ID27, ID28, ID29. Bilirubin (Total, Direct, Indirect). (μmol/l or mg/dl)

Bilirubin comes from the breakdown of senescent red blood cells and predominantly circulates in its unconjugated form tightly bound to albumin. Unconjugated bilirubin is not excreted in the urine. Conjugation by uridine 5’-diphospho (UDP)-glucuronosyltransferase makes bilirubin water-soluble (conjugated bilirubin), allowing it to be excreted in bile where it is converted by bacteria in the colon to urobilinogen, which is subsequently excreted in the urine and stool. The absence of urobilinogen gives stool its classic clay-colored appearance in those with impaired bile flow.¹

Fractionation of the bilirubin level (total serum bilirubin) to conjugated/direct (~30% of the total serum bilirubin) and unconjugated/indirect (~70% of the total serum bilirubin) forms is not done routinely as many laboratories only report total serum bilirubin, which is the sum of conjugated and unconjugated portions.

Abnormalities. Disorders or diseases caused or related.

Fractionation of total bilirubin is most helpful when the ALT, AST, and alkaline phosphatase levels are normal or near normal. If the total bilirubin is elevated and fractionation shows the majority of the elevation is unconjugated bilirubin, hepatocellular disease is unlikely to be the explanation. Conjugated bilirubin elevations are present in hepatocellular disorders as well as cholestatic disorders (e.g biliary obstruction) with impairment in bile flow.¹

Total bilirubin levels almost never exceed 6 mg/dl and are usually <3 mg/dl. Fasting or significant illness can increase the unconjugated bilirubin by 2- to 3-fold, that in turn, will decrease with eating or administration of phenobarbital.¹

Table ID27.1. Causes of elevated Bilirubin

Elevated unconjugated or indirect bilirubin is due to over-production of bilirubin (such as hemolysis), decreased hepatic uptake, or decreased hepatic conjugation. The most common cause of elevated unconjugated bilirubin is Gilbert’s syndrome, affecting 3–7% of the US population (http://ghr.nlm.nih.gov/condition/gilbert-syndrome) which is due to a genetic defect of UDP-glucuronyltranferase resulting in decreased hepatic conjugation of bilirubin. In general, in asymptomatic, healthy individuals who have mild unconjugated hyperbilirubinemia (<4 mg/dl), evaluation should exclude medications that cause hyperbilirubinemia, exclude evidence of hemolysis, and confirm normal serum transaminases and alkaline phosphatase levels. If these are found, then a presumptive diagnosis of Gilbert’s syndrome can be made and additional evaluation is not routinely necessary.

An isolated indirect hyperbilirubinemia may also be seen in the setting of hemolysis where reduced serum haptoglobin and elevated reticulocyte count and lactate dehydrogenase (LDH) level may be present. However, hemolysis infrequently causes a bilirubin level >5 mg/dl, unless co-existent renal disease, liver disease, or severe acute hemolysis is present.²

In contrast to indirect hyperbilirubinemia, conjugated (direct) hyperbilirubinemia generally implies the presence of parenchymal liver damage or biliary obstruction. This is associated with a number of hepatic disorders which result in decreased excretion of bilirubin into the bile ducts, and leakage of bilirubin from hepatocytes into the serum. Total serum bilirubin levels may exceed 30 mg/dl in cases of severe liver damage, including alcoholic hepatitis with cirrhosis, and may be seen in advanced cirrhosis patients with sepsis and/or renal failure.^3-5 In addition, an isolated hyperbilirubinemia may be seen after major surgery and typically resolves. ⁶ In hepatocellular jaundice, hepatocytes are being destructed, conjugated bilirubin excretion into the bile capillaries is impaired and it leaks into blood, where its level elevates significantly. The approach to elevated bilirubin is shown in figure below.

There are two rare inherited conditions associated with direct hyperbilirubinemia: Dubin–Johnson syndrome and Rotor syndrome where the direct bilirubin is ~50% of the total with all other liver tests being normal including alkaline phosphatase and GGT levels. It is not necessary to distinguish between the two disorders. Dubin-Johnson syndrome occurs due to a defect in the multidrug resistance canalicular enzyme while Rotor syndrome appears to be related to defective bilirubin storage by hepatocytes.⁷

Algorithm for evaluation of elevated serum total bilirubin

1.        Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. Am J Gastroenterol. 2017 Jan;112(1):18-35. doi: 10.1038/ajg.2016.517. Epub 2016 Dec 20

2.        Levine RA, Klatskin G . Unconjugated hyperbilirubinemia in the absence of overt hemolysis: Importance of acquired disease as an etiologic factor in 366 adolescent and adult subjects. Am J Med 1964; 36:541 – 52

3.        O'Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Am J Gastroenterol 2010 ; 105 : 14 – 32; quiz 33.

4.        Chand N, Sanyal AJ. Sepsis-induced cholestasis. Hepatology 2007;45: 230 – 41.

5.        Kantrowitz PA , Jones WA , Greenberger NJ , Isselbacher KJ . Greenberger and K.J. Isselbacher, Severe postoperative hyperbilirubinemia simulating obstructive jaundice. N Engl J Med 1967; 276: 590 – 8.

6.        Schmid M, Hefti ML, Gattiker R et al. Benign postoperative intrahepatic cholestasis. N Engl J Med 1965; 272: 545 – 50.

7.        Erlinger S , Arias IM , Dhumeaux D . Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology 2014; 146: 1625–38.