Cholestatic pruritus refers to the sensation of itch experienced by patients with disease processes impairing bile flow. This article aims to illustrate the burden of cholestatic pruritus, review the proposed mechanisms, and summarize its available and emerging therapies.
Recent Findings
Pruritus is experienced by many patients with cholestatic liver diseases. It is underdiagnosed and negatively impacts patients’ quality of life. Its direct cause remains unclear though multiple pathways have been explored. Current therapies are insufficient but newly approved ileal bile acid transporter (IBAT) inhibitors and emerging peroxisome proliferator-activated receptor (PPAR) agonists are promising.
Summary
Cholestatic pruritus affects many patients with cholestatic liver diseases and can be debilitating. In moderate to severe cases, current guidelines provide treatment options that are ineffective. Emerging agents such as IBAT inhibitors and PPAR agonists should be considered, including referral to clinical trials. Further exploration into the pathophysiology and effective therapeutic agents is needed.
Hinweise
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Introduction
Cholestasis is defined as the reduction of bile flow through intrahepatic canaliculi due to the gradual destruction of epithelial cells or through obstruction of the large ducts of the biliary tree. One of the consequences of chronic cholestasis is the sensation of itch, also referred to as pruritus. The pruritus experienced can be severe, leading to skin excoriations, sleep deprivation, fatigue, depression, inability to work, and in severe situations suicidal ideation. In fact, at some liver transplant centers, untreatable pruritus itself can be an indication for liver transplantation [1].
Pruritus has a known association with cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) where review articles find an incidence in 20–70% and 38% of patients affected by the respective diseases [2, 3]. In the TARGET-PBC study, a large-scale longitudinal observational study of 211 patients, pruritus was seen in 81% of the patients [4]. There are also genetic disorders of cholestasis including Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC), and benign recurrent intrahepatic cholestasis (BRIC) that are associated with pruritus. In Alagille syndrome, up to 88% of patients experience pruritus, with 45% reporting severe pruritus [5]. With PFIC, up to 76–80% of patients experience severe pruritus [6]. In BRIC, there are no official estimates of pruritus prevalence, but most patients experience sporadic and recurrent episodes of pruritus. In addition to assessing treatments of pruritus, the TARGET-PBC study also quantified pruritus with three patient-reported outcome (PRO) questioners (PBC-40, 5-D Itch, and PROMIS fatigue). Of the patients studied, 30% reported a PBC-40 itch score greater than 7, indicating their itching caused a combination of fatigue, cognitive impairment, impact to socialize, sleep disturbance, or emotional distress. Patients that completed the PROMIS fatigue questionnaire had a median score of four which is characterized as “worn out, so tired I had to force myself to do things I needed to do, if I was busy one day, I needed at least another day to recover, and I had to pace myself for day-to-day things.” This study and many others show that cholestatic pruritus is a major detriment to the quality of life in these patients [4].
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While a highly prevalent symptom, mechanistic understanding of what specifically causes pruritus in cholestatic liver diseases and effective treatment options are both limited. This has led to patients not having adequate symptom control and has negatively impacted their quality of lives, emotional status, and productivity. In the TARGET-PBC study, only 52% of patients with pruritus received any treatment for itching and a majority did not feel that their itching was adequately treated. This data and others indicate that medical providers may not be diagnosing pruritus and assessing its severity effectively in the affected patients, delaying any potential therapies [7].
This review aims to elucidate the various proposed mechanisms of cholestatic pruritus and examine its available and emerging treatments.
Mechanisms of Cholestatic Pruritus
The pathophysiology of cholestatic pruritus is complex. Many potential mechanisms have been studied but no definitive singular etiology has been discovered. Some of these include bile acids, lysophosphatidic acid (LPA), endogenous opioids, serotonin, Mas-related G protein-coupled receptor X4 (MRGPRX4), and autotaxin/LPA [8]. Below, we explore the pathophysiology of each of these candidates.
Bile Acids
Bile acids have long been suspected to cause pruritus [9]. The pathway starts at the hepatocellular level where cholesterol can become bile acid intermediates through the classical pathway or alternative pathway. The classical pathway is regulated by the rate-liming enzyme CYP7A1 and the alternative pathway is regulated by the enzyme CYP27A1. Interestingly, there is evidence that the CYP27A1 pathway is upregulated in chronic cholestatic liver diseases [10]. These bile acid intermediates are then acted on by the enzyme CYP8B1 and converted into cholic acid and chenodeoxycholic acid. These acids are then secreted into the intestines where bacterial flora convert them into deoxycholic and lithocholic acids. These two secondary bile acids are then reabsorbed in the distal ileum and transported back to the liver. Approximately 5% of the secondary bile acids are excreted as waste.
