William W. Sharr

Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation.

BACKGROUND & AIMS We investigated the efficacy of entecavir, a cyclopentyl guanosine nucleoside analogue, as monoprophylaxis in patients with chronic hepatitis B who received a liver transplant. METHODS We studied data from 80 consecutive patients who received a liver transplant (47 from living donors and 33 from deceased donors) for hepatitis B-related disease and entecavir monotherapy as prophylaxis. None of the patients received hepatitis B immunoglobulin. Indications for transplant included decompensation from cirrhosis (27.5%), acute-on-chronic hepatitis B (47.5%), and hepatocellular carcinoma (25%). The median follow-up time was 26 months (range, 5-40 months). Before transplant, 33 patients were not on antiviral therapy and 47 were on oral therapy (18 had received less than 3 months of treatment). RESULTS At the time of transplant, the median log HBV DNA level was 3.5 copies/mL (range, 1.54-8.81); 21 patients (26%) had undetectable levels of HBV DNA. The cumulative rate of hepatitis B surface antigen (HBsAg) loss was 86% and 91% after 1 and 2 years, respectively. Ten patients had reappearance of HBsAg. Eighteen patients (22.5%) were HBsAg positive at the time of their last examination; 17 of these had undetectable levels of HBV DNA, and the remaining patient had a low level of HBV DNA (217 copies/mL). There was no evidence of mutations at sites that confer resistance to entecavir among patients who were HBsAg positive. CONCLUSIONS Although only 26% of patients had complete viral suppression at the time of transplant, 91% lost HBsAg, with 98.8% achieving undetectable levels of HBV DNA. A hepatitis B immunoglobulin-free regimen of entecavir monotherapy is effective after liver transplantation for chronic hepatitis B.

Oral Nucleoside/Nucleotide Analogs Without Hepatitis B Immune Globulin After Liver Transplantation for Hepatitis B

OBJECTIVES:The long-term outcomes of oral antiviral therapy without hepatitis B immune globulin (HBIG) in prevention of reinfection with hepatitis B after liver transplantation are not known. We aimed to determine the long-term outcomes from a large population of chronic hepatitis B (CHB) liver transplant recipients using oral antiviral therapy alone.METHODS:A total of 362 consecutive CHB patients transplanted from January 2003 to May 2011 were included. None of the patients received HBIG. Viral serology, viral load, and liver biochemistry were performed at regular intervals during follow-up.RESULTS:Of the 362 patients, 176 (49%), 142 (39%), and 44 (12%) were on lamivudine (LAM), entecavir (ETV), and combination therapy (predominantly LAM+adefovir), respectively, at the time of transplant. The median follow-up length was 53 months. The rate of hepatitis B surface antigen seronegativity and hepatitis B virus (HBV) DNA suppression to undetectable levels at 8 years was 88 and 98%, respectively. The virological relapse rates (>1 log increase IU/ml) at 1, 3, 5, and 8 years was 5, 10, 13 and 16%, respectively. The virological relapse rate at 3 years for LAM, ETV, and combination group was 17, 0, and 7%, respectively (P<0.001). Forty-two patients had virological relapse, of which 36 had YMDD mutation (31 in the LAM group and 5 in the combination group). The overall 8-year survival was 83%, with no difference between the three treatment groups (P=0.94). No mortality from HBV recurrence occurred in the 362 patients.CONCLUSIONS:Oral nucleoside/nucleotide analogs without HBIG are effective in preventing graft loss secondary to hepatitis B recurrence after liver transplantation. However, new agents with a high barrier to resistance should be used to minimize drug resistance and to prevent virological rebound.

11C-Acetate and 18F-FDG PET/CT for Clinical Staging and Selection of Patients with Hepatocellular Carcinoma for Liver Transplantation on the Basis of Milan Criteria: Surgeon’s Perspective

