Scratching the surface: A systematic review of modern approaches to diagnosing and treating cholestatic pruritus

Abstract

BACKGROUND

Cholestatic pruritus (CP) is a debilitating symptom affecting patients with primary biliary cholangitis (PBC), primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, drug-induced cholestasis, and other hepatobiliary disorders. Despite its clinical significance, the pathogenesis remains multifactorial, involving bile acids, autotaxin-lysophosphatidic acid signaling, and endogenous opioids. Recent advances in noninvasive biomarkers and therapeutic options necessitate an updated synthesis of evidence.

AIM

To systematically review contemporary diagnostic modalities and evaluate the safety and efficacy of available therapies of CP.

METHODS

A systematic search of PubMed, EMBASE, and Web of Science (through February 2026) identified studies assessing diagnostic markers or treatments for CP. Eligible publications included randomized controlled trials, observational studies, systematic reviews, and guideline statements. Data were extracted on diagnostic accuracy, treatment responses, adverse effects, and comparative effectiveness. The review followed Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.

RESULTS

Serum autotaxin levels demonstrated moderate correlation with pruritus severity, though clinical scoring systems remain essential due to significant patient variability. Traditional first-line therapy with bile acid sequestrants have minimal evidence for their efficacy although they demonstrate a favorable side-effect profile. Fibrates serve as a more effective first-line therapy in the case of PBC and primary sclerosing cholangitis. Rifampin demonstrated consistent efficacy through pregnane X receptor induction. Opioid antagonists (e.g., naltrexone) and sertraline provided relief in refractory cases. Newly approved ileal bile acid transporter inhibitors significantly reduced pruritus in PBC and pediatric cholestatic disorders. Phototherapy (narrow-band ultraviolet B), dermatology co-management, and multidisciplinary supportive care may be beneficial in specialized populations. Adverse effects and drug-drug interactions remain important limiting factors.

CONCLUSION

CP requires a structured, stepwise approach integrating biomarkers, symptom scores, targeted therapies, and multidisciplinary involvement. Newer options, like fibrates and ileal bile acid transporter inhibitors, and personalized combination therapy represent promising advances.

Key Words: Cholestatic pruritus; Primary biliary cholangitis; Primary sclerosing cholangitis; Hepatobiliary diseases; Ileal bile acid transporter inhibitors

Core Tip: Cholestatic pruritus is a common and debilitating symptom in cholestatic liver diseases such as primary biliary cholangitis and primary sclerosing cholangitis. Its pathogenesis is multifactorial, involving bile acids, autotaxin-lysophosphatidic acid signaling, and endogenous opioids. This systematic review summarizes contemporary diagnostic approaches and treatment strategies. Serum autotaxin correlates moderately with itch severity but should be interpreted alongside validated clinical pruritus scales. While bile acid sequestrants remain the traditional first-line therapy due to safety, evidence for efficacy is limited. Fibrates show increasing effectiveness, particularly in primary biliary cholangitis and primary sclerosing cholangitis. Rifampin, opioid antagonists, sertraline, and newer ileal bile acid transporter inhibitors provide options for refractory disease. A stepwise, multidisciplinary approach is essential to optimize outcomes.

INTRODUCTION

Pruritus is a common and often debilitating symptom of cholestasis. It is prevalent, occurring in 80% of patients with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC), up to 60% of patients with drug-induced liver injury, and in 16%-45% of patient with biliary obstruction (Table 1)[1]. In severe cases, the relentless nature of pruritus can disrupt sleep and concentration, and without reprieve, can even lead to suicidal ideation. Research into patient quality of life confirms that cholestatic pruritus (CP) significantly degrades health-related scores across multiple domains, specifically hindering productivity, social functioning, and emotional well-being[2]. Despite this heavy burden, a staggering 78% of patients with moderate to severe pruritus remain untreated, likely due to a lack of clinical awareness regarding the symptom's impact and the available therapeutic interventions[2].

Table 1 Causes of cholestatic pruritus.

Etiology	Examples	Typical features
Autoimmune	PBC, PSC	Chronic, nocturnal pruritus
Genetic	PFIC, ALGS	Severe, early onset
Hormonal	ICP	Third trimester
Drug-induced	Antibiotics, anabolic steroids	Temporal association
Obstructive	Malignancy, stones	Jaundice-predominant

PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; PFIC: Progressive familial intrahepatic cholestasis; ALGS: Alagille syndrome; ICP: Intrahepatic cholestasis of pregnancy.

Historically, there has been a lack of effective treatment options for CP, stemming from an incomplete understanding of its pathogenesis. It is theorized that pruritogens within the enterohepatic circulation accumulate in the plasma and skin when bile flow is interrupted. These substances trigger receptors on unmyelinated C-fiber neurons which transmit the sensation of itch to the spinal cord and brain (Figure 1). This theory is supported by the fact that treatments like plasmapheresis and albumin dialysis, which physically remove substances from the serum, often provide significant relief to patients[1,3].

