Imaging

Staging of liver fibrosis, important for determining prognosis in patients with chronic liver disease and for the need to start screening for complications of cirrhosis, was traditionally done only by liver biopsy. While biopsy is still the gold standard method to stage fibrosis, noninvasive methods have been developed that can also assess disease severity.

This article briefly reviews the epidemiology and physiology of chronic liver disease and the traditional role of liver biopsy. Pros and cons of alternative fibrosis assessment methods are discussed, with a focus on their utility for patients with nonalcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) infection.

CHRONIC LIVER DISEASE: A HUGE HEALTH BURDEN

Chronic liver disease is associated with enormous health and financial costs in the United States. Its prevalence is about 15%,¹ and it is the 12th leading cause of death.² Hospital costs are estimated at about $4 billion annually.³

The most common causes of chronic liver disease are NAFLD (which may be present in up to one-third of the US population and is increasing with the epidemic of obesity), its aggressive variant, nonalcoholic steatohepatitis (NASH) (present in about 3% of the population), and HCV infection (1%).^4,5

Since direct-acting antiviral agents were introduced, HCV infection dropped from being the leading cause of liver transplant to third place.⁶ But at the same time, the number of patients on the transplant waiting list who have NASH has risen faster than for any other cause of chronic liver disease.⁷

FIBROSIS: A KEY INDICATOR OF DISEASE SEVERITY

In HCV infection, advanced fibrosis is defined as either stage 4 to 6 using the Ishak system¹⁰ or stage 3 to 4 using the Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) system.¹¹

In NAFLD, advanced fibrosis is defined as stage 3 to 4 using the NASH Clinical Research Network system.¹²

Staging fibrosis is also important so that patients with cirrhosis can be identified early to begin screening for hepatocellular carcinoma and esophageal varices to reduce the risks of illness and death. In addition, insurance companies often require documentation of fibrosis stage before treating HCV with the new direct-acting antiviral agents.

LIVER BIOPSY IS STILL THE GOLD STANDARD

Although invasive, liver biopsy remains the gold standard for determining fibrosis stage. Liver biopsies were performed “blindly” (without imaging) until the 1990s, but imaging-guided biopsy using ultrasonography was then developed, which entailed less pain and lower complication and hospitalization rates. Slightly more hepatic tissue is obtained with guided liver biopsy, but the difference was deemed clinically insignificant.¹³ Concern initially arose about the added cost involved with imaging, but imaging-guided biopsy was actually found to be more cost-effective.¹⁴

In the 2000s, transjugular liver biopsy via the right internal jugular vein became available. This method was originally used primarily in patients with ascites or significant coagulopathy. At first, there were concerns about the adequacy of specimens obtained to make an accurate diagnosis or establish fibrosis stage, but this limitation was overcome with improved techniques.^15,16 Transjugular liver biopsy has the additional advantage of enabling one to measure the hepatic venous pressure gradient, which also has prognostic significance; a gradient greater than 10 mm Hg is associated with worse prognosis.¹⁷

Disadvantages of biopsy: Complications, sampling errors

Liver biopsy has disadvantages. Reported rates of complications necessitating hospitalization using the blind method were as high as 6% in the 1970s,¹⁸ dropping to 3.2% in a 1993 study.¹⁹ Bleeding remains the most worrisome complication. With the transjugular method, major and minor complication rates are less than 1% and 7%, respectively.^15,16 Complication rates with imaging-guided biopsy are also low.

Liver biopsy is also prone to sampling error. The number of portal tracts obtained in the biopsy correlates with the accuracy of fibrosis staging, and smaller samples may lead to underestimating fibrosis stage. In patients with HCV, samples more than 15 mm long led to accurate staging diagnosis in 65% of patients, and those longer than 25 mm conferred 75% accuracy.²⁰ Also, different stages can be diagnosed from samples obtained from separate locations in the liver, although rarely is the difference more than a single stage.²¹

Histologic evaluation of liver biopsies is operator-dependent. Although significant interobserver variation has been reported for degree of inflammation, there tends to be good concordance for fibrosis staging.^22,23

Several scores based on patient characteristics and laboratory values have been developed for assessing liver fibrosis and have been specifically validated for HCV infection, NAFLD, or both. They can serve as inexpensive initial screening tests for the presence or absence of advanced fibrosis.

FIB-4 index for HCV, NAFLD

The FIB-4 index predicts the presence of advanced fibrosis using, as its name indicates, a combination of 4 factors in fibrosis: age, platelet count, and the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), according to the formula:

FIB-4 index = (age × AST [U/L]) /
(platelet count [× 10⁹/L] × √ALT [U/L]).

The index was derived from data from 832 patients co-infected with HCV and human immunodeficiency virus.²⁴ The Ishak staging system¹⁰ for fibrosis on liver biopsy was used for confirmation, with stage 4 to 6 defined as advanced fibrosis. A cutoff value of more than 3.25 had a positive predictive value of 65% for advanced fibrosis, and to exclude advanced fibrosis, a cutoff value of less than 1.45 had a negative predictive value of 90%.

The FIB-4 index has since been validated in patients with HCV infection²⁵ and NAFLD.²⁶ In a subsequent study in 142 patients with NAFLD, the FIB-4 index was more accurate in diagnosing advanced fibrosis than the other noninvasive prediction models discussed below.²⁷

NAFLD fibrosis score

The NAFLD fibrosis score, constructed and validated only in patients with biopsy-confirmed NAFLD, incorporates age, body mass index, presence of diabetes or prediabetes, albumin level, platelet count, and AST and ALT levels.

A group of 480 patients was used to construct the score, and 253 patients were used to validate it. Using the high cutoff value of 0.676, the presence of advanced fibrosis was diagnosed with a positive predictive value of 90% in the group used to construct the model (82% in the validation group). Using the low cutoff score of –1.455, advanced fibrosis could be excluded with a negative predictive value of 93% in the construction group and 88% in the validation group.²⁸ A score between the cutoff values merits liver biopsy to determine fibrosis stage. The score is more accurate in patients with diabetes.²⁹ When used by primary care physicians, the NAFLD fibrosis score is more cost-effective than transient elastography and liver biopsy for accurately predicting advanced fibrosis.³⁰

AST-to-platelet ratio index score for HCV, NAFLD

The AST-to-platelet ratio index (APRI) score was developed in 2003 using a cohort of 270 patients with HCV and liver biopsy as the standard. A cutoff value of less than or equal to 0.5 had a negative predictive value of 86% for the absence of significant fibrosis, while a score of more than 1.5 detected the presence of significant fibrosis with a positive predictive value of 88%.³¹ The APRI score was subsequently validated for NAFLD.^27,32

FibroSure uses a patented formula

FibroSure (LabCorp; labcorp.com) uses a patented mathematical formula that takes into account age, sex, and levels of gamma-glutamyl transferase, total bilirubin, haptoglobin, apolipoprotein-A, and alpha-2 macroglobulin to assess fibrosis. Developed in 2001 for use in patients with HCV infection, it was reported to have a positive predictive value of greater than 90% and a negative predictive value of 100% for clinically significant fibrosis, defined as stage 2 to 4 based on the METAVIR staging system in the prediction model.³³ The use of FibroSure in patients with HCV was subsequently validated in various meta-analyses and systematic reviews.^34,35 It is less accurate in patients with normal ALT levels.³⁶

FibroSure also has good accuracy for predicting fibrosis stage in chronic liver disease due to other causes, including NAFLD.³⁷

The prediction models discussed above use routine laboratory tests for chronic liver disease and thus are inexpensive. The high cost of additional testing needed for FibroSure, coupled with the risk of misdiagnosis, makes its cost-effectiveness questionable.³⁸

Conventional ultrasonography (with or without vascular imaging) and computed tomography can detect cirrhosis on the basis of certain imaging characteristics,^39,40 including the nodular contour of the liver, caudate lobe hypertrophy, ascites, reversal of blood flow in the portal vein, and splenomegaly. However, they cannot detect fibrosis in its early stages.

The 3 methods discussed below provide more accurate fibrosis staging by measuring the velocity of shear waves sent across hepatic tissue. Because shear-wave velocity increases with liver stiffness, the fibrosis stage can be estimated from this information.⁴¹

Transient elastography

Transient elastography uses a special ultrasound transducer. It is highly accurate for predicting advanced fibrosis for almost all causes of chronic liver disease, including HCV infection^42,43 and NAFLD.⁴⁴ The cutoff values of wave velocity to estimate fibrosis stage differ by liver disease etiology.

Transient elastography should not be used to evaluate fibrosis in patients with acute hepatitis, which transiently increases liver stiffness, resulting in a falsely high fibrosis stage diagnosis.⁴⁵ It is also not a good method for evaluating fibrosis in patients with biliary obstruction or extrahepatic venous congestion. Because liver stiffness can increase after eating,⁴⁶ the test should be done under fasting conditions.

A significant limitation of transient elastography has been its poor accuracy in patients with obesity.⁴⁷ This has been largely overcome with the use of a more powerful (XL) probe but is still a limitation for those with morbid obesity.⁴⁸ Because many patients with NAFLD are obese, this limitation can be significant.

Transient elastography has gained popularity for evaluating fibrosis in patients with chronic liver disease for multiple reasons: it is cost-effective and results are highly reproducible, with low variation in results among different observers and in individual observers.⁴⁹ Combined with a platelet count, it can also be used to detect the development of clinically significant portal hypertension in patients with cirrhosis, thus determining the need to screen for esophageal varices using endoscopy.⁵⁰ Screening endoscopy can be avoided in patients whose liver stiffness remains below 20 kPa or whose platelet count is above 150 × 10⁹/L.

Acoustic radiation force imaging

Unlike transient elastography, which requires a separate transducer probe to assess shear- wave velocity, acoustic radiation force imaging uses the same transducer for both this function and imaging. Different image modes are available when testing for liver stiffness, so a region of interest that is optimal for avoiding vascular structures or masses can be selected, increasing accuracy.⁵¹

Acoustic radiation force imaging has been tested in different causes of chronic liver disease, including HCV and NAFLD,⁵² with accuracy similar to that of transient elastography.⁵³ For overweight and obese patients, acoustic radiation force imaging is more accurate than transient elastography using the XL probe.⁵⁴ However, this method is still new, and we need more data to support using one method over the other.

Magnetic resonance elastography

Magnetic resonance elastography uses a special transducer placed under the rib cage to transmit shear waves concurrently with magnetic resonance imaging. It has been tested in patients with HCV and NAFLD and has been found to have better diagnostic accuracy than transient elastography and acoustic radiation force imaging.^55,56 Patients must be fasting for better diagnostic accuracy⁵⁷ and must hold their breath while elastography is performed. The need for breath-holding and the high cost limit the use of this method for assessing fibrosis.

BOTTOM LINE FOR ASSESSING FIBROSIS

Staging of liver fibrosis, important for determining prognosis in patients with chronic liver disease and for the need to start screening for complications of cirrhosis, was traditionally done only by liver biopsy. While biopsy is still the gold standard method to stage fibrosis, noninvasive methods have been developed that can also assess disease severity.

This article briefly reviews the epidemiology and physiology of chronic liver disease and the traditional role of liver biopsy. Pros and cons of alternative fibrosis assessment methods are discussed, with a focus on their utility for patients with nonalcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) infection.

CHRONIC LIVER DISEASE: A HUGE HEALTH BURDEN

Chronic liver disease is associated with enormous health and financial costs in the United States. Its prevalence is about 15%,¹ and it is the 12th leading cause of death.² Hospital costs are estimated at about $4 billion annually.³

The most common causes of chronic liver disease are NAFLD (which may be present in up to one-third of the US population and is increasing with the epidemic of obesity), its aggressive variant, nonalcoholic steatohepatitis (NASH) (present in about 3% of the population), and HCV infection (1%).^4,5

Since direct-acting antiviral agents were introduced, HCV infection dropped from being the leading cause of liver transplant to third place.⁶ But at the same time, the number of patients on the transplant waiting list who have NASH has risen faster than for any other cause of chronic liver disease.⁷

FIBROSIS: A KEY INDICATOR OF DISEASE SEVERITY

In HCV infection, advanced fibrosis is defined as either stage 4 to 6 using the Ishak system¹⁰ or stage 3 to 4 using the Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) system.¹¹

In NAFLD, advanced fibrosis is defined as stage 3 to 4 using the NASH Clinical Research Network system.¹²

Staging fibrosis is also important so that patients with cirrhosis can be identified early to begin screening for hepatocellular carcinoma and esophageal varices to reduce the risks of illness and death. In addition, insurance companies often require documentation of fibrosis stage before treating HCV with the new direct-acting antiviral agents.

LIVER BIOPSY IS STILL THE GOLD STANDARD

Although invasive, liver biopsy remains the gold standard for determining fibrosis stage. Liver biopsies were performed “blindly” (without imaging) until the 1990s, but imaging-guided biopsy using ultrasonography was then developed, which entailed less pain and lower complication and hospitalization rates. Slightly more hepatic tissue is obtained with guided liver biopsy, but the difference was deemed clinically insignificant.¹³ Concern initially arose about the added cost involved with imaging, but imaging-guided biopsy was actually found to be more cost-effective.¹⁴

In the 2000s, transjugular liver biopsy via the right internal jugular vein became available. This method was originally used primarily in patients with ascites or significant coagulopathy. At first, there were concerns about the adequacy of specimens obtained to make an accurate diagnosis or establish fibrosis stage, but this limitation was overcome with improved techniques.^15,16 Transjugular liver biopsy has the additional advantage of enabling one to measure the hepatic venous pressure gradient, which also has prognostic significance; a gradient greater than 10 mm Hg is associated with worse prognosis.¹⁷

Disadvantages of biopsy: Complications, sampling errors

Liver biopsy has disadvantages. Reported rates of complications necessitating hospitalization using the blind method were as high as 6% in the 1970s,¹⁸ dropping to 3.2% in a 1993 study.¹⁹ Bleeding remains the most worrisome complication. With the transjugular method, major and minor complication rates are less than 1% and 7%, respectively.^15,16 Complication rates with imaging-guided biopsy are also low.

Liver biopsy is also prone to sampling error. The number of portal tracts obtained in the biopsy correlates with the accuracy of fibrosis staging, and smaller samples may lead to underestimating fibrosis stage. In patients with HCV, samples more than 15 mm long led to accurate staging diagnosis in 65% of patients, and those longer than 25 mm conferred 75% accuracy.²⁰ Also, different stages can be diagnosed from samples obtained from separate locations in the liver, although rarely is the difference more than a single stage.²¹

Histologic evaluation of liver biopsies is operator-dependent. Although significant interobserver variation has been reported for degree of inflammation, there tends to be good concordance for fibrosis staging.^22,23

Several scores based on patient characteristics and laboratory values have been developed for assessing liver fibrosis and have been specifically validated for HCV infection, NAFLD, or both. They can serve as inexpensive initial screening tests for the presence or absence of advanced fibrosis.

FIB-4 index for HCV, NAFLD

The FIB-4 index predicts the presence of advanced fibrosis using, as its name indicates, a combination of 4 factors in fibrosis: age, platelet count, and the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), according to the formula:

FIB-4 index = (age × AST [U/L]) /
(platelet count [× 10⁹/L] × √ALT [U/L]).

The index was derived from data from 832 patients co-infected with HCV and human immunodeficiency virus.²⁴ The Ishak staging system¹⁰ for fibrosis on liver biopsy was used for confirmation, with stage 4 to 6 defined as advanced fibrosis. A cutoff value of more than 3.25 had a positive predictive value of 65% for advanced fibrosis, and to exclude advanced fibrosis, a cutoff value of less than 1.45 had a negative predictive value of 90%.

The FIB-4 index has since been validated in patients with HCV infection²⁵ and NAFLD.²⁶ In a subsequent study in 142 patients with NAFLD, the FIB-4 index was more accurate in diagnosing advanced fibrosis than the other noninvasive prediction models discussed below.²⁷

NAFLD fibrosis score

The NAFLD fibrosis score, constructed and validated only in patients with biopsy-confirmed NAFLD, incorporates age, body mass index, presence of diabetes or prediabetes, albumin level, platelet count, and AST and ALT levels.

A group of 480 patients was used to construct the score, and 253 patients were used to validate it. Using the high cutoff value of 0.676, the presence of advanced fibrosis was diagnosed with a positive predictive value of 90% in the group used to construct the model (82% in the validation group). Using the low cutoff score of –1.455, advanced fibrosis could be excluded with a negative predictive value of 93% in the construction group and 88% in the validation group.²⁸ A score between the cutoff values merits liver biopsy to determine fibrosis stage. The score is more accurate in patients with diabetes.²⁹ When used by primary care physicians, the NAFLD fibrosis score is more cost-effective than transient elastography and liver biopsy for accurately predicting advanced fibrosis.³⁰

AST-to-platelet ratio index score for HCV, NAFLD

The AST-to-platelet ratio index (APRI) score was developed in 2003 using a cohort of 270 patients with HCV and liver biopsy as the standard. A cutoff value of less than or equal to 0.5 had a negative predictive value of 86% for the absence of significant fibrosis, while a score of more than 1.5 detected the presence of significant fibrosis with a positive predictive value of 88%.³¹ The APRI score was subsequently validated for NAFLD.^27,32

FibroSure uses a patented formula

FibroSure (LabCorp; labcorp.com) uses a patented mathematical formula that takes into account age, sex, and levels of gamma-glutamyl transferase, total bilirubin, haptoglobin, apolipoprotein-A, and alpha-2 macroglobulin to assess fibrosis. Developed in 2001 for use in patients with HCV infection, it was reported to have a positive predictive value of greater than 90% and a negative predictive value of 100% for clinically significant fibrosis, defined as stage 2 to 4 based on the METAVIR staging system in the prediction model.³³ The use of FibroSure in patients with HCV was subsequently validated in various meta-analyses and systematic reviews.^34,35 It is less accurate in patients with normal ALT levels.³⁶

FibroSure also has good accuracy for predicting fibrosis stage in chronic liver disease due to other causes, including NAFLD.³⁷

The prediction models discussed above use routine laboratory tests for chronic liver disease and thus are inexpensive. The high cost of additional testing needed for FibroSure, coupled with the risk of misdiagnosis, makes its cost-effectiveness questionable.³⁸

Conventional ultrasonography (with or without vascular imaging) and computed tomography can detect cirrhosis on the basis of certain imaging characteristics,^39,40 including the nodular contour of the liver, caudate lobe hypertrophy, ascites, reversal of blood flow in the portal vein, and splenomegaly. However, they cannot detect fibrosis in its early stages.

The 3 methods discussed below provide more accurate fibrosis staging by measuring the velocity of shear waves sent across hepatic tissue. Because shear-wave velocity increases with liver stiffness, the fibrosis stage can be estimated from this information.⁴¹

Transient elastography

Transient elastography uses a special ultrasound transducer. It is highly accurate for predicting advanced fibrosis for almost all causes of chronic liver disease, including HCV infection^42,43 and NAFLD.⁴⁴ The cutoff values of wave velocity to estimate fibrosis stage differ by liver disease etiology.

Transient elastography should not be used to evaluate fibrosis in patients with acute hepatitis, which transiently increases liver stiffness, resulting in a falsely high fibrosis stage diagnosis.⁴⁵ It is also not a good method for evaluating fibrosis in patients with biliary obstruction or extrahepatic venous congestion. Because liver stiffness can increase after eating,⁴⁶ the test should be done under fasting conditions.

A significant limitation of transient elastography has been its poor accuracy in patients with obesity.⁴⁷ This has been largely overcome with the use of a more powerful (XL) probe but is still a limitation for those with morbid obesity.⁴⁸ Because many patients with NAFLD are obese, this limitation can be significant.

Transient elastography has gained popularity for evaluating fibrosis in patients with chronic liver disease for multiple reasons: it is cost-effective and results are highly reproducible, with low variation in results among different observers and in individual observers.⁴⁹ Combined with a platelet count, it can also be used to detect the development of clinically significant portal hypertension in patients with cirrhosis, thus determining the need to screen for esophageal varices using endoscopy.⁵⁰ Screening endoscopy can be avoided in patients whose liver stiffness remains below 20 kPa or whose platelet count is above 150 × 10⁹/L.

Acoustic radiation force imaging

Unlike transient elastography, which requires a separate transducer probe to assess shear- wave velocity, acoustic radiation force imaging uses the same transducer for both this function and imaging. Different image modes are available when testing for liver stiffness, so a region of interest that is optimal for avoiding vascular structures or masses can be selected, increasing accuracy.⁵¹

Acoustic radiation force imaging has been tested in different causes of chronic liver disease, including HCV and NAFLD,⁵² with accuracy similar to that of transient elastography.⁵³ For overweight and obese patients, acoustic radiation force imaging is more accurate than transient elastography using the XL probe.⁵⁴ However, this method is still new, and we need more data to support using one method over the other.

Magnetic resonance elastography

Magnetic resonance elastography uses a special transducer placed under the rib cage to transmit shear waves concurrently with magnetic resonance imaging. It has been tested in patients with HCV and NAFLD and has been found to have better diagnostic accuracy than transient elastography and acoustic radiation force imaging.^55,56 Patients must be fasting for better diagnostic accuracy⁵⁷ and must hold their breath while elastography is performed. The need for breath-holding and the high cost limit the use of this method for assessing fibrosis.

BOTTOM LINE FOR ASSESSING FIBROSIS

Staging of liver fibrosis, important for determining prognosis in patients with chronic liver disease and for the need to start screening for complications of cirrhosis, was traditionally done only by liver biopsy. While biopsy is still the gold standard method to stage fibrosis, noninvasive methods have been developed that can also assess disease severity.

This article briefly reviews the epidemiology and physiology of chronic liver disease and the traditional role of liver biopsy. Pros and cons of alternative fibrosis assessment methods are discussed, with a focus on their utility for patients with nonalcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) infection.

CHRONIC LIVER DISEASE: A HUGE HEALTH BURDEN

Chronic liver disease is associated with enormous health and financial costs in the United States. Its prevalence is about 15%,¹ and it is the 12th leading cause of death.² Hospital costs are estimated at about $4 billion annually.³

The most common causes of chronic liver disease are NAFLD (which may be present in up to one-third of the US population and is increasing with the epidemic of obesity), its aggressive variant, nonalcoholic steatohepatitis (NASH) (present in about 3% of the population), and HCV infection (1%).^4,5

Since direct-acting antiviral agents were introduced, HCV infection dropped from being the leading cause of liver transplant to third place.⁶ But at the same time, the number of patients on the transplant waiting list who have NASH has risen faster than for any other cause of chronic liver disease.⁷

FIBROSIS: A KEY INDICATOR OF DISEASE SEVERITY

In HCV infection, advanced fibrosis is defined as either stage 4 to 6 using the Ishak system¹⁰ or stage 3 to 4 using the Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) system.¹¹

In NAFLD, advanced fibrosis is defined as stage 3 to 4 using the NASH Clinical Research Network system.¹²

Staging fibrosis is also important so that patients with cirrhosis can be identified early to begin screening for hepatocellular carcinoma and esophageal varices to reduce the risks of illness and death. In addition, insurance companies often require documentation of fibrosis stage before treating HCV with the new direct-acting antiviral agents.

