57: Hyperbilirubinemia, Conjugated

An infant's direct (conjugated) serum bilirubin level is 3 mg/dL. The guidelines from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition use the following definition for abnormal direct bilirubin: direct bilirubin is >1 mg/dL if total bilirubin is <5 mg/dL, or direct bilirubin is >20% of the total if the total bilirubin is >5 mg/dL. Conjugated hyperbilirubinemia is never normal or physiologic. It occurs in 1 in every 2500 infants. A persistent or increasing elevated direct bilirubin is always pathologic and must be evaluated promptly. Early diagnosis is urgent and treatment is essential because it means a better outcome for the infant and can be potentially lifesaving (eg, biliary atresia). The goal is to complete the evaluation by 45 to 60 days of age (surgery for biliary atresia has its best outcome if performed before the age of 45–60 days).

1. Is the urine dark, and what color is the stool? It is best to examine the stools because history obtained by someone else may not be accurate. Dark urine is a nonspecific indicator of increased conjugated bilirubin. Persistent pale or clay-colored stools occur with cholestasis and obstruction needs to be ruled out. One or two pale stools usually do not indicate disease, and infants with biliary atresia have presented with normal stools. There is a high specificity of persistent pale stools.

2. Is the infant receiving total parenteral nutrition (TPN)? TPN may cause direct hyperbilirubinemia by an unknown mechanism and usually does not occur until the infant has been on TPN for >2 weeks. It is more common in sick premature infants.

3. Is the infant gaining weight? Failure to gain weight can be seen in neonatal hepatitis and some metabolic diseases.

4. Does the infant appear sick? Infants with cholestatic jaundice caused by bacterial sepsis appear acutely ill. Infection may cause hepatocellular damage, leading to increased direct bilirubin levels. Infants with urinary tract infection, galactosemia, tyrosinemia, hypopituitarism, fructosemia, hemochromatosis, any metabolic disorder, acute common duct obstruction, gallstones with cholestatic jaundice, or hemolysis can also appear ill. These disorders require immediate diagnosis and treatment.

5. Did direct hyperbilirubinemia occur only after feedings had been established? This suggests that a metabolic disorder such as galactosemia may be present.

6. Have any risk factors been identified? The most important risk factors include low gestational age, early or prolonged exposure to parenteral nutrition, lack of enteral feeding, and sepsis. Episodes of sepsis can be associated with an increase of 30% in the bilirubin level. Other risk factors include neonatal hepatitis, congenital infections, ABO incompatibility, and trisomy 21. Anesthesia may be a risk factor with direct bilirubin levels being higher in the spinal and epidural group than the inhalation group at 24 hours.

7. Is the infant being treated for jaundice for another condition and not improving? Any infant who is being treated for jaundice and whose jaundice does not resolve or improve needs to be evaluated for cholestasis.

8. How old is the infant? Conjugated hyperbilirubinemia in the first 24 hours of life is abnormal and can indicate an infection. If presentation with liver failure in the first couple of days occurs, consider the following: infection (hepatitis, herpes simplex virus [HSV], cytomegalovirus [CMV], and others), hemochromatosis, α₁-antitrypsin deficiency, inborn error of metabolism (tyrosinemia, galactosemia, others), ABO incompatibility, congenital leukemia, neuroblastoma, ischemic event (hepatic vein thrombosis and shock), biliary atresia, and hemoglobinopathy. Onset of jaundice in an asymptomatic infant after 8 days may mean a urinary tract infection. Jaundice at 2 weeks of age is common (2.4–15%) of newborns. Most is unconjugated and caused by breast milk jaundice.

See Table 99–1. Bilirubin is the main waste product of hemoglobin breakdown when the liver breaks down old red blood cells. There are 2 forms of circulating bilirubin: indirect and direct. Direct bilirubin can be measured directly in blood and is a product of bilirubin metabolism within the liver (indirect bilirubin is conjugated in the liver to become direct bilirubin). Direct bilirubin is excreted into bile, stool, and urine. Statistics vary on what are the most common causes of direct hyperbilirubinemia. The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines Committee states that the most common causes are biliary atresia and neonatal hepatitis. The most common cause in the neonatal intensive care unit (NICU) is probably TPN use in premature infants.

