18: Fatigue

Before considering the differential diagnosis, it is important to understand what the patient means by fatigue, which is conventionally defined as a sensation of exhaustion after usual activities, or a feeling of insufficient energy to begin usual activities. Most people consider the terms fatigue, tiredness, and lack of energy synonymous. However, patients sometimes use these terms when they are actually experiencing other symptoms, especially excessive sleepiness, weakness, or dyspnea on exertion.

Always ask patients what they mean when they report fatigue. Always ask directly about weakness, excessive sleepiness, and dyspnea.

Acute fatigue is common in conjunction with a variety of acute illnesses, ranging from uncomplicated viral infections to exacerbations of heart failure (HF). Fatigue is also a prominent symptom in some chronic diseases, such as multiple sclerosis and cancer. This chapter will not discuss fatigue in such patients but will focus on evaluating the symptom of fatigue lasting weeks to months in patients without already diagnosed conditions known to cause fatigue.

The differential diagnosis of fatigue is extremely broad and best organized with an organ/system approach.

1. Psychiatric

   1. Depression

   2. Anxiety

   3. Somatization disorder

   4. Substance abuse

2. Sleep disorders

   1. Insomnia

   2. Obstructive sleep apnea (OSA)

   3. Periodic leg movements

   4. Narcolepsy

3. Endocrine

   1. Thyroid disease

   2. Diabetes mellitus

   3. Hypoadrenalism

4. Medications (Table 18-1)

5. Hematologic or oncologic

   1. Anemia

   2. Cancer

6. Renal: chronic kidney disease

7. Liver disease

8. Cardiovascular: chronic heart disease

9. Pulmonary: chronic lung disease

10. Neuromuscular: myositis, multiple sclerosis

11. Infectious: chronic infections

12. Rheumatologic: autoimmune diseases

13. Fatigue of unknown etiology

    1. Chronic fatigue syndrome

    2. Idiopathic chronic fatigue: fatigue for which no medical, psychiatric, or sleep pattern explanation can be found.

Figure 18-1 outlines the diagnostic approach to fatigue.

The most common causes of fatigue are psychiatric disorders, sleep disorders, and medication side effects.

A specific causative medical disease (other than psychiatric disease and sleep disorders) that explains fatigue is found in less than 10% of patients who seek medical attention from their primary care physician. Up to 75% of patients with fatigue have psychiatric symptoms. Sleep disorders, especially OSA and insomnia syndromes, are also common in patients with fatigue, and in one referral clinic, 80% of patients with fatigue had sleep disorders. Because the differential diagnosis of fatigue is broad and difficult to limit during the initial assessment, it is necessary to explore for symptoms and signs of many possible etiologies in most patients, even those with pivotal psychiatric or sleep disorder symptoms. Patients with several somatic complaints, such as Mrs. M, are particularly likely to have psychiatric causes for fatigue, as are patients who feel tired constantly. Because sleep disorders are so common, either in association with psychiatric disorders or alone, they are always an active alternative in patients with fatigue. Patients often do not spontaneously describe sleep disturbances and psychiatric symptoms, so it is important to ask about them directly.

All patients with fatigue need a detailed psychosocial and sleep history.

Although most patients with fatigue do not have anemia, hypothyroidism, or diabetes mellitus, these conditions are important and treatable, and so are generally considered “must not miss” diagnoses. Anemia and hypothyroidism are somewhat likely in Mrs. M because of her previous history of anemia and her family history of thyroid disease. Finally, on occasion, fatigue may be the presenting symptom in patients with undiagnosed cardiac, pulmonary, renal, liver, rheumatologic, or chronic infectious disease. Table 18-2 lists the differential diagnosis.

Despite the rarity of positive results, most patients with fatigue need basic laboratory testing consisting of a blood count, chemistry panel (including glucose, electrolytes, BUN, creatinine, calcium, and liver function tests), and a TSH.

Leading Hypotheses: Depression & Anxiety

See Chapter 32, Unintentional Weight Loss.

