Smart Testing

A 41-year-old woman presented with intermittent shortness of breath that worsened with exposure to cold air and cigarette smoke. She said her symptoms got better when she used albuterol, which had been prescribed after an emergency department visit during a worsening episode.

The patient was severely obese (body mass index 48 kg/m²) and had bilateral expiratory wheezes but no other significant findings. Based on the clinical presentation, we suspected she had asthma.

To establish the diagnosis and assess the severity of her condition, we questioned her further about her symptoms, and this information increased our suspicion of asthma. Is spirometry also indicated?

SPIROMETRY’S ROLE IN DIAGNOSING ASTHMA

Asthma is a chronic inflammatory condition of the airways characterized by recurrent or persistent symptoms with evidence of variable airflow obstruction or hyperresponsiveness to certain stimuli.¹ The clinical diagnosis is based on episodic symptoms of chest tightness, wheezing, shortness of breath, or cough, but we cannot reliably diagnose asthma based on symptoms alone.

Spirometry provides an objective measure of obstruction, which adds to the reliability of the diagnosis. Therefore, it should be done in all patients in whom asthma is suspected.

Spirometry provides another diagnostic measure by quantifying whether airway obstruction reverses after the patient is given a dose of a bronchodilator. Although the exact criteria for reversibility of obstruction are unclear, the American Thoracic Society defines it as an increase in the forced expiratory volume in 1 second (FEV₁) of 12% or more from baseline and an absolute increase of 200 mL or more. It can also be an increase of more than 200 mL in the forced vital capacity (FVC).^2,3

Spirometry can also be used to evaluate or rule out other causes of chronic shortness of breath and common asthma mimics.

Failure to perform spirometry can result in a false diagnosis of asthma in patients who do not have it, or in a missed diagnosis in patients who do.^4,5 Either situation often leads to inappropriate use of medications, exposure of patients to side effects, delays in appropriate diagnosis, and ongoing morbidity.

Despite the evidence in its favor, spirometry is underused. In a 2012 Canadian study, only 42.7% of 465,866 patients with newly diagnosed asthma had any spirometry testing performed within 1 year before or 2.5 years after the diagnosis.⁶ Similarly, in a 2015 US study, only 47.6% of 134,208 patients had spirometry performed within 1 year of diagnosis.⁷ Interestingly, this study found that the use of spirometry actually decreased after publication of guidelines from the National Asthma Education and Prevention Program¹ that recommended spirometry.

CASE CONTINUED

Her baseline values were normal; her FEV₁/FVC ratio was 73.67% (lower limit of normal 72.62%) and thus was not significant for airway obstruction. However, after 4 puffs of an inhaled short-acting beta agonist, her FEV₁ increased by 15% from baseline (from 1.98 L/second before to 2.25 L/second after), a clinically significant response (defined as ≥ 12% from baseline and an absolute increase of at least 200 mL^1–3). Had we not included bronchodilator testing, given the absence of underlying baseline obstruction, her shortness of breath could have been attributed to other causes, resulting in a missed asthma diagnosis.

Nevertheless, postbronchodilator measurements should not be performed in all patients with normal baseline results unless asthma is strongly suspected on clinical grounds. In one study, only 3% of 1,394 patients with normal baseline results showed improvement with a bronchodilator.⁸ In this patient population, bronchodilator testing would add both time and cost with little benefit.

Our patient’s reversibility of obstruction helped confirm the diagnosis of asthma. Absence of reversibility, however, does not rule out asthma, because spirometry results, like clinical symptoms of asthma, can vary. If clinical suspicion remains high and spirometry does not show clinically significant reversibility, then bronchoprovocation testing (most commonly with methacholine) could be done.

Although a positive methacholine challenge test can help identify asthma in patients with atypical symptoms or normal baseline test results, conditions other than asthma can also cause positive results. The sensitivity of methacholine challenge has been reported to be as high as 96%, while its specificity averages less than 80%.⁹ Given its high negative predictive value, the test can help rule out asthma, as negative results are rarely falsely negative.

Once the diagnosis of asthma is established, its severity and control need to be assessed to guide therapy. This is typically done by ascertaining how often the patient experiences asthma symptoms, how often the patient uses short-acting beta agonists (ranging from days per month to multiple times a day), and how often he or she has nighttime symptoms. The most severe symptom or most abnormal response is used to categorize asthma as intermittent or persistent, with severity ranging from mild to severe.

Symptoms are not always effective measures of asthma control, and subjective measures of symptoms often do not correlate with asthma severity, resulting in underestimation of the degree of airway obstruction.^10,11 A review of 500 patients with an established asthma diagnosis found that in 110 patients with self-reported control of symptoms that included use of short-acting beta agonists no more than once per day, no night awakenings in the past week, and no missed school or work in the past 3 months, only 61 (55%) had an FEV₁ above 80% of predicted.¹² Further, neither the FEV₁ nor FEV₁/FVC ratio was shown to have a direct relationship with subjective measures of disease severity or control.

These observations highlight the need to use the objective findings from spirometry to assess asthma control and severity. Relying on the clinical symptoms alone likely underestimates the severity of asthma, especially in patients who are “poor perceivers” of symptoms. This can lead to undertreatment or an inappropriate step-down in therapy.

Current guidelines recommend repeating spirometry once therapy has brought the disease under control to establish a true baseline of airway function.^1–3 Spirometry should be repeated again during any prolonged loss of asthma control and at 1- to 2-year intervals in patients with well-controlled disease as a means to monitor disease progression by measuring changes in airway function over time.

ROLE IN PREDICTING EXACERBATIONS

Current questionnaire-based assessments of breathing symptoms focus on disease severity and control, not on the risk of exacerbation. Although it may seem intuitive that patients who have the most severe disease are at highest risk of exacerbations, many patients with “mild” disease and “good” control experience exacerbations that require expensive emergency department visits. Nearly half of all the money spent on direct medical care for asthma is for urgent outpatient clinic and emergency department visits and hospitalizations.¹³

Using the FEV₁, either by itself or in combination with other diagnostic tools such as questionnaires, has been shown to be superior to the clinical history alone in identifying patients at high risk of acute exacerbations.^14,15 In addition to improving patient care and quality of life, spirometry could substantially reduce costs of care.

BOTTOM LINE

Although asthma remains a clinical diagnosis based on episodic symptoms consistent with airflow obstruction, symptoms alone cannot reliably be used to diagnose the disease or assess its severity and control.

Spirometry, including FEV₁ and FVC, is an important objective measure to help with the diagnosis and should be done in all patients in whom asthma is suspected, both at the time of diagnosis and at intervals to assess disease progression. Spirometry also provides data to help assess the severity of asthma, which often does not correlate with clinical perception of symptoms, and it can be a predictive tool to identify patients at high risk for exacerbation, a common cause of emergency room visits and hospitalizations.

Some patients perceive spirometry as cumbersome and do not want to do it or cannot do it—spirometry takes quite a bit of effort and coordination while following directions. Also, it is not always easy to do, as patients with severe obstruction have a hard time maximally exhaling. Nevertheless, testing is safe, with few risks or adverse outcomes and can be easily performed in primary care settings and subspecialty clinics.

A 41-year-old woman presented with intermittent shortness of breath that worsened with exposure to cold air and cigarette smoke. She said her symptoms got better when she used albuterol, which had been prescribed after an emergency department visit during a worsening episode.

The patient was severely obese (body mass index 48 kg/m²) and had bilateral expiratory wheezes but no other significant findings. Based on the clinical presentation, we suspected she had asthma.

To establish the diagnosis and assess the severity of her condition, we questioned her further about her symptoms, and this information increased our suspicion of asthma. Is spirometry also indicated?

