Paul Marotta

Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database.

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PortoPH) are pulmonary vascular consequences of advanced liver disease associated with significant mortality after orthotopic liver transplantation (OLT). Data from 10 liver transplant centers were collected from 1996 to 2001 that characterized the outcome of patients with either HPS (n = 40) or PortoPH (n = 66) referred for OLT. Key variables (PaO2 for HPS, mean pulmonary artery pressure [MPAP], pulmonary vascular resistance [PVR], and cardiac output [CO] for PortoPH) were analyzed with respect to 3 definitive outcomes (those denied OLT, transplant hospitalization survivors, and transplant hospitalization nonsurvivors). OLT was denied in 8 of 40 patients (20%) with HPS and 30 of 66 patients (45%) with PortoPH. Patients with HPS who were denied OLT had significantly worse PaO2 compared with patients who underwent transplantation (47 vs. 52 mm Hg, P < .005). Transplant hospitalization survival was associated with higher pre‐OLT PaO2 (55 vs. 37 mm Hg; P < .005). MPAP was significantly higher (53 vs. 45 mm Hg; P < .015) and PVR was significantly worse (614 vs. 335 dynes · s · cm−5; P < .05) in patients with PortoPH who were denied OLT compared with patients who underwent transplantation. Transplant hospitalization mortality was 16% (5/32) in patients with HPS and 36% (13/36) in patients with PortoPH. All of the deaths in patients with PortoPH occurred within 18 days of OLT; 5 of the 13 deaths in patients with PortoPH occurred intraoperatively. We concluded that patients with HPS (based on a combination of low PaO2 and nonpulmonary factors) and patients with PortoPH (based on pulmonary hemodynamics) were frequently denied OLT because of pre‐OLT test results and comorbidities. For patients who subsequently underwent OLT, transplant hospitalization mortality remained significant for both those with HPS (16%) and PortoPH (36%). (Liver Transpl 2004;182:10.)

Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection.

Interferon lambda 1 (IFN‐λ1) is a type III IFN that produces intracellular responses similar to those of IFN‐α but in fewer cell types because of differences in the receptor distribution pattern, and this could potentially result in an improved safety profile. This was an open‐label three‐part study of patients with chronic hepatitis C virus (HCV) genotype 1 infection. Part 1 evaluated single‐agent pegylated interferon lambda (PEG‐IFN‐λ) at 1.5 or 3.0 μg/kg administered every 2 weeks or weekly for 4 weeks in patients who had relapsed after previous IFN‐α‐based treatment. Part 2 evaluated weekly doses of PEG‐IFN‐λ ranging from 0.5 to 2.25 μg/kg in combination with ribavirin (RBV) for 4 weeks in treatment‐relapse patients. Part 3 evaluated weekly PEG‐IFN‐λ at 1.5 μg/kg in combination with RBV for 4 weeks in treatment‐naive patients. Fifty‐six patients were enrolled: 24 patients in part 1, 25 patients in part 2, and 7 patients in part 3. Antiviral activity was observed at all PEG‐IFN‐λ dose levels (from 0.5 to 3.0 μg/kg). Two of seven treatment‐naive patients (29%) achieved rapid virological response. Treatment was well tolerated with minimal flu‐like symptoms and no significant hematologic changes other than RBV‐associated decreases in hemoglobin. The most common adverse events were fatigue (29%), nausea (12%), and myalgia (11%). Six patients experienced increases in aminotransferases that met protocol‐defined criteria for dose‐limiting toxicity (DLT) or temporarily holding therapy with PEG‐IFN‐λ. Most DLT occurred in patients with high PEG‐IFN‐λ exposure. Conclusion: Weekly PEG‐IFN‐λ with or without daily RBV for 4 weeks is well tolerated with minimal adverse events and hematologic effects and is associated with clear antiviral activity across a broad range of doses in patients with chronic HCV. (HEPATOLOGY 2010;)

Metabolic syndrome in liver transplant recipients: Prevalence and association with major vascular events

