Clinical Medicine 216 - Fatigue

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Fatigue is also known as ________ , and is a constitutional symptom that can be the result of normal physiological consequences of exertion or a symptom of illness.



Fatigue is a sensation of profound __________ that is not relieved by __________ , and does not have an objective finding of ________ .

Tiredness; rest or sleep; muscle weakness


Fatigue is a sensation that everyone experiences from time to time, however, it is the ________ of fatigue that is considered abnormal.



Common descriptors from patients with fatigue include ________ .

Lack of energy to complete tasks, exhaustion, and tiredness


What is chronic fatigue?

Generally implies fatigue persisting for 6 months


Chronic fatigue is defined as unexplained, persistent, or relapsing fatigue that is of new onset or definite onset; is not the result of ongoing exertion; is not alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social, or personal activities; and 4 or more of the following symptoms that persist or recur during 6 or more consecutive months of illness and that do not predate the fatigue. What are the following symptoms?

Self-reported impairment in short-term memory or concentration, sore throat, tender cervical or axillary nodes, muscle pain, multiple joint pain without redness or swelling, headaches of a new pattern or severity, unrefreshing sleep, and postexertional malaise lasting 24 hours


What is idiopathic fatigue?

Fatigue that has not been attributed to a psychiatric or medical illness


What is persistent fatigue?

Fatigue that generally persists for more than 1 month


Approximately _________ percent of patients with chronic fatigue are found to have a medical or psychological explanation.



What psychiatric disorders are the predominant causes of fatigue?

Depression and anxiety


What are some external factors that can contribute to the development of fatigue and depression?

Social, geographical, environmental, and genetic factors


What are some hematological causes of fatigue?

Anemia, leukaemia, or lymphoma


What are some infectious causes of fatigue?

Endocarditis, mononucleosis, tuberculosis, human immunodeficiency virus (HIV), and hepatitis


What are some neurologic causes of fatigue?

Multiple sclerosis, myasthenia gravis, oncologic, and occult malignancy


What are some rheumatological causes of fatigue?

Fibromyalgia, Lyme disease, rheumatoid arthritis, and systemic lupus erythematosus


What are some pulmonary causes of fatigue?

Chronic obstructive pulmonary disease and sleep apnea


What are some pharmacologic causes of fatigue?

Antidepressants, antihistamines, Benzodiazepines, hypnotics, and narcotics


Fatigue must be distinguished from excessive __________ , which suggests a primary sleep disturbance.

Somnolence (excessive daytime sleepiness)


Significant weight loss, night sweats, or fever suggests _________ illness as a cause of the fatigue.



What serious causes of fatigue presents with fever and night sweats?

Infection, lymphoma, or occult neoplasm (hidden neoplasm)


What serious causes of fatigue presents with a sore throat?

Infectious mononucleosis and Streptococcal pharyngitis


What benign cause of fatigue presents with a fever and night sweats, or sore throat, or lymph node enlargement, or joint pain and stiffness?

Viral illness


What serious causes of fatigue presents with lymph node enlargement?

HIV, infectious mononucleosis, lymphoma, and syphilis


What serious causes of fatigue presents with shortness of breath?

Heart failure, chronic obstructive pulmonary disease, and anemia


What benign causes of fatigue presents with shortness of breath and/or palpitations, and/or sleep disturbances, and/or chest pain?



What serious causes of fatigue presents with palpitations?

Cardiac arrhythmia and thyrotoxicosis


What serious causes of fatigue presents with joint pain and stiffness?

Rheumatoid arthritis and Lyme disease


What serious causes of fatigue presents with back pain and/or diffuse bony pain?

Metastatic carcinoma and multiple myeloma


What benign cause of fatigue presents with back pain and/or diffuse bony pain?

Mechanical lower back pain


What serious causes of fatigue presents with excessive thirst and urination?

Diabetes mellitus and diabetes insipidus


What benign causes of fatigue presents with abdominal pain?

Irritable bowel syndrome and non-ulcer dyspepsia


What serious causes of fatigue presents with abdominal pain?

