Fibrates for the treatment of cholestatic itch (FITCH): study protocol for a randomized controlled trial

BACKGROUND: Pruritus (itch) is a frequent, burdensome and difficult-to-treat symptom in patients with cholestasis. Fibrates are currently under investigation for the treatment of primary biliary cholangitis in patients with a suboptimal response to ursodeoxycholic acid. Moreover, there is empirical evidence for a possible antipruritic effect. We aim to prove this in a randomized controlled trial, including patients with cholestatic liver diseases other than primary biliary cholangitis that are accompanied by pruritus. METHODS: A multicenter investigator-initiated, double-blind, randomized placebo-controlled trial to evaluate the effect of bezafibrate on cholestatic pruritus in 84 adult patients with primary biliary cholangitis or primary/secondary sclerosing cholangitis. Primary outcome is the proportion of patients with a reduction of itch intensity of 50% or more (measured on a Visual Analog Scale) after 21 days of treatment with bezafibrate 400 mg qid or placebo. Secondary outcomes include the effect of bezafibrate on a five-dimensional itch score, liver disease-specific quality of life, serum liver tests and autotaxin activity. Safety will be evaluated through serum parameters for kidney function and rhabdomyolysis as well as precise recording of (serious) adverse events. We provide a schematic overview of the study protocol and describe the methods used to recruit and randomize patients, collect and handle data and perform statistical analyses. DISCUSSION: Given its favorable safety profile and anticholestatic properties, bezafibrate may become the new first-line treatment option for treating cholestatic pruritus

Advances in Pathogenesis and Management of Pruritus in Cholestasis

Chronic pruritus is a burdensome feature of numerous hepatobiliary disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy. Bile salts, μ-opioids, serotonin, histamine and steroids have been controversially discussed in the pathogenesis of cholestatic pruritus. However, for these substances neither a correlation with itch severity nor a causative link has ever been established. Recent findings indicate that the potent neuronal activator lysophosphatidic acid and autotaxin, the enzyme forming lysophosphatidic acid, may play a key element in the pathogenesis of cholestatic pruritus. Serum activity of autotaxin correlated with itch intensity and response to antipruritic treatment in patients with cholestatic pruritus, but not other forms of pruritus. Autotaxin activity thereby represents the first biomarker for pruritus and had a positive predictive value of 70% in differentiating cholestatic pruritus from other forms of pruritus. Treatment options for patients with cholestatic pruritus include the anion exchange resin colestyramine, the PXR agonist rifampicin, the μ-opioid antagonist naltrexone, and the serotonin reuptake inhibitor sertraline. These drugs are recommended by evidence-based guidelines as a stepwise therapeutic approach. Patients unresponsive to these drugs should be referred to specialized centers to receive experimental approaches such as UVB phototherapy, albumin dialysis, plasmapheresis or nasobiliary drainage. This review discusses pruritogen candidates in cholestasis, gives novel insights into the neuronal signaling pathway of pruritus and summarizes evidence-based treatment options for patients suffering from pruritus in cholestasis

Steroid Binding to Autotaxin Links Bile Salts and Lysophosphatidic Acid Signalling

Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA). ATX-LPA signalling is involved in multiple biological and pathophysiological processes, including vasculogenesis, fibrosis, cholestatic pruritus and tumour progression. ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function. We present crystal structures of rat ATX bound to 7α-hydroxycholesterol and the bile salt tauroursodeoxycholate (TUDCA), showing how the tunnel selectively binds steroids. A structure of ATX simultaneously harbouring TUDCA in the tunnel and LPA in the pocket, together with kinetic analysis, reveals that bile salts act as partial non-competitive inhibitors of ATX, thereby attenuating LPA receptor activation. This unexpected interplay between ATX-LPA signalling and select steroids, notably natural bile salts, provides a molecular basis for the emerging association of ATX with disorders associated with increased circulating levels of bile salts. Furthermore, our findings suggest potential clinical implications in the use of steroid drugs

The role of autotaxin in cholestatic pruritus

Puritus (jeuk) is een veelvoorkomend symptoom bij verschillende cholestatische leverziekten. Hierbij hopen stoffen die anders in de gal uitgescheiden worden zich op in de circulatie. Waarschijnlijk zorgt diffusie van één of meer van die stoffen naar de huid voor activatie van jeukzenuwen, wat leidt tot dit invaliderende symptoom. Het is onbekend welke stof(fen) (‘pruritogenen’) dit is/zijn. Eerder onderzoek van onze onderzoeksgroep toont aan dat de concentratie van lysofosfatidezuur (LPA, een pruritogeen) en de activiteit van het enzym autotaxine (ATX), dat het grootste deel van het LPA in de circulatie vormt, correleren met de jeukintensiteit van patiënten.Dit proefschrift onderzoekt de bron van verhoogd ATX en het potentieel causale verband tussen ATX activiteit in het bloed en het ontstaan van jeuk. We beschrijven onderzoek met cholestatische muismodellen, dat werd gecompliceerd door de observatie dat cholestatische muizen niet méér, maar minder gaan krabben. Andere muismodellen leerde ons dat niet verhoogde LPA-productie in het bloed alléén, maar verhoogde LPA-productie in de huid wel degelijk verhoogde krabactiviteit geeft in muizen. Daarmee blijven ATX en LPA onderwerp van verder onderzoek naar nieuwe behandelmogelijkheden voor jeuk bij cholestase. Voorts beschrijven we een verschil in de ATX-regulatie tussen mensen en muizen, als mogelijke verklaring voor het uitblijven van jeuk in cholestatische muizen. Hoofdstuk 6 beschrijft een intrigerende interactie tussen galzouten en ATX-activiteit. In hoofdstuk 7 wordt de opzet van een nog lopende multicenter klinische trial naar het effect van bezafibraat op jeuk bij cholestase beschreven

