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TROPICAL MEDICINE
DEPARTEMENT
Medical Education
Programs
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Management of prurituss in liver
diseases
By
Mahmoud Saad Desoky
Let’s Start from the Beginning …
What is itch ?
An unpleasant sensation
provoking the desire to scratch
Samuel Hafenreffer,1660
)pruritus :nitaL( Itch
that causes the sensation pruritus) is a :nitaL( Itch
to scratch and it is defined as reflex desire or
second order nociception because itch has many
pain, as both are similarities to
experiences, but their sensory unpleasant
behavioral response patterns are different. Pain
creates a withdrawal reflex while itch leads to
for nerve fibers Unmyelinated [1scratch reflex.[ a
itch and pain both originate in theskin; however,
information for them is conveyed centrally in two
distinct systems that both use the
spinothalamic tract bundle and nerve same
• Itch may dramatically impair the patient’s
quality of life by limiting normal activities, as
well as by causing sleep deprivation and even
suicidal sensations
• Indeed, in some patients, pruritus can be so
severe that it is an indication for liver
transplantation
You know that I would cut off
My hands to help you
But if I did I wouldn’t have
Anything to scratch with
And then I’d be of
No use at all.
Don Mc Gonigal, The Itch,
1991
Pruritus can be caused by numerous diseases and has
recently been classified into six different categories:
(1) Dermatological itch, which is associated with
primary
skin disorders;
(2) Systemic itch, which is caused by systemic
diseases, pregnancy, tumors and infectious diseases;
(3) Neurological itch, which is induced by anatomical
lesions of the peripheral or central nervous
system;
(4) psychogenic itch, which may occur in different
psychiatric diseases such as schizophrenia,depression, and
tactile hallucinosis;
(5) mixed forms of itch in case of coexistence of diseases;
and finally
(6) other forms of itch the origin of which cannot be
determined.1 Here, we focus on systemic itch caused
by hepatobiliary diseases.
• Pruritus is a common symptom of various, mainly
cholestatic, hepatobiliary diseases. Both, intraand extrahepatic cholestasis may cause pruritus
Intrahepatic cholestasis may be induced by pure
hepatocyte secretory failure as observed in
intrahepatic cholestasis of pregnancy (ICP), viral
hepatitis, certain forms of drug-induced
cholestasis, progressive familial intrahepatic
cholestasis (PFIC), and benign recurrent
intrahepatic cholestasis (BRIC),.
• but also by intrahepatic bile duct damage and
secondary hepatocyte secretory failure as observed in
primary biliary (PBC), primary sclerosing cholangitis
(PSC), and pediatric cholestatic syndromes such as the
Alagille syndrome
• Extrahepatic cholestatic syndromes are less frequently
associated with pruritus and are caused by various
kinds of extrahepatic biliary obstructions
• Patients with cholestatic liver disease frequently reportmost
intense itching sensations on the palms and soles, but itch may
also be generalized.
• Pruritus in cholestasis undergoes diurnal variations and is
reported by most patients to be most intense in the late
evening and early night hours. Specific skin lesions are not
observed, but scratching-induced excoriations and prurigo
nodularis are common.2 Severity of pruritus can range from
mild,in which normal activities of life are limited, moderate in
which sleep is disturbed, to severe when normal daily activities
become impossible
• Signs of chronic liver diseas
• Cholestatic liver disease should be
considered as a cause of chronic pruritus
in any patient who does not show obvious
signs of a dermatological disease.
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Pathogenesis
• Itch perception depends on a complex interplay
of receptors, peripheral nerve fibers, intraspinal
and cerebral neural pathways, as well as
cerebral processing in thalamic nuclei and
cortical areas
• Although the pathogenesis of cholestasisrelated
pruritus remains poorly understood,
peripherally acting pruritogens and altered
central neurotransmission have been implicated
as causing pruritus in cholestasis
• It is well established that itch and pain
perception are closely intertwined processes.
The previous assumption that itch signals are
transmitted via pain-sensitive nerve fibers
• itch and pain signals are transduced by different
subgroups of unmyelinated C-fibers. Thus, itch
perception is induced by stimulation of an itch
specific subgroup of mechano-insensitive Cnociceptors located in cutis and subcutis
• Interestingly, pain (e.g., scratching the skin) represses itch
sensation, and antinociception (e.g., intrathecally applied mopioid receptor agonists or anesthetics) can cause itch
Itch-specific unmyelinated C-fibres transmit their
signals from the skin through the dorsal root ganglia to
a second neuron in the dorsal horn of the spinal cord,crossing to
the contralateral side and projecting via the spinothalamic tract
to the ventromedial nucleus of the thalamus. These neurons,
which are sensitive to histamine
but insensitive to mechanical stimulation, have been first identified
in cats.
