Journal of Pediatric Gastroenterology & Nutrition:
Medical Management of Alagille Syndrome
Kamath, Binita M*; Loomes, Kathleen M†; Piccoli, David A†
*Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, USA
†Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, USA.
Received 13 July, 2009
Accepted 17 February, 2010
Address correspondence and reprint requests to Binita M. Kamath, MBBChir, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada (e-mail: firstname.lastname@example.org).
The authors report no conflicts of interest.
Alagille syndrome is a highly variable, autosomal dominant disorder that affects the liver, heart, eyes, face, skeleton, kidneys, and vascular system. Much has been learned about the genetics of this disorder, which is caused primarily by mutations in the Notch signaling pathway ligand JAGGED1; however, the medical management of this condition is complex and continues to generate controversy. The significant variability of organ involvement requires the managing physician to have an understanding of the breadth and interplay of the variable manifestations. Furthermore, the liver disease in particular requires an appreciation of the natural history and evolution of the profound cholestasis.
Alagille syndrome (AGS) is a highly variable, multisystem, autosomal dominant disorder that primarily affects the liver, heart, eyes, face, and skeleton (1–3). In addition, vascular and renal manifestations are now well described (4–6). There is significant variability in the extent to which each of these systems is affected in an individual, if at all (7,8). AGS has traditionally been diagnosed based on the presence of intrahepatic bile duct paucity on liver biopsy in association with at least 3 of the major clinical features: chronic cholestasis, cardiac disease (most often peripheral pulmonary stenosis), skeletal abnormalities (typically butterfly vertebrae), ocular abnormalities (usually posterior embryotoxon), and characteristic facial features (4).
Previously, AGS had an estimated frequency of 1 in 70,000 live births, although the advent of molecular testing has proven this to be an underestimate and this figure is closer to 1 in 30,000 (9). AGS is caused by mutations in JAGGED1 (JAG1), a gene encoding a cell surface protein that acts as a ligand in the Notch signaling pathway (10,11). JAG1 mutations are identified in more than 90% of clinically diagnosed probands (12). Molecular confirmation of a clinical diagnosis is available commercially and as a research tool. Recently, mutations in NOTCH2 have been identified in a few patients with AGS who do not have JAG1 mutations (13).
Molecular testing has allowed the identification of mildly affected individuals, some of whom have no overt liver disease and those with atypical or unusual features. This has broadened our understanding of the phenotype associated with JAG1 mutations. Because of the original descriptions of AGS as a hepatic disease, with cholestasis as a central feature, the condition has been primarily managed by gastroenterologists; however, an appreciation of the wide extent of JAG1-associated disease is important for management, diagnosis of family members, and genetic counseling.
This article is not intended as a comprehensive review, but rather as an outline of practical suggestions for the medical management of AGS. Surgical options and, in particular, transplantation are discussed in another recent review (13a). There are few controlled trials that support clinical practice, and therefore the following reflects a review of available data as well as collective clinical experience.
Molecular testing has become available for AGS, both on a research basis and now clinically (a list of laboratories conducting clinical and research testing is available at http://www.genetests.org); however, although the identification of a JAG1 mutation may be helpful in identifying mildly affected or unusual individuals with AGS, a full clinical evaluation is still warranted in all of the patients diagnosed clinically or at a molecular level. In the setting of a known JAG1 mutation in a family, preimplantation genetic diagnosis and prenatal diagnosis are available (14,15).
Many individuals with AGS present to the pediatric gastroenterologist with cholestasis, and therefore the hepatic evaluation is usually primary. Laboratory testing, including hepatic function panel, gamma-glutamyl transferase, serum bile acids, serum cholesterol with lipid panel, fat-soluble vitamin levels, and prothrombin time, is needed initially. Further monitoring of these is determined by the degree of cholestasis and any complications; however, it is recommended that fat-soluble vitamin levels be checked twice yearly in infants and young children. A liver ultrasound is usually performed as part of the evaluation for cholestasis, but there are no specific findings in AGS. Hepatobiliary scintigraphy and an intraoperative cholangiogram may be done in the cholestatic infant to distinguish AGS from biliary atresia; however, results may overlap and findings should be interpreted with caution. In 1 study of 36 infants with AGS who underwent hepatobiliary scintigraphy, excretion of tracer was delayed in 9 (25%) and absent at 24 hours in 22 (61%) (4). In addition, cholangiograms have been reported to be abnormal in a significant number of infants with AGS. Emerick et al (4) report the results of 19 cholangiograms, which showed frequent hypoplasia of the common bile duct (32%), proximal extrahepatic biliary tree (37%), and intrahepatic ducts (16%). Overall, the proximal extrahepatic biliary tree was not visualized in 37% of the studies, and the intrahepatic ducts were not visualized in 74%. Experienced interpretation of such cholangiograms is essential to avoid misdiagnosis. A liver biopsy can strongly support the AGS diagnosis if there is bile duct paucity; however, if the individual meets clinical criteria (cholestatic liver disease in association with heart disease, facies, skeletal and ocular anomalies), then a liver biopsy is not mandatory for diagnostic purposes. The requirement to perform a liver biopsy in AGS should be determined by clinical need.
