CCFP Topic: Fatigue

This varies by source, but on average about a quarter of patients presenting with unexplained fatigue will have a form of depression. Use your SIGECAPs and your PHQ-9. 

Or, to keep your review of systems tight, start with a PHQ-2 first, and if positive move on to the more thorough PHQ-9. A brief recap, the PHQ-2 focuses on just two questions:

But consider other psychiatric conditions on your differential as well, such as eating disorders, anxiety disorders or somatization. 

And don’t forget to ask about substance use. Alcohol, marijuana and opioids can all contribute to fatigue, particularly when there is overuse or dependency. Ask about stimulants too, such as cocaine and methamphetamines.

On history, your OPQRST can be helpful. Patients who fatigue with exertion or particular activities may be more likely to have a medical condition.

Whereas  “tired all the time” (air quotes), or having fatigue that does not improve with rest, is more often associated with psychological conditions, medication side effects or substance use.

Sleep is obviously important. You want to know about the quality and length of sleep, and whether sleep is restful. Symptoms like snoring or apnea should make you think about obstructive sleep apnea. Daytime sleepiness can also point to sleep apnea or to another primary sleep disorder.

In terms of your review of systems and physical exam, a systems-based approach can be helpful because the differential is so broad. And it also helps you ensure you don’t miss the big red flags for underlying disease. For example:

•  B symptoms like weight loss, fevers and night sweats and signs like lymphadenopathy should make you consider malignancy.
• Fever should of course also make you consider various infections, such as mononucleosis or endocarditis, depending on the other associated signs and symptoms.
• Ask about dyspnea and chest pain, and examine the heart and lungs to look for signs of diseases like congestive heart failure or COPD.
• Ask about heat or cold intolerance, and weight change, and look for signs like bradycardia or tachycardia, skin changes, or goiters that could point to thyroid disease.
• And ask about morning stiffness and diffuse muscle pain, and do skin and MSK exams to look for rheumatological conditions like polymyalgia rheumatica, rheumatoid arthritis, or fibromyalgia.

Condition	Symptoms	Physical findings	Supportive diagnostic studies
Cardiopulmonary
Congestive heart failure	Dyspnea on exertion, orthopnea, leg swelling	S3 gallop, inspiratory rales, elevated jugular venous distension, peripheral edema	Chest radiograph, echocardiogram
Chronic obstructive pulmonary disease	Dyspnea, chronic cough, sputum production	Evidence of hyperinflation, wheezing, rales	Chest radiograph
Sleep apnea	Snoring, interrupted breathing during sleep	Obesity, hypertension	Sleep study
Endocrinologic/metabolic
Hypothyroidism	Cold intolerance, weight gain, constipation, dry skin	Bradycardia, goiter, slow deep tendon reflex relaxation phase	Thyroid function tests
Hyperthyroidism	Heat intolerance, weight loss, diarrhea, moist skin	Tachycardia, goiter, ophthalmopathy	Thyroid function tests
Chronic renal disease	Nausea/vomiting, mental status changes, decreased urine	Hypertension, peripheral edema	Renal function tests/ serum electrolytes
Chronic hepatic disease	Abdominal distention, gastrointestinal bleeding	Jaundice, palmar erythema, gynecomastia, splenomegaly, evidence of ascites	Hepatic function tests
Adrenal insufficiency	Weight loss, salt craving, gastrointestinal complaints	Hypotension, hyperpigmentation, vitiligo	Morning cortisol/ACTH, ACTH stimulation test
Electrolyte abnormalities
Hyponatremia	Nausea, malaise, cognitive dysfunction	Generally normal exam	Serum sodium level
Hypercalcemia	Anorexia, polydipsia/polyuria, nausea	Generally normal exam	Serum calcium/albumin levels
Hematologic/neoplastic
Anemia	Dizziness, weakness, palpitations, dyspnea	Tachycardia, pallor	Complete blood count
Occult malignancy	Weight loss, localized symptoms may be present depending upon type	Variable	Variable depending upon type
Infectious diseases
Mononucleosis syndrome	Fever, sore throat, tender lymph nodes	Fever, exudate pharyngitis, tender cervical adenopathy	Complete blood/differential count, monospot
Viral hepatitis	Fever, nausea/vomiting, abdominal discomfort	Fever, jaundice, tender hepatomegaly	Hepatic function tests, viral hepatitis serologies
HIV infection	Weight loss, variable localized complaints	Variable physical findings	HIV serology
Subacute bacterial endocarditis	Fever/chills, night sweats, myalgias	Fever, new (regurgitant) murmur, peripheral manifestations	Blood cultures, echocardiogram
Tuberculosis	Fever/chills, night sweats, fatigue, weight loss	Cough, chest pain, dyspnea, hemoptysis	PPD/gamma-interferon assay, chest radiograph
Rheumatologic
Fibromyalgia	Chronic diffuse muscle pain	Multiple “tender points” on palpation	None
Polymyalgia rheumatica	Aching/morning stiffness of shoulders, neck, and hips	Decreased range of motion of shoulders, neck, and hips	Erythrocyte sedimentation rate
Psychological
Depression	Sad mood, anhedonia, altered sleep, cognitive dysfunction	Generally normal exam	Screening test (eg, PHQ-2, PHQ-9)
Anxiety disorder	Generalized nervousness, panic attacks, phobias	Tachycardia, muscle tension	Screening test (eg, GAD-7)
Somatization disorder	Multiple chronic constitutional and localized complaints	Generally normal exam	Screening test (eg, SSS-8)
Medication toxicity*
	Variable	Generally normal exam	None
Substance use¶
	Variable	Generally normal exam	None

