NEONATAL CHOLESTASIS

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CHOLESTASIS (REDUCTION IN BILE FLOW)

A. General considerations.
1. Cholestasis results from extrahepatic obstruction or hepatocellular injury, either primary or secondary to many infectious, or metabolic and toxic causes.
2. The newborn is particularly susceptible because of immature hepatobiliary function, with decrease in bile acid pool size, rate of synthesis, intraluminal concentration, and ileal uptake. Consequently, intraluminal fat digestion is impaired, and cholestatic effects of various endogenous and exogenous substances are enhanced.
3. Conjugated hyperbilirubinemia is always a problem and is accompanied by elevation of bile salts and phospholipids, indicating cholestasis. Early recognition allows prompt diagnosis and effective therapy.
B. Clinical syndromes (Box 19-3). Neonatal cholestasis occurs in 1:2500 births, with extrahepatic obstruction accounting for half of the cases. Neonatal hepatitis, biliary atresia and at-antitrypsin deficiency are the three most common causes, with an approximate incidence of 1:5000, 1:10,000, and 1:20,000, respectively.
1. Extrahepatic biliary disease.
a. Extrahepatic biliary atresia. At first, infants with extrahepatic biliary atresia pass "normal-colored" stools. By 3 to 5 weeks, conjugated hyperbilirubinemia develops. In addition to clinical icterus, these infants may have an enlarged liver and, occasionally, an enlarged spleen. Associated anomalies include polysplenia, preduodenal portal vein, malrotation, and congenital heart disease. In established cases, stools are acholic or faintly pigmented. Obstruction to bile flow is at the porta hepatis in the majority of infants. It is important to establish the patency of the extrahepatic biliary tree early to allow prompt surgical intervention. Magnetic resonance cholangiography has been useful in excluding biliary atresia. Postoperative restoration of bile flow occurs in up to 80% of infants who undergo surgery before 8 weeks of age as compared with 20% of infants operated on after 12 weeks. Hepatic portoenterostomy (Kasai procedure) is used based on results of the operative cholangiogram and histopathology of the liver.
b. Choledochal cyst. A choledochal cyst is a dilation of the extrahepatic biliary tree that produces signs and symptoms of obstruction that mimic extrahepatic biliary atresia. It is five times more common in girls than in boys. Complete surgical excision is the treatment of choice and prevents cirrhosis, portal hypertension, and cholangiocarcinoma.
2. Intrahepatic biliary disease.
a. Paucity of interlobular bile ducts.
(1) Syndromic. Alagille syndrome (arteriohepatic dysplasia) consists of hypoplastic intrahepatic bile ducts, chron

and extrahepatic anomalies, including characteristic facies (small, pointed chin; broad forehead; hypertelorism), vertebral defects (butterfly and hemivertebrae), cardiovascular abnormalities (peripheral pulmonary stenosis, coarctation of the aorta), growth retardation, and anomalies of the anterior chamber angle of the eye. Autosomal dominant inheritance with low penetrance is probable. Prognosis is variable but more favorable than the nonsyndromic form.
(2) Nonsyndromic. A progressive cholangiolitic insult leads to paucity of intrahepatic bile ducts; it is also seen as a late complication in infants with biliary atresia and as a feature of liver involvement in graft-versus-host disease. Congenital rubella, cytomegalovirus (CMV), hepatitis B, trisomies 18 and 21, and alantitrypsin deficiency have been associated.
b. Inspissated bile. Results from bilirubin overload in 10% of newborns with hemolytic anemia resulting from Rh or ABO incompatibility, spherocytosis, and G6PD deficiency. Conjugated bilirubin is elevated in cord blood because of intrauterine hemolysis. Hepatosplenomegaly is marked; transaminase levels are normal or mildly elevated, and cholestasis lasts for 4 weeks or longer.
3. Hepatocellular disease.
a. Metabolic and genetic defects.
(1) alpha1-Antitrypsin deficiency accounts for 1% to 10% of infants with cholestasis; jaundice appears at about 8 weeks of age and in 15% of cases is resolved by 7 months. Infants may have conjugated hyperbilirubinemia, jaundice, acholic stools, dark urine, and liver enlargement. After a prolonged period of apparent normal health, cirrhosis and its complications may lead to death in late childhood or early adulthood. Diagnosis is confirmed by serum alpha1-antitrypsin determination and by protease inhibitor phenotyping. Liver transplantation is the only treatment.
(2) Dubin-Johnson syndrome and Rotor's syndrome are autosomal recessive conditions that cause nonhemolytic conjugated hyperbilirubinemia. Transaminase and bile acid levels are normal; prognosis is excellent.
(3) With benign recurrent intrahepatic cholestasis, infants develop intermittent jaundice, pruritus, dark urine, pale stools, and elevated alkaline phosphatase without progressive liver disease.
(4) Peroxisomal disorders. Zellweger's cerebrohepatorenal syndrome is an autosomal recessive disorder. Clinical features include cholestatic jaundice, hepatomegaly, mental retardation, hypotonia, renal cortical cysts, and abnormal facies with epicanthal folds, hypertelorism, and prominent forehead. The defect consists of absence of peroxisomes and derangement of mitochondria. Other cholestatic disorders in this category