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As with any enzymatic process, the body also has a way to regulate the production of bile acids. In the liver, this is done by the nuclear receptor living receptor homolog (LRH-1). LRH-1 is an inhibitor of CYP7A1. As bile acids are made, they bind to the farnesoid X receptor (FXR) which stimulates Small Heterodimer Partner (SHP), a regulatory nucleotide receptor. SHP activation stimulates LRH-1 which then blocks the initial step of bile acid synthesis. In addition to FXR, peroxisome proliferator-activated receptor (PPAR) is another receptor that inhibits bile acid production and is being explored as a target to treat cholestatic pruritus. With disease processes that cause excess bile production, it is possible that this inhibitory pathway is avoided by the upregulation of the alternate pathway (CYP27A1) resulting in excess bile acids [11].
The next step is understanding why excess bile acids can cause pruritus. The initial hypothesis was that excess bile acids deposit in tissues causing pruritus [12]. This was supported by a study done in an animal model in 2013 where mice were found to have significant itching after bile acids were injected into their skin. This was suspected to be caused by activation of transmembrane G-protein coupled receptor 5 (TGR5) (itch-encoding sensory neuron receptor) since mice that had the TGR5 receptor knocked out did not have the same level of itching [13]. Other observations that supported bile acid-associated pruritus were that it is often a precursor to liver failure, ceases after liver transplantation, and ceases after mechanical obstruction of the bile ducts resolved [12]. These are disease states in which excess bile acids are circulating in serum and potentially depositing in tissues. However, it is worth noting that the elevation of bile acids is not specific to conditions of cholestasis and the degree of elevation does not correlate to the degree of itching [14]. Nevertheless, bile acids are believed to be one of the main drivers of cholestatic pruritus.
Interleukin-31 (IL-31)
Following the theory that bile acids induce pruritus, it is important to mention how the stimulation of FXR by excess bile acids could be implicated with pruritus. Recently, it has been discovered that stimulation of FXR can increase levels of T-cell-derived cytokine interleukin-31 (IL-31) [15]. IL-31 is an interleukin that is known to be involved in pruritus, skin inflammation, and hypersensitivity by directly stimulating the sensory neurons leading to the epidermis, causing pruritus [16]. In conditions that result in excess bile acids, such as cholestasis seen in PSC and PBC, FXR can be overstimulated leading to overproduction of IL-31. In a study by Xu et al., patients with metabolic-associated steatohepatitis (MASH), PSC, and PBC were given the study medication cilofexor (nonsteroidal FXR agonist), which is known to increase IL-31. Patients who were given higher doses of cilofexor had higher levels of IL-31 and consequently increased pruritus [15]. Based on these results, it is thought that the serum level of IL-31 correlates with increased pruritus in patients with PSC, PBC, and MASH, and it could be a main driver of this symptom.
Lysophosphatidic Acid (LPA)
As seen with IL-31, many other interleukins also play a role in pruritus. LPA is a phospholipid that is involved in a multitude of physiologic and pathologic processes that lead to pruritogenic interleukin production. LPA is involved in central nervous system (CNS) development, CNS angiogenesis, neuropathic pain, neurodegenerative diseases, and cancer pathogenesis and recently has been found to be a mediator of pruritus in a cholestatic setting. This molecule is mostly made intracellularly for cell membrane synthesis and acts on various G-protein coupled receptors. However, it does also have one extracellular synthesis pathway. In this pathway, phospholipids on cell membranes are converted into LPA by an enzyme called autotaxin (ATX) [17]. This extracellular pathway is thought to be heavily involved in pruritus.
There is still no consensus on how LPA causes pruritus. However, there are a few different proposed pathways and multiple studies that strongly support the importance of LPA in pruritus. For one, a study done in pregnant patients with intrahepatic cholestasis of pregnancy (ICP) found an elevated level of LPA in patients with ICP compared to pregnant patients who did not [18]. Another study also found that mice that were injected with LPA experienced significantly more itching than mice that were not injected with LPA [19].
One proposed mechanism for extracellular LPA-induced pruritus is that extracellular LPA activates the LPA5 receptor on cell membranes. This causes a series of reactions through intracellular phospholipase D (PLD) and calcium-independent phospholipase A2 (iPLA2) that activate intracellular LPA. The phosphorylation of intracellular LPA then activates gated ion channels, transient receptor potential cation channel A1 (TRPA1), and transient receptor potential cation channel subfamily V1 (TRPV1). These two gated channels, once activated, will pull in extracellular Na and Ca2+ ions that will cause an intracellular surge of ionized Ca2+ which will potentiate an action potential [17, 19].