In the evaluation of neonatal cholestasis, it can be difficult to distinguish between AGS and biliary atresia. Bile duct paucity is present in only 60% of liver biopsies of infants with AGS younger than 6 months of age (4), and bile duct proliferation is also a frequent finding in infancy (16). In addition, as described earlier, hypoplasia of the extrahepatic biliary tree is common in AGS, complicating interpretation of the intraoperative cholangiogram. Kasai portoenterostomy has been performed in infants with AGS and is reported to lead to a high rate of liver transplantation (17,18). It appears that the Kasai procedure itself leads to increased morbidity and progression of liver disease; therefore, Kasai portoenterostomy is to be avoided in AGS (18a). It is unclear whether these patients had more severe underlying liver disease as a group or the Kasai procedure itself led to morbidity and progression of liver disease, but, in general, Kasai portoenterostomy is to be avoided in AGS. Multisystem evaluation, including echocardiogram, ophthalomologic examination, and vertebral radiographs, may be helpful in reaching a correct diagnosis in this patient population.
Multiple reports exist in the literature of hepatocellular carcinoma (HCC) in young children and adolescents with AGS (19,20). Most but not all of the patients who developed HCC also had progressed to cirrhosis. Although HCC is a rare complication of AGS, it is associated with high morbidity and mortality. A high index of suspicion is crucial for early diagnosis, and periodic screening with α-fetoprotein levels and abdominal imaging may be advisable.
In the presence of a significant cardiac lesion, such as tetralogy of Fallot, the cardiac evaluation is defined by the clinical situation. In individuals without overt cardiac disease an echocardiogram is warranted, even in the absence of a murmur. It is helpful to inform the cardiologist of the presence of possible peripheral pulmonary stenosis, so that the echocardiogram is not limited to intracardiac structures only. In the setting of significant pulmonary artery stenosis, a lung-perfusion scan is helpful to determine the degree of asymmetric pulmonary vascular supply, but the cardiologist largely determines the need for this study.
A slit-lamp examination by an ophthalmologist is useful for diagnostic purposes. The typical finding of posterior embryotoxon does not have long-term implications and generally does not require follow-up. Other common findings include iris hypoplasia, anomalous optic discs, abnormalities of the retinal vessels, and pigmentary retinopathy (21). The majority of patients with AGS have normal visual acuity, but routine ophthalmologic examinations are recommended to screen for progression of disease or development of glaucoma. Examination of the face by a gastroenterologist and/or a geneticist familiar with the characteristic facies is an important diagnostic tool because this is the most penetrant clinical feature. The typical facial features of AGS have been described as triangular, with a prominent forehead, deep-set eyes, a pointed chin, and a straight nose with a bulbous tip (Fig. 1). The facies may be difficult to recognize in infancy but evolve during the first few years of life. In addition, the facial features change over time, with a more triangular shape during childhood and prominence of the jaw as patients reach adulthood (Fig. 1) (22).
Evaluation of the vertebrae for classic butterfly vertebrae and other vertebral anomalies has diagnostic value in the clinical evaluation of AGS. These typical findings rarely cause clinical problems and do not require follow-up. Other musculoskeletal findings such as the presence of supernumerary digital flexion creases may also assist diagnosis (22a). The most concerning musculoskeletal complication in AGS is severe metabolic bone disease and pathologic fractures. Susceptibility to fractures in the AGS population is likely due to a combination of factors including cholestasis, fat malabsorption, deficiencies of calcium, fat-soluble vitamins and other micronutrients, and malnutrition. Patients with AGS have been found to have deficits of bone mineral content (23); therefore, the use of dual-energy x-ray absorptiometry to assess bone density is valuable for the identification of patients at high risk for bone fractures. Optimization of nutritional status, including fat-soluble vitamin levels, is also important for this feature. Poor growth in AGS should also prompt an evaluation for fat malabsorption and steatorrhea, which may be multifactorial. A 72-hour fecal fat collection, although onerous, may be helpful in this evaluation. In addition, measurement of fecal elastase level can identify patients with exocrine pancreatic insufficiency, who may benefit from supplementation with pancreatic enzymes.
