PPT on Neonatal cholestasis by Dr.ajay k chourasia

Neonatal cholestasis Dr. Ajay Kumar Chourasia

Dr. B.C .Roy Postgraduate Institute of Peadiatric Sciences.

KOLKATA

Definition

• Biochemically as Prolonged elevation of conjugated bilirubin beyond 1st 14 days of life up to 90 days.

• Serum direct bilirubin > 1mg/dl if TSB <5mg/dlor > 20% of TSB if TSB >5mg/dl

• Any newborn with jaundice and dark yellow urine with or without pale stools should be strongly suspected to have NC.

We must evaluate for neonatal cholestasis if jaundice :-

-Appears after 2 wks of age. -Progress after 2 wks of age. -Does not resolve after 2 wks of age.

Classification

Causes of neonatal Cholestasis

• Generalized bacterial sepsis• Viral hepatitis

• Hepatitides A, B, C, D, E• Cytomegalovirus• Rubella virus• Herpesviruses: herpes simplex, human

herpesvirus 6 and 7• Varicella virus• Coxsackievirus• Echovirus• Reovirus type 3• Parvovirus B19• HIV• Adenovirus

Others• Toxoplasmosis• Syphilis• Tuberculosis• Listeriosis• Urinary tract infection

INFECTIOUS

• Disorders of amino acid

metabolism• Tyrosinemia Disorders of lipid metabolism• Wolman disease• Niemann-Pick disease (type C)• Gaucher diseaseCholesterol ester storage diseaseDisorders of carbohydrate

metabolism• Galactosemia• Fructosemia• Glycogenosis IV

Disorders of bile acid biosynthesis Other metabolic defects• α1-Antitrypsin deficiency• Cystic fibrosis• Hypopituitarism• Hypothyroidism• Zellweger (cerebrohepatorenal)

syndrome• Wilson disease• Neonatal iron storage disease• Indian childhood cirrhosis/infantile

copper overload• Congenital disorders of glycosylation• Mitochondrial hepatopa

METABOLIC

Trisomies 17, 18, 21 • “Idiopathic” neonatal hepatitis• Alagille syndrome• Intrahepatic cholestasis (progressive familial intrahepatic cholestasis• [PFIC]) • FIC-1 deficiency • BSEP (bile salt export pump) deficiency • MDR3 deficiency• Familial benign recurrent cholestasis associated with lymphedema (Aagenaes syndrome)• ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome• Caroli disease (cystic dilation of intrahepatic ducts)

GENETIC OR CHROMOSOMAL

INTRAHEPATIC CHOLESTASIS SYNDROMES

• Biliary atresia• Sclerosing cholangitis• Bile duct stricture/stenosis• Choledochal–pancreaticoductal junction anomaly• Spontaneous perforation of the bile duct• Choledochal cyst• Mass (neoplasia, stone)• Bile/mucous plug (“inspissated bile”)

EXTRAHEPATIC DISEASES

• Associated with enteritis• Associated with intestinal obstruction• Neonatal lupus erythematosus• Myeloproliferative disease (trisomy 21)• Hemophagocytic lymphohistiocytosis (HLH)• COACH syndrome (coloboma, oligophrenia, ataxia,

cerebellar vermis• Shock and hypoperfusion• hypoplasia, hepatic fibrosis)• Cholangiocyte cilia defects

MISCELLANEOUS

ETIOLOGICAL PROFILE OF NC IN INDIA

CLINICAL APPROACH

GOALS OF TIMELY EVALUATION

• Diagnose and treat known medical and/or life-threatening conditions.

• Identify disorders amenable to surgical therapy within an appropriate time-frame.

• Avoid surgical intervention in intrahepatic diseases.

EXTRA HEPATIC CHOLESTASIS

BILLARY ATRESIA

obliterative cholangiopathy 2 major types: cystic noncystic.

choledochal cysts fetal perinatal sclerosing cholangitis

• 85% of the cases, is obliteration of the entire extrahepatic biliary tree at or above the porta hepatis. difficult problem in surgical management.

C/F --normal at birth and have a postnatal progressive obliteration of bile ducts -embryonic or fetal-onset form manifests at birth associated withother congenital anomalie (situs inversus, polysplenia, intestinal malrotation, complex congenital heart

disease).

Management of Patients with SuspectedBiliary Atresia

• -To determine the presence and site of obstruction.

exploratory laparotomy and direct cholangiography biliary tree is patent but of diminished caliber, suggesting that the no

biliary tract obliteration but to bile duct paucity

further dissection into the porta hepatis should be avoided.

