Introduction

This is an extremely common presentation in General Practice. The doctor should take a systematic approach, focusing on physical, psychological and social issues with a view to discovering the true aetiology and providing rational treatment or management.

Epidemiology

Only 20 to 30% of cases will have a discernible physical disease. Up to 50% of cases have a mainly psychological cause, with tiredness as a cardinal feature of depression. Around 75% of cases can be found to be suffering from some form of psychological distress. A survey from the Royal College of Paediatrics and Child Health found that the prevalence of medically unexplained severe fatigue over 3 months in 5 to 19 year-olds was 62 per 100,000.^[1] Cases were predominantly adolescent girls and were more likely to come from practices in less deprived areas, which could reflect consulting behaviours.

Risk factors

There may be physical illness, mental illness or it may simply be a question of lifestyle. Likely illnesses are different between older and younger patients.

History

Be purposeful in the direction of your questions, but also give the patient time to talk and to expand. Remember the old adage:

Do not be afraid to ask the patient, 'What do you think is the cause of the problem?' The answer may be most enlightening:

• Define exactly what is meant by tired or fatigue:
  Is it shortness of breath on exertion? Is it mental exhaustion rather than physical? Is it present all day or just towards the end of the day? Neurological disease may present as tiredness but specific muscle groups are likely to be weak.
  
  
• Note the duration of the problem:
  Is it getting worse? Was there an apparent precipitating factor? This may have been an illness such as glandular fever or influenza, a bereavement or perhaps a spouse or partner has left and the patient has to cope alone with small children and a job.
  
  
• Ask about previous levels of energy and how these compare with the present:
  Beware of platitudes like, 'What do you expect at your age?' The active elderly person who suddenly loses energy and becomes easily fatigued has serious illness.
  
  
• Has the patient noticed any other changes?:
  This may be change in weight or appetite, polyuria and thirst or sleep disturbance. Perhaps the ankles are swollen at the end of the day and nocturia more pronounced.
  
  
• Has there been a recent start or change in medication?:
  Treatments for hypertension, especially betablockers, can cause lethargy.

Ask systematically about bodily functions:

• Is weight going up or down? How is appetite?:
  Weight gain may represent comfort eating. Contrary to popular opinion, weight gain is not very marked in hypothyroidism. Thyrotoxicosis will cause tiredness and weight loss is common. Poor appetite and loss of weight occur in depression, especially with anxiety but may also represent systemic disease. Inflammatory disease or chronic infection will cause fatigue. Fatigue is common with malignancy but it tends to accompany advanced disease rather than be a presenting feature.
  
  
• Is there polyuria or nocturia? Diabetes mellitus is not the only condition to be considered. Chronic renal failure may present with lethargy and polyuria from failure to concentrate urine.
  
  
• Ask about menstruation, if applicable. Hypothyroidism may cause menorrhagia but as a cause it is uncommon. Menorrhagia may lead to non-anaemic iron deficiency or iron deficiency anaemia. The patient may have failed to notice that her period is overdue and tiredness is due to pregnancy.
  
  
• Has the bowel habit changed? Bowels are often sluggish in depression or a change of bowel habit may indicate malignancy and, with it, anaemia.
  
  
• Ask about sleep. The early morning waking of an anxious depression is characteristic but in a retarded depression sleep may be excessive. Perhaps sleep is disturbed by the demands of young children or caring for an elderly relative.

• Ask about lifestyle:
  • Excessive consumption of alcohol:
    This may be a coping mechanism or an underlying cause, especially if cirrhosis or other alcohol-related problems are developing. If alcohol is being used as a coping mechanism it is likely to aggravate rather than alleviate the problem.
  • Ask about drug taking:
    The problems of prescribed medication have been mentioned. Patients may be surprised to learn that alternative or natural remedies are just as likely to have side-effects. Because a treatment has not been adequately researched does not mean that there are no adverse effects. Illicit drugs are a more likely problem, especially amfetamines and cocaine. It is no longer appropriate to regard cannabis as a 'safe drug', especially if taken in large amounts.
  • Ask about work:
    Perhaps very long hours are worked or the addition of parental or caring responsibilities makes it a very arduous week. Sometimes people do shift work with frequent changes of shift between early, late and even night work. The role of the pineal gland and circadian rhythms is very interesting but, constantly changing the pattern of waking and sleeping with frequent changes of shift upsets the functioning of the brain and endocrine system.
  • Has there been any significant event in the patient's life that may have sparked this episode?:
    Now is the time to ask, 'Is there anything that you think may have caused all this?'

Examination

• Look at the patient:
  What do you see? Is this someone who has lost weight recently and looks systemically unwell? Do you see anxiety, tiredness or sleep deprivation? Do you see someone with the cares of the world? There may be ankle oedema from congestive heart failure although by far the most common cause is dependent oedema, especially in overweight women.
• Examination of the pulse may be revealing:
  A slight tachycardia may occur with anxiety and stress. Anaemia and thyrotoxicosis will produce a bounding, hyperdynamic pulse. Heart failure leads to sympathetic overactivity and tachycardia. Bradycardia may be found in hypothyroidism but is more likely from ischaemic heart disease. The irregular pulse of atrial fibrillation and flutter is easily recognised.
• Weigh the patient and record body mass index (BMI):
  Note also any comment that the patient may make about weight rising or falling. Tiredness and fatigue may be the result of carrying all those extra kilograms around. Loss of weight should lead to the suspicion of systemic disease.
• Further examination should be directed by clinical suspicion from history and examination so far.

