With improvements in medical and surgical care, more children with inherited cholestatic disorders are expected to survive into adulthood and require care by adult hepatologists. In addition to their ongoing hepatic needs, new management issues, including pregnancy, disease transmission to offspring, and extrahepatic manifestations of their disease, arise in adulthood. For the purposes of this review, the discussion is limited to Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) as the hallmark and most frequently inherited disorders of cholestasis.
adenosine triphosphate–binding cassette
bile salt export pump
familial intrahepatic cholestasis 1
multidrug resistance 3
progressive familial intrahepatic cholestasis.
ALGS is an autosomal dominant condition involving the liver, heart, face, eyes, skeleton, kidneys, and vasculature (Fig. 1). The disease gene is JAGGED1 in 94% of patients and NOTCH2 in <1%, and clinical molecular testing is widely available for the former. JAGGED1 and NOTCH2 function as a ligand and a receptor, respectively, in the evolutionarily conserved Notch signaling pathway. Highly variable expressivity is a hallmark feature of ALGS.
Hepatic Disease: Implications for Adulthood
ALGS liver disease ranges from asymptomatic biochemical abnormalities to profound, unremitting cholestasis with severe pruritus and xanthomas and end-stage liver disease. The hyperlipidemia of ALGS is not thought to be associated with an increased risk of cardiovascular disease because the lipoprotein profile is characterized by an increase in lipoprotein X, which is not considered atherogenic. ALGS children with liver disease transitioning into adulthood will likely already have a declared hepatic phenotype. Those with mild liver involvement (biochemical or minimal cholestasis) virtually never have disease progression outside childhood (in the absence of another insult such as alcohol use). ALGS children with significant cholestasis who do not experience the spontaneous improvement of early childhood seen in many children may continue to progress and require liver transplantation. A small subset of individuals with ALGS have progressive fibrosis and develop cirrhosis in late childhood or adulthood with minimal cholestasis. There is no new onset of liver disease in patients with ALGS in adulthood.
Hepatocellular carcinoma (HCC) has been reported in patients with ALGS, although predominantly in isolated case reports. Approximately half the reported cases have involved adults, and it is interesting to note that they have occurred in the absence of cirrhosis. This, of course, complicates the selection of appropriate candidates for surveillance, and there is no consensus regarding this, although an annual ultrasound examination may be considered appropriate.
Liver transplantation is required for 15% to 20% of individuals with ALGS, with most cases occurring in childhood because of complications of cholestasis. The outcomes of liver transplantation for ALGS are largely excellent, although they are slightly impaired in comparison with the outcomes for biliary atresia. This difference in patient and graft outcomes seems to be attributable to the multisystem disease burden of ALGS, and renal complications are particularly frequent and require modifications to immunosuppressive regimens and increased vigilance. Similar findings have been described for ALGS adults who have undergone liver transplantation.
Extrahepatic Disease in Adulthood
The liver and cardiac disease in ALGS typically has a stable or predictable phenotype by the time of adulthood (Table 1). There is no new onset of cardiac or hepatic disease after childhood. However, this is not the case for renal or vascular involvement. Although many renal anomalies in ALGS are structural and present from birth, other anomalies manifest with age, and there are substantial reports of hypertension and renal dysfunction with onset in adulthood. Similarly, though of more concern, there are data supporting the notion of a widespread vasculopathy in ALGS, with stroke and cerebrovascular anomalies occurring at any age, even in individuals who previously had normal intracranial imaging.[7, 8] These data, although not validated in large studies, support surveillance imaging with magnetic resonance angiography in adults and certainly aggressive investigations in the event of a neurological symptom or sign.
|Known liver disease from childhood||Annual ultrasound and laboratory work as indicated by severity of hepatic involvement|
|No known liver disease in childhood||No surveillance required|
|Known cardiac anomaly||Management as indicated by severity of congenital anomaly|
|No known or significant cardiac involvement||No surveillance required|
|Kidneys||Annual urinalysis, blood pressure, laboratory work|
|Cerebrovasculature||Head magnetic resonance imaging/ magnetic resonance angiography every 5 years and before any major medical intervention|
Pregnancy and Disease Transmission
Pregnancy in ALGS is a frequent event because 40% of cases are inherited and mothers are, therefore, commonly affected. Complications arise as a result of the severity of cardiac or hepatic involvement in the mother. As an autosomal dominant condition, the risk of mutation transmission is 50% with each pregnancy. Prenatal and even pre-implantation diagnosis is possible; however, because there are no clear genotype-phenotype correlations in ALGS, the prenatal detection of a mutation provides little clinical prediction.
The 50% risk of disease transmission for ALGS is also relevant for other family members. It is important to consider genetic screening for first-degree relatives, even if they have only subtle features of ALGS, because they retain the same risk of disease transmission.
