Chapter 14 – Alagille Syndrome


Alagille syndrome (ALGS) is an autosomal dominant, multisystem disorder which was first described in 1969 by Daniel Alagille as a constellation of clinical features in five different organ systems [1]. The diagnosis was based on the presence of intrahepatic bile duct paucity on liver biopsy in association with at least three of the major clinical features: chronic cholestasis, cardiac disease (most often peripheral pulmonary stenosis), skeletal abnormalities (typically butterfly vertebrae), ocular abnormalities (primarily posterior embryotoxon), and characteristic facial features. Advances in molecular diagnostics have enabled an appreciation of the broader disease phenotype with recognition of renal and vascular involvement [2, 3]. There is significant variability in the extent to which each of these systems is affected in an individual, if at all [4, 5]. ALGS was originally estimated to have a frequency of one in 70,000 live births, though this was based on the presence of neonatal cholestasis. However, this is clearly an underestimate as molecular testing has demonstrated that many individuals with a disease-causing mutation do not have neonatal liver disease and the true frequency is likely closer to one in 30,000 [5].

Chapter 14 Alagille Syndrome

Binita M. Kamath , Nancy B. Spinner , and David A. Piccoli


Alagille syndrome (ALGS) is an autosomal dominant, multisystem disorder which was first described in 1969 by Daniel Alagille as a constellation of clinical features in five different organ systems [1]. The diagnosis was based on the presence of intrahepatic bile duct paucity on liver biopsy in association with at least three of the major clinical features: chronic cholestasis, cardiac disease (most often peripheral pulmonary stenosis), skeletal abnormalities (typically butterfly vertebrae), ocular abnormalities (primarily posterior embryotoxon), and characteristic facial features. Advances in molecular diagnostics have enabled an appreciation of the broader disease phenotype with recognition of renal and vascular involvement [2, 3]. There is significant variability in the extent to which each of these systems is affected in an individual, if at all [4, 5]. ALGS was originally estimated to have a frequency of one in 70,000 live births, though this was based on the presence of neonatal cholestasis. However, this is clearly an underestimate as molecular testing has demonstrated that many individuals with a disease-causing mutation do not have neonatal liver disease and the true frequency is likely closer to one in 30,000 [5].

Alagille syndrome is primarily caused by mutations in JAGGED1 (JAG1), a ligand in the Notch signaling pathway [6, 7]. JAG1 mutations are identified in 94% of clinically defined probands [8]. Mutations in NOTCH2 have been identified in a few patients with ALGS who do not have JAG1 mutations [9]. This discovery has enhanced our understanding of the heterogeneity of this disorder, though much remains to be understood about the tremendous variability seen in affected individuals and the likely genetic modifiers involved.

Clinical Features of Alagille Syndrome

A strikingly large number of abnormalities have been associated with ALGS. These problems are best organized into those features that are structural defects that occur during embryogenesis, functional defects resulting from these congenital defects, or complications of longstanding biochemical abnormalities. The latter are not truly features of the syndrome, but quite commonly are substantial problems. For example, the bile duct paucity is a result of a defect in organogenesis, but the coagulopathy is commonly a complication of fat malabsorption or end-stage liver disease. The severe limitations in height seen in many patients may be a feature of the skeletal development seen in ALGS or a complication of malnutrition, though clearly the two may co-exist. Similarly, the marked increase in long-bone fractures may result from an intrinsic abnormality of bone structure and development in ALGS, or be a complication of vitamin D and nutrient malabsorption, or a combination of both issues.

There are several large series of ALGS patients reported, and the characteristics of the disease are slightly divergent with respect to pattern and degree of organ involvement (Table 14.1). These retrospective studies are now 15–30 years old and include patients from an era before molecular confirmation of the diagnosis was readily available and also do not reflect the expanding clinical definition that has occurred over the last ten to15 years. Finally all of these studies have been reported by tertiary level liver centers and therefore reflect a hepatic-predominant view of ALGS [2, 1014]. These reports are also weighted with the severely affected index cases in families and thus there is a high prevalence of clinical features (Table 14.1). Kamath et al. studied the feature frequency and morbidity in mutation-positive relatives separately, thereby excluding the severely affected index cases [5]. In mutation-positive relatives, the presence of significant cardiac and hepatic disease was less than in the probands. In the relatives the frequency of liver disease was only 31%, compared to 97% in the probands and 45% of the relatives had no clinical or biochemical hepatic involvement at all. Thus, the clinical consequence of carrying a JAG1 mutation is less severe than previously thought, and the disease certainly seems to have a better overall outcome. This point is important for genetic counseling.

