Christian Jansen

Shear-wave elastography of the liver and spleen identifies clinically significant portal hypertension: A prospective multicentre study.

Clinically significant portal hypertension (CSPH) is associated with severe complications and decompensation of cirrhosis. Liver stiffness measured either by transient elastography (TE) or Shear‐wave elastography (SWE) and spleen stiffness by TE might be helpful in the diagnosis of CSPH. We recently showed the algorithm to rule‐out CSPH using sequential liver‐ (L‐SWE) and spleen‐Shear‐wave elastography (S‐SWE). This study investigated the diagnostic value of S‐SWE for diagnosis of CSPH.

Circulating MicroRNAs as a marker for liver injury in human immunodeficiency virus patients

Human immunodeficiency virus (HIV) and hepatitis virus coinfection amplify and accelerate hepatic injury. MicroRNAs (miRNAs) are small regulatory RNAs suggested as biomarkers for liver injury. We analyzed the circulating levels of miRNAs in HIV patients with regard to the extent and etiology of liver injury. Total RNA was extracted from 335 serum samples of HIV patients and 22 healthy control participants using Qiazol. Comprehensive polymerase chain reaction (PCR) array analyses (768 miRNA) were performed in serum samples of eight HIV, eight HIV/HCV (hepatitis C virus), six HCV patients, and three healthy controls. Reverse transcription (RT)‐PCR measured levels of miRNA‐122, miRNA‐22, and miRNA‐34a in serum samples of 335 patients and 19 healthy control participants. Liver injury and fibrosis in these patients were defined using aspartate aminotransferase (AST) levels, fibrosis‐4 (FIB‐4) index and AST‐to‐platelet ratio index (APRI) score. The miRNA pattern of HIV/HCV samples showed altered expression of 57 and 33 miRNA compared to HCV and HIV infection, respectively. miRNA‐122, miRNA‐22, and miRNA‐34a were highly up‐regulated in HIV/HCV patients. Analyzing the entire cohort, these miRNAs were correlated with liver function tests and were independent predictors of liver injury (AST >2 × ULN). miRNA‐122 and miRNA‐22 were associated with relevant fibrosis (FIB‐4 >1.45; APRI >1). Circulating levels of miRNA‐122 were independent predictors for relevant fibrosis in HIV patients. Interestingly, miRNA‐122 and miRNA‐34a levels were higher in HIV/HCV patients, miRNA‐22 levels were highest in HIV/HBV patients, and circulating levels of miRNA‐34a correlated positively with illicit drug use and ethanol consumption. Conclusion: Circulating miRNA‐122, miRNA‐22, and miRNA‐34a correlates with the etiology of liver injury in HIV patients. These biomarkers not only mirror different mechanisms of hepatic injury, but also are independent predictors of liver injury in HIV patients. (Hepatology 2015;61:46–55)

Algorithm to rule out clinically significant portal hypertension combining Shear-wave elastography of liver and spleen: a prospective multicentre study

Recently, the UK guidelines on variceal bleeding1 and other reports have introduced the role of elastography for the diagnosis of oesophageal varices (OVs).2 ,3 Development of OVs is likely when the hepatic venous pressure gradient is higher than 10u2005mmu2005Hg, which defines clinically significant portal hypertension (CSPH). Baveno VI implemented transient elastography (TE) as a tool to rule in CSPH in viral aetiologies and to rule out varices (need of screening endoscopy for varices).4 Furthermore, CSPH has a strong prognostic value in patients with cirrhosis.nnRecent studies introduced Shear-wave elastography of the liver (L-SWE) as a promising tool to diagnose portal hypertension. These studies find good diagnostic accuracy of L-SWE with specificity and sensitivity ranging around 80% and superior to TE. However, in more than 30% of the patients CSPH could not be ruled in or ruled out, since their SWE values were between the cut-offs.nnThis prospective multicentre study investigated the …

CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt.

