CHOLESTASIS

HASRI SALWAN
BAGIAN IKA FK UNSRI /
DEP KES ANAK RSMH PLG
Sebagian slide diambil dari:
Julfina Bisanto, Hanifah Oswari

Kolestasis :
Hambatan sekresi dan/atau aliran empedu
3 bln pertama (prolong jaundice)
Laboratoris:
bil. direk >1,5 mg% atau
>20%dari bil.total yang
Presence of jaundice with a conjugated bilirubin fraction
>15% of total bilirubin concentration (or > 1.5 mg/dl)
in any infant beyond 2 weeks old

Unconjugated hyperbilirubinemia
in older : harmless
in neonate (immature BBB): associated
with deposition of free bilirubin in neuronal
tissue and brain damage.
first appreciated in the head and progresses
caudally to the palms and soles as the serum
bilirubin increases.

Conjugated bilirubin:
elevated level: present liver disease in the
neonate.
not toxic
Clinically jaundice: the serum bilirubin
concentration
in the older child: 23 mg/dL,
in the neonate: 5 mg/dL.

Cholestasis :
Physiologically : decrease in bile flow
Pathologically : the histologic presence of bile
pigment in hepatocytes and bile ducts,
Clinically : the accumulation in blood and
extrahepatic tissues of substances normally
excreted in bile (e.g., bilirubin, bile acids, and
cholesterol).
Neonate: clinical and laboratory features of the many
liver diseases presenting with cholestasis are quite
similar.

Kolestasis masalah, karena:

Rujukan sering terlambat o.k.
Tidak difollow-up: ikterus neonatorum /pem. fraksi
bilirubin
investigasi koagulopati : tidak dilakukan
misdiagnosis kolestasis (bil. dir.) sebagai hum. milk
jaundice (bil.indir.)
rasa aman palsu o.k.bil.serum/pigmen tinja (+)
Evaluasi diagnostik tidak mudah
Penanganan dini menentukan prognosis

Karena itu agar kolestasis tidak bermasalah,

seharusnya para dokter mengetahui :
* etiologi
* patofisiologi
* evaluasi diagnostik
* tatalaksana
* prognosis

Usaha pertama adalah mengetahui penyebab

kolestasis yang bisa diobati, kemudian dirujuk segera
The initial goal must be to exclude rapidly lifethreatening but potentially treatable disorders such
as
gram-negative infection,
endocrinopathies (ex: panhypopituitarism),
galactosemia, and inborn errors of bile acid
metabolism.
Atresia billier / cyst

Pada bayi sering terjadi hiperbilirubinemia indirek

bukan direk

Predisposisi kolestasis pada neonatus, krn:

Ambilan , transportasi asam empedu
belum efisien
Konjugasi, sulfatisasi,glukuronidasi asam
empedu
Ukuran bile acid pool kecil
Konsentrasi as. empedu basal serum

Hiperbilirubinemia indirek dianggap normal,

jika:
Terjadi setelah umur 3-4 hari
Menghilang setelah 10-14 hari
Kadar billirubuin total < 12-15
Karena breast milk jaundice

Unit sekresi bilier

Sistem transportasi utama pada

pembentukan empedu

Patogenesis

1
2
6

4
3

INCIDENCE
Cholestasis: 1 in 2500 live births.
Idiopathic neonatal hepatitis : 1 in 4800 9000 live births, the most common in older
Biliary atresia : 1 in 8000 - 21,000 live
births, more frequently in Far Eastern

Insiden: 1 : 2500 kelahiran hidup

Hep. neonatal idiopatik:1 : 5000
Atresia bilier :
1 : 10.000
Def. 1 antitripsin :
1 : 20.000
Kemajuan: pencitraan, virologi, biokimia
---------> idiopatik berkurang

DIFFERENTIAL DIAGNOSIS OF NEONATAL

CHOLESTASIS

Diagnosis Diferensial Kolestasis Intrahepatik

1. Kelainan metabolik
-

karbohidrat : mis. galaktosemia

asam amino : tirosinemia
lemak
: mis. penyakit Gaucher
as. empedu : 3 -hidroksisteroid
dehidrogenase/isomerase
- lain-lain : mis. def. 1 antitripsin, fibrosis
kistik, neonatal iron storage

Diagnosis Diferensial

2. Kelainan kromosom
Mis.: sindrom Down
3. Penyakit intrahepatik yang etiologinya
tidak diketahui:
* kolest. intrahep. persisten idiopatik :sindrom
Alagille
* kolest. intrahep. Rekuren : kolest. familial
rekuren benigna