Table 14.1 Clinical Features of Alagille Syndrome from Reported Series

Alagille (1987) Deprettere (1987) Hoffenberg (1995) Emerick (1999) Quiros-Tejeira (1999) Subramaniam (2011)
Number of patients 80 27 26 92 43 117
Bile duct paucity (%) 100 81 80 85 83 75
Cholestasis (%) 91 93 100 96 100 89
Murmur (%) 85 96 96 97 98 91
Vertebral anomalies (%) 87 33 48 51 38 37
Facies (%) 95 70 92 96 98 77
Ocular anomalies (%) 88 56 85 78 73 61
Renal involvement (%) 73 19 40 50 23
Intracranial bleeding (%) 12 14 12

Hepatic Features

The majority of ALGS patients who are symptomatic with liver disease present in the first year of life. The hepatic manifestations typically vary from mild to severe cholestasis. Hepatitis (elevated AST and ALT) is present in many infants but generally is less important than the cholestasis. Synthetic liver failure is extremely uncommon in the first year of life. Hepatomegaly is recognized in 93–100% of patients with ALGS and is common in infancy [2, 10]. Splenomegaly is unusual early in the course of the disease but eventually is found in up to 70% of patients, likely related to portal hypertension [2]. Jaundice is present in the majority of symptomatic patients and typically presents as a conjugated hyperbilirubinemia in the neonatal period. The magnitude of the hyperbilirubinemia is typically less than the degrees of cholestasis and pruritus. The pruritus seen is among the most severe of any chronic liver disease. It rarely is present before three to five months of age but is seen in most children by the third year of life, even in some who are anicteric.

The most striking laboratory abnormalities are in the measures of cholestasis and bile duct damage. Elevations of serum bilirubin up to 30 times normal and serum bile salt elevations of 100 times normal are not uncommon. Bile salt elevations are common, even if the bilirubin concentration is normal. Levels of markers of bile duct damage, including γ-glutamyltransferase (GGT) and alkaline phosphatase, usually are significantly elevated. The amounts of other substances typically excreted in bile are increased in blood. Cholesterol levels may exceed 1,000–2,000 mg/dL. The hyperlipidemia of ALGS is predominantly lipoprotein X and therefore not atherogenic. The aminotransferases typically are elevated three- to tenfold but may be normal in some patients with cholestasis. Hepatic synthetic function usually is well preserved and when coagulopathy is present it is often a manifestation of vitamin K deficiency.

Multiple xanthomas are common sequelae of severe cholestasis (Figure 14.1). The timing for the formation of xanthomas relates to the severity of the cholestasis and correlates with a serum cholesterol level greater than 500 mg/dL. They 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 (Figure 14.1). These xanthomas increase in number over the first few years of life and may disappear subsequently as cholestasis improves.

Figure 14.1 Xanthomas involving the extensor surfaces of the legs and thighs in Alagille syndrome.

The natural history of the liver disease in ALGS has a unique course. For those children with significant cholestasis in infancy, the hepatic involvement generally follows a more severe course in the first five years of life after which it appears to improve for many patients. This spontaneous improvement is poorly understood, but well-documented. Depending on the cohort reported, in approximately 10–20% the cholestasis persists unabated or progresses to portal hypertension and end-stage liver disease. For those children with mild liver involvement there is no progression of liver disease in adulthood. It is difficult to prognosticate which ALGS children with cholestasis in early childhood will eventually require liver transplantation and which will spontaneously improve. There are no known genotypic or radiologic predictors of liver disease progression in ALGS. A recent review of laboratory data of patients with ALGS recently showed that high bilirubin and cholesterol levels before the age of five may aid in distinguishing high from low risk patients. More specifically, TB >6.5 mg/dL (111 μmol/L), CB >4.5 mg/dL (77 μmol/L), and cholesterol >520 mg/dL (13.3 mmol/L) are strongly associated with severe liver disease in later life whereas levels lower than this are associated with a good hepatic outcome [15]. These data may assist the clinician in predicting which children might go on to resolve their cholestasis and thereby avoid unnecessary liver transplantation in young children with ALGS.

Based on older cohorts of heterogeneous ALGS patients, liver transplantation has generally been thought to be necessary in 21–31% of patients [16]. However, recent data from a multi-center cohort of almost 300 ALGS patients, all of whom have or have had cholestasis, suggest that actually only 25% will reach the age of 18 years with their native liver. These data reveal poorer hepatic outcomes in those ALGS children with cholestasis than previously appreciated [89]. The characteristic indications for liver transplantation in ALGS are complications arising from profound cholestasis, namely intractable pruritus, bone fractures, refractory fat-soluble vitamin deficiency and growth failure (the latter being a challenge when growth failure may arise from a combination of an intrinsic genetic effect and liver disease and malnutrition). Some patients also develop portal hypertension and the associated complications. Liver transplantation for ALGS is discussed in further detail under “Management.”

There have been numerous reports of hepatocellular carcinoma (HCC) in patients with ALGS, including as young as three years of age [17, 18]. These have occurred in the presence and absence of cirrhosis. Patients with ALGS actually more commonly develop regenerative nodules which may be solitary and adjacent to the right portal vein [19, 20]. These can typically be distinguished by an experienced radiologist based on ultrasound and magnetic resonance imaging thereby avoiding an invasive biopsy.