1. Common causes. Note: The diagnosis of one disease does not exclude that another disease may also exist.

   1. Biliary atresia. This is a progressive obliterative process involving the bile ducts and is fatal if untreated. It is the most common cause of end-stage liver disease in this age group. These infants usually have clay-colored stools and dark urine. It is the most common cause in term infants. The infants usually look well.

   2. Idiopathic neonatal hepatitis/neonatal giant cell hepatitis. Diagnosed after all other known causes have been excluded. No known infectious or metabolic cause can be found. Idiopathic neonatal hepatitis can occur in premature infants due to an immature biliary tree. They can have feeding difficulties and hypoglycemia.

   3. Genetic intrahepatic cholestasis. Includes many proposed subtypes of intrahepatic cholestasis. Some of these include progressive familial intrahepatic cholestasis (PFIC1 [formerly Byler disease], PFIC2, and PFIC3), Alagille syndrome, disorders of bile acid biosynthesis and conjugation, and others. Each one of these diseases is rare, but collectively as a group this is a common cause of conjugated hyperbilirubinemia. These are chronic diseases, and many can progress and require liver transplantation.

   4. Hyperalimentation. (TPN-induced cholestasis or parenteral nutrition–associated conjugated hyperbilirubinemia). Common in premature or very low birthweight infants. Long duration of hyperalimentation is a risk factor along with prematurity/low birthweight, necrotizing enterocolitis (NEC), and sepsis. Infants can present with hepatomegaly and acholic stools. TPN can also cause biliary sludge.

   5. Infections. Cholestatic jaundice and liver enzyme abnormalities have been reported in sepsis in the neonate. In infants with conjugated bilirubin levels >0.5 mg/dL and <2 mg/dL, an infection must be ruled out.

      1. Bacteria. Most commonly sepsis or urinary tract infection (UTI). Gram-negative infections are the most common. Others are group B Streptococcus, syphilis (Treponema pallidum), Listeria monocytogenes, Staphylococcus, and tuberculosis. If the onset of jaundice occurs after 8 days of age in an asymptomatic infant, suspect a gram-negative UTI.

      2. Viral. Most common appear to be human immunodeficiency virus (HIV) and CMV. Others include Epstein-Barr virus, adenovirus, enterovirus, coxsackievirus, reovirus, herpes (simplex, HV-6, zoster) virus, hepatitis (A [rare], B, C, E), varicella zoster, and echovirus 14 and 19. Intrauterine infections include TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex virus), hepatitis B and C, and syphilis. These account for about 20% of neonatal hepatitis. CMV has been found to be the most common in some studies. Congenital parvovirus B19 and B6 infection can also be involved. Human papilloma virus has been linked to neonatal giant cell hepatitis.

      3. Parasitic. Toxoplasma gondii, malaria.

   6. Hemolytic disease. Inspissated bile syndrome is excessive bilirubin that results from hemolytic disease. It can be from vitamin K deficiency, Rh or ABO incompatibility, extracorporeal support/extracorporeal membrane oxygenation (ECMO/ECLS), and other causes. Ceftriaxone pseudolithiasis can cause inspissated bile syndrome.

   7. Choledochal cyst. Infants present with jaundice at 1–3 weeks, acholic stools; some may have obvious hepatomegaly, palpable mass in right upper quadrant, rarely vomiting or fever.

   8. α₁-Antitrypsin deficiency. This is the most common genetic cause of cholestasis (5–15% of cases). These infants can present with intrauterine growth restriction (IUGR) and hepatomegaly.

   9. Galactosemia. This the most well-known metabolic disorder that presents with prolonged jaundice.

   10. Perinatal hypoxia-ischemia. This has been identified as an important causal factor in transient neonatal cholestasis. Shock can cause hepatic insult. Acute circulatory failure from congenital heart disease, myocarditis, and severe asphyxia can cause fulminant liver failure and conjugated hyperbilirubinemia.

