Fatigue is the presenting complaint in 5–10% of GP consultations and carries a broad differential. Malignancy accounts for fewer than 1% of fatigue presentations in primary care, but the consequences of missing it are severe. The combination of weight loss, night sweats and fatigue (B-symptoms) has a high positive predictive value for lymphoma. Post-viral myocarditis is increasingly recognised, particularly post-COVID — dyspnoea on minimal exertion and exercise intolerance should prompt cardiac investigation. Suicidal ideation in the context of persistent fatigue and low mood must always be actively screened for.

Post-exertional malaise (PEM) — defined as worsening of all symptoms after even minor physical or mental effort — is the cardinal feature of ME/CFS and fundamentally changes management (graded exercise therapy is contraindicated). PHQ-2 has 97% sensitivity for depression, which is the single most common identifiable cause of fatigue in primary care. OSA is significantly underdiagnosed — up to 4% of men and 2% of women in the UK — and causes severe daytime fatigue, cardiovascular risk, and metabolic disease.

NICE NG206 (2021) fundamentally revised ME/CFS management — graded exercise therapy (GET) is no longer recommended as it worsens PEM. The new approach focuses on energy management and pacing. ME/CFS requires at least 3 months of symptoms meeting specific criteria before diagnosis — premature labelling prevents investigation of treatable causes. Iron deficiency without anaemia is a frequently missed and easily treatable cause of fatigue, particularly in women of reproductive age — ferritin <30 µg/L warrants iron supplementation even with normal haemoglobin.

Postural hypotension (drop ≥20 mmHg systolic on standing) is a key sign of Addison's disease, which can present insidiously with fatigue, weight loss, and salt craving. AF is a common underdiagnosed cause of fatigue — pulse palpation identifies this immediately. Proximal muscle weakness suggests an endocrine myopathy (hypothyroidism, Cushing's, statin-induced) rather than fatigue alone. Lymph node examination is quick and high-yield — rubbery lymphadenopathy in a fatigued patient with night sweats is a 2WW haematology referral.

A structured first-line panel detects the majority of organic causes of fatigue. Ferritin <30 µg/L (iron deficiency without anaemia) affects 15–20% of premenopausal women and causes fatigue that responds to oral iron. Coeliac disease affects 1% of the UK population and presents with fatigue (often without GI symptoms) in up to 50% of cases — anti-TTG IgA is 95% sensitive. A 9am cortisol <100 nmol/L is highly suggestive of adrenal insufficiency requiring urgent endocrinology referral. Epworth ≥10 has 80% sensitivity for clinically significant OSA.

The 2WW pathway for haematological malignancy is triggered by B-symptoms — GPs should not wait for haematology to request the referral. Early CPAP initiation for OSA reduces daytime fatigue, cardiovascular risk, and accident rates — driving ability is impaired in untreated OSA (DVLA regulations apply). ME/CFS services provide specialist assessment, energy management coaching, and support — GET and CBT aimed at activity increase are no longer recommended following NICE NG206 due to evidence of patient harm from PEM exacerbation.

Alternate-day iron dosing is supported by evidence showing equivalent absorption to daily dosing with fewer GI side effects — this improves adherence significantly. Ferrous sulfate is preferred over ferric preparations due to cost and equivalent efficacy. CPAP reduces Epworth score by 4–5 points on average (NNT ~3 for symptomatic benefit), reduces blood pressure by 3–5 mmHg, and reduces cardiovascular events in patients with moderate-severe OSA. Treating iron deficiency without anaemia resolves fatigue in 50% of affected premenopausal women within 4 weeks.

A fixed morning wake time is the single most evidence-based sleep intervention — it anchors the circadian rhythm regardless of sleep onset. Exercise is effective for fatigue in all conditions except ME/CFS — a Cochrane review found exercise reduced fatigue scores by 0.5–1.0 SD in multiple chronic conditions. The critical distinction is ME/CFS where exercise worsens outcomes through PEM — clinicians must assess for this before recommending activity. Alcohol reduces REM sleep by 25% even at low-moderate doses — this causes unrefreshing sleep and perpetuates daytime fatigue.

Persistent unexplained fatigue at 6 months warrants a fresh review — new symptoms, weight changes, or examination findings may have emerged that point towards a diagnosis. "Unexplained" fatigue is rarely truly unexplained — it is often multi-factorial (mild anaemia + poor sleep + depression) and requires addressing all contributors. Over-replacement with levothyroxine (suppressed TSH) doubles AF risk and causes significant bone loss — the target TSH is 0.5–2.5, not the lower limit. Men and postmenopausal women with iron deficiency require colorectal cancer exclusion via 2WW — GI blood loss must be excluded.