Figure 1 Mechanisms of anti-pruritic therapies. PXR: Pregnane X receptor; IBAT: Ileal bile acid transporter; PPAR: Peroxisome proliferator-activated receptor.

Bile acids were initially theorized to be the causative pruritogen of CP given their abundance in bile. This theory is challenged by studies showing that higher levels of serum bile acids do not correlate with increased pruritus burden[4]. Newer research has identified the autotaxin-lysophosphatidic acid signaling pathway as a potential mediator of itch. Patients with CP show markedly elevated levels of both the enzyme autotaxin and its product, lysophosphatidic acid, compared to non-pruritic patients with cholestasis[4-6]. Additionally, the endogenous opioid system appears to play a critical role. Itch seems to be induced by μ-opioid receptor activation and suppressed by κ-opioid receptor activation, suggesting that an imbalance between these two signals contributes to the itch sensation[4,7]. Ultimately, the etiology of CP is multifactorial, involving a complex interplay of various biochemical pathways (Figure 1).

Recent studies have made progress in elucidating the underlying mechanisms of CP as well as developing novel therapeutic strategies. These advancements have the potential to alter clinical practice by refining both diagnostic and management protocols. This systematic review aims to provide an updated evaluation of existing treatment options and summarize the integration of emerging diagnostic and prognostic biomarkers. Another aim is to provide practical guidance to the comprehensive management of CP.

MATERIALS AND METHODS

A comprehensive literature search was performed across PubMed, EMBASE, and Web of Science. The search included articles from database inception up until February 2026. The following search string was used: Cholesta (title/abstract) AND [prurit (title/abstract) OR itch (title/abstract)]. Randomized controlled trials, clinical trials, comparative studies, observational studies, practice guidelines, systematic reviews, and meta-analyses were included. Non-systematic reviews, case reports, case series, and non-English articles were excluded. The authors independently screened article titles and abstracts for eligibility, and articles were then retrieved for further evaluation of meeting eligibility criteria. Disagreements were resolved through discussion by authors to reach a consensus. A total of 736 articles were initially found (206 from PubMed, 236 from EMBASE, 294 from Web of Science). The flow diagram regarding the selection of articles is reported (Figure 2). After screening, a total of 116 articles were included in the review.

Figure 2  Preferred Reporting Items for Systematic reviews and Meta-Analyses flow diagram.

RESULTS

Diagnosis of CP

Clinical assessment of CP: Diagnosing CP relies primarily on a thorough clinical history and the exclusion of alternative causes. Unlike many dermatologic conditions, it presents without primary skin lesions, though physical exams often reveal secondary signs of chronic scratching, such as excoriations and lichenification, alongside markers of liver disease like jaundice. Patients typically experience a generalized itch that predominantly affects the palms and soles, and worsens at night, disrupting sleep and overall quality of life[8,9]. To accurately characterize severity and guide treatment, clinicians must utilize a stepwise diagnostic framework that integrates objective symptom tracking, serum biomarkers, and targeted imaging (Figure 3; Table 2).

Figure 3 Diagnostic approach to cholestatic pruritus. NRS: Numerical Rating Scale; VAS: Visual Analogue Scale; GGT: Gamma-glutamyl transferase; RUQ: Right upper quadrant; US: Ultrasound; MRCP: Magnetic resonance cholangiopancreatography; ERCP: Endoscopic retrograde cholangiopancreatography; PSC: Primary sclerosing cholangitis; FIB-4: Fibrosis-4 index; APRI: Aspartate aminotransferase/platelet ratio index; ICP: Intrahepatic cholestasis of pregnancy.

Table 2 Diagnostic tools and biomarkers.

Tool	Utility	Limitations
Serum bile acids	Reflect cholestasis	Poor correlation with symptom severity
Autotaxin	Emerging biomarker for cholestatic pruritus	Limited availability; not standardized
5-D Itch Scale	Assesses multidimensional symptom severity	Subjective patient-reported measure
Imaging	Exclude biliary obstruction or malignancy	Does not quantify itch severity

Because pruritus is inherently subjective, employing validated scoring systems is essential for effective clinical management. For routine, longitudinal monitoring, the Visual Analogue Scale (VAS) and Numerical Rating Scale (NRS) are the most commonly used tools to quantify itch intensity. These are simple, unidimensional 0-10 scales that are easy to administer and sensitive to change over time[10-12]. When the goal is to understand the broader impact of chronic itch, multidimensional instruments, like the 5-D Itch Scale, are more informative. The 5-D Itch Scale assesses five domains: Degree, duration, direction (change over time), disability, and distribution. It demonstrates strong internal consistency (Cronbach’s α > 0.80) and has been validated in patients with cholestatic liver disease[13]. Importantly, it moves beyond itch intensity alone and captures the patient’s functional impairment and quality-of-life impact.

