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Int J Lab Hematol 2019 May;41 Suppl 1:95-101

Department of Pathology, University of Utah Health, Salt Lake City, Utah.

Hereditary hemolytic anemia (HHA) is a group of genetically and phenotypically heterogeneous disorders characterized by premature destruction of red blood cells (RBCs) with clinical manifestations ranging from asymptomatic to marked hemolytic anemia. There are three main categories of HHA: (a) RBC membrane defects; (b) hemoglobinopathies/thalassemias; and (c) RBC enzyme deficiencies. Hyperbilirubinemia is a frequent consequence of hemolytic anemia and can lead to bilirubin-associated neurotoxicity in neonates and to jaundice, and formation of gall stones in adults. Read More

Endocrinology 2018 06;159(6):2435-2446

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.

Progressive familial intrahepatic cholestasis (PFIC) is a genetically heterogeneous disorder of bile flow disruption due to abnormal canalicular transport or impaired bile acid (BA) metabolism, causing excess BA accumulation and liver failure. We previously reported an intrahepatic cholestasis mouse model based on loss of function of both farnesoid X receptor (FXR; NR1H4) and a small heterodimer partner (SHP; NR0B2) [double knockout (DKO)], which has strong similarities to human PFIC5. We compared the pathogenesis of DKO livers with that of another intrahepatic cholestasis model, Bsep-/-, which represents human PFIC2. Read More

Am Fam Physician 2017 Feb;95(3):164-168

Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Jaundice in adults can be an indicator of significant underlying disease. It is caused by elevated serum bilirubin levels in the unconjugated or conjugated form. The evaluation of jaundice relies on the history and physical examination. Read More

Semin Fetal Neonatal Med 2015 Feb 2;20(1):26-30. Epub 2015 Jan 2.

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.

The pathologic phenotype of severe hyperbilirubinemia in the newborn infant is primarily due to excessive bilirubin production and/or impaired conjugation, resulting in an increased bilirubin load. This may, in turn, increase an infant's risk for the development of bilirubin-induced neurologic dysfunction (BIND). The highest-risk infants are those with increased bilirubin production rates due to hemolysis. Read More

Clin Rev Allergy Immunol 2015 Jun;48(2-3):243-53

Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, S1-172, University of Amsterdam, Meibergdreef 69, 1105BK, Amsterdam, The Netherlands,

Jaundice results from the systemic accumulation of bilirubin, the final product of the catabolism of haem. Inherited liver disorders of bilirubin metabolism and transport can result in reduced hepatic uptake, conjugation or biliary secretion of bilirubin. In patients with Rotor syndrome, bilirubin (re)uptake is impaired due to the deficiency of two basolateral/sinusoidal hepatocellular membrane proteins, organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3. Read More

Drug Metab Dispos 2014 Apr 23;42(4):561-5. Epub 2014 Jan 23.

German Cancer Research Center (DKFZ), Heidelberg, Germany.

Increased concentrations of bilirubin glucuronides in blood plasma indicate hepatocellular dysfunction. Elucidation of the transport processes of bilirubin conjugates across the basolateral (sinusoidal) and the canalicular plasma membrane domains of hepatocytes has decisively contributed to our current understanding of the molecular basis of conjugated hyperbilirubinemia in human liver diseases. Under normal conditions, unconjugated bilirubin is taken up into hepatocytes by transporters of the organic anion-transporting polypeptide (OATP) family, followed by conjugation with glucuronic acid, and ATP-dependent transport into bile. Read More

World J Gastroenterol 2013 Oct;19(38):6398-407

Eva Sticova, Milan Jirsa, Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague 4, Czech Republic.

Bilirubin, a major end product of heme breakdown, is an important constituent of bile, responsible for its characteristic colour. Over recent decades, our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates, mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes. Several inherited disorders characterised by impaired bilirubin conjugation (Crigler-Najjar syndrome type I and type II, Gilbert syndrome) or transport (Dubin-Johnson and Rotor syndrome) result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type. Read More

PLoS Med 2012 13;9(11):e1001338. Epub 2012 Nov 13.

Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.

Background: Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests.

Methods And Findings: In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination. Read More

Semin Perinatol 2011 Jun;35(3):121-6

Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA 94305-5208, USA.

Neonatal jaundice usually occurs in the transitional period after birth, presenting as an elevation of circulating bilirubin. Bilirubin neurotoxicity can occur if the levels of bilirubin become excessive (hyperbilirubinemia). This pathologic phenotype of newborn jaundice can develop because of excessive bilirubin production or impaired conjugation, with the risk for developing bilirubin-induced neurologic dysfunction, depending on the degree of the resultant bilirubin load. Read More

Drug Metab Dispos 2010 Nov 28;38(11):1907-11. Epub 2010 Jul 28.

College of Pharmacy, University of Minnesota, 308 Harvard St SE, Minneapolis, MN 55455, USA.

Bilirubin, an end product of heme catabolism, is primarily eliminated via glucuronic acid conjugation by UGT1A1. Impaired bilirubin conjugation, caused by inhibition of UGT1A1, can result in clinical consequences, including jaundice and kernicterus. Thus, evaluation of the ability of new drug candidates to inhibit UGT1A1-catalyzed bilirubin glucuronidation in vitro has become common practice. Read More

J Clin Lab Anal 2008 ;22(6):409-14

Department of Paediatrics, Harran University School of Medicine, Sanliurfa, Turkey.

Neonatal jaundice is the result of an imbalance between bilirubin production and elimination. Bilirubin conjugation in newborns is significantly impaired in the first few days; even a small increase in the rate of production can contribute to the development of hyperbilirubinemia. Hemolysis has a significant role in bilirubin increase in newborns. Read More

Expert Rev Endocrinol Metab 2008 Nov;3(6):725-737

b Paediatric Liver Centre, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9PJ, UK.

Crigler-Najjar syndrome (CN), a rare inherited disorder characterized by failure of bilirubin glucuronidation, can lead to severe disability and death from kernicterus. Gilbert syndrome is a more common, benign familial unconjugated hyperbilirubinemia. The underlying problem in both conditions is impaired bilirubin conjugation and elimination due to a mutation in uridine 5'-diphosphate glucuronyltransferase. Read More

Orv Hetil 2008 Jul;149(27):1277-82

Pécsi Tudományegyetem, Altalános Orvostudományi Kar Orvosi Genetikai és Gyermekfejlodéstani Intézet Pécs.

Gilbert disease is a benign disorder of the bilirubin conjugation, which affects 7-10% of the average population. The symptoms are usually only mild jaundice and the slightly elevated unconjugated bilirubin level, other laboratory tests and the liver functions are usually normal. In most cases, mutation of the UDP glucuronyltransferase gene leads to impaired bilirubin conjugation. Read More

Dig Liver Dis 2007 Apr 7;39(4):351-5. Epub 2007 Mar 7.

Clinical Genetics and Epidemiology, Department of Pediatrics, University of Padua, Italy.

Background And Aim: To clarify the precise mode of inheritance of Gilbert syndrome, an unconjugated familial hyperbilirubinemia, where impaired bilirubin conjugation is caused by reduced UGT1A1 activity determined by a defective function of the A(TA)6TAA promoter region of the UGT1A1 gene.

Subjects And Methods: Serum bilirubin levels were measured in a large, homogeneous resident population from North-Eastern Italy, consisting of 1.639 males (age 44. Read More

Pharmacogenet Genomics 2007 Feb;17(2):115-26

Drug Discovery and Development Technology Center (DDTC) and Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.

