Trattamento del prurito da ittero colestatico - NICSO · Trattamento del prurito da ittero...

Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016

Trattamento del prurito da ittero colestatico

Cecilia Moro, Bergamo


Vinod S Hegade Clin Med August

1, 2015 vol. 15 no. 4 351-357


EPIDEMIOLOGY

PBC-PSC: 25-80%

Colelitiasi ostruttiva :16%

Carcinoma della testa del pancreas :45%

Epatite C : 5-15%

Ritmo circadiano ( prevalente serale e notturno

Prevalente agli arti


Martin Schmelz et al. J. Neurosci. 1997;17:8003-8008

©1997 by Society for Neuroscience

PHYSIOLOGY


PHYSIOLOGY

Beuers U .

Pruritus in cholestasis: Facts and fiction, Hepatology 29 MAY 2014

http://onlinelibrary.wiley.com/doi/10.1002/hep.26909/full


Pros and Cons for Candidate Pruritogens in Cholestatic Pruritus

Beuers U .

Pruritus in cholestasis: Facts and fiction,

Hepatology 29 MAY 2014

Substance Pros Cons Comment

Bile salts • serum bile salts are increased

in cholestasis

• no correlation between itch

intensity and serum/skin tissue

concentrations of bile salt

levels in cholestatic patients

Not the pruritogen searched for

• experimental induction of

pruritus by application of bile

salts onto blister bases or

keratin-stripped human skin

• women with ICP per definition

suffer from itch, while bile salt

levels often are only mildly

increased

• some antipruritic effect of

anion exchange resins

• increased serum bile salts in

asymptomatic pregnant women

• effect of bile salt sequestrant

colesevelam does not exceed

placebo effect

• itch relief after rifampicin

treatment, nasobiliary drainage

and extracorporeal albumin

dialysis does not correlate with

serum bile salt levels




Beuers U .




Endogeno opioids • plasma opioid levels are

increased in a few

cholestatic patients

• no correlation between itch

intensity and plasma

concentrations of

endogenous opioids

Modulation of itch perception

possible, but not causative

agent

• μ-opioid antagonists

moderately improve pruritus

• endogenous opioids are

increased in advanced

stages of PBC, while pruritus

is typically seen during early

stages

• opioids can cause pruritus

mainly upon spinal / epidural

application

• μ-opioid activity not

increased in ICP compared

to pregnant controls

• Spinally administered

plasma extracts of pruritic

cholestatic patients induce

facial scratching in monekys

which was reduced by

naloxone

• antinociceptive effect of

cholestasis in mice is

mediated peripherally, not

centrally




Beuers U .




Histamine • key pruritogen of allergic reactions

• histamine-induced skin lesion are lacking in patients suffering from cholestatic pruritus

Highly unlikely to play a causative role in cholestatic pruritus

• histamine concentrations are increased in plasma of cholestatic patients

• no correlation between severity of itch and histamine concentrations

• antihistamines are mostly ineffective




Beuers U .




Serotonin

• serotonin can cause itching upon intradermal application • mild beneficial effects of selective serotonin re-uptake inhibitors

• no correlation between itch intensity and serotonin levels reported so far

Modulation of itch signaling possible, but not causative agent



Beuers U .




Progesterones and estrogens • urinary levels of disulphated

progesterone metabolites

correlated slightly with the

UDCA-induced improvement of

pruritus in women with ICP

Modulation of itch signaling

possible; in ICP even

causative role possible

• female PBC/PSC patients

complained more about pruritus

compared to male counterparts

• various steroids including

sulfated ones have a modulatory

(stimulating) effect on the GABA

receptor which in turn inhibits

pain (and thus may stimulate

itch)

• female mice display higher

scratching activity compared to

male mice



Beuers U .




Lysophosphatidic acid (LPA) • increased levels in

cholestatic patients with

pruritus

• LPA-receptor blockers and

autotaxin inhibitors yet

unavailable to test for anti-

pruritic effects

The putative pruritogen in

cholestasis

• intradermal application

induces dose-dependent

scratching behaviour in mice

• activity of the LPA-

producing enzyme autotaxin

correlated with itch intensity

• autotaxin activity closely

correlated with therapeutic

interventions in cholestatic

patients



Pathogenesis and management of pruritus in cholestatic

liver disease

Mohamad H Imam Journal of Gastroenterology and Hepatology 27 (2012) 1150–1158


Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions

Kremer Hepatology

OCT 2012;56:1391-1400



Oude Elferink R.P.J

Dig Dis 2011;29:66–71


Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions

Kremer Hepatology

OCT 2012;56:1391-1400



Rimuovere le sostanze pruritogene dal circolo enteroepatico ( resine , SNB, drenaggi transcutanei )

Modificare il metabolismo epatico dei pruritogeni con induttori di biotrasformazione epatica ( rifampicina )

Modulare la trasmissione neurogena ( antagonisti µ receptor , antagonisti del reuptake della serotonina )

Rimuovere dal circolo le sostanze pruritogene ( dialisi plasmaferesi )

APPROCCIO TERAPEUTICO


Step-wise use of drugs in the treatment of cholestatic pruritus

Clin Med August 1, 2015 vol. 15 no. 4 351-357


Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta‐analysis of prospective randomized‐controlled trials

Liver International

Khurana S,pages 943-948, 5 SEP 2006

http://onlinelibrary.wiley.com/doi/10.1111/j.1478-3231.2006.01326.x/full

Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled

study

Journal of Hepatology, Volume 37, Issue 6, 2002, 717–722



Sertraline as a first‐line treatment for cholestatic pruritus

Mayo MJ Hepatology ,45 666-674, 2007



Pruritus in cholestasis: Facts and fiction

Beuers U .

Pruritus in cholestasis: Facts and fiction, Hepatology 29 MAY 2014



CONCLUSIONS

• Pruritus is a common symptom in patients with

cholestatic disease.

• Autotaxin may increase pruritus by increasing

LPA in serum.

• The effect of bile acids on pruritus is

questionable.

• An imbalance in opiate receptors may initiate itch

through peripheral and systemic pathways.

• Steroids appear to have a convincing role in

mediating cholestatic pruritus.


CONCLUSIONS

With exception to ICP, UDCA is ineffective in

managing cholestatic pruritus.

• Cholestyramine at a daily dose of 4–16 g is

effective in managing cholestatic pruritus.

• The main factor affecting compliance with

cholestyramine therapy is unpleasant taste.


CONCLUSIONS

• Rifampin at a dose of 300 mg/day improves cholestatic pruritus.

• Monitoring of blood tests is needed in patients receiving rifampin due to risk of liver injury.

• Opioid antagonists are effective as third line agents.

• Contraindications to usage include acute hepatitis, liver

failure and severe liver insufficiency, suppression of

pulmonal function.


CONCLUSIONS

• Sertraline at a dose of 75–100 mg/day

(increased gradually by 25 mg increments

every 4–5 days from a starting dose of 25 mg)

is effective and well tolerated in managing

cholestatic pruritus.

• Evidence is lacking for typical antihistamines

including diphenhydramine.

• No randomized controlled trials exist showing

effectiveness of MARS or plasmapheresis in

relieving cholestatic pruritus.

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