Transcript Evaluation of the Baby With Persistent Jaundice

Pediatric Cholestatic Jaundice:
Differential Diagnosis of
Treatable Disorders
Saul J. Karpen, MD, PhD
Professor of Pediatrics
Raymond F. Schinazi Distinguished Biomedical Chair
Division Chief, Gastroenterology, Hepatology & Nutrition
Emory University School of Medicine
Atlanta, Georgia
A Common Clinical Challenge:
Neonatal Jaundice
Is it Physiologic or Pathologic?
Case: Full-Term Female Infant
• Weight: 7 lb, 2 oz
• Apgar score: 9
• Jaundice noted by parents while in hospital
• Elevated total serum
bilirubin level at time
of discharge on day 2
Neonatal Jaundice
• Yellowing of the skin and sclerae
 Occurs in ~60%[a] of full-term and 85%[b] of
preterm babies within 1 to 3 days of birth
 Not always easy to determine or gauge
a. American Academy of Pediatrics. Pediatrics. 2004;114:297-316.
b. NHS National Institute for Health and Clinical Excellence website.
Neonatal Jaundice (cont)
• Often due to elevated bilirubin
level in the blood when the
immature liver is not efficient
enough to remove bilirubin
from the blood for
biotransformation and fecal
elimination
• Diminishes at ~1 to 2 weeks
after birth as baby's liver
matures and the production of
bilirubin begins to decrease
Case (cont)
Recurrence of Jaundice After Initial
Improvement
• Normal baby
• Breastfed
• Returned to pediatrician for 1-week visit
– Normal exam
– Total bilirubin level remained elevated, but lower
than at discharge from hospital
• Returned to pediatrician for 2-week visit
– Total bilirubin level remained elevated
Case (cont)
Diagnosis: Prolonged Neonatal Jaundice
• Evaluate for cholestasis
‒ Measure total and direct serum bilirubin in any infant
noted to be jaundiced after 2 weeks of age
 If direct bilirubin level > 1.0 mg/dL or > 17 µmol/L, infant
should be referred for evaluation by a pediatric
gastroenterologist or hepatologist
Prolonged Neonatal Jaundice
Breast Milk-Related Jaundice
• Persists in otherwise healthy, full-term, breast-fed
babies (~0.5% to 2.4% of all newborns[a]) after
physiologic jaundice subsides
• Can last for many weeks
after birth
• Rarely serious
a. Winfield CR, et al. American Academy of Pediatrics. Archives of Disease in Childhood.
1978;53:506-516.
Prolonged Neonatal Jaundice: Is It
Noncholestatic or Cholestatic in Origin?
• Differential diagnosis is different for noncholestatic and
cholestatic neonatal jaundice
• Cholestatic jaundice
– Prevalence: ~1:2500 full-term infants[a]
– Wide range of differential diagnoses
 Biliary atresia
 Genetic disorders
– Important to make correct diagnosis because some disorders
can progress rapidly, but can be treated
• Due to reduced bile formation or flow resulting in retention of biliary
substances within the liver that are normally excreted into bile and
eliminated into the intestinal tract
a. Feldman AG, Sokol RJ. Neonatal cholestasis. Neoreviews. 2013;14:e63.
Liver Disease in the Newborn
13%
26%
10%
10%
41%
Idiopathic Cases
Preterm Birth
Biliary Artesia
Other Diagnoses
Hoerning A, et al. Front Pediatr. 2014;2:65.
