Why does itching in cholestasis worsen at night?

Why Itching Worsens in Cholestasis at Night

Cholestatic pruritus typically worsens during the late evening and night due to circadian variations in pruritogenic factors and altered skin physiology, significantly impacting patients' quality of life and sleep. 1

Pathophysiological Mechanisms

The nocturnal worsening of cholestatic pruritus involves several mechanisms:

1. Circadian Rhythm Effects:

   • Peak hours of pruritus intensity are consistently reported in the late evening and night 1
   • Diurnal variations in pruritogenic compounds may contribute to this pattern

2. Molecular Mediators:

   • Recent research has identified several potential pruritogens:
     • Lysophosphatidic acid (LPA) and its producing enzyme autotaxin 2
     • Sulfated progesterone metabolites 3
     • These compounds may accumulate or have enhanced activity at night

3. Skin Physiology Changes:

   • Increased skin temperature at night
   • Reduced sensory thresholds during evening hours
   • Decreased skin barrier function at night

4. Reduced Distraction:

   • Fewer daytime activities to distract from the sensation of itching
   • Increased focus on bodily sensations when trying to sleep

Clinical Presentation

Cholestatic pruritus typically presents with:

• Itching that is worse at night 1
• Common locations include upper and lower extremities and face, though generalized pruritus is also reported 1
• No primary skin lesions (only secondary excoriations from scratching)
• In intrahepatic cholestasis of pregnancy (ICP), pruritus without rash is the cardinal symptom 4

Management Strategies

First-Line Treatments

• Bezafibrate (PPAR agonist):

  • Now recommended as first-line treatment for moderate to severe pruritus in cholangiopathies 1
  • Demonstrated clear benefit versus placebo in the FITCH trial
  • Dosage: Not specified in guidelines, but typically 400mg daily

• Ursodeoxycholic Acid (UDCA):

  • First-line for intrahepatic cholestasis of pregnancy 4
  • Dosage: 10-20 mg/kg per day 1
  • Improves pruritus in 67-80% of ICP patients 1

Second-Line Treatments

• Rifampicin:
  • Effective second-line option 1
  • Dosage: 150-300 mg daily 1
  • Caution: May induce drug-induced hepatitis after 4-12 weeks in up to 12% of cholestatic patients 1

Additional Pharmacological Options

• Naltrexone (opioid antagonist):

  • Third-line treatment
  • Start at very low doses (12.5 mg) to avoid withdrawal-like side effects 1
  • Long-term tolerability can be an issue 1

• Sertraline (SSRI):

  • Fourth-line treatment
  • Limited evidence specifically for cholestatic pruritus 1
  • Dosage: 25-75 mg daily 1

Non-Pharmacological Approaches

• General measures:

  • Use emollients to prevent skin dryness
  • Avoid hot baths or showers (which can worsen itching)
  • Apply cooling gels (e.g., menthol) to affected areas
  • Keep nails short to minimize skin damage from scratching 1

• Timing considerations:

  • Consider taking medications with longer half-lives in the evening to better cover nighttime symptoms
  • Create a cool sleeping environment

Special Considerations

Intrahepatic Cholestasis of Pregnancy

• Pruritus is typically worse at night 4
• UDCA (10-15 mg/kg/day) is first-line treatment 4
• Delivery timing should be based on bile acid levels:
  • Consider delivery at 36 weeks for bile acids ≥100 μmol/L
  • Between 36-39 weeks for bile acids <100 μmol/L 4

Refractory Cases

For severe, treatment-resistant pruritus:

• Consider experimental approaches like UV-B phototherapy 5
• Extracorporeal albumin dialysis in extreme cases 5
• Liver transplantation is highly effective but reserved for persistent and intractable pruritus that severely impacts quality of life 1

Clinical Pitfalls to Avoid

1. Failing to recognize the significance of nighttime pruritus as a diagnostic clue for cholestasis, particularly in pregnant women

2. Inadequate dosing or duration of anti-pruritic medications before declaring treatment failure

3. Not addressing the underlying cholestasis while treating the symptom of pruritus

4. Overlooking drug interactions - particularly with cholestyramine, which can bind to and reduce the effectiveness of other medications (including UDCA) if not properly timed 1

5. Neglecting the psychological impact of chronic nighttime pruritus on sleep quality and overall well-being

By understanding the mechanisms behind nocturnal worsening of cholestatic pruritus and implementing appropriate management strategies, clinicians can significantly improve patients' quality of life and sleep.