Jaundice

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Chapter 18 Jaundice

James M. Callahan, MD, FAAP, FACEP

1 What is jaundice?

Jaundice, or icterus, is a yellow or green-yellow discoloration of the skin, mucous membranes, sclera, and body fluids caused by increased levels of circulating bilirubin. Jaundice is usually noticeable at serum bilirubin levels of 5 mg/dL.

2 Where does bilirubin come from?

The major source of bilirubin is the breakdown of heme pigment released from senescent erythrocytes. Bilirubin is usually cleared from the circulation by the liver and, once conjugated, is excreted in bile. Hemolysis that exceeds the liver’s capacity to conjugate bilirubin or processes that impair the excretion of bile cause increased bilirubin levels.

3 Is jaundice always pathologic?

Up to two-thirds of newborns develop visible jaundice at some point in the first few weeks of life. Most of these infants have “physiologic” or “breast milk jaundice” and not a pathologic process. Exclude potentially harmful causes before deciding that these benign conditions are present. In children over 3 months of age, jaundice is almost always associated with a pathologic process.

4 How do you begin the evaluation of a patient with jaundice?

First, determine whether the jaundice is due to conjugated or unconjugated hyperbilirubinemia. Conjugated hyperbilirubinemia is defined as jaundice in which the direct bilirubin level is >2 mg/dL or accounts for more than 20% of the total bilirubin. Unconjugated hyperbilirubinemia (high indirect bilirubin level) is usually due to hemolytic processes or defects in conjugation. Conjugated hyperbilirubinemia is pathologic at any age and is usually associated with cholestatic processes due to hepatic disease or anatomic obstruction to bile flow. Further workup and treatment are guided by the determination of the type of hyperbilirubinemia. The approach also varies depending on the age of the patient (newborn versus older infant/child).

6 What is kernicterus?

Kernicterus (bilirubin encephalopathy) is the most worrisome complication of neonatal unconjugated hyperbilirubinemia. At high levels, unconjugated hyperbilirubin may cross a compromised blood-brain barrier and cause lethargy, hypotonia, poor feeding, fever, seizures, and signs of increased intracranial pressure. Untreated, unrecognized, and severe cases may lead to mental retardation, cerebral palsy, and sensorineural hearing loss.

7 Which children are at risk for kernicterus?

Neonates with jaundice associated with a coexisting serious condition are most likely to develop kernicterus. Children with sepsis, hypoxia or hypercarbia, brisk hemolysis (e.g., that seen with Rh incompatibility), hypoglycemia, or prematurity are most at risk. In healthy, full-term infants, kernicterus is almost never seen at unconjugated bilirubin levels < 25 mg/dL. Premature infants and those with intercurrent illnesses may experience kernicterus at lower levels. Kernicterus, though rare, still occurs, even in otherwise healthy children born at or near term.

Ip S, Chung M, Kulig J, et al: An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics 114:e130–153, 2004.

8 What other laboratory tests are indicated in neonates with unconjugated hyperbilirubinemia?

Do a complete blood count (CBC) with differential and examination of the smear, a reticulocyte count, and direct Coombs test. Seek signs of hemolysis on the CBC. The differential may indicate an infectious process. Anemia or reticulocytosis suggest blood loss or ongoing hemolysis. If the Coombs test result is positive, isoimmunization has probably occurred (because of Rh, ABO, or minor blood group incompatibility). Determine maternal and neonatal blood types (this may be known at the hospital of delivery). Hemolysis in the absence of isoimmunization suggests a red cell defect in this age group, and a G6PD assay as well as fragility testing would be useful. Unconjugated hyperbilirubinemia in the absence of hemolysis may be seen with infections (although conjugated hyperbilirubinemia is more commonly seen), and a urinalysis, Gram stain, and culture may be helpful. If these additional studies are unremarkable, the child may have breast milk jaundice or exaggerated physiologic jaundice.