SPIROMETRY’S ROLE IN DIAGNOSING ASTHMA

Asthma is a chronic inflammatory condition of the airways characterized by recurrent or persistent symptoms with evidence of variable airflow obstruction or hyperresponsiveness to certain stimuli.¹ The clinical diagnosis is based on episodic symptoms of chest tightness, wheezing, shortness of breath, or cough, but we cannot reliably diagnose asthma based on symptoms alone.

Spirometry provides an objective measure of obstruction, which adds to the reliability of the diagnosis. Therefore, it should be done in all patients in whom asthma is suspected.

Spirometry provides another diagnostic measure by quantifying whether airway obstruction reverses after the patient is given a dose of a bronchodilator. Although the exact criteria for reversibility of obstruction are unclear, the American Thoracic Society defines it as an increase in the forced expiratory volume in 1 second (FEV₁) of 12% or more from baseline and an absolute increase of 200 mL or more. It can also be an increase of more than 200 mL in the forced vital capacity (FVC).^2,3

Spirometry can also be used to evaluate or rule out other causes of chronic shortness of breath and common asthma mimics.

Failure to perform spirometry can result in a false diagnosis of asthma in patients who do not have it, or in a missed diagnosis in patients who do.^4,5 Either situation often leads to inappropriate use of medications, exposure of patients to side effects, delays in appropriate diagnosis, and ongoing morbidity.

Despite the evidence in its favor, spirometry is underused. In a 2012 Canadian study, only 42.7% of 465,866 patients with newly diagnosed asthma had any spirometry testing performed within 1 year before or 2.5 years after the diagnosis.⁶ Similarly, in a 2015 US study, only 47.6% of 134,208 patients had spirometry performed within 1 year of diagnosis.⁷ Interestingly, this study found that the use of spirometry actually decreased after publication of guidelines from the National Asthma Education and Prevention Program¹ that recommended spirometry.

CASE CONTINUED

Her baseline values were normal; her FEV₁/FVC ratio was 73.67% (lower limit of normal 72.62%) and thus was not significant for airway obstruction. However, after 4 puffs of an inhaled short-acting beta agonist, her FEV₁ increased by 15% from baseline (from 1.98 L/second before to 2.25 L/second after), a clinically significant response (defined as ≥ 12% from baseline and an absolute increase of at least 200 mL^1–3). Had we not included bronchodilator testing, given the absence of underlying baseline obstruction, her shortness of breath could have been attributed to other causes, resulting in a missed asthma diagnosis.

Nevertheless, postbronchodilator measurements should not be performed in all patients with normal baseline results unless asthma is strongly suspected on clinical grounds. In one study, only 3% of 1,394 patients with normal baseline results showed improvement with a bronchodilator.⁸ In this patient population, bronchodilator testing would add both time and cost with little benefit.

Our patient’s reversibility of obstruction helped confirm the diagnosis of asthma. Absence of reversibility, however, does not rule out asthma, because spirometry results, like clinical symptoms of asthma, can vary. If clinical suspicion remains high and spirometry does not show clinically significant reversibility, then bronchoprovocation testing (most commonly with methacholine) could be done.

Although a positive methacholine challenge test can help identify asthma in patients with atypical symptoms or normal baseline test results, conditions other than asthma can also cause positive results. The sensitivity of methacholine challenge has been reported to be as high as 96%, while its specificity averages less than 80%.⁹ Given its high negative predictive value, the test can help rule out asthma, as negative results are rarely falsely negative.

Once the diagnosis of asthma is established, its severity and control need to be assessed to guide therapy. This is typically done by ascertaining how often the patient experiences asthma symptoms, how often the patient uses short-acting beta agonists (ranging from days per month to multiple times a day), and how often he or she has nighttime symptoms. The most severe symptom or most abnormal response is used to categorize asthma as intermittent or persistent, with severity ranging from mild to severe.

Symptoms are not always effective measures of asthma control, and subjective measures of symptoms often do not correlate with asthma severity, resulting in underestimation of the degree of airway obstruction.^10,11 A review of 500 patients with an established asthma diagnosis found that in 110 patients with self-reported control of symptoms that included use of short-acting beta agonists no more than once per day, no night awakenings in the past week, and no missed school or work in the past 3 months, only 61 (55%) had an FEV₁ above 80% of predicted.¹² Further, neither the FEV₁ nor FEV₁/FVC ratio was shown to have a direct relationship with subjective measures of disease severity or control.

These observations highlight the need to use the objective findings from spirometry to assess asthma control and severity. Relying on the clinical symptoms alone likely underestimates the severity of asthma, especially in patients who are “poor perceivers” of symptoms. This can lead to undertreatment or an inappropriate step-down in therapy.

Current guidelines recommend repeating spirometry once therapy has brought the disease under control to establish a true baseline of airway function.^1–3 Spirometry should be repeated again during any prolonged loss of asthma control and at 1- to 2-year intervals in patients with well-controlled disease as a means to monitor disease progression by measuring changes in airway function over time.

ROLE IN PREDICTING EXACERBATIONS

Current questionnaire-based assessments of breathing symptoms focus on disease severity and control, not on the risk of exacerbation. Although it may seem intuitive that patients who have the most severe disease are at highest risk of exacerbations, many patients with “mild” disease and “good” control experience exacerbations that require expensive emergency department visits. Nearly half of all the money spent on direct medical care for asthma is for urgent outpatient clinic and emergency department visits and hospitalizations.¹³

Using the FEV₁, either by itself or in combination with other diagnostic tools such as questionnaires, has been shown to be superior to the clinical history alone in identifying patients at high risk of acute exacerbations.^14,15 In addition to improving patient care and quality of life, spirometry could substantially reduce costs of care.

BOTTOM LINE

Although asthma remains a clinical diagnosis based on episodic symptoms consistent with airflow obstruction, symptoms alone cannot reliably be used to diagnose the disease or assess its severity and control.

Spirometry, including FEV₁ and FVC, is an important objective measure to help with the diagnosis and should be done in all patients in whom asthma is suspected, both at the time of diagnosis and at intervals to assess disease progression. Spirometry also provides data to help assess the severity of asthma, which often does not correlate with clinical perception of symptoms, and it can be a predictive tool to identify patients at high risk for exacerbation, a common cause of emergency room visits and hospitalizations.

Some patients perceive spirometry as cumbersome and do not want to do it or cannot do it—spirometry takes quite a bit of effort and coordination while following directions. Also, it is not always easy to do, as patients with severe obstruction have a hard time maximally exhaling. Nevertheless, testing is safe, with few risks or adverse outcomes and can be easily performed in primary care settings and subspecialty clinics.

A 41-year-old woman presented with intermittent shortness of breath that worsened with exposure to cold air and cigarette smoke. She said her symptoms got better when she used albuterol, which had been prescribed after an emergency department visit during a worsening episode.

The patient was severely obese (body mass index 48 kg/m²) and had bilateral expiratory wheezes but no other significant findings. Based on the clinical presentation, we suspected she had asthma.

To establish the diagnosis and assess the severity of her condition, we questioned her further about her symptoms, and this information increased our suspicion of asthma. Is spirometry also indicated?

SPIROMETRY’S ROLE IN DIAGNOSING ASTHMA

Asthma is a chronic inflammatory condition of the airways characterized by recurrent or persistent symptoms with evidence of variable airflow obstruction or hyperresponsiveness to certain stimuli.¹ The clinical diagnosis is based on episodic symptoms of chest tightness, wheezing, shortness of breath, or cough, but we cannot reliably diagnose asthma based on symptoms alone.