Bile duct paucity has been considered the most important and constant feature of ALGS. The normal bile duct–portal space ratio is between 0.9 and 1.8. Bile duct paucity is defined histologically in a full-term or older infant as a ratio of bile duct to portal tract that is less than 0.9 (Figure 14.2). It is important to note that bile ductules should not be included. The interlobular bile duct typically is located more centrally in the portal tract; the bile ductule is located peripherally. An adequate number of true portal tracts must be examined to arrive at an accurate ratio. It has been shown that a reasonably accurate estimation can be made with needle biopsy specimens containing as few as six portal tracts [21]. The bile duct–portal tract ratio in older infants with ALGS is usually less than 0.5–0.75 [22, 23].

Figure 14.2 Liver specimen from an infant with Alagille syndrome with bile duct paucity. The portal tract is shown without any identifiable interlobular bile duct. (Hematoxylin and eosin [H&E] staining, 200× magnification.)

(Courtesy of Pierre A. Russo, M.D.)

Bile duct paucity, however, is not present in infancy in many patients ultimately shown to have ALGS. Furthermore, a systematic study of the histopathology of adults with mild, non-cholestatic ALGS has not been performed. Paucity is present in about 89% of patients reported in large series [2, 1013]. The frequency of paucity in these series varies in large part with the criteria used to define ALGS. Older studies required paucity to consider the diagnosis of ALGS; newer studies focusing on the systemic manifestations or the presence of JAG1 mutations identify paucity in only 80–85% of patients.

Several studies of serial liver biopsies have demonstrated that paucity is more common later in infancy and childhood [2, 21, 24]. Emerick et al. found that paucity was present in 60% of 48 infants younger than six months of age but in 95% of 40 who underwent biopsy after six months [2]. The progression to paucity typically accompanies a worsening of clinical hepatic disease in infancy over a period of months or years. Occasional reports have demonstrated, however, that the progression to paucity is not an absolute feature of ALGS. Hypotheses explaining this progression to paucity include a destruction of ducts postnatally and a differential maturation of portal tracts and their incumbent ducts. The factors that lead to a decrease in the number of ducts are not yet understood (see “Notch Signaling Pathway” and “Bile Duct Development”).

Ductular proliferation is present in a small number of infants with ALGS, leading to significant potential diagnostic confusion (Figure 14.3). This is seen most commonly in association with portal inflammation. As with any infantile cholestatic condition, giant cell hepatitis may be a predominant feature in the infant with ALGS. In part because of the variability in the early histopathology of the liver in ALGS, a number of patients have been misdiagnosed as having biliary atresia (BA) [2, 12, 13]. An interesting characteristic of the hepatic histopathology of ALGS is the uncommon progression to cirrhosis (Figure 14.4). Typically, diseases with duct deficit and obstruction manifested by severe cholestasis progress to end-stage liver disease and cirrhosis. Not only does this not occur in most patients with ALGS, but the biochemical cholestasis and its clinical manifestations most commonly improve with time, despite the lack of reappearance of interlobular ducts.

Figure 14.3 Liver specimen from a one-month-old patient with Alagille syndrome demonstrating marked bile duct proliferation. (H&E staining, 100× magnification.)

(Courtesy of Pierre A. Russo, M.D.)

Figure 14.4 Liver specimen from a 16-year-old with Alagille syndrome. There is established cirrhosis. Portal tracts are expanded and fibrotic. There is a complete absence of interlobular bile ducts. (H&E staining, 100× magnification.)

(Courtesy of Pierre A. Russo, M.D.)

Cardiac Involvement

The early reports of ALGS by Watson and Miller focused on the association of cholestatic liver disease, butterfly vertebrae, and characteristic facies in patients with familial dominant pulmonary arterial stenosis [25]. In a comprehensive evaluation of 200 ALGS subjects, cardiovascular involvement was present in 94% [26], with right-sided lesions being the most prevalent (Table 14.2). Pulmonary artery anomalies are the most common abnormality identified (76%) and may occur in isolation or in combination with structural intracardiac disease [26] (Figure 14.5). Pulmonary artery involvement may result in differential lung perfusion (Figure 14.6). Intracardiac lesions were present in 24% of 92 patients with ALGS [2]. The most common congenital defect is tetralogy of Fallot (TOF), which occurs in 7–12% [2, 26]. It appears that severe forms of TOF (especially TOF with pulmonary atresia) occur with greater frequency in the ALGS population than in the general population of individuals with TOF. Approximately 40% of patients with ALGS demonstrating TOF have pulmonary atresia. There is no correlation between the type or exonic location of the JAG1 mutation and the nature of the cardiovascular involvement.