(5) Cystic fibrosis rarely causes conjugated hyperbilirubinemia. Meconium ileus may be seen in half of the cases. Jaundice resolves gradually, with increased risk of liver disease later in life.
(6) Galactosemia is an autosomal recessive disorder of carbohydrate metabolism resulting from deficiency of galactose-l-phosphate uridyltransferase, with an incidence of 1:100,000. Clinical features include lethargy, emesis, anorexia, growth failure, cholestasis, and lenticular cataract formation. Elimination of lactose- and galactose-containing products from the diet is prudent while erythrocyte enzyme determination is in progress. Galactosemia should be excluded in any infant with septic cholestasis.
(7) Hypopituitarism may cause cholestasis. Hypoglycemia, septooptic dysplasia, and hypothyroidism may be associated findings. b. Perinatal infections. Cholestasis in many intrauterine viral infections is a result of hepatic necrosis; CMV, rubella, herpes, hepatitis B, enteroviruses, coxsackievirus B, and echoviruses may produce conjugated hyperbilirubinemia. Toxoplasmosis, syphilis, and bacterial infections that cause neonatal sepsis, pyelonephritis, severe enteritis, and enterocolitis may lead to cholestasis.
c. Iatrogenic disease.
(1) Total parenteral nutrition cholestasis is seen in >50% of infants with birth weights of <1000 gm and in <10% of fullterm infants. Prematurity, prolonged fasting, and metabolic alterations (e.g., hyperglycemia and abnormal amino acids) may be contributory.
(2) Cholestasis caused by a drug or hepatotoxin is a possibility. The clinical picture will resemble viral hepatitis.
d. Idiopathic neonatal hepatitis is responsible for 40% of cases of neonatal cholestasis. Prominent physical findings include icterus and hepatomegaly.
C. Clinical presentation. Jaundice, acholic stools, and dark urine are characteristic. Pruritus, lethargy, growth failure, hepatosplenomegaly, and ascites are late signs. Diagnosis includes historical and physical findings (Table 19-3).
D. Laboratory studies (Box 19-4). Evaluation of body fluids, imaging studies, and liver biopsy may be necessary.
E. Management (Box 19-5). It is difficult to provide optimal nutrition to a cholestatic infant. Provision of medium-chain triglycerides results in better caloric intake and growth. Fat-soluble vitamins A, D, E, and K should be supplemented. Ascites and liver failure are managed by low-sodium diet and diuretics (spironolactone, 0.5 to 1.0 mg/kg every 8 hours by mouth; furosemide 1.0 to 2.0 mg/kg per dose by mouth or intravenously every 8 to 12 hours). Phenobarbital (3 to 10 mg/kg per day by mouth) and cholestyramine (0.25 to 0.50 mg/kg per day by mouth) are employed to promote bile flow and excretion

