In 2012, a task force of the European Society of Cardiology, the American College of Cardiology Foundation, the American Heart Association, and the World Heart Federation released its “third universal definition” of myocardial infarction (MI),¹ replacing the previous (2007) definition. The new consensus definition reflects the increasing sensitivity of available troponin assays, which are commonly elevated in other conditions and after uncomplicated percutaneous coronary intervention or cardiac surgery. With a more appropriate definition of the troponin threshold after these procedures, benign myocardial injury can be differentiated from pathologic MI.

TROPONINS: THE PREFERRED MARKERS

Symptoms of MI such as nausea, chest pain, epigastric discomfort, syncope, and diaphoresis may be nonspecific, and findings on electrocardiography or imaging studies may be nondiagnostic. We thus rely on biomarker elevations to identify patients who need treatment.

Cardiac troponin I and cardiac troponin T have become the preferred markers for detecting MI, as they are more sensitive and tissue-specific than their main competitor, the MB fraction of creatine kinase (CK-MB).² But the newer troponin assays, which are even more sensitive than earlier ones, have raised concerns about their ability to differentiate patients who truly have acute coronary syndromes from those with other causes of troponin elevation. This can have major effects on treatment, patient psyche, and hospital costs.

Troponin elevations can occur in patients with heart failure, end-stage renal disease, sepsis, acute pulmonary embolism, myopericarditis, arrhythmias, and many other conditions. As noted by the task force, these cases of elevated troponin in the absence of clinical supportive evidence should not be labeled as an MI but rather as myocardial injury.

Troponins bind actin and myosin filaments in a trimeric complex composed of troponins I, C, and T. Troponins are present in all muscle cells, but the cardiac isoforms are specific to myocardial tissue.

As a result, both cardiac troponin I and cardiac troponin T, as measured by fourth-generation assays, are highly sensitive (75.2%, 95% confidence interval [CI] 66.8%–83.4%) and specific (94.6%, 95% CI 93.4%–96.3%) for detecting pathologic processes involving the heart.^3,4 Nonetheless, increases in cardiac troponin T (but not I) have been documented in patients with disease of skeletal muscles, likely secondary to re-expressed isoforms of the troponin C gene present in both cardiac and skeletal myocytes.³ There has been no evidence to suggest that either cardiac troponin I nor cardiac troponin T is superior to the other as a marker of MI.

Serum troponin levels detectably rise by 2 to 3 hours after myocardial injury. This temporal pattern is similar to that of CK-MB, which rises at about 2 hours and reaches a peak in 4 to 6 hours. However, troponins are more sensitive than CK-MB during this early time period, since a greater proportion is released from the heart during times of cardiac injury.

The definition of an abnormal troponin value is set by the precision of each individual assay. The task force has designated the optimal precision for troponin assays to be at a coefficient of variation of less than 10% when describing a value exceeding the 99th percentile in a reference population. The 99th percentile, which is the upper reference limit, corresponds to a value near 0.035 μg/L for fourth-generation troponin I and troponin T assays.⁵ Most assays have been adapted to ensure that they meet such criteria.

High-sensitivity assays

Over the past few years, “high-sensitivity” assays have been developed that can detect nanogram levels of troponin.

In one study, an algorithm that incorporated high-sensitivity cardiac troponin T levels was able to rule in or rule out acute MI in 77% of patients with chest pain within 1 hour.⁶ The algorithm had a sensitivity and negative predictive value of 100%.

Other studies have shown a sensitivity of 100.0%, a specificity of 34.0%, and a negative predictive value of 100.0% when using a cardiac troponin T cutoff of 3 ng/L, while a cutoff of 14 ng/L yielded a sensitivity of 85.4%, a specificity of 82.4%, and a negative predictive value of 96.1%.⁴ With cutoffs as low as 3 ng/L, some assays detect elevated troponin in up to 90% of people in normal reference populations without MI.⁷

Physicians thus need to be aware that high-sensitivity troponin assays should mainly be used to rule out acute coronary syndrome, as their high sensitivity substantially compromises their specificity. The appropriate thresholds for various patient populations, the appropriate testing procedures with high-sensitivity assays as compared with the fourth-generation troponin assays (ie, frequency of testing, change in level, and rise), and the cost and clinical outcomes of care based on algorithms that use these values remain unclear and will require further study.^8,9

TYPES OF MYOCARDIAL INFARCTION

The task force defines the following categories of MI (Table 1):

Type 1: Spontaneous myocardial infarction

Type 1, or “spontaneous” MI, is an acute coronary syndrome, colloquially called a “heart attack.” It is primarily the result of rupture, fissuring, erosion, or dissection of atherosclerotic plaque. Most are the result of underlying atherosclerotic coronary artery disease, although some (ie, those caused by coronary dissection) are not.

To diagnose type 1 MI, a blood sample must detect a rise or fall (or both) of cardiac biomarker values (preferably cardiac troponin), with at least one value above the 99th percentile. However, an elevated troponin level is not sufficient. At least one of the following criteria must also be met:

• Symptoms of ischemia
• New ST-segment or T-wave changes or new left bundle branch block
• Development of pathologic Q waves
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality
• Finding of an intracoronary thrombus by angiography or autopsy.

Type 1 MI therapy requires antithrombotic drugs and, with the additional findings, revascularization.

Type 2 MI is caused by a supply-demand imbalance in myocardial perfusion, resulting in ischemic damage. This specifically excludes acute coronary thrombosis, but can result from marked changes in demand or supply (eg, sepsis) or from a combination of acute changes and chronic conditions (eg, tachycardia with baseline coronary artery disease). Baseline stable coronary artery disease, left ventricular hypertrophy, endothelial dysfunction, coronary artery spasm, coronary embolism, arrhythmias, anemia, respiratory failure, hypotension, and hypertension can all contribute to a supply-demand mismatch sufficient to cause permanent myocardial damage.

The criteria for diagnosing type 2 MI are the same as for type 1: both elevated troponin levels and one of the clinical criteria (symptoms of ischemia, electrocardiographic changes, new wall-motion abnormality, or intracoronary thrombus) must be present.

Of importance, unlike those with type 1 MI, most patients with type 2 MI are unlikely to immediately benefit from antithrombotic therapy, as they typically have no acute thrombosis (except in cases of coronary embolism). Therapy should instead be directed at the underlying supply-demand imbalance and may include volume resuscitation, blood pressure support or control, or control of tachyarrhythmias.

In the long term, treatment to resolve or prevent supply-demand imbalances may also include revascularization or antithrombotic drugs, but these may be contraindicated in the acute setting.

Type 3: Sudden cardiac death from MI

The third type of MI occurs when myocardial ischemia results in sudden cardiac death before blood samples can be obtained. Before dying, the patient should have had symptoms suggesting myocardial ischemia and should have had presumed new ischemic electrocardiographic changes or new left bundle branch block.

This definition of MI is not very useful clinically but is important for population-based research studies.

Type 4a: Due to percutaneous coronary intervention

A rise in CK-MB levels after percutaneous coronary intervention has been associated with a higher rate of death or recurrent MI.¹⁰ Previously, type 4 MI was defined as an elevation of cardiac biomarker values (> 3 times the 99th percentile) after percutaneous coronary intervention in a patient who had a normal baseline value (< 99th percentile).¹¹

Unfortunately, using troponin at this threshold, the number of cases is five times higher than when CK-MB is used, without a consistent correlation with the outcomes of death or complications.¹² Currently, the increase in cardiac troponin after percutaneous coronary intervention is best interpreted as a marker of the patient’s atherothrombotic burden more than as a predictor of adverse outcomes.¹³

The updated definition of MI associated with percutaneous coronary intervention now requires an elevation of cardiac troponin values greater than 5 times the 99th percentile in a patient who had normal baseline values or an increase of more than 20% from baseline within 48 hours of the procedure. As this value has been arbitrarily assigned rather than based on an established threshold with clinical outcomes, a true MI must further meet one of the following criteria:

• Symptoms suggesting myocardial ischemia
• New ischemic electrocardiographic changes or new left bundle branch block
• Angiographic loss of patency of a major coronary artery or a side branch or persistent slow-flow or no-flow or embolization
• Imaging evidence of a new loss of viable myocardium or a new wall-motion abnormality.

Given that troponin levels may be elevated in up to 65% of patients after uncomplicated percutaneous coronary intervention and this elevation may be unavoidable,¹⁴ a higher troponin threshold to diagnose MI and the clear requirement of clinical correlates may resonate with physicians as a more appropriate definition. In turn, such guidelines may better identify those with an adverse event, while partly reducing unnecessary hospitalization and observation time in those for whom it is not necessary.

Type 4b: Due to stent thrombosis

Type 4b MI is MI caused by stent thrombosis. The thrombosis must be detected by coronary angiography or autopsy in the setting of myocardial ischemia and a rise or fall of cardiac biomarker values, with at least one value above the 99th percentile.

Type 4c: Due to restenosis

Proposed is the addition of type 4c MI, ie, MI resulting from restenosis of more than 50%, because restenosis after percutaneous coronary intervention can lead to MI without thrombosis.¹⁵

Type 5: After coronary artery bypass grafting

Similar to the situation after percutaneous coronary intervention, increased CK-MB levels after coronary artery bypass graft surgery are associated with poor outcomes.¹⁶ Although some studies have indicated that increased troponin levels within 24 hours of this surgery are associated with higher death rates, no study has established a troponin threshold that correlates with outcomes.¹⁷

The task force acknowledged this lack of prognostic value but arbitrarily defined type 5 MI as requiring biomarker elevations greater than 10 times the 99th percentile during the first 48 hours after surgery, with a normal baseline value. One of the following additional criteria must also be met:

• New pathologic Q waves or new left bundle branch block
• Angiographically documented new occlusion in the graft or native coronary artery
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality.

CHANGES FROM THE 2007 DEFINITIONS

Updates to the definitions of the MI types since the 2007 task force definition can be found in Table 1.

In type 1 and 2 MI, the finding of an intracoronary thrombus by angiography or autopsy was added as one of the possible criteria for evidence of myocardial ischemia.

In type 3 MI, the definition was simplified by deleting the former criterion of finding a fresh thrombus by angiography or autopsy.

In type 4a MI, by requiring clinical correlates, the updated definition in particular moves away from relying solely on troponin levels to diagnose an infarction after percutaneous coronary intervention, as was the case in 2007. Other changes from the 2007 definition: the troponin MI threshold was previously 3 times the 99th percentile, now it is 5 times. Also, if the patient had an elevated baseline value, he or she can now still qualify as having an MI if the level increases by more than 20%.

In type 5 MI, changes to the definition similarly reflect the need to address overly sensitive troponin values when diagnosing an MI after coronary artery bypass grafting. To address such concerns, the required cardiac biomarker values were increased from more than 5 to more than 10 times the 99th percentile.

The task force raised the troponin thresholds for type 4 and type 5 MI in response to evidence showing that troponins are excessively sensitive to minimal myocardial damage during revascularization, and the lack of a troponin threshold that correlates with clinical outcomes.¹² Although higher, these values remain arbitrary, so physicians will need to exercise clinical judgment when deciding whether patients are experiencing benign myocardial injury or rather a true MI after revascularization procedures.

OTHER CONDITIONS THAT RAISE TROPONIN LEVELS

As troponin is a marker not only for MI but also for any form of cardiac injury, its levels are elevated in numerous conditions, such as heart failure, renal failure, and left ventricular hypertrophy. The task force identifies distinct troponin elevations above basal levels as the best indication of new pathology, yet several conditions other than acute coronary syndromes can also cause dynamic changes in troponin levels.

Troponin is a sensitive marker for ruling out MI and has tissue specificity for cardiac injury, but it is not specific for acute coronary syndrome as the cause of such injury. Troponin assays were tested and validated in patients in whom there was a high clinical suspicion of acute coronary syndrome, but when ordered indiscriminately, they have a poor positive predictive value (53%) for this disorder.¹⁸

Physicians must distinguish between acute coronary syndrome and other causes when deciding to give antithrombotics. Table 2 lists common causes of increased troponin other than acute coronary syndrome.

Heart failure

Some patients with acute congestive heart failure have elevated troponin levels. In one study, 6.2% of such patients had troponin I levels of 1 μg/L or higher or troponin T levels of 0.1 μg/L or higher, and these patients had poorer outcomes and more severe symptoms.¹⁹ Levels can also be elevated in patients with chronic heart failure, in whom they correlate with impaired hemodynamics, progressive ventricular dysfunction, and death.²⁰ In an overview of two large trials of patients with chronic congestive heart failure, 86% and 98% tested positive for cardiac troponin using high-sensitivity assays.²¹

Troponin levels can rise from baseline and subsequently fall in congestive heart failure due to small amounts of myocardial injury, which may be very difficult to distinguish from MI based on the similar presenting symptoms of dyspnea and chest pressure.^1,22 The increased troponin levels in chronic congestive heart failure may reflect apoptosis secondary to wall stretch or direct cell toxicity by neurohormones, alcohol, chemotherapy agents, or infiltrative disorders.^23–26

End-stage renal disease

Troponin levels are increased in end-stage renal disease, with 25% to 75% of patients having elevated levels using currently available assays.^27–29 With the advent of high-sensitivity assays, however, cardiac troponin T levels higher than the 99th percentile are found in 100% of patients who have end-stage renal disease without cardiac symptoms.³⁰

Troponin values above the 99th percentile are therefore not diagnostic of MI in this population. Rather, a diagnosis of MI in patients with end-stage renal disease requires clinical signs and symptoms and serial changes in troponin levels from baseline levels. The task force and the National Academy of Clinical Biochemistry recommend requiring an elevation of more than 20% from baseline, representing a change in troponin of more than 3 standard deviations.³¹

Increases in troponin in renal failure are thought to be the result of chronic cardiac structural changes such as coronary artery disease, left ventricular hypertrophy, and elevated left ventricular end-diastolic pressure, rather than decreased clearance.^32,33

In stable patients with end-stage renal disease, those who have high levels of cardiac troponin T have a higher mortality rate.³⁴ Although the mechanism is not completely clear, decreased clearance of uremic toxins may contribute to myocardial damage beyond that of the cardiac structural changes.³⁴

Sepsis

Approximately 50% of patients admitted to an intensive care unit with sepsis without acute coronary syndrome have elevated troponin levels.³⁵

Elevated troponin in sepsis patients has been associated with left ventricular dysfunction, most likely from hemodynamic stress, direct cytotoxicity of bacterial endotoxins, and reperfusion injury.^35,36 Critical illness places high demands on the myocardium, while oxygen supply may be diminished by hypotension, pulmonary edema, and intravascular volume depletion. This supply-demand mismatch is similar to the physiology of type 2 MI, with clinical signs and symptoms of MI potentially being the only differentiating factor.

Elevated troponin levels may represent either reversible or irreversible myocardial injury in patients with sepsis and are a predictor of severe illness and death.³⁷ However, what to do about elevated troponin in patients with sepsis is not clear. When patients are in the intensive care unit with single-organ or multi-organ failure, the diagnosis and treatment of troponin elevations may not take priority.¹ Diagnosing MI is further complicated by the inability of critically ill patients to communicate signs and symptoms. Physicians should also remember that diagnostic testing (electrocardiography, echocardiography) is often necessary to meet the clinical criteria for a type 1 or 2 MI in critically ill patients, and that treatment options may be limited.

Pulmonary embolism

Pulmonary embolism is a leading noncardiac cause of troponin elevation in patients in whom the clinical suspicion of acute coronary syndrome is initially high.³⁸ It is thought that increased troponin levels in patients with pulmonary embolism are caused by increased right ventricular strain secondary to increased pulmonary artery resistance.

The signs and symptoms of MI and of pulmonary embolism overlap, and troponin can be elevated in both conditions, making the initial diagnosis difficult. Electrocardiography and early bedside echocardiography can identify the predominant right-sided dilatation and strain in the heart secondary to pulmonary embolism. Computed tomography should be performed if there is even a moderate clinical suspicion of pulmonary embolism.

The appropriate use of thrombolytics in a normotensive patient with pulmonary embolism remains controversial. The significant risks of hemorrhage need to be balanced with the risk of hemodynamic deterioration. For these patients, the combination of cardiac troponin I measurement and echocardiography provides more prognostic information than each does individually.³⁹ Troponin elevation may therefore be a marker for poor outcomes without aggressive treatment with thrombolytics.

However, single troponin measurements in patients hospitalized early with pulmonary embolism can lead to substantial risk of misdiagnosing them with MI. Although the intensity of the peak is not particularly useful in the setting of pulmonary embolism, two consecutive troponin values 8 hours apart will allow for more appropriate risk stratification for pulmonary embolism patients, who may have a delay between right heart injury and troponin release.⁴⁰

It is reasonable to expect that myocarditis—inflammation of the myocardium—would cause release of troponin from myocytes.⁴¹ Interestingly, however, troponin levels can also be elevated in pericarditis.⁴² The reasons are not clear but have been hypothesized as being caused by nonspecific inflammation during pericarditis that also includes the superficial myocardium—hence, “myopericarditis.”

We have only limited data on the outcomes of patients who have pericarditis with troponin elevation, but troponin levels did correlate with an adverse prognosis in one study.⁴³

Arrhythmias

A number of arrhythmias have been associated with elevated troponin levels. Some studies have shown arrhythmias to be the most common cause of high troponin levels in patients who are not experiencing an acute coronary syndrome.^44,45

The reasons proposed for increased troponins in tachyarrhythmia are similar to those in other conditions of oxygen supply-demand mismatch.⁴⁶ Tachycardia alone may lead to troponin release in the absence of myodepressive factors, inflammatory mediators, or coronary artery disease.⁴⁶

Studies have provided only mixed data as to whether troponin levels predict newonset arrhythmias or recurrence of arrhythmias.^47,48 Nonetheless, elevated troponin (≥ 0.040 μg/L) in patients with atrial fibrillation has independently correlated with increased risk of stroke or systemic embolism, death, and other cardiovascular events. This is clinically important, as troponin elevations higher than these levels adds prognostic information to that given by the CHADS2 stroke score (congestive heart failure, hypertension, age ≥ 75 years diabetes mellitus, and prior stroke or transient ischemic attack) and thus can inform appropriate anticoagulation therapy.⁴⁹

USE OF TROPONIN VALUES

Troponins are highly sensitive assays with high tissue specificity for myocardial injury, but levels can be elevated in non-MI conditions and in MIs other than type 1. As with any diagnostic test applied to a population with a low prevalence of the disease, troponin elevation has a low positive predictive value—53% for acute coronary syndrome.¹⁸

Unfortunately, in clinical practice, troponins are measured in up to 50% of admitted patients, a small proportion of whom have clinical signs or symptoms of MI.⁵⁰ Often, clinicians are left with a positive troponin of unknown significance, potentially leading to unnecessary diagnostic testing that detracts from the primary diagnosis.

Dynamic changes in troponin values (eg, a change of more than 20% in a patient with end-stage renal disease) are helpful in distinguishing acute from chronic causes of troponin elevation. However, such changes can also occur with acute or chronic congestive heart failure, tachycardia, hypotension, or other conditions other than acute coronary syndrome.

The absolute numerical value of troponin can help assess the significance of troponin elevation. In most non-MI and non-acute coronary syndrome causes of troponin elevation, the troponin level tends to be lower than 1 μg/mL (Figure 1). Occasional exceptions occur, especially when multiple conditions coexist (end-stage renal disease and congestive heart failure, for example). In contrast, most patients with acute coronary syndromes have either clear symptoms or electrocardiographic changes consistent with MI and a troponin that rises above 0.5 μg/mL.

The task force discourages the use of secondary thresholds for MI, as there is no level of troponin that is considered benign. While any troponin elevation carries a negative prognosis, such prognostic knowledge may not be particularly helpful in deciding whether to anticoagulate patients or attempt revascularization procedures.

We thus recommend using a threshold higher than the 99th percentile to distinguish acute coronary syndromes from other causes of troponin elevations. The particular threshold for decision-making should vary, depending on how strongly one clinically suspects an acute coronary syndrome. For instance, a cardiac troponin I level of 0.2 μg/mL in an otherwise healthy patient with chest pain and ST-segment depression is more than sufficient to diagnose acute coronary syndrome. In contrast, an end-stage renal disease patient with hypertensive cardiomyopathy who presents only with nausea should have a level markedly higher than his or her baseline value (and likely > 0.8 μg/mL) before acute coronary syndrome should be diagnosed.

CK-MB’S ROLE IN THE TROPONIN ERA

Some proponents of troponin assays, including those on the task force, have suggested that CK-MB may no longer be necessary in the evaluation of acute MI.⁵¹ In the past, CK-MB had more research supporting its use in quantifying myocardial damage and in diagnosing reinfarction, but some data suggest that troponin may be equally useful for these applications.^52,53

These comments aside, CK-MB measurements are still widely ordered with troponin, a probable response to the clinical difficulty of determining the cause and significance of troponin elevations. Although likely less common with recent assays, a small subgroup of patients with acute coronary syndrome will be CK-MB–positive and troponin-negative and at higher risk of morbidity and death than those who are troponin- and CK-MB–negative.^54,55

Troponin levels are elevated in many chronic conditions, whereas CK-MB levels may be unaffected or less affected. In some cases, such as congestive heart failure or renal failure, troponins may be both chronically elevated and more than 20% higher than at baseline. In a clinical context in which a false-positive troponin assay is likely, the addition of a CK-MB assay may help determine if a rise (and possibly a subsequent fall) in the troponin level represents true MI. More importantly, deciding on antithrombotic therapy or revascularization is often based on whether a patient has acute coronary syndrome, rather than a small MI from demand ischemia. CK-MB may thus serve as a less sensitive but more specific marker for the larger amount of myocardial damage that one might expect from an acute coronary syndrome.

CK-MB testing also may help determine the acuity of an acute coronary syndrome for patients with known causes of increased troponin. A negative CK-MB value in the presence of a troponin value elevated above baseline could indicate an event a few days prior.

Finally, the approach of ordering both troponin and CK-MB may be particularly helpful in diagnosing type 4 and 5 MIs, as current guidelines suggest that more research is needed to determine whether current troponin thresholds lead to clinical outcomes.

CLINICAL JUDGMENT IS NECESSARY

The updated definition raises the biomarker threshold required to diagnose MI after revascularization procedures and reemphasizes the need to look for other signs of infarction. This change reflects the sometimes excessive sensitivity of troponin assays for minimal and often unavoidable myocardial damage that occurs in numerous conditions.

