Quantitative assessment of the multiple processes responsible for bilirubin homeostasis in health and disease

David G Levitt, Michael D Levitt, David G Levitt, Michael D Levitt

Abstract

Serum bilirubin measurements are commonly obtained for the evaluation of ill patients and to screen for liver disease in routine physical exams. An enormous research effort has identified the multiple mechanisms involved in the production and metabolism of conjugated (CB) and unconjugated bilirubin (UB). While the qualitative effects of these mechanisms are well understood, their expected quantitative influence on serum bilirubin homeostasis has received less attention. In this review, each of the steps involved in bilirubin production, metabolism, hepatic cell uptake, and excretion is quantitatively examined. We then attempt to predict the expected effect of normal and defective function on serum UB and CB levels in health and disease states including hemolysis, extra- and intrahepatic cholestasis, hepatocellular diseases (eg, cirrhosis, hepatitis), and various congenital defects in bilirubin conjugation and secretion (eg, Gilbert's, Dubin-Johnson, Crigler-Najjar, Rotor syndromes). Novel aspects of this review include: 1) quantitative estimates of the free and total UB and CB in the plasma, hepatocyte, and bile; 2) detailed discussion of the important implications of the recently recognized role of the hepatic OATP transporters in the maintenance of CB homeostasis; 3) discussion of the differences between the standard diazo assay versus chromatographic measurement of CB and UB; 4) pharmacokinetic implications of the extremely high-affinity albumin binding of UB; 5) role of the enterohepatic circulation in physiologic jaundice of newborn and fasting hyperbilirubinemia; and 6) insights concerning the clinical interpretation of bilirubin measurements.

Keywords: Rotor; albumin; conjugation; diazo; liver.

Figures

Figure 1
Figure 1
Major pathways involved in bilirubin production, conjugation, and excretion. Notes: Both the UB and CB forms are bound by albumin in the plasma and interstitial space and by ligandin in the hepatocyte. The mechanism responsible for transporting unconjugated bilirubin into the hepatocyte has not been identified. Bilirubin is conjugated in the liver by the UGT family of enzymes. CB is secreted into the bile by the ATP-coupled ABCC2/MRP2 transporter. CB can be recycled from the hepatocyte to plasma, leaving via, eg, the ABCC3/MRP3 transporter, and taken up by the OATP transport proteins. Renal excretion of CB can become important in obstructive diseases. The terms in red refer to the pathological conditions that influence the different pathways. The solid arrows represent the normal physiological pathways. The black dashed arrows indicate the enterohepatic circulation of bilirubin, which may occur in certain pathological conditions. The green dashed arrows indicate a possible UB excretory pathway that may be important in conditions of severe hyperbilirubinemia. Abbreviations: ATP, adenosine triphosphate; CB, conjugated bilirubin; GI, gastrointestinal; UB, unconjugated bilirubin; UGT, uridine diphosphate glycosyltransferase; ??, the mechanism is unknown.
Figure 2
Figure 2
Physiologically based theoretical prediction (PBPK) of plasma unconjugated bilirubin concentration following a bolus C dose. Notes: The line is the PBPK prediction and the solid circles are the experimental data of Berk et al for their subject MB.
Figure 3
Figure 3
Physiologically based theoretical prediction model of the free (unbound) unconjugated bilirubin concentration in the vein (solid line), muscle (long dashed line), and skin (short dashed line) following a bolus C dose.
Figure 4
Figure 4
Estimated normal human total and free (unbound) conjugated and unconjugated bilirubin in the plasma, hepatocyte, and bile duct.
Figure 5
Figure 5
Role of OATP in CB homeostasis in normal subjects with a serum CB concentration of 0.012 mg/dL. Notes: (A) Conventional view, in which plasma CB is determined by a relatively small biliary or hepatic cell leak of CB (0.14 mg/day) into the plasma which is balanced solely by renal excretion. (B) The newly postulated situation, in which there is a much more rapid CB leak (62.3 mg/day) that is countered by a very efficient OATP-facilitated reuptake by the hepatocyte. Abbreviations: CB, conjugated bilirubin; UB, unconjugated bilirubin; UGT, uridine diphosphate glycosyltransferase.
Figure 6
Figure 6
Role of OATP in CB homeostasis in a subject with hepatocellular disease and an elevated serum CB concentration of 0.36 mg/dL. Notes: (A) Conventional view, in which plasma CB is determined by a relatively small biliary or hepatic cell leak of CB (4.3 mg/day) into the plasma that is balanced solely by renal excretion. (B) The situation in which there is the predicted normal OATP-facilitated clearance and reuptake of CB by the hepatocyte, necessitating a much larger leak (1,870 mg/day) to maintain the same plasma concentration. Abbreviations: CB, conjugated bilirubin; UB, unconjugated bilirubin; UGT, uridine diphosphate glycosyltransferase.
Figure 7
Figure 7
Processes involved in bile formation and bilirubin secretion. Notes: Bile salts are transported into the liver primarily by a Na+ bile symport transporter (NTCP/SLC10A1) plus a small contribution from OATs. The canalicular bile fluid secretion results from the osmotic pressure produced by the ATP-dependent active transport of the bile salts (BSEP/ABCB11 transporter), as well as CB (MRP transporters) and other metabolites, into the canaliculus. This osmotic water flow occurs through the cell membrane and the intracellular tight junctions (solid arrows). Increased canalicular pressure produced by bile duct obstruction produces leakage of bile into the sinusoid through the ruptured tight junctions (red dashed line). The leaked CB may be taken back up into the hepatocyte by the OATP transport proteins (red dashed line). Abbreviations: CB, conjugated bilirubin; UB, unconjugated bilirubin; UGT, uridine diphosphate glycosyltransferase.
Figure 8
Figure 8
Plot of the fractional increase in total serum bilirubin (bilirubin/normal bilirubin) versus the inverse of the fractional decrease in the hepatic clearance (normal clearance/clearance) of indocyanine green (black), sulfobromophthalein (red), aminopyrine (green), and antipyrine (blue) in patients with chronic alcoholic cirrhosis. Note: The line is the predicted relationship if bilirubin is inversely proportional to clearance.

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