LIVER BIOPSY IS STILL THE GOLD STANDARD

Although invasive, liver biopsy remains the gold standard for determining fibrosis stage. Liver biopsies were performed “blindly” (without imaging) until the 1990s, but imaging-guided biopsy using ultrasonography was then developed, which entailed less pain and lower complication and hospitalization rates. Slightly more hepatic tissue is obtained with guided liver biopsy, but the difference was deemed clinically insignificant.¹³ Concern initially arose about the added cost involved with imaging, but imaging-guided biopsy was actually found to be more cost-effective.¹⁴

In the 2000s, transjugular liver biopsy via the right internal jugular vein became available. This method was originally used primarily in patients with ascites or significant coagulopathy. At first, there were concerns about the adequacy of specimens obtained to make an accurate diagnosis or establish fibrosis stage, but this limitation was overcome with improved techniques.^15,16 Transjugular liver biopsy has the additional advantage of enabling one to measure the hepatic venous pressure gradient, which also has prognostic significance; a gradient greater than 10 mm Hg is associated with worse prognosis.¹⁷

Disadvantages of biopsy: Complications, sampling errors

Liver biopsy has disadvantages. Reported rates of complications necessitating hospitalization using the blind method were as high as 6% in the 1970s,¹⁸ dropping to 3.2% in a 1993 study.¹⁹ Bleeding remains the most worrisome complication. With the transjugular method, major and minor complication rates are less than 1% and 7%, respectively.^15,16 Complication rates with imaging-guided biopsy are also low.

Liver biopsy is also prone to sampling error. The number of portal tracts obtained in the biopsy correlates with the accuracy of fibrosis staging, and smaller samples may lead to underestimating fibrosis stage. In patients with HCV, samples more than 15 mm long led to accurate staging diagnosis in 65% of patients, and those longer than 25 mm conferred 75% accuracy.²⁰ Also, different stages can be diagnosed from samples obtained from separate locations in the liver, although rarely is the difference more than a single stage.²¹

Histologic evaluation of liver biopsies is operator-dependent. Although significant interobserver variation has been reported for degree of inflammation, there tends to be good concordance for fibrosis staging.^22,23

Several scores based on patient characteristics and laboratory values have been developed for assessing liver fibrosis and have been specifically validated for HCV infection, NAFLD, or both. They can serve as inexpensive initial screening tests for the presence or absence of advanced fibrosis.

FIB-4 index for HCV, NAFLD

The FIB-4 index predicts the presence of advanced fibrosis using, as its name indicates, a combination of 4 factors in fibrosis: age, platelet count, and the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), according to the formula:

FIB-4 index = (age × AST [U/L]) /
(platelet count [× 10⁹/L] × √ALT [U/L]).

The index was derived from data from 832 patients co-infected with HCV and human immunodeficiency virus.²⁴ The Ishak staging system¹⁰ for fibrosis on liver biopsy was used for confirmation, with stage 4 to 6 defined as advanced fibrosis. A cutoff value of more than 3.25 had a positive predictive value of 65% for advanced fibrosis, and to exclude advanced fibrosis, a cutoff value of less than 1.45 had a negative predictive value of 90%.

The FIB-4 index has since been validated in patients with HCV infection²⁵ and NAFLD.²⁶ In a subsequent study in 142 patients with NAFLD, the FIB-4 index was more accurate in diagnosing advanced fibrosis than the other noninvasive prediction models discussed below.²⁷

NAFLD fibrosis score

The NAFLD fibrosis score, constructed and validated only in patients with biopsy-confirmed NAFLD, incorporates age, body mass index, presence of diabetes or prediabetes, albumin level, platelet count, and AST and ALT levels.

A group of 480 patients was used to construct the score, and 253 patients were used to validate it. Using the high cutoff value of 0.676, the presence of advanced fibrosis was diagnosed with a positive predictive value of 90% in the group used to construct the model (82% in the validation group). Using the low cutoff score of –1.455, advanced fibrosis could be excluded with a negative predictive value of 93% in the construction group and 88% in the validation group.²⁸ A score between the cutoff values merits liver biopsy to determine fibrosis stage. The score is more accurate in patients with diabetes.²⁹ When used by primary care physicians, the NAFLD fibrosis score is more cost-effective than transient elastography and liver biopsy for accurately predicting advanced fibrosis.³⁰

AST-to-platelet ratio index score for HCV, NAFLD

The AST-to-platelet ratio index (APRI) score was developed in 2003 using a cohort of 270 patients with HCV and liver biopsy as the standard. A cutoff value of less than or equal to 0.5 had a negative predictive value of 86% for the absence of significant fibrosis, while a score of more than 1.5 detected the presence of significant fibrosis with a positive predictive value of 88%.³¹ The APRI score was subsequently validated for NAFLD.^27,32

FibroSure uses a patented formula

FibroSure (LabCorp; labcorp.com) uses a patented mathematical formula that takes into account age, sex, and levels of gamma-glutamyl transferase, total bilirubin, haptoglobin, apolipoprotein-A, and alpha-2 macroglobulin to assess fibrosis. Developed in 2001 for use in patients with HCV infection, it was reported to have a positive predictive value of greater than 90% and a negative predictive value of 100% for clinically significant fibrosis, defined as stage 2 to 4 based on the METAVIR staging system in the prediction model.³³ The use of FibroSure in patients with HCV was subsequently validated in various meta-analyses and systematic reviews.^34,35 It is less accurate in patients with normal ALT levels.³⁶

FibroSure also has good accuracy for predicting fibrosis stage in chronic liver disease due to other causes, including NAFLD.³⁷

The prediction models discussed above use routine laboratory tests for chronic liver disease and thus are inexpensive. The high cost of additional testing needed for FibroSure, coupled with the risk of misdiagnosis, makes its cost-effectiveness questionable.³⁸

Conventional ultrasonography (with or without vascular imaging) and computed tomography can detect cirrhosis on the basis of certain imaging characteristics,^39,40 including the nodular contour of the liver, caudate lobe hypertrophy, ascites, reversal of blood flow in the portal vein, and splenomegaly. However, they cannot detect fibrosis in its early stages.

The 3 methods discussed below provide more accurate fibrosis staging by measuring the velocity of shear waves sent across hepatic tissue. Because shear-wave velocity increases with liver stiffness, the fibrosis stage can be estimated from this information.⁴¹

Transient elastography

Transient elastography uses a special ultrasound transducer. It is highly accurate for predicting advanced fibrosis for almost all causes of chronic liver disease, including HCV infection^42,43 and NAFLD.⁴⁴ The cutoff values of wave velocity to estimate fibrosis stage differ by liver disease etiology.

Transient elastography should not be used to evaluate fibrosis in patients with acute hepatitis, which transiently increases liver stiffness, resulting in a falsely high fibrosis stage diagnosis.⁴⁵ It is also not a good method for evaluating fibrosis in patients with biliary obstruction or extrahepatic venous congestion. Because liver stiffness can increase after eating,⁴⁶ the test should be done under fasting conditions.

A significant limitation of transient elastography has been its poor accuracy in patients with obesity.⁴⁷ This has been largely overcome with the use of a more powerful (XL) probe but is still a limitation for those with morbid obesity.⁴⁸ Because many patients with NAFLD are obese, this limitation can be significant.

Transient elastography has gained popularity for evaluating fibrosis in patients with chronic liver disease for multiple reasons: it is cost-effective and results are highly reproducible, with low variation in results among different observers and in individual observers.⁴⁹ Combined with a platelet count, it can also be used to detect the development of clinically significant portal hypertension in patients with cirrhosis, thus determining the need to screen for esophageal varices using endoscopy.⁵⁰ Screening endoscopy can be avoided in patients whose liver stiffness remains below 20 kPa or whose platelet count is above 150 × 10⁹/L.

Acoustic radiation force imaging

Unlike transient elastography, which requires a separate transducer probe to assess shear- wave velocity, acoustic radiation force imaging uses the same transducer for both this function and imaging. Different image modes are available when testing for liver stiffness, so a region of interest that is optimal for avoiding vascular structures or masses can be selected, increasing accuracy.⁵¹

Acoustic radiation force imaging has been tested in different causes of chronic liver disease, including HCV and NAFLD,⁵² with accuracy similar to that of transient elastography.⁵³ For overweight and obese patients, acoustic radiation force imaging is more accurate than transient elastography using the XL probe.⁵⁴ However, this method is still new, and we need more data to support using one method over the other.

Magnetic resonance elastography

Magnetic resonance elastography uses a special transducer placed under the rib cage to transmit shear waves concurrently with magnetic resonance imaging. It has been tested in patients with HCV and NAFLD and has been found to have better diagnostic accuracy than transient elastography and acoustic radiation force imaging.^55,56 Patients must be fasting for better diagnostic accuracy⁵⁷ and must hold their breath while elastography is performed. The need for breath-holding and the high cost limit the use of this method for assessing fibrosis.

BOTTOM LINE FOR ASSESSING FIBROSIS

A 62-year-old woman presented to our emergency department with fever, chills, hoarseness, pain on swallowing, and a painful neck. Her symptoms had begun 1 day earlier. Because acetaminophen brought no improvement, she went to an urgent care facility, where a nasal swab polymerase chain reaction test was positive for influenza A, and a throat swab rapid test was positive for group A streptococci. She was then referred to our emergency department.

She reported no pre-existing conditions predisposing her to infection. Her temperature was 99.9°F (37.7°C), pulse 112 beats per minute, and respiratory rate 24 breaths per minute. The physical examination was unremarkable except for bilateral anterior cervical adenopathy and bilateral anterior neck tenderness. Her pharynx was not injected, and no exudate, palatal edema, or petechiae were noted.

Results of initial laboratory testing were as follows:

• White blood cell count 20.5 × 10⁹/L (reference range 3.9–11)
• Neutrophils 76% (42%–75%)
• Bands 15% (0%–5%)
• Lymphocytes 3% (21%–51%)
• Erythrocyte sedimentation rate 75 mm/h (< 20 mm/h)
• C-reactive protein 247.14 mg/L (≤ 3 mg/L)
• Serum aminotransferase levels were normal.
• Polymerase chain reaction testing of a nasal swab was negative for viral infection.

Throat swabs and blood samples were sent for culture.

She was started on ceftriaxone 1 g intravenously every 24 hours, with close observation in the medical intensive care unit, where she was admitted because of epiglottitis. On hospital day 3, the throat culture was reported as negative, but the blood culture was reported as positive for Haemophilus influenzae. Thus, the clinical diagnosis was acute epiglottitis due to H influenzae, not group A streptococci.

The patient completed 10 days of ceftriaxone therapy; her recovery was uneventful, and she was discharged on hospital day 10.

INFLUENZA: CHALLENGES TO PROMPT, ACCURATE DIAGNOSIS

During influenza season, emergency departments are inundated with adults with influenza A and other viral respiratory infections. This makes prompt, accurate diagnosis a challenge,¹ given the broad differential diagnosis.^2,3 Adults with influenza and its complications as well as unrelated conditions can present a special challenge.⁴

Our patient presented with acute-onset influenza A and was then found to have acute epiglottitis, an unexpected complication of influenza A.⁵ A positive rapid test for group A streptococci done at an urgent care facility led emergency department physicians to assume that the acute epiglottitis was due to group A streptococci. Unless correlated with clinical findings, results of rapid diagnostic tests may mislead the unwary practitioner. Accurate diagnosis should be based mainly on the history and physical findings. Results of rapid diagnostic tests can be helpful if interpreted in the clinical context.^6–8

The rapid test for streptococci is appropriate for the diagnosis of pharyngitis due to group A streptococci in people under age 30 with acute-onset sore throat, fever, and bilateral acute cervical adenopathy, without fatigue or myalgias. However, the rapid test does not differentiate colonization from infection. Group A streptococci are common colonizers with viral pharyngitis. In 30% of cases of Epstein-Barr virus pharyngitis, there is colonization with group A streptococci. A positive rapid test in such cases can result in the wrong diagnosis, ie, pharyngitis due to group A streptococci rather than Epstein-Barr virus.

A 62-year-old woman presented to our emergency department with fever, chills, hoarseness, pain on swallowing, and a painful neck. Her symptoms had begun 1 day earlier. Because acetaminophen brought no improvement, she went to an urgent care facility, where a nasal swab polymerase chain reaction test was positive for influenza A, and a throat swab rapid test was positive for group A streptococci. She was then referred to our emergency department.

She reported no pre-existing conditions predisposing her to infection. Her temperature was 99.9°F (37.7°C), pulse 112 beats per minute, and respiratory rate 24 breaths per minute. The physical examination was unremarkable except for bilateral anterior cervical adenopathy and bilateral anterior neck tenderness. Her pharynx was not injected, and no exudate, palatal edema, or petechiae were noted.

Results of initial laboratory testing were as follows:

• White blood cell count 20.5 × 10⁹/L (reference range 3.9–11)
• Neutrophils 76% (42%–75%)
• Bands 15% (0%–5%)
• Lymphocytes 3% (21%–51%)
• Erythrocyte sedimentation rate 75 mm/h (< 20 mm/h)
• C-reactive protein 247.14 mg/L (≤ 3 mg/L)
• Serum aminotransferase levels were normal.
• Polymerase chain reaction testing of a nasal swab was negative for viral infection.

Throat swabs and blood samples were sent for culture.

She was started on ceftriaxone 1 g intravenously every 24 hours, with close observation in the medical intensive care unit, where she was admitted because of epiglottitis. On hospital day 3, the throat culture was reported as negative, but the blood culture was reported as positive for Haemophilus influenzae. Thus, the clinical diagnosis was acute epiglottitis due to H influenzae, not group A streptococci.

The patient completed 10 days of ceftriaxone therapy; her recovery was uneventful, and she was discharged on hospital day 10.

INFLUENZA: CHALLENGES TO PROMPT, ACCURATE DIAGNOSIS

During influenza season, emergency departments are inundated with adults with influenza A and other viral respiratory infections. This makes prompt, accurate diagnosis a challenge,¹ given the broad differential diagnosis.^2,3 Adults with influenza and its complications as well as unrelated conditions can present a special challenge.⁴

Our patient presented with acute-onset influenza A and was then found to have acute epiglottitis, an unexpected complication of influenza A.⁵ A positive rapid test for group A streptococci done at an urgent care facility led emergency department physicians to assume that the acute epiglottitis was due to group A streptococci. Unless correlated with clinical findings, results of rapid diagnostic tests may mislead the unwary practitioner. Accurate diagnosis should be based mainly on the history and physical findings. Results of rapid diagnostic tests can be helpful if interpreted in the clinical context.^6–8

The rapid test for streptococci is appropriate for the diagnosis of pharyngitis due to group A streptococci in people under age 30 with acute-onset sore throat, fever, and bilateral acute cervical adenopathy, without fatigue or myalgias. However, the rapid test does not differentiate colonization from infection. Group A streptococci are common colonizers with viral pharyngitis. In 30% of cases of Epstein-Barr virus pharyngitis, there is colonization with group A streptococci. A positive rapid test in such cases can result in the wrong diagnosis, ie, pharyngitis due to group A streptococci rather than Epstein-Barr virus.

A 62-year-old woman presented to our emergency department with fever, chills, hoarseness, pain on swallowing, and a painful neck. Her symptoms had begun 1 day earlier. Because acetaminophen brought no improvement, she went to an urgent care facility, where a nasal swab polymerase chain reaction test was positive for influenza A, and a throat swab rapid test was positive for group A streptococci. She was then referred to our emergency department.

She reported no pre-existing conditions predisposing her to infection. Her temperature was 99.9°F (37.7°C), pulse 112 beats per minute, and respiratory rate 24 breaths per minute. The physical examination was unremarkable except for bilateral anterior cervical adenopathy and bilateral anterior neck tenderness. Her pharynx was not injected, and no exudate, palatal edema, or petechiae were noted.

Results of initial laboratory testing were as follows:

• White blood cell count 20.5 × 10⁹/L (reference range 3.9–11)
• Neutrophils 76% (42%–75%)
• Bands 15% (0%–5%)
• Lymphocytes 3% (21%–51%)
• Erythrocyte sedimentation rate 75 mm/h (< 20 mm/h)
• C-reactive protein 247.14 mg/L (≤ 3 mg/L)
• Serum aminotransferase levels were normal.
• Polymerase chain reaction testing of a nasal swab was negative for viral infection.

Throat swabs and blood samples were sent for culture.

She was started on ceftriaxone 1 g intravenously every 24 hours, with close observation in the medical intensive care unit, where she was admitted because of epiglottitis. On hospital day 3, the throat culture was reported as negative, but the blood culture was reported as positive for Haemophilus influenzae. Thus, the clinical diagnosis was acute epiglottitis due to H influenzae, not group A streptococci.

The patient completed 10 days of ceftriaxone therapy; her recovery was uneventful, and she was discharged on hospital day 10.

INFLUENZA: CHALLENGES TO PROMPT, ACCURATE DIAGNOSIS

During influenza season, emergency departments are inundated with adults with influenza A and other viral respiratory infections. This makes prompt, accurate diagnosis a challenge,¹ given the broad differential diagnosis.^2,3 Adults with influenza and its complications as well as unrelated conditions can present a special challenge.⁴

Our patient presented with acute-onset influenza A and was then found to have acute epiglottitis, an unexpected complication of influenza A.⁵ A positive rapid test for group A streptococci done at an urgent care facility led emergency department physicians to assume that the acute epiglottitis was due to group A streptococci. Unless correlated with clinical findings, results of rapid diagnostic tests may mislead the unwary practitioner. Accurate diagnosis should be based mainly on the history and physical findings. Results of rapid diagnostic tests can be helpful if interpreted in the clinical context.^6–8

The rapid test for streptococci is appropriate for the diagnosis of pharyngitis due to group A streptococci in people under age 30 with acute-onset sore throat, fever, and bilateral acute cervical adenopathy, without fatigue or myalgias. However, the rapid test does not differentiate colonization from infection. Group A streptococci are common colonizers with viral pharyngitis. In 30% of cases of Epstein-Barr virus pharyngitis, there is colonization with group A streptococci. A positive rapid test in such cases can result in the wrong diagnosis, ie, pharyngitis due to group A streptococci rather than Epstein-Barr virus.

NOTE: The scenario presented here is partly based on cases reported elsewhere by Martínez-Valles et al¹ and Fernández-Rodríguez et al.²

A 55-year-old man is admitted to the hospital with generalized malaise, paresthesias, and severe hypertension. He says he had experienced agitation along with weakness on exertion 24 hours before presentation to the emergency department, with subsequent onset of paresthesias in his lower extremities and perioral area.

He is already known to have mild chronic obstructive pulmonary disease, with a ratio of forced expiratory volume in 1 second (FEV₁)to forced vital capacity (FVC) of less than 70% and an FEV₁ 85% of predicted. In addition, he was recently diagnosed with diabetes, resistant hypertension requiring maximum doses of 3 agents (a calcium channel blocker, an angiotensin-converting enzyme inhibitor, and a loop diuretic), and hyperlipidemia.

He is a current smoker with a 30-pack-year smoking history. He does not use alcohol. His family history is noncontributory.

ASSESSING ACID-BASE DISORDERS

1. What type of acid-base disorder does this patient have?

• Metabolic acidosis
• Respiratory acidosis
• Metabolic alkalosis
• Respiratory alkalosis

The patient has metabolic alkalosis.

A 5-step approach

1. Acidosis or alkalosis? The patient’s arterial pH is 7.5, which is alkalemic because it is higher than 7.44.

2. Metabolic or respiratory? The primary process in our patient is overwhelmingly metabolic, as his partial pressure of carbon dioxide (Pco₂) is slightly elevated, a direction that would cause acidosis, not alkalosis.

3. The anion gap (the serum sodium concentration minus the sum of the chloride and bicarbonate concentrations) is normal at 8 mmol/L (DRG:HYBRiD-XL Immunoassay and Clinical Chemistry Analyzer, reference range 8–16).

4. Is the disturbance compensated? We have determined that this patient has a metabolic alkalemia; the question now is whether there is any compensation for the primary disturbance.

In metabolic alkalosis, the Pco₂ may increase by approximately 0.6 mm Hg (range 0.5–0.8) above the nominal normal level of 40 mm Hg for each 1-mmol/L increase in bicarbonate above the nominal normal level of 25 mmol/L.⁴ If the patient requires oxygen, the calculation may be unreliable, however, as hypoxemia may have an overriding influence on respiratory drive.

Patients with chronically high Pco₂ levels such as those with chronic obstructive pulmonary disease can become accustomed to high carbon dioxide levels and lose their hyper-
capnic respiratory drive. Giving oxygen supplementation is thought to decrease respiratory drive in these patients, so that they will breathe slower and retain more carbon dioxide. There is some degree of respiratory compensation for metabolic alkalosis that occurs by breathing less, though it is limited overall—even in very alkalotic patients, breathing less results in CO₂ retention, which, by displacing O₂ molecules in the alveoli, will in turn result in hypoxia. The brain then senses the hypoxia and makes one breathe faster, thereby limiting this compensation. 

This patient’s serum bicarbonate level is 40 mmol/L, or 15 mmol/L higher than the nominal normal level. If he is compensating, his Pco₂ should be 40 + (15 × 0.6) = 49 mm Hg, and in fact it is 51 mm Hg, which is within the normal range of expected compensation (47.5–52 mm Hg). Therefore, yes, he is compensating for the primary disturbance.  

5. In metabolic acidosis, is there a delta gap? As our patient has metabolic alkalosis, not acidosis, this question does not apply in this case.

2. Which is the best test to order next to determine the cause of this patient’s hypokalemic metabolic alkalosis?

• Serum magnesium level
• Spot urine chloride
• Renal ultrasonography
• 24-hour urine collection for sodium, potassium, and chloride

The patient’s loop diuretic is withheld for 12 hours and a spot urine chloride is obtained, which is reported as 44 mmol/L. This high value suggests that a volume-independent hypo­kalemic metabolic alkalosis is present with potassium depletion.

As for the other answer choices:

Serum magnesium. Though hypomagnesemia can cause hypokalemia due to lack of inhibition of renal outer medullary potassium channels and subsequent increased excretion of potassium in the apical tubular membrane, it is not independently associated with acid-base disturbances.⁵

Renal ultrasonography gives information about structural kidney disease but is of limited utility in identifying the cause of hypokalemic metabolic alkalosis.