Garcia FJ, Nager AL: Jaundice as an early diagnostic sign of urinary tract in infancy. Pediatrics 109:846–851, 2002.

9 What is breast milk jaundice?

Breast-fed infants are about three times as likely as formula-fed babies to have high bilirubin levels in the first week of life. In the first few days of life, this is probably due to decreased fluid and caloric intake (until their mother’s milk is fully in) and decreased passage of meconium stools. Later in the first week of life, it has been proposed that lipase and nonesterified long-chain fatty acids in breast milk inhibit hepatic excretion of bilirubin, while the β-glucuronidase in breast milk increases enterohepatic circulation of bilirubin.

10 What is physiologic jaundice? What causes it?

Most infants (approximately two-thirds) develop visible jaundice at some point in the first week of life. The vast majority of these children have physiologic jaundice. Many factors contribute to this “normal” hyperbilirubinemia, including a large red blood cell mass, decreased survival of red blood cells, decreased hepatic uptake of bilirubin, decreased conjugation of bilirubin in the liver, and increased enterohepatic recirculation of bilirubin. Physiologic jaundice is a diagnosis of exclusion.

11 What are some indicators that jaundice is not physiologic and therefore should prompt further investigation?

Jaundice in first day of life

Bilirubin level that increases >5mg/dL per day

Conjugated bilirubin level > 1.5 mg/dL or > 10% of total bilirubin

Bilirubin level > 13 mg/dL

Jaundice beyond the first week of life

Jaundice with hepatosplenomegaly and anemia

Jaundice in infants who are ill-appearing

12 When is treatment indicated in neonates with unconjugated hyperbilirubinemia?

Healthy, full-term infants should be treated with phototherapy when their bilirubin level is >15 mg/dL in the first 2 days of life, or >18 mg/dL after that time. Some infants are lethargic, and the mother may report that the infant is not nursing well. Supportive measures with IV saline are often needed. If despite phototherapy the bilirubin level increases to >20 mg/dL, or if at any time the bilirubin level is >25 mg/dL, consider an exchange transfusion. Full-term infants who are ill (those with hemolysis, sepsis, hypoglycemia, acidosis, or hypoxia) and preterm infants should have phototherapy and exchange transfusions instituted at lower serum bilirubin levels. Temporary interruption of breast feeding may lead to a rapid and sustained decrease in bilirubin levels in children with breast milk jaundice.

American Academy of Pediatrics Subcommittee on Hyperbilirubinemia: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 114:297–316, 2004.

KEY POINTS: TREATMENT OF UNCONJUGATED HYPERBILIRUBINEMIA IN NEONATES

1 Treat healthy, full-term infants with a serum bilirubin level > 15 mg/dL in the first 2 days of life or > 18 mg/dL after 2 days of age with phototherapy.

2 Treat preterm infants and infants who are ill (e.g., sepsis or other infections or hemolytic disease) at lower levels.

3 Provide infants with good supportive care.

4 Consider exchange transfusion for infants who do not respond to phototherapy or whose bilirubin level is >25 mg/dL (lower in preterm and sick infants).

13 Is treatment for unconjugated hyperbilirubinemia an emergency?

Yes, when the level is very high. An outside laboratory or a visiting home nurse often does a bilirubin test, and the abnormal result prompts the emergency department (ED) visit. Thus, the report may be several hours old by the time the infant presents to the ED. The bilirubin level can sometimes rise quickly to a dangerous level. Avoid unnecessary delays in evaluation and management. When the unconjugated or indirect bilirubin approaches a dangerous level, as noted above, make arrangements for prompt phototherapy. This is sometimes difficult to do in an ED setting, and some believe jaundiced infants are better managed as direct admissions to the hospital, where phototherapy can begin quickly.

Maisels MJ: Jaundice in a newborn—how to head off an urgent situation. Contemp Pediatr 22:41–54, 2005.