Objectives: To explore the possible role of hetero-oligomerization among the human UDP-glucuronosyltransferases in attenuating the consequences of the pathological Y486D mutation (UGT1A1 numbering) that often causes hyperbilirubinaemia. Owing to exon sharing in the human UGT1A gene, the equivalent mutation is present in all other UGT1As of the affected individuals. It is unknown, however, if this mutation results in clinical conditions, other than impaired bilirubin conjugation by UGT1A1. Read More

Rapid Commun Mass Spectrom 2006 ;20(8):1209-17

MRC Bioanalytical Science Group, School of Biological and Chemical Sciences, Birkbeck, University of London, Malet Street, London WC1 7HX, UK.

Bilirubin is a protective antioxidant; however, when its conjugation and excretion are impaired, as in neonatal and hereditary jaundice, bilirubin accumulates and may cause severe neurotoxicity. Degradation of bilirubin takes place (a) on interaction with oxidative free radicals and (b) when cytochrome P450 (CYP) enzymes are uncoupled by polyhalogenated substrate analogues. The products of pathways (a) and (b) above have now been characterized by high-performance liquid chromatography/electrospray ionization mass spectrometry (HPLC/ESI-MS) and the mechanisms of fragmentation in part clarified. Read More

Life Sci 2006 Mar 28;78(15):1688-95. Epub 2005 Nov 28.

Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid (UCM), 28040, Madrid, Spain.

Biliary excretion is the main route of disposal of bilirubin and impaired excretion results in jaundice, a well recognisable symptom of liver disease. Conjugation of bilirubin in the liver is essential for its clearance. The glucuronidation of bilirubin is catalysed by the microsomal UDP-glucuronosyltransferase UGT1A1. Read More

J Int Assoc Physicians AIDS Care (Chic) 2003 Oct-Dec;2(4):133-9

Department of Internal Medicine and Health Care Research, University of Nevada School of Medicine, Reno, Nevada, USA.

HIV caregivers face many challenges following initiation of ART. The development of jaundice is uncommon but worrisome. In this case, two distinct and contrasting episodes of jaundice were observed. Read More

Eur J Clin Invest 2003 Nov;33(11):988-97

Department of Medicine, University of Washington School of Medicine, Seattle, WA 98108, USA.

Revised concepts of bilirubin encephalopathy have been revealed by studies of bilirubin toxicity in cultured CNS cells and in congenitally jaundiced Gunn rats. Bilirubin neurotoxicity is related to the unbound (free) fraction of unconjugated bilirubin (Bf), of which the dominant species at physiological pH is the protonated diacid, which can passively diffuse across cell membranes. As the binding affinity of plasma albumin for bilirubin decreases strikingly as albumin concentration increases, previously reported Bf values were underestimated. Read More

Minerva Pediatr 2002 Oct;54(5):373-82

Division of Neonatal, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.

Neonatal jaundice is one of the most common conditions diagnosed by the pediatrician. This normally benign transitional phenomenon is a dynamic balance between the production and elimination of bilirubin. These processes can be exacerbated by a number of pathophysiologic conditions, which cause either an increase in bilirubin production rates, such as hemolysis, or a decrease in bilirubin elimination rates, such as bilirubin conjugation defects. Read More

J Gastroenterol 2000 ;35(9):659-64

Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osakasayama, Japan.

Bilirubin is taken up from blood into hepatocytes by sinosuidal membrane transporters and then excreted into bile through the bile canalicular membrane mainly as bilirubin glucuronides. (1) Mechanism of bilirubin uptake into hepatocytes: many organic anions are incorporated into hepatocytes by organic anion transporting polypeptides (rat, oatp1, oatp2, oatp3; human, OATP), liver-specific transporter (rlst/HLST), and/or by organic anion transporters (OAT2, OAT3). Oatp1 and HLST transport bilirubin monoglucuronide. Read More

Prog Liver Dis 1995 ;13:125-50

Division of Gastrointestinal and Liver Diseases, University Hospital, Groningen, The Netherlands.

As the genes encoding the glucuronidating enzymes are discovered, it is evident that glucuronidation is a magnificent example of how in evolution, man became adapted to his "intoxicating" environment. A superfamily of genes is necessary to dispose of the toxins and carcinogens that are encountered by inhalation and ingestion. The enzymes that glucuronidate endogenous compounds are members of this large family. Read More

Gastroenterology 1994 Oct;107(4):1075-84

Division of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands.

