Cleveland Clinic Journal of Medicine

My adult nonacutely ill patient, weighing 70 kg with a glomerular filtration rate (GFR) greater than 60 mL/min/1.73 m², is admitted to the general medical service. She is to receive nothing by mouth for at least the next 24 hours for testing. Do I need to provide maintenance fluids intravenously?

The question seems like it should have an easy answer. However, there is no consensus either on the type of fluids or the need for them at all.

Mortiz and Ayus¹ have described the role of maintenance intravenous (IV) fluids in acutely ill patients and made the case for isotonic saline (0.9% NaCl) to minimize the risk of hyponatremia, while acknowledging that it provides 7 to 10 g of sodium per day.

Recommendations for IV fluids for nonacutely ill hospitalized patients range from isotonic solutions such as 0.9% NaCl and lactated Ringer’s, to hypotonic fluids such as 5% dextrose in water (D5W) in 0.45% NaCl and D5W in 0.2% NaCl.^2–5

The 2013 guidelines of the UK National Institute for Health and Care Excellence (NICE) recommend hypotonic fluids to provide 25 to 30 mL/kg/day of water with 1 mmol/kg/day of sodium. For a 70-kg patient (body surface area 1.7 m²), this would be 1,750 to 2,000 mL of water, with a maximum of 70 mEq/L of sodium (35 mEq/L).⁵ An option would be D5W in 0.2% NaCl, which has 34 mEq/L of sodium.

When choosing maintenance IV fluids, we need to consider the following questions:

• What is my patient’s volume status?
• What is the baseline serum sodium and renal function?
• Are there comorbid conditions that may affect antidiuretic hormone (ADH) status such as physiologic stimulation from volume depletion, drugs, pathologic medical conditions, or syndrome of inappropriate ADH stimulation?
• Will my patient be receiving strictly nothing by mouth?
• Are there unusual fluid losses?

SCENARIO 1: ‘USUAL’ MAINTENANCE

If the patient is euvolemic, with a normal serum osmolality, a GFR more than 60 mL/min/1.73 m², no stimuli for ADH secretion, and no unusual fluid losses, “usual” maintenance would be expected. The usual volume for this patient can be estimated by the following formulas:

• Maintenance volume: 2,550 mL (1,500 mL × 1.7 m² body surface area)
• Holliday-Segar method⁶: 2,500 mL (1,500 mL plus 20 mL/kg for every kilogram over 20 kg).

The usual sodium can be also estimated by the following formulas:

• 2 g Na/day = 2,000 mg/day = 87 mEq/day
• Holliday-Segar⁶: 3 mEq Na/100 mL and 2 mEq K/100 mL of maintenance fluid.

Maintenance IV fluids for our nonacutely ill adult patient could be:

• NICE guideline⁵: D5W in 0.2% NaCl with 20 mEq KCl, to run at 75 mL/hour
• Holliday-Segar method⁶: D5W in 0.2% NaCl with 20 mEq KCl, to run at 100 mL/hour.

Twenty-four hours later, assuming no unusual fluid losses or stimulation of ADH secretion, our patient would weigh the same and would have no significant change in serum osmolality.

OTHER OPTIONS

What if I provide 0.9% NaCl instead?

Each 1 L of normal saline provides 154 mEq of sodium, equivalent to 3.5 g of sodium. Thus, for the 24 hours, with administration of 2 to 2.5 L, the patient would receive a sodium load of 7 to 8.75 g. The consequences of this can be debated, but for 24 hours, more than likely, nothing will happen or be noticeable. The kidneys have a wonderful ability to “dump” excess sodium ingested in the diet, as evidenced by the average Western diet with a sodium load in the range of 4 g per day.^7,8

What if I provide 0.45% NaCl instead?

Each liter provides 50% of the sodium load of 0.9% NaCl. With the 24-hour administration of 2 to 2.5 L of D5W in 0.45% NaCl, the sodium load would be 3.5 to 4.8 g, and the kidneys would dump the excess sodium.

What if I provide ‘catch-up’ fluids after 24 hours, not maintenance fluids?

Assuming only usual losses and no unusual ADH stimulation except for the physiologic stimuli from volume depletion for 24 hours, our patient would lose 2 kg (1 L fluid loss = 1 kg weight loss) and 87 mEq of sodium. This is approximately 4.5% dehydration; thus, other than increased thirst, no physical findings of volume depletion would be clinically evident.

However, serum osmolality and sodium would increase. After 24 hours of nothing by mouth with usual fluid losses, there would be a rise in serum osmolality of 13.5 mOsm/L (a rise in sodium of 6 to 7 mEq/L), which would stimulate ADH in an attempt to minimize further urinary losses. There would be an intracellular volume loss of 1.3 L (Table 1). Clinically, just as with the administration of 0.9% sodium, these changes would not likely be of any clinical consequence in the first 24 hours.

SCENARIO 2: IMPAIRED WATER EXCRETION, AND FLUIDS GIVEN

If the patient is euvolemic but has or is at risk for ADH stimulation,^1,9 providing maintenance IV fluids according to the NICE or Holliday-Segar recommendations (a total of 2 L of 0.2% NaCl = 34 mEq Na/L = 68 mOsm/L) would result in an excess of free water, as an increase in ADH secretion impairs free water clearance. A potential scenario with impaired water excretion is shown in Table 2.

After 24 hours, the patient’s serum osmolality would drop by about 7 mOsm/L, and the serum sodium would decrease by 3 or 4 mEq. The consequence of the intracellular fluid shift would be seen by the expansion of the intracellular volume from 28 to 28.7 L.

If this patient were to have received 2 L of 0.9% NaCl (308 mOsm/L × 2 L = 616 Osm) as suggested by Moritz and Ayus,¹ the result would be a serum osmolality of 284 mOsm/L, thus avoiding hyponatremia and intracellular fluid shifts.

THE BOTTOM LINE

Know your patient, answer the clinical questions noted above, and decide.

For a euvolemic patient with normal serum sodium, GFR greater than 60 mL/1.73 m², and no ADH stimulation, for 24 hours it probably doesn’t matter that much, but a daily reassessment of the continued need for and type of intravenous fluids is critical.

For patients not meeting the criteria noted above such as a patient with systolic or diastolic heart failure, advanced or end-stage renal disease puts the patient at risk for early potential complications of either hyponatremia or sodium overload. For these patients, maintenance intravenous fluids need to be chosen wisely. Daily weights, examinations, and laboratory testing will let you know if something is not right and will allow for early detection and treatment.

My adult nonacutely ill patient, weighing 70 kg with a glomerular filtration rate (GFR) greater than 60 mL/min/1.73 m², is admitted to the general medical service. She is to receive nothing by mouth for at least the next 24 hours for testing. Do I need to provide maintenance fluids intravenously?

The question seems like it should have an easy answer. However, there is no consensus either on the type of fluids or the need for them at all.

Mortiz and Ayus¹ have described the role of maintenance intravenous (IV) fluids in acutely ill patients and made the case for isotonic saline (0.9% NaCl) to minimize the risk of hyponatremia, while acknowledging that it provides 7 to 10 g of sodium per day.

Recommendations for IV fluids for nonacutely ill hospitalized patients range from isotonic solutions such as 0.9% NaCl and lactated Ringer’s, to hypotonic fluids such as 5% dextrose in water (D5W) in 0.45% NaCl and D5W in 0.2% NaCl.^2–5

The 2013 guidelines of the UK National Institute for Health and Care Excellence (NICE) recommend hypotonic fluids to provide 25 to 30 mL/kg/day of water with 1 mmol/kg/day of sodium. For a 70-kg patient (body surface area 1.7 m²), this would be 1,750 to 2,000 mL of water, with a maximum of 70 mEq/L of sodium (35 mEq/L).⁵ An option would be D5W in 0.2% NaCl, which has 34 mEq/L of sodium.

When choosing maintenance IV fluids, we need to consider the following questions:

• What is my patient’s volume status?
• What is the baseline serum sodium and renal function?
• Are there comorbid conditions that may affect antidiuretic hormone (ADH) status such as physiologic stimulation from volume depletion, drugs, pathologic medical conditions, or syndrome of inappropriate ADH stimulation?
• Will my patient be receiving strictly nothing by mouth?
• Are there unusual fluid losses?

SCENARIO 1: ‘USUAL’ MAINTENANCE

If the patient is euvolemic, with a normal serum osmolality, a GFR more than 60 mL/min/1.73 m², no stimuli for ADH secretion, and no unusual fluid losses, “usual” maintenance would be expected. The usual volume for this patient can be estimated by the following formulas:

• Maintenance volume: 2,550 mL (1,500 mL × 1.7 m² body surface area)
• Holliday-Segar method⁶: 2,500 mL (1,500 mL plus 20 mL/kg for every kilogram over 20 kg).

The usual sodium can be also estimated by the following formulas:

• 2 g Na/day = 2,000 mg/day = 87 mEq/day
• Holliday-Segar⁶: 3 mEq Na/100 mL and 2 mEq K/100 mL of maintenance fluid.

Maintenance IV fluids for our nonacutely ill adult patient could be:

• NICE guideline⁵: D5W in 0.2% NaCl with 20 mEq KCl, to run at 75 mL/hour
• Holliday-Segar method⁶: D5W in 0.2% NaCl with 20 mEq KCl, to run at 100 mL/hour.

Twenty-four hours later, assuming no unusual fluid losses or stimulation of ADH secretion, our patient would weigh the same and would have no significant change in serum osmolality.

OTHER OPTIONS

What if I provide 0.9% NaCl instead?

Each 1 L of normal saline provides 154 mEq of sodium, equivalent to 3.5 g of sodium. Thus, for the 24 hours, with administration of 2 to 2.5 L, the patient would receive a sodium load of 7 to 8.75 g. The consequences of this can be debated, but for 24 hours, more than likely, nothing will happen or be noticeable. The kidneys have a wonderful ability to “dump” excess sodium ingested in the diet, as evidenced by the average Western diet with a sodium load in the range of 4 g per day.^7,8

What if I provide 0.45% NaCl instead?

Each liter provides 50% of the sodium load of 0.9% NaCl. With the 24-hour administration of 2 to 2.5 L of D5W in 0.45% NaCl, the sodium load would be 3.5 to 4.8 g, and the kidneys would dump the excess sodium.

What if I provide ‘catch-up’ fluids after 24 hours, not maintenance fluids?

Assuming only usual losses and no unusual ADH stimulation except for the physiologic stimuli from volume depletion for 24 hours, our patient would lose 2 kg (1 L fluid loss = 1 kg weight loss) and 87 mEq of sodium. This is approximately 4.5% dehydration; thus, other than increased thirst, no physical findings of volume depletion would be clinically evident.

However, serum osmolality and sodium would increase. After 24 hours of nothing by mouth with usual fluid losses, there would be a rise in serum osmolality of 13.5 mOsm/L (a rise in sodium of 6 to 7 mEq/L), which would stimulate ADH in an attempt to minimize further urinary losses. There would be an intracellular volume loss of 1.3 L (Table 1). Clinically, just as with the administration of 0.9% sodium, these changes would not likely be of any clinical consequence in the first 24 hours.

SCENARIO 2: IMPAIRED WATER EXCRETION, AND FLUIDS GIVEN

If the patient is euvolemic but has or is at risk for ADH stimulation,^1,9 providing maintenance IV fluids according to the NICE or Holliday-Segar recommendations (a total of 2 L of 0.2% NaCl = 34 mEq Na/L = 68 mOsm/L) would result in an excess of free water, as an increase in ADH secretion impairs free water clearance. A potential scenario with impaired water excretion is shown in Table 2.

After 24 hours, the patient’s serum osmolality would drop by about 7 mOsm/L, and the serum sodium would decrease by 3 or 4 mEq. The consequence of the intracellular fluid shift would be seen by the expansion of the intracellular volume from 28 to 28.7 L.

If this patient were to have received 2 L of 0.9% NaCl (308 mOsm/L × 2 L = 616 Osm) as suggested by Moritz and Ayus,¹ the result would be a serum osmolality of 284 mOsm/L, thus avoiding hyponatremia and intracellular fluid shifts.

THE BOTTOM LINE

Know your patient, answer the clinical questions noted above, and decide.

For a euvolemic patient with normal serum sodium, GFR greater than 60 mL/1.73 m², and no ADH stimulation, for 24 hours it probably doesn’t matter that much, but a daily reassessment of the continued need for and type of intravenous fluids is critical.

For patients not meeting the criteria noted above such as a patient with systolic or diastolic heart failure, advanced or end-stage renal disease puts the patient at risk for early potential complications of either hyponatremia or sodium overload. For these patients, maintenance intravenous fluids need to be chosen wisely. Daily weights, examinations, and laboratory testing will let you know if something is not right and will allow for early detection and treatment.

My adult nonacutely ill patient, weighing 70 kg with a glomerular filtration rate (GFR) greater than 60 mL/min/1.73 m², is admitted to the general medical service. She is to receive nothing by mouth for at least the next 24 hours for testing. Do I need to provide maintenance fluids intravenously?

The question seems like it should have an easy answer. However, there is no consensus either on the type of fluids or the need for them at all.

Mortiz and Ayus¹ have described the role of maintenance intravenous (IV) fluids in acutely ill patients and made the case for isotonic saline (0.9% NaCl) to minimize the risk of hyponatremia, while acknowledging that it provides 7 to 10 g of sodium per day.

Recommendations for IV fluids for nonacutely ill hospitalized patients range from isotonic solutions such as 0.9% NaCl and lactated Ringer’s, to hypotonic fluids such as 5% dextrose in water (D5W) in 0.45% NaCl and D5W in 0.2% NaCl.^2–5

The 2013 guidelines of the UK National Institute for Health and Care Excellence (NICE) recommend hypotonic fluids to provide 25 to 30 mL/kg/day of water with 1 mmol/kg/day of sodium. For a 70-kg patient (body surface area 1.7 m²), this would be 1,750 to 2,000 mL of water, with a maximum of 70 mEq/L of sodium (35 mEq/L).⁵ An option would be D5W in 0.2% NaCl, which has 34 mEq/L of sodium.

When choosing maintenance IV fluids, we need to consider the following questions:

• What is my patient’s volume status?
• What is the baseline serum sodium and renal function?
• Are there comorbid conditions that may affect antidiuretic hormone (ADH) status such as physiologic stimulation from volume depletion, drugs, pathologic medical conditions, or syndrome of inappropriate ADH stimulation?
• Will my patient be receiving strictly nothing by mouth?
• Are there unusual fluid losses?

SCENARIO 1: ‘USUAL’ MAINTENANCE

If the patient is euvolemic, with a normal serum osmolality, a GFR more than 60 mL/min/1.73 m², no stimuli for ADH secretion, and no unusual fluid losses, “usual” maintenance would be expected. The usual volume for this patient can be estimated by the following formulas:

• Maintenance volume: 2,550 mL (1,500 mL × 1.7 m² body surface area)
• Holliday-Segar method⁶: 2,500 mL (1,500 mL plus 20 mL/kg for every kilogram over 20 kg).

The usual sodium can be also estimated by the following formulas:

• 2 g Na/day = 2,000 mg/day = 87 mEq/day
• Holliday-Segar⁶: 3 mEq Na/100 mL and 2 mEq K/100 mL of maintenance fluid.

Maintenance IV fluids for our nonacutely ill adult patient could be:

• NICE guideline⁵: D5W in 0.2% NaCl with 20 mEq KCl, to run at 75 mL/hour
• Holliday-Segar method⁶: D5W in 0.2% NaCl with 20 mEq KCl, to run at 100 mL/hour.

Twenty-four hours later, assuming no unusual fluid losses or stimulation of ADH secretion, our patient would weigh the same and would have no significant change in serum osmolality.

OTHER OPTIONS

What if I provide 0.9% NaCl instead?

Each 1 L of normal saline provides 154 mEq of sodium, equivalent to 3.5 g of sodium. Thus, for the 24 hours, with administration of 2 to 2.5 L, the patient would receive a sodium load of 7 to 8.75 g. The consequences of this can be debated, but for 24 hours, more than likely, nothing will happen or be noticeable. The kidneys have a wonderful ability to “dump” excess sodium ingested in the diet, as evidenced by the average Western diet with a sodium load in the range of 4 g per day.^7,8

What if I provide 0.45% NaCl instead?

Each liter provides 50% of the sodium load of 0.9% NaCl. With the 24-hour administration of 2 to 2.5 L of D5W in 0.45% NaCl, the sodium load would be 3.5 to 4.8 g, and the kidneys would dump the excess sodium.

What if I provide ‘catch-up’ fluids after 24 hours, not maintenance fluids?

Assuming only usual losses and no unusual ADH stimulation except for the physiologic stimuli from volume depletion for 24 hours, our patient would lose 2 kg (1 L fluid loss = 1 kg weight loss) and 87 mEq of sodium. This is approximately 4.5% dehydration; thus, other than increased thirst, no physical findings of volume depletion would be clinically evident.

However, serum osmolality and sodium would increase. After 24 hours of nothing by mouth with usual fluid losses, there would be a rise in serum osmolality of 13.5 mOsm/L (a rise in sodium of 6 to 7 mEq/L), which would stimulate ADH in an attempt to minimize further urinary losses. There would be an intracellular volume loss of 1.3 L (Table 1). Clinically, just as with the administration of 0.9% sodium, these changes would not likely be of any clinical consequence in the first 24 hours.

SCENARIO 2: IMPAIRED WATER EXCRETION, AND FLUIDS GIVEN

If the patient is euvolemic but has or is at risk for ADH stimulation,^1,9 providing maintenance IV fluids according to the NICE or Holliday-Segar recommendations (a total of 2 L of 0.2% NaCl = 34 mEq Na/L = 68 mOsm/L) would result in an excess of free water, as an increase in ADH secretion impairs free water clearance. A potential scenario with impaired water excretion is shown in Table 2.

After 24 hours, the patient’s serum osmolality would drop by about 7 mOsm/L, and the serum sodium would decrease by 3 or 4 mEq. The consequence of the intracellular fluid shift would be seen by the expansion of the intracellular volume from 28 to 28.7 L.

If this patient were to have received 2 L of 0.9% NaCl (308 mOsm/L × 2 L = 616 Osm) as suggested by Moritz and Ayus,¹ the result would be a serum osmolality of 284 mOsm/L, thus avoiding hyponatremia and intracellular fluid shifts.