It should be noted that TRPV1 is found in cutaneous neurons and dendritic cells [20]. TRPA1 is found in peripheral sensory neurons and is known to sense pain, cold, itch, and environmental irritants [21]. In addition to the action potential generation, TRPV1 receptor activation is known to increase the production of IL-23 and IL-17 which are interleukins known to cause epidermis irritation in a variety of dermatologic diseases [22]. The TRPV1 receptor also can potentiate autophagy through the Ca2+ signaling pathway [23]. Given the known biochemical involvement of TRPV1 and TRPA1 in pruritic pathways and LPA elevation in cholestasis, it is likely LPA is involved in cholestatic pruritus through the mechanism discussed above.
Autotaxin (ATX)
As discussed above, ATX is a key rate-limiting enzyme in the production of LPA. Given this relation, many studies have investigated ATX as a target for the treatment of pruritus in cholestasis. In fact, one agent, rifampin decreases levels of ATX resulting in improved pruritus. Since ATX activates the production of LPA, decreasing ATX levels could decrease LPA and eventually decrease pruritus [24]. In fact, in this same study that evaluates rifampin, it was seen that ATX was only elevated in pruritus associated with cholestasis and no other origins of pruritus. Other studies have shown that in patients who receive albumin dialysis, the degree of pruritus decreased significantly. This was thought to be a result of albumin dialysis decreasing levels of ATX. Interestingly, albumin dialysis does not reduce the level of bile salts, so it is possible the ATX / LPA pathway is a more prominent etiology for pruritus in cholestasis [25]. The level of ATX has also been shown to correlate with the intensity of pruritus, making it a prime target for pharmaceutical therapies [26].
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In the discussion of ATX, it is also important to include the role of the pregnane X receptor (PXR). While the exact pathway is not known, PXR is known to decrease ATX expression in hepatocytes. In one study, it was shown that rifampin, a known PXR agonist, only worked to decrease ATX in cells that expressed PXR. This means that PXR is somehow involved in the transcription of ATX. It was also shown that decreased ATX correlated with decreased itching [24].
Endogenous Opioids
The endogenous opioid receptor pathway is also thought to potentiate cholestatic pruritus. This is thought to be secondary to increased opioid peptide circulation in the plasma of patients with cholestasis secondary to liver disease. One of the earliest studies that hinted at this relation is from 1993 where plasma extract from patients with elevated endogenous opioid levels was injected into the dorsal roots of monkeys. This resulted in increased itching in monkeys [27]. Based on this study, opioid receptor antagonists such as naloxone and naltrexone have been evaluated and are being used to treat pruritus [27‐30]. Given the evidence that endogenous opioids are a component of cholestatic itch, it is important to discuss the mechanism by which this occurs.
Enkephalins and endorphins are two main endogenous opioids that are the target of opioid antagonists in the treatment of pruritus. These are derived from the genes pre-proenkephalin A (PPE) or proopiomelanocortin (POMC) that are found primarily in pituitary tissue. POMC once transcribed and translated produces the proteins adrenocorticotropic hormone (ACTH) and beta-lipotropic hormone (B-LPH) which are then further processed into corticotropin-like intermediate peptide (CLIP), melanocyte-stimulating hormone (MSH), and B-endorphins [31]. PPE is primarily found in the pituitary tissue but also is found in the GI tract, cardiovascular system, and placenta [32]. PPE is transcribed and translated into enkephalin, which can make its way into the epithelial tissue [33]. These endogenous opioids then travel to mu-opioid receptors (MOR) and kappa-opioid receptors (KOR) to act on the itch pathway. It is currently theorized that the overactivation of MOR or deactivation of KOR can result in increased itching [34]. While this is the prevalent model, there is also evidence that this may not be the correct pathway. In a small cross-sectional study, the levels of endogenous opioids such as B-endorphins, dynorphin A, and leu- and met-enkephalin were taken and quantified through enzyme-linked immunosorbent assay (ELISA). No relation was found between endorphin levels and pruritus. Given these results, it was postulated that these endogenous opioids and receptors could be modulators and not the pruritogenic agents themselves [35].
While the role of endogenous opioids and the MO to KOR ratio in pruritus continues to be debated, it is undeniable that the opioid pathway is involved in pruritus. Therefore, it remains a viable target in the treatment of cholestatic pruritus.