Mrs. M’s sleep history clearly uncovers several sleep hygiene issues. However, she is also obese, a risk factor for OSA. Re-exploring her symptoms, it is notable that she has some morning headaches, feels fatigued even when she sleeps all night, and snores.

Revised Leading Hypothesis: Insomnia

Textbook Presentation

Patients with insomnia sometimes have trouble falling asleep, sometimes fall asleep easily but wake up during the night, and sometimes have both problems. The American Sleep Disorder Association defines insomnia as “a repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate time and opportunity for sleep and results in some form of daytime impairment and lasting for at least one month.”

Disease Highlights

1. Primary insomnia

   1. Pathogenesis is unknown but may be due to a state of hyperarousal (demonstrated on positron emission tomography (PET) scans and by measurements of adrenal hormones).

   2. Prevalence of 2–4% in the adult population

2. Secondary (comorbid) insomnia

   1. Intrinsic sleep disorders

      1. OSA or central sleep apnea

      2. Restless leg syndrome/periodic limb movement disorder

   2. Extrinsic sleep disorders

      1. Psychophysiologic insomnia: due to conditioned arousal when in the bedroom

      2. Inadequate sleep hygiene or environmental sleep disorders (due to specific environmental elements)

      3. Related to alcohol or other substance use (stimulants, withdrawal from hypnotic drugs)

   3. Circadian rhythm sleep disorders

      1. Shift work disorder

      2. Delayed or advanced sleep phase syndrome (major sleep phase late or early compared to clock time)

      3. Time zone change syndrome (jet lag)

   4. Related to medical conditions (chronic pain; nocturia; uncontrolled HF, chronic obstructive pulmonary disease/asthma, gastroesophageal reflux disease)

3. 35–50% of adults have insomnia symptoms; 12–20% have insomnia disorders

4. Risk factors for insomnia include depression, female sex, older age, lower socioeconomic status, concurrent medical and mental disorders, marital status (divorced/separated > married), race (African-American > white)

Evidence-Based Diagnosis

1. Obtaining a thorough history helps establish the diagnosis of insomnia. Ask about predisposing, precipitating and perpetuating factors. Initial screening questions include the following:

   1. Difficulty initiating sleep, staying asleep, or both?

   2. Early awakening?

   3. Nonrestorative sleep?

   4. Daytime consequences? (Lack of daytime fatigue or sleepiness suggests the insomnia is not clinically significant.)

   5. Frequency and duration?

2. Follow-up questions

   1. Precipitating events, progression, ameliorating or exacerbating factors?

   2. Sleep-wake schedule?

   3. Cognitive attitude toward sleep?

      1. Negative expectations regarding the ability to sleep and distortions about the effects of insomnia lead to perpetuation of the insomnia.

      2. Attitudes toward previous treatments are also important.

   4. Psychiatric disorder present?

   5. Substance misuse or medication use?

   6. Medical illness with nocturnal symptoms?

   7. Symptoms of sleep apnea, restless legs? (See discussion below.)

Treatment

1. Behavioral therapy

   1. Stimulus control therapy

      1. Also known as sleep hygiene

      2. Based on premise that insomnia is a conditioned response to temporal and environmental cues

      3. Has been shown to be effective for sleep onset and maintenance

      4. Principles of sleep hygiene

         • (1) Go to bed only when sleepy.

         • (2) Use the bedroom only for sleep and sex, not reading, watching television, eating, working, or using a computer

         • (3) If unable to sleep after 20 minutes in bed, get out of bed, go into another room, read or listen to quiet music, and then return to bed when sleepy.

         • (4) Maintain a consistent sleep-wake schedule; go to bed and get up at the same time each day.

         • (5) Avoid daytime napping; if napping is necessary, limit the nap to less than 30 minutes and take the nap no later than the early afternoon.

         • (6) Avoid caffeine, alcohol, and other stimulants (such as decongestants).

         • (7) Exercise regularly, but not in the late evening.

