Fatima Safira Alatas

Gastrohepatology Division, Department of Child Health,

Universitas Indonesia, Cipto Mangunkusumo Hospital

PICU NICU Update, Bali, 2018

 Objectives
• To know when cholestatic liver disease should be suspected in
infant who has jaundice

• How to evaluate a neonate with conjugated hyperbilirubinemia

• To understand the differential diagnosis for neonatal cholestasis

 Disclosure

“I have no actual or potential conflict of

interest in relation to this
program/presentation”
 Pediatric Gastrohepatology Patients in Cipto
Mangunkusumo National Hospital 2013-2017
49%

Diseases of the digestive

system(K00-K95)

4780 Certain infectious and

patients parasitic diseases (A00-
4914 B99)
patients

51%

9.694 pediatric visits to pediatric GI clinic

for their primary or secondary diagnosis.
 20 Most Common Diseases of Digestive System in Cipto
Mangunkusumo Hospital 2013-2017
600
Obstruction of bile duct

Gastro-esophageal reflux disease without esophagitis

Functional dyspepsia

500 483 Umbilical hernia without obstruction or gangrene

Constipation

Other specified disorders of gingiva and edentulous

alveolar ridge
Gastritis, unspecified
400
Other acute gastritis
353
Gastrointestinal hemorrhage, unspecified

Other and unspecified cirrhosis of liver

300 Acute appendicitis, unspecified

Caries of dentine
247
Other forms of stomatitis
214
Acute appendicitis with generalized peritonitis
200 186
Other and unspecified intestinal obstruction
158
144 Hematemesis
134 132
118 116 113
104 98 Pulpitis
100 90
80 78 75 74 Peptic ulcer, unspecified as acute or chronic, without
73
haemorrhage or perforation
Necrosis of pulp

Umbilical hernia without obstruction or gangrene

0
Diseases of Digestive System
 Jaundice
• Jaundice or icterus clinically evident (visually) when serum
bilirubin exceeds 2.5 to 3.0 mg/dL (42 – 51 micromol/L)

• Jaundice at 2 weeks of age is relatively common finding

(2.4-15% of healthy looking newborn)

Alert

Should be evaluated
Cholestasis OR Non cholestasis

Check:
serum total bilirubin and direct bilirubin
Screen for “red flags”
 Time of appearance
<24 hrs of life Hemolytic disease of newborn: Rh, ABO and
minor group incompatibility
Infections: intrauterine viral, bacterial; malaria
G-6PD deficiency
24-72 hrs of life Physiological
Sepsis neonatorum
Polycythemia
Concealed hemorrhages: cephalhematoma, SAH, IVH
Increased enterohepatic circulation
> 72 hrs Sepsis neonatorum'
Neonatal hepatitis
Extra hepatic biliary atresia
Breast milk jaundice
Metabolic disorders

cause remains uncertain multifactorial in origin

in 1/3 of cases
Why do we have to evaluate bilirubin fraction?
• Jaundice is the visible manifestation of chemical
bilirubinemia
– In neonates, evaluation of sclera is difficult because of
physiological photophobia

– Almost 60% term and 80% preterm will have total

serum bilirubin >5 mg/ dL in the first week of life and
become clinically jaundiced
Nelson Textbook of Pediatrics.17th ed
Without blood N Engl J Med 2006;354:1889-1900
examination we hardly
can evaluate cholestasis in
neonates
 Definition of Cholestasis
• Diminished bile 2017formation
Guidelinesorfrom
flow, and is
manifested by abnormal
ESPGHAN conjugated
and NASPGHAN
hyperbilirubinemia:
–an
a conjugated
abnormalbilirubin ˃1 mg/dL, if the
direct/conjugated total is
bilirubin
bilirubin is ˂5 mg/dL
defined as :
– aaconjugated
serum valuebilirubin
>1.0level ˃20%(17mmol/L)
mg/dL of the total
bilirubin, if the total bilirubin is ˃5 mg/dl
JPGN 2017;64: 154–168
Bishop WP. Paediatric Practice Gastroenterology
 Prevalence

Neonatal cholestasis
1 in 2500 live birth

Biliary atresia
1 in 10000 to 15000 infants

Idiopathic neonatal hepatitis

1 in 5000 to 10000 live birth
McKiernan PJ et al. Lancet 2000
 “Cholestasis”
• Conjugated hyperbilirubinemia due to :
– Impaired bile formation (hepatocytes)
– Impaired bile flow (bile ducts/ductules)