The kidneys in AGS should be evaluated with a baseline ultrasound to exclude structural anomalies in all patients. In addition, in the presence of poor growth and/or low serum bicarbonate, urinalysis and serum biochemistries are indicated to evaluate for renal tubular acidosis (RTA). A small percentage of patients with AGS may eventually develop chronic renal insufficiency, so periodic evaluation of renal function is recommended, especially if patients are being treated with nephrotoxic medications.
With respect to potential neurovascular complications in AGS, it has been suggested that children who do not require sedation have a baseline screening magnetic resonance imaging/magnetic resonance angiography (MRI/MRA). This practice has yet to be validated and the timing and/or necessity of surveillance head imaging are unknown. In the event of a serious head injury or neurological symptom, it is mandatory to aggressively and rapidly evaluate these children clinically and with appropriate imaging.
MEDICAL MANAGEMENT OF CHOLESTASIS
The hepatic manifestations of AGS typically appear in the first year of life and vary from mild to severe cholestasis. Conjugated hyperbilirubinemia in the neonatal period is the usual presentation. The cholestasis in AGS is commonly profound and manifests clinically with pruritus and xanthomata. The natural history of liver disease in AGS is unique. Cholestasis typically worsens until school age and then, in some children, it improves or stabilizes (24). Synthetic liver failure is uncommon in AGS in the first year of life. End-stage liver disease develops in approximately 20% of children primarily due to chronic cholestasis (4,17,24). There are no known radiological or genetic markers that can predict which children will have progression of their liver disease and in which children it will improve. Recent research has identified some biochemical thresholds in early childhood that may be useful in predicting later hepatic outcomes (24a). Thus, it is important to aggressively medically manage the pruritus and xanthomas in the early years and possibly avoid liver transplantation, because many of these children will spontaneously show improvement in cholestasis.
The pruritus seen in AGS is among the most severe of any chronic liver disease. It rarely is present before 3 to 5 months of age but is seen in most children by the third year of life. Pruritus is often debilitating, disturbing sleep, daily activities, and cognitive development. Conservative management of pruritus entails taking care to keep the skin hydrated with emollients, trimming the fingernails, and taking short baths or showers to limit drying of the skin.
Bile flow may be stimulated with choleretics, and ursodiol is the most commonly used agent. The use of ursodiol has been studied in children with AGS with improvement in pruritus, xanthomata, and biochemical markers of cholestasis (25–28). Narkewicz et al (26) conducted a 2.5-year open-label crossover study in a group of cholestatic children, of whom 4 had AGS with improvement in pruritus scores. Phenobarbital is rarely used due to its sedative effect. Bile acid–binding resins, such as cholestyramine, are often effective but not palatable. They are also difficult to administer because they must be given 2 hours apart from other medications. Colesevelam may be better tolerated but has not been studied in pediatrics. It should be noted that colesevelam is a potent bile acid–binding resin and may severely deplete the concentration of free luminal bile acids resulting in risk of fat-soluble vitamin deficiency, and these levels should therefore be monitored. Therapy with antihistamines may provide some symptomatic relief but are rarely effective alone. Rifampin has been comparatively well studied in AGS (29–31). Yerushalmi et al (31) studied 24 children with severe cholestasis, of whom 6 had AGS, and 92% of the cohort showed a response in improving pruritus. Although rifampin is associated with elevation of serum transaminases, none of these studies reported clinical or biochemical adverse events. Naltrexone has been shown to be effective against pruritus in cholestatic adults. On the basis of anecdotal experience, it can be useful in the pruritus of children with AGS as well. It should be noted that there is a black box warning for naltrexone for potential hepatotoxicity; however, this warning was based on a small amount of data when the drug was used in doses that were 5 times the recommended range. Therefore, naltrexone remains a viable option for intense pruritus in AGS with appropriate monitoring.
