Kolestasis pada bayi

Dr.Wan Nedra, Sp.A

FK.YARSI JAKARTA Ined 10 Desember 06

Kolestasis:
- Kasus hepatologi yang paling sering IKA/RSCM
- Sering kasus hepatologi ini terlambat di rujuk
- Akibatnya ----> kasus kronik !!!

• Penyakit hati pd neonatus sering tidak diketahui etiologi,

sgt sering berhubungan dengan kuning

• Conjugated hyperbilirubinemia atau kholestasis pd bayi

selalu tanda penyakit hati atau penyakit empedu
• Divisi Hepatologi RSCM : 2002-2003:
162 kholestasis pd bayi
---- 37 ( 23%) Atresia Bilier (AB)
19/37 (51%) kasus AB: cirrhosis
( 150 ± 60 hari )
• Operasi Kasai: success rate 90% at < 8 minggu
early diagnosis !!!
 Kolestasis
Kegagalan drainase empedu  sekresi / pembentukan

- Phisiologis : bile flow 

- Patologis : pigment empedu ( + ) pd hepatosit & duktus biliaris

-
- Klinis : Kuning & gejala lain yang disebabkan oleh akumulasi
empedu

normal empedu tdd:bilirubin, asam empedu & kolesterol

-------- kerusakan sel hati

- Laboratorium : conj. bil. >1,0 mg/dl (total bil.< 5 mg/dl)

or > 20% of total bil. > 5 mg/dl
(Cholestasis Guideline Committee, JPGN 39;115-128, 2004)

Bayi :  pada usia 3 bulan pertama

Ilustrasi kasus
Wanita,2 bln
Kuning sejak lahir,b.a.k seperti the tua, b.a.b
dempul sejak umur 1 minggu.Keluarga: - ,
BL:3000 g,
P.F: ikterik , BB 4000 g, H: agak keras, rata,
nyeri -. Lien : S I.,.
Lab: Bilirubin direk 7,5 mg/dl, indirek
1,2mg/dl, SGOT 75 U/l, SGPT 60 U/l
GGT 600 U/l, Cholesterol 275 mg/dl
USG: Kantong Empedu tak terlihat
WD/: kolestasis ektrahepatik e.c atresia
bilier
- Terlambat merujuk:
. Follow-up kuning pd neonatus (-)/
direct bilirubin ?
. Perdarahan gastrointestinal. Penyakit/
coagulopathy: yg tidak baik
. Misdiagnosis: kolestasis (dir. bil.)?/
breast milk jaundice (indir.bil.)?
. False security:serum bil./pigmented
stool

- Evaluation diagnosis: sulit

- Penanganan dini:----> prognosis !!!
 •Cholates •Phospholipids

•Cholesterol

•Bilirubin
•Bile salts •Protein

•Ursodeoxycholates

•Lithocholates
•Chenodeoxycholates •Deoxycholates
 •Cholesterol
•Liver

•Primary c acid
•Chenodeoxycholic acid
•Choli
•Cholic acid
•Intestinal
bacteria

•Secondary
•Deoxycholic acid •Lithocholic acid •Lithocholic acid
•Intestinal
•Liver bacteria
•Liver
Tertiary

•Sulfolithocholic acid •Ursodeoxycholic acid

The biliary secretory apparatus
Major transport systems in bile
formation
 Pathogenesis

4
3
1

2 5

6
 Patogenesis

1.Penurunan uptake asam empedu:

- Hambatan transporter
( Na+ K+ ATP-ase / NCTP )
 endotoxin, estrogen
2. Penurunan transport intracellular:
- Perubahan homeostasis calcium intracellular
- Perubahan cytoskeleton ( microtubules/
microfilament):
 drugs, toxin
 Pathogenesis

3. Penurunan sekresi asam empedu cannalicular:

- defective synthesis and secretion :
inborn error
- Dysfungsi microfilament: androgen
- transporter ( MOAT ) : endotoxin
4. Penurunan permeabilitas paracellular: tight
junction: estrogen
5. Obstructive duktus biliaris Intrahepatik
6. Obstructive duktus biliaris Ekstrahepatik
 Diagnosis Diferential
Neonatal cholestasis

Intrahepatic Extrahepatic

Liver cells Biliary system Biliary syst.