Laboratory markers: Elevated serum bile acids are the biochemical hallmark of cholestasis. Despite their prognostic value in other domains of hepatobiliary disease, such as fetal outcomes in intrahepatic cholestasis of pregnancy, serum bile acid concentrations correlate poorly with the subjective severity of CP. In PBC and PSC, severe pruritus is often reported even when bile acids are only moderately elevated, and changes in bile acid levels do not reliably parallel changes in itch intensity[8]. This dissociation underscores the complexity of pruritus pathogenesis beyond simple bile acid accumulation and points to additional mediators. Other routine liver markers, such as alkaline phosphatase, gamma-glutamyl transferase, and bilirubin, are essential to guiding disease-specific therapy but they serve as adjunctive indicators rather than specific biomarkers for pruritus[8].

Emerging evidence implicates the autotaxin-lysophosphatidic acid axis as a mechanistically compelling contributor to CP. Autotaxin is an enzyme that generates lysophosphatidic acid, which can directly stimulate peripheral unmyelinated C-fiber sensory neurons responsible for itch signaling[4-6]. In intrahepatic cholestasis of pregnancy, studies have found that autotaxin levels are notably higher than in healthy pregnancy controls and declines following interventions that relieve cholestasis[5]. Thus, elevated serum autotaxin activity appears to be specific to cholestatic itch and can potentially be used clinically as a diagnostic biomarker in the differential diagnosis for intrahepatic cholestasis of pregnancy. Despite these promising findings, standardized autotaxin assays are lacking, and current practice guidelines do not recommend routine clinical testing of autotaxin or lysophosphatidic acid.

Collectively, these data highlight that while biomarkers such as bile acids, autotaxin, and lysophosphatidic acid show diagnostic promise and warrant further investigation, there is currently no practical laboratory test that reliably quantifies patient-reported pruritus severity in cholestatic liver diseases.

Imaging and additional evaluation: While structural imaging cannot diagnose pruritus directly, it plays an important role in ruling out surgically correctable or malignant causes of cholestasis. Right upper quadrant ultrasonography is the recommended first-line modality, as it quickly identifies biliary ductal dilation, cholelithiasis, and major hepatic parenchymal abnormalities with minimal risk. If extrahepatic obstruction or complex strictures are suspected, such as in PSC, magnetic resonance cholangiopancreatography provides a more detailed picture of the biliary tree. Magnetic resonance cholangiopancreatography is the preferred noninvasive modality for visualizing biliary anatomy and for surveillance for cholangiocarcinoma. Endoscopic retrograde cholangiopancreatography is reserved for cases where intervention is anticipated, such as stricture dilation, stent placement, or tissue sampling, given its invasive nature and procedural risks. Complementing these structural assessments, transient elastography helps stage the underlying chronic disease by evaluating hepatic fibrosis[8,14,15]. Patients with CP often benefit from early involvement of multidisciplinary care. Dermatology referral is indicated when a skin disorder cannot be excluded or when secondary skin changes require targeted treatment[16]. In cases of intrahepatic cholestasis of pregnancy, close coordination with maternal-fetal medicine is essential, as high maternal bile acid levels increase risk of stillbirth and dictate delivery timing[17]. Early psychiatric evaluation should also be considered in patients with severe or persistent pruritus. The chronic insomnia, anxiety, and depression associated with relentless pruritus can profoundly amplify symptom perception and drastically impair quality of life[18].

Treatment strategies

Cholestyramine and other bile acid sequestrants: Cholestyramine remains the guideline-endorsed, first-line pharmacologic therapy for CP[8,19-21]. As a non-absorbable anion exchange resin, it binds negatively charged bile acids within the intestinal lumen, interrupting enterohepatic circulation and promoting fecal excretion[1,3]. The therapeutic rationale for cholestyramine is rooted in the long-standing assumption that retained bile acids contribute directly to pruritus. However, as mentioned in previous sections, accumulating evidence demonstrates little correlation between serum bile acid concentrations and pruritus severity. This mechanistic discrepancy likely explains the lack of evidence supporting its efficacy, despite its widespread use. Although reductions in pruritus severity have been observed in some studies, most were conducted decades ago and were limited by small sample sizes, lack of randomization, short treatment duration, and lack of a placebo-control group[22-24]. Meta-analyses have found insufficient data to confirm cholestyramine’s efficacy[25-27].