BACKGROUND & AIMSnInflammation, collagen deposition and tissue remodelling are involved in the pathogenesis and complications of cirrhosis with portal hypertension. CXCL9 and other chemokines play an important role in these processes and have been associated with liver injury and complications of liver disease in humans. However, their predictive value in patients with cirrhosis and portal hypertension remains to be established.nnnMETHODSn103 patients with liver cirrhosis who had received TIPS (transjugular intrahepatic portosystemic shunt) were included into this study. The TIPS indication was either refractory ascites or recurrent bleeding. Before and after the TIPS procedure portal and hepatic venous blood samples were obtained in 78 patients. In 25 patients blood samples were obtained from the portal vein, hepatic vein, right atrium and cubital vein at TIPS insertion. Serum levels of CXCL9 were measured by cytometric bead array and correlated with clinical parameters and overall outcome.nnnRESULTSnPortal venous levels of CXCL9 decreased after TIPS. Child-Pugh score, refractory ascites, renal dysfunction and alcoholic aetiology of cirrhosis were associated with increased CXCL9 levels. Importantly, low levels of CXCL9 in portal and hepatic vein samples were prognostic factors for the survival of patients receiving TIPS during long-time follow-up.nnnCONCLUSIONSnThe CXCR3 ligand CXCL9 affects the liver and/or is released by the liver and thereby might contribute to hepatic and extrahepatic organ dysfunction. Elevated levels of CXCL9 are associated with shorter survival in cirrhotic patients with severe portal hypertension receiving TIPS. This chemokine should be further evaluated as a novel biomarker for the outcome in patients with cirrhosis and portal hypertension and its modulation as a new therapeutic strategy.

Circulating MiRNA-122 Levels Are Associated with Hepatic Necroinflammation and Portal Hypertension in HIV/HCV Coinfection

Background Introduction of combined antiretroviral therapy (cART) has improved survival of HIV infected individuals, while the relative contribution of liver-related mortality increased. Especially in HIV/HCV-coinfected patients hepatic fibrosis and portal hypertension represent the main causes of liver-related morbidity and mortality. Circulating miRNA-122 levels are elevated in HIV patients and have been shown to correlate with severity of liver injury. However, the association of miRNA-122 levels and hepatic fibrosis and portal hypertension remains to be explored in HIV/HCV coinfection. Methods From a total of 74 (31% female) patients with HIV/HCV coinfection were included. Serum levels of miRNA-122 were analyzed by quantitative polymerase chain reaction (PCR) and normalized to SV-40 spike-in RNA. Hepatic venous pressure gradient (HVPG) was measured in 52 (70%) patients and the fibrosis stage was determined in 63 (85%) patients using transient elastography. Results The levels of circulating miRNA-122 were increased in HIV/HCV coinfected patients and significantly correlated with the alanine aminotransferase (ALT) (rs = 0.438; p<0.001) and aspartate transaminase AST values (rs = 0.336; p = 0.003), but not with fibrosis stage (p = n.s.). Interestingly, miRNA-122 levels showed an inverse correlation with hepatic venous pressure gradient (HVPG) (rs = −0.302; p = 0.03). Conclusion Elevated miRNA-122 levels are associated with liver injury, and with low HVPG. Though, miRNA-122 levels are not suitable to predict the degree of fibrosis, they might function as indicators for portal hypertension in HIV/HCV coinfected patients.

Chemokine (C-X-C motif) ligand 11 levels predict survival in cirrhotic patients with transjugular intrahepatic portosystemic shunt.

Chemokines, such as CXCR3‐ligands, have been identified to play an important role during hepatic injury, inflammation and fibrosis. While CXCL9 is associated with survival in patients receiving transjugular intrahepatic portosystemic shunt (TIPS), the role of CXCL11 in severe portal hypertension remains unknown.

The role of miRNA-34a as a prognostic biomarker for cirrhotic patients with portal hypertension receiving TIPS.

Background Circulating miRNA-34a is increased in blood of patients with different liver diseases when compared to healthy controls. However, the origin of miRNA-34a and its possible relationship with hemodynamics and outcome in cirrhotic patients with portal hypertension is unknown. We analyzed the levels of miRNA-34a in cirrhotic patients with severe portal hypertension. Methods We included 60 cirrhotic patients receiving TIPS for prevention of rebleeding and/or therapy-refractory ascites. miRNA-34a levels were measured using qPCR and normalized by SV-40 in the portal and hepatic venous blood of these patients taken at TIPS procedure. Hemodynamic and clinical parameters were assessed before TIPS and during follow-up. Results Levels of miRNA-34a were higher in the hepatic vein than in the portal vein. Circulating miRNA-34a in the hepatic vein correlated with ALT, CHE and sodium excretion after TIPS. miRNA-34a showed no correlation with portal pressure, but its levels in the portal vein correlated inversely with the congestion index. Interestingly, the levels of miRNA-34a in the portal and hepatic vein showed inverse correlation with arterial pressure. Furthermore, levels of miRNA-34a in the hepatic vein had a predictive value for survival, but MELD, creatinine at short-time follow-up 14 days after TIPS-insertion and portal pressure after TIPS performed better. Conclusion This study demonstrates for the first time, that miRNA-34a may originate to a large extent from the liver. Even though higher levels of miRNA-34a are possibly associated with better survival at long-term follow-up in cirrhotic patients with severe portal hypertension receiving TIPS, classical prognostic parameters predict the survival better.

