Evaluation of jaundice caused by unconjugated hyperbilirubinemia in children

INTRODUCTION — Jaundice is a yellowish discoloration of the skin and sclerae that is an important symptom of elevated serum bilirubin, which is caused by an abnormality of bilirubin metabolism or excretion. The bilirubin can be either unconjugated or conjugated.

Hyperbilirubinemia in children is usually unconjugated and most often caused by problems with red blood cell stability and survival or by defects in the bilirubin-conjugating enzyme uridine diphosphoglucuronate glucuronosyltransferase (UGT). In contrast, disorders that result in conjugated hyperbilirubinemia are usually caused by intrinsic liver dysfunction. However, some diseases cause both unconjugated and conjugated hyperbilirubinemia because they affect several different aspects of hepatocyte function.

This topic will present an overview of the causes of unconjugated hyperbilirubinemia in children and infants beyond the neonatal period and discuss the evaluation and management of such patients, which varies with the underlying disease.

The evaluation of unconjugated hyperbilirubinemia in neonates and the causes and diagnostic approach for the adult with jaundice, which are somewhat different, are discussed separately. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Screening" and "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia" and "Classification and causes of jaundice or asymptomatic hyperbilirubinemia".)

DEFINITIONS

Jaundice — Jaundice is a yellowish discoloration of the skin and sclerae that is an important symptom of elevated serum bilirubin, which is caused by an abnormality of bilirubin metabolism or excretion.

Hyperbilirubinemia — Hyperbilirubinemia refers to elevated serum total bilirubin. After the neonatal period, the upper limit of normal is 1 mg/dL (17 micromol/L), or 1.3 mg/dL (22 micromol/L) in some laboratories. Jaundice usually becomes clinically apparent when the serum total bilirubin concentration is greater than 2 to 3 mg/dL (34 to 51 micromol/L), but the threshold for clinically apparent jaundice may vary among patients.

Hyperbilirubinemia can be categorized as conjugated or unconjugated. Unconjugated bilirubin is a waste product of hemoglobin breakdown that is taken up by the liver, where it is converted by the enzyme uridine diphosphoglucuronate glucuronosyltransferase (UGT) into conjugated bilirubin. Conjugated bilirubin is water-soluble and is excreted into the bile to be cleared from the body. These categories have important diagnostic implications:

●Conjugated hyperbilirubinemia is defined as serum conjugated bilirubin concentration >0.5 mg/dL (8.6 micromol/L).

More commonly, the conjugated component is estimated by measuring "direct" bilirubin, which is elevated if it is >1 mg/dL (17 micromol/L) if the total bilirubin is <5 mg/dL (85 micromol/L), or more than 20 percent of the total bilirubin if the total bilirubin is >5 mg/dL (85 micromol/L). The upper limit of normal for direct-reacting bilirubin is higher because it includes conjugated bilirubin and the delta fraction, which represents bilirubin covalently bound to albumin [1].

Elevation in conjugated (or direct) bilirubin is an abnormal finding that requires further evaluation. The differential diagnosis in neonates differs from that in older children and adults and is discussed in separate topic reviews. (See "Approach to evaluation of cholestasis in neonates and young infants" and "Classification and causes of jaundice or asymptomatic hyperbilirubinemia", section on 'Disorders associated with conjugated hyperbilirubinemia'.)

●Unconjugated hyperbilirubinemia is defined as hyperbilirubinemia without an increase in the conjugated component. Thus, it is hyperbilirubinemia in which conjugated bilirubin is <1 mg/dL (17 micromol/L) if the total bilirubin is <5 mg/dL, or less than 20 percent of the total bilirubin if the total bilirubin is >5 mg/dL (85 micromol/L).

CAUSES OF UNCONJUGATED HYPERBILIRUBINEMIA — Hyperbilirubinemia in children is usually unconjugated and most often caused by Gilbert syndrome or hemolysis (table 1).

Unconjugated hyperbilirubinemia is caused by one of three basic pathophysiologic mechanisms or a combination thereof (figure 1 and algorithm 1):

●Bilirubin overproduction

●Impaired hepatic bilirubin uptake

●Impaired hepatic bilirubin conjugation

Some diseases cause both unconjugated and conjugated hyperbilirubinemia because they affect several different aspects of hepatocyte function.

Bilirubin overproduction — Bilirubin overproduction can result from increased breakdown of hemoglobin and other heme-containing proteins, typically due to extravascular or intravascular hemolysis or sometimes due to abnormal erythropoiesis. In patients with normal liver function, the liver efficiently conjugates and excretes the excess hemoglobin. As a result, the serum bilirubin concentration caused by hemolysis will rarely exceed 4 mg/dL (68.4 micromol/L) [2]. However, hemolysis can lead to severe hyperbilirubinemia in patients with concurrent liver disease, even if mild.

