Cardiac evaluation of the liver transplant candidate.

PURPOSE OF REVIEW: This review aims to summarize recent changes in the cardiac evaluation of adult liver transplant candidates. Over the last several years, there have been significant advances in the use of coronary computed tomography angiography (CCTA) with and without fractional flow reserve (FFR) and increasingly widespread availability of coronary calcium scoring for risk stratification for obstructive coronary artery disease. This has led to novel strategies for risk stratification in cirrhotic patients being considered for liver transplant and an updated American Heart Association (AHA) position paper on the evaluation of liver and kidney transplant candidates. The diagnosis of cirrhotic cardiomyopathy has been refined. These new diagnostic criteria require that specific echocardiographic parameters are evaluated in all patients. The definition of pulmonary hypertension on echocardiography has been altered and no longer utilizes right atrium (RA) pressure estimates based on inferior vena cava (IVC) size and collapse. This provides more volume neutral estimates of pulmonary pressure. RECENT FINDINGS: Although CCTA has outstanding negative predictive value, false positive results are not uncommon and often lead to further testing. Revised diagnostic criteria for cirrhotic cardiomyopathy improve risk stratification for peri-operative volume overload and outcomes. Refined pulmonary hypertension criteria provide improved guidance for right heart catheterization (RHC) and referral to subspecialists. There are emerging data regarding the safety and efficacy of TAVR for severe aortic stenosis in cirrhotic patients. SUMMARY: Increased utilization of noninvasive testing, including CCTA and/or coronary calcium scoring, can improve the negative predictive value of testing for obstructive coronary artery disease and potentially reduce reliance on coronary angiography. Application of the 2020 criteria for cirrhotic cardiomyopathy will improve systolic and diastolic function assessment and subsequent perioperative risk stratification. The use of global strain scores is emphasized, as it provides important information beyond ejection fraction and diastolic parameters. A standardized one-parameter echo cut-off for elevated pulmonary pressures simplifies both evaluation and follow-up. Innovative transcutaneous techniques for valvular stenosis and regurgitation offer new options for patients at prohibitive surgical risk.

The Evolution and Future of Telehealth for Gastroenterology and Hepatology.

Content available: Author Audio Recording.

Large Hepatic Adenomas and Hepatic Adenomatosis: A Multicenter Study of Risk Factors, Interventions, and Complications.

INTRODUCTION: Beyond oral contraceptives (OCs), metabolic factors have been suggested to increase the risk of hepatocellular adenoma (HCA). The impact of risks remains poorly defined, particularly among men and those with adenomatosis. Thus, we aimed to examine HCA clinical and outcome characteristics through a large multicenter cohort. METHODS: HCA diagnosis was made based on a combination of clinical, radiologic, and histologic criteria. Patient and clinical data including follow-up imaging, complications, and interventions were collected between 2004 and 2018 from 3 large academic centers. RESULTS: Among 187 patients (163 female and 24 male) with HCA, 75 had solitary HCA, 58 had multiple HCAs, and 54 had adenomatosis. Over a median follow-up of 3.3 years (quartile 1: 1.2, quartile 3: 8.8), 34 patients (18%) had radiologic interventions, 41 (21%) had surgical resections, 10 (5%) developed tumoral hemorrhage, and 1 had malignant transformation. OC and corticosteroid use were present in 70% and 16%, respectively. Obesity (51%), type 2 diabetes (24%), hypertension (42%), and hypertriglyceridemia (21%) were also common. Metabolic comorbidities were more common in patients with large HCAs and adenomatosis. Compared with women, men had less hepatic steatosis (4% vs 27%), smaller HCAs (2.3 cm vs 4.4 cm), and more corticosteroid use (38% vs 11%) ( P < 0.05 for all). With OC cessation, 69% had a decrease in size of HCA, but 25% eventually required advanced interventions. DISCUSSION: In this large HCA cohort, obesity and metabolic comorbidities were important risk factors associated with large HCAs and adenomatosis. Long-term adverse outcomes were infrequent, 5% had tumor hemorrhage, and 1 patient exhibited malignant transformation.