   2. Relaxation therapy

      1. Methods include progressive muscle relaxation, biofeedback to reduce somatic arousal, imagery training, and meditation.

      2. Useful for both sleep onset and maintenance

      3. Often requires practice with a trained professional

   3. Sleep restriction therapy

      1. Decreases the amount of time spent in bed in order to increase the percentage of time in bed spent sleeping

      2. Usually keep waking time constant and make bedtime later, with progressive moving up of bedtime as sleep improves

      3. Effective for sleep onset and maintenance

2. Cognitive therapy involves identifying dysfunctional beliefs about sleep and then substituting more functional attitudes that can reduce anxiety.

3. Combination therapy: combining cognitive and behavioral therapy has been shown to be superior to relaxation therapy alone.

4. Pharmacotherapy

   1. Most studies of pharmacologic agents are short (12 days to 6 months), so data about long-term effects are lacking.

   2. Basic principles for using pharmacotherapy to treat chronic insomnia

      1. Use agents with shorter half-lives to minimize daytime sedation.

      2. Use the lowest effective dose.

      3. Try to dose intermittently, such as 2–4 times per week, rather than daily.

      4. Try to limit daily use to a maximum of 3–4 weeks.

      5. Discontinue medication gradually.

      6. Monitor for rebound insomnia when medications are stopped.

      7. Side effects, including delirium, are more likely to occur in elderly patients.

      8. Commonly used sleep aids are summarized in Table 18-3.

5. Pharmacologic therapy versus cognitive behavioral therapy

   1. Data comparing pharmacotherapy with behavioral and cognitive therapy are limited.

      1. Overall, treatment effects are similar.

      2. Perhaps more rapid improvement with pharmacotherapy

      3. Perhaps more sustained improvement with behavioral therapy

   2. Studies of combined cognitive behavioral and pharmacologic therapy versus cognitive behavioral therapy alone show that the cognitive behavioral therapy alone group maintained results at 10–24 months, but the combined group did not.

Alternative Diagnosis: Obstructive Sleep Apnea

Textbook Presentation

Patients with OSA often complain of daytime sleepiness or fatigue. Bed partners often note snoring or actual apneic episodes. Most patients are obese.

Disease Highlights

1. Characterized by repetitive episodes of complete or partial upper airway obstruction during sleep

   1. An obstructive apnea is at least 10 seconds of cessation of ventilation accompanied by respiratory efforts.

   2. A hypopnea is at least a 30% reduction in air flow for 10 seconds or longer with at least a 4% reduction in oxygen saturation.

   3. A respiratory effort related arousal (RERA) is an occurrence of disordered breathing that does not meet criteria for apnea or hypopnea but does cause arousal.

   4. The apnea-hypopnea index (AHI) is the total number of apneas plus hypopneas per hour; the respiratory disturbance index (RDI) includes apneas, hypopneas, and RERAs.

      1. OSA is defined as an AHI or RDI ≥ 5 with daytime somnolence, or an AHI or RDI ≥ 15 regardless of symptoms.

      2. Mild OSA is an AHI or RDI of 5–14; moderate is an AHI or RDI of 15–30, and severe is an AHI or RDI > 30.

2. Prevalence of OSA

   1. When OSA is defined as an AHI ≥ 5, the prevalence in the community ranges from 9% to 17%, with higher rates in men.

   2. Using a threshold of ≥ 15, the prevalence is 6%.

   3. The prevalence is 50% in referral populations.

3. Pathophysiology

   1. There are normal decreases in tonic pharyngeal muscle tone and compensatory reflex dilators during sleep.

   2. Patients with OSA have smaller upper airways due to increased parapharyngeal fat, tongue prominence, elongated palate, or thickened lateral pharyngeal walls, and are unable to maintain airway stability.

   3. During inspiration, the negative upper airway pressures close these narrowed airways, resulting in apneas or hypopneas.