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Serotonin (5-Hydroxytryptamine (5-HT))
Serotonin is a monoamine neurotransmitter. It also acts as a hormone and has been proposed as an agent involved in cholestatic pruritus. Serotonin is a molecule that is synthesized from tryptophan and produced in the brain. It then binds to various receptors in the body including serotonin receptors and other receptors like TRPV4. As discussed above, TRPV4 is a receptor that stimulates itch. This interaction is the main hypothesis for how serotonin stimulates cholestatic pruritus [36].
Serotonin also binds to a variety of other receptors in the body, including the serotonin receptor. Interestingly, randomized control trials looking at the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin receptor antagonists in the treatment of cholestatic pruritus found that only SSRIs were helpful in relieving pruritus. Agents like ondansetron that are serotonin receptor antagonists did not help improve pruritus, while agents like sertraline did show a modest improvement in pruritus [37, 38].
Given this pool of evidence, serotonin is definitely a component of cholestatic pruritus, but more exploration into its mechanism of action is needed.
Mas-Related G-Protein Coupled Receptor Member X4 (MRGPRX4)
One of the most recent advances in cholestatic pruritus has been the discovery of the MRGPRX4 receptor. This is a receptor found in small sensory neurons in the skin. It is thought to be activated by bile acids and heme-metabolites that deposit in the skin. This activation potentiates sensory neuron signals to the brain that indicate focal irritation that in turn stimulates pruritus [39].
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As this is a relatively recent discovery, the evidence supporting MRGPRX4’s involvement in cholestatic pruritus of humans is not robust. However, in numerous mouse models, it was found that upregulation of this receptor increased itching [39]. Furthermore, studies have shown that increased pruritus is associated with epithelial bilirubin levels and not plasma bilirubin levels [40]. Given that evidence, it is likely that MRGPRX4 is involved in the cholestatic pruritus and is also a potential target in cholestatic pruritus.
Cholestatic pruritus is a disease with a complex pathophysiology with several proposed pathways. While many pathways exist, including the bile acid synthesis pathway, IL-31, LPA, autotaxin, opioid, serotonin, and MRGPRX4, no one pathway alone can explain pruritus. It is likely a complex and multifactorial process with a dynamic interplay between each of these proposed pathways and other undiscovered mechanisms.
Therapies
Given the multitude of proposed pathways for cholestatic pruritus, there are numerous therapeutic agents that are being used to treat pruritus, but with very limited success. Given the impact of pruritus on quality of life, finding an effective agent to control this symptom is an active area of research with a number of clinical trials evaluating novel agents. Below, we will discuss evidence behind the various available treatment options for cholestatic pruritus and review emerging therapies.
Bile Acid Resins
Bile acid resins are the first-line therapy often used for patients experiencing cholestatic pruritus per the American Association for the Study of Liver Disease’s (AASLD) PSC and PBC management guidelines [41]. This class of medications works by binding bile acids which creates an insoluble compound that cannot be reabsorbed in the ileum and is excreted as waste with feces. This decreases the buildup of serum bile acids, preventing excess bile acids from translocating to the skin which theoretically decreases activation of TGR5, preventing skin irritation and pruritus [42].
Cholestyramine is a bile acid resin that is commonly used to treat pruritus due to the availability of evidence on its efficacy from randomized control trials. Two large, randomized control trials (RTC) were done in 1984 that evaluated cholestyramine at doses of 4 g twice a day and 3 g three times a day. Both of these trials found that pruritus was significantly decreased compared to the placebo based on cumulative pruritus scores. Based on these findings, cholestyramine has been used since and is currently the first-line therapy [43, 44].
However, since the publication of these two large RCTs, a different RCT was published in 2010 that examined the use of colesevelam on cholestatic pruritus. This study found that colesevelam decreased serum bile acid levels but did not actually demonstrate a reduction in pruritus among the 38 participants. Both the placebo group (36%) and the treatment group (35%) had similar percentages of participants reaching the primary endpoint of a 40% reduction in visual analogue scale score [45]. It should also be noted that cholestyramine is often not well tolerated due to its side effects of constipation and bloating. Furthermore, if not taken correctly, it can decrease the absorption of other medications, which limits its usability.
Rifampin
Rifampin is one alternative therapy for pruritus refractory to cholestyramine and other agents. While initially used as a medication for tuberculosis, it has also been discovered to decrease pruritus. The mechanism is thought to be secondary to rifampin’s interaction with PXR. By activating PXR, there is a reciprocal decrease of ATX in hepatocytes. This means there is decreased production of LPA and decreased activation of calcium channels (TRPA1 and TRPV1) leading to decreased axon stimulation and decreased pruritus [46].
