Neonatal CholestasisDeddy S Putrahttp://www.dr-deddy.com

Cholestatic cases at IKA-FKUI/RSCMFebruary 1991-January 2000 ( 8 years )N : 203Sex : 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% ) > 4 months : 44 ( 21,7% )

Intrahepatic :141(69%),cirrhosis 11(7,8%)? CMV : 46 HBV : 1Toxoplasmosis : 1 Sepsis : 1Metabolic : 2 Alagille : 2Hemangioma : 1Extrahepatic : 62 (31%), cirrhosis 18(29%) biliary atresia: 35Choledochal cyst: 12bile plug syndrom : 12

cholestatic syndrome : jaundicedark urine stool: intermittently pigmented acholicclinical feature of disorders which cause cholestasissymptoms of chronic cholestasisClinical presentation

DefinitionPresence of jaundice with a conjugated bilirubin fraction >15% of total bilirubin concentration (or > 1.5 mg/dl) in any infant beyond 2 weeks old

IncidenceIncidence 1:2500 to 1:5000Dick M & Mowat A Arch Dis Child 1985;60:512-516Danks DM et al Arch Dis Child 1977;52:360-367Liver disease in the neonate regardless of aetiology, is frequently associated with conjugated jaundiceConjugated jaundice in infants nearly always indicates liver or biliary disease

Classification of aetiologyNeonatal HepatitisBile duct obstructionMetabolic disorders Cholestatic syndromesToxin / Drug inducedMiscellaneous

Aetiology 1Neonatal hepatitisIdiopathicViralCMV, Herpes (HS, HZ, HH6), EBV, Rubella, ReoV3, Parvo B19, AdenoV, Hep B, EnteroV, HIV Bacterial and parasiticsepsis, Listeria, TB, Toxoplasmosis, Malaria

Aetiology 2Bile duct obstructionCholangiopathiesEHBA, Choledochal cysts, Alagilles, Nonsyndromic paucity, congenital hepatic fibrosis, CarolisOther Inspissated bile, cholelithiasis, tumours

Aetiology 3Metabolic disorders1-antitrypsin deficiencyNeonatal iron storage diseaseEndocrinopathieshypopituitary, hypothyroidAmino acid disorderstyrosinaemia, hypermethionaemiaLipid DisordersNiemann-Pick, Gauchers, Wolmans, CESDUrea Cycle disordersarginase deficiency

Aetiology 4Carbohydrate disordersgalactosaemia, fructosaemia, GSD IVMitochondrial (respiratory chain defects)Peroxisomal disorders Zellwegers, Infantile RefsumBile Acid Synthetic defects3-hydroxy5C27 steroid dehydrogenase isomerase4-3-oxosteroid 5-reductaseoxysterol 7-hydroxylase

Aetiology 5Cholestatic syndromesProgressive familial intrahepatic cholestasisTypes 1 (Byler), 2 (BSEP defect), 3 (MDR3 defect)Aagenaes (hereditary cholestasis with lymphoedema)Nielsen (Greenland Eskimos)Benign recurrent intrahepatic cholestasisNeonatal Dubin-Johnson syndrome (MRP2 defic)ToxicDrugsTPNAluminium

Aetiology 4Miscellaneous associationsShock /hypoperfusionHistiocytosis XNeonatal lupusTrisomiesErythrophagocytic lymphohistiocytosisVeno-occlusive diseaseDonahue syndrome (leprechaunism)

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

Disease

Cumulative %

f / 105 live births

"Idiopathic neonatal hepatitis"

35-40

1.25

Biliary atresia

25-30

0.7

(1-AT deficiency

7-10

0.25

Intrahepatic cholestasis

5-6

0.14

Inborn errors of BA synthesis

2

HistoryWell or otherwise Primary historypregnancy, birth weight, hypoglycaemic episodesFeeding and stooling (colour) historyFamily history

ExaminationGeneralwell/sick, weight, sluggish behaviour, jaundice, pallor FaciesDysmorphic, nystagmus/eye signs, cleft lip/palateCardiacmurmurs, situs inversusAbdomenliver size (use span) and position, spleenpenis sizeSkin Rash, birthmark, petechiaeNeurologic

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 1-AT level and phenotypeSerology for infectionHep A, B, C, 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 acidsfast atom bombardment spectroscopy of urinary bile acidsgenetic testing for Alagilles, PFICEcho, spine XR, bone marrow examination, fibroblast cultures, X-rays of skull, long bonesIntraoperative cholangiogram, repeat biopsy

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

Assessment of imaging studiesUltrasoundcan assess gb size, stones, sludge, bile duct dilatation, ascites, extrahepatic lesionsCT scansimilar information to US but need sedation/GAMRCP (magnetic resonance cholangio-pancreatography)reliable in detecting CBD/ gb (pilot studies)HIDA scans helpful but 25-50% of NH fail to show excretion

Liver biopsyMost important diagnostic toolwill diagnose EHBA in 90-95% casesmain potential problem is if biopsy too early, histological changes of EHBA evolving100% 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

Surgical explorationOccasionally necessary Intraoperative 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

Consequences of chronic cholestasisReduced delivery of bile into small bowel malabsorption of fat, fat soluble vitaminsOverflow of bile constituents into systemic circulation pruritis, fatigue, hypercholesterolemia, xanthoma formationHepatotoxicity from abnormally retained substances (bile acids, cholesterol, bilirubin) portal hypertension, cirrhosis

Medical management of cholestasisAim to reduce complications:optimise nutrition to reduce effects of malabsorptionsymptomatic treatment of itch, hyperlipidemiapromote bile flow (reduce hepatotoxicity)General considerationsimmunizationsdental hygiene

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, AlfareProteinaim 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

MalabsorptionDecreased fat absorption due to a low micellar concentrationMCT oilFat Soluble Vitamins

Controlling pruritisOral bile acid binding resinscholestyraminecolestipolUrsodeoxycholic acidRifampicinOpiod receptor antagonists (naltrexone) OthersPhenobarbitoneCarbamazepinePartial external biliary diversionLiver transplantation

Hyperlipidemia and xanthomaTreatment aims:increase conversion cholesterol to bile acidsreduce biliary regurgitationenhance elimination bile acids and cholesterolNon absorbable ion resinsUrsodeoxycholic acidCholesterol synthesis-blocking agentsOthersplasmapheresispartial ileal bypassliver transplantation

Promoting bile flowUrsodeoxycholic acid (UDCA)PhenobarbitoneGlucocorticoids in short burstsnot appropriate in chronic situation but used perioperatively after EHBA surgery

ImmunisationsRecommend routine immunisationsSome delay DTP in EHBA because side effects of immunisation may mask cholangitisWould also immunise against Hep B and AUse Salk polio (inactivated) in transplant recipients and household contactsIf child > 12 mo and may need transplant, use MMR and Varicella > 1 mo before OLT

Dental HygieneTeeth discolouration may occur fromstaining by bilirubin, biliverdin, haemosiderinpoor oral hygieneoral (acidified) iron preparationsdental cariesStress good oral hygiene, regular dental examination, restrict sugary medications Permanent teeth usually OK unless cholestatic > 8yo

Outcome of NHSporadic60% recover10% persistent fibrosis or inflammation2% develop cirrhosis30% dieFamilial (or consanguinity)30% recover10% chronic liver disease or cirrhosis60% dieBalistreri WF in Schiffs Diseases of the Liver, 8th ed. 1999;1357-1512

1