With sensitive troponin assays, clinical judgment is essential for separating true MI from myocardial injury, and acute coronary syndrome from demand ischemia. Clinicians will now be forced to be cognizant of their suspicion for acute coronary syndrome in the presence of multiple noncoronary causes of increased troponin with little practical guideline guidance. In settings in which troponin elevation is expected (eg, congestive heart failure, end-stage renal failure, shock), a higher cardiac troponin threshold or CK-MB may be useful as a less sensitive but more specific marker of significant myocardial damage requiring aggressive treatment.

In 2012, a task force of the European Society of Cardiology, the American College of Cardiology Foundation, the American Heart Association, and the World Heart Federation released its “third universal definition” of myocardial infarction (MI),¹ replacing the previous (2007) definition. The new consensus definition reflects the increasing sensitivity of available troponin assays, which are commonly elevated in other conditions and after uncomplicated percutaneous coronary intervention or cardiac surgery. With a more appropriate definition of the troponin threshold after these procedures, benign myocardial injury can be differentiated from pathologic MI.

TROPONINS: THE PREFERRED MARKERS

Symptoms of MI such as nausea, chest pain, epigastric discomfort, syncope, and diaphoresis may be nonspecific, and findings on electrocardiography or imaging studies may be nondiagnostic. We thus rely on biomarker elevations to identify patients who need treatment.

Cardiac troponin I and cardiac troponin T have become the preferred markers for detecting MI, as they are more sensitive and tissue-specific than their main competitor, the MB fraction of creatine kinase (CK-MB).² But the newer troponin assays, which are even more sensitive than earlier ones, have raised concerns about their ability to differentiate patients who truly have acute coronary syndromes from those with other causes of troponin elevation. This can have major effects on treatment, patient psyche, and hospital costs.

Troponin elevations can occur in patients with heart failure, end-stage renal disease, sepsis, acute pulmonary embolism, myopericarditis, arrhythmias, and many other conditions. As noted by the task force, these cases of elevated troponin in the absence of clinical supportive evidence should not be labeled as an MI but rather as myocardial injury.

Troponins bind actin and myosin filaments in a trimeric complex composed of troponins I, C, and T. Troponins are present in all muscle cells, but the cardiac isoforms are specific to myocardial tissue.

As a result, both cardiac troponin I and cardiac troponin T, as measured by fourth-generation assays, are highly sensitive (75.2%, 95% confidence interval [CI] 66.8%–83.4%) and specific (94.6%, 95% CI 93.4%–96.3%) for detecting pathologic processes involving the heart.^3,4 Nonetheless, increases in cardiac troponin T (but not I) have been documented in patients with disease of skeletal muscles, likely secondary to re-expressed isoforms of the troponin C gene present in both cardiac and skeletal myocytes.³ There has been no evidence to suggest that either cardiac troponin I nor cardiac troponin T is superior to the other as a marker of MI.

Serum troponin levels detectably rise by 2 to 3 hours after myocardial injury. This temporal pattern is similar to that of CK-MB, which rises at about 2 hours and reaches a peak in 4 to 6 hours. However, troponins are more sensitive than CK-MB during this early time period, since a greater proportion is released from the heart during times of cardiac injury.

The definition of an abnormal troponin value is set by the precision of each individual assay. The task force has designated the optimal precision for troponin assays to be at a coefficient of variation of less than 10% when describing a value exceeding the 99th percentile in a reference population. The 99th percentile, which is the upper reference limit, corresponds to a value near 0.035 μg/L for fourth-generation troponin I and troponin T assays.⁵ Most assays have been adapted to ensure that they meet such criteria.

High-sensitivity assays

Over the past few years, “high-sensitivity” assays have been developed that can detect nanogram levels of troponin.

In one study, an algorithm that incorporated high-sensitivity cardiac troponin T levels was able to rule in or rule out acute MI in 77% of patients with chest pain within 1 hour.⁶ The algorithm had a sensitivity and negative predictive value of 100%.

Other studies have shown a sensitivity of 100.0%, a specificity of 34.0%, and a negative predictive value of 100.0% when using a cardiac troponin T cutoff of 3 ng/L, while a cutoff of 14 ng/L yielded a sensitivity of 85.4%, a specificity of 82.4%, and a negative predictive value of 96.1%.⁴ With cutoffs as low as 3 ng/L, some assays detect elevated troponin in up to 90% of people in normal reference populations without MI.⁷

Physicians thus need to be aware that high-sensitivity troponin assays should mainly be used to rule out acute coronary syndrome, as their high sensitivity substantially compromises their specificity. The appropriate thresholds for various patient populations, the appropriate testing procedures with high-sensitivity assays as compared with the fourth-generation troponin assays (ie, frequency of testing, change in level, and rise), and the cost and clinical outcomes of care based on algorithms that use these values remain unclear and will require further study.^8,9

TYPES OF MYOCARDIAL INFARCTION

The task force defines the following categories of MI (Table 1):

Type 1: Spontaneous myocardial infarction

Type 1, or “spontaneous” MI, is an acute coronary syndrome, colloquially called a “heart attack.” It is primarily the result of rupture, fissuring, erosion, or dissection of atherosclerotic plaque. Most are the result of underlying atherosclerotic coronary artery disease, although some (ie, those caused by coronary dissection) are not.

To diagnose type 1 MI, a blood sample must detect a rise or fall (or both) of cardiac biomarker values (preferably cardiac troponin), with at least one value above the 99th percentile. However, an elevated troponin level is not sufficient. At least one of the following criteria must also be met:

• Symptoms of ischemia
• New ST-segment or T-wave changes or new left bundle branch block
• Development of pathologic Q waves
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality
• Finding of an intracoronary thrombus by angiography or autopsy.

Type 1 MI therapy requires antithrombotic drugs and, with the additional findings, revascularization.

Type 2 MI is caused by a supply-demand imbalance in myocardial perfusion, resulting in ischemic damage. This specifically excludes acute coronary thrombosis, but can result from marked changes in demand or supply (eg, sepsis) or from a combination of acute changes and chronic conditions (eg, tachycardia with baseline coronary artery disease). Baseline stable coronary artery disease, left ventricular hypertrophy, endothelial dysfunction, coronary artery spasm, coronary embolism, arrhythmias, anemia, respiratory failure, hypotension, and hypertension can all contribute to a supply-demand mismatch sufficient to cause permanent myocardial damage.

The criteria for diagnosing type 2 MI are the same as for type 1: both elevated troponin levels and one of the clinical criteria (symptoms of ischemia, electrocardiographic changes, new wall-motion abnormality, or intracoronary thrombus) must be present.

Of importance, unlike those with type 1 MI, most patients with type 2 MI are unlikely to immediately benefit from antithrombotic therapy, as they typically have no acute thrombosis (except in cases of coronary embolism). Therapy should instead be directed at the underlying supply-demand imbalance and may include volume resuscitation, blood pressure support or control, or control of tachyarrhythmias.

In the long term, treatment to resolve or prevent supply-demand imbalances may also include revascularization or antithrombotic drugs, but these may be contraindicated in the acute setting.

Type 3: Sudden cardiac death from MI

The third type of MI occurs when myocardial ischemia results in sudden cardiac death before blood samples can be obtained. Before dying, the patient should have had symptoms suggesting myocardial ischemia and should have had presumed new ischemic electrocardiographic changes or new left bundle branch block.

This definition of MI is not very useful clinically but is important for population-based research studies.

Type 4a: Due to percutaneous coronary intervention

A rise in CK-MB levels after percutaneous coronary intervention has been associated with a higher rate of death or recurrent MI.¹⁰ Previously, type 4 MI was defined as an elevation of cardiac biomarker values (> 3 times the 99th percentile) after percutaneous coronary intervention in a patient who had a normal baseline value (< 99th percentile).¹¹

Unfortunately, using troponin at this threshold, the number of cases is five times higher than when CK-MB is used, without a consistent correlation with the outcomes of death or complications.¹² Currently, the increase in cardiac troponin after percutaneous coronary intervention is best interpreted as a marker of the patient’s atherothrombotic burden more than as a predictor of adverse outcomes.¹³

The updated definition of MI associated with percutaneous coronary intervention now requires an elevation of cardiac troponin values greater than 5 times the 99th percentile in a patient who had normal baseline values or an increase of more than 20% from baseline within 48 hours of the procedure. As this value has been arbitrarily assigned rather than based on an established threshold with clinical outcomes, a true MI must further meet one of the following criteria:

• Symptoms suggesting myocardial ischemia
• New ischemic electrocardiographic changes or new left bundle branch block
• Angiographic loss of patency of a major coronary artery or a side branch or persistent slow-flow or no-flow or embolization
• Imaging evidence of a new loss of viable myocardium or a new wall-motion abnormality.

Given that troponin levels may be elevated in up to 65% of patients after uncomplicated percutaneous coronary intervention and this elevation may be unavoidable,¹⁴ a higher troponin threshold to diagnose MI and the clear requirement of clinical correlates may resonate with physicians as a more appropriate definition. In turn, such guidelines may better identify those with an adverse event, while partly reducing unnecessary hospitalization and observation time in those for whom it is not necessary.

Type 4b: Due to stent thrombosis

Type 4b MI is MI caused by stent thrombosis. The thrombosis must be detected by coronary angiography or autopsy in the setting of myocardial ischemia and a rise or fall of cardiac biomarker values, with at least one value above the 99th percentile.

Type 4c: Due to restenosis

Proposed is the addition of type 4c MI, ie, MI resulting from restenosis of more than 50%, because restenosis after percutaneous coronary intervention can lead to MI without thrombosis.¹⁵

Type 5: After coronary artery bypass grafting

Similar to the situation after percutaneous coronary intervention, increased CK-MB levels after coronary artery bypass graft surgery are associated with poor outcomes.¹⁶ Although some studies have indicated that increased troponin levels within 24 hours of this surgery are associated with higher death rates, no study has established a troponin threshold that correlates with outcomes.¹⁷

The task force acknowledged this lack of prognostic value but arbitrarily defined type 5 MI as requiring biomarker elevations greater than 10 times the 99th percentile during the first 48 hours after surgery, with a normal baseline value. One of the following additional criteria must also be met:

• New pathologic Q waves or new left bundle branch block
• Angiographically documented new occlusion in the graft or native coronary artery
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality.

CHANGES FROM THE 2007 DEFINITIONS

Updates to the definitions of the MI types since the 2007 task force definition can be found in Table 1.

In type 1 and 2 MI, the finding of an intracoronary thrombus by angiography or autopsy was added as one of the possible criteria for evidence of myocardial ischemia.

In type 3 MI, the definition was simplified by deleting the former criterion of finding a fresh thrombus by angiography or autopsy.

In type 4a MI, by requiring clinical correlates, the updated definition in particular moves away from relying solely on troponin levels to diagnose an infarction after percutaneous coronary intervention, as was the case in 2007. Other changes from the 2007 definition: the troponin MI threshold was previously 3 times the 99th percentile, now it is 5 times. Also, if the patient had an elevated baseline value, he or she can now still qualify as having an MI if the level increases by more than 20%.

In type 5 MI, changes to the definition similarly reflect the need to address overly sensitive troponin values when diagnosing an MI after coronary artery bypass grafting. To address such concerns, the required cardiac biomarker values were increased from more than 5 to more than 10 times the 99th percentile.

The task force raised the troponin thresholds for type 4 and type 5 MI in response to evidence showing that troponins are excessively sensitive to minimal myocardial damage during revascularization, and the lack of a troponin threshold that correlates with clinical outcomes.¹² Although higher, these values remain arbitrary, so physicians will need to exercise clinical judgment when deciding whether patients are experiencing benign myocardial injury or rather a true MI after revascularization procedures.

OTHER CONDITIONS THAT RAISE TROPONIN LEVELS

As troponin is a marker not only for MI but also for any form of cardiac injury, its levels are elevated in numerous conditions, such as heart failure, renal failure, and left ventricular hypertrophy. The task force identifies distinct troponin elevations above basal levels as the best indication of new pathology, yet several conditions other than acute coronary syndromes can also cause dynamic changes in troponin levels.

Troponin is a sensitive marker for ruling out MI and has tissue specificity for cardiac injury, but it is not specific for acute coronary syndrome as the cause of such injury. Troponin assays were tested and validated in patients in whom there was a high clinical suspicion of acute coronary syndrome, but when ordered indiscriminately, they have a poor positive predictive value (53%) for this disorder.¹⁸

Physicians must distinguish between acute coronary syndrome and other causes when deciding to give antithrombotics. Table 2 lists common causes of increased troponin other than acute coronary syndrome.

Heart failure

Some patients with acute congestive heart failure have elevated troponin levels. In one study, 6.2% of such patients had troponin I levels of 1 μg/L or higher or troponin T levels of 0.1 μg/L or higher, and these patients had poorer outcomes and more severe symptoms.¹⁹ Levels can also be elevated in patients with chronic heart failure, in whom they correlate with impaired hemodynamics, progressive ventricular dysfunction, and death.²⁰ In an overview of two large trials of patients with chronic congestive heart failure, 86% and 98% tested positive for cardiac troponin using high-sensitivity assays.²¹

Troponin levels can rise from baseline and subsequently fall in congestive heart failure due to small amounts of myocardial injury, which may be very difficult to distinguish from MI based on the similar presenting symptoms of dyspnea and chest pressure.^1,22 The increased troponin levels in chronic congestive heart failure may reflect apoptosis secondary to wall stretch or direct cell toxicity by neurohormones, alcohol, chemotherapy agents, or infiltrative disorders.^23–26

End-stage renal disease

Troponin levels are increased in end-stage renal disease, with 25% to 75% of patients having elevated levels using currently available assays.^27–29 With the advent of high-sensitivity assays, however, cardiac troponin T levels higher than the 99th percentile are found in 100% of patients who have end-stage renal disease without cardiac symptoms.³⁰

Troponin values above the 99th percentile are therefore not diagnostic of MI in this population. Rather, a diagnosis of MI in patients with end-stage renal disease requires clinical signs and symptoms and serial changes in troponin levels from baseline levels. The task force and the National Academy of Clinical Biochemistry recommend requiring an elevation of more than 20% from baseline, representing a change in troponin of more than 3 standard deviations.³¹

Increases in troponin in renal failure are thought to be the result of chronic cardiac structural changes such as coronary artery disease, left ventricular hypertrophy, and elevated left ventricular end-diastolic pressure, rather than decreased clearance.^32,33

In stable patients with end-stage renal disease, those who have high levels of cardiac troponin T have a higher mortality rate.³⁴ Although the mechanism is not completely clear, decreased clearance of uremic toxins may contribute to myocardial damage beyond that of the cardiac structural changes.³⁴

Sepsis

Approximately 50% of patients admitted to an intensive care unit with sepsis without acute coronary syndrome have elevated troponin levels.³⁵

Elevated troponin in sepsis patients has been associated with left ventricular dysfunction, most likely from hemodynamic stress, direct cytotoxicity of bacterial endotoxins, and reperfusion injury.^35,36 Critical illness places high demands on the myocardium, while oxygen supply may be diminished by hypotension, pulmonary edema, and intravascular volume depletion. This supply-demand mismatch is similar to the physiology of type 2 MI, with clinical signs and symptoms of MI potentially being the only differentiating factor.

Elevated troponin levels may represent either reversible or irreversible myocardial injury in patients with sepsis and are a predictor of severe illness and death.³⁷ However, what to do about elevated troponin in patients with sepsis is not clear. When patients are in the intensive care unit with single-organ or multi-organ failure, the diagnosis and treatment of troponin elevations may not take priority.¹ Diagnosing MI is further complicated by the inability of critically ill patients to communicate signs and symptoms. Physicians should also remember that diagnostic testing (electrocardiography, echocardiography) is often necessary to meet the clinical criteria for a type 1 or 2 MI in critically ill patients, and that treatment options may be limited.

Pulmonary embolism

Pulmonary embolism is a leading noncardiac cause of troponin elevation in patients in whom the clinical suspicion of acute coronary syndrome is initially high.³⁸ It is thought that increased troponin levels in patients with pulmonary embolism are caused by increased right ventricular strain secondary to increased pulmonary artery resistance.

The signs and symptoms of MI and of pulmonary embolism overlap, and troponin can be elevated in both conditions, making the initial diagnosis difficult. Electrocardiography and early bedside echocardiography can identify the predominant right-sided dilatation and strain in the heart secondary to pulmonary embolism. Computed tomography should be performed if there is even a moderate clinical suspicion of pulmonary embolism.

The appropriate use of thrombolytics in a normotensive patient with pulmonary embolism remains controversial. The significant risks of hemorrhage need to be balanced with the risk of hemodynamic deterioration. For these patients, the combination of cardiac troponin I measurement and echocardiography provides more prognostic information than each does individually.³⁹ Troponin elevation may therefore be a marker for poor outcomes without aggressive treatment with thrombolytics.

However, single troponin measurements in patients hospitalized early with pulmonary embolism can lead to substantial risk of misdiagnosing them with MI. Although the intensity of the peak is not particularly useful in the setting of pulmonary embolism, two consecutive troponin values 8 hours apart will allow for more appropriate risk stratification for pulmonary embolism patients, who may have a delay between right heart injury and troponin release.⁴⁰

It is reasonable to expect that myocarditis—inflammation of the myocardium—would cause release of troponin from myocytes.⁴¹ Interestingly, however, troponin levels can also be elevated in pericarditis.⁴² The reasons are not clear but have been hypothesized as being caused by nonspecific inflammation during pericarditis that also includes the superficial myocardium—hence, “myopericarditis.”

We have only limited data on the outcomes of patients who have pericarditis with troponin elevation, but troponin levels did correlate with an adverse prognosis in one study.⁴³

Arrhythmias

A number of arrhythmias have been associated with elevated troponin levels. Some studies have shown arrhythmias to be the most common cause of high troponin levels in patients who are not experiencing an acute coronary syndrome.^44,45

The reasons proposed for increased troponins in tachyarrhythmia are similar to those in other conditions of oxygen supply-demand mismatch.⁴⁶ Tachycardia alone may lead to troponin release in the absence of myodepressive factors, inflammatory mediators, or coronary artery disease.⁴⁶

Studies have provided only mixed data as to whether troponin levels predict newonset arrhythmias or recurrence of arrhythmias.^47,48 Nonetheless, elevated troponin (≥ 0.040 μg/L) in patients with atrial fibrillation has independently correlated with increased risk of stroke or systemic embolism, death, and other cardiovascular events. This is clinically important, as troponin elevations higher than these levels adds prognostic information to that given by the CHADS2 stroke score (congestive heart failure, hypertension, age ≥ 75 years diabetes mellitus, and prior stroke or transient ischemic attack) and thus can inform appropriate anticoagulation therapy.⁴⁹

USE OF TROPONIN VALUES

Troponins are highly sensitive assays with high tissue specificity for myocardial injury, but levels can be elevated in non-MI conditions and in MIs other than type 1. As with any diagnostic test applied to a population with a low prevalence of the disease, troponin elevation has a low positive predictive value—53% for acute coronary syndrome.¹⁸

Unfortunately, in clinical practice, troponins are measured in up to 50% of admitted patients, a small proportion of whom have clinical signs or symptoms of MI.⁵⁰ Often, clinicians are left with a positive troponin of unknown significance, potentially leading to unnecessary diagnostic testing that detracts from the primary diagnosis.

Dynamic changes in troponin values (eg, a change of more than 20% in a patient with end-stage renal disease) are helpful in distinguishing acute from chronic causes of troponin elevation. However, such changes can also occur with acute or chronic congestive heart failure, tachycardia, hypotension, or other conditions other than acute coronary syndrome.

The absolute numerical value of troponin can help assess the significance of troponin elevation. In most non-MI and non-acute coronary syndrome causes of troponin elevation, the troponin level tends to be lower than 1 μg/mL (Figure 1). Occasional exceptions occur, especially when multiple conditions coexist (end-stage renal disease and congestive heart failure, for example). In contrast, most patients with acute coronary syndromes have either clear symptoms or electrocardiographic changes consistent with MI and a troponin that rises above 0.5 μg/mL.

The task force discourages the use of secondary thresholds for MI, as there is no level of troponin that is considered benign. While any troponin elevation carries a negative prognosis, such prognostic knowledge may not be particularly helpful in deciding whether to anticoagulate patients or attempt revascularization procedures.

We thus recommend using a threshold higher than the 99th percentile to distinguish acute coronary syndromes from other causes of troponin elevations. The particular threshold for decision-making should vary, depending on how strongly one clinically suspects an acute coronary syndrome. For instance, a cardiac troponin I level of 0.2 μg/mL in an otherwise healthy patient with chest pain and ST-segment depression is more than sufficient to diagnose acute coronary syndrome. In contrast, an end-stage renal disease patient with hypertensive cardiomyopathy who presents only with nausea should have a level markedly higher than his or her baseline value (and likely > 0.8 μg/mL) before acute coronary syndrome should be diagnosed.

CK-MB’S ROLE IN THE TROPONIN ERA

Some proponents of troponin assays, including those on the task force, have suggested that CK-MB may no longer be necessary in the evaluation of acute MI.⁵¹ In the past, CK-MB had more research supporting its use in quantifying myocardial damage and in diagnosing reinfarction, but some data suggest that troponin may be equally useful for these applications.^52,53

These comments aside, CK-MB measurements are still widely ordered with troponin, a probable response to the clinical difficulty of determining the cause and significance of troponin elevations. Although likely less common with recent assays, a small subgroup of patients with acute coronary syndrome will be CK-MB–positive and troponin-negative and at higher risk of morbidity and death than those who are troponin- and CK-MB–negative.^54,55

Troponin levels are elevated in many chronic conditions, whereas CK-MB levels may be unaffected or less affected. In some cases, such as congestive heart failure or renal failure, troponins may be both chronically elevated and more than 20% higher than at baseline. In a clinical context in which a false-positive troponin assay is likely, the addition of a CK-MB assay may help determine if a rise (and possibly a subsequent fall) in the troponin level represents true MI. More importantly, deciding on antithrombotic therapy or revascularization is often based on whether a patient has acute coronary syndrome, rather than a small MI from demand ischemia. CK-MB may thus serve as a less sensitive but more specific marker for the larger amount of myocardial damage that one might expect from an acute coronary syndrome.

