Alagille syndrome

INTRODUCTION — Alagille syndrome is a genetic disorder that primarily causes cholestatic liver disease but is also associated with defects in multiple other organ systems. The clinical manifestations and severity vary widely even among individuals within the same family.

The clinical manifestations, diagnosis, and management of Alagille syndrome are discussed below. Related content is available in other topic reviews:

●(See "Approach to evaluation of cholestasis in neonates and young infants".)

●(See "Causes of cholestasis in neonates and young infants".)

●(See "Inherited disorders associated with conjugated hyperbilirubinemia".)

EPIDEMIOLOGY — Reported incidence rates of Alagille syndrome are between 1:70,000 and 1:100,000 live births. With increased case detection due to molecular diagnosis, the true incidence is probably closer to 1 in 30,000 [1].

GENETICS AND PATHOGENESIS — Alagille syndrome (MIM #118450) is inherited in an autosomal dominant fashion. Pathogenic variants in the JAG1 gene on chromosome 20p12 are responsible for Alagille syndrome in almost 95 percent of patients. A small percentage (approximately 2.5 percent) have pathogenic variants in the NOTCH2 gene. These genes encode a ligand and receptor, respectively, in the Notch signaling pathway, which is involved in development and function of multiple organs [2].

More than 600 pathogenic JAG1 variants and 20 NOTCH2 variants have been reported for Alagille syndrome [3]. The JAG1 variants tend to be protein-truncating variants, and a disease pathomechanism of haploinsufficiency has been proposed [4-6]. The NOTCH2 variants tend to be predominantly missense, and the mechanism for pathogenicity has not been confirmed [7,8]. The clinical features and severity vary widely even among individuals within the same family or with the same identified variant [2]. This suggests a role for variants in other gene(s) that modify the effects of the JAG1 pathogenic variants, and several candidate genetic modifiers have been proposed [9-12].

In approximately 3.4 percent of individuals with a confident clinical diagnosis of Alagille syndrome, standard genetic testing detects no pathogenic variants of JAG1 or NOTCH2. Utilization of genome sequencing reduces the percentage of individuals without a molecular diagnosis to 2.5 percent [13].

CLINICAL FEATURES — Alagille syndrome affects multiple organ systems and has a wide range of clinical severity, ranging from life-threatening liver or cardiac disease to only subclinical manifestations. Individuals with severe liver or cardiac manifestations typically present in infancy. Those who present after the neonatal period tend to have a milder course and may not be diagnosed until later in childhood or even adulthood [14].

The clinical features of Alagille syndrome are summarized in the table (table 1) and described below [14-18].

Cholestatic liver disease — Cholestatic liver disease is one of the most common features of Alagille syndrome [18]. It typically presents in the neonatal period with direct hyperbilirubinemia and has variable severity and clinical course. In some infants, the liver disease improves during early childhood and is unlikely to recur later in life. In others, the liver disease progressively worsens during early childhood [14,16]. Although the clinical course is difficult to predict, more severe cholestasis (total bilirubin >6.5 mg/dL, conjugated bilirubin >4.5 mg/dL, and cholesterol >520 mg/dL) in a young child is associated with sustained and more severe liver disease [19]. In infants 6 to 12 months old, median total bilirubin levels are correlated with the risk of developing clinically evident portal hypertension [20]. The frequency of hepatic disease is high in case series in which Alagille syndrome is identified by symptoms and much lower when cases are identified by genetic screening of family members [1].

Important clinical consequences of severe cholestatic liver disease include pruritus (which is often debilitating), xanthomas, fat-soluble vitamin deficiency, malnutrition and growth failure, and cirrhosis with portal hypertension. (See 'Medical management' below.)

The most consistently reported histologic feature of Alagille syndrome is bile duct paucity (defined as having a bile duct-to-portal tract ratio <0.5, compared with normal ratio ranges from 0.9 to 1.8), but this feature may not be detectable prior to six months of age [16,21]. Other histologic features including ductular proliferation and giant cell hepatitis can be present in infancy, and liver biopsies with these features may be difficult to distinguish from biliary atresia.