Rifampin has multiple studies that support its use for cholestatic pruritus. The first study that supported rifampin was in 1988 and consisted of only 9 patients with PBC who were treated with varying doses. Rifampin was also administered with cholestyramine in this study and 8 out of 9 patients reported preferring rifampin use for pruritus control as opposed to the placebo. After this initial evidence, two other trials were done in 1991 and 1992 that showed a significant decrease in pruritus with rifampin. Most recently, in 2006, a meta-analysis was done of the 5 randomized clinical trials that tested rifampin and found that 77% of patients using rifampin reported a decrease in symptoms [47‐52]. Given these findings, rifampin has been shown to decrease pruritus in patients with cholestatic pruritus and is an appropriate agent for treatment.
It is important to note that rifampin can be hepatotoxic in some patients. Based on current studies, it carries an incidence of 7.3% and can cause a 10–20% increase in serum aminotransferance levels [53, 54]. As a result, it is important to monitor patients for drug-induced hepatitis while they are on this medication. It is also recommended to start patients at a dose of 150 mg/day and slowly increase the dose every 2 weeks if the hepatic panel at that time interval has not worsened.
Naltrexone (Mu-Opioid Receptor Antagonist)
Naltrexone is another alternative option in the treatment of cholestatic pruritus. It works by blocking the mu-opioid receptor. An increase in mu-opioid receptor activation is thought to worsen pruritus, so a decrease would likely help alleviate pruritus. Naltrexone also blocks the kappa-opioid receptor but to a much lesser extent. Since pruritus is purported to be a result of the ratio of MOR being elevated compared to KOR, by lowering the ratio pruritus is improved [55].
The earliest study that supported the use of naltrexone was in 1988 and examined the use of naltrexone in a group of 11 patients with PBC that noted improvement in pruritus, fatigue, and also plasma bilirubin. After this study, there were three additional clinical trials done in the 1990s that showed naltrexone improved pruritus in patients with cholestasis, further supporting its use. Naltrexone also has the most recent controlled clinical trial done out of the first three agents used for pruritus, with a study done in 2006 that showed significant improvement in pruritus. However, this study also showed that naltrexone was associated with increased side effects of withdrawal reaction, gastrointestinal distress, and insomnia, which were self-limited. Given these findings, naltrexone is an appropriate therapy to reduce cholestatic pruritus but it is important to keep in mind the side effects from its usage [28, 56‐59].
PPAR agonists are a newer drug class being evaluated to treat PBC and shown to also improve pruritus and patients’ quality of lives based on emerging evidence. Over the past decade, there have been multiple new agents in this class that have been introduced and others currently in clinical trials that show promising results. PPAR has multiple subtypes. These include PPAR-alpha, which is found in multiple tissues including skeletal muscles and liver and is involved in bile acid metabolism. PPAR-gamma is found in adipose and colonic tissue and is involved in increasing fatty acid storage and PPAR-delta is ubiquitously expressed and is involved in increased fatty acid oxidation. The FXR gene is known to produce more PPAR-alpha which results in more secretion of bile acids from the liver and stimulates bile acid detoxification through the CYP3A4 pathway. In a mouse model, it was found that the direct injection of PPAR-alpha into mouse tissue caused decreased bile acid synthesis as well [60].
Medications included in this class are bezafibrate (PPAR-alpha, delta, gamma agonist), fenofibrate (PPAR-alpha agonist), elafibranor (PPAR-alpha and delta agonist), and seladelpar (PPAR-delta) which are been evaluated in the treatment of PBC. This class has been shown to be anti-fibrotic and anti-inflammatory and also has anti-cholestatic benefits.
Bezafibrate, a fibrate which is not available in the USA, but is a second-line treatment agent recommended by the European Association for Study of Liver Disease (EASL) for cholestatic pruritus in Europe following cholestyramine. It works by pan-activating PPARs and is shown to normalize alkaline phosphatase (ALP) in 67% of patients with PBC with incomplete biochemical response or intolerant to UDCA in a phase 3 clinical trial in Europe, the BEZURSO study. It also showed improvements in pruritus, fatigue, and liver stiffness but no significant difference in quality-of-life scores [61]. It has also been examined as a treatment for cholestatic pruritus. Recently, the FITCH trial, a double-blind placebo-controlled trial, showed evidence in support for bezafibrate for the treatment of pruritus. The trial found that patients with PSC and PBC with moderate to severe itching had reduced morning and evening intensity of pruritus and improved 5D-itch scores with the use of bezafibrate compared to placebo [62]. Fibrates as a class are known to cause transient mild transaminitis in some cases, mild rise in creatinine, and risk of rhabdomyolysis. However, these side effects are not common and caution should be exercised in those patients with chronic kidney disease (CKD) [63]. There is also emerging data on the anticholestatic and antipruritic benefit for fenofibrates (PPAR-alpha), available in the USA, in patients with PBC. A recent meta-analysis found significant decreases in ALP, gamma-glutamyl transferase (GGT), and pruritus in patients with PBC [64].