Prevalence and Factors Associated With Statin Use Among Patients With Nonalcoholic Fatty Liver Disease in the TARGET-NASH Study.

Patients with nonalcoholic fatty liver disease (NAFLD) are at an increased risk of cardiovascular disease. Hydoxy-3-methyglutaryl-coenzyme reductase inhibitors, statins, reduce the risk of cardiovascular events.1 Studies have shown that statins are safe among patients with liver disease, including those with compensated cirrhosis,2 and their use is associated with lower mortality, hepatic decompensation, and possibly hepatocellular carcinoma.3,4 Despite these data, statins are under prescribed among patients with liver disease due to concerns about hepatotoxicity.5 This study aimed to assess prevalence and patient factors associated with indicated statin use in patients with NAFLD in a real-world cohort.

The Mucosally-Adherent Rectal Microbiota Contains Features Unique to Alcohol-Related Cirrhosis.

Most studies examining correlations between the gut microbiota and disease states focus on fecal samples due to ease of collection, yet there are distinct differences when compared to samples collected from the colonic mucosa. Although fecal microbiota has been reported to be altered in cirrhosis, correlation with mucosal microbiota characterized via rectal swab has not been previously described in this patient population. We conducted a cross-sectional analysis using 39 stool and 39 rectal swabs from adult patients with cirrhosis of different etiologies and performed shotgun metagenomic sequencing. Bacterial growth studies were performed with Escherichia coli. Two asaccharolytic bacterial taxa, Finegoldia magna and Porphyromonas asaccharolytica, were increased in rectal swabs relative to stool (FDR < 0.01). Genomic analysis of the microbiome revealed 58 genes and 16 pathways that differed between stool and rectal swabs (FDR < 0.05), where rectal swabs were enriched for pathways associated with protein synthesis and cellular proliferation but decreased in carbohydrate metabolism. Although no features in the fecal microbiome differentiated cirrhosis etiologies, the mucosal microbiome revealed decreased abundances of E. coli and Enterobacteriaceae in alcohol-related cirrhosis relative to non-alcohol related cirrhosis (FDR < 0.05). In vitro bacterial culture studies showed that physiological concentrations of ethanol and its oxidative metabolites inhibited E. coli growth in a pH- and concentration-dependent manner. Characterization of the mucosally associated gut microbiome via rectal swab revealed findings consistent with amino acid/nitrogen abundance versus carbohydrate limitation in the mucosal microenvironment as well as unique features of alcohol-related cirrhosis possibly consistent with the influence of host-derived metabolites on the composition of mucosally adherent microbiota.

Predictors, Presentation, and Treatment Outcomes of Recurrent Hepatocellular Carcinoma After Liver Transplantation: A Large Single Center Experience.

BACKGROUND: Liver transplantation (LT) is an accepted therapeutic option for hepatocellular carcinoma (HCC) in patients with cirrhosis. Despite careful candidate selection, HCC recurrence occurs. We aimed to describe the predictors of recurrence, clinical presentation, and predictors of survival after HCC recurrence post-LT. METHODS: Patients with recurrent HCC after LT between January 1996 and December 2017 were retrospectively reviewed. RESULTS: Of 711 patients, 96 (13.5%) patients had post-LT HCC recurrence. The median time to recurrence was 17.1 months, and the median survival was 10.1 months. Initial recurrence was more often in the graft (34.4%), and most (60.4%) had multiple recurrent lesions, and 26% were in multiple sites. In multivariate analysis, factors associated with shorter survival were poorly differentiated histology in explant (Hazard ratio [HR] = 1.96; p = 0.027), bilirubin ≥1.2 mg/dL (HR = 2.47; p = 0.025), and albumin <3.5 mg/dL (HR = 2.13; p = 0.014) at recurrence, alpha-fetoprotein at recurrence ≥ 1000 ng/mL (HR = 2.96; p = 0.005), and peritoneal disease (HR = 3.20; p = 0.022). There was an increased survival in patients exposed to sirolimus (HR = 0.32; p < 0.0001). CONCLUSIONS: Recurrent HCC after LT is often in extrahepatic sites with a decreased survival in those with poorly differentiated explant pathology, high bilirubin, low albumin, marked elevation of alpha-fetoprotein at recurrence, and peritoneal recurrence. Sirolimus-based immunosuppression may provide benefit.