Porta hepatis

fibrous ductal remnant

Hepatic artery

Traingular Cord sign

15-day-old female neonate with unknown cause of infantile cholestasis. Sonogram reveals tubular echogenic cord (arrows). "Triangular cord" was 0.3–0.4 cm wide and 1.3–1.6 cm long.

CHOLEDOCHAL CYSTS

• Choledochal cysts are congenital dilatations of the common bile duct

• that can cause progressive biliary obstruction and biliary cirrhosis.. • pathogenesis due to reflux of pancreatic enzymes into the

common bile duct, causing inflammation, localized weakness, and dilation of the duct

• C/F-The infant typically presents with cholestatic jaundice; severe liver dysfunction including ascites and coagulopathy .

• Treatment of choice is primary excision of the cyst and a Rouxen- Y choledochojejunostomy.

Cystic Dilation of the Intrahepatic Bile Ducts(Caroli Disease)

Congenital saccular dilation of intrahepatic bile ducts. associated with Choledochal cysts Pathogenesis dilation leads to stagnation of bile and formation of biliary sludge

and intraductal lithiasis. Clinical features- portal hypertensive bleeding . Diagnosis- • Ultrasonography-• percutaneous transhepatic, endoscopic, or MR cholangiography. Management- Cholangitis and sepsis are treated with appropriate antibiotics.

Calculi can require surgery.

INTRAHEPATIC CHOLESTASIS

Proposed Subtypes of Intrahepatic Cholestasis

• Disorders of bile acid biosynthesis and conjugation

• Disorders of membrane transport and secretion• Disorders of embryogenesis• Unclassified (idiopathic “neonatal hepatitis”):

Bile acid biosynthesis.

1

2

3

B. Disorders of bile acid biosynthesis and conjugation

3β-hydroxy-5-C27-steroid dehydrogenase/isomerase deficiency(HSD3B7)

3-oxoΔ-4-steroid 5β-reductase deficiency.(AKR1D1) Oxysterol 7α-hydroxylase deficiency

.

Bile acid-coenzyme A (CoA) ligase deficiency.

BAAT deficiency (familial hypercholanemia)

Deficiency of 3β-hydroxy-Δ5-C27-steroid oxidoreductase(3β-HSD)

the 2nd step in bile acid biosynthesis, causes progressive familial intrahepatic cholestasis. C/F--jaundice with increased aminotransferase levels -hepatomegaly; -GGT levels are normal. Histology - ranging from giant cell hepatitis to chronic hepatitis. Diagnosis- by mass spectrometry detection of C24 bile acids in

urine, which retain the 3β-hydroxy-Δ5 structure.Management-Primary bile acid therapy, administered orally to

down regulate cholesterol 7α-hydroxylase activity, to limit the production of 3β-hydroxy-Δ5 bile acids, and to facilitate hepatic clearance, has been effective in reversing hepatic injury

1

Deficiency of Δ4-3-oxosteroid-5β reductase(AKR1D1)

• The 4th step in the pathway of cholesterol degradation to the primary bile acids,

C/F-cholestasis and liver failure developing shortly after birth, with coagulopathy and metabolic liver injury resembling tyrosinemia.

Hepatic histology is characterized by lobular disarray with giant cells, pseudoacinar transformation, and

canalicular bile stasis. Diagnosis- Mass spectrometry is required to document increased urinary

bile acid excretion and the predominance of oxo-hydroxy and oxo-dihydroxy cholenoic acids.

Treatment with cholic acid and ursodeoxycholic acid is associated with normalization of

biochemical, histologic, and clinical features

2

Bile acid–CoA Ligase deficiency & Bile acid –CoA:aminoacid N-acetyl transferase

deficiency (BAAT) Conjugation with the amino acids glycine and taurine is the final step in

bile acid synthesis. Two enzymes catalyze the amidation of bile acids.• first reaction, a CoA thioester is formed by the rate-limiting Bileacid-

CoA Ligase.• Other reaction coupling of glycine or taurine and is catalyzed by a

cytosolic Bile acid–CoA:amino acid N-acyltransferaseC/F- conjugated hyperbilirubinemia, growth failure, or fat-soluble vitamin

deficiency,Diagnosis- identified with mutation of the bile acid–CoA ligase gene.Management-Administration of conjugates of the primary bile acid,

glycocholic acid may be beneficial and can correct the fat-soluble vitamin malabsorption improve growth.

