Neonatal cholestasis: A missed opportunity

1
Neonatal cholestasis A missed opportunity

• Rene D. Gomez-Esquivel, M.D.
• Pediatric Gastroenterology Fellow
• University of Texas Health Science Center at
  Houston

2
Abstract

• Biliary atresia is the most common cause for
  pediatric liver transplantation in the US and
  Canada. It presents with cholestatic jaundice
  early in life. Here we report the case of a 4
  month old female with cholestatic jaundice, that
  required a liver transplantation. The timely
  diagnosis and management in biliary atresia are
  crucial for the prognosis. Therefore special
  emphasis should be given to instruct the
  caregivers to return to the pediatrician if
  jaundice persist beyond 2 weeks of age or if
  there is acholia.

3
Objectives

• To recognize the causes of jaundice
• Highlight the importance of direct
  hyperbilirubinemia
• Highlight the prognostic value of a timely
  diagnosis and treatment of Biliary atresia.

4
Case Presentation

• 4 month old Hispanic female presented for
  evaluation for a liver transplantation. At the
  time of evaluation the only complaint was
  jaundice. The patient had been gaining weight,
  had good appetite, and no change in the color of
  the stools (no acholia).

5
Past Medical History

• Born vaginally at term, no pre or post natal
  complications.
• There was a history of jaundice since birth.
• She was hospitalized at 2 months of age with
  pneumonia, at that time jaundice was also
  noticed, and was attributed to Hepatitis A, and
  referred for evaluation with GI.

6
Past Medical History

• Appointment with GI was not scheduled.
• At 4 month check up, patient was noticed to be
  jaundiced by PCP, and at this time the patient
  was hospitalized and found to have elevated
  transaminases, direct hyperbilirubinemia and
  elevated alkaline phosphatase.
• A radionuclide hepatobiliary scan (HIDA scan),
  showed adequate uptake by the liver but no bowel
  excretion by 24 hours.

7
Past Medical History

• Then the patient had an intra-operative
  cholangiogram that showed no evidence of
  intrahepatic ducts or drainage into the duodenum.
• A wedge liver biopsy showed intracellular
  cholestasis, no giant cell changes. Severe
  biliary cirrhosis.

8
Physical Exam

• Weight and height were at the 50th percentile.
• Visibly jaundiced, non dysmorphic.
• CV no murmurs.
• GI Enlarged liver 5 cm bellow costal margin,
  spleen not palpable.
• Neuro good tone.
• Remainder of the exam was unremarkable.

9
Laboratory

• Hepatitis B surface Antigen negative, core IgM Ab
  negative.
• CMV negative
• Acylcarnitine panel negative
• TORCH negative
• WBC 14.3, H/H 9.9/30.7, Platelets 300k
• AST 348 u/L, ALT 268 u/L
• Total Bilirubin 10.5 mg/dl, Direct 8.8 mg/dl
• Alkaline Phosphatase 1378 u/L, GGT 1367 u/L

10
Diagnostics

• Liver ultrasound with Doppler showed normal flow
  in the portal veins, hepatic veins, and hepatic
  artery.

11
Clinical Course

• Patient was listed and received the liver
  transplant at 7 months of age.

12
Explant liver biopsy

• Extensive inflammatory response, vacuolated
  histiocytes, many filled with pigment. In the
  residual parenchyma, no normal structure is
  present. The individual lobules are embedded in
  dense sheets of connective tissue surrounded by
  proliferating bile ducts with varying degrees of
  cholestasis and inflammation of the epithelium.

13
Explant liver biopsies

• Varying degrees of inspissation and inflammatory
  destruction of the epithelium, all accompanied by
  vacuolated, pigmented macrophages.

