Progression of fibrosis in liver transplant recipients with hepatitis C before and after sustained virologic response.

BACKGROUND: Liver transplant (LT) recipients with untreated hepatitis C (HCV) are at risk for cirrhosis graft failure. The advent of direct acting antiviral agents (DAA) has improved outcomes in HCV. AIMS: We aim to examine liver transplant outcomes and allograft fibrosis development/progression after sustained virologic response (SVR). METHODS: We performed a retrospective cohort study of 226 consecutive liver transplant recipients with HCV from 2007 to 2018. The cohort was split into transplants pre (Group A) and post (Group B) 2014 to reflect the introduction of DAAs. Fibrosis was monitored with liver biopsy and non-invasive imaging. RESULTS: Group B had significantly improved HCV treatment rates and earlier SVR compared to Group A, with a cumulative incidence rate of SVR at 2 years of 86.7% versus 15.4% (HR = .11, p < .001). Prior to achieving SVR, Group A demonstrated worsening of fibrosis stage per year (+.21, p < .001) whereas Group B showed minimal change on protocol annual biopsy (-.02, p = .80). After SVR, most patients were followed non-invasively and demonstrated stable or improved fibrosis stage over time. Patients undergoing transient elastography showed regression in fibrosis stage per year (-.19, p < .001). CONCLUSION: HCV patients undergoing LT after 2014 had higher rates of SVR and improved clinically relevant transplant outcomes, namely less graft loss and death relating to HCV. Fibrosis progression halted or improved after SVR in both cohorts, suggesting that LT recipients with SVR do not require fibrosis monitoring even with established fibrosis prior to SVR.

Factors Impacting Survival in Those Transplanted for NASH Cirrhosis: Data From the NailNASH Consortium.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is the leading indication for liver transplant (LT) in women and the elderly. Granular details into factors impacting survival in this population are needed to optimize management and improve outcomes. METHODS: Patients receiving LT for NASH cirrhosis from 1997 to 2017 across 7 transplant centers (NailNASH consortium) were analyzed. The primary outcome was all-cause mortality, and causes of death were enumerated. All outcomes were cross referenced with United Network for Organ Sharing and adjudicated at each individual center. Cox regression models were constructed to elucidate clinical factors impacting mortality. RESULTS: Nine hundred thirty-eight patients with a median follow-up of 3.8 years (interquartile range, 1.60-7.05 years) were included. The 1-, 3-, 5-, 10-, and 15-year survival of the cohort was 93%, 88%, 83%, 69%, and 46%, respectively. Of 195 deaths in the cohort, the most common causes were infection (19%), cardiovascular disease (18%), cancer (17%), and liver-related (11%). Inferior survival was noted in patients >65 years. On multivariable analysis, age >65 (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.04-2.77; P = .04), end-stage renal disease (HR, 1.55; 95% CI, 1.04-2.31; P = .03), black race (HR, 5.25; 95% CI, 2.12-12.96; P = .0003), and non-calcineurin inhibitors-based regimens (HR, 2.05; 95% CI, 1.19-3.51; P = .009) were associated with increased mortality. Statin use after LT favorably impacted survival (HR, 0.38; 95% CI, 0.19-0.75; P = .005). CONCLUSIONS: Despite excellent long-term survival, patients transplanted for NASH at >65 years or with type 2 diabetes mellitus at transplant had higher mortality. Statin use after transplant attenuated risk and was associated with improved survival across all subgroups, suggesting that careful patient selection and implementation of protocol-based management of metabolic comorbidities may further improve clinical outcomes.

CD117, BAP1, MTAP, and TdT Is a Useful Immunohistochemical Panel to Distinguish Thymoma from Thymic Carcinoma.

