Confirmation of cholestasis

In babies born at a gestational age of 37 weeks or more with jaundice lasting more than 14 days, and in babies born at a gestational age of less than 37 weeks and jaundice lasting more than 21 days: 1

Cholestasis should be suspected as soon as: 2

Jaundice or icterus is clinically evident when the total serum bilirubin level exceeds 42-51 µmol/L (or 25-30 mg/L). 4

A first assessment should be made by any practitioner caring for a newborn who is listless or who becomes jaundiced at 14 days or beyond.4 This assessment should include the following:2

Family history

Prenatal history

Infant history

The clinician performing the physical examination should not only focus on the abdomen, but should also consider extrahepatic signs, such as dysmorphic features, poor growth, dermatologic, neurologic, or pulmonary symptoms4.

Important points: 4

The clinical features of newborn cholestatic jaundice are clearly distinct from those of unconjugated bilirubin jaundice (clear urine, coloured stools, no hepatomegaly) which can persist beyond the 10th day of life and whose aetiology is different. 5 Among the signs listed above, cholestatic jaundice is associated with partial or complete prolonged discolouration of stools, dark stained urine and, most frequently, hepatomegaly.5 In the presence of neonatal jaundice, stool discolouration should be investigated from the first days of life by the maternity pediatrician.5 Pruritus only very rarely occurs in cholestatic newborns.6

Physical findings in children with neonatal cholestasis 4

Assessment of general health

Sickly appearance may indicate infection or metabolic disease.

Infants with biliary atresia typically appear well.

General appearance

The characteristic features of Alagille syndrome in neonate are rare and difficult to recognize. They may exhibit a characteristic facial appearance comprising a broad nasal bridge, triangular facies, and deep-set eyes. Typical facial features more often appear at around 6 months of age, but are often nonspecific.7

Vision/slit-lamp examination, hearing

Congenital infection, storage disease, septo-optic dysplasia, posterior embryotoxon, cataract.

Cardiac examination: murmur, signs of heart failure

Congenital heart disease: Alagille syndrome, biliary atresia, splenic malformation syndrome.

Abdominal examination

Presence of ascites, abdominal wall veins, liver size and consistency, spleen size and consistency (or absence thereof), abdominal masses, umbilical hernia.

Stool examination (crucial)

Acholic or hypopigmented stools suggest cholestasis or biliary obstruction.

The primary physician should make every effort to observe stool colour

( click here to access the “Yellow alert” awareness campaign ) 3

Neurological

Overall vigour and tone should be noted.

During evaluation of infants with cholestasis, laboratory investigations are essential for determining the aetiology and severity of the liver disease and detecting treatable conditions.4

It is crucial to evaluate serum conjugated (direct) bilirubin (DB). If elevated, it is a reliable laboratory indicator of cholestasis at this age.4 If cholestasis is suspected, certain specific investigations are recommended.4

STEP 1

Perform the following tests after cholestasis has been established to: 4

Blood

Complete + differential blood count, INR, AST, ALT, ALP, GGT, TB, DB (or conjugated bilirubin), albumin and glucose. Check α-1-antitrypsin phenotype (Pi typing) and level, as well as TSH and T4 levels if newborn screening results not readily available.

Urine

Urinalysis, urine culture, reducing substances (rule out galactosaemia).

Consider performing bacterial cultures of blood, urine and other fluids, especially if the infant is clinically ill.

