Clinical Review

Epidemiologic data suggest that patients with chronic hepatitis C virus (HCV) infection have an increased risk for insulin resistance—and for overt diabetes.^1,2 Specifically, Serfaty and Capteau have reported evidence for “a triangular interaction” between steatosis, inflammatory processes, and insulin resistance.¹

Averting these metabolic risks is essential for several reasons: Most importantly, their development is associated with increased liver inflammation and progression to fibrosis and cirrhosis, as well as impaired response to antiviral medications.^3,4 Additionally, type 2 diabetes in patients with chronic HCV has been associated with a 1.7-fold increased risk for hepatocellular carcinoma (HCC) and other malignancies.^5,6

Though never directly linked with the metabolic syndrome, HCV has been associated with impaired insulin signaling and insulin resistance, in addition to hypocholesterolemia and steatosis. Lonardo et al went so far as to mark this constellation of effects as “a distinct HCV-associated dysmetabolic syndrome.” ⁴

The dysmetabolic syndrome places affected patients at increased risk for cardiovascular disease, according to Rzouq et al. Statins, they report, are safe and effective in patients with chronic HCV and appear to confer anti-HCV proliferative benefits, making them a potentially “life-saving therapy.”⁷

Because insulin resistance in the hepatic and peripheral tissues is at the very least “an obvious and significantly detrimental pathophysiologic feature of HCV infection,” Kawaguchi and Mazuta suggest that patients with chronic HCV be encouraged to follow the same dietary and lifestyle recommendations made to those with diabetes, obesity, and metabolic syndrome.² Maintaining a healthy body weight and following a reasonable regimen of diet and exercise help protect the liver in HCV-infected patients, whereas overweight and obesity, high cholesterol levels, and fatty liver are associated with accelerated liver damage.³

Continue for another component of diabetes risk reduction >>

Another component of diabetes risk reduction in patients with HCV is controlling hypertension.⁸ Of note, treatment with angiotensin-blocking agents has been associated with reduced liver fibrosis in HCV patients, compared with those receiving no antihypertensives or diuretics, vasodilators, or calcium channel antagonists.^8,9

Patients with HCV who do develop diabetes are advised against using insulin or a sulfonylurea (ie, glipizide, glimepiride, glyburide).² Metformin is considered a safer option, and its use has been linked to a reduced risk for HCC.^2,10 Diabetic patients with HCV can also reduce their risk for HCC by maintaining an A1C level below 7.0%, according to Arase et al.⁵

REFERENCES

1. Serfaty L, Capteau J. Hepatitis C, insulin resistance and diabetes: clinical and pathogenic data. Liver Int. 2009;29(suppl 2):13-25.

2. Kawaguchi Y, Mazuta T. Interaction between hepatitis C virus and metabolic factors. World J Gasterentol. 2014;20(11):2888-2901.

3. US Department of Veterans Affairs. Viral hepatitis: diet and nutrition. http://www.hepatitis.va.gov/patient/daily/diet/single-page.asp. Accessed May 26, 2015.

4. Lonardo A, Loria P, Carulli N. Dysmetabolic changes associated with HCV: a distinct syndrome? Intern Emerg Med. 2008;3(2):99-108.

5. Arase Y, Kobayashi M, Suzuki F, et al. Effect of type 2 diabetes on risk for malignancies includes hepatocellular carcinoma in chronic hepatitis C. Hepatology. 2013;57(3):964-973.

6. Takahashi H, Mizuta T, Eguchi Y, et al. Post-challenge hyperglycemia is a significant risk factor for the development of hepatocellular carcinoma in patients with chronic hepatitis C. J Gastroenterol. 2011;46(6):790-798.

7. Rzouq F, Alahdab F, Olyaee M. Statins and hepatitis C virus infection: an old therapy with new scope. Am J Med Sci. 2014;348(5):426-430.

8. Arase Y, Suzuki F, Suzuki Y, et al. Losartan reduces the onset of type 2 diabetes in hypertensive Japanese patients with chronic hepatitis C. J Med Virol. 2009;81(9):1584-1590.

9. Corey KE, Shah N, Misdraji J, et al. The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C. Liver Int. 2009; 29(5):748-753.