(hepatocel.) (obstructive)

Genetic/metabolic: Paucity BA
- Galactosemia Caroli,etc
-PFIC Choledoc.cyst
-etc Biliary sludge /
Infection:viral,bacter.(sepsis/UTI) stone/plug
Toxic:TPN Idiopathic etc
 Dugaan Kolestasi intrahepatik pd neonatus

• Inefisien Uptake, transportation

asam empedu
• Conjugation, sulfatisation,
glucuronidation asam empedu 
• Mengecilnya ukuran pool asam empedu
• Konsentrasi garam empedu dan asam
empedu 
 Differential diagnosis
Intrahepatik:
1. Kelainan Genetic and metabolic
- KH : c/ galactosemia
- amino acid: e.g. tyrosinemia
- lipid : e.g. Gaucher’s disease
- bile acid : 3 B-hidroksisteroid
dehidrogenase/ isomerase
- chromosome : e.g. Down’s syndrome
- lain2: c/ alfa 1 antitrypsin deficiency,
cystic fibrosis , neonatal iron
storage disease
 Differential diagnosis

2. Kolestasis intrahepatik
- Displasia Arteriohepatic ( Alagille’s
syndrome)
- Nonsyndromic paucity of duktus
intrahepatic
- Byler’s disease
- Kolestasis berulang
- Kolestasis Herediter dg lymphedema
 Differential diagnosis
3. Hepatitis
- Infeksi : cytomegalovirus, rubella,
herpes, varicella, Echovirus,
Coxsacki, Reovirus type 3,
hepatitis B,C, toxoplasmosis,
leptospirosis, tuberculosis
- Sepsis Bacterial
4. Toxic : parenteral nutrition, drugs
5. Idiopathic:”idiopathic neonatal
hepatitis”
6. Immunologic : neonatal LE
 Differential diagnosis
Extrahepatik
• Atresia Bilier
• Kista duktus Choledokus
• Stenosis duktus biliaris
• Anomali hubungan Choledocho-
pancreatico-ductal
• Sindrom penumpukan empedu (Bile
plug syndrome)
• Cholelithiasis
• Kompresi duktus Biliaris
 differential diagnosis of
Kolestasis noenatal
• 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
Insiden
1. Atresia Bilier 25-30% 1:2500-10.000
lahir hidup (AB: obliterasi
progressive cholangiopathy 
cirrhosis/ kematian pd usia 1 thn)
2. Neonat.hepatitis Idiopatik 1:5000
3.  1 antitrypsin def. 1 : 20.000
 Cholestasis in infancy at King’s College Hospital
1970 -1990 (n:1086)
Diagnosis N %
• Biliary atresia 377 34,7
• Idiop. neon. hepatitis 331 30,5
  1 antitrypsin 189 17,4
• Other hepatitis 94 8,7
• Alagille syndrome 61 5,6
• Choledochal cyst 34 3,1
 Subdiv. Hepatology RSCM: 2002-2003
(cholestasis in infancy: 162 cases)

• Intr.Chol.: • Extra. Chol.:

119 (73,5%) 43 (26,5%)
- idiopathic:31(26,1%)
- UTI : 28(23,5%) - AB : 37 (86%)
- Sepsis :23 ( 19,3%) - Choledoc.cyst: 2
- CMV: 9 ( 7,6%) - ? : 4
- PFIC: 4 ( 3,4%)

- Alagille: 3 ( 2,5%)

- ? : 21 (17,6%)
Gejala klinis

• cholestatic syndrome :
 kuning
 urine gelap seperti teh
 BAB: intermittently
pigmentedacholic/dempul
• Gejala klinik lain yg disebabkan
kolestasi
 Cholestasis
( bile flow )
:
Retention/ Intraluminal bile acid
regurgitation concentration 
•- Malabsorption
- Bile acid - fat
* pruritus * malnutrition
* hepatotoxic * growth retardation
-- Bilirubin - fat soluble vitamin
* jaundice A-xerophthalmia
D-osteopenia
- cholesterol E-neuromuscular
* xanthoma degeneration
- *hipercholesterolemia
- - trace element -hemolytic anemia
(copper, etc) Progressive liver disease K-hypoprothrombinemia
-
( biliary cirrhosis)
Portal hypertension
Liver failure
• Diarrhea/
Hypersplenism Ascites Bleeding (varices) steatorhea
 Pendekatan Diagnostik
Every neonatal jaundice: > 2 weeks
(breast fed infants : 3 weeks)

cholestasis ? BA ?

Acutely ill Looked well

• Sepsis - BA
• UTI - Choledoch.cyst
• Metabolic - TPN
• etc -Alagille
-etc
 Pendekatan Diagnostik
The goal of management:
complete the diagnostic evaluation or
at least exclude Biliary atresia by 45-60
days

 Historical
 Physical exam.
 Biochemical/Lab. gambaran
 Ultrasound
 Histological
 Pendekatan Diagnostik

• Riwayat: kuning, urine gelap, pucat/ BAB

dempul,muntah, perdarahan
( sex, BW,morbidity, family history, source
of nutrition, drug used, transfusion) )
• Pemeriksaan Fisik: vital signs (general
health), weight, length (nutritional status),
lingkaran kepala, slit lamps (if necessary),
heart, abdominal wall, asites ,size/
consistency of the liver and spleen
 -------- Diagnostic