Diagnosis Diferensial
4. Hepatitis
Infeksi :
* virus: CMV, rubella, herpes, varisela,
Echovirus, Coxsacki,
Reovirus tipe 3,
hepatitis A, B,C.
* lain: sifilis, toksoplasma, leptospirosis,
tuberkulosis
5. Toksik: nutrisi parenteral, obat,sepsis
6. Imunologik : LE neonatal
7. Lain-lain : histiositosis

Diagnosis Diferensial

Kolestasis ekstrahepatik
-

Atresia bilier (90%)

Kista duktus koledokus (5%)
Koledokolitiasis
Stenosis duktus biliaris
Anomali choledochol-pancreatico-ductal
junction
- Bile plug syndrome
- Kompresi duktus biliaris ekstrinsik

Gejala klinik
sindrom kolestasis :
* ikterus
* urine berwarna gelap
* tinja pucat akholik

gejala penyakit dasar

gejala sekuele kolestasis kronik

Kolestasis

(aliran empedu )
Konsentrasi asam
Retensi/regurgitasi :
empedu
- Asam empedu
intraluminal
* Malabsorpsi
pruritus
hepatotoksik
- Bilirubin
ikterus
- Kolesterol
xantomatosis

hiperkolesterolemia
- trace element
(tembaga, dll)

lemak
* malnutrisi
* retardasi pertumbuhan
* diare/steatorea

vit. larut dalam lemak

A - kulit tebal,rabun senja
D - osteopenia
E - degenerasi
neromuskuler

Penyakit hati progresif

- anemia hemolitik
(sirosis bilier)
K - hipoprotrombinemia

Hipertensi porta

Hiperspleni Asites
sme

Perdarahan
(varises)

Mineral (Ca dll)

Gagal hati

Evaluasi diagnostik
Segera bedakan:
* Kolest. hepatoseluler / intrahepatik ?
* Kolest, obstruktif ( atresia bilier!) ?
Anamnesis:
riwayat penyakit keluarga (Genetik)
Prenatal (TORCH)
kelahiran (BL, infeksi)
morbidibitas perinatal
nutrisi parenteral, obat, transfusi

Pem. fisik :
BB/ TB/ lingkaran kepala
Hepar/ lien / massa abdomen
Pemeriksaan tinja: tinja 3 porsi
Pem. penunjang :
Laboratorium rutin dan khusus
- Rutin : darah perifer lengkap, fraksi
bilirubin,
transaminase, GGT, alkali fosfatase, PT, elektroforesis
protein, kolesterol, gula darah,
ureum,
kreatinin,urinalisis
- Khusus: defisiensi 1 antitripsin, TORCH

EHBA vs Neonatal Hepatitis

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

Investigating EHBA vs NH

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

Kriteria klinis terpenting untuk

membedakan kolestasis ekstrahepatik
dan intrahepatik

* Mean SE ** Jumlah pasien

Data laboratorium awal pada bayi kolestasis

Pencitraan
USG hepatobilier- 2 fase
puasa dan 1-2 jam setelah minum
* Atresia bilier
. puasa
: ( - ) / kecil
. post fatty meal : tidak berubah
* Kol. intrahepatik
. puasa
:(+)
. post fatty meal : mengecil
----> Akurasi diagnostik: 80%

Ultrasound:
Prenatal: type 1 / 2 BA (rare): suspected
cystic structure in liver hilum
post natal US should be performed
DD/ choledochal cyst
US :
* 12 hours fasting and after feeding
gallbladder is not visualized/ small
(after feeding : same size )
* triangular cord sign / cyst: liver hilum

USG Doppler
Sirosis/hipertensiporta
Splenoportografi
Biopsi hati
Akurasi diagnostik: 95-96,8%
Intrahepatik : Giant cell transform.,
balloning sitoplasma
Ekstrahepatik : Dilatasi duktulus
biliaris, bile plug,
proliferasi duktulus
Lain-lain : sesuai indikasi

Liver biopsy
Valuable procedure most reliable
discriminatory evidence
BA:
* bile ductular proliferation
* bile plugs
* portal / perilobular edema and fibrosis
* intact hepatic lobular architecture

Liver biopsy
will diagnose EHBA in 90-95% cases
main potential problem is if biopsy too early,
histological changes of EHBA envolving
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

 Skintigrafi (Isotop Tc-DIBRIDA):

- obstruksi bilier: ekskresi ke usus ( - )
- hepatoseluler : ambilan terlambat
ekskresi ke usus ( + )
!! * realibilitas < : bil. direk >>(>20mg/dl)
* false +/- : 10%. o.k . Waktu pemeriksaan lama -->
tidak banyak digunakan
Kolangiografi: intraoperatif ---> laparotomi
eksplorasi
ERCP: jarang dilakukan

