Aqel, Bashar

Abstract Background and Aims The NASH Clinical Research Network histologic scoring system, the gold‐standard NASH histology assessment for clinical trials, has demonstrated intrarater and interrater variability. An expert panel in a previous systematic Research and Development/University of California Los Angeles (RAND/UCLA) study determined that existing histologic scoring systems do not fully capture NASH disease activity and fibrosis, and standardized definitions of histologic features are needed. We evaluated the reliability of existing and alternate histologic measures and their correlations with a disease activity visual analog scale to propose optimal components for an expanded NAFLD activity score (NAS). Approach and Results Four liver pathologists who were involved in the prior RAND/UCLA study underwent standardized training and multiple discussions with the goal of improving agreement. They were blinded to clinical information and scored histologic measures twice, ≥2 weeks apart, for 40 liver biopsies representing the full spectrum of NAFLD. Index intraclass correlation coefficient (ICC) estimates demonstrated intrarater (0.80–0.85) and interrater (0.60–0.72) reliability. Hepatocyte ballooning items had similar interrater ICCs (0.68–0.79), including those extending scores from 0–2 to 0–4. Steatosis measures (interrater ICCs, 0.72–0.80) correlated poorly with disease activity. Correlations with disease activity were largest for hepatocyte ballooning and Mallory‐Denk bodies (MDBs), with both used to develop the expanded NAS (intrarater ICC, 0.90; interrater ICC, 0.80). Fibrosis measures had ICCs of 0.70–0.87. Conclusions After extensive preparation among a group of experienced pathologists, we demonstrated improved reliability of multiple existing histologic NAFLD indices and fibrosis staging systems. Hepatocyte ballooning and MDBs most strongly correlated with disease activity and were used for the expanded NAS. Further validation including evaluation of responsiveness is required.

Background. As the number of donation after circulatory death (DCD) liver transplants (LTs) performed in the United States continues to increase annually, there has been interest by policy makers to develop a more robust exception point safety net for patients who develop ischemic cholangiopathy (IC) following DCD LT. As such, there is a need for better understanding of the clinical course and long-term outcomes in patients who develop IC, as well as determining if IC can be classified into distinct categories with distinctly different clinical outcomes. Methods. All DCD LT performed at Mayo Clinic Florida, Mayo Clinic Arizona, and Mayo Clinic Rochester from January 1999 to March 2020 were included (N = 770). Outcomes were compared between 4 distinct radiologic patterns of IC: diffuse necrosis, multifocal progressive, confluence dominant, and minor form. Results. In total, 88 (11.4%) patients developed IC, of which 42 (5.5%) were listed for retransplantation of liver (ReLT). Patients with diffuse necrosis and multifocal progressive patterns suffered from frequent hospital admissions for cholangitis in the first year following DCD LT (median 3 and 2), were largely stent dependent (100% and 85.7%), and almost universally required ReLT. Patients with confluence dominant disease were managed with multiple stents and frequently recovered, ultimately becoming stent free without need for ReLT. Patients with the minor form IC did well with limited need for stent placement or repeat procedures and did not require ReLT. Graft survival was different between the 4 distinct IC patterns ( P < 0.001). Conclusions. The present analysis provides a detailed analysis on the natural history and clinical course of IC. Patients developing IC can be classified into 4 distinct patterns with distinct clinical courses.

Statin therapy may reduce the risk of venous thromboembolism (VTE), which may impact solid organ transplant outcomes. We evaluated the incidence of VTE and other complications after liver transplantation stratified by hyperlipidemia status and statin use using a retrospective cohort study approach. We reviewed all primary orthotopic liver transplantation (OLT) records from January 2014 to December 2019 from our center. Intraoperative deaths were excluded. Recipient, donor clinical and demographic data were collected. We developed risk‐adjusted models to assess the effect of statin use on the occurrence of VTE, hepatic artery complications (HACs), graft failure, and death, accounting for clinical covariates and competing risks. A total of 672 OLT recipients were included in the analysis. Of this cohort, 11.9% (n = 80) received statin therapy. A total of 47 patients (7.0%) had VTE events. HACs occurred in 40 patients (6.0%). A total of 42 (6.1%) patients experienced graft loss, whereas 9.1% (n = 61) of the cohort died during the study interval. Eighty OLT recipients (29.8%) were treated with statins. In the statin treated group, 0% of patients had VTE versus 7.9% of those not on statins (P = 0.02). HACs were identified in 1.2% of the statin group and 6.8% of the nonstatin group. Untreated hyperlipidemia was associated with a 2.1‐fold higher risk of HACs versus patients with no hyperlipidemia status (P = 0.05). Statin therapy was associated with significantly better risk‐adjusted thromboembolic event‐free survival (absence of VTE, cerebrovascular accident, myocardial infarction, HACs, and death); hazard ratio, 2.7; P = 0.01. These data indicate that statin therapy is correlated with a lower rate of VTE and HACs after liver transplantation.

