Neonatal Cholestasis

Prof. Ahmed Abdalla
Prof. of Pediatrics & Director of GI Unit Mansoura University

2009

Definition
Reduction in conalicular bile flow with

retention of substances which are dependent on bile flow as bile acids with histopathologic features reflecting the nature and degree of disturbances.

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Differential diagnosis
The major causes of cholestasis in inflancy: 1-Obstructive cholestasis:
- Biliary atresia. Congenital bile duct anomalies (choledochal cyst). Cholelithiasis.

Cholongis associated histiocytosis.

with

longerhan’s

cell

Primary sclerosing cholengitis.

2-Cholestasis with ductal paucity:
 Alagille’s syndrome.  Nonsyndromic ductal paucity.  Ductopenic allograft rejection.

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3-Hepatocellular cholestasis:
- Hepatitis.

_ alpha-1 antitrypsin deficiency. - Inborn errors of bile acid synthesis. - Drug-induced cholestasis. - TPN associated cholestasis. -Progressive familial intrahepatic cholestasis. Biliary atresia and idiopathic neonatal hepatitis are the most frequent etiologic diagnosis.

Idiopathic neonatal hepatitis
Clinical presentation:
 Jaundice: within the 1st week.  Course: variable.  Failure to thrive: common. Liver-firm, enlarged. Spleen: firm, enlarged. Bleeding diathesis: in severe cases. Stool: acholic +. www.MansFans.com

Laboratory findings:
Serum bilirubin: mild to moderate. Transaminases: mild to moderate. Alkaline phoshatase: variable. Serum bile acid: markedly increased.

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Pathology:
1- Parenchyma:
- Disarray of lobular architecture. - Focal necrosis. - Ballooning of the cells. - Giant cell.

2- Portal tracts:
- Expanded. - Inflammatory cells lymphocytes and PMNs. - Fibrosis. - Extramedullary hematoposesis. - Few bile ducts/ductules.

3- Bile stasis:
- Present in hepatocytes and canaliculi. - Absent in portal tract.

Prognosis
Prognosis is difficult to estimate due to:
- Variable clinical course. - ILL defined pathogenesis. -Factors perpetuating cholestatic process are not fully understood. -No specific biochemical or histologic correlates with clinical outcome have been identified.

Biliary atresia
Idiopathic and progressive disease characterized by dynamic fibro-obliteration of the bile ducts. 1/3 of cases of neonatal cholestasis. Extrahepatic as well as intrahepatic ducts are invoved. Associated malformations cardiovascular anomalies, polysplenia, maltotation, situs inversus viscerum may be found.

2 types
1- Fetal type:
- Jaundice: since birth. - No bile duct remnats were seen in porta hepatis.

2- Perinatal:
- Jaundice: delayed. - No associated malformations. - Bile duct remnants were present in the porta hepatis.

Key features
The clinical presentation, histopathological findings and the prognosis correlate with the developmental stage at which obliterative process begins.

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Etiology
Reovirus type 3 has been suggested with no confirmation. Rotavirus type A and CMV are frequently detected in cases with biliary atresia.

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Clinical presentation
Jaundice: appears at birth but may be delayed to 3-5 the week of life. Stool: acholic. Liver: firm enlarged.

www.MansFans.com Spleen: firm enlarged.

Laboratory findings
Bilirubin: mild to moderate.  Transaminases: mild to moderate. Alkaline phosphatse: markeldly. Serum bile acids: moderate.

Pathology
1- Parenchyma (intact early). 2- Portal tracts:
- Bile ductule proliferation. - Fibrosis: portal or perilobular. - No or little cellular infiltration.

3- Bile stasis:
- Bile plug in portal ducts → specific. - Cellular, canalicular bile stasis → infrequent.

Management
1- Correctable lesions:  Distal atresia with patent proximal portion of the extra hepatic duct.  Direct drainage of the biliary system into the intestine. 2- Non-correctable lesions:  Obstruction at or above the porta hepatis.  In 75-85% of the cases of BA.  Direct drainage of the biliary system into the intestine (Kasai procedure). Liver transplantation: in 80% of cases despite surgery. Prognosis: Overally 10 years survival rate -33%.

Evaluation of the infant with cholestasis: Staged evaluation of neonatal cholestasis:
1- Differentiate cholestasis from physiologic or breast milk jaundice: A-Clinical evaluation (history, physical examination). B- Fractionated serum bilirubin (+bile acids). C- Aminotransferase levels. D- Stool color. E- Index of hepatic “synthetic” function (serum albumin, prothrombin time).