Peptic ulcer disease, inflammatory bowel disease, intra-abdonimal malignancy, and mesenteric ischemia


What benign causes of fatigue presents with jaundice?

Gilbert's syndrome


What serious causes of fatigue presents with jaundice?

Hepatitis, pancreatic cancer, cirrhosis, and drug reaction


What serious causes of fatigue presents with chest pain?

Coronary artery disease


What benign causes of fatigue presents with chest pain?

Anxiety or panic disorder and gastroesophageal reflux disease


What serious causes of fatigue presents with diarrhea?

Inflammatory bowel disease, malabsorption, and intestinal parasite


What benign causes of fatigue presents with diarrhea?

Irritable bowel syndrome and laxative abuse


What serious causes of fatigue presents with rectal bleeding?

Inflammatory bowel disease and colon cancer


What benign causes of fatigue presents with rectal bleeding?



What serious causes of fatigue presents with double vision, difficulty speaking or chewing, and/or pain with chewing?

Myasthenia gravis (MG), temporal arteritis, and multiple sclerosis


What serious causes of fatigue presents with sleep disturbance?

Depression and sleep apnea


Fatigue can also be related to _________ procedures and pregnancy .

Surgery (postoperative fatigue) and radiation therapy (postradiotherapy fatigue)


A cause of fatigue that improves after a good night's rest is _________ .

Sleep deprivation


Fatigue that improves over the weekend is due to ________ .

Chronic occupational stress


Fatigue that only happens with exertion is suggestive of ________ .

Muscle weakness or cardiopulmonary disease


What is Gilbert's syndrome?

A benign hereditary condition in which reduced bilirubin transferase activity results in intermittent hyperbilirubinaemia


Fatigue can be caused by a disruption in the ability of the body's energy production to meet demand as can be seen in ________ .

Lack of fuel, lack of oxygen supply, interruption in mitochondrial function, increased metabolic rate, decreased metabolic rate, poor waste removal, deconditioning, HPA axis derangement, and inflammation (mediated by cytokines)


Normal finding on the Epworth Sleepiness Scale is less than ________ .



Primary labs for fatigue consist of:

CBC and ferritin, ESR and CRP, TSH, T3, T4, urinary analysis, hCG, glucose, HbA1c, liver function tests, GFR, creatinine, and blood urea nitrogen (BUN)


Secondary labs for fatigue consist of:

HIV, Monospot, TB, Lyme titres, chest radiograph, ECG and echo, pulmonary function tests, toxicology, brain MRI, ANA and celiac indicators, TIBC, B12, and folate


On a CBC, what is the defining feature of anemia?



What are the microcytic anemias (low MCV)?

Iron deficiency anemia (IDA), anemia of chronic inflammation (ACI), and thalassemia


What is thalassemia?

Describes a group of inherited disorders characterized by reduced or absent amounts of hemoglobin, due to the underproduction of particular global chains


With iron deficiency anemia (IDA), what labs test results are decreased?

Serum ferritin level, serum iron level, and transferrin saturation


With anemia of chronic inflammation (ACI), what labs test results are increased?

Serum ferritin level and soluble transferrin receptor


With iron deficiency anemia (IDA), what labs test results are increased?

Soluble transferrin receptor, total iron-binding capacity (TIBC), and red blood cell distribution width (RDW)


Megaloblastic anemia (elevated MCV) is due to _______ .

Ineffective erythropoiesis and abnormal maturation of RBC that have a characteristic nucleus


What can cause megaloblastic anemia?

Drugs (methotrexate, 5-fluroouracil, etc.), B12 or folate deficiency (can cause neurologic manifestation), and myelodysplastic conditions (e.g., leukaemia)


Non-megaloblastic causes or anemia with elevated MCV are:

Alcoholism, hypothyroidism, multiple myeloma, and aplastic anemia


Normocytic anemia can be caused by:

Decreased production (anemia of chronic inflammation and aplastic anemia), increased destruction or loss (hemolysis or post-hemorrhagic), uncompensated increase in plasma volume (pregnancy, fluid overload), and mixture of microcytic and macrocytic


What is sickle cell anemia?