Guidelines recommend initiation at 4 g per dose, titrated to a maximum of 16 g daily as tolerated[8,19-21]. It is not recommended in the setting of complete biliary obstruction or advanced cholestasis with markedly reduced bile flow into the intestine, as both cases would diminish the therapeutic benefit of the luminal binding mechanism. Another practical consideration is cholestyramine’s nonselective binding of concomitantly administered oral medications, which may reduce systemic absorption. Ursodeoxycholic acid (UDCA) and other hepatically active agents are particularly susceptible to this interaction[19,28]. To minimize interference, cholestyramine should be administered at least one hour after or four hours before other oral therapies. With prolonged use, impaired absorption of fat-soluble vitamin A, vitamin D, vitamin E, and vitamin K may occur, necessitating periodic monitoring and supplementation when indicated[8]. Predominant side effects are gastrointestinal symptoms, including bloating, constipation, diarrhea, and difficulty tolerating the powder formulation[1,3]. Systemic toxicity is uncommon as it is not absorbed from the gastrointestinal tract.

Other bile acid sequestrants have been considered as alternatives but lack robust clinical support. Colesevelam is better tolerated by patients due to its availability as an oral tablet, although randomized trials failed to demonstrate a significant benefit over placebo[25,27,29]. Colestilan has also been evaluated in small studies, but available data are insufficient to support routine use or incorporation into contemporary treatment algorithms[27]. At present, cholestyramine remains the most consistently recommended bile acid sequestrant therapy.

Rifampin: Rifampin is among the most extensively studied agents in stepwise treatment algorithms for CP[8,19-21]. Rifampin systemically modulates pruritogenic pathways by activating the pregnane X receptor. This activation stimulates hepatic detoxification processes, including cytochrome P450 enzymes, and modulates bile acid transportation and metabolism[30]. Additionally, rifampin suppresses hepatic autotaxin transcription in a pregnane X receptor-dependent manner, aligning with current models implicating the autotaxin-lysophosphatidic acid axis in pruritus pathogenesis[6]. This biologic coherence may explain the reproducible symptomatic benefit observed with rifampin compared to cholestyramine, although direct head-to-head comparisons remain limited[25,27,31].

Multiple randomized controlled trials and a subsequent meta-analysis have demonstrated that rifampin significantly reduces pruritus compared to placebo across diverse cholestatic populations, while maintaining a low incidence of serious adverse events[25,31-34]. Long-term cohort data in patients with PBC further supports the durability of this response[18]. At doses approximating 10 mg/kg/day, patients experienced symptomatic improvement within just two weeks, with most achieving marked reduction or complete resolution by three months[18]. These benefits were reliably maintained during continued therapy and extended follow-up. Although individual trials were modest in size and employed heterogenous pruritus assessment instruments, the consistency of therapeutic effect across studies supports confidence in rifampin’s efficacy.

Hepatotoxicity and drug-drug interactions remain the principal safety concerns when prescribing rifampin for CP. Early observational data reported hepatocellular injury consistent with drug-induced liver injury in a minority of treated patients, typically within the first two months of therapy[35]. Pooled analyses of randomized trials suggest a relatively low incidence of clinically significant liver injury when appropriate patient selection and monitoring are employed[31]. Current guidelines recommend baseline liver function testing and close monitoring during the first four to eight weeks of therapy, when risk appears greatest[8,19-21,35]. Additionally, as rifampin is a potent inducer of cytochrome P450 enzymes, it can substantially accelerate the metabolism of concomitant, hepatically metabolized medications. Therefore, careful medication reconciliation and biochemical monitoring are essential when initiating rifampin.

Opioid pathway modulation: Opioid antagonists interfere with the increased endogenous opioid levels in patients with CP and are associated with improvement in itching symptoms. Naltrexone, an oral opioid antagonist, is considered a second or third-line agent in the management of CP. Multiple randomized control trials have found that naltrexone significantly reduces itch in cholestatic patients compared to placebo, although these studies had small samples sizes (n ≤ 34)[36-39]. A meta-analysis found that opiate antagonists are significantly more likely to reduce pruritus as compared to placebo[26]. The most notable side effects are captured under the opioid withdrawal-like reaction: Abdominal pain, hypertension, tachycardia, goose bumps, nightmares, and depersonalization[40]. Though some studies suggest that these side effects are self-limited within 48 hours, others report early discontinuation of opioid antagonists due to intolerability[26,36-39]. To mitigate side effects, naltrexone should be introduced slowly, starting at 12.5 mg daily and titrated by 12.5 mg every 3-7 days, depending on tolerability, to a maximum dose of 50 mg daily. Patients may also be admitted for intravenous naloxone, followed by conversion to oral naltrexone[40]. Opioid antagonists are not the best long-term strategy, not only due to the acute side effects, but also the long-term risk of reducing pain thresholds and unmasking chronic pain and should be used cautiously in patients using exogenous opioids for analgesia[41,42]. The final consideration is drug-induced liver injury - though it is quite rare from naltrexone, it is recommended to follow liver panels while on treatment.

