Pediatric cholestatic liver disease: Successful transition of care

Cleveland Clinic Journal of Medicine. 2019 July;86(7):454-464 | 10.3949/ccjm.86a.18140
July 1, 2019|Cleveland Clinic Journal of Medicine
Praveen Kumar Conjeevaram Selvakumar, MD;Vera Hupertz, MD;Naveen Mittal, MD;Kris V. Kowdley, MD;Naim Alkhouri, MD
Author and Disclosure Information

Praveen Kumar Conjeevaram Selvakumar, MD
Department of Pediatric Gastroenterology and Hepatology, Cleveland Clinic

Vera Hupertz, MD
Department of Pediatric Gastroenterology and Hepatology, Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Naveen Mittal, MD
Texas Liver Institute, University of Texas Health, San Antonio, TX

Kris V. Kowdley, MD
Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, WA

Naim Alkhouri, MD
Director of the Metabolic Center, Texas Liver Institute, University of Texas Health, San Antonio, TX

Address: Naim Alkhouri, MD, Metabolic Center, Texas Liver Institute, University of Texas Health, 607 Camden Street, San Antonio, TX 78215; alkhouri@txliver.com

Dr. Kowdley has disclosed financial relationships (consulting, independent contracting, serving on advisory committee or review panels, teaching and speaking, or holding intellectual property rights) with Enanta Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, High Tide Health, Intercept Pharmaceuticals, and UpToDate.

Release date: July 1, 2019
Expiration date: June 30, 2020
Estimated time of completion: 1 hour

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ABSTRACT

With recent medical advances, more patients with childhood-onset liver disease and more pediatric liver transplant recipients are surviving into adulthood, generating distinctive challenges to adult primary care providers. Young adults with pediatric liver disease are a unique cohort of patients with different evaluation and monitoring strategies, treatment, complications, and comorbidities. This creates a critical need for successful transition of these patients into adult care, with incorporation of a formal transitional model and multidisciplinary team.

KEY POINTS

  • The causes of cholestasis in children are different from those in adults, with genetic inherited causes more common in childhood.
  • Cholestasis in children can be caused by biliary tract obstruction such as in biliary atresia or defects in forming and excreting bile acids and other components of bile.
  • With the growing number of people with childhood-onset liver disease surviving into adulthood, it is important for internists to be aware of unique problems and challenges in continuing management of this population.
  • In addition to medical comorbidities, these patients may also have impaired psychosocial functioning and quality of life.

ALAGILLE SYNDROME

Alagille syndrome is an autosomal-dominant multisystemic disease caused by mutations in the JAG1 gene (accounting for > 95% of cases) and the NOTCH2 gene, with highly variable expression.18

Extrahepatic manifestations include butterfly vertebral defects, facial dysmorphism (eg, deep-set and low-set eyes, with characteristic “triangular” facies), posterior embryotoxon (a congenital defect of the eye characterized by an opaque ring around the margin of the cornea), peripheral pulmonary stenosis, renal abnormalities, and vascular malformations.

Hepatic manifestations vary from asymptomatic laboratory abnormalities to progressive cholestasis starting in early infancy with intractable pruritus, xanthomas, failure to thrive, and end-stage liver disease requiring liver transplant in childhood in 15% to 20% of patients.19

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Implications of Alagille syndrome in adulthood

Transplant. Interestingly, the phenotype of hepatic disease is already established in childhood, with minimal or no progression in adulthood. Most children with minimal liver disease experience spontaneous resolution, whereas those with significant cholestasis might ultimately develop progressive liver fibrosis or cirrhosis requiring liver transplant in childhood. Only a small subset of children with minimal cholestasis progress to end-stage liver disease in late childhood or early adulthood.20 Therefore, liver transplant for progressive liver disease from significant cholestasis almost always occurs in childhood, usually between ages 1 and 4.21

In a retrospective study comparing posttransplant outcomes in children with Alagille syndrome and biliary atresia, 1-year patient survival was excellent overall in children with Alagille syndrome, although slightly lower than in children with biliary atresia, most likely owing to extrahepatic morbidities of Alagille syndrome and especially the use of immunosuppression in those with renal disease.21 Similarly, 1- and 5-year patient and graft survival outcomes of liver transplant in adults with Alagille syndrome were also excellent compared with those who received a liver transplant in childhood for Alagille syndrome or in adulthood for biliary atresia.22

Hepatocellular carcinoma has occurred in these patients in the absence of cirrhosis, which makes implementation of prognostic and surveillance strategies almost impossible to design for them. Annual ultrasonography with alpha-fetoprotein testing might be applicable in Alagille syndrome patients. However, deciding which patients should undergo this testing and when it should start will be challenging, given the paucity of data.

Cardiovascular disease. Cardiac phenotype is also mostly established in childhood, with the pulmonary vasculature being most commonly involved.19 In contrast, renal and other vascular abnormalities can manifest in adulthood. Renal manifestations vary and include structural anomalies such as hyperechoic kidneys or renal cysts, which can manifest in childhood, and some abnormalities such as hypertension and renal artery stenosis that can manifest in adulthood.23,24

Vasculopathy is reported to involve the intracranial, renal, and intra-abdominal blood vessels.25 Neurovascular accidents such as stroke and intracranial hemorrhage can occur at any age, with significant rates of morbidity and death.26 Therefore, some experts recommend magnetic resonance angiography every 5 years and before any major intervention to prevent these devastating complications.20

Pregnancy. Successful pregnancies have been reported. Preexisting cardiac and hepatic disease can complicate pregnancy depending on the severity of the disease. Because of the autosomal-dominant pattern of inheritance, infants have a 50% risk of the disease, so genetic counseling should be seriously considered before conception.27 Prenatal diagnosis is possible, but the lack of genotype-phenotype correlation precludes its use in clinical practice.

PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal-recessive conditions associated with disruption of bile formation causing cholestatic liver disease in infants and young children. Three types have been described, depending on the genetic mutation in the hepatobiliary transport pathway:

  • PFIC 1 (Byler disease) is caused by impaired bile salt secretion due to mutations in the ATP8B1 gene encoding for the familial intrahepatic cholestasis 1 (FIC 1) protein
  • PFIC 2 is caused by impaired bile salt secretion due to mutations in the ABCB11 gene encoding for the bile salt export pump (BSEP) protein
  • PFIC 3 is caused by impaired biliary phospholipid secretion due to a defect in ABCB4 encoding for multidrug resistance 3 (MDR3) protein.28

PFIC 1 and 2 manifest with low gamma-glutamyl transferase (GGT) cholestasis, whereas PFIC 3 presents with high GGT cholestasis.

PFIC 1 and PFIC 2 usually cause cholestasis in early infancy, but PFIC 3 can cause cholestasis in late infancy, childhood, and even adulthood.

Because ATP8B1 is expressed in other tissues, PFIC 1 is characterized by extrahepatic manifestations such as sensorineural hearing loss, growth failure, severe diarrhea, and pancreatic insufficiency.