Hepatic Pruritus Research Articles

Recommended diagnostics for pruritus affecting primary non-lesional skin

Chronic pruritus affecting primary non-lesional skin (CPNL) manifests as acommon symptom across aspectrum of diseases spanning various medical specialties. Given the diverse etiological factors involved, diagnosing the underlying condition poses asignificant challenge. To provide acomprehensive overview of clinical, laboratory, and imaging diagnostics for CPNL. Athorough literature search on the diagnostics of chronic pruritus was conducted using PubMed with specific keywords "chronic pruritus AND non-lesional skin", "chronic itch AND non-lesional skin", "chronic pruritus AND diagnostics", "chronic itch AND diagnostics", "CKD-aP", "hepatic pruritus", "cholestatic pruritus", and "myeloproliferative neoplasms AND pruritus". Asystematic diagnostic approach is recommended for patients with CPNL, guided by the prevalence of pruritus-associated diseases. Initial basic diagnostics facilitate acost-effective and focused evaluation during the initial medical assessment. Information pertaining to underlying diseases can be further refined through specialized diagnostic procedures. CPNL often presents adiagnostic dilemma. Adopting astepwise diagnostic strategy facilitates the identification of underlying etiologies, which is crucial for recognizing diseases and administering pruritus-specific pharmacotherapy.

Aetiology, pathogenesis and management of neuropathic itch: A narrative review with recent updates.

Neuropathic itch is a relatively common yet under-reported cause of systemic pruritus. It is a debilitating condition often associated with pain, which impairs the patient's quality of life. Although much literature exists about renal and hepatic pruritus, there is a dearth of information and awareness about neuropathic itch. The pathogenesis of neuropathic itch is complex and can result from an insult at any point along the itch pathway, ranging from the peripheral receptors and nerves until the brain. There are several causes of neuropathic itch, many of which do not produce any skin lesions and are thus, often missed. A detailed history and clinical examination are necessary for the diagnosis, while laboratory and radiologic investigations may be needed in select cases. Several therapeutic strategies currently exist involving both non-pharmacological and pharmacological measures, the latter including topical, systemic, and invasive options. Further research is ongoing to clarify its pathogenesis and to design newer targeted therapies with minimal adverse effects. This narrative review highlights the current understanding of this condition, focusing on its causes, pathogenesis, diagnosis, and management, along with newer investigational drugs.

Cholestatic Itch: Our Current Understanding of Pathophysiology and Treatments.

Hepatic pruritus is common in liver conditions, including cholestasis and nonalcoholic fatty liver disease. The pruritus can be severe enough to diminish sleep and decrease quality of life. The pathophysiology likely involves many molecules and receptors, including bile acids, bilirubin, lysophosphatidic acid (LPA), endogenous opioids, and serotonin. Recent advances suggest a significant role of Mas-related G protein-coupled receptor X4 (MRGPRX4) and autotaxin/LPA as key players in cholestatic pruritus. Further research is needed to develop increasingly targeted therapies with greater efficacy, especially given that many patients report itch refractory to various treatments. Cholestyramine was the only US FDA-approved drug for cholestatic pruritus until recent approval of ileal bile acid transporter (IBAT) inhibitors for use in the pediatric cholestatic conditions, progressive familial intrahepatic cholestasis and Alagille syndrome. Both medications decrease the bile acid pool. IBAT inhibitors are under investigation for broader use, and targeting LPA receptors and MRGPR4 are additional attractive options.

Systemic pruritus: what is new in diagnosis and treatment?

HintergrundChronischer Pruritus ist ein häufiges Symptom zahlreicher internistischer Erkrankungen. Insbesondere sind Patienten mit chronischer Niereninsuffizienz, hepatobiliären Erkrankungen und myeloproliferativen Neoplasien betroffen.Ziel der ArbeitDieser Übersichtsartikel soll einen Überblick über die laborchemische und bildgebende Diagnostik sowie aktuelle und neuartige Therapieansätze des Pruritus systemischer Erkrankungen geben.Material und MethodenEs erfolgte eine ausführliche PubMed-Recherche.ErgebnisseZur Abklärung des chronischen Pruritus wird eine Stufendiagnostik empfohlen, die sich an der Häufigkeit der mit Pruritus assoziierten Erkrankungen orientiert. Eine Basisdiagnostik ermöglicht dabei eine kostengünstige und gezielte Abklärung auf hausärztlicher Ebene. Aktuelle topische und medikamentöse Therapieempfehlungen des Pruritus bei chronischer Niereninsuffizienz, hepatobiliären Erkrankungen und myeloproliferativen Neoplasien sowie selteneren Ursachen wurden übersichtlich zusammengefasst. Daneben werden neuartige Therapieansätze wie der κ‑Opioidrezeptor-Agonist Difelikefalin, Bezafibrat, Inhibitoren des „ileal bile acid transporter“ (IBAT) und des JAK(Januskinase)-STAT(„signal transducers and activators of transcription“)-Signalweges aufgezeigt.DiskussionChronischer Pruritus bei systemischen Erkrankungen kann eine diagnostische Herausforderung darstellen. Eine Stufendiagnostik erleichtert die Identifikation der zugrunde liegenden Erkrankung. Ein verbessertes pathophysiologisches Verständnis hat zu ersten zugelassenen Therapieoptionen bei „chronic kidney disease“-assoziiertem und hepatischem Pruritus geführt.