Spirometry provides an objective measure of obstruction, which adds to the reliability of the diagnosis. Therefore, it should be done in all patients in whom asthma is suspected.

Spirometry provides another diagnostic measure by quantifying whether airway obstruction reverses after the patient is given a dose of a bronchodilator. Although the exact criteria for reversibility of obstruction are unclear, the American Thoracic Society defines it as an increase in the forced expiratory volume in 1 second (FEV₁) of 12% or more from baseline and an absolute increase of 200 mL or more. It can also be an increase of more than 200 mL in the forced vital capacity (FVC).^2,3

Spirometry can also be used to evaluate or rule out other causes of chronic shortness of breath and common asthma mimics.

Failure to perform spirometry can result in a false diagnosis of asthma in patients who do not have it, or in a missed diagnosis in patients who do.^4,5 Either situation often leads to inappropriate use of medications, exposure of patients to side effects, delays in appropriate diagnosis, and ongoing morbidity.

Despite the evidence in its favor, spirometry is underused. In a 2012 Canadian study, only 42.7% of 465,866 patients with newly diagnosed asthma had any spirometry testing performed within 1 year before or 2.5 years after the diagnosis.⁶ Similarly, in a 2015 US study, only 47.6% of 134,208 patients had spirometry performed within 1 year of diagnosis.⁷ Interestingly, this study found that the use of spirometry actually decreased after publication of guidelines from the National Asthma Education and Prevention Program¹ that recommended spirometry.

CASE CONTINUED

Her baseline values were normal; her FEV₁/FVC ratio was 73.67% (lower limit of normal 72.62%) and thus was not significant for airway obstruction. However, after 4 puffs of an inhaled short-acting beta agonist, her FEV₁ increased by 15% from baseline (from 1.98 L/second before to 2.25 L/second after), a clinically significant response (defined as ≥ 12% from baseline and an absolute increase of at least 200 mL^1–3). Had we not included bronchodilator testing, given the absence of underlying baseline obstruction, her shortness of breath could have been attributed to other causes, resulting in a missed asthma diagnosis.

Nevertheless, postbronchodilator measurements should not be performed in all patients with normal baseline results unless asthma is strongly suspected on clinical grounds. In one study, only 3% of 1,394 patients with normal baseline results showed improvement with a bronchodilator.⁸ In this patient population, bronchodilator testing would add both time and cost with little benefit.

Our patient’s reversibility of obstruction helped confirm the diagnosis of asthma. Absence of reversibility, however, does not rule out asthma, because spirometry results, like clinical symptoms of asthma, can vary. If clinical suspicion remains high and spirometry does not show clinically significant reversibility, then bronchoprovocation testing (most commonly with methacholine) could be done.

Although a positive methacholine challenge test can help identify asthma in patients with atypical symptoms or normal baseline test results, conditions other than asthma can also cause positive results. The sensitivity of methacholine challenge has been reported to be as high as 96%, while its specificity averages less than 80%.⁹ Given its high negative predictive value, the test can help rule out asthma, as negative results are rarely falsely negative.

Once the diagnosis of asthma is established, its severity and control need to be assessed to guide therapy. This is typically done by ascertaining how often the patient experiences asthma symptoms, how often the patient uses short-acting beta agonists (ranging from days per month to multiple times a day), and how often he or she has nighttime symptoms. The most severe symptom or most abnormal response is used to categorize asthma as intermittent or persistent, with severity ranging from mild to severe.

Symptoms are not always effective measures of asthma control, and subjective measures of symptoms often do not correlate with asthma severity, resulting in underestimation of the degree of airway obstruction.^10,11 A review of 500 patients with an established asthma diagnosis found that in 110 patients with self-reported control of symptoms that included use of short-acting beta agonists no more than once per day, no night awakenings in the past week, and no missed school or work in the past 3 months, only 61 (55%) had an FEV₁ above 80% of predicted.¹² Further, neither the FEV₁ nor FEV₁/FVC ratio was shown to have a direct relationship with subjective measures of disease severity or control.

These observations highlight the need to use the objective findings from spirometry to assess asthma control and severity. Relying on the clinical symptoms alone likely underestimates the severity of asthma, especially in patients who are “poor perceivers” of symptoms. This can lead to undertreatment or an inappropriate step-down in therapy.

Current guidelines recommend repeating spirometry once therapy has brought the disease under control to establish a true baseline of airway function.^1–3 Spirometry should be repeated again during any prolonged loss of asthma control and at 1- to 2-year intervals in patients with well-controlled disease as a means to monitor disease progression by measuring changes in airway function over time.

ROLE IN PREDICTING EXACERBATIONS

Current questionnaire-based assessments of breathing symptoms focus on disease severity and control, not on the risk of exacerbation. Although it may seem intuitive that patients who have the most severe disease are at highest risk of exacerbations, many patients with “mild” disease and “good” control experience exacerbations that require expensive emergency department visits. Nearly half of all the money spent on direct medical care for asthma is for urgent outpatient clinic and emergency department visits and hospitalizations.¹³

Using the FEV₁, either by itself or in combination with other diagnostic tools such as questionnaires, has been shown to be superior to the clinical history alone in identifying patients at high risk of acute exacerbations.^14,15 In addition to improving patient care and quality of life, spirometry could substantially reduce costs of care.

BOTTOM LINE

Although asthma remains a clinical diagnosis based on episodic symptoms consistent with airflow obstruction, symptoms alone cannot reliably be used to diagnose the disease or assess its severity and control.

Spirometry, including FEV₁ and FVC, is an important objective measure to help with the diagnosis and should be done in all patients in whom asthma is suspected, both at the time of diagnosis and at intervals to assess disease progression. Spirometry also provides data to help assess the severity of asthma, which often does not correlate with clinical perception of symptoms, and it can be a predictive tool to identify patients at high risk for exacerbation, a common cause of emergency room visits and hospitalizations.

Some patients perceive spirometry as cumbersome and do not want to do it or cannot do it—spirometry takes quite a bit of effort and coordination while following directions. Also, it is not always easy to do, as patients with severe obstruction have a hard time maximally exhaling. Nevertheless, testing is safe, with few risks or adverse outcomes and can be easily performed in primary care settings and subspecialty clinics.

A 72-year-old woman is admitted with fever and shortness of breath. Chest radiography demonstrates a consolidation in the right lower lobe, and ceftriaxone and azithromycin are given to treat community-acquired pneumonia. After initial improvement she develops abdominal discomfort and profuse diarrhea on day 5 of hospitalization. What stool testing should be ordered?

Most cases of diarrhea in hospitalized patients are not due to infection, but the most common infectious cause is Clostridium difficile. In the absence of unusual circumstances such as a norovirus outbreak or diarrhea in an immunocompromised patient, testing for C difficile is the only recommended assay. A multistep algorithm with a combination of antigen detection and nucleic acid amplification techniques provides the best sensitivity and specificity. Repeated testing after an initially negative test and performing a test of cure are of limited utility and incur added costs, and thus are not recommended.

CAUSES OF DIARRHEA IN THE HOSPITAL

Diarrhea is defined as at least 1 day with three or more unformed stools or a significant increase in stool frequency above baseline.

