Interpretation of Selected Findings in Evaluating Fatigue

Symptoms	Possible Causes	Tests to Consider*
Anorexia, abdominal pain, weight loss, or steatorrhea	Undernutrition secondary to gastrointestinal tract disorder, cancer	Endoscopy, MRI of abdomen, MRCP
Anorexia, abdominal pain, weight loss, orthostatic hypotension, skin hyperpigmentation	Adrenal insufficiency	Blood electrolyte, cortisol, and ACTH levels; Sometimes synthetic ACTH 1-24 (Cortrosyn®) stimulation test
Fever, night sweats, or weight loss	Infection, rheumatologic disorder (including vasculitis)	Chest x-ray, CBC, ESR, blood or other cultures, rheumatoid factor and ANA
Dyspnea with cough or hemoptysis	HIV/AIDS (with Pneumocystis jirovecii pneumonia), fungal pneumonia, tuberculosis, COVID-19	Chest x-ray, chest CT or PET-CT, HIV test, sputum cytology and/or culture, pulmonary function tests, PPD, molecular test for SARS-CoV-2
Dyspnea, orthopnea, and/or edema	Chronic kidney disease, heart failure	Chest x-ray, renal function tests, echocardiography (if orthopnea)
Dyspnea, Roth spots, Janeway lesions, new or changing heart murmurs, IV drug use	Endocarditis	Multiple blood cultures, echocardiography
Decreased exercise tolerance with dyspnea on exertion, pallor	Anemia	CBC
Generalized lymphadenopathy	HIV/AIDS, leukemia, lymphoma, mononucleosis	HIV test, CBC, EBV serologic tests
Combined arthritis, rash, and/or other organ involvement	Rheumatologic disorder (including vasculitis)	CBC, ESR, rheumatoid factor, ANA
Jaundice, ascites, confusion	Hepatitis	Liver tests, viral hepatitis serologies
Polydipsia, polyuria, increased appetite, weight gain or loss	Diabetes	Fasting plasma glucose level, HbA1C, glucose tolerance testing
Cold intolerance, weight gain, constipation, coarse skin	Hypothyroidism, pituitary insufficiency	Thyroid function tests
Weight loss or atrial fibrillation in older patient	Hyperthyroidism (including apathetic)	Thyroid function tests
Fatigue worse with exposure to heat, past neurologic symptoms (eg, numbness, ataxia, weakness), particularly > 1 episode	Multiple sclerosis	Brain and/or spinal cord MRI with contrast
Headache, jaw claudication, temporal artery tenderness or thickening, and/or muscle pains in an older adult	Giant cell arteritis	ESR, brain MRI or CT, temporal artery biopsy
Anxiety, sadness, anorexia, unexplained sleep disturbance	Anxiety, depression, domestic violence, somatization disorder	Clinical evaluation
Recent sore throat, lymphadenopathy, splenomegaly	Mononucleosis, myalgic encephalomyelitis/systemic exertion intolerance disease/chronic fatigue syndrome	EBV serologic tests; CBC, ESR, TSH, chemistries (as for suspected chronic fatigue syndrome)
Lymphadenopathy, splenomegaly	CMV infection	EBV serologic tests, sometimes CMV antibody testing
Frequent or opportunistic infections, candidiasis, lymphadenopathy, splenomegaly	HIV/AIDS	HIV testing
Chronic, widespread musculoskeletal extra-articular pain, trigger points, irritable bowel symptoms, migraines, anxiety	Fibromyalgia	ESR or C-reactive protein, CK, TSH, hepatitis C serology
Weight loss, steatorrhea, inadequate oral intake	Undernutrition, pancreatic insufficiency
Constipation, lethargy, bone pain (eg, at night)	Hypercalcemia	Serum chemistries, including calcium
Postexertional malaise, unrefreshing sleep, difficulty with concentration or short-term memory, orthostatic intolerance, sore throat, myalgias, headaches	Myalgic encephalomyelitis/systemic exertion intolerance disease/chronic fatigue syndrome	CBC, ESR, TSH, serum electrolytes, glucose, calcium, renal and liver tests
* Choice of specific tests is dictated by which causes are clinically suspected.
ACTH = adrenocorticotropic hormone; ANA = antinuclear antibodies; CBC = complete blood count; CK = creatine kinase; CMV = cytomegalovirus; EBV = Epstein-Barr virus; ESR = erythrocyte sedimentation rate; MRCP = magnetic resonance cholangiopancreatography; PET = positron emission tomography; PPD = purified protein derivative; TSH = thyroid-stimulating hormone.

