Cholestatic Pruritus

Cholestatic pruritus is a type of severe itching that affects people with liver diseases that impair bile flow. This itching can be relentless and debilitating, often interfering with sleep and daily activities, and requires specific medical management.

Table of contents

• What is cholestatic pruritus?
• Medical identification codes
• Other names
• Associated anatomy
• Who gets cholestatic pruritus?
• What causes cholestatic pruritus?
• Symptoms and characteristics
• Impact on quality of life
• Diagnosis and assessment
• Treatment options
• Non-drug management approaches
• Outlook and prognosis

What is cholestatic pruritus?

Cholestatic pruritus is a type of severe itching that occurs in people with cholestatic liver diseases. The term “cholestatic” means the flow of bile from the liver is slowed or blocked. Cholestasis is defined as impaired secretion of bile, which is a fluid produced by the liver that helps with digestion^[1][3].

This type of itching is different from ordinary itching. While most itching is caused by histamine, cholestatic pruritus is multifactorial, meaning it has several causes, and is much more difficult to treat^[10]. It can occur in any disease where there is bile duct damage in the liver, reduced secretion of bile by the liver, or obstruction to the flow of bile inside or outside the liver^[3].

Medical identification codes

L29.81
EC90.11

Other names

Pruritus of cholestasis, Hepatic pruritus, Biliary pruritus

Associated anatomy

• Liver
• Bile ducts
• Skin

Who gets cholestatic pruritus?

Cholestatic pruritus is experienced by 80 to 100 percent of patients with cholestatic liver disease^[3][10][15]. Interestingly, the severity of the pruritus has no correlation to the severity of the cholestasis^[3].

The likelihood of experiencing pruritus varies depending on the underlying liver disease. In intrahepatic cholestasis of pregnancy, most women will experience pruritus^[3]. Women with cholestasis of pregnancy can experience severe itching especially in the third trimester, and the pruritus resolves itself after delivery^[1].

In primary biliary cirrhosis and primary sclerosing cholangitis, up to 80 percent of people experience pruritus^[3]. Pruritus is more common in conditions characterized by bile duct inflammatory destruction and ductopenia (loss of small bile ducts), including primary biliary cirrhosis, than in those characterized by hepatocellular injury such as chronic viral hepatitis^[1].

People with malignant biliary obstruction have a 45 percent chance of experiencing pruritus, while those with benign biliary obstruction have a 16 to 17 percent chance^[3]. In chronic viral hepatitis, 5 to 15 percent of people with chronic hepatitis C infections complain of pruritus, whereas those with chronic hepatitis B infection rarely complain of pruritus^[3].

What causes cholestatic pruritus?

The exact cause of cholestatic pruritus is not fully understood. It is thought that cholestasis leads to the accumulation of unknown pruritogenic substances (substances that cause itching) that bind to receptors on primary itch neurons called C-fibers in the skin. This signal gets transmitted across neuronal pathways to the central nervous system, resulting in the sensation of itch^[2][9][14].

Several potential pruritogens have been proposed, including bile acids, endogenous opioids, lysophosphatidic acid, serotonin, and progesterone derivatives^{[2][3][8][10]}. However, a definitive culprit has not been identified^[2][9].

A genetic component is also likely to be a factor, as not all patients with cholestasis experience pruritus^[3]. It is thought that the pruritogens mediating cholestatic pruritus are made in the liver and excreted in bile, triggering the sensation of itch through activation of a complex neural network^[3].

This is supported by the fact that itching improves or resolves with liver transplantation and may reduce in intensity with advancing liver failure as the liver’s ability to produce these substances becomes progressively impaired^[1][3].

Symptoms and characteristics

Cholestatic pruritus tends to be generalized, affecting the entire body, but is usually localized to the limbs, soles of the feet, and palms of the hands^[1][2][3]. Symptoms are often most intense at night, which interferes with sleep and exacerbates fatigue^[2][9].

The itching leads to scratching, sometimes violent, resulting in visible skin changes. There is no primary rash associated with cholestatic pruritus, but patients often develop lesions secondary to scratching such as excoriations (scratch marks), lichenification (thickened skin), folliculitis (inflammation of hair follicles), and nodular prurigo (firm bumps on the skin)^[1][3].

The intensity of the pruritus is variable throughout the course of the cholestatic disease and tends to cease as the disease progresses towards liver failure^[1][3]. The pruritus can persist and remit throughout the course of the disease^[1].

The itching can be made worse by stress, heat, certain fabrics such as wool, or hormonal changes such as the premenstrual period, menopause, or hormone replacement therapy^[3].

In young babies who cannot yet scratch, cholestatic pruritus may be hard to identify. They may show signs such as irritability, sleep poorly, or dig at their ears and eyes, which are often the first areas to show bleeding and scarring^[5][16].

Impact on quality of life

Cholestatic pruritus can be a distressing and debilitating symptom, causing significant impairment in quality of life^[12][18]. This type of pruritus can lead to sleep deprivation, and in some patients, to suicidal ideations^[1].

An Internet survey conducted via the PBCers organization found that 69 percent of respondents with primary biliary cholangitis reported itch. Seventeen percent of the respondents reported that the itch was “relentless” or so severe that it led to wanting to “tear (the) skin off,” and 3.6 percent of the subjects stated that they scratched until they bled. Seventy-four percent of the respondents who addressed the question reported that the itch affected sleep, 65 percent said the itch was worse at night, and 11 percent reported that nothing relieved the itch^[1].

The scratching interferes with normal activities and sleep and may therefore hinder learning and schoolwork. Because it interferes with a child’s sleep, it may also adversely impact sleep in the family, which can have profound effects on an entire family^[16].