Advances in pathogenesis and treatment of pruritus

The pathogenesis of itch during cholestasis is largely unknown and treatment options are limited. Lysophosphatidate, female steroid hormones, and endogenous opioids are among the agents discussed as potential pruritogens in cholestasis. The itch-alleviating action of guideline-based therapeutic interventions with anion exchanger resins, rifampicin, opioid antagonists, and serotonin reuptake inhibitors are studied to unravel the molecular pathogenesis of itch. Still, a considerable part of the patients is in need of alternative experimental therapeutic approaches (eg, UV-B phototherapy, extracorporeal albumin dialysis, nasobiliary drainage), providing additional information about the enigmatic pathophysiology of cholestatic pruritu

Lysophosphatidic acid and signaling in sensory neurons

Lysophosphatidic acid is a potent signaling lipid molecule that has initially been characterized as a growth factor. However, later studies have revealed many more functions such as modulation of cell shape, cell migration, prevention of apoptosis, platelet aggregation, wound healing, osteoclast differentiation, vasopressor activity, embryo implantation, angiogenesis, lung fibrosis, hair growth and more. The molecule mainly acts through the activation of a set of at least 6 G-protein-coupled receptors (LPA1-6), but intracellular LPA was also shown to signal through the activation of the nuclear receptor PPARγ. In this short review we discuss the recent observations which suggest that in pathological conditions LPA also modulates signaling in sensory neurons. Thus, LPA has been shown to play a role in the initiation of neuropathic pain and, more recently, a relation was observed between increased LPA levels in the circulation and cholestatic itch. The mechanism by which this occurs remains to be elucidated. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomic

Pharmacological Approaches for the Management of Persistent Pain in Older Adults What Nurses Need to Know

The current article addresses pharmacological treatment issues regarding the management of persistent pain in later life, which is a worldwide problem associated with substantial disability. Recommendations from guidelines were reviewed and data are presented regarding the benefits and risks of commonly prescribed analgesic medications. The evidence base supports a stepwise approach with acetaminophen as first-line therapy for mild-to-moderate pain. Oral nonsteroidal anti-inflammatory drugs are not recommended for long-term use. In properly selected older patients, opioid drugs should be considered if pain is not adequately controlled. Careful surveillance to monitor for benefits and harms of therapy is critical, given that advancing age increases risk for adverse effects. Key aspects of the pain care process that nurses routinely engage in are covered, including conducting pain assessments prior to initiating therapy, addressing barriers to effective pain care, educating patients and family members about the importance of reducing pain, discussing treatment-related risks and benefits, and formulating strategies to monitor for treatment outcomes. Finally, a case is presented to illustrate issues that arise in the care of affected patient

Pruritus in cholestasis: facts and fiction

Pruritus is a common symptom in patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, or hereditary pediatric cholestatic disorders and may accompany, although less frequently, many other liver diseases. Recent findings indicate that lysophosphatidic acid (LPA), a potent neuronal activator, and autotaxin (ATX; ectonucleotide pyrophosphatase/phosphodiesterase 2), the enzyme which forms LPA, may form a key element of the long-sought pruritogenic signaling cascade in cholestatic patients suffering from itch. Serum ATX, but no other pruritogen candidate studied so far, correlates with pruritus intensity and responds to therapeutic interventions. In this comprehensive review, we provide a short update on actual insights in signal transmission related to pruritus and discuss pruritogen candidates in cholestasis. We also summarize evidence-based and guideline-approved as well as experimental therapeutic approaches for patients suffering from pruritus in cholestasi

Problem Adaptation Therapy for Pain (PATH-Pain): A Psychosocial Intervention for Older Adults with Chronic Pain and Negative Emotions in Primary Care

Chronic pain is highly prevalent in older adults, contributes to activity restriction and social isolation, disrupts family and interpersonal relationships, and poses a significant economic burden to society. Negative emotions such as sadness, anxiety, helplessness, and hopelessness are associated with chronic pain and contribute to poor quality of life, impaired interpersonal and social functioning, and increased disability. Psychosocial interventions for older adults with chronic pain have been historically developed for, and are almost exclusively delivered to, cognitively intact patients. Therefore, many older adults with chronic pain and comorbid cognitive deficits have limited treatment options. Our multidisciplinary team developed Problem Adaptation Therapy for Pain in Primary Care (PATH-Pain), a psychosocial intervention for older adults with chronic pain, negative emotions, and a wide range of cognitive functioning, including mild-to-moderate cognitive impairment. In the current article, we describe the principles underlying PATH-Pain, review the steps taken to adapt the original PATH protocol, outline the treatment process, and present a case illustrating its potential valu