2. Less common causes of direct hyperbilirubinemia

   1. Cholelithiasis (gallstones), biliary sludge.

   2. Paucity of intrahepatic bile ducts.

   3. Cholecystitis (acute and chronic).

   4. Bile duct stenosis/spontaneous perforation of the bile duct.

   5. Neonatal sclerosing cholangitis. Etiology is unknown; presents in early infancy and then resolves.

   6. Inborn errors of metabolism. Wolman disease, Niemann-Pick diseases A and C, glycogen storage disease type IV, Gaucher disease, Zellweger syndrome (cerebrohepatorenal syndrome), neonatal hemochromatosis, tyrosinemia, fructosemia, mevalonic aciduria, and citrullinemia. Cystic fibrosis rarely presents with liver disease in the neonatal period. Bile acid synthetic defects, disorders of fatty acid oxidation, and citrin deficiency can all cause cholestasis. Mitochondrial respiratory chain defects can cause liver failure.

   7. Endocrine disorders. Hypothyroidism, panhypopituitarism.

   8. Congenital. Rotor syndrome exhibits high direct and indirect hyperbilirubinemia. Dubin-Johnson syndrome is a genetic defect in the canalicular transport system that exhibits high direct and indirect hyperbilirubinemia. Caroli disease is a congenital disease that has saccular dilatations of the intrahepatic bile ducts and is associated with polycystic kidney disease. Other rare diseases include Aagenaes syndrome, North American Indian familial cirrhosis, and hair-like bile duct syndrome.

   9. Genetic. Trisomy 21, 18, 13; monosomy X; partial trisomy 11; cat-eye syndrome.

   10. Neoplasm (rare). Includes mesenchymal hamartoma, rhabdomyosarcoma of the biliary tree, neuroblastoma, and neonatal leukemia.

   11. Medications. Prolonged use of chloral hydrate. Drugs that can cause cholestasis: anticonvulsants, cephalosporins, trimethoprim-sulfamethoxazole, and fluconazole.

The clinical hallmarks of the disease include icterus, acholic or pale stools, dark urine, hepatomegaly, and splenomegaly. See Figure 57–1 for an approach to an infant with cholestasis.

1. History. Should include prenatal (evaluate for intrauterine infection or hemolytic disease) and postnatal (feeding history with questions about the composition of formula, as well as the presence of any acholic stools). Have other family members had this problem? This can imply genetic disease. Consanguinity increases the risk of autosomal recessive inheritance. Was a fetal ultrasound done, and what are the results? This may identify a choledochal cyst (cystic structure inferior to the liver or incomplete gastric obstruction by a large cyst) or other abnormalities such as bowel duplication. Is there excessive bleeding, which could signify a coagulopathy or vitamin K deficiency? Is the infant lethargic or irritable? Lethargy can mean hypothyroidism or panhypopituitarism. Irritability can signify a metabolic disorder. Does the formula contain galactose (galactosemia); does it contain fructose or sucrose (hereditary fructose intolerance)? Vomiting may indicate pyloric stenosis, metabolic disease, or bowel obstruction. Delayed stooling is associated with hypothyroidism or cystic fibrosis (CF). With failure to thrive, neonatal hepatitis and metabolic disease are to be ruled out.

2. Physical examination. Does the infant appear sick? Think of sepsis, hypopituitarism, galactosemia, or gallstone. Vital signs, weight assessment (small for gestational age [SGA] implies fetal involvement), and general assessment of nutrition and observation for any signs of sepsis. Is there macroglossia (hypothyroid)? Check for bruises or petechiae on the skin (coagulopathy). Is there evidence of pneumonia on the chest examination? Is there a murmur or evidence of heart failure (Alagille syndrome or biliary atresia)? Be familiar with the characteristics of the syndromes noted here in the differential. Attention should be given to examination of the abdomen. Is it distended? Palpate for an enlarged liver or spleen or for any masses. Check for a palpable mass in the right side of the abdomen (choledochal cyst). Splenomegaly is more common in neonatal hepatitis but can be a late sign in biliary atresia. Jaundice has a greenish hue compared with unconjugated jaundice, which is more yellow. “Bronze baby syndrome” (a bronze discoloration of the skin as a result of dermal accumulation of coproporphyrins) occurs in infants with direct hyperbilirubinemia who are exposed to phototherapy. Ask the nurses about the diaper examination. Is the urine dark (conjugated hyperbilirubinemia), and what color are the stools (light stools suggest cholestasis)?