THE BOTTOM LINE

Know your patient, answer the clinical questions noted above, and decide.

For a euvolemic patient with normal serum sodium, GFR greater than 60 mL/1.73 m², and no ADH stimulation, for 24 hours it probably doesn’t matter that much, but a daily reassessment of the continued need for and type of intravenous fluids is critical.

For patients not meeting the criteria noted above such as a patient with systolic or diastolic heart failure, advanced or end-stage renal disease puts the patient at risk for early potential complications of either hyponatremia or sodium overload. For these patients, maintenance intravenous fluids need to be chosen wisely. Daily weights, examinations, and laboratory testing will let you know if something is not right and will allow for early detection and treatment.

A 66-year-old man presented to the emergency department with increasing shortness of breath and productive cough, which had begun 5 days earlier. Three years previously, he had been diagnosed with chronic obstructive pulmonary disease (COPD).

One week before the current presentation, he developed a sore throat, rhinorrhea, and nasal congestion, and the shortness of breath had started 2 days after that. Although he could speak in sentences, he was breathless even at rest. His dyspnea was associated with noisy breathing and cough productive of yellowish sputum; there was no hemoptysis. He reported fever, but he had no chills, night sweats, chest pain, or paroxysmal nocturnal dyspnea. The review of other systems was unremarkable.

His COPD was known to be mild, in Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1, group A. His postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC) was less than 0.70, and his FEV₁ was 84% of predicted. Apart from mild intermittent cough with white sputum, his COPD had been under good control with inhaled ipratropium 4 times daily and inhaled albuterol as needed. He said he did not have shortness of breath except when hurrying on level ground or walking up a slight hill (Modified Medical Research Council dyspnea scale grade 1; COPD Assessment Test score < 10). In the last 3 years, he had 2 exacerbations of COPD, 1 year apart, both requiring oral prednisone and antibiotic therapy.

Other relevant history included hypertension and dyslipidemia of 15-year duration, for which he was taking candesartan 16 mg twice daily and atorvastatin 20 mg daily. He was compliant with his medications.

Though he usually received an influenza vaccine every year, he did not get it the previous year. Also, 3 years previously, he received the 23-valent pneumococcal polysaccharide vaccine (PPSV23), and the year before that he received the pneumococcal conjugate vaccine (PCV13). In addition, he was immunized against herpes zoster and tetanus.

The patient had smoked 1 pack per day for the past 38 years. His primary care physician had advised him many times to quit smoking. He had enrolled in a smoking cessation program 2 years previously, in which he received varenicline in addition to behavioral counseling in the form of motivational interviewing and a telephone quit-line. Nevertheless, he continued to smoke.

He was a retired engineer. He did not drink alcohol or use illicit drugs.

PHYSICAL EXAMINATION

On physical examination, the patient was sitting up in bed, leaning forward. He was alert and oriented but was breathing rapidly and looked sick. He had no cyanosis, clubbing, pallor, or jaundice. His blood pressure was 145/90 mm Hg, heart rate 110 beats per minute and regular, respiratory rate 29 breaths per minute, and oral temperature 38.1°C (100.6°F). His oxygen saturation was 88% while breathing room air. His body mass index was 27.1 kg/m².

His throat was mildly congested. His neck veins were flat, and there were no carotid bruits. His thyroid examination was normal, without goiter, nodules, or tenderness.

Intercostal retractions were noted around the anterolateral costal margins. He had no chest wall deformities. Chest expansion was reduced bilaterally. There was hyperresonance bilaterally. Expiratory wheezes were heard over both lungs, without crackles.

His heart had no murmurs or added sounds. There was no lower-limb edema or swelling. The rest of his physical examination was unremarkable.

Results of initial laboratory testing are shown in Table 1.

Assessment: A 66-year-old man with GOLD grade 1, group A COPD, presenting with a severe exacerbation, most likely due to viral bronchitis.

The patient was given oxygen 28% by Venturi mask, and his oxygen saturation went up to 90%. He was started on nebulized albuterol 2.5 mg with ipratropium bromide 500 µg every 4 hours, prednisone 40 mg orally daily for 5 days, and ceftriaxone 1 g intravenously every 24 hours. The first dose of each medication was given in the emergency department.

The patient was then admitted to a progressive care unit, where he was placed on noninvasive positive pressure ventilation, continuous cardiac monitoring, and pulse oximetry. He was started on enoxaparin 40 mg subcutaneously daily to prevent venous thromboembolism, and the oral medications he had been taking at home were continued. Because he was receiving a glucocorticoid, his blood glucose was monitored in the fasting state, 2 hours after each meal, and as needed.

Two hours after he started noninvasive positive pressure ventilation, his arterial blood gases were remeasured and showed the following results:

• pH 7.35
• Partial pressure of carbon dioxide (Paco₂) 52 mm Hg
• Bicarbonate 28 mmol/L
• Partial pressure of oxygen (Pao₂) 60 mm Hg
• Oxygen saturation 90%.

HOSPITAL COURSE

On hospital day 3, his dyspnea had slightly improved. His respiratory rate was 26 to 28 breaths per minute. His oxygen saturation remained between 90% and 92%.

At 10:21 pm, his cardiac monitor showed an episode of focal atrial tachycardia at a rate of 129 beats per minute that lasted for 3 minutes and 21 seconds, terminating spontaneously. He denied any change in his clinical condition during the episode, with no chest pain, palpitation, or change in dyspnea. There was no change in his vital signs. He had another similar asymptomatic episode lasting 4 minutes and 9 seconds at 6:30 am of hospital day 4.

Because of these episodes, the attending physician ordered thyroid function tests.

THYROID FUNCTION TESTING

1. Which thyroid function test is most likely to be helpful in the assessment of this patient’s thyroid status?

• Serum thyroid-stimulating hormone (TSH) alone
• Serum TSH and total thyroxine (T₄)
• Serum TSH and total triiodothyronine (T₃)
• Serum TSH and free T₄
• Serum TSH and free T₃

There are several tests to assess thyroid function: the serum TSH, total T₄, free T₄, total T₃, and free T₃ concentrations.¹

In normal physiology, TSH from the pituitary stimulates the thyroid gland to produce and secrete T₄ and T₃, which in turn inhibit TSH secretion through negative feedback. A negative log-linear relation exists between serum free T₄ and TSH levels.² Thus, the serum free T₄ level can remain within the normal reference range even if the TSH level is high or low. 

TSH assays can have different detection limits. A third-generation TSH assay with a detection limit of 0.01 mU/L is recommended for use in clinical practice.³

TSH testing alone. Given its superior sensitivity and specificity, serum TSH measurement is considered the best single test for assessing thyroid function in most cases.⁴ Nevertheless, measurement of the serum TSH level alone could be misleading in several situations, eg, hypothalamic or pituitary disorders, recent treatment of thyrotoxicosis, impaired sensitivity to thyroid hormone, and acute nonthyroidal illness.⁴

Free vs total T₄ and T₃ levels

Serum total T₄ includes a fraction that is bound, mainly to thyroxin-binding globulin, and a very small unbound (free) fraction. The same applies to T₃. Only free thyroid hormones represent the “active” fraction available for interaction with their protein receptors in the nucleus.⁸ Patients with conditions that can affect the thyroid-binding protein concentrations usually have altered serum total T₄ and T₃ levels, whereas their free hormone concentrations remain normal. Accordingly, measurement of free hormone levels, especially free T₄, is usually recommended.

Although equilibrium dialysis is the method most likely to provide an accurate serum free T₄ measurement, it is not commonly used because of its limited availability and high cost. Thus, most commercial laboratories use “direct” free T₄ measurement or, to a lesser degree, the free T₄ index.⁹ However, none of the currently available free T₄ tests actually measure free T₄ directly; rather, they estimate it.¹⁰

Commercial laboratories can provide a direct free T₃ estimate, but it may be less reliable than total T₃. If serum T₃ measurement is indicated, serum total T₃ is usually measured. However, total T₃ measurement is rarely indicated for patients with hypothyroidism because it usually remains within the normal reference range.¹¹ Nevertheless, serum total T₃ measurement could be useful in patients with T₃ toxicosis and in those who are acutely ill.

Accordingly, in acutely ill hospitalized patients like ours, measuring serum TSH using a third-generation assay and free T₄ is essential to assess thyroid function. Many clinicians also measure serum total T₃.

The attending physician ordered serum TSH, free T₄, and total T₃ measurements, which yielded the following:

• TSH 0.1 mU/L (0.5–5.0)
• Total T₃ 55 ng/dL (80–180)
• Free T₄ 0.9 ng/dL (0.9–2.4).

2. Which best explains this patient’s abnormal thyroid test results?

• His acute illness
• Central hypothyroidism due to pituitary infarction
• His albuterol therapy
• Subclinical thyrotoxicosis
• Hashimoto thyroiditis

Since euthyroid patients with an acute illness may have abnormal thyroid test results (Table 2),^5–7 thyroid function testing is not recommended unless there is a strong indication for it, such as new-onset atrial fibrillation, atrial flutter, or focal atrial tachycardia.¹ In such patients, it is important to know whether the test abnormalities represent true thyroid disorder or are the result of a nonthyroidal illness.

Thyroid function testing in patients with nonthyroidal illness usually shows low serum total T₃, normal or low serum TSH, and normal, low, or high serum free T₄. However, transient mild serum TSH elevation can be seen in some patients during the recovery period.¹⁶ These abnormalities with their mechanisms are shown in Table 2.^5–7 In several commercial kits, serum direct free T₄ can be falsely decreased or increased.⁸

THE DIFFERENTIAL DIAGNOSIS

Our patient had low serum TSH, low-normal serum direct free T₄, and low serum total T₃. This profile could be caused by a nonthyroidal illness, “true” central hypothyroidism, or his glucocorticoid treatment. The reason we use the term “true” in this setting is that some experts suggest that the thyroid function test abnormalities in patients with acute nonthyroidal illness represent a transient central hypothyroidism.¹⁷ The clinical presentation is key in differentiating true central hypothyroidism from nonthyroidal illness.

In addition, measuring serum cortisol may help to differentiate between the 2 states, as it would be elevated in patients with nonthyroidal illness as part of a stress response but low in patients with true central hypothyroidism, since it is usually part of combined pituitary hormone deficiency.¹⁸ Of note, some critically ill patients have low serum cortisol because of transient central adrenal insufficiency.^19,20

The serum concentration of reverse T₃ has been suggested as a way to differentiate between hypothyroidism (low) and nonthyroidal illness (high); however, further studies showed that it does not reliably differentiate between the conditions.²¹

GLUCOCORTICOIDS AND THYROID FUNCTION TESTS

By inhibiting D1, glucocorticoids can decrease peripheral conversion of T₄ to T₃ and thus decrease serum total T₃. This effect depends on the type and dose of the glucocorticoid and the duration of therapy.

In one study,²² there was a significant reduction in serum total T₃ concentration 24 hours after a single oral dose of dexamethasone 12 mg in normal participants. This effect lasted 48 hours, after which serum total T₃ returned to its pretreatment level.

In another study,²³ a daily oral dose of betamethasone 1.5 mg for 5 days did not significantly reduce the serum total T₃ in healthy volunteers, but a daily dose of 3 mg did. This effect was more pronounced at a daily dose of 4.5 mg, whereas a dose of 6.0 mg had no further effect.

Long-term glucocorticoid therapy also decreases serum total T₄ and total T₃ by lowering serum thyroid-binding globulin.²⁴

Finally, glucocorticoids can decrease TSH secretion by directly inhibiting thyrotropin-releasing hormone.^25,26 However, chronic hypercortisolism, whether endogenous or exogenous, does not cause clinically central hypothyroidism, possibly because of the negative feedback mechanism of low thyroid hormones on the pituitary and the hypothalamus.²⁷

Other drugs including dopamine, dopamine agonists, dobutamine, and somatostatin analogues can suppress serum TSH. As with glucocorticoids, these drugs do not cause clinically evident central hypothyroidism.²⁸ Bexarotene, a retinoid X receptor ligand used in the treatment of cutaneous T-cell lymphoma, has been reported to cause clinically evident central hypothyroidism by suppressing TSH and increasing T₄ clearance.²⁹

While there is general agreement that beta-adrenergic antagonists (beta-blockers) do not affect the serum TSH concentration, conflicting data have been reported concerning their effect on other thyroid function tests. This may be due to several factors, including dose, duration of therapy, the patient’s thyroid status, and differences in laboratory methodology.³⁰

In studies of propranolol, serum total T₄ concentrations did not change or were increased with daily doses of 160 mg or more in both euthyroid participants and hyperthyroid patients^31–33; serum total T₃ concentrations did not change or were decreased with 40 mg or more daily³⁴; and serum reverse T₃ concentrations were increased with daily doses of 80 mg or more.³¹ It is most likely that propranolol exerts these changes by inhibiting D1 activity in peripheral tissues.

Furthermore, a significant decrease in serum total T₃ concentrations was observed in hyperthyroid patients treated with atenolol 100 mg daily, metoprolol 100 mg daily, and alprenolol 100 mg daily, but not with sotalol 80 mg daily or nadolol (up to 240 mg daily).^35,36

On the other hand, beta-adrenergic agonists have not been reported to cause significant changes in thyroid function tests.³⁷

SUBCLINICAL THYROTOXICOSIS OR HASHIMOTO THYROIDITIS?

Our patient’s thyroid function test results are more likely due to his nonthyroidal illness and glucocorticoid therapy, as there is no clinical evidence to point to a hypothalamic-pituitary disorder accounting for true central hypothyroidism.

The other options mentioned in question 2 are unlikely to explain our patient’s thyroid function test results.

Subclinical thyrotoxicosis is characterized by suppressed serum TSH, but both serum free T₄ and total T₃ remain within the normal reference ranges. In addition, the serum TSH level may help to differentiate between thyrotoxicosis and nonthyroidal illness. In the former, serum TSH is usually suppressed (< 0.01 mU/L), whereas in the latter it is usually low but detectable (0.05– 0.3 mU/L).^38,39

Hashimoto thyroiditis is a chronic autoimmune thyroid disease characterized by diffuse lymphocytic infiltration of the thyroid gland. Almost all patients with Hashimoto thyroiditis have elevated levels of antibodies to thyroid peroxidase or thyroglobulin.⁴⁰ Clinically, patients with Hashimoto thyroiditis can either be hypothyroid or have normal thyroid function, which is not the case in our patient.

CASE CONTINUED

An endocrinologist, consulted for a second opinion, agreed that the patient’s thyroid function test results were most likely due to his nonthyroidal illness and glucocorticoid therapy.

3. In view of the endocrinologist’s opinion, which should be the next step in the management of the patient’s thyroid condition?

• Start levothyroxine (T₄) therapy
• Start liothyronine (T₃) therapy
• Start N-acetylcysteine therapy
• Start thyrotropin-releasing hormone therapy
• Remeasure thyroid hormones after full recovery from his acute illness

It is not clear whether the changes in thyroid hormone levels during an acute illness are a pathologic alteration for which thyroid hormone therapy may be beneficial, or a physiologic adaptation for which such therapy would not be indicated.⁴¹

However, current data argue against thyroid hormone therapy using T₄ or T₃ for patients with nonthyroidal illness syndrome (also called euthyroid sick syndrome).⁴² Indeed, several randomized controlled trials showed that thyroid hormone therapy is not beneficial in such patients and may be detrimental.^41,43

Therapies other than thyroid hormone have been investigated to ameliorate thyroid hormone abnormalities in patients with nonthyroidal illness. These include N-acetylcysteine, thyrotropin-releasing hormone therapy, and nutritional support.

Some studies showed that giving N-acetyl­cysteine, an antioxidant, increased serum T₃ and decreased serum reverse T₃ concentrations in patients with acute myocardial infarction.⁴⁴ Nevertheless, the mortality rate and length of hospitalization were not affected. Further studies are needed to know whether N-acetylcysteine therapy is beneficial for such patients.

Similarly, a study using a thyrotropin-releasing hormone analogue along with growth hormone-releasing peptide 2 showed an increase in serum TSH, T₄, and T₃ levels in critically ill patients.⁴⁵ The benefit of this therapy has yet to be determined. On the other hand, early nutritional support was reported to prevent thyroid hormonal changes in patients postoperatively.⁴⁶

Measuring thyroid hormone levels after full recovery is the most appropriate next step in our patient, as the changes in thyroid hormone concentrations subside as the acute illness resolves.⁴⁷

The patient continued to improve. On hospital day 6, he was feeling better but still had mild respiratory distress. There had been no further episodes of arrhythmia since day 4. His blood pressure was 136/86 mm Hg, heart rate 88 beats per minute and regular, respiratory rate 18 breaths per minute, and oral temperature 37.1°C. His oxygen saturation was 92% on room air.

Before discharge, he was encouraged to quit smoking. He was offered behavioral counseling and medication therapy, but he only said that he would think about it. He was discharged on oral cefixime for 4 more days and was instructed to switch to a long-acting bronchodilator along with his other home medications and to return in 1 week to have his thyroid hormones checked.

One week later, his laboratory results were:

• TSH 11.2 mU/L (reference range 0.5–5.0)
• Free T₄ 1.2 ng/dL (0.9–2.4)
• Total T₃ 92 ng/dL (80–180).

Clinically, the patient was euthyroid, and examination of his thyroid was unremarkable.

4. Based on these last test results, which statement is correct?

• Levothyroxine therapy should be started
• His serum TSH elevation is most likely transient
• Thyroid ultrasonography is strongly indicated
• A radioactive iodine uptake study should be performed
• Measurement of thyroid-stimulating immunoglobulins is indicated

During recovery from nonthyroidal illness, some patients may have elevated serum TSH levels that are usually transient and modest (< 20 mU/L).⁴⁸ Normalization of the thyroid function tests including serum TSH may take several weeks⁴⁹ or months.⁵⁰ However, a systematic review found that the likelihood of permanent primary hypothyroidism is high in patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness.⁵¹

Ultrasonography is useful for evaluating patients with thyroid nodules or goiter but is of little benefit for patients like ours, in whom the thyroid is normal on examination.