CK-MB testing also may help determine the acuity of an acute coronary syndrome for patients with known causes of increased troponin. A negative CK-MB value in the presence of a troponin value elevated above baseline could indicate an event a few days prior.

Finally, the approach of ordering both troponin and CK-MB may be particularly helpful in diagnosing type 4 and 5 MIs, as current guidelines suggest that more research is needed to determine whether current troponin thresholds lead to clinical outcomes.

CLINICAL JUDGMENT IS NECESSARY

The updated definition raises the biomarker threshold required to diagnose MI after revascularization procedures and reemphasizes the need to look for other signs of infarction. This change reflects the sometimes excessive sensitivity of troponin assays for minimal and often unavoidable myocardial damage that occurs in numerous conditions.

With sensitive troponin assays, clinical judgment is essential for separating true MI from myocardial injury, and acute coronary syndrome from demand ischemia. Clinicians will now be forced to be cognizant of their suspicion for acute coronary syndrome in the presence of multiple noncoronary causes of increased troponin with little practical guideline guidance. In settings in which troponin elevation is expected (eg, congestive heart failure, end-stage renal failure, shock), a higher cardiac troponin threshold or CK-MB may be useful as a less sensitive but more specific marker of significant myocardial damage requiring aggressive treatment.

In 2012, a task force of the European Society of Cardiology, the American College of Cardiology Foundation, the American Heart Association, and the World Heart Federation released its “third universal definition” of myocardial infarction (MI),¹ replacing the previous (2007) definition. The new consensus definition reflects the increasing sensitivity of available troponin assays, which are commonly elevated in other conditions and after uncomplicated percutaneous coronary intervention or cardiac surgery. With a more appropriate definition of the troponin threshold after these procedures, benign myocardial injury can be differentiated from pathologic MI.

TROPONINS: THE PREFERRED MARKERS

Symptoms of MI such as nausea, chest pain, epigastric discomfort, syncope, and diaphoresis may be nonspecific, and findings on electrocardiography or imaging studies may be nondiagnostic. We thus rely on biomarker elevations to identify patients who need treatment.

Cardiac troponin I and cardiac troponin T have become the preferred markers for detecting MI, as they are more sensitive and tissue-specific than their main competitor, the MB fraction of creatine kinase (CK-MB).² But the newer troponin assays, which are even more sensitive than earlier ones, have raised concerns about their ability to differentiate patients who truly have acute coronary syndromes from those with other causes of troponin elevation. This can have major effects on treatment, patient psyche, and hospital costs.

Troponin elevations can occur in patients with heart failure, end-stage renal disease, sepsis, acute pulmonary embolism, myopericarditis, arrhythmias, and many other conditions. As noted by the task force, these cases of elevated troponin in the absence of clinical supportive evidence should not be labeled as an MI but rather as myocardial injury.

Troponins bind actin and myosin filaments in a trimeric complex composed of troponins I, C, and T. Troponins are present in all muscle cells, but the cardiac isoforms are specific to myocardial tissue.

As a result, both cardiac troponin I and cardiac troponin T, as measured by fourth-generation assays, are highly sensitive (75.2%, 95% confidence interval [CI] 66.8%–83.4%) and specific (94.6%, 95% CI 93.4%–96.3%) for detecting pathologic processes involving the heart.^3,4 Nonetheless, increases in cardiac troponin T (but not I) have been documented in patients with disease of skeletal muscles, likely secondary to re-expressed isoforms of the troponin C gene present in both cardiac and skeletal myocytes.³ There has been no evidence to suggest that either cardiac troponin I nor cardiac troponin T is superior to the other as a marker of MI.

Serum troponin levels detectably rise by 2 to 3 hours after myocardial injury. This temporal pattern is similar to that of CK-MB, which rises at about 2 hours and reaches a peak in 4 to 6 hours. However, troponins are more sensitive than CK-MB during this early time period, since a greater proportion is released from the heart during times of cardiac injury.

The definition of an abnormal troponin value is set by the precision of each individual assay. The task force has designated the optimal precision for troponin assays to be at a coefficient of variation of less than 10% when describing a value exceeding the 99th percentile in a reference population. The 99th percentile, which is the upper reference limit, corresponds to a value near 0.035 μg/L for fourth-generation troponin I and troponin T assays.⁵ Most assays have been adapted to ensure that they meet such criteria.

High-sensitivity assays

Over the past few years, “high-sensitivity” assays have been developed that can detect nanogram levels of troponin.

In one study, an algorithm that incorporated high-sensitivity cardiac troponin T levels was able to rule in or rule out acute MI in 77% of patients with chest pain within 1 hour.⁶ The algorithm had a sensitivity and negative predictive value of 100%.

Other studies have shown a sensitivity of 100.0%, a specificity of 34.0%, and a negative predictive value of 100.0% when using a cardiac troponin T cutoff of 3 ng/L, while a cutoff of 14 ng/L yielded a sensitivity of 85.4%, a specificity of 82.4%, and a negative predictive value of 96.1%.⁴ With cutoffs as low as 3 ng/L, some assays detect elevated troponin in up to 90% of people in normal reference populations without MI.⁷

Physicians thus need to be aware that high-sensitivity troponin assays should mainly be used to rule out acute coronary syndrome, as their high sensitivity substantially compromises their specificity. The appropriate thresholds for various patient populations, the appropriate testing procedures with high-sensitivity assays as compared with the fourth-generation troponin assays (ie, frequency of testing, change in level, and rise), and the cost and clinical outcomes of care based on algorithms that use these values remain unclear and will require further study.^8,9

TYPES OF MYOCARDIAL INFARCTION

The task force defines the following categories of MI (Table 1):

Type 1: Spontaneous myocardial infarction

Type 1, or “spontaneous” MI, is an acute coronary syndrome, colloquially called a “heart attack.” It is primarily the result of rupture, fissuring, erosion, or dissection of atherosclerotic plaque. Most are the result of underlying atherosclerotic coronary artery disease, although some (ie, those caused by coronary dissection) are not.

To diagnose type 1 MI, a blood sample must detect a rise or fall (or both) of cardiac biomarker values (preferably cardiac troponin), with at least one value above the 99th percentile. However, an elevated troponin level is not sufficient. At least one of the following criteria must also be met:

• Symptoms of ischemia
• New ST-segment or T-wave changes or new left bundle branch block
• Development of pathologic Q waves
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality
• Finding of an intracoronary thrombus by angiography or autopsy.

Type 1 MI therapy requires antithrombotic drugs and, with the additional findings, revascularization.

Type 2 MI is caused by a supply-demand imbalance in myocardial perfusion, resulting in ischemic damage. This specifically excludes acute coronary thrombosis, but can result from marked changes in demand or supply (eg, sepsis) or from a combination of acute changes and chronic conditions (eg, tachycardia with baseline coronary artery disease). Baseline stable coronary artery disease, left ventricular hypertrophy, endothelial dysfunction, coronary artery spasm, coronary embolism, arrhythmias, anemia, respiratory failure, hypotension, and hypertension can all contribute to a supply-demand mismatch sufficient to cause permanent myocardial damage.

The criteria for diagnosing type 2 MI are the same as for type 1: both elevated troponin levels and one of the clinical criteria (symptoms of ischemia, electrocardiographic changes, new wall-motion abnormality, or intracoronary thrombus) must be present.

Of importance, unlike those with type 1 MI, most patients with type 2 MI are unlikely to immediately benefit from antithrombotic therapy, as they typically have no acute thrombosis (except in cases of coronary embolism). Therapy should instead be directed at the underlying supply-demand imbalance and may include volume resuscitation, blood pressure support or control, or control of tachyarrhythmias.

In the long term, treatment to resolve or prevent supply-demand imbalances may also include revascularization or antithrombotic drugs, but these may be contraindicated in the acute setting.

Type 3: Sudden cardiac death from MI

The third type of MI occurs when myocardial ischemia results in sudden cardiac death before blood samples can be obtained. Before dying, the patient should have had symptoms suggesting myocardial ischemia and should have had presumed new ischemic electrocardiographic changes or new left bundle branch block.

This definition of MI is not very useful clinically but is important for population-based research studies.

Type 4a: Due to percutaneous coronary intervention

A rise in CK-MB levels after percutaneous coronary intervention has been associated with a higher rate of death or recurrent MI.¹⁰ Previously, type 4 MI was defined as an elevation of cardiac biomarker values (> 3 times the 99th percentile) after percutaneous coronary intervention in a patient who had a normal baseline value (< 99th percentile).¹¹

Unfortunately, using troponin at this threshold, the number of cases is five times higher than when CK-MB is used, without a consistent correlation with the outcomes of death or complications.¹² Currently, the increase in cardiac troponin after percutaneous coronary intervention is best interpreted as a marker of the patient’s atherothrombotic burden more than as a predictor of adverse outcomes.¹³

The updated definition of MI associated with percutaneous coronary intervention now requires an elevation of cardiac troponin values greater than 5 times the 99th percentile in a patient who had normal baseline values or an increase of more than 20% from baseline within 48 hours of the procedure. As this value has been arbitrarily assigned rather than based on an established threshold with clinical outcomes, a true MI must further meet one of the following criteria:

• Symptoms suggesting myocardial ischemia
• New ischemic electrocardiographic changes or new left bundle branch block
• Angiographic loss of patency of a major coronary artery or a side branch or persistent slow-flow or no-flow or embolization
• Imaging evidence of a new loss of viable myocardium or a new wall-motion abnormality.

Given that troponin levels may be elevated in up to 65% of patients after uncomplicated percutaneous coronary intervention and this elevation may be unavoidable,¹⁴ a higher troponin threshold to diagnose MI and the clear requirement of clinical correlates may resonate with physicians as a more appropriate definition. In turn, such guidelines may better identify those with an adverse event, while partly reducing unnecessary hospitalization and observation time in those for whom it is not necessary.

Type 4b: Due to stent thrombosis

Type 4b MI is MI caused by stent thrombosis. The thrombosis must be detected by coronary angiography or autopsy in the setting of myocardial ischemia and a rise or fall of cardiac biomarker values, with at least one value above the 99th percentile.

Type 4c: Due to restenosis

Proposed is the addition of type 4c MI, ie, MI resulting from restenosis of more than 50%, because restenosis after percutaneous coronary intervention can lead to MI without thrombosis.¹⁵

Type 5: After coronary artery bypass grafting

Similar to the situation after percutaneous coronary intervention, increased CK-MB levels after coronary artery bypass graft surgery are associated with poor outcomes.¹⁶ Although some studies have indicated that increased troponin levels within 24 hours of this surgery are associated with higher death rates, no study has established a troponin threshold that correlates with outcomes.¹⁷

The task force acknowledged this lack of prognostic value but arbitrarily defined type 5 MI as requiring biomarker elevations greater than 10 times the 99th percentile during the first 48 hours after surgery, with a normal baseline value. One of the following additional criteria must also be met:

• New pathologic Q waves or new left bundle branch block
• Angiographically documented new occlusion in the graft or native coronary artery
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality.

CHANGES FROM THE 2007 DEFINITIONS

Updates to the definitions of the MI types since the 2007 task force definition can be found in Table 1.

In type 1 and 2 MI, the finding of an intracoronary thrombus by angiography or autopsy was added as one of the possible criteria for evidence of myocardial ischemia.

In type 3 MI, the definition was simplified by deleting the former criterion of finding a fresh thrombus by angiography or autopsy.

In type 4a MI, by requiring clinical correlates, the updated definition in particular moves away from relying solely on troponin levels to diagnose an infarction after percutaneous coronary intervention, as was the case in 2007. Other changes from the 2007 definition: the troponin MI threshold was previously 3 times the 99th percentile, now it is 5 times. Also, if the patient had an elevated baseline value, he or she can now still qualify as having an MI if the level increases by more than 20%.

In type 5 MI, changes to the definition similarly reflect the need to address overly sensitive troponin values when diagnosing an MI after coronary artery bypass grafting. To address such concerns, the required cardiac biomarker values were increased from more than 5 to more than 10 times the 99th percentile.

The task force raised the troponin thresholds for type 4 and type 5 MI in response to evidence showing that troponins are excessively sensitive to minimal myocardial damage during revascularization, and the lack of a troponin threshold that correlates with clinical outcomes.¹² Although higher, these values remain arbitrary, so physicians will need to exercise clinical judgment when deciding whether patients are experiencing benign myocardial injury or rather a true MI after revascularization procedures.

OTHER CONDITIONS THAT RAISE TROPONIN LEVELS

As troponin is a marker not only for MI but also for any form of cardiac injury, its levels are elevated in numerous conditions, such as heart failure, renal failure, and left ventricular hypertrophy. The task force identifies distinct troponin elevations above basal levels as the best indication of new pathology, yet several conditions other than acute coronary syndromes can also cause dynamic changes in troponin levels.

Troponin is a sensitive marker for ruling out MI and has tissue specificity for cardiac injury, but it is not specific for acute coronary syndrome as the cause of such injury. Troponin assays were tested and validated in patients in whom there was a high clinical suspicion of acute coronary syndrome, but when ordered indiscriminately, they have a poor positive predictive value (53%) for this disorder.¹⁸

Physicians must distinguish between acute coronary syndrome and other causes when deciding to give antithrombotics. Table 2 lists common causes of increased troponin other than acute coronary syndrome.

Heart failure

Some patients with acute congestive heart failure have elevated troponin levels. In one study, 6.2% of such patients had troponin I levels of 1 μg/L or higher or troponin T levels of 0.1 μg/L or higher, and these patients had poorer outcomes and more severe symptoms.¹⁹ Levels can also be elevated in patients with chronic heart failure, in whom they correlate with impaired hemodynamics, progressive ventricular dysfunction, and death.²⁰ In an overview of two large trials of patients with chronic congestive heart failure, 86% and 98% tested positive for cardiac troponin using high-sensitivity assays.²¹

Troponin levels can rise from baseline and subsequently fall in congestive heart failure due to small amounts of myocardial injury, which may be very difficult to distinguish from MI based on the similar presenting symptoms of dyspnea and chest pressure.^1,22 The increased troponin levels in chronic congestive heart failure may reflect apoptosis secondary to wall stretch or direct cell toxicity by neurohormones, alcohol, chemotherapy agents, or infiltrative disorders.^23–26

End-stage renal disease

Troponin levels are increased in end-stage renal disease, with 25% to 75% of patients having elevated levels using currently available assays.^27–29 With the advent of high-sensitivity assays, however, cardiac troponin T levels higher than the 99th percentile are found in 100% of patients who have end-stage renal disease without cardiac symptoms.³⁰

Troponin values above the 99th percentile are therefore not diagnostic of MI in this population. Rather, a diagnosis of MI in patients with end-stage renal disease requires clinical signs and symptoms and serial changes in troponin levels from baseline levels. The task force and the National Academy of Clinical Biochemistry recommend requiring an elevation of more than 20% from baseline, representing a change in troponin of more than 3 standard deviations.³¹

Increases in troponin in renal failure are thought to be the result of chronic cardiac structural changes such as coronary artery disease, left ventricular hypertrophy, and elevated left ventricular end-diastolic pressure, rather than decreased clearance.^32,33

In stable patients with end-stage renal disease, those who have high levels of cardiac troponin T have a higher mortality rate.³⁴ Although the mechanism is not completely clear, decreased clearance of uremic toxins may contribute to myocardial damage beyond that of the cardiac structural changes.³⁴

Sepsis

Approximately 50% of patients admitted to an intensive care unit with sepsis without acute coronary syndrome have elevated troponin levels.³⁵

Elevated troponin in sepsis patients has been associated with left ventricular dysfunction, most likely from hemodynamic stress, direct cytotoxicity of bacterial endotoxins, and reperfusion injury.^35,36 Critical illness places high demands on the myocardium, while oxygen supply may be diminished by hypotension, pulmonary edema, and intravascular volume depletion. This supply-demand mismatch is similar to the physiology of type 2 MI, with clinical signs and symptoms of MI potentially being the only differentiating factor.

Elevated troponin levels may represent either reversible or irreversible myocardial injury in patients with sepsis and are a predictor of severe illness and death.³⁷ However, what to do about elevated troponin in patients with sepsis is not clear. When patients are in the intensive care unit with single-organ or multi-organ failure, the diagnosis and treatment of troponin elevations may not take priority.¹ Diagnosing MI is further complicated by the inability of critically ill patients to communicate signs and symptoms. Physicians should also remember that diagnostic testing (electrocardiography, echocardiography) is often necessary to meet the clinical criteria for a type 1 or 2 MI in critically ill patients, and that treatment options may be limited.

Pulmonary embolism

Pulmonary embolism is a leading noncardiac cause of troponin elevation in patients in whom the clinical suspicion of acute coronary syndrome is initially high.³⁸ It is thought that increased troponin levels in patients with pulmonary embolism are caused by increased right ventricular strain secondary to increased pulmonary artery resistance.

The signs and symptoms of MI and of pulmonary embolism overlap, and troponin can be elevated in both conditions, making the initial diagnosis difficult. Electrocardiography and early bedside echocardiography can identify the predominant right-sided dilatation and strain in the heart secondary to pulmonary embolism. Computed tomography should be performed if there is even a moderate clinical suspicion of pulmonary embolism.

The appropriate use of thrombolytics in a normotensive patient with pulmonary embolism remains controversial. The significant risks of hemorrhage need to be balanced with the risk of hemodynamic deterioration. For these patients, the combination of cardiac troponin I measurement and echocardiography provides more prognostic information than each does individually.³⁹ Troponin elevation may therefore be a marker for poor outcomes without aggressive treatment with thrombolytics.

However, single troponin measurements in patients hospitalized early with pulmonary embolism can lead to substantial risk of misdiagnosing them with MI. Although the intensity of the peak is not particularly useful in the setting of pulmonary embolism, two consecutive troponin values 8 hours apart will allow for more appropriate risk stratification for pulmonary embolism patients, who may have a delay between right heart injury and troponin release.⁴⁰

It is reasonable to expect that myocarditis—inflammation of the myocardium—would cause release of troponin from myocytes.⁴¹ Interestingly, however, troponin levels can also be elevated in pericarditis.⁴² The reasons are not clear but have been hypothesized as being caused by nonspecific inflammation during pericarditis that also includes the superficial myocardium—hence, “myopericarditis.”

We have only limited data on the outcomes of patients who have pericarditis with troponin elevation, but troponin levels did correlate with an adverse prognosis in one study.⁴³

Arrhythmias

A number of arrhythmias have been associated with elevated troponin levels. Some studies have shown arrhythmias to be the most common cause of high troponin levels in patients who are not experiencing an acute coronary syndrome.^44,45

The reasons proposed for increased troponins in tachyarrhythmia are similar to those in other conditions of oxygen supply-demand mismatch.⁴⁶ Tachycardia alone may lead to troponin release in the absence of myodepressive factors, inflammatory mediators, or coronary artery disease.⁴⁶

Studies have provided only mixed data as to whether troponin levels predict newonset arrhythmias or recurrence of arrhythmias.^47,48 Nonetheless, elevated troponin (≥ 0.040 μg/L) in patients with atrial fibrillation has independently correlated with increased risk of stroke or systemic embolism, death, and other cardiovascular events. This is clinically important, as troponin elevations higher than these levels adds prognostic information to that given by the CHADS2 stroke score (congestive heart failure, hypertension, age ≥ 75 years diabetes mellitus, and prior stroke or transient ischemic attack) and thus can inform appropriate anticoagulation therapy.⁴⁹

USE OF TROPONIN VALUES

Troponins are highly sensitive assays with high tissue specificity for myocardial injury, but levels can be elevated in non-MI conditions and in MIs other than type 1. As with any diagnostic test applied to a population with a low prevalence of the disease, troponin elevation has a low positive predictive value—53% for acute coronary syndrome.¹⁸

Unfortunately, in clinical practice, troponins are measured in up to 50% of admitted patients, a small proportion of whom have clinical signs or symptoms of MI.⁵⁰ Often, clinicians are left with a positive troponin of unknown significance, potentially leading to unnecessary diagnostic testing that detracts from the primary diagnosis.

Dynamic changes in troponin values (eg, a change of more than 20% in a patient with end-stage renal disease) are helpful in distinguishing acute from chronic causes of troponin elevation. However, such changes can also occur with acute or chronic congestive heart failure, tachycardia, hypotension, or other conditions other than acute coronary syndrome.

The absolute numerical value of troponin can help assess the significance of troponin elevation. In most non-MI and non-acute coronary syndrome causes of troponin elevation, the troponin level tends to be lower than 1 μg/mL (Figure 1). Occasional exceptions occur, especially when multiple conditions coexist (end-stage renal disease and congestive heart failure, for example). In contrast, most patients with acute coronary syndromes have either clear symptoms or electrocardiographic changes consistent with MI and a troponin that rises above 0.5 μg/mL.

The task force discourages the use of secondary thresholds for MI, as there is no level of troponin that is considered benign. While any troponin elevation carries a negative prognosis, such prognostic knowledge may not be particularly helpful in deciding whether to anticoagulate patients or attempt revascularization procedures.

We thus recommend using a threshold higher than the 99th percentile to distinguish acute coronary syndromes from other causes of troponin elevations. The particular threshold for decision-making should vary, depending on how strongly one clinically suspects an acute coronary syndrome. For instance, a cardiac troponin I level of 0.2 μg/mL in an otherwise healthy patient with chest pain and ST-segment depression is more than sufficient to diagnose acute coronary syndrome. In contrast, an end-stage renal disease patient with hypertensive cardiomyopathy who presents only with nausea should have a level markedly higher than his or her baseline value (and likely > 0.8 μg/mL) before acute coronary syndrome should be diagnosed.

CK-MB’S ROLE IN THE TROPONIN ERA

Some proponents of troponin assays, including those on the task force, have suggested that CK-MB may no longer be necessary in the evaluation of acute MI.⁵¹ In the past, CK-MB had more research supporting its use in quantifying myocardial damage and in diagnosing reinfarction, but some data suggest that troponin may be equally useful for these applications.^52,53

These comments aside, CK-MB measurements are still widely ordered with troponin, a probable response to the clinical difficulty of determining the cause and significance of troponin elevations. Although likely less common with recent assays, a small subgroup of patients with acute coronary syndrome will be CK-MB–positive and troponin-negative and at higher risk of morbidity and death than those who are troponin- and CK-MB–negative.^54,55

Troponin levels are elevated in many chronic conditions, whereas CK-MB levels may be unaffected or less affected. In some cases, such as congestive heart failure or renal failure, troponins may be both chronically elevated and more than 20% higher than at baseline. In a clinical context in which a false-positive troponin assay is likely, the addition of a CK-MB assay may help determine if a rise (and possibly a subsequent fall) in the troponin level represents true MI. More importantly, deciding on antithrombotic therapy or revascularization is often based on whether a patient has acute coronary syndrome, rather than a small MI from demand ischemia. CK-MB may thus serve as a less sensitive but more specific marker for the larger amount of myocardial damage that one might expect from an acute coronary syndrome.

