CHOLESTASIS

HASRI SALWANBAGIAN IKA FK UNSRI / DEP KES ANAK RSMH PLGSebagian slide diambil dari:Julfina Bisanto, Hanifah Oswari

Kolestasis :Hambatan sekresi dan/atau aliran empedu3 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 : harmlessin 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 toxicClinically jaundice: the serum bilirubin concentration in the older child: 23 mg/dL, in the neonate: 5 mg/dL.

Cholestasis :Physiologically : decrease in bile flowPathologically : 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.

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

Kolestasis masalah, karena:

Karena itu agar kolestasis tidak bermasalah, seharusnya para dokter mengetahui : * etiologi * patofisiologi * evaluasi diagnostik * tatalaksana * prognosis

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

Pada bayi sering terjadi hiperbilirubinemia indirek bukan direkPredisposisi kolestasis pada neonatus, krn: Ambilan , transportasi asam empedu belum efisienKonjugasi, sulfatisasi,glukuronidasi asam empedu Ukuran bile acid pool kecilKonsentrasi as. empedu basal serum

Hiperbilirubinemia indirek dianggap normal, jika:Terjadi setelah umur 3-4 hariMenghilang setelah 10-14 hariKadar billirubuin total < 12-15Karena breast milk jaundice

Unit sekresi bilier

Sistem transportasi utama pada pembentukan empedu

Patogenesis124563

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

Insiden: 1 : 2500 kelahiran hidupHep. neonatal idiopatik:1 : 5000Atresia bilier : 1 : 10.000Def. 1 antitripsin : 1 : 20.000 Kemajuan: pencitraan, virologi, biokimia ---------> idiopatik berkurang

DIFFERENTIAL DIAGNOSIS OF NEONATAL CHOLESTASIS

Diagnosis Diferensial Kolestasis Intrahepatik1. 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

2. Kelainan kromosom Mis.: sindrom Down3. Penyakit intrahepatik yang etiologinya tidak diketahui: * kolest. intrahep. persisten idiopatik :sindrom Alagille * kolest. intrahep. Rekuren : kolest. familial rekuren benignaDiagnosis Diferensial

4. Hepatitis Infeksi : * virus: CMV, rubella, herpes, varisela, Echovirus, Coxsacki, Reovirus tipe 3, hepatitis A, B,C.* lain: sifilis, toksoplasma, leptospirosis, tuberkulosis5. Toksik: nutrisi parenteral, obat,sepsis6. Imunologik : LE neonatal7. Lain-lain : histiositosisDiagnosis Diferensial

Kolestasis ekstrahepatik

Atresia bilier (90%)Kista duktus koledokus (5%)KoledokolitiasisStenosis duktus biliarisAnomali choledochol-pancreatico-ductal junctionBile plug syndromeKompresi duktus biliaris ekstrinsikDiagnosis Diferensial

Gejala kliniksindrom kolestasis : * ikterus* urine berwarna gelap* tinja pucat akholikgejala penyakit dasargejala sekuele kolestasis kronik

Kolestasis (aliran empedu ) Retensi/regurgitasi :Konsentrasi asam empedu intraluminal - Asam empedu pruritus hepatotoksik - Bilirubin ikterus - Kolesterol xantomatosis hiperkolesterolemia - trace element (tembaga, dll)* Malabsorpsi lemak * malnutrisi * retardasi pertumbuhan * diare/steatorea vit. larut dalam lemak A - kulit tebal,rabun senja D - osteopenia E - degenerasi neromuskuler - anemia hemolitik K - hipoprotrombinemia Mineral (Ca dll)

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

Pem. fisik :BB/ TB/ lingkaran kepala Hepar/ lien / massa abdomenPemeriksaan tinja: tinja 3 porsiPem. penunjang :Laboratorium rutin dan khususRutin : darah perifer lengkap, fraksi bilirubin, transaminase, GGT, alkali fosfatase, PT, elektroforesis protein, kolesterol, gula darah, ureum, kreatinin,urinalisisKhusus: defisiensi 1 antitripsin, TORCH

EHBA vs Neonatal HepatitisAlagille D. Prog Liver Dis 1979;6:471-485

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%

Investigating EHBA vs NHSuchy FJ in Liver disease in Children, 2nd ed. 2000;187-194

Investigation

EHBA

NH

Duod. Aspirate

No bile

Bile present

Ultrasound

Gb absent/small

triangular cord

Gb present

HIDA scan

Normal uptake, no excretion

Poor uptake, Nl . excretion

Liver Biopsy

Bd proliferation, bile plugs, portal fibrosis

Giant cells, inflammation, focal necrosis

Kriteria klinis terpenting untuk membedakan kolestasis ekstrahepatik dan intrahepatik

* Mean SE ** Jumlah pasien

Data laboratorium awal pada bayi kolestasis

Kolestasis

Ekstrahepatik

Intrahepatik

Bilirubin total (mg/dl)

