Cholestatic Pruritus Research Articles

Structure-Activity Relationships and Target Selectivity of Phenylsulfonylamino-Benzanilide Inhibitors Based on S1647 at the SLC10 Carriers ASBT, NTCP, and SOAT.

The intestinal bile acid carrier ASBT (SLC10A2), the hepatic bile acid carrier NTCP (SLC10A1), and the steroid sulfate carrier SOAT (SLC10A6), all members of the solute carrier family SLC10, are established drug targets. The ASBT inhibitors odevixibat, maralixibat, and elobixibat are used to treat intrahepatic cholestasis, cholestatic pruritus, and obstipation. The peptide drug bulevirtide blocks binding of the hepatitis B and D viruses to NTCP and thereby inhibits the virus's entry into hepatocytes. Experimental SOAT inhibitors have antiproliferative effects on hormone-dependent breast cancer cells. The phenylsulfonylamino-benzanilide S1647 is an inhibitor of ASBT and SOAT. The present study aimed to comparatively analyze a set of newly synthesized and commercially available S1647 derivatives for their transport inhibition against ASBT, NTCP, and SOAT. Structure-activity relationships were systematically analyzed regarding potency and target specificity to elucidate whether this compound class is worth being further developed in preclinical studies for pharmacological ASBT, NTCP, and/or SOAT inhibition.

S149 Safety and Tolerability of TH104, Buccal Nalmefene, in Patients With Cholestatic Liver Disease and Pruritus

S149 Safety and Tolerability of TH104, Buccal Nalmefene, in Patients With Cholestatic Liver Disease and Pruritus

Itching for Answers: A Comprehensive Review of Cholestatic Pruritus Treatments

Cholestasis is a clinical and laboratory syndrome indicating impaired bile production or excretion. One of the hallmark symptoms of cholestasis is pruritus. Itch can be severe and debilitating for patients, impacting their quality of life similarly to pain, and, in some cases, it can be refractory. Current therapies like anion exchange resins and rifampicin, offer partial relief but with side effects. Effective, well-tolerated treatments are urgently needed. This literature review examines existing options (bile acid sequestrants, antihistamines, opioid antagonists, sertraline, and rifampicin) and explores novel therapies (monoclonal antibodies, PPAR agonists, and bile-acid-based therapies). We analyze mechanisms, limitations, and adverse effects to aid clinicians and researchers. Novel approaches include monoclonal antibodies to inhibit bile recirculation and PPAR agonists targeting pruritus signaling. Despite the limited current options, ongoing research promises better treatments for cholestatic pruritus, addressing its distressing impact. In summary, cholestasis-associated pruritus poses a significant challenge with limited treatments. Advancements in understanding its pathophysiology offer hope for more effective therapies in the future.

Cutaneous Manifestations of Liver Disease: A Narrative Review.

Chronic liver disease is a major cause of morbidity and mortality. The most common extrahepatic manifestations are dermatological. The pathophysiology of these dermatological manifestations is not clear, but it is postulated that the mechanisms involved include generalized vasodilatation, hyperdynamic blood circulation, and altered estrogen metabolism. The most common cutaneous manifestations of liver disease are Terry's nails and pruritus. Terry's nails consist of leukonychia with a distal pink band and the absence of the lunula. The main differential diagnosis is Lindsay's nails. Vascular manifestations of liver disease include palmar erythema and arachnoid nevi, the latter located in the vascular territory of the superior vena cava and occurring in chronic alcohol-associated liver disease. Dermatological manifestations generally resolve with improvement or remission of liver disease, and there is no specific treatment for them. However, bile acid chelators are the first line of treatment for cholestatic pruritus. Studying dermatological manifestations of liver disease contributes to early diagnosis and treatment, potentially improving the patient's prognosis.

Pharmacological interventions for pruritus in adult palliative care patients.

Pharmacological interventions for pruritus in adult palliative care patients.

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.