Tacrolimus and Indomethacin Are Safe and Effective at Reducing Pancreatitis After Endoscopic Retrograde Cholangiopancreatography in Patients Who Have Undergone Liver Transplantation.

BACKGROUND & AIMS: Biliary complications occur in up to 25% of patient following liver transplantation and are often managed by endoscopic retrograde cholangiopancreatography (ERCP). Pancreatitis is the most common adverse event after ERCP (PEP). Tacrolimus and rectal indomethacin have each been reported to reduce risk of PEP. We investigated the incidence of PEP in patients who have undergone ERCP after liver transplantation and the effectiveness of tacrolimus and/or indomethacin in reducing risk of PEP. METHODS: We performed a retrospective study of 337 patients who underwent ERCP (n = 937 procedures) for biliary complications after liver transplantation from June 1, 2007 through December 1, 2015. After June 1, 2012, rectal indomethacin (100 mg) was routinely administered at the conclusion of the ERCP unless patients had contraindications. Indomethacin was given after 286 ERCP procedures. After excluding patients with acute/chronic rejection, 323 patients were maintained on a stable dose of tacrolimus prior to ERCP (901 procedures). We collected data on demographic and clinical variables, pre-procedural tacrolimus trough levels, and development of PEP. We calculated adjusted odds ratios (ORs) for the association between tacrolimus and indomethacin use and risk of PEP using mixed-effects multivariable logistic regression. The primary outcome was development of PEP; secondary outcomes included the development moderate-to-severe PEP, cholangitis and bleeding. RESULTS: PEP occurred after 2.2% of ERCP procedures. A trough level of tacrolimus above 2.5 ng/mL was associated with 79% lower odds of PEP (OR, 0.21; 95% CI, 0.06-0.72; P = .01). Indomethacin was associated with a 91% reduction in risk of PEP (OR, 0.09; 95% CI, 0.01-0.85; P = .03). Indomethacin use did not affect rates of bleeding or cholangitis or decrease in glomerular filtration rate. In patients with trough levels of tacrolimus above 2.5 ng/mL, addition of indomethacin reduced the odds of PEP by 93% compared with patients who were unexposed to indomethacin. (OR, 0.07; 95% CI, 0.01-0.90; P = .04). CONCLUSIONS: In a retrospective study of patients who underwent ERCP for biliary complications after liver transplantation, we found trough levels of tacrolimus above 2.5 ng/mL to significantly reduce risk for PEP. Rectal administration of indomethacin after ERCP significantly decreased rates of pancreatitis, and reduced risk further in patients given tacrolimus. Administration of both drugs prevented patients from developing moderate or severe pancreatitis. Indomethacin did not worsen renal function in patients with chronic kidney disease.

Transient elastography reliably estimates liver fibrosis in autoimmune hepatitis.