Background/aims: Hyperbilirubinemia associated with sepsis is frequently observed in humans. In this study, an experimental rat model was developed to study bilirubin metabolism and transport during endotoxemia.

Methods: Rats were injected intravenously with a single bolus of lipopolysaccharide (1 mg/kg); after 18 hours, the liver was removed for single-pass perfusion. Read More

Nihon Rinsho 1994 Jan;52(1):138-44

Department of Laboratory Medicine, Faculty of Medicine, University of Tokyo.

The serum bilirubin concentration is a specific marker of liver disease but the sensitivity is low for detecting liver damage and remains within normal limits in many patients with compensated liver cirrhosis. In liver cirrhosis, portal blood flow is distorted accompanied by a decrease in hepatic clearance of bilirubin. In addition, portosystemic shunting as well as splenomegaly results in an increase in hemolysis and production of bilirubin. Read More

Mol Pharmacol 1993 May;43(5):722-5

Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Israel.

The homozygous recessive jaundiced Gunn rat lacks expression of bilirubin UDP-glucuronosyltransferase and serves as a model for Crigler-Najjar syndrome type I, in which high and toxic plasma levels of bilirubin result from this genetic defect in bilirubin conjugation. Both rats and humans dispose of this heme waste product by an alternate metabolic route that involves oxidation of the compound, followed by biliary excretion of the more polar metabolites. To determine the role of cytochrome P450 in this process, hepatic levels of cytochrome P450 mRNA and protein were measured in jaundiced and nonjaundiced Gunn rats as a function of age and sex. Read More

Pharmacogenetics 1992 Feb;2(1):38-45

Department of Pharmacology, University of Toronto, Ontario, Canada.

Acetaminophen (paracetamol) is extensively conjugated with glucuronic acid and sulfate prior to renal excretion. A minor metabolic route involves microsomal oxidation of acetaminophen to a hepatotoxic reactive intermediate, which subsequently undergoes glutathione (GSH) conjugation, yielding cysteine and mercapturate conjugates, both of which are excreted in the urine (Slattery et al., 1987). Read More

J Hepatol 1988 Oct;7(2):229-38

Department of Medical Research, U.Z. Gasthuisberg, Leuven, Belgium.

This study was undertaken in the Wistar R/A Pfd rat to investigate the effects of hypothyroidism and of hyperthyroidism on the maximal biliary excretion (Tm) of bilirubin and on the concentration and composition of bilirubin in liver and plasma at the end of a bilirubin load. Hypothyroidism caused a cholestatic condition with a 50% decrease in bile flow and in bilirubin Tm, and with an increased proportion of conjugated bilirubin in liver and plasma. This was associated with an increased ratio of bilirubin diconjugates to monoconjugates in bile, liver, and plasma, which can be ascribed to the increased hepatic conjugation activity towards bilirubin and/or to the prolonged retention of bile pigments in the hepatocytes with increased conversion of monoconjugates to diconjugates. Read More

Pediatr Res 1988 Feb;23(2):163-6

Department of Pediatrics, University of Southern California School of Medicine, Los Angeles 90027.

Tin-protoporphyrin (SnP) is actively being investigated for treatment of exaggerated neonatal hyperbilirubinemia. Because both bilirubin conjugation and excretion are immature in the human newborn, we investigated the effect of SnP on bilirubin-conjugating mechanisms and the efficacy of SnP in suppressing serum bilirubin levels in adult rats made cholestatic by surgical bile duct ligation. Male Sprague-Dawley rats received SnP (100 mumol/kg body weight) subcutaneously either 24 h before or 24 or 48 h after bile duct ligation. Read More

Gastroenterology 1987 Nov;93(5):1094-103

Division of Gastrointestinal and Liver Diseases, St. Radboud University Hospital, Nijmegen, the Netherlands.