3. Laboratory studies. Check the newborn screen for hypothyroidism (unconjugated and early-onset conjugated hyperbilirubinemia) and galactosemia as these conditions require urgent treatment to prevent or decrease serious sequelae. If it was not done, a repeat one can be sent, or urine for reducing substance and serum thyroxine and serum thyroid-stimulating hormone (TSH) can be obtained. Sepsis evaluation should also be done early in any ill infant with jaundice to improve outcome. Perform tests based on results of history and physical examination first and rule out the most common etiologies.

   1. In infants with a conjugated bilirubin level >0.5 mg/dL and <2mg/dL infection must be ruled out (most are unexplained). If the conjugated bilirubin continues to increase and is ≥2 mg/dL, assessment of the hepatobiliary system is needed.

   2. Testing guidelines from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Any infant with jaundice at 2 weeks of age should be evaluated for cholestasis by getting a total and direct bilirubin. Breast-fed infants should be evaluated at 3 weeks of age (if the history and physical examination is normal with no dark urine or light stools). Retest any infant with an acute illness or one whose jaundice does not improve with treatment.

   3. American Academy of Pediatrics (AAP) guidelines for jaundiced infants ≥35 weeks' gestation. Total and direct bilirubin should be obtained in any sick infant, or if jaundice is present at or beyond 3 weeks of age. If the direct bilirubin is elevated, do a urinalysis and urine culture. Perform a sepsis evaluation if indicated by history and physical examination. Evaluate for causes of cholestasis including checking the results of the newborn thyroid and galactosemia screen. Look for signs and symptoms of hypothyroidism in the infant.

   4. Common causes. The workup is as follows:

      1. Bilirubin levels (total and direct) are the most important tests. A urine bilirubin detects a substantial elevation of conjugated bilirubin. When serum levels exceed 3–4 mg/dL, bilirubin will be found in the urine.

      2. Liver function tests. Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase, and gamma-glutamyltranspeptidase (GGTP). Elevated levels of AST and ALT signify hepatocellular damage. Elevated alkaline phosphatase levels may signify biliary obstruction (nonspecific because it is found in the liver, kidney, and bone). Elevated GGTP is a sensitive but nonspecific marker of biliary obstruction or inflammation. It was used in the past to differentiate biliary atresia from neonatal hepatitis, but wide variability in results makes interpretation difficult. Elevated GGTP suggests bile duct obstruction: biliary atresia or diseases that damage the bile ducts. Low/normal GGTP suggests progressive familial intrahepatic cholestasis type 1 or 2, bile acid synthesis defect, or neonatal hepatitis (giant cell hepatitis on histology). A very low GGTP and high alkaline phosphatase suggests metabolic and genetic causes of intracellular cholestasis. Lipoprotein X is not routinely recommended.

      3. CBC with differential and platelet count. May help determine whether infection is present. Blood and urine cultures if sepsis or urinary tract infection suspected. A C-reactive protein (CRP) as a screen for infection.

      4. Urine analysis and culture. Indicated for any infant with elevated direct bilirubin.

      5. Serum glucose levels. Hypoglycemia can be seen in metabolic liver disease, poor hepatic reserve, or hypopituitarism.

      6. Direct Coombs test. Used to test for hemolytic disease/inspissated bile syndrome.

      7. Serum cholesterol, triglycerides, and albumin levels. Cholesterol and triglycerides can be checked for assessment of liver failure and albumin for hepatic function.

      8. Prothrombin time and partial thromboplastin time. To evaluate hepatic function.

      9. Reticulocyte count. May be elevated (ie, >4–5%) if bleeding has occurred or hemolysis is present.

      10. Testing for viral disease. Determine the serum total immunoglobulin M (IgM) level. If high, test for TORCH infections (see Chapter 141). Urine is tested for cytomegalovirus, and a serum hepatitis profile is obtained (hepatitis surface antigen and IgM hepatitis A antibody). Hepatitis B markers should be tested in both the mother and the infant with polymerase chain reaction (PCR) studies being the most specific.