Congenital heart disease — Congenital heart disease is common in Alagille syndrome. The most common finding is stenosis/hypoplasia of the branch pulmonary arteries; other anomalies include tetralogy of Fallot, patent ductus arteriosus, septal defects, or coarctation of the aorta [22].

Vascular anomalies — Vascular anomalies are common in Alagille syndrome and can lead to significant morbidity and mortality [23]. Up to one-quarter of individuals with Alagille syndrome have intracranial bleeds, and the vast majority have no other risk factors [24]. Both arterial and venous anomalies have been reported [25].

Other features

●Kidney disease – Renal abnormalities are present in some individuals with Alagille syndrome and may include renal dysplasia (most common), glomerular mesangiolipidosis, or renal tubular acidosis [26].

●Skeletal anomalies – Butterfly vertebrae are the most common skeletal abnormalities in Alagille syndrome. This finding has no structural significance, and patients are asymptomatic [27]. Various other skeletal abnormalities can occur, including temporal bone abnormalities and middle ear bone defects, which can lead to chronic otitis media and hearing loss [28]. There is also an increased risk of long bone fragility fracture due to the nutritional consequences of cholestasis as well as the skeletal effects of the intrinsic genetic and hormonal disturbances in people with Alagille syndrome [29]. Unilateral coronal craniosynostosis has also been reported in patients with Alagille syndrome and pathogenic variants in JAG1 [30,31].

●Facies – Dysmorphic facies noted in many infants consist of a broad nasal bridge, triangular facies (broad forehead and pointed chin), and deep-set eyes (picture 1). These features change over time to a prominent lower face and mandible and less prominent upper face and forehead [32]. This is the clinical feature with the highest penetrance, with almost universal occurrence in JAG1 mutation-positive probands and relatives [1].

●Ophthalmologic abnormalities – Posterior embryotoxon (a prominent Schwalbe ring) is the most common ocular feature in Alagille syndrome, although it is also common in the general population. Optic disc drusen may be more specific for diagnosis [33]. Other findings may include hypopigmentation of the peripheral retina, pseudopapilledema, and true papilledema (associated with intracranial hypertension) [34].

●Growth failure – Growth failure is common in Alagille syndrome. More than one-half of patients have height and/or weight below the 5^th percentile for their age [2,35]. The growth failure is likely multifactorial; it may be related to malabsorption (due to cholestasis), the underlying genetic defects, or, possibly, to growth hormone insensitivity [36,37].

●Cognition and psychosocial function – Almost one-half of children with cholestatic Alagille syndrome have neurocognitive deficits and the need for special education. In a multicenter study, children with Alagille syndrome had slightly lower full-scale intelligence quotient scores compared with those with progressive familial intrahepatic cholestasis or alpha-1 antitrypsin deficiency [38]. Furthermore, some individuals experience impaired quality of life and mental health issues related to intractable pruritus and xanthomas [39,40].

EVALUATION — Most patients with Alagille syndrome present with cholestatic jaundice during early infancy [14]. A minority present later in infancy or childhood with signs of cholestatic liver disease (jaundice, pruritus) or are identified by genetic screening because a sibling or parent has known Alagille syndrome. The focus and extent of the evaluation depends on the clinical presentation:

Cholestatic infants: Exclude biliary atresia — For cholestatic infants, the first priority is to evaluate for biliary atresia. Biliary atresia is the most common cause of cholestatic liver disease in young infants, and outcomes depend on prompt diagnosis and treatment. Diagnosis and management of biliary atresia are discussed separately. (See "Biliary atresia".)

If biliary atresia is excluded, the infant should be evaluated for Alagille syndrome and other causes of neonatal cholestasis. (See "Approach to evaluation of cholestasis in neonates and young infants" and "Causes of cholestasis in neonates and young infants".)

Family members of a proband: Start with genetic testing — For asymptomatic first-degree relatives of a proband with Alagille syndrome (parents or siblings), an efficient approach is to start with genetic testing. If genetic testing reveals a pathogenic variant in JAG1 or NOTCH2, then the patient should have a full evaluation for associated anomalies, as outlined below. (See 'Genetic testing' below.)

All ages: Evaluate for associated anomalies — Patients with suspected or confirmed Alagille syndrome should be evaluated for the presence and severity of associated anomalies:

●Laboratory testing

•General – Complete blood count, electrolytes, blood urea nitrogen, creatinine.

