Cholestasis is a defining clinical feature of Alagille syndrome (ALGS), but it is not found exclusively in ALGS patients. In fact, neonatal and infantile cholestasis (NIC) affects 1 in 2500 children at term and can have multiple etiology. The wide spectrum of potential causes, which include medical (eg, ALGS or alpha-1 antitrypsin deficiency [AATD]) and surgical conditions, makes the diagnostic process difficult and time-consuming.
In patients with ALGS, an accurate characterization of cholestasis is essential, as discussed by Kamath et al. “It is imperative to better understand the natural history of cholestasis in ALGS in order to optimize management strategies, such as the timing of liver transplantation, to provide improved prognostic information for patients and their families, and to design clinical trials to evaluate novel therapies for this disorder.”
Kamath and colleagues conducted a large multicenter observational study to monitor the natural history of cholestasis in ALGS. The study enrolled 293 participants diagnosed with ALGS who kept their native liver.
“We highlight a previously underrecognized and high burden of progressive liver disease in cholestatic ALGS manifested first by pruritus, xanthomas, and fractures during toddlerhood, with a second wave of portal hypertension and associated complications later in adolescence,” they wrote.
This history of progressive liver disease in cholestatic ALGS patients resulted in high rates of liver transplantation. According to their estimates, “less than 25% of children with ALGS-related liver disease will reach the age of 19 years with their native liver.”
The SIGENP Project
In 2019, in response to an invitation by the Italian National Institute of Health, the Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) started a new project to define a set of recommendations for the diagnosis and management of NIC. The multidisciplinary working group was composed of pediatric hepatologists, pediatric surgeons, radiologists, neonatologists, a metabolic diseases specialist, a pathologist, and a geneticist.
The resultant recommendations were recently published in the journal Digestive and Liver Disease. In this article, we will present and discuss some of those recommendations.
- A detailed pre-, peri–, and postnatal medical and family history should be collected for all children with prolonged jaundice or suspected or confirmed cholestasis.
- A complete physical examination should be performed in infants with jaundice. Attention should be particularly given to the presence of hepatomegaly and/or splenomegaly, dysmorphic features, growth and nutritional status, skin lesions, cardiac murmurs, and neurologic examination.
- The clinical evaluation of infants with jaundice should include direct visualization and monitoring of stool color.
- Acholic stools, totally decolored with a clay-like aspect, are usually suggestive of biliary obstructive disease, ALGS, AATD, or cystic fibrosis.
- Measurements of serum total and conjugated bilirubin should be evaluated in infants with jaundice persisting after 2 weeks of age.
- The following scenarios are considered diagnostic of cholestasis and warrant further investigation: conjugated bilirubin >1 mg/dL (17 mmol/L) if total bilirubin is <5 mg/dL or >20% if total bilirubin is >5 mg/dL
Initial biochemical analyses are determinants to evaluate the type and severity of liver involvement. In addition, these tests might help with differential diagnosis. For instance, AATD can present with neonatal hepatitis syndrome mimicking biliary atresia (BA). Also, ALGS can lead to a false positive intraoperative cholangiogram.
Hence, the authors recommend ruling out AATD, ALGS, and cystic fibrosis in cholestatic infants by performing specific tests before any invasive diagnostic procedure, since these diseases may mimic BA.
- Infants with cholestasis should undergo liver ultrasound to exclude biliary obstructive conditions other than BA (eg, choledochal malformations or gallstone disease).
- Ancillary findings (eg, absence of the gallbladder or its dysmorphic aspect) and other minor features suggestive of BA should be searched for at liver ultrasound.
- The diagnosis of BA and neonatal sclerosing cholangitis is established by surgical exploration and direct evaluation of the biliary tract by cholangiogram.
- Neither hepatobiliary scintigraphy nor magnetic resonance cholangio-pancreatography should be used as single test in BA diagnosis due to their scarce specificity.
- Liver biopsy helps to discriminate between extrahepatic and intrahepatic causes of NIC and may point to specific etiologies when performed in the appropriate time frame and evaluated by an experienced pathologist.
- Percutaneous liver biopsy should be avoided when histology is not expected to add value on NIC etiology, the diagnosis of BA is very likely based on clinical and ultrasound findings, and surgical exploration and treatment could be delayed.
Genetic Testing and Diagnostic Scores
- Next-generation sequencing-based genetic testing has high diagnostic accuracy in identifying monogenic liver disorders causing NIC and should be considered upon exclusion of BA, in parallel with metabolic work-up, and based on local availability.
- The standard work-up should not be replaced by clinical scoring systems for BA due to the lack of validation in clinical setting.
A number of risk factors for developing transient neonatal cholestasis have been identified. These include prematurity, long-term parenteral nutrition, sepsis, delayed enteral intakes, intrauterine growth retardation, asphyxia, surgery, hemodynamic instability, and male sex.
“Preventative measures should include the use of adequate caloric intakes and appropriate proportion of fish oil-based lipid emulsions in children requiring parenteral support, the early introduction of enteral feeding, as well as prompt recognition and treatment of infectious comorbidities,” Ranucci et al wrote in their recommendations.
NIC is generally self-limiting. However, when direct bilirubin levels >2 mg/dL persist after 2 weeks, other causes should be investigated to allow for prompt diagnosis of any underlying primary liver disease.
Ranucci G, Della Corte C, Alberti D, et al. Diagnostic approach to neonatal and infantile cholestasis: a position paper by the SIGENP liver disease working group. Dig Liver Dis. Published online October 20, 2021. doi:10.1016/j.dld.2021.09.011
Kamath BM, Ye W, Goodrich NP, et al. Outcomes of childhood cholestasis in Alagille syndrome: results of a multicenter observational study. Hepatol Commun. 2020;4(3):387-398. doi:10.1002/hep4.1468