Similarly, a radioactive iodine uptake study is not indicated, as it is principally used to help differentiate between types of thyrotoxicosis. (Radioactive iodine is also used to treat differentiated thyroid cancer.)

Thyroid-stimulating immunoglobins are TSH receptor-stimulating antibodies that cause Graves disease. Nevertheless, measuring them is not routinely indicated for its diagnosis. However, their measurement is of significant help in the diagnosis of Graves disease if a radioactive iodine uptake study cannot be performed (as in pregnancy) and in atypical presentations such as euthyroid Graves ophthalmopathy.⁵² Other indications for thyroid-stimulating immunoglobin measurement are beyond the scope of the article. Our patient’s test results are not consistent with hyperthyroidism, so measuring thyroid-stimulating immunoglobins is not indicated.

CASE CONCLUSION: BETTER, BUT STILL SMOKING

The patient missed his 1-month clinic follow-up, but he visited the clinic for follow-up 3 months later. He was feeling well with no complaints. Test results including serum TSH, free T₄, and total T₃ were within normal ranges. His COPD was under control, with an FEV₁ 88% of predicted.

He was again encouraged to quit smoking and was offered drug therapy and behavioral counseling, but he declined. In addition, he was instructed to adhere to his annual influenza vaccination.

KEY POINTS

• In patients with acute illness, it is recommended that thyroid function not be assessed unless there is a strong indication.
• If thyroid function assessment is indicated for critically ill patients, serum TSH and free T₄ concentrations should be measured. Some clinicians also measure serum total T₃ level.
• Thyroid function testing in critically ill patients usually shows low serum total T₃, normal or low serum TSH, and normal or low serum free T₄.
• Many drugs can alter thyroid hormone levels.
• Thyroid hormone therapy is not recommended for critically ill patients with low T₃, low T₄, or both.
• During recovery from nonthyroidal illness, some patients may have mild elevation in serum TSH levels (< 20 mU/L).
• Thyroid hormone levels may take several weeks or months to return to normal after the acute illness.
• Patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness are more likely to have permanent primary hypothyroidism.

A 66-year-old man presented to the emergency department with increasing shortness of breath and productive cough, which had begun 5 days earlier. Three years previously, he had been diagnosed with chronic obstructive pulmonary disease (COPD).

One week before the current presentation, he developed a sore throat, rhinorrhea, and nasal congestion, and the shortness of breath had started 2 days after that. Although he could speak in sentences, he was breathless even at rest. His dyspnea was associated with noisy breathing and cough productive of yellowish sputum; there was no hemoptysis. He reported fever, but he had no chills, night sweats, chest pain, or paroxysmal nocturnal dyspnea. The review of other systems was unremarkable.

His COPD was known to be mild, in Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1, group A. His postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC) was less than 0.70, and his FEV₁ was 84% of predicted. Apart from mild intermittent cough with white sputum, his COPD had been under good control with inhaled ipratropium 4 times daily and inhaled albuterol as needed. He said he did not have shortness of breath except when hurrying on level ground or walking up a slight hill (Modified Medical Research Council dyspnea scale grade 1; COPD Assessment Test score < 10). In the last 3 years, he had 2 exacerbations of COPD, 1 year apart, both requiring oral prednisone and antibiotic therapy.

Other relevant history included hypertension and dyslipidemia of 15-year duration, for which he was taking candesartan 16 mg twice daily and atorvastatin 20 mg daily. He was compliant with his medications.

Though he usually received an influenza vaccine every year, he did not get it the previous year. Also, 3 years previously, he received the 23-valent pneumococcal polysaccharide vaccine (PPSV23), and the year before that he received the pneumococcal conjugate vaccine (PCV13). In addition, he was immunized against herpes zoster and tetanus.

The patient had smoked 1 pack per day for the past 38 years. His primary care physician had advised him many times to quit smoking. He had enrolled in a smoking cessation program 2 years previously, in which he received varenicline in addition to behavioral counseling in the form of motivational interviewing and a telephone quit-line. Nevertheless, he continued to smoke.

He was a retired engineer. He did not drink alcohol or use illicit drugs.

PHYSICAL EXAMINATION

On physical examination, the patient was sitting up in bed, leaning forward. He was alert and oriented but was breathing rapidly and looked sick. He had no cyanosis, clubbing, pallor, or jaundice. His blood pressure was 145/90 mm Hg, heart rate 110 beats per minute and regular, respiratory rate 29 breaths per minute, and oral temperature 38.1°C (100.6°F). His oxygen saturation was 88% while breathing room air. His body mass index was 27.1 kg/m².

His throat was mildly congested. His neck veins were flat, and there were no carotid bruits. His thyroid examination was normal, without goiter, nodules, or tenderness.

Intercostal retractions were noted around the anterolateral costal margins. He had no chest wall deformities. Chest expansion was reduced bilaterally. There was hyperresonance bilaterally. Expiratory wheezes were heard over both lungs, without crackles.

His heart had no murmurs or added sounds. There was no lower-limb edema or swelling. The rest of his physical examination was unremarkable.

Results of initial laboratory testing are shown in Table 1.

Assessment: A 66-year-old man with GOLD grade 1, group A COPD, presenting with a severe exacerbation, most likely due to viral bronchitis.

The patient was given oxygen 28% by Venturi mask, and his oxygen saturation went up to 90%. He was started on nebulized albuterol 2.5 mg with ipratropium bromide 500 µg every 4 hours, prednisone 40 mg orally daily for 5 days, and ceftriaxone 1 g intravenously every 24 hours. The first dose of each medication was given in the emergency department.

The patient was then admitted to a progressive care unit, where he was placed on noninvasive positive pressure ventilation, continuous cardiac monitoring, and pulse oximetry. He was started on enoxaparin 40 mg subcutaneously daily to prevent venous thromboembolism, and the oral medications he had been taking at home were continued. Because he was receiving a glucocorticoid, his blood glucose was monitored in the fasting state, 2 hours after each meal, and as needed.

Two hours after he started noninvasive positive pressure ventilation, his arterial blood gases were remeasured and showed the following results:

• pH 7.35
• Partial pressure of carbon dioxide (Paco₂) 52 mm Hg
• Bicarbonate 28 mmol/L
• Partial pressure of oxygen (Pao₂) 60 mm Hg
• Oxygen saturation 90%.

HOSPITAL COURSE

On hospital day 3, his dyspnea had slightly improved. His respiratory rate was 26 to 28 breaths per minute. His oxygen saturation remained between 90% and 92%.

At 10:21 pm, his cardiac monitor showed an episode of focal atrial tachycardia at a rate of 129 beats per minute that lasted for 3 minutes and 21 seconds, terminating spontaneously. He denied any change in his clinical condition during the episode, with no chest pain, palpitation, or change in dyspnea. There was no change in his vital signs. He had another similar asymptomatic episode lasting 4 minutes and 9 seconds at 6:30 am of hospital day 4.

Because of these episodes, the attending physician ordered thyroid function tests.

THYROID FUNCTION TESTING

1. Which thyroid function test is most likely to be helpful in the assessment of this patient’s thyroid status?

• Serum thyroid-stimulating hormone (TSH) alone
• Serum TSH and total thyroxine (T₄)
• Serum TSH and total triiodothyronine (T₃)
• Serum TSH and free T₄
• Serum TSH and free T₃

There are several tests to assess thyroid function: the serum TSH, total T₄, free T₄, total T₃, and free T₃ concentrations.¹

In normal physiology, TSH from the pituitary stimulates the thyroid gland to produce and secrete T₄ and T₃, which in turn inhibit TSH secretion through negative feedback. A negative log-linear relation exists between serum free T₄ and TSH levels.² Thus, the serum free T₄ level can remain within the normal reference range even if the TSH level is high or low. 

TSH assays can have different detection limits. A third-generation TSH assay with a detection limit of 0.01 mU/L is recommended for use in clinical practice.³

TSH testing alone. Given its superior sensitivity and specificity, serum TSH measurement is considered the best single test for assessing thyroid function in most cases.⁴ Nevertheless, measurement of the serum TSH level alone could be misleading in several situations, eg, hypothalamic or pituitary disorders, recent treatment of thyrotoxicosis, impaired sensitivity to thyroid hormone, and acute nonthyroidal illness.⁴

Free vs total T₄ and T₃ levels

Serum total T₄ includes a fraction that is bound, mainly to thyroxin-binding globulin, and a very small unbound (free) fraction. The same applies to T₃. Only free thyroid hormones represent the “active” fraction available for interaction with their protein receptors in the nucleus.⁸ Patients with conditions that can affect the thyroid-binding protein concentrations usually have altered serum total T₄ and T₃ levels, whereas their free hormone concentrations remain normal. Accordingly, measurement of free hormone levels, especially free T₄, is usually recommended.

Although equilibrium dialysis is the method most likely to provide an accurate serum free T₄ measurement, it is not commonly used because of its limited availability and high cost. Thus, most commercial laboratories use “direct” free T₄ measurement or, to a lesser degree, the free T₄ index.⁹ However, none of the currently available free T₄ tests actually measure free T₄ directly; rather, they estimate it.¹⁰

Commercial laboratories can provide a direct free T₃ estimate, but it may be less reliable than total T₃. If serum T₃ measurement is indicated, serum total T₃ is usually measured. However, total T₃ measurement is rarely indicated for patients with hypothyroidism because it usually remains within the normal reference range.¹¹ Nevertheless, serum total T₃ measurement could be useful in patients with T₃ toxicosis and in those who are acutely ill.

Accordingly, in acutely ill hospitalized patients like ours, measuring serum TSH using a third-generation assay and free T₄ is essential to assess thyroid function. Many clinicians also measure serum total T₃.

The attending physician ordered serum TSH, free T₄, and total T₃ measurements, which yielded the following:

• TSH 0.1 mU/L (0.5–5.0)
• Total T₃ 55 ng/dL (80–180)
• Free T₄ 0.9 ng/dL (0.9–2.4).

2. Which best explains this patient’s abnormal thyroid test results?

• His acute illness
• Central hypothyroidism due to pituitary infarction
• His albuterol therapy
• Subclinical thyrotoxicosis
• Hashimoto thyroiditis

Since euthyroid patients with an acute illness may have abnormal thyroid test results (Table 2),^5–7 thyroid function testing is not recommended unless there is a strong indication for it, such as new-onset atrial fibrillation, atrial flutter, or focal atrial tachycardia.¹ In such patients, it is important to know whether the test abnormalities represent true thyroid disorder or are the result of a nonthyroidal illness.

Thyroid function testing in patients with nonthyroidal illness usually shows low serum total T₃, normal or low serum TSH, and normal, low, or high serum free T₄. However, transient mild serum TSH elevation can be seen in some patients during the recovery period.¹⁶ These abnormalities with their mechanisms are shown in Table 2.^5–7 In several commercial kits, serum direct free T₄ can be falsely decreased or increased.⁸

THE DIFFERENTIAL DIAGNOSIS

Our patient had low serum TSH, low-normal serum direct free T₄, and low serum total T₃. This profile could be caused by a nonthyroidal illness, “true” central hypothyroidism, or his glucocorticoid treatment. The reason we use the term “true” in this setting is that some experts suggest that the thyroid function test abnormalities in patients with acute nonthyroidal illness represent a transient central hypothyroidism.¹⁷ The clinical presentation is key in differentiating true central hypothyroidism from nonthyroidal illness.

In addition, measuring serum cortisol may help to differentiate between the 2 states, as it would be elevated in patients with nonthyroidal illness as part of a stress response but low in patients with true central hypothyroidism, since it is usually part of combined pituitary hormone deficiency.¹⁸ Of note, some critically ill patients have low serum cortisol because of transient central adrenal insufficiency.^19,20

The serum concentration of reverse T₃ has been suggested as a way to differentiate between hypothyroidism (low) and nonthyroidal illness (high); however, further studies showed that it does not reliably differentiate between the conditions.²¹

GLUCOCORTICOIDS AND THYROID FUNCTION TESTS

By inhibiting D1, glucocorticoids can decrease peripheral conversion of T₄ to T₃ and thus decrease serum total T₃. This effect depends on the type and dose of the glucocorticoid and the duration of therapy.

In one study,²² there was a significant reduction in serum total T₃ concentration 24 hours after a single oral dose of dexamethasone 12 mg in normal participants. This effect lasted 48 hours, after which serum total T₃ returned to its pretreatment level.

In another study,²³ a daily oral dose of betamethasone 1.5 mg for 5 days did not significantly reduce the serum total T₃ in healthy volunteers, but a daily dose of 3 mg did. This effect was more pronounced at a daily dose of 4.5 mg, whereas a dose of 6.0 mg had no further effect.

Long-term glucocorticoid therapy also decreases serum total T₄ and total T₃ by lowering serum thyroid-binding globulin.²⁴

Finally, glucocorticoids can decrease TSH secretion by directly inhibiting thyrotropin-releasing hormone.^25,26 However, chronic hypercortisolism, whether endogenous or exogenous, does not cause clinically central hypothyroidism, possibly because of the negative feedback mechanism of low thyroid hormones on the pituitary and the hypothalamus.²⁷

Other drugs including dopamine, dopamine agonists, dobutamine, and somatostatin analogues can suppress serum TSH. As with glucocorticoids, these drugs do not cause clinically evident central hypothyroidism.²⁸ Bexarotene, a retinoid X receptor ligand used in the treatment of cutaneous T-cell lymphoma, has been reported to cause clinically evident central hypothyroidism by suppressing TSH and increasing T₄ clearance.²⁹

While there is general agreement that beta-adrenergic antagonists (beta-blockers) do not affect the serum TSH concentration, conflicting data have been reported concerning their effect on other thyroid function tests. This may be due to several factors, including dose, duration of therapy, the patient’s thyroid status, and differences in laboratory methodology.³⁰

In studies of propranolol, serum total T₄ concentrations did not change or were increased with daily doses of 160 mg or more in both euthyroid participants and hyperthyroid patients^31–33; serum total T₃ concentrations did not change or were decreased with 40 mg or more daily³⁴; and serum reverse T₃ concentrations were increased with daily doses of 80 mg or more.³¹ It is most likely that propranolol exerts these changes by inhibiting D1 activity in peripheral tissues.

Furthermore, a significant decrease in serum total T₃ concentrations was observed in hyperthyroid patients treated with atenolol 100 mg daily, metoprolol 100 mg daily, and alprenolol 100 mg daily, but not with sotalol 80 mg daily or nadolol (up to 240 mg daily).^35,36

On the other hand, beta-adrenergic agonists have not been reported to cause significant changes in thyroid function tests.³⁷

SUBCLINICAL THYROTOXICOSIS OR HASHIMOTO THYROIDITIS?

Our patient’s thyroid function test results are more likely due to his nonthyroidal illness and glucocorticoid therapy, as there is no clinical evidence to point to a hypothalamic-pituitary disorder accounting for true central hypothyroidism.

The other options mentioned in question 2 are unlikely to explain our patient’s thyroid function test results.

Subclinical thyrotoxicosis is characterized by suppressed serum TSH, but both serum free T₄ and total T₃ remain within the normal reference ranges. In addition, the serum TSH level may help to differentiate between thyrotoxicosis and nonthyroidal illness. In the former, serum TSH is usually suppressed (< 0.01 mU/L), whereas in the latter it is usually low but detectable (0.05– 0.3 mU/L).^38,39

Hashimoto thyroiditis is a chronic autoimmune thyroid disease characterized by diffuse lymphocytic infiltration of the thyroid gland. Almost all patients with Hashimoto thyroiditis have elevated levels of antibodies to thyroid peroxidase or thyroglobulin.⁴⁰ Clinically, patients with Hashimoto thyroiditis can either be hypothyroid or have normal thyroid function, which is not the case in our patient.

CASE CONTINUED

An endocrinologist, consulted for a second opinion, agreed that the patient’s thyroid function test results were most likely due to his nonthyroidal illness and glucocorticoid therapy.

3. In view of the endocrinologist’s opinion, which should be the next step in the management of the patient’s thyroid condition?

• Start levothyroxine (T₄) therapy
• Start liothyronine (T₃) therapy
• Start N-acetylcysteine therapy
• Start thyrotropin-releasing hormone therapy
• Remeasure thyroid hormones after full recovery from his acute illness

It is not clear whether the changes in thyroid hormone levels during an acute illness are a pathologic alteration for which thyroid hormone therapy may be beneficial, or a physiologic adaptation for which such therapy would not be indicated.⁴¹

However, current data argue against thyroid hormone therapy using T₄ or T₃ for patients with nonthyroidal illness syndrome (also called euthyroid sick syndrome).⁴² Indeed, several randomized controlled trials showed that thyroid hormone therapy is not beneficial in such patients and may be detrimental.^41,43

Therapies other than thyroid hormone have been investigated to ameliorate thyroid hormone abnormalities in patients with nonthyroidal illness. These include N-acetylcysteine, thyrotropin-releasing hormone therapy, and nutritional support.

Some studies showed that giving N-acetyl­cysteine, an antioxidant, increased serum T₃ and decreased serum reverse T₃ concentrations in patients with acute myocardial infarction.⁴⁴ Nevertheless, the mortality rate and length of hospitalization were not affected. Further studies are needed to know whether N-acetylcysteine therapy is beneficial for such patients.

Similarly, a study using a thyrotropin-releasing hormone analogue along with growth hormone-releasing peptide 2 showed an increase in serum TSH, T₄, and T₃ levels in critically ill patients.⁴⁵ The benefit of this therapy has yet to be determined. On the other hand, early nutritional support was reported to prevent thyroid hormonal changes in patients postoperatively.⁴⁶

Measuring thyroid hormone levels after full recovery is the most appropriate next step in our patient, as the changes in thyroid hormone concentrations subside as the acute illness resolves.⁴⁷

The patient continued to improve. On hospital day 6, he was feeling better but still had mild respiratory distress. There had been no further episodes of arrhythmia since day 4. His blood pressure was 136/86 mm Hg, heart rate 88 beats per minute and regular, respiratory rate 18 breaths per minute, and oral temperature 37.1°C. His oxygen saturation was 92% on room air.

Before discharge, he was encouraged to quit smoking. He was offered behavioral counseling and medication therapy, but he only said that he would think about it. He was discharged on oral cefixime for 4 more days and was instructed to switch to a long-acting bronchodilator along with his other home medications and to return in 1 week to have his thyroid hormones checked.

