Key Facts

Fatigue is one of the most common symptoms in primary care. It encompasses physical tiredness, mental exhaustion, and lack of motivation. A structured approach is needed as the differential is broad, spanning organic disease, psychological conditions, medications, and lifestyle factors.

Epidemiology

• Prevalence of significant fatigue in the community: 10-20%
• More common in women (1.5:1 ratio)
• Accounts for approximately 5-7% of GP consultations
• An organic cause is identified in about 50% of cases
• Psychological cause identified in 20-30%

Aetiology

• Haematological: iron deficiency anaemia, B12/folate deficiency, haemolytic anaemia
• Endocrine: hypothyroidism, diabetes mellitus, Addison disease, hypercalcaemia
• Infection: post-viral fatigue, EBV, hepatitis, HIV, TB
• Cardiac: heart failure, valvular disease
• Respiratory: COPD, sleep apnoea
• Autoimmune: coeliac disease, SLE, rheumatoid arthritis
• Malignancy: any cancer (fatigue may be presenting symptom)
• Psychological: depression, anxiety, chronic stress
• Lifestyle: sleep deprivation, excessive alcohol, sedentary behaviour, poor nutrition
• Medications: beta-blockers, statins, SSRIs, antihistamines, opioids

Pathophysiology

• Fatigue is a complex symptom with central (brain-mediated) and peripheral (muscular) components
• In anaemia, reduced oxygen-carrying capacity leads to tissue hypoxia
• Hypothyroidism reduces basal metabolic rate
• Depression is associated with altered serotonin, noradrenaline, and dopamine signalling
• CFS/ME pathophysiology is incompletely understood but may involve immune dysregulation, autonomic dysfunction, and altered energy metabolism

History Assessment

• Duration and onset (acute vs chronic)
• Character: physical vs mental vs both
• Impact on daily activities and function
• Sleep quality and quantity (screen for obstructive sleep apnoea)
• Mood assessment (PHQ-9 for depression, GAD-7 for anxiety)
• Menstrual history in women (menorrhagia)
• Weight change, appetite change
• Medications and alcohol/substance use
• Occupational and psychosocial history

Clinical Features Suggesting Specific Diagnoses

• Pallor, tachycardia, koilonychia — anaemia
• Cold intolerance, weight gain, constipation, dry skin — hypothyroidism
• Polyuria, polydipsia, weight loss — diabetes
• Lymphadenopathy, night sweats, weight loss — lymphoma/malignancy
• Joint pain, rash, oral ulcers — SLE/autoimmune
• Bloating, diarrhoea, weight loss — coeliac disease
• Snoring, daytime somnolence, obesity — obstructive sleep apnoea

Red Flags

• Unexplained weight loss (>5% over 3 months)
• Night sweats
• Lymphadenopathy
• New focal neurological signs
• Rectal bleeding or change in bowel habit in patients >50
• Progressive breathlessness
• Suicidal ideation

Bedside

• BMI and weight
• Blood pressure
• Urinalysis (glycosuria, proteinuria)
• PHQ-9 and GAD-7 questionnaires
• Epworth Sleepiness Scale if sleep apnoea suspected

Bloods

• FBC: anaemia (microcytic, macrocytic), lymphocytosis, pancytopenia
• Ferritin: iron deficiency (low ferritin <30 mcg/L is diagnostic; consider <50 mcg/L as cut-off in presence of inflammation)
• U&Es: renal failure, electrolyte disturbance
• TFTs: hypothyroidism
• HbA1c: diabetes mellitus
• LFTs: liver disease
• CRP/ESR: inflammation, infection, malignancy
• Coeliac screen: anti-tTG IgA + total IgA
• Calcium: hypercalcaemia
• B12 and folate: macrocytic anaemia

Imaging

• CXR if respiratory or cardiac cause suspected
• Echocardiogram if heart failure suspected

Special Tests

• Polysomnography/home sleep study if obstructive sleep apnoea suspected
• Short Synacthen test if Addison disease suspected
• HIV test if risk factors present
• CT chest/abdomen/pelvis if malignancy suspected

Non-pharmacological

• Sleep hygiene education
• Graded return to physical activity (unless CFS/ME — energy management approach per NICE NG206)
• Dietary advice: balanced diet, adequate iron and B12 intake
• Alcohol reduction advice
• Psychological support: CBT for fatigue, depression, anxiety
• Address occupational and psychosocial stressors
• Self-management support

Pharmacological

• Treat underlying cause:
  • Iron deficiency: ferrous sulphate 200mg BD-TDS for 3 months after Hb normalises
  • Hypothyroidism: levothyroxine, starting dose 25-50mcg OD (lower in elderly/cardiac disease), titrate to normalise TSH
  • B12 deficiency: hydroxocobalamin 1mg IM on alternate days for 2 weeks, then every 3 months
  • Depression: SSRI (sertraline 50mg OD, increase to 100-200mg) as first-line; consider mirtazapine 15-45mg nocte if insomnia prominent
  • Diabetes: manage per NICE NG28
• CFS/ME: no specific pharmacological treatment recommended; manage symptoms (pain: low-dose amitriptyline 10mg nocte; sleep disturbance: melatonin 2mg MR)

Surgical

• Not generally applicable unless specific surgical cause (e.g. uterine artery embolisation for menorrhagia)

Referral Criteria

• Suspected malignancy: 2-week-wait referral
• Suspected CFS/ME: refer to specialist CFS/ME service if no improvement after 3 months (NICE NG206)
• Suspected sleep apnoea: sleep clinic referral
• Refractory or unexplained fatigue after initial investigation: secondary care review

• Iron deficiency anaemia: Hb normalises within 6-8 weeks of iron supplementation; fatigue often improves within 2-4 weeks
• Hypothyroidism: symptoms improve within 3-6 months of levothyroxine replacement
• Depression: 50-60% respond to first-line SSRI; recurrence rate 50% after single episode
• CFS/ME: 40-60% show some improvement over time; full recovery in 5-10%; 25% remain severely affected
• Post-viral fatigue: most recover within 6-12 months
• In cases with no identified cause, 50-70% report improvement over 1-2 years with supportive management

Recommended Fatigue Screening Bloods

CFS/ME Diagnostic Criteria (NICE NG206)