      11. Serum ammonia levels. If elevated, can be caused by liver failure.

      12. Serum ferritin levels are elevated, serum transferrin level is low but hypersaturated and lactate dehydrogenase (LDH) is elevated in neonatal hematochromatosis.

      13. Urine testing for reducing substances. If galactosemia is suspected. Galactose in the urine results in a positive reducing substance in the urine on a Clinitest, but will have a negative urine test for glucose (glucose oxidase). Urine for succinylacetone should be done and if detected can be seen in hereditary tyrosinemia type 1.

      14. Serum thyroxine and thyroid-stimulating hormone levels. If hypothyroidism is suspected.

   5. Less common causes. Perform the following:

      1. Sweat chloride test/immunoreactive trypsin. To rule out cystic fibrosis.

      2. Serum cortisol.

      3. Plasma and urine amino acid screening. Urine organic acid and plasma amino acid are screens for inborn errors that cause liver dysfunction.

      4. Karyotype. To test for genetic disorders.

      5. Serum α 1 -antitrypsin levels and phenotype. To rule out deficiency.

4. Imaging and other studies

   1. Chest radiograph. To check for cardiovascular or situs anomalies that may suggest biliary atresia. Infants with biliary atresia can have polysplenia syndrome. Alagille syndrome may have butterfly vertebrae on chest x-ray.

   2. Ultrasonography of the liver and the biliary tract (hepatic ultrasound). Recommended for all infants with cholestasis per guidelines. It can rule out anatomic abnormalities such as choledochal cyst (cystic mass seen), stones, tumor, and masses and also provide information on the gallbladder. The absence of or finding a small gallbladder suggests, but cannot be used to rule out, biliary atresia. The procedure is operator dependent. “Triangular cord” (thickness of the echogenic anterior wall of the right portal vein of more than 4 mm on longitudinal scan) and an abnormal gallbladder length may be positive in the diagnosis of biliary atresia.

   3. Magnetic resonance imaging (MRI). Best study for neonatal hemochromatosis to detect excess iron in the liver.

   4. Hepatobiliary scanning (scintigraphy). Radionuclide scans such as hepatobiliary iminodiacetic acid (HIDA), diisopropyl iminodiacetic acid (DISIDA), or paraisopropyl iminodiacetic acid (PIPIDA) scans allow evaluation of the biliary anatomy. Injected radioactive material is normally excreted into the intestine. If there is no visualization after 24 hours, biliary obstruction or hepatocellular dysfunction may be present (high sensitivity for biliary atresia but low specificity). Tests are expensive, time-consuming, and have many false-positive and false-negative results and are not routinely recommended.

   5. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP). These can be done for diagnosis and therapy for bile duct stones. They are not routinely done, but ERCP may be useful if done by an experienced operator. MRCP requires deep sedation or general anesthesia and is not routinely recommended.

   6. Percutaneous liver biopsy. Typically performed after extensive evaluation without definitive diagnosis and is guideline recommended. It is useful in infants with cholestasis of unknown etiology. Evidence indicates that this test can be performed safely in small infants. Some studies have shown that this procedure had the greatest diagnostic accuracy and should be done before surgery to diagnose biliary atresia. Results should be interpreted by a pathologist with pediatric liver disease expertise and experience.

   7. Duodenal aspirate. May be useful in remote areas where other tests are not available. Fluid is obtained from the duodenum and then the aspirate is sent for bilirubin concentration. With obstruction the aspirate bilirubin concentration is less than or equal to the bilirubin concentration in the serum.

   8. Exploratory laparotomy and operative cholangiography. These should be considered if all other tests have been done and are inconclusive, and biliary atresia needs to be diagnosed.

