Bilirubin Metabolism and Jaundice

Wolkoff, Allan W.; Berk, Paul D.

doi:10.1002/9781119251316.ch5

Cited by 5 publications

(8 citation statements)

References 247 publications

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“…15,16 In the hepatocyte, the conjugation of bilirubin with glucuronic acid is mediated by UGT1A1, an enzyme that is in the endoplasmic reticulum. 2,3 Conjugated bilirubin is transported across the bile canalicular membrane and is excreted in bile. 2,17 In the present study, these steps of bilirubin metabolism were examined in test systems to elucidate the mechanism by which atazanavir administration causes hyperbilirubinemia.…”

Section: Discussionmentioning

confidence: 99%

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Drug‐ and Drug Abuse–Associated Hyperbilirubinemia: Experience With Atazanavir

Roy‐Chowdhury

Listowsky

et al. 2017

Clinical Pharm in Drug Dev

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Hyperbilirubinemia is a common finding in individuals with a history of substance abuse. Although this may indicate a serious disorder of liver function, this is not always the case. An understanding of bilirubin formation, metabolism, and transport can provide a helpful approach to dealing with these patients. This is typified by studies of patients treated with the antiretroviral drug atazanavir. Atazanavir has been associated with hyperbilirubinemia in as many as one-third of individuals for whom it has been prescribed, evoking concerns of hepatotoxicity. The studies in this report were designed to determine mechanisms by which this occurs. The data show that this drug inhibits the enzyme UDP-glucuronosyl transferase-1A1, responsible for conjugating bilirubin with glucuronic acid. This conjugation step is required for bilirubin excretion into bile and when it is inhibited, bilirubin refluxes from the liver into the circulation, causing unconjugated hyperbilirubinemia. Other parameters of bilirubin formation, binding to albumin in the circulation, uptake into hepatocytes, and intracellular protein binding in hepatocytes were unaffected by atazanavir. The effect of atazanavir on serum bilirubin levels is reversible, consistent with lack of structural damage to the liver.

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Section: Discussionmentioning

confidence: 99%

“…However, there are situations, such as inheritable disorders and specific drug inhibitors, in which disruption of a specific step of bilirubin processing may result in hyperbilirubinemia. 1,3 In the present study, the effect of atazanavir on the component steps of the bilirubin pathway were determined.…”

mentioning

confidence: 99%

Drug‐ and Drug Abuse–Associated Hyperbilirubinemia: Experience With Atazanavir

Roy‐Chowdhury

Listowsky

et al. 2017

Clinical Pharm in Drug Dev

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“…151,152 Total bilirubin levels in Gilbert's Syndrome are usually mildly elevated, but rarely greater than 4-5 mg/dL. 153,154 Gilbert's Syndrome is caused by a reduction of the level of the enzyme uridine 5'-diphospho--glucuronyl-transferase to 20-30% of its normal amount which results in impaired conjugation of bilirubin with glucuronic acid. 151 It is important to accurately identify Gilbert's Syndrome in clinical trials, especially clinical trials in cholestatic liver diseases, as misdiagnosis may result in unnecessary diagnostic testing, incorrect assignment of causality, as well as drug interruption or discontinuation.…”

Section: Additional Cons Ider Ations For Clini C Al Trial S Of Pbc mentioning

confidence: 99%

Consensus guidelines: best practices for detection, assessment and management of suspected acute drug‐induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease

Palmer

Regev

Lindor

et al. 2019

Aliment Pharmacol Ther

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Summary Background Improved knowledge of the molecular pathophysiology and immunopathogenesis of cholestatic liver diseases in recent years has led to an increased interest in developing novel therapies. Patients with cholestatic liver disease often require different approaches to assessment and management of suspected drug‐induced liver injury (DILI) compared to those with healthy livers and those with parenchymal liver diseases. At present, there are no regulatory guidelines or society position papers, that systematically address best practices pertaining to detection of DILI in these patients. Aims To outline best practices for detection, assessment and management of suspected acute DILI during clinical trials in adults with the cholestatic liver diseases – Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). Methods This is one of the several papers developed by the IQ DILI Initiative, which is comprised of members from 16 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. The contents are the result of an extensive literature review, as well as in‐depth discussions among industry, regulatory and academic DILI experts, to achieve consensus recommendations on DILI‐related issues occurring during clinical trials for cholestatic liver diseases. Results Recommended best practices are outlined pertaining to hepatic eligibility criteria, monitoring of liver tests, approach to a suspected DILI signal, and hepatic discontinuation rules. Conclusions This paper provides a framework for the approach to detection, assessment and management of suspected acute DILI occurring during clinical trials in adults with cholestatic liver disease.

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“…Neonatal jaundice (NNJ) is caused by the accumulation of unconjugated bilirubin (UCB) in blood and tissues. The normal physiology of bilirubin production, transport, and excretion has been well described (69)(70)(71)710). However, the neonatal period is in many respects unique in regard to bilirubin metabolism, as very significant elevations of UCB concentrations in serum occur only exceptionally after this age.…”

Section: Introductionmentioning

confidence: 99%

Molecular Physiology and Pathophysiology of Bilirubin Handling by the Blood, Liver, Intestine, and Brain in the Newborn

Hansen

Wong

Stevenson

2020

Physiological Reviews

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Bilirubin is the end product of heme catabolism formed during a process that involves oxidation-reduction reactions and conserves iron body stores. Unconjugated hyperbilirubinemia is common in newborn infants, but rare later in life. The basic physiology of bilirubin metabolism, such as production, transport, and excretion, has been well described. However, in the neonate, numerous variables related to nutrition, ethnicity, and genetic variants at several metabolic steps may be superimposed on the normal physiological hyperbilirubinemia that occurs in the first week of life and results in bilirubin levels that may be toxic to the brain. Bilirubin exists in several isomeric forms that differ in their polarities and is considered a physiologically important antioxidant. Here we review the chemistry of the bilirubin molecule and its metabolism in the body with a particular focus on the processes that impact the newborn infant, and how differences relative to older children and adults contribute to the risk of developing both acute and long-term neurological sequelae in the newborn infant. The final section deals with the interplay between the brain and bilirubin and its entry, clearance, and accumulation. We conclude with a discussion of the current state of knowledge regarding the mechanism(s) of bilirubin neurotoxicity.

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Bilirubin Metabolism and Jaundice

Cited by 5 publications

References 247 publications

Drug‐ and Drug Abuse–Associated Hyperbilirubinemia: Experience With Atazanavir

Drug‐ and Drug Abuse–Associated Hyperbilirubinemia: Experience With Atazanavir

Consensus guidelines: best practices for detection, assessment and management of suspected acute drug‐induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease

Molecular Physiology and Pathophysiology of Bilirubin Handling by the Blood, Liver, Intestine, and Brain in the Newborn

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