•Liver function and cholestasis – Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase, coagulation studies, total and direct bilirubin, serum cholesterol, triglycerides, serum bile acids.

•Genetic testing – Usually performed during the initial evaluation, although results may not be immediately available. (See 'Genetic testing' below.)

●Imaging

•Liver ultrasound

•Renal ultrasound

•Spine radiograph (anteroposterior)

●Specialty evaluation

•Hepatology evaluation – This may include liver biopsy, depending on the clinical scenario. For example, in a cholestatic infant, a liver biopsy may be required to make a timely diagnosis of biliary atresia, rather than waiting for results of genetic tests for Alagille syndrome. (See "Approach to evaluation of cholestasis in neonates and young infants".)

•Cardiology evaluation – Including echocardiogram. (See "Diagnosis and initial management of cyanotic heart disease in the newborn".)

•Ophthalmologic evaluation – Specifically for posterior embryotoxon, optic Drusen, and papilledema.

•Nutritional assessment – Including evaluation for fat-soluble vitamin deficiencies in those with cholestatic liver disease.

DIAGNOSIS — Alagille syndrome is suspected in individuals who present with suggestive features (especially otherwise unexplained cholestatic liver disease) (table 1) or those with a first-degree relative with Alagille syndrome. The diagnosis should be confirmed by genetic testing whenever possible. Occasionally, the diagnosis is made based on clinical criteria alone.

Genetic testing — The diagnosis of Alagille syndrome is confirmed by genetic testing, usually with next-generation sequencing (NGS) panels for cholestatic liver disease. The vast majority of individuals with Alagille syndrome have a heterozygous autosomal dominant pathogenic variant in JAG1 or NOTCH2 (see 'Genetics and pathogenesis' above). Genomic diagnostics typically include sequencing and deletion/duplication testing of JAG1 and NOTCH2. The interpretation and characterization of variants of uncertain significance in JAG1 and NOTCH2 can be challenging, especially with the widespread use of NGS panels. Information about genetic testing and a clinical review are available at the Genetic Testing Registry website.

Occasionally, genetic testing confirms a diagnosis of Alagille syndrome despite few or no clinical manifestations of the syndrome; this is more common in individuals with NOTCH2 variants but can also occur in those with JAG1-related disease [1,8,41].

Clinical criteria — Before the advent of genetic testing, Alagille syndrome was diagnosed clinically, based on the presence of intrahepatic bile duct paucity and at least three other clinical features: chronic cholestasis, cardiac disease, ocular abnormalities, skeletal abnormalities, and/or characteristic facial features. Although not included in the classical clinical criteria, renal and vascular disease are common features. (See 'Clinical features' above.)

Alagille syndrome may be diagnosed based on the above clinical criteria if genetic testing is not available or if genetic testing is negative but the patient has strong clinical features of Alagille syndrome (approximately 2.5 percent of cases). (See 'Genetics and pathogenesis' above.)

Differential diagnosis

●Cholestatic liver disease – Biliary atresia is the most common cause of cholestatic liver disease in infants. The clinical features of biliary atresia and Alagille syndrome can be similar, so a high index of suspicion is required to distinguish between these disorders. Infants with biliary atresia classically have absent excretion on hepatobiliary scintigraphy, proliferation of intrahepatic bile ducts on liver biopsy, and cholangiogram that fails to show the intrahepatic tree, but these findings can also be seen in infants with Alagille syndrome. Therefore, it is critical to evaluate all infants with cholestatic liver disease carefully for any syndromic features or a family history of Alagille syndrome and to perform genetic testing if there is any question of Alagille syndrome.

The evaluation of an infant presenting with cholestatic liver disease is discussed separately. (See "Approach to evaluation of cholestasis in neonates and young infants".)

●Bile duct paucity – The histologic finding of paucity of interlobular bile ducts found in Alagille syndrome also may be observed in several other cholestatic disorders, including alpha-1 antitrypsin deficiency, cystic fibrosis, infection (eg, cytomegalovirus, syphilis), mitochondrial disorders, progressive familial intrahepatic cholestasis types 1 and 2, or arthrogryposis-renal dysfunction-cholestasis syndrome [42]. (See "Causes of cholestasis in neonates and young infants", section on 'Infectious causes' and "Causes of cholestasis in neonates and young infants", section on 'Genetic/metabolic disorders'.)