4. Risk factors

   1. Obesity

      1. The strongest risk factor for OSA

      2. There is a 6-fold increase in the risk of OSA with a 10% weight gain.

      3. Neck circumference, a measurement of upper body obesity, is a predictor of OSA.

   2. Gender: OSA is 2–3 times more common in men than women.

   3. Menopausal status: 4-fold increase in risk in postmenopausal compare to premenopausal women

   4. Craniofacial morphology, especially mandibular length, may explain presence of OSA in otherwise low-risk patients.

5. Consequences of OSA

   1. Increased rate of motor vehicle accidents (relative risk = 2.5–5)

   2. Hypertension (relative risk = 2.89)

   3. HF (relative risk = 2.38)

   4. Higher rates of mortality and adverse cardiac events in patients with coronary artery disease and untreated OSA.

   5. An association with impaired glucose tolerance has been observed.

   6. Long-standing, severe OSA can lead to cor pulmonale.

Evidence-Based Diagnosis

1. History and physical exam

   1. Excessive daytime sleepiness is reported by about 35–40% of patients with OSA and by about 18% of patients without sleep disordered breathing

   2. Lack of energy, tiredness, or fatigue is reported by about 60% of patients with OSA.

   3. Depressive symptoms occur in up to 50% of OSA patients.

   4. Cognitive impairment, especially in motor coordination, executive function, and some memory functions, can occur.

   5. Individual clinical symptoms are not very useful in identifying patients with OSA.

      1. Nocturnal choking/gasping has the best LR+ (3.3), with morning headache having an LR+ of 2.6.

      2. The symptoms reported apnea, excessive daytime sleepiness, and snoring all have LR+ of < 1.5.

      3. The absence of snoring has an LR– ranging from 0.12 to 0.45; all other individual symptoms have an LR– near 1.

   6. Several clinical decision rules have been developed to identify patients at high risk for OSA, but none is recommended for widespread use due to suboptimal or inconsistent test characteristics.

      1. The Berlin, STOP-Bang, and Snoring Severity Scale are somewhat useful in reducing the likelihood a patient has OSA; none of them significantly increases the likelihood a patient has OSA.

      2. Berlin Questionnaire (10 questions about snoring, observed apneas, sleepiness, BP, body mass index [BMI])

         • (1) For AHI > 5: LR+, 1.4; LR–, 0.43

         • (2) For AHI > 15: LR+, 1.5; LR–, 0.28

      3. STOP-Bang (snoring, tiredness, observed apnea, BP, BMI, age, neck circumference, gender)

         • (1) For AHI > 5: LR+, 1.8; LR–, 0.23

         • (2) For AHI > 15: LR+, 1.4; LR–, 0.20

      4. Snoring Severity Scale (0–3 points each to frequency of nights with snoring, duration of snoring, and loudness of snoring)

         • (1) In patients with a BMI > 26 and a positive score, defined as ≥ 4

         • (2) LR+, 1.5; LR–, 0.07

2. Polysomnography

   1. Records electroencephalogram, electromyelogram, ECG, heart rate, respiratory effort, airflow, and oxygen saturation during sleep

   2. Gold standard for diagnosis of OSA

   3. One study found a sensitivity of 66% for the first night study in patients who underwent 2 consecutive night studies; the sensitivity increased by 25% after the second night.

   4. The more severe the OSA, the less variability in the night-to-night polysomnogram results.

Treatment

1. Risk factor modification

   1. Weight loss, smoking cessation, avoiding alcohol or hypnotics before bedtime

   2. A 10% weight loss leads to a 25–30% reduction in the AHI.

2. Nasal therapies (external dilator strips, internal nasal dilators, lubricants): limited data, generally not sufficient treatment

3. Continuous positive airway pressure (CPAP)

   1. Pneumatically splints the upper airway throughout the respiratory cycle

   2. The pressure must be determined during polysomnography (a “CPAP titration”) and is set to eliminate, or at least reduce, apneas and hypopneas.

   3. CPAP has been shown to reduce symptoms of sleepiness/fatigue and slightly lower BP; observational studies suggest better cardiovascular outcomes in treated patients compared to untreated patients. There is minimal evidence of benefit in patients without daytime sleepiness.

