Portopulmonary Hypertension: Still an Appropriate Consideration for Liver Transplantation?

Transcription

1 ORIGINAL ARTICLE VERMA ET AL. Portopulmonary Hypertension: Still an Appropriate Consideration for Liver Transplantation? Suman Verma, 1 * Fiona Hand, 2 * Matthew J. Armstrong, 3 Marie de Vos, 4 Douglas Thorburn, 4 Terry Pan, 5 John Klinck, 5 Rachel H. Westbrook, 1 Georg Auzinger, 1 Andrew Bathgate, 6 Steven Masson, 7 Andrew Holt, 3 Diarmaid D. Houlihan, 2 and James W. Ferguson 3 1 Institute of Liver Studies, King s College Hospital, London, United Kingdom; 2 National Liver Unit, St. Vincent s University Hospital, Dublin, Ireland; 3 University Birmingham Hospital Trust, Birmingham, United Kingdom; 4 Royal Free Hospital, London, United Kingdom; 5 Addenbrooke s Hospital, Cambridge, United Kingdom; 6 Scottish Transplant Unit, Edinburgh, United Kingdom; and 7 Freeman Hospital, Newcastle, United Kingdom Liver transplantation (LT) in patients with portopulmonary hypertension (PoPH) has historically resulted in unpredictable and often poor outcomes. The United Kingdom experience for the period is reported in this article. A retrospective analysis of patients, preoperatively fulfilling the PoPH European Respiratory Society Task Force on Pulmonary- Hepatic Vascular Disorders diagnostic criteria was conducted across all UK LT centers. Data collection included comorbidities, use of preoperative and postoperative pharmacotherapy, patient survival, and cause of death. To enable survival stratification, PoPH was classified as mild, moderate, or severe based on mean pulmonary pressure of <35 mm Hg, mm Hg, and 50 mm Hg, respectively. Of 127 patients reported to have PoPH, just 28 fulfilled the diagnostic criteria (14 mild, 9 moderate, 5 severe). Twenty (71.4%) patients were male with median age and Model for End-Stage Liver Disease of 50 years (range, years) and 18 (range, 6-43), respectively. Twelve (42.9%) patients died within 5 years of LT. The majority of deaths (10 of 12; 83%) occurred within the first 6 months after LT, aetiologies of which included right heart failure (n 5 3), progressive PoPH (n 5 2), and sepsis (n 5 2). Of those receiving preoperative pharmacotherapy (n 5 8), 5 are currently alive and were classified as mild to moderate PoPH. Both severe PoPH patients optimized preoperatively with pharmacotherapy died within a year of LT. Development of effective vasodilatory therapies in the setting of pulmonary arterial hypertension has led to a dramatic improvement in patient survival. The available data indicate that in this era of pharmacotherapy, PoPH in isolation no longer represents a valid consideration to transplant. Liver Transplantation AASLD. Received May 14, 2016; accepted August 9, SEE EDITORIAL ON PAGE 1633 Portopulmonary hypertension (PoPH), a rare complication of end-stage liver disease, is characterized by the Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; CTP, Child-Turcotte-Pugh; GVHD, graftversus-host disease; HCV, hepatitis C virus; IPAH, ideopathic pulmonary arterial hypertension; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; MI, myocardial infarction; MOF, multiorgan failure; MPAP, mean pulmonary artery pressure; NASH, nonalcoholic steatohepatitis; PAH, pulmonary arterial hypertension; PAWP, pulmonary artery wedge pressure; PBC, primary biliary cirrhosis; PoPH, portopulmonary hypertension; PSC, primary sclerosing cholangitis; PVR, peripheral vascular resistance; REVEAL, Registry to Evaluate Early and Longtem Pulmonary Arterial Hypertension Disease Management; RHF, right heart failure; UKLED, United Kingdom Model for End-Stage Liver Disease. coexistence of pulmonary arterial hypertension (PAH) and portal hypertension, in the absence of another etiology of PAH. (1) Right heart catheterization is the gold standard for diagnosis (2,3) with a mean pulmonary artery pressure (MPAP) > 25 mm Hg, a pulmonary artery wedge pressure (PAWP) 15 mm Hg, and a peripheral vascular resistance (PVR) > 240 dynes/s/cm 25 being diagnostic. (4) Prospective studies indicate its prevalence among patients with cirrhosis at 2%-6% (5,6) occurring typically in patients with severe longstanding portal hypertension in combination with refractory ascites. (7) The natural history of PoPH is variable. Early reports suggest that survival of patients with PoPH is poor with a median survival of 15 months. (8,9) Indeed, the Mayo Clinic experience showed that without treatment, 54% of patients with PoPH succumbed to their disease within a year. (10) Traditionally, the prognosis ORIGINAL ARTICLE 1637