A 24-hour urine collection is unnecessary in this setting and would ultimately result in delay in diagnosis, as spot urine chloride is a more efficient means of rapidly distinguishing volume-responsive vs volume-independent causes of hypokalemic metabolic alkalosis.⁶

IS HIS HYPERTENSION SECONDARY? IF SO, WHAT IS THE CAUSE?

Several features of this case suggest that the patient’s hypertension is secondary rather than primary. It is of recent onset. The patient’s family history is noncontributory, and his hypertension is resistant to the use of maximum doses of 3 antihypertensive agents.

3. Which of the following causes of secondary hypertension is not commonly associated with hypokalemia and metabolic alkalosis?

• Hyperaldosteronism
• Liddle syndrome
• Cushing syndrome
• Renal parenchymal disease
• Chronic licorice ingestion

Renal parenchymal disease is a cause of resistant hypertension, but it is not characterized by metabolic alkalosis, hypokalemia, and  elevated urine chloride,⁷ while the others listed here—hyperaldosteronism, Liddle syndrome, Cushing syndrome, and chronic licorice ingestion­—are. Other common causes of resistant hypertension without these metabolic abnormalities include obstructive sleep apnea, alcohol abuse, and nonadherence to treatment.

While treatment of hypertension with loop diuretics can result in hypokalemia and metabolic alkalosis due to the effect of these drugs on potassium reabsorption in the loop of Henle, the patient’s hypokalemia persisted after this agent was withdrawn.⁸

Causes of hypokalemic metabolic alkalosis with and without hypertension are further delineated in Figure 1.

Additional diagnostic testing: Plasma renin and plasma aldosterone

At this juncture, the differential diagnosis for this patient’s potassium depletion, metabolic alkalosis, high urine chloride, and hypertension has been narrowed to primary or secondary hyperaldosteronism, surreptitious mineralocorticoid ingestion, Cushing syndrome, licorice ingestion, Liddle syndrome, or one of the 3 hydroxylase deficiencies (11-, 17-, and 21-) (Figure 1).

Although clues in the history, physical examination, and imaging may suggest a specific cause of his abnormal laboratory values, the next step in the diagnostic workup is to measure the plasma renin and aldosterone levels (Table 3).

HYPERALDOSTERONISM

4. Hyperaldosteronism is associated with which of the following patterns of renin and aldosterone values?

• High renin, high aldosterone, normal ratio of plasma aldosterone concentration (PAC) to plasma renin activity (PRA)
• Low renin, low aldosterone, normal PAC–PRA ratio
• Low renin, high aldosterone, high PAC–PRA ratio
• High renin, low aldosterone, low PAC–PRA ratio

The pattern of low renin, high aldosterone, and high PAC–PRA ratio is associated with hyperaldosteronism.

Primary hyperaldosteronism

Primary hyperaldosteronism is one of the most common causes of resistant hypertension and is underappreciated, being diagnosed in up to 20% of patients referred to hypertension specialty clinics.⁷ Potassium levels may be normal, likely contributing to its lack of recognition in this target population.

Primary hyperaldosteronism should be suspected in patients who have a plasma aldosterone PAC–PRA ratio greater than 20 with elevated plasma aldosterone concentrations
(> 15 ng/dL).

Persistently elevated aldosterone levels in the setting of elevated plasma volume is proof that aldosterone secretion is independent of the renin-angiotensin-aldosterone axis, and therefore is autonomous (secondary to adrenal tumor or hyperplasia). Further testing in the form of oral salt loading, saline infusion, or fludrocortisone (a sodium-retaining steroid) administration is thus required to confirm inappropriate, autonomous aldosterone secretion.⁹

After establishing the diagnosis of primary hyperaldosteronism, one should determine the subtype (ie, due to an adrenal carcinoma, unilateral hypersecreting adenoma, or unilateral or bilateral hyperplasia). Further testing includes adrenal computed tomography (CT) to rule out adrenal carcinomas, which are suspected with adenomas larger than 4 cm. Though part of the diagnostic workup, CT as a means of confirmational testing alone does not preclude the possibility of bilateral adrenal hyperplasia in some patients, even in the presence of an adrenal adenoma. For this reason, adrenal venous sampling is required to definitively determine whether the condition is due to a hypersecreting adrenal adenoma or unilateral or bilateral hyperplasia.^9,10

Treatment of primary hyperaldosteronism depends on the subtype of the disease and involves salt restriction in addition to an aldosterone antagonist (spironolactone or eplerenone in the case of bilateral disease) or surgery (unilateral disease).^9,11,12

Secondary hyperaldosteronism

Secondary hyperaldosteronism should be suspected when plasma renin and aldosterone levels are both elevated with a PAC–PRA ratio less than 10.

This pattern is most commonly seen with diuretic use but can also be a consequence of renal artery stenosis or, rarely, a renin-secreting tumor.¹³ Renal artery stenosis is a common finding in patients with hypertension undergoing cardiac catheterization, which is not surprising as more than 90% of such stenoses are atherosclerotic.⁷ Renin-secreting tumors are exceedingly rare, with fewer than 100 cases reported in the literature, and are more common in younger individuals.¹³

Our patient has low-normal aldosterone and plasma renin

On further testing, this patient’s plasma aldosterone level is 2.55 ng/dL (normal < 15 ng/dL), his plasma renin activity is 0.53 ng/mL/hour (normal 0.2–2.8 ng/mL/hour), and his PAC–PRA ratio is therefore 4.81.

The categories discussed thus far have included primary and secondary hyperaldosteronism, which typically do not present with low to normal levels of both renin and aldosterone. Surreptitious mineralocorticoid use could present in this manner, but is unlikely in this patient, whose medications do not include fludrocortisone.

The low-normal values thus lead to consideration of a third category: apparent mineralocorticoid excess. Diseases in this category such as Cushing disease or adrenocorticotropic hormone (ACTH) excess are characterized by increases in corticosteroids so that the potassium depletion, metabolic alkalosis, and hypertension are not a consequence of renin and aldosterone but rather the excess corticosteroids.¹⁴

Causes of apparent mineralocorticoid excess

There are several possible causes of mineralocorticoid excess associated with hypertension and hypokalemic metabolic alkalosis not due to renin and aldosterone.

Chronic licorice ingestion in high volumes is one such cause and is thought to result in inhibition of 11B-hydroxysteroid dehydrogenase or possibly cortisol oxidase by licorice’s active component, glycyrrhetinic acid. This inhibition results in an inability to convert cortisol to cortisone. The cortisol excess binds to mineralocorticoid receptors, and acting like aldosterone, results in hypertension and hypokalemic metabolic alkalosis as well as feedback inhibition of renin and aldosterone levels.¹⁵

Partial hydroxylase deficiencies, though rare, should also be considered as a cause of hypokalemic metabolic alkalosis, hypertension, and, potentially, hirsutism and clitoromegaly in women. They can be diagnosed with elevated levels of 17-ketosteroids and dehydroepiandrosterone sulfate, both of which, in excess, may act on aldosterone receptors in a manner similar to cortisol.¹⁶

Liddle syndrome, a rare autosomal dominant condition, may also present with suppressed levels of both renin and aldosterone. In contrast to the disorders of nonaldosterone mineralocorticoid excess, however, the sodium channel defect in Liddle syndrome is characterized by a primary increase in sodium reabsorption in the collecting tubule and potassium wasting. The resultant volume expansion leads to suppressed renin and aldosterone levels and hypertension with low potassium and elevated bicarbonate concentrations.¹⁷

Liddle syndrome is commonly diagnosed in childhood but may go unrecognized due to occasional absence of hypokalemia at presentation. Potassium-sparing diuretics such as amiloride or triamterene are the mainstays of treatment.¹⁸

Rates of cardiovascular and all-cause mortality are increased in patients with long-term hypercortisolism, even after plasma concentrations of cortisol are normalized.²¹

Figure 2 shows the cascade of the hypothalamic-pituitary-adrenal axis.

Given the patient’s clinical presentation and laboratory and imaging findings with normal plasma renin and aldosterone levels, a workup for suspected hypercortisolism is initiated.

Initial diagnostic testing for hypercortisolism depends on the degree of clinical suspicion. In those with low probability of the disease, testing should consist of 1 of the following, as a single negative test may be sufficient to rule out the disease:

• 24-hour urinary cortisol levels
• Overnight dexamethasone suppression testing
• Late-night salivary cortisol measurements.

In those with a high index of suspicion, 2 of the aforementioned tests should be performed, as 1 normal result may not be sufficient to exclude the diagnosis.^22,23

A 24-hour urinary cortisol collection and overnight dexamethasone suppression test are obtained. His 24-hour urinary free cortisol level is elevated at 6,600 µg (normal 4–100), and suppression testing with 8 mg of dexamethasone (a form of “high-dose” testing)demonstrates only an 8% decline in serum cortisol levels. Cortisol should generally drop more than 90%.

Morning serum cortisol concentration is less than 5 µg/dL (140 nmol/L) in most patients with Cushing disease (ie, a pituitary tumor), and is usually undetectable in normal subjects. Only about 50% of neuroendocrine ACTH-secreting tumors will suppress with this test.

The patient’s clinical presentation, in conjunction with his diagnostic testing, are thus consistent with Cushing syndrome.

CUSHING SYNDROME

Cushing syndrome is most often exogenous or iatrogenic, ie, a result of supraphysiologic doses of glucocorticoids used to treat a variety of inflammatory, autoimmune, and neoplastic conditions.

Endogenous Cushing syndrome, on the other hand, is rare, with an estimated prevalence of 0.7 to 2.4 cases per million per year. ACTH-dependent causes account for 80% of endogenous Cushing syndrome cases, with ACTH-secreting pituitary adenomas (Cushing disease) accounting for 75% to 80% and ectopic ACTH secretion accounting for 15% to 20%. Less than 1% of cases are due to tumors that produce corticotropin-releasing hormone (CRH).

ACTH-independent Cushing syndrome is diagnosed in 20% of endogenous cases and is most commonly caused by a unilateral adrenal tumor. Rare causes of ACTH-independent disease include adrenal carcinoma, McCune-Albright syndrome, and adrenal hyperplasia.²⁴

The patient’s ACTH is high

To determine whether this is an ACTH-dependent or independent process, the next step is to order an ACTH level. His ACTH level is high at 107 pg/mL (normal < 46 pg/mL), confirming the diagnosis of ACTH-dependent Cushing syndrome.

To find out if this ACTH-dependent process is due to a pituitary adenoma, magnetic resonance imaging (MRI) of the pituitary is obtained but is normal.

Large masses (> 6 mm) strongly suggest Cushing disease, but these tumors are often small and may be missed even with more advanced imaging techniques. Corticotropin-secreting adenomas arising from normal cells in the pituitary retain some sensitivity to glucocorticoid negative feedback and CRH stimulation, and thus high-dose dexamethasone suppression testing in conjunction with CRH stimulation testing can be used to differentiate Cushing disease from ectopic ACTH secretion.^24,25 Both of these tests have poor diagnostic accuracy, however, and thus inferior petrosal sampling remains the gold standard for the diagnosis of Cushing disease.

ACTH-SECRETING TUMORS

5. Cushing syndrome due to ectopic ACTH secretion is most commonly attributed to which of the following tumors?

• Small-cell lung carcinoma
• Pancreatic carcinoma
• Medullary thyroid carcinoma
• Gastrinoma

Severe cases of Cushing syndrome are often attributable to ectopic ACTH secretion due to an underlying malignancy, most commonly small-cell lung carcinoma or neuroendocrine tumors of pulmonary origin. Other causes include pancreatic and thymic neuroendocrine tumors, gastrinomas, and medullary thyroid carcinoma.^25,26

Because most ACTH-producing tumors are intrathoracic, initial imaging in cases of suspected ectopic ACTH secretion should focus on the chest, with CT the usual first choice. Octreotide scintigraphy can also be useful in localizing disease, as many neuroendocrine tumors express somatostatin receptors. Specialized positron-emission tomography scans may also be helpful in tumor identification.²⁴

6. Which of the following is most appropriate medical therapy for suppression of cortisol secretion in Cushing syndrome due to ectopic ACTH secretion?

• Spironolactone
• Dexamethasone
• Somatostatin
• Estrogen
• Ketoconazole

Hyperglycemia, hypokalemia, hypertension, psychiatric disturbances, venous thromboembolism, and systemic infections appear to be common in ectopic ACTH syndrome and often correlate with the degree of hypercortisolemia. Severe Cushing syndrome due to ectopic ACTH secretion is an emergency requiring prompt control of cortisol secretion.

First-line treatments include steroidogenesis inhibitors (ketoconazole, metyrapone, etomidate, mitotane) and glucocorticoid receptor antagonists (mifepristone). High-dose spironolactone and eplerenone can also be used to treat the hypertension and hypokalemia associated with mineralocorticoid receptor stimulation. Definitive treatment involves surgical resection, chemotherapy, or radiotherapy when applicable.^24,25

After confirmation of the diagnosis, the patient is prescribed ketoconazole and spironolactone, with substantial improvement. He subsequently is started on combination chemotherapy and radiation therapy for his small-cell lung carcinoma.

DISCUSSION

The differential diagnosis for hypokalemia is broad and relies on information obtained during the history and physical examination, followed by interpretation of selected laboratory results. Myriad pathologies in diverse organ systems, eg, diarrhea, renal tubular acidosis, and adrenal disease, may be responsible for a low serum potassium. Further categorizing potassium depletion on the basis of an associated acid-base disturbance, such as metabolic alkalosis, allows one to use an algorithmic approach that can identify specific etiologies responsible for both the potassium and the acid-base disturbances.

Using the spot urine chloride in the setting of hypokalemic metabolic alkalosis with or without hypertension can narrow the differential diagnosis and allow additional clinical findings to guide clinical problem-solving and decision-making, even for conditions not commonly encountered in routine medical practice.

Obtaining renin and aldosterone measurements in patients with potassium depletion, metabolic alkalosis, high urine chloride excretion, and hypertension permits further categorization into 3 clinical groups: elevated aldosterone and renin (secondary hyperaldosteronism), elevated aldosterone and low renin (primary hyperaldosteronism), or apparent mineralocorticoid excess wherein neither renin nor aldosterone are responsible for the syndrome.

The patient in our case had apparent mineralocorticoid excess as a consequence of an ACTH-producing small-cell carcinoma.

NOTE: The scenario presented here is partly based on cases reported elsewhere by Martínez-Valles et al¹ and Fernández-Rodríguez et al.²

A 55-year-old man is admitted to the hospital with generalized malaise, paresthesias, and severe hypertension. He says he had experienced agitation along with weakness on exertion 24 hours before presentation to the emergency department, with subsequent onset of paresthesias in his lower extremities and perioral area.

He is already known to have mild chronic obstructive pulmonary disease, with a ratio of forced expiratory volume in 1 second (FEV₁)to forced vital capacity (FVC) of less than 70% and an FEV₁ 85% of predicted. In addition, he was recently diagnosed with diabetes, resistant hypertension requiring maximum doses of 3 agents (a calcium channel blocker, an angiotensin-converting enzyme inhibitor, and a loop diuretic), and hyperlipidemia.

He is a current smoker with a 30-pack-year smoking history. He does not use alcohol. His family history is noncontributory.

ASSESSING ACID-BASE DISORDERS

1. What type of acid-base disorder does this patient have?

• Metabolic acidosis
• Respiratory acidosis
• Metabolic alkalosis
• Respiratory alkalosis

The patient has metabolic alkalosis.

A 5-step approach

1. Acidosis or alkalosis? The patient’s arterial pH is 7.5, which is alkalemic because it is higher than 7.44.

2. Metabolic or respiratory? The primary process in our patient is overwhelmingly metabolic, as his partial pressure of carbon dioxide (Pco₂) is slightly elevated, a direction that would cause acidosis, not alkalosis.

3. The anion gap (the serum sodium concentration minus the sum of the chloride and bicarbonate concentrations) is normal at 8 mmol/L (DRG:HYBRiD-XL Immunoassay and Clinical Chemistry Analyzer, reference range 8–16).

4. Is the disturbance compensated? We have determined that this patient has a metabolic alkalemia; the question now is whether there is any compensation for the primary disturbance.

In metabolic alkalosis, the Pco₂ may increase by approximately 0.6 mm Hg (range 0.5–0.8) above the nominal normal level of 40 mm Hg for each 1-mmol/L increase in bicarbonate above the nominal normal level of 25 mmol/L.⁴ If the patient requires oxygen, the calculation may be unreliable, however, as hypoxemia may have an overriding influence on respiratory drive.

Patients with chronically high Pco₂ levels such as those with chronic obstructive pulmonary disease can become accustomed to high carbon dioxide levels and lose their hyper-
capnic respiratory drive. Giving oxygen supplementation is thought to decrease respiratory drive in these patients, so that they will breathe slower and retain more carbon dioxide. There is some degree of respiratory compensation for metabolic alkalosis that occurs by breathing less, though it is limited overall—even in very alkalotic patients, breathing less results in CO₂ retention, which, by displacing O₂ molecules in the alveoli, will in turn result in hypoxia. The brain then senses the hypoxia and makes one breathe faster, thereby limiting this compensation. 

This patient’s serum bicarbonate level is 40 mmol/L, or 15 mmol/L higher than the nominal normal level. If he is compensating, his Pco₂ should be 40 + (15 × 0.6) = 49 mm Hg, and in fact it is 51 mm Hg, which is within the normal range of expected compensation (47.5–52 mm Hg). Therefore, yes, he is compensating for the primary disturbance.  

5. In metabolic acidosis, is there a delta gap? As our patient has metabolic alkalosis, not acidosis, this question does not apply in this case.

2. Which is the best test to order next to determine the cause of this patient’s hypokalemic metabolic alkalosis?

• Serum magnesium level
• Spot urine chloride
• Renal ultrasonography
• 24-hour urine collection for sodium, potassium, and chloride

The patient’s loop diuretic is withheld for 12 hours and a spot urine chloride is obtained, which is reported as 44 mmol/L. This high value suggests that a volume-independent hypo­kalemic metabolic alkalosis is present with potassium depletion.

As for the other answer choices:

Serum magnesium. Though hypomagnesemia can cause hypokalemia due to lack of inhibition of renal outer medullary potassium channels and subsequent increased excretion of potassium in the apical tubular membrane, it is not independently associated with acid-base disturbances.⁵

Renal ultrasonography gives information about structural kidney disease but is of limited utility in identifying the cause of hypokalemic metabolic alkalosis.

A 24-hour urine collection is unnecessary in this setting and would ultimately result in delay in diagnosis, as spot urine chloride is a more efficient means of rapidly distinguishing volume-responsive vs volume-independent causes of hypokalemic metabolic alkalosis.⁶

IS HIS HYPERTENSION SECONDARY? IF SO, WHAT IS THE CAUSE?

Several features of this case suggest that the patient’s hypertension is secondary rather than primary. It is of recent onset. The patient’s family history is noncontributory, and his hypertension is resistant to the use of maximum doses of 3 antihypertensive agents.

3. Which of the following causes of secondary hypertension is not commonly associated with hypokalemia and metabolic alkalosis?

• Hyperaldosteronism
• Liddle syndrome
• Cushing syndrome
• Renal parenchymal disease
• Chronic licorice ingestion

Renal parenchymal disease is a cause of resistant hypertension, but it is not characterized by metabolic alkalosis, hypokalemia, and  elevated urine chloride,⁷ while the others listed here—hyperaldosteronism, Liddle syndrome, Cushing syndrome, and chronic licorice ingestion­—are. Other common causes of resistant hypertension without these metabolic abnormalities include obstructive sleep apnea, alcohol abuse, and nonadherence to treatment.

While treatment of hypertension with loop diuretics can result in hypokalemia and metabolic alkalosis due to the effect of these drugs on potassium reabsorption in the loop of Henle, the patient’s hypokalemia persisted after this agent was withdrawn.⁸

Causes of hypokalemic metabolic alkalosis with and without hypertension are further delineated in Figure 1.

Additional diagnostic testing: Plasma renin and plasma aldosterone

At this juncture, the differential diagnosis for this patient’s potassium depletion, metabolic alkalosis, high urine chloride, and hypertension has been narrowed to primary or secondary hyperaldosteronism, surreptitious mineralocorticoid ingestion, Cushing syndrome, licorice ingestion, Liddle syndrome, or one of the 3 hydroxylase deficiencies (11-, 17-, and 21-) (Figure 1).

Although clues in the history, physical examination, and imaging may suggest a specific cause of his abnormal laboratory values, the next step in the diagnostic workup is to measure the plasma renin and aldosterone levels (Table 3).

HYPERALDOSTERONISM

4. Hyperaldosteronism is associated with which of the following patterns of renin and aldosterone values?

• High renin, high aldosterone, normal ratio of plasma aldosterone concentration (PAC) to plasma renin activity (PRA)
• Low renin, low aldosterone, normal PAC–PRA ratio
• Low renin, high aldosterone, high PAC–PRA ratio
• High renin, low aldosterone, low PAC–PRA ratio

The pattern of low renin, high aldosterone, and high PAC–PRA ratio is associated with hyperaldosteronism.

Primary hyperaldosteronism

Primary hyperaldosteronism is one of the most common causes of resistant hypertension and is underappreciated, being diagnosed in up to 20% of patients referred to hypertension specialty clinics.⁷ Potassium levels may be normal, likely contributing to its lack of recognition in this target population.

Primary hyperaldosteronism should be suspected in patients who have a plasma aldosterone PAC–PRA ratio greater than 20 with elevated plasma aldosterone concentrations
(> 15 ng/dL).

Persistently elevated aldosterone levels in the setting of elevated plasma volume is proof that aldosterone secretion is independent of the renin-angiotensin-aldosterone axis, and therefore is autonomous (secondary to adrenal tumor or hyperplasia). Further testing in the form of oral salt loading, saline infusion, or fludrocortisone (a sodium-retaining steroid) administration is thus required to confirm inappropriate, autonomous aldosterone secretion.⁹

After establishing the diagnosis of primary hyperaldosteronism, one should determine the subtype (ie, due to an adrenal carcinoma, unilateral hypersecreting adenoma, or unilateral or bilateral hyperplasia). Further testing includes adrenal computed tomography (CT) to rule out adrenal carcinomas, which are suspected with adenomas larger than 4 cm. Though part of the diagnostic workup, CT as a means of confirmational testing alone does not preclude the possibility of bilateral adrenal hyperplasia in some patients, even in the presence of an adrenal adenoma. For this reason, adrenal venous sampling is required to definitively determine whether the condition is due to a hypersecreting adrenal adenoma or unilateral or bilateral hyperplasia.^9,10

Treatment of primary hyperaldosteronism depends on the subtype of the disease and involves salt restriction in addition to an aldosterone antagonist (spironolactone or eplerenone in the case of bilateral disease) or surgery (unilateral disease).^9,11,12

Secondary hyperaldosteronism

Secondary hyperaldosteronism should be suspected when plasma renin and aldosterone levels are both elevated with a PAC–PRA ratio less than 10.

