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.

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.

Systemic Venous Hypertension and Low Output Are Prevalent at Catheterization in Adults with Pulmonary Atresia and Intact Ventricular Septum Regardless of Repair Strategy.

Patients with pulmonary atresia and intact ventricular septum (PA-IVS) require intervention early in life, and most survive to a definitive procedure of either Fontan circulation or right ventricle to pulmonary artery (RV-PA) repair. It remains unknown how surgical strategy impacts hemodynamics and comorbidities in adults. Retrospective analysis of adults (age ≥18 years) with PA-IVS undergoing hemodynamic catheterization at Mayo Clinic, MN between January 2000 through January 2020 was performed. 14 patients in the RV-PA group (71% biventricular, 29% 1.5 ventricle repair) and 19 post-Fontan patients [9 lateral tunnel (48%), 6 atriopulmonary (32%), and 4 extracardiac (21%)] were identified. Median age was 29 (21, 34) years. There were no differences in demographics and laboratory data (including MELD-XI) between groups. All patients assessed for liver disease had evidence of hepatic congestion or cirrhosis (14 in the Fontan group and 4 in the RV-PA group). Invasive hemodynamics were comparable between groups with the Fontan and RV-PA groups having similar systemic venous pressure (15.7±4.4 vs. 14.3±6.2, p = .44) and cardiac output (2.2±0.6 vs. 2.0±0.4 L/min/m2, p = .23). There was no difference in transplant-free survival (p = .92; 5-year transplant-free survival RV-PA 84%, Fontan 80%). Hemodynamic derangements, namely elevated systemic venous pressure and low cardiac output, are prevalent in patients with PA-IVS undergoing cardiac catheterization regardless of surgical strategy.

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.

Cholestatic Liver Diseases: A Primer for Generalists and Subspecialists.

Cholestasis describes impairment in bile formation or flow which can manifest clinically with fatigue, pruritus, and jaundice. The differential diagnosis of cholestatic liver diseases is broad, and the etiologies of cholestasis vary in the anatomical location of the defect and acuity of presentation. Cholestasis may occur in a variety of clinical scenarios. Therefore, it is important for a diverse audience with varied clinical practices to have a basic understanding of manifestations of cholestatic liver diseases.

An update on primary sclerosing cholangitis epidemiology, outcomes and quantification of alkaline phosphatase variability in a population-based cohort.

BACKGROUND: Contemporary primary sclerosing cholangitis (PSC) population-based cohorts describing the epidemiology, natural history, and long-term fluctuations in serum alkaline phosphatase (SAP) and their prognostic relevance are lacking. Therefore, we investigated the incidence and natural history of PSC and quantified SAP fluctuations among those with PSC in Olmsted County, Minnesota over the last 41 years. METHODS: The Rochester Epidemiology Project was used to identify 56 subjects diagnosed with PSC between 1976 and 2017 in Olmsted County. The primary endpoint (n = 19) included liver transplantation, hepatic decompensation, and cholangiocarcinoma. RESULTS: The age- and sex-adjusted incidence of PSC (per 100,000 person years) nearly doubled from 2001 to 2017 compared to 1976-2000 (1.47; 95% CI 0.99-1.96 versus 0.79; 95% CI 0.42-1.16, p = 0.02). This increase paralleled a rise in patients with markers of a milder phenotype at the time of diagnosis: normal SAP (26.32% versus 0%, p < 0.01) and lower Mayo PSC risk score [0.36 (- 0.57 to 1.55) versus - 0.50 (- 1.25 to 0.35), p = 0.03]. Intra-individual SAP fluctuates with a median coefficient of variation of 36.20%. SAP normalization and dropping below 1.5 × upper limit of normal (ULN) occurs at a rate of 5% and 10% per year, respectively. SAP less than 1.5 × ULN was associated with a lower risk of PSC-related complications (hazard ratio 0.11; 95% CI 0.03-0.42). CONCLUSIONS: The patients with PSC are increasingly being diagnosed with a milder phenotype. While a lower SAP is associated with improved outcomes, the high intra-individual variation of SAP levels calls into question the practice of using a single SAP value as a surrogate endpoint in clinical trials.

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.

The Liver in Circulatory Disturbances.

Liver diseases frequently coexist with heart disease. The causes of coexistent heart and liver disease are categorized into four groups: (1) heart disease affecting the liver, (2) liver disease affecting the heart, (3) cardiac and hepatic manifestations of a common cause, and (4) coexistent heart and liver disease with distinct causes. Discerning the cause of cardiac and liver dysfunction is important in the management of these conditions, particularly when considering surgical intervention or heart or liver transplantation.

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.

Dominant strictures in primary sclerosing cholangitis: A multicenter survey of clinical definitions and practices.

Dominant strictures (DSs) of the biliary tree occur in approximately 50% of patients with primary sclerosing cholangitis (PSC) and may cause significant morbidity. Nevertheless, the definition and management of DSs lacks consensus. We aimed to better understand current perceptions and practices regarding PSC-associated DSs. We conducted an anonymous, 23-question, survey-based study wherein electronic surveys were distributed to 131 faculty in the Division of Gastroenterology and Hepatology at the three Mayo Clinic campuses (Rochester, Scottsdale, and Jacksonville) as well as the affiliated practice network. Responses were aggregated and compared, where applicable, to practice guidelines of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver. A total of 54 faculty (41.2%) completed the survey, of whom 24 (44.4%) were hepatologists, 21 (38.9%) gastroenterologists, and 9 (16.7%) advanced endoscopists. One of the major study findings was that there was heterogeneity among participants' definition, evaluation, management, and follow-up of DSs in PSC. The majority of participant responses were in accordance with societal practice guidelines, although considerable variation was noted. Conclusion: Despite the prevalence and morbidity of DSs in PSC, clinical perceptions and practices vary widely among hepatologists, gastroenterologists, and advanced endoscopists who manage these patients, even within a single health care system. Further studies are needed to address these variations, develop general and evidence-based consensus, and increase adherence to societal guidelines. (Hepatology Communications 2018;2:836-844).

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.