Bilirubin

In any patient with jaundice, the total serum bilirubin should be fractionated, as the differential diagnosis of unconjugated hyperbilirubinemia is distinct from that of conjugated hyperbilirubinemia (see Figs. 15.2 and 15.3 ). On occasion, hemolysis interferes with some assays and may result in a falsely elevated conjugated fraction. This can be problematic with specimens obtained by heelstick or fingerstick. If the clinical picture is consistent with unconjugated hyperbilirubinemia, the assay should be repeated with a venous sample.

Aminotransferases

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are frequently used as markers of hepatocellular injury. AST is expressed in mitochondria of the liver and cytosol of red blood cells and muscles; thus it is not specific for liver injury. Since ALT is less abundant outside of the liver, an increased ALT level is more suggestive of liver disease. Levels of both are markedly elevated (>5- to 10-fold normal) with hepatocellular injury caused by hepatitis, hepatotoxicity, ischemia, genetic or metabolic liver disorders. Elevation of AST in excess of ALT suggests extrahepatic source of injury. With acute biliary obstruction, there are initial sharp increases in ALT and AST levels and a rapid decline in 12-72 hours as obstruction is relieved. In chronic cholestasis, aminotransferases are usually only mildly elevated. With hepatocellular injury, ALT and AST levels tend to remain more significantly elevated longer. In acute liver failure a rapid decline in ALT and AST levels with worsening coagulopathy is a poor prognostic factor.

It is important to remember that aminotransferases reflect cell injury, not liver function. There is no correlation between the severity of the liver dysfunction and the degree of elevation of ALT and AST levels. Temporal trends in serum aminotransferase levels are useful in monitoring disease activity in chronic viral and autoimmune hepatitis.

Alkaline Phosphatase

Alkaline phosphatase is an enzyme found in bile ducts, bone, intestine, placenta, and tumors. Elevations in the serum alkaline phosphatase level occur with hepatobiliary disease but also normal growth, healing fractures, vitamin D deficiency, bone disease, pregnancy, and malignancy. Fractionation of the alkaline phosphatase isoenzymes can help to determine its site of origin. A mild increase can be seen transiently in normal individuals. In the evaluation of conjugated hyperbilirubinemia, an alkaline phosphatase level of greater than 3 times normal indicates cholestasis; a milder elevation is more consistent with hepatocellular disease.

γ-Glutamyltransferase

The γ -glutamyltransferase (GGT) level is more specific for biliary tract disease than are ALT and AST levels. GGT elevations are inducible by alcohol and certain drugs, including phenytoin and phenobarbital. GGT is found in a variety of tissues and can be elevated in chronic pulmonary disease, renal failure, and diabetes mellitus. The GGT concentration is most helpful in confirming that an elevated alkaline phosphatase level is a result of liver disease rather than bone disease and in differentiating familial cholestatic syndromes.

Bile Acids

Serum bile acids are a very sensitive measure of cholestatic disease. Bile acid levels may be elevated before an increase in bilirubin. Levels are generally very high in primary cholestasis and biliary obstruction but only mildly increased (more than twice normal) in hepatocellular disease. Bile acids should be measured while fasting.

Albumin

Albumin is produced in the liver, and levels can reflect hepatic synthetic function. Serum albumin levels can be useful in monitoring progression of chronic liver disease and in discriminating an acute illness from a previously unrecognized chronic disorder. Hypoalbuminemia can also be secondary to nephrotic syndrome or a protein-losing enteropathy. Due to a long half-life (20 days), albumin is of limited use in assessing synthetic dysfunction in acute liver failure.

Prothrombin Time

Prothrombin time (PT) is the best marker of hepatic synthetic function, as most clotting factors are produced in the liver. It is important not only to measure the PT but also to document the response to parenteral administration of vitamin K because vitamin K deficiency may be an alternative explanation of the elevation of the PT. With severe hepatocellular injury, there is little improvement in the PT. Disseminated intravascular coagulation and thrombosis of a major blood vessel should not be overlooked as the cause of a prolonged PT.