BACKGROUND: The morphologic distinction between thymic carcinomas and thymomas, specifically types B3, A, and occasionally micronodular thymomas with lymphoid stroma (MNTLS) can be challenging, as has also been shown in interobserver reproducibility studies. Since thymic carcinomas have a worse prognosis than thymomas, the diagnosis is important for patient management and treatment. This study aimed to identify a panel of immunohistochemical (IHC) markers that aid in the distinction between thymomas and thymic carcinomas in routine practice. MATERIALS AND METHOD: Thymic carcinomas, type A and B3 thymomas, and MNTLS were identified in an institutional database of thymic epithelial tumors (TET) (1963-2021). IHC was performed using antibodies against TdT, Glut-1, CD5, CD117, BAP1, and mTAP. Percent tumor cell staining was recorded (Glut-1, CD5, CD117); loss of expression (BAP1, mTAP) was considered if essentially all tumor cells were negative; TdT was recorded as thymocytes present or absent (including rare thymocytes). RESULTS: 81 specimens included 44 thymomas (25 type A, 11 type B3, 8 MNTLS) and 37 thymic carcinomas (including 24 squamous cell carcinomas). Using BAP1, mTAP, CD117 (cut-off, 10%), and TdT, 88.9% of thymic carcinomas (95.7% of squamous cell carcinomas) and 77.8% of thymomas could be predicted. Glut-1 expression was not found to be useful in that distinction. All tumors that expressed CD5 in ≥50% of tumor cells also expressed CD117 in ≥10% of tumor cells. In four carcinomas with homozygous deletion of CDKN2A, mTAP expression was lost in two squamous cell carcinomas and in a subset of tumor cells of an adenocarcinoma and was preserved in a lymphoepithelial carcinoma. CONCLUSION: A panel of immunostains including BAP1, mTAP, CD117 (using a cut-off of 10% tumor cell expression), and TdT can be useful in the distinction between thymomas and thymic carcinomas, with only a minority of cases being inconclusive.

Bariatric surgery proves long-term benefit in patients with cirrhosis.

BACKGROUND: Obesity is commonly observed in patients with cirrhosis, especially with the increasing prevalence of non-alcoholic steatohepatitis (NASH). Bariatric surgery has been avoided in these patients given concerns about increased perioperative risk; therefore, data are lacking regarding long-term outcomes. In this study, we aimed to evaluate the long-term outcomes of patients with cirrhosis who underwent bariatric surgery. METHODS: We reviewed the charts of adult patients with compensated cirrhosis who underwent bariatric surgery after they were prospectively enrolled between February 23, 2009 and November 9, 2011, and followed in a pilot study for evaluation of bariatric surgery outcomes. Only patients with more than 4 years of follow-up were included in the analysis. Data regarding their liver disease, metabolic status, and survival were collected. A descriptive analysis was performed. RESULTS: The cohort consisted of 10 patients, of whom 7 were females. The median post-surgical follow-up was 8.7 years (± 1.4 years). All patients had biopsy-proven NASH; two patients had concurrent, untreated hepatitis C infection. During the observation period, there was a mean weight loss of 24 kg (19.2% of total body weight pre surgery, P < 0.001) and only one patient regained weight to the baseline pre-surgical measurement. One patient who was not eligible for transplant developed hepatic encephalopathy 3 years after surgery and later died. The remainder of the patients did not have any hepatic decompensation, cardiovascular event, or mortality. Except for one patient with Gilbert syndrome, bilirubin was normal in all patients at last follow-up. CONCLUSIONS: Bariatric surgery in patients with compensated cirrhosis can lead to sustained weight loss and stable hepatic function on long-term follow-up.

Cirrhotic Cardiomyopathy Predicts Posttransplant Cardiovascular Disease: Revelations of the New Diagnostic Criteria.