Research Progress of Cholestatic Liver Disease-Related Pruritus in Chinese Medicine and Western Medicine

AbstractPruritus is common in cholestatic liver disease, with a high clinical incidence rate and complex pathogenesis. Accumulation of potential pruritus inducers such as steroids, bile acids, and lysophosphatidic acid in the systemic circulation is the main cause of pruritus in cholestatic liver disease. Currently, clinical treatment of cholestatic liver disease-related pruritus mainly includes medication, intervention therapy, and some experimental methods. However, there are still problems, such as unclear pathological mechanisms and unsatisfactory treatment responses in some patients with cholestatic liver disease-related pruritus. Effective treatment for patients still faces challenges. By extensively screening patients' plasma (and/or bile) samples through clinical trials, potential pruritus inducers can be identified comprehensively, which can provide a deeper understanding of the itch signaling pathways in cholestatic liver disease and a basis for the development of treatment strategies. Traditional Chinese medicine (TCM) has shown certain characteristics and advantages in clinical treatment. Based on the etiology and pathogenesis, external application, internal administration, and TCM-specific therapies have achieved good clinical efficacy. Similarly, the combination of Chinese medicine and Western medicine has also achieved more effective treatment for patients with cholestatic liver disease-related pruritus. This article will introduce the latest progress in the study of pruritus inducers in cholestatic liver disease and its treatment in TCM and Western medicine.

Serum bile acid change correlates with improvement in pruritus in patients with primary biliary cholangitis receiving linerixibat.

Total serum bile acid (TSBA) levels are elevated in patients with primary biliary cholangitis (PBC) and may mediate cholestatic pruritus. Linerixibat, an ileal bile acid transporter inhibitor, improved pruritus in patients with PBC. We explored the relationship between linerixibat dose, TSBA concentration, and pruritus. Data from Phase 1/2 trials were used to develop a population kinetic-pharmacodynamic model to characterize the linerixibat dose-TSBA relationship. Individual Bayesian parameter estimates for participants in the GLIMMER study were used to derive the area under the TSBA concentration curve over 24 h (AUC0-24). Time-matched post hoc estimates of AUC0-24 were correlated with pruritus reported on a 0-10 numerical rating scale. Baseline TSBA concentration was correlated with change from baseline (ΔBL) in monthly itch score (MIS). ΔBL in model-estimated TSBA AUC0-24 was correlated with time-matched ΔBL in weekly itch score (WIS) or MIS. Linerixibat dose dependently reduced TSBA AUC0-24, reaching steady state after 5 days. Baseline TSBA levels in GLIMMER did not correlate with ΔBL in MIS. ΔBL in TSBA AUC0-24 correlated with improved WIS over 12 weeks of treatment (r = 0.52, p < 0.0001). Of participants with a ≥30% decrease in TSBA AUC0-24, 60% were pruritus responders (≥2-point improvement in WIS from baseline). Linerixibat treatment leads to rapid, dose-dependent TSBA reductions. Baseline TSBA levels do not correlate with on-treatment pruritus change, suggesting they do not predict linerixibat response. Change in TSBA AUC0-24 correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC.

Maralixibat (Livmarli)

CADTH recommends that Livmarli should be reimbursed by public drug plans for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) if certain conditions are met. Livmarli should only be covered to treat patients aged 12 months and older with a diagnosis of ALGS and who have impaired bile flow demonstrated by at least 1 of the following: elevated serum bile acids (sBAs), conjugated bilirubin, or gamma-glutamyl transferase; fat-soluble vitamin deficiency; and/or intractable itch. Patients must experience moderate to severe itch symptoms and must be currently or have been previously treated with systemic medication for itch. Livmarli should only be reimbursed if it is prescribed under the care of a specialist with experience in managing ALGS, if patients experience an improvement in their itching after using Livmarli for 6 months, and if the cost of Livmarli is reduced. Livmarli should be stopped if the patient receives a liver transplant or biliary diversion surgery.

Odevixibat: A Review of a Bioactive Compound for the Treatment of Pruritus Approved by the FDA.

Odevixibat is synthesized through chemical modification of Benzothiazepine's structure. It is a tiny chemical that inhibits the ileal bile acid transporter and is used to treat a variety of cholestatic illnesses, including progressive familial intrahepatic cholestasis (PFIC). For cholestatic pruritus and liver disease development, bile acid transporter inhibition is a unique treatment strategy. Odevixibat reduces enteric bile acid reuptake. Oral odevixibat was also studied in children with cholestatic liver disease. Odevixibat received its first approval in the European Union (EU) in July 2021 for the treatment of PFIC in patients aged 6 months, followed by approval in the USA in August 2021 for the treatment of pruritus in PFIC patients aged 3 months. Bile acids in the distal ileum can be reabsorbed by the ileal sodium/bile acid cotransporter, a transport glycoprotein. Odevixibat is a sodium/bile acid co-transporter reversible inhibitor. An average 3 mg once-daily dose of odevixibat for a week resulted in a 56% reduction in the area under the curve of bile acid. A daily dose of 1.5 mg resulted in a 43% decrease in the area under the curve for bile acid. Odevixibat is also being evaluated in many countries for the treatment of other cholestatic illnesses, including Alagille syndrome and biliary atresia. This article reviews the updated information on odevixibat with respect to its clinical pharmacology, mechanism of action, pharmacokinetics, pharmacodynamics, metabolism, drug-drug interactions, pre-clinical studies, and clinical trials.