A hemoglobinopathy due to a genetic mutation


What is dyssomnia?

Difficulty initiating or maintaining sleep resulting in excessive sleepiness


What is obstructive sleep apnea syndrome?

Upper airway obstruction during sleep, sleep fragmentation, and nocturnal hypoxia


Risk factors for obstructive sleep apnea syndrome?

Increases with age, obesity, tonsillar or adenoid hypertrophy, nasal septal deviation


The patient history of obstructive sleep apnea syndrome may present as _________ .

Restless sleep, snoring, excessive daytime sleepiness, decreased performance, and decreased vigilance


Common symptoms of obstructive sleep apnea syndrome are:

Restless sleep, loud snoring, excessive daytime sleepiness, observed apnea, chocking or gasping episodes, morning fatigue, memory loss, decreased cognitive function, indigestion and GERD, depression and psychosis, personality changes, decreased libido and impotence, morning and nocturnal headaches, xerostomia, nocturnal sweating, and nocturnal enuresis


What acronym can help with the diagnosis of obstructive sleep apnea syndrome? High risk is a score of yes to 5 to 8 questions.



Imaging for obstructive sleep apnea syndrome?

Nasopharyngoscopy, radiography, and nocturnal polysomnography


What is a polysomnography?

An overnight test to evaluate sleep disorders, and including the monitoring of the patient's airflow through the nose and mouth, blood pressure, electrocardiographic activity, blood oxygen level, brain wave pattern, eye movement, and the movement of respiratory muscle and limbs


How does having cancer relate to a cause of fatigue?

Cachexia, anemia, hypogonadism, infection, impaired sleep, deconditioning and inactivity, anorexia and malnutrition, direct organ damage, drug side effects, pain, psychological distress, inflammatory cytokines, dehydration, chemotherapy, and radiation


In infections, the body uses energy to mobilize an immune system response and conserves energy and resources for that purpose. The immune response is largely mediated by the mechanisms of the _______ .

Acute-phase reaction


What is the causative bacterium of Lyme disease, that must be attached for 36 hours to transmit? (classic bulls-eye rash)

Borrelia burgdorferi


What are the symptoms of early dissemination of Lyme disease?

Neurological (Bell's palsy, meningitis, radiculopathy), cardiac symptoms (arrhythmia, pericarditis, myocarditis, vasculitis), secondary skin rash, arthritic symptoms, and extreme fatigue and general weakness


What are the symptoms of late dissemination of Lyme disease when untreated or when treatment fails? (months to years later)

A huge range of symptoms that can mimic chronic fatigue syndrome (CFS), inflammatory arthritis (especially the knee), autoimmune conditions, neurodegenerative conditions, chronic infections, polyneuropathy, and encephalitis


Post-Lyme disease syndrome could be due to?

Reservoirs of spirochetes or an autoimmune activation


Testing for Lyme disease is done via?

ELISA - screening assay


What is myopathy?

Muscle diseases with symptoms of weakness, dysfunction, and absence of sensory symptoms


What is myasthenia gravis (MG)?

An autoimmune disease that causes muscle weakness. It affects the neuromuscular junction, interrupting the communication between nerve and muscle, and thereby causing weakness


Non-infectious inflammatory myopathy presents with:

Slow, symmetric proximal muscle weakness and myalgia (e.g., getting up from a chair, climbing stairs)


Myopathy can occur as an infectious, non-infectious inflammatory, inherited (muscular dystrophy), or toxic disease. It can also be the result of immune-mediated systemic diseases such as _______ .

Rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis, etc.


Examples of non-infectious inflammatory myopathy:

Dermatomyositis, polymyositis, and association with visceral diseases such as interstitial lung disease, congestive heart failure, ventricular hypertrophy, lung cancers, etc.


With non-infectious inflammatory myopathy, polymyositis presents with ________ symptoms, and dermatomyositis presents with _________ symptoms.