Ultrasonography

Ultrasound studies are useful, noninvasive, relatively inexpensive diagnostic tools for the evaluation of liver disease. Ultrasonography provides information on the size and consistency of the liver and spleen and anatomic abnormalities of the biliary tree, gallstones, and hepatic masses such as cysts, tumors, or abscesses. Dilated intrahepatic ducts may indicate extrahepatic obstruction; however, the absence of dilatation on ultrasonography cannot exclude obstruction, and further studies are required for definitive diagnosis. The utility of ultrasonography is limited in obese patients and in patients with excessive bowel gas. Doppler ultrasonography also demonstrates dynamic flow in hepatic blood vessels and the portal vein; it can identify vascular anomalies of the liver and suggest presence of portal hypertension.

Scintigraphy

Hepatobiliary scintigraphy can aid in the diagnosis of biliary atresia. In a healthy individual, hepatic uptake and excretion of the radionuclide via the biliary system are prompt. When there is an injury to the hepatocyte, the uptake of radionuclide by the liver is diminished; however, the tracer should eventually be visualized in the intestinal tract. With obstructive processes, such as biliary atresia, uptake should be relatively normal unless the problem has been present long enough to have caused hepatocellular injury; however, there is no excretion into the intestinal tract. Administration of phenobarbital (5 mg/kg/day) for 5 days before the study may increase bile flow and thus can increase the diagnostic accuracy. Unfortunately, a significant percentage of patients with intrahepatic cholestasis and neonatal hepatitis do not demonstrate biliary excretion, and further evaluation is needed; thus final diagnosis is delayed. In patients with high level of suspicion for biliary atresia (acholic stools, high GGT), liver biopsy and percutaneous cholangiogram provide a faster and more direct way to reach the diagnosis.

Computed Tomography

Computed tomography (CT) is useful for identifying mass lesions within the liver and when there are technical problems with ultrasonography. CT with contrast can be used to define nature of liver tumors. CT angiography can define the anatomy of portal and hepatic circulation. CT has limited value in the evaluation of biliary anatomy.

Magnetic Resonance

MR studies provide valuable information regarding the anatomy of the liver. Since many imaging protocols can be used depending on the purpose of the study, contacting a radiologist prior to ordering the study is recommended. Cost and frequent need for sedation make MR evaluation the tool for secondary evaluation after screening imaging with ultrasound leaves diagnostic questions. MR imaging can demonstrate storage of heavy metals, such as iron in neonatal iron storage disease. MR with contrast can define the nature of liver tumors. MR angiography is useful in studying the vascular system, including the vascular supply of tumors. MR cholangiopancreatography (MRCP) visualizes abnormalities of the intrahepatic and extrahepatic biliary tree and is also quite useful in evaluating the pancreatic duct system. At this point resolution of MRCP is inadequate to diagnose biliary atresia. Unlike endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC), MRCP is noninvasive.

Endoscopic Retrograde Cholangiopancreatography

ERCP is performed for the evaluation of biliary anatomy. Unlike MRCP, ERCP is both diagnostic and potentially therapeutic for common duct stones and for strictures. Complications of the procedure include cholangitis and pancreatitis. ERCP is recommended for evaluation of biliary tree when therapeutic intervention is likely.

Percutaneous Transhepatic Cholangiography

PTC can be used as an alternative to ERCP as a diagnostic and therapeutic tool in evaluating the biliary tree. Under ultrasound guidance, a needle is passed through the liver and into the biliary tree, and contrast material is injected. If obstruction is identified, biliary drainage, if required, can be performed at the same time. PTC is contraindicated if there is marked ascites or irreversible coagulopathy. The complications of PTC include bleeding, pneumothorax, infection, and bile leakage.

Liver Biopsy

Percutaneous liver biopsy is often necessary to determine the cause of conjugated hyperbilirubinemia. In some instances, a specific pattern of injury, such as paucity of bile ducts or bile duct proliferation, may be evident. In other cases, specific markers of disease may be identified (the distinctive inclusions in α ₁ -antitrypsin deficiency) or measured (metabolic enzyme activity). Ultrasound-guided biopsy is useful when a specific lesion needs to be evaluated or if there is abnormal anatomy of the liver. An open biopsy may be necessary when a large sample of tissue is needed or when there are contraindications to the percutaneous approach, such as ascites or coagulopathy. Transjugular liver biopsy can reduce the risk of bleeding in patients with coagulopathy. The complications of liver biopsy are the same as those for PTC.