Check results of treatable disorders (such as galactosaemia and hypothyroidism) after newborn screening

Obtain a fasting ultrasound

A disciplined and stepwise approach is required for the infant with confirmed cholestasis in concert with a paediatric gastroenterologist or hepatologist ensure appropriate laboratory tests are prescribed and to conduct a targeted workup. 4

STEP 2

Aim to complete a targeted evaluation in concert with a paediatric gastroenterologist/hepatologist 4

General

TSH and T4 values, serum bile acids, cortisol level

Consideration of specific aetiologies

Metabolic

Serum ammonia, lactate level, cholesterol, red blood cells, galactose-1-phosphate uridyltransferase, urine for succinylacetone and organic acids. Consider bile salt species profiling in the urine

Infectious diseases

Direct nucleic acid testing via PCR for CMV, HSV, listeria

Genetics

In discussion with a paediatric gastroenterologist/hepatologist, with a low threshold for gene panels or exome sequencing

Sweat chloride analysis

Serum immunoreactive trypsinogen level or CFTR genetic testing, as appropriate

Imaging

Chest X-ray (CXR): lung and heart disease

Spine: spinal abnormalities (such as butterfly vertebrae)

Echocardiogram: cardiac abnormalities observed in Alagille syndrome

Cholangiogram

Liver biopsy

(Timing and approach vary according to the institution and expertise)

Other relevant specialist consultations: Ophthalmology

Metabolic/genetic (consider when required, especially when gene panels or whole exome sequencing may be helpful)

Cardiology/ECHO (in case of murmur or hypoxia, poor cardiac function)

General paediatric surgery

Nutrition/dietician

Abdominal ultrasound is a sensitive and non-invasive examination that is useful for the assessment of the condition of the bile ducts, vessels and liver parenchyma. 2-4

Abdominal ultrasound should be performed on an empty stomach (≥ 6h after the last meal).

A fasting abdominal ultrasound is a simple and effective method that can be used to visualise obstructing lesions of the biliary tree, identify choledochal cysts, or signs of advanced liver disease and other splenic abnormalities. 4-8

The following hepatic ultrasound features may contribute to the diagnosis of biliary atresia, although no single sign can confirm a diagnosis on its own:9-13

Many, but not all infants with biliary atresia have a small or undetectable gall bladder. Findings such as abdominal heterotaxy, midline liver, polysplenia, asplenia, and preduodenal portal vein increase the suspicion of biliary atresia with malformations. Moreover, normal ultrasound does not rule out non-syndromic biliary atresia.

1. Jaundice in newborn babies under 28 days. London: NICE: National Institute for Health and Care Excellence; 2010.

2. Protocole national de diagnostic et de soins : Déficits de synthèse des acides biliaires primaires. In: Génétiques CdRCdlAdVBedC, ed.2019.

3. L’Alerte Jaune, campagne nationale d’informations pour le dépistage des cholestases néonatales. Association Maladies Foie Enfants (AMFE). (Accessed April, 2020, at http://www.alertejaune.com/.)

4. Fawaz R, Baumann U, Ekong U, et al. Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2017;64:154-68.

5. Gonzales E, Jacquemin E. Cholestases néonatales. Pédiatrie 2006:4-060-A-15.

6. Ling SC. Congenital cholestatic syndromes: what happens when children grow up? Can J Gastroenterol 2007;21:743-51.

7. Kamath BM, Loomes KM, Oakey RJ, et al. Facial features in Alagille syndrome: specific or cholestasis facies? Am J Med Genet 2002;112:163-70.

8. Balistreri WF. Neonatal cholestasis. J Pediatr 1985;106:171-84.

9. Mittal V, Saxena AK, Sodhi KS, et al. Role of abdominal sonography in the preoperative diagnosis of extrahepatic biliary atresia in infants younger than 90 days. AJR Am J Roentgenol 2011;196:W438-45.

10. Humphrey TM, Stringer MD. Biliary atresia: US diagnosis. Radiology 2007;244:845-51.

11. Lee HJ, Lee SM, Park WH, Choi SO. Objective criteria of triangular cord sign in biliary atresia on US scans. Radiology 2003;229:395-400.

12. Kim WS, Cheon JE, Youn BJ, et al. Hepatic arterial diameter measured with US: adjunct for US diagnosis of biliary atresia. Radiology 2007;245:549-55.

13. Tan Kendrick AP, Phua KB, Ooi BC, Tan CE. Biliary atresia: making the diagnosis by the gallbladder ghost triad. Pediatr Radiol 2003;33:311-5.