3

Transport & Secretion of Bile acid

PHYSIOLOGY OF TRANSPORT

• Albumin-bound bile acids that reach the liver mainly via the portal blood are efficiently removed by transport proteins located at the sinusoidal membrane of hepatocytes.

In the overall process of bile acid transport from blood to bile, canalicular secretion is the limiting step. This

• transport for mono anionic amidated bile acids, which constitute the majority of secreted bile acids is ATPdependent and is mainly performed by the bile salt export pump (BSEP, gene symbol ABCB11)

• Bile acids conjugated with sulfate or glucuronic acid are dianionic and are transported by other canalicular pumps, such as MRP2(ABCC2 gene) and BCRP (ABCG2 gene).

Disorders of membrane transport and secretion

1. Disorders of canalicular secretiona. Bile acid transport: BSEP deficiency• i. Persistent, progressive (PFIC type 2)• ii. Recurrent, benign (BRIC type 2)b. Phospholipid transport:MDR3 deficiency (PFIC type 3)c. Ion transport: cystic fibrosis (CFTR) 2. Complex or multiorgan disordersa. FIC1 deficiency• i. Persistent, progressive (PFIC type 1, Byler disease)• ii. Recurrent, benign (BRIC type 1)b. Neonatal sclerosing cholangitis (CLDN1)c. Arthrogryposis-renal dysfunction-cholestasis syndrome(VPS33B)

Progressive familial intrahepatic cholestasis type 1 (PFIC 1) or FIC1disease

(formerly known as Byler disease)• present with steatorrhea, pruritus,vitamin D–deficient rickets,

gradually developing cirrhosis, and low γ-glutamyl transpeptidase (GGT) levels.

Locus chromosome 18q12 defect in the gene for F1C1 . • F1C1 is p type ATPase that facilitating the transfer of phosphotydyl

serine(role in intestinal bile absorption). • Defective F1C1 might a result intrahepatic cholestasis

• Nonsense,frame shift, and deletional mutations cause PFIC type 1• missense and split-type mutations result in BRIC type I.

PFIC type 2 (BSEP deficiency)

• is mapped to chromosome 2q24 and• The disease results from defects in the canalicular

adenosine triphosphate–dependent bile acid transporter BSEP(ABCB11).

• The progressive liver disease results from accumulation of bile acids secondary to reduction in canalicular bile acid secretion.

• Mutation in ABC11 is also described in another disorder, BRIC type2, characterized by recurrent bouts of cholestasis

PFIC type 3 (MDR3disease)

The disease results from defects in acanalicular phospholipids flippase, MDR3 (ABCB4),

which results in deficient translocation of phosphatidylcholine across the canalicular membrane. Mothers who are heterozygous for this gene can develop intrahepatic cholestasis during pregnancy.

Familial hypercholanemia• is characterized by elevated serum bile acid

concentration, pruritus, failure to thrive, and coagulopathy.

• mutation of bile acid coenzyme A (CoA), amino acid N-acyltransferase(encoded by BAAT)

• Mutation of both BAAT and TJP 2 can disrupt bile acid transport and circulation.

• Patients with familial hypercholanemia usually respond to the administration of ursodeoxycholic acid.

DISORDERS OF EMBRYOGENESIS

C. Disorders of embryogenesis. Alagille syndrome (Jagged1 defect, syndromic bile ductpaucity). Ductal plate malformation (ARPKD, ADPLD, Caroli disease)

Alagille syndrome (arteriohepatic dysplasia) Intrahepatic bile duct paucity. often erroneously called intrahepatic biliary atresia Clinical manifestations - facial characteristics (broad forehead; deep-set, widely spaced eyes; long, straight nose; and an underdeveloped mandible). ocular abnormalities - microcornea, optic disk drusen, shallow anterior chamber)cardiovascular abnormalities usually peripheral pulmonic stenosis, sometimes tetralogy of Fallot, pulmonary atresia, VSD, ASD, aortic coarctation), vertebral defects (butterfly vertebrae, fused vertebrae,spina bifida occulta, rib anomalies), and tubulointerstitial nephropathy. pancreatic insufficiency, anddefective spermatogenesis can reflect or produce nutritional deficiency.

• The prognosis for prolonged survival is good, but patients are likely to

have pruritus, xanthomas with markedly elevated serum cholesterol levels, and neurologic complications of vitamin E deficiency if untreated.

