Neonatal Cholestasis

NEONATAL CHOLESTASIS Gregory J. Semancik, M.D. Major, Medical Corps, U.S. Army Fellow, Pediatric Gastroenterology and Nutrition Walter Reed Army Medical Center

OBJECTIVES Know the differential diagnosis for neonatal cholestasis. Understand how to evaluate the neonate with conjugated hyperbilirubinemia. Know the therapeutic management of neonates with cholestasis.

DEFINITION Neonatal cholestasis is defined as conjugated hyperbilirubinemia developing within the first 90 days of extrauterine life. Conjugated bilirubin exceeds 1.5 to 2.0 mg/dl. Conjugated bilirubin generally exceeds 20% of the total bilirubin.

ETIOLOGIES Basic distinction is between: Extrahepatic etiologies Intrahepatic etiologies

EXTRAHEPATIC ETIOLOGIES Extrahepatic biliary atresia Choledochal cyst Bile duct stenosis Spontaneous perforation of the bile duct Cholelithiasis Inspissated bile/mucus plug Extrinsic compression of the bile duct

INTRAHEPATIC ETIOLOGIES Idiopathic Toxic Genetic/Chromosomal Infectious Metabolic Miscellaneous

INTRAHEPATIC ETIOLOGIES Idiopathic Neonatal Hepatitis Toxic TPN-associated cholestasis Drug-induced cholestasis Genetic/Chromosomal Trisomy 18 Trisomy 21

INTRAHEPATIC ETIOLOGIES Infectious Bacterial sepsis (E. coli, Listeriosis, Staph. aureus) TORCHES Hepatitis B and C Varicella Coxsackie virus Echo virus Tuberculosis

INTRAHEPATIC ETIOLOGIES Metabolic Disorders of Carbohydrate Metabolism Galactosemia Fructosemia Glycogen Storage Disease Type IV Disorders of Amino Acid Metabolism Tyrosinemia Hypermethioninemia

INTRAHEPATIC ETIOLOGIES Metabolic (cont.) Disorders of Lipid Metabolism Niemann-Pick disease Wolman disease Gaucher disease Cholesterol ester storage disease Disorders of Bile Acid Metabolism 3B-hydroxysteroid dehydrogenase/isomerase Trihydroxycoprostanic acidemia

INTRAHEPATIC ETIOLOGIES Metabolic (cont.) Peroxisomal Disorders Zellweger syndrome Adrenoleukodystrophy Endocrine Disorders Hypothyroidism Idiopathic hypopituitarism

INTRAHEPATIC ETIOLOGIES Metabolic (cont.) Miscellaneous Metabolic Disorders Alpha-1-antitrypsin deficiency Cystic fibrosis Neonatal iron storage disease North American Indian cholestasis

INTRAHEPATIC ETIOLOGIES Miscellaneous Arteriohepatic dysplasia (Alagille syndrome) Nonsyndromic paucity of intrahepatic bile ducts Caroli’s disease Byler’s disease Congenital hepatic fibrosis

INTRAHEPATIC ETIOLOGIES Miscellaneous (cont.) Familial benign recurrent intrahepatic cholestasis Hereditary cholestasis with lymphedema (Aagenaes) Histiocytosis X Shock Neonatal lupus

COMMON ETIOLOGIES Premature infants Sepsis/Acidosis TPN-associated Drug-induced Idiopathic neonatal hepatitis Extrahepatic biliary atresia Alpha-1-antitrypsin deficiency Intrahepatic cholestasis syndromes

CLINICAL PRESENTATION Jaundice Scleral icterus Hepatomegaly Acholic stools Dark urine Other signs and symptoms depend on specific disease process

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.

EVALUATION Basic evaluation History and physical examination (includes exam of stool color) CBC and reticulocyte count Electrolytes, BUN, creatinine, calcium, phosphate SGOT, SGPT, GGT, alkaline phosphatase Total and direct bilirubin Total protein, albumin, cholesterol, PT/PTT

EVALUATION Tests for infectious causes Indicated cultures of blood, urine, CSF TORCH titers, RPR/VDRL Urine for CMV Hepatitis B and C serology Ophthalmologic examination

EVALUATION Metabolic work-up Protein electrophoresis, alpha-1-antitrypsin level and phenotype Thyroid function tests Sweat chloride Urine/serum amino acids Review results of newborn metabolic screen Urine reducing substances Urine bile acids

