An Approach to the Cholestatic Infant

Alyssa Goldberg

Case

A 5-day-old female born at 38 6/7 weeks with uncomplicated pregnancy and delivery, her newborn course complicated by hyperbilirubinemia requiring phototherapy for 20 hours starting at day of life 3.  Due to persistence of jaundice, her PCP obtained a fractionated bilirubin on day of life 5 which was elevated with Tbili/Dbili 16.8/2.8.  PCP repeated labs on DOL7 Tbili/Dbili 15.7/2.8 and DOL9 Tbili/Dbili 14/2.5 and thus she is referred to pediatric hepatology.

She is exclusively breastfed, eating every 2-3 hours, not on any other medication nor supplements. Having 6 bright-yellow seedy stools a day, normal number of wet diapers and regained birthweight prior to 2 weeks of age. No fevers, no easy bleeding nor bruising, no pruritus, no other symptoms reported by parents, other than jaundice is clinically well appearing.

Which of these laboratory evaluations should be included in the first tier of laboratory evaluation?

Correct Answer:

Urinalysis and urine culture

First-tier evaluation of neonatal cholestasis should include basic chemistries and evaluation of treatable conditions including UTI.  See Figure 1.

Our patient

Upon referral to pediatric hepatology on DOL18 her fractionated bilirubin was found to be persistently elevated to 2.5 out of a total of 11.7.   Initial evaluation reveals a UTI with strep viridans and klebsiella and she is immediately started on antibiotic therapy.  However, 1-week post-UTI treatment on DOL 27 Tbili/Dbili 9/1.9. Therefore, further evaluation was planned.

An MMP7 level was checked and was elevated at 132.2 (high probability of BA based on internal assay levels).

Additional evaluation included MMP7 as a serum biomarker for biliary atresia in addition to alpha-1-antitrypsin level and phenotype, urine CMV, hepatic function panel and GGT. MMP7 has been shown to be the most specific predictor of biliary atresia other than liver biopsy. However, liver biopsy is still considered the gold standard at this time and should not be delayed for laboratory results from MMP7 due to time-sensitive nature of biliary atresia diagnosis with outcomes inversely proportional to age at time of therapeutic portoenterostomy surgery.

Back to the Basics:

Hyperbilirubinemia:

Hyperbilirubinemia in infancy is defined as serum conjugated/direct bilirubin level >1 mg/dL and > 20% of the total bilirubin.

When to be concerned about an infant with jaundice:

Jaundice at or beyond 2 weeks of age should be evaluated with fractionation of serum bilirubin. With data from the past decade, 1mg/dL conjugated/direct bilirubin should be the threshold to do further evaluation for hepatobiliary causes rather than just 20% of total bilirubin as this has level has been shown in the newborn period to be a specific threshold for biliary atresia patients. 

Overview of approach to an infant with cholestasis, evaluate for:

  1. Anatomic anomalies or evidence of obstruction including biliary atresia (classic but non-diagnostic findings include small or absent gallbladder, triangle cord sign), evidence of biliary atresia with splenic malformation caused by genetic defects (polysplenia, laterality defects), or choledochal cyst with abdominal ultrasound
  2. Infectious etiology such as UTI, TORCH infection (commonly CMV) or any septicemia
  3. Genetic or metabolic disorders with hepatic involvement including Alagille’s, alpha-1-antityrpsin deficiency, cystic fibrosis, Dubin-Johnson syndrome, tyrosinemia, bile transporter defects and galactosemia
  4. Endocrine abnormality including hypothyroidism, panhypopituitarism
  5. Toxins including drugs, TPN, and some herbal products
  6. Immune Mediated/Other: HLH/GALD, ischemic/hypoxic/congestive injury, oncologic, idiopathic neonatal hepatitis (INH)

Figure 1: Diagnostic Approach:

Figure 2: Key points from history or physical and related etiologies of neonatal cholestasis

Taken from: Feldman, Sokol. Seminars in Pediatric Surgery, 2020

Back to the case

Along with elevated MMP7 and persistently elevated direct bilirubin, her abdominal ultrasound was read as “Gallbladder is small in size despite fasting, no choledochal cyst or intra or extrahepatic duct dilation.” Other testing including her newborn screen, alpha-1-antitrypsin level, thyroid tests and urine CMV were all normal. Thus, she underwent liver biopsy which was notable for marked hepatocyte and canalicular cholestasis with bile duct plugs, expanded portal tracts with bile duct proliferation, fibrosis and peri-portal inflammation.   With evaluation as above, she underwent an intraoperative cholangiogram showing extrahepatic biliary duct obstruction consistent with biliary atresia and subsequently had a hepatoportoenterostomy (Kasai procedure) with down trending bilirubin levels in the subsequent days.

The era of personalized medicine:

It has been discussed that genetic panels may become the new gold standard and may supersede other testing in the near future as these technologies become more efficient and affordable.  Currently available testing includes targeted gene panels, whole exome sequencing, or whole genome sequencing

Highlighted manifestations of inherited disorders of cholestasis in adulthood

Recommended reading in Clinical Liver Disease

 Figure 3: Genes and Associated Cholestatic Disorders

Adapted from: Goldberg, Mack, Clinical Liver Disease, 2020

References:

  1. Feldman A , Suchy FJ . Approach to the infant with cholestasis. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. New York City: Cam- bridge University Press; 2014:101–110
  2. Harpavat S , Finegold MJ , Karpen SJ . Patients with biliary atresia have elevated direct/conjugated bilirubin levels shortly after birth. Pediatrics . 2011;128(6):e1428–e1433
  3. Jiang J , Wang J , Shen Z , Lu X , Chen G , Huang Y , et al. Serum MMP-7 in the diagnosis of biliary atresia. Pediatrics . 2019;144(5)
  4. Serinet MO, Wildhaber BE, Broué P, Lachaux A, Sarles J, Jacquemin E, Gauthier F, Chardot C. Impact of age at Kasai operation on its results in late childhood and adolescence: a rational basis for biliary atresia screening. Pediatrics. 2009 May;123(5):1280-6.
  5. Fawaz R , Baumann U , Ekong U , Fischler B , Hadzic N , Mack CL , 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(1):154–168 .
  6. De Bruyne R, Van Biervliet S, Vande Velde S, Van Winckel M. Clinical practice: neonatal cholestasis. Eur J Pediatr. 2011 Mar;170(3):279-84
  7. Brumbaugh D, Mack C. Conjugated hyperbilirubinemia in children. Pediatr Rev. 2012 Jul;33(7):291-302.
  8. Suchy FJ . Neonatal cholestasis. Pediatr Rev . 2004;25(11):388–396 .
  9. Goldberg A, Mack CL. Inherited Cholestatic Diseases in the Era of Personalized Medicine. Clin Liver Dis (Hoboken). 2020 Apr 4;15(3):105-109.

Take Home Points

  • Timeline of diagnosis of biliary atresia is time-sensitive as Kasai procedure is most successful before 2 months of age or even before 30-45 days of life.
  • One underlying diagnosis of cholestasis such as UTI does not preclude another and bilirubin profiles should continue to be trended
  • Diagnostic evaluation should begin with basic chemistry panel and then should be tailored to patient presentation
  • Genetic evaluation is becoming a more readily available diagnostic tool to evaluate neonatal cholestatic syndromes, however ruling out biliary atresia in a timely matter often means pursuing further invasive testing prior to having genetic results back

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