Differential diagnoses^[2]

• Depression
• Obesity; obstructive sleep apnoea
• Poor sleep pattern; hard work; stress
• Treatment with a sedative; caffeine withdrawal
• Chronic fatigue syndrome
• Anaemia; iron deficiency; cancer; renal disease; liver disease; heart failure; thyroid disease; diabetes; autoimmune disease

Investigations

• Urinalysis for glucose and albumin screen for diabetes and renal disease respectively.
• FBC checks for anaemia and these may even reveal the unexpected such as leukaemia. Atypical mononuclear cells occur in glandular fever but, when lethargy presents, they have normally disappeared. If anaemia is found, the cause will need investigation.
• U&E and creatinine are basic tests that could demonstrate unsuspected renal disease. There may be weakness and lethargy from hypokalaemia due to laxative abuse and purgation.
• LFTs are also a good baseline test. The pattern of abnormal LFTs may suggest alcohol abuse. Alcohol abuse diagnosis and management in primary care can be far from simple. There may be subclinical hepatitis or metastatic disease in the liver.
• Other tests may include ESR, C-reactive protein and monospot test for glandular fever.
• Thyroid function tests are not routinely indicated in younger patients unless there is clinical suspicion but in older patients there is more likely to be unsuspected abnormality.
• If the doctor thinks that the patient is depressed but is uncertain or the patient is sceptical about the diagnosis, a validated questionnaire such as the Patient Health Questionnaire (PHQ-9) may be a useful tool.

Management

Although many patients may have little wrong medically, remember that in some there may be serious underlying disease and it is imperative that the patient does not think that you see them as a time waster or a hypochondriac. Take them seriously. Be systematic and see this consultation as a challenge to your clinical skills rather than an imposition. Management will depend upon cause:

• Physical problems such as diabetes, heart failure or serious systemic disease need appropriate management. Anaemia should be corrected. A study from primary care in Switzerland found that iron supplementation for unexplained fatigue in non-anaemic women was beneficial in a randomised placebo-controlled trial, as many subjects had low ferritin and it would be wrong to assume that iron deficiency is only a problem when anaemia occurs.^[3]
• Psychological distress is common with lethargy and fatigue and it is difficult to ascertain if this is the primary cause of the complaint or the result of it. Prescription of antidepressants may be valuable but it is a vexed question of who benefits from antidepressants? Almost all the literature is written by psychiatrists and so, presumably, based on the most severe 5% or so who get referred to a psychiatrist, and may not be valid for the rest. Antidepressants, especially selective serotonin re-uptake inhibitors (SSRIs), should be used with great care, if at all, in the young. Counselling may be beneficial.
• Fatigue and somnolence may be associated with respiratory failure and carbon dioxide retention. Obstructive sleep apnoea is associated with somnolence, lethargy and poor concentration. It may be the result of obesity as Charles Dickens noticed and this is sometimes called Pickwickian syndrome after the fat boy in The Pickwick Papers. Loss of weight is beneficial.
• The doctor may help the patient to identify social and lifestyle issues that are responsible in part or in whole. The patient may be in a position to address them but, even if they are unavoidable, the mere fact that someone has discussed them and lent an empathetic ear can be therapeutic.
• Drug or alcohol abuse may need to be addressed.

Even if no cause has been found the patient may be reassured that a diligent search has failed to find one. Hence, the patient may be happy to await spontaneous resolution. A therapeutic trial of antidepressants may be worthwhile.

Prognosis

• A study from Holland followed up 12,000 employees over just 2 years. 2,108 complained of severe fatigue but were not on sick leave. There was typically remission and relapse with time but the absolute risk of long-term absenteeism was small. Factors that predicted recovery included lower levels of severity of fatigue, work-related exhaustion and anxious mood, absence of conflicts with colleagues, and good self-rated health at baseline. Older age, low decision authority, female sex, working nightshift, a physical attribution of fatigue, and a history of absenteeism were predictors of the start of long-term absenteeism. They concluded that prevention and treatment of fatigue should be aimed at health perception and emotional well-being.^[4]
• The management of medically unexplained physical symptoms (MUPS) involves collaborative approaches between doctor and patient to identify problems. There has to be assessment of medical importance of the symptoms and readiness of the patient to initiate change of behaviour. Negotiated treatment goals and outcomes, gradual physical activity and exercise prescription are all beneficial. In addition, efforts should be made to teach and support active rather than passive coping with the symptoms.^[5]

Chronic fatigue syndrome

See separate article Chronic Fatigue Syndrome.

This is a complex disorder of unknown aetiology. Until relatively recently, many clinicians had remained sceptical over its existence as a disease entity; however, it has now gained acceptance in most circles and much research is currently underway in an attempt to learn more about the disorder.^[6] It is a chronic debilitating disorder in which chronic fatigue is the primary symptom. National Institute for Health and Clinical Excellence (NICE) guidelines were published recently.^[7]