Management of cardiac diseases in liver transplant recipients: Comprehensive review and multidisciplinary practice-based recommendations.

Cardiac diseases are one of the most common causes of morbidity and mortality following liver transplantation (LT). Prior studies have shown that cardiac diseases affect close to one-third of liver transplant recipients (LTRs) long term and that their incidence has been on the rise. This rise is expected to continue as more patients with advanced age and/or non-alcoholic steatohepatitis undergo LT. In view of the increasing disease burden, a multidisciplinary initiative was developed to critically review the existing literature (between January 1, 1990 and March 17, 2021) surrounding epidemiology, risk assessment, and risk mitigation of coronary heart disease, arrhythmia, heart failure, and valvular heart disease and formulate practice-based recommendations accordingly. In this review, the expert panel emphasizes the importance of optimizing management of metabolic syndrome and its components in LTRs and highlights the cardioprotective potential for the newer diabetes medications (e.g., sodium glucose transporter-2 inhibitors) in this high-risk population. Tailoring the multidisciplinary management of cardiac diseases in LTRs to the cardiometabolic risk profile of the individual patient is critical. The review also outlines numerous knowledge gaps to pave the road for future research in this sphere with the ultimate goal of improving clinical outcomes.

Liver transplantation for hepatocellular carcinoma: Management after the transplant.

Hepatocellular carcinoma (HCC) is an increasingly common indication for liver transplantation (LT) in the United States and in many parts of the world. In the last decade, significant work has been done to better understand how to risk stratify LT candidates for recurrence of HCC following transplant using a combination of biomarker and imaging findings. However, despite the high frequency of HCC in the LT population, guidance regarding posttransplant management is lacking. In particular, there is no current evidence to support specific post-LT surveillance strategies, leading to significant heterogeneity in practices. In addition, there are no current recommendations regarding recurrence prevention, including immunosuppression regimen or secondary prevention with adjuvant chemotherapy. Finally, guidance on treatment of disease recurrence is also lacking and there is significant controversy about the use of immunotherapy in transplant recipients due to the risk of rejection. Thus, outcomes for patients with recurrence are poor. This paper therefore provides a comprehensive review of the current literature on post-LT management of patients with HCC and identifies gaps in our current knowledge that are in urgent need of further investigation.

Outcomes of Liver Transplantation Among Older Recipients With Nonalcoholic Steatohepatitis in a Large Multicenter US Cohort: the Re-Evaluating Age Limits in Transplantation Consortium.

The liver transplantation (LT) population is aging, with the need for transplant being driven by the growing prevalence of nonalcoholic steatohepatitis (NASH). Older LT recipients with NASH may be at an increased risk for adverse outcomes after LT. Our objective is to characterize outcomes in these recipients in a large multicenter cohort. All primary LT recipients ≥65 years from 2010 to 2016 at 13 centers in the Re-Evaluating Age Limits in Transplantation (REALT) consortium were included. Of 1023 LT recipients, 226 (22.1%) were over 70 years old, and 207 (20.2%) had NASH. Compared with other LT recipients, NASH recipients were older (68.0 versus 67.3 years), more likely to be female (47.3% versus 32.8%), White (78.3% versus 68.0%), Hispanic (12.1% versus 9.2%), and had higher Model for End-Stage Liver Disease-sodium (21 versus 18) at LT (P < 0.05 for all). Specific cardiac risk factors including diabetes with or without chronic complications (69.6%), hypertension (66.3%), hyperlipidemia (46.3%), coronary artery disease (36.7%), and moderate-to-severe renal disease (44.4%) were highly prevalent among NASH LT recipients. Graft survival among NASH patients was 90.3% at 1 year and 82.4% at 3 years compared with 88.9% at 1 year and 80.4% at 3 years for non-NASH patients (log-rank P = 0.58 and P = 0.59, respectively). Within 1 year after LT, the incidence of graft rejection (17.4%), biliary strictures (20.9%), and solid organ cancers (4.9%) were comparable. Rates of cardiovascular (CV) complications, renal failure, and infection were also similar in both groups. We observed similar posttransplant morbidity and mortality outcomes for NASH and non-NASH LT recipients. Certain CV risk factors were more prevalent in this population, although posttransplant outcomes within 1 year including CV events and renal failure were similar to non-NASH LT recipients.