Nosocomial diarrhea is an acute episode of diarrhea in a hospitalized patient that was not present on admission and that arises after 3 days of hospitalization. It is fairly common, developing in 12% to 32% of patients at some point during their hospitalization.¹

Most cases of nosocomial diarrhea are not due to infection, but rather secondary to enteral feeding, medications, and underlying illness. C difficile is the most common infectious cause and accounts for 10% to 20% of all cases of nosocomial diarrhea.² Other pathogens associated with nosocomial diarrhea are unusual, although outbreaks of norovirus in healthcare facilities have occurred,³ and isolated cases of Klebsiella oxytoca causing acute abdominal pain, bloody diarrhea, and leukocytosis after exposure to antibiotics have been reported.¹

RECOMMENDED TESTING

The evaluation of a hospitalized patient in whom diarrhea develops should initially focus on the clinical presentation, with attention to signs of sepsis. Stable patients with mild symptoms may respond to withdrawal of the offending agent (if any), while patients with moderate or severe symptoms (including those with fever, hypotension, leukocytosis, acute kidney injury, or a decreased serum bicarbonate level) should be tested for C difficile infection (Figure 1).

In general, stool testing should adhere to the “3-day rule”—ie, fecal specimens from patients with diarrhea that develops after 3 days of hospitalization have a very low yield when cultured for standard bacteria or examined for ova and parasites. Thus, only testing for C difficile infection should be ordered.⁴

In an outbreak of norovirus, especially if vomiting is present, norovirus testing by reverse transcriptase polymerase chain reaction (PCR) could be considered.

Fecal white blood cell testing should not be ordered, as it neither sensitive nor specific.⁵

Immunocompromised patients (such as those with organ transplants or late-stage human immunodeficiency virus infection) occasionally contract diarrhea due to causes other than C difficile, and consultation with a gastroenterologist or an infectious diseases physician could be considered if diarrhea persists and no cause is apparent.

In the rare situation when a patient is hospitalized after very recent overseas travel and then contracts diarrhea, causes of traveler’s diarrhea should be considered.

TESTING FOR C DIFFICILE INFECTION

A number of diagnostic tests for C difficile infection are available.

Toxigenic culture (culture followed by detection of a toxigenic isolate) and C difficile cytotoxin neutralization assay are considered the reference standards, having high sensitivity and specificity. However, both are time- and labor-intensive, with turnaround times of at least 2 to 3 days and up to 9 days, limiting their clinical utility and resulting in delay in both diagnosis and implementation of infection control measures.^2,6

Enzyme immunoassays (EIAs) are faster. EIAs are available to detect glutamate dehydrogenase (GDH) and toxins A and B, all produced by C difficile. The GDH EIA is 92% sensitive and 93% specific but should not be used alone as it does not distinguish between toxigenic and nontoxigenic strains of C difficile.^2,6 The toxin A/B EIA is 97% specific, but since its sensitivity may be as low as 73%, it too should not be used alone.⁶

Nucleic acid amplification tests such as PCR and loop-mediated isothermal amplification (LAMP) identify toxigenic C difficile by detecting tcdA, tcdB, or tcdC genes, which regulate toxin production. These tests have sensitivities and specificities well over 90%.⁶

Since molecular tests (ie, nucleic acid amplification tests) for C difficile infection became available in 2009, they have been widely adopted and are commercially available.⁷ Facilities that use them have reported a 50% to 100% increase in C difficile infection rates,⁷ but the increase may not be real. Rather, it may reflect increased detection of colonization by the more-sensitive tests.

In a prospective, observational, cohort study,⁷ 1,416 hospitalized patients with diarrhea that developed 72 hours after hospitalization were tested for C difficile infection by both toxin EIA and PCR. Those with positive results on both tests had a longer duration of diarrhea, more C difficile infection-related complications, more C difficile infection-related deaths, and greater risk of diarrhea during follow-up. For those who had negative results on toxin EIA testing, the results of PCR testing made no difference, and neither did treatment for C difficile infection, suggesting that most patients with negative toxin test results do not need treatment for C difficile even if PCR testing is positive.

In light of the limited sensitivity of some toxin EIAs and the increased identification of asymptomatic colonization with nucleic acid amplification testing, the optimal approach may be to combine rapid testing methods. Algorithms that include nucleic acid amplification testing have the best sensitivity (68% to 100%) and specificity (92% to 100%).⁷ Clinical guidelines suggest using a GDH EIA as the initial step, and then confirming positive results with either nucleic acid amplification testing alone or toxin EIA followed by nucleic acid amplification testing if the toxin EIA is negative.⁸ However, the best diagnostic approach remains controversial, and multistep algorithms may be impractical in some laboratories.

Knowledge of the laboratory test used can help clinicians appreciate the limitations of specimen testing. Table 1 outlines some of the performance characteristics of the available assays.^9–11

The preferred approach at our institution is a multistep algorithm using both the GDH and toxin EIAs in the initial step, followed by a LAMP assay for the C difficile toxin genes in cases of discordant EIA results.

Repeat testing after an initial negative test may be positive in fewer than 5% of cases, can increase the chance of false-positive results, does not improve sensitivity and negative predictive values, and is therefore not recommended.^2,8 Similarly, a test of cure after symptoms resolve is not recommended, as the toxin EIA can be positive for up to 30 days after resolution of symptoms, and a positive nucleic acid amplification test may only reflect colonization.^2,8

RETURNING TO OUR PATIENT

Returning to the patient hospitalized with community-acquired pneumonia, C difficile infection is the most likely cause of her diarrhea. If her respiratory symptoms have improved, then cessation of ceftriaxone and azithromycin should be considered because she has completed 5 days of therapy. In addition, given her profuse diarrhea, testing for C difficile is recommended with a multistep approach.

A 72-year-old woman is admitted with fever and shortness of breath. Chest radiography demonstrates a consolidation in the right lower lobe, and ceftriaxone and azithromycin are given to treat community-acquired pneumonia. After initial improvement she develops abdominal discomfort and profuse diarrhea on day 5 of hospitalization. What stool testing should be ordered?

Most cases of diarrhea in hospitalized patients are not due to infection, but the most common infectious cause is Clostridium difficile. In the absence of unusual circumstances such as a norovirus outbreak or diarrhea in an immunocompromised patient, testing for C difficile is the only recommended assay. A multistep algorithm with a combination of antigen detection and nucleic acid amplification techniques provides the best sensitivity and specificity. Repeated testing after an initially negative test and performing a test of cure are of limited utility and incur added costs, and thus are not recommended.

CAUSES OF DIARRHEA IN THE HOSPITAL

Diarrhea is defined as at least 1 day with three or more unformed stools or a significant increase in stool frequency above baseline.

Nosocomial diarrhea is an acute episode of diarrhea in a hospitalized patient that was not present on admission and that arises after 3 days of hospitalization. It is fairly common, developing in 12% to 32% of patients at some point during their hospitalization.¹

Most cases of nosocomial diarrhea are not due to infection, but rather secondary to enteral feeding, medications, and underlying illness. C difficile is the most common infectious cause and accounts for 10% to 20% of all cases of nosocomial diarrhea.² Other pathogens associated with nosocomial diarrhea are unusual, although outbreaks of norovirus in healthcare facilities have occurred,³ and isolated cases of Klebsiella oxytoca causing acute abdominal pain, bloody diarrhea, and leukocytosis after exposure to antibiotics have been reported.¹

RECOMMENDED TESTING

The evaluation of a hospitalized patient in whom diarrhea develops should initially focus on the clinical presentation, with attention to signs of sepsis. Stable patients with mild symptoms may respond to withdrawal of the offending agent (if any), while patients with moderate or severe symptoms (including those with fever, hypotension, leukocytosis, acute kidney injury, or a decreased serum bicarbonate level) should be tested for C difficile infection (Figure 1).

In general, stool testing should adhere to the “3-day rule”—ie, fecal specimens from patients with diarrhea that develops after 3 days of hospitalization have a very low yield when cultured for standard bacteria or examined for ova and parasites. Thus, only testing for C difficile infection should be ordered.⁴

In an outbreak of norovirus, especially if vomiting is present, norovirus testing by reverse transcriptase polymerase chain reaction (PCR) could be considered.

