Laboratory evaluation for fatigue

Laboratory evaluation for fatigue

  • CBC 
    • Decreased hemoglobin or hematocrit values indicating anemia could explain fatigue, requiring further evaluation for underlying causes
    • Pancytopenia is concerning for hematologic malignancy but could also be due to nutritional deficits or sequelae of viral illnesses
  • Serum chemistry panel
    • Abnormalities in electrolyte levels, glucose level, or liver or renal function test results could explain fatigue
    • Hyponatremia may indicate volume overload states (eg, chronic kidney disease, congestive heart failure) or syndrome of inappropriate antidiuretic hormone (which accompanies several chronic illnesses)
    • Hypokalemia may indicate aldosteronism
    • Combination of hyponatremia and hyperkalemia may indicate adrenal insufficiency
    • Low BUN and creatinine levels indicate malnutrition and decreased muscle mass, whereas elevated BUN and creatinine levels indicate renal failure
    • Hypercalcemia of hyperparathyroidism, cancer, or sarcoidosis can be associated with fatigue
    • Increased bilirubin level may indicate hemolysis or hepatitis
  • Thyroid function tests
    • TSH-only testing is appropriate for most patients, but if there is high index of suspicion for thyroid disease, then obtain both TSH and peripheral thyroid hormone levels (serum free T₄ and serum total T₃)
    • For most patients, a subnormal TSH level indicates hyperthyroidism, whereas an elevated TSH level reflects subclinical or overt hypothyroidism
  • Ferritin level
    • Iron deficiency can be present even without anemia 
    • Ferritin level below 20 nanograms/mL suggests iron deficiency
  • Urinalysis
    • Proteinuria may indicate (any of several types of) underlying renal disease
  • Brief Fatigue Inventory 
    • 9-item scale that measures fatigue severity
    • Originally developed for rapid assessment of fatigue severity in patients with cancer, but it is suitable and often used for patients with other conditions as well
  • MFI-20 (Multidimensional Fatigue Inventory, 20-item version) 
    • Includes 20 items that explore several domains in seeking source of fatigue (eg, physical or mental)
    • Provides detailed descriptions of the nature and intensity of fatigue and estimates its impact on usual daily activities
  • PROMIS (Patient-Reported Outcome Measurement Information System) 
    • PROMIS short-form questionnaire is a 7-item series that can be used to assess the temporal nature of fatigue on a daily basis 
      • PROMIS questionnaires are designed to enhance communication between clinicians and patients in both research and clinical settings
      • Scores from the PROMIS scale can be tracked over time to assess consistency or detect variability, as when fatigue changes with the underlying medical condition, improves with therapy, or worsens as a medication adverse effect
    • PROMIS questionnaires measure fatigue with t scores 
      • Mean t score in US general population is 50 and standard deviation is 10 (a higher score indicates more severe fatigue) 
        • PROMIS t score of 60 is 1 standard deviation worse than the standard US population average 
    • Thresholds for PROMIS t scores are as follows: 
      • Less than 55: within reference limits
      • Range of 55 to 60: mild symptoms
      • Range of 61 to 70: moderate symptoms
      • Range of 71 to 80: severe symptoms
  • Edmonton Symptom Assessment Scale 
    • Validated clinical tool to document and monitor symptom burden over time in patients with advanced cancer or with other chronic illnesses (eg, chronic kidney disease, heart failure)
    • It consists of 10 items that patients rate on a scale from 0 to 10 (ie, pain, fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, appetite, well-being, sleep)
    • Generally, in clinical practice, ratings are grouped as 0 (none), 1 to 3 (mild), 4 to 6 (moderate), and 7 to 10 (severe)

Directed laboratory evaluation for fatigue

Laboratory test or imaging studyCharacteristics of patients to consider testing
Ferritin level
History of menorrhagia 
Findings of pale conjunctiva or pallor on examination
Chest radiograph or CT
Symptoms of cough, dyspnea, or hemoptysis
Current or former tobacco use
History of exposure to asbestos
Exposure to tuberculosis
Erythrocyte sedimentation rate
Concern for inflammatory arthritis
Older adult (older than 65 years)
Antinuclear antigen test
Concern for vasculitis
Concern for systemic lupus erythematosus
Anti–cyclic citrullinated peptide antibodies test
History or examination findings concerning for rheumatoid arthritis (eg, morning stiffness, tender warm joints)
C-reactive protein level
History or examination findings suggestive of polymyalgia rheumatica (eg, pain in shoulders and hips, inability to actively abduct shoulders past 90°)

Caption: CT, computed tomography. These laboratory or imaging studies should not be considered standard or routine, but they may be appropriate if the initial laboratory evaluation is unrevealing and/or specific signs and symptoms characteristic of the condition are present.

Standard laboratory evaluation for fatigue

Laboratory testCharacteristics of patients to consider testing
Presence of pallor, tachycardia, or dyspnea
Dietary risk for anemia (eg, vegetarian diet, vegan diet)
Older adult (older than 65 years)
WBC count
Fever or other symptom/sign of infection
Unexplained weight loss
Older adult (older than 65 years)
Electrolyte levels
Use of diuretics
Concern for medical condition causing electrolyte imbalance (eg, aldosteronism, Addison disease, renal tubular acidosis)
Renal function tests
Findings of elevated blood pressure or peripheral edema
Use of medication affecting renal function (eg, ACE inhibitor)
Liver function tests
Stigmata of liver disease, such as jaundice or ascites
History of IV drug use
Occupational exposure to blood products
Fasting serum glucose level or hemoglobin A1C
History of gestational diabetes 
Symptoms of polyuria, polydipsia, or peripheral neuropathy
Adult older than 45 years
TSH or thyroid function tests* 
Symptoms of cold intolerance, dry skin, constipation, amenorrhea, or weight gain
Symptoms of palpitations, heat intolerance, diaphoresis, or weight loss
History of thyroiditis
Family history of thyroid disease

Caption: *Obtain TSH level at a minimum, but if high suspicion of thyroid disease exists, also obtain serum free T₄ level, and possibly serum total T₃ level.


Citation: Data from Godwin M et al: Investigating fatigue of less than 6 months’ duration: guidelines for family physicians. Can Fam Physician. 45:373-9, 1999.


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