Real-Time Ultrasound-Guided Paracentesis by Radiologists: Near Zero Risk of Hemorrhage without Correction of Coagulopathy.

PURPOSE: To evaluate the rate and risk factors for hemorrhage in patients undergoing real-time, ultrasound-guided paracentesis by radiologists without correction of coagulopathy. MATERIALS AND METHODS: This was a retrospective study of all patients who underwent real-time, ultrasound-guided paracentesis at a single institution over a 2-year period. In total, 3116 paracentesis procedures were performed: 757 (24%) inpatients and 2,359 (76%) outpatients. Ninety-five percent of patients had a diagnosis of cirrhosis. Mean patient age was 56.6 years. Mean international normalized ratio (INR) was 1.6; INR was > 2 in 437 (14%) of cases. Mean platelet count was 122 x 103/µL; platelet count was < 50 x 103/µL in 368 (12%) of patients. Seven hundred seven (23%) patients were dialysis dependent. Patients were followed for 2 weeks after paracentesis to assess for hemorrhage requiring transfusion or rescue angiogram/embolization. Univariate analysis was performed to determine risk factors for hemorrhage. Blood product and cost saving analysis were performed. RESULTS: Significant post-paracentesis hemorrhage occurred in 6 (0.19%) patients, and only 1 patient required an angiogram with embolization. No predictors of post-procedure bleeding were found, including INR and platelet count. Transfusion of 1125 units of fresh frozen plasma and 366 units of platelets were avoided, for a transfusion-associated cost savings of $816,000. CONCLUSIONS: Without correction of coagulation abnormalities with prophylactic blood product transfusion, post-procedural hemorrhage is very rare when paracentesis is performed with real-time ultrasound guidance by radiologists.

Immune Reconstitution Syndrome with Initiation of Treatment of HBV/HIV Co-infection: Activity Flare associated with E antigen Seroconversion.

Immune reconstitution syndrome is a recognized complication with initiation of highly active antiretroviral therapy for acquired immune deficiency syndrome patients co-infected with hepatitis B. Hepatitis B flares are seen in 20%-25% of patients after initiation of highly active antiretroviral therapy, an estimated 1%-5% of whom develop clinical hepatitis. We present a case of highly active antiretroviral therapy initiation for HIV that led to a flare of HBV activity despite antiviral therapy directed towards both. Liver biopsy and longitudinal serologic evaluation lend support to the hypothesis that the flare in activity was representative of IRIS. Importantly, we document eAg/eAb seroconversion with the IRIS phenomenon.

Direct intrahepatic portocaval shunt for treatment of portal thrombosis and Budd-Chiari syndrome.

Budd-Chiari syndrome (BCS) refers to hepatic venous outflow obstruction that in severe cases can lead to acute liver failure prompting consideration of revascularization or transplantation. Here, a 22 year old female with angiographically proven BCS secondary to JAK2/V617F positive Polycythemia vera on therapeutic warfarin presented with acute liver failure (ALF). Imaging revealed a new, near complete thrombotic occlusion of the main portal vein with extension into the superior mesenteric vein. An emergent direct intrahepatic portocaval shunt (DIPS) was created and liver function promptly normalized. She has been maintained on rivaroxaban since that time. Serial assessment over 1 year demonstrated continued shunt patency and improved flow in the mesenteric vasculature on ultrasound as well as normal liver function. DIPS is a viable alternative in the treatment of ALF from BCS when standard recanalization is not feasible. Improved blood flow may also improve portal/mesenteric clot burden. While further investigation is needed, new targeted anticoagulants may be viable as a long term anticoagulation strategy.

Validation of the Prague C & M criteria for the endoscopic grading of Barrett's esophagus by gastroenterology trainees: a multicenter study.