The success of liver transplantation (LT) for hepatocellular carcinoma (HCC) is enhanced by careful patient selection on the basis of the Milan criteria. The criteria are traditionally assessed by contrast CT, which is known to be affected by structural or architectural changes in cirrhotic livers. We aimed to compare dual-tracer (11C-acetate and 18F-FDG) PET/CT with contrast CT for patient selection on the basis of the Milan criteria. Methods: Patients who had HCC and had undergone both preoperative dual-tracer PET/CT and contrast CT within a 1-mo interval were retrospectively studied. They then underwent either LT (n = 22) or partial hepatectomy (PH) (n = 21; HCC of ≤ 8 cm). Imaging data were compared with data from postoperative pathologic analysis for accuracy in assessment of parameters specified by the Milan criteria (tumor size and extent, vascular invasion, and metastasis), TNM staging, and patient selection for LT. Results: Dual-tracer PET/CT performed equally well in both LT and PH groups for HCC detection (94.1% vs. 95.8%) and TNM staging (90.9% vs. 90.5%). Contrast CT performed reasonably well in the LT group but not in the PH group for HCC detection (67.6% vs. 37.5%) and TNM staging (54.5% vs. 28.6%). In the LT group, the sensitivity and specificity of contrast CT for patient selection on the basis of the Milan criteria were 43.8% and 66.7%, respectively (comparable to values in the literature); the sensitivity and specificity of dual-tracer PET/CT were 93.8% and 100%, respectively (both Ps < 0.05). From the surgeon’s perspective, we tended to perform transplantation for patients with higher diagnostic certainty (stricter CT criteria) because of a shortage of donor grafts. Patients who were not transplant candidates usually underwent up-front hepatectomy without the benefit of reassessment contrast CT, resulting in lower accuracies for the PH group. The overall sensitivity (96.8%) and specificity (91.7%) of dual-tracer PET/CT for patient selection for LT were significantly higher than those of contrast CT (41.9% and 33.0%, respectively) (both Ps < 0.05). Sources of error for contrast CT were related to cirrhosis or previous treatment and included difficulty in differentiating cirrhotic nodules from HCC (39%) and estimation of tumor size (14%). Overstaging of vascular invasion (4.6%) and extrahepatic metastases (4.6%) was infrequent. The rate of false-negative results of dual-tracer PET/CT was 4.7%. Conclusion: Dual-tracer PET/CT was significantly less affected by cirrhotic changes than contrast CT for HCC staging and patient selection for LT on the basis of the Milan criteria. The inclusion of dual-tracer PET/CT in pretransplant workup may warrant serious consideration.

Can positron emission tomography with the dual tracers [11C]acetate and [18F]fludeoxyglucose predict microvascular invasion in hepatocellular carcinoma?

Microvascular invasion is a poor prognostic indicator of the recurrence of hepatocellular carcinoma (HCC) after surgical treatment. Positron emission tomography (PET) with [18F]fludeoxyglucose ([18F]FDG) as a tracer has been employed to predict the prognosis before surgery for various kinds of tumors, but it has not been found to be sensitive enough for HCC. Thus, [11C]acetate has been adopted as an additional tracer. This study was designed to evaluate the ability of dual‐tracer PET ([18F]FDG and [11C]acetate) to predict microvascular invasion before liver resection or transplantation. Fifty‐eight HCC patients who were preoperatively examined with whole‐body dual‐tracer PET were studied. Twenty‐five patients were [18F]FDG‐positive, and 56 were [11C]acetate‐positive. The sensitivity of [18F]FDG in detecting primary HCC was 43%, and the sensitivity of [11C]acetate was 93%. Twenty‐nine patients had HCC with microvascular invasion according to the final pathological examination. The sensitivity, specificity, positive predictive value, and negative predictive value of [18F]FDG PET in predicting microvascular invasion were 55.2%, 69%, 64%, and 60.6%, respectively; the corresponding rates for [11C]acetate PET were 93.1%, 0%, 48.2%, and 0%. The factors associated with HCC recurrence, which included multifocal involvement, a large tumor size, microsatellite lesions, poor HCC differentiation, and an advanced stage of disease, were analyzed and compared with positive PET results. A tumor size greater than 5 cm was significantly associated with positive [18F]FDG PET results; [11C]acetate was not associated with poor prognostic indicators. Preoperative [18F]FDG PET may predict microvascular invasion. The addition of [11C]acetate improves the overall sensitivity of PET, but it has no incremental value in predicting microvascular invasion. Liver Transpl 17:1218–1225, 2011.

Bile duct anastomotic stricture after adult-to-adult right lobe living donor liver transplantation.

