier LT, which could be confirmed in the VC. Importantly, LV myocardial contractility had no impact on survival of patients not receiving LT or on post‐LT survival. In conclusion, this study demonstrates for the first time that increased myocardial contractility in decompensated patients identifies patients who require LT earlier, but without increased post‐LT mortality. Liver Transplantation 24 15–25 2018 AASLD.

Evolution of nodule stiffness might predict response to local ablative therapy: A series of patients with hepatocellular carcinoma

Background Early information on treatment response of HCC to local ablative therapy is crucial. Elastography as a non-invasive method has recently been shown to play a potential role in distinguishing between benign and malignant liver lesions. Elastography of hepatocellular carcinoma (HCC) in early response to local ablative therapy has not been studied to date. Methods We prospectively included a cohort of 14 patients with diagnosis of HCC who were treated with local ablative therapy (transarterial chemoembolization, TACE and/or radiofrequency ablation, RFA). We used 2D shear-wave elastography (RT 2D-SWE) to examine stiffness of HCC lesion before and 3, 30 and 90 days after local ablative therapy. Contrast-enhanced imaging after 90 days was performed to evaluate treatment response. Primary endpoint was stiffness of HCC in response to local ablative therapy. Secondary end point was tumor recurrence. Results Stiffness of HCC nodules and liver showed no significant difference prior to local ablative therapy. As early as three days after treatment, stiffness of responding HCC was significantly higher compared to non-responding. Higher stiffness before treatment was significantly associated with tumor recurrence. Conclusion Nodule stiffness in general and RT 2D-SWE in particular could provide a useful tool for early prediction of HCC response to local ablative therapy.

Fibroblast growth factor 21 is an early predictor of acute-on-chronic liver failure in critically ill patients with cirrhosis

Acute‐on‐chronic liver failure (ACLF) develops in acute decompensation (AD) of cirrhosis and shows high mortality. In critically ill patients, early diagnosis of ACLF could be important for therapeutic decisions (eg, renal replacement, artificial liver support, liver transplantation). This study evaluated fibroblast growth factor 21 (FGF21) as a marker of mitochondrial dysfunction in the context of ACLF. The study included 154 individuals (112 critically patients and 42 healthy controls) divided into a training and a validation cohort. In the training cohort of 42 healthy controls and 34 critically ill patients (of whom 24 were patients with cirrhosis), levels of FGF21, interleukin (IL) 6, and IL8 were measured. In the validation cohort of 78 patients with cirrhosis, 17 patients were admitted with or developed ACLF during follow‐up and underwent daily clinical and nutritional assessment. Levels of FGF21 were higher in critically ill patients, especially in patients with cirrhosis admitted to the intensive care unit (ICU). Moreover, FGF21 as well as IL6 and IL8 levels were higher in patients with ACLF, but they did not increase with the severity of ACLF. Interestingly, in the validation cohort, FGF21 was also elevated in the patients who developed ACLF in the next 7 days. In these patients, FGF21 levels were an independent predictor of ACLF presence and development in multivariate analysis together with Child‐Pugh score. FGF21 levels had no impact on the survival of critically ill patients with cirrhosis. In conclusion, this study demonstrates that FGF21 levels are of specific diagnostic value regarding the presence and development of ACLF in patients admitted to ICU for AD of liver cirrhosis. Further studies are warranted to address pathophysiological and possible therapeutic implications. Liver Transplantation 24 595–605 2018 AASLD.

MicroRNA-155 is upregulated in ascites in patients with spontaneous bacterial peritonitis

MircoRNA’s (miR) have been recognised as important modulators of gene expression and potential biomarkers. However, they have been rarely investigated in bio fluids apart from blood. We investigated the association of miR-125b and miR-155 with complications of cirrhosis. Ascites was prospectively collected from patients with cirrhosis undergoing paracentesis at our department. miR’s were determined in the supernatant using qPCR and normalized by SV-40. Clinical parameters were assessed at paracentesis and during follow-up. 76 specimens from 72 patients were analysed. MiR’s were not associated to age, sex or aetiology of cirrhosis. MiR-125b levels differed between patients with low and high MELD score, and miR-125b levels showed an inverse correlation to serum creatinine (r2 = −0.23; p = 0.05). MiR-155 was elevated in patients with spontaneous bacterial peritonitis (SBP) (n = 10; p = 0.04). MiR-155 levels differed between patients with and without 30-day survival (p = 0.02). No association of ascites levels of investigated miR’s to size of varices, episodes of gastrointestinal bleeding or hepatorenal syndrome was observed. While miR-125b levels in ascites seem to be associated with liver and renal dysfunction, miR-155 might be implicated in local immune response in SBP.

Severe abnormal Heart Rate Turbulence Onset is associated with deterioration of liver cirrhosis

Background In patients with liver cirrhosis, cardiac dysfunction is frequent and is associated with increased morbidity and mortality. Cardiac dysfunction in cirrhosis seems to be linked to autonomic dysfunction. This study investigates the role of autonomic dysfunction assessed by Heart Rate Turbulence (HRT) analyses in patients with liver cirrhosis. Methods and patients Inclusion criteria was (1) diagnosis of cirrhosis by clinical, imaging or biopsy and (2) evaluation by standard 12-lead-ECG and 24h holter monitoring and (3) at least 3 premature ventricular contractions. The exclusion criterion was presence of cardiac diseases, independent of liver cirrhosis. Biochemical parameters were analysed using standard methods. HRT was assessed using Turbulence onset (TO) and slope (TS). The endpoint was deterioration of liver cirrhosis defined as increased MELD and readmission for complications of liver cirrhosis. Results Out of 122 cirrhotic patients, 82 patients (63% male) with median Child score of 6 (range 5–12) and median MELD score of 10 (range 6–32) were included. Increasing Child score, INR and decreasing albumin were correlated with TO. In addition, decompensated patients with ascites showed more abnormal TO and TS. During the observation period, patients with more abnormal TO showed significantly higher rate of rising MELD Score at 6 months (p = 0.03). Nevertheless, at least in our collective HRT-parameters were not independent predictors of deterioration of cirrhosis. Conclusion Parameters of HRT are closely associated with deterioration of cirrhosis and might be helpful in its prediction.