2 VERMA ET AL. LIVER TRANSPLANTATION, December 2016 for patients with PoPH is worse than for idiopathic PAH, with projected 5-year survival rates of 38% (95% confidence interval [CI], 14%-63%) and 72% (95% CI, 54%-85%), respectively. (9) Advancements in therapy with routine use of vasodilators, such as prostanoids, phosphodiesterase inhibitors, and endothelin receptor antagonists either singly or in combination have however significantly improved patient survival. (11-13) Recent guidelines propose that PoPH should be treated according to functional status in a similar fashion to PAH, with an escalating regimen of vasodilator therapy. (14) The positive impact of vasodilatory therapy is now evident in more recent large cohort studies evaluating survival of patients with PoPH. The Registry to Evaluate Early and Longterm Pulmonary Arterial Hypertension Disease Management (REVEAL Registry), a 55-center, observational, US-based study, was designed to provide current information about demographics, course, and management of patients with group 1 pulmonary hypertension. (15) A recent analysis of these data showed that patients with PoPH were more likely to have delayed commencement of pharmacotherapy and a more haphazard treatment regimen than that employed for the ideopathic pulmonary arterial hypertension (IPAH) cohort. This resulted in poorer overall survival in those with PoPH (40% versus 67% for those with IPAH) despite better hemodynamic indices. In a large French series, 154 patients with PoPH followed over a 20-year period demonstrated a Address reprint requests to Fiona Hand, M.Sc., National Liver Unit, St. Vincent s University Hospital, Elm Park, Dublin 4, Ireland. Telephone: ; FAX: ; fionahand@rcsi.ie James W. Ferguson consults for and is on the speaker s bureau of Astellas. *These authors contributed equally to this work. Suman Verma and Fiona Hand contributed to data collection and interpretation, manuscript preparation, literature review, and manuscript appraisal. Matthew J. Armstrong contributed to the critical review of the data, literature review, and manuscript appraisal. Marie de Vos, Douglas Thorburn, Terry Pan, John Klinck, Rachel H. Westbrook, Georg Auzinger, Andrew Bathgate, Steven Masson, and Andrew Holt contributed to data collection and manuscript appraisal. Diarmaid D. Houlihan and James W. Ferguson contributed to critical review of the data, analysis, and the manuscript. Copyright VC 2016 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /lt year survival of 68% from time of diagnosis. All patients with functional class III or IV were treated with either oral or intravenous vasodilator therapy. A multivariate analysis identified Child-Turcotte-Pugh (CTP) scores B and C and cardiac index as independent prognostic factors. The 5-year survival for CTP A, B, and C was 71%, 55%, and 58%, respectively. (16) Therapeutic options for patients with PoPH have continued to evolve, such that they now encompass liver transplantation (LT). However, initial experiences reported unacceptably high postoperative mortality (in the immediate/early postoperative period) due to cardiopulmonary failure. (17,18) This has led to the rationalization of treatment with transplantation, to include the routine use of pharmacotherapy and careful patient selection. Five-year survival rates for carefully selected patients have been reported by several centers at approximately 70%. (19,20) Furthermore, American Association for the Study of Liver Diseases guidelines now recommend that LT be considered for patients with PoPH when preoperative vasodilatory therapy results in reduction of MPAP to 35 mm Hg. (21) The UK outcomes for patients transplanted for PoPH have largely been unexplored. In this retrospective study, we analyze the outcomes of LT in