4. Oral appliances

   1. Designed to advance the mandible, pulling the tongue forward and opening the pharyngeal airway

   2. Less effective than CPAP

   3. Indicated in patients with mild to moderate OSA who prefer an oral appliance or do not respond to positive airway pressure therapy

5. Surgery

   1. Considered second-line therapy unless there are specific, correctible anatomic abnormalities

   2. Data on outcomes limited; maxillary and mandibular advancement procedures can result in improvement similar to that seen with CPAP.

   3. Tracheostomy is reserved for patients with life-threatening disease who do not respond to other treatments.

Periodic Limb Movement Disorder (PLMD)

Textbook Presentation

The patient complains of daytime sleepiness or fatigue, and the bed partner complains that the patient is very restless, even kicking the bed partner.

Disease Highlights

1. Periodic episodes of repetitive and stereotyped limb movements occurring during non-REM sleep, generally consisting of big toe extension in combination with partial flexion of the ankle, knee, and hip.

2. The movements recur at regular intervals of 20–40 seconds and cause arousal, although the patient is usually unaware.

3. Rare in persons younger than 30 years; found in 5% of persons aged 30–50, 33% in persons aged 50–65, and in 44% of persons older than 65 years.

4. Primary cause of insomnia in 17% of patients

5. Can be unmasked after successful treatment of OSA

6. Accompanied by restless leg syndrome (RLS) in 25% of patients

   1. Diagnostic criteria for RLS

      1. The urge to move the legs, accompanied by uncomfortable or unpleasant sensations, often described as “creeping” or “crawling”

      2. Worsening of symptoms when inactive

      3. Partial symptom relief with movement

      4. Presence of symptoms only in the evening or at night, or worsening of daytime symptoms in the evening

   2. Found in 2–15% of the general population, and 10–35% of patients over 65

   3. Accompanied by PLMD in 85% of cases

   4. Can be primary or secondary to iron deficiency anemia, chronic kidney disease, or peripheral neuropathy; possibly related to celiac disease; all patients with PLMD should have iron studies done

Evidence-Based Diagnosis

1. PLMD is confirmed by polysomnography

2. RLS is a clinical diagnosis

Treatment of PLMD

Effective medications include dopamine agonists (pramipexole or ropinirole) and anti-epileptics (such as gabapentin, pregabalin, or carbamazepine).

Hypothyroidism

Textbook Presentation

Patients with hypothyroidism commonly complain of fatigue, constipation, or cold intolerance.

Disease Highlights

This discussion focuses on primary hypothyroidism in nonpregnant adults.

1. Epidemiology

   1. Prevalence of overt hypothyroidism (elevated TSH with low free T4) is 0.1% in men and 1–2% in women (see below for a discussion of subclinical hypothyroidism)

   2. Prevalence increases with age

   3. 10 times more common in women than men

2. Etiology

   1. Primary hypothyroidism: failure of the thyroid gland to produce adequate thyroid hormone

      1. Most common cause in iodine sufficient areas is chronic autoimmune (Hashimoto) thyroiditis

         • (1) Both cell-mediated and antibody-mediated destruction of the thyroid gland

         • (2) Autoantibodies against thyroid peroxidase, thyroglobulin, and TSH receptor

         • (3) Patients may or may not have a goiter on presentation

      2. Iodine deficiency is a common cause worldwide; patients have large goiters

      3. Thyroidectomy or radioactive iodine therapy both cause hypothyroidism

         • (1) Patients with partial thyroidectomy may not need replacement but should be monitored annually.

         • (2) Postablative hypothyroidism develops several weeks after the radioactive iodine therapy.