* Benzodiazepines, antidepressants, muscle relaxants, first-generation antihistamines, beta-blockers, opioids, GABA analogues.

¶ Alcohol, marijuana, opioids, cocaine/other stimulants.

Ask about both prescriptions and over the counter medications, vitamins and supplements.

Common culprits include benzodiazepines, antidepressants, muscle relaxants, first-generation (and sometimes second-generation) antihistamines, beta-blockers, opioids, and GABA analogues.

When patients have renal or hepatic impairment, consider whether they could be developing toxicity with their medications and ensure proper dose adjustments. Environmental exposure to toxins like lead or arsenic are way less common these days, but still worth thinking about, especially if relevant to the patient’s occupation or home environment.

Your physical exam and history should guide your investigations. This includes making sure any age-specific cancer and medical screening tests – like FIT testing, mammograms, A1Cs, all that stuff – are up to date.

And consider whether your patient has specific risk factors that should prompt particular testing – for example, if your patient has a life-long history of smoking or strong family history of particular cancers, then extra screening might be appropriate.

Serologic screening for conditions like HIV or Hepatitis B and C are not appropriate to do routinely for everyone – but consider doing them if your patient has never had them done before at all, or if they engage in activities that put them at an increased risk.

Ok. But what if your patient’s screening is already up to date and your assessment hasn’t revealed any specific indications for labs or imaging? Can’t I just order everything but the kitchen sink and hope I find the answer?

There isn’t much evidence on this – but if your pre-test probability for a particular condition is already low, investigations are unlikely to be helpful. The few studies we found suggest labs affect management or clarify the cause of fatigue in only about 5 to 8% of patients! 

A Systematic Review in 2016 in BMC Family Practice found that a presenting complaint of tiredness led to a diagnosis of:

• anaemia in 2.8% of cases
• malignancy in 0.6% of cases
• serious somatic disease in 4.3% of cases
• and depression in 18.5% of cases.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072300/

In acute fatigue, if you’ve already determined that your patient has a likely underlying cause that doesn’t require further investigations, then it’s reasonable to trial treatment or conservative management first, as appropriate. If your patient has depression, treat the depression!

All that said, most sources do still recommend a few routine labs, especially if symptoms persist beyond a few weeks.

Consider ordering a CBC and differential, chemistries like electrolytes, a random glucose and hemoglobin A1c, calcium, renal and hepatic function tests, and a TSH – these will rule out your most common secondary causes, like anemia, and some more serious conditions like cancer.

Some sources would also recommend considering a CRP, a Vitamin B12, a urinalysis and pregnancy tests, but again, mileage will vary.

Ok. But now what if these all come back normal, and there are no other localized findings? Then can I start looking for zebras?

Well, then there is not much evidence that repeating tests will be helpful, unless something in the patient’s presentation changes. And if those basic labs are normal, there is no good evidence for going fishing for rare immunological conditions or vitamin deficiencies.

This means you don’t need to go ordering tests like an ANA, or Lyme serologies, or Vitamin D levels, unless you’ve really got a good reason.

Though we didn’t find good Canadian sources for this, Australian Family physician published a document regarding investigations for Fatigue in Primary Care. We will link to this and the shownotes include a pathway they recommend, which is very much as we just review, as well as some red flags to look for that should prompt further investigations. https://www.rcpa.edu.au/getattachment/17c38096-b72f-4f30-82d8-5426b93ee623/Investigating-fatigue.aspx

On average, only about two-thirds of primary care patients with chronic fatigue will receive a specific diagnosis to explain it. For that other third, it’s important to acknowledge their fatigue as real even when you can’t find a medical explanation.

Exploring the psychosocial factors and behaviours that may be at play can help your patients recognize the causes of their fatigue, which is also the first step to potentially address them.  If fatigue becomes chronic, it’s also important to consider the diagnosis of Chronic Fatigue Syndrome, which we will talk about in the next objective.

