Introduction and Context
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that commonly coexists with one of the symptom burdens clinicians and patients find most debilitating: fatigue. Although PBC is often discussed in terms of biochemical cholestasis, cirrhosis risk and specific liver-directed therapies, fatigue is a major determinant of health-related quality of life and functional status. Fatigue in PBC ranges from mild weariness to profound physical and cognitive exhaustion that can persist despite biochemical control of the liver disease.
In October 2025 the PBC working group of the European Reference Network for Rare Liver Diseases (ERN RARE-LIVER) published a position paper that systematically reviewed available evidence and produced pragmatic guidance for clinicians and researchers on PBC-related fatigue (Koc et al., Lancet Gastroenterol Hepatol. 2025). The document addresses six key questions, synthesizes measurement tools and interventions, and introduces a practical ASK‑MEASURE‑TREAT algorithm for routine clinical practice. This article summarizes the core content and expert recommendations from that position paper, highlights what’s new compared with earlier PBC guidance, and outlines implications for clinicians and researchers.
Why this position paper matters now
– Fatigue is highly prevalent in PBC and frequently persists even after successful disease-modifying therapy.
– Historically, fatigue has been under-assessed in hepatology clinics and under-represented in clinical trials.
– The ERN position paper fills an unmet need by consolidating evidence, promoting standardized measurement and proposing an implementable clinical pathway while identifying research priorities.
New Guideline Highlights
Major themes and takeaways
– Prevalence and impact: Fatigue affects a large proportion of people with PBC and substantially impairs health-related quality of life across physical, cognitive and social domains.
– Routine identification: Clinicians should routinely ask every person with PBC about fatigue at clinic visits.
– Standardized measurement: Adopt simple, validated tools and prefer longitudinal tracking rather than one-off assessment.
– Treat contributors: Before attributing fatigue solely to PBC, screen and treat reversible or coexisting contributors (e.g., hypothyroidism, anaemia, sleep disorders, depression, medications).
– Non-pharmacological management: Pilot data support structured non-drug approaches (exercise programmes, cognitive-behavioural therapy, energy-conservation strategies) and merit further study.
– Pharmacological therapies: Current evidence does not support routine prescription of any drug specifically for PBC-related fatigue; modafinil and other agents remain investigational.
– Research agenda: Priorities include natural-history cohort studies, mechanistic studies, validated longitudinal tools, and randomized controlled trials (RCTs) of non-pharmacological and pharmacological interventions.
Key practice recommendation (summary)
– “Ask” every patient about fatigue; “Measure” with validated, easy-to-use instruments and track over time; “Treat” by addressing reversible causes and offering evidence-based non-pharmacological interventions while avoiding unproven drugs.
Updated Recommendations and Key Changes from Previous Guidance
How this position paper moves the field forward
– Focus shift: Previous PBC guidelines (EASL, AASLD) centered on diagnosis, biochemical monitoring and pharmacotherapy but offered limited operational advice on symptom management. The ERN paper places fatigue assessment and management squarely in routine care.
– Standardization: The position paper recommends specific practical instruments for clinic use and advocates longitudinal monitoring—an upgrade from prior advice that often lacked concrete measurement strategies.
– Algorithmic care: The ASK‑MEASURE‑TREAT algorithm is a new, pragmatic workflow designed for everyday practice; prior guidelines lacked this concise clinical pathway.
– Therapeutics stance: While earlier reports discussed potential agents (e.g., modafinil) mostly from small case series, the ERN working group emphasizes that no pharmacologic therapy can currently be recommended for PBC fatigue outside clinical trials, a stronger, evidence‑based caution.
Summary table (high-level)
– Routine enquiry about fatigue: Strong recommendation (ERN).
– Use of validated tools and longitudinal tracking: Strong recommendation (ERN).
– Screen for reversible causes (endocrine, haematologic, sleep, psychiatric): Strong recommendation.