Endogenous Opioid Levels Do Not Correlate With Itch Intensity and Therapeutic Interventions in Hepatic Pruritus.

Background: Chronic pruritus affects up to 70% of patients with immune-mediated hepatobiliary disorders. Antagonists of the μ-opioid receptor (MOR) and agonists of the κ-opioid receptor (KOR) are used to treat hepatic itch, albeit with limited success. An imbalance between ligands of MOR and KOR receptors has recently been suggested as a potential mechanism of hepatic pruritus. In this study, we therefore investigated systemic levels of important endogenous opioids such as β-endorphin, dynorphin A, Leu- and Met-enkephalin in plasma of a large cohort of well-characterized patients with immune-mediated cholestatic disorders, including patients with liver cirrhosis, and during effective anti-pruritic therapy.Methods: Plasma samples and clinical data were prospectively collected from well-characterized patients with primary/secondary sclerosing cholangitis (PSC/SSC), primary biliary cholangitis (PBC) and overlap syndromes suffering from pruritus (n = 29) and age-, gender- and disease-matched controls without pruritus (n = 27) as well as healthy controls (n = 20). General laboratory testing for hepatobiliary and renal function was performed. Levels of β-endorphin, dynorphin A, Leu- and Met-enkephalin were quantified in plasma by ELISA. Intensity of pruritus over the last week was evaluated using a visual analog scale (VAS, 0–10).Results: PBC and PSC patients with or without pruritus did neither differ in disease entity, disease stage, nor in the presence of cirrhosis. While both dynorphin A and β-endorphin concentrations were lower in pruritic patients compared to those without pruritus and healthy controls, the MOR/KOR ligand ratio was unaltered. No significant differences were observed for Leu- and Met-enkephalin concentrations. Opioid levels correlated with neither itch intensity nor stage of disease. Cirrhotic patients displayed higher concentrations of MOR agonist Leu-enkephalin and KOR agonist dynorphin A. Endogenous opioid levels remained largely unchanged after successful treatment with the potent anti-pruritic drugs rifampicin and bezafibrate.Conclusions: Endogenous opioid levels and the MOR/KOR ligand ratio neither correlate with itch intensity nor differentiate pruritic from non-pruritic patients with immune-mediated liver diseases. Thus, endogenous opioids may modulate signaling pathways involved in hepatic pruritus, but are unlikely to represent the major pruritogens in liver disease.

Effect of treating chronic hepatitis C with direct-acting antivirals on extrahepatic cutaneous manifestations.

BACKGROUNDHepatitis C virus (HCV) is a disease with a significant global impact, affecting approximately 2%-2.5% of the world’s population. New direct-acting antivirals (DAAs) have been introduced over the past few years with great success in viral eradication. The association of chronic HCV infection with a wide spectrum of cutaneous manifestations has been widely reported in the literature.AIMTo assess the effect of treating HCV with DAAs on the extrahepatic cutaneous manifestations of HCV.METHODSThis prospective observational study included 1039 HCV positive Egyptian patients who were eligible to receive DAAs. A total of 30 patients were diagnosed with extrahepatic cutaneous manifestations and fulfilled the inclusion criteria of the study. Of these patients, 6 had classic lichen planus, 8 were diagnosed with psoriasis vulgaris and 16 had pruritus. All patients received DAAs from October 2018 to July 2019 in the form of a three-month course of sofosbuvir/daclatasvir combination. Patients with lichen planus or psoriasis were dermoscopically evaluated before treatment and 6 mo after treatment, while patients with hepatic pruritus were assessed using the 12-Item Pruritus Severity Scale over the same period.RESULTSAll patients with psoriasis showed significant improvement in all psoriatic plaques, and all patients with hepatic pruritus scored 0 on the 12-Item Pruritus Severity Scale indicating total improvement of pruritus. In addition, four of six patients with lichen planus showed complete improvement.CONCLUSIONTreatment of HCV with DAAs was significantly effective in improving virus-related extrahepatic cutaneous manifestations.

Dupilumab for the Treatment of Moderate to Severe Chronic Hepatic Pruritus

Dupilumab for the Treatment of Moderate to Severe Chronic Hepatic Pruritus

Treatment of Pruritus Secondary to Liver Disease.