History

Evaluation of the infant with jaundice starts with a thorough history, including age at onset and duration of jaundice (see Fig. 15.2 ). In the neonate, the causes of jaundice range from a benign, self-limited process associated with immaturity of bilirubin excretion (physiologic jaundice) to life-threatening biliary atresia or metabolic disorders (galactosemia, fructosemia, tyrosinemia). In older infants, there are fewer benign explanations for jaundice. For example, physiologic jaundice generally resolves by 1-2 weeks of age, and jaundice associated with breast milk usually resolves by the time the infant is 1 month old.

Acholic stools usually indicate obstruction of the biliary tree; however, nonpigmented stools can be seen with severe hepatocellular injury. The clinician should document the presence or absence of acholic stool in every infant evaluated for jaundice. The center of the stool should be examined because the outside may be lightly pigmented from sloughed jaundiced cells of the intestinal tract. Delayed passage of meconium may be secondary to cystic fibrosis or Hirschsprung disease. Delayed passage of stools, by itself, can lead to increased enterohepatic circulation of bilirubin.

Clues to the diagnosis of hyperbilirubinemia are often found in the prenatal and perinatal history ( Table 15.1 ). Maternal infections that can be transmitted to the fetus or neonate, such as syphilis, toxoplasmosis, cytomegalovirus (CMV), hepatitis B, enterovirus, herpes simplex, and human immunodeficiency virus, are rare causes of cholestatic liver disease in the neonate. Prenatal growth pattern should be carefully evaluated. Perinatal infections such as CMV, rubella, and toxoplasmosis can present with intrauterine growth restriction. Premature infants are prone to higher bilirubin levels and more prolonged hyperbilirubinemia; they are also more likely to have risk factors for hyperbilirubinemia, such as delayed enteral feedings, require parenteral nutrition, and have perinatal insults with hypoxia and acidosis.

Delay of feeding can contribute to both conjugated and unconjugated hyperbilirubinemia; this effect is usually transient and should not be overinterpreted. Breast-feeding is associated with higher levels of unconjugated bilirubin and a longer duration of jaundice than in formula-feeding. Even when diagnosis of breast milk jaundice is likely, conjugated bilirubin should be checked because it provides an easy screening tool for liver disorders, including biliary atresia. Galactosemia does not manifest in the infant who receives a lactose-free formula. Hereditary fructose intolerance is not clinically apparent until the infant ingests fluids or solids containing fructose or sucrose. Infants with metabolic disorders often present with a history of vomiting, lethargy, and poor feeding. Vomiting may also be a symptom of intestinal obstruction including malrotation/volvulus.

The family history can often provide direction to the evaluation, particularly with some of the less common hereditary disorders. This can include most of the metabolic disorders, hemolytic diseases, and disorders associated with intrahepatic cholestasis ( Tables 15.2 and 15.3 ).

Physical Examination

With increasing levels of bilirubin, neonatal icterus becomes more extensive, spreading in a cephalopedal direction. Pallor may indicate hemolytic disease. Petechiae alert the clinician to thrombocytopenia, possible sepsis, congenital infections, or severe hemolytic disease.

Dysmorphic face can be present in Zellweger syndrome or Alagille syndrome (see Table 15.1 ). The characteristic facies of Alagille syndrome may not be recognizable until later in childhood. Microcephaly that accompanies jaundice is associated with congenital viral infections.

An ophthalmologic examination can demonstrate a variety of abnormalities. Cataracts are seen in galactosemia and rubella. Chorioretinitis accompanies congenital infections (toxoplasmosis, syphilis, rubella, CMV, herpes simplex virus). Nystagmus with hypoplasia of the optic nerve suggests hypopituitarism associated with septo-optic dysplasia. Posterior embryotoxon is found in Alagille syndrome.

A heart murmur may be caused by an underlying congenital heart disease, which may be associated with Alagille syndrome, one of the trisomies, and syndromic forms of biliary atresia (polysplenia syndrome). Heart disease that results in hepatic ischemia or congestion can be a cause of conjugated or unconjugated hyperbilirubinemia.

Hepatomegaly, splenomegaly, and ascites may be caused by both hepatic and nonhepatic etiologies, but they always require evaluation as they are not associated with physiologic or breast milk jaundice.

Microphallus can be associated with septo-optic dysplasia and hypopituitarism.