– Offer structured exercise and cognitive-behavioural support where feasible: Conditional recommendation (based on pilot data).
– Routine pharmacotherapy for fatigue: Not recommended pending RCT evidence.
Topic-by-Topic Recommendations
1) Identification and screening
– Ask simply and routinely: e.g., “Have you been feeling more tired than usual? Is tiredness limiting your daily activities?”
– Frequency: At baseline and at every follow-up visit (or at least annually) or sooner if clinical circumstances change.
2) Measurement tools and tracking
– Preferred characteristics: short, validated, easy to administer, sensitive to change.
– Examples discussed by the ERN working group: disease-specific instruments (PBC-40 fatigue domain), and generic scales (Fatigue Severity Scale [FSS], Fatigue Impact Scale). For cognitive fatigue, brief cognitive screening tools may be useful.
– Practical recommendation: Use one core instrument in clinic (takes <5 minutes), plus a brief functional question set. Emphasize longitudinal assessment—document baseline and serial scores to identify trajectory and treatment response.
3) Initial clinical work-up: rule out reversible contributors
– Basic tests to consider: full blood count (anaemia), thyroid function tests, fasting glucose/HbA1c, liver biochemical profile, vitamin B12/folate where indicated.
– Sleep evaluation: screen for obstructive sleep apnoea and insomnia; refer for sleep study if clinically suspected.
– Medication review: sedating medications (opiates, benzodiazepines, some antihistamines), polypharmacy.
– Mental health: screen for depression and anxiety; consider referral to psychology or psychiatry if indicated.
4) Treatment pathways
– Address reversible causes: treat anaemia, hypothyroidism, optimize sleep disorders, adjust sedating medications.
– Non-pharmacological interventions (evidence from pilot trials and analogous conditions):
– Supervised graded exercise or tailored physical activity programmes—improves physical fatigue and function in pilot studies.
– Cognitive-behavioural therapy (CBT) and energy-management strategies to improve coping and functional capacity.
– Sleep hygiene education and treatment for sleep apnoea where present.
– Multidisciplinary rehabilitation (physiotherapy, occupational therapy) for severely affected patients.
– Pharmacological treatments: No drug is currently endorsed by the ERN working group for routine management of PBC-related fatigue. Small pilot studies have tested agents such as modafinil or psychostimulants with mixed results; these should be confined to clinical trials until larger RCT data emerge.
5) Special populations and considerations
– Patients with advanced liver disease or cirrhosis: fatigue in these patients may reflect multifactorial contributors including sarcopenia, hepatic encephalopathy and systemic inflammation; individualized assessment and multidisciplinary care are recommended.
– Coexisting autoimmune disease: autoimmune thyroid disease and other comorbidities are common and must be actively screened.
– Occupational and social implications: discuss work capacity, disability needs and social supports; involve social work when required.
ASK‑MEASURE‑TREAT: A Practical Algorithm
The ERN position paper introduces a three-step clinical algorithm intended for use in all patients with PBC:
– ASK: Systematically enquire about fatigue at each clinical encounter. Use simple screening questions and document presence, severity and impact.
– MEASURE: Use a validated, brief fatigue instrument and repeat it over time. Combine with basic screening tests for common contributors. If cognitive complaints are present, add brief cognitive tests.
– TREAT: Treat reversible causes; offer or refer for non-pharmacological interventions (structured exercise, CBT, sleep therapy); avoid unproven pharmacological treatments outside trials.
Clinical application (condensed checklist)
1. Ask: Document fatigue yes/no; impact on work/ADLs.
2. Measure: Administer PBC-40 fatigue domain or FSS; record score.
3. Screen tests: CBC, TSH, glucose, review meds, sleep history, mental health screen.
4. Treat: Address abnormalities; offer exercise/CBT; arrange referrals; consider trial enrolment for investigational therapies.
Expert Commentary and Insights
Panel consensus and controversies
– Consensus: Everyone agreed fatigue is common and under-recognized; routine enquiry and structured assessment are essential and feasible.