NO skin; skin


What is polymyositis (PM)?

An inflammatory disorder in which muscle tissue becomes inflamed and deteriorates, causing weakness and pain


What is dermatomyositis?

An autoimmune disease where the immune system cells attack healthy cells of small blood vessels in the muscle and skin. Over time, this causes muscle fiber to shrink and sometimes cuts off blood supply to the muscle


________ is an inflammatory muscle disease causing weakness and pain. ________ is identical to polymyositis with the addition of a characteristic skin rash.

Polymyositis; Dermatomyositis


What is the characteristic skin rash of dermatomyositis?

Helitrophe: red-purple oedematous on the upper eyelid, and red-purple keratitis, atrophic erythema or macule on extensor surfaces of finger joints, elbows, or knees (Gottron's sign). Also Shawl- or V-sign, and skin looking like a mechanic's hand


With myopathy, how can one confirm the presence of muscle disease?

With labs such as: creatine phosphokinase, aldolase, liver function tests, lactate dehydrogenase levels, and muscle biopsy


What is the most common complication of taking a Statin drug?



What is multiple sclerosis?

A multifocal area of demyelination in the CNS. An autoimmune mediated attack of myelin with free radical injury that impairs nerve impulse transmission


Pathophysiology of multiple sclerosis:

1. Pathogenic T cells recognize antigens within the CNS,

2. Which are fragments of myelin proteins or viral antigens.

3. Activated T cells release proinflammatory cytokines that directly injure myelin and activate macrophages.

4. Activated macrophages release cytokines, free radicals, and proteases that,

5. Injure myelin and axons.

6. Plasma cells within the CNS release antimyelin antibodies that bind to myelin and cause demyelination by complement activation or by assisting myelin phagocytosis by macrophages.

7. Regulatory T cells enter the CNS, release regulatory cytokines that downregulate pathogenic T cells and help to "turn off" the acute inflammatory response.


What are some factors that can increase the risk of multiple sclerosis?

Sodium, saturated fats, hypercaloric diet, obesity, cow's milk protein, and smoking


What are some nutritional factors that decrease the risk of multiple sclerosis?

Vitamin D, antioxidants and polyphenols, pre-biotics, and probiotics


What can look like multiple sclerosis?

Disc herniation, tumour, HIV, Lyme disease, Ebstein bar virus, small vessel cerebrovascular disease, and inflammatory conditions (SLE, B12 deficiency, thyroid disease)


The sensory changes of multiple sclerosis typically ________.

Lack a dermatomal pattern and are asymmetrical (distal to proximal)


The vision changes of multiple sclerosis often affect just one eye, and present with ________ .

Acute demyelinating optic neuritis


The motor changes of multiple sclerosis present with the classical symptoms of ________.

Weakness and physical fatigue, worse with exertion and heat (foot drop, hand failure), lack of upper motor neuron (UMN) inhibition (hyperreflexia, Babinski's, clonus, spasticity), ataxia (complicated by vision changes, ataxic gait), and tremor


The organ changes of multiple sclerosis present with ________ .

Bladder symptoms (frequency, urgency, incontinence, retention, UTI's), bowel symptoms (constipation), and sexual symptoms (erectile dysfunction, loss of libido)


The ________ can be used to help rule in multiple sclerosis.

McDonald criteria


Hypothyroidism as a cause for fatigue presents with:

Lethargy, decreased reflexes, mental sluggishness, depression, weigh gain, myxoedema (decreased CO, puffy eyelids, hoarse voice), ovulatory failure, irregular menses, oligospermia, erectile dysfunction, decreased libido, atherosclerosis, constipation, dry-course-cool skin, and poor wound healing

McDonald criteria


Assessment for goiter:

Thyroid gland palpation (imprecise), TSH, free T4, free T3, total T4, total T3, antithyroid peroxidase (anti-TPO) antibodies, and ultrasound


Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis and Hashimoto's disease, is an autoimmune disease in which the thyroid gland is gradually destroyed, with eventual _______ .

