Jaundice is caused by the deposition of bile pigment in the skin and other tissues as a result of an elevated serum bilirubin concentration. Bilirubin is formed from the degradation of hemoglobin as well as other heme-containing proteins, mainly within cells of the reticuloendothelial system. Bilirubin is carried in the circulation bound to albumin and taken up in the liver by the hepatocytes, where it is conjugated with glucuronic acid before being secreted into bile. Conjugated bilirubin is then converted to urobilirubins by intestinal bacteria, preventing its reabsorption and permitting its excretion in the feces. Jaundice in the neonatal period (<1 month) is present in up to 60% of full-term and 80% of premature infants; usually it is a physiological phenomenon related to the developmental nature of bilirubin metabolism. Infants of certain racial background (oriental, Greek, North American native) may be particularly susceptible.

Physiological jaundice generally appears around the third to fifth day, rises by no more than 85 µmol/L/day and resolves by the end of the second week of life. Hyperbilirubinemia is always of the unconjugated fraction. Peak levels rarely exceed 150 µmol/L in full-term infants, although in premature infants levels of 200 µmol/L are not uncommon and the resolution may be slower. Several mechanisms that contribute to the development of physiological jaundice, including increased bilirubin load and decreased capacity to process bilirubin, are shown in Table 8.

After birth the placenta is no longer available for bilirubin metabolism and the immature liver has a limited capacity for uptake of bilirubin from plasma and for its binding, conjugation and secretion into bile. Blood flow may not immediately favor hepatic perfusion (shunting via the ductus venosus). An increased bilirubin load derives from the neonate's elevated hematocrit combined with a reduced red blood cell life-span. Delayed feedings result in retention of meconium containing significant amounts of bilirubin within the intestine, which initially has reduced bacterial flora. This limits the conversion of conjugated bilirubin into urobilinogens. Also present is b-glucuronidase, which converts conjugated bilirubin into a reabsorbable form.

Jaundice is quantified by measuring the serum bilirubin composed, in general, of unconjugated and conjugated fractions. Because it is impossible to differentiate visually between jaundice caused by unconjugated hyperbilirubinemia and that caused by conjugated hyperbilirubinemia, each of which has different etiologies, therapies and prognosis, the first step in evaluating a jaundiced baby is to determine the total and conjugated bilirubin concentrations. Potentially life-threatening illnesses may present with neonatal jaundice, so it is important that the initial evaluation distinguish between physiological and pathological causes of jaundice in order to start any therapy without delay. Pathological jaundice is suggested and requires investigation when any of the following conditions arises:

1. jaundice appearing within the first 24 hours;
2. a rate of rise of more than 85 µmol/L/24 hours;
3. total bilirubin >250 µmol/L in breastfed infants, or >200 µmol/L in formula-fed infants;
4. persistence of jaundice beyond 2 weeks of age; or
5. a conjugated fraction >34 µmol/L, or >15% of the total bilirubin concentration.

In practice, jaundice is caused either by increased production or decreased clearance of bilirubin by the liver. The pathological causes of unconjugated hyperbilirubinemia are shown in Table 9.

Any process that presents a greater bilirubin load to the liver than can be processed will result in hyperbilirubinemia. Thus, red blood cell hemolysis from a variety of causes, including maternal-infant blood group incompatibility (Rh, ABO, minor groups), membrane defects, red cell enzyme deficiencies and toxic effects of drugs, increases the load of unconjugated bilirubin presented to the liver. Hemoglobinopathies rarely present in the neonatal period because of the presence of a large proportion of the relatively stable fetal hemoglobin (Hgb F). Massive hemolysis may occasionally also raise conjugated bilirubin levels to 25-30% of the total, possibly resulting from the toxic effects of bilirubin secretion into bile. Conditions resulting in increased red cell breakdown, especially hematomas, elevate the serum bilirubin; these are relatively more important in smaller premature infants. Finally, some conditions accentuate the normally high neonatal hemoglobin, resulting in polycythemia. Examples are maternal-infant transfusion, delayed umbilical cord clamping at birth, and conditions that result in relative intrauterine hypoxia (maternal diabetes mellitus, high altitude, newborn small for gestational age).

