Mortality and morbidity after combined heart and liver transplantation in the failing Fontan: An updated dual center retrospective study.

INTRODUCTION: As the adult Fontan population with Fontan associated liver disease continues to increase, more patients are being referred for transplantation, including combined heart and liver transplantation. METHODS: We report updated mortality and morbidity outcomes after combined heart and liver transplant in a retrospective cohort series of 40 patients (age 14 to 49 years) with Fontan circulation across two centers from 2006-2022. RESULTS: The 30-day, 1-year, 5-year and 10-year survival rate was 90%, 80%, 73% and 73% respectively. Sixty percent of patients met a composite comorbidity of needing either post-transplant mechanical circulatory support, renal replacement therapy or tracheostomy. Cardiopulmonary bypass time > 283 min (4.7 h) and meeting the composite comorbidity were associated with mortality by Kaplan Meier analysis. CONCLUSION: Further study to mitigate early mortality and the above comorbidities as well as the high risk of bleeding and vasoplegia in this patient population is warranted.

Imaging of Fontan-Associated Liver Disease.

ABSTRACT: The Fontan procedure is the definitive treatment for patients with single-ventricle physiology. Surgical advances have led to a growing number of patients surviving into adulthood. Fontan-associated liver disease (FALD) encompasses a spectrum of pathologic liver changes that occur secondary to altered physiology including congestion, fibrosis, and the development of liver masses. Assessment of FALD is difficult and relies on using imaging alongside of clinical, laboratory, and pathology information. Ultrasound, computed tomography, and magnetic resonance imaging are capable of demonstrating physiologic and hepatic parenchymal abnormalities commonly seen in FALD. Several novel imaging techniques including magnetic resonance elastography are under study for use as biomarkers for FALD progression. Imaging has a central role in detection and characterization of liver masses as benign or malignant. Benign FNH-like masses are commonly encountered; however, these can display atypical features and be mistaken for hepatocellular carcinoma (HCC). Fontan patients are at elevated risk for HCC, which is a feared complication and has a poor prognosis in this population. While imaging screening for HCC is widely advocated, no consensus has been reached regarding an optimal surveillance regimen.

Issues in multi-organ transplantation of the liver with kidney or heart in polycystic liver-kidney disease or congenital heart disease: Current practices and immunological aspects.

Solid organ transplantation has become an integral part of the management of patients with end-stage diseases of the kidney, liver, heart and lungs. Most procedures occur in isolation, but multi-organ transplantation of the liver with either the kidney or heart has become an option. As more patients with congenital heart disease and cardiac cirrhosis survive into adulthood, particularly after the Fontan procedure, liver transplant teams are expected to face questions regarding multi-organ (heart-liver) transplantation. Similarly, patients with polycystic kidneys and livers may be managed by multi-organ transplantation. Herein, we review the indications and outcomes of simultaneous liver-kidney transplantation for polycystic liver-kidney disease, and discuss the indications, timing and procedural aspects of combined heart-liver transplantation. We also summarise the evidence for, and potential mechanisms underlying, the immunoprotective impact of liver allografts on the simultaneously transplanted organs.

Triple-Phase Computed Tomography May Replace Dual-Energy X-ray Absorptiometry Scan for Evaluation of Osteoporosis in Liver Transplant Candidates.

Assessment of bone density is an important part of liver transplantation (LT) evaluation for early identification and treatment of osteoporosis. Dual-energy X-ray absorptiometry (DXA) is currently the standard clinical test for osteoporosis; however, it may contribute to the appointment burden on LT candidates during the cumbersome evaluation process, and there are limitations affecting its accuracy. In this study, we evaluate the utility of biomechanical analysis of vertebral images obtained during dual-energy abdominal triple-phase computed tomography (TPCT) in diagnosing osteoporosis among LT candidates. We retrospectively reviewed cases evaluated for LT between January 2017 and March 2018. All patients who underwent TPCT within 3 months of DXA were included. The biomechanical computed tomography (BCT) analysis was performed at a centralized laboratory (O.N. Diagnostics, Berkeley, CA) by 2 trained analysts blinded to the DXA data. DXA-based osteoporosis was defined as a T score ≤-2.5 at the hip or spine. BCT-based osteoporosis was defined as vertebral strength ≤4500 N for women or ≤6500 N for men or trabecular volumetric bone mineral density ≤80 mg/cm3 . Comparative data were available for 91 patients who had complete data for both DXA and BCT: 31 women and 60 men, age 54 ± 11 years (mean ± standard deviation), mean body mass index 28 ± 6 kg/m2 . Using DXA as the clinical reference, sensitivity of BCT to detect DXA-defined osteoporosis was 83.3% (20/24 patients) and negative predictive value was 91.7%; specificity and positive predictive value were 65.7% and 46.5%, respectively. BCT analysis of vertebral images on triple-phase computed tomography, routinely obtained during transplant evaluation, can reliably rule out osteoporosis in LT candidates. Patients with suspicion of osteoporosis on TPCT may need further evaluation by DXA.

Quantitative assessment of portal hypertension with bi-parametric dual-frequency hepatic MR elastography in mouse models.