Fibrotic atrophy


Autoimmune thyroid disease (AITD) and systemic autoimmune disease has a strong association with familial (HLA-DR3/DR5) and

Diabetes mellitus I, primary biliary cirrhosis, autoimmune hepatitis, SLE, pSS, and myasthenia gravis


Subclinical hypothyroidism labs often show an ________ .

Elevated TSH and normal-range fT4


Environmental toxins can affect the thyroid by:

1. Interference with iodide uptake (smoking)

2. Downregulation of thyroperoxidase (e.g., soy, goitrogenic foods)

3. Increased hormone clearance by liver detoxification

4. Displace thyroid hormone from binding globulin

5. Interference with thyroid hormone metabolism

6. Interference with thyroid hormone transmembrane transport


Depressive disorders affect one's quality of life and can increase the risk of ________ .

Suicide and ischemic heart disease


In ________ , symptoms cause clinically significant distress impairment in social, occupational, or other important areas of functioning. Symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism).

Major depressive disorder


In major depressive disorder, at least one of the symptoms is either ________ or ________ .

Depressed mood most of the day nearly every day; loss of interest or pleasure in all, or almost all, activities most of the day nearly every day


Clinician-rated scales for major depressive disorder symptoms:

Hamilton Depression rating scale (HAM-D, HAM-7), Montgomery-Asberg depression Rating Scale (MADRS), and Inventory for Depressive symptomatology (IDS)


Patient-rated scales for major depressive disorder symptoms:

Patient Health Questionnaire (PHQ-2, PHQ-9), Quick Inventory for Depression Symptomatology-Self-rated (QIDS-SR), Clinically Useful Depression Outcome Scale (CUDOS)


On the Patient Health Questionnaire-2 (PHQ-2), any _________ answer means that you proceed to the Patient Health Questionnaire-9 (PHQ-9).



On the Patient Health Questionnaire-9 (PHQ-9), the cutoff for diagnosis is ________ symptoms. (For severity: 0-4 none; 5-9 mild; 10-14 moderate; 15-19 major; 20-27 severe)



In the adrenal gland, the cortex produces _________ and the medulla produces ________ .

Glucocorticoids (cortisol), mineralocorticoids (aldosterone), and sex hormones (estrogens and androgens); catecholamines (epinephrine)


What is known as hypoadrenalism? It is a disease with bilateral destruction of the adrenal cortex, which impacts the production of glucocorticoids, mineralocorticoids, and adrenal androgens.

Addison disease


Addison's disease presents with:

Weakness, chronic fatigue, nausea, vomiting, diarrhea, intolerance to temperature, abdominal pain, amenorrhea, craving for salty foods, depression, dizziness, orthostatic hypotension, hyperpigmentation, and vitiligo


Adrenal crisis presents with:

Extreme hypotension, circulatory collapse, fever of unknown etiology, weight loss, dehydration, hypoglycaemia, and sharp sudden pain in abdomen, legs, or low back


Diagnosis of Addison disease:

First morning plasma cortisol (decreased), ACTH (increased), rapid ACTH stimulation (gold standard), and abdominal radiograph and CT (to identify cause)


Hypothalamus-Pituitary-Adrenal dysregulation is also known as ________ .

Adrenal fatigue


The adaptive response of the HPA-axis:

1. Mobilization of fuel (glugoneogenesis - liver, reduction in protein synthesis and increased catabolism, and mobilization of fatty acids and elevated triglycerides)

2. Moderately decreased glucose utilization (especially if not responding physically)

3. Anti-inflammatory and immune system suppression; improves wound healing


A prolonged response of the HPA-axis can lead to:

1. Elevated insulin and blood sugar leading to dysglycemia (adrenal diabetes)

2. Complex impact on immune system and inflammation

3. Potentiates SNS

4. Inhibits hypothalamus and pituitary leading to hypogonadism, and low GH

5. Inhibits bone formation

6. Visceral fat accumulation

7. Diminished blood and nerve supply to gastrointestinal tract

8. Over time: exhaustion


In the exhaustion phase of HPA dysregulation, there is an elevation in the activity of the ________, and one is unable to ________ ,

SNS (anxiety, insomnia, hypertension, digestive issues); control inflammation


Chronic fatigue syndrome is a multisymptomatic syndrome with an abrupt onset of chronic, unexplained fatigue, with ________ .