Occasionally, paucity of the interlobular bile ducts is observed without features of Alagille syndrome or the above disorders, in which case, the disorder is termed "nonsyndromic" paucity of the interlobular bile ducts [43].

MEDICAL MANAGEMENT — Medical management of patients with Alagille syndrome requires a multidisciplinary approach, tailored to the patient's disease manifestations and severity [44].

Pruritus — Pruritus is a common complication of chronic cholestasis, occurring in 80 percent of patients with Alagille syndrome in one series [17,45]. Pruritus can be severe, has adverse effects on quality of life, and can lead to excoriations. Initial measures to help minimize itching and excoriations include skin emollients, cutting nails short, and avoiding bathing in hot water.

Medical therapy is required for individuals with problematic pruritus despite the initial measures; available drugs are summarized in the table (table 2). Combinations of these medications are often required and should be added in a stepwise fashion, based on the individual patient's level of symptoms, response, and adverse effects. Our stepwise approach is outlined below:

●Ursodeoxycholic acid (UDCA) – We start most patients on UDCA for supportive treatment of chronic cholestasis, and this drug may also be beneficial for cholestatic pruritus. UCDA is a choleretic that stimulates bile flow and is commonly used as a treatment for cholestasis. A small clinical trial suggests that UCDA improves pruritus in approximately one-half of individuals with Alagille syndrome but probably does not alter progression of liver disease [46]. These findings are consistent with our own experience.

●Antihistamines – If pruritus is refractory to optimized dosing of UDCA and interferes with sleep, a bedtime dose of an antihistamine (eg, diphenhydramine or hydroxyzine) can be started and gradually increased to three to four times per day as needed; however, daytime drowsiness may limit the use of these drugs.

●Rifampin – If the pruritus remains problematic, we typically add rifampin as an adjunct to UDCA (+/- antihistamines). The mechanism for the effect on pruritus may involve modulation of pruritogen-modulating factors that are targeted by the pregnane X receptor (present in both hepatocytes and enterocytes). In a small, open-label trial, rifampin was found to be safe and effective therapy to reduce pruritus in 90 percent of children with chronic cholestasis and severe pruritus unresponsive to other treatments (UDCA, antihistamines) [47].

●Ileal bile acid transport (IBAT) inhibitors

•Maralixibat – Maralixibat is an IBAT inhibitor that acts on the apical sodium-dependent bile acid transporter. It is a first- or second-line agent for the treatment of cholestatic pruritus in patients with Alagille syndrome and is approved by the US Food and Drug Administration (FDA) for individuals ≥3 months of age [48]. Most clinicians will have likely tried UDCA, antihistamines, and/or rifampin prior to escalating to maralixibat due to high cost. Selection of medications may change as data on long-term outcomes accumulate.

The starting dose of maralixibat is 190 micrograms/kg daily for seven days, and the dose is then increased to 380 micrograms/kg daily (maximum dose 28.5 mg daily) [48]. Maralixibat may be used in combination with UDCA for patients with severe pruritus. It generally should not be used in combination with bile acid sequestrants (which bind maralixibat in the intestinal lumen, thereby inhibiting its activity). If bile acid resins are used, there should be a four-hour gap between their administration and that of maralixibat.

Because maralixibat inhibits bile acid absorption, it may cause diarrhea due to the effect of the unabsorbed bile salts on colonic epithelium. Additionally, bile salt depletion can cause malabsorption of fat and fat-soluble vitamins (vitamins A, D, E, and K), which may need supplementation. Although maralixibat is poorly absorbed, in some cases, it may exacerbate abnormalities of liver function tests. Therefore, serum bilirubin, alanine and aspartate aminotransferases (ALT and AST), alkaline phosphatase, gamma-glutamyl transferase, and prothrombin time (international normalized ratio) should be monitored at baseline and during the course of therapy.

In a combined analysis of two randomized trials and their extensions in 57 children with Alagille syndrome and severe cholestasis, maralixibat improved pruritus and quality of life and one-third of participants had complete resolution of pruritus [49]. At week 48, decreases in serum bile acids, cholesterol, and platelet count were noted, while serum ALT increased; nine participants discontinued study drug due to ALT rise or other treatment-emergent events.