Differential Diagnosis of Neonatal Cholestasis

EXTRAHEPATIC BILIARY DISEASE
Extrahepatic biliary atresia

Choledochal cyst

Bile-duct stenosis

Spontaneous perforation of the bile duct

Neoplasm
Cholelithiasis
 

INTRAHEPATIC BILIARY DISEASE

Intrahepatic bile-duct paucity

    Syndromic form (Alagille syndrome)

    Nonsyndromic forms
Inspissated bile
Caroli disease (cystic dilation of the intrahepatic bile ducts)

Congenital hepatic fibrosis and infantile polycystic disease

HEPATOCELLULAR DISEASE
Metabolic and genetic diseases
    Disorders of amino acid metabolism (tyrosinemia)

    Disorders of lipid metabolism

        Wolman disease

        Niemann-Pick disease

        Gaucher disease

    Disorders of carbohydrate metabolism

        Galactosemia
        Hereditary fructose intolerance

        Glycogenosis type IV

    Peroxisomal disorders
        Zellweger syndrome (cerebrohepatorenal syndrome)

        Adrenoleukodystrophy
        Glutaric aciduria type II

        Olivocerebellar atrophy

    Endocrine disorders

        Idiopathic hypopituitarism

        Hypothyroidism

Familial with uncharacterized excretory defect

    Dubin-Johnson syndrome
    Rotor syndrome

    Byler syndrome

    Aagenaes syndrome (hereditary cholestasis with lymphedema)

    Familial benign recurrent intrahepatic cholestasis
Defective bile acid synthesis (trihydroxycoprostanic acidemia)

Defective protein synthesis
    alpha1-Antitrypsin deficiency

    Cystic fibrosis

Chromosomal disorders

    Trisomy 21
    Trisomy 17-18
    Donahue leprechaunism

Infectious
    Viral

        Cytomegalovirus

        Rubella
        Herpes

        Toxoplasmosis

        Syphilis

         Hepatitis B

        Hepatitis C

        Varicella

        Coxsackievirus
        Enteric cytopathogenic human orphan (ECHO) virus

    Bacterial-sepsis, urinary tract infection, gastroenteritis, listeriosis

Iatrogenic
    Total parenteral nutrition Drug or toxin
    Idiopathic (neonatal hepatitis)

Miscellaneous (shock or hypoperfusion)
 

Screening assessment of patient's general status and liver sufficiency(for cholestasis)

    Complete blood count, smear, reticulocyte count
    Liver enzymes (aspartate and alanine aminotransferases, alkaline phosphatase, and gamma-               glutamyltransferase)
    Total protein and albumin
    Prothrombin and partial thromboplastin times

    Serum bile acids
    Stool pigment

Body fluid examination for etiologic identification

    Blood
        Serology (Cytomegalovirus, herpes, rubella, toxoplasmosis, rapid plasma reagin test)
        Hepatitis B markers (infant and mother) alpha1-Antitrypsin level with protease                 inhibitor typing

        Thyroxine and thyroid-stimulating hormone

        Plasma amino acids
        Blood culture
    Urine
        Urine culture

        Urine-reducing substance
        Urine metabolic screen (amino acids)

    Sweat chloride test
    Intestine
        Stool culture
        24-hour duodenal intubation

Radiologic examination

    Ultrasound
    Radionucleotide examination

    Operative cholangiogram(if operated on for extrahepatic obstruction)

Liver Biopsy

    Percutaneous or operative

Treatment (for cholestasis)

Medical Management

Treat specific etiology

Nutrition
    Provide adequate calories
    Supplement diet with medium-chain triglycerides

    Supplement diet with fat-soluble vitamins A, D, E, and K

Pruritis and xanthoma
    Phenobarbital

    Cholestyramine

Ascites
    Low-sodium diet, 1-2 mEq/kg per day
    Diuretics (spironolactone preferred over furosemide unless acute diuresis is required)
Liver failure, life-threatening portal hypertension, inability to provide adequate growth and development (consider liver transplant)