15 Which laboratory tests are helpful in determining the etiology of conjugated hyperbilirubinemia in neonates?

Obtain CBC with differential, urinalysis, Gram stain, blood culture, and urine cultures to look for signs of sepsis or urinary tract infection. A urinalysis with increased reducing substances other than glucose suggests of galactosemia, especially in a patient with hypoglycemia. Viral and toxoplasmosis titers may help establish the diagnosis of a TORCH infection. Any vesicular lesions of the skin or mucous membranes can be tested with immunofluorescence assays and cultured for herpes simplex virus. Hepatic aminotransferase levels that are markedly elevated suggest hepatitis. Sweat chloride testing (to rule out cystic fibrosis), α-1–antitrypsin phenotyping, and repeated thyroid hormone testing may be needed in some infants. Albumin and clotting studies will reflect the synthetic capabilities of the liver. Closely monitor serum glucose because infants with hepatic disease may be at risk for hypoglycemia.

KEY POINTS: APPROACH TO NEONATAL JAUNDICE

1 Determine whether the jaundice is due to conjugated or unconjugated hyperbilirubinemia.

2 Conjugated hyperbilirubinemia is always due to a pathologic process in this age group and requires further diagnostic workup (including imaging studies to rule out biliary obstruction) and hospital admission.

3 Most children with unconjugated hyperbilirubinemia will have physiologic or breast milk jaundice, but the history, physical examination, and diagnostic workup must be thorough enough to exclude pathologic causes.

16 What imaging studies are helpful?

Abdominal ultrasonography can evaluate the extrahepatic biliary tract, looking for choledochal cysts as well as other signs of obstruction. A radionuclide scan (DISIDA [diisopropyl iminodiacetic acid] scan) that demonstrates excretion of radionuclide into the bowel excludes biliary atresia. Absence of excretion means that biliary atresia remains a possibility and further workup (hepatic biopsy) is warranted. Early diagnosis of biliary atresia is imperative to preserve hepatic function. The above studies are generally obtained on the inpatient unit rather than in the ED.

17 What treatment is required for neonates with conjugated hyperbilirubinemia?

Since conjugated hyperbilirubinemia always indicates a pathologic process, admit all infants with conjugated hyperbilirubinemia and consult with a gastroenterologist. While diagnostic testing is in progress, supportive therapy, including IV fluids and dextrose; antibiotics or antivirals if indicated (e.g., acyclovir for neonatal herpes infection); vitamin K; and clotting factor replacement may be required. Specific therapy is based on the outcome of the diagnostic evaluation and does not usually occur in the ED. Phototherapy is not helpful unless there is also a markedly elevated indirect bilirubin level.

18 In older infants and children, can anything else be mistaken for jaundice?

Yes. Children who eat large amounts of yellow, orange, or red vegetables can develop a yellow discoloration of their skin. Carotene-containing vegetables can produce carotodermia, while red vegetables (e.g., tomatoes) can produce lycopenemia. Unlike jaundice, this discoloration does not affect the sclerae, and the child should be thriving and appear well.

19 What are the causes of unconjugated hyperbilirubinemia in older infants and children?

Unconjugated hyperbilirubinemia after the neonatal period is due to either hemolysis or decreases in the hepatic conjugation of bilirubin. Hemolysis is seen in children with hemoglobinopathies (e.g., sickle cell disease), red blood cell defects (e.g., G6PD deficiency after exposure to an oxidant stress or children with hereditary spherocytosis or elliptocytosis), autoimmune hemolytic anemia, or Wilson’s disease. Unconjugated hyperbilirubinemia in the absence of hemolysis is seen in Gilbert disease or Crigler-Najjar syndrome.

20 What is the diagnostic approach to children with unconjugated hyperbilirubinemia?

Obtain a CBC with examination of the smear, reticulocyte count, and direct Coombs test. In the absence of hemolysis, there is probably a defect in hepatic uptake of albumin-bound bilirubin, as seen with Gilbert disease and Crigler-Najjar syndrome. Seek a gastroenterology consultation.

