What causes nocturnal (night-time) pruritus (itching) in liver disease?

From the Guidelines

Nocturnal pruritus in liver disease is primarily caused by the accumulation of bile acids in the blood, which stimulates itching receptors in the skin.

Pathophysiology of Nocturnal Pruritus

• The exact mechanism of cholestatic pruritus is not fully understood, but it is thought to be related to the accumulation of bile acids in the blood, which can stimulate itching receptors in the skin 1.
• The intensity of pruritus can vary, but daily peak hours are usually reported in the late evening and night, suggesting a possible circadian rhythm involvement 1.
• The molecular pathogenesis of cholestatic pruritus has not been fully unravelled, but major pathophysiological insights have been achieved during the last decade, including the role of bile acids and other factors such as autotaxin and lysophosphatidic acid 1.

Clinical Features of Nocturnal Pruritus

• Pruritus affects the majority of people with primary sclerosing cholangitis (PSC) during the course of the disease and may become their major clinical burden, dramatically impairing quality of life and even leading to suicidal ideations in the most severe cases 1.
• The skin in hepatic pruritus is often generally hyperpigmented and excoriated, with the hands and feet being the worst-affected areas 1.
• There is a poor correlation between pruritus and bile acid levels, suggesting that other factors may be relevant 1.

Treatment of Nocturnal Pruritus

• Pharmacological treatment of moderate to severe pruritus in sclerosing cholangitis with bezafibrate or rifampicin is recommended, with bezafibrate being proposed as the first-line pharmacological treatment for moderate to severe pruritus in PSC and other forms of fibrosing cholangiopathy 1.
• Cholestyramine is widely used as first-line treatment, although the evidence basis to support this is limited, and it can impair the absorption of various medications such as ursodeoxycholic acid (UDCA) 1.
• Other agents such as naltrexone, sertraline, and gabapentin may be used as third- or fourth-line treatments, but their effectiveness and tolerability are not well established 1.

From the Research

Causes of Nocturnal Pruritus in Liver Disease

• The exact pathogenesis of nocturnal pruritus in liver disease is still not clearly defined 2, 3, 4, 5, 6
• Several potential pruritogens have been identified, including:
  • Bile salts 2, 3, 4, 5, 6
  • Histamine 2, 3, 5
  • Progesterone metabolites 2, 3, 5
  • Endogenous opioids 2, 3
  • Lysophosphatidic acid (LPA) and its forming enzyme, autotaxin (ATX) 3, 4, 5
• Cholestatic itching often peaks in the evening and early night, and mainly occurs on the palms of the hands and soles of the feet, but can also occur more generalized 5
• The ATX-LPA-axis may represent a key element in the pathogenesis of cholestatic pruritus, as ATX activity correlates with itch severity and effectiveness of several anti-pruritic therapeutic interventions in cholestatic patients 3, 4

Characteristics of Nocturnal Pruritus in Liver Disease

• Pruritus is a common symptom in patients with cholestatic liver diseases, such as primary biliary cirrhosis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, or hereditary pediatric cholestatic disorders 2, 3, 4, 5, 6
• Pruritus may accompany almost any other liver disease, although less frequently 2, 3, 4, 5, 6
• The symptom can greatly reduce the quality of life, and treatment is aimed at eliminating pruritogens, managing the metabolism of pruritogens, and influencing the perception of itch by the central nervous system 2, 3, 4, 5, 6