EVALUATION Radiological evaluation Ultrasonography Patient should be NPO to increase likelihood of visualizing the gallbladder Feeding with exam may demonstrate a functioning gallbladder Hepatobiliary scintigraphy Premedicate with phenobarbital 5mg/kg/d for 3-5 days

EVALUATION Invasive studies Duodenal intubation Percutaneous liver biopsy Percutaneous transhepatic cholangiography Endoscopic retrograde cholangiopancreatography (ERCP) Exploratory laparotomy with intraoperative cholangiogram

EXTRAHEPATIC BILIARY ATRESIA Generally acholic stools with onset at about 2 weeks-old Average birth weight Hepatomegaly with firm to hard consistency Female predominance No well-documented familial cases

EXTRAHEPATIC BILIARY ATRESIA Increased incidence of polysplenia syndrome and intra-abdominal vascular anomalies Normal uptake on radionucleotide scan with absent excretion Biopsy shows bile duct proliferation, bile plugs, portal or perilobular fibrosis and edema, and intact lobular structure

IDIOPATHIC NEONATAL HEPATITIS Generally normal stools or acholic stools with onset at one month-old Low birth weight Normal liver on exam or hepatomegaly with normal to firm consistency Male predominance Familial cases (15-20%)

IDIOPATHIC NEONATAL HEPATITIS Impaired uptake on radionucleotide scan with normal excretion Biopsy shows intralobular inflammation with focal hepatocellular necrosis and disruption of the hepatic architecture. No alteration of the bile ducts. Giant cell transformation occurs but is non-specific.

ALPHA-1-ANTITRYPSIN DEFICIENCY Alpha-1-antitrypsin makes up 90% of alpha-1-globulin fraction Associated with PiZZ (about 10-20% will have liver disease) and rarely with PiSZ and PiZ-null phenotypes Biopsy shows hepatocellular edema, giant cell transformation, necrosis, and pseudoacinar transformation.

ALPHA-1-ANTITRYPSIN DEFICIENCY Biopsy also shows accumulation of PAS-positive, diastase-resistant globules in the cytoplasm of periportal hepatocytes. Varying degrees of fibrosis correlate with disease prognosis.

INTRAHEPATIC CHOLESTASIS SYNDROMES Includes several diagnostic entities. Biopsies show cholestasis. May show paucity of intrahepatic bile ducts, giant cell transformation, and/or fibrosis.

TREATMENT Surgical Kasai procedure for biliary atresia Limited bile duct resection and re-anastomosis Choledochal cyst excision Cholecystectomy Liver transplantation

KASAI PROCEDURE Performed for biliary atresia that is not surgically correctable with excision of a distal atretic segment. Roux-en-Y portoenterostomy Bile flow re-established in 80-90% if performed prior to 8 weeks-old. Bile flow re-established in less than 20% if performed after 12 weeks-old

KASAI PROCEDURE Success of the operation is dependent on the presence and size of ductal remnants, the extent of the intrahepatic disease, and the experience of the surgeon. Complications are ascending cholangitis and reobstruction as well as failure to re-establish bile flow.

LIVER TRANSPLANTATION Survival rates approach 80% at 1 year and 70% at 5 years. Biliary atresia is the most common indication for transplant and may be the initial treatment when detected late or may be used as a salvage procedure for a failed Kasai. Used early in cases of tyrosinemia.

TREATMENT Medical management Nutritional support Treatment of pruritus Choleretics and bile acid-binders Management of portal hypertension and its consequences

TREATMENT Nutritional support Adequate calories and protein Supplement calories with medium chain triglycerides Maintain levels of essential long-chain fatty acids Treatment and/or prophylaxis for fat-soluble vitamin deficiencies (vitamins A, D, E, and K)

TREATMENT Nutritional support (cont.) Supplemental calcium and phosphate when bone disease is present Prophylaxis for zinc deficiency Low-copper diet as poorly excreted Sodium restriction when ascites present

TREATMENT Treatment of pruritus Bile acid-binders: cholestyramine, cholestipol Ursodeoxycholic acid Phenobarbital as a choleretic Naloxone Rifampin

TREATMENT Management of portal hypertension and its consequences Variceal bleeding Fluid rescuscitation Blood products Sclerotherapy Balloon tamponade Portovenous shunting Propanolol

TREATMENT Management of portal hypertension and its consequences (cont.) Ascites Sodium restriction Diuretics: spironolactone, furosemide Albumin Paracentesis Thrombocytopoenia managed with platelet infusions when clinically indicated

Neonatal Cholestasis

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Neonatal Cholestasis