Serotonergic agents: Serotonergic agents, namely sertraline, have demonstrated moderate efficacy for CP and are considered a third-line treatment option[43-45]. Similar to opioid antagonists, selective serotonin reuptake inhibitors are thought to interrupt potential pruritic pathways involving serotonin as a neurotransmitter. Sertraline remains the most extensively studied serotonergic agent in the treatment of CP. In a randomized, double-blind, placebo-controlled study by Mayo et al[44], involving 12 patients with CP, it was found that sertraline at doses of 75-100 mg daily significantly improved pruritus compared to placebo. Pruritus severity was assessed using a VAS, alongside a clinical assessment that captured distribution, temporal patterns, functional disability, and physical evidence of scratching. The anti-pruritic effect of sertraline was found to be independent from sertraline’s anti-depressant effect. Moreover, sertraline may have sustained long-term benefit, as suggested by a prospective study which followed patients for a mean of 7.5 years[43]. According to American Association for the Study of Liver Diseases Practice Guidelines, sertraline is typically initiated slowly because it is metabolized by the liver, starting at 25 mg daily and titrated by 25 mg every 4-5 days to 75-100 mg daily. Paroxetine and ondansetron have also been studied as anti-pruritic agents. A prospective double-blind, crossover trial compared paroxetine to placebo in reducing pruritus secondary to a variety of conditions found that paroxetine was effective, although only 3 out of 26 participants had CP[46]. While ondansetron was found to be an effective anti-pruritic agent in a placebo-controlled trial, subsequent more rigorous trials did not replicate this benefit[47,48].

Fibrates: Fibrates induce activation of peroxisome proliferator-activated receptors (PPARs) which serve as intracellular transcription factors that can reprogram bile acid synthesis and detoxification pathways. Although fibrates have been widely studied for their use in hyperlipidemia, their impact on liver and bile metabolism provides a plausible mechanistic bridge to improving cholestatic itch. The most pruritus-centric evidence supports the use of bezafibrate. In the Fibrates for Itch in Fibrosing Cholangiopathies double-blind randomized controlled trial, bezafibrate 400 mg daily for 21 days achieved the prespecified endpoint of a ≥ 50% reduction by VAS in 45% vs 11% on placebo (P = 0.003) in patients with PBC, PSC, or secondary sclerosing cholangitis (SSC)[49]. Treatment improved morning and evening scores on both the VAS and 5D-Itch questionnaire and reduced alkaline phosphatase levels, while serum bile acids and autotaxin activity were unchanged and creatinine trended modestly upward[49]. Other studies, including three recent meta-analyses, have confirmed the efficacy of bezafibrate compared to placebo in PBC patients with CP[50-53]. Bezafibrate has generally been well tolerated, with the most frequently reported side effects being myalgia and a transient increase in serum creatinine and aminotransferases. A key implementation constraint is that while bezafibrate is widely used in other countries, it is not currently approved by the United States Food and Drug Administration (FDA), limiting its use in the United States. Fenofibrate is therefore used off label as the fibrate option in United States practice but the evidence for its anti-pruritic effects is largely non-randomized. Retrospective studies have found fenofibrate to reduce pruritus and improve biochemical parameters in patients with refractory CP, although these studies were limited by small sample sizes and lacked a control group[54,55]. A placebo-controlled PSC trial of fenofibrate 200 mg/day for 6 months demonstrated substantial alkaline phosphatase reductions, but symptom-specific outcomes in relation to pruritus was not a core endpoint, limiting inference for CP management[56]. There are multiple ongoing studies examining the efficacy of novel PPAR agonists. The RESPONSE trial showed that seladelpar, a PPAR-δ agonist, achieved a significant biochemical response and reduction in pruritus over placebo in patients with PBC[57]. Based on this study, seladelpar was granted FDA approval in 2024 to treat PBC but its use in other causes of CP may be worth examining. Elafibranor, a dual PPAR α/δ agonist, was found to induce a biochemical response in PBC patients but did not significantly improve pruritus[58]. Other PPAR agents currently being studied in ongoing clinical trials include pemafibrate and saroglitazar[59,60]. The landscape of fibrate use may very well look vastly different in the near future.

UDCA: UDCA is the recommended 1^st-line treatment for CP in cases of intrahepatic cholestasis of pregnancy. Outside of intrahepatic cholestasis of pregnancy, UDCA is not considered to be an effective anti-pruritic agent despite its use in treating hepatobiliary diseases such as PBC and PSC. Mechanistically, UDCA is proposed to improve cholestasis through upregulation of hepatic bile acid transporters and has a cytoprotective effect on hepatocytes and cholangiocytes in the setting of impaired hepatocellular secretion[61]. In the PITCHES multicenter double-blind randomized controlled trial (n = 605), UDCA given at 500 mg twice daily did not improve perinatal outcomes but did modestly improve maternal itch with a -5.7 mm mean difference vs placebo on the 100-mm VAS[62]. However, investigators interpreted this effect as unlikely to be clinically significant, and other meta-analyses including a Cochrane review similarly conclude that while UDCA likely reduces pruritus in intrahepatic cholestasis of pregnancy, the effect size is small and may not provide a clinically meaningful benefit for many patients[62-65].