At any stage in the processing of bilirubin - uptake, transport, conjugation, excretion -abnormalities may affect the unconjugated bilirubin concentration. The Crigler-Najjar syndrome is an inherited disorder characterized by absent or low hepatic glucuronyl transferase activity. Type I is associated with very high levels of bilirubin and with kernicterus, whereas type II has lower bilirubin levels and is responsive to enzyme induction with phenobarbital to lower the serum bilirubin. Gilbert's syndrome, an autosomal dominant condition, is a mild form of elevated bilirubin with reduced glucuronyl transferase activity, in which jaundice (which is rarely observed in the newborn) is often provoked by stress or fasting. It requires no treatment. The Lucey-Driscoll syndrome is a transient form of acquired reduction in glucuronyl transferase activity in the newborn, caused by a factor in maternal serum. Endocrine disorders such as panhypopituitarism and hypothyroidism affect bile conjugation by unclear mechanisms.

Jaundice induced by breast milk occurs in approximately 1 in 200 infants. Jaundice may present in the first week in the early form or after the first week in the late form, which is associated with higher bilirubin levels. The degree of hyperbilirubinemia is quite variable (171-462 µmol/L) and may last from 3 to 10 weeks. Despite the occasional presence of very elevated unconjugated bilirubin levels, kernicterus has not been reported in normal term newborns with breast milk-induced jaundice. Several breast milk components have been implicated, including free fatty acids, an isomer of naturally occurring steroids and b-glucuronidase. Hyperbilirubinemia may also be caused by antibiotic-induced reductions in intestinal flora that increase the level of intestinal conjugated bilirubin, the preferred substrate for b-glucuronidase, whose action produces unconjugated bilirubin that is readily absorbed.

The importance of determining an etiology for unconjugated hyperbilirubinemia lies in directing appropriate treatment to prevent kernicterus. Severe unconjugated hyperbilirubinemia is associated with brain toxicity possibly secondary to cellular hypoxia induced by bilirubin. Early symptoms are nonspecific - e.g., lethargy, vomiting, poor feeding and loss of the Moro reflex. Progressive injury leads to respiratory difficulties, bulging fontanelles, a high-pitched cry, loss of deep tendon reflexes and opisthotonos, finally resulting in gaze paresis, convulsions and death. In survivors long-term sequelae include choreoathetosis, spasticity, seizures and sensorineural hearing loss.

Although the lowest level of bilirubin predictive of kernicterus is not known, it is almost universal at levels >500 µmol/L, present in one-third of full-term infants >342 µmol/L, and rare below this latter level. However, numerous factors play a role in increasing bilirubin toxicity at lower levels. Some concern exists that more subtle long-term effects may occur in any infant with raised unconjugated bilirubin concentration; motor development may be affected by levels greater than 255 µmol/L. Bilirubin toxicity may be increased by factors that reduce binding to albumin, such as hypoproteinemia, acidosis, hypothermia, hypoglycemia-induced elevations of plasma free fatty acids and drugs (sulfa, salicylates, heparin, hematin, ceftriaxone, sodium benzoate), or by factors affecting the permeability of the blood-brain barrier, such as prematurity, asphyxia, hyperosmolarity, infection, respiratory distress syndrome, acidosis and intraventricular hemorrhage. Such factors are frequent in very low birth weight infants, in whom kernicterus may occur at unconjugated bilirubin levels as low as 255 µmol/L.

In contrast to cholestatic infants, those with unconjugated hyperbilirubinemia have normal colored stools, the urine is not dark and the liver is only rarely enlarged and is not firm or nodular. When unconjugated hyperbilirubinemia is confirmed, initial management should identify maternal and infant risk factors according to the causes shown in Table 9. Correction of underlying illnesses (sepsis, hypothermia, acidosis, hypoxia) should be initiated. Specific investigations should include maternal and infant blood group, Coombs' test, hemoglobin or hematocrit, red cell indices and morphology to identify polycythemia, hemolysis or red blood cell disorders. Early feedings should be instituted where possible. For high-risk infants with early jaundice (appearing within the first 24 hours), rapidly rising levels of bilirubin (>85 µmol/L/24 hours) or elevated levels of bilirubin (>250 µmol/L in breastfed or >200 µmol/L in formula-fed infants), specific therapy usually includes phototherapy, exchange transfusion or occasionally oral administration of bilirubin binding agents such as charcoal or agar. Phenobarbital may be given to stimulate the enzymes responsible for bilirubin conjugation. Inhibition of bilirubin formation from its heme precursors may in the future be achieved with agents like tin-protoporphyrin, an inhibitor of heme oxygenase. Breast milk jaundice usually does not require treatment other than maintaining good hydration of the infant with more frequent feedings and occasionally supplemental water or formula, as well as periodic serum bilirubin determinations. Cessation of breast milk feedings for 36 to 48 hours will significantly reduce bilirubin levels that are of concern.

