Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
Trattamento del prurito da ittero colestatico
Cecilia Moro, Bergamo
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
Vinod S Hegade Clin Med August
1, 2015 vol. 15 no. 4 351-357
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
Martin Schmelz et al. J. Neurosci. 1997;17:8003-8008
©1997 by Society for Neuroscience
PHYSIOLOGY
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
PHYSIOLOGY
Beuers U .
Pruritus in cholestasis: Facts and fiction, Hepatology 29 MAY 2014
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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
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
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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
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
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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
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
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
Beuers U .
Pruritus in cholestasis: Facts and fiction,
Hepatology 29 MAY 2014
Substance Pros Cons Comment
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
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
Beuers U .
Pruritus in cholestasis: Facts and fiction,
Hepatology 29 MAY 2014
Substance Pros Cons Comment
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
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
Pathogenesis and management of pruritus in cholestatic
liver disease
Mohamad H Imam Journal of Gastroenterology and Hepatology 27 (2012) 1150–1158
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
Oude Elferink R.P.J
Dig Dis 2011;29:66–71
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
Step-wise use of drugs in the treatment of cholestatic pruritus
Clin Med August 1, 2015 vol. 15 no. 4 351-357
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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
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
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
Sertraline as a first‐line treatment for cholestatic pruritus
Mayo MJ Hepatology ,45 666-674, 2007
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
Pruritus in cholestasis: Facts and fiction
Beuers U .
Pruritus in cholestasis: Facts and fiction, Hepatology 29 MAY 2014
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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.
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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.
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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.
Cecilia Moro - Grandangolo in Oncologia. Focus su terapie di supporto 2016 - Bologna, 10 maggio 2016
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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