patients with PoPH transplanted in the United Kingdom, assessing their outcomes to identify those subgroups that would receive the greatest benefit from LT. Patients and Methods Between 1992 and 2012, a retrospective analysis of patients undergoing LT for PoPH was conducted across all 7 UK LT centers. Information was sought from The Royal Free Hospital (London), King s College Hospital (London), Addenbrooke s Hospital (Cambridge), Queen Elizabeth Hospital (Birmingham), Freeman Hospital (Newcastle), St. James Hospital (Leeds), and The Royal Infirmary (Edinburgh). Data required specifically focused on patient comorbidities, preoperative and postoperative pharmacotherapy regimens for PoPH, patient survival, and causes of death. Six centers responded to this study and identified patients with a diagnosis of PoPH who underwent transplantation in their unit. The completed data sets were returned to the primary investigator in the Queen Elizabeth Hospital in Birmingham for compilation. Patients fulfilling the European Respiratory Society Task Force on Pulmonary-Hepatic Vascular Disorders diagnostic criteria for PoPH preoperatively or immediately prior to surgery were included for analysis ORIGINAL ARTICLE

3 LIVER TRANSPLANTATION, Vol. 22, No. 12, 2016 VERMA ET AL. TABLE 1. Demographic Data Demographic Data Values (n 5 28) Sex Male 20 (71.4) Female 8 (28.6) Etiology of liver disease Alcohol 9 (32.1) HCV 6 (21.4) Autoimmune/PSC/PBC 5 (17.9) Cryptogenic 4 (14.3) Hepatitis B 2 (7.1) NASH 1 (3.6) Hepatic artery occlusion 1 (3.6) Prognostic scores MELD 18 (6-43) UKELD 52.5 (41-69) Child-Pugh 9 (5-13) Cardiovascular comorbidity Prior MI 1 (3.6) Ischemic heart disease 1 (3.6) Hypertension 4 (14.3) Hypercholesterolemia 2 (7.1) Respiratory comorbidity Asthma 1 (3.6) COPD 1 (3.6) Current smoker 6 (21.4) Ex-smoker 5 (17.9) Pretransplant medications Ambrisentan 1 (3.6) Sildenafil 7 (25) Epoprostenol 1 (3.6) NOTE: Data are given as n (%) or median (range). Further stratification was made on the basis of the MPAP, with mild, moderate, and severe PoPH being defined as MPAP < 35 mm Hg, mm Hg, and 50 mm Hg, respectively. This stratification enabled determination of differences in mortality outcome. Similarly, patients were stratified according to baseline Model for End-Stage Liver Disease (MELD) and overall survival. Although the exact date of death was not always available for all patients, survival at 1, 3, and 5 years was clearly defined and hence these were used as endpoints. Parametric data were expressed as mean (standard deviation); nonparametric data were expressed as median (range). BASELINE CHARACTERISTICS OF COHORT Just 30 patients met the diagnostic criteria for PoPH as previously defined. Two patients were further excluded due to lack of documented follow-up. The remaining patients had a mean age of 49 years (range, years) with an average MELD score of 18 (range, 6-43). Prevalent hepatic etiologies included alcoholic liver disease (32.1%), hepatitis C virus (HCV; 21.4%), and autoimmune liver disease (17.9%). Selected demographics and patient characteristics are shown in Table 1. BASELINE HEMODYNAMIC DATA The median MPAP was 34 mm Hg (range, mm Hg), median cardiac output was 9.47 L/minute (range, L/minute), median PAWP was 11 mm Hg (range, 5-15 mm Hg), and median PVR was 302 dynes/s/cm 25 (range, dynes/s/cm 25 ). In total, 14 (50%) patients had mild PoPH (MPAP < 35 mm Hg), 9 (32%) had moderate PoPH (35 mm Hg MPAP < 50 mm Hg) and 5 (18%) had severe PoPH (MPAP 50 mm Hg). PREOPERATIVE PHARMACOTHERAPY Pharmacotherapy for PoPH was commenced preoperatively in 8 (28.6%) patients. Four of the moderate cohort and 2 of the mild cohort were treated with sildenafil alone. A single patient from the severe group was treated with dual therapy ambriesentan and sildenafil. One further patient from the severe group was treated preoperatively with epoprostanol. Postoperatively, a single patient from each of the mild, moderate, and severe groups was treated with iloprost. Notably, the patient with severe PoPH who received postoperative iloprost was the same individual treated with preoperative dual ambriesentan and sildenafil. COMORBIDITIES Respiratory