Ileal bile acid transporter inhibitors: Ileal bile acid transporter (IBAT) inhibitors block the reuptake of bile acids in the ileum, thus interrupting enterohepatic circulation and increasing fecal excretion of bile acids. These novel agents, specifically linerixibat, odevixibat, and maralixibat, are currently undergoing study via numerous clinical trials, the results of which will be summarized below. Linerixibat has shown promise in treating adult PBC patients. The phase 3 GLISTEN trial is a randomized, double-blind, placebo-controlled multi-center study involving 238 PBC patients with moderate-to-severe itch (Worst Itch-NRS ≥ 4) and results demonstrate that linerixibat significantly improved itch compared to placebo over 24 weeks (adjusted mean NRS difference 0.72)[66]. Linerixibat is currently under review for FDA approval for treatment of CP in patients with PBC. Odevixibat and maralixibat have mainly been studied in pediatric genetic cholestatic diseases, such as Alagille syndrome and progressive familial intrahepatic cholestasis. Several phase 3 randomized controlled trials (PEDFIC 1/2, ASSERT) have demonstrated that odevixibat effectively reduces pruritus per caregiver-reported outcome measures while remaining generally well-tolerated[67,68]. Based on these results, odevixibat was approved by the FDA and European Medicines Agency for the treatment of pruritus in patients 3 months of age and older with progressive familial intrahepatic cholestasis and Alagille syndrome. The ICONIC trial studied maralixibat in patients with Alagille syndrome in an 18-week placebo-controlled randomized withdrawal period study and found that switching from maralixibat to placebo caused significant worsening of pruritus while continuing treatment-maintained improvements[69]. Maralixibat has also been studied in other diseases, such as PBC and progressive familial intrahepatic cholestasis, although results have been mixed with regards to its efficacy in reducing pruritus[70-72]. Currently, maralixibat is FDA-approved for treating pruritus in Alagille syndrome. The 2024 guidelines from the European Association for the Study of the Liver (EASL) recommend IBAT inhibitor therapy as the 2^nd-line treatment behind rifampin for CP in patients with Alagille syndrome and progressive familial intrahepatic cholestasis[21]. Long-term safety considerations are largely class-driven as bile acid malabsorption can cause diarrhea and volume depletion. Reduced micellar bile acid availability in the intestinal lumen can worsen fat-soluble vitamin absorption. United States prescribing information for both odevixibat and maralixibat emphasizes diarrhea and dehydration management and monitoring for fat-soluble vitamin deficiency (vitamin A, vitamin D, vitamin E, and vitamin K).

Dermatologic and phototherapy interventions: Ultraviolet B phototherapy has been successfully used to treat pruritus in patients without liver disease, although evidence in CP remains limited but may be relevant in refractory cases[73]. In an observational case series of 13 patients with refractory pruritus due to various cholestatic disorders (PBC, PSC, drug-induced liver injury, and post-transplant cholestasis), ultraviolet B phototherapy reduced median VAS from 8.0 to 2.0 after a mean 26 irradiations over an average of 8 weeks[74]. The study did not observe meaningful changes in cholestatic serum markers, and 4 patients (30%) required an additional phototherapy course for pruritus recurrence[74]. The therapy was well tolerated, except in two patients who developed notable erythema in one case and paresthesia in the other upon retreatment[74]. Topical agents are adjunctive and best suited for localized breakthrough symptoms. For mild localized cholestatic itch, aqueous cream plus 1% menthol is supported as a low-risk cooling strategy[75]. Pramoxine can provide rapid local anesthetic relief in other chronic pruritus settings, but cholestasis-specific trial validation is sparse[76]. Capsaicin has been tested across pruritus conditions, however systematic review-level evidence concluded that convincing benefit is lacking overall[77].

Multidisciplinary and supportive care

CP consistently causes clinically meaningful impairment in health-related quality of life. Multiple studies, including one systematic review, demonstrate that worsening itch severity corresponds to a progressive decline across physical, emotional, and functional outcomes[2,8,18,78]. Providing more granular insight into these specific domains, analyses from the Phase 2b GLIMMER program reveal that greater pruritus severity is associated with increased sleep interference and lower health utility scores[79,80]. This decline is most pronounced among patients experiencing concomitant depressive symptoms, emphasizing the profound interrelationship between itch intensity, sleep disruption, and psychological distress[79,80]. Indeed, patients with pruritic PBC experience significantly higher rates of sleep disorders, depression, and anxiety compared to their non-pruritic counterparts[81].