One week later, his laboratory results were:

• TSH 11.2 mU/L (reference range 0.5–5.0)
• Free T₄ 1.2 ng/dL (0.9–2.4)
• Total T₃ 92 ng/dL (80–180).

Clinically, the patient was euthyroid, and examination of his thyroid was unremarkable.

4. Based on these last test results, which statement is correct?

• Levothyroxine therapy should be started
• His serum TSH elevation is most likely transient
• Thyroid ultrasonography is strongly indicated
• A radioactive iodine uptake study should be performed
• Measurement of thyroid-stimulating immunoglobulins is indicated

During recovery from nonthyroidal illness, some patients may have elevated serum TSH levels that are usually transient and modest (< 20 mU/L).⁴⁸ Normalization of the thyroid function tests including serum TSH may take several weeks⁴⁹ or months.⁵⁰ However, a systematic review found that the likelihood of permanent primary hypothyroidism is high in patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness.⁵¹

Ultrasonography is useful for evaluating patients with thyroid nodules or goiter but is of little benefit for patients like ours, in whom the thyroid is normal on examination.

Similarly, a radioactive iodine uptake study is not indicated, as it is principally used to help differentiate between types of thyrotoxicosis. (Radioactive iodine is also used to treat differentiated thyroid cancer.)

Thyroid-stimulating immunoglobins are TSH receptor-stimulating antibodies that cause Graves disease. Nevertheless, measuring them is not routinely indicated for its diagnosis. However, their measurement is of significant help in the diagnosis of Graves disease if a radioactive iodine uptake study cannot be performed (as in pregnancy) and in atypical presentations such as euthyroid Graves ophthalmopathy.⁵² Other indications for thyroid-stimulating immunoglobin measurement are beyond the scope of the article. Our patient’s test results are not consistent with hyperthyroidism, so measuring thyroid-stimulating immunoglobins is not indicated.

CASE CONCLUSION: BETTER, BUT STILL SMOKING

The patient missed his 1-month clinic follow-up, but he visited the clinic for follow-up 3 months later. He was feeling well with no complaints. Test results including serum TSH, free T₄, and total T₃ were within normal ranges. His COPD was under control, with an FEV₁ 88% of predicted.

He was again encouraged to quit smoking and was offered drug therapy and behavioral counseling, but he declined. In addition, he was instructed to adhere to his annual influenza vaccination.

KEY POINTS

• In patients with acute illness, it is recommended that thyroid function not be assessed unless there is a strong indication.
• If thyroid function assessment is indicated for critically ill patients, serum TSH and free T₄ concentrations should be measured. Some clinicians also measure serum total T₃ level.
• Thyroid function testing in critically ill patients usually shows low serum total T₃, normal or low serum TSH, and normal or low serum free T₄.
• Many drugs can alter thyroid hormone levels.
• Thyroid hormone therapy is not recommended for critically ill patients with low T₃, low T₄, or both.
• During recovery from nonthyroidal illness, some patients may have mild elevation in serum TSH levels (< 20 mU/L).
• Thyroid hormone levels may take several weeks or months to return to normal after the acute illness.
• Patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness are more likely to have permanent primary hypothyroidism.

A 66-year-old man presented to the emergency department with increasing shortness of breath and productive cough, which had begun 5 days earlier. Three years previously, he had been diagnosed with chronic obstructive pulmonary disease (COPD).

One week before the current presentation, he developed a sore throat, rhinorrhea, and nasal congestion, and the shortness of breath had started 2 days after that. Although he could speak in sentences, he was breathless even at rest. His dyspnea was associated with noisy breathing and cough productive of yellowish sputum; there was no hemoptysis. He reported fever, but he had no chills, night sweats, chest pain, or paroxysmal nocturnal dyspnea. The review of other systems was unremarkable.

His COPD was known to be mild, in Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1, group A. His postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC) was less than 0.70, and his FEV₁ was 84% of predicted. Apart from mild intermittent cough with white sputum, his COPD had been under good control with inhaled ipratropium 4 times daily and inhaled albuterol as needed. He said he did not have shortness of breath except when hurrying on level ground or walking up a slight hill (Modified Medical Research Council dyspnea scale grade 1; COPD Assessment Test score < 10). In the last 3 years, he had 2 exacerbations of COPD, 1 year apart, both requiring oral prednisone and antibiotic therapy.

Other relevant history included hypertension and dyslipidemia of 15-year duration, for which he was taking candesartan 16 mg twice daily and atorvastatin 20 mg daily. He was compliant with his medications.

Though he usually received an influenza vaccine every year, he did not get it the previous year. Also, 3 years previously, he received the 23-valent pneumococcal polysaccharide vaccine (PPSV23), and the year before that he received the pneumococcal conjugate vaccine (PCV13). In addition, he was immunized against herpes zoster and tetanus.

The patient had smoked 1 pack per day for the past 38 years. His primary care physician had advised him many times to quit smoking. He had enrolled in a smoking cessation program 2 years previously, in which he received varenicline in addition to behavioral counseling in the form of motivational interviewing and a telephone quit-line. Nevertheless, he continued to smoke.

He was a retired engineer. He did not drink alcohol or use illicit drugs.

PHYSICAL EXAMINATION

On physical examination, the patient was sitting up in bed, leaning forward. He was alert and oriented but was breathing rapidly and looked sick. He had no cyanosis, clubbing, pallor, or jaundice. His blood pressure was 145/90 mm Hg, heart rate 110 beats per minute and regular, respiratory rate 29 breaths per minute, and oral temperature 38.1°C (100.6°F). His oxygen saturation was 88% while breathing room air. His body mass index was 27.1 kg/m².

His throat was mildly congested. His neck veins were flat, and there were no carotid bruits. His thyroid examination was normal, without goiter, nodules, or tenderness.

Intercostal retractions were noted around the anterolateral costal margins. He had no chest wall deformities. Chest expansion was reduced bilaterally. There was hyperresonance bilaterally. Expiratory wheezes were heard over both lungs, without crackles.

His heart had no murmurs or added sounds. There was no lower-limb edema or swelling. The rest of his physical examination was unremarkable.

Results of initial laboratory testing are shown in Table 1.

Assessment: A 66-year-old man with GOLD grade 1, group A COPD, presenting with a severe exacerbation, most likely due to viral bronchitis.

The patient was given oxygen 28% by Venturi mask, and his oxygen saturation went up to 90%. He was started on nebulized albuterol 2.5 mg with ipratropium bromide 500 µg every 4 hours, prednisone 40 mg orally daily for 5 days, and ceftriaxone 1 g intravenously every 24 hours. The first dose of each medication was given in the emergency department.

The patient was then admitted to a progressive care unit, where he was placed on noninvasive positive pressure ventilation, continuous cardiac monitoring, and pulse oximetry. He was started on enoxaparin 40 mg subcutaneously daily to prevent venous thromboembolism, and the oral medications he had been taking at home were continued. Because he was receiving a glucocorticoid, his blood glucose was monitored in the fasting state, 2 hours after each meal, and as needed.

Two hours after he started noninvasive positive pressure ventilation, his arterial blood gases were remeasured and showed the following results:

• pH 7.35
• Partial pressure of carbon dioxide (Paco₂) 52 mm Hg
• Bicarbonate 28 mmol/L
• Partial pressure of oxygen (Pao₂) 60 mm Hg
• Oxygen saturation 90%.

HOSPITAL COURSE

On hospital day 3, his dyspnea had slightly improved. His respiratory rate was 26 to 28 breaths per minute. His oxygen saturation remained between 90% and 92%.

At 10:21 pm, his cardiac monitor showed an episode of focal atrial tachycardia at a rate of 129 beats per minute that lasted for 3 minutes and 21 seconds, terminating spontaneously. He denied any change in his clinical condition during the episode, with no chest pain, palpitation, or change in dyspnea. There was no change in his vital signs. He had another similar asymptomatic episode lasting 4 minutes and 9 seconds at 6:30 am of hospital day 4.

Because of these episodes, the attending physician ordered thyroid function tests.

THYROID FUNCTION TESTING

1. Which thyroid function test is most likely to be helpful in the assessment of this patient’s thyroid status?

• Serum thyroid-stimulating hormone (TSH) alone
• Serum TSH and total thyroxine (T₄)
• Serum TSH and total triiodothyronine (T₃)
• Serum TSH and free T₄
• Serum TSH and free T₃

There are several tests to assess thyroid function: the serum TSH, total T₄, free T₄, total T₃, and free T₃ concentrations.¹

In normal physiology, TSH from the pituitary stimulates the thyroid gland to produce and secrete T₄ and T₃, which in turn inhibit TSH secretion through negative feedback. A negative log-linear relation exists between serum free T₄ and TSH levels.² Thus, the serum free T₄ level can remain within the normal reference range even if the TSH level is high or low. 

TSH assays can have different detection limits. A third-generation TSH assay with a detection limit of 0.01 mU/L is recommended for use in clinical practice.³

TSH testing alone. Given its superior sensitivity and specificity, serum TSH measurement is considered the best single test for assessing thyroid function in most cases.⁴ Nevertheless, measurement of the serum TSH level alone could be misleading in several situations, eg, hypothalamic or pituitary disorders, recent treatment of thyrotoxicosis, impaired sensitivity to thyroid hormone, and acute nonthyroidal illness.⁴

Free vs total T₄ and T₃ levels

Serum total T₄ includes a fraction that is bound, mainly to thyroxin-binding globulin, and a very small unbound (free) fraction. The same applies to T₃. Only free thyroid hormones represent the “active” fraction available for interaction with their protein receptors in the nucleus.⁸ Patients with conditions that can affect the thyroid-binding protein concentrations usually have altered serum total T₄ and T₃ levels, whereas their free hormone concentrations remain normal. Accordingly, measurement of free hormone levels, especially free T₄, is usually recommended.

Although equilibrium dialysis is the method most likely to provide an accurate serum free T₄ measurement, it is not commonly used because of its limited availability and high cost. Thus, most commercial laboratories use “direct” free T₄ measurement or, to a lesser degree, the free T₄ index.⁹ However, none of the currently available free T₄ tests actually measure free T₄ directly; rather, they estimate it.¹⁰

Commercial laboratories can provide a direct free T₃ estimate, but it may be less reliable than total T₃. If serum T₃ measurement is indicated, serum total T₃ is usually measured. However, total T₃ measurement is rarely indicated for patients with hypothyroidism because it usually remains within the normal reference range.¹¹ Nevertheless, serum total T₃ measurement could be useful in patients with T₃ toxicosis and in those who are acutely ill.

Accordingly, in acutely ill hospitalized patients like ours, measuring serum TSH using a third-generation assay and free T₄ is essential to assess thyroid function. Many clinicians also measure serum total T₃.

The attending physician ordered serum TSH, free T₄, and total T₃ measurements, which yielded the following:

• TSH 0.1 mU/L (0.5–5.0)
• Total T₃ 55 ng/dL (80–180)
• Free T₄ 0.9 ng/dL (0.9–2.4).

2. Which best explains this patient’s abnormal thyroid test results?

• His acute illness
• Central hypothyroidism due to pituitary infarction
• His albuterol therapy
• Subclinical thyrotoxicosis
• Hashimoto thyroiditis

Since euthyroid patients with an acute illness may have abnormal thyroid test results (Table 2),^5–7 thyroid function testing is not recommended unless there is a strong indication for it, such as new-onset atrial fibrillation, atrial flutter, or focal atrial tachycardia.¹ In such patients, it is important to know whether the test abnormalities represent true thyroid disorder or are the result of a nonthyroidal illness.

Thyroid function testing in patients with nonthyroidal illness usually shows low serum total T₃, normal or low serum TSH, and normal, low, or high serum free T₄. However, transient mild serum TSH elevation can be seen in some patients during the recovery period.¹⁶ These abnormalities with their mechanisms are shown in Table 2.^5–7 In several commercial kits, serum direct free T₄ can be falsely decreased or increased.⁸

THE DIFFERENTIAL DIAGNOSIS

Our patient had low serum TSH, low-normal serum direct free T₄, and low serum total T₃. This profile could be caused by a nonthyroidal illness, “true” central hypothyroidism, or his glucocorticoid treatment. The reason we use the term “true” in this setting is that some experts suggest that the thyroid function test abnormalities in patients with acute nonthyroidal illness represent a transient central hypothyroidism.¹⁷ The clinical presentation is key in differentiating true central hypothyroidism from nonthyroidal illness.

In addition, measuring serum cortisol may help to differentiate between the 2 states, as it would be elevated in patients with nonthyroidal illness as part of a stress response but low in patients with true central hypothyroidism, since it is usually part of combined pituitary hormone deficiency.¹⁸ Of note, some critically ill patients have low serum cortisol because of transient central adrenal insufficiency.^19,20

The serum concentration of reverse T₃ has been suggested as a way to differentiate between hypothyroidism (low) and nonthyroidal illness (high); however, further studies showed that it does not reliably differentiate between the conditions.²¹

GLUCOCORTICOIDS AND THYROID FUNCTION TESTS

By inhibiting D1, glucocorticoids can decrease peripheral conversion of T₄ to T₃ and thus decrease serum total T₃. This effect depends on the type and dose of the glucocorticoid and the duration of therapy.

In one study,²² there was a significant reduction in serum total T₃ concentration 24 hours after a single oral dose of dexamethasone 12 mg in normal participants. This effect lasted 48 hours, after which serum total T₃ returned to its pretreatment level.

In another study,²³ a daily oral dose of betamethasone 1.5 mg for 5 days did not significantly reduce the serum total T₃ in healthy volunteers, but a daily dose of 3 mg did. This effect was more pronounced at a daily dose of 4.5 mg, whereas a dose of 6.0 mg had no further effect.

Long-term glucocorticoid therapy also decreases serum total T₄ and total T₃ by lowering serum thyroid-binding globulin.²⁴

Finally, glucocorticoids can decrease TSH secretion by directly inhibiting thyrotropin-releasing hormone.^25,26 However, chronic hypercortisolism, whether endogenous or exogenous, does not cause clinically central hypothyroidism, possibly because of the negative feedback mechanism of low thyroid hormones on the pituitary and the hypothalamus.²⁷

Other drugs including dopamine, dopamine agonists, dobutamine, and somatostatin analogues can suppress serum TSH. As with glucocorticoids, these drugs do not cause clinically evident central hypothyroidism.²⁸ Bexarotene, a retinoid X receptor ligand used in the treatment of cutaneous T-cell lymphoma, has been reported to cause clinically evident central hypothyroidism by suppressing TSH and increasing T₄ clearance.²⁹

While there is general agreement that beta-adrenergic antagonists (beta-blockers) do not affect the serum TSH concentration, conflicting data have been reported concerning their effect on other thyroid function tests. This may be due to several factors, including dose, duration of therapy, the patient’s thyroid status, and differences in laboratory methodology.³⁰

In studies of propranolol, serum total T₄ concentrations did not change or were increased with daily doses of 160 mg or more in both euthyroid participants and hyperthyroid patients^31–33; serum total T₃ concentrations did not change or were decreased with 40 mg or more daily³⁴; and serum reverse T₃ concentrations were increased with daily doses of 80 mg or more.³¹ It is most likely that propranolol exerts these changes by inhibiting D1 activity in peripheral tissues.

Furthermore, a significant decrease in serum total T₃ concentrations was observed in hyperthyroid patients treated with atenolol 100 mg daily, metoprolol 100 mg daily, and alprenolol 100 mg daily, but not with sotalol 80 mg daily or nadolol (up to 240 mg daily).^35,36

On the other hand, beta-adrenergic agonists have not been reported to cause significant changes in thyroid function tests.³⁷

SUBCLINICAL THYROTOXICOSIS OR HASHIMOTO THYROIDITIS?

Our patient’s thyroid function test results are more likely due to his nonthyroidal illness and glucocorticoid therapy, as there is no clinical evidence to point to a hypothalamic-pituitary disorder accounting for true central hypothyroidism.

The other options mentioned in question 2 are unlikely to explain our patient’s thyroid function test results.

Subclinical thyrotoxicosis is characterized by suppressed serum TSH, but both serum free T₄ and total T₃ remain within the normal reference ranges. In addition, the serum TSH level may help to differentiate between thyrotoxicosis and nonthyroidal illness. In the former, serum TSH is usually suppressed (< 0.01 mU/L), whereas in the latter it is usually low but detectable (0.05– 0.3 mU/L).^38,39

Hashimoto thyroiditis is a chronic autoimmune thyroid disease characterized by diffuse lymphocytic infiltration of the thyroid gland. Almost all patients with Hashimoto thyroiditis have elevated levels of antibodies to thyroid peroxidase or thyroglobulin.⁴⁰ Clinically, patients with Hashimoto thyroiditis can either be hypothyroid or have normal thyroid function, which is not the case in our patient.

CASE CONTINUED

An endocrinologist, consulted for a second opinion, agreed that the patient’s thyroid function test results were most likely due to his nonthyroidal illness and glucocorticoid therapy.

3. In view of the endocrinologist’s opinion, which should be the next step in the management of the patient’s thyroid condition?

• Start levothyroxine (T₄) therapy
• Start liothyronine (T₃) therapy
• Start N-acetylcysteine therapy
• Start thyrotropin-releasing hormone therapy
• Remeasure thyroid hormones after full recovery from his acute illness

It is not clear whether the changes in thyroid hormone levels during an acute illness are a pathologic alteration for which thyroid hormone therapy may be beneficial, or a physiologic adaptation for which such therapy would not be indicated.⁴¹

However, current data argue against thyroid hormone therapy using T₄ or T₃ for patients with nonthyroidal illness syndrome (also called euthyroid sick syndrome).⁴² Indeed, several randomized controlled trials showed that thyroid hormone therapy is not beneficial in such patients and may be detrimental.^41,43

Therapies other than thyroid hormone have been investigated to ameliorate thyroid hormone abnormalities in patients with nonthyroidal illness. These include N-acetylcysteine, thyrotropin-releasing hormone therapy, and nutritional support.

Some studies showed that giving N-acetyl­cysteine, an antioxidant, increased serum T₃ and decreased serum reverse T₃ concentrations in patients with acute myocardial infarction.⁴⁴ Nevertheless, the mortality rate and length of hospitalization were not affected. Further studies are needed to know whether N-acetylcysteine therapy is beneficial for such patients.