 Pemeriksaan BAB : 3 porsi

•Pagi
•Siang
•Malam
 Laboratorium/Biochemical
• Tentukan kolestasis: Bilirubin total & direk
• Tentukan kerusakan hati & disfungsi biliaris:
SGOT, SGPT, GGT, cholesterol
• Tentukan infeksi and gangguan metabolic (Tampak
sakit besat/tidak): kultur bakteri (darah, urine),
Protrombin Time, Gula darah, Urinalisis, serology
viral
• Diagnosis spesifik:
urgency untuk diagnosis atresia biliar (EHBA)
sehingga dapat dilakukan intervensi <60hari)
 Ultrasound:
• Atresia Bilier
* 12 jam puasa & setelah makan
 gallbladder tidak tampak atau menegcil
(non-visualized)
(Seteah makan: ukuran sama)
* triangular cord sign / cyst: liver hilum

• Intrahepatic: 4 – 6 jam puasa

. Puasa : ( + )
. Post fatty meal: <
Diagnostic accuracy: 80%
 Specific Investigations
Tergantung pd kondisi/gambaran klinis
• Serology unt infeksi
• CMV,Toxo, EBV, HSV, VDRL,
• Skrining Metabolic
• urine and serum amino and organic acids
• TFTs, and cortisol/GH jk 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 Alagille’s, PFIC
– Echo, spine XR, bone marrow examination, X-
rays of skull, long bones
Scintigraphy (Isotope Tc-DIBRIDA)
 Obstructive : intraluminal isotope ( - )
 Hepatocellular: - uptake : 
- intraluminal isotope:( + )

Realibility <<: Direct. bil.>>(> 20 mg%)

False + / - : 10 %
Time consuming
Cost
 Liver biopsy
• (should be done after the age of 1 month - gambaran
histologis AB)
• AB:
* bile ductular proliferation
* bile plugs
* portal / perilobular edema and fibrosis
* intact hepatic lobular architecture
• Kolestasis Intrahepatik / hepatitis neonatal:
* giant cell transformation
* Cytoplasma: ballooning

* Dapat menilai penyebab: viral inclusions,

abnormal storage material etc
 EHBA vs Neonatal Hepatitis
EHBA NH
Family History Rare 15-20%
Gender F>M M>F
Birth Weight Normal Often low
Onset jaundice Mean 23d Mean 11d
Acholic stools 75% Maybe
Firm Hepatomegaly 87% 53%

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

Kriteria klinik penting untuk membedakan
kolestasis intra dan ekstra hepatik
Cholestasis
Clinical data
Extrahepatic Intrahepatic
Stool colour
- pale 79% 26%  0,001
- yellow 21% 74%
Birth weight (g) 3226  45* 2678  55*  0,001

Acholic stool -age 16  1,5* 30  2*  0,001

(days)
Liver
- normal (%) 13 47
- enlarged
- normalconsistency 12 35  0,001
dense 63 47
hard/firm 24 6
* Mean ± SE ** N patients
Hasil Laboratoium pada awal kolestasis
Cholestasis
Extrahepatic Intrahepatic
Total.bil. 10,2  4,5 12,1  9,6
(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 Gb present

“triangular cord”
HIDA scan Normal uptake, Poor uptake, Nl .
no excretion excretion
Liver Biopsy Bd proliferation, Giant cells,
bile plugs, portal inflammation,
fibrosis focal necrosis

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

 Management

 Perubahan aliran empedu 

- Etiology
Extrahepatic : operative
Intrahepatic : non-operative

Biliary atresia: portoenterostomy

Kasai:60 days:success rate > 75%
90 days:success rate 20-30%
 Medical management of
cholestasis

Tujuan : mengurangi komplikasi:

• Nutrisi optimal untuk mengurangi efek
malabsorbsi
• Mengurangi gejala gatal-2, hiperlipidemia
• promote bile flow (reduce
hepatotoxicity)
- Bile flow inducer
 Phenobarbital : hepatic
microsomal enzymes inducer

- glucuronyl transferase
- cytochrome P-450
- N+ K+ ATP-ase

Dosis : 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/ komplikasi:
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
-
 Neonatus > 2 weeks/ breastfed inf. > 3 weeks: Jaundice,
darked colored urine, pale/acholic stool

acutely ill conjungated hyperbilirubinemia looked well

ALT,AST,PT
albumin, glukose,
GGT,cholesterol, culture ,serologic
triglyceride
USG

patency ( - ) patency ( + )
clin/lab/US)
notmatched culture

Biopsy infection( - )/ infection ( +)UTI

improvement (-)

paucity ( + ) bil atresia Neonat.hep.

medicamentosa
supportive/ op.cholangiog. sup/ symptomatis
symptomatis
improvement (+)
 Kesimpulan
Kolestasis: kondis patologis dari
sistem hepatobilier 
 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 !!!! (???)
* Get yourself motivated
to recognize cholestasis
early:
- Jaundice > 14 days
(breastfed: 3 wks) or
- Jaundice + dark
urine/acholic/
persistent light yellow stool

* Spread the knowledge

* Let’s work hand in hand
to overcome the problem
 Thank you

FK.YARSI JAKARTA Ined 10 Desember 06