Mutations in human Jagged 1 gene (JAG1), which encodes a ligand for the notch receptor, are linked to Alagille syndrome

Idiopathic neonatal hepatitis, is a disease of unknown cause. sporadic familial formMetabolic /viral disease . Genetic /metabolic abbreation

Idiopathic Neonatal Hepatitis

Aagenaes syndrome

• idiopathic familial intrahepatic cholestasis associated with lymphedema of the lower extremities.

-may be attributable to decreased hepatic lymph flow or hepaticlymphatic hypoplasia. - present with episodic cholestasis -with elevation of serum aminotransferases, alkaline phosphatase,and bile acids. Between episodes, the patients are usually normal• have a relatively good prognosis because more than 50% canexpect a normal life span. • The locus for Aagenaes syndrome is mappedchromosome 15q.

Zellweger syndrome (cerebrohepatorenal)

• is a rare autosomalrecessive genetic disorder• marked by progressive degeneration of the liver and kidneys • the disease is usually fatal in 6-12 mo.C/F :-• generalized hypotonia and • markedly impaired neurologic function with psychomotor

retardation. • Patients have an abnormal head shape and unusual facies• hepatomegaly , renal cortical cysts• stippled calcifications of the patellas and greater trochanter• ocular abnormalities. • Hepatic cells has absence of peroxisomes

Four patients with Zellweger cerebrohepatorenal syndrome.Note the high forehead, epicanthal folds, and hypoplasia ofsupraorbital ridges and midface.

Neonatal iron storage disease (neonatal hemochromatosis)

• increased iron depositionin the liver, heart, and endocrine organs with multiorgan failure

. This is an alloimmune disorder with maternal antibodies directed against the fetal liver.

• C/F- hypoglycemia, hyperbilirubinemia,hypoalbuminemia, elevated ferritin and profound hypoprothrombinemia.Diagnosis - confirmedby buccal mucosal biopsy MRI demonstrating extrahepatic siderosis.• The prognosis is poor;liver transplantation can be curative..

METABOLIC

α1-ANTITRYPSIN DEFICIENCY Deficiency of the major serum protease inhibitor α1-antitrypsin manifest neonatal cholestasis or later-onset childhood cirrhosis. --mutation in the SERPINA1 gene and it is an autosomal recessive usually PiZZ homozygotes .Enzyme modification and folding defect

Diagnosis- in Biopsy- polymerized α1-antitrypsin peptide, hepatocellular necrosis, inflammatory cell infiltration, bile duct proliferation, periportal fibrosis, or cirrhosis

C/FJaundice, acholic stools hepatomegaly are present in the 1st wk of lifebut the jaundice usually clears in the 2nd-4th months.persistent liver disease, or the development of cirrhosis can Follow..

Therapy is supportive; liver transplantation has been curative

INFECTION

CMV infection• CMV present in saliva,urine,genital secretions,

breast milk and blood in ifected person and this is the source of infection.

• Primary infection in asymptomatic in older infant and children

• But infection in early gestational age carries high risk fatal disease in new born.

C/F of Congenital early--petechie ,pupura(79%)-Hepatosplenomegaly(74%)-Jaundice (63%)Diagnosis-In Congenital infection CMV identifies in urine ,blood,saliva within

2 wks of ageIn perinatal infection negative in 1st weeks and positive in 4 wks.CMV PCRCMV antigenCMV IgG & IgM(negative IgG in both mother & baby – Exclude CMV If Positive in baby then repeat after 4 wks- if titer decresing or absent --

it was due to transplacentally derived.)

Treatment

• Ganciclovir – In congenital infection (6mg/kg/dose BD)for 1st

6wks of life .Prophylactic with oral Valgalciclovir to mother

(900mg OD )for 90 days.

Management

Investigations:

Urgent investigations:– CBC with PS, – LFT: Total and direct bilirubin, SGOT, SGPT, alkaline

phosphatase, GGT,PT/PTTK.– Electrolytes.– Blood culutre.– Urine culture, routine microscopy.– RBS (pre-feed).– Ascitic tap (if ascitis).

Further tests:Ophthalmologic examination.Serum/ urine bile acid levels.DCT and coomb’s test.Cord blood IGM.FTA-ABS, CFT for rubella, CMV, herpes. Sweat

chloride.HBsAG in mother and infant.Liver biopsy:

light microscopy. specific enzyme assay.