Xanthomata typically form on the extensor surfaces of the fingers, the palmar creases, the nape of the neck, the ears, the popliteal fossa, the buttocks, and around the inguinal creases. They are typically worse in areas of friction, such as the diaper area. They tend to occur with serum cholesterol levels greater than 500 mg/dL. Xanthomata increase in number during the first few years of life and may disappear subsequently as cholestasis improves (24). Xanthomata are cosmetically disfiguring and may interfere with fine motor function, although they are not considered painful. Occasionally, xanthomata on the inner canthus may interfere with visual development and require removal, but generally they do not require surgery.
The hypercholesterolemia of AGS is often staggering; however, this high level of plasma cholesterol is largely associated with lipoprotein-X (32). Lipoprotein-X is in the low-density lipid range and resists oxidation, thereby protecting against atherosclerosis. Thus, the hypercholesterolemia of AGS does not appear to carry an increased risk of cardiovascular disease and dietary modifications or medical therapy are not necessary for this indication (33,34). There is no specific threshold at which a lipid-lowering medication is indicated. Medical therapies directed toward cholestasis may lower the serum cholesterol; however, cholestyramine, for instance, does not appear to improve the lipid profile (32,35). The use of statins has not been studied in children for this indication and should be reserved for those with particularly debilitating xanthomata.
A sequential approach to cholestasis therapy in AGS is most appropriate. The most commonly used agents are listed in Table 1, with common adverse effects. The first-line therapy would be ursodiol or a bile salt–binding resin such as cholestyramine. Antihistamines may be used as adjuvants, on an as-needed basis for symptomatic relief, especially overnight. Rifampin and colesevelam would be considered second- or third-line therapy. The use of opioid antagonists or statins is not well established in pediatrics but anecdotally has been used with success. Partial external biliary diversion (PEBD) has been successful in a number of patients with AGS and is now a viable option for intractable pruritus and xanthomata (36–40). Biliary diversion should be considered in all children with AGS when medical management of pruritus fails. It should be noted, however, that the outcome of PEBD is poor in the setting of hepatic fibrosis, and therefore a liver biopsy should be considered before offering this therapy.
Cardiac disease in AGS varies from the presence of a heart murmur to profound intracardiac lesions, such as tetralogy of Fallot (41). Involvement of the peripheral pulmonary arteries is characteristic. Management of the cardiac disease in AGS is clearly lesion specific. Nonsurgical invasive techniques have been used successfully for patients with AGS, including valvuloplasty, balloon dilatation, and stent implantation (42,43). Heart–lung transplantation has been performed in combination with liver transplantation in a child with AGS (44).
Cardiac disease is an important determinant of survival in AGS and accounts for nearly all early deaths. Individuals with AGS and intracardiac disease have approximately a 40% rate of survival to 6 years of life, compared with a 95% survival rate in patients with AGS without intracardiac lesions (4). Patients with AGS may undergo standard cardiac interventions; however, their survival is uniformly poorer as compared with children without AGS with the same cardiac lesions (4,41,45). This may be a result, in part, of the common presence of significant stenoses in the distal pulmonary artery, or of other systemic manifestations of the syndrome.
GROWTH AND NUTRITION
Growth failure, malnutrition, and pubertal delay are common in AGS and should be aggressively treated (46). The growth failure is likely multifactorial, related to the primary defect in JAG1, skeletal involvement, insufficient caloric intake, steatorrhea due to pancreatic and/or liver disease, and significant cardiac disease (46–49). Resting energy expenditure was not found to be increased in patients with AGS as compared with control subjects of similar body composition (48). Several of these etiologies are amenable to therapy and, therefore, should be investigated and addressed. A growth chart specific for AGS is available but has not been validated.
Malnutrition due to inadequate energy should be treated with aggressive nutritional therapy (Table 2). The optimal percentage and distribution of fat energy has not been determined systematically. There is significant malabsorption of long-chain fat, and therefore formulas supplemented with medium-chain triglycerides (MCTs) are advantageous. Carbohydrate supplementation may improve overall caloric deficit. Fat malabsorption in AGS may be due to cholestasis and/or pancreatic insufficiency. Pancreatic enzyme supplementation has been suggested but not yet studied systematically.