Fecal white blood cell testing should not be ordered, as it neither sensitive nor specific.⁵

Immunocompromised patients (such as those with organ transplants or late-stage human immunodeficiency virus infection) occasionally contract diarrhea due to causes other than C difficile, and consultation with a gastroenterologist or an infectious diseases physician could be considered if diarrhea persists and no cause is apparent.

In the rare situation when a patient is hospitalized after very recent overseas travel and then contracts diarrhea, causes of traveler’s diarrhea should be considered.

TESTING FOR C DIFFICILE INFECTION

A number of diagnostic tests for C difficile infection are available.

Toxigenic culture (culture followed by detection of a toxigenic isolate) and C difficile cytotoxin neutralization assay are considered the reference standards, having high sensitivity and specificity. However, both are time- and labor-intensive, with turnaround times of at least 2 to 3 days and up to 9 days, limiting their clinical utility and resulting in delay in both diagnosis and implementation of infection control measures.^2,6

Enzyme immunoassays (EIAs) are faster. EIAs are available to detect glutamate dehydrogenase (GDH) and toxins A and B, all produced by C difficile. The GDH EIA is 92% sensitive and 93% specific but should not be used alone as it does not distinguish between toxigenic and nontoxigenic strains of C difficile.^2,6 The toxin A/B EIA is 97% specific, but since its sensitivity may be as low as 73%, it too should not be used alone.⁶

Nucleic acid amplification tests such as PCR and loop-mediated isothermal amplification (LAMP) identify toxigenic C difficile by detecting tcdA, tcdB, or tcdC genes, which regulate toxin production. These tests have sensitivities and specificities well over 90%.⁶

Since molecular tests (ie, nucleic acid amplification tests) for C difficile infection became available in 2009, they have been widely adopted and are commercially available.⁷ Facilities that use them have reported a 50% to 100% increase in C difficile infection rates,⁷ but the increase may not be real. Rather, it may reflect increased detection of colonization by the more-sensitive tests.

In a prospective, observational, cohort study,⁷ 1,416 hospitalized patients with diarrhea that developed 72 hours after hospitalization were tested for C difficile infection by both toxin EIA and PCR. Those with positive results on both tests had a longer duration of diarrhea, more C difficile infection-related complications, more C difficile infection-related deaths, and greater risk of diarrhea during follow-up. For those who had negative results on toxin EIA testing, the results of PCR testing made no difference, and neither did treatment for C difficile infection, suggesting that most patients with negative toxin test results do not need treatment for C difficile even if PCR testing is positive.

In light of the limited sensitivity of some toxin EIAs and the increased identification of asymptomatic colonization with nucleic acid amplification testing, the optimal approach may be to combine rapid testing methods. Algorithms that include nucleic acid amplification testing have the best sensitivity (68% to 100%) and specificity (92% to 100%).⁷ Clinical guidelines suggest using a GDH EIA as the initial step, and then confirming positive results with either nucleic acid amplification testing alone or toxin EIA followed by nucleic acid amplification testing if the toxin EIA is negative.⁸ However, the best diagnostic approach remains controversial, and multistep algorithms may be impractical in some laboratories.

Knowledge of the laboratory test used can help clinicians appreciate the limitations of specimen testing. Table 1 outlines some of the performance characteristics of the available assays.^9–11

The preferred approach at our institution is a multistep algorithm using both the GDH and toxin EIAs in the initial step, followed by a LAMP assay for the C difficile toxin genes in cases of discordant EIA results.

Repeat testing after an initial negative test may be positive in fewer than 5% of cases, can increase the chance of false-positive results, does not improve sensitivity and negative predictive values, and is therefore not recommended.^2,8 Similarly, a test of cure after symptoms resolve is not recommended, as the toxin EIA can be positive for up to 30 days after resolution of symptoms, and a positive nucleic acid amplification test may only reflect colonization.^2,8

RETURNING TO OUR PATIENT

Returning to the patient hospitalized with community-acquired pneumonia, C difficile infection is the most likely cause of her diarrhea. If her respiratory symptoms have improved, then cessation of ceftriaxone and azithromycin should be considered because she has completed 5 days of therapy. In addition, given her profuse diarrhea, testing for C difficile is recommended with a multistep approach.

A 72-year-old woman is admitted with fever and shortness of breath. Chest radiography demonstrates a consolidation in the right lower lobe, and ceftriaxone and azithromycin are given to treat community-acquired pneumonia. After initial improvement she develops abdominal discomfort and profuse diarrhea on day 5 of hospitalization. What stool testing should be ordered?

Most cases of diarrhea in hospitalized patients are not due to infection, but the most common infectious cause is Clostridium difficile. In the absence of unusual circumstances such as a norovirus outbreak or diarrhea in an immunocompromised patient, testing for C difficile is the only recommended assay. A multistep algorithm with a combination of antigen detection and nucleic acid amplification techniques provides the best sensitivity and specificity. Repeated testing after an initially negative test and performing a test of cure are of limited utility and incur added costs, and thus are not recommended.

CAUSES OF DIARRHEA IN THE HOSPITAL

Diarrhea is defined as at least 1 day with three or more unformed stools or a significant increase in stool frequency above baseline.

Nosocomial diarrhea is an acute episode of diarrhea in a hospitalized patient that was not present on admission and that arises after 3 days of hospitalization. It is fairly common, developing in 12% to 32% of patients at some point during their hospitalization.¹

Most cases of nosocomial diarrhea are not due to infection, but rather secondary to enteral feeding, medications, and underlying illness. C difficile is the most common infectious cause and accounts for 10% to 20% of all cases of nosocomial diarrhea.² Other pathogens associated with nosocomial diarrhea are unusual, although outbreaks of norovirus in healthcare facilities have occurred,³ and isolated cases of Klebsiella oxytoca causing acute abdominal pain, bloody diarrhea, and leukocytosis after exposure to antibiotics have been reported.¹

RECOMMENDED TESTING

The evaluation of a hospitalized patient in whom diarrhea develops should initially focus on the clinical presentation, with attention to signs of sepsis. Stable patients with mild symptoms may respond to withdrawal of the offending agent (if any), while patients with moderate or severe symptoms (including those with fever, hypotension, leukocytosis, acute kidney injury, or a decreased serum bicarbonate level) should be tested for C difficile infection (Figure 1).

In general, stool testing should adhere to the “3-day rule”—ie, fecal specimens from patients with diarrhea that develops after 3 days of hospitalization have a very low yield when cultured for standard bacteria or examined for ova and parasites. Thus, only testing for C difficile infection should be ordered.⁴

In an outbreak of norovirus, especially if vomiting is present, norovirus testing by reverse transcriptase polymerase chain reaction (PCR) could be considered.

Fecal white blood cell testing should not be ordered, as it neither sensitive nor specific.⁵

Immunocompromised patients (such as those with organ transplants or late-stage human immunodeficiency virus infection) occasionally contract diarrhea due to causes other than C difficile, and consultation with a gastroenterologist or an infectious diseases physician could be considered if diarrhea persists and no cause is apparent.

In the rare situation when a patient is hospitalized after very recent overseas travel and then contracts diarrhea, causes of traveler’s diarrhea should be considered.

TESTING FOR C DIFFICILE INFECTION

A number of diagnostic tests for C difficile infection are available.