Table 14.2 Frequent Cardiovascular Anomalies in a Large Alagille Syndrome Cohort*

Primary cardiovascular anomaly % (N = 200)
Cardiovascular anomalies seen on imaging 75
Right-sided anomalies: 55
 • Tetralogy of Fallot  12
 • Valvar pulmonary stenosis  8
 • Branch pulmonary artery stenosis  35
Left-sided anomalies: aortic stenosis, aortic coarctation etc. 7
Other anomalies: 14
 • Ventricular septal defect  5
 • Atrial septal defect  5
 • Other  4
Normal or not imaged 25
Peripheral pulmonary stenosis murmur, without documented anomaly 19
No peripheral pulmonary stenosis murmur, with normal or no imaging 7

* Adapted from McElhinney, 2002.

Figure 14.5 Right pulmonary arteriogram demonstrating multiple stenoses (black arrows) in a patient with prior surgery for tetralogy of Fallot, peripheral pulmonic stenoses, a butterfly vertebrae (white arrow), and a deletion of chromosome 20p12.

Figure 14.6 Lung perfusion scan from a patient with Alagille syndrome demonstrating differential blood flow within the pulmonary tree. The right lung receives more than 86% of pulmonary blood flow secondary to stenosis of the left pulmonary artery.

The exact incidence of severe neonatal cardiac disease is probably underestimated in patients with ALGS due to the reliance on hepatic disease for ascertainment in these series. Family members of ALGS probands with the full phenotype have been described with apparent isolated cardiac disease and the same familial JAG1 mutation [5]. A small number of cases with non-syndromic cardiac disease and JAG1 mutations have been reported. 144 individuals with isolated right-sided cardiac defects were screened for JAG1 mutations and 3% of the cases with TOF and 6% of the cases with PS/PPS had JAG1 mutations [27]. None of these children had identifiable liver disease, thus further expanding the phenotype associated of JAG1-associated ALGS.

In a large ALGS series, cardiac surgery was performed in infancy in 11% [2]. The mortality rates were 33% for those with TOF and 75% for those with TOF with pulmonary atresia. The survival of patients with ALGS with these lesions is markedly lower than for patients (with these lesions) without ALGS. 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 (Figure 15.5). Nonsurgical invasive techniques have been used successfully for patients with ALGS, including valvuloplasty, balloon dilatation, and stent implantation. Heart–lung transplantation has been performed in combination with liver transplantation in a child with ALGS.

Cardiac disease accounts for nearly all of the early deaths in ALGS. Patients with intracardiac disease have approximately a 40% rate of survival to six years of life, compared with a 95% survival rate in patients with ALGS without intracardiac lesions [2].

Vascular Involvement

Vascular anomalies have been noted in ALGS from some of the earliest descriptions of this syndrome. Pulmonary artery involvement is a hallmark feature of the condition and one of the most common manifestations. However, the literature documents multiple case reports of intracranial vessel abnormalities and other systemic vascular anomalies in ALGS. The presence of widespread vascular anomalies in ALGS is consistent with the intrinsic role of the Notch signaling pathway in vascular morphogenesis, angiogenesis, and vessel homeostasis.

Unexplained intracranial bleeding is a recognized complication and cause of mortality in ALGS. Intracranial bleeds occur in approximately 15% of patients, and in 30–50% of these events, the hemorrhage is fatal [2, 12]. There does not seem to be any pattern to the location and/or severity of the intracranial bleeding, which ranges from massive fatal events to asymptomatic cerebral infarcts. Epidural, subdural, subarachnoid, and intraparenchymal bleeding have been reported. The majority of this bleeding has occurred in the absence of significant coagulopathy. Head trauma, typically of a minor degree, has been associated with the bleeding in a number of patients. The majority of cases of bleeding are spontaneous, however, with no clear risk factors. Lykavieris studied a cohort of 174 individuals with ALGS and identified 38 patients (22%) who had 49 bleeding episodes [28]. All these hemorrhages occurred in the absence of liver failure, with normal median platelet counts and prothrombin times, suggesting that ALGS patients may be at particular risk for bleeding.