Tatalaksana
Memperbaiki aliran empedu
- Etiologik
Ekstrahepatik : operasi
Intrahepatik : non-operasi
- Stimulasi aliran empedu
Fenobarbital : induksi enzim
- glukuronil transferase
- sitokrom P-450
- N+ K+ ATP-ase
Dosis : 3-10 mg/kgBB/hari

 Ursodeoksikolat : Dosis : 10-30 mg/kgBB/hari

- Competitive binding empedu toksik

- Bile fow inducer
- Suplemen empedu
- Hepatoprotektor

Kolestiramin :Dosis : 0,25-0,5 g/kgBB/hari

- Menyerap empedu toksik
- Menghilangkan gatal
Rifampicin : Dosis : 10 mg/kgBB/hari
- aktivitas enzim mikrosom
- ambilan as. empedu oleh sel hati

 Terapi suportif : ---> tumbuh kembang optimal

- Nutrisi : MCT
- Vitamin :
A : 5.000 - 25.000 U/ hari
D : D3 calcitriol : 0,05 - 0,2ug/ kgBB/hr
E : 25 - 50 IU/ kgBB/ hr
K : K1 2,5 - 5 mg/ 2-7x/ minggu
- Mineral , trace element : Ca, P, Mn, Zn,
Selenium, Fe.
Terapi komplikasi : mis .
* hiperlipidemia/xantelasma kolestipol
* gagal hati: transplantasi ( !!! )

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 (eg
Generaid) 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

Surgical intervention
Kasai :hepato-porto-enterostomy
(preceeded by cholangiography
for definitive diagnosis)
Predictive factors of poor outcome
* bridging liver fibrosis
* postop. cholangitis

Liver transplantation: failure of Kasai

to restore bile flow

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

Experience of surgeon very important in

outcome
Prognosis will be worse if Kasai is
performed on Alagilles patients

Prognosis
Sindrom hepatitis neonatal:
* Sporadis: baik ( 60% sembuh ) .
* Familial : buruk ( 60% meninggal )
Atresia bilier: Operasi (-) : umur 2 th
Operasi (+): < 60 hari: 91%
61-70 hari: 56 %
71-90 hari: 31 %
> 90 hari: 17%
Survival post Kasai: 5 th : 47 - 60 %
10 th: 25 - 35%

Kolestasis di Bag. IKA-FKUI/RSCM

Februari 1991 - Januari 2000 ( 9 th )
Jumlah

: 203 ----> 23 kasus/th t

Jns Kel

: Laki-laki : 129 ( 63,5 %)

Perempuan : 74 ( 36,5 %)

Umur

: 1 bln - 19 bln

Distribusi

< 1 bulan

: 18 ( 8,9% )

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

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

: 44 ( 21,7% )

(!!!!)

Intrahepatik:141( 69,5%), sirosis 11 (7,8%)

? CMV
Toksoplasma
Metabolik
Hemangioma
HBV
Sepsis
Alagille

:
:
:
:
:
:
:

46
1
2
1
1
1
2

Ekstrahepatik:62(30,5%),sirosis 18 (29 %)
atresia bilier

: 35

kista duktus koledokus : 12

bile plug syndroms

: 15

Diagnostic approach BA
Jaundice, dark urine, pale/ acholic stool
( female, BW N , family history - )
Hepatomegaly : firm consistency
Late stage: splenomegaly, ascites,
hemorrhage (
can be intracranial !)
Conjungated hyperbilirubinemia, cholesterol, GGT
Exclude medical causes of neonatal cholestasis

Jaundice, darked colored urine, pale/acholic stool

conjungated hyperbilirubinemia

ALT,AST,GGT,PT,albumin,cholesterol,triglyceride,bil

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

USG
patency ( - ) clin/lab/US
patency ( + )
notmatched
Biopsy
infection( - )/ infection ( +)UTI
clin.worst
paucity ( + )

supportive/
symptomatis

bil atresia
op.cholangiog.

Neonat.hep.
sup/ symptomatis

medicamentosa

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

Initial Investigations
Confirm cholestasis
bilirubin total and conjugated fraction

Exclude sepsis
urine, blood other culture
Assess liver injury
ALT, AST, AP, GGT

Assess liver synthetic function

PT / INR, glucose, albumin, cholesterol

Look for rapidly treatable conditions

serum glucose, urine reducing substances

Specific Investigations
Abdominal US
Serology for infection
CMV, 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)
Liver biopsy
Also
serum and urine bile acids
Genetic testing for Alagilles, PFIC
Echo, spine XR, bone marrow examination, Xrays of skull, long bones

Intraoperative cholangiogram, repeat biopsy