Long-term outcomes of treatment with maralixibat are beginning to emerge. In one study, long-term treatment with maralixibat (84 patients treated for up to six years) was associated with better six-year event-free survival (EFS) compared with 469 untreated patients in a disease registry (71 versus 50 percent; adjusted hazard ratio 0.305, 95% CI 0.189-0.491) [50]. EFS was defined as lack of variceal bleeding, ascites requiring therapy, surgical biliary diversion, liver transplantation, or death. A separate study on the same cohort (76 individuals, mean treatment duration 4.7 years), found that predictors of EFS and transplant-free survival included >1 point improvement in pruritus score, serum bilirubin <6.5 mg/dL, and bile acids <200 micromol/L at week 48, as well as baseline bilirubin [51]. Sixteen participants (21 percent) in this cohort progressed to liver transplant, decompensation, death, or surgical biliary diversion (10, 3, 2, and 1 participants, respectively). These findings suggest that patients who display clinical improvements in these parameters within the first year of maralixibat therapy are more likely to have long-term benefits in EFS and transplant-free survival.

•Odevixibat – Odevixibat is another IBAT inhibitor. In a phase 2, open-label study in children with Alagille syndrome and other cholestatic disorders, odevixibat (10 to 200 micrograms/kg daily for four weeks) appeared to reduce serum bile acids and pruritus [52]. In a 24-week trial in children with pruritus and nonsevere cholestatic liver disease due to Alagille syndrome, odevixibat significantly reduced a scratching score (NCT04674761) [53]. This trial was the basis for the FDA's approval of odevixibat for the treatment of cholestatic pruritus in patients ≥12 months of age with Alagille syndrome. Long-term follow-up studies of odevixibat are ongoing (NCT05035030). Previous experience with odevixibat was for treatment of cholestasis in people with progressive familial intrahepatic cholestasis. (See "Inherited disorders associated with conjugated hyperbilirubinemia", section on 'Progressive familial intrahepatic cholestasis'.)

●Naltrexone – Naltrexone, an opioid-antagonist, was also commonly trialed for refractory cholestatic pruritus prior to the availability of maralixibat and odevixibat. It is somewhat effective for pruritus in cholestatic liver disease, as suggested by several case series and one small randomized trial [54-57]. In our experience, naltrexone is effective in a dose-dependent manner for a subset of patients, using the doses outlined in the table (table 2).

●Other

•Sertraline – Sertraline, a serotonin reuptake inhibitor, was commonly trialed for refractory cholestatic pruritus prior to the availability of maralixibat. Sertraline was evaluated as adjunctive treatment in a prospective observational study in 20 children with refractory cholestatic pruritus, including 13 children with Alagille syndrome [58]. All participants were on maximal doses of UCDA and rifampin at the start of the study and continued these medications during the study. After three months of therapy, pruritus, median itch score, skin scratch marks, and sleep quality improved with a tolerable side effect profile.

•Atorvastatin – Atorvastatin is a lipid-lowering agent that is sometimes used for treatment of xanthomas in Alagille syndrome but rarely for pruritus. Pediatric data are limited to anecdotal reports. (See 'Xanthomas' below.)

•Bile acid sequestrants (eg, cholestyramine, colesevelam) – Bile acid sequestrants are now infrequently used for cholestatic pruritus due to their drug interactions, adverse effects, and tedious administration schedule. Colesevelam (Welchol) is available in pill form that may be more palatable than cholestyramine or other bile acid resins [59].

In historical series (prior to the availability of maralixibat), pruritus was refractory to medical treatment in approximately 40 percent of affected patients. In these cases, surgical biliary diversion or liver transplantation may be indicated [17,45,60]. (See 'Surgery' below.)

Xanthomas — These lesions can form on areas with high friction when cholesterol levels are >500 mg/dL and can be disfiguring. No specific treatment is required, as they typically resolve as cholestasis improves. However, anecdotal reports describe the use of statins in patients with severe, debilitating xanthomas with beneficial effects [44].