Toxigenic culture (culture followed by detection of a toxigenic isolate) and C difficile cytotoxin neutralization assay are considered the reference standards, having high sensitivity and specificity. However, both are time- and labor-intensive, with turnaround times of at least 2 to 3 days and up to 9 days, limiting their clinical utility and resulting in delay in both diagnosis and implementation of infection control measures.^2,6

Enzyme immunoassays (EIAs) are faster. EIAs are available to detect glutamate dehydrogenase (GDH) and toxins A and B, all produced by C difficile. The GDH EIA is 92% sensitive and 93% specific but should not be used alone as it does not distinguish between toxigenic and nontoxigenic strains of C difficile.^2,6 The toxin A/B EIA is 97% specific, but since its sensitivity may be as low as 73%, it too should not be used alone.⁶

Nucleic acid amplification tests such as PCR and loop-mediated isothermal amplification (LAMP) identify toxigenic C difficile by detecting tcdA, tcdB, or tcdC genes, which regulate toxin production. These tests have sensitivities and specificities well over 90%.⁶

Since molecular tests (ie, nucleic acid amplification tests) for C difficile infection became available in 2009, they have been widely adopted and are commercially available.⁷ Facilities that use them have reported a 50% to 100% increase in C difficile infection rates,⁷ but the increase may not be real. Rather, it may reflect increased detection of colonization by the more-sensitive tests.

In a prospective, observational, cohort study,⁷ 1,416 hospitalized patients with diarrhea that developed 72 hours after hospitalization were tested for C difficile infection by both toxin EIA and PCR. Those with positive results on both tests had a longer duration of diarrhea, more C difficile infection-related complications, more C difficile infection-related deaths, and greater risk of diarrhea during follow-up. For those who had negative results on toxin EIA testing, the results of PCR testing made no difference, and neither did treatment for C difficile infection, suggesting that most patients with negative toxin test results do not need treatment for C difficile even if PCR testing is positive.

In light of the limited sensitivity of some toxin EIAs and the increased identification of asymptomatic colonization with nucleic acid amplification testing, the optimal approach may be to combine rapid testing methods. Algorithms that include nucleic acid amplification testing have the best sensitivity (68% to 100%) and specificity (92% to 100%).⁷ Clinical guidelines suggest using a GDH EIA as the initial step, and then confirming positive results with either nucleic acid amplification testing alone or toxin EIA followed by nucleic acid amplification testing if the toxin EIA is negative.⁸ However, the best diagnostic approach remains controversial, and multistep algorithms may be impractical in some laboratories.

Knowledge of the laboratory test used can help clinicians appreciate the limitations of specimen testing. Table 1 outlines some of the performance characteristics of the available assays.^9–11

The preferred approach at our institution is a multistep algorithm using both the GDH and toxin EIAs in the initial step, followed by a LAMP assay for the C difficile toxin genes in cases of discordant EIA results.

Repeat testing after an initial negative test may be positive in fewer than 5% of cases, can increase the chance of false-positive results, does not improve sensitivity and negative predictive values, and is therefore not recommended.^2,8 Similarly, a test of cure after symptoms resolve is not recommended, as the toxin EIA can be positive for up to 30 days after resolution of symptoms, and a positive nucleic acid amplification test may only reflect colonization.^2,8

RETURNING TO OUR PATIENT

Returning to the patient hospitalized with community-acquired pneumonia, C difficile infection is the most likely cause of her diarrhea. If her respiratory symptoms have improved, then cessation of ceftriaxone and azithromycin should be considered because she has completed 5 days of therapy. In addition, given her profuse diarrhea, testing for C difficile is recommended with a multistep approach.

A 28-year-old woman returns for follow-up of her hypothyroidism. She was diagnosed 4 years ago when she presented with fatigue, “foggy” thinking, poor concentration, cold intolerance, and constipation. Her thyroid-stimulating hormone (TSH) level at that time was elevated at 15 mIU/L (reference range 0.4–4). She was started on 50 µg of levothyroxine daily, which helped her symptoms, but she continued to complain of tiredness and the inability to lose weight. She has been on 100 µg of levothyroxine daily since her last visit 1 year ago.

On examination, she has a small, diffuse, and firm goiter; she has no Cushing-like features, visual field abnormalities, or signs of hypothyroidism.

Her TSH level today is 1.2 mIU/L. Based on this, you recommend no change in her daily levothyroxine dose. She expresses dissatisfaction that you had ordered only a TSH, and she asks you to order thyroxine (T₄) and triiodothyronine (T₃) measurements because she read on the Internet that those were needed to determine the appropriateness of the levothyroxine dose.

Should T₄ or T₃ be routinely measured when adjusting thyroid replacement therapy?

IN PRIMARY HYPOTHYROIDISM, TSH IS ENOUGH

In a patient with primary hypothyroidism and no suspicion of pituitary abnormality, a serum TSH is sufficient for monitoring thyroid status and adjusting the dose of thyroid hormone.

Hypothyroidism is one of the most common endocrine disorders, affecting about 4% of the adult US population.¹ In areas of iodine sufficiency, primary hypothyroidism is due predominantly to Hashimoto thyroiditis.

The role of the lack of thyroid hormone in the pathogenesis of myxedema was recognized in the late 19th century through the observation of a “cretinoid” state occurring in middle-aged women, associated with atrophy of the thyroid gland and a similar severe state noted after total thyroidectomy.²

In 1891, George R. Murray was able to “cure” myxedema in a patient by injecting sheep thyroid extract subcutaneously. Thyroid extracts continued to be the only treatment for hypothyroidism until 1950, when levothyroxine was introduced and later became the main treatment. Around that time, T₃ was discovered and was described as being the physiologically active thyroid hormone. Later, it was noted that 80% to 90% of circulating T₃ is generated through peripheral deiodination of T₄, the latter being considered a prohormone.²

The pituitary-thyroid axis is regulated through negative feedback. At concentrations of free T₄ below normal, plasma TSH rises rapidly with small decrements in T₄ levels.³ The opposite phenomenon occurs with free T₄ concentrations above normal. Since T₄ has a long disappearance half-time—about 7 days—a normal TSH tends to stay relatively stable in the same individual.⁴ The relationship between TSH and T₄ was long thought to be inverse log-linear, but Hadlow et al⁵ found that it is complex and nonlinear and differs by age and sex. TSH and T₄ concentrations have narrower within-individual variability than inter-individual variability. Although environmental factors may affect this hypothalamic-pituitary set-point, there is evidence that heritability is a major determinant of individual variability.⁶

GUIDELINES AND CHOOSING WISELY

In 2014, the American Thyroid Association published comprehensive, evidence-based guidelines for the treatment of hypothyroidism.⁷ The guidelines state that the goal of thyroid hormone replacement is to achieve clinical and biochemical euthyroidism.⁷ TSH continues to be the most reliable marker of adequacy of thyroid hormone replacement in primary hypothyroidism. The guidelines recommend aiming for a TSH in the normal range (generally 0.4–4 mIU/L).

Most studies of the risks associated with hypothyroidism or thyrotoxicosis have looked at TSH levels. Significantly increased risk of cardiovascular mortality and morbidity is seen in individuals with TSH levels higher than 10 mIU/L.⁸ On the other hand, excess thyroid hormone leading to a TSH level lower than 0.1 mIU/L has been associated with an increased risk of atrial fibrillation in older persons and osteoporosis in postmenopausal women.