If hemolysis is present, findings of sickle cells, spherocytes, or elliptocytes on the CBC smear may be diagnostic. Hemoglobin electrophoresis or osmotic fragility tests may confirm these diagnoses. If the Coombs test result is positive, the patient is probably experiencing autoimmune-mediated hemolysis. Hemolysis without suggestive RBC morphology and a negative Coombs test result may be seen in patients with G6PD deficiency (usually after exposure to salicylates, sulfonamides, naphthalene, etc.) or Wilson’s disease (usually accompanied by psychiatric problems and physical or laboratory signs of hepatic disease).

22 What medications can cause cholestasis leading to conjugated hyperbilirubinemia?

Anticonvulsants (phenobarbital, phenytoin, carbamazepine, and valproic acid); antibiotics (estolate preparations of erythromycin, tetracycline, sulfonamides, isoniazid, rifampin, ketoconazole, and griseofulvin); corticosteroids; oral contraceptives; acetaminophen; salicylates; chlorpromazine; cimetidine; and immunosuppressants (cyclosporine, azathioprine, and methotrexate) have all been associated with cholestasis.

23 What is the diagnostic approach to children with conjugated hyperbilirubinemia?

Consider biliary tract disease in patients with a predisposition to hemolysis (e.g., sickle cell disease) and in patients with severe right-upper-quadrant pain and vomiting. Cholelithiasis and other entities causing biliary tract obstruction are more likely in these patients. Abdominal ultrasonography is indicated.

If the onset of jaundice is acute, consider toxic and infectious causes. Hepatic aminotransferase levels are usually increased in these patients. Seek history of medication use or toxic exposures. A prodrome of nonspecific symptoms and fever are more often seen with infections. Obtain viral serologic tests.

A less acute onset and jaundice associated with signs of chronic, systemic disease should prompt investigations of possible genetic or autoimmune causes (e.g., Pi typing to rule out α-1–antitrypsin deficiency or a sweat test to exclude cystic fibrosis).

24 When does a child with jaundice require admission to the hospital?

Children with dehydration, hypoglycemia, signs or laboratory findings of active biliary tract disease, severe bacterial infections, ongoing hemolysis, or signs of systemic disease should be admitted to the hospital. Any patient with indications of hepatic failure must be admitted and monitored closely. When the underlying diagnosis is uncertain, admission for continued diagnostic investigations is often warranted.

Children without signs of hepatic failure who are able to maintain oral hydration and have laboratory evidence of intact hepatic synthetic function (normal albumin, normal prothrombin time) often can be safely discharged. Many of these patients will have viral hepatitis. If discharged, serologic tests should have been obtained and close follow-up must be ensured.

KEY POINTS: HEPATIC FAILURE IN PATIENTS WITH JAUNDICE

1 In all patients with jaundice, be sure that there are no signs of hepatic failure.

2 Abnormal albumin, prothrombin time, and ammonia levels indicate hepatic failure and warrant admission, close observation, and supportive care, including treatment with vitamin K (fresh frozen plasma if there is active hemorrhage).

25 What are the complications of severe hepatic disease (i.e., hepatic failure)?

Abnormal bleeding and a decreased level of consciousness are the most worrisome complications of severe hepatic disease. Decreased hepatic synthetic function leads to decreased levels of coagulation proteins and prolonged bleeding. The prothrombin time is elevated. Spontaneous hemorrhages, including intracerebral hemorrhages, may occur. Increased plasma ammonia levels and cerebral edema are associated with hepatic encephalopathy.

26 What treatment is required for an older infant or child with jaundice?

The main goal is to determine the etiology of the patient’s jaundice so that specific therapies can be started. While the diagnostic evaluation is proceeding, supportive treatment may involve the administration of IV fluids, vitamin K, or clotting factors as necessary; lactulose and neomycin for the treatment of hepatic encephalopathy; and possible intubation and ventilatory support in patients with a decreased level of consciousness.

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