Pediatric Cholestatic Jaundice: Differential Diagnosis of T - PowerPoint Presentation

Slide1

Pediatric Cholestatic Jaundice: Differential Diagnosis of Treatable Disorders

Saul J. Karpen, MD, PhDProfessor of PediatricsRaymond F. Schinazi Distinguished Biomedical ChairDivision Chief, Gastroenterology, Hepatology & NutritionEmory University School of MedicineAtlanta, GeorgiaSlide2

A Common Clinical Challenge: Neonatal Jaundice

Is it Physiologic or Pathologic?Slide3

Case: Full-Term Female Infant

Weight: 7 lb, 2 ozApgar score: 9Jaundice noted by parents while in hospital

Elevated total serum bilirubin level at time of discharge on day 2Slide4

Neonatal Jaundice

Yellowing of the skin and scleraeOccurs in ~60%[a] of full-term and 85%[b] of preterm babies within 1 to 3 days of birthNot 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.

Slide5

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 eliminationDiminishes at ~1 to 2 weeks after birth as baby's liver matures and the production of bilirubin begins to decreaseSlide6

Case (cont)

Recurrence of Jaundice After Initial ImprovementNormal babyBreastfedReturned to pediatrician for 1-week visitNormal examTotal bilirubin level

remained elevated, but lower than at discharge from hospital

Returned

to pediatrician

for 2-week visit

T

otal

bilirubin

level

remained elevated

Slide7

Case (cont)Diagnosis: Prolonged Neonatal Jaundice

Evaluate for cholestasisMeasure 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 hepatologistSlide8

Prolonged Neonatal JaundiceBreast 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

a. Winfield CR, et al. American

Academy of Pediatrics

.

Archives of Disease in Childhood

.

1978;53:506-516

.

Can last for many weeks after birth

Rarely seriousSlide9

Prolonged Neonatal Jaundice: Is It Noncholestatic or Cholestatic in Origin?

Differential diagnosis is different for noncholestatic and cholestatic neonatal jaundiceCholestatic jaundicePrevalence: ~1:2500 full-term infants[a]Wide range of differential diagnosesBiliary atresiaGenetic disordersImportant 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

. Slide10

Liver Disease in the Newborn

Hoerning A, et

al.

Front Pediatr

. 2014;2:65. Slide11

Differential Diagnosis of Cholestasis in NewbornsThink Anatomic

Extrahepatic biliary tree:can make bile normally, but it gets stuck on its wayout of the liverIntrahepatic biliary tree:can make bile normally,but can't handle bile formed in the intrahepatictreeHepatocytes: metabolic disordersSlide12

Differential Diagnosis of Cholestasis in Newborns (cont)

Bile duct obstruction, eg – structural, hepatocellular abnormalitiesMetabolic disorders, eg – storage diseasesEndocrine disorders, eg – hypothyroidismToxic disorders, eg – due to soy lipid infusion

Rare immunologic

disorders

Infections, eg

–

CMV

Rare vascular

malformations

Miscellaneous,

eg – hematologic

, oncologic, intestinal disordersSlide13

Evaluating Prolonged Neonatal JaundiceVisual Assessment is Observer Dependent

Difficult to correlate visual recognition of jaundice with serum bilirubin levelEven experienced clinicians cannot visually assess the total serum bilirubin with accuracy The true color of an infant's skin is not necessarily apparent at birthNewborns often have their eyes closed so scleral icterus can be missedLevel of bilirubin required for jaundice to be visually apparent is unknown, but thought to be ~5 mg/dLCannot 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.Slide14

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) hyperbilirubinemiaAny 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

]

Slide15

Evaluation of the Baby With Persistent Jaundice

Neonatal screening testsBlood tests*Organic acid disordersFatty acid oxidation disordersAmino acid disorders (eg, tyrosinemia)Hemoglobinopathy disordersOther

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.

Slide16

Evaluation of the Baby With Persistent Jaundice (cont)

HistoryMedication history in mother and infant: vitamin K supplementation at birthNormal 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 observationsPale or alcholic

stools are a hallmark of cholestasis because bilirubin gives stool its color

Dark urine

is indicative

of cholestasis

Timing of o

nset

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]

Slide17

Physical Examination of the Baby With Persistent Jaundice: Head to Toe

Examine for presence of dysmorphic features: visual clues to chromosomal abnormalitiesAssess 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)Slide18

Physical Examination of the Baby With Persistent Jaundice: Head to Toe (cont)

Perform neurologic examPresence of poor (floppy) toneUnable to suck and swallow normally is a clue to mitochondrial disordersLook at skin for signs of infection, eg – rashA 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]