Pruritus is a common extrahepatic symptom in various liver disorders, in particularly those with cholestatic features. This review summarizes epidemiology, pathophysiology, evidence-based therapeutic recommendations and currently investigated drugs for pruritus in hepatobiliary disorders. Recent epidemiological data suggest pruritus as a common and relevant symptom in immune-mediated liver diseases, i.e., primary biliary cholangitis (PBC) with over 70% affected patients, up to 56% suffering from chronic pruritus. The better pathophysiological understanding of hepatic pruritus has led to the identification of novel therapeutic targets, addressed in drug trials using KOR agonists, PPAR agonists, and ileal bile acid transporter inhibitors. Hepatic itch remains among the most agonizing symptoms for affected patients and a clinical challenge for physicians. Therapeutic recommendations include a guideline-based stepwise approach starting with cholestyramine, followed by rifampicin, naltrexone, and sertraline. Bezafibrate and ileal bile acid transporter inhibitors represent promising future anti-pruritic treatment options.

Lysophosphatidic acid activates satellite glia cells and Schwann cells.

Pruritus is a common and disabling symptom in patients with hepatobiliary disorders, particularly in those with cholestatic features. Serum levels of lysophosphatidic acid (LPA) and its forming enzyme autotaxin were increased in patients suffering from hepatic pruritus, correlated with itch severity and response to treatment. Here we show that in a culture of dorsal root ganglia LPA 18:1 surprisingly activated a large fraction of satellite glia cells, and responses to LPA 18:1 correlated inversely with responses to neuronal expressed transient receptor potential channels. LPA 18:1 caused only a marginal activation of heterologously expressed TRPV1, and responses in dorsal root ganglion cultures from TRPV1-deficient mice were similar to controls. LPA 18:1 desensitized subsequent responsiveness to chloroquine and TGR5 agonist INT-777. The LPA 18:1-induced increase in cytoplasmatic calcium stems from the endoplasmatic reticulum. LPA receptor expression in dorsal root ganglia and Schwann cells, LPAR1 immunohistochemistry, and pharmacological results indicate a signaling pathway through LPA receptor 1. Peripheral rat Schwann cells, which are of glial lineage as the satellite glia cells, were also responsive to LPA 18:1. Summarizing, LPA 18:1 primarily activates rather glial cells than neurons, which may subsequently modulate neuronal responsiveness and sensory sensations such as itch and pain.

Supportive care in end-stage liver disease: a clinical review

This clinical review aims to describe the complexity of care planning for patients with end-stage liver disease (ESLD). There is no definition of ESLD and no guidelines for the supportive care of patients. A few screening tools can be used to assess ESLD and the prognosis. Complications include hepatic encephalopathy, ascites, malnutrition, gastrointestinal bleeding, pruritus, infections and muscle cramps. Several complications to liver disease might be treated in a different way when the patients are at this stage. Focus shifts from symptom control to palliative care and optimising the patients' quality of life. When limiting alcohol intake, clinicians and patients need to balance its impacts on quality of life. This review addresses how these changes can be carried out by the liver nurses as a part of the liver multidisciplinary team (MDT).

Nerve growth factor (NGF) expression in correlation with severity of pruritus in cirrhotic patients

Background:Hepatic pruritus is a very common symptom among different chronic liver diseases, particularly in those related to cholestasis. Its prevalence is variable among liver diseases, ranging from 5% in chronic hepatitis C virus infection to 70% in primary biliary cirrhosis. Its etiopathogenesis remains poorly understood.Nerve growth factor (NGF) is a member of neurotrophins. many studies clearly demonstrate their role in pruritus. Nerve growth factor (NGF) is overexpressed in prurigonodularis and its therapeutic administration is pruritogenic. In atopic dermatitis, NGF is released by keratinocytes, mast cells and fibroblasts and plasma levels of NGF are also elevated and correlate with disease activity.This study examines the hypothesis that expression of NGF protein is altered in cirrhotic patients with pruritus. Patients and Methods: To test our hypothesis, we examined the expression patterns of NGF protein in cirrhotic patients with pruritus, cirrhotic patients without pruritus and corresponding healthy (control). skin biopsies (20 specimens each) were evaluated using immunoperoxidase staining techniques. Results: We found variations between the skins of cirrhotic patients with and without pruritus and healthy skin. In healthy skin, the expression of NGF protein was strong (basal cell keratinocytes), moderate (spinouslayer), and weak or abscent (granular cell layer). In contrast, marked expression of NGF protein was observed in all layers of skin (total NGF epidermis and dermis) incirrhotic patients with pruritus in comparison with cirrhotic patients without pruritus and healthy control and this was statistically significant. NGF protein expression was strong (basal cell keratinocytes), moderate (spinous layer), and weak or abscent (granular cell layer). The expression of NGF protein was strong in the adnexal structures. Conclusions: We report, for the first time, increased expression of NGF protein in the epidermal keratinocytes of cirrhotic patients with pruritus skin. Our findings suggest possible roles for this protienin pathophysiology of hepatic pruritus. The clinical ramifications of these observations mandate further investigations.