AIM OF THE STUDY: Autoimmune hepatitis (AIH) may result in liver fibrosis and cirrhosis. While the gold standard for staging fibrosis is biopsy, transient elastography (TE) represents a non-invasive alternative. TE has been validated in several chronic liver diseases, but no data exist to establish an association between histologic fibrosis on biopsy and TE liver stiffness measurements among a United States cohort of AIH patients. MATERIAL AND METHODS: We conducted a retrospective cohort study of 53 AIH patients who received TE assessment and liver biopsy. Histologic fibrosis was classified as advanced (F3-F4) or mild/moderate (F0-F2). Liver stiffness by TE was measured in kilopascals (kPa). We performed a score test for trend to test the association between histologic fibrosis stage and increasing TE kPa categories. Analyses incorporated probe type (medium or extra-large) and body mass index (BMI). Linear regression was used to generate predicted associations between median kPa and histologic fibrosis score with the medium probe. RESULTS: The cohort was primarily female (83%) with median age 56.3 years. Increasing kPa category was associated with worsening fibrosis stage when using the medium probe (p = 0.04), but not the extra-large probe (p = 0.40). BMI, however, differed between these groups (median 25.8 vs. 33.1, respectively, p < 0.001). In adjusted linear regression, increasing median kPa corresponded well to worsening fibrosis stage (p = 0.003). CONCLUSIONS: In a United States AIH cohort, increasing TE kPa measurements are associated with worsening histologic fibrosis staging. While medium probe performance was superior to the extra-large probe, significant variation in BMI between groups may explain this difference.

An Automated Text Message Navigation Program Improves the Show Rate for Outpatient Colonoscopy.

Background. Numerous barriers to outpatient colonoscopy completion exist, causing undue procedure cancellations and poor bowel preparation. We piloted a text message navigation program to improve colonoscopy adherence. Method. We conducted a prospective study of patients aged 18 to 75 years scheduled for outpatient colonoscopy at an urban endoscopy center in April 2018. An intervention arm consisting of bidirectional, automated text messages prior to the procedure was compared with a usual care arm. We enrolled 21 intervention patients by phone and randomly selected 50 controls. Outcomes included colonoscopy appointment adherence, bowel preparation quality, and colonoscopy completion. Results. The arms had similar demographics and comorbidities. Intervention patients had higher colonoscopy appointment adherence (90% vs. 62%, p = 0.049). There were no significant differences in preparation quality or procedure completeness. Poststudy surveys indicated high patient satisfaction and perceived usefulness of the program. Conclusion. A bidirectional, automated texting navigation program improved colonoscopy adherence rates as compared with usual care.

Improving cirrhosis care: The potential for telemedicine and mobile health technologies.

Decompensated cirrhosis is a condition associated with significant morbidity and mortality. While there have been significant efforts to develop quality metrics that ensure high-value care of these patients, wide variations in clinical practice exist. In this opinion review, we discuss the quality gap in the care of patients with cirrhosis, including low levels of compliance with recommended cancer screening and other clinical outcome and patient-reported outcome measures. We posit that innovations in telemedicine and mobile health (mHealth) should play a key role in closing the quality gaps in liver disease management. We highlight interventions that have been performed to date in liver disease and heart failure-from successful teleconsultation interventions in the care of veterans with cirrhosis to the use of telemonitoring to reduce hospital readmissions and decrease mortality rates in heart failure. Telemedicine and mHealth can effectively address unmet needs in the care of patients with cirrhosis by increasing preventative care, expanding outreach to rural communities, and increasing high-value care. We aim to highlight the benefits of investing in innovative solutions in telemedicine and mHealth to improve care for patients with cirrhosis and create downstream cost savings.

An Advanced Practice Practitioner-Based Program to Reduce 30- and 90-Day Readmissions After Liver Transplantation.