This pattern is most commonly seen with diuretic use but can also be a consequence of renal artery stenosis or, rarely, a renin-secreting tumor.¹³ Renal artery stenosis is a common finding in patients with hypertension undergoing cardiac catheterization, which is not surprising as more than 90% of such stenoses are atherosclerotic.⁷ Renin-secreting tumors are exceedingly rare, with fewer than 100 cases reported in the literature, and are more common in younger individuals.¹³

Our patient has low-normal aldosterone and plasma renin

On further testing, this patient’s plasma aldosterone level is 2.55 ng/dL (normal < 15 ng/dL), his plasma renin activity is 0.53 ng/mL/hour (normal 0.2–2.8 ng/mL/hour), and his PAC–PRA ratio is therefore 4.81.

The categories discussed thus far have included primary and secondary hyperaldosteronism, which typically do not present with low to normal levels of both renin and aldosterone. Surreptitious mineralocorticoid use could present in this manner, but is unlikely in this patient, whose medications do not include fludrocortisone.

The low-normal values thus lead to consideration of a third category: apparent mineralocorticoid excess. Diseases in this category such as Cushing disease or adrenocorticotropic hormone (ACTH) excess are characterized by increases in corticosteroids so that the potassium depletion, metabolic alkalosis, and hypertension are not a consequence of renin and aldosterone but rather the excess corticosteroids.¹⁴

Causes of apparent mineralocorticoid excess

There are several possible causes of mineralocorticoid excess associated with hypertension and hypokalemic metabolic alkalosis not due to renin and aldosterone.

Chronic licorice ingestion in high volumes is one such cause and is thought to result in inhibition of 11B-hydroxysteroid dehydrogenase or possibly cortisol oxidase by licorice’s active component, glycyrrhetinic acid. This inhibition results in an inability to convert cortisol to cortisone. The cortisol excess binds to mineralocorticoid receptors, and acting like aldosterone, results in hypertension and hypokalemic metabolic alkalosis as well as feedback inhibition of renin and aldosterone levels.¹⁵

Partial hydroxylase deficiencies, though rare, should also be considered as a cause of hypokalemic metabolic alkalosis, hypertension, and, potentially, hirsutism and clitoromegaly in women. They can be diagnosed with elevated levels of 17-ketosteroids and dehydroepiandrosterone sulfate, both of which, in excess, may act on aldosterone receptors in a manner similar to cortisol.¹⁶

Liddle syndrome, a rare autosomal dominant condition, may also present with suppressed levels of both renin and aldosterone. In contrast to the disorders of nonaldosterone mineralocorticoid excess, however, the sodium channel defect in Liddle syndrome is characterized by a primary increase in sodium reabsorption in the collecting tubule and potassium wasting. The resultant volume expansion leads to suppressed renin and aldosterone levels and hypertension with low potassium and elevated bicarbonate concentrations.¹⁷

Liddle syndrome is commonly diagnosed in childhood but may go unrecognized due to occasional absence of hypokalemia at presentation. Potassium-sparing diuretics such as amiloride or triamterene are the mainstays of treatment.¹⁸

Rates of cardiovascular and all-cause mortality are increased in patients with long-term hypercortisolism, even after plasma concentrations of cortisol are normalized.²¹

Figure 2 shows the cascade of the hypothalamic-pituitary-adrenal axis.

Given the patient’s clinical presentation and laboratory and imaging findings with normal plasma renin and aldosterone levels, a workup for suspected hypercortisolism is initiated.

Initial diagnostic testing for hypercortisolism depends on the degree of clinical suspicion. In those with low probability of the disease, testing should consist of 1 of the following, as a single negative test may be sufficient to rule out the disease:

• 24-hour urinary cortisol levels
• Overnight dexamethasone suppression testing
• Late-night salivary cortisol measurements.

In those with a high index of suspicion, 2 of the aforementioned tests should be performed, as 1 normal result may not be sufficient to exclude the diagnosis.^22,23

A 24-hour urinary cortisol collection and overnight dexamethasone suppression test are obtained. His 24-hour urinary free cortisol level is elevated at 6,600 µg (normal 4–100), and suppression testing with 8 mg of dexamethasone (a form of “high-dose” testing)demonstrates only an 8% decline in serum cortisol levels. Cortisol should generally drop more than 90%.

Morning serum cortisol concentration is less than 5 µg/dL (140 nmol/L) in most patients with Cushing disease (ie, a pituitary tumor), and is usually undetectable in normal subjects. Only about 50% of neuroendocrine ACTH-secreting tumors will suppress with this test.

The patient’s clinical presentation, in conjunction with his diagnostic testing, are thus consistent with Cushing syndrome.

CUSHING SYNDROME

Cushing syndrome is most often exogenous or iatrogenic, ie, a result of supraphysiologic doses of glucocorticoids used to treat a variety of inflammatory, autoimmune, and neoplastic conditions.

Endogenous Cushing syndrome, on the other hand, is rare, with an estimated prevalence of 0.7 to 2.4 cases per million per year. ACTH-dependent causes account for 80% of endogenous Cushing syndrome cases, with ACTH-secreting pituitary adenomas (Cushing disease) accounting for 75% to 80% and ectopic ACTH secretion accounting for 15% to 20%. Less than 1% of cases are due to tumors that produce corticotropin-releasing hormone (CRH).

ACTH-independent Cushing syndrome is diagnosed in 20% of endogenous cases and is most commonly caused by a unilateral adrenal tumor. Rare causes of ACTH-independent disease include adrenal carcinoma, McCune-Albright syndrome, and adrenal hyperplasia.²⁴

The patient’s ACTH is high

To determine whether this is an ACTH-dependent or independent process, the next step is to order an ACTH level. His ACTH level is high at 107 pg/mL (normal < 46 pg/mL), confirming the diagnosis of ACTH-dependent Cushing syndrome.

To find out if this ACTH-dependent process is due to a pituitary adenoma, magnetic resonance imaging (MRI) of the pituitary is obtained but is normal.

Large masses (> 6 mm) strongly suggest Cushing disease, but these tumors are often small and may be missed even with more advanced imaging techniques. Corticotropin-secreting adenomas arising from normal cells in the pituitary retain some sensitivity to glucocorticoid negative feedback and CRH stimulation, and thus high-dose dexamethasone suppression testing in conjunction with CRH stimulation testing can be used to differentiate Cushing disease from ectopic ACTH secretion.^24,25 Both of these tests have poor diagnostic accuracy, however, and thus inferior petrosal sampling remains the gold standard for the diagnosis of Cushing disease.

ACTH-SECRETING TUMORS

5. Cushing syndrome due to ectopic ACTH secretion is most commonly attributed to which of the following tumors?

• Small-cell lung carcinoma
• Pancreatic carcinoma
• Medullary thyroid carcinoma
• Gastrinoma

Severe cases of Cushing syndrome are often attributable to ectopic ACTH secretion due to an underlying malignancy, most commonly small-cell lung carcinoma or neuroendocrine tumors of pulmonary origin. Other causes include pancreatic and thymic neuroendocrine tumors, gastrinomas, and medullary thyroid carcinoma.^25,26

Because most ACTH-producing tumors are intrathoracic, initial imaging in cases of suspected ectopic ACTH secretion should focus on the chest, with CT the usual first choice. Octreotide scintigraphy can also be useful in localizing disease, as many neuroendocrine tumors express somatostatin receptors. Specialized positron-emission tomography scans may also be helpful in tumor identification.²⁴

6. Which of the following is most appropriate medical therapy for suppression of cortisol secretion in Cushing syndrome due to ectopic ACTH secretion?

• Spironolactone
• Dexamethasone
• Somatostatin
• Estrogen
• Ketoconazole

Hyperglycemia, hypokalemia, hypertension, psychiatric disturbances, venous thromboembolism, and systemic infections appear to be common in ectopic ACTH syndrome and often correlate with the degree of hypercortisolemia. Severe Cushing syndrome due to ectopic ACTH secretion is an emergency requiring prompt control of cortisol secretion.

First-line treatments include steroidogenesis inhibitors (ketoconazole, metyrapone, etomidate, mitotane) and glucocorticoid receptor antagonists (mifepristone). High-dose spironolactone and eplerenone can also be used to treat the hypertension and hypokalemia associated with mineralocorticoid receptor stimulation. Definitive treatment involves surgical resection, chemotherapy, or radiotherapy when applicable.^24,25

After confirmation of the diagnosis, the patient is prescribed ketoconazole and spironolactone, with substantial improvement. He subsequently is started on combination chemotherapy and radiation therapy for his small-cell lung carcinoma.

DISCUSSION

The differential diagnosis for hypokalemia is broad and relies on information obtained during the history and physical examination, followed by interpretation of selected laboratory results. Myriad pathologies in diverse organ systems, eg, diarrhea, renal tubular acidosis, and adrenal disease, may be responsible for a low serum potassium. Further categorizing potassium depletion on the basis of an associated acid-base disturbance, such as metabolic alkalosis, allows one to use an algorithmic approach that can identify specific etiologies responsible for both the potassium and the acid-base disturbances.

Using the spot urine chloride in the setting of hypokalemic metabolic alkalosis with or without hypertension can narrow the differential diagnosis and allow additional clinical findings to guide clinical problem-solving and decision-making, even for conditions not commonly encountered in routine medical practice.

Obtaining renin and aldosterone measurements in patients with potassium depletion, metabolic alkalosis, high urine chloride excretion, and hypertension permits further categorization into 3 clinical groups: elevated aldosterone and renin (secondary hyperaldosteronism), elevated aldosterone and low renin (primary hyperaldosteronism), or apparent mineralocorticoid excess wherein neither renin nor aldosterone are responsible for the syndrome.

The patient in our case had apparent mineralocorticoid excess as a consequence of an ACTH-producing small-cell carcinoma.

NOTE: The scenario presented here is partly based on cases reported elsewhere by Martínez-Valles et al¹ and Fernández-Rodríguez et al.²

A 55-year-old man is admitted to the hospital with generalized malaise, paresthesias, and severe hypertension. He says he had experienced agitation along with weakness on exertion 24 hours before presentation to the emergency department, with subsequent onset of paresthesias in his lower extremities and perioral area.

He is already known to have mild chronic obstructive pulmonary disease, with a ratio of forced expiratory volume in 1 second (FEV₁)to forced vital capacity (FVC) of less than 70% and an FEV₁ 85% of predicted. In addition, he was recently diagnosed with diabetes, resistant hypertension requiring maximum doses of 3 agents (a calcium channel blocker, an angiotensin-converting enzyme inhibitor, and a loop diuretic), and hyperlipidemia.

He is a current smoker with a 30-pack-year smoking history. He does not use alcohol. His family history is noncontributory.

ASSESSING ACID-BASE DISORDERS

1. What type of acid-base disorder does this patient have?

• Metabolic acidosis
• Respiratory acidosis
• Metabolic alkalosis
• Respiratory alkalosis

The patient has metabolic alkalosis.

A 5-step approach

1. Acidosis or alkalosis? The patient’s arterial pH is 7.5, which is alkalemic because it is higher than 7.44.

2. Metabolic or respiratory? The primary process in our patient is overwhelmingly metabolic, as his partial pressure of carbon dioxide (Pco₂) is slightly elevated, a direction that would cause acidosis, not alkalosis.

3. The anion gap (the serum sodium concentration minus the sum of the chloride and bicarbonate concentrations) is normal at 8 mmol/L (DRG:HYBRiD-XL Immunoassay and Clinical Chemistry Analyzer, reference range 8–16).

4. Is the disturbance compensated? We have determined that this patient has a metabolic alkalemia; the question now is whether there is any compensation for the primary disturbance.

In metabolic alkalosis, the Pco₂ may increase by approximately 0.6 mm Hg (range 0.5–0.8) above the nominal normal level of 40 mm Hg for each 1-mmol/L increase in bicarbonate above the nominal normal level of 25 mmol/L.⁴ If the patient requires oxygen, the calculation may be unreliable, however, as hypoxemia may have an overriding influence on respiratory drive.

Patients with chronically high Pco₂ levels such as those with chronic obstructive pulmonary disease can become accustomed to high carbon dioxide levels and lose their hyper-
capnic respiratory drive. Giving oxygen supplementation is thought to decrease respiratory drive in these patients, so that they will breathe slower and retain more carbon dioxide. There is some degree of respiratory compensation for metabolic alkalosis that occurs by breathing less, though it is limited overall—even in very alkalotic patients, breathing less results in CO₂ retention, which, by displacing O₂ molecules in the alveoli, will in turn result in hypoxia. The brain then senses the hypoxia and makes one breathe faster, thereby limiting this compensation. 

This patient’s serum bicarbonate level is 40 mmol/L, or 15 mmol/L higher than the nominal normal level. If he is compensating, his Pco₂ should be 40 + (15 × 0.6) = 49 mm Hg, and in fact it is 51 mm Hg, which is within the normal range of expected compensation (47.5–52 mm Hg). Therefore, yes, he is compensating for the primary disturbance.  

5. In metabolic acidosis, is there a delta gap? As our patient has metabolic alkalosis, not acidosis, this question does not apply in this case.

2. Which is the best test to order next to determine the cause of this patient’s hypokalemic metabolic alkalosis?

• Serum magnesium level
• Spot urine chloride
• Renal ultrasonography
• 24-hour urine collection for sodium, potassium, and chloride

The patient’s loop diuretic is withheld for 12 hours and a spot urine chloride is obtained, which is reported as 44 mmol/L. This high value suggests that a volume-independent hypo­kalemic metabolic alkalosis is present with potassium depletion.

As for the other answer choices:

Serum magnesium. Though hypomagnesemia can cause hypokalemia due to lack of inhibition of renal outer medullary potassium channels and subsequent increased excretion of potassium in the apical tubular membrane, it is not independently associated with acid-base disturbances.⁵

Renal ultrasonography gives information about structural kidney disease but is of limited utility in identifying the cause of hypokalemic metabolic alkalosis.

A 24-hour urine collection is unnecessary in this setting and would ultimately result in delay in diagnosis, as spot urine chloride is a more efficient means of rapidly distinguishing volume-responsive vs volume-independent causes of hypokalemic metabolic alkalosis.⁶

IS HIS HYPERTENSION SECONDARY? IF SO, WHAT IS THE CAUSE?

Several features of this case suggest that the patient’s hypertension is secondary rather than primary. It is of recent onset. The patient’s family history is noncontributory, and his hypertension is resistant to the use of maximum doses of 3 antihypertensive agents.

3. Which of the following causes of secondary hypertension is not commonly associated with hypokalemia and metabolic alkalosis?

• Hyperaldosteronism
• Liddle syndrome
• Cushing syndrome
• Renal parenchymal disease
• Chronic licorice ingestion

Renal parenchymal disease is a cause of resistant hypertension, but it is not characterized by metabolic alkalosis, hypokalemia, and  elevated urine chloride,⁷ while the others listed here—hyperaldosteronism, Liddle syndrome, Cushing syndrome, and chronic licorice ingestion­—are. Other common causes of resistant hypertension without these metabolic abnormalities include obstructive sleep apnea, alcohol abuse, and nonadherence to treatment.

While treatment of hypertension with loop diuretics can result in hypokalemia and metabolic alkalosis due to the effect of these drugs on potassium reabsorption in the loop of Henle, the patient’s hypokalemia persisted after this agent was withdrawn.⁸

Causes of hypokalemic metabolic alkalosis with and without hypertension are further delineated in Figure 1.

Additional diagnostic testing: Plasma renin and plasma aldosterone

At this juncture, the differential diagnosis for this patient’s potassium depletion, metabolic alkalosis, high urine chloride, and hypertension has been narrowed to primary or secondary hyperaldosteronism, surreptitious mineralocorticoid ingestion, Cushing syndrome, licorice ingestion, Liddle syndrome, or one of the 3 hydroxylase deficiencies (11-, 17-, and 21-) (Figure 1).

Although clues in the history, physical examination, and imaging may suggest a specific cause of his abnormal laboratory values, the next step in the diagnostic workup is to measure the plasma renin and aldosterone levels (Table 3).

HYPERALDOSTERONISM

4. Hyperaldosteronism is associated with which of the following patterns of renin and aldosterone values?

• High renin, high aldosterone, normal ratio of plasma aldosterone concentration (PAC) to plasma renin activity (PRA)
• Low renin, low aldosterone, normal PAC–PRA ratio
• Low renin, high aldosterone, high PAC–PRA ratio
• High renin, low aldosterone, low PAC–PRA ratio

The pattern of low renin, high aldosterone, and high PAC–PRA ratio is associated with hyperaldosteronism.

Primary hyperaldosteronism

Primary hyperaldosteronism is one of the most common causes of resistant hypertension and is underappreciated, being diagnosed in up to 20% of patients referred to hypertension specialty clinics.⁷ Potassium levels may be normal, likely contributing to its lack of recognition in this target population.

Primary hyperaldosteronism should be suspected in patients who have a plasma aldosterone PAC–PRA ratio greater than 20 with elevated plasma aldosterone concentrations
(> 15 ng/dL).

Persistently elevated aldosterone levels in the setting of elevated plasma volume is proof that aldosterone secretion is independent of the renin-angiotensin-aldosterone axis, and therefore is autonomous (secondary to adrenal tumor or hyperplasia). Further testing in the form of oral salt loading, saline infusion, or fludrocortisone (a sodium-retaining steroid) administration is thus required to confirm inappropriate, autonomous aldosterone secretion.⁹

After establishing the diagnosis of primary hyperaldosteronism, one should determine the subtype (ie, due to an adrenal carcinoma, unilateral hypersecreting adenoma, or unilateral or bilateral hyperplasia). Further testing includes adrenal computed tomography (CT) to rule out adrenal carcinomas, which are suspected with adenomas larger than 4 cm. Though part of the diagnostic workup, CT as a means of confirmational testing alone does not preclude the possibility of bilateral adrenal hyperplasia in some patients, even in the presence of an adrenal adenoma. For this reason, adrenal venous sampling is required to definitively determine whether the condition is due to a hypersecreting adrenal adenoma or unilateral or bilateral hyperplasia.^9,10

Treatment of primary hyperaldosteronism depends on the subtype of the disease and involves salt restriction in addition to an aldosterone antagonist (spironolactone or eplerenone in the case of bilateral disease) or surgery (unilateral disease).^9,11,12

Secondary hyperaldosteronism

Secondary hyperaldosteronism should be suspected when plasma renin and aldosterone levels are both elevated with a PAC–PRA ratio less than 10.

This pattern is most commonly seen with diuretic use but can also be a consequence of renal artery stenosis or, rarely, a renin-secreting tumor.¹³ Renal artery stenosis is a common finding in patients with hypertension undergoing cardiac catheterization, which is not surprising as more than 90% of such stenoses are atherosclerotic.⁷ Renin-secreting tumors are exceedingly rare, with fewer than 100 cases reported in the literature, and are more common in younger individuals.¹³

Our patient has low-normal aldosterone and plasma renin

On further testing, this patient’s plasma aldosterone level is 2.55 ng/dL (normal < 15 ng/dL), his plasma renin activity is 0.53 ng/mL/hour (normal 0.2–2.8 ng/mL/hour), and his PAC–PRA ratio is therefore 4.81.

The categories discussed thus far have included primary and secondary hyperaldosteronism, which typically do not present with low to normal levels of both renin and aldosterone. Surreptitious mineralocorticoid use could present in this manner, but is unlikely in this patient, whose medications do not include fludrocortisone.

The low-normal values thus lead to consideration of a third category: apparent mineralocorticoid excess. Diseases in this category such as Cushing disease or adrenocorticotropic hormone (ACTH) excess are characterized by increases in corticosteroids so that the potassium depletion, metabolic alkalosis, and hypertension are not a consequence of renin and aldosterone but rather the excess corticosteroids.¹⁴

Causes of apparent mineralocorticoid excess

There are several possible causes of mineralocorticoid excess associated with hypertension and hypokalemic metabolic alkalosis not due to renin and aldosterone.

Chronic licorice ingestion in high volumes is one such cause and is thought to result in inhibition of 11B-hydroxysteroid dehydrogenase or possibly cortisol oxidase by licorice’s active component, glycyrrhetinic acid. This inhibition results in an inability to convert cortisol to cortisone. The cortisol excess binds to mineralocorticoid receptors, and acting like aldosterone, results in hypertension and hypokalemic metabolic alkalosis as well as feedback inhibition of renin and aldosterone levels.¹⁵

Partial hydroxylase deficiencies, though rare, should also be considered as a cause of hypokalemic metabolic alkalosis, hypertension, and, potentially, hirsutism and clitoromegaly in women. They can be diagnosed with elevated levels of 17-ketosteroids and dehydroepiandrosterone sulfate, both of which, in excess, may act on aldosterone receptors in a manner similar to cortisol.¹⁶

Liddle syndrome, a rare autosomal dominant condition, may also present with suppressed levels of both renin and aldosterone. In contrast to the disorders of nonaldosterone mineralocorticoid excess, however, the sodium channel defect in Liddle syndrome is characterized by a primary increase in sodium reabsorption in the collecting tubule and potassium wasting. The resultant volume expansion leads to suppressed renin and aldosterone levels and hypertension with low potassium and elevated bicarbonate concentrations.¹⁷

Liddle syndrome is commonly diagnosed in childhood but may go unrecognized due to occasional absence of hypokalemia at presentation. Potassium-sparing diuretics such as amiloride or triamterene are the mainstays of treatment.¹⁸

Rates of cardiovascular and all-cause mortality are increased in patients with long-term hypercortisolism, even after plasma concentrations of cortisol are normalized.²¹

Figure 2 shows the cascade of the hypothalamic-pituitary-adrenal axis.

Given the patient’s clinical presentation and laboratory and imaging findings with normal plasma renin and aldosterone levels, a workup for suspected hypercortisolism is initiated.

Initial diagnostic testing for hypercortisolism depends on the degree of clinical suspicion. In those with low probability of the disease, testing should consist of 1 of the following, as a single negative test may be sufficient to rule out the disease:

• 24-hour urinary cortisol levels
• Overnight dexamethasone suppression testing
• Late-night salivary cortisol measurements.

