Background
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.
Pathophysiology
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.
Etiology
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] :
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Prospective/retrospective case series or cohort study with at least 10 patients
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Consecutive infants who presented with conjugated hyperbilirubinemia
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Patients who received appropriate diagnostic work-up for conjugated hyperbilirubinemia
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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)
I. Acute or Chronic Hepatocellular Dysfunction |
II. Diseases That Prevent Flow of Bile into the Intestine |
A. Infection |
A. Damage to Intrahepatic Bile Ducts or Portal Tracts |
Viral hepatitis A-E Cytomegalovirus (CMV) hepatitis Epstein-Barr virus hepatitis Sepsis |
Primary biliary cholangitis Veno-occlusive disease |
B. Inflammation Without Infection |
B. Damage to or Obstruction of Larger Bile Ducts |
Toxic liver injury Drug toxicity (eg, acetaminophen) Halothane hepatitis Alcoholic hepatitis Iron overload (hemochromatosis) Copper overload (Wilson disease) Autoimmune hepatitis |
Sclerosing cholangitis AIDS cholangiopathy Hepatic arterial chemotherapy Postsurgical strictures Bile duct cancers Developmental disorders of the bile ducts (eg, Caroli disease) Extrinsic compression of the bile duct Tumors Acute pancreatitis |
C. Metabolic Dysfunction |
C. Diffuse Infiltrative Diseases |
Ischemia ("shock liver") Acute fatty liver of pregnancy Alpha-1 antitrypsin deficiency Preeclampsia Reye syndrome Total parenteral nutrition |
Granulomatous diseases Sarcoidosis Disseminated mycobacterial infections Lymphoma Wegener granulomatosis Diffuse malignancy |
D. Inborn Errors of Metabolism |
D. Diseases That Interfere with Biliary Secretion of Bilirubin |
Dubin-Johnson syndrome Rotor syndrome Benign recurrent cholestasis |
Drug-induced cholestasis, as with the following: - Chlorpromazine - Erythromycin - Estrogens - Anabolic steroids - Many others |
Epidemiology
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.
Prognosis
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.
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Gross liver specimen from a patient with Dubin-Johnson syndrome showing multiple areas of dark pigmentation. Image courtesy of Cirilo Sotelo-Avila, MD.
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Microscopic histology of the liver in Dubin-Johnson syndrome showing multiple areas of granulated pigment. Fontana Mason stain. Image courtesy of Cirilo Sotelo-Avila, MD.
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Liver biopsy specimen showing ground-glass appearance of hepatocytes in a patient with hepatitis B.
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Plain abdominal radiograph in a patient with a clinical diagnosis of acute cholecystitis. The diagnosis was confirmed by means of abdominal ultrasonography. The radiograph shows faint opacities in the region of the gallbladder fossa (red circle) and dilated loops of small bowel in the epigastrium and midabdomen secondary to localized ileus.
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A 26-year-old man known to be human immunodeficiency virus (HIV) positive presented with pain in the right upper quadrant and mild jaundice. Axial sonogram through the gallbladder (GB) and pancreas (P) shows sludge within the gallbladder and the lower common bile duct (arrow). A diagnosis of acalculous cholecystitis was confirmed. A = aorta; IVC = inferior vena cava; S = splenic vein.