G&H Why is cholestatic pruritus important, and how can it affect patients?
KB Cholestatic pruritus, or itch, is important because it affects the majority of patients who have various forms of cholestatic liver disease. According to the literature, 75% to 80% of patients with cholestatic liver disease report pruritus when asked. The problem is that only a minority of patients are asked about it. Looking at records of patients who have cholestatic liver disease, itching is recorded in only approximately 30% to 35%. Failing to address pruritus in patients with cholestatic liver disease can lead to delays in recognition and treatment.
Furthermore, quality of life is significantly reduced in patients who have cholestatic pruritus. It can interfere with their mood, potentially leading to depression. It can also interfere with their sleep, work-life balance, school education, and so forth. Thus, cholestatic pruritus is an important potential side effect in patients who have cholestatic liver disease, but it is not recorded or asked about in all patients.
G&H What is the current understanding of the pathophysiology of this condition?
KB There has been a lot more interest and study in this area over the past 5 years or so. We have always recognized that there are substances known as pruritogens that can be exogenous (outside the body) or endogenous (inside the body) that are sensed by neurons in the skin. Many signals are then transmitted to the spinal cord and to the brain, where itch is then perceived. There are several
targets now that have been identified in terms of these pruritogens. The most common are bile acids, which we have known about for quite some time. We now recognize that endogenous opioids that we produce ourselves can be one of the pruritogens or triggers as well as lysophosphatidic acid. In addition, there are many receptors that have been identified as active in causing pruritus. As mediators and receptors are identified in pruritus, investigators have opportunities to develop potential directed therapies.
G&H What makes clinicians start to think about the liver as the cause of itching?
KB One of the issues early on is that if patients complain to their physician about itching for any reason, they are often referred to dermatology. I often see patients who are referred to dermatology first and are delayed in seeing a liver specialist until skin-related disorders are excluded. The key is to recognize underlying liver disease in the patient, which is often evidenced by elevated liver enzymes (alkaline phosphatase or bilirubin). Further education of providers so they understand that pruritus may be a sign in patients with cholestatic liver disease is critical. This association may be more challenging for primary care providers than for providers in gastroenterology or hepatology.
G&H How can cholestatic pruritus be best evaluated currently?
KB It is important to evaluate patients at baseline and at follow-up. A number of scales have been developed, including the 5-D itch scale and the PBC-40 scale, to document the degree of itching in patients. Likely the easiest one for clinicians is the Visual Analogue Scale, which is simple and goes from 0 for no itching to 10 for the worst possible itching. It is important to try to identify where on the scale a patient is when they first come to a provider and what is happening over time by using the scale at each subsequent visit. Furthermore, this provides a longitudinal assessment of patients in response to therapies that may have been initiated.
G&H What are the traditional therapies for cholestatic pruritus?
KB Many different therapies have been used for this condition. Bile acid sequestrants such as cholestyramine can be used to bind bile acids, for example, and prevent recirculation. These therapies are essentially safe and can be effective in many patients with cholestatic pruritus. The biggest issue is that these therapies will bind other medications as well, which can be a problem in patients with primary biliary cholangitis (PBC) who are taking ursodeoxycholic acid. If such a patient is also administered cholestyramine, it is important to recognize that those 2 treatments have to be separated to prevent binding of the ursodeoxycholic acid in the gut. A second-line medication that many patients go to is rifampin. A fairly significant percentage of patients will respond to this agent, which is an agonist of the pregnane X receptor. The downfall to rifampin is that it has been associated with hepatitis in some cases. In patients receiving rifampin, the provider needs to be aware of the potential for hepatotoxicity and monitor the patient accordingly. Increasingly common are opioid antagonists such as naltrexone or naloxone. Circulating endogenous opioids have been identified as potential triggers for pruritus. Opioid antagonists have been used successfully to decrease itching in some patients. These agents have been shown to be beneficial in patients who have cholestatic pruritus. The agents can precipitate withdrawal and should be used with caution in patients receiving opioids. Selective serotonin reuptake inhibitors, the most common of which is probably sertraline, have been shown to have possible benefit as well. Some of the receptors to these medications are present within the skin. I have also used phenobarbital, which is sedating. Itching in these patients is worse at night, so it can be beneficial to help patients with sleep. Although many providers use ursodeoxycholic acid for pruritus, clinical trials have been mixed as to its effectiveness for this indication. However, as a proven therapy for patients with PBC, it is known to be safe.
G&H Could you discuss the use of the novel agents seladelpar and elafibranor for cholestatic pruritus?
KB Seladelpar (Livdelzi, Gilead) and elafibranor (Iqirvo, Ipsen) are peroxisome proliferator-activated receptor (PPAR) agonists that were recently approved by the US Food and Drug Administration (FDA) for the treatment of PBC. Many of the trials now for PBC, as well as for primary sclerosing cholangitis (PSC), include itching as an endpoint. Treatment trials years ago did not do so, making it difficult to obtain that information. Seladelpar was shown to have greater improvements in itching than placebo, as measured by the Visual Analogue Scale. Additionally, interleukin (IL) 31 levels were shown to be decreased with the use of seladelpar. IL-31 levels have been found to be increased in patients with PBC. This may relate to another mechanism for itching. For elafibranor, there were no significant changes in the Numerical Rating Scale score in patients who had moderate or severe itching (a score of 4 or greater); however, favorable results were found with 2 other measurements, the PBC-40 scale and 5-D itch scale. Thus, both of these agents were shown to have potential benefit in patients who had itching.