Similarly, a study using a thyrotropin-releasing hormone analogue along with growth hormone-releasing peptide 2 showed an increase in serum TSH, T₄, and T₃ levels in critically ill patients.⁴⁵ The benefit of this therapy has yet to be determined. On the other hand, early nutritional support was reported to prevent thyroid hormonal changes in patients postoperatively.⁴⁶

Measuring thyroid hormone levels after full recovery is the most appropriate next step in our patient, as the changes in thyroid hormone concentrations subside as the acute illness resolves.⁴⁷

The patient continued to improve. On hospital day 6, he was feeling better but still had mild respiratory distress. There had been no further episodes of arrhythmia since day 4. His blood pressure was 136/86 mm Hg, heart rate 88 beats per minute and regular, respiratory rate 18 breaths per minute, and oral temperature 37.1°C. His oxygen saturation was 92% on room air.

Before discharge, he was encouraged to quit smoking. He was offered behavioral counseling and medication therapy, but he only said that he would think about it. He was discharged on oral cefixime for 4 more days and was instructed to switch to a long-acting bronchodilator along with his other home medications and to return in 1 week to have his thyroid hormones checked.

One week later, his laboratory results were:

• TSH 11.2 mU/L (reference range 0.5–5.0)
• Free T₄ 1.2 ng/dL (0.9–2.4)
• Total T₃ 92 ng/dL (80–180).

Clinically, the patient was euthyroid, and examination of his thyroid was unremarkable.

4. Based on these last test results, which statement is correct?

• Levothyroxine therapy should be started
• His serum TSH elevation is most likely transient
• Thyroid ultrasonography is strongly indicated
• A radioactive iodine uptake study should be performed
• Measurement of thyroid-stimulating immunoglobulins is indicated

During recovery from nonthyroidal illness, some patients may have elevated serum TSH levels that are usually transient and modest (< 20 mU/L).⁴⁸ Normalization of the thyroid function tests including serum TSH may take several weeks⁴⁹ or months.⁵⁰ However, a systematic review found that the likelihood of permanent primary hypothyroidism is high in patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness.⁵¹

Ultrasonography is useful for evaluating patients with thyroid nodules or goiter but is of little benefit for patients like ours, in whom the thyroid is normal on examination.

Similarly, a radioactive iodine uptake study is not indicated, as it is principally used to help differentiate between types of thyrotoxicosis. (Radioactive iodine is also used to treat differentiated thyroid cancer.)

Thyroid-stimulating immunoglobins are TSH receptor-stimulating antibodies that cause Graves disease. Nevertheless, measuring them is not routinely indicated for its diagnosis. However, their measurement is of significant help in the diagnosis of Graves disease if a radioactive iodine uptake study cannot be performed (as in pregnancy) and in atypical presentations such as euthyroid Graves ophthalmopathy.⁵² Other indications for thyroid-stimulating immunoglobin measurement are beyond the scope of the article. Our patient’s test results are not consistent with hyperthyroidism, so measuring thyroid-stimulating immunoglobins is not indicated.

CASE CONCLUSION: BETTER, BUT STILL SMOKING

The patient missed his 1-month clinic follow-up, but he visited the clinic for follow-up 3 months later. He was feeling well with no complaints. Test results including serum TSH, free T₄, and total T₃ were within normal ranges. His COPD was under control, with an FEV₁ 88% of predicted.

He was again encouraged to quit smoking and was offered drug therapy and behavioral counseling, but he declined. In addition, he was instructed to adhere to his annual influenza vaccination.

KEY POINTS

• In patients with acute illness, it is recommended that thyroid function not be assessed unless there is a strong indication.
• If thyroid function assessment is indicated for critically ill patients, serum TSH and free T₄ concentrations should be measured. Some clinicians also measure serum total T₃ level.
• Thyroid function testing in critically ill patients usually shows low serum total T₃, normal or low serum TSH, and normal or low serum free T₄.
• Many drugs can alter thyroid hormone levels.
• Thyroid hormone therapy is not recommended for critically ill patients with low T₃, low T₄, or both.
• During recovery from nonthyroidal illness, some patients may have mild elevation in serum TSH levels (< 20 mU/L).
• Thyroid hormone levels may take several weeks or months to return to normal after the acute illness.
• Patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness are more likely to have permanent primary hypothyroidism.

Myopathies can present with a wide variety of symptoms, so patients with muscle weakness are often seen initially by a general practitioner. Nonrheumatologists should be able to evaluate a patient presenting with muscle weakness or myalgia and be aware of red flags indicating potentially dangerous syndromes that require a prompt, thorough investigation.

This article reviews selected causes of muscle weakness, such as statin-induced and autoimmune disorders, and systemic features of inflammatory myopathies beyond myositis, such as dermatologic and pulmonary manifestations.

FOCUSING THE EVALUATION

The evaluation of a patient presenting with muscle weakness should include several assessments: 

Temporal progression. Was the onset of symptoms rapid or insidious? Patterns of onset may give clues to etiology, including the possibility of an associated autoimmune condition.

Location of muscle weakness. Are symptoms global or localized? And if localized, are they proximal or distal? Proximal weakness can be manifested by difficulty rising from a chair (hip muscles) or combing one’s hair (shoulder muscles), whereas distal weakness can involve difficulty standing on toes (gastrocnemius and soleus muscles) or performing fine motor activities (intrinsic hand muscles).

Symmetry. A focal or asymmetric pattern often has a neurologic etiology, but this could also be consistent with inclusion body myositis.

Other symptoms. Arthritis, rash, and swallowing problems point to a possible underlying rheumatologic disease. Weight gain or loss may indicate a thyroid disorder.

Family history. Some patients report that others in their family have this pattern of weakness, indicating a likely genetic myopathy. If the patient reports a relative with multiple sclerosis, lupus erythematosus, rheumatoid arthritis, or another autoimmune disease, then an immune-mediated myopathy should be considered.

Medications should be reviewed, particularly statins.

CASE 1: SLOWLY PROGRESSIVE WEAKNESS

A 65-year-old man presented with the insidious onset of muscle weakness and episodes of falling. On review of his medical record, his serum creatine kinase (CK) levels were elevated at various periods at 2 to 4 times the upper limit of normal. Electromyography (EMG) previously showed a myopathic pattern, and a muscle biopsy was abnormal, consistent with endomysial inflammation (term is consistent with “polymyositis”). He was treated for polymyositis for several years with prednisone alone, with steroids plus methotrexate, and with combined immunosuppression including methotrexate and azathioprine, but with no improvement. Eventually, another muscle biopsy revealed inclusion bodies with rimmed vacuoles, consistent with inclusion body myositis.

Inclusion body myositis

Inclusion body myositis is the most common myopathy in middle-aged to elderly people, especially men. These patients are often told “You are just getting old,” but they have a defined condition. It should also be considered in patients failing to respond to treatment or with those with “refractory” polymyositis.

The onset of muscle weakness is insidious and painless, and the weakness progresses slowly. The pattern is distal and asymmetric (eg, foot drop), and muscle atrophy typically affects the forearm flexors, quadriceps, and intrinsic muscles of the hands.¹

Magnetic resonance imaging may show marked muscle atrophy. Unfortunately, no treatment has shown efficacy, and most neuromuscular and rheumatology experts do not treat inclusion body myositis with immunosuppressive drugs. 

CASE 2: MILD MYALGIA WITHOUT WEAKNESS

A black 52-year-old man was referred because of myalgia and a CK level of 862 U/L (reference range < 200). His physician wanted to start him on a statin but was hesitant to do so without first consulting a rheumatologist.

The patient had a long history of mild arthralgias and myalgias without muscle weakness. He had dyslipidemia and hypertension. He reported no family history of myopathy and no illicit drug use. He was formerly an athlete. Medications included a thiazide diuretic and a beta-blocker. On examination, his muscles were strong (rated 5 on a scale of 5) in the upper and lower extremities, without atrophy.

His records showed that his CK levels had risen and fallen repeatedly over the past few years, ranging from 600 to 1,100 U/L. On further questioning, he reported that when he had joined the army 30 years previously, a physician had recommended he undergo a liver biopsy in view of elevated liver function tests, but that he had refused because he felt fine.

Currently, his gamma-glutamyl transpeptidase levels were normal.

Idiopathic ‘hyperCKemia’

So-called idiopathic hyperCKemia is not a form of myositis but merely a laboratory result outside the “normal” range. Reference ranges are based predominantly on measurements in white people and on an assumption that the distribution is Gaussian (bell-shaped). A normal CK level is usually defined as less than 200 U/L. Using this standard, up to 20% of men and 5% of women have hyperCKemia.²

However, CK levels vary by sex and ethnicity, with mean levels highest in black men, followed by black women, white men, and white women. The mean level in black men is higher than the standard cutoff point for normal, and especially in this population, there is wide fluctuation around the mean, leading to hyperCKemia quite frequently in black men. Exercise and manual labor also drive up CK levels.^3–5 

Idiopathic hyperCKemia is benign. D’Adda et al⁶ followed 55 patients for a mean of 7.5 years. CK levels normalized in 12 patients or at least decreased in 24. Most remained symptom-free or had minimal symptoms. 

Idiopathic hyperCKemia: Bottom line

Before prescribing a statin, determine the baseline CK level. If slightly elevated (ie, up to 3 to 5 times the upper limit of normal, or even higher) in the setting of normal muscle strength, there is no need for electromyography or muscle biopsy, and the patient can certainly receive a statin. Most of these patients do not need to see a rheumatologist but can simply have their CK and muscle strength monitored.

Myositis (idiopathic inflammatory myopathy) is a heterogeneous group of autoimmune syndromes of unknown cause characterized by chronic muscle weakness and inflammation of striated muscle. These syndromes likely arise as a result of genetic predisposition and an environmental or infectious “hit.”

Myositis is rare, with an incidence of 5 to 10 cases per million per year and an estimated prevalence of 50 to 90 cases per million. It has 2 incidence peaks: 1 in childhood (age 5–15) and another in adult midlife (age 30–50). Women are affected 2 to 3 times more often than men, with black women most commonly affected.

Myositis is traditionally classified as follows:

• Adult polymyositis
• Adult dermatomyositis
• Juvenile myositis (dermatomyositis much more frequent than polymyositis)
• Malignancy-associated myositis (usually dermatomyositis)
• Myositis overlapping with another autoimmune disease
• Inclusion body myositis.

However, polymyositis is less common than we originally thought, and the term necrotizing myopathy is now used in many patients, as noted in the case studies below. Further, myositis overlap syndromes are being increasingly diagnosed, likely related to the emergence of autoantibodies and clinical “syndromes” associated with these autoantibody subsets (discussed in cases below).

Dermatomyositis

Dermatomyositis is characterized by muscle weakness and a rash that can be obvious or subtle. Classic skin lesions are Gottron papules, which are raised, flat-topped red or purplish lesions over the knuckles, elbows, or knees.

Lesions may be confused with those of psoriasis. There can also be a V-neck rash over the anterior chest or upper back (“shawl sign”) or a rash over the lateral thigh (“holster sign”). A facial rash may occur, but unlike lupus, dermatomyositis does not spare the nasolabial area. However, the V-neck rash can be similar to that seen in lupus.

Dermatomyositis may cause muscle pain, perhaps related to muscle ischemia, whereas polymyositis and necrotizing myopathy are often painless. However, pain is also associated with fibromyalgia, which may be seen in many autoimmune conditions. It is important not to overtreat rheumatologic diseases with immunosuppression to try to control pain if the pain is actually caused by fibromyalgia.

Polymyositis mimics

Hypothyroid myopathy can present as classic polymyositis. The serum CK may be elevated, and there may be myalgias, muscle hypertrophy with stiffness, weakness, cramps, and even features of a proximal myopathy, and rhabdomyolysis. The electromyogram can be normal or myopathic. Results of muscle biopsy are often normal but may show focal necrosis and mild inflammatory infiltrates, thus mimicking that seen with inflammatory myopathy.⁷

Drug-induced or toxic myopathies can also mimic polymyositis. Statins are among the most commonly prescribed drugs in the United States, with more than 35 million people taking them. Statins are generally well tolerated but have a broad spectrum of toxicity, ranging from myalgias to life-threatening rhabdomyolysis. Myalgias lead to about 5% to 10% of patients refusing to take a statin or stopping it on their own.

Myalgias affect up to 20% of statin users in clinical practice.^8,9 A small cross-sectional study¹⁰ of 1,000 patients in a primary care setting found that the risk of muscle complaints in statin users was 1.5 times higher than in nonstatin users, similar to findings in other studies.

My strategy for managing a patient with possible statin-induced myopathy is illustrated in Figure 1.

CASE 3: WEAKNESS, VERY HIGH CK ON A STATIN

In March 2010, a 67-year-old woman presented with muscle weakness. She had a history of hypertension, hyperlipidemia, and, more than 10 years previously, uterine cancer. In 2004, she was given atorvastatin for dyslipidemia. Four years later, she developed lower-extremity weakness, which her doctor attributed to normal aging. A year after that, she found it difficult to walk up steps and lift her arms overhead. In June 2009, she stopped taking the atorvastatin on her own, but the weakness did not improve.

In September 2009, she returned to her doctor, who found her CK level was 6,473 U/L but believed it to be an error, so the test was repeated, with a result of 9,375 U/L. She had no rash or joint involvement.

She was admitted to the hospital and underwent muscle biopsy, which showed myonecrosis with no inflammation or vasculitis.  She was treated with prednisone 60 mg/day, and her elevated CK level and weakness improved.

Immune-mediated necrotizing myopathy associated with statins

The hallmark of necrotizing myopathy is myonecrosis without significant inflammation.¹² This pattern contrasts with that of polymyositis, which is characterized by lymphocytic inflammation.

Although statins became available in the United States in 1987, immune-mediated necrotizing myopathy associated with statins was first described only in 2010. In that report, Grable-Esposito et al¹³ described 25 patients from 2 neuromuscular centers seen between 2000 and 2008 who had elevated CK and proximal weakness during or after statin use, both of which persisted despite stopping the statin. Patients improved with immunosuppressive agents but had a relapse when steroids were stopped or tapered, a pattern typical in autoimmune disease.

Also in 2010, Christopher-Stine et al¹⁴ reported an antibody associated with necrotizing myopathy. Of 38 patients with the condition, 16 were found to have an abnormal “doublet” autoantibody recognizing 200- and 100-kDa proteins. All patients had weakness and a high CK level, and 63% had statin exposure before the weakness (this percentage increased to 83% in patients older than 50). All responded to immunosuppressive therapy, and many had a relapse when it was withdrawn.

Statins lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-Co A reductase (HMGCR), and paradoxically, they also upregulate it. HMGCR has a molecular weight of 97 kDa. Mammen et al¹⁵ identified HMGCR as the 100-kDa target of the identified antibody and developed an enzyme-linked immunosorbent assay for it. Of 750 patients presenting to one center, only 45 (6%) had anti-HMGCR autoantibodies, but all 16 patients who had the abnormal doublet antibody tested positive for anti-HMGCR. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response after statins are discontinued.

Case 3 continued: Intravenous immunoglobulin brings improvement

In March 2010, when the 67-year-old patient presented to our myositis center, her CK level was 5,800 U/L, which increased as prednisone was tapered. She still felt weak. On examination, her muscle strength findings were deltoids 4+/5, neck flexors 4/5, and iliopsoas 3+/5. She was treated with methotrexate and azathioprine without benefit. She was next treated with intravenous immunoglobulin, and after 3 months, her strength normalized for the first time in years. Her CK level decreased but did not normalize. Testing showed that she was positive for anti-HMGCR auto­antibody, as this test had become commercially available.

In 2015, Mammen and Tiniakou¹⁶ suggested using intravenous immunoglobulin as first-line therapy for statin-associated autoimmune necrotizing myopathy, based on experience at a single center with 3 patients who declined glucocorticoid treatment.

Necrotizing myopathy: Bottom line

Myositis overlap syndromes

Heterogeneity is the rule in myositis, and it can present with a wide variety of signs and symptoms as outlined in Table 2.

CASE 4: FEVER, NEW ‘RHEUMATOID ARTHRITIS,’ AND LUNG DISEASE

A 52-year-old woman with knee osteoarthritis saw her primary care physician in November 2013 for dyspnea and low-grade fever. The next month, she presented with polyarthritis, muscle weakness, and Raynaud phenomenon.

In January 2014, she developed acrocyanosis of her fingers. Examination revealed hyperkeratotic, cracked areas of her fingers. Her oxygen saturation by pulse oximetry was low. She was admitted to the hospital. Her doctor suspected new onset of rheumatoid arthritis, but blood tests revealed a negative antinuclear antibody, so an autoimmune condition was deemed unlikely. Her CK was mildly elevated at 350 U/L.

Because of her dyspnea, an open-lung biopsy was performed. High-resolution computed tomography (CT) revealed infiltrates and ground-glass opacities, leading to the diagnosis of nonspecific interstitial pneumonia. A rheumatologist was consulted and recommended pulse methylprednisolone, followed by prednisone 60 mg/day and mycophenolate mofetil. Testing for Jo-1 antibodies was positive.

Antisynthetase syndrome

The antisynthetase syndrome is a clinically heterogeneous condition that can occur with any or all of the following:

• Fever
• Myositis
• Arthritis (often misdiagnosed as rheumatoid arthritis)
• Raynaud phenomenon
• Mechanic’s hands (hyperkeratotic  roughness with fissures on the lateral aspects of the fingers and finger pads)
• Interstitial lung disease.

The skin rashes and myositis may be subtle, making the presentation “lung-dominant,” and nonrheumatologists should be aware of this syndrome. Although in our patient the condition developed in a classic manner, with all of the aforementioned features of the antisynthetase syndrome, some patients will manifest one or a few of the features.