BACKGROUND: The Prague C & M criteria, developed for the endoscopic grading of Barrett's esophagus (BE), (C = circumferential length, M = maximal length) were previously validated among a panel of 29 expert endoscopists with a special interest in BE. Its performance among gastroenterology trainees is unknown. OBJECTIVE: To test interobserver agreement among gastroenterology trainees for the Prague C & M criteria, identification of the gastroesophageal junction (GEJ) and the diaphragmatic hiatus. DESIGN: A prospective study. SETTING: Two tertiary referral centers. PATIENTS AND INTERVENTIONS: Standardized endoscopic videos were used. MAIN OUTCOME MEASUREMENTS: Interobserver agreement. RESULTS: Eighteen high-quality videos (normal esophagus, short and long lengths of BE, equally distributed) were independently evaluated by 18 gastroenterology trainees (year 1, n = 5; year 2, n = 6; year 3, n = 7) after administration of a formal teaching module by an expert endoscopist. Overall intraclass correlation coefficients for assessment of the C and M extent of the endoscopic BE segment above the GEJ were 0.94 (95% CI, 0.89-0.98) and 0.96 (95% CI, 0.94-0.98), respectively. The overall intraclass correlation coefficients for GEJ and diaphragmatic hiatus location recognition were 0.92 (0.86-0.96) and 0.90 (0.82-0.95), respectively. The year of training did not affect interobserver agreement. LIMITATIONS: The use of videos for endoscopic evaluation. CONCLUSION: After standardized teaching, the Prague C & M criteria have high overall validity among gastroenterology trainees irrespective of the level of training for endoscopic evaluation of visualized BE lengths as well as key endoscopic landmarks.

Immune response to extracellular matrix collagen in chronic hepatitis C-induced liver fibrosis.

Hepatitis C virus (HCV) infection and its recurrence after orthotopic liver transplantation (OLT) are associated with the remodeling of extracellular matrix (ECM) components [particularly collagen (Col)], which leads to fibrosis. Our aim was to determine whether the development of antibodies (Abs) to self-antigen Col in HCV-infected patients correlates with the fibrosis stage and the peripheral cytokine response. Patients with chronic HCV infection, patients with HCV recurrence after OLT who had undergone a biopsy procedure, and healthy control subjects were enrolled. The HCV subjects (n = 70) were stratified as follows: (1) a non-OLT group without fibrosis (Scheuer stages 0-2), (2) a non-OLT group with fibrosis (Scheuer stages 3-4), (3) a post-OLT group without fibrosis (Scheuer stages 0-2), and (4) a post-OLT group with fibrosis (Scheuer stages 3-4). Serum samples were analyzed for Abs against Col1, Col2, Col4, Col5, and vimentin with enzyme-linked immunosorbent assays. Serum levels of cytokines were measured with multiplex bead immunoassays. The levels of Abs to Col1 were higher in the fibrosis groups versus the no-fibrosis groups and the controls for both non-OLT patients (P < 0.001) and post-OLT patients (P = 0.01). There were increased levels of Abs to Col2, Col4, Col5, and vimentin in the non-OLT fibrosis group (Col2, P = 0.0001; Col4, P = 0.122; Col5, P < 0.0001; vimentin, P = 0.36) and in the post-OLT fibrosis group (Col2, P = 0.006; Col4, P = 0.19; Col5, P < 0.0001; vimentin, P = 0.24) in comparison with the no-fibrosis groups. The non-OLT and post-OLT fibrosis groups demonstrated significantly higher T helper 2 (T(h) 2) and T helper 17 (T(h) 17) cytokine levels and lower T helper 1 cytokine levels in comparison with the no-fibrosis groups. Our results demonstrate that in HCV-infected patients, the levels of Abs to ECM Col1, Col2, and Col5 positively correlate with liver fibrosis, which is associated with a predominantly T(h) 2 and T(h) 17 cytokine profile.

Rapid Development of De Novo Thoracic Aneurysm After Liver Transplant.

The development of aortic aneurysms in post-transplant patients is a rare but potentially lethal problem. De novo aortic aneurysm formation and rapid growth are postulated to result from an imbalance between pro- and anti-inflammatory vascular endothelial factors after transplant. Here, we present a case of de novo thoracic aneurysm formation within 2 months of orthotopic liver transplant. Prompt clinical recognition allowed for successful endovascular repair. Transplant clinicians should be aware of this potentially life-threatening complication and monitor at-risk recipients accordingly.

Alloimmunity and autoimmunity in chronic rejection.