14
Jaundice Background

• Jaundice is a common occurrence in pediatrics.
• In the AAP policy statement for hospital stay for
  healthy newborns , those newborns discharged
  before 48hrs of life need to be seen within
  48hrs. 1
• In that follow up the infant should be assessed
  for general health, weight, feeding, hydration,
  and for jaundice. 1
• Again due to the frequent occurrence the AAP also
  developed a Policy statement on the management of
  Hyperbilirubinemia in the newborn infant. 2

15
Jaundice Background

• However, these 2 policy statements deal mainly
  with the most common cause of jaundice, i.e.
  indirect hyperbilirubinemia.
• Most common causes for unconjugated
  hyperbilirubinemia
• Breast milk jaundice -- physiologic jaundice
• Sepsis -- hemolysis
• Infants with persistent jaundice beyond 2 weeks
  should be assessed for direct hyperbilirubinemia.
  3

16
Cholestatic JaundiceDefinitions

• Elevation of conjugated bilirubin ( direct ) 3
• Direct gt1mg/dL if total is lt5mg/dL
• Or
• Direct gt 20 of the total if total gt5mg/ dL
• It is not uncommon for patients to be missed by
  primary care physicians, as in the case of the
  presented patient.
• Due to the rarity of this disease compared to
  indirect hyperbilirubinemia
• The spacing between follow ups from 2 week-old to
  8 week-old.

17
Conjugated Hyperbilirubinemia

• Conjugated hyperbilirubinemia most common causes
  
• Biliary Atresia
• Neonatal hepatitis
• Alpha 1 antitrypsin
• Check State Screen
• Galactosemia
• Hypothyroidism
• Affects 1 2,500 infants

18
Cholestatic Jaundice

• Need to be aggressive in looking for cholestasis
  and biliary atresia (BA) because earlier
  recognition of BA, and treatment improves
  survival after Kasai portoenterostomy, and/or
  liver transplant. 4-6
• Successful bile flow after Kasai is better in
  patients that have the procedure before 60-90
  days of age. Furthermore, Kasai before 30 days
  of age versus 90 day of age had a survival with
  native liver of 52 vs 21 6
• Secondly, after the 2 week check up there is a
  long gap where the patient will not be assessed
  by the physician until the 2 month check up.

19
Biliary Atresia

• In the largest database of the pediatric liver
  transplants performed in the US and Canada
  Biliary Atresia was the 1 cause for pediatric
  liver transplantation.7
• Biliary atresia is an inflammatory cholangiopathy
  affecting both the intra and extrahepatic biliary
  tree, with resulting fibrosis and subsequent
  cirrhosis.
• BA occurs in 15000-18000 live births.6

20
Biliary Atresia

• Once BA is diagnosed the patients undergo a
  biliary-enteric anastomosis or Kasai procedure.
• Many consider this a temporizing procedure.
• Kasai will restore the bile flow in approximately
  2/3 of the patients. 8
• In the pre-transplant era, the five year survival
  was 34.7-63 . In a gt20 year follow up by Shinkai
  et al, 40 of the survivors had cirrhosis, even
  after Kasai. 5
• Liver transplantation is considered the
  definitive treatment.

21
Evaluation of Cholestasis

• Alpha 1 antitrypsin
• Hypothyroidism
• Ultrasound to exclude choledochal cyst,
  polysplenia syndrome
• Radionuclide hepatobiliary scan (HIDA scan)
• Liver Biopsy

22
Biliary Atresia-Differential

• Choledochal cyst
• Bile duct strictures
• Alpha 1 antitrypsin deficiency
• Cholestasis secondary to total parenteral
  nutrition
• Cystic fibrosis
• Alagille syndrome

23
Conclusions

• Check for direct and total bilirubin in patients
  with jaundice beyond 2 weeks of age.
• At the 2-week-old visit Instruct the parents or
  care takers to return to the pediatrician if
  there is jaundice or acholia.
• Cholestatic jaundice if direct bilirubin gt1md/dL
  if total is less than 5mg/dL. Or if direct gt20
  of the total.
• Consult Gastroenterologist early for evaluation
  of cholestatic jaundice.

24
Acknowledgements

• Dr. Ruben E. Quiros-Tejeira
• Dr. Ana Lucia Cota

25
References

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