– Clinical equipoise: There is expert disagreement about pharmacological options. While some clinicians have seen individual patient benefit with stimulants (e.g., modafinil), the ERN group concluded that current evidence from small, uncontrolled or underpowered studies is insufficient to support general recommendations.
– Measurement debate: Experts emphasized pragmatism—prefer short, clinic-friendly tools even if they are less comprehensive than research batteries, because of better uptake in routine care.
– Integration into care pathways: Some panelists advocated embedding fatigue assessment into electronic medical records as a checkbox and score field to facilitate longitudinal tracking and quality improvement.
Selected expert perspectives (paraphrase)
– “Fatigue must be treated as a core symptom domain in PBC, not an optional complaint.” — hepatology working group lead.
– “We need large, multi-center RCTs of behavioural and pharmacologic interventions; patients deserve better evidence.” — clinical trialist on the panel.
Research Agenda and Knowledge Gaps
Top priorities identified by the ERN working group
– Longitudinal cohort studies to map the natural history and trajectories of fatigue in PBC.
– Mechanistic research: neuroimaging, neurochemical studies and peripheral biomarkers to disentangle central (brain) versus peripheral contributors.
– Development and validation of short, responsive, patient-centered measurement tools for clinical and trial use.
– Well-designed RCTs of non-pharmacological interventions (exercise programmes, CBT, sleep therapy) and of candidate drugs (modafinil and others) with standardized outcome measures and sufficiently long follow-up.
– Implementation research on embedding the ASK‑MEASURE‑TREAT approach into routine hepatology care across varied health systems.
Practical Implications for Clinicians
– Change in routine: Make fatigue enquiry routine for all people living with PBC and document it in the medical record.
– Use a simple tool and track scores over time to identify worsening or improvement and to measure response to interventions.
– Prioritize identification and treatment of reversible contributors before labeling fatigue as “PBC-related”.
– Refer to or collaborate with physiotherapy, psychology, sleep medicine and occupational therapy for multidisciplinary care.
– Discuss trial options with patients; encourage enrolment into high-quality studies whenever possible.
Patient vignette (illustrative)
– Sarah, a 48-year-old woman with well-controlled PBC on ursodeoxycholic acid, reports progressive daytime exhaustion interfering with her part-time job. Using ASK‑MEASURE‑TREAT: the clinician asks about fatigue, measures it with a short fatigue questionnaire, orders tests (CBC, TSH), identifies mild hypothyroidism and suspected sleep apnoea, treats the thyroid disease, refers for a sleep study and to a physiotherapist for a graded exercise plan. Over 6 months, her fatigue score improves and she regains work capacity.
References
– Koc OM, Toussaint AK, Untas A, et al. Fatigue in people with primary biliary cholangitis: a position paper from the European Reference Network for Rare Liver Diseases. Lancet Gastroenterol Hepatol. 2025 Oct 10: S2468-1253(25)00257-2. doi:10.1016/S2468-1253(25)00257-2. PMID: 41082897.
– Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69(1):394-437. doi:10.1002/hep.30145.
– European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017. doi:10.1016/j.jhep.2017.03.010.
Note: The ERN position paper is the primary source for the recommendations summarized here. Earlier PBC guidelines (AASLD, EASL) provided broader disease management context but did not focus operationally on fatigue; clinicians should continue to follow those documents for diagnostic and pharmacologic guidance for liver disease itself.
Conclusion
Fatigue in PBC is common, impactful and under-addressed. The ERN position paper provides a practical, evidence‑informed framework—ASK‑MEASURE‑TREAT—that clinicians can adopt immediately. For now, management centers on routine identification, measurement and treating reversible contributors, together with offering or referring patients for structured, non-pharmacological interventions when available. The field urgently needs longitudinal and interventional research to clarify mechanisms and identify effective treatments. Meanwhile, routine assessment and a multidisciplinary approach will improve recognition, patient support and the quality of clinical care.