10,2 ( 4,5

12,1 ( 9,6

Bilirubin direk (mg/dl)

6,2 ( 2,6

8,0 ( 6,8

SGOT (U/l)

< 5xN

> 10xN/>800

SGPT (U/l)

< 5xN

> 10xN/>800

GGT (U/l)

> 5xN/>600

< 5xN/N

PencitraanUSG 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 cystUS : * 12 hours fasting and after feeding gallbladder is not visualized/ small (after feeding : same size ) * triangular cord sign / cyst: liver hilum

USG Doppler Sirosis/hipertensiportaSplenoportografiBiopsi hati Akurasi diagnostik: 95-96,8%Intrahepatik : Giant cell transform., balloning sitoplasmaEkstrahepatik : Dilatasi duktulus biliaris, bile plug, proliferasi duktulusLain-lain : sesuai indikasi

Liver biopsyValuable procedure most reliable discriminatory evidenceBA: * bile ductular proliferation * bile plugs * portal / perilobular edema and fibrosis * intact hepatic lobular architecture

Liver biopsy

will diagnose EHBA in 90-95% casesmain potential problem is if biopsy too early, histological changes of EHBA envolving100% sensitive but 76% specific in detecting EHBAZerbini MC et al Mod Pathol 1997;10:793-799also 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

TatalaksanaMemperbaiki aliran empedu EtiologikEkstrahepatik : operasiIntrahepatik : non-operasiStimulasi 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 : MCTVitamin : A : 5.000 - 25.000 U/ hariD : D3 calcitriol : 0,05 - 0,2ug/ kgBB/hrE : 25 - 50 IU/ kgBB/ hrK : K1 2,5 - 5 mg/ 2-7x/ mingguMineral , trace element : Ca, P, Mn, Zn, Selenium, Fe. Terapi komplikasi : mis .* hiperlipidemia/xantelasma kolestipol * gagal hati: transplantasi ( !!! )

Nutritional managementCaloriesaim for 125% of RDA based in ideal body wtmay need supplemental tube feedsFatMCT better absorbed than LCT so consider using these formulae eg. Pregestamil, Pepti JuniorProteinaim for 2-3 g/kg/d unless encephalopathicbranched chain amino acid formula (eg Generaid) improves nutritional status

Nutrition management 2Essential Fatty Acidslinoleic, linolenic, arachidonic acids may need supplementing with corn, safflower, walnut oil or lipid emulsionsFat Soluble Vitaminsvitamins A, D, E, Kmay need to monitor levelsWater Soluble Vitaminsunknown whether deficient in cholestasisrecommend 1-2 x RDA

Surgical interventionKasai :hepato-porto-enterostomy (preceeded by cholangiography for definitive diagnosis) Predictive factors of poor outcome * bridging liver fibrosis * postop. cholangitisLiver transplantation: failure of Kasai to restore bile flow

Surgical procedureIntraoperative cholangiogram and liver biopsyLook for features of EHBAcoarse, fibrotic, green liver with subcapsular telangiectasiaExperience of surgeon very important in outcomePrognosis will be worse if Kasai is performed on Alagilles patients

PrognosisSindrom 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 tJns Kel : Laki-laki : 129 ( 63,5 %) Perempuan : 74 ( 36,5 %)Umur : 1 bln - 19 blnDistribusi : < 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 : 46Toksoplasma : 1Metabolik : 2Hemangioma : 1HBV : 1Sepsis : 1Alagille : 2Ekstrahepatik:62(30,5%),sirosis 18 (29 %) atresia bilier : 35kista duktus koledokus : 12bile 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,bile 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 ( + ) bil atresia Neonat.hep. medicamentosa supportive/ op.cholangiog. sup/ symptomatis symptomatis BA Kasai bile plug drainage

Approach to cholestatic infantConfirm cholestasisAssess severity of liver dysfunctionExclude potentially treatable infectious and metabolic disordersAim for specific diagnosis urgency in diagnosis of biliary atresia (EHBA) as prognosis depends on early (

Initial InvestigationsConfirm cholestasisbilirubin total and conjugated fractionExclude sepsisurine, blood other cultureAssess liver injuryALT, AST, AP, GGTAssess liver synthetic functionPT / INR, glucose, albumin, cholesterolLook for rapidly treatable conditionsserum glucose, urine reducing substances

Specific InvestigationsAbdominal US Serology for infection CMV, EBV, HSV, VDRL, Metabolic screenurine and serum amino and organic acidsTFTs, and cortisol/GH if suspect hypopit.Serum iron, ferritin, transferrin saturationGalactose-1-phosphate uridyl transferase

Very specific investigationsHepatobiliary scintigraphy (HIDA scans)Liver biopsyAlsoserum and urine bile acidsGenetic testing for Alagilles, PFICEcho, spine XR, bone marrow examination, X-rays of skull, long bonesIntraoperative cholangiogram, repeat biopsy