10. Harris K, Smith L. Safety and efficacy of metformin in patients with type 2 diabetes mellitus and chronic hepatitis C. Ann Pharmacother. 2013;47(10):1348-1352.

Epidemiologic data suggest that patients with chronic hepatitis C virus (HCV) infection have an increased risk for insulin resistance—and for overt diabetes.^1,2 Specifically, Serfaty and Capteau have reported evidence for “a triangular interaction” between steatosis, inflammatory processes, and insulin resistance.¹

Averting these metabolic risks is essential for several reasons: Most importantly, their development is associated with increased liver inflammation and progression to fibrosis and cirrhosis, as well as impaired response to antiviral medications.^3,4 Additionally, type 2 diabetes in patients with chronic HCV has been associated with a 1.7-fold increased risk for hepatocellular carcinoma (HCC) and other malignancies.^5,6

Though never directly linked with the metabolic syndrome, HCV has been associated with impaired insulin signaling and insulin resistance, in addition to hypocholesterolemia and steatosis. Lonardo et al went so far as to mark this constellation of effects as “a distinct HCV-associated dysmetabolic syndrome.” ⁴

The dysmetabolic syndrome places affected patients at increased risk for cardiovascular disease, according to Rzouq et al. Statins, they report, are safe and effective in patients with chronic HCV and appear to confer anti-HCV proliferative benefits, making them a potentially “life-saving therapy.”⁷

Because insulin resistance in the hepatic and peripheral tissues is at the very least “an obvious and significantly detrimental pathophysiologic feature of HCV infection,” Kawaguchi and Mazuta suggest that patients with chronic HCV be encouraged to follow the same dietary and lifestyle recommendations made to those with diabetes, obesity, and metabolic syndrome.² Maintaining a healthy body weight and following a reasonable regimen of diet and exercise help protect the liver in HCV-infected patients, whereas overweight and obesity, high cholesterol levels, and fatty liver are associated with accelerated liver damage.³

Continue for another component of diabetes risk reduction >>

Another component of diabetes risk reduction in patients with HCV is controlling hypertension.⁸ Of note, treatment with angiotensin-blocking agents has been associated with reduced liver fibrosis in HCV patients, compared with those receiving no antihypertensives or diuretics, vasodilators, or calcium channel antagonists.^8,9

Patients with HCV who do develop diabetes are advised against using insulin or a sulfonylurea (ie, glipizide, glimepiride, glyburide).² Metformin is considered a safer option, and its use has been linked to a reduced risk for HCC.^2,10 Diabetic patients with HCV can also reduce their risk for HCC by maintaining an A1C level below 7.0%, according to Arase et al.⁵

REFERENCES

1. Serfaty L, Capteau J. Hepatitis C, insulin resistance and diabetes: clinical and pathogenic data. Liver Int. 2009;29(suppl 2):13-25.

2. Kawaguchi Y, Mazuta T. Interaction between hepatitis C virus and metabolic factors. World J Gasterentol. 2014;20(11):2888-2901.

3. US Department of Veterans Affairs. Viral hepatitis: diet and nutrition. http://www.hepatitis.va.gov/patient/daily/diet/single-page.asp. Accessed May 26, 2015.

4. Lonardo A, Loria P, Carulli N. Dysmetabolic changes associated with HCV: a distinct syndrome? Intern Emerg Med. 2008;3(2):99-108.

5. Arase Y, Kobayashi M, Suzuki F, et al. Effect of type 2 diabetes on risk for malignancies includes hepatocellular carcinoma in chronic hepatitis C. Hepatology. 2013;57(3):964-973.

6. Takahashi H, Mizuta T, Eguchi Y, et al. Post-challenge hyperglycemia is a significant risk factor for the development of hepatocellular carcinoma in patients with chronic hepatitis C. J Gastroenterol. 2011;46(6):790-798.

7. Rzouq F, Alahdab F, Olyaee M. Statins and hepatitis C virus infection: an old therapy with new scope. Am J Med Sci. 2014;348(5):426-430.

8. Arase Y, Suzuki F, Suzuki Y, et al. Losartan reduces the onset of type 2 diabetes in hypertensive Japanese patients with chronic hepatitis C. J Med Virol. 2009;81(9):1584-1590.