Fat-soluble vitamin deficiency — Individuals with cholestasis (eg, direct bilirubin >1 mg/dL) may have fat malabsorption due to insufficient bile acids in the bowel lumen, with associated fat-soluble vitamin deficiency. Monitoring and management of fat-soluble vitamin deficiency is similar to that in patients with biliary atresia (table 3). Fixed-ratio multivitamin supplements (eg, DEKAs) are frequently used but may result in excessive intake of some vitamins when given in sufficient doses to treat insufficiency of other vitamins. In that case, vitamins may need to be dosed individually. (See "Biliary atresia", section on 'Fat-soluble vitamin supplements'.)

Nutrition — Malnutrition, with associated growth failure, and pubertal delay are common in children with Alagille syndrome. The cause is likely multifactorial (malabsorption and/or the genetic defect) and should be treated proactively with high-energy supplements (often requiring nasogastric or gastrostomy feeding) and fat-soluble vitamin supplements. (See 'Fat-soluble vitamin deficiency' above.)

Pancreatic insufficiency appears to be uncommon in Alagille syndrome, so supplementation with pancreatic enzymes is unlikely to be an effective therapy for malnutrition [61].

Liver disease progression — Patients with persistent cholestatic liver disease sometimes develop progressive hepatic fibrosis and cirrhosis, which can lead to portal hypertension. Complications of portal hypertension include hypersplenism with related thrombocytopenia, esophageal varices with risk of variceal bleeding, and ascites.

Monitoring and management of the cirrhosis and portal hypertension are similar to that for biliary atresia and other chronic liver diseases, as discussed separately:

●(See "Biliary atresia", section on 'Portal hypertension and variceal bleeding'.)

●(See "Portal hypertension in adults".)

●(See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

Hepatocellular carcinoma and hepatic nodules — Hepatic lesions reported in Alagille syndrome include benign regenerative nodules (which usually do not require intervention) or hepatocellular carcinoma (HCC). Both types of lesions are reported, but their true incidence is unknown. HCC has been documented in both children and adults with a wide range of Alagille syndrome phenotypes and differing degrees of liver involvement [62,63]. Dysfunctional Notch signaling has been implicated in HCC and intrahepatic cholangiocarcinoma [64].

There is no consensus and considerable uncertainty regarding patient selection or protocols for screening for HCC. Common practice is to perform routine screening for individuals with advanced liver disease. Screening consists of close monitoring of liver enzymes, serial measurements of serum alpha-fetoprotein, and periodic ultrasound and advanced liver imaging, similar to protocols for children with hepatitis B virus infection (see "Management of hepatitis B virus infection in children and adolescents", section on 'Hepatocellular carcinoma surveillance'). However, the utility of routine screening is questionable because HCC is very rare (<40 cases reported to date) [62]. Moreover, screening only people with advanced liver disease would miss the few cases that have been reported in individuals with mild liver disease, so further evidence is required to enable early detection and treatment in people with Alagille syndrome [62].

Vascular anomalies — Cerebral vascular anomalies are an important cause of morbidity due to intracranial bleeding, which occurs in up to one-quarter of individuals with Alagille syndrome [24,25]. Screening brain magnetic resonance imaging/magnetic resonance angiography is recommended in all Alagille syndrome patients when they reach an age where they do not require sedation for the examination. There should be a low threshold for brain imaging in the setting of head injury or neurologic symptoms. (See "Vascular malformations of the central nervous system" and "Brain arteriovenous malformations" and "Posterior circulation cerebrovascular syndromes".)

Cardiac and renal anomalies — The extent of cardiac or renal disease and vascular anomalies is highly variable, and management is tailored to the involvement in the individual patient. Related UpToDate content includes:

●Cardiac – (See "Pulmonic stenosis in infants and children: Clinical manifestations and diagnosis" and "Pulmonic stenosis in infants and children: Management and outcome" and "Tetralogy of Fallot (TOF): Management and outcome".)

●Renal – (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)".)

SURGERY — Kasai hepatoportoenterostomy (HPE) is not recommended for individuals with Alagille syndrome. The procedure provides no added benefit for this population and, rather, may worsen outcomes (early liver transplantation or mortality) [65]. By contrast, HPE is a mainstay of treatment for biliary atresia. (See "Biliary atresia", section on 'Kasai procedure'.)

