Fatigue is one of the commonest presenting complaints in general practice and carries a broad differential. In a primary-care cohort, clear somatic pathology was diagnosed within a year in about 8% of people presenting with fatigue and malignancy was uncommon (Nijrolder et al, CMAJ 2009), but the consequences of missing it are severe. B symptoms (fever, night sweats, weight loss) are not referral triggers on their own in NICE NG12 (updated April 2026) — they are weighed when deciding on a suspected cancer pathway referral for unexplained lymphadenopathy or splenomegaly. 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 one of the four core features of ME/CFS in NICE NG206 (2021) and fundamentally changes management (NG206: do not offer graded exercise therapy). Two verbally asked screening questions had 97% sensitivity (67% specificity) for depression in general practice (Arroll et al, BMJ 2003); depression is among the commonest identifiable causes of fatigue in primary care. OSA is significantly underdiagnosed — the Wisconsin cohort estimated OSA syndrome in about 4% of men and 2% of women aged 30–60 (Young et al, NEJM 1993, US data) — and causes daytime sleepiness and fatigue and is linked with hypertension 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. NG206 lets you suspect ME/CFS at 6 weeks in adults (4 weeks in children and young people) so that early advice can start, but the diagnosis requires the four core symptoms for 3 months — 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 — in a primary-care RCT of non-anaemic menstruating women, oral iron for 12 weeks reduced fatigue more than placebo, with most benefit when ferritin was below 50 µg/L (Vaucher et al, CMAJ 2012), so a trial of iron is reasonable with low ferritin even when haemoglobin is normal — interpreting ferritin in the light of inflammation and investigating the cause.

Postural hypotension (systolic fall ≥20 mmHg or diastolic fall ≥10 mmHg after standing for at least 1 minute — NICE NG136) 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 — unexplained lymphadenopathy in a fatigued patient should prompt consideration of a suspected cancer pathway referral for lymphoma, weighing night sweats and other B symptoms (NICE NG12 (updated April 2026)).

Targeted first-line tests, chosen from the history and examination, detect common treatable organic causes while limiting incidental findings. A low ferritin (iron deficiency without anaemia) is common in premenopausal women and can cause fatigue that responds to oral iron. Coeliac disease affects about 1 in 100 people and can present with fatigue, often without GI symptoms — IgA tTG with total IgA is the first-choice test (NICE NG20). When adrenal insufficiency is clinically suspected, an 8–9am cortisol below 150 nmol/L means adrenal insufficiency is likely: start management and refer to endocrinology; 151–300 nmol/L is a grey zone (refer, short Synacthen test or repeat); above 300 nmol/L makes it very unlikely (NICE NG243, 2024; modern immunoassays). The Epworth score assesses sleepiness but is not used alone to decide OSA referral (NICE NG202).

In NICE NG12 (updated April 2026) the lymphoma trigger is unexplained lymphadenopathy (± splenomegaly for non-Hodgkin); B symptoms are weighed in that decision rather than triggering a referral alone, and persistent fatigue prompts you to consider a very urgent FBC rather than a referral. CPAP is started by the sleep service after diagnosis and improves daytime sleepiness; driving ability is impaired in untreated OSA (DVLA regulations apply). ME/CFS services provide specialist assessment, energy management coaching, and support — NICE NG206 (2021) says not to offer graded exercise therapy, and CBT may be offered only to support symptom management, not as a treatment or cure, given harm reported from post-exertional symptom exacerbation.

Alternate-day single doses of iron increase fractional absorption compared with daily divided doses (Stoffel et al, Lancet Haematol 2017) and BSG 2021 suggests alternate days if daily iron is not tolerated — this can improve adherence. BSG 2021 recommends a ferrous salt (sulfate, fumarate or gluconate) first-line. CPAP improves daytime sleepiness and quality of life and modestly lowers blood pressure, but the SAVE trial did not show fewer cardiovascular events with CPAP in moderate–severe OSA (McEvoy et al, NEJM 2016). Treating iron deficiency without anaemia reduced fatigue more than placebo over 12 weeks in non-anaemic menstruating women, most clearly when ferritin was below 50 µg/L (Vaucher et al, CMAJ 2012).

A fixed morning wake time is a cornerstone of sleep advice — it anchors the circadian rhythm regardless of sleep onset. Graded activity can help deconditioning-related fatigue, but not ME/CFS, where NICE NG206 (2021) advises against graded exercise therapy. The critical distinction is ME/CFS where exercise worsens outcomes through PEM — clinicians must assess for this before recommending activity. Alcohol suppresses and fragments REM sleep, especially in the second half of the night, even at 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) was associated with more dysrhythmias (adjusted HR 1.6) and fractures (HR 2.0) in a Tayside cohort (Flynn et al, J Clin Endocrinol Metab 2010) — NICE NG145 advises aiming for TSH within the reference range. Men and postmenopausal women with iron deficiency anaemia need GI investigation: FIT per NICE HTG690 (2023), with a suspected cancer pathway referral if FIT ≥10 µg Hb/g, and BSG 2021 bidirectional endoscopy via the local suspected GI cancer / iron-deficiency pathway — GI blood loss and malignancy must be excluded.