• Consequences :
– Secondary liver damage
• Bile acid-induced hepatocyte injury
• Secondary biliary cirrhosis

– Failure of substances secreted in bile to reach intestine

• Bile acid deficiency in gut
• Fat malabsorption/fat-soluble vitamin malabsorption
 “Clinical Features”
• Pruritus
• Fatigue
• Xanthomas
• Hepatic Osteodystrophy : back pain from osteoporosis
• Pale stools/steatorrhea
• Evidence of fat-soluble vitamin deficiency
• Enlarged liver with a firm smooth non-tender edge
 Differential diagnosis of neonatal cholestasis
Category
Extrahepatic causes
Intrahepatic causes
Familial (inherited) causes of
intrahepatic cholestasis
Disorders of embryogenesis
Disorder of membrane transport
and secretion
Causes of neonatal cholestasis
Biliary atresia
Choledocal cyst; Caroli’s disease
Inspisated bile syndrome
Spontaneous perforation of bile duct
Neonatal sclerosing cholangitis (NSC)
Alagille syndrome
Ductal plate malformation (Caroli’s disease)
Disorder of canalicular secretion
Bile salt export pump (BSEP) deficiency
• PFIC type 2 (progressive)
• BRIC type 2 (benign, recurrent)
Phospholipid transport – MDR3 deficiency
• PFIC type 3
Ion transport
• Cystic fibrosis
FIC1 deficiency
• PFIC type 1 (progressive)
• α -antitrypsin deficiency
Differential diagnosis of neonatal cholestasis……………..
Category Causes of neonatal cholestasis
Intrahepatic causes (contd….)
Disorder of bile acid biosynthesis Bile acid synthetic enzyme deficiencis
and conjugation
Metabolic disorders Cystic fibrosis
Galactosemia
Tyrosinemia type 1
Citrin deficiency
Neonatal hemochromatosis, etc
Sporadic causes of intrahepatic
cholestasis
Infections Bacterial, viral, sepsis, syphilis, TORCH
intrauterine infections
Endocrinopathies Congenital hypothyroidism
Congenital hypopituitarism
Toxin effect Drug induced, Parenteral nutrition induced
Miscellaneous Neonatal hemophagocytic lymphohistiocytosis
Neonatal lupus
 Cholestatic liver diseases
Causes of neonatal cholestasis in
Dr. Cipto Mangunkusumo National Hospital, Jakarta
No Etiology Percentage

1 Biliary atresia 23

2 Urinary tract infection 17

3 Sepsis 14

4 CMV Infection 5.5

5 Alagille syndrome 2

6 Others 9.5
 Number of patients referred to Cipto
Mangunkusumo Hospital

New cases of suspected Biliary Atresia in

Cipto Mangunkusumo Hospital, Jakarta
80 73
70
60 55
50
40 34 34
30
20
11
10 3
0
2012 2013 2014 2015 2016 2017
Number of patients 7 (July 2017)
Gender 86% Female
Age when first diagnosed/
referred to tertiary care 59.33 days (range : 51-116 days)

Age when Kasai Procedure was

performed 76.33 days (range : 71 -122 days)

Recurrent ascending
Outcome
cholangitis/sepsis/malnutrition

Not Good
 | DEFINITION 18
WHAT IS BILIARY ATRESIA?

“ Biliary atresia: a state characterized

by progressive obliteration of the
extrahepatic and intrahepatic
biliary ducts which causes
resistance of the bile flow and

”
chronic cholestasis in infants.

4. Moreira RK, Cabral R, Cowles RA, Lobritto SJ. Biliary atresia: a multidisciplinary approach to diagnosis and management. Arch Pathol Lab
Med. 2012;136:746-60 .
5. Gu YH, Yokoyama K, Mizuta K, Tsuchioka T, Kudo T, Sasaki H, dkk. Stool color card screening for early detection of biliary atresia and long-
term native liver survival: a 19-year cohort study in Japan. J Pediatr. 2015;166:897-902.
. | CLINICAL MANIFESTATION Stool color
19
Classical Triad

APPEARS AS
A HEALTHY,
NORMAL
1 2 3
JAUNDICE PALE DARK
BABY STOOL URINE
Difficult to With stool color card
differentiate with Sensitivity 89.7%
physiologic jaundice Specificity 99.9%
PPV 28.6%
NPV 99.9&

Portal hypertention  Sphlenomegaly + Ascites (NOT OBVIOUS AT EARLY STAGE!)

