Portopulmonary hypertension in liver transplant candidates

Pulmonary vascular disorders including portopulmonary hypertension(PoPHT) are among the common complications of liver disease and are prognostically significant. Survival is very low without medical treatment and liver transplantation. With advances in medical therapy for elevated pulmonary artery pressure(PAP) and liver transplant surgery, survival of patients with Po PHT and advanced liver disease is significantly improved. Because of the prognostic significance of Po PHT and the limited donor pool, a comprehensive preoperative cardio-pulmonary assessment is of great importance in cirrhotic patients prior to transplant surgery. Therefore, a detailed transthoracic Doppler echocardiographic examination must be an essential component of this evaluation. Patients with mild Po PHT can safely undergo liver transplant surgery. In cases of moderate to severe Po PHT, right heart catheterization(RHC) should be performed. In patients with moderate to severe Po PHT on RHC(mean PAP 35-45 mm Hg), vasodilator therapy should be attempted. Liver transplantation should be encouraged in cases that demonstrate a positive response. Bridging therapy with specific pulmonary arterial hypertension treatment agents should be considered until the transplant surgery and should be continued during the peri- and post-operative periods as needed.     

Hepatopulmonary syndrome and portopulmonary hypertension

Opinion statement The incidence of pulmonary vascular disorders is significantly increased in patients with liver disease. Intrapulmonary shunting with hypoxemia in patients with liver disease is diagnosed as hepatopulmonary syndrome (HPS), whereas precapillary pulmonary vessel obliteration is identified as portopulmonary hypertension (PPHTN). Because the symptoms of liver disease can mimic those of pulmonary vascular disease, all patients with hepatic failure should be screened for these two diseases. Pulse oximetry effectively screens for hypoxemia associated with HPS, whereas an elevated right ventricular systolic pressure estimated by echocardiography identifies patients at risk of having PPHTN. Liver transplantation is the only effective medical therapy for HPS. However, those who have a resting arterial oxygenation less than 50 mm Hg or a shunt measured by scintigraphic perfusion greater than 20% have an unacceptably high mortality rate following surgery. Compared with HPS, there are more therapeutic options that can bridge patients with PPHTN to transplantation. Drugs used to manage idiopathic pulmonary hypertension have shown promise in the treatment of PPHTN. Prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors have improved transplant survival. Despite treatment, however, perioperative mortality for patients with PPHTN remains high. Even with successful transplantation, HPS and PPHTN can persist or develop de novo. Long-term follow-up and surveillance of liver transplant recipients is thus indicated to identify HPS and PPHTN following surgery.     

Portopulmonary hypertension: state of the art: Concise Review

Portopulmonary hypertension is an uncommon but treatable pulmonary vascular consequence of portal hypertension, which can lead to significant morbidity and mortality. Portopulmonary hypertension results from excessive pulmonary vasoconstriction and vascular remodeling that eventually leads to right-heart failure and death if left untreated. Although pulmonary vascular disease in these patients may be asymptomatic or associated with subtle and nonspecific symptoms (dyspnea, fatigue and lower extremity swelling), it should be looked for especially if patients are potential candidates for liver transplantation. Patients with clinical suspicion of portopulmonary hypertension should undergo screening testing, specifically echocardiography. Right heart catheterization remains the gold standard for the diagnosis. The existence of moderate to severe disease poses higher risks and challenges for liver transplantation. The disease has a substantial impact on survival and requires focused pharmacological therapy. New and evolving medical therapies, such as prostanoids (intravenous, inhaled or oral), endothelin receptors antagonists, phosphodiesterases inhibitors, combination therapy and other experimental drugs might change the natural course of the disease. Case reports and cases series have been published regarding the efficacy and safety of pharmacological therapy, but randomized, controlled multicenter trials are urgently needed. Liver transplantation is not the treatment of choice for portopulmonary hypertension, but after optimal hemodynamic and clinical improvement with medical therapy as a bridge, liver transplant can be considered an option in selected patients.     

