TROPICAL MEDICINE DEPARTEMENT Medical Education Programs بسم الله الرحمن الرحيم

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

Itch (Latin: pruritus)Latin Itch (Latin: pruritus) is a sensation that causes the desire or reflex to scratch and it is defined as second order nociception because itch has many similarities to pain, as both are unpleasant sensory experiences, but their behavioral response patterns are different. Pain creates a withdrawal reflex while itch leads to a scratch reflex.[1] Unmyelinated nerve fibers for itch and pain both originate in theskin; however, information for them is conveyed centrally in two distinct systems that both use the same nerve bundle and spinothalamic tractLatin sensation reflex pain sensory scratch reflex[1] nerve fibersskin nerve spinothalamic tract

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, intra- and 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.

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 C- nociceptors located in cutis and subcutis

Interestingly, pain (e.g., scratching the skin) represses itch sensation, and antinociception (e.g., intrathecally applied m- opioid 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.

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.

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.