In those with a high index of suspicion, 2 of the aforementioned tests should be performed, as 1 normal result may not be sufficient to exclude the diagnosis.^22,23

A 24-hour urinary cortisol collection and overnight dexamethasone suppression test are obtained. His 24-hour urinary free cortisol level is elevated at 6,600 µg (normal 4–100), and suppression testing with 8 mg of dexamethasone (a form of “high-dose” testing)demonstrates only an 8% decline in serum cortisol levels. Cortisol should generally drop more than 90%.

Morning serum cortisol concentration is less than 5 µg/dL (140 nmol/L) in most patients with Cushing disease (ie, a pituitary tumor), and is usually undetectable in normal subjects. Only about 50% of neuroendocrine ACTH-secreting tumors will suppress with this test.

The patient’s clinical presentation, in conjunction with his diagnostic testing, are thus consistent with Cushing syndrome.

CUSHING SYNDROME

Cushing syndrome is most often exogenous or iatrogenic, ie, a result of supraphysiologic doses of glucocorticoids used to treat a variety of inflammatory, autoimmune, and neoplastic conditions.

Endogenous Cushing syndrome, on the other hand, is rare, with an estimated prevalence of 0.7 to 2.4 cases per million per year. ACTH-dependent causes account for 80% of endogenous Cushing syndrome cases, with ACTH-secreting pituitary adenomas (Cushing disease) accounting for 75% to 80% and ectopic ACTH secretion accounting for 15% to 20%. Less than 1% of cases are due to tumors that produce corticotropin-releasing hormone (CRH).

ACTH-independent Cushing syndrome is diagnosed in 20% of endogenous cases and is most commonly caused by a unilateral adrenal tumor. Rare causes of ACTH-independent disease include adrenal carcinoma, McCune-Albright syndrome, and adrenal hyperplasia.²⁴

The patient’s ACTH is high

To determine whether this is an ACTH-dependent or independent process, the next step is to order an ACTH level. His ACTH level is high at 107 pg/mL (normal < 46 pg/mL), confirming the diagnosis of ACTH-dependent Cushing syndrome.

To find out if this ACTH-dependent process is due to a pituitary adenoma, magnetic resonance imaging (MRI) of the pituitary is obtained but is normal.

Large masses (> 6 mm) strongly suggest Cushing disease, but these tumors are often small and may be missed even with more advanced imaging techniques. Corticotropin-secreting adenomas arising from normal cells in the pituitary retain some sensitivity to glucocorticoid negative feedback and CRH stimulation, and thus high-dose dexamethasone suppression testing in conjunction with CRH stimulation testing can be used to differentiate Cushing disease from ectopic ACTH secretion.^24,25 Both of these tests have poor diagnostic accuracy, however, and thus inferior petrosal sampling remains the gold standard for the diagnosis of Cushing disease.

ACTH-SECRETING TUMORS

5. Cushing syndrome due to ectopic ACTH secretion is most commonly attributed to which of the following tumors?

• Small-cell lung carcinoma
• Pancreatic carcinoma
• Medullary thyroid carcinoma
• Gastrinoma

Severe cases of Cushing syndrome are often attributable to ectopic ACTH secretion due to an underlying malignancy, most commonly small-cell lung carcinoma or neuroendocrine tumors of pulmonary origin. Other causes include pancreatic and thymic neuroendocrine tumors, gastrinomas, and medullary thyroid carcinoma.^25,26

Because most ACTH-producing tumors are intrathoracic, initial imaging in cases of suspected ectopic ACTH secretion should focus on the chest, with CT the usual first choice. Octreotide scintigraphy can also be useful in localizing disease, as many neuroendocrine tumors express somatostatin receptors. Specialized positron-emission tomography scans may also be helpful in tumor identification.²⁴

6. Which of the following is most appropriate medical therapy for suppression of cortisol secretion in Cushing syndrome due to ectopic ACTH secretion?

• Spironolactone
• Dexamethasone
• Somatostatin
• Estrogen
• Ketoconazole

Hyperglycemia, hypokalemia, hypertension, psychiatric disturbances, venous thromboembolism, and systemic infections appear to be common in ectopic ACTH syndrome and often correlate with the degree of hypercortisolemia. Severe Cushing syndrome due to ectopic ACTH secretion is an emergency requiring prompt control of cortisol secretion.

First-line treatments include steroidogenesis inhibitors (ketoconazole, metyrapone, etomidate, mitotane) and glucocorticoid receptor antagonists (mifepristone). High-dose spironolactone and eplerenone can also be used to treat the hypertension and hypokalemia associated with mineralocorticoid receptor stimulation. Definitive treatment involves surgical resection, chemotherapy, or radiotherapy when applicable.^24,25

After confirmation of the diagnosis, the patient is prescribed ketoconazole and spironolactone, with substantial improvement. He subsequently is started on combination chemotherapy and radiation therapy for his small-cell lung carcinoma.

DISCUSSION

The differential diagnosis for hypokalemia is broad and relies on information obtained during the history and physical examination, followed by interpretation of selected laboratory results. Myriad pathologies in diverse organ systems, eg, diarrhea, renal tubular acidosis, and adrenal disease, may be responsible for a low serum potassium. Further categorizing potassium depletion on the basis of an associated acid-base disturbance, such as metabolic alkalosis, allows one to use an algorithmic approach that can identify specific etiologies responsible for both the potassium and the acid-base disturbances.

Using the spot urine chloride in the setting of hypokalemic metabolic alkalosis with or without hypertension can narrow the differential diagnosis and allow additional clinical findings to guide clinical problem-solving and decision-making, even for conditions not commonly encountered in routine medical practice.

Obtaining renin and aldosterone measurements in patients with potassium depletion, metabolic alkalosis, high urine chloride excretion, and hypertension permits further categorization into 3 clinical groups: elevated aldosterone and renin (secondary hyperaldosteronism), elevated aldosterone and low renin (primary hyperaldosteronism), or apparent mineralocorticoid excess wherein neither renin nor aldosterone are responsible for the syndrome.

The patient in our case had apparent mineralocorticoid excess as a consequence of an ACTH-producing small-cell carcinoma.

I have been assured by a very knowing American of my acquaintance in London, that a young healthy child well nursed is at a year old, a most delicious, nourishing, and wholesome food, whether stewed, roasted, baked, or boiled, and I make no doubt that it will equally serve in a fricassee, or ragout.

—Jonathan Swift, A Modest Proposal¹

Large-scale cancer screening programs have the unintended consequences of false-positive results and overdiagnosis, leading to anxiety and overtreatment. The magnitude of these harms continues to be clarified after decades of screening.

Recognizing the trade-off between benefits and harms, the US Preventive Services Task Force (USPSTF) has changed several of its recommendations in recent years. Breast cancer screening recommendations have gone from yearly mammograms starting at age 40 to biennial mammograms starting at age 50 for women at average risk.² Prostate cancer screening is no longer recommended for men age 70 and older, and even for men between 55 and 69, screening is now an individual decision.³

Newer screening programs are targeting high-risk groups rather than the general population, with the aim of increasing the likelihood of benefits and limiting the harms. For example, lung cancer screening is recommended only for current smokers or smokers who have quit within the past 15 years, are between 55 and 80, and have at least a 30 pack-year smoking history.⁴

The movement toward less-frequent screening and screening in a narrower population has evoked strong reactions from advocates of cancer screening. One professor of radiology writes, “It borders on unethical to suggest that the benefit of having your life saved by screening and living another 40 years can be balanced against the ‘harm’ of being recalled for additional mammographic views for what proves to not be a cancer.”⁵ Another notes, “It does not make any sense to throw away the lives saved by screening to avoid over-treating a small number of cancers.”⁶ Both of these authors defend the position that the goal of screening is to minimize cause-specific mortality, irrespective of overdiagnosis, overtreatment, or false-positive results. In other words, harm should have little to no weight in screening recommendations.

Although the debate on cancer screening is moving toward a more balanced discussion of benefits and harms, many patients are still subjected to screening that is more aggressive than the USPSTF recommends, which may be due to an underlying belief that no harm is greater than the benefit of saving a life.

IS MORE-AGGRESSIVE SCREENING THE ANSWER?

One may wonder if more-aggressive screening could prevent deaths that occur despite standard screening. For example, more-frequent screening or use of additional screening methods such as ultrasonography or magnetic resonance imaging has been suggested for patients at high risk of breast cancer.

A MODEST PROPOSAL

If one holds the view that benefits alone should be considered when writing recommendations about screening, the logical conclusion extends beyond screening. We would therefore like to propose a different approach to reducing cancer deaths in the general population:

Why not just remove everybody’s breasts, prostate gland, and colon before cancer arises?

Currently, we offer prophylactic surgery to patients at high risk of cancer. For example, women with BRCA1/BRCA2 mutations are offered prophylactic mastectomy as one of several options for reducing risk of breast cancer. In 2013, the first case of prophylactic prostatectomy was performed in a man who had a BRCA1/BRCA2 mutation. Total colectomy is considered in men and women who have hereditary nonpolyposis colon cancer, instead of segmental resection, to prevent future cancer.

If prophylactic surgery were extended to the general population, it would greatly reduce the number of cancer deaths. Assuming that removing an organ almost always precludes development of cancer, we may predict that prophylactic mastectomy, prostatectomy, or colectomy would save the lives of most of the patients who are still dying of cancer of these organs. The effectiveness rates would approach, but not reach 100%; such is the case with prophylactic mastectomy.

Consider prostate-specific antigen (PSA) screening. Even using the favorable estimate of the impact of PSA screening, arising from the European Randomised Study of Screening for Prostate Cancer trial, 27 men have to be diagnosed, most undergoing local therapy (the trial was conducted before active surveillance became routine), to avert 1 death from prostate cancer over 13 years.⁹

Contrast this “number needed to diagnose” with the number needed to treat for a strategy of routine prostate removal at age 45 or 50. Given that the lifetime risk of death from prostate cancer approaches 3%, and few cases arise before this age, a prophylactic surgical strategy would avert 1 death per 33 operations. If proponents of screening are willing to accept a number needed to diagnose of 27 over a 13-year interval, they may be willing to consider a number needed to treat of 33 over a lifetime.

There may be harms such as perioperative and postoperative complications. Mastectomy could lead to emotional stress from altered body image. Prostatectomy can have long-term complications such as urinary incontinence and sexual dysfunction. Nevertheless, prophylactic organ removal would save far more lives than current screening practices. It also could decrease mental burden, as patients could rest assured that they will never develop cancer, whereas screening often involves ambiguous test results, follow-up tests, and interventions, increasing patient anxiety.

FINDING THE BALANCE BETWEEN BENEFITS AND HARMS

In truth, we do not really advocate universal mastectomy, prostatectomy, and colectomy to prevent cancer, no more than Swift¹ really wanted to eat the children of Ireland to alleviate poverty and famine in that country.  Rather, we use it as an extreme proposal to highlight the scope and depth of harms that inevitably arise from screening.

If proponents of aggressive screening believe that the goal is to reduce cause-specific mortality as much as possible, giving little weight or consideration to overdiagnosis and overtreatment, then they ought to embrace universal prophylactic surgery as well. Recognition of this logical consequence reminds us that we must make screening recommendations that balance benefits and harms.

Considering an extreme perspective can help in recognizing our bias toward saving lives from cancer and discounting the harms. Aggravating this bias, it is impossible to know whether an individual patient has avoided fatal cancer or undergone unnecessary treatment. Moreover, changing practice is more difficult if it involves rolling back interventions that were once the standard.

Balancing benefits and harms is especially difficult when trying to compare the benefit of preventing a single cancer death against a harm that is less serious but more common. Medicine has always involved difficult trade-offs, as seen in cost-benefit analysis of new treatments or balancing quality of life with quantity of life in a single patient. In addition, each individual may place different values on benefits of screening and avoiding possible harms.

There is an undeniable trade-off with screening, and we must make a conscious decision on where to draw the line when harms outweigh the benefits. We must proceed with caution when subjecting large numbers of men and women to the possibility of psychological burden and decreased quality of life.

Given the growing appreciation of the harms of screening, it is likely that future guidance will continue to move toward less- frequent screening or focusing resources on high-risk populations, where the absolute magnitude of benefit is greater. Cancer screening is also likely to become an individual decision based on personal values and informed decisions.

I have been assured by a very knowing American of my acquaintance in London, that a young healthy child well nursed is at a year old, a most delicious, nourishing, and wholesome food, whether stewed, roasted, baked, or boiled, and I make no doubt that it will equally serve in a fricassee, or ragout.

—Jonathan Swift, A Modest Proposal¹

Large-scale cancer screening programs have the unintended consequences of false-positive results and overdiagnosis, leading to anxiety and overtreatment. The magnitude of these harms continues to be clarified after decades of screening.

Recognizing the trade-off between benefits and harms, the US Preventive Services Task Force (USPSTF) has changed several of its recommendations in recent years. Breast cancer screening recommendations have gone from yearly mammograms starting at age 40 to biennial mammograms starting at age 50 for women at average risk.² Prostate cancer screening is no longer recommended for men age 70 and older, and even for men between 55 and 69, screening is now an individual decision.³

Newer screening programs are targeting high-risk groups rather than the general population, with the aim of increasing the likelihood of benefits and limiting the harms. For example, lung cancer screening is recommended only for current smokers or smokers who have quit within the past 15 years, are between 55 and 80, and have at least a 30 pack-year smoking history.⁴

The movement toward less-frequent screening and screening in a narrower population has evoked strong reactions from advocates of cancer screening. One professor of radiology writes, “It borders on unethical to suggest that the benefit of having your life saved by screening and living another 40 years can be balanced against the ‘harm’ of being recalled for additional mammographic views for what proves to not be a cancer.”⁵ Another notes, “It does not make any sense to throw away the lives saved by screening to avoid over-treating a small number of cancers.”⁶ Both of these authors defend the position that the goal of screening is to minimize cause-specific mortality, irrespective of overdiagnosis, overtreatment, or false-positive results. In other words, harm should have little to no weight in screening recommendations.

Although the debate on cancer screening is moving toward a more balanced discussion of benefits and harms, many patients are still subjected to screening that is more aggressive than the USPSTF recommends, which may be due to an underlying belief that no harm is greater than the benefit of saving a life.

IS MORE-AGGRESSIVE SCREENING THE ANSWER?

One may wonder if more-aggressive screening could prevent deaths that occur despite standard screening. For example, more-frequent screening or use of additional screening methods such as ultrasonography or magnetic resonance imaging has been suggested for patients at high risk of breast cancer.

A MODEST PROPOSAL

If one holds the view that benefits alone should be considered when writing recommendations about screening, the logical conclusion extends beyond screening. We would therefore like to propose a different approach to reducing cancer deaths in the general population:

Why not just remove everybody’s breasts, prostate gland, and colon before cancer arises?

Currently, we offer prophylactic surgery to patients at high risk of cancer. For example, women with BRCA1/BRCA2 mutations are offered prophylactic mastectomy as one of several options for reducing risk of breast cancer. In 2013, the first case of prophylactic prostatectomy was performed in a man who had a BRCA1/BRCA2 mutation. Total colectomy is considered in men and women who have hereditary nonpolyposis colon cancer, instead of segmental resection, to prevent future cancer.

If prophylactic surgery were extended to the general population, it would greatly reduce the number of cancer deaths. Assuming that removing an organ almost always precludes development of cancer, we may predict that prophylactic mastectomy, prostatectomy, or colectomy would save the lives of most of the patients who are still dying of cancer of these organs. The effectiveness rates would approach, but not reach 100%; such is the case with prophylactic mastectomy.

Consider prostate-specific antigen (PSA) screening. Even using the favorable estimate of the impact of PSA screening, arising from the European Randomised Study of Screening for Prostate Cancer trial, 27 men have to be diagnosed, most undergoing local therapy (the trial was conducted before active surveillance became routine), to avert 1 death from prostate cancer over 13 years.⁹

Contrast this “number needed to diagnose” with the number needed to treat for a strategy of routine prostate removal at age 45 or 50. Given that the lifetime risk of death from prostate cancer approaches 3%, and few cases arise before this age, a prophylactic surgical strategy would avert 1 death per 33 operations. If proponents of screening are willing to accept a number needed to diagnose of 27 over a 13-year interval, they may be willing to consider a number needed to treat of 33 over a lifetime.

There may be harms such as perioperative and postoperative complications. Mastectomy could lead to emotional stress from altered body image. Prostatectomy can have long-term complications such as urinary incontinence and sexual dysfunction. Nevertheless, prophylactic organ removal would save far more lives than current screening practices. It also could decrease mental burden, as patients could rest assured that they will never develop cancer, whereas screening often involves ambiguous test results, follow-up tests, and interventions, increasing patient anxiety.

FINDING THE BALANCE BETWEEN BENEFITS AND HARMS

In truth, we do not really advocate universal mastectomy, prostatectomy, and colectomy to prevent cancer, no more than Swift¹ really wanted to eat the children of Ireland to alleviate poverty and famine in that country.  Rather, we use it as an extreme proposal to highlight the scope and depth of harms that inevitably arise from screening.

If proponents of aggressive screening believe that the goal is to reduce cause-specific mortality as much as possible, giving little weight or consideration to overdiagnosis and overtreatment, then they ought to embrace universal prophylactic surgery as well. Recognition of this logical consequence reminds us that we must make screening recommendations that balance benefits and harms.

Considering an extreme perspective can help in recognizing our bias toward saving lives from cancer and discounting the harms. Aggravating this bias, it is impossible to know whether an individual patient has avoided fatal cancer or undergone unnecessary treatment. Moreover, changing practice is more difficult if it involves rolling back interventions that were once the standard.

Balancing benefits and harms is especially difficult when trying to compare the benefit of preventing a single cancer death against a harm that is less serious but more common. Medicine has always involved difficult trade-offs, as seen in cost-benefit analysis of new treatments or balancing quality of life with quantity of life in a single patient. In addition, each individual may place different values on benefits of screening and avoiding possible harms.

There is an undeniable trade-off with screening, and we must make a conscious decision on where to draw the line when harms outweigh the benefits. We must proceed with caution when subjecting large numbers of men and women to the possibility of psychological burden and decreased quality of life.

Given the growing appreciation of the harms of screening, it is likely that future guidance will continue to move toward less- frequent screening or focusing resources on high-risk populations, where the absolute magnitude of benefit is greater. Cancer screening is also likely to become an individual decision based on personal values and informed decisions.

I have been assured by a very knowing American of my acquaintance in London, that a young healthy child well nursed is at a year old, a most delicious, nourishing, and wholesome food, whether stewed, roasted, baked, or boiled, and I make no doubt that it will equally serve in a fricassee, or ragout.

—Jonathan Swift, A Modest Proposal¹

Large-scale cancer screening programs have the unintended consequences of false-positive results and overdiagnosis, leading to anxiety and overtreatment. The magnitude of these harms continues to be clarified after decades of screening.

Recognizing the trade-off between benefits and harms, the US Preventive Services Task Force (USPSTF) has changed several of its recommendations in recent years. Breast cancer screening recommendations have gone from yearly mammograms starting at age 40 to biennial mammograms starting at age 50 for women at average risk.² Prostate cancer screening is no longer recommended for men age 70 and older, and even for men between 55 and 69, screening is now an individual decision.³

Newer screening programs are targeting high-risk groups rather than the general population, with the aim of increasing the likelihood of benefits and limiting the harms. For example, lung cancer screening is recommended only for current smokers or smokers who have quit within the past 15 years, are between 55 and 80, and have at least a 30 pack-year smoking history.⁴

The movement toward less-frequent screening and screening in a narrower population has evoked strong reactions from advocates of cancer screening. One professor of radiology writes, “It borders on unethical to suggest that the benefit of having your life saved by screening and living another 40 years can be balanced against the ‘harm’ of being recalled for additional mammographic views for what proves to not be a cancer.”⁵ Another notes, “It does not make any sense to throw away the lives saved by screening to avoid over-treating a small number of cancers.”⁶ Both of these authors defend the position that the goal of screening is to minimize cause-specific mortality, irrespective of overdiagnosis, overtreatment, or false-positive results. In other words, harm should have little to no weight in screening recommendations.

Although the debate on cancer screening is moving toward a more balanced discussion of benefits and harms, many patients are still subjected to screening that is more aggressive than the USPSTF recommends, which may be due to an underlying belief that no harm is greater than the benefit of saving a life.

IS MORE-AGGRESSIVE SCREENING THE ANSWER?

One may wonder if more-aggressive screening could prevent deaths that occur despite standard screening. For example, more-frequent screening or use of additional screening methods such as ultrasonography or magnetic resonance imaging has been suggested for patients at high risk of breast cancer.

A MODEST PROPOSAL

If one holds the view that benefits alone should be considered when writing recommendations about screening, the logical conclusion extends beyond screening. We would therefore like to propose a different approach to reducing cancer deaths in the general population:

Why not just remove everybody’s breasts, prostate gland, and colon before cancer arises?

Currently, we offer prophylactic surgery to patients at high risk of cancer. For example, women with BRCA1/BRCA2 mutations are offered prophylactic mastectomy as one of several options for reducing risk of breast cancer. In 2013, the first case of prophylactic prostatectomy was performed in a man who had a BRCA1/BRCA2 mutation. Total colectomy is considered in men and women who have hereditary nonpolyposis colon cancer, instead of segmental resection, to prevent future cancer.

If prophylactic surgery were extended to the general population, it would greatly reduce the number of cancer deaths. Assuming that removing an organ almost always precludes development of cancer, we may predict that prophylactic mastectomy, prostatectomy, or colectomy would save the lives of most of the patients who are still dying of cancer of these organs. The effectiveness rates would approach, but not reach 100%; such is the case with prophylactic mastectomy.

Consider prostate-specific antigen (PSA) screening. Even using the favorable estimate of the impact of PSA screening, arising from the European Randomised Study of Screening for Prostate Cancer trial, 27 men have to be diagnosed, most undergoing local therapy (the trial was conducted before active surveillance became routine), to avert 1 death from prostate cancer over 13 years.⁹

Contrast this “number needed to diagnose” with the number needed to treat for a strategy of routine prostate removal at age 45 or 50. Given that the lifetime risk of death from prostate cancer approaches 3%, and few cases arise before this age, a prophylactic surgical strategy would avert 1 death per 33 operations. If proponents of screening are willing to accept a number needed to diagnose of 27 over a 13-year interval, they may be willing to consider a number needed to treat of 33 over a lifetime.

There may be harms such as perioperative and postoperative complications. Mastectomy could lead to emotional stress from altered body image. Prostatectomy can have long-term complications such as urinary incontinence and sexual dysfunction. Nevertheless, prophylactic organ removal would save far more lives than current screening practices. It also could decrease mental burden, as patients could rest assured that they will never develop cancer, whereas screening often involves ambiguous test results, follow-up tests, and interventions, increasing patient anxiety.

