Diagnosis of Neonatal and Infantile Cholestasis

Cholestasis is defined as an impairment in bile formation and/or flow (with all its constituents). Neonatal and infantile cholestasis (NIC) has diverse set of etiologies, some of which are treatable while others are not. Its clinical presentation also varies from a self-limited illness to acute liver failure. Timely detection, being often recognized in our health care settings late, identification of the etiology, particularly treatable ones, and proper management are crucial for patient outcome. The most common recognizable cause of NIC is biliary atresia (BA), in which an early surgical referral is needed to optimize the success rate. A timely diagnosis also allows for prompt specific treatment and a better outcome in other treatable inherited metabolic conditions, such as galactosemia or the rare inborn errors of bile acid synthesis.

This guideline focuses on diagnosing neonatal and infantile cholestasis in Egypt. It provides evidence-based guidance to help in early detection of NIC and in the diagnosis of its etiology.

After revising inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guideline (CPG):

-   Ranucci G, Della Corte C, Alberti D, Bondioni MP, Boroni G, Calvo PL, Cananzi M, Candusso M, Clemente MG, D'Antiga L, Degrassi I, De Ville De Goyet J, Di Dato F, Di Giorgio A, Vici CD, Ferrari F, Francalanci P, Fuoti M, Fusaro F, Gaio P, Grimaldi C, Iascone M, Indolfi G, Iorio R, Maggiore G, Mandato C, Matarazzo L, Monti L, Mosca F, Nebbia G, Nuti F, Paolella G, Pinon M, Roggero P, Sciveres M, Serranti D, Spada M, Vajro P, Nicastro E. Diagnostic approach to neonatal and infantile cholestasis: A position paper by the SIGENP liver disease working group. Dig Liver Dis. 2022 Jan;54(1):40-53. doi: 10.1016/j.dld.2021.09.011. Epub 2021 Oct 20. PMID: 34688573.

We conducted an adolopment for this position paper (Adoption, Adaptation, and Development)

• Adoption for most of the recommendations.
• Adaptation for 2 recommendations according to GRADE criteria to be suitable to our Economic implications (Evidence-to-Decision (EtD) table was done)
• Development of Good Practice Statements

This version of the CPG includes recommendations and good practice statements on the following sub-sections:

A.    Definition and Etiology:

Neonatal/infantile cholestasis (NIC) is defined as an impairment in bile formation and/or flow, presenting during the first year of life—usually within the first three months—and resulting in retention of bile and biliary substances within the liver that cause liver damage. Strength of recommendation: Strong

Serum conjugated bilirubin greater than 1 mg/dl (17 μmol/L) when total bilirubin is less than 5 mg/dl, or greater than 20% of total bilirubin when total bilirubin exceeds 5 mg/dl, is considered diagnostic of cholestasis and warrants further evaluation. Strength of recommendation: Strong

Once cholestasis has been documented in an infant, achieving a rapid etiological definition is of primary importance. Given the wide spectrum of potential causes, a complex diagnostic approach is required, guided by the accompanying clinical picture. For practical purposes, causes of cholestasis are divided into surgical and medical conditions. Strength of recommendation: Good practice statement

B.    Emergency treatment of Neonatal and Infantile cholestasis

In jaundiced infants with suspected or confirmed cholestasis, a detailed pre‑, peri‑, and postnatal medical and family history should be obtained. Strength of recommendation: Strong

Infants with jaundice should receive a complete physical examination, in particular searching for the presence of hepatomegaly and/or splenomegaly, dysmorphic features, growth and nutritional status, skin lesions, cardiac murmurs, and neurologic examination. Strength of recommendation: Strong

Direct visualization of stool color and its monitoring should be part of the clinical evaluation of any infant with jaundice. Strength of recommendation: Strong

Infants with jaundice persisting after 2 weeks of age should be evaluated for cholestasis by measurements of serum total and direct reacting (conjugated) bilirubin. Strength of recommendation: Strong

Upon evaluating causes of cholestasis, a stepwise approach is important to rule out first diseases with available treatment such as sepsis, congenital hypothyroidism, galactosemia, and surgical causes including biliary atresia and choledochal cyst. Strength of recommendation: Strong

In infants with cholestasis, inborn errors of metabolism (IEM) should always be considered in the differential diagnosis. Clinicians should be aware of which IEM causing cholestasis are included in the expanded newborn screening of their own region or country. Strength of recommendation: Strong

A careful clinical evaluation, combined with first‑level laboratory testing, may raise the suspicion of specific IEM, indicating second‑level laboratory analyses for confirmatory diagnosis. Strength of recommendation: Strong

Infants with cholestasis should undergo liver ultrasound to exclude biliary obstructive conditions other than biliary atresia, such as choledochal malformations or gallstone disease. Strength of recommendation: Strong

Findings such as the absence of the gallbladder or its dysmorphic aspect, along with other minor features suggestive of biliary atresia, should always be searched for at liver ultrasound. Strength of recommendation: Strong

Endoscopic or direct surgical exploration and evaluation of the biliary tract by cholangiogram is considered the gold standard to positively and definitively establish the diagnosis of biliary atresia (as well as neonatal sclerosing cholangitis). Strength of recommendation: Strong

Magnetic Resonance Cholangio‑Pancreatography (MRCP) is not reliable as the normal biliary tract is not consistently visualized in children under 3 months of age; false negative results are thus common. Strength of recommendation: Strong

Hepatobiliary scintigraphy is not recommended anymore. Strength of recommendation: Strong

Liver biopsy is useful to discriminate between extrahepatic and intrahepatic causes of NIC and may provide important clues for specific underlying etiologies, when performed at the appropriate timing and evaluated by an experienced pathologist. Liver biopsy should only be done after consultation with a pediatric hepatologist. Strength of recommendation: Strong / Good practice statement

Infants with cholestatic liver disease may present acutely with complications such as bleeding due to vitamin K deficiency. Indicators of complications in cholestatic neonates and infants include episodes of acute metabolic decompensation (hypoglycemia, hyperammonemia, acidosis, or acute liver failure), recurrent or chronic vomiting, neurological signs, multi‑organ involvement, ill appearance suggesting infection or metabolic disease, lethargy, and poor feeding. These are managed in parallel to the rapid diagnostic work‑up. Strength of recommendation: Strong / Good practice statement

At first encounter with a cholestatic infant (proven or suspected), 2 mg Vitamin K1 should be given intramuscularly. Strength of recommendation: Good practice statement

All age‑appropriate immunizations should be given to infants with cholestasis if there are no other contraindications. Strength of recommendation: Good practice statement

➡️Guideline Registration

PREPARE (Practice guideline REgistration for transPAREncy), WHO Collaborating Center for Guideline Implementation and Knowledge Translation, EBM Center, University of Lanzhou, Lanzhou, China. Registration Number: ((submitted and in process)). Link: http://www.guidelines-registry.org/