Elafibranor acts on both PPAR-alpha and gamma as an agonist. It has a phase 2 clinical trial in PBC patients who have failed ursodeoxycholic acid (UDCA) therapy. The study has found that patients had decreased pruritus over a 12-week period of using the medication [65]. In addition to the phase 2 study, recently, the ELATIVE phase 3 trial, a year-long double-blinded placebo-controlled trial looked at 161 patients and found that elafibranor normalized ALP in 15% of patients compared to 0% in the placebo group at 52 weeks. Elafibranor did show reductions in pruritus at week 52 in PBC-40 Itch and 5D itch scales that were statistically significant (p = 0.0070 and 0.0199, respectively) However, with the WI NRS there was no significant improvement [66].
Seladelpar, a selective PPAR-delta agonist, is another agent in investigation for the management of PBC and cholestatic pruritus. Recent data from phase 2 and phase 3 clinical trials support its efficacy in PBC. Seladelpar works by activating the PPAR-delta pathway. This causes a decrease in CYP7A1. As mentioned above, CYP7A1 is involved in bile acid synthesis. By decreasing the level of CYP7A1, bile acid synthesis is decreased, leading to less bile acid deposit in tissues and circulating in serum, resulting in decreased pruritus [67].
The first trial for Seladelpar was a double-blind, randomized control phase 2, proof of concept clinical trial. This study was done in 2017 and conducted over a 12-week period using various doses of the medication. In this study, no significant decrease in pruritus was observed [68]. In 2022, a second phase 2 randomized control study was done that looked at patients over a 52-week-period and found a decrease in pruritus at 5 and 10 mg doses of the medication [69]. Over this past year, there have also been two phase 3 studies that have been published with encouraging data. The ENHANCE trial, a phase 3, double-blind, randomized, and placebo-controlled study that evaluated 240 patients over 1 year showed a 30% improvement in ALP and pruritus with a dose of 10 mg [70]. In another phase 3 trial, the RESPONSE study, a placebo-controlled trial, found that patients treated with seladelpar had a decrease of the numerical rating scale (NRS) for pruritus of 3.2 compared to only 1.7 for the placebo group (p < 0.005) [71].
Based on this data, in addition to effective treatments for PBC, seladelpar and elafibranor may add a viable pharmaceutical option to treat pruritus in patients with PBC.
Ileal Bile Acid Transporter (IBAT) Inhibitors
Over the past decade, new targets of cholestatic pruritus have been explored. One of these new targets is the ileal bile acid transporter inhibitors. As discussed above, the main mechanism of bile acid synthesis includes the transportation of bile acid intermediates into the small bowel, where they are converted into bile acids by gut flora. They are then reabsorbed into the bloodstream through ileal transporters and sent back into the hepatobiliary system [72].
Therefore, one of the newer approaches has been to target the source of re-uptake at the ileum itself. Currently, there are four drugs approved or being studied, maralixibat, odevixibat, linerixibat, and volixibat. Maralixibat has multiple randomized control trials in progress, including a phase 2 study for pruritus in PBC. It has also received first approval recently for use in cholestatic pruritus in patients with PFIC and Alagille syndrome [73].
Odevixibat has also shown evidence as a promising agent in the treatment of cholestatic pruritus. In a phase 3 clinical trial for patients with PFIC and Alagille syndrome, published in 2022, over half the patient population reported a decrease in pruritus. However, this trial also found that many patients suffered side effects of frequent diarrhea and bowel movements [74]. Currently, it has been approved for patients older than 12 months with Alagille syndrome.
Linerixibat has one ongoing investigation assessing its efficacy for cholestatic pruritus in patients with PBC. The GLISTEN study is currently in phase 3, with published data from its phase 2 study (GLIMMER) that showed doses of linerixibat at 40 mg, 90 mg, and 180 mg daily significantly decreased itch over the 12-week treatment period from patients with moderate to severe itching (NRS > 4/10) in all quality-of-life domains in the PBC-40 questionnaire [75].