Overview of lung transplantation and criteria for selection of candidates

Lung or heart-lung transplantation is a viable option for diverse end-stage pulmonary parenchymal or pulmonary vascular disorders. However, mortality associated with lung transplant (LT) is appreciable, with 3 and 5 year survival rates of approximately 60 and 50%, respectively. Thus LT is reserved for patients with life-threatening disease refractory to medical therapy. Four diagnoses (i.e., chronic obstructive pulmonary disease; idiopathic pulmonary fibrosis; cystic fibrosis; alpha-1-antitrypsin deficiency emphysema) account for approximately 80% of LT recipients; diverse interstitial and pulmonary vascular disorders account for the remaining cases. Given the potential morbidity and mortality associated with LT, the decision to refer patients for LT is difficult. Which patients are acceptable candidates for LT? What are the projected benefits of LT? What criteria should be used to estimate mortality with medical therapy alone? Given the uncertainty of waiting time, when should patients be listed for LT? Identifying appropriate candidates for LT and determining when to list for LT is determined by a risk analysis of the likelihood of mortality during the projected waiting period versus the likely mortality following LT. In this review, we discuss the major diseases treated with LT and the appropriate criteria for LT.     

Does heart transplantation confer additional benefit over medical therapy to patients who have waited >6 months for heart transplantation?

Objectives. This study compared the survival of patients with heart failure who have waited > 6 months for heart transplantation with that of patients who undergo heart transplantation after a similarly prolonged waiting period.Background. There are little data describing outcome in patients with severe heart failure who have waited for extended periods of time on the heart transplant waiting list.Methods. Sixty-three consecutive patients who spent >6 months on the heart transplant waiting list were examined. Mean (± SD) age was 53 ± 9 years, mean left ventricular ejection fraction was 19 ± 6%, and all were taking digoxin and diuretic and vasodilator agents. Patients who underwent transplantation during the follow-up period were censored from the pretransplantation analysis, and their survival was examined as part of the posttransplantation phase of the study.Results. Of the 63 original patients examined, 25 underwent transplantation, 10 during inotropic or mechanical circulatory support. The pretransplantation mortality rate was 6% at 6 months after the 6-month milestone on the waiting list, 12% at 12 months and 22% at 18 months. The posttransplantation mortality rate was 5% at 6 months, 10% at 12 months and 24% at 18 months. There were no differences in survival at any time between the two phases of the study.Conclusions. Survival of patients who have survived >6 months on the heart transplant waiting list is generally good. Although heart transplantation did not appear to confer additional survival advantage over medical therapy, a large proportion of the patients who underwent transplantation were critically ill at the time of transplantation and would undoubtedly have died of progressive heart failure had they not undergone transplantation. We conclude that heart transplantation should still be considered a therapeutic alternative in patients with heart failure even after a prolonged waiting period on the heart transplant waiting list.     

Primary pulmonary hypertension: Current therapy

Because the causes of primary pulmonary hypertension (PPH) remains unknown, the therapeutic approach of the disease can be only empirical, based on the pathology and pathobiology of pulmonary circulation. Despite the inability to cure the disease, therapeutic advances over the past 20 years have contributed to an improvement of quality of life and prolonged survival in PPH patients. Current therapeutic approach of PPH mostly includes limitation of physical activity, long-term anticoagulation, and vasodilator therapy. Among all tested oral vasodilators, calcium-channel blockers are the most efficient long-term therapies by improving symptoms and hemodynamics in a subset of PPH patients (10% to 15%) who acutely respond to such drugs. Acute pulmonary vasodilator response to inhalation of nitric oxide can predict acute and chronic responses to oral calcium-channel blockers. A better understanding of the pathogenesis of PPH has changed the focus of medical treatments from purely chronic vasodilator therapy to the evaluation of agents, such as prostaglandins, that may reverse the proliferation of pulmonary vascular cells and result in regression of the pulmonary vascular hypertrophy and remodeling. Long-term treatment with intravenous epoprostenol (prostaglandin I(2) or prostacyclin) improves exercise capacity, hemodynamics and survival in most patients with PPH in functional class NYHA III or IV, and may be currently considered as the "gold standard" therapy for severe patients. However, response to long-term epoprostenol therapy may be incomplete, adverse effects are common, and survival remains unsatisfactory (55% at 5 years). In such patients with severe pulmonary hypertension refractory to medical therapy, atrioseptostomy and lung transplantation can be indicated.     

