How can I differentiate between primary fatigue and fatigue secondary to underlying medical conditions?

To differentiate between primary fatigue and fatigue secondary to underlying medical conditions, start with a thorough clinical assessment to identify any potential underlying causes such as infections, anaemia, thyroid dysfunction, medication side effects, sleep problems, anxiety, or depression. Primary fatigue, such as that seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), often presents with characteristic features including post-exertional malaise, flu-like symptoms, cognitive fatigue, and rapid loss of muscle strength after activity. In contrast, secondary fatigue is usually linked to identifiable medical conditions or factors such as chronic diseases (e.g., multiple sclerosis, Crohn's disease, ulcerative colitis), medication side effects, or psychological conditions. Investigations should be guided by clinical suspicion and may include blood tests (full blood count, ferritin, vitamin B12, thyroid function), and imaging if cancer or other serious pathology is suspected. Referral to specialists is appropriate when fatigue is persistent, unexplained, or when diagnostic uncertainty exists, especially if criteria for ME/CFS are met or if an underlying condition cannot be managed in primary care.

Key differentiating features include:

• Primary fatigue (e.g., ME/CFS) often has fluctuating symptoms, post-exertional malaise, and multisystem involvement without an alternative diagnosis after thorough assessment.
• Secondary fatigue is associated with symptoms or signs of an underlying condition (e.g., pain, anaemia, inflammation, infection, psychological distress) and may improve with treatment of that condition.
• Fatigue related to chronic diseases like MS may be exacerbated by heat, stress, or overexertion and requires assessment for other contributing factors such as sleep disturbance or depression.

Overall, a careful history, examination, and targeted investigations are essential to distinguish primary fatigue from fatigue secondary to other medical causes, with appropriate referral when needed.

References: ¹,²,³,⁴,⁵,⁶