The diagnostic criteria for cirrhotic cardiomyopathy (CCM) were recently revised to reflect the contemporary advancements in echocardiographic technology. This study evaluates the prevalence of CCM, according to the new criteria, and its impact on posttransplant cardiovascular disease (CVD). This is a single-center retrospective matched cohort study of liver transplantation (LT) recipients who underwent LT between January 1, 2008 and November 30, 2017. A total of 3 cohorts with decompensated cirrhosis (nonalcoholic steatohepatitis, alcohol-related liver disease, or other etiologies) were matched based on age, sex, and year of transplant after excluding patients listed without evidence of hepatic decompensation. CCM was defined, according to 2020 criteria, as having diastolic dysfunction, left ventricular ejection fraction ≤50%, and/or a global longitudinal strain (GLS) absolute value <18%. The study echocardiographers were blinded to the clinical data. Posttransplant CVD included new coronary artery disease, congestive heart failure, atrial and ventricular arrhythmia, and stroke. The study included 141 patients of whom 59 were women. The mean age at LT was 57.8 (±7.6) years. A total of 49 patients (34.8%) had CCM. Patients with CCM were at an increased risk for post-LT CVD (hazard ratio, 2.57; 95% confidence interval, 1.2-5.5; P = 0.016). Changes in CCM individual parameters pretransplant, such as GLS, early diastolic transmitral flow to early diastolic mitral annular velocity, and left atrial volume index were associated with an increased risk for posttransplant CVD. CCM, defined by the new diagnostic criteria, affects approximately one-third of decompensated LT candidates. CCM predicts an increased risk for new CVD following LT. Studies into addressing and follow-up to mitigate these risks are needed.

Incidence and outcomes of prosthetic valve endocarditis in adults with tetralogy of Fallot.

BACKGROUND: The risk of endocarditis varies with CHD complexity and the presence of prosthetic valves. The purpose of the study was therefore to describe incidence and outcomes of prosthetic valve endocarditis in adults with repair tetralogy of Fallot. METHODS: Retrospective review of adult tetralogy of Fallot patients who underwent prosthetic valve implantation, 1990-2017. We defined prosthetic valve endocarditis-related complications as prosthetic valve dysfunction, perivalvular extension of infection such abscess/aneurysm/fistula, heart block, pulmonary/systemic embolic events, recurrent endocarditis, and death due to sepsis. RESULTS: A total of 338 patients (age: 37 ± 15 years) received 352 prosthetic valves (pulmonary [n = 308, 88%], tricuspid [n = 13, 4%], mitral [n = 9, 3%], and aortic position [n = 22, 6%]). The annual incidence of prosthetic valve endocarditis was 0.4%. There were 12 prosthetic valve endocarditis-related complications in six patients, and these complications were prosthetic valve dysfunction (n = 4), systemic/pulmonary embolic events (n = 2), heart block (n = 1), aortic root abscess (n = 1), recurrent endocarditis (n = 2), and death due to sepsis (n = 1). Three (50%) patients required surgery at 2 days, 6 weeks, and 23 weeks from the time of prosthetic valve endocarditis diagnosis. Altogether three of the six (50%) patients died, and one of these deaths was due to sepsis. CONCLUSIONS: The incidence, complication rate, and outcomes of prosthetic valve endocarditis in tetralogy of Fallot patients underscore some of the risks of having a prosthetic valve. It is important to educate the patients on the need for early presentation if they develop systemic symptoms, have a high index of suspicion for prosthetic valve endocarditis, and adopt a multi-disciplinary care approach in this high-risk population.

Usefulness of Right Ventricular Volumetric and Afterload Indices for Risk Stratification in Patients With Tetralogy of Fallot.

Right ventricular (RV) volume overload due to chronic pulmonary regurgitation is the common mechanism for hemodynamic deterioration after tetralogy of Fallot (TOF) repair. As a result, RV volumetric indices are used for clinical risk stratification in this population. Since RV afterload is a determinant of RV hemodynamic performance, we hypothesized that afterload-adjusted RV volumetric indices will have a better correlation with disease severity compared with RV volumetric indices alone in patients with TOF. Cross-sectional study of adults with previous TOF repair that received care at Mayo Clinic, 2002-2015. We defined disease severity as atrial arrhythmia and/or impaired exercise capacity. We created afterload-adjusted RV volumetric indices by indexing these indices to RV systolic pressure (RVSP) as follows: RV end-diastolic volume (RVEDVi)/RVSP, RV end-systolic volume (RVESVi)/RVSP, and RV ejection fraction (RVEF)/RVSP. The RV volumetric indices were: RVEDVi 141 ± 43 ml/m2, RVESVi 79 ± 38 ml/m2, and RVEF 44 ± 10%, and RVSP was 48 ± 9 mm Hg. RVESVi was the only RV volumetric parameter that was associated with disease severity (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.01 to 1.32, p = 0.041) with area under the curve (AUC) of 0.612. In contrast RVEF/RVSP (OR 0.73, 95% CI 0.38 to 0.92, p = 0.037, AUC 0.649), and RVESVi/RVSP (OR 1.28, 95% CI 1.14-1.55, p = 0.008, AUC 0.798) were associated with disease severity. Compared with RV volumetric indices alone, the combined RV volumetric and afterload indices had better correlation with disease severity as measured by AUC. Afterload-adjusted RV volumetric indices had better correlation with disease severity, and may potentially improve risk stratification in this population.