Wang KS. Newborn screening for biliary atresia. Pediatr. 2015;136:1663-9.
| OHI CLASSIFICATION 20
86-90%

“
5-12%

2%

I II II

”
I 4,5

Atresia of the distal bile duct.

Patent hepatic duct, cystic duct, and
gallbladder

Atresia of the hepatic duct with or

without atresia of bile duct, cystic
duct, or the gallbladder.
Or
Atresia of the bile duct and cystic duct
of the bile
Patent hepatic duct and gallbladder

Atresia of the hepatic duct,

Wang KS. Newborn screening for biliary atresia. Pediatr. 2015;136:1663-9. gallbladder, and the cystic duct
 | DIAGNOSIS WORKUP 21

LAB + RADIOLOGY
+ HISTO-
PATHOLOGY
+ GOLD
STANDARD

Cholestasis
>> Liver Function
Ultrasonography Liver Biopsy Intraoperative
98% accuracy (operator 85% accuracy Cholangiography
GGT >300 IU/L dependent) (if done by an 100% diagnostic
(98.1% specific) Radionucleotide expert)8 accuracy
Persistent coagulopathy scintigraphy
Hypoalbuminemia
Early detection !
66% compared to 49% - the first 60 days.
Early Kasai Porto Enterostomy, Higher Native Liver Survival Rate (>20%)
Gu YH, Yokoyama K, Mizuta K, Tsuchioka T, Kudo T, Sasaki H, dkk. Stool color card screening for early detection of biliary atresia and long-term native liver survival: a 19-year
cohort study in Japan. J Pediatr. 2015;166:897-902.
How to evaluate a
JAUNDICED
Infant?
 “Case scenario”
• A 2-month-old infant who has been referred from a general
practitioner (GP) for persistent neonatal jaundice. His total
bilirubin level done by GP was 6 mg/dL.

• He was born at term, vaginal delivery, AGA, he was noted to

be increasingly jaundiced over the past 2 weeks.

• At examination, he appears well-thrived but deeply jaundiced,

no pallor. He is vigorous, has a firm hepatomegaly measuring
5 cm from the right costal margin and a palpable splenic tip.
No ascites.
• His stool looks cream-colored and his mother said the stool
have changed from green/black to this paler color over the
past three weeks.
 “Case scenario”
• A 2-month-old infant who has been referred from a general
practitioner (GP) for persistent neonatal jaundice. His total
Inbythis
bilirubin level done kind6 mg/dL.
GP was of case

• He was born at term, vaginal delivery, AGA, he was noted to

Please DO NOT
be increasingly jaundiced over the past 2 weeks.
asked the mother to put the child
• underhethe
At examination, morning
appears sun without
well-thrived but deeply jaundiced,
no pallor. He is vigorous, has a firm hepatomegaly measuring
further
5 cm from the right costalexamination!!
margin and a palpable splenic tip.
No ascites.
• His stool looks cream-colored
Find some and his mother
cardinal signs!!said the stool
have changed from green/black to this paler color over the
past three weeks.
 Parameters of clinical interest in the history of the
cholestatic infant
Family history
Consanguinity
Neonatal cholestasis in the parents of siblings
History of repeated fetal loss or early demise
Hemolytic diseases
Prenatal history
Prenatal ultrasonography findings
Cholestasis of pregnancy
Maternal infections
Infant history
Gestational age
SGA
Glucose-6-P-dehydrogenase deficiency, hydrops fetalis
Neonatal infection
Stool color
Urine characteristics (smell and color)
Irritability, lethargy
Abdominal surgery, Breast milk, formula, Parenteral nutrition
 Physical findings in children
with neonatal cholestasis
Assessment of Ill appearance may indicate infection or metabolic
general health disease, infants with biliary atresia typically appear
well
General appearance Dysmorphic features: Alagille syndrome in the
neonate rarely exhibits characteristic facial
appearance with a broad nasal bridge, triangular
facies, and deep-set eyes. Typical facial features
may appear at around 6 months of age, but are
often nonspecific
Vision/slit lamp Congenital infection, storage disease, septo-optic
examination; dysplasia, posterior embryotoxon, cataracts, CMV
Hearing infection
Cardiac Congenital heart disease: Alagille syndrome,
examination: biliary atresia splenic malformation syndrome
murmur, signs of
heart failure
Physical findings in children with neonatal cholestasis………….

