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


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


Metabolic– Disorders of Carbohydrate Metabolism

• Galactosemia• Fructosemia• Glycogen Storage Disease Type IV

– Disorders of Amino Acid Metabolism• Tyrosinemia• Hypermethioninemia


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


Metabolic (cont.)– Peroxisomal Disorders

• Zellweger syndrome• Adrenoleukodystrophy

– Endocrine Disorders• Hypothyroidism• Idiopathic hypopituitarism


Metabolic (cont.)– Miscellaneous Metabolic Disorders

• Alpha-1-antitrypsin deficiency• Cystic fibrosis• Neonatal iron storage disease• North American Indian cholestasis


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


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

Health & Medicine

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