Andrew P. Keaveny

Diagnostic performance of magnetic resonance elastography in staging liver fibrosis: a systematic review and meta-analysis of individual participant data.

BACKGROUND & AIMSnMagnetic resonance elastography (MRE) is a noninvasive tool for staging liver fibrosis. We conducted a meta-analysis of individual participant data collected from published studies to assess the diagnostic accuracy of MRE for staging liver fibrosis in patients with chronic liver diseases (CLD).nnnMETHODSnThrough a systematic literature search of multiple databases (2003-2013), we identified studies on diagnostic performance of MRE for staging liver fibrosis in patients with CLD with native anatomy, using liver biopsy as the standard. We contacted study authors to collect data on each participants age, sex, body mass index (BMI), liver stiffness (measured by MRE), fibrosis stage, staging system used, degree of inflammation, etiology of CLD, and interval between MRE and biopsy. Through a pooled analysis, we calculated cluster-adjusted area under the receiver-operating curve, sensitivity, and specificity of MRE for any fibrosis (≥stage 1), significant fibrosis (≥stage 2), advanced fibrosis (≥stage 3), and cirrhosis (stage 4).nnnRESULTSnWe analyzed data from 12 retrospective studies, comprising 697 patients (mean age, 55 ± 13 y; 59.4% male; mean BMI, 26.9 ± 6.7 kg/m(2); 92.1% with <1 year interval between MRE and biopsy; and 47.1% with hepatitis C). Overall, 19.5%, 19.4%, 15.5%, 15.9%, and 29.7% patients had stage 0, 1, 2, 3, and 4 fibrosis, respectively. The mean area under the receiver-operating curve values (and 95% confidence intervals) for the diagnosis of any (≥stage 1), significant (≥stage 2), advanced fibrosis (≥stage 3), and cirrhosis, were as follows: 0.84 (0.76-0.92), 0.88 (0.84-0.91), 0.93 (0.90-0.95), and 0.92 (0.90-0.94), respectively. A similar diagnostic performance was observed in stratified analysis based on sex, obesity, and etiology of CLD. The overall rate of failure of MRE was 4.3%.nnnCONCLUSIONSnBased on a pooled analysis of data from individual participants, MRE has a high accuracy for the diagnosis of significant or advanced fibrosis and cirrhosis, independent of BMI and etiology of CLD. Prospective studies are warranted to better understand the diagnostic performance of MRE.

Liver Transplantation Using Controlled Donation After Cardiac Death Donors: An Analysis of a Large Single-Center Experience

The use of donation after cardiac death (DCD) donors may provide a valuable source of organs for liver transplantation. Concerns regarding primary nonfunction (PNF) and intrahepatic biliary stricture (IHBSs) have limited the enthusiasm for their use. A retrospective analysis of 1436 consecutive deceased donor liver transplants performed between December 1998 and October 2006 was conducted. These included 108 DCD liver transplants, which were compared to 1328 transplants performed with organs from donors meeting the criteria for donation after brain death (DBD). The median follow‐up was 48 months. The 1‐, 3‐, and 5‐year patient survival and graft survival for DCD donors were 91.5%, 88.1%, and 88.1% and 79.3%, 74.5%, and 71.0%, respectively. The 1‐, 3‐, and 5‐year patient survival and graft survival for DBD donors were 87.3%, 81.1%, and 77.2% and 81.6%, 74.7%, and 69.1%, respectively. Patient survival and graft survival were not significantly different between DCD donors less than 60 years old, DCD donors greater than 60 years old, and DBD donors. Causes of graft loss included IHBSs (n = 9), PNF (n = 4), recurrent hepatitis C virus (n = 4), hepatic artery thrombosis (n = 1), rejection (n = 2), and patient death (n = 13). Contrary to previously published data, excellent long‐term patient survival and graft survival can be obtained with DCD allografts, and in our experience, they are equivalent to those obtained from DBD allografts. Liver Transpl 15: 1028–1035, 2009.

Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 after liver transplant.