Differential Diagnosis

When a neonate has jaundice, a thorough history, including the obstetric history, and physical examination should provide most of the information necessary to determine whether the condition represents physiologic jaundice (see Fig. 15.2 ). A total and fractionated bilirubin measurement should be performed if there is any question about the diagnosis of physiologic jaundice.

Physiologic and Breast Milk Jaundice

In neonates, increased bilirubin production is caused by the normally increased neonatal red blood cell mass and the decreased life span of the red blood cells (80 vs 120 days). Albumin binding is decreased because of lower albumin concentrations and diminished binding capacity, which results in decreased transport of UCB to the liver with increased deposition in tissues. Uptake of bilirubin by the hepatocytes during the 1st weeks of life is defective. Low levels of glutathione S-transferase B decrease intracellular binding, which may impede the transport of UCB to the endoplasmic reticulum. Conjugation is impaired by decreased activity of UDPGT. Secretion into the canaliculi is impaired. There is increased enterohepatic circulation of unconjugated bilirubin as a result of increased concentrations of β-glucuronidase in the intestinal lumen and as a result of decreased intestinal bacterial flora, leading to diminished urobilinogen formation (see Fig. 15.1 ).

These features contribute in varying degrees to physiologic jaundice , characterized by a peak bilirubin level of less than 13 mg/dL on postnatal days 3-5, a decrease to normal by 2 weeks of age, and a conjugated fraction of less than 20%. In premature, breast-fed infants of diabetic mothers and in Asian and Native American infants, the peak is higher and lasts longer. Conjugated bilirubin should be checked if there is any question of the nature of jaundice.

Breast-feeding has been associated with an increased incidence of unconjugated hyperbilirubinemia outside the expected range (>13 mg/dL). Jaundice of this level may occur in 10-25% of breast-fed infants, in contrast to 4-7% of formula-fed infants. It can occur within the 1st 5 days of life and is referred to as “early” or “breast-feeding” jaundice. Breast-feeding jaundice is seen in infants who are not feeding adequately and may be dehydrated or malnourished. In a second group of breast-fed infants, the jaundice develops slowly, occurring after the 1st week of life, and peaks between the 2nd and 3rd weeks of life at 10-20 mg/dL. This is referred to as “late” or “breast milk” jaundice. The precise cause of increased bilirubin levels in this latter setting has not been established; alternative theories include inhibition of glucuronosyltransferase activity and increased enterohepatic circulation of UCB. Kernicterus appears to be very rare but has been reported in association with breast-feeding. No treatment is necessary for physiologic jaundice. Practices that support breast-feeding, such as rooming-in on the maternity ward and frequent feedings, decrease the risk for breast-feeding jaundice. If the bilirubin exceeds 20 mg/dL in the breast-fed infant, discontinuing breast-feeding for 24 hours results in a decreased bilirubin level. Phototherapy or exchange transfusion may also be needed.

If there are any red flags, uncertainty about the diagnosis ( Table 15.4 ), or if treatment is being considered, the hyperbilirubinemia should be investigated further, including fractionation of the bilirubin. Any abnormality identified by history or physical examination is a matter of concern.

TABLE 15.4

Red Flags in the Evaluation of Infants with Jaundice

Onset

<24 hr of age

>2 wk of age

Bilirubin

Conjugated

>20% of total or >2 mg/dL

Total

>13 mg/dL formula-fed

>14-15 mg/dL breast-fed

Course

Increases by >5 mg/dL/day

Persists beyond 14 days of age

Prenatal History

Maternal infection

Maternal diabetes mellitus

Maternal drug use

Polyhydramnios

Intrauterine growth restriction

Delivery

Prematurity

Perinatal asphyxia

Small for gestational age

Feeding

Delayed enteral feeding

Vomiting

Poor feeding

Associated with change in formula

Stools

Acholic

Delayed passage of meconium

Family History

Jaundice

Anemia

Liver disease

Splenectomy

Cholecystectomy

Physical Examination

Ill-appearing

Pallor

Petechiae

Hematoma or ecchymoses

Chromosomal stigmata

Abnormal facies

Microcephaly

Cataracts

Chorioretinitis

Nystagmus

Optic nerve hypoplasia

Posterior embryotoxon

Heart murmur

Hepatosplenomegaly (or isolated hepatomegaly or splenomegaly)

Ascites

Acholic stools

Dark urine

Microphallus

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