G&H Which other PPAR agonists have been studied for itching?
KB There are a number of other PPAR agonists that have been studied. The PPAR-alpha agonist fenofibrate has not been approved for cholestatic liver disease or cholestatic itching but has been shown in some studies to cause a reduction in itching. Bezafibrate, which is not approved in the United States but is approved in Europe, has been studied extensively for itching and has been shown to have benefit. There is also a study looking at bezafibrate in conjunction with the PBC therapy obeticholic acid (Ocaliva, Intercept). The dual PPAR-alpha and -gamma agonist saroglitazar is also currently being studied in patients with PBC.
G&H Which ileal bile acid transporter inhibitors are undergoing investigation for cholestatic pruritus?
KB This is an interesting class of drugs. There are 2 ileal bile acid transporter (IBAT) inhibitors that are currently approved by the FDA for Alagille syndrome and progressive familial intrahepatic cholestasis in children, maralixibat (Livmarli, Mirum) and odevixibat (Bylvay, Ipsen). Maralixibat is currently being evaluated for pruritus associated with a number of cholestatic conditions. Trials using odevixibat were terminated in adult cholestatic disease because of gastrointestinal side effects. Linerixibat is another IBAT inhibitor, which is currently being studied. A phase 2 trial in PBC showed significant reduction in itch, and there is an ongoing phase 3 trial with early data showing significant reduction in itching at 24 weeks. Additionally, an early phase 2 trial is looking at volixibat in PBC. Hopefully, as these trials are completed, we may have additional medications approved for cholestatic itching in our patients.
G&H Which other strategies, including nonpharmacologic ones, have been used and investigated in this area?
KB A number of other modalities have been tried in the treatment of patients with cholestatic pruritus. One nonpharmacologic treatment that I have used is ultraviolet light. However, there has only been a small number of cases using this approach, so there is no significant proven benefit. Similarly, plasmapheresis and the Molecular Adsorbent Recirculating System (MARS) have been used. MARS removes certain circulating toxins and may have a benefit in patients who have cholestatic pruritus. However, plasmapheresis and MARS are very expensive modalities that are not widely available and require specialized centers to deploy. There have been studies in the past of nasobiliary drainage, which is an interesting concept. However, it is cumbersome to use and would not be particularly patient-friendly. Additionally, because this procedure involves manipulation of the biliary tree, complications, including cholangitis and pancreatitis, have been reported. There has also been early investigation into monoclonal antibodies that would inhibit bile acid circulation. I do not think any of these approaches are going to step up to the forefront of cholestatic pruritus treatment, but may be reserved for patients who have not responded to other modalities.
G&H What are the biggest research needs in this area?
KB First of all, I am pleased to see that there is research going on in this area. Cholestatic pruritus is not something that has always been addressed. Prior studies looking at treatments for cholestatic liver disease have not uniformly addressed their impact on pruritus. It is important to identify why some patients respond to treatment while others do not. I suspect that as with other diseases, combination therapy addressing different targets may prove to be beneficial. Studies in PSC are lacking in large part owing to the heterogeneity of this population. Although patients with PSC have cholestasis and in some cases pruritus, many of the aforementioned therapeutic approaches have not been specifically investigated in this population. Additional research is needed on other side effects, particularly fatigue. Fatigue is very common in patients with cholestatic liver disease but is difficult to measure; it is not often asked about, and good therapies are not currently available to address it.
Disclosures
Dr Brown has served on the speakers bureau and advisory board of Ipsen, Gilead, and Intercept.
Suggested Reading
Ebhohon E, Chung RT. Systematic review: efficacy of therapies for cholestatic pruritus. Therap Adv Gastroenterol. 2023;16:17562848231172829.
Gabrielli F, Crepaldi E, Cavicchioli A, et al. Itching for answers: a comprehensive review of cholestatic pruritus treatments. Biomolecules. 2024;14(10):1227.
Hirschfield GM, Bowlus CL, Mayo MJ, et al; RESPONSE Study Group. A phase 3 trial of seladelpar in primary biliary cholangitis. N Engl J Med. 2024;390(9):783-794.
Kowdley KV, Bowlus CL, Levy C, et al; ELATIVE Study Investigators’ Group. Efficacy and safety of elafibranor in primary biliary cholangitis. N Engl J Med. 2024;390(9):795-805.
Medina-Morales E, Barba Bernal R, Gerger H, et al. Pharmacological therapy of pruritus in primary biliary cholangitis: a systematic review and meta-analysis of randomized clinical trials. J Clin Gastroenterol. 2023;57(2):143-152.
Smith HT, de Souza AR, Thompson AH, et al. Cholestatic pruritus treatments in primary biliary cholangitis and primary sclerosing cholangitis: a systematic literature review. Dig Dis Sci. 2023;68(6):2710-2730.