Intrahepatic cholestasis of pregnancy. Case report

We present a patient diagnosed with intrahepatic cholestasis of pregnancy which was reported in the context of a series of 10 similar cases diagnosed and monitored within 1 year in two obstetrics and ginecology centres of Bucharest. The particularity of the case is a differential diagnosis in the case of 32 weeks pregnant patient, accusing pruritus associated with hepatic cytolysis and elevated transaminases revealed by laboratory tests. An emphasis must be put on the importance of early diagnosis of intrahepatic cholestasis of pregnancy and elimination of other severe conditions associated with hepatic cytolysis syndrome and pruritus.

Potentiation of the Transient Receptor Potential Vanilloid 1 Channel Contributes to Pruritogenesis in a Rat Model of Liver Disease

Persistent pruritus is a common disabling dermatologic symptom associated with different etiologic factors. These include primary skin conditions, as well as neuropathic, psychogenic, or systemic disorders like chronic liver disease. Defective clearance of potential pruritogenic substances that activate itch-specific neurons innervating the skin is thought to contribute to cholestatic pruritus. However, because the underlying disease-specific pruritogens and itch-specific neuronal pathways and mechanism(s) are unknown, symptomatic therapeutic intervention often leads to no or only limited success. In the current study, we aimed to first validate rats with bile duct ligation (BDL) as a model for hepatic pruritus and then to evaluate the contribution of inflammation, peripheral neuronal sensitization, and specific signaling pathways and subpopulations of itch-responsive neurons to scratching behavior and thermal hypersensitivity. Chronic BDL rats displayed enhanced scratching behavior and thermal hyperalgesia indicative of peripheral neuroinflammation. BDL-induced itch and hypersensitivity involved a minor contribution of histaminergic/serotonergic receptors, but significant activation of protein-activated receptor 2 (PAR2) receptors, prostaglandin PGE2 formation, and potentiation of transient receptor potential vanilloid 1 (TRPV1) channel activity. The sensitization of dorsal root ganglion nociceptors in BDL rats was associated with increased surface expression of PAR2 and TRPV1 proteins and an increase in the number of PAR2- and TRPV1-expressing peptidergic neurons together with a shift of TRPV1 receptor expression to medium sized dorsal root ganglion neurons. These results suggest that pruritus and hyperalgesia in chronic cholestatic BDL rats are associated with neuroinflammation and involve PAR2-induced TRPV1 sensitization. Thus, pharmacological modulation of PAR2 and/or TRPV1 may be a valuable therapeutic approach for patients with chronic liver pruritus refractory to conventional treatments.

Lack of Efficacy of Topical Capsaicin in Serotonin-Induced Itch1

Capsaicin (CAP) has been demonstrated to be an effective topical inhibitor of cutaneous vasodilatation, pain and pruritus induced by a variety of chemical and physical stimuli. In a previous study, we showed a significantly inhibitory effect of topical CAP treatment on histamine-induced itch and cutaneous vascular reactions in healthy subjects compared to atopic eczema patients. As serotonin is proposed to play a pathophysiological role in some types of pruritus (e.g. uremic and hepatic pruritus) and CAP has been described to be successful in hemodialysis-related pruritus, we investigated the antipruritic effect of topical CAP on serotonin-induced reactions in 10 healthy volunteers in comparison to untreated skin (UPS) and placebo substance (vehicle)-treated skin (VS). On the first day, serotonin iontophoresis was performed in untreated skin. One week later, the treatments started, using either CAP 0.05% liniment or a placebo liniment (vehicle) 3 times daily over a 5-day period. On day 6, serotonin was applied by iontophoresis within the pretreated skin. After another 1-week break, the treatments were performed vice versa on the corresponding infrascapular region. Weal and flare areas were planimetrically evaluated. Itch sensations were documentated by the volunteer on a scale over a 24-min follow-up period. The examination also comprised alloknesis, which stands for induction of perifocal sensations by usually non-itching stimuli. In CAP-treated skin, serotonin-induced wheals were significantly larger post-application compared to non-pretreated skin. Wheals were significantly larger in VS than in UPS. Comparison of serotonin-induced flares in the different study arms did not reveal any significant differences. Itch sensations were not significantly reduced by topical CAP application. The areas of alloknesis were smaller in capsaicin-treated skin compared to VS and UPS, but did not reach significant value. In conclusion, topical CAP application is not effective in serotonin-induced itching in healthy volunteers. Serotonin is most unlikely to play a role in the mechanism of action of CAP.