Conjugated hyperbilirubinemia in the newborn is a sign of cholestasis and always requires further investigation. Because cholestasis implies impairment of bile flow at any point from its formation in the hepatocyte to its excretion from the common bile duct, the causes of neonatal cholestasis are many. However, therapeutic interventions that will significantly affect the outcome are relatively few. For certain conditions, notably infections, some metabolic and endocrine disorders and biliary atresia, early intervention is associated with better outcome. The goal, therefore, is to identify treatable causes as early as possible.

The more common causes of cholestatic jaundice in the neonate are outlined in Table 10. Although several groups of illnesses are recognized (infectious, metabolic/endocrine, disorders of the bile ducts, cholestatic syndromes), in practice the diagnostic approach consists initially of differentiating biliary obstruction (which requires surgical intervention) from intrahepatic causes of cholestasis. Idiopathic neonatal cholestasis is commonly, but less precisely (because true hepatitis is not often present), referred to as neonatal hepatitis. Neonatal hepatitis is used as a general name for a wide variety of different disorders that present similarly and together with biliary atresia account for 70- 80% of all neonatal cholestasis. As specific diseases are elucidated the proportion accounted for by true idiopathic neonatal hepatitis appears to be diminishing. A possible diagnostic approach is shown in Figure 6.

A maternal history of unexplained illness, rash, exposure to cats or uncooked meat may provide clues to infectious causes. A history of blood transfusion or intravenous drug abuse should be sought, although cholestasis is unusual in the neonate with vertically transmitted hepatitis B or C, or human immunodeficiency virus. The family history is especially important for metabolic disorders such as galactosemia, fructosemia, tyrosinemia, Niemann-Pick, a1-antitrypsin deficiency, peroxisomal disorders or cystic fibrosis as well as familial disorders such as Alagille's syndrome or familial progressive intrahepatic cholestasis (Byler's disease). A history of previous infant deaths in the family due to unexplained liver disease may be important now that previously lethal familial diseases (such as bile acid synthesis defects) can be successfully treated.

The infant's presentation may also suggest a particular etiology. Lethargy, poor feeding or vomiting may signify sepsis or hypoglycemia associated with pituitary dysfunction. Forceful vomiting may indicate intestinal obstruction, but may also occur with galactosemia and fructosemia. While the normal neonate usually does not have fructose in the diet, several medications have a sucrose-based vehicle that is metabolized to fructose. Jaundice with acholic stools in the first 24 hours of life may suggest a bile duct lesion (stone, stricture, perforation). A well appearing infant of full-term gestation and normal birth weight with gradual onset of persistently acholic stools is likely to have extrahepatic biliary atresia.

The physical examination frequently may guide subsequent investigations. The particular facies and high-pitched cry associated with the murmur of peripheral pulmonic stenosis may suggest Alagille's syndrome. A small for gestational age infant with petechiae, rash, retinal lesions, hepatosplenomegaly and adenopathy portrays the clinical appearance of congenital viral infection. An enlarged, firm and/or nodular liver suggests fibrosis, most commonly due to biliary atresia. Biliary atresia also may be associated with situs inversus and a murmur of congenital heart disease. A palpable right upper quadrant mass may signify a choledochal cyst. A micropenis in the male, optic disk atrophy or midline facial defects such as cleft lip may be a clue to hypopituitarism. Severe hypotonia is associated with peroxisomal disorders. Finally the rectal examination may provide stool to determine the presence or absence of bile.

If the stool is persistently white, investigations should be directed toward possible extrahepatic biliary obstruction. Although acholic stools may occasionally occur with severe intrahepatic disease, Alagille's syndrome and cystic fibrosis, additional clinical features and laboratory investigations usually are diagnostic. An abdominal ultrasound will detect a choledochal cyst, cholelithiasis, dilated bile ducts from obstruction or stenosis, and intrahepatic or extrahepatic masses. Elements of the polysplenia syndrome (preduodenal portal vein, situs inversus, abnormal inferior vena cava), associated with biliary atresia, may also be detected. At this stage it would be appropriate to refer to a pediatric surgeon for surgery and intraoperative cholangiogram. Some^®) are equivocal. (Confusion may arise because yellow secretions or urine will color otherwise acholic stools. This often can be avoided by obtaining stool by rectal examination or by breaking open the stool to reveal its true color.) In such cases hepatobiliary scintigraphy using a ^99mTc-labeled iminodiacetic acid derivative, following five days of treatment with phenobarbital to enhance excretion, may demonstrate patency of the biliary tree. If excretion into the intestine is demonstrated, further diagnostic laboratory investigations are indicated. The absence of excretion is less specific and may arise with intrahepatic cholestasis, as previously mentioned.