      4. Can develop years later in patients who have undergone external neck radiation

      5. Amiodarone and lithium commonly cause hypothyroidism

      6. Less common etiologies include infiltrative diseases, such as sarcoidosis, and thyroid agenesis

   2. Central hypothyroidism: reduction in TSH due to pituitary or hypothalamic disorder

      1. Pituitary adenoma is the most common cause; also can occur post neurosurgery or brain radiation or as a complication of postpartum hemorrhage

      2. Granulomatous diseases, especially sarcoidosis, can infiltrate the hypothalamus.

3. Clinical manifestations

   1. Metabolic: Decreased metabolism that can lead to weight gain, cold intolerance, and increased total and LDL cholesterol (due to decreased clearance)

   2. Cardiac: Reduction in myocardial contractility and heart rate

   3. Skin: Nonpitting edema, due to accumulation of glycosaminoglycans; dry skin; coarse, fragile hair

   4. CNS: fatigue, delayed relaxation phase of the deep tendon reflexes

   5. Pulmonary: hypoventilation seen with severe hypothyroidism

   6. GI: reduced intestinal motility causes constipation

   7. Reproductive: menstrual abnormalities, reduced fertility, increased risk of miscarriage.

Evidence-Based Diagnosis

1. The signs and symptoms of hypothyroidism all lack sensitivity and specificity.

2. The TSH is the best screening test for both primary hypothyroidism and hyperthyroidism; it is not necessary to measure thyroid hormone levels initially unless central hypothyroidism is suspected.

3. If the TSH is normal, no further testing is necessary (LR– for hypothyroidism is < 0.01)

4. If the TSH is elevated (LR+ for hypothyroidism is > 99), the free T₄ should be ordered next.

   1. Most of T₄ is bound to thyroxine-binding globulin and albumin.

   2. The levels of these binding proteins are affected by a variety of medical conditions, thus altering the level of total T₄.

   3. Free T₄ better reflects the patient’s thyroid function than total T₄.

      To assess thyroid function, order a TSH followed by a measurement of free T₄; do not order a total T₄ (TT₄). It is not necessary to order a T₃ when evaluating patients for hypothyroidism.

5. If the TSH is elevated, and the free T₄ is decreased, the patient has overt hypothyroidism and should be treated.

6. If the TSH is elevated and the free T₄ is normal, the patient may have subclinical hypothyroidism.

   1. The TSH and free T₄ should be repeated to confirm the diagnosis.

   2. The most common cause is chronic autoimmune (Hashimoto) thyroiditis.

   3. The overall prevalence is 4–8% but is up to 20% in women over 60.

   4. The progression rate to overt hypothyroidism is 4–18%/year; patients with higher levels of TSH and positive thyroid antibodies are more likely to progress.

   5. A recent study found an increased risk of coronary heart disease events (relative risk 1.89) and coronary heart disease mortality (relative risk 1.58) in patients with subclinical hypothyroidism and a TSH ≥ 10; whether treatment lowers this risk is not known.

   6. Other causes of an elevated TSH with a normal T₄ include recovery from non-thyroidal illness and the recovery phase of subacute thyroiditis.

Treatment

1. Overt hypothyroidism

   1. All patients should be treated with levothyroxine (T₄).

   2. The full replacement dose is 1.6 mcg/kg/day, but in older patients or those with underlying coronary disease, it is preferable to start with a lower of dose of 25–50 mcg/day.

   3. Levothyroxine is best absorbed on an empty stomach, with a 40% reduction in absorption if taken with food; calcium, iron, antacids, proton pump inhibitors, and anticonvulsants also interfere with absorption.

   4. The half-life of levothyroxine is 7 days, so steady state concentration is reached in about 6 weeks.

   5. The TSH level should be checked 6 weeks after every dose adjustment, with the goal of increasing the dose until the TSH is within the normal range.

   6. Once the dose is stable, it is sufficient to check the TSH annually.

2. Subclinical hypothyroidism

   1. Experts agree that patients with a TSH > 10 mcU/mL should be treated; many experts would also treat patients with TSH levels of 5–10, and elevated LDL, symptoms, or positive thyroid antibodies.

   2. Patients may report improved symptoms with treatment; effects on LDL and cardiovascular outcomes are inconclusive.