Clinically, patients with the Jo-1 antisynthetase syndrome often present differently than those with non-Jo-1 antisynthetase autoantibodies. When we compared 122 patients with Jo-1 vs 80 patients with a non-Jo-1 antisynthetase autoantibody, patients with Jo-1 antibodies were more likely to have initially received a diagnosis of myositis (83%), while  myositis was the original diagnosis in only 17% of those possessing non-Jo-1 antisynthetase autoantibodies. In fact, many patients (approximately 50%) were diagnosed as having undifferentiated connective tissue disease or an overlap syndrome, and 13% had scleroderma as their first diagnosis.¹⁷

We also found that the survival rate was higher in patients with Jo-1 syndrome compared with patients with non-Jo-1 antisynthetase syndromes. We attributed the difference in survival rates to a delayed diagnosis in the non-Jo-1 group, perhaps due to their “nonclassic” presentations of the antisynthetase syndrome, delaying appropriate treatment. Patients received a diagnosis of Jo-1 antibody syndrome after a mean of 0.4 year (range 0.2–0.8), while those with a non-Jo-1 antisynthetase autoantibody had a delay in diagnosis of 1.0 year (range 0.4–5.1) (P < .01).¹⁷

In nearly half the cases in this cohort, pulmonary fibrosis was the cause of death, with primary pulmonary hypertension being the second leading cause (11%).

Antisynthetase syndrome: Bottom line

Antisynthetase syndrome is an often fatal disease that does not always present in a typical fashion with symptoms of myositis, as lung disease may be the predominant feature. A negative antinuclear antibody test result does not imply antibody negativity, as the autoantigen in these diseases is not located in the nucleus. Prompt diagnosis and appropriate immunosuppressive therapy are critical to improving outcomes.

CASE 5: FEVER, UNDIAGNOSED LUNG DISEASE, NO MYOSITIS

In January 2001, a 39-year-old woman was admitted to the hospital after 5 weeks of fever (temperatures 103°–104°F) and myalgias. An extensive workup was negative except for low-titer antinuclear antibody and for mild basilar fibrosis noted on chest radiography. She left the hospital against medical advice because of frustration with a lack of a specific diagnosis (“fever of unknown origin”).

Two months later, at a follow-up rheumatology consult, she reported more myalgias and arthralgias, as well as fever. Chest radiography now showed pleural effusions. Her fingers had color changes consistent with Raynaud phenomenon. At that time, I diagnosed an undifferentiated connective tissue disease and told her that I suspected an autoimmune condition that would need time to reveal itself. In the meantime, I treated her empirically with prednisone.

In April, she returned, much more short of breath and with more prominent diffuse pulmonary infiltrates. Physical examination revealed subtle Gottron changes. Testing revealed poor pulmonary function: forced vital capacity (FVC) 56%, forced expiratory volume in 1 second (FEV₁) 52%, and diffusing capacity for carbon monoxide (Dlco) 40%. Blood testing was positive for anti-PL-12 antibody, one of the non-Jo-1 antisynthetase antibodies. At this time, we treated her with glucocorticoids and tacrolimus.

More than 15 years later, this patient is doing well. Her skin rash, joint symptoms, and fever have not returned, and interestingly, she never developed myositis. Her Raynaud symptoms are mild. Her most recent pulmonary function test results (January 2018) were FVC  75%, FEV₁ 87%, and Dlco 78%. Although these results are not normal, they are much improved and allow her to be completely functional without supplemental oxygen. Echocardiography showed  normal pulmonary artery systolic pressure (25 mm Hg). She was still taking tacrolimus and prednisone. When we tried to stop tacrolimus after she had done well for many years, her condition flared.

Non-Jo-1 antisynthetase syndrome: Bottom line

Patients with a non-Jo-1 antisynthetase syndrome often present without myositis symptoms and may never manifest myositis symptoms. Likely because of this presentation, diagnosis of a specific connective tissue disorder is delayed, perhaps leading to increased mortality risk from pulmonary disease. Chronic immunosuppression is often required for these autoimmune conditions.

CASE 6: DERMATOMYOSITIS, RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE

A 58-year-old woman presented in the summer of 2012 with a photosensitive rash. The following January, she returned with polyarthritis, mild muscle weakness, and a dermatomyositis-pattern rash. Her CK level was normal, and her antinuclear antibody and Sjögren syndrome antibody test results were negative. She improved on low-dose prednisone and methotrexate.

She was originally referred to me in May of that year for worsening rash and mild weakness. She denied pulmonary symptoms, but examination revealed faint basilar crackles. I increased her prednisone dosage to 20 mg/day and started mycophenolate mofetil mainly for the mild cutaneous and myositis features. I also recommended high-resolution CT of the lungs and pulmonary function tests, which she underwent in early June. High-resolution CT showed nonspecific mild infiltrates with minimal ground-glass opacities.

On July 1, she presented to her local emergency department with severe shortness of breath, requiring oxygen 12 L/min. She had a palmar rash. Repeat high-resolution CT showed dramatic worsening compared with the scan the previous month. Because of continued inadequate oxygenation, she was transferred to our center. A blood test later was positive for antimelanoma differentiation-associated gene 5 (MDA-5) autoantibody, previously known as anticlinically amyopathic dermatomyositis (anti-CADM)-140 antibody (based on immunoprecipitation results).

She died on the third day after transfer, just 2 months after I had originally seen her, at which time she had had no pulmonary symptoms.

Clinically amyopathic dermatomyositis

Anti-CADM-140, first reported from Asia,^18–20 is an autoantibody-associated disease but not an antisynthetase. It is associated with dermatomyositis; patients often have a “vasculopathy” with cutaneous ulcerations and palmar papules.

MDA-5 is a cytoplasmic protein that “senses” viral RNA and induces production of type 1 interferon. It is involved in the innate immune defense against viruses.

Anti-MDA-5 positivity is associated with a poor pulmonary outcome.²¹ In our cohort from the University of Pittsburgh, many patients died within 3 years, compared with about a 40% survival rate in patients with dermatomyositis who tested negative for this antibody. That being said, many patients with anti-MDA-5 do not develop rapidly progressive interstitial lung disease.

Autoimmune interstitial lung disease: Bottom line

Autoimmune interstitial lung disease is easy to miss, especially in the case of a non-Jo-1 syndrome, for 3 important reasons:

• The autoimmune features may initially be subtle (eg, Raynaud phenomena, mild dermatomyositis rash, undifferentiated connective tissue disease)
• Autoantibody testing is not often ordered, is not standardized, or may be unavailable 
• Providers are mistakenly reassured that a patient who tests negative for antinuclear antibody does not have an autoimmune condition.

To emphasize the last point, in a cohort of 202 patients who tested positive for an antisynthetase antibody, only half were antinuclear antibody-positive, but nearly three-quarters demonstrated anticytoplasmic staining on indirect immunofluorescence (due to the location of the autoantigen in the cytoplasm), making the latter a better screening test for an antisynthetase antibody. For scleroderma, 99% were antinculear antibody-positive, but for myositis, this test is much less sensitive.²²

Myopathies can present with a wide variety of symptoms, so patients with muscle weakness are often seen initially by a general practitioner. Nonrheumatologists should be able to evaluate a patient presenting with muscle weakness or myalgia and be aware of red flags indicating potentially dangerous syndromes that require a prompt, thorough investigation.

This article reviews selected causes of muscle weakness, such as statin-induced and autoimmune disorders, and systemic features of inflammatory myopathies beyond myositis, such as dermatologic and pulmonary manifestations.

FOCUSING THE EVALUATION

The evaluation of a patient presenting with muscle weakness should include several assessments: 

Temporal progression. Was the onset of symptoms rapid or insidious? Patterns of onset may give clues to etiology, including the possibility of an associated autoimmune condition.

Location of muscle weakness. Are symptoms global or localized? And if localized, are they proximal or distal? Proximal weakness can be manifested by difficulty rising from a chair (hip muscles) or combing one’s hair (shoulder muscles), whereas distal weakness can involve difficulty standing on toes (gastrocnemius and soleus muscles) or performing fine motor activities (intrinsic hand muscles).

Symmetry. A focal or asymmetric pattern often has a neurologic etiology, but this could also be consistent with inclusion body myositis.

Other symptoms. Arthritis, rash, and swallowing problems point to a possible underlying rheumatologic disease. Weight gain or loss may indicate a thyroid disorder.

Family history. Some patients report that others in their family have this pattern of weakness, indicating a likely genetic myopathy. If the patient reports a relative with multiple sclerosis, lupus erythematosus, rheumatoid arthritis, or another autoimmune disease, then an immune-mediated myopathy should be considered.

Medications should be reviewed, particularly statins.

CASE 1: SLOWLY PROGRESSIVE WEAKNESS

A 65-year-old man presented with the insidious onset of muscle weakness and episodes of falling. On review of his medical record, his serum creatine kinase (CK) levels were elevated at various periods at 2 to 4 times the upper limit of normal. Electromyography (EMG) previously showed a myopathic pattern, and a muscle biopsy was abnormal, consistent with endomysial inflammation (term is consistent with “polymyositis”). He was treated for polymyositis for several years with prednisone alone, with steroids plus methotrexate, and with combined immunosuppression including methotrexate and azathioprine, but with no improvement. Eventually, another muscle biopsy revealed inclusion bodies with rimmed vacuoles, consistent with inclusion body myositis.

Inclusion body myositis

Inclusion body myositis is the most common myopathy in middle-aged to elderly people, especially men. These patients are often told “You are just getting old,” but they have a defined condition. It should also be considered in patients failing to respond to treatment or with those with “refractory” polymyositis.

The onset of muscle weakness is insidious and painless, and the weakness progresses slowly. The pattern is distal and asymmetric (eg, foot drop), and muscle atrophy typically affects the forearm flexors, quadriceps, and intrinsic muscles of the hands.¹

Magnetic resonance imaging may show marked muscle atrophy. Unfortunately, no treatment has shown efficacy, and most neuromuscular and rheumatology experts do not treat inclusion body myositis with immunosuppressive drugs. 

CASE 2: MILD MYALGIA WITHOUT WEAKNESS

A black 52-year-old man was referred because of myalgia and a CK level of 862 U/L (reference range < 200). His physician wanted to start him on a statin but was hesitant to do so without first consulting a rheumatologist.

The patient had a long history of mild arthralgias and myalgias without muscle weakness. He had dyslipidemia and hypertension. He reported no family history of myopathy and no illicit drug use. He was formerly an athlete. Medications included a thiazide diuretic and a beta-blocker. On examination, his muscles were strong (rated 5 on a scale of 5) in the upper and lower extremities, without atrophy.

His records showed that his CK levels had risen and fallen repeatedly over the past few years, ranging from 600 to 1,100 U/L. On further questioning, he reported that when he had joined the army 30 years previously, a physician had recommended he undergo a liver biopsy in view of elevated liver function tests, but that he had refused because he felt fine.

Currently, his gamma-glutamyl transpeptidase levels were normal.

Idiopathic ‘hyperCKemia’

So-called idiopathic hyperCKemia is not a form of myositis but merely a laboratory result outside the “normal” range. Reference ranges are based predominantly on measurements in white people and on an assumption that the distribution is Gaussian (bell-shaped). A normal CK level is usually defined as less than 200 U/L. Using this standard, up to 20% of men and 5% of women have hyperCKemia.²

However, CK levels vary by sex and ethnicity, with mean levels highest in black men, followed by black women, white men, and white women. The mean level in black men is higher than the standard cutoff point for normal, and especially in this population, there is wide fluctuation around the mean, leading to hyperCKemia quite frequently in black men. Exercise and manual labor also drive up CK levels.^3–5 

Idiopathic hyperCKemia is benign. D’Adda et al⁶ followed 55 patients for a mean of 7.5 years. CK levels normalized in 12 patients or at least decreased in 24. Most remained symptom-free or had minimal symptoms. 

Idiopathic hyperCKemia: Bottom line

Before prescribing a statin, determine the baseline CK level. If slightly elevated (ie, up to 3 to 5 times the upper limit of normal, or even higher) in the setting of normal muscle strength, there is no need for electromyography or muscle biopsy, and the patient can certainly receive a statin. Most of these patients do not need to see a rheumatologist but can simply have their CK and muscle strength monitored.

Myositis (idiopathic inflammatory myopathy) is a heterogeneous group of autoimmune syndromes of unknown cause characterized by chronic muscle weakness and inflammation of striated muscle. These syndromes likely arise as a result of genetic predisposition and an environmental or infectious “hit.”

Myositis is rare, with an incidence of 5 to 10 cases per million per year and an estimated prevalence of 50 to 90 cases per million. It has 2 incidence peaks: 1 in childhood (age 5–15) and another in adult midlife (age 30–50). Women are affected 2 to 3 times more often than men, with black women most commonly affected.

Myositis is traditionally classified as follows:

• Adult polymyositis
• Adult dermatomyositis
• Juvenile myositis (dermatomyositis much more frequent than polymyositis)
• Malignancy-associated myositis (usually dermatomyositis)
• Myositis overlapping with another autoimmune disease
• Inclusion body myositis.

However, polymyositis is less common than we originally thought, and the term necrotizing myopathy is now used in many patients, as noted in the case studies below. Further, myositis overlap syndromes are being increasingly diagnosed, likely related to the emergence of autoantibodies and clinical “syndromes” associated with these autoantibody subsets (discussed in cases below).

Dermatomyositis

Dermatomyositis is characterized by muscle weakness and a rash that can be obvious or subtle. Classic skin lesions are Gottron papules, which are raised, flat-topped red or purplish lesions over the knuckles, elbows, or knees.

Lesions may be confused with those of psoriasis. There can also be a V-neck rash over the anterior chest or upper back (“shawl sign”) or a rash over the lateral thigh (“holster sign”). A facial rash may occur, but unlike lupus, dermatomyositis does not spare the nasolabial area. However, the V-neck rash can be similar to that seen in lupus.

Dermatomyositis may cause muscle pain, perhaps related to muscle ischemia, whereas polymyositis and necrotizing myopathy are often painless. However, pain is also associated with fibromyalgia, which may be seen in many autoimmune conditions. It is important not to overtreat rheumatologic diseases with immunosuppression to try to control pain if the pain is actually caused by fibromyalgia.

Polymyositis mimics

Hypothyroid myopathy can present as classic polymyositis. The serum CK may be elevated, and there may be myalgias, muscle hypertrophy with stiffness, weakness, cramps, and even features of a proximal myopathy, and rhabdomyolysis. The electromyogram can be normal or myopathic. Results of muscle biopsy are often normal but may show focal necrosis and mild inflammatory infiltrates, thus mimicking that seen with inflammatory myopathy.⁷

Drug-induced or toxic myopathies can also mimic polymyositis. Statins are among the most commonly prescribed drugs in the United States, with more than 35 million people taking them. Statins are generally well tolerated but have a broad spectrum of toxicity, ranging from myalgias to life-threatening rhabdomyolysis. Myalgias lead to about 5% to 10% of patients refusing to take a statin or stopping it on their own.

Myalgias affect up to 20% of statin users in clinical practice.^8,9 A small cross-sectional study¹⁰ of 1,000 patients in a primary care setting found that the risk of muscle complaints in statin users was 1.5 times higher than in nonstatin users, similar to findings in other studies.

My strategy for managing a patient with possible statin-induced myopathy is illustrated in Figure 1.

CASE 3: WEAKNESS, VERY HIGH CK ON A STATIN

In March 2010, a 67-year-old woman presented with muscle weakness. She had a history of hypertension, hyperlipidemia, and, more than 10 years previously, uterine cancer. In 2004, she was given atorvastatin for dyslipidemia. Four years later, she developed lower-extremity weakness, which her doctor attributed to normal aging. A year after that, she found it difficult to walk up steps and lift her arms overhead. In June 2009, she stopped taking the atorvastatin on her own, but the weakness did not improve.

In September 2009, she returned to her doctor, who found her CK level was 6,473 U/L but believed it to be an error, so the test was repeated, with a result of 9,375 U/L. She had no rash or joint involvement.

She was admitted to the hospital and underwent muscle biopsy, which showed myonecrosis with no inflammation or vasculitis.  She was treated with prednisone 60 mg/day, and her elevated CK level and weakness improved.

Immune-mediated necrotizing myopathy associated with statins

The hallmark of necrotizing myopathy is myonecrosis without significant inflammation.¹² This pattern contrasts with that of polymyositis, which is characterized by lymphocytic inflammation.

Although statins became available in the United States in 1987, immune-mediated necrotizing myopathy associated with statins was first described only in 2010. In that report, Grable-Esposito et al¹³ described 25 patients from 2 neuromuscular centers seen between 2000 and 2008 who had elevated CK and proximal weakness during or after statin use, both of which persisted despite stopping the statin. Patients improved with immunosuppressive agents but had a relapse when steroids were stopped or tapered, a pattern typical in autoimmune disease.

Also in 2010, Christopher-Stine et al¹⁴ reported an antibody associated with necrotizing myopathy. Of 38 patients with the condition, 16 were found to have an abnormal “doublet” autoantibody recognizing 200- and 100-kDa proteins. All patients had weakness and a high CK level, and 63% had statin exposure before the weakness (this percentage increased to 83% in patients older than 50). All responded to immunosuppressive therapy, and many had a relapse when it was withdrawn.

Statins lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-Co A reductase (HMGCR), and paradoxically, they also upregulate it. HMGCR has a molecular weight of 97 kDa. Mammen et al¹⁵ identified HMGCR as the 100-kDa target of the identified antibody and developed an enzyme-linked immunosorbent assay for it. Of 750 patients presenting to one center, only 45 (6%) had anti-HMGCR autoantibodies, but all 16 patients who had the abnormal doublet antibody tested positive for anti-HMGCR. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response after statins are discontinued.

Case 3 continued: Intravenous immunoglobulin brings improvement

In March 2010, when the 67-year-old patient presented to our myositis center, her CK level was 5,800 U/L, which increased as prednisone was tapered. She still felt weak. On examination, her muscle strength findings were deltoids 4+/5, neck flexors 4/5, and iliopsoas 3+/5. She was treated with methotrexate and azathioprine without benefit. She was next treated with intravenous immunoglobulin, and after 3 months, her strength normalized for the first time in years. Her CK level decreased but did not normalize. Testing showed that she was positive for anti-HMGCR auto­antibody, as this test had become commercially available.

In 2015, Mammen and Tiniakou¹⁶ suggested using intravenous immunoglobulin as first-line therapy for statin-associated autoimmune necrotizing myopathy, based on experience at a single center with 3 patients who declined glucocorticoid treatment.