PURPOSE OF REVIEW: Recent studies demonstrate an increasing role for alloimmune responses in the disruption of self-tolerance leading to immune responses to self-antigens that play a role in the immunopathogenesis of chronic rejection following solid organ transplantation. This review summarizes recent studies and implications for the alloimmune-response-induced de-novo development of autoimmune responses following solid organ transplantations. RECENT FINDINGS: Immediately following organ transplantation, several factors lead to enduring an inflammatory milieu. Studies from our laboratory and others have demonstrated that development of antihuman leukocyte antigen antibodies precedes the development of chronic rejection. Using an in-vivo murine model, we have demonstrated that administration of anti-major histocompatibility complex (MHC) class I directly into the native lungs leads to chronic rejection pathology. Further, the in-vitro ligation of epithelial cell surface MHC class I molecules by specific anti-MHC can lead to cell activation and production of fibrinogenic growth factors. SUMMARY: On the basis of these findings, we hypothesized that alloimmune responses can lead to autoimmunity, thus playing an important role in chronic rejection. Characterization of both the temporal occurrence and functional significance of antibodies to self-antigens may provide insight into the pathogenesis of chronic rejection and these antibodies can serve as clinically useful biomarkers.

Utility of Transjugular Intrahepatic Portosystemic Shunt Placement for Maintaining Portal Vein Patency in Candidates on Wait Lists Who Develop Thrombus.

OBJECTIVES: Although no longer a contraindication to liver transplant, portal vein thrombosis may lead to longer operative time and complexities in venous reconstruction. Strategies to maintain preoperative patency include systemic anticoagulation and/or transjugular intrahepatic portosystemic shunt placement. The former may not be ideal in cirrhotic patients prone to luminal gastrointestinal tract bleeding, and factors that predict improvements in portal vein thrombosis with the latter have not been well defined. Our goal was to evaluate the effectiveness of transjugular intrahepatic portosystemic shunt placement as monotherapy to improve and/or resolve portal vein thrombosis in otherwise eligible liver transplant candidates with partial or complete portal vein thrombosis and to identify factors predicting success. MATERIALS AND METHODS: We identified 30 patients from 2010 to 2015 who had transjugular intrahepatic portosystemic shunt placementfor primary indication to maintain portal vein patency. RESULTS: The main portal vein was completely thrombosed in 5 of 30 (16.6%), nearly completely thrombosed in 9 of 30 (30%), and partially thrombosed in 16 patients (53.3%). Twenty-four patients (80%) had improvement and/or resolution of portal vein thrombosis after transjugular intrahepatic portosystemic shunt placement, with 18 of these (75%) having complete resolution. All 5 patients (20.8%) with complete thrombosis had improvement/resolution of portal vein thrombosis. Nine patients (30%) required hospitalization within 3 months for hepatic encephalopathy. There were 3 deaths (10%) not related to transjugular intrahepatic portosystemic shunt placement (10%). Nine patients underwent liver transplant after shunt placement (median 2.9 mo; range, 0.3-32 mo); all 9 received endto-end anastomosis without need for intraoperative thrombectomy. CONCLUSIONS: Transjugular intrahepatic portosystemic shunt placement may be effective as monotherapy for maintaining or restoring portal vein patency in selected livertransplant candidates, even in those with complete portal vein thrombosis. Further studies are needed to define potential responders to this approach.

Treatment of chronic hepatitis B: are we ready for combination therapy?

Treatment of chronic hepatitis B virus (HBV) infection currently involves the use of immunomodulators such as interferon and nucleoside or nucleotide analogues. Treatment aims to suppress levels of HBV DNA and induce clearance of the hepatitis B e antigen (HBeAg) or surface antigen (HBsAg) and seroconversion. At present, no single treatment has been shown to reliably suppress HBV DNA and induce durable HBsAg loss. Nucleoside or nucleotide analogues induce the production of HBV-resistant mutations that may lead to virologic and clinical breakthrough. Combination therapy, using either immunomodulators in combination or with nucleoside or nucleotide analogues, represents an emerging strategy for treating chronic HBV infection. The theoretical benefits of combining agents with varying mechanisms of action include more efficacious viral suppression and potentially durable HBsAg loss. Although combination therapy has proven successful in chronic hepatotropic viral infections and in chronic, noninfectious medical conditions, its benefits must be weighed against risks such as increased toxicity, resistance, and cost.

Intensive Care Management of Acute Liver Failure: Considerations While Awaiting Liver Transplantation.

