Cholestasis in infancy

Julfina Bisanto

Department of child health FKUI/RSCM

Cholestasis:
- Most frequently hepatologic cases at
IKA/RSCM
- Most frequently referred hepatologic
cases
- ----> delayed -----> chronic cases!!!

- Delay in referral:
. Follow-up of neonatal jaundice (-)/
direct bilirubin ?
. Investigation hemorrh. disease/
coagulopathy: inadequate
. Misdiagnosis: cholestasis (dir. bil.)?/
breast milk jaundice (indir.bil.)?
. False security:serum bil./pigmented
stool
- Diagnostic evaluation: difficult
- Early management:----> prognosis !!!

 Liver disease in the neonate regardless of

aetiology, is frequently associated with
jaundice
Conjugated hyperbilirubinemia in
infants nearly always indicates liver or
biliary disease

Cholestasis :
Disturbance of formation, secretion or drainage of bile -->
physiological, morphological, clinical and biochemical changes

Physiologically: decrease in bile flow

Pathologically: presence of bile pigment in
hepatocytes and bile ducts
Clinically: accumulation of substances normally excreted in bile (e.g., bilirubin, bile
acids and cholesterol)

-------- liver

cell damage

Laboratory: conjungated bilirubin> 1.5 mg% /

first 3 months of age

bilirubin direk>1,5 mg% atau >20% dari total

penumpukan komponen empedu dalam sel hati
regurgitasi komponen empedu ke dalam plasma

kerusakan sel hati

>15% total bilirubin

Cholates

Phospholipids

Cholesterol

Bile salts

Protein

Bilirubin

Ursodeoxycholates
Chenodeoxycholat Deoxycholates
es

Lithocholates

Cholesterol
Liver
Cho
lic
acid

Primary

Chenodeoxycholic
acid

Cholic acid
Intestinal
bacteria
Secondary
Deoxycholic
acid

Lithocholic acid
Liver

Lithocholic acid
Intestinal
bacteria
Liver

Tertiary
Sulfolithocholic acidUrsodeoxycholic acid

The biliary secretory apparatus

Major transport systems in bile

formation

Pathogenesis

Pathogenesis
1
2
6

4
3

Pathogenesis
1.Decreased bile acid uptake :
- inhibition of transporter ( Na+ K+ ATP-ase / NCTP )
endotoxin, estrogen

2. Decreased intracellular transport :

- altered intracellular calcium homeostasis
- altered cytoskeleton ( microtubules/ microfilament):
drugs, toxin

Pathogenesis

3. Decreased cannalicular secretion of bile acids:

- defective synthesis and secretion : inborn

error
- microfilament dysfunction: androgen
- transporter ( MOAT ) : endotoxin
4. Increased permeability of paracellular

pathway: tight junction : estrogen

5. Intrahepatic bile ducts obstruction
6. Extrahepatic bile ducts obstruction

Differential diagnosis
Intrahepatic:
1. Genetic and metabolic disorders
-

carbohydrate : e.g. galactosemia

amino acid: e.g. tyrosinemia
lipid : e.g. Gauchers disease
bile acid : 3 B-hidroksisteroid dehidrogenase/
isomerase
- chromosome : e.g. Downs syndrome
- Others: e.g. alfa 1 antitrypsin deficiency,
cystic fibrosis , neonatal iron storage
disease

Differential diagnosis
2. Persistent intrahepatic cholestasis
- Arteriohepatic dysplasia ( Alagilles
syndrome)
- Nonsyndromic paucity of intrahepatic
ducts
- Bylers disease
- Benign recurrent cholestasis
- Hereditary cholestasis with lymphedema

Differential diagnosis
3. Hepatitis
- Infection : cytomegalovirus, rubella,
herpes, varicella, Echovirus, Coxsacki,
Reovirus type 3, hepatitis B,C,
toxoplasmosis, leptospirosis, tuberculosis
- Bacterial sepsis

4. Toxic : parenteral nutrition, drugs

5. Idiopathic:idiopathic neonatal hepatitis
6. Immunologic : neonatal LE

Neonatal susceptibility to
intrahepatic cholestasis
Uptake, transportation of bile acid
inefficient
Conjugation, sulfatisation,
glucuronidation of bile acid
Small size of bile acid pool
Base bile acid concentrationl

