Cholestatic pruritus

What is cholestatic pruritus?

Cholestasis is defined as a decrease in bile flow secondary to impairment or obstruction of bile secretion. Cholestatic pruritus is pruritus that occurs in people with cholestatic liver diseases, of which there are numerous types.

Pruritus may occur in any cholestatic disease. This includes diseases in which 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.

Cholestatic pruritus may also be referred to as the pruritus of cholestasis.

Who gets cholestatic pruritus?

Cholestatic pruritus is experienced by 80-100% of patients with cholestatic liver disease. Interestingly, the severity of the pruritus has no correlation to the severity of the cholestasis.

The prevalence of cholestatic pruritus varies depending on the underlying disease:

• Intrahepatic cholestasis of pregnancy (ICP): most women will experience pruritus, with rare cases of subclinical ICP characterised by elevated serum bile acids without pruritus
• Primary biliary cirrhosis: up to 80% of people experience pruritus
• Primary sclerosing cholangitis: up to 80% of people experience pruritus
• Malignant biliary obstruction: 45% of people experience pruritus
• Benign biliary obstruction: 16-17% of people experience pruritus
• Chronic viral hepatitis: 5-15% of people with chronic hepatitis C infections complain of pruritus, whereas those with chronic hepatitis B infection rarely complain of pruritus
• Alcoholic or non-alcoholic steatohepatitis: rarely develop pruritus
• Non-alcoholic fatty liver disease with cholestasis: rarely develop pruritus

What causes cholestatic pruritus?

The exact cause is unknown. Several theories have been proposed but it is deemed most likely that cholestatic pruritus is mediated by several pruritogenic substances, including bile acids, serotonin, progesterone derivatives, endogenous opioids, and lysophosphatidic acids. These substances are often elevated in cholestatic liver disease.

A genetic component is also likely to be a factor, as not all patients with cholestasis experience pruritus.

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, although the pathophysiological mechanism is still not well defined. 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 exocrine function becomes progressively impaired.

What are the clinical features of cholestatic pruritus?

Cutaneous features

• There is no primary rash associated with cholestatic pruritus. Patients often develop lesions secondary to scratching such as lichenification, excoriations, folliculitis and nodular prurigo.

Non-cutaneous features

• Cholestatic pruritus may be generalized, but is usually localized to the limbs, soles of the feet, and palms
• 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
• It is usually worse in the evening and night
• It can be made worse by stress, heat, certain fabrics such as wool, or hormonal changes (eg, premenstrual period, menopause, or hormone replacement therapy).

How do clinical features vary in differing types of skin?

Cholestatic pruritus has no specific cutaneous features. Skin lesions caused by scratching may appear different in darker skin types compared to lighter skin types, for example, nodular prurigo tends to be firmer, larger, and darker in those with darker skin.

What are the complications of cholestatic pruritus?

• Lichenification
• Excoriations
• Folliculitis
• Scarring of the skin
• Psychological distress, reduced quality of life, sleep deprivation, and suicidal ideation

How is cholestatic pruritus diagnosed?

Cholestatic pruritus can be diagnosed in a patient with cholestasis who complain of itching. Provided the underlying cholestatic disease is known, an extensive diagnostic evaluation is unnecessary.

Other causes of pruritus must be excluded. This requires detailed history and examination, blood tests, and may include imaging studies.

What is the differential diagnosis for cholestatic pruritus?

Cholestatic pruritus has a broad differential diagnosis, as even if someone has a diagnosed cholestatic liver disease they may have a concurrent issue causing pruritus.

Some differential diagnoses include:

• Atopic eczema
• Contact dermatitis
• Uremic pruritus
• Drug-induced pruritus
• Chronic spontaneous urticaria
• Neoplastic diseases such as cutaneous T cell lymphoma and Hodgkin lymphoma
• Infectious diseases, such as scabies
• Systemic causes of pruritus eg, hyperthyroidism and hypothyroidism, type 2 diabetes mellitus, iron deficiency, polycythaemia vera
• Psychiatric diseases such as somatoform pruritus, delusions of parasitosis, or compulsive picking.

What is the treatment for cholestatic pruritus?

General measures

• Avoiding heat, or applying cold water to the skin
• Aqueous cream plus menthol 1% for its coolant effect
• Avoiding psychological stress
• Avoiding contact with wool
• Antihistamines have been proven mostly ineffective; however, antihistamines are frequently prescribed for their sedative effects in patients with nocturnal pruritus
• Shortening of fingernails to avoid breaking of the skin.

Specific measures

The first step of treatment for cholestatic pruritus is the identification and treatment of the underlying cholestatic disease.

Treatments specific to certain types of cholestatic liver diseases are as follows:

• Biliary obstruction: Radiological or surgical treatment eg, endoscopic management of strictures in primary sclerosing cholangitis or bile duct stenting in malignant biliary obstruction.
• Drug-induced cholestasis: Cease causative medication.
• Intrahepatic cholestasis of pregnancy: Ursodeoxycholic acid (UDCA) is usually given as there is evidence to suggest that it improves fetal outcomes, reduces itch, and is safe to use in pregnancy. Labour is commonly induced in severe disease to reduce the risk of fetal and maternal complications.

In addition to the above, for those who do not have intrahepatic cholestasis of pregnancy, there are four classes of medications commonly used to manage cholestatic pruritus. One option is usually given for 2-4 weeks, before being replaced with the next line of therapy.

1. First-line: Colestyramine, a non-absorbable anion-exchange resin thought to act by binding to potential pruritogens (bile salts) and therefore reducing their absorption and increasing fecal excretion.
2. Second-line: Rifampicin, an enzyme inducer, is thought to relieve itch by reducing serum autotaxin levels, thereby reducing the production of lysophosphatidic acid (likely pruritogen in cholestasis).
3. Third-line: Selective μ-opioid receptor antagonists (eg, naltrexone), which decrease the effect of endogenous opioids (likely pruritogens in cholestasis).
4. Fourth-line: Selective serotonin reuptake inhibitors (eg, sertraline), which modify central itch signalling by influencing the endogenous serotonergic system.

Refractory cholestatic pruritus:

• If the above treatments fail and pruritus is severe and impacting quality of life, liver transplantation may be the only effective treatment.
• In certain centres, patients can also be offered ultraviolet B phototherapy, endoscopic nasobiliary drainage, plasmapheresis, or participation in clinical trials of novel therapies.

How do you prevent cholestatic pruritus?

There is no known way to prevent cholestatic pruritus.

What is the outcome for cholestatic pruritus?

• The intensity of cholestatic pruritus varies over the course of the disease and may improve with the development of end-stage liver disease.
• In women with intrahepatic cholestasis of pregnancy, pruritus usually intensifies as pregnancy progresses and then improves/resolves following delivery.
• In some cases, patients require liver transplantation to alleviate their pruritus if medical treatments are ineffective.