Background: Direct-acting antivirals (DAA) are highly effective for the treatment of hepatitis C (HCV), although there are limited data on the safety and efficacy of DAA therapy in hepatitis C-positive individuals awaiting liver transplantation for hepatocellular carcinoma (HCC). Methods: We conducted a retrospective cohort study of HCV-positive patients who underwent liver transplantation for HCC at 3 liver transplant centers across the United States from 2014 to 2017 with follow-up to July 2018. Transplant recipients who received DAA before transplant were compared with those who did not (DAA naive) for posttransplant HCC recurrence rate, sustained virological response (SVR), allograft failure, and death using Kaplan-Meier analysis and Cox proportional hazard models. Results: A total of 171 HCV-HCC transplant recipients (99 pretransplant DAA; 72 DAA naive controls) were included, with a median follow-up of 24 months. The overall posttransplant HCC recurrence rate was 9% (15/171). Pretransplant DAA was not associated with HCC recurrence (5% versus 14%; P = 0.07), graft failure (7% versus 3%; P = 0.21), or death (12% versus 19%; P = 0.19) as compared with DAA naive patients. SVR rates were significantly lower (P < 0.01) with pretransplant DAA (75%, 39/52) than posttransplant DAA (97%, 59/61) therapies. Those who received pretransplant DAA and those who did not were not statistically different in age, gender, alpha fetal protein levels, model for end-stage liver disease scores, or transplant wait time. Conclusions: Pretransplant DAA for HCV was not associated with an increased risk of posttransplant HCC recurrence, though pretransplant DAA had lower efficacy than posttransplant DAA in HCV-HCC transplant recipients.

Hepatic artery stenosis after liver transplant is often treated with endovascular stent placement. Our institution has adopted use of drug-eluting stents, particularly in small-caliber arteries. We aimed to compare patency rates of drug-eluting stents vs. traditional bare-metal stents. This was a single-institution, retrospective study of liver transplant hepatic artery stenosis treated with stents. Primary patency was defined as time from stent placement to resistive index on Doppler ultrasonography (<0.5), hepatic artery thrombosis, or any intervention including surgery. Fifty-two patients were treated with stents (31 men; mean age, 57 years): 15, drug-eluting stents; 37, bare-metal stents. Mean arterial diameters were 4.1 mm and 5.1 mm, respectively. Technical success was 100% (52/52). At 6 months, 1, 2, and 3 years, primary patency for drug-eluting stents was 80%, 71%, 71%, and 71%; bare-metal stents: 76%, 65%, 53%, and 46% (p = 0.41). Primary patency for small-caliber arteries (3.5–4.5 mm) with drug-eluting stents was 93%, 75%, 75%, and 75%; bare-metal stents: 60%, 60%, 50%, and 38% (p = 0.19). Overall survival was 100%, 100%, 94%, and 91%. Graft survival was 100%, 98%, 96%, and 90%. Stenting for hepatic artery stenosis was safe and effective. While not statistically significant, patency improved with drug-eluting stents compared with bare-metal stents, especially in arteries < 4.5 mm in diameter. Drug-eluting stents can be considered for liver transplant hepatic artery stenosis, particularly in small-caliber arteries.

Background. Portopulmonary hypertension (POPH) is the presence of pulmonary arterial (PA) hypertension in patients with portal hypertension and is associated with significant morbidity and mortality. In a cohort of POPH patients, we describe the clinical outcomes of POPH patients who underwent liver transplantation (LT). Methods. Retrospectively collected data from a prospectively assembled cohort of all consecutive POPH adults evaluated in 3 transplant centers from 1996 to 2019. Results. From a cohort of 228 POPH patients, 50 patients underwent LT. Significant hemodynamic improvement after PA-targeted therapy was observed, with 58% receiving only monotherapy pretransplant. After LT, 21 (42%) patients were able to discontinue and remained off PA-targeted therapy. The 1-, 3-, and 5-y unadjusted survival rates after LT were 72%, 63%, and 60%, respectively. An elevated pulmonary vascular resistance (PVR) before LT was associated with worse survival rate (HR, 1.91; 95% CI, 1.07-3.74, P = 0.04). No survival difference was observed in those granted MELD exception or transplants performed before or after the year 2010. Conclusions. Significant number of POPH patients discontinued PA-targeted therapy after LT. Higher PVR before LT was associated with worse survival, as was monotherapy use. Despite effective PA-targeted therapies, POPH survival outcomes after LT in our cohort were modest and may reflect the need for more aggressive therapy.