Cardiac and cerebral vascular diseases are leading causes of morbidity and death in solid organ transplant recipients. Immunosuppressant drugs are associated with dyslipidemia, hypertension, and hyperglycemia, which along with obesity are the main features of metabolic syndrome. In the nontransplant population, metabolic syndrome is associated with increased risk for major vascular complications. We postulated that metabolic syndrome is common post–liver transplantation and plays a significant role leading to cardiac and cerebrovascular events. Our Multi‐Organ Transplant Program database was reviewed for all liver transplant recipients between January 1998 and June 2004 with follow‐up until December 2005. We adapted the 2001 National Cholesterol Education Program‐Adult Treatment Panel III Guidelines to define posttransplantation metabolic syndrome (PTMS) as the presence at least 3 of the following: 1) obesity (body mass index >30 kg/m2); 2) serum triglyceride level ≥1.7 mmol/L; 3) high density lipoprotein level <1 mmol/L in men and <1.3 mmol/L in women; 4) hypertension; and 5) fasting plasma glucose ≥5.6 mmol/L. A total of 118 patients were included. Among them, 69 patients (58%) had PTMS. The mean (± standard deviation) time from transplant was 59 ± 21 months (no significant difference in patients with or without metabolic syndrome). Overall, patients with metabolic syndrome had a significantly higher average age, posttransplantation body mass index, fasting glucose, high‐density lipoprotein levels, and serum triglycerides. There was no difference in creatinine, hemoglobin, or prednisone average dose between the 2 groups. There were 25 major vascular events affecting 21% of patients. There were significantly more vascular events in patients with metabolic syndrome posttransplantation than in those without (30% vs. 8%; P = 0.003) during the study period. In conclusion, the prevalence of metabolic syndrome post–liver transplant is significantly higher than that estimated in the general population. Metabolic syndrome appears to be associated with an increased risk of major vascular events in our liver transplant population. Liver Transpl 13:1109–1114, 2007.

Historical epidemiology of hepatitis C virus (HCV) in selected countries

Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6 358 000 cases in 2008 and Brazil with 2 106 000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV‐infected populations are critical for addressing HCV‐related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.

Strategies to manage hepatitis C virus (HCV) disease burden

The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV‐related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3–5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical.

Report of the first international liver transplantation society expert panel consensus conference on renal insufficiency in liver transplantation

Michael R. Charlton, William J. Wall, Akinlolu O. Ojo, Pere Gines, Stephen Textor, Fuad S. Shihab, Paul Marotta, Marcelo Cantarovich, James D. Eason, Russell H. Wiesner, Michael A. Ramsay, Juan C. Garcia-Valdecasas, James M. Neuberger, Sandy Feng, Connie L. Davis, Thomas A. Gonwa, and the International Liver Transplantation Society Expert Panel Mayo Clinic, Rochester MN; Department of General Surgery, London Health Science Center, London, Ontario, Canada; Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI; Liver Unit, Hospital Clinic, University of Barcelona School of Medicine, Barcelona, Spain; Department of Nephrology, University of Utah School of Medicine, Salt Lake City, UT; Medical School, University of Western Ontario, London, Ontario, Canada; Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada; Transplant Institute, University of Tennessee, Memphis, TN; Baylor University Medical Center, Dallas, TX; Hospital Clinic I Provincial, Barcelona, Spain; Queen Elizabeth Hospital, Birmingham, England; Department of Transplant Surgery, University of California San Francisco Medical Center, San Francisco, CA; Department of Medicine, University of Washington Medical Center, Seattle, WA; and Mayo Clinic, Jacksonville, FL

Evaluation of renal function in liver transplant recipients receiving daclizumab (Zenapax), mycophenolate mofetil, and a delayed, low-dose tacrolimus regimen vs. a standard-dose tacrolimus and mycophenolate mofetil regimen: A multicenter randomized clinical trial

Posttransplant chronic renal failure, secondary to calcineurin inhibitor agents, is emerging as a major problem in liver transplantation. We report a randomized clinical trial comparing daclizumab, delayed low‐dose tacrolimus (target trough level 4‐8 ng/mL, starting day 4‐6), Investigational Arm (n = 72), to standard tacrolimus induction/maintenance dosing, Standard Arm (n = 76), with mycophenolate mofetil and tapering corticosteroids in both study arms. The end‐points were renal function indicated by the Modification of Diet in Renal Disease (MDRD). There was no significant difference in patient survival (86.6% Investigational Arm vs. 92.9% Standard Arm; P = 0.21) or acute rejection (23.2% vs. 27.7%, respectively; P = 0.68). Statistically significant differences in median glomerular filtration rate (GFR) were found in favor of the Investigational Arm. With the CG equation, the GFR at the end of the first week was 110.7 vs. 89.6 mL/min (P = 0.019) without significant differences thereafter. With the MDRD, statistically significant differences extended to the first posttransplant month (86.8 vs. 70.1 mL/min/1.73 m2; P < 0.001) with and was seen at month 6 (75.4 vs. 69.5 mL/min/1.73 m2; P = 0.038). In conclusion, delayed low‐dose tacrolimus, in combination with daclizumab and mycophenolate mofetil, preserves early renal function post–liver transplantation without the cost of increased acute rejection. (Liver Transpl 2005;11:1064–1072.)