Symptoms

Possible Causes

Tests to Consider*

Anorexia, abdominal pain, weight loss, or steatorrhea

Undernutrition secondary to gastrointestinal tract disorder, cancer

Endoscopy, MRI of abdomen, MRCP

Anorexia, abdominal pain, weight loss, orthostatic hypotension, skin hyperpigmentation

Adrenal insufficiency

Blood electrolyte, cortisol, and ACTH levels; Sometimes synthetic ACTH 1-24 (Cortrosyn®) stimulation test

Fever, night sweats, or weight loss

Infection, rheumatologic disorder (including vasculitis)

Chest x-ray, CBC, ESR, blood or other cultures, rheumatoid factor and ANA

Dyspnea with cough or hemoptysis

HIV/AIDS (with Pneumocystis jirovecii pneumonia), fungal pneumonia, tuberculosis, COVID-19

Chest x-ray, chest CT or PET-CT, HIV test, sputum cytology and/or culture, pulmonary function tests, PPD, molecular test for SARS-CoV-2

Dyspnea, orthopnea, and/or edema

Chronic kidney disease, heart failure

Chest x-ray, renal function tests, echocardiography (if orthopnea)

Dyspnea, Roth spots, Janeway lesions, new or changing heart murmurs, IV drug use

Endocarditis

Multiple blood cultures, echocardiography

Decreased exercise tolerance with dyspnea on exertion, pallor

Anemia

CBC

Generalized lymphadenopathy

HIV/AIDS, leukemia, lymphoma, mononucleosis

HIV test, CBC, EBV serologic tests

Combined arthritis, rash, and/or other organ involvement

Rheumatologic disorder (including vasculitis)

CBC, ESR, rheumatoid factor, ANA

Jaundice, ascites, confusion

Hepatitis

Liver tests, viral hepatitis serologies

Polydipsia, polyuria, increased appetite, weight gain or loss

Diabetes

Fasting plasma glucose level, HbA1C, glucose tolerance testing

Cold intolerance, weight gain, constipation, coarse skin

Hypothyroidism, pituitary insufficiency

Thyroid function tests

Weight loss or atrial fibrillation in older patient

Hyperthyroidism (including apathetic)

Thyroid function tests

Fatigue worse with exposure to heat, past neurologic symptoms (eg, numbness, ataxia, weakness), particularly > 1 episode

Multiple sclerosis

Brain and/or spinal cord MRI with contrast

Headache, jaw claudication, temporal artery tenderness or thickening, and/or muscle pains in an older adult

Giant cell arteritis

ESR, brain MRI or CT, temporal artery biopsy

Anxiety, sadness, anorexia, unexplained sleep disturbance

Anxiety, depression, domestic violence, somatization disorder

Clinical evaluation

Recent sore throat, lymphadenopathy, splenomegaly

Mononucleosis, myalgic encephalomyelitis/systemic exertion intolerance disease/chronic fatigue syndrome

EBV serologic tests; CBC, ESR, TSH, chemistries (as for suspected chronic fatigue syndrome)

Lymphadenopathy, splenomegaly

CMV infection

EBV serologic tests, sometimes CMV antibody testing

Frequent or opportunistic infections, candidiasis, lymphadenopathy, splenomegaly

HIV/AIDS

HIV testing

Chronic, widespread musculoskeletal extra-articular pain, trigger points, irritable bowel symptoms, migraines, anxiety

Fibromyalgia

ESR or C-reactive protein, CK, TSH, hepatitis C serology

Weight loss, steatorrhea, inadequate oral intake

Undernutrition, pancreatic insufficiency

Constipation, lethargy, bone pain (eg, at night)

Hypercalcemia

Serum chemistries, including calcium

Postexertional malaise, unrefreshing sleep, difficulty with concentration or short-term memory, orthostatic intolerance, sore throat, myalgias, headaches

Myalgic encephalomyelitis/systemic exertion intolerance disease/chronic fatigue syndrome

CBC, ESR, TSH, serum electrolytes, glucose, calcium, renal and liver tests

* Choice of specific tests is dictated by which causes are clinically suspected.

ACTH = adrenocorticotropic hormone; ANA = antinuclear antibodies; CBC = complete blood count; CK = creatine kinase; CMV = cytomegalovirus; EBV = Epstein-Barr virus; ESR = erythrocyte sedimentation rate; MRCP = magnetic resonance cholangiopancreatography; PET = positron emission tomography; PPD = purified protein derivative; TSH = thyroid-stimulating hormone.

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Fatigue