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Decisions with regard to transplant and organ allocation in patients with multi-system organ dysfunction are significantly complex. By nature, genetic syndromes often involve congenital abnormalities in multiple organ systems, Alagille syndrome being a prime example with paucity of bile ducts resulting in cholestatic hepatic dysfunction and cardiac and pulmonary vascular abnormalities. Transplantation of the liver is indicated in 21–33% of patients; however, eligibility may be hindered by congenital cardiopulmonary defects [
]. These congenital heart defects may impose adverse hemodynamic effects prior to, during, and following transplantation. Clinical indications for liver transplantation in patients with Alagille syndrome include chronic liver disease, portal hypertension and impaired quality of life with growth failure secondary to severe cholestasis, xanthomatosis, and refractory pruritus. We report the case of a young woman with hepatic, pulmonary vascular, and cardiac dysfunction as a result of Alagille syndrome and describe how a transcatheter therapeutic approach aided clinical optimization of her cardiopulmonary system prior to liver transplantation.
This 40-year-old woman with a diagnosis of Alagille syndrome with significant hepatic and cardiopulmonary involvement was referred for an evaluation in a multidisciplinary transplant clinic. The patient was initially diagnosed with Alagille syndrome at age 3 when she presented with cholestasis which was treated medically. In her early thirties, she developed worsening jaundice and pruritus and underwent biliary diversion with almost complete resolution of her symptoms. She subsequently developed hematochezia due to cancerous rectal polyps requiring abdominoperineal resection, colostomy, and take down of the biliary diversion. As a result, she developed recurrent cholestasis complicated by cirrhosis, portal hypertension, and malabsorption. Given the patient's portal hypertension she was not a candidate for further abdominal surgeries as a source of therapeutic intervention of cholestasis and thus a liver transplantation evaluation was initiated. Her cardiac and pulmonary comorbidities, however, required further evaluation.
The patient had previously undergone surgical ligation of a patent ductus arteriosus at 2 months of age, surgical closure of an atrial septal defect at age 2 and a surgical pulmonary valvotomy at age 18. Upon initial clinical evaluation she reported recent progressively worsening dyspnea on exertion, worsening exercise tolerance and intermittent headaches. She denied chest pain, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema or syncope. Physical examination demonstrated a well-nourished, well-developed female with Alagille facies in no apparent distress with a grade 2/6 systolic and diastolic murmur at the left upper sternal border. 12-Lead ECG demonstrated normal sinus rhythm with first-degree atrioventricular block and rightward axis. Transthoracic echocardiogram showed left ventricular function to be at the lower limits of normal with estimated ejection fraction of 50–54%, a normal functioning right ventricle, bicuspid aortic valve without significant stenosis and right ventricular hypertension with an estimated right ventricular systolic pressure of 60–65 mm Hg.
As a result, the patient underwent diagnostic coronary angiogram and cardiac catheterization that demonstrated no evidence of significant coronary disease, but she had hemodynamics suggestive of severe right and left main pulmonary artery stenosis (hemodynamics reported in Table 1). Computed tomography angiography showed severe right atrial and right ventricular enlargement with severe stenosis of the right pulmonary artery trunk and moderate stenosis of the left pulmonary artery trunk (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8). A bicuspid aortic valve was seen and the aortic root was dilated at 4 cm. Cardiovascular magnetic resonance imaging demonstrated normal estimated right ventricular function with estimated ejection fraction of 66%. There was evidence of mild right ventricular enlargement and hypertrophy with estimated right ventricular end diastolic volume of 166 ml and end systolic volume 51 ml. There was moderate pulmonary insufficiency with a regurgitant volume of 50 ml and regurgitant fraction of 45%. In summary, although the patient had significant pulmonic regurgitation, the right ventricular pressure overload as a result of bilateral main branch PA stenosis was felt to be the main hemodynamic lesion.
Fig. 1Coronary CT angiogram demonstrating bilateral pulmonary artery stenoses. RPA = right pulmonary artery, LPA = left pulmonary artery, AA = ascending aorta, DA = descending aorta, RMB = right main bronchus, LMB = left main bronchus.
Fig. 23D reconstruction of pulmonary artery stenoses. SVC = superior vena cava, LA = left atrium, RPA = right pulmonary artery, LPA = left pulmonary artery.