Causes of hemolytic anemia in children are summarized in the table (table 2):

●Extravascular hemolysis – Extravascular (extrinsic) hemolysis is mainly caused by:

•Extravasation of blood into tissues (hematomas, pulmonary blood, and other collections of extravasated blood)

•Hypersplenism of various causes (including splenic sequestration in sickle cell disease) (see "Overview of hemolytic anemias in children", section on 'Mechanical damage')

●Intravascular hemolysis – In most populations, the most common noninfectious causes of intravascular (intrinsic) hemolysis in children are inherited red blood cell disorders:

•Hemoglobinopathies (eg, sickle cell disease and related disorders) (see "Overview of compound sickle cell syndromes")

•Thalassemias (disorders of hemoglobin chain synthesis) (see "Diagnosis of thalassemia (adults and children)")

•Erythrocyte membrane defects (hereditary spherocytosis, hereditary elliptocytosis, and related disorders) (see "Overview of hemolytic anemias in children", section on 'Erythrocyte membrane defects')

•Erythrocyte enzyme deficiencies (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency) (see "Overview of hemolytic anemias in children", section on 'Enzyme deficiencies' and "Genetics and pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency")

Acquired hemolytic anemias include:

•Drug-induced hemolytic anemias (see "Overview of hemolytic anemias in children", section on 'Drugs and toxins' and "Drug-induced hemolytic anemia")

•Autoimmune hemolytic anemia (see "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis")

•Microangiopathic anemias (hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, and Wilson disease) (see "Overview of hemolytic anemias in children", section on 'Microangiopathies')

•Certain infections such as malaria and babesiosis (see "Anemia in malaria" and "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Infections (RBC parasites and intracellular bacteria)')

●Other – Other pathways leading to bilirubin overproduction include dyserythropoiesis (eg, megaloblastic and sideroblastic anemias) and enhanced erythropoiesis due to stress. The mechanisms underlying heme metabolism in these disorders are discussed in detail separately. (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia".)

Impaired hepatic bilirubin uptake — Impaired delivery of bilirubin to the liver and disorders affecting bilirubin uptake by hepatocytes result in reduced hepatic bilirubin uptake and therefore increased levels of circulating unconjugated bilirubin.

●Reduced hepatic blood flow – Conditions causing reduced hepatic blood flow and delivery of bilirubin to hepatocytes include heart failure and portosystemic shunts (spontaneously occurring collaterals in cirrhosis or surgical shunts). The hyperbilirubinemia caused by these disorders is predominantly unconjugated.

●Drugs – Administration of several drugs (eg, rifamycin antibiotics, probenecid, flavaspidic acid, and the cholecystographic agent bunamiodyl) can impair bilirubin uptake. Such effects will usually resolve within 48 hours of drug discontinuation.

Impaired bilirubin conjugation — Gilbert syndrome and Crigler-Najjar syndrome types I and II are among the inherited disorders that cause decreased or absent uridine diphosphoglucuronate glucuronosyltransferase (UGT) activity, an enzyme responsible for bilirubin conjugation with glucuronic acid (figure 1).

Gilbert syndrome — Gilbert syndrome is a common cause of unconjugated hyperbilirubinemia in adolescents and adults. Individuals with this condition have reduced bilirubin-UGT activity. They typically present with intermittent episodes of mild jaundice, often triggered by an intercurrent illness, physical exertion, fasting, or interactions with certain drugs. Affected individuals have a benign prognosis. Given the high frequency of this mutation and lack of pathologic consequences, it may be considered a normal variant. Thus, management is directed at establishing the diagnosis of this disorder and thereby avoiding unnecessary evaluation. (See "Gilbert syndrome".)

Crigler-Najjar syndrome — Crigler-Najjar syndrome types I and II are characterized by the absence or deficiency of the enzyme bilirubin-UGT, respectively. Type I is the more severe form, which presents soon after birth with severe persistent unconjugated hyperbilirubinemia (no conjugated component) and no evidence of hemolysis or underlying liver disease. If the hyperbilirubinemia is not treated promptly and effectively, the patient may develop bilirubin-induced neurologic dysfunction (BIND), or kernicterus, which usually develops after 14 days of age. Even with optimal medical management, many patients eventually develop BIND. Type II also typically presents in infancy but occasionally is diagnosed later in childhood; it is generally associated with lower serum bilirubin concentrations, but values can overlap with type I, especially when there is underlying acute illness or hemolysis. (See "Crigler-Najjar syndrome".)