Underlying vessel abnormalities in the central nervous system that could explain the occurrence of bleeding and stroke in ALGS have been described in some of these patients [3, 12, 29]. Aneurysms of the basilar and middle cerebral arteries and various internal carotid artery anomalies have been described. Moyamoya disease (progressive intracranial arterial occlusive disease) also has been previously described in several children with ALGS (Figure 14.7). The most common complication associated with these anomalies in ALGS is stroke, either ischemic or hemorrhagic. Ischemic stroke is typically associated with moyamoya, while cerebral aneurysms represent the most common causes of hemorrhagic stroke. Emerick et al. prospectively studied 26 patients with ALGS using magnetic resonance imaging (MRI) with angiography of the head. Cerebrovascular abnormalities were detected in ten of 26 patients (38%). One hundred percent of symptomatic patients had detected abnormalities, and 23% of screened, asymptomatic patients had detected anomalies [29]. These results suggest that MRI with angiography is useful in detecting these lesions and may have a valuable role in screening for treatable lesions such as aneurysms (Figure 14.8). Given the relatively high prevalence of silent cerebrovascular disease in ALGS, it is now suggested that all asymptomatic ALGS patients have a screening head MRI/magnetic resonance angiography (MRA) as a baseline, typically around the age of eight years when general anesthesia is not required for imaging. Furthermore, physicians should have a low threshold for re-imaging ALGS patients in the event of any symptoms, head trauma, or suspicious neurologic signs. In addition, neuroimaging is recommended prior to any major surgery such as liver transplantation. There are currently insufficient data to recommend a frequency for repeating imaging in the absence of symptoms or events, however there are clearly reports of patients who go on to develop cerebrovascular anomalies (and events) after a normal MRI/MRA.

Figure 14.7 Moyamoya in Alagille syndrome. Cerebral angiogram demonstrating multiple areas of vascular stenoses.

Figure 14.8 Aneurysm of the external carotid artery in a 17-year-old with Alagille syndrome without central nervous system symptoms found by routine screening.

There are no Alagille-specific recommendations for the treatment of cerebrovascular anomalies, though referral to a neurosurgeon is generally warranted. Recently, Baird et al. reported outcomes of five children with ALGS undergoing revascularization surgery due to symptomatic moyamoya [30]. During long-term follow-up, patients remained clinically and radiologically stroke-free demonstrating that revascularization surgery may be considered for selected patients with ALGS and moyamoya.

Systemic vascular abnormalities have also been well documented in ALGS. Aortic aneurysms and coarctations, renal artery, celiac artery, superior mesenteric artery, and subclavian artery anomalies have all been described. Abdominal vascular anomalies rarely cause clinical symptoms in ALGS but may complicate liver transplant surgery. Kohaut et al. retrospectively evaluated abdominal vascular abnormalities in children with ALGS undergoing liver transplantation [31]. In this series, stenosis of the celiac trunk was the most common vascular anomaly identified 48.0% (12/25) and resulted in almost two-thirds of patients requiring aortic conduit reconstruction during the transplant surgery.

Kamath et al. evaluated a large cohort of ALGS patients and identified 9% (25 of 268) with non-cardiac vascular anomalies or events [3]. In addition, vascular accidents accounted for 34% of the mortality in this cohort. These findings suggest that vascular abnormalities have been under-recognized as a potentially devastating complication of ALGS.

Skeletal Involvement

Vertebral abnormalities are described in the initial reports of this syndrome. The most characteristic finding is the sagittal cleft or butterfly vertebrae, which is found in 33–87% of patients with ALGS [2, 1113] (Figures 14.9 and 14.10). This relatively uncommon anomaly may occur in normal individuals and is also seen in other multisystem abnormalities, such as 22q deletion syndrome and VATER (vertebral defects, anal atresia, tracheoesophageal fistula, radial and renal defect) syndrome. The affected vertebral bodies are split sagittally into paired hemivertebrae because of a failure of the fusion of the anterior arches of the vertebrae. The mildly affected vertebrae have a central lucency. A fully affected vertebra has a pair of separate triangular hemivertebrae whose apices face each other like the wings of a butterfly. Generally, these anomalies are asymptomatic and of no clinical significance. Other associated skeletal abnormalities include an abnormal narrowing of the adjusted interpedicular space in the lumbar spine, a pointed anterior process of C1, spina bifida occulta, fusion of the adjacent vertebrae, hemivertebrae, the absence of the twelfth rib, and the presence of a bony connection between ribs. In addition, supernumerary digital flexion creases have been described in one-third of patients [32].

Figure 14.9 Butterfly vertebrae at T5 and T6, with vertebral anomalies at T4, T7, T8, and T9, in an infant with Alagille syndrome.

Figure 14.10 Vertebral anomalies in Alagille syndrome. (a) Computed tomographic (CT) scan of a butterfly vertebral body. (b) CT scan image of a vertebral body with a posterior sagittal cleft. (c) CT scan image of a vertebral body with marked cortical irregularity. (d) CT scan image of a nearly normal vertebral body.

Severe metabolic bone disease with osteoporosis and pathologic fractures is common in patients with ALGS. Recurrent fractures, particularly of the femur, have been cited as an indication for hepatic transplantation. Preliminary survey data suggests that there is a propensity toward pathologic lower extremity long bone fractures in ALGS [33]. A number of factors may contribute to osteopenia and fractures, including severe chronic malnutrition, vitamin D and vitamin K deficiency, chronic hepatic and renal disease. It is not yet known whether there is an intrinsic defect in cortical or trabecular structure of the bones in patients with ALGS. Olsen evaluated bone status in prepubertal children with ALGS and identified significant deficits in bone size and bone mass that were related to fat absorption but not dietary intake [34]. Recently, in a study from the Childhood Liver Disease Research Network (ChiLDReN) 49 ALGS patients and 99 children with other inherited chronic liver diseases underwent dual-energy X-ray absorptiometry (DXA) scans [35]. In ALGS, DXA measures were found to be low, but improved after adjustment for weight and height. Of note, DXA Z-scores in the ALGS population correlated negatively with measures of cholestasis including TB and serum bile acid levels. These data support multifactorial influences on bone density in ALGS, with possible contribution of impaired Notch signaling.