CK-MB testing also may help determine the acuity of an acute coronary syndrome for patients with known causes of increased troponin. A negative CK-MB value in the presence of a troponin value elevated above baseline could indicate an event a few days prior.

Finally, the approach of ordering both troponin and CK-MB may be particularly helpful in diagnosing type 4 and 5 MIs, as current guidelines suggest that more research is needed to determine whether current troponin thresholds lead to clinical outcomes.

CLINICAL JUDGMENT IS NECESSARY

The updated definition raises the biomarker threshold required to diagnose MI after revascularization procedures and reemphasizes the need to look for other signs of infarction. This change reflects the sometimes excessive sensitivity of troponin assays for minimal and often unavoidable myocardial damage that occurs in numerous conditions.

With sensitive troponin assays, clinical judgment is essential for separating true MI from myocardial injury, and acute coronary syndrome from demand ischemia. Clinicians will now be forced to be cognizant of their suspicion for acute coronary syndrome in the presence of multiple noncoronary causes of increased troponin with little practical guideline guidance. In settings in which troponin elevation is expected (eg, congestive heart failure, end-stage renal failure, shock), a higher cardiac troponin threshold or CK-MB may be useful as a less sensitive but more specific marker of significant myocardial damage requiring aggressive treatment.

A 42-year-old woman is admitted to the hospital with worsening shortness of breath on exertion, poor exercise tolerance, leg edema, and swelling of the abdomen. Her symptoms have been getting worse over the last 4 months. She reports no history of fever, chills, night sweats, bleeding disorder, joint pain, weight loss, or loss of appetite.

She has type 2 diabetes mellitus and hypothyroidism. She had rheumatoid arthritis but said it was “inactive,” not requiring treatment for the last 18 years. Three months ago, she underwent a total hysterectomy and salpingo-oophorectomy for a complex adnexal mass, biopsy of which revealed a benign mucinous ovarian cyst.

Her current medications include furosemide, levothyroxine, and metformin. She is an ex-smoker with a 7 pack-year history. She drinks a glass of wine on social occasions only. Her family history is unremarkable.

On examination, she is not in distress and she has no fever. She has jugular venous distention of 5 cm, tense ascites, and marked edema of the legs, as well as hyperpigmented patches and erythematous plaques over both shins. Neck palpation reveals no lymphadenopathy or thyromegaly.

Her liver and the tip of the spleen are palpable following paracentesis, once ascitic fluid is removed.

The cardiovascular examination is normal. Chest auscultation reveals decreased breath sounds at the right lung base with bibasilar crackles. No focal neurologic deficit is noted on clinical examination.

Laboratory testing at the time of hospital admission (Table 1) includes a hepatitis panel (negative for exposure to hepatitis A, B, and C) and ascitic fluid studies. Chest radiography shows a right pleural effusion. Echocardiography demonstrates moderate pericardial effusion without tamponade; left and right ventricular function is normal. Cardiac magnetic resonance imaging finds no evidence of pericardial constriction or restrictive cardiomyopathy. Pressures are normal on pulmonary artery catheterization.

FINDING THE CAUSE OF ASCITES

1. What is the most likely cause of ascites in this patient?

• Cirrhosis
• Recent abdominal surgery
• Congestive heart failure
• Abdominal malignancy
• Nephrotic syndrome

The serum-ascites albumin gradient—ie, the serum albumin concentration minus the ascitic fluid albumin concentration—helps determine whether ascites is related to portal hypertension.¹ A high gradient (ie, above 1.1 g/dL) is seen in cirrhosis, alcoholic hepatitis, congestive heart failure, vascular occlusion syndromes (eg, Budd-Chiari syndrome), and metastatic liver disease.

From the values in Table 1, our patient’s gradient is 0.8 g/dL, which is considered low. However, we cannot completely rule out cirrhosis as the cause of her ascites because she was taking a diuretic, and diuretics can falsely decrease the gradient. Heart failure is unlikely, based on the results of echocardiography and catheterization. In addition, the 24-hour urinary protein concentration is normal, as is alpha-1 antitrypsin secretion in the stool, ruling out protein-losing nephropathy or enteropathy as the cause of her low albumin and ascites.

A high triglyceride content in her ascitic fluid (> 150 mg/dL) is consistent with chylous ascites, which is seen in patients with previous abdominal surgery or with lymphatic obstruction due to malignancy. A high neutrophil count in the ascitic fluid and a negative culture are also consistent with chylous ascites. However, in this patient, recent surgery as the cause of chylous ascites does not explain the systemic features of hepatosplenomegaly, anemia, thrombocytosis, and low albumin. Moreover, her high C-reactive protein value suggests an ongoing inflammatory process, although her erythrocyte sedimentation rate is not significantly elevated.

Therefore, the most likely cause of ascites in this patient is abdominal malignancy.

WHAT SHOULD BE DONE NEXT?

2. Which of the following studies is reasonable in this patient at this point?

• Serum protein electrophoresis
• Computed tomography (CT) of the chest, abdomen, and pelvis
• Liver biopsy
• Cytologic study of the ascitic fluid

All of these studies would be reasonable and in fact were done in this patient.

Serum protein electrophoresis (Table 2) identified a monoclonal protein band in the immunoglobulin G (IgG) kappa region.

Cytologic study of the ascitic fluid was negative for malignant cells.

Chest CT revealed bilateral pleural effusions, pericardial effusion, and bilateral axillary lymphadenopathy. CT of the abdomen and pelvis was normal, except for ascites, and no pelvic tumor was noted.

Liver biopsy was done to look for the source of her unexplained ascites with elevated alkaline phosphatase, as all other investigations so far were normal. It revealed mild centrilobular scarring, but the rest of the parenchymal architecture was normal, with no evidence of bridging fibrosis or nodular regenerative hyperplasia (Figure 1).

Transjugular measurement of the hepatic vein pressure revealed a hepatic vein pressure gradient of 9 mm Hg, indicating mild portal hypertension. Venography showed widely patent hepatic and portal veins. Her high inflammatory marker levels could have been caused by smoldering rheumatoid arthritis; however, since the patient has had no joint symptoms for 18 years, this is very unlikely. It is more likely to be caused by a plasma cell disorder, as suggested by a monoclonal protein on electrophoresis.

WHAT IS THE DIAGNOSIS?

3. What is the most likely diagnosis in our patient?

• Rheumatoid arthritis
• Cryoglobulinemia
• Capillary leak syndrome
• Hematologic malignancy
• Syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)

Rheumatoid arthritis can present with hepatosplenomegaly, lymphadenopathy, ascites, and skin rash, particularly if antinuclear antibody and rheumatoid factor are elevated. Ascites is known to occur in association with rheumatoid arthritis in the setting of Felty syndrome or nodular regenerative hyperplasia of the liver.² However, our patient did not have leukopenia or evidence of regenerative hyperplasia on liver biopsy. Moreover, her rheumatoid arthritis had remained clinically inactive for a long time.

Cryoglobulinemia was possible, given her ascites, neuropathy, and splenomegaly, but her serum hepatic antibody and C4 complement values were normal.³ Also, the appearance of her rash was not typical of cryoglobulinemia.

Capillary leak syndrome was ruled out by the absence of hypotensive episodes, edema of the face or upper extremities, or renal failure.⁴

Lymphoma was excluded by flow cytometry.

A monoclonal protein on serum electrophoresis may suggest multiple myeloma, but this patient had multisystem involvement including organomegaly, endocrinopathy, and skin abnormalities. Thus, POEMS syndrome is the most likely diagnosis.

4. Which test should be done at this time to confirm the diagnosis of POEMS syndrome?

• Bone marrow biopsy
• Vascular endothelial growth factor testing
• Nerve conduction study
• Complete x-ray bone survey

A test for vascular endothelial growth factor should be done. This growth factor is almost always elevated in POEMS, and a positive test helps confirm the diagnosis of POEMS. Our patient’s level was elevated at 1,664 pg/mL (reference range 31–86).

POEMS is thought to be a variant of plasma cell dyscrasia, and all patients with POEMS have a monoclonal protein on electrophoresis. On this background, multiple myeloma is an important consideration.

Our patient underwent bone marrow biopsy, which revealed mild plasmacytosis (< 10%) (Figure 2). A complete bone survey showed generalized osteopenia without blastic or lytic lesions. To complete the workup for POEMS syndrome, a nerve conduction study was done to look for neuropathy; it showed bilateral sensory motor neuropathy with features of both a demyelinating process and axonal loss.

POEMS SYNDROME

POEMS syndrome is a constellation of features such as organomegaly and endocrine and skin abnormalities in association with neuropathy and a monoclonal protein on electrophoresis.⁵ In 2003, Dispenzieri et al⁶ described the major and minor diagnostic criteria based on a retrospective analysis of 99 patients with POEMS syndrome.⁶ Later, elevated vascular endothelial growth factor was added as a confirmatory diagnostic criterion.⁷ This growth factor is also an indicator of prognosis in POEMS syndrome, and its level can be used to monitor the response to treatment.⁷

Our patient met both major criteria for POEMS syndrome, ie, polyneuropathy (based on nerve conduction studies) and a monoclonal protein. Polyneuropathy in POEMS syndrome usually occurs as sensorimotor peripheral neuropathy of insidious onset and is seldom painful. Nerve biopsy study reveals demyelination with features of axonal loss. Interestingly, although our patient had neuropathy as diagnosed by electromyography, she remained clinically asymptomatic.

The monoclonal protein in POEMS syndrome is commonly IgA or IgG. Light chains are always present and are mainly the lambda type; kappa light chains are also reported in rare cases. Our patient had IgG kappa light chains.

Our patient met a number of the minor criteria for POEMS syndrome: ie, organomegaly (hepatosplenomegaly, lymphadenopathy), endocrinopathy (hypothyroidism, diabetes), skin changes (hyperpigmentation and plaques of the lower extremities), edema, pleural effusion, and ascites.

Endocrine disorders in POEMS syndrome

The endocrine abnormalities most often described in POEMS syndrome are hypogonadism, hypothyroidism, and diabetes mellitus. But because hypothyroidism and diabetes are common in the general population, it is debatable whether either of these could constitute the endocrine component of POEMS syndrome. Nevertheless, in three large series,^6,7 occurrences of these two disorders were common, although less specific than adrenal or pituitary involvement.

In the analysis by Dispenzieri et al,⁶ 67% of patients had at least one endocrine abnormality. Our patient had no evidence of an adrenal disorder.

Skin, skeletal, and other changes

The skin changes in POEMS syndrome are often nonspecific and include hyperpigmentation, sclerodema-like thickening, and plaques.

Skeletal changes are noted in up to 97% of patients. A skeletal survey in our patient revealed generalized osteopenia as opposed to osteosclerotic lesions, which are common in POEMS syndrome.

Anemia and thrombocytosis (as in our patient) are usually seen in POEMS syndrome and are induced by cytokines.⁶ POEMS syndrome also leads to increased thrombotic complications from the release of inflammatory cytokines.

Hypoalbuminemia and anasarca including ascites are often seen in POEMS syndrome (prevalence 29% to 89%) and are attributed to cytokine-induced increased vascular permeability. In POEMS syndrome, the serum-ascites albumin gradient is usually less than 1.1 g/dL, as in our patient.

Stepani et al⁸ reported one case of culture-negative neutrocytic ascites with portal hypertension in POEMS syndrome.⁸ (Culture-negative neutrocytic ascites is defined as an ascitic fluid polymorphonuclear count greater than 250/mm³ and a negative ascitic fluid culture in the absence of previous antibiotic therapy.) Chylous ascites has not yet been described in POEMS syndrome. However, chylous ascites is predominantly lymphocytic, whereas our patient had neutrocytic ascites.

We concluded that the cause of our patient’s ascites was multifactorial and included previous surgery and POEMS syndrome.

Nonclassic presentation

In addition to its classic presentation, POEMS syndrome is often reported in association with other “unusual features” such as cardiomyopathy, pulmonary hypertension, and cryoglobulinemia.⁶

So far, very few cases of portal hypertension in POEMS syndrome have been reported. Stepani et al⁸ described a patient who had POEMS syndrome and portal hypertension with extensive portal fibrosis without cirrhosis on liver biopsy. Inoue et al⁹ reported a liver biopsy feature consistent with idiopathic portal hypertension, also noting a case with mild fibrosis and few lymphocytic infiltrates in the portal tract.⁹

The etiopathogenesis of POEMS syndrome is attributed to proangiogenic vascular endothelial growth factor, and other inflammatory cytokines (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha) also play a key role in pulmonary hypertension.^10,11 A similar pathogenesis could also contribute to the development of portal hypertension (Figure 3).

CASE CONCLUDED

We started our patient on oral prednisone 60 mg daily for a month, tapered to a maintenance dose of 15 mg to suppress clonal proliferation of plasma cells. Her symptoms improved. Her vascular endothelial growth factor level decreased from 1,664 to 624 pg/mL. She was enrolled in a National Institutes of Health study to evaluate the effect of a potential new immunomodulator treatment for POEMS syndrome.

In conclusion, POEMS syndrome is rare and can present with many atypical features. A high index of suspicion is needed to detect it in a patient who has noncirrhotic portal hypertension with ascites and multisystem involvement.

A 42-year-old woman is admitted to the hospital with worsening shortness of breath on exertion, poor exercise tolerance, leg edema, and swelling of the abdomen. Her symptoms have been getting worse over the last 4 months. She reports no history of fever, chills, night sweats, bleeding disorder, joint pain, weight loss, or loss of appetite.

She has type 2 diabetes mellitus and hypothyroidism. She had rheumatoid arthritis but said it was “inactive,” not requiring treatment for the last 18 years. Three months ago, she underwent a total hysterectomy and salpingo-oophorectomy for a complex adnexal mass, biopsy of which revealed a benign mucinous ovarian cyst.

Her current medications include furosemide, levothyroxine, and metformin. She is an ex-smoker with a 7 pack-year history. She drinks a glass of wine on social occasions only. Her family history is unremarkable.

On examination, she is not in distress and she has no fever. She has jugular venous distention of 5 cm, tense ascites, and marked edema of the legs, as well as hyperpigmented patches and erythematous plaques over both shins. Neck palpation reveals no lymphadenopathy or thyromegaly.

Her liver and the tip of the spleen are palpable following paracentesis, once ascitic fluid is removed.

The cardiovascular examination is normal. Chest auscultation reveals decreased breath sounds at the right lung base with bibasilar crackles. No focal neurologic deficit is noted on clinical examination.

Laboratory testing at the time of hospital admission (Table 1) includes a hepatitis panel (negative for exposure to hepatitis A, B, and C) and ascitic fluid studies. Chest radiography shows a right pleural effusion. Echocardiography demonstrates moderate pericardial effusion without tamponade; left and right ventricular function is normal. Cardiac magnetic resonance imaging finds no evidence of pericardial constriction or restrictive cardiomyopathy. Pressures are normal on pulmonary artery catheterization.

FINDING THE CAUSE OF ASCITES

1. What is the most likely cause of ascites in this patient?

• Cirrhosis
• Recent abdominal surgery
• Congestive heart failure
• Abdominal malignancy
• Nephrotic syndrome

The serum-ascites albumin gradient—ie, the serum albumin concentration minus the ascitic fluid albumin concentration—helps determine whether ascites is related to portal hypertension.¹ A high gradient (ie, above 1.1 g/dL) is seen in cirrhosis, alcoholic hepatitis, congestive heart failure, vascular occlusion syndromes (eg, Budd-Chiari syndrome), and metastatic liver disease.

From the values in Table 1, our patient’s gradient is 0.8 g/dL, which is considered low. However, we cannot completely rule out cirrhosis as the cause of her ascites because she was taking a diuretic, and diuretics can falsely decrease the gradient. Heart failure is unlikely, based on the results of echocardiography and catheterization. In addition, the 24-hour urinary protein concentration is normal, as is alpha-1 antitrypsin secretion in the stool, ruling out protein-losing nephropathy or enteropathy as the cause of her low albumin and ascites.

A high triglyceride content in her ascitic fluid (> 150 mg/dL) is consistent with chylous ascites, which is seen in patients with previous abdominal surgery or with lymphatic obstruction due to malignancy. A high neutrophil count in the ascitic fluid and a negative culture are also consistent with chylous ascites. However, in this patient, recent surgery as the cause of chylous ascites does not explain the systemic features of hepatosplenomegaly, anemia, thrombocytosis, and low albumin. Moreover, her high C-reactive protein value suggests an ongoing inflammatory process, although her erythrocyte sedimentation rate is not significantly elevated.

Therefore, the most likely cause of ascites in this patient is abdominal malignancy.

WHAT SHOULD BE DONE NEXT?

2. Which of the following studies is reasonable in this patient at this point?

• Serum protein electrophoresis
• Computed tomography (CT) of the chest, abdomen, and pelvis
• Liver biopsy
• Cytologic study of the ascitic fluid

All of these studies would be reasonable and in fact were done in this patient.

Serum protein electrophoresis (Table 2) identified a monoclonal protein band in the immunoglobulin G (IgG) kappa region.

Cytologic study of the ascitic fluid was negative for malignant cells.

Chest CT revealed bilateral pleural effusions, pericardial effusion, and bilateral axillary lymphadenopathy. CT of the abdomen and pelvis was normal, except for ascites, and no pelvic tumor was noted.

Liver biopsy was done to look for the source of her unexplained ascites with elevated alkaline phosphatase, as all other investigations so far were normal. It revealed mild centrilobular scarring, but the rest of the parenchymal architecture was normal, with no evidence of bridging fibrosis or nodular regenerative hyperplasia (Figure 1).

Transjugular measurement of the hepatic vein pressure revealed a hepatic vein pressure gradient of 9 mm Hg, indicating mild portal hypertension. Venography showed widely patent hepatic and portal veins. Her high inflammatory marker levels could have been caused by smoldering rheumatoid arthritis; however, since the patient has had no joint symptoms for 18 years, this is very unlikely. It is more likely to be caused by a plasma cell disorder, as suggested by a monoclonal protein on electrophoresis.

WHAT IS THE DIAGNOSIS?

3. What is the most likely diagnosis in our patient?

• Rheumatoid arthritis
• Cryoglobulinemia
• Capillary leak syndrome
• Hematologic malignancy
• Syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)

Rheumatoid arthritis can present with hepatosplenomegaly, lymphadenopathy, ascites, and skin rash, particularly if antinuclear antibody and rheumatoid factor are elevated. Ascites is known to occur in association with rheumatoid arthritis in the setting of Felty syndrome or nodular regenerative hyperplasia of the liver.² However, our patient did not have leukopenia or evidence of regenerative hyperplasia on liver biopsy. Moreover, her rheumatoid arthritis had remained clinically inactive for a long time.

Cryoglobulinemia was possible, given her ascites, neuropathy, and splenomegaly, but her serum hepatic antibody and C4 complement values were normal.³ Also, the appearance of her rash was not typical of cryoglobulinemia.

Capillary leak syndrome was ruled out by the absence of hypotensive episodes, edema of the face or upper extremities, or renal failure.⁴

Lymphoma was excluded by flow cytometry.

A monoclonal protein on serum electrophoresis may suggest multiple myeloma, but this patient had multisystem involvement including organomegaly, endocrinopathy, and skin abnormalities. Thus, POEMS syndrome is the most likely diagnosis.

4. Which test should be done at this time to confirm the diagnosis of POEMS syndrome?

• Bone marrow biopsy
• Vascular endothelial growth factor testing
• Nerve conduction study
• Complete x-ray bone survey

A test for vascular endothelial growth factor should be done. This growth factor is almost always elevated in POEMS, and a positive test helps confirm the diagnosis of POEMS. Our patient’s level was elevated at 1,664 pg/mL (reference range 31–86).

POEMS is thought to be a variant of plasma cell dyscrasia, and all patients with POEMS have a monoclonal protein on electrophoresis. On this background, multiple myeloma is an important consideration.

Our patient underwent bone marrow biopsy, which revealed mild plasmacytosis (< 10%) (Figure 2). A complete bone survey showed generalized osteopenia without blastic or lytic lesions. To complete the workup for POEMS syndrome, a nerve conduction study was done to look for neuropathy; it showed bilateral sensory motor neuropathy with features of both a demyelinating process and axonal loss.

POEMS SYNDROME

POEMS syndrome is a constellation of features such as organomegaly and endocrine and skin abnormalities in association with neuropathy and a monoclonal protein on electrophoresis.⁵ In 2003, Dispenzieri et al⁶ described the major and minor diagnostic criteria based on a retrospective analysis of 99 patients with POEMS syndrome.⁶ Later, elevated vascular endothelial growth factor was added as a confirmatory diagnostic criterion.⁷ This growth factor is also an indicator of prognosis in POEMS syndrome, and its level can be used to monitor the response to treatment.⁷

Our patient met both major criteria for POEMS syndrome, ie, polyneuropathy (based on nerve conduction studies) and a monoclonal protein. Polyneuropathy in POEMS syndrome usually occurs as sensorimotor peripheral neuropathy of insidious onset and is seldom painful. Nerve biopsy study reveals demyelination with features of axonal loss. Interestingly, although our patient had neuropathy as diagnosed by electromyography, she remained clinically asymptomatic.

The monoclonal protein in POEMS syndrome is commonly IgA or IgG. Light chains are always present and are mainly the lambda type; kappa light chains are also reported in rare cases. Our patient had IgG kappa light chains.

Our patient met a number of the minor criteria for POEMS syndrome: ie, organomegaly (hepatosplenomegaly, lymphadenopathy), endocrinopathy (hypothyroidism, diabetes), skin changes (hyperpigmentation and plaques of the lower extremities), edema, pleural effusion, and ascites.