Mutant rats with a selective defect for the hepatobiliary excretion of organic anions (GT+TR- rats) are valuable models to study hepatic transport processes. However, retained conjugates in the livers of these rats may secondarily affect hepatic uptake, metabolism, and excretion of other compounds and this may confound the interpretation of test results. We have developed double mutants (GT-TR-) rats with both a conjugation and an excretion defect by cross-breeding uridine 5'-diphosphate-glucuronyl-transferase-deficient GT-TR+ Gunn rats with transport-deficient GT+TR- rats. Read More

Gastroenterology 1987 Feb;92(2):309-17

The pattern of serum bilirubins was determined in serum of humans and rats with unconjugated hyperbilirubinemia due to increased pigment load or defective hepatic conjugation. Bilirubin ester conjugates were present in all serum samples tested and were identified as bilirubin 1-O-acyl glucuronides. In Gilbert's syndrome, the concentration of total conjugates was comparable to the values in healthy control subjects. Read More

Aviat Space Environ Med 1984 May;55(5):377-80

Bilirubin metabolism was studied in rats injected with unconjugated bilirubin (0, 0.5, 1.5, 3. Read More

Z Gastroenterol 1983 May;21(5):228-33

The behaviour of some cholephilic anions has been studied in three male patients (two of whom are brothers) affected with Rotor syndrome. The unconjugated bilirubin clearance was markedly reduced with impairment of the plasma-liver transfer constant rate (uptake defect). BSP retention at 45 min. Read More

Clin Sci (Lond) 1982 Jun;62(6):643-9

1. The kinetics of non-radioactive bilirubin were investigated in 100 patients with chronic non-haemolytic unconjugated hyperbilirubinaemia and in nine normal volunteers. 2. Read More

Boll Soc Ital Biol Sper 1981 Apr;57(8):891-5

Crystalline bilirubin and chenodeoxycholic acid were administered intravenously and intraduodenally respectively in 19 anesthetized Sprague-Dawley rats in order to verify whether there exists an interference between their biliary excretion. When these two compounds were administered together, the biliary excretion of bilirubin and bile salts was significantly reduced the conjugation of bilirubin was not impaired while bile flow remained constant during the whole exerpimental period. These data seem to indicate a mutual interference between chenodeoxycholic and bilirubin metabolisms. Read More

Acta Hepatogastroenterol (Stuttg) 1977 Jun;24(3):175-81

The metabolism of unconjugated bilirubin from the plasma was studied in 17 patients with chronic hepatitis and 7 normal subjects following a single injection of bilirubin of 2 mg per kg body weight. From the plasma disappearance curves of unconjugated bilirubin, hepatic uptake, reflux from the liver to the plasma and hepatic conjugation were calculated by 2 compartmental analysis. The clearance remained within normal range in 5 patients with chronic persistent hepatitis but was significantly impaired in 12 patients with chronic aggressive hepatitis, in which corticosteroid treatment improved the clearance significantly (p less than 0. Read More

Digestion 1975 ;13(1-2):42-8

Administration of paracetamol (acetaminophen) 13.3 mmol kg-1 body weight to rats led 2 h later to an impaired capacity to conjugate an intravenous load of bilirubin, in the absence of biochemical signs of liver damage and before the reactive metabolite of the drug had become bound within the liver. In addition, paracetamol inhibited the excretion into the bile of conjugated bilirubin, although the plasma levels of the uncomjugated pigment only were elevated. Read More

J Clin Invest 1971 Dec;50(12):2606-13

The effect of phenobarbital on bilirubin excretion was studied in rats with different capacities for bilirubin conjugation. Drug treatment induced substantial increases in bilirubin UDP-glucuronyl transferase activity in the liver of both normal and heterozygous Gunn rats, but not homozygous Gunn rats in which enzyme activity is completely absent. However, enhancement of bilirubin excretion in vivo was observed only in heterozygous Gunn rats. Read More