The neuroanatomy of pruritus of
cutaneous origin
Pruritogen
Free nerve endings
Unmyelinated C nerve fibers
Dorsal horn of spinal cord
Contralateral spinothalamic tract
Postolateral ventral thalamic nucleus
Somatosensory cortex (post central cingulate
gyrus)
•
•
•
•
•
•
Direct stimulation of itch-specific C-fibers
Histamine
Papain
Kallikrein
Interleukin-2
Acethylcholine
•
•
•
•
•
•
Effect via histamine-release
Chymase (triptase)
Trypsin (tryptase)
Substance P
Serotonin
Bradykinin
• Weak or no pruritogenic effect; potentiates histamine
• Prostaglandins
• Neuropeptides
•
•
•
•
•
•
Neurokinin A (NKA), Substance P(SP),
Calcitonin gene related peptide (CGRP)
Vasoactive intestinal Peptide (VIP)
Release from nociceptive C fiber
Plays roles in inflammation
SP: histamine release from mast cell
• Protease
• Mast cell mediators: Tryptase, chymase
• Have direct pruritic effects
• Opioid
•
pruritic effect centrally and peripherally
Treatment
• Therapeutic efforts to alleviate pruritus associated
with cholestasis should include an adequate therapy of
the underlying hepatobiliary disease, which may result
in relief of pruritus.
• In extrahepatic malignant biliary obstruction, stenting,
nasobiliary or transcutaneous drainage, or surgical
biliodigestive anastomoses are usually effective in
eliminating pruritus.21 In intrahepatic cholestasis, a
number of therapeutic approaches have been
evaluated to alleviate or relieve pruritus
The rationale for medical and
interventional therapeutic
approaches is:
1. to remove the pruritogens from the
enterohepatic cycle by non-absorbable,
anion exchange resins such as
cholestyramine, colestipol, and
colesevelam in mild pruritus or
interventions such as nasobiliary and
transcutaneous drainage or external
biliary diversion in desperate cases
2. to alter the metabolism of the presumed pruritogens
in the liver and/or the gut by biotransformation
enzyme inducers such as rifampicin
3. to modify central itch and/or pain signalling by
influencing the endogenous opioidergic and
serotoninergic system via opioid-antagonists and
selective serotonin re-uptake inhibitors, respectively;
4 . to remove the potential pruritogen(s) from the
systemic circulation by invasive methods such as anion
absorption,plasmapheresis or extracorporeal albumin
dialysis.
• Ursodeoxycholic acid (UDCA) exerts beneficial
anticholestatic effects and is, therefore,
administered to several cholestatic disorders
such as primary biliary cirrhosis, primary
sclerosing cholangitis, intrahepatic cholestasis of
pregnancy, cystic fibrosis-associated liver
disease, and paediatric cholestatic syndromes.
Although UDCA was reported to effectively
diminish itching in some paediatric cholestatic
disorders
The anion exchange resins cholestyramine and colestipol
have been extensively used to treat cholestatic pruritus
and ameliorated pruritus in small trials within 2 weeks.
Cholestyramine is recommended as a 4 g dose 1 hour
before and after breakfast and may be extended to 44
g/d. Resins should, however, be taken at least 4 hours
prior to any other medication as they may interfere
with their intestinal absorption
Adverse effects include abdominal discomfort, bloating,
diarrhoea, hypertrigliceridemia,and rarely bleeding
after long-term use.
• The pregnane X receptor (PXR) agonist, rifampicin, is
recommended as second line therapy and is thought to
exert its antipruritic effect by the induction of phase I,
II and III biotransformation enzymes and transporters
such as CYP3A4, UGT1A1, SULT2A1 and MRP2
[124,125], thereby enhancing metabolism and/or
secretion of potential pruritogens. Additionally,
rifampicin may alter intestinal metabolism of potential
pruritogens by its antibiotic effect on the intestinal
flora.
• Hepatotoxicity, after treatment for several weeks or
months, may be an adverse effect of rifampicin in up to
12% of cholestatic patients
If rifampicin is ineffective, the -opoid antagonist
naltrexone should be regarded as third line therapy.
Several clinical trials showed a moderate antipruritic
effect of naltrexoneat doses of 25—50 mg/d
[87,88,90,91]. This drug is mostly well-tolerated during
long-term treatment. Naltrexone should, however, be
started at doses of 12.5 mg/d as severe opiate
withdrawal-like reactions may occur in somecholestatic
patients during the first days of treatment To prevent a
breakthrough phenomenon with concomitant
reoccurrence of pruritus naltrexone treatment can be
interrupted for 1 or 2 days per week
• Finally, the serotonin-reuptake
inhibitor (SSRI) sertraline was
moderately effective in reducing itch
intensity in cholestatic patients and is,
therefore, recommended as fourth
line therapy.
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• If all the above-mentioned drugs are ineffective,
experimental treatments can be considered. These
treatment options include :
1. Phototherapy such as UVA and UVB light on the skin
and bright light directed towards the eyes.
2. As experimental drug therapies propofol
lidocaine,phenobarbital , flumecinol , stanozolol,
ondansentrone , dronabinol and butorphanolhave
been used in the past with variable success.
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Furthermore, invasive procedures such as
plasmapharesis, molecular adsorbent recirculating
system therapy, plasma separation/anion absorption ,
transcutaneous and nasobiliary drainage have been
beneficial in severe, untreatable cholestatic pruritus in
case series.
Finally, future strategies might include LPA-receptor
blockers and autotaxin inhibitors (which are currently
developed) if the pathophysiological role of
lysophosphatidic acid and autotaxin in pruritus can be
further substantiated.