Collectively, these data strongly advocate for the incorporation of psychiatric and palliative care into the comprehensive management of CP (Figure 4). Unfortunately, critical gaps remain in the current evidence base. There is a notable scarcity of prospective data evaluating how multidisciplinary care impacts quality-of-life outcomes in this population, alongside a complete absence of research focusing on behavioral strategies to minimize itching and mitigate skin damage. These unstudied yet clinically relevant topics provide an opportunity for future research endeavors.

Figure 4  Proposed multidisciplinary model of care.

Treatment algorithm and clinical decision making

Initiation of anti-itch medications for CP should be done in a stepwise manner in order to assess for efficacy of each agent. It is essential to rule out other potential causes of pruritus as well as address the underlying cause of cholestasis, such as starting UDCA for PBC. Baseline severity should be quantified using validated tools like the VAS or NRS to establish a benchmark for frequent monitoring and guide prompt therapeutic escalation if adequate relief is not obtained.

The EASL 2009 guidelines for management of cholestatic liver disease recommend cholestyramine as the first-choice agent, with rifampin, naltrexone, and sertraline as the 2^nd line, 3^rd line, and 4^th line choices, respectively[8]. More recent studies have elucidated newer agents that may provide better itch control in certain patient populations (see Tables 3 and 4). Synthesizing these new findings requires an update of the approach to treating cholestatic itch that is tailored to the underlying cause of cholestasis (Figure 5).

Figure 5 Stepwise management algorithm for cholestatic pruritus. PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; SSC: Secondary sclerosing cholangitis; IBAT: Ileal bile acid transporter; UVB: Ultraviolet B; PFIC: Progressive familial intrahepatic cholestasis; ICP: Intrahepatic cholestasis of pregnancy; UDCA: Ursodeoxycholic acid.

Table 3 Pharmacologic therapies for cholestatic pruritus.

Therapy	Mechanism	Evidence	Key adverse effects
Cholestyramine	Bile acid binding	Low	GI intolerance
Rifampin	PXR induction	Strong	Hepatotoxicity
Naltrexone	Opioid blockade	Moderate	Withdrawal symptoms
Sertraline	Central modulation	Low-moderate	Sexual dysfunction, weight gain
Fibrates	PPAR activator	Strong (recent)	Myalgia, transaminitis
IBAT inhibitors	BA circulation blockade	Strong (recent)	Diarrhea

IBAT: Ileal bile acid transporter; PXR: Pregnane X receptor; PPAR: Peroxisome proliferator-activated receptor; BA: Bile acid; GI: Gastrointestinal.

Table 4 Emerging and advanced therapies.

Therapy	Population studied	Clinical role
Odevixibat	PFIC, ALGS	Refractory pruritus
Maralixibat	ALGS	Pediatric cholestasis
Linerixibat	PBC	Adult cholestasis
Fibrates	PBC, PSC, SSC	Cholestatic pruritus
UVB phototherapy	Mixed etiologies	Adjunctive

UVB: Ultraviolet B; PFIC: Progressive familial intrahepatic cholestasis; ALGS: Alagille syndrome; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; SSC: Secondary sclerosing cholangitis.

For treatment of pruritus in PSC patients, the guidelines from the EASL and the American Association for the Study of Liver Diseases (AASLD) differ slightly. The AASLD 2023 guidelines for PSC-induced pruritus recommend using cholestyramine as a 1^st line agent, with sertraline, rifampin, and naltrexone serving as 2^nd line options[20]. The EASL 2022 guidelines recommend bezafibrate as the 1^st-line for moderate-to-severe pruritus in PSC and other fibrosing cholangiopathies, with rifampin and naltrexone as 2^nd line and 3^rd line agents, respectively[82]. The EASL did not recommend cholestyramine due to lack of evidence regarding its efficacy. For treatment of pruritus in PBC patients, the EASL 2017 and AASLD 2018 guidelines both recommended bile sequestrants as the 1^st line agent, citing its favorable safety profile while acknowledging the limited evidence base[14,18]. Rifampin, opioid antagonists, and serotonin modulators were recommended as 2^nd, 3^rd, and 4^th line agents respectively[14,18]. Notably, both PBC guidelines were written before the landmark Fibrates for Itch in Fibrosing Cholangiopathies trial, which showed that bezafibrate could effectively treat cholestatic itch in PBC, PSC, and SSC[49].

Taken together, it is our opinion that while cholestyramine may be an appropriate choice in mild pruritus, it is not an appropriate first choice for treating moderate-to-severe pruritus in patients with PBC, PSC, and SSC, and may only serve to delay treatment. Bezafibrate is the first-choice agent if available, and rifampin is another viable first-line options if bezafibrate is unavailable, such as in the United States. If an inadequate response is observed with bezafibrate or rifampin, naltrexone and sertraline are the choice 2^nd and 3^rd line options for moderate-to-severe pruritus, respectively. If only partial relief is observed with a single agent, it may be reasonable to combine several agents to achieve greater symptom relief. However, combining agents should be done with the utmost caution due to the potential for drug-drug interaction and polypharmacy.