Cardiac examination: Congenital heart disease: Alagille

murmur, signs of heart failure
Abdominal examination
Stool examination (crucial—the
primary physician should make
every effort to view stool pigment) obstruction
syndrome, biliary atresia splenic
malformation syndrome
Presence of ascites; abdominal
wall veins, liver size and
consistency, spleen size and
consistency (or absence),
abdominal masses, umbilical
hernia
Acholic or hypopigmented stools
suggest cholestasis or biliary
 “Clue from history”
Prolonged jaundice > 2 weeks after birth
Pale stool Persistent : BA; Intermittent: INH
Dark urine Cholestasis
Abdominal distention Organomegaly
Lethargic/Vomitting Galactosemia, neonatal infection
Pruritus Cholestasis
Antenatal
Fever/Rash TORCH
Abortion/miscarriage Metabolic
Gestational age Term: BA; Preterm: INH
Birth weight AGA : BA; SGA/LBW: INH/genetic
Postnatal Hypothyroidism
Onset of jaundice, Poor feeding,
Lethargy, Hoarse cry, Constipation,
Delayed passage of meconium
 “Clue from physical examination”
Appearance
Irritable, lethargic
Dysmorphic
Head
Wide anterior fontanelle
Seborrheic Dermatitis
Wide frontal/forehead
Heart
Murmur/cyanotic signs
Abdomen
Pott belly, Umbilical hernia
Splenomegaly
Right hypochondriac mass
Congenital infection
Metabolic diseases
Alagille syndrome
Down syndrome; Hypothyroidism
Organomegaly
Hypothyroidism; Down’s syndrome
Histiocytosis X
Alagille syndrome
Alagille syndrome; Down’s syndrome
Hypothyroidism
BA, Congenital infection
Choledochal cyst
 Investigations
Initial investigations Fractionated Bilirubin, Liver function test
Additional (according CBC, Urinalysis, Cultures of blood & urine
to clinical findings) Serum T4, TSH
To detect metabolic conditions- Urinalysis
(glucose reducing substance), blood gas analysis
TORCHS IgM screening
To differentiate Imaging studies
extrahepatic from • Ultrasonography  very important, fasting
intrahepatic & post fatty meal
cholestasis (Absent/Small/non visualized gall bladder, lack of
post prandial contraction of GB, Triangular cord sign,
Choledochal cyst, Choledocholithiasis, biliary
sludging, Perforation of bile duct)
• Hepatobiliary scintigraphy
• MRCP
Percutaneous liver biopsy
Intraoperative cholangiography
 Hepatobiliary Scintigraphy

HIDA: 99m Tc labelled imino-diacetic acid

• Neonatal Hepatitis: delayed uptake, normal excretion
• Biliary Atresia: normal uptake, absent excretion
 Histologically

Proliferation of the ductulus Bile plugs (bilirubinostasis)

Small-bile-duct destruction Feathery degeneration of
hepatocytes (cholate stasis)
Peri cholangitis
Bile lakes and infarcts
Portal edema
Biliary cirrhosis
“Practical algorithm” Neonatal Jaundice

Unconjugated hyperbilirubinemia Conjugated hyperbilirubinemia (direct)

(indirect)
Pigmented stools Pale stools
• Physiological
jaundice
• Hemolysis Investigations Inspisated Choledochal Liver biopsy
• Breast milk bile malformation
jaundice
• Gilbert‘s syndrome
• Crigler-Najjar Congenital Diagnosis of Abnormalities NSC Metabolic Endocrine
syndrome type 1 infections exclusion of the bile acid diseases diseases
and 2 Multifactorial- metabolism Galactosemia Hypopituitarism
sepsis, Tyrosinemia Hypothyroidism
prematurity, CF,
hypoxia, PN Lysosomal
storage/
Peroxisomal
disease

Abnormalities Bile duct paucity PFIC Biliary Atresia

of the bile acid Alagille syndromes Idiopathic
metabolism nonsyndromic neonatal hepatitis
α1-antitrypsin def,
NSC: Neonatal sclerosing cholangitis; CF: cystic fibrosis NSC