FINDING THE BALANCE BETWEEN BENEFITS AND HARMS

In truth, we do not really advocate universal mastectomy, prostatectomy, and colectomy to prevent cancer, no more than Swift¹ really wanted to eat the children of Ireland to alleviate poverty and famine in that country.  Rather, we use it as an extreme proposal to highlight the scope and depth of harms that inevitably arise from screening.

If proponents of aggressive screening believe that the goal is to reduce cause-specific mortality as much as possible, giving little weight or consideration to overdiagnosis and overtreatment, then they ought to embrace universal prophylactic surgery as well. Recognition of this logical consequence reminds us that we must make screening recommendations that balance benefits and harms.

Considering an extreme perspective can help in recognizing our bias toward saving lives from cancer and discounting the harms. Aggravating this bias, it is impossible to know whether an individual patient has avoided fatal cancer or undergone unnecessary treatment. Moreover, changing practice is more difficult if it involves rolling back interventions that were once the standard.

Balancing benefits and harms is especially difficult when trying to compare the benefit of preventing a single cancer death against a harm that is less serious but more common. Medicine has always involved difficult trade-offs, as seen in cost-benefit analysis of new treatments or balancing quality of life with quantity of life in a single patient. In addition, each individual may place different values on benefits of screening and avoiding possible harms.

There is an undeniable trade-off with screening, and we must make a conscious decision on where to draw the line when harms outweigh the benefits. We must proceed with caution when subjecting large numbers of men and women to the possibility of psychological burden and decreased quality of life.

Given the growing appreciation of the harms of screening, it is likely that future guidance will continue to move toward less- frequent screening or focusing resources on high-risk populations, where the absolute magnitude of benefit is greater. Cancer screening is also likely to become an individual decision based on personal values and informed decisions.

SNOWMASS, COLO. – Cardiac MRI is the go-to tiebreaker when uncertainty exists as to whether cardiac remodeling in a competitive athlete is physiological or pathological, according to Matthew W. Martinez, MD, medical director of the Sports Cardiology and Hypertrophic Cardiomyopathy Center at the Lehigh Valley Health Network in Allentown, Pa.

Bruce Jancin/MDedge News

“The MRI may be the single test that best helps you sort out when you’re not quite sure. If you think about a single study that’s going to help you identify cardiac arrest etiologies – hypertrophic cardiomyopathy, myocarditis, anomalous coronaries, left-sided disease, right-sided disease like arrhythmogenic right ventricular cardiomyopathy, valvular heart disease, aortic disease – MRI is a very powerful tool because it will help you evaluate all of those groups more than 90% of the time,” he said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Dr. Martinez, who serves as lead cardiologist for U.S. Major League Soccer and is also heavily involved with the National Football League, spends a lot of time with elite professional or Olympic athletes who fall into what he calls “the gray zone,” with a left ventricular wall thickness of 12-15 mm as measured on echocardiography. While that would clearly be considered abnormal in a nonathlete or a recreational sports enthusiast, his experience as well as that of other sports cardiologists working with professional soccer, football, and basketball players, bicyclists, and high-level track and field competitors has been that wall thickness in the 12- to 15-mm range in elite athletes can represent physiological adaptation to their enormous cardiovascular workloads. For example, more than 10% of National Football League players have a maximum left ventricular wall thickness of 13 mm or more, as do more than 10% of National Basketball Association players.

But what if that echocardiographic measurement of wall thickness is off by a millimeter or two, as is often par for the course?

“It’s well described that MRI gives a better look at wall thickness than echocardiography, especially where there’s areas of hypertrophy next to normal wall. In that gray zone, where we have to know if it’s really 10-12 or 14-16 mm, the MRI better identifies the actual thickness,” he said.

In addition, cardiac MRI readily provides accurate, reproducible measurements of left and right ventricular chamber size. But the most important way in which cardiac MRI helps in evaluating the significance of cardiac remodeling in athletes is via the gadolinium study. Late gadolinium enhancement is a concerning finding. It indicates the presence of myocardial fibrosis and scar, which at least in the general population is a prognostic sign for worse outcome.

“If you detect fibrosis, the search for pathology has to start,” the cardiologist emphasized.

He noted that the most comprehensive review to date of myocardial fibrosis in endurance athletes identified the intraventricular septum and the junction of the right ventricle and septum as the most common sites of involvement. The investigators concluded that, while there is a lack of compelling data on the clinical impact and prognosis of myocardial fibrosis in athletes, potential mechanisms include exercise-induced repetitive microinjury, pulmonary artery pressure overload, genetic predisposition, and silent myocarditis (Mayo Clin Proc. 2016 Nov;91[11]:1617-31).

That being said about the value of cardiac MRI as a tiebreaker, Dr. Martinez asserted that “there’s no specific test that’s going to get you out of jail. ... I would submit to you that you have to load the boat. Be comprehensive and try to build a case for one side or the other. And I would encourage you to ask for help; we do it all the time.”

Dilated chambers outside the normal range are common in competitive athletes. Don’t accept the echocardiographic hard numeric cutoffs that have been established as “normal” in the general population. For example, 36% of National Basketball Association players have a left ventricular end diastolic dimension (LVEDD) greater than 60 mm.

“I’ve seen LVEDDs up to 70 mm in cyclists. And all but a handful have a normal left ventricular ejection fraction greater than 50%,” he noted.

Dilated chambers in elite athletes are reassuring, provided stroke volume is preserved or, as is more often the case, enhanced.

“One of the hallmarks of being an athlete is the ability to suck in blood and increase stroke volume as a result. A typical stroke volume in an athlete is well above normal, with 85-90 cc or more being common. On tissue Doppler assessment, you shouldn’t have a normal inflow pattern or normal relaxation. A septal E prime velocity of 11-14 cm/sec is what I typically expect in an athlete. A lower E prime velocity suggests early pathologic change. If you find an E prime velocity of less than 9 cm/sec on tissue Doppler, or an elevated filling pressure like 15 mm Hg, that correlates with a greater than 90% sensitivity for pathology, such as hypertrophic cardiomyopathy. The average E prime velocity in Major League Soccer players is about 13 cm/sec, so that’s an important number to keep in your head,” according to the cardiologist.

Cardiac remodeling in elite athletes tends towards one of two forms, depending upon their sport. Endurance athletes, such as marathon runners, are repetitively volume challenged, so expect a tendency towards aortic regurgitation. For pressure-challenged athletes, such as power weightlifters, the tendency is toward aortic stenosis.

“But also expect a blend. It’s rarely just one or the other. Understanding that can help you discern the gray zone athlete,” he said.

Dr. Martinez reported having no financial conflicts of interest regarding his presentation.

[email protected]

SNOWMASS, COLO. – Cardiac MRI is the go-to tiebreaker when uncertainty exists as to whether cardiac remodeling in a competitive athlete is physiological or pathological, according to Matthew W. Martinez, MD, medical director of the Sports Cardiology and Hypertrophic Cardiomyopathy Center at the Lehigh Valley Health Network in Allentown, Pa.

Bruce Jancin/MDedge News

“The MRI may be the single test that best helps you sort out when you’re not quite sure. If you think about a single study that’s going to help you identify cardiac arrest etiologies – hypertrophic cardiomyopathy, myocarditis, anomalous coronaries, left-sided disease, right-sided disease like arrhythmogenic right ventricular cardiomyopathy, valvular heart disease, aortic disease – MRI is a very powerful tool because it will help you evaluate all of those groups more than 90% of the time,” he said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Dr. Martinez, who serves as lead cardiologist for U.S. Major League Soccer and is also heavily involved with the National Football League, spends a lot of time with elite professional or Olympic athletes who fall into what he calls “the gray zone,” with a left ventricular wall thickness of 12-15 mm as measured on echocardiography. While that would clearly be considered abnormal in a nonathlete or a recreational sports enthusiast, his experience as well as that of other sports cardiologists working with professional soccer, football, and basketball players, bicyclists, and high-level track and field competitors has been that wall thickness in the 12- to 15-mm range in elite athletes can represent physiological adaptation to their enormous cardiovascular workloads. For example, more than 10% of National Football League players have a maximum left ventricular wall thickness of 13 mm or more, as do more than 10% of National Basketball Association players.

But what if that echocardiographic measurement of wall thickness is off by a millimeter or two, as is often par for the course?

“It’s well described that MRI gives a better look at wall thickness than echocardiography, especially where there’s areas of hypertrophy next to normal wall. In that gray zone, where we have to know if it’s really 10-12 or 14-16 mm, the MRI better identifies the actual thickness,” he said.

In addition, cardiac MRI readily provides accurate, reproducible measurements of left and right ventricular chamber size. But the most important way in which cardiac MRI helps in evaluating the significance of cardiac remodeling in athletes is via the gadolinium study. Late gadolinium enhancement is a concerning finding. It indicates the presence of myocardial fibrosis and scar, which at least in the general population is a prognostic sign for worse outcome.

“If you detect fibrosis, the search for pathology has to start,” the cardiologist emphasized.

He noted that the most comprehensive review to date of myocardial fibrosis in endurance athletes identified the intraventricular septum and the junction of the right ventricle and septum as the most common sites of involvement. The investigators concluded that, while there is a lack of compelling data on the clinical impact and prognosis of myocardial fibrosis in athletes, potential mechanisms include exercise-induced repetitive microinjury, pulmonary artery pressure overload, genetic predisposition, and silent myocarditis (Mayo Clin Proc. 2016 Nov;91[11]:1617-31).

That being said about the value of cardiac MRI as a tiebreaker, Dr. Martinez asserted that “there’s no specific test that’s going to get you out of jail. ... I would submit to you that you have to load the boat. Be comprehensive and try to build a case for one side or the other. And I would encourage you to ask for help; we do it all the time.”

Dilated chambers outside the normal range are common in competitive athletes. Don’t accept the echocardiographic hard numeric cutoffs that have been established as “normal” in the general population. For example, 36% of National Basketball Association players have a left ventricular end diastolic dimension (LVEDD) greater than 60 mm.

“I’ve seen LVEDDs up to 70 mm in cyclists. And all but a handful have a normal left ventricular ejection fraction greater than 50%,” he noted.

Dilated chambers in elite athletes are reassuring, provided stroke volume is preserved or, as is more often the case, enhanced.

“One of the hallmarks of being an athlete is the ability to suck in blood and increase stroke volume as a result. A typical stroke volume in an athlete is well above normal, with 85-90 cc or more being common. On tissue Doppler assessment, you shouldn’t have a normal inflow pattern or normal relaxation. A septal E prime velocity of 11-14 cm/sec is what I typically expect in an athlete. A lower E prime velocity suggests early pathologic change. If you find an E prime velocity of less than 9 cm/sec on tissue Doppler, or an elevated filling pressure like 15 mm Hg, that correlates with a greater than 90% sensitivity for pathology, such as hypertrophic cardiomyopathy. The average E prime velocity in Major League Soccer players is about 13 cm/sec, so that’s an important number to keep in your head,” according to the cardiologist.

Cardiac remodeling in elite athletes tends towards one of two forms, depending upon their sport. Endurance athletes, such as marathon runners, are repetitively volume challenged, so expect a tendency towards aortic regurgitation. For pressure-challenged athletes, such as power weightlifters, the tendency is toward aortic stenosis.

“But also expect a blend. It’s rarely just one or the other. Understanding that can help you discern the gray zone athlete,” he said.

Dr. Martinez reported having no financial conflicts of interest regarding his presentation.

[email protected]

SNOWMASS, COLO. – Cardiac MRI is the go-to tiebreaker when uncertainty exists as to whether cardiac remodeling in a competitive athlete is physiological or pathological, according to Matthew W. Martinez, MD, medical director of the Sports Cardiology and Hypertrophic Cardiomyopathy Center at the Lehigh Valley Health Network in Allentown, Pa.

Bruce Jancin/MDedge News

“The MRI may be the single test that best helps you sort out when you’re not quite sure. If you think about a single study that’s going to help you identify cardiac arrest etiologies – hypertrophic cardiomyopathy, myocarditis, anomalous coronaries, left-sided disease, right-sided disease like arrhythmogenic right ventricular cardiomyopathy, valvular heart disease, aortic disease – MRI is a very powerful tool because it will help you evaluate all of those groups more than 90% of the time,” he said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Dr. Martinez, who serves as lead cardiologist for U.S. Major League Soccer and is also heavily involved with the National Football League, spends a lot of time with elite professional or Olympic athletes who fall into what he calls “the gray zone,” with a left ventricular wall thickness of 12-15 mm as measured on echocardiography. While that would clearly be considered abnormal in a nonathlete or a recreational sports enthusiast, his experience as well as that of other sports cardiologists working with professional soccer, football, and basketball players, bicyclists, and high-level track and field competitors has been that wall thickness in the 12- to 15-mm range in elite athletes can represent physiological adaptation to their enormous cardiovascular workloads. For example, more than 10% of National Football League players have a maximum left ventricular wall thickness of 13 mm or more, as do more than 10% of National Basketball Association players.

But what if that echocardiographic measurement of wall thickness is off by a millimeter or two, as is often par for the course?

“It’s well described that MRI gives a better look at wall thickness than echocardiography, especially where there’s areas of hypertrophy next to normal wall. In that gray zone, where we have to know if it’s really 10-12 or 14-16 mm, the MRI better identifies the actual thickness,” he said.

In addition, cardiac MRI readily provides accurate, reproducible measurements of left and right ventricular chamber size. But the most important way in which cardiac MRI helps in evaluating the significance of cardiac remodeling in athletes is via the gadolinium study. Late gadolinium enhancement is a concerning finding. It indicates the presence of myocardial fibrosis and scar, which at least in the general population is a prognostic sign for worse outcome.

“If you detect fibrosis, the search for pathology has to start,” the cardiologist emphasized.

He noted that the most comprehensive review to date of myocardial fibrosis in endurance athletes identified the intraventricular septum and the junction of the right ventricle and septum as the most common sites of involvement. The investigators concluded that, while there is a lack of compelling data on the clinical impact and prognosis of myocardial fibrosis in athletes, potential mechanisms include exercise-induced repetitive microinjury, pulmonary artery pressure overload, genetic predisposition, and silent myocarditis (Mayo Clin Proc. 2016 Nov;91[11]:1617-31).

That being said about the value of cardiac MRI as a tiebreaker, Dr. Martinez asserted that “there’s no specific test that’s going to get you out of jail. ... I would submit to you that you have to load the boat. Be comprehensive and try to build a case for one side or the other. And I would encourage you to ask for help; we do it all the time.”

Dilated chambers outside the normal range are common in competitive athletes. Don’t accept the echocardiographic hard numeric cutoffs that have been established as “normal” in the general population. For example, 36% of National Basketball Association players have a left ventricular end diastolic dimension (LVEDD) greater than 60 mm.

“I’ve seen LVEDDs up to 70 mm in cyclists. And all but a handful have a normal left ventricular ejection fraction greater than 50%,” he noted.

Dilated chambers in elite athletes are reassuring, provided stroke volume is preserved or, as is more often the case, enhanced.

“One of the hallmarks of being an athlete is the ability to suck in blood and increase stroke volume as a result. A typical stroke volume in an athlete is well above normal, with 85-90 cc or more being common. On tissue Doppler assessment, you shouldn’t have a normal inflow pattern or normal relaxation. A septal E prime velocity of 11-14 cm/sec is what I typically expect in an athlete. A lower E prime velocity suggests early pathologic change. If you find an E prime velocity of less than 9 cm/sec on tissue Doppler, or an elevated filling pressure like 15 mm Hg, that correlates with a greater than 90% sensitivity for pathology, such as hypertrophic cardiomyopathy. The average E prime velocity in Major League Soccer players is about 13 cm/sec, so that’s an important number to keep in your head,” according to the cardiologist.

Cardiac remodeling in elite athletes tends towards one of two forms, depending upon their sport. Endurance athletes, such as marathon runners, are repetitively volume challenged, so expect a tendency towards aortic regurgitation. For pressure-challenged athletes, such as power weightlifters, the tendency is toward aortic stenosis.

“But also expect a blend. It’s rarely just one or the other. Understanding that can help you discern the gray zone athlete,” he said.

Dr. Martinez reported having no financial conflicts of interest regarding his presentation.

[email protected]

Functional MRI can measure patterns of connectivity to determine levels of consciousness in nonresponsive patients with brain injury, according to results from a multicenter, cross-sectional, observational study.

E. Tagliazucchi &amp; A. Demertzi

Blood oxygen level–dependent (BOLD) fMRI showed that brain-wide coordination patterns of high complexity became increasingly common moving from unresponsive patients to those with minimal consciousness to healthy individuals, reported lead author Athena Demertzi, PhD, of GIGA Research Institute at the University of Liège in Belgium, and her colleagues.

“Finding reliable markers indicating the presence or absence of consciousness represents an outstanding open problem for science,” the investigators wrote in Science Advances.

In medicine, an fMRI-based measure of consciousness could supplement behavioral assessments of awareness and guide therapeutic strategies; more broadly, image-based markers could help elucidate the nature of consciousness itself.

“We postulate that consciousness has specific characteristics that are based on the temporal dynamics of ongoing brain activity and its coordination over distant cortical regions,” the investigators wrote. “Our hypothesis stems from the common stance of various contemporary theories which propose that consciousness relates to a dynamic process of self-sustained, coordinated brain-scale activity assisting the tuning to a constantly evolving environment, rather than in static descriptions of brain function.”

There is a need for a reliable way of distinguishing consciousness from unconscious states, the investigators said. “Given that nonresponsiveness can be associated with a variety of brain lesions, varying levels of vigilance, and covert cognition, we highlight the need to determine a common set of features capable of accounting for the capacity to sustain conscious experience.”

To search for patterns of brain signal coordination that correlate with consciousness, four independent research centers performed BOLD fMRI scans of participants at rest or under anesthesia with propofol. Of 159 total participants, 47 were healthy individuals and 112 were patients in a vegetative state/with unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS), based on standardized behavioral assessments. The main data analysis, which included 125 participants, assessed BOLD fMRI signal coordination between six brain networks known to have roles in cognitive and functional processes.

The researchers’ analysis revealed four distinct and recurring brain-wide coordination patterns ranging on a scale from highest activity (pattern 1) to lowest activity (pattern 4). Pattern 1, which exhibited most long-distance edges, spatial complexity, efficiency, and community structure, became increasingly common when moving from UWS patients to MCS patients to healthy control individuals (UWS < MCS < HC, rho = 0.7, Spearman rank correlation between rate and group, P less than 1 x 10^-16).

In contrast, pattern 4, characterized by low interareal coordination, showed an inverse trend; it became less common when moving from vegetative patients to healthy individuals (UWS > MCS > HC, Spearman rank correlation between rate and group, rho = –0.6, P less than 1 x 10^-11). Although patterns 2 and 3 occurred with equal frequency across all groups, the investigators noted that switching between patterns was most common and predictably sequential in healthy individuals, versus patients with UWS, who were least likely to switch patterns. A total of 23 patients who were scanned under propofol anesthesia were equally likely to exhibit pattern 4, regardless of health status, suggesting that pattern 4 depends upon fixed anatomical pathways. Results were not affected by scanning site or other patient characteristics, such as age, gender, etiology, or chronicity.

“We conclude that these patterns of transient brain signal coordination are characteristic of conscious and unconscious brain states,” the investigators wrote, “warranting future research concerning their relationship to ongoing conscious content, and the possibility of modifying their prevalence by external perturbations, both in healthy and pathological individuals, as well as across species.”

The study was funded by a James S. McDonnell Foundation Collaborative Activity Award, INSERM, the Belgian National Funds for Scientific Research, the Canada Excellence Research Chairs program, and others. The authors declared having no conflicts of interest.

SOURCE: Demertzi A et al. Sci Adv. 2019 Feb 6. doi: 10.1126/sciadv.aat7603.

Functional MRI can measure patterns of connectivity to determine levels of consciousness in nonresponsive patients with brain injury, according to results from a multicenter, cross-sectional, observational study.

E. Tagliazucchi &amp; A. Demertzi

Blood oxygen level–dependent (BOLD) fMRI showed that brain-wide coordination patterns of high complexity became increasingly common moving from unresponsive patients to those with minimal consciousness to healthy individuals, reported lead author Athena Demertzi, PhD, of GIGA Research Institute at the University of Liège in Belgium, and her colleagues.

“Finding reliable markers indicating the presence or absence of consciousness represents an outstanding open problem for science,” the investigators wrote in Science Advances.

In medicine, an fMRI-based measure of consciousness could supplement behavioral assessments of awareness and guide therapeutic strategies; more broadly, image-based markers could help elucidate the nature of consciousness itself.

“We postulate that consciousness has specific characteristics that are based on the temporal dynamics of ongoing brain activity and its coordination over distant cortical regions,” the investigators wrote. “Our hypothesis stems from the common stance of various contemporary theories which propose that consciousness relates to a dynamic process of self-sustained, coordinated brain-scale activity assisting the tuning to a constantly evolving environment, rather than in static descriptions of brain function.”

There is a need for a reliable way of distinguishing consciousness from unconscious states, the investigators said. “Given that nonresponsiveness can be associated with a variety of brain lesions, varying levels of vigilance, and covert cognition, we highlight the need to determine a common set of features capable of accounting for the capacity to sustain conscious experience.”

To search for patterns of brain signal coordination that correlate with consciousness, four independent research centers performed BOLD fMRI scans of participants at rest or under anesthesia with propofol. Of 159 total participants, 47 were healthy individuals and 112 were patients in a vegetative state/with unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS), based on standardized behavioral assessments. The main data analysis, which included 125 participants, assessed BOLD fMRI signal coordination between six brain networks known to have roles in cognitive and functional processes.

The researchers’ analysis revealed four distinct and recurring brain-wide coordination patterns ranging on a scale from highest activity (pattern 1) to lowest activity (pattern 4). Pattern 1, which exhibited most long-distance edges, spatial complexity, efficiency, and community structure, became increasingly common when moving from UWS patients to MCS patients to healthy control individuals (UWS < MCS < HC, rho = 0.7, Spearman rank correlation between rate and group, P less than 1 x 10^-16).

In contrast, pattern 4, characterized by low interareal coordination, showed an inverse trend; it became less common when moving from vegetative patients to healthy individuals (UWS > MCS > HC, Spearman rank correlation between rate and group, rho = –0.6, P less than 1 x 10^-11). Although patterns 2 and 3 occurred with equal frequency across all groups, the investigators noted that switching between patterns was most common and predictably sequential in healthy individuals, versus patients with UWS, who were least likely to switch patterns. A total of 23 patients who were scanned under propofol anesthesia were equally likely to exhibit pattern 4, regardless of health status, suggesting that pattern 4 depends upon fixed anatomical pathways. Results were not affected by scanning site or other patient characteristics, such as age, gender, etiology, or chronicity.