The impacts of the itch can also frequently lead to skin damage, irritability, negative impact on social activities, cognitive impact, physical discomfort, impaired school performance, decreased physical function, and burning, tingling, or prickling sensations^[5].

Intractable pruritus from liver disease is an indication for liver transplantation even in the absence of liver failure^[1]. Accordingly, pruritus is a complication of liver disease that requires specific management and intense research in an effort to design effective antipruritic medications^[1].

Diagnosis and assessment

Despite a significant impact on quality of life, pruritus is undertreated in cholestatic liver disease. In a study of primary biliary cholangitis, a third of patients with clinically significant itch had never received any medical treatment for pruritus^[2][9]. Treatment of pruritus necessitates recognition of this as a symptom of cholestasis, a connection that may not be made by patients. Thus, it is important that providers ask about pruritus in all patients with cholestatic liver disease^[2][9][14].

While it can be challenging to evaluate pruritus due to its subjective nature, assessment of itch severity can be done through use of a Visual Analog Scale, or other scoring systems, such as the 5D-Itch Scale, PBC-40 questionnaire, or the Itch Reported Outcome (ItchRO) scale^[2][5][9]. These scoring systems can be particularly helpful when evaluating response to treatments^[2].

The ItchRO scale is an assessment tool that measures itch-related symptoms in patients suffering from cholestatic pruritus. The scale determines symptom severity using a 0 to 4 scale, where 0 is “not itchy at all” and 4 is “extremely itchy.” ItchRO takes itch-related symptoms into consideration, including patients’ skin damage, sleep, and irritability^[5].

Treatment options

Several treatment options exist for cholestatic pruritus with varying efficacy. Healthcare providers use a stepwise approach to managing cholestatic pruritus, moving on to more intensive therapies only as needed^[2][9][17].

Cholestyramine is considered the first-line treatment for managing itching from cholestatic pruritus. It is a bile acid-binding resin that works by binding bile acids in the gut, which reduces circulating levels that contribute to itching^{[2][9][11][17]}. If you decrease the bile load, you, hopefully, will decrease the itching^[17]. The consistency of cholestyramine makes it somewhat unpleasant to take, and it may cause some gastrointestinal discomfort. It must be taken separately from other medications, as it can interfere with their absorption^[17].

Rifampicin (also called rifampin) is a second-line agent that acts as a potent enzyme inducer, helping reduce circulating pruritogens by changing liver enzyme activity^[17][19]. It requires careful monitoring and may be suitable if bile acid sequestrants like cholestyramine are not effective^[17]. A 2018 study found that 95 percent of adults with primary sclerosing cholangitis and primary biliary cholangitis, including those with jaundice and advanced liver disease, took rifampicin safely^[19].

At present, evidence-based treatment options for pruritus in fibrosing cholangiopathies, such as primary biliary cholangitis and primary sclerosing cholangitis, are the peroxisome proliferator-associated receptor (PPAR) agonist bezafibrate and the pregnane X receptor (PXR) agonist rifampicin^[8].

Naltrexone is a third-line agent and is an opioid antagonist that helps to counteract the central opioid pathways that are related to itching. This medication is introduced very slowly at first, and the dose will be increased gradually to minimize side effects, such as gastrointestinal discomfort or mood changes^[17][19].

Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, are fourth-line agents. These medications, commonly used in the treatment of depression, can also be a benefit for people with cholestatic pruritus. SSRIs work in the same pathways in the brain that the excess bile triggers when you have cholestatic pruritus, and can help to block the signals that trigger itch^[11][17]. The trouble with SSRIs may be that it can take a strong dose to affect your itch, and the mood-altering effects may not be tolerable in some people^[17].

Ileal bile acid transporter (IBAT) inhibitors are a newer class of medication that works by blocking the ileal bile acid transporter, which recycles bile acids back to the liver from the intestines^[7][17].

In pruritus of intrahepatic cholestasis of pregnancy, ursodeoxycholic acid is recommended and might be supported in the third trimester by rifampicin if needed^[8].

Alternatively, non-absorbable anion exchange resins, such as cholestyramine, can be administered, albeit with poor trial evidence^[8].

Antihistamines are generally not effective for treating cholestatic pruritus because histamine is not believed to cause this kind of itch^[2][9][17]. However, sedating antihistamines may help some people sleep through the discomfort^[17].

Non-drug management approaches

Lifestyle interventions are the first step in management of cholestatic pruritus^[2][9][14]. These include use of emollients to prevent dry skin, avoiding tight clothing, bathing with tepid rather than hot water, using menthol cooling gels for localized pruritus, and keeping fingernails shortened to minimize excoriations^[2][9][14].

For cholestatic pruritus due to obstruction of the common bile duct, the condition can sometimes be relieved by inserting an intra-ductal stent^[11]. Treatment approaches can also include warm baths and emollients, and topical antipruritic medications such as levomenthol cream^[11].

Cognitive behavioral therapy and acupuncture have been effective in treating non-cholestatic causes of pruritus, though their effectiveness for cholestatic pruritus is less well established^[2][9].

Outlook and prognosis

Treatment of pruritus in liver diseases can be challenging and requires specific management with early initiation and a step-wise approach using specific drugs^[12][18].

In patients with primary biliary cholangitis, the pruritus can persist and remit throughout the course of the disease, and as the disease progresses to liver failure, the pruritus tends to cease, as if a certain degree of liver function were necessary for pruritogen(s) or its cofactors to be produced or for the sensation to be perceived^[1].

Liver transplantation for intolerable refractory pruritus has become an extremely rare therapeutic strategy^[8]. The fact that itching improves or resolves with liver transplantation supports the idea that the substances causing the itch are made in the liver^[3].

Although new therapies show promise, further research is needed to confirm the pathophysiology of cholestatic pruritus so that targeted therapy can be developed^[10][15].