• TORCH, VDRL, Hepatitis B/C, HIV• T4, TSH• Serum cortisol• Alfa -1 AT levels and phenotype• Galactose -1 Phosphate Uridyl transferase(to r/o galactosemia)• Urinary succinyl acetone (to r/otyrosinemia)• Cholesterol, triglycerides• S. iron and ferritin levels (to r/o neonatalhemachromatosis)

Radiological evaluation

Ultrasonography

Excludes choledochal cyst, dilated CBD. Findings s/o BA:

1. GB length (<1.5cm long/small lumen)2. GB contraction [CI<86% ± 18% (mean ± SD) in 6-week-

old infants and 67% ± 42% in 4-month-old infants]3. Triangular cord sign: a triangular- or tubular-shaped

echogenic density that was located immediately cranial to the portal vein bifurcation and was 3 mm or more thick (Kanegawa et al. AJR 2003;181:1387)

Sonogram illustrates method of measuring gallbladder length (long arrow) and width (short arrow). These measurements were obtained using maximal longitudinal image.

Hepatobiliary Scintigraphy:

Tc labelled IDA dyes used.Depends on hepatocellular function & patency

of biliary tract.Neonatal Hepatitis: delayed uptake, n.

excretion.Biliary Atresia: normal uptake, absent excretion.Sensitive (97%) not specific (80%) for EHBA.Phenobarbitol priming (5mg/kg x 5d)

Invasive studies

– Duodenal intubation– Percutaneous liver biopsy– Percutaneous transhepatic cholangiography– ERCP– MRCP– Exploratory laparotomy with intraoperative

cholangiogram

ERCP image

intra- and extrahepatic (c) biliary dilatation, as well as focal intrahepatic biliary cystic dilatations (arrows). g = gallbladder.

Percutaneous transhepatic cholangiography

LIVER BIOPSY:

Most imp. Inv in differentiating NH and BA.Accuracy of 83% to 97%.Prerequisites: Normal PT & platelet count.Complications: Bleeding Bile peritonitis Pneumothorax

IMPAIRMENT MANAGEMENT(NASPGHAN)

MANAGEMENTIAP

Malabsorption Medium chain TGs given Medium chain TGs given,breast feeding cont, 200 Kcal/kg/d,1-2 gm protein/kg/d

Fat soluble vit malabsorptionVit A deficiency 10,000-15,000 IU/d

AQUASOL-A50,000 IU i.m –at diagnosis10,000 IU monthly

Vit E deficiency

50-400 IU/d; oral alfa tocopherol

50-200 mg/d orally

Vit D deficiency 5000 -8000IU/d of D23-5 mcg/kg/d of 25 HCC

30,000 IU i.m –at diagnosis& monthly

Vit K deficiency 2.5 -5.0 mg alternate day as water soluble derivative of menadione.

5 mg/d im x3 days,5 mg wkly.Perform PT monthly.

Microutrient deficiency Ca, P, Zn supplementation Ca, P, Zn supplementation

Water soluble Vit def. 2 times RDA supplementation 2-5 times RDA supplementation

Hepatoportoenterostomy (Kasai) procedure

• Performed for biliary atresia that is not surgically correctable with excision of a distal atretic segment.

• The rationale for this operation is that minute bile duct remnants, representing residual channels, may be present in the fibrous tissue of the porta hepatis

• Roux-en-Y portoenterostomy• Bile flow re-established in 80-90% if performed prior to 8 weeks-

old.• If microscopic channels of patency > 150 μm in diameter are

found, postoperative establishment of bile flow is likely.• Bile flow re-established in less than 20% if performed after 12

weeks-old

Liver transplantation

Indications:1) Decompensated liver disease(ascites and/or

encephelopathy) .2) Failed portoenterostomy.

• 1-year survival rate- 85-90%• 5-8 year survival rate- 75-80%• 1/3 to 1/2patients are of Biliary Atresia.(Whitington et

al SEMIN LIVER DIS1994;14:303-317)

Prognosis

Biliary Atresia:• Age(< 8 wks): the single most important

determinant in successful management of BA. • Of pts. Undergoing Kasai’s procedure,80%

jaundice free if done before 60 days, as against 25-35% of infants operated later on.(Mieli –Vergani et al. LANCET 1989;1:421-423)

Neonatal Hepatitis:• No indicators to predict prognosis.

Long term outcome

Biliary Atresia: • Mean survival in untreated pts. :19 mths (Hays et al. SURGERY 1963;54:373-375)

• 3-year survival : <10% (Karrer et al J PEDIATR SURG 1990;25:1076-1080)

Neonatal Hepatitis:• Upto 60% of pts.with idiopathis NH recover completely

without any specific therapy.• Upto 10% die acutely of bleeding manifetstations or

fulminant hepatic failure.• 30 % progress to liver cirrhosis and death due to CLD.