Necrotizing myopathy: Bottom line

Myositis overlap syndromes

Heterogeneity is the rule in myositis, and it can present with a wide variety of signs and symptoms as outlined in Table 2.

CASE 4: FEVER, NEW ‘RHEUMATOID ARTHRITIS,’ AND LUNG DISEASE

A 52-year-old woman with knee osteoarthritis saw her primary care physician in November 2013 for dyspnea and low-grade fever. The next month, she presented with polyarthritis, muscle weakness, and Raynaud phenomenon.

In January 2014, she developed acrocyanosis of her fingers. Examination revealed hyperkeratotic, cracked areas of her fingers. Her oxygen saturation by pulse oximetry was low. She was admitted to the hospital. Her doctor suspected new onset of rheumatoid arthritis, but blood tests revealed a negative antinuclear antibody, so an autoimmune condition was deemed unlikely. Her CK was mildly elevated at 350 U/L.

Because of her dyspnea, an open-lung biopsy was performed. High-resolution computed tomography (CT) revealed infiltrates and ground-glass opacities, leading to the diagnosis of nonspecific interstitial pneumonia. A rheumatologist was consulted and recommended pulse methylprednisolone, followed by prednisone 60 mg/day and mycophenolate mofetil. Testing for Jo-1 antibodies was positive.

Antisynthetase syndrome

The antisynthetase syndrome is a clinically heterogeneous condition that can occur with any or all of the following:

• Fever
• Myositis
• Arthritis (often misdiagnosed as rheumatoid arthritis)
• Raynaud phenomenon
• Mechanic’s hands (hyperkeratotic  roughness with fissures on the lateral aspects of the fingers and finger pads)
• Interstitial lung disease.

The skin rashes and myositis may be subtle, making the presentation “lung-dominant,” and nonrheumatologists should be aware of this syndrome. Although in our patient the condition developed in a classic manner, with all of the aforementioned features of the antisynthetase syndrome, some patients will manifest one or a few of the features.

Clinically, patients with the Jo-1 antisynthetase syndrome often present differently than those with non-Jo-1 antisynthetase autoantibodies. When we compared 122 patients with Jo-1 vs 80 patients with a non-Jo-1 antisynthetase autoantibody, patients with Jo-1 antibodies were more likely to have initially received a diagnosis of myositis (83%), while  myositis was the original diagnosis in only 17% of those possessing non-Jo-1 antisynthetase autoantibodies. In fact, many patients (approximately 50%) were diagnosed as having undifferentiated connective tissue disease or an overlap syndrome, and 13% had scleroderma as their first diagnosis.¹⁷

We also found that the survival rate was higher in patients with Jo-1 syndrome compared with patients with non-Jo-1 antisynthetase syndromes. We attributed the difference in survival rates to a delayed diagnosis in the non-Jo-1 group, perhaps due to their “nonclassic” presentations of the antisynthetase syndrome, delaying appropriate treatment. Patients received a diagnosis of Jo-1 antibody syndrome after a mean of 0.4 year (range 0.2–0.8), while those with a non-Jo-1 antisynthetase autoantibody had a delay in diagnosis of 1.0 year (range 0.4–5.1) (P < .01).¹⁷

In nearly half the cases in this cohort, pulmonary fibrosis was the cause of death, with primary pulmonary hypertension being the second leading cause (11%).

Antisynthetase syndrome: Bottom line

Antisynthetase syndrome is an often fatal disease that does not always present in a typical fashion with symptoms of myositis, as lung disease may be the predominant feature. A negative antinuclear antibody test result does not imply antibody negativity, as the autoantigen in these diseases is not located in the nucleus. Prompt diagnosis and appropriate immunosuppressive therapy are critical to improving outcomes.

CASE 5: FEVER, UNDIAGNOSED LUNG DISEASE, NO MYOSITIS

In January 2001, a 39-year-old woman was admitted to the hospital after 5 weeks of fever (temperatures 103°–104°F) and myalgias. An extensive workup was negative except for low-titer antinuclear antibody and for mild basilar fibrosis noted on chest radiography. She left the hospital against medical advice because of frustration with a lack of a specific diagnosis (“fever of unknown origin”).

Two months later, at a follow-up rheumatology consult, she reported more myalgias and arthralgias, as well as fever. Chest radiography now showed pleural effusions. Her fingers had color changes consistent with Raynaud phenomenon. At that time, I diagnosed an undifferentiated connective tissue disease and told her that I suspected an autoimmune condition that would need time to reveal itself. In the meantime, I treated her empirically with prednisone.

In April, she returned, much more short of breath and with more prominent diffuse pulmonary infiltrates. Physical examination revealed subtle Gottron changes. Testing revealed poor pulmonary function: forced vital capacity (FVC) 56%, forced expiratory volume in 1 second (FEV₁) 52%, and diffusing capacity for carbon monoxide (Dlco) 40%. Blood testing was positive for anti-PL-12 antibody, one of the non-Jo-1 antisynthetase antibodies. At this time, we treated her with glucocorticoids and tacrolimus.

More than 15 years later, this patient is doing well. Her skin rash, joint symptoms, and fever have not returned, and interestingly, she never developed myositis. Her Raynaud symptoms are mild. Her most recent pulmonary function test results (January 2018) were FVC  75%, FEV₁ 87%, and Dlco 78%. Although these results are not normal, they are much improved and allow her to be completely functional without supplemental oxygen. Echocardiography showed  normal pulmonary artery systolic pressure (25 mm Hg). She was still taking tacrolimus and prednisone. When we tried to stop tacrolimus after she had done well for many years, her condition flared.

Non-Jo-1 antisynthetase syndrome: Bottom line

Patients with a non-Jo-1 antisynthetase syndrome often present without myositis symptoms and may never manifest myositis symptoms. Likely because of this presentation, diagnosis of a specific connective tissue disorder is delayed, perhaps leading to increased mortality risk from pulmonary disease. Chronic immunosuppression is often required for these autoimmune conditions.

CASE 6: DERMATOMYOSITIS, RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE

A 58-year-old woman presented in the summer of 2012 with a photosensitive rash. The following January, she returned with polyarthritis, mild muscle weakness, and a dermatomyositis-pattern rash. Her CK level was normal, and her antinuclear antibody and Sjögren syndrome antibody test results were negative. She improved on low-dose prednisone and methotrexate.

She was originally referred to me in May of that year for worsening rash and mild weakness. She denied pulmonary symptoms, but examination revealed faint basilar crackles. I increased her prednisone dosage to 20 mg/day and started mycophenolate mofetil mainly for the mild cutaneous and myositis features. I also recommended high-resolution CT of the lungs and pulmonary function tests, which she underwent in early June. High-resolution CT showed nonspecific mild infiltrates with minimal ground-glass opacities.

On July 1, she presented to her local emergency department with severe shortness of breath, requiring oxygen 12 L/min. She had a palmar rash. Repeat high-resolution CT showed dramatic worsening compared with the scan the previous month. Because of continued inadequate oxygenation, she was transferred to our center. A blood test later was positive for antimelanoma differentiation-associated gene 5 (MDA-5) autoantibody, previously known as anticlinically amyopathic dermatomyositis (anti-CADM)-140 antibody (based on immunoprecipitation results).

She died on the third day after transfer, just 2 months after I had originally seen her, at which time she had had no pulmonary symptoms.

Clinically amyopathic dermatomyositis

Anti-CADM-140, first reported from Asia,^18–20 is an autoantibody-associated disease but not an antisynthetase. It is associated with dermatomyositis; patients often have a “vasculopathy” with cutaneous ulcerations and palmar papules.

MDA-5 is a cytoplasmic protein that “senses” viral RNA and induces production of type 1 interferon. It is involved in the innate immune defense against viruses.

Anti-MDA-5 positivity is associated with a poor pulmonary outcome.²¹ In our cohort from the University of Pittsburgh, many patients died within 3 years, compared with about a 40% survival rate in patients with dermatomyositis who tested negative for this antibody. That being said, many patients with anti-MDA-5 do not develop rapidly progressive interstitial lung disease.

Autoimmune interstitial lung disease: Bottom line

Autoimmune interstitial lung disease is easy to miss, especially in the case of a non-Jo-1 syndrome, for 3 important reasons:

• The autoimmune features may initially be subtle (eg, Raynaud phenomena, mild dermatomyositis rash, undifferentiated connective tissue disease)
• Autoantibody testing is not often ordered, is not standardized, or may be unavailable 
• Providers are mistakenly reassured that a patient who tests negative for antinuclear antibody does not have an autoimmune condition.

To emphasize the last point, in a cohort of 202 patients who tested positive for an antisynthetase antibody, only half were antinuclear antibody-positive, but nearly three-quarters demonstrated anticytoplasmic staining on indirect immunofluorescence (due to the location of the autoantigen in the cytoplasm), making the latter a better screening test for an antisynthetase antibody. For scleroderma, 99% were antinculear antibody-positive, but for myositis, this test is much less sensitive.²²

Myopathies can present with a wide variety of symptoms, so patients with muscle weakness are often seen initially by a general practitioner. Nonrheumatologists should be able to evaluate a patient presenting with muscle weakness or myalgia and be aware of red flags indicating potentially dangerous syndromes that require a prompt, thorough investigation.

This article reviews selected causes of muscle weakness, such as statin-induced and autoimmune disorders, and systemic features of inflammatory myopathies beyond myositis, such as dermatologic and pulmonary manifestations.

FOCUSING THE EVALUATION

The evaluation of a patient presenting with muscle weakness should include several assessments: 

Temporal progression. Was the onset of symptoms rapid or insidious? Patterns of onset may give clues to etiology, including the possibility of an associated autoimmune condition.

Location of muscle weakness. Are symptoms global or localized? And if localized, are they proximal or distal? Proximal weakness can be manifested by difficulty rising from a chair (hip muscles) or combing one’s hair (shoulder muscles), whereas distal weakness can involve difficulty standing on toes (gastrocnemius and soleus muscles) or performing fine motor activities (intrinsic hand muscles).

Symmetry. A focal or asymmetric pattern often has a neurologic etiology, but this could also be consistent with inclusion body myositis.

Other symptoms. Arthritis, rash, and swallowing problems point to a possible underlying rheumatologic disease. Weight gain or loss may indicate a thyroid disorder.

Family history. Some patients report that others in their family have this pattern of weakness, indicating a likely genetic myopathy. If the patient reports a relative with multiple sclerosis, lupus erythematosus, rheumatoid arthritis, or another autoimmune disease, then an immune-mediated myopathy should be considered.

Medications should be reviewed, particularly statins.

CASE 1: SLOWLY PROGRESSIVE WEAKNESS

A 65-year-old man presented with the insidious onset of muscle weakness and episodes of falling. On review of his medical record, his serum creatine kinase (CK) levels were elevated at various periods at 2 to 4 times the upper limit of normal. Electromyography (EMG) previously showed a myopathic pattern, and a muscle biopsy was abnormal, consistent with endomysial inflammation (term is consistent with “polymyositis”). He was treated for polymyositis for several years with prednisone alone, with steroids plus methotrexate, and with combined immunosuppression including methotrexate and azathioprine, but with no improvement. Eventually, another muscle biopsy revealed inclusion bodies with rimmed vacuoles, consistent with inclusion body myositis.

Inclusion body myositis

Inclusion body myositis is the most common myopathy in middle-aged to elderly people, especially men. These patients are often told “You are just getting old,” but they have a defined condition. It should also be considered in patients failing to respond to treatment or with those with “refractory” polymyositis.

The onset of muscle weakness is insidious and painless, and the weakness progresses slowly. The pattern is distal and asymmetric (eg, foot drop), and muscle atrophy typically affects the forearm flexors, quadriceps, and intrinsic muscles of the hands.¹

Magnetic resonance imaging may show marked muscle atrophy. Unfortunately, no treatment has shown efficacy, and most neuromuscular and rheumatology experts do not treat inclusion body myositis with immunosuppressive drugs. 

CASE 2: MILD MYALGIA WITHOUT WEAKNESS

A black 52-year-old man was referred because of myalgia and a CK level of 862 U/L (reference range < 200). His physician wanted to start him on a statin but was hesitant to do so without first consulting a rheumatologist.

The patient had a long history of mild arthralgias and myalgias without muscle weakness. He had dyslipidemia and hypertension. He reported no family history of myopathy and no illicit drug use. He was formerly an athlete. Medications included a thiazide diuretic and a beta-blocker. On examination, his muscles were strong (rated 5 on a scale of 5) in the upper and lower extremities, without atrophy.

His records showed that his CK levels had risen and fallen repeatedly over the past few years, ranging from 600 to 1,100 U/L. On further questioning, he reported that when he had joined the army 30 years previously, a physician had recommended he undergo a liver biopsy in view of elevated liver function tests, but that he had refused because he felt fine.

Currently, his gamma-glutamyl transpeptidase levels were normal.

Idiopathic ‘hyperCKemia’

So-called idiopathic hyperCKemia is not a form of myositis but merely a laboratory result outside the “normal” range. Reference ranges are based predominantly on measurements in white people and on an assumption that the distribution is Gaussian (bell-shaped). A normal CK level is usually defined as less than 200 U/L. Using this standard, up to 20% of men and 5% of women have hyperCKemia.²

However, CK levels vary by sex and ethnicity, with mean levels highest in black men, followed by black women, white men, and white women. The mean level in black men is higher than the standard cutoff point for normal, and especially in this population, there is wide fluctuation around the mean, leading to hyperCKemia quite frequently in black men. Exercise and manual labor also drive up CK levels.^3–5 

Idiopathic hyperCKemia is benign. D’Adda et al⁶ followed 55 patients for a mean of 7.5 years. CK levels normalized in 12 patients or at least decreased in 24. Most remained symptom-free or had minimal symptoms. 

Idiopathic hyperCKemia: Bottom line

Before prescribing a statin, determine the baseline CK level. If slightly elevated (ie, up to 3 to 5 times the upper limit of normal, or even higher) in the setting of normal muscle strength, there is no need for electromyography or muscle biopsy, and the patient can certainly receive a statin. Most of these patients do not need to see a rheumatologist but can simply have their CK and muscle strength monitored.

Myositis (idiopathic inflammatory myopathy) is a heterogeneous group of autoimmune syndromes of unknown cause characterized by chronic muscle weakness and inflammation of striated muscle. These syndromes likely arise as a result of genetic predisposition and an environmental or infectious “hit.”

Myositis is rare, with an incidence of 5 to 10 cases per million per year and an estimated prevalence of 50 to 90 cases per million. It has 2 incidence peaks: 1 in childhood (age 5–15) and another in adult midlife (age 30–50). Women are affected 2 to 3 times more often than men, with black women most commonly affected.

Myositis is traditionally classified as follows:

• Adult polymyositis
• Adult dermatomyositis
• Juvenile myositis (dermatomyositis much more frequent than polymyositis)
• Malignancy-associated myositis (usually dermatomyositis)
• Myositis overlapping with another autoimmune disease
• Inclusion body myositis.

However, polymyositis is less common than we originally thought, and the term necrotizing myopathy is now used in many patients, as noted in the case studies below. Further, myositis overlap syndromes are being increasingly diagnosed, likely related to the emergence of autoantibodies and clinical “syndromes” associated with these autoantibody subsets (discussed in cases below).

Dermatomyositis

Dermatomyositis is characterized by muscle weakness and a rash that can be obvious or subtle. Classic skin lesions are Gottron papules, which are raised, flat-topped red or purplish lesions over the knuckles, elbows, or knees.

Lesions may be confused with those of psoriasis. There can also be a V-neck rash over the anterior chest or upper back (“shawl sign”) or a rash over the lateral thigh (“holster sign”). A facial rash may occur, but unlike lupus, dermatomyositis does not spare the nasolabial area. However, the V-neck rash can be similar to that seen in lupus.

Dermatomyositis may cause muscle pain, perhaps related to muscle ischemia, whereas polymyositis and necrotizing myopathy are often painless. However, pain is also associated with fibromyalgia, which may be seen in many autoimmune conditions. It is important not to overtreat rheumatologic diseases with immunosuppression to try to control pain if the pain is actually caused by fibromyalgia.

Polymyositis mimics

Hypothyroid myopathy can present as classic polymyositis. The serum CK may be elevated, and there may be myalgias, muscle hypertrophy with stiffness, weakness, cramps, and even features of a proximal myopathy, and rhabdomyolysis. The electromyogram can be normal or myopathic. Results of muscle biopsy are often normal but may show focal necrosis and mild inflammatory infiltrates, thus mimicking that seen with inflammatory myopathy.⁷

Drug-induced or toxic myopathies can also mimic polymyositis. Statins are among the most commonly prescribed drugs in the United States, with more than 35 million people taking them. Statins are generally well tolerated but have a broad spectrum of toxicity, ranging from myalgias to life-threatening rhabdomyolysis. Myalgias lead to about 5% to 10% of patients refusing to take a statin or stopping it on their own.

Myalgias affect up to 20% of statin users in clinical practice.^8,9 A small cross-sectional study¹⁰ of 1,000 patients in a primary care setting found that the risk of muscle complaints in statin users was 1.5 times higher than in nonstatin users, similar to findings in other studies.

My strategy for managing a patient with possible statin-induced myopathy is illustrated in Figure 1.

CASE 3: WEAKNESS, VERY HIGH CK ON A STATIN

In March 2010, a 67-year-old woman presented with muscle weakness. She had a history of hypertension, hyperlipidemia, and, more than 10 years previously, uterine cancer. In 2004, she was given atorvastatin for dyslipidemia. Four years later, she developed lower-extremity weakness, which her doctor attributed to normal aging. A year after that, she found it difficult to walk up steps and lift her arms overhead. In June 2009, she stopped taking the atorvastatin on her own, but the weakness did not improve.

In September 2009, she returned to her doctor, who found her CK level was 6,473 U/L but believed it to be an error, so the test was repeated, with a result of 9,375 U/L. She had no rash or joint involvement.

She was admitted to the hospital and underwent muscle biopsy, which showed myonecrosis with no inflammation or vasculitis.  She was treated with prednisone 60 mg/day, and her elevated CK level and weakness improved.

Immune-mediated necrotizing myopathy associated with statins

The hallmark of necrotizing myopathy is myonecrosis without significant inflammation.¹² This pattern contrasts with that of polymyositis, which is characterized by lymphocytic inflammation.