Hospital readmissions after liver transplantation (LT) are common and associated with increased morbidity and cost. High readmission rates at our center motivated a change in practice with adoption of a nurse practitioner (NP)-based posttransplant care program. We sought to determine if this program was effective in reducing 30- and 90-day readmissions after LT and to identify variables associated with readmission. We performed a retrospective cohort study of all patients undergoing LT from July 1, 2014, to June 30, 2017, at a tertiary LT referral center. A NP-based posttransplant care program with weekend in-house nurse coordination providers and increased outpatient NP clinic availability was instituted on January 1, 2016. Postdischarge readmission rates at 30 and 90 days were compared in the pre-exposure and postexposure groups, adjusting for associated risk factors. A total of 362 patients were included in the analytic cohort. There were no significant differences in demographics, comorbidities, or index hospitalization characteristics between groups. In the adjusted analyses, the risk of readmission in the postexposure group was significantly reduced relative to baseline at 30 days (hazard ratio [HR] 0.60, 95% confidence interval [CI], 0.39-0.90; P = 0.02) and 90 days (HR, 0.49; 95% CI, 0.34-0.71; P < 0.001). Risk factors positively associated with 30-day readmission included peritransplant dialysis (HR, 1.70; 95% CI, 1.13-2.58; P = 0.01) and retransplant on index hospitalization (HR, 10.21; 95% CI, 3.39-30.75; P < 0.001). Male sex was protective against readmission (HR, 0.66; 95% CI, 0.45-0.97; P = 0.03). In conclusion, implementation of expanded NP-based care after LT was associated with significantly reduced 30- and 90-day readmission rates. LT centers and other service lines using significant postsurgical resources may be able to reduce readmissions through similar programs.

Exploring opportunities to prevent cirrhosis admissions in the emergency department: A multicenter multidisciplinary survey.

Patients with cirrhosis have high admission and readmission rates, and it is estimated that a quarter are potentially preventable. Little data are available regarding nonmedical factors impacting triage decisions in this patient population. This study sought to explore such factors as well as to determine provider perspectives on low-acuity clinical presentations to the emergency department, including ascites and hepatic encephalopathy. A survey was distributed in four liver transplant centers to both emergency medicine and hepatology providers, who included attending physicians, house staff, and advanced practitioners; 196 surveys were returned (estimated response rate 50.6%). Emergency medicine providers identified several influential nonmedical factors impacting inpatient triage decisions, including input from a hepatologist (77.7%), inadequate patient access to outpatient specialty care (68.6%), and patient need for diagnostic testing for a procedure (65.6%). When given patient-based scenarios of low-acuity cases, such as ascites requiring paracentesis, only 7.0% believed patients should be hospitalized while 48.9% said these patients would be hospitalized at their institution (P < 0.0001). For mild hepatic encephalopathy, the comparable numbers were 19.5% and 55.2%, respectively (P < 0.001). Several perceived barriers were cited for this discrepancy, including limited resources both in the outpatient setting and emergency department. Most providers believed that an emergency department observation unit protocol would influence triage toward an emergency department observation unit visit instead of inpatient admission for both ascites requiring large volume paracentesis (83.2%) and mild hepatic encephalopathy (79.4%). Conclusion: Many nonmedical factors that influence inpatient triage for patients with cirrhosis could be targeted for quality improvement initiatives. In some scenarios, providers are limited by resource availability, which results in triage to an inpatient admission even when they believe this is not the most appropriate disposition. (Hepatology Communications 2018;2:237-244).

Hepatopulmonary Syndrome and Portopulmonary Hypertension: Implications for Liver Transplantation.

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH) represent serious pulmonary complications of advanced liver diseases. Orthotopic liver transplantation (OLT) is capable of completely resolving the underlying abnormalities associated with HPS. On the other hand, post-OLT response in patients with PoPH is less predictable, although heavily influenced by pre-OLT mean pulmonary arterial pressure. It remains the case that the opportunity to reverse 2 potentially fatal organ dysfunctions in the liver and the lung make HPS and PoPH more than worthy for further clinical investigations.

Safety and efficacy of current direct-acting antiviral regimens in kidney and liver transplant recipients with hepatitis C: Results from the HCV-TARGET study.

