Alagille Syndrome

Introduction

Alagille syndrome (ALGS) is a rare multisystem disorder and one of the most frequent inherited causes of cholestatic liver disease in children. Traditionally, ALGS has been characterized by the presence of at least three of the following five principal clinical features: bile duct paucity and/or cholestasis, cardiac involvement (typically peripheral pulmonary artery stenosis), skeletal anomalies (often butterfly vertebrae), ophthalmological involvement (usually posterior embryotoxon), and/or characteristic facies. However, since 2000, the phenotypic spectrum has expanded and now includes both renal and vascular anomalies as disease-defining characteristics. The multisystem nature of ALGS stems from heterozygous mutations in one of two genes in the Notch signaling pathway, which is fundamental in early development; JAGGED1 (JAG1) mutations are reported in up to 94% of cases, and mutations in the NOTCH2 receptor are found in 1% to 2%. De novo mutations account for approximately 60% of ALGS cases.

There is considerable variation in the clinical course and ultimate prognosis of liver disease in ALGS. ALGS typically manifests as jaundice, high gamma-glutamyltransferase cholestasis, and failure to thrive in infancy. Remarkably, many of these patients achieve spontaneous resolution of their cholestasis during the first 5 years of life; others develop progressively worsening cholestatic liver disease and eventually biliary cirrhosis, necessitating liver transplantation (LT). There are no known genotypic predictors of hepatic outcome in ALGS. There have been some attempts to identify clinical parameters, present in early childhood, to predict eventual hepatic outcomes in children with ALGS. In a multicenter international study of 144 ALGS patients, Mouzaki et al. identified a serum total bilirubin cutoff of 3.8 mg/dL (65 mmol/L) between 12 and 24 months of life as a threshold to distinguish between children with good and poor hepatic outcomes later in life, where a poor outcome was defined by the need for biliary diversion or LT.

Based on historical data from heterogenous cohorts of ALGS patients, LT is indicated in 20% to 50% of pediatric cases. More recent data suggest that up to 70% of children presenting with severe cholestasis require LT during childhood. Indications for transplantation in children with ALGS can be categorized into two groups: (1) those with one or a combination of complications secondary to chronic cholestasis, including refractory pruritus and disfiguring xanthomas, failure to thrive, fat-soluble vitamin deficiency, and/or recurrent pathological fractures; and (2) those with biliary cirrhosis and/or evidence of portal hypertension. The former represent the most common indication for LT in ALGS. Transplantation for pruritus as the primary indication in early childhood remains somewhat controversial because symptoms can resolve or stabilize in select children by school age.

Determining the optimal timing of referral and LT listing in ALGS is another challenge for clinicians, and several factors should be taken into consideration, particularly the extent and degree of systemic disease involvement. In this chapter, we will provide an overview of challenges and management issues associated with LT in children with ALGS.

Growth and Nutrition

Growth impairment and nutritional deficiencies are an ongoing and significant issue in infants and children with ALGS, with a reported prevalence of 50% to 87%. The underlying causes of growth deficits in ALGS are multifactorial and stem from a combination of increased energy expenditure, decreased absorption of fats and fat-soluble vitamins, and the presence of congenital cardiac or renal disease.

Attention to the nutritional and growth status of ALGS transplantation candidates is critical and has significant prognostic implications. Data from the Studies of Pediatric Liver Transplantation (SPLIT) registry showed that more than half of ALGS transplant candidates had a documented height (66%) and weight deficit (63%) at the time of transplantation listing in comparison with only 22% and 21% of children with biliary atresia (BA), respectively. Surprisingly, only 24% of ALGS patients received perioperative nutrition support. These data highlight a need for more aggressive nutritional management in ALGS patients during the pre-transplantation evaluation and waiting list period.

Children with ALGS exhibit catch-up growth following successful LT; however, pre-transplantation growth faltering is not completely reversed. The SPLIT study of LT in ALGS demonstrated that in comparison with children with BA, a significant deficit in linear growth persisted in the ALGS group throughout the 5-year follow-up period. This may reflect an intrinsic limitation of growth potential in ALGS. However, this study also showed that ALGS patients experience greater growth velocity than age-matched BA counterparts in the first 24 months post-LT ( Fig. 35.1 ). These data suggest that growth failure is not an inevitable feature of ALGS and can certainly be ameliorated in those with liver disease, also implying that growth failure be considered an important indication for LT in ALGS.