The classic symptoms and signs of hypothyroidism correlate with biochemical hypothyroidism and usually improve with the restoration of euthyroidism. Some of these symptoms, however, lack sensitivity and specificity, especially with modest degrees of hypothyroidism.⁷ A randomized controlled trial showed that patients were unable to detect any difference in symptoms when the levothyroxine dose was changed by about 20%.⁹

HARMS ASSOCIATED WITH ORDERING T₄ AND T₃

Other than the financial burden to the patient and society, there is no major morbidity caused by obtaining T₄ or T₃ levels, or both. However, knowing the T₄ or T₃ level does not help with management beyond the information offered by the TSH value. Hypothyroid patients treated with levothyroxine to maintain a normal TSH generally have higher free T₄ levels and lower free T₃ levels than euthyroid patients with similar TSH values.¹⁰ Therefore, reacting to a high T₄ level or a low T₃ level in a treated hypothyroid patient with a normal TSH may lead to inappropriate dose adjustment. On the other hand, increasing the dose of thyroid hormone in a patient with a low TSH whose T₃ level is low-normal may lead to morbidity.

SPECIAL SCENARIO: PITUITARY COMPROMISE

We assume that the patient described above has primary hypothyroidism and that her pituitary-thyroid axis is intact. Primary hypothyroidism is diagnosed by a high TSH along with a low or low-normal T₄. In this typical case, TSH can be used to guide therapy without the need for other tests.

However, when there is pituitary compromise (hypopituitarism, congenital central hypothyroidism), the TSH will not be reliable to monitor the adequacy of thyroid hormone replacement therapy. The aim of levothyroxine management in these patients is to maintain a free T₄ concentration in the upper half of the normal range. If the free T₃ concentration is followed and is found to be elevated, the dose of levothyroxine should be reduced.¹¹

CLINICAL BOTTOM LINE

Since our patient’s dose of levothyroxine has been stable and her TSH is not elevated, measuring serum levels of T₄ and T₃ would not contribute to her management. For such a patient, if the TSH were less than 3 mIU/L, increasing the dose would be unlikely to offer clinical benefit.

On the other hand, if her TSH was higher than 4 mIU/L, then it would be legitimate to tweak the dose upward and reassess her thyroid state clinically and biochemically 6 to 8 weeks later. One would need to be careful not to induce thyrotoxicosis through such an intervention because of the potential morbidity.

The TSH level is typically monitored every 6 to 12 months when the patient is clinically stable. It should be measured sooner in circumstances that include the following:

• Symptoms of hypothyroidism or thyrotoxicosis
• Starting a new medication known to affect thyroid hormone levels
• Significant weight change
• Hospitalization
• Pregnancy.

A 28-year-old woman returns for follow-up of her hypothyroidism. She was diagnosed 4 years ago when she presented with fatigue, “foggy” thinking, poor concentration, cold intolerance, and constipation. Her thyroid-stimulating hormone (TSH) level at that time was elevated at 15 mIU/L (reference range 0.4–4). She was started on 50 µg of levothyroxine daily, which helped her symptoms, but she continued to complain of tiredness and the inability to lose weight. She has been on 100 µg of levothyroxine daily since her last visit 1 year ago.

On examination, she has a small, diffuse, and firm goiter; she has no Cushing-like features, visual field abnormalities, or signs of hypothyroidism.

Her TSH level today is 1.2 mIU/L. Based on this, you recommend no change in her daily levothyroxine dose. She expresses dissatisfaction that you had ordered only a TSH, and she asks you to order thyroxine (T₄) and triiodothyronine (T₃) measurements because she read on the Internet that those were needed to determine the appropriateness of the levothyroxine dose.

Should T₄ or T₃ be routinely measured when adjusting thyroid replacement therapy?

IN PRIMARY HYPOTHYROIDISM, TSH IS ENOUGH

In a patient with primary hypothyroidism and no suspicion of pituitary abnormality, a serum TSH is sufficient for monitoring thyroid status and adjusting the dose of thyroid hormone.

Hypothyroidism is one of the most common endocrine disorders, affecting about 4% of the adult US population.¹ In areas of iodine sufficiency, primary hypothyroidism is due predominantly to Hashimoto thyroiditis.

The role of the lack of thyroid hormone in the pathogenesis of myxedema was recognized in the late 19th century through the observation of a “cretinoid” state occurring in middle-aged women, associated with atrophy of the thyroid gland and a similar severe state noted after total thyroidectomy.²

In 1891, George R. Murray was able to “cure” myxedema in a patient by injecting sheep thyroid extract subcutaneously. Thyroid extracts continued to be the only treatment for hypothyroidism until 1950, when levothyroxine was introduced and later became the main treatment. Around that time, T₃ was discovered and was described as being the physiologically active thyroid hormone. Later, it was noted that 80% to 90% of circulating T₃ is generated through peripheral deiodination of T₄, the latter being considered a prohormone.²

The pituitary-thyroid axis is regulated through negative feedback. At concentrations of free T₄ below normal, plasma TSH rises rapidly with small decrements in T₄ levels.³ The opposite phenomenon occurs with free T₄ concentrations above normal. Since T₄ has a long disappearance half-time—about 7 days—a normal TSH tends to stay relatively stable in the same individual.⁴ The relationship between TSH and T₄ was long thought to be inverse log-linear, but Hadlow et al⁵ found that it is complex and nonlinear and differs by age and sex. TSH and T₄ concentrations have narrower within-individual variability than inter-individual variability. Although environmental factors may affect this hypothalamic-pituitary set-point, there is evidence that heritability is a major determinant of individual variability.⁶

GUIDELINES AND CHOOSING WISELY

In 2014, the American Thyroid Association published comprehensive, evidence-based guidelines for the treatment of hypothyroidism.⁷ The guidelines state that the goal of thyroid hormone replacement is to achieve clinical and biochemical euthyroidism.⁷ TSH continues to be the most reliable marker of adequacy of thyroid hormone replacement in primary hypothyroidism. The guidelines recommend aiming for a TSH in the normal range (generally 0.4–4 mIU/L).

Most studies of the risks associated with hypothyroidism or thyrotoxicosis have looked at TSH levels. Significantly increased risk of cardiovascular mortality and morbidity is seen in individuals with TSH levels higher than 10 mIU/L.⁸ On the other hand, excess thyroid hormone leading to a TSH level lower than 0.1 mIU/L has been associated with an increased risk of atrial fibrillation in older persons and osteoporosis in postmenopausal women.

The classic symptoms and signs of hypothyroidism correlate with biochemical hypothyroidism and usually improve with the restoration of euthyroidism. Some of these symptoms, however, lack sensitivity and specificity, especially with modest degrees of hypothyroidism.⁷ A randomized controlled trial showed that patients were unable to detect any difference in symptoms when the levothyroxine dose was changed by about 20%.⁹

HARMS ASSOCIATED WITH ORDERING T₄ AND T₃

Other than the financial burden to the patient and society, there is no major morbidity caused by obtaining T₄ or T₃ levels, or both. However, knowing the T₄ or T₃ level does not help with management beyond the information offered by the TSH value. Hypothyroid patients treated with levothyroxine to maintain a normal TSH generally have higher free T₄ levels and lower free T₃ levels than euthyroid patients with similar TSH values.¹⁰ Therefore, reacting to a high T₄ level or a low T₃ level in a treated hypothyroid patient with a normal TSH may lead to inappropriate dose adjustment. On the other hand, increasing the dose of thyroid hormone in a patient with a low TSH whose T₃ level is low-normal may lead to morbidity.

SPECIAL SCENARIO: PITUITARY COMPROMISE

We assume that the patient described above has primary hypothyroidism and that her pituitary-thyroid axis is intact. Primary hypothyroidism is diagnosed by a high TSH along with a low or low-normal T₄. In this typical case, TSH can be used to guide therapy without the need for other tests.