Acute liver failure is a unique clinical phenomenon characterized by abrupt deterioration in liver function and altered mentation. The development of high-grade encephalopathy and multisystem organ dysfunction herald poor prognosis. Etiologic-specific treatments and supportive measures are routinely employed; however, liver transplantation remains the only chance for cure in those who do not spontaneously recover. The utility of artificial and bioartificial assist therapies as supportive care-to allow time for hepatic recovery or as a bridge to liver transplantation-has been examined but studies have been small, with mixed results. Given the severity of derangements, intensive critical care is needed to successfully bridge patients to transplant, and evaluation of candidates occurs rapidly in parallel with serial reassessments of operative fitness. Psychosocial assessment is often suboptimal and relative contraindications to transplant, such as ventilator-dependence may be overlooked. While often employed to guide evaluation, no single prognostic model discriminates those who will spontaneously recover and those who will require transplant. The purpose of this review will be to summarize approaches in critical care, prognostic modeling, and medical evaluation of the acute liver failure transplant candidate.

Lymphovascular invasion on explant is associated with presenting tumor characteristics and not direct acting antiviral utilization in hepatitis C candidates undergoing liver transplantation.

AIM OF THE STUDY: Utilization of direct acting antiviral (DAA) therapy in candidates with well-compensated hepatitis C virus (HCV) cirrhosis and hepatocellular carcinoma (HCC) accruing end stage liver disease (MELD) exception points is highly variable among transplant centers based on center location, local organ procurement dynamics, HCV(+) organ availability, and patient preference. The association between DAA utilization prior to transplant and incidence of lymphovascular invasion on explant is unknown. MATERIAL AND METHODS: Retrospective evaluation from 2013-2017 of patients on a liver transplant (LT) waitlist with HCV-related cirrhosis, MELD-Na < 15, and HCC (within T2/Milan criteria). The cohort was divided into the pre-LT DAA treated group and untreated group with clinical/viral demographics collected. Tumor presenting characteristics, locoregional treatments, wait time to LT, dropout rates and explant pathology were compared. RESULTS: DAAs were used in 44 patients prior to LT (SVR12 of 37/44 [84%]) and 19 left untreated with LT performed in 81% (51/63) of the waitlisted cohort. No significant differences were found between groups with regards to clinical/viral demographics, local-regional therapy (LRT) sessions, or frequency of lymphovascular invasion on explant. The untreated cohort had a higher rate of dropout (6.3% vs. 3.2%) (p = 0.041). On subgroup analysis of 51 subjects undergoing LT, AFP > 250 ng/ml (p = 0.003) and multifocal HCC (> 1 lesion) (p = 0.006) were associated with lymphovascular invasion on explant while DAA therapy was not (p = 0.578). CONCLUSIONS: DAA therapy for waitlist active HCV candidates accruing MELD exception points has no deleterious effects on bridging LRT, nor is it associated with increased frequency of lymphovascular invasion on explant. The latter appears driven by tumor related characteristics (AFP and number of lesions) irrespective of DAA utilization prior to LT.

Drug-Induced Liver Failure Requiring Liver Transplant: Report and Review of the Role of Albendazole in Managing Echinococcal Infection.

Albendazole is often used as adjunctive therapy in the treatment of echinococcal infection to reduce cyst viability before and prevent recurrence after surgical treatment. In this report, we present a 38-year-old Iraqi woman with Echinococcus initiated on albendazole therapy who developed acute liver failure 6 weeks after treatment. Investigation for common viral and autoimmune causes of liver injury was unremarkable, and a liver biopsy revealed changes consistent with severe, drug-induced liver injury. Despite discontinuation of albendazole, liver function continued to deteriorate, prompting rescue with an orthotopic liver transplant. Often used perioperatively in the management of Echinococcus infection, albendazole can induce idiosyncratic severe liver injury, mandating close monitoring for hepatotoxicity.

Rapid reversal of colonic pneumatosis with restoration of mesenteric arterial supply.

Pneumatosis cystoides intestinalis (PCI) is characterized by gas-filled cystic lesions within the wall of the large intestine and presents along a spectrum of clinical severity ranging from benign to life threatening. Etiopathogenesis is multifactorial and postulated to result from either mechanical or bacterial causes. In this report, we present a patient with chronic abdominal pain evaluated with colonoscopy revealing segmental PCI isolated to the distal colon. Further investigation revealed an abdominal aortic aneurysm (AAA) compromising the inferior mesenteric artery takeoff. Endovascular repair of the AAA resulted in clinical resolution of abdominal pain and endoscopic resolution of PCI. To our knowledge, this is the first report to document endoscopic resolution of PCI with restoration of mesenteric arterial supply, highlighting vascular insufficiency as a predisposing and reversible pathogenic mechanism.