Portopulmonary hypertension

The development of pulmonary arterial hypertension in the setting of portal hypertension is known as portopulmonary hypertension. Portal hypertension is thought to predispose patients to disturbances in the homeostatic regulation of numerous neurohumoral and vasoactive mediators that induce the development of pulmonary arterial hypertension. Portopulmonary hypertension is pathologically indistinguishable from idiopathic pulmonary arterial hypertension and is characterized by the development of vasoconstriction, vascular remodeling, and thrombosis within the pulmonary vasculature. Although described in patients with both cirrhotic and noncirrhotic portal hypertension, portopulmonary hypertension is most prevalent among patients with end-stage liver disease, and its severity seems to be independent of the etiology or severity of liver disease. All liver transplant candidates must be screened for the presence of portopulmonary hypertension because of the high perioperative mortality risk of liver transplantation associated with this condition. Primary screening for portopulmonary hypertension consists of Doppler-estimated pulmonary artery systolic pressure measurement during echocardiography. However, the diagnosis of portopulmonary hypertension is based on unique hemodynamic criteria as determined by right heart catheterization. Untreated portopulmonary hypertension portends a poor prognosis, and the efficacy of current treatment modalities is limited. At present, the primary goals of therapy are to provide symptomatic relief, prolong survival, and improve pulmonary hemodynamics to facilitate safe and successful liver transplantation.     

Primary pulmonary hypertension

Primary pulmonary hypertension has become a very treatable disease given the recent advances in medical therapy. Any patient with unexplained right ventricular enlargement or pulmonary hypertension needs a thorough workup to determine the cause. Patients with primary pulmonary hypertension should be referred to a specialized "Center of Excellence" to evaluate potential therapies on a case-by-case basis. Warfarin anticoagulation is generally recommended in all patients. Some patients (approximately 20%) will have a dramatic response to high doses of calcium channel blockers; the remainder are generally helped by the use of continuous intravenous prostacyclin therapy. Lung transplantation remains the final treatment option for patients in whom medical therapy fails.     

Liver transplantation in cystic fibrosis.

Liver disease is the second most common cause of death in patients with cystic fibrosis (CF). Improvement in surgical techniques, medical management, and imaging modalities has broadened the range of options for treatment of these patients. Medical management with ursodeoxycholic acid and nutritional support may help decelerate the progression of liver disease. A timely evaluation of CF patients with liver involvement for transplantation is important. Such evaluation should not be delayed until signs of hepatic decompensation occur. Combined lung-liver transplant can be considered for patients with advanced pulmonary disease. Pretransplant management of portal hypertension with a portosystemic shunt procedure is an option for patients with well-preserved synthetic liver function. Improvement in lung function after liver transplantation and no significant risk of pulmonary infection with immunosuppressive therapy have been reported. Review of individual center experiences have shown satisfactory survival and improved quality of life for CF patients undergoing liver transplant.     

Left ventricular assist devices for the treatment of congestive heart failure

Optional statement The mainstay of heart failure therapy is aggressive medical management with consideration of resynchronization therapy and automatic implantable cardioverter-defibrillator. This is best done with the support of a multidisciplinary team. Transplantation, when possible, remains the therapy of choice for patients who are refractory to medical therapy. Other options short of left ventricular assist device (LVAD) that should be considered include revascularization, mitral valve repair, and left ventricular remodeling procedures. LVAD therapy as a bridge to transplantation should be considered in patients with heart failure who are clinically deteriorating while on the transplant waiting list. This should be initiated prior to the onset of irreversible end-organ damage. In nontransplant candidates, an LVAD can be considered as an alternative to transplantation (destination therapy). However, cost and the availability of expertise continue to limit this therapy to quaternary care and research institutions.     

Decreasing survival benefit from cardiac transplantation for outpatients as the waiting list lengthens

Many patients are accepted for cardiac transplantation during a period of clinical instability associated with a high risk of death, even though most can be discharged home to await transplantation. As the waiting lists lengthen, priority is awarded solely on the basis of the waiting time of outpatients, who now usually undergo transplantation after they have already survived a major period of jeopardy. To determine the impact of the current waiting times and priority system on the previously expected benefit offered by transplantation, 1-year actuarial survival without transplantation was recalculated after each month without transplantation for 214 potential candidates with an ejection fraction of 0.17 +/- 0.05 discharged on tailored medical therapy after evaluation. These data were compared with the 1-year survival data of 88 outpatients who underwent transplantation. Actuarial survival after 1 year was 67% on tailored therapy compared with 88% after transplantation (p = 0.009). Death without transplantation was sudden in 43 of 51 patients, resulting from hemodynamic decompensation in 8. For outpatients already surviving 6 months without transplantation, actuarial survival over the next 12 months was 83% without transplantation. Thus, the expected improvement in survival after transplantation would be only 5% over the subsequent year for patients waiting 6 months, which is the waiting time for many outpatients. Such patients should be reevaluated to determine whether transplantation remains indicated during the next year.     