“We conclude that these patterns of transient brain signal coordination are characteristic of conscious and unconscious brain states,” the investigators wrote, “warranting future research concerning their relationship to ongoing conscious content, and the possibility of modifying their prevalence by external perturbations, both in healthy and pathological individuals, as well as across species.”

The study was funded by a James S. McDonnell Foundation Collaborative Activity Award, INSERM, the Belgian National Funds for Scientific Research, the Canada Excellence Research Chairs program, and others. The authors declared having no conflicts of interest.

SOURCE: Demertzi A et al. Sci Adv. 2019 Feb 6. doi: 10.1126/sciadv.aat7603.

Functional MRI can measure patterns of connectivity to determine levels of consciousness in nonresponsive patients with brain injury, according to results from a multicenter, cross-sectional, observational study.

E. Tagliazucchi &amp; A. Demertzi

Blood oxygen level–dependent (BOLD) fMRI showed that brain-wide coordination patterns of high complexity became increasingly common moving from unresponsive patients to those with minimal consciousness to healthy individuals, reported lead author Athena Demertzi, PhD, of GIGA Research Institute at the University of Liège in Belgium, and her colleagues.

“Finding reliable markers indicating the presence or absence of consciousness represents an outstanding open problem for science,” the investigators wrote in Science Advances.

In medicine, an fMRI-based measure of consciousness could supplement behavioral assessments of awareness and guide therapeutic strategies; more broadly, image-based markers could help elucidate the nature of consciousness itself.

“We postulate that consciousness has specific characteristics that are based on the temporal dynamics of ongoing brain activity and its coordination over distant cortical regions,” the investigators wrote. “Our hypothesis stems from the common stance of various contemporary theories which propose that consciousness relates to a dynamic process of self-sustained, coordinated brain-scale activity assisting the tuning to a constantly evolving environment, rather than in static descriptions of brain function.”

There is a need for a reliable way of distinguishing consciousness from unconscious states, the investigators said. “Given that nonresponsiveness can be associated with a variety of brain lesions, varying levels of vigilance, and covert cognition, we highlight the need to determine a common set of features capable of accounting for the capacity to sustain conscious experience.”

To search for patterns of brain signal coordination that correlate with consciousness, four independent research centers performed BOLD fMRI scans of participants at rest or under anesthesia with propofol. Of 159 total participants, 47 were healthy individuals and 112 were patients in a vegetative state/with unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS), based on standardized behavioral assessments. The main data analysis, which included 125 participants, assessed BOLD fMRI signal coordination between six brain networks known to have roles in cognitive and functional processes.

The researchers’ analysis revealed four distinct and recurring brain-wide coordination patterns ranging on a scale from highest activity (pattern 1) to lowest activity (pattern 4). Pattern 1, which exhibited most long-distance edges, spatial complexity, efficiency, and community structure, became increasingly common when moving from UWS patients to MCS patients to healthy control individuals (UWS < MCS < HC, rho = 0.7, Spearman rank correlation between rate and group, P less than 1 x 10^-16).

In contrast, pattern 4, characterized by low interareal coordination, showed an inverse trend; it became less common when moving from vegetative patients to healthy individuals (UWS > MCS > HC, Spearman rank correlation between rate and group, rho = –0.6, P less than 1 x 10^-11). Although patterns 2 and 3 occurred with equal frequency across all groups, the investigators noted that switching between patterns was most common and predictably sequential in healthy individuals, versus patients with UWS, who were least likely to switch patterns. A total of 23 patients who were scanned under propofol anesthesia were equally likely to exhibit pattern 4, regardless of health status, suggesting that pattern 4 depends upon fixed anatomical pathways. Results were not affected by scanning site or other patient characteristics, such as age, gender, etiology, or chronicity.

“We conclude that these patterns of transient brain signal coordination are characteristic of conscious and unconscious brain states,” the investigators wrote, “warranting future research concerning their relationship to ongoing conscious content, and the possibility of modifying their prevalence by external perturbations, both in healthy and pathological individuals, as well as across species.”

The study was funded by a James S. McDonnell Foundation Collaborative Activity Award, INSERM, the Belgian National Funds for Scientific Research, the Canada Excellence Research Chairs program, and others. The authors declared having no conflicts of interest.

SOURCE: Demertzi A et al. Sci Adv. 2019 Feb 6. doi: 10.1126/sciadv.aat7603.

Managing patients with malignant pleural effusion can be challenging. Symptoms are often distressing, and its presence signifies advanced disease. Median survival after diagnosis is 4 to 9 months,^1–3 although prognosis varies considerably depending on the type and stage of the malignancy.

How patients are best managed depends on clinical circumstances. Physicians should consider the risks and benefits of each option while keeping in mind realistic goals of care.

This article uses brief case presentations to review management strategies for malignant pleural effusion.

CANCER IS A COMMON CAUSE OF PLEURAL EFFUSION

Physicians and surgeons, especially in tertiary care hospitals, must often manage malignant pleural effusion.⁴ Malignancy is the third leading cause of pleural effusion after heart failure and pneumonia, accounting for 44% to 77% of exudates.⁵ Although pleural effusion can arise secondary to many different malignancies, the most common causes are lung cancer in men and breast cancer in women; these cancers account for about 75% of all cases of malignant pleural effusion.^6,7

A WOMAN ON CHEMOTHERAPY WITH ASYMPTOMATIC PLEURAL EFFUSION

An 18-year-old woman with non-Hodgkin lymphoma has received her first cycle of chemotherapy and is now admitted to the hospital for diarrhea. A routine chest radiograph reveals a left-sided pleural effusion covering one-third of the thoracic cavity. She is asymptomatic and reports no shortness of breath at rest or with exertion. Her oxygen saturation level is above 92% on room air without supplemental oxygen.

Thoracentesis reveals an exudative effusion, and cytologic study shows malignant lymphoid cells, consistent with a malignant pleural effusion. Cultures are negative.

What is the appropriate next step to manage this patient’s effusion?

Observation is reasonable

This patient is experiencing no symptoms and has just begun chemotherapy for her lymphoma. Malignant pleural effusion associated with lymphoma, small-cell lung cancer, and breast cancer is most sensitive to chemotherapy.⁵ For patients who do not have symptoms from the pleural effusion and who are scheduled to receive further chemotherapy, a watch-and-wait approach is reasonable.

It is important to follow the patient for developing symptoms and obtain serial imaging to evaluate for an increase in the effusion size. We recommend repeat imaging at 2- to 4-week intervals, and sooner if symptoms develop.

If progression is evident or if the patient’s oncologist indicates that the cancer is unresponsive to systemic therapy, further intervention may be necessary with one of the options discussed below.

A MAN WITH LUNG CANCER WITH PLEURAL EFFUSION, LUNG COLLAPSE

A 42-year-old man with a history of lung cancer is admitted for worsening shortness of breath. Chest radiography reveals a large left-sided pleural effusion with complete collapse of the left lung and contralateral shift of midline structures (Figure 1). Large-volume thoracentesis improves his symptoms. Pleural fluid cytology is positive for malignant cells. A repeat chest radiograph shows incomplete expansion of the left lung, thick pleura, and pneumothorax, indicating a trapped lung (ie, one unable to expand fully). Two weeks later, his symptoms recur, and chest radiography reveals a recurrent effusion.

How should this effusion be managed?

Indwelling pleural catheter placement

In a retrospective cohort study,⁸ malignant pleural effusion recurred in 97% of patients within 1 month (mean, 4.2 days) of therapeutic aspiration, highlighting the need for definitive treatment.

In the absence of lung expansion, pleuro­desis is rarely successful, and placing an indwelling pleural catheter in symptomatic patients is the preferred strategy. The US Food and Drug Administration approved this use in 1997.⁹

Indwelling pleural catheters are narrow (15.5 French, or about 5 mm in diameter) and soft (made of silicone), with distal fenestrations. The distal end remains positioned in the pleural cavity to enable drainage of pleural fluid. The middle portion passes through subcutaneous tissue, where a polyester cuff prevents dislodgement and infection. The proximal end of the catheter remains outside the patient’s skin and is connected to a 1-way valve that prevents air or fluid flow into the pleural cavity.

Pleural fluid is typically drained every 2 or 3 days for palliation. Patients must be educated about home drainage and proper catheter care.

Although indwelling pleural catheters were first used for patients who were not candidates for pleurodesis, they are now increasingly used as first-line therapy.

Since these devices were introduced, several clinical series including more than 800 patients have found that their use for malignant pleural infusion led to symptomatic improvement in 89% to 100% of cases, with 90% of patients needing no subsequent pleural procedures after catheter insertion.^10–13

Davies et al¹⁴ randomized 106 patients with malignant pleural effusion to either receive an indwelling pleural catheter or undergo pleurodesis. In the first 6 weeks, the 2 groups had about the same incidence of dyspnea, but the catheter group had less dyspnea at 6 months, shorter index hospitalization (0 vs 4 days), fewer hospital days in the first year for treatment-related complications (1 vs 4.5 days), and fewer patients needing follow-up pleural procedures (6% vs 22%). On the other hand, adverse events were more frequent in the indwelling pleural catheter group (40% vs 13%). The most frequent events were pleural infection, cellulitis, and catheter blockage.

Fysh et al¹⁵ also compared indwelling pleural catheter insertion and pleurodesis (based on patient choice) in patients with malignant pleural effusion. As in the previous trial, those who received a catheter required significantly fewer days in the hospital and fewer additional pleural procedures than those who received pleurodesis. Safety profiles and symptom control were comparable.

Indwelling pleural catheters have several other advantages. They have been found to be more cost-effective than talc pleurodesis in patients not expected to live long (survival < 14 weeks).¹⁶ Patients with an indwelling pleural catheter can receive chemotherapy, and concurrent treatment does not increase risk of infection.¹⁷ And a systematic review¹⁸ found a 46% rate of autopleurodesis at a median of 52 days after insertion of an indwelling pleural catheter.

Drainage rate may need to be moderated

Chest pain has been reported with the use of indwelling pleural catheters, related to rapid drainage of the effusion in the setting of failed reexpansion of the trapped lung due to thickened pleura. Drainage schedules may need to be adjusted, with more frequent draining of smaller volumes, to control dyspnea without causing significant pain.

A WOMAN WITH RECURRENT PLEURAL EFFUSION, GOOD PROGNOSIS

A 55-year-old woman with a history of breast cancer presents with shortness of breath. Chest radiography reveals a right-sided effusion, which on thoracentesis is found to be malignant. After fluid removal, repeat chest radiography shows complete lung expansion.

One month later, she returns with symptoms and recurrence of the effusion. Ultrasonography does not reveal any adhesions in the pleural space. Her oncologist informs you that her expected survival is in years.

What is the next step?

Chemical pleurodesis

Chemical pleurodesis involves introducing a sclerosant into the pleural space to provoke an intense inflammatory response, creating adhesions and fibrosis that will obliterate the space. The sclerosing agent (typically talc) can be delivered by tube thoracostomy, video-assisted thoracic surgery (VATS), or medical pleuroscopy. Although the latter 2 methods allow direct visualization of the pleural space and, in theory, a more even distribution of the sclerosing agent, current evidence does not favor 1 option over the other,¹⁹ and practice patterns vary between institutions.

Tube thoracostomy. Typically, the sclerosing agent is administered once a chest radiograph shows lung reexpansion, and tube output of pleural fluid is less than 150 mL/day.¹⁹ However, some studies indicate that if pleural apposition can be confirmed using ultrasonography, then sclerosant administration at that time leads to optimal pleurodesis efficacy and shorter hospitalization.^20,21

VATS is usually done in the operating room with the patient under general anesthesia. A double-lumen endotracheal tube allows for single-lung ventilation; a camera is then inserted into the pleural space of the collapsed lung. Multiple ports of entry are usually employed, and the entire pleural space can be visualized and the sclerosing agent instilled uniformly. The surgeon may alternatively choose to perform mechanical pleurodesis, which entails abrading the visceral and parietal pleura with dry gauze to provoke diffuse petechial hemorrhage and an inflammatory reaction. VATS can also be used to perform biopsy, lobectomy, and pneumonectomy.

Medical pleuroscopy. Medical pleuroscopy is usually done using local anesthesia with the patient awake, moderately sedated, and not intubated. Because no double-lumen endotracheal tube is used, lung collapse may not be complete, making it difficult to completely visualize the entire pleural surfaces.

Although no randomized study of VATS vs medical pleuroscopy exists, a retrospective case-matched study²² comparing VATS (under general anesthesia) to single-port VATS (under local anesthesia) noted equivalent rates of pleurodesis. However, the local anesthesia group had a lower perioperative mortality rate (0% vs 2.3%), a lower postoperative major morbidity rate (5.2% vs 9%), earlier improvement in quality of life, and shorter hospitalization (3 vs 5 days).²² In general, the diagnostic sensitivity of pleuroscopy for pleural malignancy is similar to that of VATS (93% vs 97%).^23,24

A MAN WITH PLEURAL EFFUSION AND A POOR PROGNOSIS

A 60-year-old man with metastatic pancreatic cancer is brought to the clinic for worsening shortness of breath over the past 2 months. During that time, he has lost 6 kg and has become bedridden.

On examination, he has severe cachexia and is significantly short of breath at rest with associated hypoxia. His oncologist expects him to survive less than 3 months.

His laboratory investigations reveal hypoalbuminemia and leukocytosis. A chest radiograph shows a large left-sided pleural effusion that was not present 2 months ago.

What should be done for him?

Thoracentesis, repeat as needed

Malignant pleural effusion causing dyspnea is not uncommon in certain advanced malignancies and may contribute to significant suffering at the end of life. A study of 298 patients with malignant pleural effusion noted that the presence of leukocytosis, hypoalbuminemia, and hypoxemia was associated with a poorer prognosis. Patients having all 3 factors had a median survival of 42 days.²⁵

Thoracentesis, the least invasive option that may improve dyspnea, can be done in the clinic setting and is a reasonable strategy for patients with advanced cancer and an expected survival of less than 3 months.²⁶ Although recurrence is expected, it may take up to a few weeks, and repeat thoracentesis can be performed as needed.

Managing patients with malignant pleural effusion can be challenging. Symptoms are often distressing, and its presence signifies advanced disease. Median survival after diagnosis is 4 to 9 months,^1–3 although prognosis varies considerably depending on the type and stage of the malignancy.

How patients are best managed depends on clinical circumstances. Physicians should consider the risks and benefits of each option while keeping in mind realistic goals of care.

This article uses brief case presentations to review management strategies for malignant pleural effusion.

CANCER IS A COMMON CAUSE OF PLEURAL EFFUSION

Physicians and surgeons, especially in tertiary care hospitals, must often manage malignant pleural effusion.⁴ Malignancy is the third leading cause of pleural effusion after heart failure and pneumonia, accounting for 44% to 77% of exudates.⁵ Although pleural effusion can arise secondary to many different malignancies, the most common causes are lung cancer in men and breast cancer in women; these cancers account for about 75% of all cases of malignant pleural effusion.^6,7

A WOMAN ON CHEMOTHERAPY WITH ASYMPTOMATIC PLEURAL EFFUSION

An 18-year-old woman with non-Hodgkin lymphoma has received her first cycle of chemotherapy and is now admitted to the hospital for diarrhea. A routine chest radiograph reveals a left-sided pleural effusion covering one-third of the thoracic cavity. She is asymptomatic and reports no shortness of breath at rest or with exertion. Her oxygen saturation level is above 92% on room air without supplemental oxygen.

Thoracentesis reveals an exudative effusion, and cytologic study shows malignant lymphoid cells, consistent with a malignant pleural effusion. Cultures are negative.

What is the appropriate next step to manage this patient’s effusion?

Observation is reasonable

This patient is experiencing no symptoms and has just begun chemotherapy for her lymphoma. Malignant pleural effusion associated with lymphoma, small-cell lung cancer, and breast cancer is most sensitive to chemotherapy.⁵ For patients who do not have symptoms from the pleural effusion and who are scheduled to receive further chemotherapy, a watch-and-wait approach is reasonable.

It is important to follow the patient for developing symptoms and obtain serial imaging to evaluate for an increase in the effusion size. We recommend repeat imaging at 2- to 4-week intervals, and sooner if symptoms develop.

If progression is evident or if the patient’s oncologist indicates that the cancer is unresponsive to systemic therapy, further intervention may be necessary with one of the options discussed below.

A MAN WITH LUNG CANCER WITH PLEURAL EFFUSION, LUNG COLLAPSE

A 42-year-old man with a history of lung cancer is admitted for worsening shortness of breath. Chest radiography reveals a large left-sided pleural effusion with complete collapse of the left lung and contralateral shift of midline structures (Figure 1). Large-volume thoracentesis improves his symptoms. Pleural fluid cytology is positive for malignant cells. A repeat chest radiograph shows incomplete expansion of the left lung, thick pleura, and pneumothorax, indicating a trapped lung (ie, one unable to expand fully). Two weeks later, his symptoms recur, and chest radiography reveals a recurrent effusion.

How should this effusion be managed?

Indwelling pleural catheter placement

In a retrospective cohort study,⁸ malignant pleural effusion recurred in 97% of patients within 1 month (mean, 4.2 days) of therapeutic aspiration, highlighting the need for definitive treatment.

In the absence of lung expansion, pleuro­desis is rarely successful, and placing an indwelling pleural catheter in symptomatic patients is the preferred strategy. The US Food and Drug Administration approved this use in 1997.⁹

Indwelling pleural catheters are narrow (15.5 French, or about 5 mm in diameter) and soft (made of silicone), with distal fenestrations. The distal end remains positioned in the pleural cavity to enable drainage of pleural fluid. The middle portion passes through subcutaneous tissue, where a polyester cuff prevents dislodgement and infection. The proximal end of the catheter remains outside the patient’s skin and is connected to a 1-way valve that prevents air or fluid flow into the pleural cavity.

Pleural fluid is typically drained every 2 or 3 days for palliation. Patients must be educated about home drainage and proper catheter care.

Although indwelling pleural catheters were first used for patients who were not candidates for pleurodesis, they are now increasingly used as first-line therapy.

Since these devices were introduced, several clinical series including more than 800 patients have found that their use for malignant pleural infusion led to symptomatic improvement in 89% to 100% of cases, with 90% of patients needing no subsequent pleural procedures after catheter insertion.^10–13

Davies et al¹⁴ randomized 106 patients with malignant pleural effusion to either receive an indwelling pleural catheter or undergo pleurodesis. In the first 6 weeks, the 2 groups had about the same incidence of dyspnea, but the catheter group had less dyspnea at 6 months, shorter index hospitalization (0 vs 4 days), fewer hospital days in the first year for treatment-related complications (1 vs 4.5 days), and fewer patients needing follow-up pleural procedures (6% vs 22%). On the other hand, adverse events were more frequent in the indwelling pleural catheter group (40% vs 13%). The most frequent events were pleural infection, cellulitis, and catheter blockage.

Fysh et al¹⁵ also compared indwelling pleural catheter insertion and pleurodesis (based on patient choice) in patients with malignant pleural effusion. As in the previous trial, those who received a catheter required significantly fewer days in the hospital and fewer additional pleural procedures than those who received pleurodesis. Safety profiles and symptom control were comparable.

Indwelling pleural catheters have several other advantages. They have been found to be more cost-effective than talc pleurodesis in patients not expected to live long (survival < 14 weeks).¹⁶ Patients with an indwelling pleural catheter can receive chemotherapy, and concurrent treatment does not increase risk of infection.¹⁷ And a systematic review¹⁸ found a 46% rate of autopleurodesis at a median of 52 days after insertion of an indwelling pleural catheter.

Drainage rate may need to be moderated

Chest pain has been reported with the use of indwelling pleural catheters, related to rapid drainage of the effusion in the setting of failed reexpansion of the trapped lung due to thickened pleura. Drainage schedules may need to be adjusted, with more frequent draining of smaller volumes, to control dyspnea without causing significant pain.

A WOMAN WITH RECURRENT PLEURAL EFFUSION, GOOD PROGNOSIS

A 55-year-old woman with a history of breast cancer presents with shortness of breath. Chest radiography reveals a right-sided effusion, which on thoracentesis is found to be malignant. After fluid removal, repeat chest radiography shows complete lung expansion.

One month later, she returns with symptoms and recurrence of the effusion. Ultrasonography does not reveal any adhesions in the pleural space. Her oncologist informs you that her expected survival is in years.

What is the next step?

Chemical pleurodesis

Chemical pleurodesis involves introducing a sclerosant into the pleural space to provoke an intense inflammatory response, creating adhesions and fibrosis that will obliterate the space. The sclerosing agent (typically talc) can be delivered by tube thoracostomy, video-assisted thoracic surgery (VATS), or medical pleuroscopy. Although the latter 2 methods allow direct visualization of the pleural space and, in theory, a more even distribution of the sclerosing agent, current evidence does not favor 1 option over the other,¹⁹ and practice patterns vary between institutions.

Tube thoracostomy. Typically, the sclerosing agent is administered once a chest radiograph shows lung reexpansion, and tube output of pleural fluid is less than 150 mL/day.¹⁹ However, some studies indicate that if pleural apposition can be confirmed using ultrasonography, then sclerosant administration at that time leads to optimal pleurodesis efficacy and shorter hospitalization.^20,21

VATS is usually done in the operating room with the patient under general anesthesia. A double-lumen endotracheal tube allows for single-lung ventilation; a camera is then inserted into the pleural space of the collapsed lung. Multiple ports of entry are usually employed, and the entire pleural space can be visualized and the sclerosing agent instilled uniformly. The surgeon may alternatively choose to perform mechanical pleurodesis, which entails abrading the visceral and parietal pleura with dry gauze to provoke diffuse petechial hemorrhage and an inflammatory reaction. VATS can also be used to perform biopsy, lobectomy, and pneumonectomy.

Medical pleuroscopy. Medical pleuroscopy is usually done using local anesthesia with the patient awake, moderately sedated, and not intubated. Because no double-lumen endotracheal tube is used, lung collapse may not be complete, making it difficult to completely visualize the entire pleural surfaces.

Although no randomized study of VATS vs medical pleuroscopy exists, a retrospective case-matched study²² comparing VATS (under general anesthesia) to single-port VATS (under local anesthesia) noted equivalent rates of pleurodesis. However, the local anesthesia group had a lower perioperative mortality rate (0% vs 2.3%), a lower postoperative major morbidity rate (5.2% vs 9%), earlier improvement in quality of life, and shorter hospitalization (3 vs 5 days).²² In general, the diagnostic sensitivity of pleuroscopy for pleural malignancy is similar to that of VATS (93% vs 97%).^23,24

A MAN WITH PLEURAL EFFUSION AND A POOR PROGNOSIS

A 60-year-old man with metastatic pancreatic cancer is brought to the clinic for worsening shortness of breath over the past 2 months. During that time, he has lost 6 kg and has become bedridden.