Drugs — Some drugs inhibit bilirubin glucuronidation, including several protease inhibitors used to treat HIV disease, ketoconazole, and amitriptyline [3,4]. Ethinyl estradiol alone competitively inhibits glucuronidation, whereas combination oral contraceptives typically increase UGT activity and promote glucuronidation.

Other — Liver diseases cause hyperbilirubinemia through several different mechanisms, which may include disruption of bilirubin conjugation. Examples include chronic persistent hepatitis, advanced cirrhosis, and Wilson disease. In some cases, both unconjugated and conjugated bilirubin are elevated (algorithm 2). (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia".)

Rarely, hyperthyroidism is associated with hyperbilirubinemia, which can be unconjugated or conjugated. The mechanism is unclear and may be due to the effects of antithyroid drugs or to an underlying defect in bilirubin metabolism (such as Gilbert syndrome) that was unmasked by superimposed hyperthyroidism [5-7].

DIAGNOSTIC APPROACH — The initial laboratory evaluation of a child presenting with jaundice should begin with measurement of the total serum bilirubin with fractionation (conjugated and unconjugated bilirubin), followed by serum alanine aminotransferase and aspartate aminotransferase, complete blood count with reticulocyte count, and microscopic examination of the blood smear.

These tests will help to categorize the jaundice by answering the following questions:

●Are there signs or symptoms of sepsis? – Jaundice with fever, toxic appearance, or abnormal white blood cell count suggests sepsis and calls for prompt evaluation and empiric treatment with antibiotics if indicated.

●Is the jaundice caused by hyperbilirubinemia?

•Jaundice usually becomes clinically apparent when the serum total bilirubin concentration is greater than 2 to 3 mg/dL (34 to 51 micromol/L), but the threshold varies among patients.

•If the serum bilirubin level is not elevated, the patient's yellow-appearing skin is not true jaundice and is probably due to carotenemia, which also can be distinguished from jaundice during a physical examination because there is no scleral icterus in carotenemia. (See 'Other results' below.)

●Is the hyperbilirubinemia unconjugated? – If hyperbilirubinemia is present, the next step is to determine whether it is unconjugated or conjugated.

•Unconjugated – The hyperbilirubinemia is unconjugated if there is only a small conjugated component (ie, conjugated bilirubin <1 mg/dL if the total bilirubin is <5 mg/dL, or less than 20 percent of the total bilirubin if the total bilirubin is >5 mg/dL). In this case, the evaluation proceeds as described below.

•Conjugated – Hyperbilirubinemia with a large conjugated component (conjugated bilirubin >1 mg/dL, or more than 20 percent of the total bilirubin) indicates a very different set of diagnostic possibilities. (See 'Other results' below.)

●Is the patient anemic? – If the hyperbilirubinemia is unconjugated and the child is well-appearing, the presence or absence of anemia will determine the likely diagnostic possibilities. Algorithmic approaches are provided for the subsequent evaluation:

•Unconjugated hyperbilirubinemia with anemia (see 'Unconjugated hyperbilirubinemia with anemia and/or hemolysis' below)

•Unconjugated hyperbilirubinemia without anemia (algorithm 3) (see 'Unconjugated hyperbilirubinemia without anemia or hemolysis' below)

HISTORY AND PHYSICAL EXAMINATION — The differential diagnosis of unconjugated hyperbilirubinemia is broad and requires a thorough history and physical examination as part of the initial evaluation (table 1).

History — A general clinical history is the first step in the evaluation of the child with unconjugated hyperbilirubinemia. Attention should focus on the following historical details:

●Age of the patient at first presentation

●History of inherited disorder (including liver diseases and hemolytic disorders), including a family history of jaundice or anemia

●Race or ethnicity (may be relevant to risks for specific disorders)

●History of medication/toxic exposure

●Dietary history (appetite, carotene intake, fava bean ingestion if glucose-6-phosphate dehydrogenase [G6PD] deficiency is suspected)

●Travel history

Physical examination

●General appearance – A toxic appearance suggests sepsis or other serious underlying condition.

●Skin and sclerae – The sclerae and skin should be examined closely under adequate light. In patients with dark skin, the palms and soles are less pigmented and may be easier to evaluate for jaundice or pallor [8].

•In patients with mild hyperbilirubinemia (eg, 2 to 3 mg/dL), jaundice may be subtle and seen only in the sclerae.

•Jaundice should be distinguished from carotenemia. In carotenemia, the sclerae are not discolored and the skin color is characteristically more yellow-orange rather than yellow and more noticeable over the palms and soles; serum bilirubin is normal. (See 'Other results' below.)