9. Corey KE, Shah N, Misdraji J, et al. The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C. Liver Int. 2009; 29(5):748-753.

10. Harris K, Smith L. Safety and efficacy of metformin in patients with type 2 diabetes mellitus and chronic hepatitis C. Ann Pharmacother. 2013;47(10):1348-1352.

Epidemiologic data suggest that patients with chronic hepatitis C virus (HCV) infection have an increased risk for insulin resistance—and for overt diabetes.^1,2 Specifically, Serfaty and Capteau have reported evidence for “a triangular interaction” between steatosis, inflammatory processes, and insulin resistance.¹

Averting these metabolic risks is essential for several reasons: Most importantly, their development is associated with increased liver inflammation and progression to fibrosis and cirrhosis, as well as impaired response to antiviral medications.^3,4 Additionally, type 2 diabetes in patients with chronic HCV has been associated with a 1.7-fold increased risk for hepatocellular carcinoma (HCC) and other malignancies.^5,6

Though never directly linked with the metabolic syndrome, HCV has been associated with impaired insulin signaling and insulin resistance, in addition to hypocholesterolemia and steatosis. Lonardo et al went so far as to mark this constellation of effects as “a distinct HCV-associated dysmetabolic syndrome.” ⁴

The dysmetabolic syndrome places affected patients at increased risk for cardiovascular disease, according to Rzouq et al. Statins, they report, are safe and effective in patients with chronic HCV and appear to confer anti-HCV proliferative benefits, making them a potentially “life-saving therapy.”⁷

Because insulin resistance in the hepatic and peripheral tissues is at the very least “an obvious and significantly detrimental pathophysiologic feature of HCV infection,” Kawaguchi and Mazuta suggest that patients with chronic HCV be encouraged to follow the same dietary and lifestyle recommendations made to those with diabetes, obesity, and metabolic syndrome.² Maintaining a healthy body weight and following a reasonable regimen of diet and exercise help protect the liver in HCV-infected patients, whereas overweight and obesity, high cholesterol levels, and fatty liver are associated with accelerated liver damage.³

Continue for another component of diabetes risk reduction >>

Another component of diabetes risk reduction in patients with HCV is controlling hypertension.⁸ Of note, treatment with angiotensin-blocking agents has been associated with reduced liver fibrosis in HCV patients, compared with those receiving no antihypertensives or diuretics, vasodilators, or calcium channel antagonists.^8,9

Patients with HCV who do develop diabetes are advised against using insulin or a sulfonylurea (ie, glipizide, glimepiride, glyburide).² Metformin is considered a safer option, and its use has been linked to a reduced risk for HCC.^2,10 Diabetic patients with HCV can also reduce their risk for HCC by maintaining an A1C level below 7.0%, according to Arase et al.⁵

REFERENCES

1. Serfaty L, Capteau J. Hepatitis C, insulin resistance and diabetes: clinical and pathogenic data. Liver Int. 2009;29(suppl 2):13-25.

2. Kawaguchi Y, Mazuta T. Interaction between hepatitis C virus and metabolic factors. World J Gasterentol. 2014;20(11):2888-2901.

3. US Department of Veterans Affairs. Viral hepatitis: diet and nutrition. http://www.hepatitis.va.gov/patient/daily/diet/single-page.asp. Accessed May 26, 2015.

4. Lonardo A, Loria P, Carulli N. Dysmetabolic changes associated with HCV: a distinct syndrome? Intern Emerg Med. 2008;3(2):99-108.

5. Arase Y, Kobayashi M, Suzuki F, et al. Effect of type 2 diabetes on risk for malignancies includes hepatocellular carcinoma in chronic hepatitis C. Hepatology. 2013;57(3):964-973.

6. Takahashi H, Mizuta T, Eguchi Y, et al. Post-challenge hyperglycemia is a significant risk factor for the development of hepatocellular carcinoma in patients with chronic hepatitis C. J Gastroenterol. 2011;46(6):790-798.

7. Rzouq F, Alahdab F, Olyaee M. Statins and hepatitis C virus infection: an old therapy with new scope. Am J Med Sci. 2014;348(5):426-430.