Many patients are unable to eat enough to provide the substantial quantities of energy required for growth. In 1 recent study, despite physician recommendations for a high-energy diet, only one quarter of the patients were actually consuming more than 100% of the recommended daily allowance (48). In these situations, nasogastric or gastrostomy tube feedings can provide necessary supplementation. As in all children with chronic liver disease, the risks and benefits of gastrostomy tube placement must be weighed carefully in any patient who is at risk for the development of portal hypertension. Overall, a high-energy, moderate fat (mostly MCT) diet is likely to be most beneficial with regular input from a registered pediatric dietician (Table 2).
Fat-soluble vitamin deficiency is present to a variable degree in most patients with significant AGS. Multivitamin preparations provide a fixed ratio of fat-soluble vitamins, which may result in excess intake of some vitamins, with inadequate intake of others. It is therefore recommended that vitamins be administered as individual supplements tailored to the specific needs of the patient (Table 3). Administration of other fat-soluble vitamins along with water-soluble vitamin E may result in improved absorption (50). Close monitoring (every 3–6 months) of fat-soluble vitamin levels, with dose adjustments as needed, is crucial to maintain optimal vitamin levels and avoid complications of vitamin deficiencies, particularly in the first years of life. A complete review of fat-soluble vitamin dosing and monitoring is outside the scope of this article; further information may be found in Liver Disease in Children (50a).
Intracranial vessel anomalies are a well-established feature in AGS, occurring in approximately 15% of patients (5,17,51,52). These lesions are detectable on magnetic resonance angiography and may be symptomatic (52). There are several reported series documenting intracranial and other extracerebral vascular involvement in AGS including cerebral aneurysms, narrowing of the internal carotid artery, abdominal coarctations, and renal artery stenosis, to name a few (5,17,18,51,53–60). In a large retrospective review of 268 individuals with AGS, 9% had a vascular anomaly or significant bleeding event, and, of note, vasculopathy accounted for 34% of the mortality (5).
Although the existence of a vasculopathy in AGS is well documented, the management of this issue remains 1 of the most controversial aspects of AGS care. No prospective studies to determine the nature and prevalence of vascular anomalies in AGS have been performed as yet and there remains discussion regarding the ethics of diagnosing asymptomatic lesions. Some centers recommend a baseline head and neck MRI/MRA in individuals with AGS. In the event of a new neurologic symptom, clearly, imaging is warranted. Certainly there seems to be a rationale for performing vascular imaging of the abdomen with computed tomography or magnetic resonance before liver transplant to identify any intraabdominal vessel anomalies. No AGS-specific treatments exist for intra- or extracerebral vessel anomalies, and consultation with a vascular surgeon or neurosurgeon must be sought if an anomaly is found. Without longitudinal data available, the risks and benefits of surgery in an isolated intracranial vascular anomaly should be balanced carefully. In the case of known progressive disease, such as Moyamoya, which has been described in AGS, the risk of recurrent stroke usually mandates surgical intervention.
The kidneys are often affected in AGS (6,53,61,62). Reported renal involvement ranges from structural renal anomalies to intrinsic renal disease, such as tubulointerstitial nephropathy and mesangiolipidosis (4,63). Renal cysts are also frequently detected on ultrasound both pre- and postnatally, ranging from simple cysts without functional consequences, to multicystic dysplastic kidneys, to cystic kidneys leading to renal insufficiency during infancy (4,64). Renal vascular involvement is also reported; if symptomatic, it can be treated with stenting, as in other non-AGS cases (61). RTA is a potential and treatable cause of growth failure. At our center, we routinely screen for RTA and treat with bicarbonate replacement. Rarely, renal disease in AGS may progress to renal failure, requiring dialysis or transplantation. In addition, renal disease has been reported rarely as a presenting sign of AGS in adult patients (62).
AGS is a highly variable multisystem disorder. The liver disease contributes significantly to the morbidity of this condition, but mortality arises largely from cardiac and vascular disease (4,5). Previously, intractable pruritus and xanthomata were common indications for liver transplantation, in addition to more global problems such as synthetic failure; however, various management strategies are available, which, although not all have been systematically evaluated, do offer viable options for patients with AGS with severe cholestasis. Because the natural history of this condition is that the cholestasis of infancy worsens and then improves in early childhood, with only 10% to 30% of individuals with AGS ultimately requiring transplantation, it seems imperative to optimize all of the nontransplant therapies while maintaining quality of life in children with AGS. This is especially important in the preschool age range. Finally, the multisystem nature of this condition should always be considered in the management, in particular in addressing life-threatening complications, such as intracerebral bleeding. Clearly, systematic studies are necessary to determine the optimal management for these potentially devastating complications.
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