•Pallor and/or vital sign changes, such as tachycardia and hypotension, may indicate anemia secondary to hemolysis or blood loss.

•Large areas of bruising or hematoma formation suggest extravascular hemolysis as the cause of the unconjugated hyperbilirubinemia.

●Abdomen

•Hepatomegaly or liver tenderness suggests the possibility of hepatitis (eg, viral or drug-induced), which can cause hyperbilirubinemia due to hepatocellular dysfunction.

•Splenomegaly may indicate a hypersplenic state such as splenic sequestration in sickle cell disease, portal hypertension, or autoimmune hemolysis as may occur in systemic lupus erythematosus.

LABORATORY TESTING — The serum total bilirubin measurement with fractionation is the first test in the evaluation of the patient with jaundice. Transcutaneous bilirubin devices provide useful measures of bilirubin levels in neonates but do not distinguish between conjugated and unconjugated bilirubin [9]. This technique has not been validated in older infants and children and is not recommended for use beyond the neonatal period.

If unconjugated hyperbilirubinemia is confirmed, further testing is warranted to determine the underlying etiology. This includes complete blood count and reticulocyte count. Serum aminotransferases should also be measured. Elevated values suggest the presence of liver disease (though isolated elevation of aspartate aminotransferase [AST] is also seen in hemolysis), and measurement of the prothrombin time and partial thromboplastin time may be warranted to assess hepatocyte function. (See "Approach to the patient with abnormal liver biochemical and function tests".)

Unconjugated hyperbilirubinemia with anemia and/or hemolysis — For patients with anemia and/or evidence of hemolysis, a peripheral blood smear should be examined microscopically and a direct antiglobulin (Coombs) test should be performed to look for evidence of autoimmune hemolysis. Causes of hemolytic anemia in children are listed in the table (table 2) and discussed separately. (See "Overview of hemolytic anemias in children" and "Approach to the child with anemia".)

Testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency should be considered in children with relevant risk factors. Boys of African or Mediterranean descent are most likely to have symptomatic disease, which may be triggered by infection or exposure to certain drugs (eg, sulfamethoxazole and some antimalarial agents). Of note, testing for G6PD activity may yield false-negative results in some patients who are tested during a severe hemolytic episode. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Splenomegaly is a common manifestation of hemolytic anemias due to sequestration of destroyed red blood cells (hypersplenism). Liver disease can also cause hypersplenism as a result of portal hypertension. (See "Approach to the child with an enlarged spleen".)

Unconjugated hyperbilirubinemia without anemia or hemolysis — Patients without anemia or evidence of hemolysis who have no laboratory abnormality other than a serum unconjugated bilirubin level less than 5 mg/dL have Gilbert syndrome (algorithm 3). Confirmation of the diagnosis can be made by detecting a reduction in hepatic bilirubin-uridine diphosphoglucuronate glucuronosyltransferase (UGT) activity, which is approximately 30 percent of normal [10,11]. However, this test is not necessary to establish the diagnosis of Gilbert syndrome if the patient is otherwise healthy and has no evidence of hemolysis or liver disease [12]. (See "Gilbert syndrome".)

Children with serum unconjugated bilirubin levels well above 5 mg/dL should be evaluated for Crigler-Najjar syndrome. (See "Crigler-Najjar syndrome".)

Other results — Patients presenting with jaundice who do not have unconjugated hyperbilirubinemia fall into the following categories:

●Yellow-appearing skin without hyperbilirubinemia – The most likely cause is carotenemia. Carotenemia is usually found in infants and toddlers whose diets consist of large amounts of strained yellow vegetables, particularly carrots. Unlike jaundice, the sclerae are not discolored. In carotenemia, the skin color is characteristically more yellow-orange rather than yellow and more noticeable over the palms and soles (see 'Physical examination' above). Although the diet is a major cause of carotenemia in childhood, other causes include nephrotic syndrome, diabetes mellitus, anorexia nervosa, liver disease, and hypothyroidism. (See "The pediatric physical examination: Back, extremities, nervous system, skin, and lymph nodes", section on 'Yellow discoloration'.)

●Conjugated hyperbilirubinemia – The finding of hyperbilirubinemia with a large conjugated component calls for a different approach to the work-up. The causes of conjugated hyperbilirubinemia are largely distinct from those of unconjugated hyperbilirubinemia, although some cases may have mixed mechanisms. Causes of conjugated hyperbilirubinemia include biliary obstruction (eg, gallstones), liver disease causing hepatocellular dysfunction (eg, hepatitis), and several inherited disorders (eg, Dubin-Johnson or Rotor syndrome). Some disorders, including sickle cell disease, can present with either unconjugated or conjugated hyperbilirubinemia, depending upon the presence of infection, biliary obstruction, or hepatocyte injury that prevents efficient conjugation and clearance of bilirubin. (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia", section on 'Disorders associated with conjugated hyperbilirubinemia' and "Inherited disorders associated with conjugated hyperbilirubinemia".)

