Differential Diagnosis

Common Diagnoses

Occasional Diagnoses

Rare Diagnoses

  • Malignant Disease
  • Chronic Infection (e.g. Tb, Hepatitis, HIV, Lyme Disease)
  • Chronic Neurological Disorders (Parkinson’s Disease, Myasthenia Gravis, MS, Motor Neurone Disease)
  • Other Endocrine Disorders and Deficiency States (e.g. Addison’s Disease, Hypo- or Hypercalcaemia, Hyponatraemia, Hypokalaemia)
  • Connective Tissue Diseases (RA, Polymyalgia Rheumatica [PMR], SLE)
  • Carbon Monoxide Poisoning
  • Postural tachycardia syndrome (PoTS)

Ready Reckoner

Key distinguishing features of the most common diagnoses

Diurnal VariationYesPossibleNoNoNo
Identifiable Life Event TriggersPossibleYesNoNoNo
Recent IllnessPossiblePossiblePossibleYesNo
Mucosal/Nailbed PallorNoNoYesNoPossible
Cold, Dry SkinNoNoPossibleNoYes

Possible Investigations

Likely:Urinalysis, FBC, blood glucose or HbA1c, TFT.

Possible:ESR/CRP, U&E, LFT, ferritin, calcium, anti-endomysial and anti-gliadin antibodies.

Small Print:CXR, autoantibody screen, sleep studies, further blood tests as indicated such as HIV, glandular fever test, hepatitis or Lyme disease serology, Tilt table test.

  • Urinalysis: Simple screen for diabetes and renal disease.
  • Blood glucose or HbA1c: For diabetes.
  • TFT for hypo- or hyperthyroidism.
  • FBC: The anaemias, infection and alcohol abuse.
  • ESR/CRP: Raised in a host of causes; not diagnostic but suggests a possible underlying physical cause.
  • U&E: Deranged in renal failure, hyponatraemia, hypokalaemia and Addison’s disease.
  • LFT: For liver disease (malignancy, alcohol abuse and hepatitis).
  • Ferritin: Iron deficiency may cause tiredness in the absence of anaemia.
  • Calcium: Hyper- or hypocalcaemia may cause tiredness.
  • Anti-endomysial and anti-gliadin antibodies: Will suggest a diagnosis of coeliac disease.
  • Autoantibody screen: For connective tissue disease.
  • Sleep studies: To explore the possibility of sleep apnoea.
  • Further blood tests: These will be dictated by the clinical picture and might include HIV, glandular fever or hepatitis or Lyme disease testing.
  • CXR: May reveal malignancy, cardiac failure or TB.
  • Tilt table test: if suspicion of PoTS

Top Tips

  • Tiredness as a presenting symptom, in the absence of other significant volunteered symptoms – particularly weight loss or gain – is unlikely to have a physical cause.
  • The longer tiredness has been a problem, the less likely you will find any remediable cause.
  • Make eye contact with the patient and shake hands – your first impressions as to whether or not the patient is actually ‘ill’ are likely to prove correct, and may give early clues to easily overlooked causes such as Parkinson’s disease.
  • If you suspect depression, enquire directly about relevant symptoms – you do not have to ‘exclude’ physical illness before making a presumptive diagnosis of this sort.
  • Investigations ordered are often more therapeutic than diagnostic.
  • Ask about other household members’ health and well-being. Carbon monoxide poisoning would be likely to affect them too.
  • Do not be too trigger-happy with the usual ‘blood screen’. Many patients ‘promised’ blood tests if their symptoms persist another month do not return. Also, checking blood quite often raises irrelevant abnormalities which concern the patient and confuse the issue.

Red Flags

  • Take tiredness associated with weight loss seriously – this combination suggests malignant disease or hyperthyroidism.
  • Don’t miss depressive illness by being coy in enquiry or colluding with patient denial.
  • Don’t miss easy-to-find signs when physical illness seems a real possibility – check pulse rate, mucous membranes for pallor, lymph nodes, chest and abdomen.
  • Consider a rare cause if the symptoms progress and the patient starts to look unwell.
  • Beware the very rare attender. Although the overall pick-up rate for significant physical disease is low when tiredness is presented in the absence of other significant symptoms, this does not hold for rare attenders, in whom any symptom, no matter how vague, should be taken very seriously.
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