Alagille syndrome patients are frequently found to have short stature, and this is likely multifactorial in origin, resulting from cholestasis and malabsorption, congenital heart disease and genetic predisposition. A validated growth curve for ALGS individuals is not yet available.

Facial Features

A characteristic facial appearance is described in the original reports of ALGS and is probably one of the most penetrant features of the syndrome (for JAG1-associated disease). These features include a prominent forehead, deep-set eyes with moderate hypertelorism, a pointed chin, and a saddle or straight nose with a bulbous tip. The combination of these features gives the face a triangular appearance (Figure 14.11). The facies may be present early in infancy but in general becomes more dramatic with increasing age. In one study photographs of patients with ALGS and patients with other known early-onset liver diseases were presented to dysmorphologists, who were able to correctly identify patients with JAG1 mutations 79% of the time [36]. The facies in adults were the least well identified in this study. They also reported that the facies change with age (Figure 14.12). In adults, the forehead is much less prominent and the protruding chin is more noticeable. The correct identification of these adults, who commonly have minimal signs and symptoms of ALGS, would help physicians in the evaluation of adults with apparently idiopathic cardiac, hepatic, or renal disease. It should be noted that amongst the few patients reported to date, there appears to be a lower penetrance of characteristic facial features in ALGS patients with NOTCH2 mutations and it is therefore a less valuable diagnostic tool in this group [37].

Figure 14.11 Characteristic facies of children with Alagille syndrome.

(Courtesy of Ian D. Krantz, M.D.)

Figure 14.12 Characteristic facies of adults with Alagille syndrome.

(Courtesy of Ian D. Krantz, M.D.)

Ocular Involvement

The ocular abnormalities of patients with ALGS do not generally affect vision but are important as diagnostic tools. A large and varied number of ocular abnormalities have been described, though posterior embryotoxon is the most important diagnostically. Posterior embryotoxon is a prominent, centrally positioned Schwalbe ring (or line) at the point at which the corneal endothelium and the uveal trabecular meshwork join (Figure 14.13). Posterior embryotoxon occurs in 56–88% of patients with ALGS (Table 14.1) and was also detected in 22% of children evaluated in a general ophthalmology clinic [38]. Posterior embryotoxon is seen in other multisystem disorders as well, such as chromosome 22q deletion. The Axenfeld anomaly, seen in 13% of patients with ALGS, is a prominent Schwalbe ring with attached iris strands and is associated with glaucoma. In addition, Rieger anomaly, microcornea, keratoconus, congenital macular dystrophy, shallow anterior chambers, exotropia, ectopic pupil, band keratopathy, cataracts, strabismus, iris hypoplasia, choroidal folds, and anomalous optic disks have been reported in ALGS.

Figure 14.13 Posterior embryotoxon and prominent Schwalbe line (arrows).

For color reproduction, see Color Plate 14.13.

In a large series of patients with ALGS studied systematically, Hingorani et al. identified posterior embryotoxon in 95% of 22 patients, iris abnormalities in 45%, diffuse fundic hypopigmentation in 57%, speckling of the retinal pigment epithelium in 33%, and optic disk abnormalities in 76% [39]. The frequency of these findings, higher than in other reported series, suggests that a formal ophthalmologic slit-lamp examination can provide one of the most crucial clues to the diagnosis of ALGS in infancy.

Nischal et al. found ultrasound evidence of optic disk drusen using ocular ultrasonography in at least one eye in 95% and bilateral disk drusen in 80% of patients with ALGS but in none of the liver patients without ALGS whom they studied [40]. This was substantiated in a recent study in which 91% of ALGS patients had optic nerve drusen [41]. This is markedly higher than the incidence in the normal population (0.3–2%), suggesting that this newer ophthalmologic sign may be an extremely useful diagnostic tool.

Renal Involvement

Renal involvement in ALGS has been widely reported on an individual case basis or as part of a larger report on general features of ALGS and is explicable by the role of the Notch signaling in kidney development [42] (Figure 14.14). The prevalence of renal involvement in larger series ranges from 40% to 70% such that it has been proposed that renal anomalies now be considered a disease-defining criterion in ALGS (Table 14.1). In a large retrospective study, there was a prevalence of 39% of renal anomalies or disease and the most common renal involvement was renal dysplasia (58.9%) (as defined by echogenicity on ultrasound), with renal tubular acidosis (9.5%), vesico-ureteric reflux (8.2%) and urinary obstruction (8.2%) following [43]. End-stage renal disease requiring renal replacement therapy or transplantation is relatively uncommon in ALGS but has been reported. Hypertension in patients with ALGS could be of cardiac, vascular or renal etiology.