In neonates and young infants, the causes and diagnostic approach to conjugated hyperbilirubinemia are somewhat different, calling for a different diagnostic approach. (See "Causes of cholestasis in neonates and young infants" and "Approach to evaluation of cholestasis in neonates and young infants".)

IMAGING — Imaging is not routinely needed for the evaluation of a patient with unconjugated hyperbilirubinemia. It may be helpful in select cases in which a particular cause of hyperbilirubinemia is suspected that requires evaluation with imaging. Examples include:

●Ultrasonography might be considered for patients with hemolytic anemia because of their increased risk for gallstones, particularly if there is any elevation of conjugated bilirubin, suggesting biliary obstruction. (See 'Bilirubin overproduction' above.)

●Computed tomography or magnetic resonance imaging may be indicated in a patient with bruising or a history of trauma to assess for extravasated blood, which may be the cause of the hyperbilirubinemia. (See 'Bilirubin overproduction' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Abnormal liver biochemical tests" and "Society guideline links: Pediatric liver disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Gilbert syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions – Jaundice is the clinical finding caused by hyperbilirubinemia; it usually becomes apparent at serum bilirubin concentrations above 2 to 3 mg/dL (34 to 51 micromol/L), which is twice the upper limit of normal. The hyperbilirubinemia is "unconjugated" if the conjugated bilirubin concentration represents a small component of the total bilirubin (eg, direct bilirubin <1 mg/dL, or <20 percent of the total bilirubin if total bilirubin is >5 mg/dL). (See 'Definitions' above.)

●Causes of unconjugated hyperbilirubinemia – In most jaundiced infants and children, the hyperbilirubinemia is exclusively or primarily unconjugated. This can be caused by bilirubin overproduction (eg, hemolysis), impaired hepatic bilirubin uptake (eg, reduced hepatic blood flow or certain drugs), or impaired bilirubin conjugation (algorithm 1 and table 1). (See 'Causes of unconjugated hyperbilirubinemia' above.)

Gilbert syndrome is a common cause of unconjugated hyperbilirubinemia, particularly in adolescents and adults. It is a heritable defect in bilirubin glucuronidation and presents with mild transient elevations of unconjugated bilirubin, often triggered by an intercurrent illness. Management is directed at recognition of the disorder and its inconsequential nature to avoid unnecessary evaluation. (See 'Gilbert syndrome' above.)

●Diagnostic approach – Jaundice is a yellowish discoloration of the sclerae and skin, often most visible in the palms and soles. (See 'Physical examination' above.)

•Measure bilirubin – For infants and children with jaundice, the first step is to measure total and conjugated bilirubin.

-Unconjugated hyperbilirubinemia is present if total bilirubin is elevated with a minimal conjugated component. Most children with jaundice will have total bilirubin greater than 2 to 3 mg/dL (34 to 51 micromol/L). (See 'Hyperbilirubinemia' above.)

-If the serum bilirubin is normal but the patient appears jaundiced, they most likely have carotenemia, which also can be distinguished from jaundice during a physical examination. (See 'Other results' above and 'Physical examination' above.)

-The finding of hyperbilirubinemia with a large conjugated component calls for a different approach to the work-up. The causes of conjugated hyperbilirubinemia are largely distinct from those of unconjugated hyperbilirubinemia, although some cases may have mixed mechanisms (algorithm 2). (See 'Other results' above.)

•Exclude sepsis – Patients with hyperbilirubinemia who are ill-appearing should be evaluated promptly for sepsis. Sepsis can cause hyperbilirubinemia through several mechanisms, including intravascular hemolysis (bilirubin overproduction). (See 'History and physical examination' above.)

•Further evaluation – For patients with unconjugated hyperbilirubinemia, next steps are:

-If anemia is present, evaluate for hemolysis and then for specific hemolytic disorders (table 2). (See 'Unconjugated hyperbilirubinemia with anemia and/or hemolysis' above and "Approach to the child with anemia".)

-If there is no anemia, the patient should be evaluated for the possibility of underlying liver disease, versus inherited disorders of impaired bilirubin conjugation (Gilbert or Crigler-Najjar syndrome) (algorithm 3). (See 'Unconjugated hyperbilirubinemia without anemia or hemolysis' above.)