Differential diagnosis
Extrahepatic
Biliary atresia
Choledochal cyst
Bile duct stenosis
Choledocho-pancreatico-ductal
anomaly
Bile plug syndrome
Cholelithiasis
Bile duct compression

junction

Short differential diagnosis of

neonatal cholestasis
Anatomical: Biliary atresia, Choledochal cyst, Biliary
hypoplasia
Infectious : Toxoplasmosis, Rubella,CMV, Herpes S,
Syphilis
Metabolic : Galactosemia, Tyrosinaemia
Endocrine : Hypothyroidism, Hypocortisolism
Genetic
: Alagille syndrome, PFIC
Various
: Bacterial infection, esp. UTI

Incidence
1:2500-10.000 live births

25-30%
biliary atresia

--->. Idiopath. Neonat.hepatitis:1 : 5000

. Biliary atresia :
1 : 10.000
. 1 antitrypsin def. :
1 : 20.000
Improvement * radiological
* virology
* biochemical

---------> idiopathic <<

Relative frequency of various clinical

forms of neonatal cholestasis
5
Disease

Cumulative % f / 10 live births

"Idiopathic neonatal
hepatitis"
Biliary atresia

35-40

1.25

25-30

0.7

1-AT deficiency

7-10

0.25

Intrahepatic cholestasis

5-6

0.14

Inborn errors of BA
synthesis
CMV, Rubella, Herpes

<0.1

4-6

<0.1

Endocrine disorders

<0.1

Galactosemia

<0.1

Balistreri WF in Schiffs Diseases of the Liver, 8th ed. 1999;1357-1512.

CholestasisininfancyatKingsCollegeHospital
1970 -1990 (n:1086)
Diagnosis
Biliary atresia
Idiop. neon. hepatitis
1 antitrypsin
Other hepatitis
Alagille syndrome
Choledochal cyst

N
377
331
189
94
61
34

%
34,7
30,5
17,4
8,7
5,6
3,1

Clinical presentation
cholestatic syndrome :

jaundice
dark urine
stool: intermittently pigmented
acholic

clinical feature of disorders which

cause cholestasis
symptoms of chronic cholestasis

Consequences of chronic
cholestasis
Delivery of bile into small bowel
malabsorption of fat, fat soluble vitamins
Overflow of bile constituents into
systemic circulation pruritis, fatigue,
hypercholesterolemia, xanthoma formation
Hepatotoxicity from abnormally retained
substances (bile acids) portal
hypertension, cirrhosis

Cholestasis
( bile flow )

:
Retention/
regurgitation

Intraluminal bile
acid
- Malabsorption
concentration

- fat
* malnutrition
* growth retardation
- fat soluble vitamin
A-xerophthalmia
D-osteopenia
E-neuromuscular
degeneration

- Bile acid
* pruritus
* hepatotoxic
-- Bilirubin
* jaundice

- cholesterol
* xanthoma
-hemolytic anemia
*hipercholesterolemia
- - trace elementProgressive liver disease
K(copper, etc)
( biliary cirrhosis)hypoprothrombinemia
Portal hypertension

Liver failure

Hypersplenis Ascites Bleeding (varices)

m

Diarrhea/ steatorhea

Approach to cholestatic
infant
Confirm cholestasis
Assess severity of liver dysfunction
Exclude potentially treatable infectious
and metabolic disorders
Aim for specific diagnosis
urgency in diagnosis of biliary atresia (EHBA)
as prognosis depends on early (<60d)
intervention

Diagnostic evaluation
--> .History . illness
. family
. prenatal
. delivery (BW, infection)
. Perinatalmorbidity:
hypoglycaemic episode
. Parenteral nutrition,
drug, transfusion

Diagnostic evaluation

Physical examination: BW, BL, head

circumference
Liver/ spleen/ mass
Stool examination
: 3 portion

Initial Investigations
Confirm cholestasis
blood: bilirubin total and conjugated fraction
urine: bilirubin, urobilinogen

Exclude sepsis
urine, blood culture
Assess liver injury and cholestatic enzymes
ALT, AST, (AP), GGT

Assess liver synthetic function

PT / INR, glucose, albumin, cholesterol

Look for rapidly treatable conditions

serum glucose, urine reducing substances

Radiological examination
USG - 2 phase
* Biliary Atresia :
. fasting
: ( - ) / small
. post fatty meal : same
+triangular cord (+)
* Intrahepatic :
. fasting
: ( + )
. post fatty meal
:
----> Diagnostic accuracy : 80%

Specific Investigations
Serology for infection
CMV,Toxo, EBV, HSV, VDRL,

Metabolic screen
urine and serum amino and organic acids

TFTs, and cortisol/GH if suspect hypopit.