Treatment with an all‐oral interferon‐free antiviral regimen using simeprevir and sofosbuvir with or without ribavirin (RBV) for 12 weeks resulted in high sustained virologic response (SVR) rates along with minimal adverse events in non–liver transplant (LT) patients with hepatitis C virus (HCV) genotype 1 infection. This is the first multicenter report on the efficacy, safety, and tolerability of this regimen in LT recipients. A total of 123 patients (76% male, 74% white, 60% genotype 1a, 30% METAVIR F3‐F4, 4% decompensation, 11% cholestatic recurrence, 7% had kidney transplant, and 82% previously failed pegylated interferon/RBV‐based regimens) received treatment and were followed for a median of 30 weeks (range 12‐53 weeks). The median time from LT to treatment was 32 months (range 2‐317 months). Tacrolimus was the primary immunosuppression in 91% of patients. Minimal immunosuppression dose adjustments were required. An SVR 12 weeks after treatment completion (SVR12) was achieved in 90% of patients (95% confidence interval 84%‐96%). In patients with genotype 1a infection, the SVR12 rate was significantly lower in those with METAVIR F3‐F4 (71%) compared to those with F0‐F2 (91%). Half of the patients achieved undetected HCV RNA at treatment week 4, and their SVR12 rate was significantly higher (96%) compared to those with detectable HCV RNA (83%). Treatment was very well tolerated with mild degrees of adverse events, except for one death possibly due to drug‐induced lung injury. In the 25 patients who received RBV, 72% developed anemia requiring intervention. Conclusion: An all‐oral interferon‐free antiviral regimen using simeprevir and sofosbuvir with or without RBV for 12 weeks was very well tolerated and resulted in excellent SVR12 rates in LT recipients with HCV genotype 1 infection. (Hepatology 2015;61:1880–1886)

Multicenter experience using telaprevir or boceprevir with peginterferon and ribavirin to treat hepatitis C genotype 1 after liver transplantation

The safety, efficacy, and effect on immunosuppression levels of telaprevir (TVR) or boceprevir (BOC) in combination with peginterferon (PEG‐IFN) and ribavirin (RBV) in recipients of liver transplantation (LT) with hepatitis C virus (HCV) genotype 1 have not been defined. We report our 3 centers preliminary experiences with administering triple antiviral treatment protocols containing PEG‐IFN, RBV, and TVR or BOC. Patients with biopsy‐proven HCV recurrence (METAVIR gradeu2009≥u20093 and/or stageu2009≥u20092) received TVR with PEG‐IFN/RBV for 12 weeks and then PEG‐IFN/RBV for 36 weeks or BOC with PEG‐IFN/RBV for 44 weeks after 4 weeks of lead‐in PEG‐IFN/RBV. Maintenance immunosuppression was changed to cyclosporine whenever possible, and the levels were followed closely. PEG‐IFN/RBV dose adjustments were based on patients tolerance. Sixty patients started triple antiviral treatment, and they were followed for up to 66 weeks (meanu2009=u200935 weeks); all were followed at least 12 weeks. Thirty of the 35 patients treated with TVR (86%) achieved undetectable HCV RNA levels after an average of 6 weeks, whereas 12 patients (48%) in the BOC‐treated group achieved undetectable HCV RNA levels after a mean of 11 weeks. According to an intention‐to‐treat analysis, 14 of 21 TVR‐treated patients (67%) and 10 of 22 patients who received BOC (45%) achieved undetectable HCV RNA levels at week 24 without viral breakthrough at the last follow‐up. Cytopenias complicated both regimens; all patients required dose reductions of PEG‐IFN and/or RBV or the administration of hematological growth factors. One death occurred in each group on triple antiviral treatment. In conclusion, TVR or BOC combined with PEG‐IFN/RBV achieved on‐treatment virological response rates of approximately 50% to 60% in patients with recurrent HCV after LT, but significant side effects were common. Liver Transpl 19:690–700, 2013.