A percutaneous liver biopsy will usually differentiate extrahepatic biliary obstruction, particularly biliary atresia, from intrahepatic causes of cholestasis. Typically, biliary atresia is associated with fibrous expansion of the portal tracts, bile ductular proliferation and portal bile plugs. Idiopathic neonatal cholestasis is characterized by disorganization of the structure of the lobule, mononuclear cell infiltration, focal hepatocyte necrosis and more diffuse presence of giant cells than found with other disorders. Bile duct paucity is suggested by absence of intralobular bile ducts, but an adequate number of portal spaces must be present to confirm the diagnosis. Early biopsies may suggest idiopathic cholestasis, requiring clinical suspicion and repeat biopsy to arrive at the correct diagnosis. The less common nonsyndromic forms of bile duct paucity may ultimately be shown to be secondary forms because the list of diseases associated with this histological picture appears to be increasing with time.

Laboratory investigations useful in the evaluation of the cholestatic neonate are outlined in Table 11. Serum bilirubin measures the degree of cholestasis. Alkaline phosphatase and g-glutamyl transpeptidase (GGT) are greatly elevated with biliary obstruction. However, with prolonged cholestasis alkaline phosphatase may be elevated on the basis of the effects of vitamin D malabsorption on bone; g-glutamyl transpeptidase is normally elevated in the neonatal period. A measure of hepatic synthetic function is provided by INR/prothrombin time, serum albumin and, where available, factor V levels. The most urgent investigations search for possible bacterial infection and certain metabolic/endocrine disorders for which prompt therapy will reverse the cholestasis as well as treat the underlying disease state. Thus, bacterial cultures of the urine and/or blood; urine for reducing substances (while the infant is ingesting lactose in the form of breast milk or lactose-based formula) or serum galactose-1-phosphate uridyltransferase to diagnose galactosemia; and tests of pituitary function (thyroxin, thyroid stimulating hormone, cortisol and growth hormone levels), in the appropriate clinical setting, are indicated. Serum for very long chain fatty acids may aid in the diagnosis of peroxisomal disorders. Recently, bile acid synthesis defects have been described that respond to specific bile acid replacement therapy if begun early in the course. The presentation and liver biopsy resemble idiopathic neonatal cholestasis (neonatal hepatitis), although the GGT is normal. The diagnosis requires bile acid metabolite analysis of the urine, a technique available in only a few tertiary pediatric centers. The only other cause of neonatal cholestasis with normal or low GGT is progressive familial intrahepatic cholestasis (Byler's disease). The diagnosis of many infections is made serologically, particularly with specific IgM antibody titers. Maternal titers may be required to interpret elevated IgG titers in the face of possible placental transfer. The sweat chloride test is specific for cystic fibrosis but requires a sufficient collection of sweat to be interpretable. Ophthalmologic evaluation may detect the chorioretinitis common in congenital infections, cataracts that develop with galactosemia or the posterior embryotoxon of Alagille's syndrome. Vertebral radiographs may demonstrate the butterfly vertebrae of Alagille's syndrome and long bone radiographs may be abnormal in some congenital infections. Intracranial calcifications that accompany congenital infections may be detected with skull films, ultrasound or CT scan.

Treatment for many of these disorders is supportive. Ensuring optimal caloric intake for growth may at times require nasogastric tube feeding to supplement a poor intake. Fat malabsorption is common as a result of lack of intestinal luminal bile acids; it may be treated with supplemental medium-chain triglycerides, which can be absorbed in the absence of luminal bile acids. Supplemental fat-soluble vitamins are required to prevent rickets (vitamin D), coagulopathy (vitamin K), peripheral neuropathy (vitamin E) or xerophthalmia (vitamin A). Only vitamin E is available in a well-absorbed oral form (d-alpha-tocopheryl polyethylene glycol succinate); intramuscular administration of other fat-soluble vitamins is frequently necessary. Pruritus is treated with variable success with the agents and procedures listed in Table 12. Progression of cholestasis requires monitoring the child for the development of cirrhosis and treating its complications of ascites, portal hypertension and liver failure.