Underlying disease risk among patients with fatigue: a population-based cohort study in primary care

Becky White; Nadine Zakkak; Cristina Renzi; Meena Rafiq; Arturo Gonzalez-Izquierdo; Spiros Denaxas; Brian D Nicholson; Georgios Lyratzopoulos; Matthew E Barclay

doi:10.3399/BJGP.2025.0093

Underlying disease risk among patients with fatigue: a population-based cohort study in primary care

Br J Gen Pract. 2024 Dec 10:BJGP.2025.0093. doi: 10.3399/BJGP.2025.0093. Online ahead of print.

Authors

Becky White¹, Nadine Zakkak², Cristina Renzi³, Meena Rafiq⁴, Arturo Gonzalez-Izquierdo⁵, Spiros Denaxas⁶, Brian D Nicholson⁷, Georgios Lyratzopoulos¹, Matthew E Barclay¹

Affiliations

¹ Epidemiology of Cancer Healthcare and Outcomes (ECHO) Research Group, Department of Behavioural Science and Health, Institute of Epidemiology & Health Care, University College London, London, UK.
² Department of Behavioural Science and Health, Institute of Epidemiology & Health Care, University College London, London; Cancer Intelligence, Cancer Research UK, London, UK.
³ ECHO Research Group, Department of Behavioural Science and Health, Institute of Epidemiology & Health Care, University College London, London, UK; associate professor, Faculty of Medicine, University Vita-Salute San Raffaele, Milan, Italy.
⁴ ECHO Research Group, Department of Behavioural Science and Health, Institute of Epidemiology & Health Care, University College London, London, UK; Department of General Practice and Primary Care, Centre for Cancer Research, University of Melbourne, Melbourne, Australia.
⁵ Centre for Health Data Science, Institute of Applied Health Research, University of Birmingham, Birmingham; Institute of Health Informatics (IHI), University College London, London, UK.
⁶ IHI, University College London, London; British Heart Foundation Data Science Centre, London, UK.
⁷ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

PMID: 39658074
DOI: 10.3399/BJGP.2025.0093

Abstract

Background: Presenting to primary care with fatigue is associated with a wide range of conditions, including cancer, although their relative likelihood is unknown.

Aim: To quantify associations between new-onset fatigue presentation and subsequent diagnosis of various diseases, including cancer.

Design and setting: A cohort study of patients presenting in English primary care with new-onset fatigue during 2007-2017 (the fatigue group) compared with patients who presented without fatigue (the non-fatigue group), using Clinical Practice Research Datalink data linked to hospital episodes and national cancer registration data.

Method: The excess short-term incidence of 237 diseases in patients who presented with fatigue compared with those who did not present with fatigue is described. Disease-specific 12-month risk by sex was modelled and the age-adjusted risk calculated.

Results: The study included 304 914 people in the fatigue group and 423 671 in the non-fatigue group. In total, 127 of 237 diseases studied were more common in men who presented with fatigue than in men who did not, and 151 were more common in women who presented with fatigue. Diseases that were most strongly associated with fatigue included: depression; respiratory tract infections; insomnia and sleep disturbances; and hypo/hyperthyroidism (women only). By age 80 years, cancer was the third most common disease and had the fourth highest absolute excess risk in men who presented with fatigue (fatigue group: 7.01%, 95% confidence interval [CI] = 6.54 to 7.51; non-fatigue group: 3.36%, 95% CI = 3.08 to 3.67; absolute excess risk 3.65%). In women, cancer remained relatively infrequent; by age 80 years it had the thirteenth highest excess risk in patients who presented with fatigue.

Conclusion: This study ranked the likelihood of possible diagnoses in patients who presented with fatigue, to inform diagnostic guidelines and doctors' decisions. Age-specific findings support recommendations to prioritise cancer investigation in older men (aged ≥70 years) with fatigue, but not in women at any age, based solely on the presence of fatigue.

Keywords: cancer; cohort studies; diagnosis; fatigue; primary health care; prodromal symptoms.