Events in procurement as risk factors for ischemic cholangiopathy in liver transplantation using donation after cardiac death donors

The use of donation after cardiac death (DCD) liver grafts is controversial because of the overall increased rates of graft loss and morbidity, which are mostly related to the consequences of ischemic cholangiopathy (IC). In this study, we sought to determine the factors leading to graft loss and the development of IC and to compare patient and graft survival rates for recipients of DCD liver grafts and recipients of donation after brain death (DBD) liver grafts in a large series at a single transplant center. Two hundred liver transplants with DCD donors were performed between 1998 and 2010 at Mayo Clinic Florida. Logistic regression models were used in the univariate and multivariate analyses of predictors for the development of IC. Additional analyses using Cox regression models were performed to identify predictors of graft survival and to compare outcomes for DCD and DBD graft recipients. In our series, the patient survival rates for the DCD and DBD groups at 1, 3, and 5 years was 92.6%, 85%, and 80.9% and 89.8%, 83.0%, and 76.6%, respectively (P = not significant). The graft survival rates for the DCD and DBD groups at 1, 3, and 5 years were 80.9%, 72.7%, and 68.9% and 83.3%, 75.1%, and 68.6%, respectively (P = not significant). In the DCD group, 5 patients (2.5%) had primary nonfunction, 7 patients (3.5%) had hepatic artery thrombosis, and 3 patients (1.5%) experienced hepatic necrosis. IC was diagnosed in 24 patients (12%), and 11 of these patients (5.5%) required retransplantation. In the multivariate analysis, the asystole‐to‐cross clamp duration [odds ratio = 1.161, 95% confidence interval (CI) = 1.021‐1.321] and African American recipient race (odds ratio = 5.374, 95% CI = 1.368‐21.103) were identified as significant factors for predicting the development of IC (P < 0.05). This study has established a link between the development of IC and the asystole‐to‐cross clamp duration. Procurement techniques that prolong the nonperfusion period increase the risk for the development of IC in DCD liver grafts. Liver Transpl 18:101–112, 2012.

Serum fibrosis markers can predict rapid fibrosis progression after liver transplantation for hepatitis C

Although recurrent hepatitis C virus (HCV) after liver transplantation (LT) is universal, a minority of patients will develop cirrhosis within 5 years of surgery, which places them at risk for allograft failure. This retrospective study investigated whether 2 serum fibrosis markers, serum hyaluronic acid (HA) and YKL‐40, could be used to predict rapid fibrosis progression (RFP) post‐LT. These markers were compared with conventional laboratory tests, histological assessment, and hepatic stellate cell activity (HSCA), a key step in fibrogenesis, as assessed by immunohistochemical staining for alpha‐smooth muscle actin. Serum and protocol liver biopsy samples were obtained from 46 LT recipients at means of 5 ± 2 (biopsy 1) and 39 ± 6 (biopsy 2) months post‐LT, respectively. RFP was defined as an increase in the fibrosis score ≥ 2 from biopsy 1 to biopsy 2 (a mean interval of 33 ± 6 months). The ability of parameters at biopsy 1 to predict RFP was compared with the areas under receiver operating characteristic curves (AUROCs). Of the 46 subjects, 15 developed RFP. Serum HA and YKL‐40 performed significantly better than conventional parameters and HSCA in predicting RFP post‐LT for HCV at biopsy 1, with AUROCs of 0.89 and 0.92, respectively. The accuracy of serum HA ≥ 90 μg/L and YKL‐40 ≥ 200 μg/L in predicting RFP at biopsy 1 was 80% and 96%, respectively. In conclusion, we found that elevated levels of serum HA and YKL‐40 within the first 6 months after LT accurately predicted RFP. Larger studies evaluating the role of serum HA and YKL‐40 in post‐LT management are warranted. Liver Transpl 14:1294–1302, 2008.

Kidney allocation to liver transplant candidates with renal failure of undetermined etiology: Role of percutaneous renal biopsy

The feasibility, value and risk of percutaneous renal biopsy (PRB) in liver transplant candidates with renal failure are unknown. PRB was performed on 44 liver transplant candidates with renal failure of undetermined etiology and glomerular filtration rate (GFR) <40 mL/min/1.73 m2 (n = 37) or on renal replacement therapy (RRT) (n = 7). Patients with ≥30% interstitial fibrosis (IF), ≥40% global glomerulosclerosis (gGS) and/or diffuse glomerulonephritis were approved for simultaneous‐liver‐kidney (SLK) transplantation. Prebiopsy GFR, urinary sodium indices, dependency on RRT and kidney size were comparable between 27 liver‐transplant‐alone (LTA) and 17 SLK candidates and did not relate to the biopsy diagnosis. The interobserver agreement for the degree of IF or gGS was moderate‐to‐excellent. After a mean of 78 ± 67 days, 16 and 8 patients received LTA and SLK transplants. All five LTA recipients on RRT recovered kidney function after transplantation and serum creatinine was comparable between LTA and SLK recipients at last follow‐up. Biopsy complications developed in 13, of these, five required intervention. PRB is feasible in liver transplant candidates with renal failure and provides reproducible histological information that does not relate to the pretransplant clinical data. Randomized studies are needed to determine if PRB can direct kidney allocation in this challenging group of liver transplant candidates.