Serum iron, ferritin, transferrin saturation
Galactose-1-phosphate uridyl transferase

Very specific investigations

Hepatobiliary scintigraphy (HIDA scans)

ERCP
Intraoperative cholangiogram,
Liver biopsy / repeated
Also
serum and urine bile acids
Genetic testing for Alagilles, PFIC
Echo, spine XR, bone marrow examination, Xrays of skull, long bones

Scintigraphy (Isotope Tc-DIBRIDA)

obstructive : intraluminal isotope ( - )
Intrahepatic: - uptake :
- intraluminal isotope : ( + )
Realibility <<: . Direct. bil. >> (> 20 mg%)
. False + / - : 10 %

 Liver biopsy : accuracy : 95-96,8%

Intrahepatic :.
. Giant cell transformation
. cytoplasma: ballooning
Extrahepatic : - bile duct dilatation,
- bile plug
- duct. proliferation

EHBA vs Neonatal Hepatitis

EHBA

NH

Family History

Rare

15-20%

Gender

F>M

M>F

Normal

Often low

Onset jaundice

Mean 23d

Mean 11d

Acholic stools

75%

Maybe

Firm Hepatomegaly

87%

53%

Birth Weight

Alagille D. Prog Liver Dis 1979;6:471-485

Most important clinical criteria to

Cholestasis
differentiate
intra and extrahepatic
Clinical data
Extrahepatic Intrahepatic
cholestasis
Stool colour
- pale
- yellow
Birth weight (g)
Acholic stool -age
(days)
Liver
- normal (% )
- enlarged
- normalconsistency
dense
hard/ firm

79%
21%
3226 45*

26%
74%
2678 55*

0,001

16 1,5*

30 2*

0,001

13

47

12
63
24

35
47
6

* Mean SE ** N patients

0,001

0,001

Initial laboratory data of neonatal

cholestasis
Cholestasis
Extrahepatic I ntrahepatic
Total.bilirubi
10,2 4,5
12,1 9,6
n (mg/ dl)
Conj.
6,2 2,6
8,0 6,8
bilirubin
(mg/ dl)
SGOT
< 5x
> 10x/ >800
SGPT
< 5x
> 10x/ >800
GGT
> 5x/ 600
< 5x

Investigating EHBA vs NH
Investigation

EHBA

NH

Duod. Aspirate

No bile

Bile present

Ultrasound

Gb absent/small
triangular cord
Normal uptake,
no excretion
Bd proliferation,
bile plugs, portal
fibrosis

Gb present

HIDA scan
Liver Biopsy

Poor uptake, Nl .
excretion
Giant cells,
inflammation,
focal necrosis

Suchy FJ in Liver disease in Children, 2nd ed. 2000;187-194

Liver biopsy
Most important diagnostic tool
will diagnose EHBA in 90-95% cases
main potential problem is if biopsy too early,
histological changes of EHBA evolving
100% sensitive but 76% specific in detecting
EHBA
Zerbini MC et al Mod Pathol 1997;10:793-799

also useful in assessing aetiology of

cholestasis as can detect viral inclusions,
abnormal storage material in cells etc

Diagnostic accuracy
Lai MW et al JPGN 1994; 18; 121-127

126 infants studied prospectively

42 EHBA, 84 NH

Diagnostic accuracy of methods

96.8% liver histology
91.6% duodenal juice
84.2% peak radioisotope in duodenal
juice (HIDA)
80.2% ultrasound
80.2% persistent pale stools

Management
Bile flow improvement
- Etiology
Extrahepatic : operative
Intrahepatic : non-operative
Biliary atresia: portoenterostomy
Kasai:60 days:success rate > 75%
90 days:success rate 20-30%

Surgical procedure
Intraoperative cholangiogram and liver
biopsy
Look for features of EHBA
coarse, fibrotic, brown-green liver with
subcapsular telangiectasia

Experience of surgeon very important in

outcome

Medical management of
cholestasis
Aim to reduce complications:
optimise nutrition to reduce effects of
malabsorption
symptomatic treatment of itch,
hyperlipidemia
promote bile flow (reduce hepatotoxicity)