Although statins became available in the United States in 1987, immune-mediated necrotizing myopathy associated with statins was first described only in 2010. In that report, Grable-Esposito et al¹³ described 25 patients from 2 neuromuscular centers seen between 2000 and 2008 who had elevated CK and proximal weakness during or after statin use, both of which persisted despite stopping the statin. Patients improved with immunosuppressive agents but had a relapse when steroids were stopped or tapered, a pattern typical in autoimmune disease.

Also in 2010, Christopher-Stine et al¹⁴ reported an antibody associated with necrotizing myopathy. Of 38 patients with the condition, 16 were found to have an abnormal “doublet” autoantibody recognizing 200- and 100-kDa proteins. All patients had weakness and a high CK level, and 63% had statin exposure before the weakness (this percentage increased to 83% in patients older than 50). All responded to immunosuppressive therapy, and many had a relapse when it was withdrawn.

Statins lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-Co A reductase (HMGCR), and paradoxically, they also upregulate it. HMGCR has a molecular weight of 97 kDa. Mammen et al¹⁵ identified HMGCR as the 100-kDa target of the identified antibody and developed an enzyme-linked immunosorbent assay for it. Of 750 patients presenting to one center, only 45 (6%) had anti-HMGCR autoantibodies, but all 16 patients who had the abnormal doublet antibody tested positive for anti-HMGCR. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response after statins are discontinued.

Case 3 continued: Intravenous immunoglobulin brings improvement

In March 2010, when the 67-year-old patient presented to our myositis center, her CK level was 5,800 U/L, which increased as prednisone was tapered. She still felt weak. On examination, her muscle strength findings were deltoids 4+/5, neck flexors 4/5, and iliopsoas 3+/5. She was treated with methotrexate and azathioprine without benefit. She was next treated with intravenous immunoglobulin, and after 3 months, her strength normalized for the first time in years. Her CK level decreased but did not normalize. Testing showed that she was positive for anti-HMGCR auto­antibody, as this test had become commercially available.

In 2015, Mammen and Tiniakou¹⁶ suggested using intravenous immunoglobulin as first-line therapy for statin-associated autoimmune necrotizing myopathy, based on experience at a single center with 3 patients who declined glucocorticoid treatment.

Necrotizing myopathy: Bottom line

Myositis overlap syndromes

Heterogeneity is the rule in myositis, and it can present with a wide variety of signs and symptoms as outlined in Table 2.

CASE 4: FEVER, NEW ‘RHEUMATOID ARTHRITIS,’ AND LUNG DISEASE

A 52-year-old woman with knee osteoarthritis saw her primary care physician in November 2013 for dyspnea and low-grade fever. The next month, she presented with polyarthritis, muscle weakness, and Raynaud phenomenon.

In January 2014, she developed acrocyanosis of her fingers. Examination revealed hyperkeratotic, cracked areas of her fingers. Her oxygen saturation by pulse oximetry was low. She was admitted to the hospital. Her doctor suspected new onset of rheumatoid arthritis, but blood tests revealed a negative antinuclear antibody, so an autoimmune condition was deemed unlikely. Her CK was mildly elevated at 350 U/L.

Because of her dyspnea, an open-lung biopsy was performed. High-resolution computed tomography (CT) revealed infiltrates and ground-glass opacities, leading to the diagnosis of nonspecific interstitial pneumonia. A rheumatologist was consulted and recommended pulse methylprednisolone, followed by prednisone 60 mg/day and mycophenolate mofetil. Testing for Jo-1 antibodies was positive.

Antisynthetase syndrome

The antisynthetase syndrome is a clinically heterogeneous condition that can occur with any or all of the following:

• Fever
• Myositis
• Arthritis (often misdiagnosed as rheumatoid arthritis)
• Raynaud phenomenon
• Mechanic’s hands (hyperkeratotic  roughness with fissures on the lateral aspects of the fingers and finger pads)
• Interstitial lung disease.

The skin rashes and myositis may be subtle, making the presentation “lung-dominant,” and nonrheumatologists should be aware of this syndrome. Although in our patient the condition developed in a classic manner, with all of the aforementioned features of the antisynthetase syndrome, some patients will manifest one or a few of the features.

Clinically, patients with the Jo-1 antisynthetase syndrome often present differently than those with non-Jo-1 antisynthetase autoantibodies. When we compared 122 patients with Jo-1 vs 80 patients with a non-Jo-1 antisynthetase autoantibody, patients with Jo-1 antibodies were more likely to have initially received a diagnosis of myositis (83%), while  myositis was the original diagnosis in only 17% of those possessing non-Jo-1 antisynthetase autoantibodies. In fact, many patients (approximately 50%) were diagnosed as having undifferentiated connective tissue disease or an overlap syndrome, and 13% had scleroderma as their first diagnosis.¹⁷

We also found that the survival rate was higher in patients with Jo-1 syndrome compared with patients with non-Jo-1 antisynthetase syndromes. We attributed the difference in survival rates to a delayed diagnosis in the non-Jo-1 group, perhaps due to their “nonclassic” presentations of the antisynthetase syndrome, delaying appropriate treatment. Patients received a diagnosis of Jo-1 antibody syndrome after a mean of 0.4 year (range 0.2–0.8), while those with a non-Jo-1 antisynthetase autoantibody had a delay in diagnosis of 1.0 year (range 0.4–5.1) (P < .01).¹⁷

In nearly half the cases in this cohort, pulmonary fibrosis was the cause of death, with primary pulmonary hypertension being the second leading cause (11%).

Antisynthetase syndrome: Bottom line

Antisynthetase syndrome is an often fatal disease that does not always present in a typical fashion with symptoms of myositis, as lung disease may be the predominant feature. A negative antinuclear antibody test result does not imply antibody negativity, as the autoantigen in these diseases is not located in the nucleus. Prompt diagnosis and appropriate immunosuppressive therapy are critical to improving outcomes.

CASE 5: FEVER, UNDIAGNOSED LUNG DISEASE, NO MYOSITIS

In January 2001, a 39-year-old woman was admitted to the hospital after 5 weeks of fever (temperatures 103°–104°F) and myalgias. An extensive workup was negative except for low-titer antinuclear antibody and for mild basilar fibrosis noted on chest radiography. She left the hospital against medical advice because of frustration with a lack of a specific diagnosis (“fever of unknown origin”).

Two months later, at a follow-up rheumatology consult, she reported more myalgias and arthralgias, as well as fever. Chest radiography now showed pleural effusions. Her fingers had color changes consistent with Raynaud phenomenon. At that time, I diagnosed an undifferentiated connective tissue disease and told her that I suspected an autoimmune condition that would need time to reveal itself. In the meantime, I treated her empirically with prednisone.

In April, she returned, much more short of breath and with more prominent diffuse pulmonary infiltrates. Physical examination revealed subtle Gottron changes. Testing revealed poor pulmonary function: forced vital capacity (FVC) 56%, forced expiratory volume in 1 second (FEV₁) 52%, and diffusing capacity for carbon monoxide (Dlco) 40%. Blood testing was positive for anti-PL-12 antibody, one of the non-Jo-1 antisynthetase antibodies. At this time, we treated her with glucocorticoids and tacrolimus.

More than 15 years later, this patient is doing well. Her skin rash, joint symptoms, and fever have not returned, and interestingly, she never developed myositis. Her Raynaud symptoms are mild. Her most recent pulmonary function test results (January 2018) were FVC  75%, FEV₁ 87%, and Dlco 78%. Although these results are not normal, they are much improved and allow her to be completely functional without supplemental oxygen. Echocardiography showed  normal pulmonary artery systolic pressure (25 mm Hg). She was still taking tacrolimus and prednisone. When we tried to stop tacrolimus after she had done well for many years, her condition flared.

Non-Jo-1 antisynthetase syndrome: Bottom line

Patients with a non-Jo-1 antisynthetase syndrome often present without myositis symptoms and may never manifest myositis symptoms. Likely because of this presentation, diagnosis of a specific connective tissue disorder is delayed, perhaps leading to increased mortality risk from pulmonary disease. Chronic immunosuppression is often required for these autoimmune conditions.

CASE 6: DERMATOMYOSITIS, RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE

A 58-year-old woman presented in the summer of 2012 with a photosensitive rash. The following January, she returned with polyarthritis, mild muscle weakness, and a dermatomyositis-pattern rash. Her CK level was normal, and her antinuclear antibody and Sjögren syndrome antibody test results were negative. She improved on low-dose prednisone and methotrexate.

She was originally referred to me in May of that year for worsening rash and mild weakness. She denied pulmonary symptoms, but examination revealed faint basilar crackles. I increased her prednisone dosage to 20 mg/day and started mycophenolate mofetil mainly for the mild cutaneous and myositis features. I also recommended high-resolution CT of the lungs and pulmonary function tests, which she underwent in early June. High-resolution CT showed nonspecific mild infiltrates with minimal ground-glass opacities.

On July 1, she presented to her local emergency department with severe shortness of breath, requiring oxygen 12 L/min. She had a palmar rash. Repeat high-resolution CT showed dramatic worsening compared with the scan the previous month. Because of continued inadequate oxygenation, she was transferred to our center. A blood test later was positive for antimelanoma differentiation-associated gene 5 (MDA-5) autoantibody, previously known as anticlinically amyopathic dermatomyositis (anti-CADM)-140 antibody (based on immunoprecipitation results).

She died on the third day after transfer, just 2 months after I had originally seen her, at which time she had had no pulmonary symptoms.

Clinically amyopathic dermatomyositis

Anti-CADM-140, first reported from Asia,^18–20 is an autoantibody-associated disease but not an antisynthetase. It is associated with dermatomyositis; patients often have a “vasculopathy” with cutaneous ulcerations and palmar papules.

MDA-5 is a cytoplasmic protein that “senses” viral RNA and induces production of type 1 interferon. It is involved in the innate immune defense against viruses.

Anti-MDA-5 positivity is associated with a poor pulmonary outcome.²¹ In our cohort from the University of Pittsburgh, many patients died within 3 years, compared with about a 40% survival rate in patients with dermatomyositis who tested negative for this antibody. That being said, many patients with anti-MDA-5 do not develop rapidly progressive interstitial lung disease.

Autoimmune interstitial lung disease: Bottom line

Autoimmune interstitial lung disease is easy to miss, especially in the case of a non-Jo-1 syndrome, for 3 important reasons:

• The autoimmune features may initially be subtle (eg, Raynaud phenomena, mild dermatomyositis rash, undifferentiated connective tissue disease)
• Autoantibody testing is not often ordered, is not standardized, or may be unavailable 
• Providers are mistakenly reassured that a patient who tests negative for antinuclear antibody does not have an autoimmune condition.

To emphasize the last point, in a cohort of 202 patients who tested positive for an antisynthetase antibody, only half were antinuclear antibody-positive, but nearly three-quarters demonstrated anticytoplasmic staining on indirect immunofluorescence (due to the location of the autoantigen in the cytoplasm), making the latter a better screening test for an antisynthetase antibody. For scleroderma, 99% were antinculear antibody-positive, but for myositis, this test is much less sensitive.²²

For too many of us, a good night’s sleep is a rare occurrence. Lack of quality sleep has profound negative effects on our health, safety, and wellbeing. An estimated 50 to 70 million Americans have sleep disturbances, including 10% to 17% of men and 3% to 9% of women with moderate to severe obstructive sleep apnea (OSA).¹ Not only is OSA highly prevalent, 82% to 93% of individuals with moderate to severe OSA are unaware they have it, and it remains undiagnosed.²

OSA is a potentially serious medical disorder affecting the heart, brain, and metabolism. These physiological changes negatively impact public safety, occupational and academic achievement, and even mortality.

This Cleveland Clinic Journal of Medicine supplement presents a state-of-the-art review of OSA, including the health and societal consequences of OSA and current treatment options. The goal of this publication is to inform and educate healthcare providers from all backgrounds and levels of care who are interested in improving patient outcomes through attention to sleep medicine.

Because OSA is prevalent and underdiagnosed, Jessica Vensel Rundo, MD, MS, reviews the symptoms of OSA, clinical presentation, and the readily available, effective screening tools for detecting sleep apnea. Greater awareness and screening for sleep disturbances informs the need for further diagnostic tests such as laboratory polysomnography and home sleep apnea testing.

The link between OSA and the heart is presented by Reena Mehra, MD, MS, with an overview of the physiology of sleep-heart interactions and the association of OSA and cardiovascular health. Dr. Mehra also reviews central sleep apnea and discusses 2 newer therapies for it: adaptive servoventilation and phrenic nerve stimulation.

Beyond heart health, OSA also adversely affects quality of life, safety, and other important health factors. Harneet Walia, MD, discusses consequences of sleep apnea such as daytime sleepiness, fatigue, drowsy driving, depression, metabolic diseases, and cognitive impairment.

Several treatment options exist for patients diagnosed with OSA. Positive airway pressure (PAP) therapy is the gold standard for treatment of OSA. Colleen G. Lance, MD, reviews and presents case scenarios about the efficacy of PAP therapy, features of continuous PAP therapy, and innovative strategies to improve adherence to therapy.

In addition to PAP therapy, there are alternative treatments for OSA that may benefit some patients.  Tina Waters, MD, considers alternatives to PAP therapy, such as lifestyle changes, expiratory PAP therapy, oral appliances, upper airway surgery, and hypoglossal nerve stimulation.

I hope you enjoy this supplement and find it useful to improving the health and quality-of-life outcomes of patients in your care.

For too many of us, a good night’s sleep is a rare occurrence. Lack of quality sleep has profound negative effects on our health, safety, and wellbeing. An estimated 50 to 70 million Americans have sleep disturbances, including 10% to 17% of men and 3% to 9% of women with moderate to severe obstructive sleep apnea (OSA).¹ Not only is OSA highly prevalent, 82% to 93% of individuals with moderate to severe OSA are unaware they have it, and it remains undiagnosed.²

OSA is a potentially serious medical disorder affecting the heart, brain, and metabolism. These physiological changes negatively impact public safety, occupational and academic achievement, and even mortality.

This Cleveland Clinic Journal of Medicine supplement presents a state-of-the-art review of OSA, including the health and societal consequences of OSA and current treatment options. The goal of this publication is to inform and educate healthcare providers from all backgrounds and levels of care who are interested in improving patient outcomes through attention to sleep medicine.

Because OSA is prevalent and underdiagnosed, Jessica Vensel Rundo, MD, MS, reviews the symptoms of OSA, clinical presentation, and the readily available, effective screening tools for detecting sleep apnea. Greater awareness and screening for sleep disturbances informs the need for further diagnostic tests such as laboratory polysomnography and home sleep apnea testing.

The link between OSA and the heart is presented by Reena Mehra, MD, MS, with an overview of the physiology of sleep-heart interactions and the association of OSA and cardiovascular health. Dr. Mehra also reviews central sleep apnea and discusses 2 newer therapies for it: adaptive servoventilation and phrenic nerve stimulation.

Beyond heart health, OSA also adversely affects quality of life, safety, and other important health factors. Harneet Walia, MD, discusses consequences of sleep apnea such as daytime sleepiness, fatigue, drowsy driving, depression, metabolic diseases, and cognitive impairment.

Several treatment options exist for patients diagnosed with OSA. Positive airway pressure (PAP) therapy is the gold standard for treatment of OSA. Colleen G. Lance, MD, reviews and presents case scenarios about the efficacy of PAP therapy, features of continuous PAP therapy, and innovative strategies to improve adherence to therapy.

In addition to PAP therapy, there are alternative treatments for OSA that may benefit some patients.  Tina Waters, MD, considers alternatives to PAP therapy, such as lifestyle changes, expiratory PAP therapy, oral appliances, upper airway surgery, and hypoglossal nerve stimulation.

I hope you enjoy this supplement and find it useful to improving the health and quality-of-life outcomes of patients in your care.

For too many of us, a good night’s sleep is a rare occurrence. Lack of quality sleep has profound negative effects on our health, safety, and wellbeing. An estimated 50 to 70 million Americans have sleep disturbances, including 10% to 17% of men and 3% to 9% of women with moderate to severe obstructive sleep apnea (OSA).¹ Not only is OSA highly prevalent, 82% to 93% of individuals with moderate to severe OSA are unaware they have it, and it remains undiagnosed.²

OSA is a potentially serious medical disorder affecting the heart, brain, and metabolism. These physiological changes negatively impact public safety, occupational and academic achievement, and even mortality.

This Cleveland Clinic Journal of Medicine supplement presents a state-of-the-art review of OSA, including the health and societal consequences of OSA and current treatment options. The goal of this publication is to inform and educate healthcare providers from all backgrounds and levels of care who are interested in improving patient outcomes through attention to sleep medicine.

Because OSA is prevalent and underdiagnosed, Jessica Vensel Rundo, MD, MS, reviews the symptoms of OSA, clinical presentation, and the readily available, effective screening tools for detecting sleep apnea. Greater awareness and screening for sleep disturbances informs the need for further diagnostic tests such as laboratory polysomnography and home sleep apnea testing.

The link between OSA and the heart is presented by Reena Mehra, MD, MS, with an overview of the physiology of sleep-heart interactions and the association of OSA and cardiovascular health. Dr. Mehra also reviews central sleep apnea and discusses 2 newer therapies for it: adaptive servoventilation and phrenic nerve stimulation.

Beyond heart health, OSA also adversely affects quality of life, safety, and other important health factors. Harneet Walia, MD, discusses consequences of sleep apnea such as daytime sleepiness, fatigue, drowsy driving, depression, metabolic diseases, and cognitive impairment.

Several treatment options exist for patients diagnosed with OSA. Positive airway pressure (PAP) therapy is the gold standard for treatment of OSA. Colleen G. Lance, MD, reviews and presents case scenarios about the efficacy of PAP therapy, features of continuous PAP therapy, and innovative strategies to improve adherence to therapy.

In addition to PAP therapy, there are alternative treatments for OSA that may benefit some patients.  Tina Waters, MD, considers alternatives to PAP therapy, such as lifestyle changes, expiratory PAP therapy, oral appliances, upper airway surgery, and hypoglossal nerve stimulation.

I hope you enjoy this supplement and find it useful to improving the health and quality-of-life outcomes of patients in your care.