Fig. 6Fluoroscopy in the left anterior oblique projection demonstrating full expansion of the right pulmonary artery stent and partial inflation of the left pulmonary artery stent with the inner balloon only. RPAs = right pulmonary artery stent, LPAs = left pulmonary artery stent.
Given the patient's symptomatology and hemodynamics, it was deemed that the patient should undergo therapeutic intervention of her pulmonary arterial disease prior to consideration for liver tranplant. Since the patient had significant liver pathology secondary to Alagille syndrome and multiple prior cardiac surgeries, a catheter-based treatment approach was planned rather than open surgical repair.
Prior to intervention the patient was intubated and initiated on mechanical ventilation supported by a fraction of inspired oxygen of 60%. Complete hemodynamics under general anesthesia were acquired prior to intervention (Table 1). Following hemodynamics and angiography, wire access was obtained in both the right and left distal pulmonary arteries, and then sequential stenting of the right main followed by the left main pulmonary artery performed by placement of a Palmaz XL P3110 stent (Johnson and Johnson, New Brunswick, NJ) deployed by an 18 mm and 20 mm NuMED Balloon-in-Balloon (BIB) catheter (NuMED, Hopkinton, New York), respectively. Kissing balloon post-dilation was performed using an 18 mm and 20 mm Atlas balloon (Bard Inc., Tempe, AZ) at high pressures. During deflation, however, the right PA stent appeared to recoil, and therefore a second stent was implanted within the first to add radial strength (EV3 Mega-LD 36 mm on 18 mm BIB balloon Covidien, Mansfield, MA). Final hemodynamics demonstrated an elevation in filling pressures, but no residual gradient from the RV to the distal PAs bilaterally (Table 1). The patient was successfully extubated in the catheterization lab and transferred in stable condition to the intensive care unit for post-procedure monitoring. She was subsequently discharged the day after her procedure. On follow-up, she reported significant improvement in her symptoms.
Evaluation for liver transplantation in patients with Alagille syndrome is a complex process because of the multitude of clinical manifestations of the disease as well as its inherent multi-organ involvement. Specifically, pulmonary artery stenosis with right ventricular pressure overload is a common issue in patients with Alagille syndrome, and right ventricular hypertension may contribute to congestive hepatopathy in the allograft post liver transplant in addition to the inherent morbidity of right heart failure. Congenital heart transcatheter intervention may be beneficial in palliating and optimizing the hemodynamics of these patients prior to transplant.
There have been conflicting reports on the effect of high right ventricular pressures and severity of pulmonary stenosis on outcomes in patients with Alagille Syndrome undergoing liver transplantation. In a series by Tzakis et al. 23 patients with Alagille syndrome and cardiac malformations underwent liver transplantation. Mean survival was 57% at 4.4 years, with three deaths attributed to cardiopulmonary disease [
]. This led to the conclusion that patients with cardiopulmonary abnormalities were at increased mortality risk following liver transplantation. In contrast, in a series reported by Png et al. that involved 16 children, no correlation between severity of pulmonary artery stenosis and hemodynamic changes during transplantation was found [
]. Due to the limited experience of patients with Alagille syndrome undergoing liver transplantation and the heterogeneity of cardiac manifestations of the disease one must extrapolate the literature with caution and individualize therapeutic options for patients with Alagille syndrome and cardiac manifestations of the disease.