Cardiac Involvement

Cardiac anomalies are a hallmark feature of ALGS, with a reported prevalence of 94%. The extent and pattern of cardiac involvement is highly variable, ranging from an asymptomatic murmur, or peripheral pulmonary stenosis (PPS), to more complex intracardiac anomalies, such as tetralogy of Fallot, with or without pulmonary atresia. PPS accounts for approximately 73% of reported cardiac anomalies in ALGS and can lead to pressure or volume overload of the right ventricle (RV), RV hypertrophy, and, in severe cases, right-sided heart failure.

Evaluation of prospective LT candidates with ALGS requires careful assessment of the cardiovascular system, with special emphasis on the functional capacity of the RV. Elevated right heart pressures and hypertrophy impair the heart’s ability to respond to the marked preload changes when the inferior vena cava is clamped during transplantation surgery. To address this, the King’s College Group suggested a cardiac catheterization and dynamic stress test with dobutamine to simulate perioperative conditions in the LT evaluation of ALGS patients. A dynamic stress exercise (DSE) induces peripheral vasodilation and increases cardiac output, thereby mirroring the conditions of graft reperfusion. If the transplant candidate achieves a cardiac output of more than 40% during DSE, the patient’s cardiac reserve is considered sufficient for transplantation. This approach is clearly physiologically relevant but may not be required for all ALGS LT candidates and can be targeted toward those considered at risk of increased RV pressures based on echocardiography and expert pediatric cardiology opinion.

Stenosis and/or hypoplasia of the pulmonary arteries may contribute to post-reperfusion hemodynamic instability and adverse post-transplantation outcomes in ALGS patients. Again, expert pediatric cardiology input is crucial to manage cardiac anomalies before LT. Cardiac interventions reported in ALGS patients before LT include balloon valvuloplasty and stenting, as well as more invasive cardiac surgery. In the presence of complex intracardiac anomalies, the risk-benefit ratio of LT must be carefully weighed, and detailed pre-operative screening should be undertaken by an experienced multidisciplinary team. In the setting of very complex cardiac involvement and advanced liver disease in ALGS, especially in infancy, palliation is not unreasonable. Combined heart-LT has been reported in only a few ALGS cases.

Renal Involvement

Structural and/or functional abnormalities of the renal system have been documented in 40% to 85.7% of children with ALGS. Renal dysplasia (with or without cysts), renal tubular acidosis, and vesico-ureteral reflux are among the most common findings. Additional but less common abnormalities include a horseshoe kidney, duplex collecting system, and renal artery stenosis with or without midaortic syndrome. Given the high rate of renal involvement in ALGS, a detailed evaluation of the kidneys is indicated in all transplant candidates, including a measured glomerular filtration rate (GFR) and, in some institutions, determination of serum cystatin C. A kidney ultrasound should also be performed to assess kidney size, cortical thickness, and echogenicity of renal parenchyma and Doppler studies of the renal arteries.

Renal impairment is frequent in ALGS patients awaiting LT and does not appear to reverse or stabilize with transplantation. In the study of the SPLIT ALGS cohort, Kamath et al. found that renal insufficiency, defined as a calculated GFR (cGFR) less than 90 mL/min/1.73 m ² , was three times more prevalent among ALGS transplant candidates in comparison with those with BA (18% vs. 5%; P < .001). Children with ALGS were also noted to have considerably higher pre-transplantation serum creatinine levels (41.5 ± 2.7 μmol/L vs. 29.2 ± 0.9 μmol/L; P < .001). Following transplantation, resolution of pre-transplantation renal injury was more frequent in children with BA compared with ALGS. This observation likely reflects an intrinsic renal defect among individuals with ALGS, which has limited potential for reversibility with LT. The ALGS group also showed a significantly higher rate of renal complications during the first 30 days after LT (9.9% vs. 3.4%; P = .02; Table 35.1 ). Collectively, these data provide support for heightened awareness and ongoing surveillance of renal function in ALGS transplant candidates throughout the pre- and post-transplantation periods.

Table 35.1

Renal complications following liver transplantation in children with Alagille syndrome and biliary atresia enrolled in the studies of Pediatric Liver Transplantation Registry (SPLIT) ^a

(Modified from Kamath BM, Yin W, Miller H, et al. Studies of pediatric liver transplantation. Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience. Liver Transpl. 2012;18(8):940-948.)