Endocrine disorders in POEMS syndrome

The endocrine abnormalities most often described in POEMS syndrome are hypogonadism, hypothyroidism, and diabetes mellitus. But because hypothyroidism and diabetes are common in the general population, it is debatable whether either of these could constitute the endocrine component of POEMS syndrome. Nevertheless, in three large series,^6,7 occurrences of these two disorders were common, although less specific than adrenal or pituitary involvement.

In the analysis by Dispenzieri et al,⁶ 67% of patients had at least one endocrine abnormality. Our patient had no evidence of an adrenal disorder.

Skin, skeletal, and other changes

The skin changes in POEMS syndrome are often nonspecific and include hyperpigmentation, sclerodema-like thickening, and plaques.

Skeletal changes are noted in up to 97% of patients. A skeletal survey in our patient revealed generalized osteopenia as opposed to osteosclerotic lesions, which are common in POEMS syndrome.

Anemia and thrombocytosis (as in our patient) are usually seen in POEMS syndrome and are induced by cytokines.⁶ POEMS syndrome also leads to increased thrombotic complications from the release of inflammatory cytokines.

Hypoalbuminemia and anasarca including ascites are often seen in POEMS syndrome (prevalence 29% to 89%) and are attributed to cytokine-induced increased vascular permeability. In POEMS syndrome, the serum-ascites albumin gradient is usually less than 1.1 g/dL, as in our patient.

Stepani et al⁸ reported one case of culture-negative neutrocytic ascites with portal hypertension in POEMS syndrome.⁸ (Culture-negative neutrocytic ascites is defined as an ascitic fluid polymorphonuclear count greater than 250/mm³ and a negative ascitic fluid culture in the absence of previous antibiotic therapy.) Chylous ascites has not yet been described in POEMS syndrome. However, chylous ascites is predominantly lymphocytic, whereas our patient had neutrocytic ascites.

We concluded that the cause of our patient’s ascites was multifactorial and included previous surgery and POEMS syndrome.

Nonclassic presentation

In addition to its classic presentation, POEMS syndrome is often reported in association with other “unusual features” such as cardiomyopathy, pulmonary hypertension, and cryoglobulinemia.⁶

So far, very few cases of portal hypertension in POEMS syndrome have been reported. Stepani et al⁸ described a patient who had POEMS syndrome and portal hypertension with extensive portal fibrosis without cirrhosis on liver biopsy. Inoue et al⁹ reported a liver biopsy feature consistent with idiopathic portal hypertension, also noting a case with mild fibrosis and few lymphocytic infiltrates in the portal tract.⁹

The etiopathogenesis of POEMS syndrome is attributed to proangiogenic vascular endothelial growth factor, and other inflammatory cytokines (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha) also play a key role in pulmonary hypertension.^10,11 A similar pathogenesis could also contribute to the development of portal hypertension (Figure 3).

CASE CONCLUDED

We started our patient on oral prednisone 60 mg daily for a month, tapered to a maintenance dose of 15 mg to suppress clonal proliferation of plasma cells. Her symptoms improved. Her vascular endothelial growth factor level decreased from 1,664 to 624 pg/mL. She was enrolled in a National Institutes of Health study to evaluate the effect of a potential new immunomodulator treatment for POEMS syndrome.

In conclusion, POEMS syndrome is rare and can present with many atypical features. A high index of suspicion is needed to detect it in a patient who has noncirrhotic portal hypertension with ascites and multisystem involvement.

A 42-year-old woman is admitted to the hospital with worsening shortness of breath on exertion, poor exercise tolerance, leg edema, and swelling of the abdomen. Her symptoms have been getting worse over the last 4 months. She reports no history of fever, chills, night sweats, bleeding disorder, joint pain, weight loss, or loss of appetite.

She has type 2 diabetes mellitus and hypothyroidism. She had rheumatoid arthritis but said it was “inactive,” not requiring treatment for the last 18 years. Three months ago, she underwent a total hysterectomy and salpingo-oophorectomy for a complex adnexal mass, biopsy of which revealed a benign mucinous ovarian cyst.

Her current medications include furosemide, levothyroxine, and metformin. She is an ex-smoker with a 7 pack-year history. She drinks a glass of wine on social occasions only. Her family history is unremarkable.

On examination, she is not in distress and she has no fever. She has jugular venous distention of 5 cm, tense ascites, and marked edema of the legs, as well as hyperpigmented patches and erythematous plaques over both shins. Neck palpation reveals no lymphadenopathy or thyromegaly.

Her liver and the tip of the spleen are palpable following paracentesis, once ascitic fluid is removed.

The cardiovascular examination is normal. Chest auscultation reveals decreased breath sounds at the right lung base with bibasilar crackles. No focal neurologic deficit is noted on clinical examination.

Laboratory testing at the time of hospital admission (Table 1) includes a hepatitis panel (negative for exposure to hepatitis A, B, and C) and ascitic fluid studies. Chest radiography shows a right pleural effusion. Echocardiography demonstrates moderate pericardial effusion without tamponade; left and right ventricular function is normal. Cardiac magnetic resonance imaging finds no evidence of pericardial constriction or restrictive cardiomyopathy. Pressures are normal on pulmonary artery catheterization.

FINDING THE CAUSE OF ASCITES

1. What is the most likely cause of ascites in this patient?

• Cirrhosis
• Recent abdominal surgery
• Congestive heart failure
• Abdominal malignancy
• Nephrotic syndrome

The serum-ascites albumin gradient—ie, the serum albumin concentration minus the ascitic fluid albumin concentration—helps determine whether ascites is related to portal hypertension.¹ A high gradient (ie, above 1.1 g/dL) is seen in cirrhosis, alcoholic hepatitis, congestive heart failure, vascular occlusion syndromes (eg, Budd-Chiari syndrome), and metastatic liver disease.

From the values in Table 1, our patient’s gradient is 0.8 g/dL, which is considered low. However, we cannot completely rule out cirrhosis as the cause of her ascites because she was taking a diuretic, and diuretics can falsely decrease the gradient. Heart failure is unlikely, based on the results of echocardiography and catheterization. In addition, the 24-hour urinary protein concentration is normal, as is alpha-1 antitrypsin secretion in the stool, ruling out protein-losing nephropathy or enteropathy as the cause of her low albumin and ascites.

A high triglyceride content in her ascitic fluid (> 150 mg/dL) is consistent with chylous ascites, which is seen in patients with previous abdominal surgery or with lymphatic obstruction due to malignancy. A high neutrophil count in the ascitic fluid and a negative culture are also consistent with chylous ascites. However, in this patient, recent surgery as the cause of chylous ascites does not explain the systemic features of hepatosplenomegaly, anemia, thrombocytosis, and low albumin. Moreover, her high C-reactive protein value suggests an ongoing inflammatory process, although her erythrocyte sedimentation rate is not significantly elevated.

Therefore, the most likely cause of ascites in this patient is abdominal malignancy.

WHAT SHOULD BE DONE NEXT?

2. Which of the following studies is reasonable in this patient at this point?

• Serum protein electrophoresis
• Computed tomography (CT) of the chest, abdomen, and pelvis
• Liver biopsy
• Cytologic study of the ascitic fluid

All of these studies would be reasonable and in fact were done in this patient.

Serum protein electrophoresis (Table 2) identified a monoclonal protein band in the immunoglobulin G (IgG) kappa region.

Cytologic study of the ascitic fluid was negative for malignant cells.

Chest CT revealed bilateral pleural effusions, pericardial effusion, and bilateral axillary lymphadenopathy. CT of the abdomen and pelvis was normal, except for ascites, and no pelvic tumor was noted.

Liver biopsy was done to look for the source of her unexplained ascites with elevated alkaline phosphatase, as all other investigations so far were normal. It revealed mild centrilobular scarring, but the rest of the parenchymal architecture was normal, with no evidence of bridging fibrosis or nodular regenerative hyperplasia (Figure 1).

Transjugular measurement of the hepatic vein pressure revealed a hepatic vein pressure gradient of 9 mm Hg, indicating mild portal hypertension. Venography showed widely patent hepatic and portal veins. Her high inflammatory marker levels could have been caused by smoldering rheumatoid arthritis; however, since the patient has had no joint symptoms for 18 years, this is very unlikely. It is more likely to be caused by a plasma cell disorder, as suggested by a monoclonal protein on electrophoresis.

WHAT IS THE DIAGNOSIS?

3. What is the most likely diagnosis in our patient?

• Rheumatoid arthritis
• Cryoglobulinemia
• Capillary leak syndrome
• Hematologic malignancy
• Syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)

Rheumatoid arthritis can present with hepatosplenomegaly, lymphadenopathy, ascites, and skin rash, particularly if antinuclear antibody and rheumatoid factor are elevated. Ascites is known to occur in association with rheumatoid arthritis in the setting of Felty syndrome or nodular regenerative hyperplasia of the liver.² However, our patient did not have leukopenia or evidence of regenerative hyperplasia on liver biopsy. Moreover, her rheumatoid arthritis had remained clinically inactive for a long time.

Cryoglobulinemia was possible, given her ascites, neuropathy, and splenomegaly, but her serum hepatic antibody and C4 complement values were normal.³ Also, the appearance of her rash was not typical of cryoglobulinemia.

Capillary leak syndrome was ruled out by the absence of hypotensive episodes, edema of the face or upper extremities, or renal failure.⁴

Lymphoma was excluded by flow cytometry.

A monoclonal protein on serum electrophoresis may suggest multiple myeloma, but this patient had multisystem involvement including organomegaly, endocrinopathy, and skin abnormalities. Thus, POEMS syndrome is the most likely diagnosis.

4. Which test should be done at this time to confirm the diagnosis of POEMS syndrome?

• Bone marrow biopsy
• Vascular endothelial growth factor testing
• Nerve conduction study
• Complete x-ray bone survey

A test for vascular endothelial growth factor should be done. This growth factor is almost always elevated in POEMS, and a positive test helps confirm the diagnosis of POEMS. Our patient’s level was elevated at 1,664 pg/mL (reference range 31–86).

POEMS is thought to be a variant of plasma cell dyscrasia, and all patients with POEMS have a monoclonal protein on electrophoresis. On this background, multiple myeloma is an important consideration.

Our patient underwent bone marrow biopsy, which revealed mild plasmacytosis (< 10%) (Figure 2). A complete bone survey showed generalized osteopenia without blastic or lytic lesions. To complete the workup for POEMS syndrome, a nerve conduction study was done to look for neuropathy; it showed bilateral sensory motor neuropathy with features of both a demyelinating process and axonal loss.

POEMS SYNDROME

POEMS syndrome is a constellation of features such as organomegaly and endocrine and skin abnormalities in association with neuropathy and a monoclonal protein on electrophoresis.⁵ In 2003, Dispenzieri et al⁶ described the major and minor diagnostic criteria based on a retrospective analysis of 99 patients with POEMS syndrome.⁶ Later, elevated vascular endothelial growth factor was added as a confirmatory diagnostic criterion.⁷ This growth factor is also an indicator of prognosis in POEMS syndrome, and its level can be used to monitor the response to treatment.⁷

Our patient met both major criteria for POEMS syndrome, ie, polyneuropathy (based on nerve conduction studies) and a monoclonal protein. Polyneuropathy in POEMS syndrome usually occurs as sensorimotor peripheral neuropathy of insidious onset and is seldom painful. Nerve biopsy study reveals demyelination with features of axonal loss. Interestingly, although our patient had neuropathy as diagnosed by electromyography, she remained clinically asymptomatic.

The monoclonal protein in POEMS syndrome is commonly IgA or IgG. Light chains are always present and are mainly the lambda type; kappa light chains are also reported in rare cases. Our patient had IgG kappa light chains.

Our patient met a number of the minor criteria for POEMS syndrome: ie, organomegaly (hepatosplenomegaly, lymphadenopathy), endocrinopathy (hypothyroidism, diabetes), skin changes (hyperpigmentation and plaques of the lower extremities), edema, pleural effusion, and ascites.

Endocrine disorders in POEMS syndrome

The endocrine abnormalities most often described in POEMS syndrome are hypogonadism, hypothyroidism, and diabetes mellitus. But because hypothyroidism and diabetes are common in the general population, it is debatable whether either of these could constitute the endocrine component of POEMS syndrome. Nevertheless, in three large series,^6,7 occurrences of these two disorders were common, although less specific than adrenal or pituitary involvement.

In the analysis by Dispenzieri et al,⁶ 67% of patients had at least one endocrine abnormality. Our patient had no evidence of an adrenal disorder.

Skin, skeletal, and other changes

The skin changes in POEMS syndrome are often nonspecific and include hyperpigmentation, sclerodema-like thickening, and plaques.

Skeletal changes are noted in up to 97% of patients. A skeletal survey in our patient revealed generalized osteopenia as opposed to osteosclerotic lesions, which are common in POEMS syndrome.

Anemia and thrombocytosis (as in our patient) are usually seen in POEMS syndrome and are induced by cytokines.⁶ POEMS syndrome also leads to increased thrombotic complications from the release of inflammatory cytokines.

Hypoalbuminemia and anasarca including ascites are often seen in POEMS syndrome (prevalence 29% to 89%) and are attributed to cytokine-induced increased vascular permeability. In POEMS syndrome, the serum-ascites albumin gradient is usually less than 1.1 g/dL, as in our patient.

Stepani et al⁸ reported one case of culture-negative neutrocytic ascites with portal hypertension in POEMS syndrome.⁸ (Culture-negative neutrocytic ascites is defined as an ascitic fluid polymorphonuclear count greater than 250/mm³ and a negative ascitic fluid culture in the absence of previous antibiotic therapy.) Chylous ascites has not yet been described in POEMS syndrome. However, chylous ascites is predominantly lymphocytic, whereas our patient had neutrocytic ascites.

We concluded that the cause of our patient’s ascites was multifactorial and included previous surgery and POEMS syndrome.

Nonclassic presentation

In addition to its classic presentation, POEMS syndrome is often reported in association with other “unusual features” such as cardiomyopathy, pulmonary hypertension, and cryoglobulinemia.⁶

So far, very few cases of portal hypertension in POEMS syndrome have been reported. Stepani et al⁸ described a patient who had POEMS syndrome and portal hypertension with extensive portal fibrosis without cirrhosis on liver biopsy. Inoue et al⁹ reported a liver biopsy feature consistent with idiopathic portal hypertension, also noting a case with mild fibrosis and few lymphocytic infiltrates in the portal tract.⁹

The etiopathogenesis of POEMS syndrome is attributed to proangiogenic vascular endothelial growth factor, and other inflammatory cytokines (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha) also play a key role in pulmonary hypertension.^10,11 A similar pathogenesis could also contribute to the development of portal hypertension (Figure 3).

CASE CONCLUDED

We started our patient on oral prednisone 60 mg daily for a month, tapered to a maintenance dose of 15 mg to suppress clonal proliferation of plasma cells. Her symptoms improved. Her vascular endothelial growth factor level decreased from 1,664 to 624 pg/mL. She was enrolled in a National Institutes of Health study to evaluate the effect of a potential new immunomodulator treatment for POEMS syndrome.

In conclusion, POEMS syndrome is rare and can present with many atypical features. A high index of suspicion is needed to detect it in a patient who has noncirrhotic portal hypertension with ascites and multisystem involvement.

Density: The quality or state of being dense; the quantity per unit volume, unit area, or unit length; the degree of opacity of a translucent medium, or the common logarithm of the opacity.

—Merriam-Webster’s dictionary¹

For more than a decade, federal law in the United States has compelled breast imaging centers to give every mammography patient a letter explaining her result.²

See related editorial

Often, however, the first person a woman speaks to about her findings is her primary care clinician, particularly if she has had a screening mammogram at a center where films are “batch-read” and are not viewed by the radiologist at the time of the appointment. Internal medicine physicians are often called on to help women understand their findings and to order follow-up tests recommended by the radiologist—a not uncommon occurrence. Also, internists often need to address patients’ anxieties about the possibility of breast cancer and provide them with enough information to make an informed decision about an appropriate action plan.

Meanwhile, discussing mammography has become more complicated. In 2009, the United States Preventive Services Task Force stopped recommending that women under age 50 be routinely screened for breast cancer, and instead stated that the decision to begin screening these women should consider “patient context” and the patient’s personal “values”³—with the implication that women’s primary clinicians would play an important role in helping them weigh the test’s potential benefits and harms.

More and more, internists must grapple with the task of how to help women decipher the concept of “breast density,” understand their personal density results, and make an informed decision about whether to undergo additional imaging studies, such as ultrasonography and magnetic resonance imaging (MRI).

LEGISLATION REQUIRING DENSITY NOTIFICATION

The impetus for this change in practice has been spurred in large part by patient advocates, who have argued that women deserve to know their density because mammography is less sensitive in women with dense breasts. So far, at least 12 states have enacted laws requiring breast imaging centers to add information about breast density in the result notification letters they mail to patients. Legislatures in several other states are considering breast density notification laws,⁴ and federal legislation has been proposed.

Some of the state laws, such as those in Connecticut, Texas, and Virginia, require informing all mammography patients about their density findings, whether or not they have dense breast tissue. Other states, such as California, Hawaii, and New York, require informing only those found to have dense tissue. And some states, such as California, Connecticut, Hawaii, Texas, and Virginia, require specific wording in the density notification letter (Table 1).

The details of all these notification laws may differ in how they specify which patients must be notified and in how the information should be worded, but the goal is the same: to raise women’s awareness so that they can embark on an informed decision with their physician about whether to undergo further testing.

Because of liability concerns, some breast imaging centers in states that currently lack such notification laws have begun informing women about their density results.

Unfortunately, at this point clinicians have no clear guidelines for helping patients with dense breasts decide whether to undergo additional testing. In addition, the evidence is equivocal, and the tests have risks as well as benefits. The patient needs to understand all this by discussing it with her physician. And to discuss this decision effectively, the physician must be well versed in the evolving literature on breast density. Below, we present important points to keep in mind as we foster these discussions with our patients.

BREAST TISSUE DENSITY IS STILL A SUBJECTIVE MEASUREMENT

Breast density limits the sensitivity of mammography. This is widely established. Yet the interpretation of breast density today is subjective. It is determined by the interpreting radiologist based on the Breast Imaging and Reporting Data System (BI-RADS), which defines “heterogeneously dense” breasts as those containing 50% to 75% dense tissue and “dense” breasts as those with more than 75%⁵ (Figure 1). This subjective measurement is based on two-dimensional imaging, which may underestimate or overestimate the percentage of breast density because of tissue summation. Ideally, density should be measured using three-dimensional imaging with automated software,⁶ but this technology is not yet widely available.

INCREASED DETECTION OF BENIGN LESIONS

Although adding ultrasonography to mammography in patients with dense breast tissue detects additional cancers,^7,8 it also leads to a significant increase in the detection of lesions that are not malignant yet require additional workup or biopsy.

The largest study to examine this was the American College of Radiology Imaging Network Protocol 6666 (ACRIN 6666),⁷ a multi-institutional study evaluating the diagnostic yield, sensitivity, and specificity of adding ultrasonography in high-risk patients who presented with negative mammograms and had heterogeneously dense tissue in at least one quadrant.⁷ (High risk was defined as a threefold higher risk of breast cancer as determined by risk factors such as personal history of breast cancer or high-risk lesions, or elevated risk using the Gail or Claus model.) The supplemental yield was 4.2 cancers per 1,000 women (95% confidence interval 1.1 to 7.2 per 1,000) on a single prevalent screen. Of 12 cancers detected solely by ultrasonography, 11 were invasive and had a median size of 10 mm. Of those reported, 8 of 9 were node-negative. Despite this additional yield, the positive predictive value of biopsy prompted by ultrasonography was only 8.9%.⁷ Other investigators have reported similar findings.⁸

RELATIONSHIP BETWEEN DENSITY AND CANCER RISK STILL NOT CLEAR

The relationship between breast density and cancer risk is not entirely clear. Higher breast density has been associated with a higher risk of breast cancer,^9,10 presumably because cancer usually develops in parenchyma, and not fatty tissue. Yet obesity and age, which are inversely associated with density, are also risk factors for the development of breast cancer. Some prominent radiologists have cast doubt on the methodology used in these density studies, which relied on density measurements calculated by two-dimensional views of the breast, and have called for a re-evaluation of the relationship between density and cancer risk.⁶

LIMITED HEALTH LITERACY: A CHALLENGE

The term “breast density” is unfamiliar to most lay people. As physicians, we need to keep in mind that more than a third of US adults have limited health literacy and thus have difficulty processing basic health information.¹¹ But even the 1 in 10 US women with “proficient” health literacy skills may find the term “density” confusing.

As the definition at the opening of this article suggests, the word itself is nuanced and has different meanings. Anecdotally, both of the authors, a general internist (E.M.) and a breast imaging specialist (M.Y.), have encountered numerous quizzical and sometimes distrustful reactions when telling patients—including some with graduate degrees—that they have “dense” breast tissue and might benefit from additional ultrasonographic testing. Avoiding jargon is key; studies have found that terms such as “benign” can be confusing when used in a mammogram result notification letter.¹²

How can we explain the concept of breast density to our patients?

Supplemental educational materials that feature simple pictures can also be helpful in conveying complex health information,¹³ although their effect on the communication of breast density has not been studied. The American College of Radiology and the Society of Breast Imaging produce a freely available, downloadable patient brochure on breast density that includes photographs of mammograms with high and low breast density. The brochure is available from the American College of Radiology online at www.acr.org, under “Tools you can use.”

We recommend introducing women to the concept of breast density before they undergo mammography—at the time the test is ordered—and provide them with supplemental materials such as the above-mentioned brochure. About 1 out of every 10 women who undergo screening mammography has a result requiring additional testing that does not result in a cancer diagnosis. Yet a body of research suggests that many women don’t realize that mammograms don’t always yield a cut-and-dried “cancer” or “no cancer” result. In past studies, women have said they were unaware of how common it is to be called back after routine screening mammography, and they wanted to be prepared for this in advance.^12,14 Similarly, many women are unaware of the concept of breast density and don’t know that they may be told about these findings when they get their mammogram report.

Avoid causing anxiety

When explaining results to women with dense breasts, we should emphasize that there are no abnormalities on the current mammogram, and that the only reason to consider additional imaging is the breast density. But regardless of the ultimate outcome, an abnormal mammogram can trigger long-standing anxiety, ¹⁵ and it is reasonable to assume that some women will become anxious when told they have highly dense breasts. It is important that clinicians be aware of this potential anxiety and inquire about any personal cancer-related concerns at the time they discuss their findings.¹⁶

Helping the patient choose the type of additional screening

If a patient is found to have dense breasts and chooses to undergo additional screening, the decision about which test—ultrasonography or MRI—can be based on the woman’s lifetime risk of breast cancer.