Long-term outcomes of donation after cardiac death liver allografts from a single center.

Abstract:u2002 Organ shortage continues to be a major challenge in transplantation. Recent experience with controlled non‐heart‐beating or donation after cardiac death (DCD) are encouraging. However, long‐term outcomes of DCD liver allografts are limited. In this study, we present outcomes of 19 DCD liver allografts with follow‐up >4.5u2003years. During 1998–2001, 19 (4.1%) liver transplants (LT) with DCD allografts were performed at our center. Conventional heart‐beating donors included 234 standard criteria donors (SCD) and 214 extended criteria donors (ECD). We found that DCD allografts had equivalent rates of primary non‐function and biliary complications as compared with SCD and ECD. The overall one‐, two‐, and five‐yr DCD graft and patient survival was 73.7%, 68.4%, and 63.2%, and 89.5%, 89.5%, and 89.5%, respectively. DCD graft survival was similar to graft survival of SCD and ECD in non hepatitis C virus (HCV) recipients (pu2003>u20030.370). In contrast, DCD graft survival was significantly reduced in HCV recipients (pu2003=u20030.007). In conclusion, DCD liver allografts are durable and have acceptable long‐term outcomes. Further research is required to assess the impact of HCV on DCD allograft survival.

Use of liver grafts from donation after cardiac death donors for recipients with hepatitis C virus

Hepatitis C virus (HCV) infection is the most common indication for orthotopic liver transplantation in the United States. Although studies have addressed the use of expanded criteria donor organs in HCV+ patients, to date the use of liver grafts from donation after cardiac death (DCD) donors in HCV+ patients has been addressed by only a limited number of studies. This retrospective analysis was undertaken to study the outcomes of DCD liver grafts used in HCV+ recipients. Seventy‐seven HCV+ patients who received DCD liver grafts were compared to 77 matched HCV+ patients who received donation after brain death (DBD) liver grafts and 77 unmatched non‐HCV patients who received DCD liver grafts. There were no differences in 1‐, 3‐, and 5‐year patient or graft survival among the groups. Multivariate analysis showed that the Model for End‐Stage Liver Disease score [hazard ratio (HR) = 1.037, 95% confidence interval (CI) = 1.006‐1.069, P = 0.018] and posttransplant cytomegalovirus infection (HR = 3.367, 95% CI = 1.493‐7.593, P = 0.003) were significant factors for graft loss. A comparison of the HCV+ groups for fibrosis progression based on protocol biopsy samples up to 5 years post‐transplant did not show any difference; in multivariate analysis, HCV genotype 1 was the only factor that affected progression to stage 2 fibrosis (genotype 1 versus non‐1 genotypes: HR = 2.739, 95% CI = 1.047‐7.143, P = 0.040). In conclusion, this match‐controlled, retrospective analysis demonstrates that DCD liver graft utilization does not cause untoward effects on disease progression or patient and graft survival in comparison with DBD liver grafts in HCV+ patients. Liver Transpl 17:641‐649, 2011.

Clinicopathologic Findings and Outcomes of Liver Transplantation Using Grafts From Donors With Unrecognized and Unusual Diseases

Despite certain strict criteria for suitable organ donors, some unrecognized and unusual diseases have been transmitted through liver transplantation to recipients. In the current series, we review our experience with 14 patients who underwent liver transplantation using donor grafts with unusual pathology, including amyloidosis (6), schistosomiasis (3), iron overload (2), and α‐1 antitrypsin deficiency (3). One of 6 patients who received grafts with amyloidosis developed vasculitis associated with the presence of arterial amyloid. With proper management, patients with donor schistosomiasis, iron overload and α‐1 antitrypsin deficiency appear to have outcomes comparable to liver transplantation using grafts without these findings. In conclusion, long‐term follow‐up is necessary to confirm these findings and understand the impact of using these grafts. Liver Transpl 12:310–315, 2006.