Volixibat is another agent that is currently under investigation to treat pruritus associated with PSC and PBC. It is currently in phase 2 randomized double-blind placebo-controlled studies, called VANTAGE for PBC and VISTAS for PSC which are actively enrolling patients [76].
The IBAT class represents a recent advance in treatment and likely has a promising future as a therapeutic option in a wider range of patients with cholestatic itch and could improve quality of life.
IL-31 As a Targeted Pathway
In the recent discovery of the IL-31 and FXR pathway, coupled with the 2023 study by Xu et al., IL-31 presents a promising new target for new pharmaceutical interventions for cholestatic pruritus. Currently, there are medications developed for atopic dermatitis and psoriasis that target the IL-31 pathway [77]. It is possible that future studies explore the use of these medications in patients with cholestatic pruritus. Another interesting discovery published in June of 2023 in the phase 3 ENCHANCE trail showed that seladelpar, a PPAR-agonist, decreased serum IL-31 levels and decreased pruritus [78]. Given the purported link between PPAR and FXR, it is possible that seladelpar is dampening the stimulation of FXR, causing decreased production of IL-31 and consequently decreasing pruritus. Given these recent discoveries, the IL-31 pathway presents an exciting opportunity for future targeted therapies.
Other Approaches
While these pharmacologic approaches to cholestatic pruritus are available, there are other approaches to consider as well, such as topical over-the-counter agent and for refractory cases, plasmaphoresis, molecular adsorbent recirculating system (MARS), and transplant. Topical emollients have long been used to help with pruritus. Regular application with emollients that contain 1–2% menthol is currently recommended as a general approach to pruritus [79]. Another approach is plasmapheresis, which involves the removal of pruritogens from plasma that can improve symptoms in severe cases. Currently, this approach has few case reports in pregnant patients with cholestatic pruritus [80]. Another approach is the molecular adsorbent recirculating system (MARS), where albumin dialysis is done to remove pruritogenic molecules that are bound to albumin. This therapy functions in a similar fashion to plasmaphoresis and has limited data. Finally, in severe cases, a liver transplantation can be done if there is access to a liver transplant and has shown to be highly effective in patients with refractory disease [81].
Conclusion
Cholestatic pruritus is a complicated disease process that continues to be undertreated and underrecognized. In diseases like PBC, PSC, obstructive cholangiopathies, and genetic conditions that cause cholestasis, a majority of patients suffer from this condition. Currently, guideline-directed therapies by the AASLD and EASL underscore the limited treatment options. Both societies recommend starting with cholestyramine, a medication that can be effective but has a high burden of side effects. As a step-wise approach after cholestyramine, rifampin and naltrexone are the next recommendations, and in Europe, bezafibrate can also be used as a second line. As a result, pruritus is a symptom that seldom has complete symptomatic control in most patients. There are many new promising drug classes and agents in clinical trials, including PPAR agonists and iBAT inhibitors, summarized in Table 1. We suggest a step-wise approach in treating cholestatic pruritus as seen in Fig. 1 that takes into account previous AASLD and EASL guidelines with the addition of access to emerging therapies. With these promising agents, we hope that cholestatic pruritus may be a condition that can be adequately treated in the future.
Table 1
A summary of emerging therapies for management of cholestatic pruritus
Emerging therapies for management of cholestatic pruritus
Drug class
Drug
Study published year
Clinical trial phase
Disease studied
Author
Summary
IBAT- inhibitors
Maralixibat
(FDA Approval for Alagille syndrome, PFIC, and biliary atresia)
2021
Phase 2
ICONIC
Alagille syndrome
Gonzales E. et al.
ICONIC trial: RCT phase 2 study: showed participants who took maralixibat showed a sustained decrease in sBA by 50% compared to patients who discontinued and went back to placebo
Odevixibat
(FDA Approval for Alagille syndrome, PFIC, and biliary atresia)
2022
Phase 3
PFIC
Thompson R. et al.
In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated
2021
Phase 2
Alagille syndrome
Baumann U et al.
Orally administered odevixibat was well tolerated, reduced serum bile acids, and improved pruritus and sleep disturbance in children with cholestatic diseases
Linerixibat
2023
Phase 2b
GLIMMER
PBC
Levy C et al.