Slide19

Evaluation of the Baby With Persistent JaundiceAdditional Laboratory Tests

Core liver function tests: ALT, AST, AP (less helpful in infancy), total and direct bilirubinGGTP for determining presence of bile duct damage, cholangiopathyPT, INR for determining presence of coagulopathyAlbuminGlucoseAmmoniaSlide20

Evaluation of the Baby With Persistent JaundiceAdditional Laboratory Tests (cont)

Serum metabolites for amino acids, lipids, bile acidsUrine metabolites to determine presence of inborn errors of metabolismSuccinylacetone (elevated with tyrosinemia)Urine organic acidsAcylglycinesBacterial 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

developedSlide21

Differential Diagnosis: Intrahepatic CholestasisRed Flags That Require Early Intervention

Look forFailure to thrivePoor feedingLethargyHepatomegalySplenomegalyLaboratory testsHyperbilirubinemia (direct)Elevated liver function testsHypoglycemia,

especially

with absent urinary

ketones

HyperammonemiaSlide22

Differential Diagnosis of Treatable Disorders: Single-Gene DefectsIdentification and Early Intervention Can Make a Difference

TyrosinemiaBile acid synthetic disorders3-beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiencyAlpha-methylacyl-CoA racemase (AMACR) deficiencyAmino acid n-acyltransferase deficiencyBile acid CoA ligase deficiencyCholesterol 7-alpha-hydroxylase deficiencyDelta4-3-oxosteroid 5-beta-reductase deficiencyOxysterol 7-alpha-hydroxylase deficiency

Sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis)

Trihydroxycholestanoic acid CoA oxidase deficiencySlide23

Origins of Neonatal Cholestasis

Extrahepatic Bile DuctIntrahepatic Bile DuctHepatocytes

Biliary atresia

Bile duct hypoplasia

Bile duct duplication

Agenesis of extrahepatic ducts

Choledocholithiasis

Inspissated

bile syndrome

Miscellaneous

Panhypopituitarianism

Hypothyroidism

Neonatal hemochromatosis

TPN-associated cholestasis

Bile duct paucity

Alagile syndrome (JAG1, Notch2)

Nonsyndromic

Ductal plate malformation

Caroli disease

ARPKD, ADPKD

Von Meyenburg complexes

Indeterminant (neonatal hepatitis)

Viral infection (HSV, CMV)

Bacterial or parasitic infection

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 toxicitySlide24

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

.

Slide25

NASPGHAN/ESPGHAN Recommendations

The role of imagingThe 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]

Slide26

NASPGHAN/ESPGHAN Recommendations (cont)

The role of imagingLimited specificity precludes the use of the HBS scan as a stand-alone test in making a definitive diagnosis of biliary atresiaDefinitively-demonstrated bile flow (patency) by selective use of HBS may be of value in excluding biliary atresiaLimited 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]

Slide27

Diagnosis of biliary atresia

Cannot make diagnosis by lab tests, stool color, or physical examinationEvaluation 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 cholestasisCan 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

Recommendations (cont)Slide28

NASPGHAN/ESPGHAN RecommendationConsider 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 testsConsultation with pediatric surgeon for consideration of intraoperative cholangiogram

Fawaz R, et al.

J Pediatr Gastroenterol Nut

.

2016 Jul 16. [Epub ahead of print]

Slide29

Liver Biopsy for Biliary AtresiaDoes the Patient Need An Intraoperative Cholangiogram?

Hallmark featuresBile duct proliferationBile duct fibrosisBile duct plugsInflammationInfants 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

.

Slide30

Biliary Atresia

Biliary atresia: one or more bile ducts are abnormally narrow, blocked, or absentThe earlier the diagnosis is made and the earlier the surgical intervention is performed, the better the outcome50% can benefit from Kasai procedure[a]

Chardot C

, et al.

J Hepatol.

2013;58:1209-1217

.

Slide31

Therapies Are Available for Some Cholestatic Disorders

No effective therapies for cholestasis in generalEarly diagnosis with urine tests and gene tests/panels is important because there are therapies for some specific gene defectsCystic fibrosis, depending on the genotypeTyrosinemia, depending on the genotypeBile acid synthesis defectsSlide32

Concluding RemarksTake-Home Messages

Observer-assessment of jaundice is not a good or reliable marker of serum bilirubinConjugated hyperbilirubinemia (>1 mg/dL or > 35 µmol/L) is never normalShould prompt a referral to a pediatric gastroenterologist or hepatologistEarly detection, diagnosis, and referral!Slide33

AbbreviationsSlide34

Abbreviations (cont)