Heart-lung transplantation: adult indications and outcomes

Combined heart-lung transplantation remains the only definitive therapy for patients who have both end-stage heart failure and end-stage lung failure. The most common indication is congenital heart disease (CHD) and the proportion is increasing for acquired heart disease concomitant with pulmonary hypertension and/or intrinsic lung diseases. Previously, idiopathic pulmonary hypertension was the most common indication. However, it has been shown that right ventricular failure can be reversed after double lung transplantation. Therefore, patients with idiopathic pulmonary arterial hypertension (IPAH) should not undergo combined heart-lung transplantation unless left ventricular dysfunction co-exists. The ISHLT registry data shows survival after heart-lung transplantation is improving, but still its survival rates are 71% at 3 months, 63% at 1 year, 44% at 5 years and 31% at 10 years. With appropriate patient selection and surgical expertise, these outcomes should improve further.     

Liver transplantation in adults: Choosing the appropriate timing

Liver transplantation is indicated in patients with acute liver failure,decompensated cirrhosis,hepatocellular carcinoma and rare liver-based genetic defects that trigger damage of other organs.Early referral to a transplant center is crucial in acute liver failure due to the high mortality with medical therapy and its unpredictable evolution.Referral to a transplant center should be considered when at least one complication of cirrhosis occurs during its natural history.However,because of the shortage of organ donors and the short-term mortality after liver transplantation on one hand and the possibility of managing the complications of cirrhosis with other treatments on the other,patients are carefully selected by the transplant center to ensure that transplantation is indicated and that there are no medical,surgical and psychological contraindications.Patients approved for transplantation are placed on the transplant waiting list and prioritized according to disease severity.Thus,the appropriate timing of transplantation depends on recipient disease severity and,although this is still a matter of debate,also on donor quality.These two variables are known to determine the "transplant benefit"(i.e.,when the expected patient survival is better with,than without,transplantation) and should guide donor allocation.     

Timing of lung transplantation for patients with fibrotic lung diseases

Idiopathic pulmonary fibrosis (IPF) is typically a fatal disease that fails to respond to medical therapy. For these patients lung transplantation offers the promise of improved quality and duration of life. The initial reports of successful transplantation for IPF date back to the mid-1980s although recent data suggest IPF patients make up nearly 20% of all single lung transplants. The survival rates following lung transplantation for IPF are estimated at 67% for 1 year, 52% for 3 years, and 35% for 5 years. Mortality rates following lung transplantation for IPF are higher than emphysema, but are generally comparable to primary pulmonary hypertension. Given the relatively high mortality following transplant the decision of when to transplant a patient is of paramount importance. Although individual patients differ, generalizations predicting a poor prognosis include the diagnosis of usual interstitial pneumonia (UIP), a forced vital capacity or total lung capacity of less than 65% predicted, a diffusion capacity for carbon monoxide (DL(CO)) less than 45% of predicted, and the presence of extensive honeycombing on high-resolution computed tomographic scans. The presence of any of these features should prompt the patient and physician to consider lung transplantation as a potential therapeutic modality. Patients with interstitial lung disease related to collagen vascular diseases or other causes need to be considered on an individual basis; their prognosis is usually better than patients with IPF, and the potential for systemic involvement may preclude listing for lung transplantation.     

Hepatitis C infection in hemodialysis patients: A review

Hepatitis C virus(HCV)-related liver disease is a significant cause of morbidity and mortality in patients with end-stage renal disease(ESRD) who is treated with dialysis or kidney transplantation(KT). The survival rate for HCV-infected renal transplant recipients is better than that for HCV-infected hemodialysis patients on transplant waiting lists. Early diagnosis and treatment HCV infection prior to KT prevents complications posttransplantation and reduces mortality. In addition to screening for anti-HCV antibodies and detecting HCV RNA, percutaneous liver biopsy is particularly valuable for assessing the stage of liver damage in HCV-infected patients, because the stage of fibrosis is importantdetermining optimal treatment for HCV. Studies have been demonstrated that with conventional interferon(IFN) monotherapy or pegylated IFN monotherapy are similar efficacy and safety in HCV-infected hemodialysis patients. Sustained viral responses(SVRs) with these monotherapies have ranged approximately 30% to 40%. Limited reports support the use of IFN and ribavirin combination therapy as antiviral treatment for ESRD patients or patients on hemodialysis. Ribavirin can be started at low dose and careful monitoring for side effects. Patients that show SVR after treatment are strong candidates for KT. It is also generally accepted that ESRD patients with decompensated cirrhosis and portal hypertension should be referred to the liver transplant team for consideration of combined liver-KT.     