PFIC
Differential Diagnosis of Cholestasis
in Newborns
Think Anatomic
Extrahepatic biliary tree:
can make bile normally,
but it gets stuck on its way
out of the liver
Intrahepatic biliary tree: Hepatocytes: metabolic
can make bile normally,
disorders
but can't handle bile
formed in the intrahepatic
tree
Differential Diagnosis of Cholestasis
in Newborns (cont)
• Bile duct obstruction, eg – structural,
hepatocellular abnormalities
• Metabolic disorders, eg – storage diseases
• Endocrine disorders, eg – hypothyroidism
• Toxic disorders, eg – due to soy lipid infusion
• Rare immunologic disorders
• Infections, eg – CMV
• Rare vascular malformations
• Miscellaneous, eg – hematologic, oncologic,
intestinal disorders
Evaluating Prolonged Neonatal
Jaundice
Visual Assessment is Observer Dependent
• Difficult to correlate visual recognition of jaundice with
serum bilirubin level
• Even experienced clinicians cannot visually assess the total
serum bilirubin with accuracy
– The true color of an infant's skin is not necessarily apparent at
birth
– Newborns often have their eyes closed so scleral icterus can be
missed
– Level of bilirubin required for jaundice to be visually apparent is
unknown, but thought to be ~5 mg/dL
– Cannot determine whether jaundice is due to indirect (cause is
physiologic) or direct (cause is liver disease) hyperbilirubinemia
Kramer LI. Amer J Dis Child. 1969;118:454-458.
Moyer VA, et al. Arch Pediatr Adolesc Med. 2000;154:391-394.
NASPGHAN/ESPGHAN: Recommendations
for Evaluation of the Potential for
Cholestatic Liver Diseases
• Measurements of serum bilirubin should always be fractionated into
unconjugated (indirect) or conjugated (direct) hyperbilirubinemia
• Any formula-fed infant noted to be jaundiced after 2 weeks of age
should be evaluated for cholestasis with measurement of total and
conjugated (direct) serum bilirubin
• Depending upon local practice, breast-fed babies that appear
otherwise well may be followed clinically until 3 weeks of age, at
which time, if they appear icteric, should then undergo serum
evaluation of total and conjugated (direct) serum bilirubin
• Conjugated (direct) hyperbilirubinemia (> 1.0 mg/dL [17umol/L]) is
considered pathological and warrants diagnostic evaluation
Fawaz R, et al. J Pediatr Gastroenterol Nut. 2016 Jul 16. [Epub ahead of print]
Evaluation of the Baby With Persistent
Jaundice
• Neonatal screening tests
– Blood tests*
 Organic acid disorders
 Fatty acid oxidation disorders
 Amino acid disorders (eg,
tyrosinemia)
 Hemoglobinopathy disorders
 Other disorders (eg, cystic
fibrosis)
– Hearing test
– Pulse oximetry for critical
congenital heart diseases
*Blood tests are state specific, these are required in the state of Georgia
Georgia Department of Public Health website.
Evaluation of the Baby With Persistent
Jaundice (cont)
• History
 Medication history in mother and infant: vitamin K
supplementation at birth
 Normal behaviors: feeding, normal interactions, sleeping
 Direct visualization of stool pigment is a key aspect of a complete
evaluation of the jaundiced infant[a]
 Changes in stool and urine pigmentation: caregivers should make
direct observations
 Pale or alcholic stools are a hallmark of cholestasis because bilirubin
gives stool its color
 Dark urine is indicative of cholestasis
 Timing of onset of jaundice
• Other family history
 Liver disease in newborns
 Unexplained death
a. Fawaz R, et al. J Pediatr Gastroenterol Nut. 2016 Jul 16. [Epub ahead of print]
Physical Examination of the Baby
With Persistent Jaundice: Head to Toe
• Examine for presence of dysmorphic features: visual clues
to chromosomal abnormalities
• Assess for abnormal behavioral interactivity
• Auscultate chest for presence of
heart murmur
• Palpate abdomen just above the
pelvic brim
– Normal finding is a soft liver edge
below the right costal margin
– Negative findings: spleen, fluid
waves, abdominal tenseness, hard
masses, cirrhosis (later in life)
Physical Examination of the Baby With
Persistent Jaundice: Head to Toe (cont)
• Perform neurologic exam
– Presence of poor (floppy) tone
– Unable to suck and swallow normally is a clue to
mitochondrial disorders
• Look at skin for signs of infection, eg – rash
• A thorough physical examination is crucial to the
proper evaluation of the jaundiced infant.