Long-term outcomes in adults with repaired tetralogy of Fallot and pulmonary atresia.

BACKGROUND: There are limited outcome data in adults with tetralogy of Fallot and pulmonary atresia. The purpose of this study was to describe re-operations and all-cause mortality in adults with tetralogy of Fallot and pulmonary atresia. METHODS: Retrospective review of adults with repaired tetralogy of Fallot and pulmonary atresia who received care at the Mayo Adult Congenital Heart Disease Clinic, 1990-2016. All-cause mortality was calculated as events per 100 patient-years from the time of first presentation to the Adult Congenital Heart Disease Clinic. RESULTS: Of the 221 patients, the age at initial tetralogy of Fallot repair was 6 (5-13) years, and the age at first presentation to the clinic was 27 - 8 years. All patients had at least one right ventricular to pulmonary artery conduit re-operation. There were 31 deaths (14%) at mean age of 41 - 14 years. The causes of death were end-stage heart failure (n = 17), sudden cardiac death (n=9), post-operative death after cardiac surgery (n = 2), sepsis with multi-system organ failure (n = 2), and unknown (n = 1). All-cause mortality rate was 1.7 per 100 patient-years. The risk factors for all-cause mortality were older age (>12 years) at the time of repair (hazard ratio 1.41, 95 confidence interval 1.06-2.02, p = 0.033), non-sustained ventricular tachycardia (hazard ratio 1.36, 95 confidence interval 1.17-2.47, p = 0.015), and left ventricular ejection fraction <50% (hazard ratio 1.39, 95 confidence interval 1.08-2.31, p = 0.031). CONCLUSION: Based on a review of 221 adults with repaired tetralogy of Fallot and pulmonary atresia, all patients had re-operations and all-cause mortality rate was 1.7 events per 100 patient-years. The current study provides important outcomes data for risk stratification in adults with tetralogy of Fallot and pulmonary atresia.

Role of Doppler echocardiography for assessing right ventricular cardiac output in patients with atrial septal defect.

BACKGROUND: Although Doppler echocardiography is routinely used to assess left ventricle cardiac output, there are limited data about the feasibility of Doppler echocardiography for right ventricular (RV) cardiac output assessment in patients with left-to-right shunt. The purpose of the study was to determine the correlation between Doppler-derived and Fick-derived RV cardiac index (CI), and the interobserver correlation in Doppler-derived RV CI assessment. METHODS: Retrospective study of patients (age ≥18 years) with unrepaired atrial septal defect who underwent cardiac catheterization and echocardiography (within 3 days), 2004-2017. RV CI was calculated using the hydraulic orifice formula: [.785 × (right ventricle outflow tract diameter)2  × right ventricular outflow tract (RVOT) time velocity integral × heart rate]/body surface area. RESULTS: A total of 128 patients (age 52 ± 17 years; female 88 [69%]) met the inclusion criteria. There was a modest correlation between Doppler-derived and Fick-derived RV CI (r = .57, P < .001), and the mean difference between Doppler-derived and Fick-derived RV CI was -.3 (95% confidence interval of agreement, -.8 to +.9) L/min/m2 . There was also a modest correlation between Doppler-derived RV CI from observer #1 and observer #2 (r = .62, P < .001), and the mean difference between Doppler-derived RV CI from observer #1 and observer #2 was -.2 (95% confidence interval of agreement, -.9 to +.6). CONCLUSIONS: The current study demonstrated a modest correlation between Doppler-derived and Fick-derived RV cardiac output, and a modest interobserver correlation in Doppler-derived RV cardiac output assessment. Further studies are required to validate these results and to explore other potential applications such as in patients with chronic pulmonary regurgitation.