OBJECTIVES: To determine the potential of bi-parametric dual-frequency hepatic MR elastography (MRE) for predicting portal pressure (PP) in mouse models of portal hypertension (PHTN) with the presence of varying hepatic fibrosis. METHODS: We studied 73 wild-type male mice, including 22 mice with hepatic congestion, 20 mice with cholestatic liver injury, and 31 age-matched sham mice. Hepatic shear stiffness (SS) and volumetric strain (VS) were calculated by 3D MRE acquired at 80 and 200 Hz. We measured PP immediately after MRE. Liver fibrosis was verified by hydroxyproline assay. We predicted PP by fitting generalized linear models with single- and dual-frequency SS and VS, respectively. The relationship between predicted and actual PP was evaluated by Spearman's correlation. We compared the prediction accuracy of portal hypertension for all models with DeLong tests at a significance level of 0.05. RESULTS: Animals with congestive or cholestatic liver disease developed significant PHTN and hepatic fibrosis to varying degrees. In both models, SS increased, while VS decreased significantly compared with shams. All bi-parametric models had high diagnostic accuracy for PHTN. The dual-frequency models (AUCs: 0.90 [81-95%], 0.91 [81-95%]) had substantially or significantly higher accuracy than single-frequency ones (AUCs: 0.83 [71-91%], and 0.78 [66-87%]). The predicted PP of dual-frequency models also showed stronger correlations with actual PP than single-frequency predictions. CONCLUSIONS: The bi-parametric dual-frequency model improved the diagnostic accuracy of liver MRE in diagnosing PHTN in preclinical models. This technical advance has the potential to monitor PHTN progression and treatment efficacy in the presence of varying fibrosis. KEY POINTS: • Bi-parametric hepatic MR elastography can predict portal pressure. • The prediction models of shear stiffness and volumetric strain with dual-frequency measurements demonstrate high diagnostic accuracy (AUCs > 0.9) in two different portal hypertension mouse models with varying fibrosis.

Neutrophil Extracellular Traps and Liver Disease.

Neutrophil extracellular traps, or NETs, are heterogenous, filamentous structures which consist of extracellular DNA, granular proteins, and histones. NETs are extruded by a neutrophil in response to various stimuli. Although NETs were initially implicated in immune defense, subsequent studies have implicated NETs in a spectrum of disease processes, including autoimmune disease, thrombosis, and cancer. NETs also contribute to the pathogenesis of several common liver diseases, including alcohol-associated liver disease and portal hypertension. Although there is much interest in the therapeutic potential of NET inhibition, future clinical applications must be balanced against potential increased risk of infection.

Mechanical Stretch Increases Expression of CXCL1 in Liver Sinusoidal Endothelial Cells to Recruit Neutrophils, Generate Sinusoidal Microthombi, and Promote Portal Hypertension.

BACKGROUND & AIMS: Mechanical forces contribute to portal hypertension (PHTN) and fibrogenesis. We investigated the mechanisms by which forces are transduced by liver sinusoidal endothelial cells (LSECs) into pressure and matrix changes. METHODS: We isolated primary LSECs from mice and induced mechanical stretch with a Flexcell device, to recapitulate the pulsatile forces induced by congestion, and performed microarray and RNA-sequencing analyses to identify gene expression patterns associated with stretch. We also performed studies with C57BL/6 mice (controls), mice with deletion of neutrophil elastase (NE-/-) or peptidyl arginine deiminase type IV (Pad4-/-) (enzymes that formation of neutrophil extracellular traps [NETs]), and mice with LSEC-specific deletion of Notch1 (Notch1iΔEC). We performed partial ligation of the suprahepatic inferior vena cava (pIVCL) to simulate congestive hepatopathy-induced portal hypertension in mice; some mice were given subcutaneous injections of sivelestat or underwent bile-duct ligation. Portal pressure was measured using a digital blood pressure analyzer and we performed intravital imaging of livers of mice. RESULTS: Expression of the neutrophil chemoattractant CXCL1 was up-regulated in primary LSECs exposed to mechanical stretch, compared with unexposed cells. Intravital imaging of livers in control mice revealed sinusoidal complexes of neutrophils and platelets and formation of NETs after pIVCL. NE-/- and Pad4-/- mice had lower portal pressure and livers had less fibrin compared with control mice after pIVCL and bile-duct ligation; neutrophil recruitment into sinusoidal lumen of liver might increase portal pressure by promoting sinusoid microthrombi. RNA-sequencing of LSECs identified proteins in mechanosensitive signaling pathways that are altered in response to mechanical stretch, including integrins, Notch1, and calcium signaling pathways. Mechanical stretch of LSECs increased expression of CXCL1 via integrin-dependent activation of transcription factors regulated by Notch and its interaction with the mechanosensitive piezo calcium channel. CONCLUSIONS: In studies of LSECs and knockout mice, we identified mechanosensitive angiocrine signals released by LSECs which promote PHTN by recruiting sinusoidal neutrophils and promoting formation of NETs and microthrombi. Strategies to target these pathways might be developed for treatment of PHTN. RNA-sequencing accession number: GSE119547.

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).

Pre-Procedural Patient Education Reduces Fall Risk in an Outpatient Endoscopy Suite.

The purpose of this article was to determine whether scripted pre-procedural fall risk patient education and nurses' intention to assist patients after receiving sedation improves receptiveness of nursing assistance during recovery and decreases fall risk in an outpatient endoscopy suite. We prospectively identified high fall risk patients using the following criteria: (1) use of an assistive device, (2) fallen two or more times within the last year, (3) sustained an injury in a fall within a year, (4) age greater than 85 years, or (5) nursing judgment of high fall risk. Using a scripted dialogue, nurses educated high-risk patients of their fall risk and the nurses' intent to assist them to and in the bathroom. Documentation of patient education, script use, and assistance was monitored. Over 24 weeks, 892 endoscopy patients were identified as high fall risk; 790 (88.5%) accepted post-procedural assistance. Documentation of assistance significantly increased from 33% to 100%. Patients receiving education and postprocedural assistance increased from 27.9% to 100% at week 24. No patient falls occurred 12 months following implementation among patients identified as high fall risk. Scripted pre-procedural fall risk education increases patient awareness and receptiveness to assistance and can lead to decreased fall rates.

Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces.

UNLABELLED: 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 ß-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.

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

UNLABELLED:  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.