Post hoc analysis of change from baseline in monthly itch score over the treatment period (phase 3 endpoint) showed significant differences between placebo and linerixibat 180 mg once daily (p = .0424), 40 mg twice daily (p = .0105), and 90 mg twice daily (p = .0370)
Volixibat
2023
Phase 2
PSC (VISTA study)
PBC (VANTAGE study)
Mirum Pharmaceutical
Currently enrolling
IBAT inhibitor A4250
2018
Phase 1
PBC
Al-Dury S et al.
IBAT studied in 10 patients. Experienced side effects of abdominal pain and diarrhea. But pruritus did improve
Fibrate
Bezafibrate
2021
Phase 2
(FITCH)
PSC
PBC
SSC
Elsemieke V. et al.
In 74 studied patients, bezafibrate led to > 50% decrease in pruritus in 45% of patients on the medication vs 11% in the placebo group
35% reduction in ALP vs placebo
Serum bile acid and ATX unchanged
2018
Phase 3
(BEZURO)
PBC
Corpechot C. et al.
Complete biochemical response (normalization of bilirubin, ALT, aminotransferases, and albumin) occurred in 31% of patients with bezafibrate vs 0% in placebo
Patients treated with bezafibrate also had decreased pruritus
67% achieved normalization of ALP with bezafibrate
PPAR-agonists
Seladelpar
2023
Phase 3
RESPONSE
PBC
Kremer AE et al.
Composite biochemical response (alkaline phosphatase (ALP) < 1.67 × upper limit of normal (ULN), ≥ 15% ALP decrease from baseline, and total bilirubin ≤ ULN) met in 61.7% patients treated with seladelpar vs 20% placebo (p < 0.0001)
ALP normalized in 25% patients treated with seladelpar vs 0% placebo (p < 0.0001)
Significantly reduced pruritus in seladelpar treated group compared to placebo (p < 0.005)
2023
Phase 3
ENHANCE
PBC
Hirschfield GM et al.
Seladelpar treatment group met composite biochemical response (alkaline phosphatase (ALP) < 1.67 × upper limit of normal (ULN), ≥ 15% ALP decrease from baseline, and total bilirubin ≤ ULN) in 57.1% for 5 mg and 78.2% for 10 mg and 12.5% for placebo (p < 0.0001)
ALP normalized in 5.4% for 5 mg and 27.3% for 10 mg and 0% for placebo (p < 0.0001)
Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo (p =0.02)
2022
Phase 2
PBC
Bowlus et al.
At week 52, composite response (ALP < 1.67 × ULN, ≥ 15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5 mg and 10 mg cohorts
2017
Phase 2
PBC
Jones D et al.
Decrease in alkaline phosphatase by −2% in placebo vs −53% in the seladelpar 50 mg and −63% in the seladelpar 200 mg group. Changes in both seladelpar (p < 0·0001)
All five patients who received seladelpar had normalized ALP
Elafibranor
2021
Phase 2
PBC
Schattenberg JM et al.
At 12 weeks:
80 mg group:
− ALP was reduced by -48.3 ± 14.8% vs +3.2 ± 14.8% increase in the placebo (p < 0.001)
− 67% treated had decrease of ALP > 15% and total bilirubin below the ULN vs. 6.7% patients in the placebo group (p < 0.001)
− gamma-glutamyl transferase decreased by 37.0 ± 25.5% vs no change in the placebo group (p < 0.001)
120 mg group
− ALP was reduced by -40.6 ± 17.4% vs +3.2 ± 14.8% increase in the placebo (p < 0.001)
− 79% treated had decrease of ALP > 15% and total bilirubin below the ULN vs 6.7% patients in the placebo group (p < 0.001)
− gamma-glutamyl transferase decreased by 40.0 ± 24.1% vs no change in the placebo group (p < 0.001)
2023
Phase 3
PBC
Bowlus et al.
51% of patients treated with elafibranor had ALP < 1.67 × ULN with > 15% reduction in ALP baseline and normalization of total bilirubin vs 4% in placebo (p < 0.0001)
15% had normalization of ALP vs 0% in placebo (p = 0.0019)
Reduction in pruritus (p =0.0070)
Mu-opioid receptor partial agonist-antagonist
Butorphanol
2020
Pilot study
PBC
PSC
Golpanian RS et al.
Butorphanol improved itch based on qualitative metrics
FXR-Agonist
Tropifexor
2022
Phase 2
PBC
Schramm C et al.
By day 28, tropifexor caused 26–72% reduction in GGT from baseline at 30- to 150-μg doses (p < 0.001)
Fig. 1
A stepwise approach for treatment of cholestatic pruritus
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Conflict of Interest
The authors declare that they have no conflict of interest.
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