2- Exclusion of treatable disorders:
A- Bacterial cultures (blood, urine). B- HBsAg, other viral serology as indicated. C- Alpha 1- antitrypsin phenotype (level if phenotype not available). D- T4 and TSH (to rule out hypothyroidism). E-Metabolic screen (urine-reducing substances, urine bile acids, serum amino acids), ferritin. F- Sweat chloride test.

3- Differentiation of extra hepatic biliary obstruction from intrahepatic disorders:
A- Ultrasonography. B- Hepatobiliary scintigraphy C- Liver biopsy.

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1- History and physical examination:
1- Irritability, poor feeding and vomiting: - Generalized infection. - Metabolic disorders:
- Galactosemia. - Tyrosinemia.

2- Vertebral arch anomalies, post embryotoxon and the murmur of peripheral pulmonic stenosis: arteriohepatic dysplasia (alagille’s syndrome). 3- Stool examination:
- Acholic stool persistent suggest BA for 10 days. - Pigmeneted stool exclude BA.

Laboratory evaluation:
1- Urine – reducing substances (+ve in galactosemia). 2-↓ RBC galactose -1- phosphate uridyl transferase activity = galactosemia. 3-↑serum succinylacetone, succinylacetoactic “(tyrosinemia). 4-Alpha- antirypsin phenotyping for alpha-1 antitrypsin deficiency. 5- TORCH: - Low diagnostic yield. - Culture is more specific. 6- Duodenal intubation with analysis of fluid for bilirubin content: green or pigmental fliud exclude BA.

3- Radiological evaluation:
1- Ultrasonography:
- Choledochal cyst. - Absence of a gallbladder → BA.

2- Radionuclide imaging: TC labeled iminodiacetic acid: BA:
- Radioisotope uptake by hepatocytes is good. - Absent intestinal excretion.

Neonatal hepatitis:
- Radioisotope uptake by hepatocytes is delayed. - Intestinal excretion is +ve. Pretreatment with oral phenobarbital (5mg/kg/day) for 5 days enhances biliary excretion of the isotope and increases sensitivity 94%.

4- PTC & ERCP:
 Per cuteneous transhepatic cholangiography.
 Endoscopic retrograde cholongio pancreatography.

5- Liver biopsy:
 Most reliable and definitive procedure.  Correct diagnosis in 90-95% of cases by experienced pathologist.

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Diminished bile flow will lead to:
1- Retention of substances dependent on bile secretion bile acids, bilirubin and cholesterol. 2- Decreased bile acid delivery to the intestine fat and fat-soluble vitamin malabsorption. 3-Progressive hepatocellular damage → portal hypertension → liver failure.

Management:
No specific therapy either reverse existing cholestasis or prevent ongoing damage. Therapy is empirical and aim at improving nutritional status and maximizing growth potential and minimizing discomfort. The success of this therapeutic intervention is limited by:
A- Residual capcity of the liver. B- Rate of progression of the underlying disorder.

Malabsorption and malnutrition:
Decreased intraluminal bile acids. Long-chain triglyceride → not absorbed. Medium-chain triglyceride → readily absorbed. Fat-soluble vitamins (A,D,E and K): 2-4 times the daily requirement.

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Recommended oral vitamin supplementation:
Vitamin A Vitamin D Vitamin K Vitamin E Water soluble Aquasol A, 5.000-25.000 IU/day Cholecalciferol, 2.500-5.000IU/day or 25-OH cholecalciferol, 3-5Ug/kg/day Phytonadione (KI), 2.5-5 mg every other day. Aquasol E, 50-400IU/day, Twice the recommended daily allowance.

Pruritus xanthomas:
1- Cholestyramin: - Anion exchange resin that enhances bile flow by interrupting the enterohepatic circulation of bile acid.
- Dose 0.25-0.5gm/kg/day in 2-3 doses. - Side effects:
- Obstruction. - steatorrhea. - Hyperchloremic acidosis. - Unpalatabe.

2- Phenobarbital:
- Stimulates bile acid-independent flow. - Dose 5-10mg/kg/day.

3- Ursodeoxycholic acid: 15-30mg/kg/day. 4- Rifampin: inhibiis hepatic bile acid uptake, 15-30mg/kg/day. 5- Opioid antagonists. 6- Partial external biliary diversion: in intractable pruritis.

Portal hypertension:
1- Ascties:
- Na restriction 1-2mEq.kg/day. - Diuretics. - Paracentesis + albumin.

2- Esophageal varices:
- Vasopressin influsion 0.3ul/1.73m2/min. - Endoscopic sclerotherapy. - Beta blockers propranolol. 3-End-stage disease: Orthotopic transplantation.

liver

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