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

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
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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
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•
•
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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
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•
•
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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.)
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–
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–
–
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 alpha1-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 PASpositive, 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.
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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 reestablish 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
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Fluid rescuscitation
Blood products
Sclerotherapy
Balloon tamponade
Portovenous shunting
Propanolol
TREATMENT

Management of portal hypertension and its
consequences (cont.)
– Ascites
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Sodium restriction
Diuretics: spironolactone, furosemide
Albumin
Paracentesis
– Thrombocytopoenia managed with platelet
infusions when clinically indicated