- Bile flow inducer

Phenobarbital : hepatic
microsomal enzymes inducer
- glucuronyl transferase
- cytochrome P-450
- N+ K+ ATP-ase
Dose : 3-10 mg / kg BW/day

 Ursodeoxycholic acid :
- Competitive binding of toxic bile acids
- Bile fow inducer
- Bile acid supplement
- Hepatoprotector
Dose : 10-30 mg / kg BW / day

Cholestyramine :
- Bind bile acids, cholesterol, drug, other toxic agents
- relief pruritus
Dose : 0,25-0,5 g / kg BW / day

Rifampicin :

- microsomal enzyme activity

- inhibition of bile acid uptake
Dose : 10 mg / kg BW / day

 Supportive :
- Nutrition : MCT
- Vitamin :
A : 5000-25000 U/day
D : D3 -Calcitriol:0,05 -0,2 ugr/kgBW/day
E : 25-50 IU/kg BW/day
K : K1 2,5-5 mg/ 2-7x /week
- Mineral and trace element : Ca, P, Mn, Zn,
Selenium, Fe.
Th/ complication : e.g.
hyperlipidemia/xantelasma colestipol
Liver failure: transplantation !!!!(???)

Nutritional management
Calories
aim for 125% of RDA based in ideal body wt
may need supplemental tube feeds

Fat
MCT better absorbed than LCT so consider
using these formulae eg. Pregestamil, Pepti
Junior

Protein
aim for 2-3 g/kg/d unless encephalopathic
branched chain amino acid formula improves
nutritional status

Nutrition management 2
Essential Fatty Acids
linoleic, linolenic, arachidonic acids
may need supplementing with corn, safflower,
walnut oil or lipid emulsions

Fat Soluble Vitamins

vitamins A, D, E, K
may need to monitor levels

Water Soluble Vitamins

unknown whether deficient in cholestasis
recommend 1-2 x RDA

General management
Immunization
Dental hyegine

Prognosis

Idiopathic neonatal hepatitis :

* Sporadic: good (recovery: 60% )
Familial : poor ( t 60% )

Biliary atresia : Surgery (-) : age 2 y

Surgery (+): < 60 days: 91%
61-70 days: 56 %
71-90 days: 31 %
> 90 days: 17%

Post Kasai survival

Bile flow + :
1996: 5 years : 47 - 60 %
10 years : 25 - 35 %
2002: 5 years : 75 % ( Netherland)
20 years : 50 % (U.S)
Bile flow : almost all within one year
after surgery

Jaundice, darked colored urine, pale/acholic stool

conjungated hyperbilirubinemia

ALT,AST,GGT,PT,albumin,cholesterol,triglyceride,bile acid, glucose

Urine: leucocyte, reduction, culture ,TORCH, met.screening: : TSH,FT4

USG
patency ( - )
Biopsy

patency ( + )
infection ( - )

infectio n ( + ),

UTI
paucity ( + )

bil atresia

supportive/
symptomatis

op.cholangiog.

Biopsy
Neonatal hep.

medicamentosa

Cholestatic cases at IKAFKUI/RSCM

February 1991-January 2000 ( 8 years )
N : 203
Sex : male : 129 ( 63,5 % )
female : 74 ( 36,5 %)

Age :

1 month - 19 months

< 1 month :

18 ( 8,9 % )

> 1-2 months : 64 ( 31,5% )

> 2-4 months : 77 ( 37,9% )

59,6%

> 4 months :

(!!!)

44 ( 21,7% )

Intrahepatic: 141 (69%), cirrhosis 11(7,8%)

? CMV
: 46
Toxoplasmosis : 1
Metabolic
:2
Hemangioma : 1

HBV : 1
Sepsis : 1
Alagille: 2

Extrahepatic : 62 (31%), cirrhosis

18(29%)
biliary atresia
choledochal cysts

: 35
: 12

bile plug syndromes : 15

Conclusion

Cholestasis: a pathologic condition of

hepatobiliary system
should be early recognized:
jaundice, dark urine, pale --> acholic stool

extrahepatic or intrahepatic ? ----->

perinatal history, stool color and laboratory findings

early intervention/ management : based on

etiology (if possible)

supportive treatment : . Nutrition/ vitamin

. Symptomatic
-->>Liver failure : transplantation !!!! (???)

FINAL MESSAGE