On examination, he has severe cachexia and is significantly short of breath at rest with associated hypoxia. His oncologist expects him to survive less than 3 months.

His laboratory investigations reveal hypoalbuminemia and leukocytosis. A chest radiograph shows a large left-sided pleural effusion that was not present 2 months ago.

What should be done for him?

Thoracentesis, repeat as needed

Malignant pleural effusion causing dyspnea is not uncommon in certain advanced malignancies and may contribute to significant suffering at the end of life. A study of 298 patients with malignant pleural effusion noted that the presence of leukocytosis, hypoalbuminemia, and hypoxemia was associated with a poorer prognosis. Patients having all 3 factors had a median survival of 42 days.²⁵

Thoracentesis, the least invasive option that may improve dyspnea, can be done in the clinic setting and is a reasonable strategy for patients with advanced cancer and an expected survival of less than 3 months.²⁶ Although recurrence is expected, it may take up to a few weeks, and repeat thoracentesis can be performed as needed.

Managing patients with malignant pleural effusion can be challenging. Symptoms are often distressing, and its presence signifies advanced disease. Median survival after diagnosis is 4 to 9 months,^1–3 although prognosis varies considerably depending on the type and stage of the malignancy.

How patients are best managed depends on clinical circumstances. Physicians should consider the risks and benefits of each option while keeping in mind realistic goals of care.

This article uses brief case presentations to review management strategies for malignant pleural effusion.

CANCER IS A COMMON CAUSE OF PLEURAL EFFUSION

Physicians and surgeons, especially in tertiary care hospitals, must often manage malignant pleural effusion.⁴ Malignancy is the third leading cause of pleural effusion after heart failure and pneumonia, accounting for 44% to 77% of exudates.⁵ Although pleural effusion can arise secondary to many different malignancies, the most common causes are lung cancer in men and breast cancer in women; these cancers account for about 75% of all cases of malignant pleural effusion.^6,7

A WOMAN ON CHEMOTHERAPY WITH ASYMPTOMATIC PLEURAL EFFUSION

An 18-year-old woman with non-Hodgkin lymphoma has received her first cycle of chemotherapy and is now admitted to the hospital for diarrhea. A routine chest radiograph reveals a left-sided pleural effusion covering one-third of the thoracic cavity. She is asymptomatic and reports no shortness of breath at rest or with exertion. Her oxygen saturation level is above 92% on room air without supplemental oxygen.

Thoracentesis reveals an exudative effusion, and cytologic study shows malignant lymphoid cells, consistent with a malignant pleural effusion. Cultures are negative.

What is the appropriate next step to manage this patient’s effusion?

Observation is reasonable

This patient is experiencing no symptoms and has just begun chemotherapy for her lymphoma. Malignant pleural effusion associated with lymphoma, small-cell lung cancer, and breast cancer is most sensitive to chemotherapy.⁵ For patients who do not have symptoms from the pleural effusion and who are scheduled to receive further chemotherapy, a watch-and-wait approach is reasonable.

It is important to follow the patient for developing symptoms and obtain serial imaging to evaluate for an increase in the effusion size. We recommend repeat imaging at 2- to 4-week intervals, and sooner if symptoms develop.

If progression is evident or if the patient’s oncologist indicates that the cancer is unresponsive to systemic therapy, further intervention may be necessary with one of the options discussed below.

A MAN WITH LUNG CANCER WITH PLEURAL EFFUSION, LUNG COLLAPSE

A 42-year-old man with a history of lung cancer is admitted for worsening shortness of breath. Chest radiography reveals a large left-sided pleural effusion with complete collapse of the left lung and contralateral shift of midline structures (Figure 1). Large-volume thoracentesis improves his symptoms. Pleural fluid cytology is positive for malignant cells. A repeat chest radiograph shows incomplete expansion of the left lung, thick pleura, and pneumothorax, indicating a trapped lung (ie, one unable to expand fully). Two weeks later, his symptoms recur, and chest radiography reveals a recurrent effusion.

How should this effusion be managed?

Indwelling pleural catheter placement

In a retrospective cohort study,⁸ malignant pleural effusion recurred in 97% of patients within 1 month (mean, 4.2 days) of therapeutic aspiration, highlighting the need for definitive treatment.

In the absence of lung expansion, pleuro­desis is rarely successful, and placing an indwelling pleural catheter in symptomatic patients is the preferred strategy. The US Food and Drug Administration approved this use in 1997.⁹

Indwelling pleural catheters are narrow (15.5 French, or about 5 mm in diameter) and soft (made of silicone), with distal fenestrations. The distal end remains positioned in the pleural cavity to enable drainage of pleural fluid. The middle portion passes through subcutaneous tissue, where a polyester cuff prevents dislodgement and infection. The proximal end of the catheter remains outside the patient’s skin and is connected to a 1-way valve that prevents air or fluid flow into the pleural cavity.

Pleural fluid is typically drained every 2 or 3 days for palliation. Patients must be educated about home drainage and proper catheter care.

Although indwelling pleural catheters were first used for patients who were not candidates for pleurodesis, they are now increasingly used as first-line therapy.

Since these devices were introduced, several clinical series including more than 800 patients have found that their use for malignant pleural infusion led to symptomatic improvement in 89% to 100% of cases, with 90% of patients needing no subsequent pleural procedures after catheter insertion.^10–13

Davies et al¹⁴ randomized 106 patients with malignant pleural effusion to either receive an indwelling pleural catheter or undergo pleurodesis. In the first 6 weeks, the 2 groups had about the same incidence of dyspnea, but the catheter group had less dyspnea at 6 months, shorter index hospitalization (0 vs 4 days), fewer hospital days in the first year for treatment-related complications (1 vs 4.5 days), and fewer patients needing follow-up pleural procedures (6% vs 22%). On the other hand, adverse events were more frequent in the indwelling pleural catheter group (40% vs 13%). The most frequent events were pleural infection, cellulitis, and catheter blockage.

Fysh et al¹⁵ also compared indwelling pleural catheter insertion and pleurodesis (based on patient choice) in patients with malignant pleural effusion. As in the previous trial, those who received a catheter required significantly fewer days in the hospital and fewer additional pleural procedures than those who received pleurodesis. Safety profiles and symptom control were comparable.

Indwelling pleural catheters have several other advantages. They have been found to be more cost-effective than talc pleurodesis in patients not expected to live long (survival < 14 weeks).¹⁶ Patients with an indwelling pleural catheter can receive chemotherapy, and concurrent treatment does not increase risk of infection.¹⁷ And a systematic review¹⁸ found a 46% rate of autopleurodesis at a median of 52 days after insertion of an indwelling pleural catheter.

Drainage rate may need to be moderated

Chest pain has been reported with the use of indwelling pleural catheters, related to rapid drainage of the effusion in the setting of failed reexpansion of the trapped lung due to thickened pleura. Drainage schedules may need to be adjusted, with more frequent draining of smaller volumes, to control dyspnea without causing significant pain.

A WOMAN WITH RECURRENT PLEURAL EFFUSION, GOOD PROGNOSIS

A 55-year-old woman with a history of breast cancer presents with shortness of breath. Chest radiography reveals a right-sided effusion, which on thoracentesis is found to be malignant. After fluid removal, repeat chest radiography shows complete lung expansion.

One month later, she returns with symptoms and recurrence of the effusion. Ultrasonography does not reveal any adhesions in the pleural space. Her oncologist informs you that her expected survival is in years.

What is the next step?

Chemical pleurodesis

Chemical pleurodesis involves introducing a sclerosant into the pleural space to provoke an intense inflammatory response, creating adhesions and fibrosis that will obliterate the space. The sclerosing agent (typically talc) can be delivered by tube thoracostomy, video-assisted thoracic surgery (VATS), or medical pleuroscopy. Although the latter 2 methods allow direct visualization of the pleural space and, in theory, a more even distribution of the sclerosing agent, current evidence does not favor 1 option over the other,¹⁹ and practice patterns vary between institutions.

Tube thoracostomy. Typically, the sclerosing agent is administered once a chest radiograph shows lung reexpansion, and tube output of pleural fluid is less than 150 mL/day.¹⁹ However, some studies indicate that if pleural apposition can be confirmed using ultrasonography, then sclerosant administration at that time leads to optimal pleurodesis efficacy and shorter hospitalization.^20,21

VATS is usually done in the operating room with the patient under general anesthesia. A double-lumen endotracheal tube allows for single-lung ventilation; a camera is then inserted into the pleural space of the collapsed lung. Multiple ports of entry are usually employed, and the entire pleural space can be visualized and the sclerosing agent instilled uniformly. The surgeon may alternatively choose to perform mechanical pleurodesis, which entails abrading the visceral and parietal pleura with dry gauze to provoke diffuse petechial hemorrhage and an inflammatory reaction. VATS can also be used to perform biopsy, lobectomy, and pneumonectomy.

Medical pleuroscopy. Medical pleuroscopy is usually done using local anesthesia with the patient awake, moderately sedated, and not intubated. Because no double-lumen endotracheal tube is used, lung collapse may not be complete, making it difficult to completely visualize the entire pleural surfaces.

Although no randomized study of VATS vs medical pleuroscopy exists, a retrospective case-matched study²² comparing VATS (under general anesthesia) to single-port VATS (under local anesthesia) noted equivalent rates of pleurodesis. However, the local anesthesia group had a lower perioperative mortality rate (0% vs 2.3%), a lower postoperative major morbidity rate (5.2% vs 9%), earlier improvement in quality of life, and shorter hospitalization (3 vs 5 days).²² In general, the diagnostic sensitivity of pleuroscopy for pleural malignancy is similar to that of VATS (93% vs 97%).^23,24

A MAN WITH PLEURAL EFFUSION AND A POOR PROGNOSIS

A 60-year-old man with metastatic pancreatic cancer is brought to the clinic for worsening shortness of breath over the past 2 months. During that time, he has lost 6 kg and has become bedridden.

On examination, he has severe cachexia and is significantly short of breath at rest with associated hypoxia. His oncologist expects him to survive less than 3 months.

His laboratory investigations reveal hypoalbuminemia and leukocytosis. A chest radiograph shows a large left-sided pleural effusion that was not present 2 months ago.

What should be done for him?

Thoracentesis, repeat as needed

Malignant pleural effusion causing dyspnea is not uncommon in certain advanced malignancies and may contribute to significant suffering at the end of life. A study of 298 patients with malignant pleural effusion noted that the presence of leukocytosis, hypoalbuminemia, and hypoxemia was associated with a poorer prognosis. Patients having all 3 factors had a median survival of 42 days.²⁵

Thoracentesis, the least invasive option that may improve dyspnea, can be done in the clinic setting and is a reasonable strategy for patients with advanced cancer and an expected survival of less than 3 months.²⁶ Although recurrence is expected, it may take up to a few weeks, and repeat thoracentesis can be performed as needed.

The next day, routine radiography showed widely separated sternal wires (Figure 3), indicating significant progression of sternal dehiscence. The patient subsequently underwent open reduction and internal fixation of the sternum.

STERNAL DEHISCENCE

Physical examination may reveal tenderness to palpation, but findings that are more characteristic are an audible click and rocking of the sternum with coughing or forced chest movements.³

Plain chest radiography can clearly show early signs of sternal dehiscence; however, physicians rarely scrutinize the films for wire placement. Subtle signs include loss of sternal alignment with shifting of the segments and central sternal lucency. Gross signs start to appear when 2 or more wires are displaced; these signs are dramatic and rarely missed.

Loss of alignment and central sternal lucency are the earliest radiographic signs of dehiscence. Awareness of early subtle signs can lead to prompt diagnosis and treatment to prevent progression to gross sternal dehiscence.

The next day, routine radiography showed widely separated sternal wires (Figure 3), indicating significant progression of sternal dehiscence. The patient subsequently underwent open reduction and internal fixation of the sternum.

STERNAL DEHISCENCE

Physical examination may reveal tenderness to palpation, but findings that are more characteristic are an audible click and rocking of the sternum with coughing or forced chest movements.³

Plain chest radiography can clearly show early signs of sternal dehiscence; however, physicians rarely scrutinize the films for wire placement. Subtle signs include loss of sternal alignment with shifting of the segments and central sternal lucency. Gross signs start to appear when 2 or more wires are displaced; these signs are dramatic and rarely missed.

Loss of alignment and central sternal lucency are the earliest radiographic signs of dehiscence. Awareness of early subtle signs can lead to prompt diagnosis and treatment to prevent progression to gross sternal dehiscence.

The next day, routine radiography showed widely separated sternal wires (Figure 3), indicating significant progression of sternal dehiscence. The patient subsequently underwent open reduction and internal fixation of the sternum.

STERNAL DEHISCENCE

Physical examination may reveal tenderness to palpation, but findings that are more characteristic are an audible click and rocking of the sternum with coughing or forced chest movements.³

Plain chest radiography can clearly show early signs of sternal dehiscence; however, physicians rarely scrutinize the films for wire placement. Subtle signs include loss of sternal alignment with shifting of the segments and central sternal lucency. Gross signs start to appear when 2 or more wires are displaced; these signs are dramatic and rarely missed.

Loss of alignment and central sternal lucency are the earliest radiographic signs of dehiscence. Awareness of early subtle signs can lead to prompt diagnosis and treatment to prevent progression to gross sternal dehiscence.

Clinical question: Does a negative computed tomography pulmonary angiography rule out venous thromboembolism (VTE)?

Background: Computed tomography pulmonary angiography (CTPA) is the most common diagnostic modality used to diagnose pulmonary embolism (PE) and has a high negative predictive value in patients with a low 3-month risk of VTE. In patients with higher pretest probability of PE, it is unknown whether CTPA is sufficient to rule out VTE.

Study design: Meta-analysis.

Setting: Published prospective outcome studies of patients with suspected PE using CTPA as a diagnostic strategy.

Synopsis: The authors reviewed 3,143 publications from MEDLINE, EMBASE, and the Cochrane Library and identified 22 prospective outcome studies to include in their meta-analysis. A VTE was diagnosed in 3,923 out of 11,872 participants (33%) using CTPA. Of the 7,863 patients with a negative CTPA, 148 patients had an acute VTE confirmed by venous ultrasound, ventilation/perfusion scan, or angiography, and 74 patients experienced VTE during a 3-month follow-up period, yielding an overall proportion of 2.4% of patients (95% confidence interval, 1.3%-3.8%).

Subgroup analysis showed that cumulative occurrence of VTE was related to pretest prevalence. In the subgroup of patients with a VTE prevalence greater than 40%, VTE was observed in 8.1% of patients with a negative CTPA (95% CI, 3.4%-14.5%).

Bottom line: CTPA may be insufficient to rule out VTE in patients with a high pretest probability of PE.

Citation: Belzile D et al. Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysisof the management outcome studies. J Thromb Haemost. 2018 Jun;16(6):1107-20.

Dr. Jenkins is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.

Clinical question: Does a negative computed tomography pulmonary angiography rule out venous thromboembolism (VTE)?

Background: Computed tomography pulmonary angiography (CTPA) is the most common diagnostic modality used to diagnose pulmonary embolism (PE) and has a high negative predictive value in patients with a low 3-month risk of VTE. In patients with higher pretest probability of PE, it is unknown whether CTPA is sufficient to rule out VTE.

Study design: Meta-analysis.

Setting: Published prospective outcome studies of patients with suspected PE using CTPA as a diagnostic strategy.

Synopsis: The authors reviewed 3,143 publications from MEDLINE, EMBASE, and the Cochrane Library and identified 22 prospective outcome studies to include in their meta-analysis. A VTE was diagnosed in 3,923 out of 11,872 participants (33%) using CTPA. Of the 7,863 patients with a negative CTPA, 148 patients had an acute VTE confirmed by venous ultrasound, ventilation/perfusion scan, or angiography, and 74 patients experienced VTE during a 3-month follow-up period, yielding an overall proportion of 2.4% of patients (95% confidence interval, 1.3%-3.8%).

Subgroup analysis showed that cumulative occurrence of VTE was related to pretest prevalence. In the subgroup of patients with a VTE prevalence greater than 40%, VTE was observed in 8.1% of patients with a negative CTPA (95% CI, 3.4%-14.5%).

Bottom line: CTPA may be insufficient to rule out VTE in patients with a high pretest probability of PE.

Citation: Belzile D et al. Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysisof the management outcome studies. J Thromb Haemost. 2018 Jun;16(6):1107-20.

Dr. Jenkins is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.

Clinical question: Does a negative computed tomography pulmonary angiography rule out venous thromboembolism (VTE)?

Background: Computed tomography pulmonary angiography (CTPA) is the most common diagnostic modality used to diagnose pulmonary embolism (PE) and has a high negative predictive value in patients with a low 3-month risk of VTE. In patients with higher pretest probability of PE, it is unknown whether CTPA is sufficient to rule out VTE.

Study design: Meta-analysis.

Setting: Published prospective outcome studies of patients with suspected PE using CTPA as a diagnostic strategy.

Synopsis: The authors reviewed 3,143 publications from MEDLINE, EMBASE, and the Cochrane Library and identified 22 prospective outcome studies to include in their meta-analysis. A VTE was diagnosed in 3,923 out of 11,872 participants (33%) using CTPA. Of the 7,863 patients with a negative CTPA, 148 patients had an acute VTE confirmed by venous ultrasound, ventilation/perfusion scan, or angiography, and 74 patients experienced VTE during a 3-month follow-up period, yielding an overall proportion of 2.4% of patients (95% confidence interval, 1.3%-3.8%).

Subgroup analysis showed that cumulative occurrence of VTE was related to pretest prevalence. In the subgroup of patients with a VTE prevalence greater than 40%, VTE was observed in 8.1% of patients with a negative CTPA (95% CI, 3.4%-14.5%).

Bottom line: CTPA may be insufficient to rule out VTE in patients with a high pretest probability of PE.

Citation: Belzile D et al. Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysisof the management outcome studies. J Thromb Haemost. 2018 Jun;16(6):1107-20.

Dr. Jenkins is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.

The American College of Cardiology, the American Heart Association, and other groups have jointly released an appropriate use criteria (AUC) document regarding the use of imaging modalities in diagnosing nonvalvular (that is, structural) heart disease.

Imaging plays an important role in diagnosing both valvular and nonvalvular heart diseases, so the goal of the document was to help clinicians provide high-quality care by standardizing the decision-making process. To do so, a committee was formed to devise scenarios that reflected situations in real-world practice; these scenarios were considered within categories to prevent the list from being too exhaustive. The scenarios were then reviewed by a rating panel in terms of how appropriate certain modalities were in each situation. The panel members first evaluated the scenarios independently then face to face as a panel before giving their final scores (from 1 to 9) independently.

For example, for the indication of nonsustained ventricular tachycardia, the panelists rated transthoracic echocardiography with or without 3-D and with contrast as needed as a 8, which means it’s an “appropriate test,” whereas they gave CT for the same indication a 3, which means “rarely appropriate.” For sustained ventricular tachycardia or ventricular fibrillation, they gave a 9 and a 6, respectively; this latter score indicates the test “may be appropriate.” These scenarios and the respective scores for any given test are organized into tables, such as initial evaluation or follow-up.

This AUC document “signals a shift from documents evaluating a single modality in various disease states to documents evaluating multiple imaging modalities and focusing on evidence and clinical experience within a given disease category,” the authors wrote. “We believe this approach better reflects clinical decision making in real-world scenarios and offers the diagnostic choices available to the clinician.”

The full document can be viewed in JACC.
 

[email protected]

The American College of Cardiology, the American Heart Association, and other groups have jointly released an appropriate use criteria (AUC) document regarding the use of imaging modalities in diagnosing nonvalvular (that is, structural) heart disease.

Imaging plays an important role in diagnosing both valvular and nonvalvular heart diseases, so the goal of the document was to help clinicians provide high-quality care by standardizing the decision-making process. To do so, a committee was formed to devise scenarios that reflected situations in real-world practice; these scenarios were considered within categories to prevent the list from being too exhaustive. The scenarios were then reviewed by a rating panel in terms of how appropriate certain modalities were in each situation. The panel members first evaluated the scenarios independently then face to face as a panel before giving their final scores (from 1 to 9) independently.

For example, for the indication of nonsustained ventricular tachycardia, the panelists rated transthoracic echocardiography with or without 3-D and with contrast as needed as a 8, which means it’s an “appropriate test,” whereas they gave CT for the same indication a 3, which means “rarely appropriate.” For sustained ventricular tachycardia or ventricular fibrillation, they gave a 9 and a 6, respectively; this latter score indicates the test “may be appropriate.” These scenarios and the respective scores for any given test are organized into tables, such as initial evaluation or follow-up.

This AUC document “signals a shift from documents evaluating a single modality in various disease states to documents evaluating multiple imaging modalities and focusing on evidence and clinical experience within a given disease category,” the authors wrote. “We believe this approach better reflects clinical decision making in real-world scenarios and offers the diagnostic choices available to the clinician.”

The full document can be viewed in JACC.
 

[email protected]

The American College of Cardiology, the American Heart Association, and other groups have jointly released an appropriate use criteria (AUC) document regarding the use of imaging modalities in diagnosing nonvalvular (that is, structural) heart disease.

Imaging plays an important role in diagnosing both valvular and nonvalvular heart diseases, so the goal of the document was to help clinicians provide high-quality care by standardizing the decision-making process. To do so, a committee was formed to devise scenarios that reflected situations in real-world practice; these scenarios were considered within categories to prevent the list from being too exhaustive. The scenarios were then reviewed by a rating panel in terms of how appropriate certain modalities were in each situation. The panel members first evaluated the scenarios independently then face to face as a panel before giving their final scores (from 1 to 9) independently.

For example, for the indication of nonsustained ventricular tachycardia, the panelists rated transthoracic echocardiography with or without 3-D and with contrast as needed as a 8, which means it’s an “appropriate test,” whereas they gave CT for the same indication a 3, which means “rarely appropriate.” For sustained ventricular tachycardia or ventricular fibrillation, they gave a 9 and a 6, respectively; this latter score indicates the test “may be appropriate.” These scenarios and the respective scores for any given test are organized into tables, such as initial evaluation or follow-up.

This AUC document “signals a shift from documents evaluating a single modality in various disease states to documents evaluating multiple imaging modalities and focusing on evidence and clinical experience within a given disease category,” the authors wrote. “We believe this approach better reflects clinical decision making in real-world scenarios and offers the diagnostic choices available to the clinician.”

The full document can be viewed in JACC.
 

[email protected]