Duct‐to‐duct anastomosis (DDA) and hepaticojejunostomy (HJ) are options for biliary reconstruction in patients undergoing adult‐to‐adult right lobe living donor liver transplantation (ARLDLT), after which biliary anastomotic stricture (BAS) is common as a complication. The risk factors for BAS are not clearly defined. We aimed to determine the rate of post‐ARLDLT BAS in our center and its associated factors. In 265 ARLDLT recipients, 55 (20.8%) developed postoperative BAS. The diagnosis was based on clinical, biochemical, histological, and radiological results. The BAS rates were 21.4% (43/201) for recipients undergoing DDA during transplantation, 18.9% (10/53) for recipients undergoing HJ, and 18.2% (2/11) for recipients undergoing both procedures. BAS and non‐BAS patients had comparable demographics. The number of graft bile duct openings (P = 0.516) and the size of the grafts smallest bile duct (5 versus 5 mm, P = 0.4) were not significantly different between BAS and non‐BAS patients. Univariate analysis showed that the factors associated with postoperative BAS were the recipient warm ischemia time (55 versus 51 minutes, P = 0.026), graft cold ischemia time (120 versus 108 minutes, P = 0.046), stent use (21.8% versus 7.1%, P = 0.001), postoperative acute cellular rejection (29.1% versus 11.0%, P = 0.001), and University of Wisconsin solution use (21.8% versus 7.1%, P = 0.001). Multivariate analysis showed that the cold ischemia time (odds ratio = 1.012, 95% confidence interval = 1.002‐1.023, P = 0.014) and acute rejection (odds ratio = 3.180, 95% confidence interval = 1.606‐6.853, P = 0.002) were significant factors. The graft survival rates of BAS and non‐BAS patients were comparable. One patient required retransplantation for secondary biliary cirrhosis. In conclusion, BAS remains common after ARLDLT regardless of DDA or HJ. The graft cold ischemia time and postoperative acute cellular rejection are significantly associated with postoperative BAS. Liver Transpl 17:47–52, 2011.

High-intensity focused ultrasound ablation: An effective bridging therapy for hepatocellular carcinoma patients

AIM To analyze whether high-intensity focused ultrasound (HIFU) ablation is an effective bridging therapy for patients with hepatocellular carcinoma (HCC). METHODS From January 2007 to December 2010, 49 consecutive HCC patients were listed for liver transplantation (UCSF criteria). The median waiting time for transplantation was 9.5 mo. Twenty-nine patients received transarterial chemoembolization (TACE) as a bringing therapy and 16 patients received no treatment before transplantation. Five patients received HIFU ablation as a bridging therapy. Another five patients with the same tumor staging (within the UCSF criteria) who received HIFU ablation but not on the transplant list were included for comparison. Patients were comparable in terms of Child-Pugh and model for end-stage liver disease scores, tumor size and number, and cause of cirrhosis. RESULTS The HIFU group and TACE group showed no difference in terms of tumor size and tumor number. One patient in the HIFU group and no patient in the TACE group had gross ascites. The median hospital stay was 1 d (range, 1-21 d) in the TACE group and two days (range, 1-9 d) in the HIFU group (P < 0.000). No HIFU-related complication occurred. In the HIFU group, nine patients (90%) had complete response and one patient (10%) had partial response to the treatment. In the TACE group, only one patient (3%) had response to the treatment while 14 patients (48%) had stable disease and 14 patients (48%) had progressive disease (P = 0.00). Seven patients in the TACE group and no patient in the HIFU group dropped out from the transplant waiting list (P = 0.559). CONCLUSION HIFU ablation is safe and effective in the treatment of HCC for patients with advanced cirrhosis. It may reduce the drop-out rate of liver transplant candidate.

Modulation of graft vascular inflow guided by flowmetry and manometry in liver transplantation

BACKGROUND Survival of the partial graft after living donor liver transplantation owes much to its tremendous regenerative ability. With excellent venous outflow capacity, a graft within a wide range of graft-to-standard-liver-volume ratios can cope with portal hypertension that is common in liver transplant recipients. However, when the ratio range is exceeded, modulation of graft vascular inflow becomes necessary for graft survival. The interplay between graft-to-standard-liver-volume ratio and portal pressure, in the presence of portosystemic shunt or otherwise, requires individualized modulation of graft portal and arterial inflows. Boosting of portal inflow by shunt ligation can be guided by transonic flowmetry, whereas muting of portal inflow by splenic artery ligation can be monitored by portal electronic manometry. METHOD We describe four cases to illustrate the above. RESULTS One patient had hepatic artery thrombosis resulting from splenic artery steal syndrome which was the sequela of small-for-size syndrome. Emergency splenic artery ligation and re-anastomosis of the hepatic artery successfully muted the portal inflow and boosted the hepatic arterial inflow. Another patient with portal vein thrombosis underwent thrombendvenectomy. Portal inflow was boosted with ligation of portosystemic shunt, which is often present in these patients with portal hypertension. The coexistence of splenic aneurysm and splenorenal shunt required ligation of both in the third patient. The fourth patient, with portal pressure and flow monitoring, avoided ligation of a coronary vein which became a main portal inflow after portal thrombendvenectomy. CONCLUSION Management of graft inflow modulation guided selectively by transonic flowmetry or portal manometry was described.