The American Cancer Society recommends that patients with a lifetime risk of 20% or greater—according to a risk model such as BRCAPRO, Tyrer-Cuzick, or BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm)—should be screened annually with breast MRI regardless of breast density. Patients in this category are those who carry the BRCA gene mutations and their untested first-degree relatives, and patients with Li-Fraumeni, Cowden, or Bannayan-Riley-Ruvalcaba syndrome. Also considered are women who underwent chest radiation between the ages of 10 and 30, and patients who have more than one first-degree relative with breast cancer but who do not have an identifiable genetic mutation.¹⁷

Patients with dense breasts who have an increased lifetime risk but who do not meet these criteria and those who are at average risk may be offered breast ultrasonography. If risk factors are unclear, genetic counseling can help determine the lifetime risk and thus help the patient choose the additional screening test.¹⁸

MORE WORK TO DO

Clearly, we still do not know how to explain breast density results to our patients in a way that will help them make a fully informed decision about additional screening. Research suggests that letters alone are insufficient,^13,19,20 and there is no guarantee that simply adding breast density notification language to result letters will enhance a woman’s understanding and empower her to choose a course of action that is sensitive to her personal preferences.

As more states adopt notification legislation, we must develop effective methods to improve our patients’ understanding of the meaning and implications of having dense breasts and to help them decide how to proceed. Such tools could include videos, Web sites, and pictorials, as well as specialized training for patient educators and health navigators. Otherwise, including this additional, conceptually difficult information to result notification letters could make the doctor-patient interaction even more “dense”—and could increase women’s uncertainty and anxiety about their personal risk of cancer.²¹

Density: The quality or state of being dense; the quantity per unit volume, unit area, or unit length; the degree of opacity of a translucent medium, or the common logarithm of the opacity.

—Merriam-Webster’s dictionary¹

For more than a decade, federal law in the United States has compelled breast imaging centers to give every mammography patient a letter explaining her result.²

See related editorial

Often, however, the first person a woman speaks to about her findings is her primary care clinician, particularly if she has had a screening mammogram at a center where films are “batch-read” and are not viewed by the radiologist at the time of the appointment. Internal medicine physicians are often called on to help women understand their findings and to order follow-up tests recommended by the radiologist—a not uncommon occurrence. Also, internists often need to address patients’ anxieties about the possibility of breast cancer and provide them with enough information to make an informed decision about an appropriate action plan.

Meanwhile, discussing mammography has become more complicated. In 2009, the United States Preventive Services Task Force stopped recommending that women under age 50 be routinely screened for breast cancer, and instead stated that the decision to begin screening these women should consider “patient context” and the patient’s personal “values”³—with the implication that women’s primary clinicians would play an important role in helping them weigh the test’s potential benefits and harms.

More and more, internists must grapple with the task of how to help women decipher the concept of “breast density,” understand their personal density results, and make an informed decision about whether to undergo additional imaging studies, such as ultrasonography and magnetic resonance imaging (MRI).

LEGISLATION REQUIRING DENSITY NOTIFICATION

The impetus for this change in practice has been spurred in large part by patient advocates, who have argued that women deserve to know their density because mammography is less sensitive in women with dense breasts. So far, at least 12 states have enacted laws requiring breast imaging centers to add information about breast density in the result notification letters they mail to patients. Legislatures in several other states are considering breast density notification laws,⁴ and federal legislation has been proposed.

Some of the state laws, such as those in Connecticut, Texas, and Virginia, require informing all mammography patients about their density findings, whether or not they have dense breast tissue. Other states, such as California, Hawaii, and New York, require informing only those found to have dense tissue. And some states, such as California, Connecticut, Hawaii, Texas, and Virginia, require specific wording in the density notification letter (Table 1).

The details of all these notification laws may differ in how they specify which patients must be notified and in how the information should be worded, but the goal is the same: to raise women’s awareness so that they can embark on an informed decision with their physician about whether to undergo further testing.

Because of liability concerns, some breast imaging centers in states that currently lack such notification laws have begun informing women about their density results.

Unfortunately, at this point clinicians have no clear guidelines for helping patients with dense breasts decide whether to undergo additional testing. In addition, the evidence is equivocal, and the tests have risks as well as benefits. The patient needs to understand all this by discussing it with her physician. And to discuss this decision effectively, the physician must be well versed in the evolving literature on breast density. Below, we present important points to keep in mind as we foster these discussions with our patients.

BREAST TISSUE DENSITY IS STILL A SUBJECTIVE MEASUREMENT

Breast density limits the sensitivity of mammography. This is widely established. Yet the interpretation of breast density today is subjective. It is determined by the interpreting radiologist based on the Breast Imaging and Reporting Data System (BI-RADS), which defines “heterogeneously dense” breasts as those containing 50% to 75% dense tissue and “dense” breasts as those with more than 75%⁵ (Figure 1). This subjective measurement is based on two-dimensional imaging, which may underestimate or overestimate the percentage of breast density because of tissue summation. Ideally, density should be measured using three-dimensional imaging with automated software,⁶ but this technology is not yet widely available.

INCREASED DETECTION OF BENIGN LESIONS

Although adding ultrasonography to mammography in patients with dense breast tissue detects additional cancers,^7,8 it also leads to a significant increase in the detection of lesions that are not malignant yet require additional workup or biopsy.

The largest study to examine this was the American College of Radiology Imaging Network Protocol 6666 (ACRIN 6666),⁷ a multi-institutional study evaluating the diagnostic yield, sensitivity, and specificity of adding ultrasonography in high-risk patients who presented with negative mammograms and had heterogeneously dense tissue in at least one quadrant.⁷ (High risk was defined as a threefold higher risk of breast cancer as determined by risk factors such as personal history of breast cancer or high-risk lesions, or elevated risk using the Gail or Claus model.) The supplemental yield was 4.2 cancers per 1,000 women (95% confidence interval 1.1 to 7.2 per 1,000) on a single prevalent screen. Of 12 cancers detected solely by ultrasonography, 11 were invasive and had a median size of 10 mm. Of those reported, 8 of 9 were node-negative. Despite this additional yield, the positive predictive value of biopsy prompted by ultrasonography was only 8.9%.⁷ Other investigators have reported similar findings.⁸

RELATIONSHIP BETWEEN DENSITY AND CANCER RISK STILL NOT CLEAR

The relationship between breast density and cancer risk is not entirely clear. Higher breast density has been associated with a higher risk of breast cancer,^9,10 presumably because cancer usually develops in parenchyma, and not fatty tissue. Yet obesity and age, which are inversely associated with density, are also risk factors for the development of breast cancer. Some prominent radiologists have cast doubt on the methodology used in these density studies, which relied on density measurements calculated by two-dimensional views of the breast, and have called for a re-evaluation of the relationship between density and cancer risk.⁶

LIMITED HEALTH LITERACY: A CHALLENGE

The term “breast density” is unfamiliar to most lay people. As physicians, we need to keep in mind that more than a third of US adults have limited health literacy and thus have difficulty processing basic health information.¹¹ But even the 1 in 10 US women with “proficient” health literacy skills may find the term “density” confusing.

As the definition at the opening of this article suggests, the word itself is nuanced and has different meanings. Anecdotally, both of the authors, a general internist (E.M.) and a breast imaging specialist (M.Y.), have encountered numerous quizzical and sometimes distrustful reactions when telling patients—including some with graduate degrees—that they have “dense” breast tissue and might benefit from additional ultrasonographic testing. Avoiding jargon is key; studies have found that terms such as “benign” can be confusing when used in a mammogram result notification letter.¹²

How can we explain the concept of breast density to our patients?

Supplemental educational materials that feature simple pictures can also be helpful in conveying complex health information,¹³ although their effect on the communication of breast density has not been studied. The American College of Radiology and the Society of Breast Imaging produce a freely available, downloadable patient brochure on breast density that includes photographs of mammograms with high and low breast density. The brochure is available from the American College of Radiology online at www.acr.org, under “Tools you can use.”

We recommend introducing women to the concept of breast density before they undergo mammography—at the time the test is ordered—and provide them with supplemental materials such as the above-mentioned brochure. About 1 out of every 10 women who undergo screening mammography has a result requiring additional testing that does not result in a cancer diagnosis. Yet a body of research suggests that many women don’t realize that mammograms don’t always yield a cut-and-dried “cancer” or “no cancer” result. In past studies, women have said they were unaware of how common it is to be called back after routine screening mammography, and they wanted to be prepared for this in advance.^12,14 Similarly, many women are unaware of the concept of breast density and don’t know that they may be told about these findings when they get their mammogram report.

Avoid causing anxiety

When explaining results to women with dense breasts, we should emphasize that there are no abnormalities on the current mammogram, and that the only reason to consider additional imaging is the breast density. But regardless of the ultimate outcome, an abnormal mammogram can trigger long-standing anxiety, ¹⁵ and it is reasonable to assume that some women will become anxious when told they have highly dense breasts. It is important that clinicians be aware of this potential anxiety and inquire about any personal cancer-related concerns at the time they discuss their findings.¹⁶

Helping the patient choose the type of additional screening

If a patient is found to have dense breasts and chooses to undergo additional screening, the decision about which test—ultrasonography or MRI—can be based on the woman’s lifetime risk of breast cancer.

The American Cancer Society recommends that patients with a lifetime risk of 20% or greater—according to a risk model such as BRCAPRO, Tyrer-Cuzick, or BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm)—should be screened annually with breast MRI regardless of breast density. Patients in this category are those who carry the BRCA gene mutations and their untested first-degree relatives, and patients with Li-Fraumeni, Cowden, or Bannayan-Riley-Ruvalcaba syndrome. Also considered are women who underwent chest radiation between the ages of 10 and 30, and patients who have more than one first-degree relative with breast cancer but who do not have an identifiable genetic mutation.¹⁷

Patients with dense breasts who have an increased lifetime risk but who do not meet these criteria and those who are at average risk may be offered breast ultrasonography. If risk factors are unclear, genetic counseling can help determine the lifetime risk and thus help the patient choose the additional screening test.¹⁸

MORE WORK TO DO

Clearly, we still do not know how to explain breast density results to our patients in a way that will help them make a fully informed decision about additional screening. Research suggests that letters alone are insufficient,^13,19,20 and there is no guarantee that simply adding breast density notification language to result letters will enhance a woman’s understanding and empower her to choose a course of action that is sensitive to her personal preferences.

As more states adopt notification legislation, we must develop effective methods to improve our patients’ understanding of the meaning and implications of having dense breasts and to help them decide how to proceed. Such tools could include videos, Web sites, and pictorials, as well as specialized training for patient educators and health navigators. Otherwise, including this additional, conceptually difficult information to result notification letters could make the doctor-patient interaction even more “dense”—and could increase women’s uncertainty and anxiety about their personal risk of cancer.²¹

Density: The quality or state of being dense; the quantity per unit volume, unit area, or unit length; the degree of opacity of a translucent medium, or the common logarithm of the opacity.

—Merriam-Webster’s dictionary¹

For more than a decade, federal law in the United States has compelled breast imaging centers to give every mammography patient a letter explaining her result.²

See related editorial

Often, however, the first person a woman speaks to about her findings is her primary care clinician, particularly if she has had a screening mammogram at a center where films are “batch-read” and are not viewed by the radiologist at the time of the appointment. Internal medicine physicians are often called on to help women understand their findings and to order follow-up tests recommended by the radiologist—a not uncommon occurrence. Also, internists often need to address patients’ anxieties about the possibility of breast cancer and provide them with enough information to make an informed decision about an appropriate action plan.

Meanwhile, discussing mammography has become more complicated. In 2009, the United States Preventive Services Task Force stopped recommending that women under age 50 be routinely screened for breast cancer, and instead stated that the decision to begin screening these women should consider “patient context” and the patient’s personal “values”³—with the implication that women’s primary clinicians would play an important role in helping them weigh the test’s potential benefits and harms.

More and more, internists must grapple with the task of how to help women decipher the concept of “breast density,” understand their personal density results, and make an informed decision about whether to undergo additional imaging studies, such as ultrasonography and magnetic resonance imaging (MRI).

LEGISLATION REQUIRING DENSITY NOTIFICATION

The impetus for this change in practice has been spurred in large part by patient advocates, who have argued that women deserve to know their density because mammography is less sensitive in women with dense breasts. So far, at least 12 states have enacted laws requiring breast imaging centers to add information about breast density in the result notification letters they mail to patients. Legislatures in several other states are considering breast density notification laws,⁴ and federal legislation has been proposed.

Some of the state laws, such as those in Connecticut, Texas, and Virginia, require informing all mammography patients about their density findings, whether or not they have dense breast tissue. Other states, such as California, Hawaii, and New York, require informing only those found to have dense tissue. And some states, such as California, Connecticut, Hawaii, Texas, and Virginia, require specific wording in the density notification letter (Table 1).

The details of all these notification laws may differ in how they specify which patients must be notified and in how the information should be worded, but the goal is the same: to raise women’s awareness so that they can embark on an informed decision with their physician about whether to undergo further testing.

Because of liability concerns, some breast imaging centers in states that currently lack such notification laws have begun informing women about their density results.

Unfortunately, at this point clinicians have no clear guidelines for helping patients with dense breasts decide whether to undergo additional testing. In addition, the evidence is equivocal, and the tests have risks as well as benefits. The patient needs to understand all this by discussing it with her physician. And to discuss this decision effectively, the physician must be well versed in the evolving literature on breast density. Below, we present important points to keep in mind as we foster these discussions with our patients.

BREAST TISSUE DENSITY IS STILL A SUBJECTIVE MEASUREMENT

Breast density limits the sensitivity of mammography. This is widely established. Yet the interpretation of breast density today is subjective. It is determined by the interpreting radiologist based on the Breast Imaging and Reporting Data System (BI-RADS), which defines “heterogeneously dense” breasts as those containing 50% to 75% dense tissue and “dense” breasts as those with more than 75%⁵ (Figure 1). This subjective measurement is based on two-dimensional imaging, which may underestimate or overestimate the percentage of breast density because of tissue summation. Ideally, density should be measured using three-dimensional imaging with automated software,⁶ but this technology is not yet widely available.

INCREASED DETECTION OF BENIGN LESIONS

Although adding ultrasonography to mammography in patients with dense breast tissue detects additional cancers,^7,8 it also leads to a significant increase in the detection of lesions that are not malignant yet require additional workup or biopsy.

The largest study to examine this was the American College of Radiology Imaging Network Protocol 6666 (ACRIN 6666),⁷ a multi-institutional study evaluating the diagnostic yield, sensitivity, and specificity of adding ultrasonography in high-risk patients who presented with negative mammograms and had heterogeneously dense tissue in at least one quadrant.⁷ (High risk was defined as a threefold higher risk of breast cancer as determined by risk factors such as personal history of breast cancer or high-risk lesions, or elevated risk using the Gail or Claus model.) The supplemental yield was 4.2 cancers per 1,000 women (95% confidence interval 1.1 to 7.2 per 1,000) on a single prevalent screen. Of 12 cancers detected solely by ultrasonography, 11 were invasive and had a median size of 10 mm. Of those reported, 8 of 9 were node-negative. Despite this additional yield, the positive predictive value of biopsy prompted by ultrasonography was only 8.9%.⁷ Other investigators have reported similar findings.⁸

RELATIONSHIP BETWEEN DENSITY AND CANCER RISK STILL NOT CLEAR

The relationship between breast density and cancer risk is not entirely clear. Higher breast density has been associated with a higher risk of breast cancer,^9,10 presumably because cancer usually develops in parenchyma, and not fatty tissue. Yet obesity and age, which are inversely associated with density, are also risk factors for the development of breast cancer. Some prominent radiologists have cast doubt on the methodology used in these density studies, which relied on density measurements calculated by two-dimensional views of the breast, and have called for a re-evaluation of the relationship between density and cancer risk.⁶

LIMITED HEALTH LITERACY: A CHALLENGE

The term “breast density” is unfamiliar to most lay people. As physicians, we need to keep in mind that more than a third of US adults have limited health literacy and thus have difficulty processing basic health information.¹¹ But even the 1 in 10 US women with “proficient” health literacy skills may find the term “density” confusing.

As the definition at the opening of this article suggests, the word itself is nuanced and has different meanings. Anecdotally, both of the authors, a general internist (E.M.) and a breast imaging specialist (M.Y.), have encountered numerous quizzical and sometimes distrustful reactions when telling patients—including some with graduate degrees—that they have “dense” breast tissue and might benefit from additional ultrasonographic testing. Avoiding jargon is key; studies have found that terms such as “benign” can be confusing when used in a mammogram result notification letter.¹²

How can we explain the concept of breast density to our patients?

Supplemental educational materials that feature simple pictures can also be helpful in conveying complex health information,¹³ although their effect on the communication of breast density has not been studied. The American College of Radiology and the Society of Breast Imaging produce a freely available, downloadable patient brochure on breast density that includes photographs of mammograms with high and low breast density. The brochure is available from the American College of Radiology online at www.acr.org, under “Tools you can use.”

We recommend introducing women to the concept of breast density before they undergo mammography—at the time the test is ordered—and provide them with supplemental materials such as the above-mentioned brochure. About 1 out of every 10 women who undergo screening mammography has a result requiring additional testing that does not result in a cancer diagnosis. Yet a body of research suggests that many women don’t realize that mammograms don’t always yield a cut-and-dried “cancer” or “no cancer” result. In past studies, women have said they were unaware of how common it is to be called back after routine screening mammography, and they wanted to be prepared for this in advance.^12,14 Similarly, many women are unaware of the concept of breast density and don’t know that they may be told about these findings when they get their mammogram report.

Avoid causing anxiety

When explaining results to women with dense breasts, we should emphasize that there are no abnormalities on the current mammogram, and that the only reason to consider additional imaging is the breast density. But regardless of the ultimate outcome, an abnormal mammogram can trigger long-standing anxiety, ¹⁵ and it is reasonable to assume that some women will become anxious when told they have highly dense breasts. It is important that clinicians be aware of this potential anxiety and inquire about any personal cancer-related concerns at the time they discuss their findings.¹⁶

Helping the patient choose the type of additional screening

If a patient is found to have dense breasts and chooses to undergo additional screening, the decision about which test—ultrasonography or MRI—can be based on the woman’s lifetime risk of breast cancer.

The American Cancer Society recommends that patients with a lifetime risk of 20% or greater—according to a risk model such as BRCAPRO, Tyrer-Cuzick, or BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm)—should be screened annually with breast MRI regardless of breast density. Patients in this category are those who carry the BRCA gene mutations and their untested first-degree relatives, and patients with Li-Fraumeni, Cowden, or Bannayan-Riley-Ruvalcaba syndrome. Also considered are women who underwent chest radiation between the ages of 10 and 30, and patients who have more than one first-degree relative with breast cancer but who do not have an identifiable genetic mutation.¹⁷

Patients with dense breasts who have an increased lifetime risk but who do not meet these criteria and those who are at average risk may be offered breast ultrasonography. If risk factors are unclear, genetic counseling can help determine the lifetime risk and thus help the patient choose the additional screening test.¹⁸

MORE WORK TO DO

Clearly, we still do not know how to explain breast density results to our patients in a way that will help them make a fully informed decision about additional screening. Research suggests that letters alone are insufficient,^13,19,20 and there is no guarantee that simply adding breast density notification language to result letters will enhance a woman’s understanding and empower her to choose a course of action that is sensitive to her personal preferences.

As more states adopt notification legislation, we must develop effective methods to improve our patients’ understanding of the meaning and implications of having dense breasts and to help them decide how to proceed. Such tools could include videos, Web sites, and pictorials, as well as specialized training for patient educators and health navigators. Otherwise, including this additional, conceptually difficult information to result notification letters could make the doctor-patient interaction even more “dense”—and could increase women’s uncertainty and anxiety about their personal risk of cancer.²¹

Recently, Nevada,¹ North Carolina, and Oregon joined a number of other US states (as of this writing, nine other states) in enacting laws that require informing women if they have dense breast tissue detected on mammography.² Laws are pending in other states. Federal legislation has also been introduced in the US House of Representatives.

See related commentary

THE POWER OF ADVOCACY TO CHANGE MEDICAL PRACTICE

One such bill³ was introduced as a result of the advocacy of a single patient, Nancy Cappello, a Connecticut woman who was not informed that she had dense breasts and was later found to have node-positive breast cancer.⁴

While new medical practices are rarely credited to the efforts of single physician or researcher, these “dense-breast laws” show the power a single patient may play in health care. The evidence behind these laws and their implications bring to the forefront the role of advocacy and legislation in the practice of medicine.

Dense-breast laws are the latest chapter in how legislative action can change the practice of medicine. Proof that advocacy could use law to change medical practice emerged in the early 1990s in the wake of AIDS activism. Patient-advocacy activists lobbied for early access to investigational agents, arguing that traditional pathways of clinical testing would deprive terminally ill patients of potentially lifesaving treatments. These efforts led the US Food and Drug Administration (FDA) to create the Accelerated Approval Program, which allows new drugs to garner approval based on surrogate end-point data for terminal or neglected diseases. Accelerated approval was codified into law in 1997 in the FDA’s Modernization Act.⁵ In 2012, legislative action further broadened the ability of the FDA to approve new products based on surrogate data,⁶ with the FDA’s Safety and Innovation Act, which provides for first-time approval of a drug based on “pharmacologic” end points that are even more limited.⁶

Although proponents have declared success when legislative action lowers the bar for drug and device approval, independent analyses have been more critical. In 2009, accelerated approval underwent significant scrutiny when the Government Accountability Office issued a report summarizing 16 years of the program.⁷ Over the program’s life span, the FDA called for 144 postmarketing studies, but more than one-third of these remained incomplete. Moreover, in 13 years, the FDA never exercised its power to expedite the withdrawal of a drug from the market.

Many accelerated approvals have created considerable controversy. Bevacizumab for metastatic breast cancer was ultimately found to confer no survival benefit, and its approval was revoked.⁸ Gemtuzumab ozogamicin for acute myeloid leukemia may be effective, but not at the dose that was approved.⁹ And midodrine hydrochloride and many other drugs remain untested.¹⁰

DOES THIS INFORMATION HELP PATIENTS? WHAT WOULD THEY DO WITH IT?

