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

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.

Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia: Review and German Expert Opinion on Treatment with nab-Paclitaxel plus Gemcitabine

“…haemolysis, resulting in unconjugated hyperbilirubinaemia, (2) intrahepatic dysfunction, e.g. intrahepatic biliary obstruction or liver damage caused by hepatotoxic drugs, leading to predominantly conjugated hyperbilirubinaemia, and (3) posthepatic biliary obstruction resulting in predominantly conjugated hyperbilirubinaemia [21,24]. As outlined, in the majority of patients with pancreatic cancer, hyperbilirubinaemia is caused by obstruction of the common bile duct due to a tumour in the pancreas head [5].…”

“…Therefore, a combination of laboratory parameters should be analysed since patterns of abnormalities are more meaningful than elevations or reductions of individual parameters [21] (table 1). Since the laboratory test results in most cases do not exactly identify the aetiology of predominant conjugated hyperbilirubinaemia, imaging techniques including sonography, computed tomography (CT) and magnetic resonance imaging (MRI) are essential to precisely determine the specific problem [24]. In order to direct therapy and to predict the survival of patients with chronic liver disease, scoring systems have been developed [26].…”

Modulation of multidrug resistance-associated proteins function in erythrocytes in glycerol-induced acute renal failure rats

“…The plasma concentrations of total bilirubin and direct bilirubin were significantly increased in glycerol‐induced ARF rats, compared to control rats (Table ), possibly due to the haemolysis caused by glycerol. Indirect bilirubin (unconjugated bilirubin) is a compound with high permeability through lipid bilayer membrane . Recently, the uphill transport of indirect bilirubin from plasma to the liver was also reported .…”

Optimization of phenylhydrazine induced hyperbilirubinemia in experimental rabbit

“…It gets associated with albumin in blood and is transported to liver where it undergoes the process of conjugation with glucoronic acid catalyzed by UDP-glucoronosyl transferase. The conjugated bilirubin, generally known as direct bilirubin (DB), is soluble in water and is excreted through bile into small intestine and finally into feces [20, 29]. Excessive hemolysis, abnormal hepatic uptake of unconjugated bilirubin, abnormalities in conjugation process, such as in hepatitis and liver cirrhosis, and obstruction in biliary excretion of DB are responsible for elevation in serum bilirubin level, a clinical condition known as hyperbilirubinemia.…”

“…Excessive hemolysis, abnormal hepatic uptake of unconjugated bilirubin, abnormalities in conjugation process, such as in hepatitis and liver cirrhosis, and obstruction in biliary excretion of DB are responsible for elevation in serum bilirubin level, a clinical condition known as hyperbilirubinemia. Unconjugated bilirubin, being insoluble in water, deposits in adipose tissue resulting in a physiological condition known as jaundice [6, 20]. …”