Prospective Evaluation of Passive Expansion of Partially Dilated Transjugular Intrahepatic Portosystemic Shunt Stent Grafts-A Three-Dimensional Sonography Study.

PURPOSEnTo prospectively investigate early expansion kinetics of underdilated self-expanding stent grafts used for transjugular intrahepatic portosystemic shunt (TIPS) creation.nnnMATERIALS AND METHODSnTwenty patients (7 female; mean age 66 y; range, 31-80 y) with liver cirrhosis undergoing TIPS creation for variceal bleeding (n = 5), refractory ascites (n = 14), or both (n = 1) with underdilation of 10-mm stent grafts received two-dimensional (2-D) and three-dimensional (3-D) ultrasound (US) examinations immediately after TIPS creation and 1 and 6 weeks later. Orthogonal views of the TIPS within the parenchymal tract were reconstructed from 3-D volume data sets acquired in longitudinal orientation of the stent. 2-D images and reconstructed 3-D images were used for blinded diameter measurements. Measurement technique was validated with intrainterventional plain radiographs with a sizing catheter as the gold standard. Diameter changes over time and interrelations with patient characteristics (null hypothesis: no expansion, no interrelation) were analyzed using a general linear model for repeated measures.nnnRESULTSnAfter dilation to 8-mm diameter, 2-D and 3-D measurements showed stent recoil (mean diameter 7.7 mm ± 0.21 and 7.6 mm ± 0.17, respectively). Diameter increased significantly from initial measurements to measurements at 1 and 6 weeks (2-D, 8.8 mm ± 0.24 and 9.4 mm ± 0.15, both P < .001; 3-D, 8.7 mm ± 0.27 and 9.4 mm ± 0.11, both P < .001). Validation measurements showed no significant differences between 2-D or 3-D US and gold standard. There were no statistically significant associations between stent expansion and clinical parameters (sex, P = .78; age, P = .82; etiology/grade of cirrhosis, P = .99; indication for TIPS, P = .78, liver stiffness, P = .70).nnnCONCLUSIONSnUnderdilated self-expanding stent grafts used for TIPS creation significantly expand within first 6 weeks after intervention. These changes can be noninvasively monitored using 3-D US.

Sequential shear-wave elastography of liver and spleen rules out clinically significant portal hypertension in compensated advanced chronic liver disease

With interest we read the letter entitled ‘Ruling in and ruling out with elastography in compensated advanced chronic liver disease’ by Agustin et al 1 to our study ‘Algorithm to rule-out clinically significant portal hypertension combining Shear-wave elastography of liver and spleen: a prospective multi-centre study’.2 Indeed, we would like to thank our colleagues for their interest in our study and deciphering the strengths and weaknesses of this study. Besides acknowledging the merits of the study, the colleagues commented on the selection of patients regarding severity and aetiology of advanced chronic liver disease (ACLD), as well as the clinical importance of ruling out or ruling in clinically significant portal hypertension (CSPH).nnThe criticism about the selection of patients stimulated us to perform new calculations. Even though the algorithm was calculated including patients with decompensated ACLD (dACLD), it performed much better in …

Circulating Elastin Fragments Are Not Affected by Hepatic, Renal and Hemodynamic Changes, But Reflect Survival in Cirrhosis with TIPS

Background and AimsProgressive fibrosis increases hepatic resistance and causes portal hypertension with complications. During progressive fibrosis remodeling and deposition of collagens and elastin occur. Elastin remodeling is crucially involved in fibrosis progression in animal models and human data. This study investigated the association of circulating elastin with the clinical outcome in cirrhotic patients with severe portal hypertension receiving transjugular intrahepatic porto-systemic shunt (TIPS).MethodsWe analyzed portal and hepatic venous samples of 110 cirrhotic patients obtained at TIPS insertion and 2xa0weeks later. The circulating levels of elastin fragments (ELM) were determined using specific monoclonal ELISA. The relationship of ELM with clinical short-time follow-up and long-term outcome was investigated.ResultsCirculating levels of ELM showed a gradient across the liver before TIPS with higher levels in the hepatic vein. Interestingly, the circulating ELM levels remained unchanged after TIPS. The circulating levels of ELM in portal and hepatic veins correlated with platelet counts and inversely with serum sodium. Hepatic venous levels of ELM were higher in CHILD C compared to CHILD A and B and were associated with the presence of ascites. Patients with high levels of ELM in the hepatic veins before TIPS showed poorer survival. In multivariate analysis ELM levels in the hepatic veins and MELD were independent predictors of mortality in these patients.ConclusionThis study demonstrated that circulating levels of ELM are not associated with hemodynamic changes, but might reflect fibrosis remodeling and predict survival in patients with severe portal hypertension receiving TIPS independently of MELD.