Conjugated Hyperbilirubinemia

Bilirubin is a tetrapyrrole produced by the normal breakdown of heme. Most bilirubin is produced during the breakdown of hemoglobin and other hemoproteins. Accumulation of bilirubin or its conjugates in body tissues produces jaundice (ie, icterus), which is characterized by high plasma bilirubin levels and the deposition of yellow bilirubin pigments in the skin, sclerae, mucous membranes, and other less visible tissues. ^{[1, 2, 3, 4]}

Because bilirubin is highly insoluble in water, it must be converted into a soluble conjugate before elimination from the body. In the liver, uridine diphosphate (UDP)-glucuronyl transferase converts bilirubin to a mixture of monoglucuronides and diglucuronides, referred to as conjugated bilirubin, which is then secreted into the bile by an ATP-dependent transporter. This process is highly efficient under normal conditions, so plasma unconjugated bilirubin concentrations remain low.

A large number of disease states lead to bilirubin accumulation in plasma. Diseases that increase the rate of bilirubin formation, such as hemolysis, or diseases that reduce the rate of bilirubin conjugation, such as Gilbert syndrome, produce unconjugated hyperbilirubinemia.

Diseases that reduce the rate of secretion of conjugated bilirubin into the bile or the flow of bile into the intestine produce a mixed or predominantly conjugated hyperbilirubinemia due to the reflux of conjugates back into the plasma. Elevated conjugated bilirubin levels usually indicate hepatobiliary disease.

Laboratory assays for bilirubin typically involve its cleavage in the presence of diazotized sulfanilic acid to generate a colored azodipyrrole that can be assayed spectrophotometrically. Because of its limited aqueous solubility, unconjugated bilirubin reacts slowly in the absence of an accelerator, such as ethanol, whereas conjugated bilirubin reacts rapidly. Total bilirubin is measured in the presence of an accelerator, whereas directly reacting bilirubin is measured without an accelerator. Indirectly reacting bilirubin is calculated by subtracting the directly reacting bilirubin score from the total bilirubin score.

Although the directly reacting bilirubin concentration approximates the conjugated bilirubin concentration in most cases, the 2 terms do not mean the same thing. Similarly, indirect bilirubin is not the same as unconjugated bilirubin.

The kidneys do not filter unconjugated bilirubin because of its avid binding to albumin. For this reason, the presence of bilirubin in the urine indicates the presence of conjugated hyperbilirubinemia.

Normal serum values of total bilirubin typically are 0.2-1 mg/dL (3.4-17.1 µmol/L), of which no more than 0.2 mg/dL (3.4 µmol/L) are directly reacting.

For patient education resources, see Digestive Disorders Center and Infections Center, as well as Cirrhosis, Gallstones, and Newborn Jaundice.

Conjugated hyperbilirubinemia results from reduced secretion of conjugated bilirubin into the bile, such as occurs in patients with hepatitis, or from impaired flow of bile into the intestine, as in patients with biliary obstruction. Bile formation is sensitive to various hepatic insults, including high levels of inflammatory cytokines, as may occur in patients with septic shock.

High levels of conjugated bilirubin may secondarily elevate the level of unconjugated bilirubin. Although the mechanism of this effect is not fully defined, one likely cause is reduced hepatic clearance of unconjugated bilirubin that results from competition with conjugated bilirubin for uptake or excretion.

In a review of the literature, in which Gottesman et al selected 17 studies comprising 1692 infants as meeting their selection criteria for the evaluation of the etiologies of conjugated hyperbilirubinemia, idiopathic neonatal hepatitis was the most common cause in infancy (26.0%), and extrahepatic biliary atresia (25.89%) and infection (11.4%) were the most commonly specified etiologies. ^[5] Selection criteria were noted as the following ^[5] :

• Prospective/retrospective case series or cohort study with at least 10 patients

• Consecutive infants who presented with conjugated hyperbilirubinemia

• Patients who received appropriate diagnostic work-up for conjugated hyperbilirubinemia

• No specific diagnoses were excluded in the studied cohort

A categoric listing of the most common diseases that produce conjugated hyperbilirubinemia is presented in the table below.

Table. Differential Diagnosis of Conjugated Hyperbilirubinemia (Open Table in a new window)

United States data

Conjugated hyperbilirubinemia is a common abnormality among patients with notable liver or biliary disease. It may also be observed in patients with systemic illnesses, such as sepsis and cardiogenic shock. The frequencies of the liver and biliary diseases that cause conjugated hyperbilirubinemia are described for each specific disease.

International data

In certain lesser-developed countries, parasitic diseases, such as clonorchiasis and ascariasis, commonly produce biliary obstruction. Hemolytic diseases, such as malaria, may predispose patients to biliary obstruction through the formation of pigment gallstones.

Race-, sex-, and age-related differences in incidence

Race- and sex-related differences reflect those for the specific disease states causing conjugated hyperbilirubinemia.

The age distribution of those with conjugated hyperbilirubinemia reflects the age distribution of the underlying disease states and ranges from the first month of life, as in cases of biliary atresia; through midlife, as in cases of viral hepatitis or primary biliary cholangitis; and to senescence, as in cases of biliary stones and malignancies.

Mortality/morbidity

Unlike unconjugated bilirubin, conjugated bilirubin does not bind significantly to neural tissue and does not lead to kernicterus or other forms of toxicity.

Green, discolored teeth have been reported as a late complication (later infancy) of prolonged conjugated hyperbilirubinemia in extremely low birth weight infants. ^[6] ​ ^[7]

The morbidity and mortality associated with conjugated hyperbilirubinemia result from the underlying disease process.

In certain disease states, such as alcoholic hepatitis or primary biliary cholangitis, bilirubin levels correlate strongly with, but do not contribute to, short-term mortality.