Congenital heart disease is the second most common manifestation of Alagille syndrome affecting greater than 90% of patients. Most commonly, pulmonary outflow tract is involved with peripheral pulmonary stenosis being the hallmark. In his review of 80 cases, Alagille et al. reported an incidence of 70% of isolated peripheral pulmonary stenosis [
]. Tetralogy of Fallot, ventricular septal defects, atrial septal defects, and aortic stenosis also exist and are not uncommon (approximately 15% of cases). Other reported cardiovascular malformations include hypoplasia of the pulmonary vascular tree, pulmonary atresia, truncus arteriosus, and coarctation of the aorta. It is important to note that heart disease is the most common cause of death in the infant, while liver disease is the most common cause of death in the child and adolescent patient. The twenty-year predicted life expectancy for patients with Alagille syndrome is 75% [
Alagille syndrome is an autosomal dominant disorder that is caused by defects in genes involved in the Notch signaling pathway, most frequently due to a mutation in the JAG1 gene, but occasionally NOTCH2 or others. The prevalence is 1:70,000 [
]. Like most genetic disorders, the phenotype is variable, but often includes five aspects (i.e. the ‘classic criteria’): a paucity of bile ducts and resulting cholestasis, congenital heart disease, dysmorphic facies, skeletal abnormalities, and eye pathology. Paucity of bile ducts is the most common manifestation (approximately 95% affected), similar to, but distinct from, biliary atresia. The spectrum of dysmorphic facies includes broad forehead, deep set eyes, pointed chin, and upslanting palpebral fissures. The characteristic skeletal abnormality is “butterfly vertebrae”, or failure of fusion of the anterior vertebral arches. The typical eye finding of Alagille syndrome is posterior embryotoxon, a mostly benign finding that occurs in 15% of the normal population. Other features of Alagille syndrome include intracranial hemorrhage, vascular anomalies, dysplastic kidneys, renal tubular acidosis, failure to thrive, pancreatic insufficiency, and mental retardation [
]. Following the diagnosis of Alagille syndrome, management involves a multidisciplinary approach. A pediatrician, geneticist, gastroenterologist, cardiologist and other specialists pertaining to manifested pathology should be involved in routine care. Patients should have comprehensive assessment of liver function, detailed cardiac assessment, AP spinal X-ray, ophthalmic assessment, renal ultrasound and renal function testing. Monitoring of growth, development, diet and nutritional status should be emphasized and expert opinion should be sought if needed.
While surgical intervention remains the most commonly employed modality in the care of patients with complex congenital defects in Alagille syndrome, most centers favor a catheter-based approach for intervention in peripheral pulmonary arterial stenoses secondary to the high rate of restenosis (up to 60%) with surgical intervention [
]. This high rate of restenosis is seen primarily with proximal pulmonary artery lesions while distal lesions are often numerous and are difficult to access surgically. These factors favor a transcatheter interventional approach to pulmonary artery stenoses. The goal for intervention on pulmonary artery stenosis is to alleviate the elevation of right ventricular pressure that will ultimately lead to clinical right-sided heart failure as well as significant hemodynamic sequelae when the patient becomes eligible for liver transplantation.
Intravascular stenting to the pulmonary artery has been employed in children since the mid-1980s [
]. Pulmonary artery balloon angioplasty and/or stenting, is one of the most common procedures performed in cardiac catheterization laboratories treating congenital heart disease. The success rate with low-pressure balloons varies in the literature ranges from 34 to 71%. With high-pressure balloons the success rate approaches 56–72% [
]. For branch pulmonary artery stenosis, balloon dilation with intravascular stent placement yields a greater increase in vessel diameter and greater reduction in pressure gradient than does sole balloon dilation [
]. The double balloon technique, which employs the use of two smaller balloons rather than one large balloon thereby resulting in less trauma to the femoral veins, has been shown to be successful [
]. In the cases of pulmonary valve stenosis, percutaneous pulmonary valvuloplasty is the preferred method of therapeutic intervention. Studies have shown good long-term outcomes [
]. Clinical experience involving pulmonary rehabilitation in Alagille syndrome is limited. To date, there are no reports addressing the natural history of either elevated right ventricular pressures or pulmonary arterial hypertension in Alagille syndrome or the impact of surgical or catheter-based intervention on survival. A recent multi-institutional registry demonstrated a 10% procedure-related risk of high severity adverse events in patients undergoing pulmonary artery rehabilitation. Presence of >2 indicators of hemodynamic vulnerability, low weight, use of cutting balloons and operator experience of less than 10 years were significant risk factors for high severity related procedures [
Balloon angioplasty and stenting of branch pulmonary arteries: adverse events and procedural characteristics: results of a multi-institutional registry.
This case highlights the utility of transcatheter intervention as a viable method of therapeutic management in adult patients with Alagille syndrome who may present with clinical signs of right heart failure secondary to pulmonary artery stenosis. Given the complexity of cardiac manifestations of Alagille syndrome, clinical and hemodynamic optimization may be accomplished with catheter-based therapeutic intervention and optimize hemodynamics in patients prior to liver transplantation and may even preclude the need for concomitant heart transplant consideration. Pulmonary arterial interventions should be limited to specialized centers with congenital and pediatric interventionalists with high volume labs.
References
Emerick K.M.
Rand E.B.
Goldmuntz E.
Krantz I.D.
Spinner N.B.
PIccoli D.A.
Features of Alagille syndrome in 92 patients: frequency and relation to prognosis.
Balloon angioplasty and stenting of branch pulmonary arteries: adverse events and procedural characteristics: results of a multi-institutional registry.
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