Outcomes and Mortality
Approximately 70% of ALGS children with liver involvement reach adulthood, although these data are derived from patient series from hepatology centers, and there are likely more JAGGED1-positive adults than appreciated.[10, 11] Mortality from ALGS in childhood can largely be predicted by the severity of cardiac involvement. Causes of death in large series of ALGS patients that include young adults are complex congenital heart disease, intracranial bleeding, and factors related to hepatic disease or transplantation.
PFIC is a heterogeneous group of disorders encompassing familial intrahepatic cholestasis 1 (FIC1; ATP8B1) and bile salt export pump (BSEP) deficiency [adenosine triphosphate–binding cassette B11 (ABCB11)], low–gamma-glutamyltransferase (GGT) inherited cholestatic conditions, and multidrug resistance 3 (MDR3) deficiency (ABCB4), which results in high-GGT cholestasis and other clinical scenarios. ATP8B1 and ABCB11 are autosomal recessive conditions caused by mutations in ATP8B1 and ABCB11, respectively. Mutations are detected in approximately 60% of clinically defined patients.
Children with ATP8B1 and ABCB11 deficiencies manifest with profound cholestasis and pruritus. Patients with BSEP deficiency have aggressive hepatobiliary disease and develop HCC at a high frequency. ATP8B1 disease is characterized by extrahepatic manifestations in addition to cholestasis such as failure to thrive, short stature, diarrhea, pancreatic disease, and sensorineural hearing loss. ABCB4 deficiency is associated with a wide phenotypic spectrum ranging from neonatal cholestasis to cirrhosis in young adults (Table 2).
|Disease||Familial intrahepatic cholestasis 1||Bile salt export protein deficiency||Multi-drug resistance 3 deficiency|
|Extrahepatic features||Diarrhea, Hearing loss, Pancreatitis, Pruritus||Gallstones, Pruritus||Gallstones, Pruritus|
|Risk of HCC||Low||High||Low|
|Recurrence of antibody-mediated disease after transplant||No||Yes||No|
Hepatic Disease: Implications for Adulthood
Low-GGT PFIC patients typically progress to end-stage liver disease before adulthood, and before reaching adulthood, almost all patients will undergo either liver transplantation or a surgical intervention via a biliary diversion procedure.
Biliary diversion can relieve pruritus and slow disease progression in patients without cirrhosis. Biliary stoma losses can contribute to severe dehydration in gastroenteritis. Transplantation should be considered for patients who have progressive liver dysfunction or continue to have symptoms of pruritus, cholestasis, liver cirrhosis, and growth retardation despite external biliary diversion. Persistent diarrhea, graft steatosis, growth failure, and pancreatitis have all been observed after liver transplantation in children with ATP8B1 disease.[14, 15] Patients with ABCB11 disease have demonstrated good graft survival with a rapid increase in growth acceleration after liver transplantation. Notably, the recurrence of low-GGT cholestasis associated with the presence of anti-BSEP antibodies in patients with ABCB11 deficiency who have undergone liver transplantation has been described. This appears to be an immune-mediated recognition of the new hepatic antigen (ABCB11 protein) in the donor organ by the transplant recipient. The remission of these episodes may be achieved by the intensification of the immunosuppressive regimen.
HCC has been identified in many children with severe ABCB11 disease, with the largest study demonstrating malignancy in 15% of patients.[18, 19] HCC has been identified even in patients with biochemical and symptomatic improvements after biliary diversion, and patients should be screened with ultrasonography at regular intervals according to American Association for the Study of Liver Diseases guidelines.
MDR3 defects have been reported in children and adults with intrahepatic lithiasis, in adults with chronic hepatitis, biliary cirrhosis, and fibrosing cholestasis, and in patients with drug-induced liver injuries. There appears to be an association between heterozygosity for ABCB4 defects and a propensity for the development of cholestasis of pregnancy. Gallstone patients with ABCB4 mutations may have low-phospholipid–associated cholelithiasis syndrome, which is characterized by cholesterol gallstones and intrahepatic microlithiasis, along with recurrent biliary symptoms despite cholecystectomy.
Extrahepatic Disease in Adulthood
The extrahepatic features of ATP8B1 disease have been mentioned previously. All PFIC patients, regardless of whether they have undergone biliary diversion or transplantation, also have significant metabolic bone disease when they reach adulthood. All patients should have close follow-up and monitoring for osteopenia and osteoporosis.
In addition to HCC, other malignancies in patients with ABCB11 disease, including cholangiocarcinoma and pancreatic adenocarcinoma, have been described.[22, 23] As such, clinicians should consider the increased risk of cancer when they consider surveillance for patients with ABCB11 disease.
Pregnancy and Disease Transmission
PFIC patients have had successful pregnancies after biliary diversion, although all have had significant intrahepatic cholestasis of pregnancy (Peter F. Whitington, M.D., personal communication). A prenatal diagnosis is possible for PFIC as long as the mutations have been identified in the proband and the heterozygosity of the parents has been confirmed.