Moira Hilscher

Chronic Passive Venous Congestion drives Hepatic Fibrogenesis via Sinusoidal Thrombosis and Mechanical Forces

Chronic passive hepatic congestion (congestive hepatopathy) leads to hepatic fibrosis; however, the mechanisms involved in this process are not well understood. We developed a murine experimental model of congestive hepatopathy through partial ligation of the inferior vena cava (pIVCL). C57BL/6 and transgenic mice overexpressing tissue factor pathway inhibitor (SM22α‐TFPI) were subjected to pIVCL or sham. Liver and blood samples were collected and analyzed in immunohistochemical, morphometric, real‐time polymerase chain reaction, and western blot assays. Hepatic fibrosis and portal pressure were significantly increased after pIVCL concurrent with hepatic stellate cell (HSC) activation. Liver stiffness, as assessed by magnetic resonance elastography, correlated with portal pressure and preceded fibrosis in our model. Hepatic sinusoidal thrombosis as evidenced by fibrin deposition was demonstrated both in mice after pIVCL as well as in humans with congestive hepatopathy. Warfarin treatment and TFPI overexpression both had a protective effect on fibrosis development and HSC activation after pIVCL. In vitro studies show that congestion stimulates HSC fibronectin (FN) fibril assembly through direct effects of thrombi as well as by virtue of mechanical strain. Pretreatment with either Mab13 or Cytochalasin‐D, to inhibit β‐integrin or actin polymerization, respectively, significantly reduced fibrin and stretch‐induced FN fibril assembly. Conclusion: Chronic hepatic congestion leads to sinusoidal thrombosis and strain, which in turn promote hepatic fibrosis. These studies mechanistically link congestive hepatopathy to hepatic fibrosis. (Hepatology 2015;61:648‐659)

Mechanosensing and fibrosis

Tissue injury disrupts the mechanical homeostasis that underlies normal tissue architecture and function. The failure to resolve injury and restore homeostasis gives rise to progressive fibrosis that is accompanied by persistent alterations in the mechanical environment as a consequence of pathological matrix deposition and stiffening. This Review focuses on our rapidly growing understanding of the molecular mechanisms linking the altered mechanical environment in injury, repair, and fibrosis to cellular activation. In particular, our focus is on the mechanisms by which cells transduce mechanical signals, leading to transcriptional and epigenetic responses that underlie both transient and persistent alterations in cell state that contribute to fibrosis. Translation of these mechanobiological insights may enable new approaches to promote tissue repair and arrest or reverse fibrotic tissue remodeling.

Surveillance for liver complications after the Fontan procedure.

The physiological consequences of the Fontan circulation impose risk for hepatic dysfunction and may culminate in hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Consensus regarding appropriate surveillance modalities to diagnose liver disease in Fontan patients is lacking, in part due to the relative lack of strong evidence and prospective studies in this patient population. The goal of this paper is to critically review the current evidence and provide recommendations for the surveillance of hepatic complications in the post-Fontan patient population.

Alkaline phosphatase normalization is a biomarker of improved survival in primary sclerosing cholangitis

INTRODUCTION Recent studies suggest that serum alkaline phosphatase may represent a prognostic biomarker in patients with primary sclerosing cholangitis. However, this association remains poorly understood. Therefore, the aim of this study was to investigate the prognostic significance and clinical correlates of alkaline phosphatase normalization in primary sclerosing cholangitis. MATERIAL AND METHODS This was a retrospective cohort study of patients with a new diagnosis of primary sclerosing cholangitis made at an academic medical center. The primary endpoint was time to hepatobiliaryneoplasia, liver transplantation, or liver-related death. Secondary endpoints included occurrence of and time to alkaline phosphatase normalization. Patients who did and did not achieve normalization were compared with respect to clinical characteristics and endpoint-free survival, and the association between normalization and the primary endpoint was assessed with univariate and multivariate Cox proportional-hazards analyses. RESULTS Eighty-six patients were included in the study, with a total of 755 patient-years of follow-up. Thirty-eight patients (44%) experienced alkaline phosphatase normalization within 12 months of diagnosis. Alkaline phosphatase normalization was associated with longer primary endpoint-free survival (p = 0.0032) and decreased risk of requiring liver transplantation (p = 0.033). Persistent normalization was associated with even fewer adverse endpoints as well as longer survival. In multivariate analyses, alkaline phosphatase normalization (adjusted hazard ratio 0.21, p = 0.012) and baseline bilirubin (adjusted hazard ratio 4.87, p = 0.029) were the only significant predictors of primary endpoint-free survival. CONCLUSIONS Alkaline phosphatase normalization, particularly if persistent, represents a robust biomarker of improved long-term survival and decreased risk of requiring liver transplantation in patients with primary sclerosing cholangitis.

Surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma (CCA) and gallbladder carcinoma (GBCa). Surveillance for GBCa is recommended, but the clinical utility of surveillance for other hepatobiliary cancers (HBCa) in PSC, namely CCA and hepatocellular carcinoma (HCC), remains unclear. We aimed to determine whether surveillance is associated with better survival after diagnosis of HBCa in patients with PSC. Medical records of PSC patients seen at the Mayo Clinic Rochester from 1995 to 2015 were reviewed. Patients were included if they had ≥1 year of follow‐up and developed HBCa. Patients were categorized according to their surveillance status (abdominal imaging, carbohydrate antigen 19‐9, and alpha‐fetoprotein). The primary endpoints were HBCa recurrence, HBCa‐related death, and all‐cause mortality. Overall survival was assessed by the Kaplan‐Meier survival method; HBCa‐related survival was assessed using competing risk regression. Tests of significance were two‐tailed, and a P value <0.05 was considered statistically significant. From 1995 to 2015, a total of 79 of 830 PSC patients were diagnosed with HBCa. Cumulative follow‐up was 712 and 283 person‐years pre‐ and post‐HBCa diagnosis, respectively. Seventy‐eight percent of patients (54/79) developed CCA, 21% (17/79) HCC, 6% (5/79) GBCa, 3% (2/79) both CCA and HCC, and 1% (1/79) both HCC and GBCa. Fifty‐one percent (40/79) were under HBCa surveillance, and 49% (39/79) were not. Patients in the surveillance group had significantly higher 5‐year overall survival (68% versus 20%, respectively; P < 0.001) and significantly lower 5‐year probability of experiencing an HBCa‐related adverse event (32% versus 75%, respectively; P < 0.001) compared with the no‐surveillance group. Conclusion: This study demonstrates that HBCa surveillance significantly improves outcomes, including survival, in patients with PSC. (Hepatology 2018;67:2338‐2351).

Congestive hepatopathy: Congestive Hepatopathy

The liver is a highly vascular organ that receives approximately 25% of cardiac output and is prone to a spectrum of circulatory disturbances and vascular insult. Congestive hepatopathy describes the manifestations of chronic, passive congestion of the liver in the setting of heart failure or other cardiac defects that result in elevation of the central venous pressure. Circulatory impairment of the liver can also occur in the setting of a spectrum of primary vascular disorders that arise at different anatomic locations in the liver, including sinusoidal obstruction syndrome, portal vein thrombosis, Budd-Chiari syndrome, and peliosis hepatitis. This article focuses on the pathophysiology and clinical features of passive congestive disorders related to cardiac dysfunction.

Endothelial JAK2V617F does not enhance liver lesions in mice with Budd-Chiari syndrome

To the Editor: Budd-Chiari syndrome is defined as hepatic venous outflow obstruction in the absence of congestive or restrictive heart disease. Myeloproliferative neoplasms are the leading cause of Budd-Chiari syndrome, diagnosed in 25–50% of such patients. In most patients with Budd-Chiari syndrome and myeloproliferative neoplasms, Janus kinase 2 gene (JAK2) V617F mutation is found in myeloid cells. JAK2 has also been detected in liver endothelial cells of patients with Budd-Chiari syndrome, attributed to a common cell of origin for myeloid and endothelial cells, called hemangioblast. In Budd-Chiari syndrome, JAK2 is associated with poorer prognostic features at presentation and earlier need for hepatic decompression procedures. This observation leads to the hypothesis that JAK2 enhances liver injury and fibrosis induced by hepatic venous outflow obstruction, thus worsening Budd-Chiari syndrome. In order to test this hypothesis, we applied a recently described surgical model of Budd-Chiari syndrome to mice expressing JAK2. JAK2 expression in myeloid cells promotes major vasodilation and hemostasis impairment,

The Utility of MR Elastography to Differentiate Nodular Regenerative Hyperplasia from Cirrhosis

Nodular regenerative hyperplasia (NRH) is characterized by diffuse parenchymal nodularity of the liver with small regenerative nodules, leading to possible portal hypertension. Differentiating NRH from cirrhosis on standard imaging is difficult. We evaluated the potential utility of MRI and MR Elastography (MRE) in differentiating NRH and cirrhosis. This article is protected by copyright. All rights reserved.