The question with dense-breast laws is similar to that facing other legal efforts to change medicine: Does it actually help patents? Will the information doctors disclose lead to appropriate interventions that improve health outcomes, or, instead, lead to cascades of testing and biopsies that worsen overdiagnosis?

Like accelerated approval, mandating disclosure of breast density is an intervention with uncertain efficacy. While increased breast density has been shown to increase a woman’s risk of developing breast cancer, it is also neutral regarding a woman’s chances of dying of breast cancer.¹¹ In other words, it does not identify patients who experience aggressive disease.

Next comes the larger question of what women would do with this information. Will they simply be more compliant with existing screening recommendations, or will they seek additional testing? This is where the greatest uncertainty lies. The utility of additional testing with ultrasonography or magnetic resonance imaging (MRI) remains uncertain in this population. We will certainly find more cancers if we use MRI to screen women, but it remains unclear if this translates to improved outcomes.

A recent study shows just this.¹² In Connecticut, breast density notification is mandatory, as is insurance coverage for screening (or whole-breast) ultrasonography. Since the passage of these laws, the Yale Medical Center has screened 935 women with dense breasts using ultrasonography. Over this time, they performed roughly 16,000 mammograms; thus, the breast density law applied roughly to 1 out of 16 (6.25%) studies. Of the 935 women, biopsies were performed in 54 (5.8%). These were mostly needle biopsies (46), but 3 patients underwent surgical excision, and five cysts were aspirated. From these efforts, two sub-centimeter cancers were found and one case of ductal carcinoma in situ was found. Thus, only 3.7% of women undergoing biopsy and fewer than 1% of women undergoing ultrasonography were found to have cancer.

Of course, given the nature of this study, we cannot know what would have happened without referral and testing. However, empirical research suggests that detecting a breast cancer with screening does not mean a life was saved.¹³ In fact, only a minority of such women (13%) can credit screening with a survival gain.¹³

In a study¹⁴ that compared women with dense breasts who underwent annual vs biannual screening, no difference in the rate of advanced or metastatic disease was seen with more frequent screening, but the rates of false-positive results and biopsies were higher.¹⁴

Notably, dense-breast legislation comes at a time when fundamental questions have been raised about the impact of screening on breast cancer. A prominent study of trends in US breast cancer incidence and death rates over the last 30 years shows that even under the most favorable assumptions, mammography has led to a huge surplus in the diagnosis of breast cancer but little change in the breast cancer mortality rate.¹⁵ It is entirely possible that more-aggressive screening in women with dense breasts will only exacerbate this problem. Advocacy may harm rather than help these patients.

We are often told that laws such as the dense-breast bills are motivated by the public’s desire and patient advocacy. However, we are unsure if the vocal proponents of dense-breast laws represent the average women’s desires. These efforts may simply be another case of how a vocal and passionate minority can overcome a large and indifferent majority.¹⁶

LEGISLATING MEDICAL PRACTICE IS A BOLD STEP

Dense-breast laws present an additional challenge: they cannot be changed as quickly as scientific understanding. In other words, if the medical field comes to believe that notification is generally harmful because it leads to increased biopsies but not better health, can the law be changed rapidly enough to reflect this? There is a large precedent for the reversal of medical practices,^17,18 particularly those based on scant evidence, including cases of recommended screening tests (most notably, recent changes to prostate-specific antigen guidelines). But in all these other cases, law did not mandate the practice or recommendation. Laws are often slow to adapt to changes in understanding.

Legislating medical practice is a bold step, and even those who feel it is occasionally warranted must hold themselves to a rational guiding principle. We have incontrovertible evidence that flexible sigmoidoscopy can reduce the number of deaths from colorectal cancer, but no state mandates that doctors inform their patients of this fact. A patient’s ejection fraction serves as a marker of benefit for several lifesaving drugs and devices, yet no state mandates that physicians disclose this information to patients after echocardiography.

All of us in health care—physicians, researchers, nurses, practitioners, and patients—are patient advocates, and we all want policies that promote human health. However, doing so means adhering to practices grounded in evidence. Dense-breast laws serve as a reminder that good intentions and good people may be necessary—but are not sufficient—for sound policy.

Recently, Nevada,¹ North Carolina, and Oregon joined a number of other US states (as of this writing, nine other states) in enacting laws that require informing women if they have dense breast tissue detected on mammography.² Laws are pending in other states. Federal legislation has also been introduced in the US House of Representatives.

See related commentary

THE POWER OF ADVOCACY TO CHANGE MEDICAL PRACTICE

One such bill³ was introduced as a result of the advocacy of a single patient, Nancy Cappello, a Connecticut woman who was not informed that she had dense breasts and was later found to have node-positive breast cancer.⁴

While new medical practices are rarely credited to the efforts of single physician or researcher, these “dense-breast laws” show the power a single patient may play in health care. The evidence behind these laws and their implications bring to the forefront the role of advocacy and legislation in the practice of medicine.

Dense-breast laws are the latest chapter in how legislative action can change the practice of medicine. Proof that advocacy could use law to change medical practice emerged in the early 1990s in the wake of AIDS activism. Patient-advocacy activists lobbied for early access to investigational agents, arguing that traditional pathways of clinical testing would deprive terminally ill patients of potentially lifesaving treatments. These efforts led the US Food and Drug Administration (FDA) to create the Accelerated Approval Program, which allows new drugs to garner approval based on surrogate end-point data for terminal or neglected diseases. Accelerated approval was codified into law in 1997 in the FDA’s Modernization Act.⁵ In 2012, legislative action further broadened the ability of the FDA to approve new products based on surrogate data,⁶ with the FDA’s Safety and Innovation Act, which provides for first-time approval of a drug based on “pharmacologic” end points that are even more limited.⁶

Although proponents have declared success when legislative action lowers the bar for drug and device approval, independent analyses have been more critical. In 2009, accelerated approval underwent significant scrutiny when the Government Accountability Office issued a report summarizing 16 years of the program.⁷ Over the program’s life span, the FDA called for 144 postmarketing studies, but more than one-third of these remained incomplete. Moreover, in 13 years, the FDA never exercised its power to expedite the withdrawal of a drug from the market.

Many accelerated approvals have created considerable controversy. Bevacizumab for metastatic breast cancer was ultimately found to confer no survival benefit, and its approval was revoked.⁸ Gemtuzumab ozogamicin for acute myeloid leukemia may be effective, but not at the dose that was approved.⁹ And midodrine hydrochloride and many other drugs remain untested.¹⁰

DOES THIS INFORMATION HELP PATIENTS? WHAT WOULD THEY DO WITH IT?

The question with dense-breast laws is similar to that facing other legal efforts to change medicine: Does it actually help patents? Will the information doctors disclose lead to appropriate interventions that improve health outcomes, or, instead, lead to cascades of testing and biopsies that worsen overdiagnosis?

Like accelerated approval, mandating disclosure of breast density is an intervention with uncertain efficacy. While increased breast density has been shown to increase a woman’s risk of developing breast cancer, it is also neutral regarding a woman’s chances of dying of breast cancer.¹¹ In other words, it does not identify patients who experience aggressive disease.

Next comes the larger question of what women would do with this information. Will they simply be more compliant with existing screening recommendations, or will they seek additional testing? This is where the greatest uncertainty lies. The utility of additional testing with ultrasonography or magnetic resonance imaging (MRI) remains uncertain in this population. We will certainly find more cancers if we use MRI to screen women, but it remains unclear if this translates to improved outcomes.

A recent study shows just this.¹² In Connecticut, breast density notification is mandatory, as is insurance coverage for screening (or whole-breast) ultrasonography. Since the passage of these laws, the Yale Medical Center has screened 935 women with dense breasts using ultrasonography. Over this time, they performed roughly 16,000 mammograms; thus, the breast density law applied roughly to 1 out of 16 (6.25%) studies. Of the 935 women, biopsies were performed in 54 (5.8%). These were mostly needle biopsies (46), but 3 patients underwent surgical excision, and five cysts were aspirated. From these efforts, two sub-centimeter cancers were found and one case of ductal carcinoma in situ was found. Thus, only 3.7% of women undergoing biopsy and fewer than 1% of women undergoing ultrasonography were found to have cancer.

Of course, given the nature of this study, we cannot know what would have happened without referral and testing. However, empirical research suggests that detecting a breast cancer with screening does not mean a life was saved.¹³ In fact, only a minority of such women (13%) can credit screening with a survival gain.¹³

In a study¹⁴ that compared women with dense breasts who underwent annual vs biannual screening, no difference in the rate of advanced or metastatic disease was seen with more frequent screening, but the rates of false-positive results and biopsies were higher.¹⁴

Notably, dense-breast legislation comes at a time when fundamental questions have been raised about the impact of screening on breast cancer. A prominent study of trends in US breast cancer incidence and death rates over the last 30 years shows that even under the most favorable assumptions, mammography has led to a huge surplus in the diagnosis of breast cancer but little change in the breast cancer mortality rate.¹⁵ It is entirely possible that more-aggressive screening in women with dense breasts will only exacerbate this problem. Advocacy may harm rather than help these patients.

We are often told that laws such as the dense-breast bills are motivated by the public’s desire and patient advocacy. However, we are unsure if the vocal proponents of dense-breast laws represent the average women’s desires. These efforts may simply be another case of how a vocal and passionate minority can overcome a large and indifferent majority.¹⁶

LEGISLATING MEDICAL PRACTICE IS A BOLD STEP

Dense-breast laws present an additional challenge: they cannot be changed as quickly as scientific understanding. In other words, if the medical field comes to believe that notification is generally harmful because it leads to increased biopsies but not better health, can the law be changed rapidly enough to reflect this? There is a large precedent for the reversal of medical practices,^17,18 particularly those based on scant evidence, including cases of recommended screening tests (most notably, recent changes to prostate-specific antigen guidelines). But in all these other cases, law did not mandate the practice or recommendation. Laws are often slow to adapt to changes in understanding.

Legislating medical practice is a bold step, and even those who feel it is occasionally warranted must hold themselves to a rational guiding principle. We have incontrovertible evidence that flexible sigmoidoscopy can reduce the number of deaths from colorectal cancer, but no state mandates that doctors inform their patients of this fact. A patient’s ejection fraction serves as a marker of benefit for several lifesaving drugs and devices, yet no state mandates that physicians disclose this information to patients after echocardiography.

All of us in health care—physicians, researchers, nurses, practitioners, and patients—are patient advocates, and we all want policies that promote human health. However, doing so means adhering to practices grounded in evidence. Dense-breast laws serve as a reminder that good intentions and good people may be necessary—but are not sufficient—for sound policy.

Recently, Nevada,¹ North Carolina, and Oregon joined a number of other US states (as of this writing, nine other states) in enacting laws that require informing women if they have dense breast tissue detected on mammography.² Laws are pending in other states. Federal legislation has also been introduced in the US House of Representatives.

See related commentary

THE POWER OF ADVOCACY TO CHANGE MEDICAL PRACTICE

One such bill³ was introduced as a result of the advocacy of a single patient, Nancy Cappello, a Connecticut woman who was not informed that she had dense breasts and was later found to have node-positive breast cancer.⁴

While new medical practices are rarely credited to the efforts of single physician or researcher, these “dense-breast laws” show the power a single patient may play in health care. The evidence behind these laws and their implications bring to the forefront the role of advocacy and legislation in the practice of medicine.

Dense-breast laws are the latest chapter in how legislative action can change the practice of medicine. Proof that advocacy could use law to change medical practice emerged in the early 1990s in the wake of AIDS activism. Patient-advocacy activists lobbied for early access to investigational agents, arguing that traditional pathways of clinical testing would deprive terminally ill patients of potentially lifesaving treatments. These efforts led the US Food and Drug Administration (FDA) to create the Accelerated Approval Program, which allows new drugs to garner approval based on surrogate end-point data for terminal or neglected diseases. Accelerated approval was codified into law in 1997 in the FDA’s Modernization Act.⁵ In 2012, legislative action further broadened the ability of the FDA to approve new products based on surrogate data,⁶ with the FDA’s Safety and Innovation Act, which provides for first-time approval of a drug based on “pharmacologic” end points that are even more limited.⁶

Although proponents have declared success when legislative action lowers the bar for drug and device approval, independent analyses have been more critical. In 2009, accelerated approval underwent significant scrutiny when the Government Accountability Office issued a report summarizing 16 years of the program.⁷ Over the program’s life span, the FDA called for 144 postmarketing studies, but more than one-third of these remained incomplete. Moreover, in 13 years, the FDA never exercised its power to expedite the withdrawal of a drug from the market.

Many accelerated approvals have created considerable controversy. Bevacizumab for metastatic breast cancer was ultimately found to confer no survival benefit, and its approval was revoked.⁸ Gemtuzumab ozogamicin for acute myeloid leukemia may be effective, but not at the dose that was approved.⁹ And midodrine hydrochloride and many other drugs remain untested.¹⁰

DOES THIS INFORMATION HELP PATIENTS? WHAT WOULD THEY DO WITH IT?

The question with dense-breast laws is similar to that facing other legal efforts to change medicine: Does it actually help patents? Will the information doctors disclose lead to appropriate interventions that improve health outcomes, or, instead, lead to cascades of testing and biopsies that worsen overdiagnosis?

Like accelerated approval, mandating disclosure of breast density is an intervention with uncertain efficacy. While increased breast density has been shown to increase a woman’s risk of developing breast cancer, it is also neutral regarding a woman’s chances of dying of breast cancer.¹¹ In other words, it does not identify patients who experience aggressive disease.

Next comes the larger question of what women would do with this information. Will they simply be more compliant with existing screening recommendations, or will they seek additional testing? This is where the greatest uncertainty lies. The utility of additional testing with ultrasonography or magnetic resonance imaging (MRI) remains uncertain in this population. We will certainly find more cancers if we use MRI to screen women, but it remains unclear if this translates to improved outcomes.

A recent study shows just this.¹² In Connecticut, breast density notification is mandatory, as is insurance coverage for screening (or whole-breast) ultrasonography. Since the passage of these laws, the Yale Medical Center has screened 935 women with dense breasts using ultrasonography. Over this time, they performed roughly 16,000 mammograms; thus, the breast density law applied roughly to 1 out of 16 (6.25%) studies. Of the 935 women, biopsies were performed in 54 (5.8%). These were mostly needle biopsies (46), but 3 patients underwent surgical excision, and five cysts were aspirated. From these efforts, two sub-centimeter cancers were found and one case of ductal carcinoma in situ was found. Thus, only 3.7% of women undergoing biopsy and fewer than 1% of women undergoing ultrasonography were found to have cancer.

Of course, given the nature of this study, we cannot know what would have happened without referral and testing. However, empirical research suggests that detecting a breast cancer with screening does not mean a life was saved.¹³ In fact, only a minority of such women (13%) can credit screening with a survival gain.¹³

In a study¹⁴ that compared women with dense breasts who underwent annual vs biannual screening, no difference in the rate of advanced or metastatic disease was seen with more frequent screening, but the rates of false-positive results and biopsies were higher.¹⁴

Notably, dense-breast legislation comes at a time when fundamental questions have been raised about the impact of screening on breast cancer. A prominent study of trends in US breast cancer incidence and death rates over the last 30 years shows that even under the most favorable assumptions, mammography has led to a huge surplus in the diagnosis of breast cancer but little change in the breast cancer mortality rate.¹⁵ It is entirely possible that more-aggressive screening in women with dense breasts will only exacerbate this problem. Advocacy may harm rather than help these patients.

We are often told that laws such as the dense-breast bills are motivated by the public’s desire and patient advocacy. However, we are unsure if the vocal proponents of dense-breast laws represent the average women’s desires. These efforts may simply be another case of how a vocal and passionate minority can overcome a large and indifferent majority.¹⁶

LEGISLATING MEDICAL PRACTICE IS A BOLD STEP

Dense-breast laws present an additional challenge: they cannot be changed as quickly as scientific understanding. In other words, if the medical field comes to believe that notification is generally harmful because it leads to increased biopsies but not better health, can the law be changed rapidly enough to reflect this? There is a large precedent for the reversal of medical practices,^17,18 particularly those based on scant evidence, including cases of recommended screening tests (most notably, recent changes to prostate-specific antigen guidelines). But in all these other cases, law did not mandate the practice or recommendation. Laws are often slow to adapt to changes in understanding.

Legislating medical practice is a bold step, and even those who feel it is occasionally warranted must hold themselves to a rational guiding principle. We have incontrovertible evidence that flexible sigmoidoscopy can reduce the number of deaths from colorectal cancer, but no state mandates that doctors inform their patients of this fact. A patient’s ejection fraction serves as a marker of benefit for several lifesaving drugs and devices, yet no state mandates that physicians disclose this information to patients after echocardiography.

All of us in health care—physicians, researchers, nurses, practitioners, and patients—are patient advocates, and we all want policies that promote human health. However, doing so means adhering to practices grounded in evidence. Dense-breast laws serve as a reminder that good intentions and good people may be necessary—but are not sufficient—for sound policy.

Current evidence suggests no absolute contraindication to angiotensin receptor blockers (ARBs) in patients who have had angioedema attributable to an angiotensin-converting enzyme (ACE) inhibitor. However, since ARBs can also cause angioedema, they should be prescribed with extreme caution after a thorough risk-benefit analysis and after educating the patient to watch for signs of angioedema while taking the drug.

A GROWING PROBLEM

Angioedema is a potentially life-threatening swelling of the skin and subcutaneous tissues, often affecting the lips and tongue (Figure 1), and in some cases interfering with breathing and requiring tracheostomy.¹ The incidence rate of angioedema in patients taking ACE inhibitors ranges from 0.1% to 0.7%.^2–4 Although this rate may seem low, the widespread and growing use of ACE inhibitors and ARBs in patients with diabetes, diabetic nephropathy, and congestive heart failure⁵ makes angioedema fairly common in clinical practice.

ACE inhibitor-induced angioedema most commonly occurs within days of initiating therapy, but it also may occur weeks, months, or even years after the start of treatment.¹ Patients who are over age 65, black, or female are at higher risk, as are renal transplant recipients taking mTOR inhibitors such as sirolimus. Diabetes appears to be associated with a lower risk.^4,6,7 This adverse reaction to ACE inhibitors is thought to be a class side effect, and the future use of this class of drugs would be contraindicated.^8,9

ACE inhibitors cause angioedema by direct interference with the degradation of bradykinin, thereby increasing bradykinin levels and potentiating its biologic effect, leading to increased vascular permeability, inflammation, and activation of nociceptors.⁸

EVIDENCE TO SUPPORT THE USE OF ARBs

ACE inhibitors and ARBs both block the renin-angiotensin-aldosterone pathway and confer similar advantages in patients with congestive heart failure, renal failure, and diabetes. But since ARBs directly inhibit the angiotensin receptor and do not interfere with bradykinin degradation, how they cause angioedema is unclear, and clinicians have questioned whether these agents might be used safely in patients who have had angioedema on an ACE inhibitor.

In a large meta-analysis of randomized clinical trials, Makani et al² investigated the risk of angioedema with ARB use in 35,479 patients and compared this with other commonly used antihypertensive drugs. The weighted incidence of angioedema was 0.30% with an ACE inhibitor, 0.11% with an ARB, and 0.07% with placebo.² In seven trials included in this study that compared ARBs with placebo, there was no significant difference in the risk of angioedema. Even in such a large study, the event rate was small, making definite conclusions difficult.

In a retrospective observational study of 4 million patients by Toh et al,³ patients on beta-blockers were used as a reference, and propensity scoring was used to estimate the hazard ratio of angioedema separately for drugs targeting the renin-angiotensin-aldosterone system, including ACE inhibitors and ARBs. The risk of angioedema, as measured by the cumulative incidence and incidence rate, was highest for ACE inhibitors and was similar between ARBs and beta-blockers. The risk of serious angioedema was three times higher with ACE inhibitors than with beta-blockers, and there was no higher risk of serious angioedema with ARBs than with beta-blockers.³

Looking specifically at the use of ARBs in patients who developed angioedema on an ACE inhibitor, Haymore et al¹⁰ performed a meta-analysis evaluating only three studies that showed the estimated risk of angioedema with an ARB was between 3.5% and 9.4% in patients with a history of ACE inhibitor-induced angioedema. Later, when the results of the Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease trial¹¹ were published, the previous meta-analysis was updated¹²: the risk of angioedema with an ARB was only 2.5% (95% confidence interval 0%–6.6%), and there was no statistically significant difference in the odds (odds ratio 1.1; 95% confidence interval 0.07–17) of angioedema between ARBs and placebo.^10,12 Again, these results should be interpreted with caution, as only two patients in the ARB (telmisartan) group and three patients in the placebo group developed angioedema.

In another review, Beavers et al¹³ advised that the prescribing practitioner should carefully perform a risk-benefit analysis before substituting an ARB in patients with ACE inhibitor-induced angioedema. They concluded that an ARB could be considered in patients who are likely to have a large clinical benefit from an ARB, such as those with heart failure. They also suggested that angioedema related to ARBs was less severe and occurred earlier than with that linked to ACE inhibitors.

No large clinical trial has yet been specifically designed to address the use of ARBs in patients with a history of ACE inhibitor-induced angioedema. The package insert for the ARB losartan mentions that the risk of this adverse reaction might be higher in patients who have had angioedema on an ACE inhibitor. However, the issue of recurrent angioedema is not further addressed for this or other commonly used ARBs.

GENERAL RECOMMENDATIONS

The mechanisms of ARB-induced angioedema are yet unknown. However, studies have shown that the incidence of angioedema while on an ARB is low and is probably comparable to that of placebo.^2,3,12–14 And since ARBs share many of the cardiac and renal protective effects of ACE inhibitors, ARBs may be beneficial for patients who discontinue an ACE inhibitor because of adverse effects including angioedema.^9,15,16 Based on the discussion above, there is no clear evidence to suggest that ARBs are contraindicated in such patients, especially if there is a compelling indication for an ARB.

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines on hypertension in chronic kidney disease recommend caution when substituting an ARB for an ACE inhibitor after angioedema.¹⁵ The joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA) for the diagnosis and management of heart failure in adults advise “extreme caution.”^9,16

The risks and benefits of ARB therapy in this setting should be analyzed by the prescribing physician and discussed with the patient. The patient should be closely monitored for the recurrence of angioedema and should be given a clear plan of action should symptoms recur.

