Tired all the time - red flag symptoms

Red flag symptoms, appropriate investigations in primary care, how to rule out serious pathology and when to refer.

(Photo: Getty Images)
(Photo: Getty Images)

Red flag symptoms1

  • Significant unexplained weight loss
  • Lymphadenopathy with features of malignancy or infection such as HIV
  • Other features of malignancy - haemoptysis, dysphagia, rectal bleeding, altered bowel habit, breast lump, postmenopausal bleeding (also see NICE guidance on suspected cancer2)
  • Muscle or joint pain suggestive of inflammatory joint or connective tissue disease
  • Localising or focal neurological signs
  • Suicidal ideation

'Tired all the time' (TATT) is a common yet nebulous symptom that can be difficult to manage, with numerous differentials and the potential to miss serious illness.

However, nearly three-quarters of TATT episodes are isolated and will improve with time and careful communication.3 Clarifying the patient's concerns and expectations early may help to avoid progression to chronic fatigue.4

Possible causes

  • Iron deficiency anaemia (menstruation)
  • Malignancy
  • Post-infectious
  • Psychological illness
  • Social/lifestyle stressors
  • Systemic illness
  • Toxic exposure such as carbon monoxide poisoning

Taking the history

In primary care we aim to consider physical, psychological, social and environmental causes while, at the same time, excluding serious pathology. Taking a good history is essential to narrowing down a potentially enormous array of differentials, all of which cannot be covered here. Specific points to consider are listed below.

Appetite - Loss of appetite can suggest serious pathology, but a poor diet and inadequate hydration can also cause fatigue.

Cognitive changes - For example, ‘brain fog’ which can be experienced in conditions such as thyroid disease and perimenopause.

Infectious illness - Viral or post-viral fatigue including Epstein-Barr virus and post-acute COVID-19; risk factors for chronic infection such as TB, HIV or hepatitis.

Medications - Including prescribed medicines – such as antihypertensives, statins, antihistamines, antidepressants, opioids – and over-the-counter or herbal remedies.

Menstruation - Menorrhagia leading to anaemia, oligo/amenorrhoea (for example, as a result of menopause or pregnancy).

Neurological symptoms - Parkinson's disease, MS, neurodegenerative conditions.

Polyuria/nocturia - Diabetes, kidney disease.

Symptoms of inflammatory or autoimmune conditions - For example, thyroid disease, Addison's disease, coeliac disease and inflammatory bowel disease.

Symptoms or past history of chronic disease - For example COPD, ischaemic heart disease, liver disease and chronic skin conditions.

Symptoms of anxiety or depression - Anxiety and depression can present with fatigue and tiredness.

Sleep patterns - Working night shifts, frequent travel, stress, sleep apnoea, restless legs, allergic rhinitis, cough, and GORD can all disrupt sleep patterns. Consider excessive daytime sleepiness (see next page).

Weight changes - Being overweight or obese can in itself cause tiredness. Being underweight may be a direct or indirect cause (for example, as a result of malignancy, hyperthyroidism, or an eating disorder).

Family history - For example, cancer, diabetes, thyroid disease, autoimmune disease or early menopause.

Social history - Smoking, alcohol, caffeine, drug misuse, carbon monoxide poisoning, stressors (such as childcare, relationship problems, other significant life events).

Occupational history - For example, asbestos exposure, working hours.

Travel, insect or tick bites - Consider tropical infection or Lyme disease.

Questions to ask

  • What exactly does the patient mean by 'tired'?
  • What is 'all the time'? Duration, pattern, diurnal variation.
  • What is the patient's usual level of functioning and have there been any previous episodes of fatigue? Beware, an active elderly person who suddenly loses energy may have serious pathology.
  • What is a typical day in the patient's life? What is the effect of their tiredness on daily activities, life, work, and relationships?
  • Are there any associated symptoms? Conduct a quick systems review.
  • How is the patient's mood?
  • Ask the patient: 'Is there anything that you think may have caused this?'

Excessive daytime sleepiness

Excessive daytime sleepiness (EDS) is the inability to maintain wakefulness and alertness during the major waking episodes of the day, with sleep occurring unintentionally or at inappropriate times almost daily for at least three months. It is different from fatigue/TATT.

