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.

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.

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.

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.

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.

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.

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.

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.

Race and Gradient Difference Are Associated with Increased Risk of Hepatic Encephalopathy Hospital Admission After Transjugular Intrahepatic Portosystemic Shunt Placement.

BACKGROUND/AIMS: Hepatic encephalopathy (HE) is a well-recognized complication of transjugular intrahepatic portosystemic shunt (TIPS) placement. The aim of this investigation was to evaluate incidence and predictors of post-TIPS HE necessitating hospital admission in a non-clinical trial setting. METHODS: We performed a retrospective cohort study identifying 273 consecutive patients undergoing TIPS from 2010 to 2015 for any indication; 210 met inclusion/exclusion criteria. The primary endpoint was incidence of post-TIPS HE defined as encephalopathy with no other identifiable cause requiring hospitalization within 90 days of TIPS. Clinical demographics and procedural variables were collected and analyzed to determine predictors of readmission for post-TIPS HE. Categorical variables were analyzed using Fisher's exact test; continuous variables were compared using Levene's t-test and student's t-test; P < 0.05, significant. RESULTS: Forty-two of 210 patients (20%) developed post-TIPS HE requiring hospitalization within 90 days. On analysis of cohorts (post-TIPS HE vs. no post-TIPS HE): non-white race (31.0% vs. 17.5%, P = 0.022) and increased hepatic venous pressure gradient (HVPG) difference during TIPS (10.5 vs. 8.9 mmHg, P = 0.030) were associated with an increased incidence of HE requiring readmission within 90 days. CONCLUSIONS: HE remains a common complication of TIPS. Non-Caucasian race is a significant clinical demographic associated with increased risk for readmission. Independent of initial or final HVPG, HVPG difference appears to be a significant modifiable technical risk factor. In the absence of clear preventative strategies for post-TIPS encephalopathy, non-Caucasians with HVPG reductions >9 mmHg may require targeted follow up evaluation to prevent hospital readmission.

Refractory Hepatic Encephalopathy After Elective Transjugular Intrahepatic Portosystemic Shunt: Risk Factors and Outcomes with Revision.

BACKGROUND AND AIMS: Hepatic encephalopathy (HE) is a common complication of elective transjugular intrahepatic portosystemic shunt (TIPS) placement and is often successfully medically managed. Risk factors for refractory hepatic encephalopathy (RHE) necessitating revision of TIPS are not well defined. We evaluated the incidence, predictors, and outcomes of post-TIPS RHE necessitating TIPS revision. METHODS: In a retrospective cohort study of 174 consecutive patients undergoing elective TIPS placement (2010-2015), we evaluated the incidence of post-TIPS RHE. Clinical demographics and procedural variables were collected. 1-year outcomes after revision were collected. RESULTS: Ten of 174 patients (5.7%) developed post-TIPS RHE requiring revision. Significant differences between RHE and non-refractory groups were shunt size > 8 versus ≤ 8 mm (18.5 vs. 3.4%, p = 0.001), history of HE (14 vs. 2%, p = 0.007), and serum albumin levels ≤ 2.5 versus > 2.5 g/dL (13.1 vs. 3.1%, p = 0.020). On multivariate analysis, shunt size > 8 mm (p = 0.001), history of HE prior to TIPS (p = 0.006), and low serum albumin (≤ 2.5 g/dL) (p = 0.022) remained independent predictors of RHE, controlling for age and Model for End-Stage Liver Disease score. RHE improved in 8 of 10 patients but survival at 1 year without liver transplantation (LT) was only 10%. CONCLUSION: While TIPS revision successfully improves RHE in most cases, 1-year mortality rates are high, limiting the value of revision in non-LT candidates. Patients with previous history of HE and low serum albumin levels prior to TIPS may benefit most from the use of shunt sizes < 8 mm to mitigate the risk of RHE. LEVEL OF EVIDENCE: Level 4, case series.

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.

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.

Predictors of intermediate-term survival with destination locoregional therapy of hepatocellular cancer in patients either ineligible or unwilling for liver transplantation.

Intra-arterial or percutaneous locoregional therapies (LRT) are often employed to maintain potential liver transplant (LT) recipients with hepatocellular carcinoma (HCC) within T2/Milan criteria. Predictors of survival when LRT is used as destination therapy in those who are either ineligible or unwilling for LT remain poorly defined. We evaluated predictors of 3-year survival with destination LRT in a population of cirrhotic patients diagnosed with HCC, presenting within T2 criteria, and either ineligible or unwilling for LT. The cohort surviving 3 years had a significantly lower model for end-stage liver disease (MELD) score at HCC diagnosis (9.7 vs. 11.4, P=0.037) and MELD following initial locoregional therapy (10.7 vs. 13.3, P=0.008) compared to those not surviving three years despite similar demographic, tumor, and treatment variables. LRT as destination therapy results in modest intermediate term survival, with liver function at presentation and immediately following initiation of LRT predicting intermediate survival with this approach.

Profiling Neutrophil-to-Lymphocyte Ratio Changes in Response to Nucleoside Analog Therapy for Chronic Hepatitis B Infection.

BACKGROUND/AIM: The neutrophil-lymphocyte ratio (NLR) has gained attention as an index of inflammation in patients with chronic hepatitis B virus (HBV); however, changes with nucleoside analog therapy require investigation. PATIENTS AND METHODS: We carried out a retrospective study identifying monoinfected HBV patients initiated on therapy with NLR follow-up over 1 year. Biochemistries recorded at treatment initiation and 1 year included alanine aminotransferase (ALT), Model for End Stage Liver Disease (MELD) score, and NLR. RESULTS: A total of 67 patients were initiated on therapy and had baseline characteristics including e-antigen (eAg) (50, 74.6%) and cirrhosis (19, 28.4%). On subgroup analysis among those with HBV-associated cirrhosis, the NLR decreased over 1 year (3.08±0.39 vs. 1.77±0.18, p<0.001) as did MELD and ALT. Among the non-cirrhotic cohort, there was no difference in NLR (1.99±0.89 vs. 2.14±1.03, p=0.134) despite a decrease in ALT. CONCLUSION: Nucleoside analog therapy in HBV cirrhosis is associated with a decrease in NLR over 1 year that tracks with changes of established indices of inflammation/global hepatic function.