Biliary diversion — A few case reports describe surgical biliary diversion or ileal resection for patients with Alagille syndrome and severe refractory cholestasis, with partial relief of symptoms [60,66-69]. Advances in medical treatment for pruritus, especially use of inhibitor of ileal bile acid transport (IBAT) inhibitors such as maralixibat, will very likely reduce the need for surgical biliary diversion.

Liver transplantation — In registry studies, more than one-half of individuals with hepatic manifestations of Alagille syndrome eventually required liver transplantation. (See 'Natural history of liver disease' below.)

●Indications for referral for transplant evaluation – Typical indications for liver transplant in Alagille syndrome include persistent cholestasis, complications of persistent cholestasis (intractable pruritus, growth failure, metabolic bone disease, fat-soluble vitamin deficiency), cirrhosis, and manifestations of portal hypertension (ascites, variceal bleeding requiring intervention) [20].

●Pretransplant evaluation – Pretransplant evaluation must include cardiac and renal assessments. Occasionally, individuals with Alagille syndrome require cardiac or renal transplant at the time of liver transplant. Cardiac disease should be repaired prior to liver transplant when possible. The extent of renal disease involvement may impact choice of post-transplant immunosuppression regimen. Other considerations include head and abdominal imaging to identify vascular anomalies, which could impact bleeding risk and technical aspects of the transplant procedure. (See 'Cardiac and renal anomalies' above.)

●Outcomes – Patient and graft survival one and five years after liver transplant have been reported to be lower for Alagille syndrome patients compared with biliary atresia patients, with one retrospective analysis showing a clustering of deaths for Alagille syndrome patients within the first 30 days [70,71]. Similar survival rates (five-year patient survival approximately 80 percent) are seen in Alagille syndrome patients receiving a living-related donor graft [72]. A more recent study from 2022, however, showed no difference in patient and graft survival between Alagille syndrome and biliary atresia [73]. Renal insufficiency in Alagille syndrome patients has been shown to worsen after liver transplant, supporting the need to follow renal-sparing immunosuppression protocols [71]. All potential living-related donors should undergo genetic testing, and any potential donor with a JAG1 mutation should be eliminated from consideration, even if no overt liver disease is present [72].

PROGNOSIS

Natural history of liver disease — In large registry studies, more than one-half of individuals with hepatic manifestations of Alagille syndrome eventually required liver transplantation; the risk varied depending on the degree of cholestasis. In a cohort study (ChilLDReN) of 293 children with Alagille syndrome presenting with cholestasis, 24 percent survived to early adulthood with native liver [37]. Despite improvement of cholestasis, 40 percent of participants developed definite portal hypertension by 20 years of age. In another international cohort study (GALA Study Group) that included more than 1000 individuals with Alagille syndrome, 10- and 18-year native liver survival was 54 and 40 percent, respectively [20]. By 10 and 18 years, 51.5 and 66.0 percent of children with Alagille syndrome experienced ≥1 adverse liver-related event (clinically evident portal hypertension, transplant, or death), respectively. Children with a median total bilirubin level <5 mg/dL at 6 to 12 months of age had higher rates of native liver survival, with 79 percent reaching adulthood with native liver. This contrasts with a 4.8-fold increased risk of liver transplant in children with a median total bilirubin level between ≥5 to <10 mg/dL at 6 to 12 months of age [20].

If cholestasis is not present during childhood, it does not develop during adulthood. However, these individuals are still at risk for developing liver cancer, as described in a few case reports. (See 'Hepatocellular carcinoma and hepatic nodules' above.)

Notably, these studies reflect management prior to the availability of ileal bile acid transport (IBAT) inhibitors; whether use of these medications reduces the need for liver transplantation is an active area of research.

Individuals who are identified by screening family members of probands have substantially lower incidence of liver and cardiac disease. In one such cohort with JAG1 variants, 55 percent had liver abnormalities, compared with 100 percent of probands [1].