Data outside of clinical trials with direct-acting antiviral regimens with or without ribavirin as treatment of chronic hepatitis C virus in solid organ transplant recipients are limited. Liver transplant (LT), kidney transplant (KT), and dual liver kidney (DLK) transplant recipients from the Hepatitis C Therapeutic Registry and Research Network database, a multicenter, longitudinal clinical care treatment cohort, treated with direct-acting antiviral regimens between January 1, 2014, and February 15, 2016, were included to assess safety and efficacy. Included were 443 posttransplant patients (KT = 60, LT = 347, DLK = 36); 42% had cirrhosis, and 54% had failed prior antiviral therapy. Most had genotype (GT) 1 (87% with 52% GT1a, 27% GT1b, and 8% GT1 no subtype) and were treated with sofosbuvir (SOF)/ledipasvir ± ribavirin (85%) followed by SOF + daclatasvir ± ribavirin (9%) and ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (6%). Rates of sustained virologic response (SVR) at 12 weeks were available on 412 patients, and 395 patients (95.9%) achieved SVR at 12 weeks: 96.6%, 94.5%, and 90.9% among LT, KT, and DLK transplant recipients, respectively. Ribavirin did not influence SVR rates and was more often used in those with higher BMI, higher estimated glomerular filtration rate and lower creatinine. Female gender, baseline albumin ≥3.5 g/dL, baseline total bilirubin ≤1.2 mg/dL, absence of cirrhosis, and hepatic decompensation predicted SVR at 12 weeks. Six episodes of acute rejection (n = 2 KT, 4 LT) occurred, during hepatitis C virus treatment in 4 and after cessation of treatment in 2. CONCLUSION: In a large prospective observational cohort study, direct-acting antiviral therapy with SOF/ledipasvir, ombitasvir/paritaprevir/ritonavir + dasabuvir, and SOF plus daclatasvir was efficacious and safe in LT, KT, and DLK transplant recipients; ribavirin did not influence SVR, and graft rejection was rare. (Hepatology 2017;66:1090-1101).

Characterizing the Risk of False-Positive Hepatocellular Carcinoma in Recipients Transplanted With T2 MELD Exceptions.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) can receive Model for End-Stage Liver Disease (MELD) exception points to increase waitlist priority for liver transplantation. This process does not require a biopsy and is based on radiologic criteria. However, imaging modalities are imperfect, and some will ultimately have no HCC on explant. METHODS: This was a retrospective cohort study using national explant pathology data from 2012 to 2015. False-positive HCC was defined as answering "no" to the question: "was evidence of HCC (viable or nonviable) found in the explant?" in patients with T2 MELD exceptions. RESULTS: Four thousand one hundred seventeen patients received T2 MELD exceptions, of which 245 (6%) had false-positive HCC. Maximal tumor diameter of 3 to 5 cm and serum α fetoprotein (AFP) greater than 100 ng/mL at transplant yielded a 50% lower risk of false-positive HCC (odds ratio [OR], 0.45; 95% confidence interval [CI], 0.27-0.73 and OR, 0.57; 95% CI, 0.37-0.88, respectively). Recipients with immune-mediated liver disease were twice as likely to have no HCC on explant (OR, 2.12; 95% CI, 1.18-3.83) and had a predicted probability of false positive HCC greater than 10% regardless of largest tumor size or AFP. Significant among-center variability in the rate of false-positive HCC was seen. CONCLUSIONS: The risk of false-positive HCC is markedly higher in certain groups, such that biopsy may be warranted before T2 MELD exception point approval. Transplant centers with high false-positive HCC rates may benefit from greater oversight.

Nonalcoholic Fatty Liver Disease: Pathophysiology and Management.

Nonalcoholic fatty liver disease (NAFLD) is an important cause of morbidity and mortality worldwide and is rapidly becoming the leading cause of end-stage liver disease and liver transplant. With a prevalence of 30% in the United States, it has reached epidemic proportions. The clinical syndrome of NAFLD spans from bland steatosis to steatohepatitis, which can progress to fibrosis and cirrhosis. The pathogenesis includes the roles of hormones, nutritional and intestinal dysbiosis, insulin resistance, lipotoxicity, hepatic inflammation, and genes. Noninvasive testing and liver biopsy indications are reviewed. Approved and investigational therapies for NAFLD and nonalcoholic steatohepatitis are outlined in this article.