The role of echocardiography for quantitative assessment of right ventricular size and function in adults with repaired tetralogy of Fallot.

BACKGROUND: Quantitative assessment of right ventricular (RV) systolic function by echocardiography is challenging in patients with congenital heart disease because of the complex geometry of the RV and the iatrogenic structural abnormalities resulting from prior cardiac surgeries. The purpose of this study was to determine the correlation between echocardiographic indices of RV systolic function and cardiac magnetic resonance imaging (CMRI) derived RV ejection fraction (RVEF) in adults with repaired tetralogy of Fallot (TOF). METHODS: Quantitative assessment of RV function was performed with RV tissue Doppler systolic velocity (RV s'), tricuspid annular plane systolic excursion (TAPSE), and fractional area change (FAC). These echocardiographic indices were compared to RVEF from CMRI performed on the same day as echocardiogram. RESULTS: Of 209 patients, the mean RV FAC was 39 ± 9%, TAPSE was 18 ± 4 mm, RV s' was 10 ± 2 cm/s, and RVEF was 40 ± 10%. There was a good correlation between TAPSE and RVEF (r = 0.79, P < .001), good correlation between RV s' and RVEF (r = 0.71, P < .001), and modest correlation between FAC and RVEF (r = 0.66, P < .001). TAPSE < 17 mm effectively discriminated between patients with RV systolic dysfunction defined as RVEF < 47% (sensitivity 81%, specificity 79%, area under the curve [AUC] 0.805). FAC < 40% was associated with RVEF < 47% (sensitivity 72%, specificity 63%, AUC 0.719). RV s' < 11 cm was associated with RVEF < 47% (sensitivity 83%, specificity 68%, AUC 0.798). CONCLUSION: Despite the structural and functional abnormalities of the RV in patients with repaired TOF, quantitative assessment of RV systolic function by echocardiography is feasible and had good correlation with CMRI-derived RVEF.

Coronary artery disease in adults with tetralogy of Fallot.

BACKGROUND: There are limited data about outcomes of coronary artery disease (CAD) in adults with repaired tetralogy of Fallot (TOF). The purpose of this study was to describe the prevalence and treatment of CAD in adults with TOF, and the impact of CAD on long-term survival. METHODS: Retrospective review of MACHD database for adults with repaired TOF who underwent aortic root/selective coronary angiogram, 1990-2017. Patients were categorized into three groups: (1) No CAD defined as normal coronary angiogram; (2) Mild CAD defined as ≤50% stenosis in all vessels; and, (3) Significant CAD defined as >50% stenosis in any vessel. RESULTS: We identified 105 (23%) of 465 TOF patients that had angiograms; mean age 47 ± 12 years. The prevalence of mild CAD and significant CAD was 19% (20 patients) and 15% (16 patients), respectively. Of these 16 patient with significant CAD, 9 (56%), 3 (19%), and 4 (24%) patients received guideline directed medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, respectively. Significant CAD was an independent risk factor for mortality (HR: 2.03, 95% CI 1.64-4.22, P = .022) after adjustment for differences in age, and prevalence of atrial fibrillation and renal dysfunction. CONCLUSIONS: Based on a review of a selected cohort of 105 TOF patients, the prevalence of mild CAD and significant CAD was 19% and 15%, respectively. Significant CAD was an independent risk factor for mortality. There is need for more research to determine optimal noninvasive diagnostic strategies and optimal patient selections and methods for revascularization.

The evolution and impact of sarcopenia pre- and post-liver transplantation.