Mortality — An early retrospective study of 92 individuals with Alagille syndrome determined that the factors that contributed significantly to mortality were complex congenital heart disease, intracranial bleeding, and hepatic disease or liver transplantation [16]. Overall mortality was 17 percent, with the major causes of death being hepatic death (average age 7.5 years), intracranial bleed (average age 2.9 years), and multisystem/cardiac failure (average age 1.6 years). The 20-year predicted life expectancy was 75 percent for all patients, 80 percent for those not requiring liver transplant, and 60 percent for those requiring liver transplant. In a more recent longitudinal cohort study (ChilLDReN) of 293 individuals with Alagille syndrome with native liver, 11 (4 percent) died with native liver during the study follow-up (median 2.7 years, range 0 to 10 years). Only three deaths were directly related to liver disease, with the remainder due to cardiac involvement, pulmonary hemorrhage, and "other" [37].

RESOURCES

●Childhood Liver Disease Research Network (ChilDReN)

●Alagille Syndrome Alliance

●Global Alagille Alliance (GALA) Study Group

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric liver disease" and "Society guideline links: Neonatal jaundice" and "Society guideline links: Inherited liver disease" and "Society guideline links: Portal hypertension and ascites".)

SUMMARY AND RECOMMENDATIONS

●Genetics and pathogenesis – Alagille syndrome is an autosomal dominant disorder, usually caused by pathogenic variants in the JAG1 or NOTCH2 genes. (See 'Genetics and pathogenesis' above.)

●Clinical manifestations – Alagille syndrome affects multiple organ systems and has a wide range of clinical severity. The most clinically important manifestations are cholestatic liver disease, congenital heart disease, and cerebrovascular anomalies (table 1). Other common features include characteristic facies (picture 1), renal disease, ocular abnormalities, skeletal abnormalities, and growth failure. (See 'Clinical features' above.)

●Evaluation – Alagille syndrome is suspected in individuals who present with suggestive features (especially otherwise unexplained cholestatic liver disease) or those with a parent or sibling with Alagille syndrome. The sequence and pace of the evaluation depends on the individual patient. For young infants who present with cholestatic liver disease, the first priority is to evaluate for biliary atresia. For family members of an individual with Alagille syndrome, the first step is genetic testing. Those with suspected or confirmed Alagille syndrome should have a full evaluation for associated anomalies. (See 'Evaluation' above.)

●Diagnosis – The diagnosis of Alagille syndrome should be confirmed by genetic testing whenever possible. Occasionally, the diagnosis is made based on clinical criteria alone. (See 'Diagnosis' above.)

●Management – Medical management of patients with Alagille syndrome is tailored to the patient's disease manifestations and severity.

•Liver disease – Cholestatic liver disease often requires intensive management for:

-Pruritus, which can be debilitating. It is initially managed with medications (table 2) and may be an indication for liver transplantation. For most patients with pruritus, we suggest initial treatment with ursodeoxycholic acid (UDCA) and an antihistamine as needed rather than other drugs (Grade 2C). For refractory pruritus, add-on medications may include ileal bile acid transport (IBAT) inhibitors (maralixibat or odevixibat), rifampin, and/or naltrexone. (See 'Pruritus' above and 'Surgery' above.)

-Fat malabsorption, with fat-soluble vitamin deficiencies, which requires monitoring and vitamin replacement (table 3). (See 'Nutrition' above and 'Fat-soluble vitamin deficiency' above.)

-Cirrhosis with portal hypertension, hypersplenism, ascites, and esophageal varices with risk of variceal bleeding. Management is similar to that for other causes of portal hypertension and may include liver transplantation. (See 'Liver disease progression' above and 'Liver transplantation' above.)

-Risk for hepatocellular carcinoma (HCC). Common practice is to monitor for HCC in individuals with advanced liver disease, but there is no consensus on patient selection or monitoring protocols. (See 'Hepatocellular carcinoma and hepatic nodules' above.)

•Vascular anomalies – Cerebral vascular anomalies are an important cause of morbidity due to intracranial bleeding, which occurs in up to one-quarter of individuals with Alagille syndrome. All patients should be screened with advanced brain imaging and evaluated promptly if they develop concerning symptoms. (See 'Vascular anomalies' above.)

•Other – Management of congenital heart disease and renal anomalies is similar to that for individuals without Alagille syndrome. (See "Pulmonic stenosis in infants and children: Management and outcome" and "Tetralogy of Fallot (TOF): Management and outcome" and "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)".)