The Evolution of Pruritus Management for People with Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a progressive, immune-mediated liver disease that can be chronic and, in some cases, fatal. Cholestatic pruritus is a common symptom of PBC; however, it is consistently underassessed and undertreated. The pruritus can be moderate to severe, and persistent over years. Patients can experience changes in severity over the course of the day, with pruritus often being most troublesome in the evening and at night. Occurrence is associated with sleep disturbance, leading to daytime fatigue and mood disorders, as well as having a huge impact on health-related quality of life (HRQoL). Assessment of cholestatic pruritus should be carried out by healthcare professionals (HCP) at every consult with a patient with PBC to ascertain occurrence, severity, and the effect on HRQoL. Severity assessment can be carried out using a simple 0–10 numerical rating, or visual analogue scale, and the patient’s quality of life can be assessed with more involved measures, such as the PBC-40 tool. Patients can also track changes in symptoms over time on dedicated phone apps, and share these data at consults. Treatment for PBC is primarily with ursodeoxycholic acid (UDCA); however, this drug has not been shown to significantly improve cholestatic pruritus. Guidelines recommend anion-exchange resins as first-line treatment for pruritus, with pregnane X receptor agonists, oral opiate antagonists, and selective serotonin reuptake inhibitors also suggested as second/third-line treatment. Of note though, few of these have been specifically licensed for cholestatic pruritus and clinical trial data supporting their use remain limited. Other measures include training patients to stop the itch-scratch-itch cycle and the use of moisturising and/or cooling creams. At the American Association for the Study of Liver Diseases (AASLD) 2023 Liver Meeting in Boston, Massachusetts, USA, two HCPs with expertise in PBC, along with a patient representative, discussed these aspects of cholestatic pruritus, and how patients with this symptom can be recognised, assessed, and helped.

Impact of maralixibat on cholestatic pruritus in young adults aged 16 years and older with Alagille syndrome

Impact of maralixibat on cholestatic pruritus in young adults aged 16 years and older with Alagille syndrome

Immunological and non-immunological mechanisms in cholestatic pruritus

Immunological and non-immunological mechanisms in cholestatic pruritus

Alagille syndrome and liver: an adult case report

BackgroundAlagille syndrome is a rare autosomal-dominant disorder, representing 10 to 15% of the causes of neonatal cholestasis with no gender predominance. The diagnosis is based on the association of liver, heart, eye, skeleton abnormalities, and characteristic facial appearance.Case presentationAn 18-year-old male patient, with a family history of benign recurrent intrahepatic cholestasis in a brother, was diagnosed at birth with bile duct paucity. He consulted in adulthood for cholestatic jaundice and pruritus. Physical exam found cutaneous jaundice, particular face, skeletal abnormality of fingers, posterior embryotoxon, and splenomegaly. An echocardiogram found cardiovascular abnormalities. The diagnosis of Alagille syndrome was made in front of five major criteria. A liver biopsy revealed a cirrhosis liver. Upper gastrointestinal endoscopy revealed grade II esophageal varices of portal hypertension. Laboratory tests revealed bicytopenia related to hypersplenism, hypoferritinemia, cytolysis with cholestasis, high bilirubin levels, low prothrombin time, hypoalbuminemia, decreased factor V activity, and hypocholesterolemia. The patient had vitamin K supplementation and was put on ursodeoxycholic acid, propranolol for the liver disease, a high protein hypercaloric diet for malnutrition, vitamin D supplementation and bisphosphonate for the osteoporosis, therapeutic abstention with monitoring for the asymptomatic cardiac disease. After a year of treatment, the patient had an overall health status improvement. Abdominal ultrasound found liver nodules. A biliary MRI showed a multinodular liver. The complement by CT hepatic angiography did not show any nodules while the MRI angiography revealed multiple dysplastic nodules. A liver biopsy was performed and found regenerative nodules.ConclusionThe treatment of Alagille syndrome is based on managing the cholestasis and its complications, especially pruritus because it can have a significant impact on quality of life. Due to the complexity of presentation and multi-organ involvement, management of cases with Alagille syndrome should be done by a multidisciplinary team. Liver disease is responsible for morbidity while cardiac disease is a mortality risk factor in this population.