	30 Days			Year 1			Year 2
Complication	ALGS ( n = 91)	BA ( n = 236)	P	ALGS ( n = 91)	BA ( n = 236)	P	ALGS ( n = 59)	BA ( n = 159)	P
Renal complications	9.9%	3.4%	0.02	4.3%	0.5%	0.03	1.7%	0.0%	0.10
cGFR ≤ 90 mL/min/1.73 m ²	No data collected			21.7%	8.2%	0.001	16.9%	6.9%	0.03
Serum creatinine (mg/dL)	0.49 ± 0.31	0.36 ± 0.24	0.001	0.54 ± 0.31	0.47 ± 0.27	0.06	0.57 ± 0.28	0.48 ± 0.17	0.01

NOTE: Bolded values are statistically significant ( P < 0.05).

ALGS, Alagille syndrome; BA , biliary atresia; cGFR , calculated glomerular filtration rate.

a Data presented as means and standard deviations.

Renal dysfunction is a well-known long-term complication of pediatric LT; however, children with ALGS are particularly susceptible, given the essential role of JAG1 and NOTCH2 in kidney development. To prevent subsequent renal injury during the post-transplantation course, we advocate using of a renal-sparing protocol in all ALGS transplant recipients, regardless of pre-transplantation renal function. At our institution, a two-dose regimen of basiliximab (Simulect; Novartis) and mycophenolate mofetil along with delayed entry of calcineurin inhibitors (CNIs) is used in all pediatric LT recipients with documented renal impairment and/or a genetic predisposition. We further recommend an annual surveillance of the cGFR.

Vascular Involvement

Vascular anomalies are an important and under-recognized feature of ALGS. To date, three primary cerebrovascular phenotypes have been described: (1) cerebral aneurysms, (2) moyamoya syndrome, and (3) carotid artery stenosis. A wide spectrum of systemic vascular anomalies has also been reported in ALGS, such as coarctation of the aorta, stenosis of the renal arteries, and anomalies of the abdominal vasculature. Currently, there is no consensus regarding the screening and management of vasculopathies in ALGS, and prospective studies are lacking. We recommend that all ALGS transplant candidates undergo detailed imaging of the cerebral and intraabdominal vasculature with contrast computed tomography angiography and/or magnetic resonance angiography (MRA). If vascular anomalies are detected, consultation with a multidisciplinary team should occur before LT listing.

Management of cerebral vasculopathies in children with ALGS undergoing LT presents a unique set of challenges, and current experience is limited. One case report details the peri-transplantation management of a 10 year-old girl with ALGS and a basilar artery aneurysm associated with moyamoya. To optimize the child’s health status before transplantation, a bilateral encephalo-duro-arterio-synangiosis was performed to treat the moyamoya, followed by endovascular repair of the cerebral aneurysm. Following successful pre-transplantation intervention, the child underwent an uneventful deceased donor split LT and remained in good neurological health over 4 years of follow-up. In the setting of advanced liver disease complicated by cerebral vasculopathies, the study authors suggested that vascular intervention(s) should be initiated before transplantation in an effort to minimize complication risks.

Anomalies of the intra-abdominal vasculature have been increasingly cited in ALGS, and the presence of such anomalies may lead to surgical modifications during LT. The SPLIT transplant registry revealed that an arterial anastomotic interposition was performed twice as often in children with ALGS in comparison with a matched control group with BA (20% vs. 9%; P = .007). Alterations to the surgical approach did not correlate with vascular complications or early transplantation outcomes in either group; however, this study clearly demonstrates a higher prevalence of underlying vessel anomalies among ALGS transplant recipients. A subsequent retrospective series of 55 children with ALGS undergoing LT revealed that an aortic conduit reconstruction (ACR) was performed in 63.7% of subjects ( n = 35/55). Notably, those who underwent ACR had significantly lower rates of arterial complications following transplantation (5.7% vs. 35.0%; P = .0079). In addition, available pre-transplantation vascular imaging revealed celiac trunk stenosis in two-thirds of ALGS patients (48.0%; Fig. 35.2 ). Taken together, these data reinforce the importance of pretransplantation vascular imaging and careful surgical planning in children with ALGS undergoing LT.