IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read
Diagnosis and treatment of exercise-induced bronchospasm: A review; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to
www.aapa.org and searching for keyword
JAAPA post-tests. All others may complete and submit the post-test online at no charge at
www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.
KEY POINTS
■ To appreciate the differential diagnosis of jaundice requires an understanding of the fundamental metabolism of bilirubin; the risk factors, epidemiology, and pathophysiology of common causes of jaundice; and the available serologic and imaging studies used in the workup of jaundiced patients.
■ The diagnostic possibilities can be narrowed considerably, and many clues to the etiology of hyperbilirubinemia and the presence of liver pathology can be ascertained from a carefully performed history and physical examination, basic laboratory test results, and biochemical and serological markers.
■ The differential diagnosis for jaundice is based on whether the disease responsible for jaundice is prehepatic (primarily unconjugated hyperbilirubinemia), hepatic (mixed hyperbilirubinemia), or posthepatic (conjugated hyperbilirubinemia).
■ The PA plays an essential role in the evaluation of adult patients with new-onset jaundice and should be able to recognize risk factors, perform an appropriate workup, and provide initial management and referral.
Jaundice, or icterus, is yellowish discoloration of the skin, mucous membranes, sclerae, and body fluids resulting from excess accumulation and deposition of bilirubin in the body in the presence of serum hyperbilirubinemia. The yellow hue may be mimicked by carotenemia, but in the latter condition, no scleral icterus is present and bilirubin levels are normal.1 To appreciate the differential diagnosis of jaundice requires an understanding of the fundamental metabolism of bilirubin; the risk factors, epidemiology, and pathophysiology of common causes of jaundice; and the available serologic and imaging studies
used in the workup of jaundiced patients. This article focuses on assessment of the adult patient with new-onset jaundice, reviews guidelines for selecting appropriate tests, and discusses interpretation of results.
NORMAL BILIRUBIN METABOLISM
Bilirubin is a breakdown product of hemoglobin in RBCs (Figure 1). Approximately 80% of bilirubin is formed from the breakdown of heme in reticuloendothelial cells, primarily the spleen and liver. The remainder comes from heme molecules in other proteins, such as myoglobin. Heme is converted to biliverdin by heme oxygenase and then to bilirubin by biliverdin reductase. The bilirubin formed by these enzymatic reactions is unconjugated or indirect and is highly insoluble in water. It is transported in the blood tightly but reversibly bound to albumin, escaping kidney filtration and readily taken up by the liver for conjugation. Normally, 90% to 95% of circulating bilirubin is unconjugated. Hypoalbuminemia, displacement of bilirubin from the albumin molecules by various medications, and/or elevated levels of unconjugated bilirubin in the blood may cause diffusion of bilirubin across the blood-brain barrier. When unconjugated bilirubin levels in the blood reach
15 to 20 mg/dL, bilirubin encephalopathy or kernicterus may occur.
Hepatic uptake of unconjugated bilirubin across the sinusoidal membrane occurs, and within the hepatocyte, bilirubin is conjugated by microsomal uridine diphosphoglucuronyl transferase (UDPGT) to a direct, water-soluble form facilitating its excretion into bile. Bilirubin that spills into the urine therefore is conjugated bilirubin. Biliary excretion is mediated by an ATP-dependent canalicular multispecific organic anion transporter. This process is highly efficient under normal conditions, so plasma unconjugated bilirubin concentrations remain low.2 Normal serum values for total bilirubin are 0.2 to 1.0 mg/dL; for conjugated bilirubin, 0.1 to 0.3 mg/dL; and for unconjugated bilirubin, 0.2 to 0.8 mg/dL.
The first manifestation of conjugated hyperbilirubinemia is commonly tea-colored urine; scleral icterus may be present but usually reflects unconjugated bilirubin, which binds more easily to tissues.2 Conjugated bilirubin is excreted in bile into the duodenum and then metabolized by gut bacteria into urobilinogen. Some of this product is excreted in the feces as oxidized stercobilin (which gives feces a brown color), and some is reabsorbed, entering the portal venous circulation to be re-excreted by the liver. A small amount escapes hepatic uptake, passes into systemic circulation, and is excreted in urine as urobilinogen (normal levels of urobilinogen in urine are 0 to 0.2 mg/dL).
Two clues to bilirubin dysfunction can be gathered from simple urine and stool analysis. First, increased conjugated bilirubin may spill into the urine, rendering it tea-colored, which indicates a problem past the UDPGT conjugation. Second, the stool may appear acholic and light gray in cases of biliary obstruction or stasis in the absence of stercobilin.2