and cardiovascular comorbidities were infrequent among our patient cohort. At initial consultation for transplantation, 1 patient with mild PoPH had suffered a previous myocardial infarct and a further 4 (3 mild severity and 1 moderate PoPH) had a previous diagnosis of hypertension. In total, 5 (17.9%) patients had ceased smoking, and 6 (21.4%) were still active smokers. Results There were 12 (42.9%) deaths within 5 years of LT in our cohort. Two patients underwent transplantation within 5 years of data collection; thus, complete 5-year follow-up was not possible. Most patient deaths (n 5 10, 83%) occurred within the first year following transplantation. Common causes of mortality in this ORIGINAL ARTICLE 1639

4 VERMA ET AL. LIVER TRANSPLANTATION, December 2016 TABLE 2. Baseline Hemodynamics and Cause of Death Mortality at 6 Months Mortality at 1 Year Mortality at 3 Years Mortality at 5 Years Mild PoPH (n 5 14) Hemorrhage (n 5 1) PoPH (n 5 1) Sepsis (n 5 2) GVHD (n 5 1) Moderate PoPH (n 5 9) MOF (n 5 1) RHF (n 5 1) Severe PoPH (n 5 5) RHF (n 5 2) PoPH (n 5 1) Recurrent HCV (n 5 1) RHF (n 5 1) TABLE 3. Baseline Hemodynamics and Patient Survival Alive at 6 Months Alive at 1 Year Alive at 3 Years Alive at 5 Years Mild PoPH (n 5 14) 69.2% (n 5 9/13) 69.2% (n 5 9/13) 69.2% (n 5 9/13) 61.5% (n 5 8/13) Moderate PoPH (n 5 9) 77.8% (n 5 7/9) 77.8% (n 5 7/9) 77.8% (n 5 7/9) 75% (n 5 6/8) Severe PoPH (n 5 5) 40% (n 5 2/5) 20% (n 5 1/5) 0% (n 5 0/5) 0% (n 5 0/5) period (outlined in Table 2) were as follows: right heart failure (RHF; n 5 3), progressive PoPH (n 5 2), and sepsis (n 5 2). Other causes of death included graftversus-host disease (GVHD; n 5 1), hemorrhage (n 5 1), and multiorgan failure (MOF; n 5 1). Patient outcomes according to hemodynamics and native MELD are shown in Tables 3 and 4. Of the patients who received preoperative pharmacotherapy (n 5 8), 5 were still alive at the time of data collection. Two patients with mild severity PoPH were treated with sildenafil preoperatively; 1 remained alive at completion of the data set, the other died within 6 months of transplantation. All moderate severity PoPH patients who received pharmacotherapy preoperatively (n 5 4) were alive at the time of data collection. However, both patients with severe PoPH who were preoperatively optimized died. The patient preoperatively optimized with ambriesentan and sildenafil succumbed to right ventricular failure within 6 months of transplantation, and the other patient treated with epoprostanol died within a year of transplantation due to graft failure. Discussion This is the first report documenting patient outcomes following LT for PoPH in the United Kingdom. The overall 5-year survival from the UK data set was 53.8% (n 5 14/26). Progressive PoPH and RHF was a major cause of mortality in the cohort (n 5 5, 19.2%). These data are consistent with other published series from Rochester and Detroit that demonstrate 5-year survivals in the region of 40%-67%. (15,19) Subgroup analysis suggests that patients with severe PoPH have an unacceptably high mortality after transplantation (4 of 5 patients dead at 1 year). Patients with mild to moderate PoPH fared better with 14 of 21 (66.6%) still alive 5 years following their LT. However, when these data are compared with 5-year survival for patients transplanted primarily for other disease etiologies where the expected exceeds 80%, (21) the outcomes are still inferior. This may in part reflect the fact that a minority (28.5%) of patients were treated preoperatively with pharmacotherapy. Notably, 62.5% (5/8) of these patients were still alive at the time of data capture. These data raise significant concerns about the survival benefit of LT for patients with PoPH. Poor outcomes following LT for severe PoPH have been previously described. (18) Initial experiences of LT for PoPH were disappointing due to unacceptably high perioperative mortality. Indeed, a multicenter prospective study demonstrated a postoperative mortality rate of 36% with most deaths occurring in the immediate postoperative period following transplantation. (17) These data are similar to published data from Wisconsin, which demonstrated that patients with severe pulmonary hypertension (MPAP > 60 mm Hg) had mortality rates of 42% at 9 months and 71% at 3 years following surgery. (21) Our data would support the TABLE 4. Native MELD and Patient Survival Alive at 6 Months Alive at 1 Year Alive at 3 Years Alive at 5 Years MELD < 10 (n 5 3) 66.6% (n 5 2/3) 66.6% (n 5 2/3) 66.6% (n 5 2/3) 66.6% (n 5 2/3) MELD (n 5 8) 37.5% (n 5 3/8) 37.5% (n 5 3/8) 37.5% (n 5 3/8) 25% (n 5 2/8) MELD (n 5 10) 77.8% (n 5 7/9) 66.6% (n 5 6/9) 66.6% (n 5 6/9) 62.5% (n 5 5/8) MELD 25 (n 5 7) 71.4% (n 5 5/7) 71.4% (n 5 5/7) 71.4% (n 5 5/7) 71.4% (n 5 5/7) 1640 ORIGINAL ARTICLE