Attention to hepatomegaly, splenomegaly, and ill
appearance warrants special considerations[a]
a. Fawaz R, et al. J Pediatr Gastroenterol Nut. 2016 Jul 16. [Epub ahead of print]
Evaluation of the Baby With Persistent
Jaundice
Additional Laboratory Tests
• Core liver function tests: ALT, AST, AP (less helpful
in infancy), total and direct bilirubin
• GGTP for determining presence of bile duct
damage, cholangiopathy
• PT, INR for determining presence of coagulopathy
• Albumin
• Glucose
• Ammonia
Evaluation of the Baby With Persistent
Jaundice
Additional Laboratory Tests (cont)
• Serum metabolites for amino acids, lipids, bile acids
• Urine metabolites to determine presence of inborn errors of
metabolism
‒ Succinylacetone (elevated with tyrosinemia)
‒ Urine organic acids
‒ Acylglycines
• Bacterial and urine cultures to determine presence of sepsis
• Viral studies: birth-acquired HSV, CMV
• Genetic testing is evolving: perhaps order individual gene tests if
a single diagnosis is likely, but panels or genome-wide studies are
currently being developed
Differential Diagnosis: Intrahepatic
Cholestasis
Red Flags That Require Early Intervention
• Look for
–
–
–
–
–
–
Failure to thrive
Poor feeding
Lethargy
Hepatomegaly
Splenomegaly
Laboratory tests




Hyperbilirubinemia (direct)
Elevated liver function tests
Hypoglycemia, especially with absent urinary ketones
Hyperammonemia
Differential Diagnosis of Treatable
Disorders: Single-Gene Defects
Identification and Early Intervention Can Make a
Difference
• Tyrosinemia
• Bile acid synthetic disorders
–
–
–
–
–
–
–
–
–
3-beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency
Alpha-methylacyl-CoA racemase (AMACR) deficiency
Amino acid n-acyltransferase deficiency
Bile acid CoA ligase deficiency
Cholesterol 7-alpha-hydroxylase deficiency
Delta4-3-oxosteroid 5-beta-reductase deficiency
Oxysterol 7-alpha-hydroxylase deficiency
Sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis)
Trihydroxycholestanoic acid CoA oxidase deficiency
Origins of Neonatal Cholestasis
Extrahepatic Bile Duct
Biliary atresia
Bile duct hypoplasia
Bile duct duplication
Agenesis of extrahepatic ducts
Choledocholithiasis
Inspissated bile syndrome
Miscellaneous
• Panhypopituitarianism
• Hypothyroidism
• Neonatal hemochromatosis
• TPN-associated cholestasis
Intrahepatic Bile Duct
Hepatocytes
Bile duct paucity
• Alagile syndrome (JAG1,
Notch2)
• Nonsyndromic
Indeterminant (neonatal
hepatitis)
Viral infection (HSV, CMV)
Bacterial or parasitic infection
Ductal plate malformation
• Caroli disease
• ARPKD, ADPKD
• Von Meyenburg complexes
Transporter (bile acids,
phospholipids) gene defects
• PFIC1 (ATPB1)
• PFIC2 (ATPB11)
• PFIC3 (ABCB4)
Metabolic/storage diseases
• Neimann-Pic
• Tyrosinemia
• Galactosemia
• Zellweger's
• Mitochondrial
enzymopathies
• OTC deficiency
• 1-antitrypsin deficiency
Drug toxicity
Emory Cholestasis 57 Gene Panel*
Only 1 Blood Sample Required to Identify
Key Genes: Example of a Gene Panel
Genes Included on the Neonatal and Adult Cholestasis Panel
ABCB11
CC2D2A
HNF1B
NPC2
PEX7
PKHD1
UGT1A1
ABCB4
CFTR
HSD3B7
NPHP1
PEX10
POLG
VPS33b
ABCC2
CLDN1
INVS
NPHP3
PEX11B
SERPINA1
ABCD1
CYP27A1
JAG1
NPHP4
PEX12
SLC25A13
ABCG5
CYP7A1
LIPA
PEX1
PEX13
SLC27A5
ABCG8
CYPB1
MKS1
PEX2
PEX14
SMPD1
AKR1D1
DGUOK
MPV17
PEX3
PEX16
TJP2
ATP8B1
DHCR7
NOTCH2
PEX5
PEX19
TMEM216
BAAT
FAH
NCPC1
PEX6
PEX26
TRMU
*CLIA-approved laboratory
Emory Genetics Laboratory website.