Pilot study of high‐intensity focused ultrasound ablation as a bridging therapy for hepatocellular carcinoma patients wait‐listed for liver transplantation

The objective of this study was to investigate the outcomes of high‐intensity focused ultrasound (HIFU) ablation as a bridging therapy for patients with hepatocellular carcinoma (HCC) who had been wait‐listed for deceased donor liver transplantation (DDLT). Adult patients with unresectable and unablatable HCCs within the University of California San Francisco criteria who had been wait‐listed for DDLT were screened for their suitability for HIFU ablation as a bridging therapy if they were not suitable for transarterial chemoembolization (TACE). Treatment outcomes for patients receiving HIFU ablation, TACE, and best medical treatment (BMT) were compared. Fifty‐one patients were included in the analysis. Before the introduction of HIFU ablation, only 39.2% of the patients had received bridging therapy (TACE only, n = 20). With HIFU ablation in use, the rate increased dramatically to 80.4% (TACE + HIFU, n = 41). The overall dropout rate was 51% (n = 26). Patients in the BMT group had a significantly higher dropout rate (P = 0.03) and significantly poorer liver function as reflected by higher Model for End‐Stage Liver Disease scores and higher Child‐Pugh grading. Clinically relevant ascites was found in 5 patients in the HIFU group and 2 patients in the BMT group, but none was found in the TACE group (P = 0.01 and P = 0.03, respectively). The TACE and HIFU groups had comparable percentages of tumor necrosis in excised livers (P = 0.35), and both were significantly higher than that in the BMT group (P = 0.01 and P = 0.02, respectively). In conclusion, HIFU ablation was safe even for HCC patients with Child‐Pugh C disease. Its adoption increased the percentage of patients receiving bridging therapy from 39.2% to 80.4%. A randomized controlled trial for further validation of its efficacy is warranted. Liver Transpl 20:912–921, 2014.

Outcomes of living donor liver transplantation for patients with preoperative type 1 hepatorenal syndrome and acute hepatic decompensation.

This study investigated the outcomes of living donor liver transplantation (LDLT) for patients with preoperative type 1 hepatorenal syndrome (HRS) and acute hepatic decompensation. Prospectively collected data for 104 patients who had fulminant hepatic failure, acute decompensation of cirrhosis, or an acute flare of chronic hepatitis B were analyzed. Thirty‐three patients (31.7%) had HRS (the HRS group), and 71 patients (68.3%) did not (the non‐HRS group). The median follow‐up period was 60 months. The HRS group had significantly more preoperative intensive care unit (ICU) admissions (84.8% versus 60.6%, P = 0.01), worse preoperative blood test results (creatinine, 248 versus 88 μmol/L, P < 0.001; total bilirubin, 630 versus 555 μmol/L, P = 0.001), more hemodialysis (48.5% versus 0%, P < 0.001), more blood transfusions (9 versus 4 U, P < 0.001), longer postoperative ICU stays (8 versus 4 days, P < 0.001), worse postoperative blood test results (creatinine at 1 year, 108 versus 96 μmol/L, P = 0.006), and poorer overall survival (P < 0.001). In a multivariate analysis, only HRS was associated with poorer overall survival (hazard ratio = 8.592, 95% confidence interval = 1.782‐41.431, P = 0.007). In conclusion, HRS patients had worse postoperative renal function and overall survival than non‐HRS patients. However, their 5‐year overall survival rate was still nearly 80%, which is satisfactory. Therefore, LDLT can be considered for patients who have acute hepatic decompensation with or without HRS. Liver Transpl, 2012.

Living donor liver transplantation: the Asian perspective.

Preoperative evaluation of donors for living-donor liver transplantation aims to select a suitable donor with optimal graft quality and to ensure donor safety. Hepatic steatosis, a common finding in living liver donors, not only influences the outcome of liver transplantation for the recipient but also affects the recovery of the living donor after partial hepatectomy. Histopathologic analysis is the reference standard to detect and quantify fat in the liver, but it is invasive, and results are vulnerable to sampling error. Imaging can be repeated regularly and allows assessment of the entire liver, thus avoiding sampling error. Selection of appropriate imaging methods demands understanding of their advantages and limitations and the suitable clinical setting. This article describes potential clinical applications for liver fat quantification of imaging methods for fat detection and quantification, with an emphasis on the advantages and limitations of ultrasonography, computed tomography, and magnetic resonance imaging for quantifying liver fat.