Evaluation of the Use of Naltrexone for Cholestatic Pruritus.

Pruritus is a common symptom of liver disease, managed with various medications including opioid antagonists like naltrexone. Current literature surrounding the safety and efficacy of naltrexone for cholestatic pruritus is limited. Our objective was to describe naltrexone prescribing practices for cholestatic pruritus. We conducted a single-center, retrospective review of inpatients who received naltrexone for cholestatic pruritus. We gathered information on naltrexone dosing, frequency, dose adjustments, duration, elevations in liver function tests (LFTs), and use of additional antipruritic agents. Thirty-nine patients and 122 dosing regimens were included for analysis. Most patients were male (56.4%) with a median age of 6.32 years (range, 0.63-18.89). The median weight-based doses of naltrexone were 1.45 mg/kg/dose (IQR, 0.84-2.81) and 1.86 mg/kg/day (IQR, 0.97-3.37). The median flat doses were 25 mg/dose (IQR, 12.25-50) and 50 mg/day (IQR, 25-50). The median number of additional antipruritic agents used before and after naltrexone initiation was 3 (IQR, 2-4) and 4 (IQR, 3-5), respectively (p < 0.001). The most common elevated LFTs were total bilirubin and alanine aminotransferase (ALT), occurring in 15% of patients. Naltrexone dosing ranged between 1 and 2 mg/kg/dose once or twice daily, with larger weight-based doses prescribed in younger and lower-weight patients. Naltrexone was commonly added as a fourth-line agent and did not lead to discontinuation of other antipruritic therapies. Larger, prospective, controlled studies are needed to assess the safety and efficacy of naltrexone for cholestatic pruritus.

Long-term Plasmapheresis for Cholestatic Pruritus

Cholestatic pruritus is commonly associated with many hepatobiliary disorders and can be typically controlled with conventional treatment. Therapeutic plasma exchange (TPE) has shown success in improving untreatable cholestatic pruritus with great success. We report on the use of TPE to alleviate debilitating pruritus in one patient with a two-year history of chronic pruritus refractory to conventional treatment. The patient presented with an acute onset of diffuse pruritus that did not fully respond to first or second-line treatments, including bile acid sequestrants. Pruritus significantly affected her quality of life, interfering with daily activity, causing insomnia and weight loss. Due to the severity of her symptoms, biweekly TPE with 5% albumin infusions were initially trialed. Patient found symptoms to be much improved until about the fifth day after each TPE. TPEs were scheduled twice per week alternating with once per week. TPE appeared to be an effective treatment for this patient with chronic cholestatic pruritus. For our patient, TPE seemed to provide relief for about 3-5 days after each TPE.

Treatment of Cholestasis in Infants and Young Children.

Cholestasis is characterized by a conjugated hyperbilirubinemia secondary to impaired bile synthesis, transport, or excretion from the liver. It is always pathologic and can be indicative of an underlying hepatobiliary, genetic, or metabolic disorder, several of which require timely diagnosis to ensure proper management and optimal outcomes. This review provides an overview of the evaluation of cholestasis with a focus on current and emerging treatment strategies. Increased accessibility of next generation sequencing (NGS) allows for utilization of genetic testing early in the diagnostic process. This may alter the clinical algorithm for diagnosis of cholestatic disorders. An enhanced understanding of the underlying pathophysiology may help guide future development of targeted therapies, such as ileal bile acid transporter (IBAT) inhibitors. These were recently approved for treatment of cholestatic pruritus in patients with Alagille syndrome and Progressive Familial Intrahepatic Cholestasis. Current management of cholestasis is aimed at the biochemical consequences of impaired bile flow, including malnutrition, pruritus, and progressive fibrosis. NGS has led to an enhanced understanding of biliary pathology and may guide development of future treatment modalities based on specific gene mutations. Rapid discernment of the underlying etiology is essential as new treatment modalities emerge.