Significant impairment in daily activities


According to the Fukuda criteria, chronic fatigue must be unexplained, incapacitating fatigue of at least 6 months duration, in combination with at least four out of eight minor criteria, which are:

1. Postexertional malaise lasting for at least 24 hours

2. Sore throat

3. Tender lymph nodes

4. Muscle pain

5. Multi-joint pain without swelling or erythema

6. Headache of a new type, pattern, or severity

7. Significant impairment in memory and concentration

8. Unrefreshing sleep


Testing considerations for chronic fatigue syndrome:

Urinalysis, CBC, TSH, CRP/ESR, LFTs, electrolytes, creatinine/BUN/GFR, IgA endomysial antibodies, drug screen, ANA, RF, and viral titres


With chronic fatigue syndrome, make sure you rule out any _________ conditions.

Endocrine, psychiatric, rheumatological, neurological, hematological/oncologic, infectious, and others (e.g., celiac disease, heart failure, heavy metal toxicity, sleep apnea, vitamin deficiency, and pharmacologic adverse affects)


Red flag symptoms in someone with chronic fatigue are:

Cheat pain (cardiac disease), focal neurologic deficits (central nervous system malignancy or abscess, MS), inflammatory signs or joint pain (autoimmune disease), lymphadenopathy or weigh loss (malignancy), and shortness of breath (pulmonary disease)


Fatigue can be caused by factors that interfere with restorative mechanisms such as:

Sleep and rest, nutritional state, and mechanisms that remove or regulate wastes


Fatigue can indicate a disease such as:

Hypothyroidism, hyperthyroidism, heart failure, anemia, chronic obstructive pulmonary disease (COPD), sleep apnea, autoimmune disorder, or cancer


Diabetes type II is often associated with fatigue along with ________ .

Polydipsia, polyphagia, and polyuria


In children with ________ , severe fatigue that seems to be more severe than expected with the degree of joint pain involvement is seen.

Juvenile rheumatoid arthritis (JRH)


Clinical examination: An elevated pulse rate may be associated with ________ .

Anxiety, anemia, dehydration, and hyperthyroidism


Clinical examination: Hypothyroidism is associated with _________ .

Dry hair, dry skin, and thickening of the nails


Clinical examination: Hyperthyroidism is associated with ________ .

Fine limp hair and warm skin


Clinical examination: Dry, cracked, and ulcerated mucosa can indicate a _________ .

Nutritional deficiency


Clinical examination: An increased AP diameter indicates __________ .

Chronic obstructive pulmonary disease (COPD)


Clinical examination: Listen for bowel sounds: Anxiety, gastrointestinal irritation, and hunger can _________ the frequency and loudness of bowel sounds, while __________ can decrease bowel sounds.

Increase; depression


Clinical examination: Bilateral tenderness of at least 11 to 18 tender points (joints) is diagnostic of ________ .



Clinical examination: Audible 3rd or 4th heart sounds in an adult may indicate ________ .

Heart failure


Multiple myeloma is a cancer in which ________ grow in an uncontrolled and invasive (malignant) manner. The ________ can spread through the bone marrow and hard outer portions of the large bones of the body.

Antibody-producing plasma cells; cells


In multiple myeloma, the myeloma cells may form tumors called ________ . Eventually, multiple soft spots or holes, called osteolytic lesions, form in the bones.



What is Bell’s palsy?

A unilateral facial muscle paralysis of sudden onset, resulting from trauma, compression, or infection of the facial nerve and characterized by muscle weakness and a distorted facial expression


Addison disease is caused by partial or total failure of adrenocortical function, which is characterized by a ________ .

Darkening of the skin and mucous membranes, anemia, weakness, and low blood pressure