Figure 14.14 Diffuse renal cystic dysplasia in a patient with paucity of bile ducts.

(Courtesy of Pierre A. Russo, M.D.)

Functional and structural evaluation of the kidneys should be undertaken in all patients, especially during evaluation for hepatic transplantation. Kamath et al. reviewed outcomes after liver transplantation for ALGS patients captured in the Studies in Pediatric Liver Transplantation (SPLIT) database [44]. In this study 91 ALGS patients were compared to 236 patients transplanted for BA. At the time of transplantation, 18% of the ALGS patients had estimated glomerular filtration rate (GFR) of <90 ml/min/1.73 m2 compared to only 5% of the BA patients. Additionally, at the time of transplantation, ALGS patients had higher serum creatinine than BA transplant recipients. Of note, after transplantation, 22% of ALGS liver transplant recipients versus 8% of the BA patients had developed renal insufficiency by estimated GFR after two years. Furthermore, pre-transplant renal insufficiency did not resolve post-transplantation in ALGS as it did in BA patients, suggesting that the renal dysfunction in ALGS at the time of liver transplantation was not attributable to hepatorenal syndrome or other reversible causes of renal dysfunction. Given the clear risk of renal compromise in ALGS liver transplant recipients, careful monitoring and adoption of a renal-sparing immunosuppressive protocol should be strongly considered.


Severe growth retardation is seen in 50–87% of patients [2, 10, 12, 13]. Malnutrition resulting from malabsorption is a major factor in this failure to thrive, and chronic wasting as documented by height, weight, and anthropometry is severe in patients with ALGS [45, 46]. Rovner et al. assessed growth failure in 26 prepubertal children with ALGS and found that more than half the children were less than fifth percentile for weight and height and 20% had a diet poor in calories, fat, and other nutrients [46]. There appear to be limitations to linear growth even if protein-calorie malnutrition is not evident. Patients with growth failure appear to be insensitive to exogenous growth hormone [47]. Many adults appear to have short stature, although a systematic study of adult height in ALGS has not been completed.

Diarrhea in a patient with ALGS may be due to cholestasis and/or pancreatic insufficiency. Virtually all ALGS patients had steatorrhea in a prior series [46]. Early data suggested that pancreatic insufficiency was an important problem in ALGS, however more recent data utilizing fecal elastase as a sensitive and specific measure of pancreatic exocrine insufficiency indicate that this is not true [48, 49]. Routine surveillance of pancreatic function in ALGS is not necessary.

Neurodevelopment and Quality of Life

Assessment of neurocognitive outcomes and health-related quality of life (HRQOL) is particularly complicated in ALGS due to the variable expression of disease in organ systems that can affect these outcomes, especially liver, cardiac and cerebrovascular involvement.

Intellectual impairment was reported in the earliest description of ALGS in which 30% of the children had an IQ of 60–80 [22]. Alagille et al. went on to review 80 cases and found that 16% had an IQ of less than 80, in the range that all of these children would qualify for special academic services [10] – it should be emphasized that both of these studies are now more than 30 years old. It is certainly possible that these reports include children that did not receive adequate nutritional support in the earlier years, contributing to these findings. In the comprehensive study by Emerick et al., 16% (15 out of 92) of ALGS subjects studied had delayed gross motor skills and 2% had an intellectual disability [2]. There was an increased prevalence of mental health illness particularly depression and ADHD which may negatively affect neurocognitive functioning. A questionnaire-based study noted that 49% of children with ALGS were in or had received special education, suggestive of a high prevalence of developmental delay or learning disabilities [50]. Most recently, in a large prospective observational cohort (n = 207, 32% with ALGS), Leung et al. reported ALGS patients, compared to alpha-1-antitrypsin deficiency (A1ATD) have a significantly lower mean IQ (94 vs. 101, p = 0.011). Their IQ distribution (≥100, 85–99, <85) was significantly lower than normal (p = 0.0008) while A1ATD and other cholestatic diseases were not. ALGS diagnosis, severe pruritus, xanthomas, low weight and height z scores were significant predictors of below average (<85) IQ, while cardiac disease was not [51].

There have been two large studies of HRQOL in pediatric ALGS patients in the last ten years. Elisofon et al. studied 71 ALGS patients aged 5 to 18 years with the Child Health Questionnaire Parent Form 50 (CHQ-PF50) and compared them to normal children and those other chronic disease states [52]. Children with ALGS had a lower HRQOL in comparison with a normal pediatric population across all subscales of the CHQ except family cohesion. When compared to children with arthritis, ALGS patients had similar physical function, and lower emotional/behavioral, mental health and self-esteem subscale scores. This suggests they may have a greater psychosocial burden related to their specific disease.