NASPGHAN/ESPGHAN Recommendations
• The role of imaging
– The abdominal ultrasound is useful in excluding
choledochal cyst or gallstone disease causing
extrahepatic bile duct obstruction (eg, cyst, stone,
mass)
 It may demonstrate an absent or abnormal gallbladder, or
other features suggestive, but not diagnostic, of biliary
atresia
Fawaz R, et al. J Pediatr Gastroenterol Nut. 2016 Jul 16. [Epub ahead of print]
NASPGHAN/ESPGHAN Recommendations
(cont)
• The role of imaging
– Limited specificity precludes the use of the HBS scan
as a stand-alone test in making a definitive diagnosis
of biliary atresia
– Definitively-demonstrated bile flow (patency) by
selective use of HBS may be of value in excluding
biliary atresia
– Limited specificity of MRCP, ERCP, PTC has a limited
role in the general guidance to caregivers toward
diagnosing biliary atresia in the present era
Fawaz R, et al. J Pediatr Gastroenterol Nut. 2016 Jul 16. [Epub ahead of print]
NASPGHAN/ESPGHAN Recommendations
(cont)
• Diagnosis of biliary atresia
– Cannot make diagnosis by lab tests, stool color, or physical
examination
– Evaluation by intraoperative cholangiogram and histological
examination of the duct remnant is considered the gold
standard for diagnosis of biliary atresia[a]
• Diagnosis of diseases other than biliary atresia that cause
cholestasis
– Can be determined via histologic examination of the liver for
evidence of:[a]




Biliary tract obstruction
Storage disease
Other specific pathologic features
Rule out other diagnoses
a. Fawaz R, et al. J Pediatr Gastroenterol Nut. 2016 Jul 16. [Epub ahead of print]
NASPGHAN/ESPGHAN Recommendation
Consider Whether a Liver Biopsy Would Be
Helpful
• In the hands of an experienced pediatric
pathologist, histopathological findings of bile duct
proliferation, bile plugs, and fibrosis in an
appropriately timed liver biopsy is the most
supportive test in the evaluation of the infant with
protracted conjugated hyperbilirubinemia[a]
– Precludes the need for specialized genetic or other
tests
– Consultation with pediatric surgeon for consideration
of intraoperative cholangiogram
Fawaz R, et al. J Pediatr Gastroenterol Nut. 2016 Jul 16. [Epub ahead of print]
Liver Biopsy for Biliary Atresia
Does the Patient Need An Intraoperative
Cholangiogram?
• Hallmark features
– Bile duct
proliferation
– Bile duct fibrosis
– Bile duct plugs
– Inflammation
• Infants identified and referred in a timely manner
will benefit from specific therapy
– Kasai procedure (hepatoportoenterostomy): if done
within first 60 days of life, bile flow established in ~70%[a]
– Avoid liver transplantation
Chardot C, et al. J Hepatol. 2013;58:1209-1217.
Biliary Atresia
• Biliary atresia: one or more bile ducts are
abnormally narrow, blocked, or absent
– The earlier the diagnosis is made and the
earlier the surgical intervention is
performed, the better the outcome
– 50% can benefit from Kasai procedure[a]
Chardot C, et al. J Hepatol. 2013;58:1209-1217.
Therapies Are Available for Some
Cholestatic Disorders
• No effective therapies for cholestasis in general
• Early diagnosis with urine tests and gene
tests/panels is important because there are
therapies for some specific gene defects
– Cystic fibrosis, depending on the genotype
– Tyrosinemia, depending on the genotype
– Bile acid synthesis defects
Concluding Remarks
Take-Home Messages
• Observer-assessment of jaundice is not a good or
reliable marker of serum bilirubin
• Conjugated hyperbilirubinemia (>1 mg/dL or > 35
µmol/L) is never normal
‒ Should prompt a referral to a pediatric
gastroenterologist or hepatologist
• Early detection, diagnosis, and referral!