If pruritus remains refractory to these measures, there are newer therapies that can be considered. Maralixibat and odevixibat are approved to treat pruritus in Alagille syndrome and they may be used off-label to treat other causes of CP although this would be a costly option. Fenofibrate can be used as an off-label treatment in the United States, although data supporting its usage is not placebo-controlled[54,55]. Dermatologic approaches, such as ultraviolet B phototherapy, can be considered as well. In using experimental agents, shared decision-making with the patient is critical, so they understand the relative paucity of data and potential costs of using off-label medications.

The treatment algorithm will change for other causes of cholestasis (Figure 5). As mentioned in previous sections, IBAT inhibitors are considered the 2^nd line agents behind rifampin for treating pruritus due to Alagille syndrome and progressive familial intrahepatic cholestasis[21]. In intrahepatic cholestasis of pregnancy, UDCA is the 1^st line option for relieving pruritus, with rifampin serving as the 2^nd line agent in cases of refractory pruritus[83,84].

Finally, it is important to involve a multidisciplinary approach from the start. Given the potentially profound impact that pruritus can have on quality of life, it is important to screen for mood and sleep disturbance in all patients and consider the need for psychotherapy interventions. Specific psychological interventions, such as relaxation techniques and habit-reversal training, may also be useful in cases of addictive or stress-related itching[85,86]. Additionally, counseling on skin care to prevent potential dermatologic complications from arising is prudent. General measures include using skin emollients, shortening nails, avoiding hot baths and showers, applying cooling gel, and using antihistamines to eliminate a potential additive allergen[14,87].

DISCUSSION

Pruritus remains one of the most challenging complications of cholestatic liver disease, severely impairing patients' quality of life while notoriously resisting clinical management. Although numerous therapeutic options exist, the symptom is persistently undertreated due to a lack of robust efficacy data supporting current interventions. The development of a definitive, targeted treatment is limited by our incomplete understanding of the pathogenetic mechanisms driving cholestatic itch.

Recent guidelines, such as the EASL 2009 guidelines for management of cholestatic liver diseases and the AASLD guidelines for management of PBC and PSC as described earlier, continue to recommend cholestyramine as the first-line choice for CP. This appears to largely be driven by its long history of clinical use, favorable safety profile, and low cost. A meta-analysis by Tandon et al[26] highlighted this striking evidentiary gap, identifying only two randomized, placebo-controlled crossover studies supporting its use, both of which were conducted in the 1980s and included ten or fewer patients. There is a critical need for modern, well-designed, placebo-controlled trials to definitively establish cholestyramine’s efficacy. Without such data, clinicians risk prolonging patient suffering by wasting valuable time on an unproven medication before escalating to more effective alternative therapies

The development of IBAT inhibitors and PPAR agonists offers promising avenues for managing refractory CP. While IBAT inhibitors have thus far been restricted to pediatric genetic cholestasis, linerixibat is currently under FDA review for use in adults with PBC, which could expand its clinical application. In Europe, robust efficacy data have already propelled bezafibrate to replace cholestyramine as the first-line agent. Although bezafibrate remains unapproved by the FDA for use in the United States, further studies investigating the use of fenofibrate in cholestatic itch could be both practical and beneficial, as it is already readily available in the United States. Meanwhile, novel PPAR agonists like seladelpar are advancing through clinical trials. Although these emerging therapies are promising, their higher costs will likely introduce significant financial barriers to patient access.

Ultimately, significant knowledge gaps exist in the comprehensive management of CP. Future research should prioritize elucidating the precise pathogenetic mechanisms of itch, as this could lead to discovering novel therapeutic targets and establishing reliable diagnostic and prognostic biomarkers. For example, a study comparing the liver transcriptomes and proteomes of CP patients to those with non-pruritic cholestasis could elucidate new proteins specific to the pathogenesis of cholestatic itch. Concurrently, clinical studies must evaluate the efficacy of multidisciplinary support systems. Specifically, the potential benefits of integrating psychotherapy, behavioral modification, and palliative care for patients with refractory itch remain largely unexplored and warrant robust investigation.

CONCLUSION

In summary, the treatment of CP should involve a personalized approach, involving the sequential use of medications, frequent monitoring of effect using subjective and objective methods, and potential collaboration with a multidisciplinary team. There exists a significant lack of evidence around the efficacy of many of the current treatment options. While new treatments, such as fibrates and IBATs are promising, more research about pathogenesis of cholestatic itch is needed to discover targeted therapeutics.