Pruritus in cholestatic and other liver diseases

Mela, Maria; Mancuso, Andrea; Burroughs, A K

doi:10.1046/j.1365-2036.2003.01458.x

Cited by 113 publications

(87 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The findings that BA levels are elevated in serum and skin of cholestatic patients (18,19), that BAs cause itch (20,21), and that BA-binding resins are an effective treatment (22) implicate BAs as causative agents of cholestatic itch. We observed hyperexcitability of DRG neurons and release of transmitters of itch and analgesia at BA concentrations, in line with the elevated levels of total BAs detected in serum of patients with cholestatic disease (61).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The TGR5 receptor mediates bile acid–induced itch and analgesia

et al. 2013

View full text Add to dashboard Cite

Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucineenkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide-and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Bile acids (BAs) are potential mediators, since cholestatic patients have increased BA concentrations in the circulation (18) and skin (19), and application of BAs to the skin causes itch (20,21), whereas bile salt-binding resins relieve cholestatic pruritus (22). Alterations in opioids and their receptors may also contribute.…”

Section: Introductionmentioning

confidence: 99%

The TGR5 receptor mediates bile acid–induced itch and analgesia

et al. 2013

View full text Add to dashboard Cite

show abstract

“…27 Rifampicin is used as second-line therapy for controlling pruritus in PBC. [36][37][38] It is a potent inducer of intestinal and hepatic CYP3A via activation of the pregnane X receptor/steroid and xenobiotic receptor. 39 Activation of this nuclear receptor explains the coordinate induction of the intestinal drug transporter P-glycoprotein.…”

Section: Discussionmentioning

confidence: 99%

No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis

et al. 2005

View full text Add to dashboard Cite

Induction of cytochrome P450 3A (CYP3A) has been suggested as a mechanism of action of ursodeoxycholic acid (UDCA) in cholestasis. CYP3A is of key importance in human drug metabolism, being involved in presystemic extraction of more than 50% of all drugs currently available and of various endogenous compounds. Therefore, we compared the induction potential of UDCA with that of the prototypical inducer rifampicin in a human model study with the CYP3A substrates budesonide and cortisol. Twelve patients with early-stage primary biliary cirrhosis and eight healthy volunteers were treated with UDCA (15 mg/kg daily) for 3 weeks and subsequently with rifampicin (600 mg/d) for 1 week. Extensive pharmacokinetic profiling of oral budesonide (3 mg) was performed by determination of budesonide and phase I metabolites (6␤-hydroxybudesonide, 16␣-hydroxyprednisolone) in plasma and urine at baseline and at the end of each treatment. In parallel, urinary 6␤-hydroxycortisol, a validated marker of CYP3A induction, was determined. UDCA did not affect biotransformation of budesonide and urinary excretion of 6␤-hydroxycortisol either in patients or in healthy volunteers. Ratios of areas under plasma concentration-time curves (AUC 0-12 h during UDCA/AUC 0-12 h before UDCA) of both metabolites were not higher than those of budesonide itself. In contrast, administration of rifampicin markedly induced CYP3A metabolism, resulting in abolished budesonide plasma levels and high urinary excretion of 6␤-hydroxycortisol. Metabolite formation was enhanced by rifampicin, but not by UDCA (e.g., AUC 16␣-hydroxyprednisolone /AUC budesonide in patients: baseline, 8.6 ؎ 3.9; UDCA, 10.7 ؎ 7.1; rifampicin, 527.0 ؎ 248.7). In conclusion, UDCA is not a relevant inducer of CYP3A enzymes in humans. (HEPATOLOGY 2005;41:595-602.)

show abstract

“…67 Potential mechanisms of response probably reside in the removal of bile acids or plasma opioids, such as met-enkephalins. 65,66,68 Anecdotal reports have also described successful use of MARS for overdose or toxicity with non-dialysable protein-bound substances, such as Amanitapoisoning, phenytoin toxicity and others. 42,69 as well as for progressive intrahepatic cholestasis because of chronic graft-vs.-host disease 70 or heart failure with associated forward-and backward-induced liver failure.…”

Section: -61mentioning

confidence: 99%

Review article: non‐biological liver support in liver failure

Laleman¹,

Wilmer²,

Evenepoel³

et al. 2006

Aliment Pharmacol Ther

View full text Add to dashboard Cite

SUMMARYLiver failure, whether acute or acute-on-chronic, remains an important cause of morbidity and mortality. The lack of liver detoxification, metabolic and regulatory functions of the liver leads to life-threatening complications, such as renal failure, altered immune response, hepatic coma and systemic haemodynamic dysfunction, eventually culminating in multiorgan failure.Current medical therapy involves the management of the precipitating event and treatment of complications until the liver eventually recovers, leaving us with no other treatment options than transplantation if these attempts fail. However, the shortage in cadaveric organs and other transplant-related problems, have prompted the need for alternative methods to provide liver support.As liver failure is often potentially reversible, considerable effort has been invested in the development of liver support systems. Currently, most of the experience is available for non-biological support systems. They represent the focus of this review, which aims to define the goals of liver support, to describe the design of the different existing devices and to analyse the available data to determine their current status in the management of patients with liver failure.

show abstract

Pruritus in cholestatic and other liver diseases

Cited by 113 publications

References 120 publications

The TGR5 receptor mediates bile acid–induced itch and analgesia

The TGR5 receptor mediates bile acid–induced itch and analgesia

No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis

Review article: non‐biological liver support in liver failure

Contact Info

Product

Resources

About