Therapeutic potential of infliximab for pruritus in mice model of cholestasis induced by bile duct ligation: Possible involvement of IL-31

BackgroundCholestatic pruritus is a distressful sensation that can cause a massive desire of scratching skin. Despite maximum medication therapy, some patients still experience pruritus. In this study, we evaluated the effect of infliximab on cholestatic pruritus induced in mice by bile duct ligation. MethodsTwenty-four balb/c mice were randomly assigned to three groups; sham, control, and treatment. The bile duct ligation procedure was performed on mice in the control and treatment groups. After six days, mice in the treatment group received subcutaneous administration of infliximab, and the next day all mice were subjected to the scratching behavior test. Skin, dorsal root ganglia (DRG), and blood samples of mice were collected and evaluated by histopathological, molecular, and biochemical tests. ResultsThe scratching behavior has significantly decreased in mice with cholestasis after the administration of infliximab. The levels of TNFα, TNFR1, TNFR2, NF-κB, and IL-31were higher in control mice compared to sham. In addition, expression levels of TNFR1, NF-κB, and IL-31 were decreased in the treatment group compared to the controls in skin and DRG, while TNFR2 levels were decreased only in DRG. ConclusionInfliximab can block TNFα interaction with receptors and inhibit further inflammatory response. Also, our results suggested that infliximab can suppress IL-31 expression indirectly, which is a well-known cytokine in pruritus pathophysiology Infliximab can be a potential therapeutic approach in resistant pruritus in cholestatic disorders.

Management of Cholestatic Pruritus in Primary Biliary Cholangitis: Ileal Bile Acid Transporter Inhibition and Holistic Care

Symptoms of the progressive cholestatic liver disease primary biliary cholangitis (PBC) include pruritus and fatigue. Pruritus can persist chronically in at least one-third of people with PBC and can range from mild to severe, with fluctuations over time, including on a daily basis. Proposed causative factors for PBC-associated pruritus include bile acids, lysophosphatidic acid (LPA), and endogenous opioids, with proposed symptom mechanisms linked to increases of these substances, or associated pathways. All offer potential routes for drug treatment to help alleviate pruritus in some patients. PBC-associated pruritus can have a significantly detrimental effect on a person’s quality of life (QoL) due to a sometimes constant feeling of ‘bugs crawling’ on their skin, and the need to ‘tear my skin off’. Pruritus may lead to secondary skin lesions, embarrassment, and social isolation. Pruritus is associated with sleep deprivation and subsequent daytime tiredness and fatigue, as well as depression, and sometimes in the worst cases, leading to suicide. Treatments for PBC-associated pruritus include bile acid sequestrants, rifampicin, opioid antagonists, sertraline, and gabapentin, as well as topical moisturisers, behavioural changes, and ultraviolet light therapy. Though not currently approved for such, ileal bile acid transporter (IBAT) inhibitors are undergoing clinical trials, as success in alleviating pruritus is shown in similar conditions. In patients where PBC-associated pruritus is very severe, liver transplantation is a consideration. At the 2023 European Association for the Study of the Liver (EASL) Congress, leading experts in the field of PBC, including clinician-researchers, a nurse specialist, and a representative from the PBC Foundation, highlighted the importance of discussing, assessing, and treating pruritus in people with PBC, using a holistic approach to understanding and caring for this QoL-affecting symptom.

Evaluation and Management of Chronic Cholestatic Liver Diseases.

Cholestasis is defined as stagnation or a marked reduction in bile secretion and flow. Cholestatic jaundice can thus be classified as intrahepatic or extrahepatic cholestatic, depending on the level of obstruction to bile flow. It is important to recognize the complications of cholestatic in patients with chronic cholestatic liver disease. The two most common complications of cholestasis are pruritus and fatigue, with the former being the most responsive to treatment. Cholestyramine is the first-line treatment for cholestatic pruritus. Rifampicin and oral opioid antagonist naltrexone are extremely effective second-line treatments. To date, there are no specific treatments for chronic cholestatic fatigue management. Osteoporosis is a complication that can arise in chronic cholestatic conditions. It appears to be more prominent in individuals with cholestatic liver disease than in patients with other chronic liver diseases with an increased risk of fracture. The evaluation of osteoporosis in individuals with chronic cholestasis is similar to that in the general population. Antiresorptive agents such as bisphosphonates are the first-line treatment choice for osteoporosis in patients with chronic cholestasis. Other less common complications include dyslipidemia, fat-soluble vitamin deficiency, and steatorrhea. Understanding and treating these conditions can have a significant impact on the morbidity and quality of life in this group of patients. This review aimed to provide further information about the complications of chronic cholestasis and to highlight evidence-based test practices for the evaluation and effective management of these complications.