5 LIVER TRANSPLANTATION, Vol. 22, No. 12, 2016 VERMA ET AL. recommendation that severe PoPH as defined as an MPAP > 50 mm Hg is considered an absolute contraindication to transplantation due to unacceptable perioperative mortality. (18) The role of LT in patients with mild or moderate disease is less clear. Our 5-year survival of patients transplanted with mild to moderate PoPH was 66.6%. A retrospective analysis carried out in patients attending the Mayo Clinic between 1994 and 2007 suggested a modest survival benefit for patients treated with pharmacotherapy combined with LT compared with pharmacotherapy alone (5-year survival 45% versus 67%, respectively). The retrospective nature of this study and small numbers of patients in the subgroup make these findings difficult to interpret. Reports from both Europe and the United States have been published documenting improved 5-year survival following LT. (20,22) In parallel with this, outcomes for patients receiving pharmacotherapy alone have also improved with 5-year survivals of approximately 70% reported in several studies. (22,23) These data would suggest that there is unlikely to be significant survival benefit from LT over and above pharmacotherapy. There are several limitations to our study. First, it is a retrospective analysis, with all potential associated biases. Relevant clinical details were obtained by recalling patient charts, and information was collected by a number of contributors across different sites. Although 127 patients were captured for inclusion in the study, <25% of the cohort (n 5 28) actually met the diagnostic criteria for PoPH. This may be attributable to aberrant coding or may indeed reflect our broad search criteria, which likely included PAH alone with vascular resistance. The study includes patients transplanted over an extended 20-year time period, during which time treatment and approach to patients with PoPH changed significantly. Date of transplantation was available for 57.2% (n 5 16) of our patient cohort, 5 of whom underwent transplantation in the first decade ( ) with 11 transplanted more recently ( ). There was a trend to transplant patients with more severe PoPH early in our series; those transplanted between 1992 and 2002 had a median MELD of 48.5 compared with 37 for those transplanted between 2002 and Correspondingly, a higher mortality was noted early in our series with a 60% early postoperative mortality in the first decade when compared with 27.3% in the second decade of data collection. Undoubtedly perioperative optimization and use of pharmacotherapeutic agents have significantly improved over this time. Patients included in this study were not uniformly medically optimized, and to date no national protocol exists to direct optimum pharmacotherapeutic interventions in this patient cohort. Data extrapolated from this study must be considered with this in mind. Only a minority of our patient cohort were treated with pharmacotherapy, the lack of which most likely compromised the outcome of patients. Despite this, PoPH is rare, and this study presents the only available outcome data for these patients treated in the United Kingdom. Our multicenter data raise concerns about the appropriateness of LT for patients with PoPH. Accurate diagnosis of PoPH remains ambiguous as previously described by Goldberg et al. (24) Despite transplant centers across the UK reporting outcomes for 127 patients in this present work, just 28 met actual diagnostic criteria for PoPH. 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