OUR ADVICE

In patients with ACE inhibitor-induced angioedema, we recommend the following:

• Determine that the patient truly has one of the evidence-based, compelling indications for an ARB. Carefully weigh the risks and benefits for the individual patient, and discuss the risk of angioedema based on age, race, sex, and medical history, and the availability of immediate medical care should angioedema occur.
• If there is an evidence-based indication for an ARB that outweighs the risk of angioedema, an ARB may be started with caution.
• Specifically discuss with the patient the possibility of recurrence of angioedema while on an ARB, and provide instructions on how to proceed if this should occur.

Current evidence suggests no absolute contraindication to angiotensin receptor blockers (ARBs) in patients who have had angioedema attributable to an angiotensin-converting enzyme (ACE) inhibitor. However, since ARBs can also cause angioedema, they should be prescribed with extreme caution after a thorough risk-benefit analysis and after educating the patient to watch for signs of angioedema while taking the drug.

A GROWING PROBLEM

Angioedema is a potentially life-threatening swelling of the skin and subcutaneous tissues, often affecting the lips and tongue (Figure 1), and in some cases interfering with breathing and requiring tracheostomy.¹ The incidence rate of angioedema in patients taking ACE inhibitors ranges from 0.1% to 0.7%.^2–4 Although this rate may seem low, the widespread and growing use of ACE inhibitors and ARBs in patients with diabetes, diabetic nephropathy, and congestive heart failure⁵ makes angioedema fairly common in clinical practice.

ACE inhibitor-induced angioedema most commonly occurs within days of initiating therapy, but it also may occur weeks, months, or even years after the start of treatment.¹ Patients who are over age 65, black, or female are at higher risk, as are renal transplant recipients taking mTOR inhibitors such as sirolimus. Diabetes appears to be associated with a lower risk.^4,6,7 This adverse reaction to ACE inhibitors is thought to be a class side effect, and the future use of this class of drugs would be contraindicated.^8,9

ACE inhibitors cause angioedema by direct interference with the degradation of bradykinin, thereby increasing bradykinin levels and potentiating its biologic effect, leading to increased vascular permeability, inflammation, and activation of nociceptors.⁸

EVIDENCE TO SUPPORT THE USE OF ARBs

ACE inhibitors and ARBs both block the renin-angiotensin-aldosterone pathway and confer similar advantages in patients with congestive heart failure, renal failure, and diabetes. But since ARBs directly inhibit the angiotensin receptor and do not interfere with bradykinin degradation, how they cause angioedema is unclear, and clinicians have questioned whether these agents might be used safely in patients who have had angioedema on an ACE inhibitor.

In a large meta-analysis of randomized clinical trials, Makani et al² investigated the risk of angioedema with ARB use in 35,479 patients and compared this with other commonly used antihypertensive drugs. The weighted incidence of angioedema was 0.30% with an ACE inhibitor, 0.11% with an ARB, and 0.07% with placebo.² In seven trials included in this study that compared ARBs with placebo, there was no significant difference in the risk of angioedema. Even in such a large study, the event rate was small, making definite conclusions difficult.

In a retrospective observational study of 4 million patients by Toh et al,³ patients on beta-blockers were used as a reference, and propensity scoring was used to estimate the hazard ratio of angioedema separately for drugs targeting the renin-angiotensin-aldosterone system, including ACE inhibitors and ARBs. The risk of angioedema, as measured by the cumulative incidence and incidence rate, was highest for ACE inhibitors and was similar between ARBs and beta-blockers. The risk of serious angioedema was three times higher with ACE inhibitors than with beta-blockers, and there was no higher risk of serious angioedema with ARBs than with beta-blockers.³

Looking specifically at the use of ARBs in patients who developed angioedema on an ACE inhibitor, Haymore et al¹⁰ performed a meta-analysis evaluating only three studies that showed the estimated risk of angioedema with an ARB was between 3.5% and 9.4% in patients with a history of ACE inhibitor-induced angioedema. Later, when the results of the Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease trial¹¹ were published, the previous meta-analysis was updated¹²: the risk of angioedema with an ARB was only 2.5% (95% confidence interval 0%–6.6%), and there was no statistically significant difference in the odds (odds ratio 1.1; 95% confidence interval 0.07–17) of angioedema between ARBs and placebo.^10,12 Again, these results should be interpreted with caution, as only two patients in the ARB (telmisartan) group and three patients in the placebo group developed angioedema.

In another review, Beavers et al¹³ advised that the prescribing practitioner should carefully perform a risk-benefit analysis before substituting an ARB in patients with ACE inhibitor-induced angioedema. They concluded that an ARB could be considered in patients who are likely to have a large clinical benefit from an ARB, such as those with heart failure. They also suggested that angioedema related to ARBs was less severe and occurred earlier than with that linked to ACE inhibitors.

No large clinical trial has yet been specifically designed to address the use of ARBs in patients with a history of ACE inhibitor-induced angioedema. The package insert for the ARB losartan mentions that the risk of this adverse reaction might be higher in patients who have had angioedema on an ACE inhibitor. However, the issue of recurrent angioedema is not further addressed for this or other commonly used ARBs.

GENERAL RECOMMENDATIONS

The mechanisms of ARB-induced angioedema are yet unknown. However, studies have shown that the incidence of angioedema while on an ARB is low and is probably comparable to that of placebo.^2,3,12–14 And since ARBs share many of the cardiac and renal protective effects of ACE inhibitors, ARBs may be beneficial for patients who discontinue an ACE inhibitor because of adverse effects including angioedema.^9,15,16 Based on the discussion above, there is no clear evidence to suggest that ARBs are contraindicated in such patients, especially if there is a compelling indication for an ARB.

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines on hypertension in chronic kidney disease recommend caution when substituting an ARB for an ACE inhibitor after angioedema.¹⁵ The joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA) for the diagnosis and management of heart failure in adults advise “extreme caution.”^9,16

The risks and benefits of ARB therapy in this setting should be analyzed by the prescribing physician and discussed with the patient. The patient should be closely monitored for the recurrence of angioedema and should be given a clear plan of action should symptoms recur.

OUR ADVICE

In patients with ACE inhibitor-induced angioedema, we recommend the following:

• Determine that the patient truly has one of the evidence-based, compelling indications for an ARB. Carefully weigh the risks and benefits for the individual patient, and discuss the risk of angioedema based on age, race, sex, and medical history, and the availability of immediate medical care should angioedema occur.
• If there is an evidence-based indication for an ARB that outweighs the risk of angioedema, an ARB may be started with caution.
• Specifically discuss with the patient the possibility of recurrence of angioedema while on an ARB, and provide instructions on how to proceed if this should occur.

Current evidence suggests no absolute contraindication to angiotensin receptor blockers (ARBs) in patients who have had angioedema attributable to an angiotensin-converting enzyme (ACE) inhibitor. However, since ARBs can also cause angioedema, they should be prescribed with extreme caution after a thorough risk-benefit analysis and after educating the patient to watch for signs of angioedema while taking the drug.

A GROWING PROBLEM

Angioedema is a potentially life-threatening swelling of the skin and subcutaneous tissues, often affecting the lips and tongue (Figure 1), and in some cases interfering with breathing and requiring tracheostomy.¹ The incidence rate of angioedema in patients taking ACE inhibitors ranges from 0.1% to 0.7%.^2–4 Although this rate may seem low, the widespread and growing use of ACE inhibitors and ARBs in patients with diabetes, diabetic nephropathy, and congestive heart failure⁵ makes angioedema fairly common in clinical practice.

ACE inhibitor-induced angioedema most commonly occurs within days of initiating therapy, but it also may occur weeks, months, or even years after the start of treatment.¹ Patients who are over age 65, black, or female are at higher risk, as are renal transplant recipients taking mTOR inhibitors such as sirolimus. Diabetes appears to be associated with a lower risk.^4,6,7 This adverse reaction to ACE inhibitors is thought to be a class side effect, and the future use of this class of drugs would be contraindicated.^8,9

ACE inhibitors cause angioedema by direct interference with the degradation of bradykinin, thereby increasing bradykinin levels and potentiating its biologic effect, leading to increased vascular permeability, inflammation, and activation of nociceptors.⁸

EVIDENCE TO SUPPORT THE USE OF ARBs

ACE inhibitors and ARBs both block the renin-angiotensin-aldosterone pathway and confer similar advantages in patients with congestive heart failure, renal failure, and diabetes. But since ARBs directly inhibit the angiotensin receptor and do not interfere with bradykinin degradation, how they cause angioedema is unclear, and clinicians have questioned whether these agents might be used safely in patients who have had angioedema on an ACE inhibitor.

In a large meta-analysis of randomized clinical trials, Makani et al² investigated the risk of angioedema with ARB use in 35,479 patients and compared this with other commonly used antihypertensive drugs. The weighted incidence of angioedema was 0.30% with an ACE inhibitor, 0.11% with an ARB, and 0.07% with placebo.² In seven trials included in this study that compared ARBs with placebo, there was no significant difference in the risk of angioedema. Even in such a large study, the event rate was small, making definite conclusions difficult.

In a retrospective observational study of 4 million patients by Toh et al,³ patients on beta-blockers were used as a reference, and propensity scoring was used to estimate the hazard ratio of angioedema separately for drugs targeting the renin-angiotensin-aldosterone system, including ACE inhibitors and ARBs. The risk of angioedema, as measured by the cumulative incidence and incidence rate, was highest for ACE inhibitors and was similar between ARBs and beta-blockers. The risk of serious angioedema was three times higher with ACE inhibitors than with beta-blockers, and there was no higher risk of serious angioedema with ARBs than with beta-blockers.³

Looking specifically at the use of ARBs in patients who developed angioedema on an ACE inhibitor, Haymore et al¹⁰ performed a meta-analysis evaluating only three studies that showed the estimated risk of angioedema with an ARB was between 3.5% and 9.4% in patients with a history of ACE inhibitor-induced angioedema. Later, when the results of the Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease trial¹¹ were published, the previous meta-analysis was updated¹²: the risk of angioedema with an ARB was only 2.5% (95% confidence interval 0%–6.6%), and there was no statistically significant difference in the odds (odds ratio 1.1; 95% confidence interval 0.07–17) of angioedema between ARBs and placebo.^10,12 Again, these results should be interpreted with caution, as only two patients in the ARB (telmisartan) group and three patients in the placebo group developed angioedema.

In another review, Beavers et al¹³ advised that the prescribing practitioner should carefully perform a risk-benefit analysis before substituting an ARB in patients with ACE inhibitor-induced angioedema. They concluded that an ARB could be considered in patients who are likely to have a large clinical benefit from an ARB, such as those with heart failure. They also suggested that angioedema related to ARBs was less severe and occurred earlier than with that linked to ACE inhibitors.

No large clinical trial has yet been specifically designed to address the use of ARBs in patients with a history of ACE inhibitor-induced angioedema. The package insert for the ARB losartan mentions that the risk of this adverse reaction might be higher in patients who have had angioedema on an ACE inhibitor. However, the issue of recurrent angioedema is not further addressed for this or other commonly used ARBs.

GENERAL RECOMMENDATIONS

The mechanisms of ARB-induced angioedema are yet unknown. However, studies have shown that the incidence of angioedema while on an ARB is low and is probably comparable to that of placebo.^2,3,12–14 And since ARBs share many of the cardiac and renal protective effects of ACE inhibitors, ARBs may be beneficial for patients who discontinue an ACE inhibitor because of adverse effects including angioedema.^9,15,16 Based on the discussion above, there is no clear evidence to suggest that ARBs are contraindicated in such patients, especially if there is a compelling indication for an ARB.

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines on hypertension in chronic kidney disease recommend caution when substituting an ARB for an ACE inhibitor after angioedema.¹⁵ The joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA) for the diagnosis and management of heart failure in adults advise “extreme caution.”^9,16

The risks and benefits of ARB therapy in this setting should be analyzed by the prescribing physician and discussed with the patient. The patient should be closely monitored for the recurrence of angioedema and should be given a clear plan of action should symptoms recur.

OUR ADVICE

In patients with ACE inhibitor-induced angioedema, we recommend the following:

• Determine that the patient truly has one of the evidence-based, compelling indications for an ARB. Carefully weigh the risks and benefits for the individual patient, and discuss the risk of angioedema based on age, race, sex, and medical history, and the availability of immediate medical care should angioedema occur.
• If there is an evidence-based indication for an ARB that outweighs the risk of angioedema, an ARB may be started with caution.
• Specifically discuss with the patient the possibility of recurrence of angioedema while on an ARB, and provide instructions on how to proceed if this should occur.

Phil Canuto, the executive editor of the Cleveland Clinic Journal of Medicine for almost 20 years, is retiring. Known to relatively few of our authors and peer reviewers, Phil has been the invisible force behind the current print and digital face and body of CCJM.

Few medical journals have a persona that connects with their readers, relating in ways that lead to a bonding between reader and journal that extends beyond the content of the monthly articles. We have strived to attain such a relationship with you, our readers, and I will take the liberty of assuming we have to some extent succeeded. I devote my space this month to talking with you about Phil and his relationship with the Journal.

I have frequently described our journalistic mission as publishing articles for our readers—not for our authors. Phil helped translate this concept into reality by insisting that articles be readable and understandable and always have a clearly stated “bottom-line” message.

Phil joined the CCJM in 1995. He came with genuine journalistic and writing skills and a conviction that medical writing for and by physicians could and should have the same clarity that provides effective information transfer in other venues. He had previously worked as a reporter and medical writer at The Akron Beacon Journal newspaper, and prior to that had been the public information officer for the USDA Food and Nutrition Service. He holds a master’s degree from Medill School of Journalism at Northwestern University.

Phil incorporated basic and sound principles of writing into CCJM, something still not uniformly done in medical journals. He pushed for each article to tell a story and clearly communicate a message to the practicing clinician that could translate into improved patient care. Bright and experienced expert clinicians were coaxed to translate their complex topics and opinions into educational messages that were accurate, relevant, and accessible. Based on unsolicited feedback from our readers and the results of standard media industry surveys, he was right on target: clarity is not the antithesis of erudition (although not all authors have shared this perspective).

He was no publishing Luddite. Phil was the driver behind continuously upgrading our open-access CCJM website—enhancing CME options, creating apps for other media, incorporating an online manuscript-tracking system, and tracking and cataloguing patterns of reader use in order to link growth to the needs of our readers. He enabled CCJM to become an early routine user of plagiarism-detection software. With all of this forward positioning, he also found time to champion the electronic archiving of all 81 years of the Journal (which you can now freely access on the Journal’s website).

These very tangible and significant contributions pale in comparison with his impact on the internal operations of the Journal and on my own maturation as editor in chief (and I speak here as well on behalf of previous physician editors). He has been a constant voice of reason, somehow able to recognize potential controversies and develop strategies to ameliorate the personal conflict while not minimizing valid intellectual differences.

A product of the publication pressures of daily newspapers, he would overlook no opportunity to remind me to move manuscripts along and think of potential topics that we should discuss—his admonition to “feed the beast” is stenciled indelibly in my brain. And he never excused himself from equal responsibility for the feeding. He regularly perused subspecialty journals looking for advances in treatment and diagnosis and through many (fortunately well-weathered) medical adventures, few of his physicians have escaped his probing question, “What’s coming that internists should know about, and who can write about it?”

We will miss his equipoise in dealing with the multiple challenges that frequently arise in the running of a monthly journal. We will miss his many skills, and his enthusiasm and commitment to the Journal’s success in achieving our mission. And I will miss his advice, his creativity, his balanced counsel and support, and his willingness to edit and provide honest feedback on whatever writings I sent his way.

From all of us at CCJM, thank you, Phil, for being you, and for a job very well done. Sleep late and read the newspaper.

PS: Phil—Please note that although too wordy, I at least introduced the “story line” in the first sentence.

Phil Canuto, the executive editor of the Cleveland Clinic Journal of Medicine for almost 20 years, is retiring. Known to relatively few of our authors and peer reviewers, Phil has been the invisible force behind the current print and digital face and body of CCJM.

Few medical journals have a persona that connects with their readers, relating in ways that lead to a bonding between reader and journal that extends beyond the content of the monthly articles. We have strived to attain such a relationship with you, our readers, and I will take the liberty of assuming we have to some extent succeeded. I devote my space this month to talking with you about Phil and his relationship with the Journal.

I have frequently described our journalistic mission as publishing articles for our readers—not for our authors. Phil helped translate this concept into reality by insisting that articles be readable and understandable and always have a clearly stated “bottom-line” message.

Phil joined the CCJM in 1995. He came with genuine journalistic and writing skills and a conviction that medical writing for and by physicians could and should have the same clarity that provides effective information transfer in other venues. He had previously worked as a reporter and medical writer at The Akron Beacon Journal newspaper, and prior to that had been the public information officer for the USDA Food and Nutrition Service. He holds a master’s degree from Medill School of Journalism at Northwestern University.

Phil incorporated basic and sound principles of writing into CCJM, something still not uniformly done in medical journals. He pushed for each article to tell a story and clearly communicate a message to the practicing clinician that could translate into improved patient care. Bright and experienced expert clinicians were coaxed to translate their complex topics and opinions into educational messages that were accurate, relevant, and accessible. Based on unsolicited feedback from our readers and the results of standard media industry surveys, he was right on target: clarity is not the antithesis of erudition (although not all authors have shared this perspective).

He was no publishing Luddite. Phil was the driver behind continuously upgrading our open-access CCJM website—enhancing CME options, creating apps for other media, incorporating an online manuscript-tracking system, and tracking and cataloguing patterns of reader use in order to link growth to the needs of our readers. He enabled CCJM to become an early routine user of plagiarism-detection software. With all of this forward positioning, he also found time to champion the electronic archiving of all 81 years of the Journal (which you can now freely access on the Journal’s website).

These very tangible and significant contributions pale in comparison with his impact on the internal operations of the Journal and on my own maturation as editor in chief (and I speak here as well on behalf of previous physician editors). He has been a constant voice of reason, somehow able to recognize potential controversies and develop strategies to ameliorate the personal conflict while not minimizing valid intellectual differences.

A product of the publication pressures of daily newspapers, he would overlook no opportunity to remind me to move manuscripts along and think of potential topics that we should discuss—his admonition to “feed the beast” is stenciled indelibly in my brain. And he never excused himself from equal responsibility for the feeding. He regularly perused subspecialty journals looking for advances in treatment and diagnosis and through many (fortunately well-weathered) medical adventures, few of his physicians have escaped his probing question, “What’s coming that internists should know about, and who can write about it?”

We will miss his equipoise in dealing with the multiple challenges that frequently arise in the running of a monthly journal. We will miss his many skills, and his enthusiasm and commitment to the Journal’s success in achieving our mission. And I will miss his advice, his creativity, his balanced counsel and support, and his willingness to edit and provide honest feedback on whatever writings I sent his way.

From all of us at CCJM, thank you, Phil, for being you, and for a job very well done. Sleep late and read the newspaper.

PS: Phil—Please note that although too wordy, I at least introduced the “story line” in the first sentence.

Phil Canuto, the executive editor of the Cleveland Clinic Journal of Medicine for almost 20 years, is retiring. Known to relatively few of our authors and peer reviewers, Phil has been the invisible force behind the current print and digital face and body of CCJM.

Few medical journals have a persona that connects with their readers, relating in ways that lead to a bonding between reader and journal that extends beyond the content of the monthly articles. We have strived to attain such a relationship with you, our readers, and I will take the liberty of assuming we have to some extent succeeded. I devote my space this month to talking with you about Phil and his relationship with the Journal.

I have frequently described our journalistic mission as publishing articles for our readers—not for our authors. Phil helped translate this concept into reality by insisting that articles be readable and understandable and always have a clearly stated “bottom-line” message.

Phil joined the CCJM in 1995. He came with genuine journalistic and writing skills and a conviction that medical writing for and by physicians could and should have the same clarity that provides effective information transfer in other venues. He had previously worked as a reporter and medical writer at The Akron Beacon Journal newspaper, and prior to that had been the public information officer for the USDA Food and Nutrition Service. He holds a master’s degree from Medill School of Journalism at Northwestern University.

Phil incorporated basic and sound principles of writing into CCJM, something still not uniformly done in medical journals. He pushed for each article to tell a story and clearly communicate a message to the practicing clinician that could translate into improved patient care. Bright and experienced expert clinicians were coaxed to translate their complex topics and opinions into educational messages that were accurate, relevant, and accessible. Based on unsolicited feedback from our readers and the results of standard media industry surveys, he was right on target: clarity is not the antithesis of erudition (although not all authors have shared this perspective).

He was no publishing Luddite. Phil was the driver behind continuously upgrading our open-access CCJM website—enhancing CME options, creating apps for other media, incorporating an online manuscript-tracking system, and tracking and cataloguing patterns of reader use in order to link growth to the needs of our readers. He enabled CCJM to become an early routine user of plagiarism-detection software. With all of this forward positioning, he also found time to champion the electronic archiving of all 81 years of the Journal (which you can now freely access on the Journal’s website).

These very tangible and significant contributions pale in comparison with his impact on the internal operations of the Journal and on my own maturation as editor in chief (and I speak here as well on behalf of previous physician editors). He has been a constant voice of reason, somehow able to recognize potential controversies and develop strategies to ameliorate the personal conflict while not minimizing valid intellectual differences.

A product of the publication pressures of daily newspapers, he would overlook no opportunity to remind me to move manuscripts along and think of potential topics that we should discuss—his admonition to “feed the beast” is stenciled indelibly in my brain. And he never excused himself from equal responsibility for the feeding. He regularly perused subspecialty journals looking for advances in treatment and diagnosis and through many (fortunately well-weathered) medical adventures, few of his physicians have escaped his probing question, “What’s coming that internists should know about, and who can write about it?”

We will miss his equipoise in dealing with the multiple challenges that frequently arise in the running of a monthly journal. We will miss his many skills, and his enthusiasm and commitment to the Journal’s success in achieving our mission. And I will miss his advice, his creativity, his balanced counsel and support, and his willingness to edit and provide honest feedback on whatever writings I sent his way.

From all of us at CCJM, thank you, Phil, for being you, and for a job very well done. Sleep late and read the newspaper.

PS: Phil—Please note that although too wordy, I at least introduced the “story line” in the first sentence.