Recurrent hepatocellular carcinoma after transplantation: Use of a pathological score on explanted livers to predict recurrence

Milan and University of California at San Francisco (UCSF) criteria are used to select patients with hepatocellular carcinoma (HCC) for liver transplantation (LT). Recurrent HCC is a significant cause of death. There is no widely accepted pathological assessment strategy to predict recurrent HCC after transplantation. This study compares the pathology of patients meeting Milan and UCSF criteria and develops a pathological score and nomogram to assess the risk of recurrent HCC after transplantation. All explanted livers with HCC from our center over the 18‐yr period 1985 to 2003 were assessed for multiple pathological features and relevant clinical data were recorded; multivariate analysis was performed to determine features associated with recurrent HCC. Using pathological variables that independently predicted recurrent HCC, a pathological score and nomogram were developed to determine the probability of recurrent HCC. Of 75 cases analyzed, 50 (67%) met Milan criteria, 9 (12%) met only UCSF criteria and 16 (21%) met neither criteria based on explant pathology. There were 20 cases of recurrent HCC and the mean follow‐up was 8 yr. Recurrent HCC was more common (67 vs. 12%; P < 0.001) and survival was lower (15 vs. 83% at 5 yr; 15 vs. 55% at 8 yr; P < 0.001) with those who met only UCSF criteria, compared to those who met Milan criteria. Cryptogenic cirrhosis (25 vs. 5%; P = 0.015), preoperative AFP >1,000 ng/mL (20 vs. 0%; P < 0.001) and postoperative OKT3 use (40 vs. 15%; P = 0.017) were more common among patients with recurrent HCC. While microvascular invasion was the strongest pathological predictor of recurrent HCC, tumor size ≥3 cm (P = 0.004; odds ratio [OR] = 7.42), nuclear grade (P = 0.044; OR = 3.25), microsatellitosis (P = 0.020; OR = 4.82), and giant/bizarre cells (P = 0.028; OR = 4.78) also predicted recurrent HCC independently from vascular invasion. The score and nomogram stratified the risk of recurrent HCC into 3 tiers: low (<5%), intermediate (40–65%), and high (>95%). In conclusion, compared to patients meeting Milan criteria, patients who meet only UCSF criteria have a worse survival and an increased rate of recurrent HCC with long‐term follow‐up, as well as more frequent occurrence of adverse histopathological features, such as microvascular invasion. Application of a pathological score and nomogram could help identify patients at increased risk for tumor recurrence, who may benefit from increased surveillance or adjuvant therapy. Liver Transpl, 2007.

Liver transplantation for incidental cholangiocarcinoma: Analysis of the Canadian experience

Cholangiocarcinoma is a biliary tumor, which not infrequently complicates primary sclerosing cholangitis. It carries a poor prognosis and, with the exception of carefully selected individuals in research protocols, contraindicates orthotopic liver transplantation. There has been some suggestion that cholangiocarcinomas incidentally discovered at the time of transplantation carry a better prognosis. The goal of this retrospective study was to perform a national review of outcomes after liver transplantation in Canadian recipients found to have incidental cholangiocarcinoma in their explanted native liver. Six of the seven liver transplant centers in Canada provided clinical and follow‐up information on all liver transplant recipients found to have incidental cholangiocarcinoma in their explants. The diagnosis or suspicion of cholangiocarcinoma prior to transplantation were exclusion criteria for this study. Ten individuals with cholangiocarcinoma were transplanted between 1996 and 2003. The median duration of follow‐up was 28 months. Eight of the 10 had PSC. All of the tumors were stage I or II. The 3‐year survival for these patients was 30%. The median time to recurrence was 26 months (95% confidence interval 13uu‐uu37), and the median time to death was 30 months (95% confidence interval 28uu‐uu53). In conclusion, although early survival of patients transplanted for incidental cholangiocarcinoma appears good, intermediate‐ and long‐term survival rates are not better than for individuals historically transplanted with known cholangiocarcinoma. Aggressive investigation for cholangiocarcinoma is mandated. Incidentally found tumours remain a difficult treatment problem, and prospective adjuvant chemo‐, radio‐, and immunotherapies should be investigated. (Liver Transpl 2005;11:1412–1416.)

Transplant immunosuppressive agents in non‐transplant chronic autoimmune hepatitis: the Canadian association for the study of liver (CASL) experience with mycophenolate mofetil and tacrolimus

Background: Conventional treatment of autoimmune hepatitis consists of either prednisone alone or in combination with azathioprine. Ten to 20% of patients do not respond to or are intolerant of this treatment. Novel drug treatments include immunosuppressive drugs such as tacrolimus (TAC), mycophenolate mofetil (MMF), methotrexate and cyclosporine. We describe a multi‐centre Canadian experience with MMF and TAC.