Kamath et al. have reported similar findings in the largest cohort of Alagille patients studied to date using the PedsQLTM Generic Core scale. Ninety-eight children were assessed, 70 of whom completed their own HRQOL scores and were compared to healthy children, children with A1ATD and other chronic cholestatic liver diseases. ALGS patients had lower PedsQLTM 4.0 scores by self and parent report vs. matched healthy controls and A1ATD patients [53]. The greatest decrement was seen in the physical domain scores. When compared to only those with A1ATD, children with ALGS reported worse HRQOL than their A1ATD counterparts, with the largest differences again seen in the physical domain. Compared to children with other cholestatic liver disease, HRQOL for subjects with ALGS was modestly impaired by child self-report.

In both these reports, patients with ALGS had worse HRQOL scores when compared with other chronic disease groups. The associations and determinants of impaired HRQOL in ALGS are difficult to unravel. In multivariate analysis, the only factor in ALGS patients associated with HRQOL was weight z-score. Weight and height z-scores were positively associated with self-reported HRQOL summary scores, but another study reported no significant associations between HRQOL scores and poor growth [52, 53].

The association between pruritus and HRQOL is mixed. The two large studies of Alagille patients described above did not find significant associations between HRQOL and itch despite parents reporting that itch was a major concern. This may be due to the difficulty of quantifying itch as many scales rely on physical signs of itch such as abrasions or mutilation [52, 53]. Sleep problems affecting the psychosocial and physical domains on the CHQ-PF50 were reported in 30% of patients, much higher than the expected 2% of the normal population. Additional data and measurement modalities are needed to study itching and sleep health simultaneously in these patients to provide physicians and caregivers insights that will lead to more effective treatment approaches.

Survival Outcomes

Cardiac, hepatic, and vascular disease account for the majority of deaths in ALGS, though the true frequency of death is variable, reflecting the heterogeneity of the disorder. The presence of complex intracardiac disease at diagnosis is the only predictor of an excessive early mortality rate, and cardiac disease accounts for the majority of deaths in early childhood. Overall, vascular events or defects account for most of the mortality in ALGS; 34% in a large series [3]. Quiros-Tejeira reported a 72% survival rate in 43 patients at a mean follow-up of 8.9 years in a population in which 47% received hepatic transplantation [13]. Hoffenberg estimated the rate of survival to age 19 without transplantation to be approximately 50% in 26 patients who presented with cholestasis, but with transplantation (which in this series had a 100% survival rate), the 20-year survival rate was estimated at 87% [12]. Emerick estimated the 20-year survival rate in 92 patients to be 75% overall, 80% for those not requiring hepatic transplantation and 60% for those requiring transplantation [2]. For patients with structural intracardiac disease, however, the survival rate was only 40% at seven years.

Diagnostic Considerations

The majority of infants with ALGS are evaluated for conjugated hyperbilirubinemia in the first weeks or months of life. The differential diagnosis and general evaluation for conjugated hyperbilirubinemia are discussed in Chapter 8. ALGS is occasionally misdiagnosed as BA because of the overlap of biochemical, scintigraphic, histologic and cholangiographic features. Serum bilirubin, bile acid, and γGT levels typically are elevated in both of these disorders. Ultrasound should identify choledochal cysts and cholelithiasis accurately, but both patients with biliary atresia and those with ALGS may have small or apparently absent gallbladders. Excretion of nuclear tracer (DISIDA) into the duodenum eliminates BA from consideration, but non-excretion of tracer is also possible in ALGS. There was no excretion of scintiscan in 61% of 36 infants with ALGS [2]. Excretion was evident only after 24-hour follow-up in another 25% of these 36 patients.

If BA remains a diagnostic possibility after the initial non-invasive evaluation, a liver biopsy should follow, particularly if the studies suggest non-communication from the liver to the duodenum. Although a liver biopsy is not mandatory to diagnose ALGS, it remains an important step in differentiating between ALGS and BA. In BA, bile duct proliferation is the typical histologic lesion. In ALGS, paucity is evident in 60% of infants younger than six months but in 95% of older patients [2]. Unfortunately, there may be a normal number of ducts early in the course of BA and also in some patients with ALGS, and bile duct proliferation occasionally occurs in infants with ALGS. In very young infants in whom the percutaneous liver biopsy is not diagnostic, it may be helpful to delay exploration for one or two weeks and repeat the biopsy (recognizing that the success of therapy for BA is correlated with surgery before 60 days of age). Giant cell hepatitis is also seen in both disorders. Finally, it should be noted that bile duct paucity, if present, is not diagnostic of ALGS and other diagnoses should be considered (Table 14.3).

Feb 26, 2021 | Posted by in GASTROENTEROLOGY | Comments Off on Chapter 14 – Alagille Syndrome

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