Causes include sleep apnoea, narcolepsy and periodic limb movement syndrome and the approach to assessment is different for each.

A useful starting question is: 'Do you feel sleepy or fall asleep when you are tired?'1


Consider the following as part of your examination:

  • General appearance, for example pallor, oedema, jaundice, lymphadenopathy, clubbing, gait, affect
  • Weight, height and BMI
  • Blood pressure and temperature
  • Pulse (rate, rhythm, character)

The rest of the examination will be guided by the history.


Investigations may be delayed for four weeks unless there are red flags, or a suggestion of an atypical or specific cause.5

Investigations in primary care may include:

  • Urinalysis: infection, glucose, protein, blood.
  • Initial blood tests1: full blood count (plus ferritin in women of childbearing age or if there are other risk factors for iron deficiency), liver function, urea and electrolytes, HbA1c, thyroid function test, IgA tissue transglutaminase and ESR or CRP.
  • Others if clinically indicated: tests for Epstein-Barr virus, hepatitis, HIV, borreliosis (Lyme), CMV and toxoplasmosis, bone biochemistry and myeloma screen, vitamin D levels, creatine kinase, PSA, CA-125, ECG, chest x-ray, spirometry.2,6

If initial tests are normal, reassurance and watchful waiting may help, along with addressing any contributing social, psychological or lifestyle factors.

Iron deficiency may be an under-recognised cause of tiredness in menstruating women.7 If ferritin is less than 50 micrograms/L, consider treatment, even if Hb is within normal range. Further management will be guided by clinical and laboratory findings.

When to refer

You should refer if:

  • there are red flags or suspected malignancy
  • symptoms are atypical or progressive and the patient appears unwell
  • a rare or serious cause is suspected or identified that could not be managed in primary care
  • there is diagnostic uncertainty and the patient would benefit from a specialist assessment

Check diagnostic criteria for chronic fatigue syndrome (CFS) if new, unexplained symptoms persist beyond four months and consider referral to a specialist CFS clinic.8

NICE guidance on suspected cancer

NICE recommends the following actions in people who present with persistent or unexplained fatigue in primary care:2

Symptom and specific featuresPossible cancerRecommendation
Fatigue (unexplained), 40 and over, ever smokedLung or mesotheliomaOffer an urgent chest X-ray (to be performed within 2 weeks)
Fatigue (unexplained), 40 and over, exposed to asbestosMesotheliomaOffer an urgent chest X-ray (to be performed within 2 weeks)
Fatigue with cough or shortness of breath or chest pain or weight loss or appetite loss (unexplained), 40 and overLung or mesotheliomaOffer an urgent chest X-ray (to be performed within 2 weeks)
Fatigue (persistent) in adultsLeukaemiaConsider a very urgent full blood count (within 48 hours)
Fatigue (unexplained) in womenOvarianCarry out tests in primary care* 

Measure serum CA125 in primary care*
*The recommendations for ovarian cancer apply to women aged 18 and over.

  • Dr Shah is a GP, primary care tutor and and public health associate in Oxford

Take a test on this article and claim your certificate on MIMS Learning


  1. NICE. CKS. Tiredness/fatigue in adults. March 2020.
  2. NICE. Suspected cancer: recognition and referral. NG12. 29 January 2021.
  3. Kenter EGH, Okkes IM, Oskam SK et al. Tiredness in Dutch family practice. Data on patients complaining of and/or diagnosed with "tiredness". Fam Pract 2003; 20(4): 434-40.
  4. Nijrolder I, Van der Windt D, Van der Horst H. Prediction of outcome in patients presenting with fatigue in primary care. Br J Gen Pract 2009; 59(561): e101-9.
  5. Koch H, Van Bokhoven MA, Ter Riet G et al. Ordering blood tests for patients with unexplained fatigue in general practice: what does it yield? Results of the VAMPIRE trial. Br J Gen Pract 2009; 59(561): e93-100.
  6. Hamilton W, Watson J, Round A. Investigating fatigue in primary care. BMJ 2010; 341(aug24_2): c4259.
  7. Vaucher P, Druais P-L, Waldvogel S et al. Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial. Can Med Assoc J 2012; 184(11): 1247-54.
  8. NICE. Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management of CFS/ME in adults and children. CG53. 22 August 2007.

This is an updated version of an article that was first published in October 2015.

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