However, when there is pituitary compromise (hypopituitarism, congenital central hypothyroidism), the TSH will not be reliable to monitor the adequacy of thyroid hormone replacement therapy. The aim of levothyroxine management in these patients is to maintain a free T₄ concentration in the upper half of the normal range. If the free T₃ concentration is followed and is found to be elevated, the dose of levothyroxine should be reduced.¹¹

CLINICAL BOTTOM LINE

Since our patient’s dose of levothyroxine has been stable and her TSH is not elevated, measuring serum levels of T₄ and T₃ would not contribute to her management. For such a patient, if the TSH were less than 3 mIU/L, increasing the dose would be unlikely to offer clinical benefit.

On the other hand, if her TSH was higher than 4 mIU/L, then it would be legitimate to tweak the dose upward and reassess her thyroid state clinically and biochemically 6 to 8 weeks later. One would need to be careful not to induce thyrotoxicosis through such an intervention because of the potential morbidity.

The TSH level is typically monitored every 6 to 12 months when the patient is clinically stable. It should be measured sooner in circumstances that include the following:

• Symptoms of hypothyroidism or thyrotoxicosis
• Starting a new medication known to affect thyroid hormone levels
• Significant weight change
• Hospitalization
• Pregnancy.

A 28-year-old woman returns for follow-up of her hypothyroidism. She was diagnosed 4 years ago when she presented with fatigue, “foggy” thinking, poor concentration, cold intolerance, and constipation. Her thyroid-stimulating hormone (TSH) level at that time was elevated at 15 mIU/L (reference range 0.4–4). She was started on 50 µg of levothyroxine daily, which helped her symptoms, but she continued to complain of tiredness and the inability to lose weight. She has been on 100 µg of levothyroxine daily since her last visit 1 year ago.

On examination, she has a small, diffuse, and firm goiter; she has no Cushing-like features, visual field abnormalities, or signs of hypothyroidism.

Her TSH level today is 1.2 mIU/L. Based on this, you recommend no change in her daily levothyroxine dose. She expresses dissatisfaction that you had ordered only a TSH, and she asks you to order thyroxine (T₄) and triiodothyronine (T₃) measurements because she read on the Internet that those were needed to determine the appropriateness of the levothyroxine dose.

Should T₄ or T₃ be routinely measured when adjusting thyroid replacement therapy?

IN PRIMARY HYPOTHYROIDISM, TSH IS ENOUGH

In a patient with primary hypothyroidism and no suspicion of pituitary abnormality, a serum TSH is sufficient for monitoring thyroid status and adjusting the dose of thyroid hormone.

Hypothyroidism is one of the most common endocrine disorders, affecting about 4% of the adult US population.¹ In areas of iodine sufficiency, primary hypothyroidism is due predominantly to Hashimoto thyroiditis.

The role of the lack of thyroid hormone in the pathogenesis of myxedema was recognized in the late 19th century through the observation of a “cretinoid” state occurring in middle-aged women, associated with atrophy of the thyroid gland and a similar severe state noted after total thyroidectomy.²

In 1891, George R. Murray was able to “cure” myxedema in a patient by injecting sheep thyroid extract subcutaneously. Thyroid extracts continued to be the only treatment for hypothyroidism until 1950, when levothyroxine was introduced and later became the main treatment. Around that time, T₃ was discovered and was described as being the physiologically active thyroid hormone. Later, it was noted that 80% to 90% of circulating T₃ is generated through peripheral deiodination of T₄, the latter being considered a prohormone.²

The pituitary-thyroid axis is regulated through negative feedback. At concentrations of free T₄ below normal, plasma TSH rises rapidly with small decrements in T₄ levels.³ The opposite phenomenon occurs with free T₄ concentrations above normal. Since T₄ has a long disappearance half-time—about 7 days—a normal TSH tends to stay relatively stable in the same individual.⁴ The relationship between TSH and T₄ was long thought to be inverse log-linear, but Hadlow et al⁵ found that it is complex and nonlinear and differs by age and sex. TSH and T₄ concentrations have narrower within-individual variability than inter-individual variability. Although environmental factors may affect this hypothalamic-pituitary set-point, there is evidence that heritability is a major determinant of individual variability.⁶

GUIDELINES AND CHOOSING WISELY

In 2014, the American Thyroid Association published comprehensive, evidence-based guidelines for the treatment of hypothyroidism.⁷ The guidelines state that the goal of thyroid hormone replacement is to achieve clinical and biochemical euthyroidism.⁷ TSH continues to be the most reliable marker of adequacy of thyroid hormone replacement in primary hypothyroidism. The guidelines recommend aiming for a TSH in the normal range (generally 0.4–4 mIU/L).

Most studies of the risks associated with hypothyroidism or thyrotoxicosis have looked at TSH levels. Significantly increased risk of cardiovascular mortality and morbidity is seen in individuals with TSH levels higher than 10 mIU/L.⁸ On the other hand, excess thyroid hormone leading to a TSH level lower than 0.1 mIU/L has been associated with an increased risk of atrial fibrillation in older persons and osteoporosis in postmenopausal women.

The classic symptoms and signs of hypothyroidism correlate with biochemical hypothyroidism and usually improve with the restoration of euthyroidism. Some of these symptoms, however, lack sensitivity and specificity, especially with modest degrees of hypothyroidism.⁷ A randomized controlled trial showed that patients were unable to detect any difference in symptoms when the levothyroxine dose was changed by about 20%.⁹

HARMS ASSOCIATED WITH ORDERING T₄ AND T₃

Other than the financial burden to the patient and society, there is no major morbidity caused by obtaining T₄ or T₃ levels, or both. However, knowing the T₄ or T₃ level does not help with management beyond the information offered by the TSH value. Hypothyroid patients treated with levothyroxine to maintain a normal TSH generally have higher free T₄ levels and lower free T₃ levels than euthyroid patients with similar TSH values.¹⁰ Therefore, reacting to a high T₄ level or a low T₃ level in a treated hypothyroid patient with a normal TSH may lead to inappropriate dose adjustment. On the other hand, increasing the dose of thyroid hormone in a patient with a low TSH whose T₃ level is low-normal may lead to morbidity.

SPECIAL SCENARIO: PITUITARY COMPROMISE

We assume that the patient described above has primary hypothyroidism and that her pituitary-thyroid axis is intact. Primary hypothyroidism is diagnosed by a high TSH along with a low or low-normal T₄. In this typical case, TSH can be used to guide therapy without the need for other tests.

However, when there is pituitary compromise (hypopituitarism, congenital central hypothyroidism), the TSH will not be reliable to monitor the adequacy of thyroid hormone replacement therapy. The aim of levothyroxine management in these patients is to maintain a free T₄ concentration in the upper half of the normal range. If the free T₃ concentration is followed and is found to be elevated, the dose of levothyroxine should be reduced.¹¹

CLINICAL BOTTOM LINE

Since our patient’s dose of levothyroxine has been stable and her TSH is not elevated, measuring serum levels of T₄ and T₃ would not contribute to her management. For such a patient, if the TSH were less than 3 mIU/L, increasing the dose would be unlikely to offer clinical benefit.

On the other hand, if her TSH was higher than 4 mIU/L, then it would be legitimate to tweak the dose upward and reassess her thyroid state clinically and biochemically 6 to 8 weeks later. One would need to be careful not to induce thyrotoxicosis through such an intervention because of the potential morbidity.

The TSH level is typically monitored every 6 to 12 months when the patient is clinically stable. It should be measured sooner in circumstances that include the following:

• Symptoms of hypothyroidism or thyrotoxicosis
• Starting a new medication known to affect thyroid hormone levels
• Significant weight change
• Hospitalization
• Pregnancy.