Investigation of a patient who is tired all the time

Investigation of a patient who is tired all the time

In this article we will describe the 7 groups of causes of a patient being tired all the time (TATT); including their red flag symptoms, and which investigations to do. Often no cause is found. But you need to think about (and exclude) the causes below first.

Key Points

These are the 7 (groups of) causes and key investigations.

• Haematology – FBC (and MCV), ferritin, B12, folate
• Endocrine – TSH, glucose, HbA1c, 9am cortisol
• Metabolic/organ dysfunction – U+E/eGFR, CK, LFTs, BNP, bone biochemistry, urate
• Pregnancy/menopause – pregnancy test
• Mental health
• Other/malignancy – SPE, SFL
• Immune/infection-related
  • Immune – ANA, dsDNA, ENA,  C3/4, Ig A/G/M, RhF, PSA (in male)
  • Infection – Monospot, HepB/C/HIV, VDRL/TPHA; Borreliosis, Toxoplasmosis, EBV, CMV

Note 1. The “HEMP-MOI” (!) mnemonic may be useful
Note 2. This article is mainly for doctors, and other health professionals.

1. Haematology 

• Anaemia – symptoms include palpitations, shortness of breath and pale skin. There are many causes, including iron, B12 and folate deficiency (each of which has underlying causes, which need investigation).

Red flag symptom: shortness of breath

Investigations:

• Full blood count (FBC, including MCV) – to assess for anaemia, polycythaemia, haematological malignancy
• Ferritin, B12 and folate – for iron, B12 and folate deficiency; that can cause anaemia.

2. Endocrine

• Diabetes – symptoms include polyuria and polydipsia (particularly at night), and weight loss.
• Thyroid disease – hypothyroidism or hyperthyroidism
  • Hypothyroidism symptoms may include: tiredness, more sensitivity to cold, constipation, dry skin, weight gain, puffy face, hoarse voice, coarse hair and skin, and constipation.
  • Hyperthyroidism symptoms may include: being hard to stay still, palpitations, nervousness, anxiety and irritability, muscle weakness, and diarrhoea.
• Hypoadrenalism (underactive adrenal gland): dizziness (symptom of low blood pressure (BP).

Red flag symptoms: polyuria/polydipsia; low BP

Investigations:

• Thyroid function tests (TFTs, including TSH) – hypo- or hyperthyroidism
• Glucose and HbA1c – type 1 or type 2 diabetes mellitus
• 9am cortisol – adrenal insufficiency.

3. Metabolic disease/organ dysfunction

• Chronic kidney disease (CKD)
• Liver dysfunction
  
• Other ‘failures’ (heart, lung, gut and brain)

Red flag symptoms: Shortness of breath, ankle swelling, whole body itching

Investigations:

• Urea and electrolytes, eGFR and CK – to assess for chronic kidney disease (CKD) and/or electrolyte imbalance; CK for muscle disorders
• Liver function tests (LFTs, now called liver enzymes) – liver disease
• B-Type Natriuretic Peptide (BNP) – chronic heart failure
• Bone biochemistry (including calcium, phosphate, alk phos (bone), magnesium, vitamin D, PTH and urate (for gout, but can be normal).

4. Pregnancy and menopause-related

• Pregnancy, especially first 12 weeks (and not known to be pregnant)
• Also, if known to be pregnant or having had a baby, dealing with associated life challenges
• Menopause.

Red flag symptoms: when was last menstrual period, and what is current menstrual history?

Investigation:

• Pregnancy test (urine)

5. Mental health

• Depression and/or anxiety (or other mental illnesses). Both depression and anxiety can present with physical symptoms including tiredness.

Red flag symptoms: not eating/weight loss; not sleeping; psychotic features; unable to work; suicidal intent

6. Other / malignancy

• Obstructive sleep apnoea (OSA) – symptoms include being tired during the day because of waking up at night; making gasping, snorting or choking noises at night and loud snoring.
• Some cancers – again partly as they may cause anaemia, e.g. myeloma.
• Neurological, muscular and neuromuscular disease – muscle weakness or stiffness, e.g. Parkinson’s disease.
• Polycystic Ovary Syndrome (PCOS).
• Postural Tachycardia Syndrome (POTS) – an under-recognised cause of tiredness.
• Iatrogenic – e.g. chemotherapy, immunosuppression, anti-hypertensives (especially if BP too low, i.e. are you over-medicating?).

Red flag symptoms: of diseases above (e.g. OSA, muscle weakness or stiffness). These are very variable

Investigation:

• Myeloma screen – serum protein electrophoresis (SPE) and serum free light chains (SFL)

7. Immune and infection-related disease 

• Post-infectious chronic fatigue syndromes (CFSs)
  • These follow a viral infection including:
    • Myalgic encephalomyelitis (ME)
    • Glandular fever (due to Epstein-Barr Virus, EBV)
    • Long COVID.
  • Symptoms include extreme fatigue for at least 3 months (making it very hard to do daily activities), problems with thinking, memory and concentration, flu-like symptoms.
• Autoimmune disease – e.g. SLE, Rheumatoid disease and Coeliac disease. These can all present without typical symptoms.
• Chronic infections – e.g. rare infections like Borreliosis (Lyme disease) and Tuberculosis.

Red flag symptoms: fever, rash, joint pain

Investigations:

• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) – may be raised in chronic infection, inflammation, autoimmune disease and neoplasia. These are good ‘trouble at mill’ tests; if normal, the cause of tiredness is less likely to be anything serious
• IgA tissue transglutaminase –  coeliac disease, which can present without bowel symptoms
• Autoimmune screen – SLE, rheumatoid arthritis and related diseases: ANA, dsDNA, ENA,  C3/4, Immunoglobulins (A, G, M), Rheumatoid factor (RhF), PSA (in a man, for prostate cancer)
• Monospot test – infectious mononucleosis
• Hepatitis B/C and HIV
• Borreliosis (Lyme disease) 
• Syphilis (VDRL, TPHA)
• Toxoplasmosis, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) – latent viral infections.

Note 1. Strangely, CRP can be low in active SLE (lupus)
Note 2. Autoimmune disease can present without fever, a rash or joint pain
Note 3. There is no specific diagnostic test (blood, sputum, nasal swab etc) for chronic fatigue syndrome (CFS) or Long COVID
Note 4. Tuberculosis can be a clinical diagnosis, with all tests normal. Sometimes, in an unwell patient, you need to treat it ad see of they get better to ‘clinch’ the diagnosis,

Lifestyle issues

These issues can  be a factor in being tired all the time. They can even be the cause.

• Not getting enough sleep or finding it hard to get to sleep (insomnia).
• An unhealthy lifestyle, such as having an unhealthy diet and not getting much exercise.
• Problems at work (especially an over-focus on) or home.

Summary

We have described the 7 groups of causes of a patient being tired all the time; and their red flag symptoms and medical investigation. Often no cause is found. But you need to think about (and exclude) the causes above first. We hope it has been helpful.

Other resources

Tired all the time: medical investigation
Tired all the time: 18 blood tests

Other (non-blood) tests

In some, blood tests are not enough. The following tests may also be needed.

Urine tests 

• Urinalysis (dipstick) – for protein, blood and glucose – to assess for urinary tract infection (UTI), inflammation, diabetes, or more rarely tumours
• Urinary ACR (protein).

Microbiology

• 3 sputum samples (AFBs) – tuberculosis (TB)
• Midstream specimen of urine (MSU) – M,C&S – UTI.

Radiology 

• Chest x-ray – TB and other chronic lung diseases
• CT chest, abdomen and pelvis (CT CAP) – if all tests are negative +/-
• MRI spine.