BACKGROUND: Sarcopenia is associated with both increased wait-list mortality and mortality following liver transplantation. AIMS: To determine the course of sarcopenia from transplant evaluation until 1 year post-transplant, and its implications on hospitalisation and mortality following liver transplantation. METHODS: Two hundred and ninety-three transplant recipients from 2002 to 2006 had pre-transplant CT scans analysed at the third lumbar region for sarcopenia, myosteatosis and abdominal visceral fat content. Half the recipients had post-transplant CT scan for interpretation (161/293). RESULTS: Sarcopenia was present in 146/293 (50%) of the patients pre-transplant. There was a significant decrease in muscle mass (loss 2.0 ± 4.9 cm2 /m2 ; P < 0.001), and an increase in myosteatosis while awaiting liver transplantation. There was no significant change in abdominal visceral fat. For every 1 cm2 /m2 decrease in muscle mass there was an increase in post-transplant length of stay by 0.36 days (P = 0.005). Post-transplant, 98/161 (61%) of patients with CT imaging had sarcopenia (25 de novo and 73 persistent), with continued increase in myosteatosis, lower Hounsfield units (-5.0 [IQR -8.6 to 0.1]; P < 0.001) and an increase in abdominal visceral fat (4.9 [IQR -4.4 to 15.6] cm2 /m2 ; P < 0.001). There was no statistically significant difference in 1-year mortality in patients with de novo sarcopenia compared to patients with sarcopenia both pre- and post-transplant (HR 1.88; P = 0.088). CONCLUSIONS: Sarcopenia progresses up to 1 year following liver transplantation and is associated with an increase in post-transplant length of stay.

Understanding and managing cardiovascular outcomes in liver transplant recipients.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is a common cause of mortality after liver transplantation. The transplant community is focused on improving long-term survival. Understanding the prevalence of CVD in liver transplant recipients, precipitating factors as well as prevention and management strategies is essential to achieving this goal. RECENT FINDINGS: CVD is the leading cause of death within the first year after transplant. Arrhythmia and heart failure are the most often cardiovascular morbidities in the first year after transplant which could be related to pretransplant diastolic dysfunction. Pretransplant diastolic dysfunction is reflective of presence of cirrhotic cardiomyopathy which is not as harmless as it was thought. Multiple cardiovascular risk prediction models have become available to aid management in liver transplant recipients. SUMMARY: A comprehensive prevention and treatment strategy is critical to minimize cardiovascular morbidity and mortality after liver transplant. Weight management and metabolic syndrome control are cornerstones to any prevention and management strategy. Bariatric surgery is an underutilized tool in liver transplant recipients. Awareness of 'metabolic-friendly' immunosuppressive regimens should be sought. Strict adherence to the cardiology and endocrine society guidelines with regard to managing metabolic derangements post liver transplantation is instrumental for CVD prevention until transplant specific recommendations can be made.

Differing Impact of Sarcopenia and Frailty in Nonalcoholic Steatohepatitis and Alcoholic Liver Disease.

Sarcopenia and frailty are commonly encountered in patients with end-stage liver disease and are associated with adverse clinical outcomes, including decompensation and wait-list mortality. The impact of these entities in patients with differing disease etiologies has not been elucidated. We aim to ascertain the change in their prevalence over time on the wait list and determine their impact on hospitalization, delisting, and wait-list survival, specifically for patients with nonalcoholic steatohepatitis (NASH) and alcoholic liver disease (ALD). Adult patients who were evaluated for their first liver transplant from 2014 to 2016 with a primary diagnosis of NASH (n = 136) or ALD (n = 129) were included. Computed tomography scans were used to determine the presence of sarcopenia and myosteatosis. Frailty was diagnosed using the Rockwood frailty index. Patients with NASH had a significantly lower prevalence of sarcopenia (22% versus 47%; P < 0.001) but a significantly higher prevalence of frailty (49% versus 34%; P = 0.03) when compared with patients with ALD at the time of listing. In patients with NASH, sarcopenia was not associated with adverse events, but a higher frailty score was associated with an increased length of hospitalization (P = 0.05) and an increased risk of delisting (P = 0.02). In patients with ALD, univariate analysis showed the presence of sarcopenia was associated with an increased risk of delisting (P = 0.01). In conclusion, sarcopenia and frailty occur with differing prevalence with variable impact on outcomes in wait-listed patients with NASH and ALD.