Cardiac retransplantation: an ethical dilemma

PURPOSE OF REVIEW: The evolution of scientific advancements that paved the way for clinical cardiac transplantation spans the era of the 20 century, heart transplantation has revolutionized therapy for end-stage heart failure. Demand far exceeds supply, resulting in a long waiting period, and an increasing number of deaths while on a waiting list. The shortage of donors poses dilemmas for allocation of organs and managing the waiting list. RECENT FINDINGS: The disparity between the demand and supply for donor hearts makes cardiac retransplantation an ethical issue with some patients being allowed a second transplant while some patients are dying on the waiting list before receiving their first transplant, especially with overall sub-optimal outcomes compared with primary transplantation. SUMMARY: The cardiac transplant community is mandated to closely monitor the results of cardiac retransplantation to identify the appropriate candidate who should receive a retransplantation.     

肝癌肝移植

肝移植和肝切除是目前肝癌的2种主要治疗方法。早期肝癌合并晚期肝病患者肝移植后疗效评估最佳;但是对于肝功能代偿尚可、不伴门静脉高压的早期肝癌患者来说,最佳的治疗方案仍存在争议。大量的研究证明肝移植后无病生存率更高,但是尚不清楚长期生存率如何。通过改进手术技术和实行补救性肝移植的方法可明显改善肝切除后患者生存率,且避免了可因切除治愈的患者因等待移植时间过长而失去机会。     

Acute pulmonary edema after lung transplantation: the pulmonary reimplantation response.

BACKGROUND: Although the development of noncardiogenic pulmonary edema or pulmonary reimplantation response (PRR) after lung transplantation has been well described, the incidence has not been established and the relationship of PRR to clinical risk factors has not been analyzed. STUDY OBJECTIVES: (1) To describe the incidence of PRR in lung transplant recipients, (2) to identify the predictors of PRR, (3) to examine the correlation of suspected predictors with the severity of PRR, and (4) to evaluate the impact of PRR on morbidity and mortality of lung transplant recipients. DESIGN: Retrospective review of clinical records and radiographic studies. SETTING: Tertiary care referral center. PATIENTS: Ninety-nine consecutive patients with end-stage lung disease undergoing lung transplantation between February 1990 and October 1995. METHODS: Review of clinical records and postoperative chest radiographs of all lung transplant recipients to identify patients who experienced PRR. Chest radiographs of patients with PRR were graded for severity on a scale of 0 (none) to 5 (very severe). Demographic, pre- and perioperative factors were also evaluated along with short- and long-term survival of patients with PRR. RESULTS: Fifty-six of 99 lung transplant recipients (57%) experienced PRR. The median ischemia time of patients with and without PRR was 168 and 180 min, respectively (p = 0.62). The incidence of PRR was 51% in patients without preoperative pulmonary hypertension, 78% in mild to moderate pulmonary hypertension, and 58% in patients with severe pulmonary hypertension (p = 0.10). Incidence and severity of PRR was similar in patients receiving right, left, or double-lung transplantation. Similarly, age and sex of the recipients and underlying lung disease did not affect the incidence or severity of PRR. The incidence and severity of PRR was higher in patients undergoing cardiopulmonary bypass during lung transplantation. Patients with PRR had prolonged duration of mechanical ventilation and ICU stay. Overall, PRR did not affect the survival of the patients. However, survival of female lung transplant recipients was significantly better than male recipients (median survival, 60 vs 21 months; p = 0.02). CONCLUSIONS: Acute pulmonary edema or PRR occurs frequently (57%) after lung transplantation. In this series, PRR was not associated with a prolonged ischemia time, preoperative pulmonary hypertension, the type of lung transplant, underlying lung disease, or age or sex of recipients. However, use of cardiopulmonary bypass during surgery was associated with increased incidence and severity of PRR. Also, the development of PRR resulted in prolonged mechanical ventilation and a longer ICU stay, but did not affect survival. Female lung transplant recipients survived significantly longer than male recipients. The reason for this difference in survival is unclear.     

Surgical therapies for pulmonary arterial hypertension

Surgical therapies for the treatment of pulmonary arterial hypertension typically are reserved for patients who are deemed to be refractory to medical therapy and have evidence of progressive right-sided heart failure. Atrial septostomy, a primarily palliative procedure, may stave off hemodynamic collapse from right-sided heart failure long enough to permit a more definitive surgical treatment such as lung or combined heart-lung transplantation. This article discusses indications for and results of atrial septostomy and lung and heart-lung transplantation in patients who have pulmonary arterial hypertension.