See Figure 57–1 for an approach to a full-term or premature infant with conjugated hyperbilirubinemia. The cause of direct hyperbilirubinemia is determined and specific treatment is directed at the cause. As few conditions are treatable, care is mostly supportive. Treatment involves dietary measures, medications, and surgery. This section also discusses some of the more common causes of conjugated hyperbilirubinemia, with more detailed management information in Chapter 99. Consultation with a pediatric gastroenterologist is recommended for all infants.

1. Diagnose the infant who appears sick and requires urgent treatment

   1. Sepsis. If signs of sepsis are present, appropriate cultures should be performed and empirical antibiotic therapy initiated.

   2. Urinary tract infection. Appropriate antibiotic therapy.

   3. Metabolic disorders. (Galactosemia, tyrosinemia, fructosemia, hematochromatosis.) Immediate elimination of lactose- and galactose-containing products from the diet is required. Hematochromatosis requires supportive care (respiratory, ventilation, pressors) and treatment with chelation and other agents. Liver transplantation may be necessary.

   4. Hypothyroidism. Treatment is l-thyroxine. See Chapter 140.

   5. Hemolytic disease/hemolysis. Treatment depends on etiology (vitamin K, etc.).

   6. Hypopituitarism. Hormone replacement, fluid, and electrolyte therapy.

   7. Gallstones with acute common duct obstruction. Surgery is indicated.

   8. Intrauterine infection. Appropriate antiviral agents or other medications should be started, if indicated.

2. Parenteral nutrition–associated cholestasis (PNAC). If the infant has been on parenteral nutrition (PN) for 2 weeks and has not been fed, then the infant may have PN-associated cholestasis. Consider stopping TPN completely, cycling TPN, or using partial parenteral nutrition with some enteral feedings. Enteral feeding can reduce the incidence and severity of PNAC. Most infants recover with clearing of cholestasis in 1–3 months after normal feedings have begun. The use of phenobarbital therapy is controversial. Ursodeoxycholic acid is being used investigationally in high-risk neonates with TPN cholestasis with good results. Cholecystokinin as a treatment or prophylactic agent has less conclusively shown benefit. Erythromycin by increasing motility may be helpful in preventing or treating PNAC. Fish oil–based lipid emulsions may be able to reverse TPN cholestasis and may be beneficial, but are not readily available. The only known effective treatment is to stop the parenteral nutrition and transition to full enteral feedings.

3. Biliary atresia. Biliary atresia must be differentiated from neonatal hepatitis. Earlier diagnosis of biliary atresia and surgical repair leads to a better outcome. Exploratory surgery with intraoperative cholangiography is often the initial step. Hepatic portoenterostomy (the Kasai procedure) is currently the initial procedure of choice in infancy. It has the greatest chance of reestablishment of bile flow and the longest-term survival of the infant's liver if performed before the age of 45–60 days. Orthotopic liver transplantation is selectively performed for those infants or children with progressive liver failure. Liver transplantation offers improved survival and quality of life to those for whom the Kasai operation is not successful.

4. Other etiologies

   1. Choledochal cyst. The treatment is surgical removal of the cyst and biliary bypass.

   2. Idiopathic neonatal hepatitis. Supportive care (medications, specific formulas, vitamins) with a fair prognosis exists. Those who develop cirrhosis may require a liver transplant.

   3. α₁-Antitrypsin deficiency. Infants initially can be managed with nutritional support, vitamins, and treatment of cholestasis. The only curative therapy is liver transplantation.

   4. Inspissated bile. Inspissated bile secondary to hemolytic disease is treated with supportive management. The use of phenobarbital is controversial.

5. General recommendations

   1. Dietary. Most of these infants require special formulas (eg, Pregestimil, Enfaport, Portagen) that include medium-chain triglycerides (MCTs) that can be absorbed better with a bile salt deficiency. Supplemental MCTs can be given to breast-fed infants. Supplemental vitamins (A, D, E, K) are needed in many of these infants. Some infants may require other dietary restrictions.

   2. Medications. Ursodeoxycholic acid, phenobarbital, and cholestyramine are used often and are discussed in detail in Chapter 99.

   3. Surgery. Surgery includes the Kasai procedure and liver transplantation.