Red flag symptoms: Tired all the time

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

Iron deficiency may be a cause of tiredness
Iron deficiency may be a cause of tiredness

Red flag symptoms

  • Significant unexplained weight loss
  • Lymphadenopathy with features of malignancy
  • Other features of malignancy - haemoptysis, dysphagia, rectal bleeding, altered bowel habit, breast lump, postmenopausal bleeding (also see below, NICE guidance on suspected cancer)
  • Localising or focal neurological signs
  • Carbon monoxide poisoning
  • Suicidal ideation

'Tired all the time' (TATT), a common yet nebulous symptom, 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.2Clarifying the patient's concerns and expectations early may help to avoid progression to chronic fatigue.3

Possible causes
  • Iron deficiency anaemia (menstruation)
  • Malignancy
  • Psychological illness
  • Social/lifestyle stressors
  • Systemic illness


In primary care we aim to distinguish between physical, psychological and lifestyle-related causes whilst at the same time excluding serious pathology. Taking a good history will be essential to narrowing down a potentially enormous array of differentials, all of which cannot be covered here. Specific points to consider include:

  • Appetite - loss can suggest serious pathology, but a poor diet and inadequate hydration can also cause fatigue.
  • Menstruation - menorrhagia leading to anaemia, oligo/amenorrhoea (for example, due to menopause, pregnancy).
  • Neurological symptoms - Parkinson's, MS, neurodegenerative conditions.
  • Polyuria/nocturia - diabetes, kidney disease.
  • Recent illness, risk factors for chronic infection such as TB, HIV or hepatitis.
  • Symptoms of inflammatory or autoimmune conditions such as thyroid disease, Addison's, coeliac disease, inflammatory bowel disease.
  • Symptoms or past history of chronic disease such as COPD, ischaemic heart disease, liver disease, chronic skin conditions.
  • Symptoms of anxiety, depression.
  • Sleep patterns - night shifts, frequent travel, stress, sleep apnoea, restless legs, allergic rhinitis, cough, GORD.
  • Weight changes - being overweight or obese can in itself cause tiredness. Being underweight may be a direct or indirect cause (for example, due to malignancy, hyperthyroidism, or eating disorder).
  • Family history - cancer, diabetes, thyroid and autoimmune disease.
  • Social history - smoking, alcohol, caffeine, drugs, carbon monoxide poisioning, stressors (such as childcare, relationship problems, other significant life events).
  • Occupational history such as 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?
  • 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?'

 Important! An active elderly person who suddenly loses energy may have serious pathology


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


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

Investigations in primary care may include:

  • Urinalysis: infection, glucose, protein, blood
  • Initial blood tests: FBC (plus ferritin in women of childbearing age or if other risk factors for iron deficiency), glucose, TSH and ESR
  • Others if clinically indicated: U&Es, LFTs, CRP, Epstein-Barr virus serology, hepatitis and HIV serology, calcium, coeliac screen, creatinine kinase, PSA, CA-125, 5,6 ECG, CXR, spirometry. 

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

  • If red flags or suspected malignancy
  • If symptoms are atypical or progressive and the patient appears unwell
  • If a rare or serious cause is suspected or identified that could not be managed in primary care
  • If there is diagnostic uncertainty and the patient would benefit from a specialist assessment
  • Check diagnostic criteria for chronic fatigue syndrome (CFS) if symptoms persist beyond four monthsand consider referral to a specialist CFS clinic

NICE guidance on suspected cancer

NICE recommends the following in people who present with persistent or unexplained fatigue in primary care:6

Symptom and specific features Possible cancer Recommendation
Fatigue (unexplained), 40 and over, ever smoked Lung or mesothelioma Offer an urgent chest X-ray (to be performed within 2 weeks)
Fatigue (unexplained), 40 and over, exposed to asbestos Mesothelioma Offer 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 over Lung or mesothelioma Offer an urgent chest X-ray (to be performed within 2 weeks)
Fatigue (persistent) in adults Leukaemia Consider a very urgent full blood count (within 48 hours)
Fatigue (unexplained) in women Ovarian Carry 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

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  1. NHS Clinical Knowledge Summaries. Tiredness/fatigue in adults. 2015.
  2. Kenter EGH, Okkes IM, Oskam SK et al. Tiredness in Dutch family practice. Fam Pract 2003; 20(4): 434-40.
  3. 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.
  4. 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
  5. Hamilton W, Watson J, Round A. Investigating fatigue in primary care. BMJ 2010; 341(aug24_2): c4259.
  6. National Institute for Health and Care Excellence. Suspected cancer: recognition and referral. 2015
  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. National Collaborating Centre for Primary Care. Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy). 2007.

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

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