Sleep is a key place to start.

Are they getting enough sleep? Patients may need to prioritize making enough time in their day for sleep, and may need some coaching on good sleep hygiene. These are things like getting up at the same time every day, reducing exposure to screens before bed, and avoiding caffeine, alcohol or eating too much later in the day.

In some cases, cognitive behavioural therapy for insomnia or pharmacotherapy may also be appropriate. Although in practice I’ve never had any luck getting patients to take me up on going for formal CBTi, this is something that you can sometimes sneak into your office visit.

Sleep can be a particular struggle for shift workers, who often struggle with altered sleep wake cycles and may require a combination of behavioural changes and medications to get their sleep back on track. 

Other areas to explore could include work stress and work hours, interpersonal relationships and risk factors for domestic violence, financial stressors, or caregiver responsibilities.

Some of these aspects can be challenging to address or will be outside your scope as a family doctor. But once you and your patient have recognized them as contributing, you can at least look to make appropriate referrals or loop them in with services like social work that might be helpful.

‘Chronic fatigue’ is defined as lasting over 6 months. It’s important to distinguish ongoing secondary fatigue that’s due to another condition, from both idiopathic chronic fatigue and chronic fatigue syndrome (CFS – also known as myalgic encephalomyelitis/Chronic fatigue syndrome, or ME/CFS).

Chronic fatigue syndrome is one of those conditions where we still have a very poor understanding of the pathophysiology or cause, nor is there a specific or sensitive test to diagnose it.

TOP (Towards Optimized Practice) has a great set of guidelines on CFS which we will link to in the show notes for more details. It is considered an uncommon cause of chronic fatigue – but while there is not a lot of good data on the prevalence in Canada, the guidelines suggest prevalence may be as high as 1.4% in Canadians over the age of 12.

A key feature on history that should make you consider CFS is:

•  pathological fatigue and post-exertional malaise that is out of proportion to the level of exertion, and
• that takes more than 24 hours to recover.

It is often associated with a precipitating cause like a flu-like illness, but it can come on gradually. It’s also important to realize that the severity of CFS can range from mild (able to work with effort) to severe (essentially bedbound).

There are several tools for diagnosing CFS in the literature. The Toward Optimized Practice (TOP) guidelines recommend the validated Canadian Consensus Criteria as the most specific to help you distinguish CFS from psychiatric conditions – they are pretty detailed, so we will include the complete criteria in the show notes. But in brief, a patient with CFS will have at least:

• a 6-month history (3 months in children) of the following:
  • fatigue,
  • post-exertional malaise or fatigue,
  • sleep dysfunction and pain;
• they also need two or more categories of neurological or cognitive manifestations, such as
  • confusion,
  • impaired concentration,
  • information processing difficulties or word finding issues,
  • disorientation, or
  • perceptual and sensory disturbances),
• and at least one symptom from at least two other categories of symptoms (these include autonomic, immune and neuroendocrine symptoms).

Typically the physical exam is normal. Patients often feel febrile, but rarely have an elevated temperature. Painful lymph nodes, especially cervical lymph nodes, are also common, but there is rarely true lymphadenopathy. And although patients often experience sore joints and muscles, on exam there is not typically any swelling or erythema, and studies like biopsies and EMGs are normal.

In terms of supportive management, any ongoing fatigue of any etiology can lead to high levels of health care utilization and disability. It’s important to realize that patients can be sicker than they look.

Regardless of the etiology, again, super important to start by acknowledge fatigue as real and trying to build that therapeutic relationship.

Many symptoms associated with fatigue are common to CFS and other chronic conditions, and can often be treated similarly, although there are some particular considerations – check out those TOP guidelines for more details on treating CFS specifically.

In general, if you think there’s a medical reason for their fatigue – like heart failure – then you should monitor their symptoms while treating the underlying condition to see if the fatigue improves. If not, then you need to consider other causes and potentially repeat your initial evaluation.

You also want to continue to support patients to address those life circumstances we talked about in Objective Five.

For patients with overlapping depressive symptoms, it may be reasonable to trial an antidepressant, even if they do not meet criteria for a major depressive disorder. First line options would include SSRIs and SNRIs. 

Cognitive behavioural therapy and group therapies can be helpful in helping patients understand their fatigue symptoms and work towards achieving personal goals. This can be particularly helpful for patients with overlapping symptoms of depression or anxiety.

For some patients, especially those in which you suspect some degree of physical deconditioning, exercise therapy may also be beneficial. 

And finally, remain vigilant for new diseases. Changes in symptoms or signs should prompt you to reconsider your original diagnosis, as underlying disease processes may declare themselves over time.