8. Arase Y, Suzuki F, Suzuki Y, et al. Losartan reduces the onset of type 2 diabetes in hypertensive Japanese patients with chronic hepatitis C. J Med Virol. 2009;81(9):1584-1590.

9. Corey KE, Shah N, Misdraji J, et al. The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C. Liver Int. 2009; 29(5):748-753.

10. Harris K, Smith L. Safety and efficacy of metformin in patients with type 2 diabetes mellitus and chronic hepatitis C. Ann Pharmacother. 2013;47(10):1348-1352.

Anatomic variations may result in abnormal return from the pulmonary veins to the right side of the heart. This group of congenital anomalies, also known as partial anomalous pulmonary venous return (PAPVR), may connect oxygenated blood from the pulmonary vein to a systemic vein before reaching the right atrium. The most common PAPVR is derived from the left upper pulmonary vein, which then connects to the left innominate vein and drains into the superior vena cava (SVC).

Scimitar syndrome is a rare PAPVR variant in which part of or the entire right lung is drained by the pulmonary vein into the inferior vena cava (IVC), giving the curvilinear dimension the appearance of a Middle Eastern sword (scimitar). The syndrome is frequently associated with other abnormalities, such as right lung hypoplasia and abnormal right lung lobation, dextroposition of the heart, right pulmonary artery hypoplasia, systemic arterial blood supply to the right lower lung from the infradiaphragmatic aorta, atrial septal defects of the secundum type, right-sided diaphragmatic hernia, and horseshoe lung.^1,2 The syndrome was first described in 1836 by Cooper during an autopsy of an infant, and Dotter diagnosed the first symptomatic patient in 1949.^3,4

Case Report

A 62-year-old man, former smoker (40 pack-year), with a past medical history of arterial hypertension and asthma visited the clinic, reporting exertional dyspnea. He also reported oppressive, retrosternally located exertional chest pain, 6/10 in intensity, of 3 minutes’ duration that radiated to the right chest and ameliorated with rest. Symptoms had occurred every other day for the past year. His physical exam was remarkable for central obesity. Lung auscultation was essentially clear. There was no jugular vein distention. The patient’s heart showed a regular rate and rhythm without evidence of murmurs or gallops. There was no evidence of leg edema or cyanosis. The patient’s resting oxygen saturation of 98% remained unchanged after exercise.

Related: Venous Thromboembolism Prophylaxis in Acutely Ill Veterans With Respiratory Disease

An electrocardiogram showed normal sinus rhythm with no ischemic changes. A pulmonary function test showed a forced expiratory volume (FEV₁) of 1.44 L (61% of predicted), forced vital capacity (FVC) of 1.99 L (68% of predicted), and slow vital capacity (SVC) of 2.09 L (60% of predicted), with an FEV₁/SVC ratio of 68% of predicted. These results suggested moderate-to-severe obstructive ventilatory impairment.

There was no response to bronchodilator therapy. Lung volumes were measured by plethysmography. The residual volume (RV), total lung capacity (TLC), and RV/TLC ratio were 2.57 L (147% of predicted), 4.66 L (88% of predicted), and 55%, respectively, suggesting severe air trapping. Diffusion lung capacity (DLCO) testing revealed 16.95 mL/min/mm Hg (73% of predicted) when corrected by hemoglobin and DLCO/alveolar volume of 4.97 mL/min/mm Hg/L (114% of predicted). This result was consistent with a mild reduction of gas transfer, which normalized when corrected by alveolar volume.

A posteroanterior chest radiograph image was remarkable for mediastinal shifting toward the right side, volume loss of the right lung, and evidence of a previous gunshot on the right chest wall (Figure 1). Previous chest imaging done in October 2009 showed an opacification of the right lower lung with indistinctness of the right cardiac border and partial obliteration of the right hemidiaphragm. The patient was treated with inhaled steroids and long- acting bronchodilators with partial improvement in dyspnea symptoms.

Myocardial perfusion imaging revealed scintigraphic evidence of heart rate-induced ischemia on the inferior and apical wall segments of the left ventricular myocardium. A transthoracic echocardiogram showed a very poor echocardiographic window. Left ventricular function seemed preserved. Transesophageal echocardiography was scheduled, but the patient missed the appointment.

Cardiac catheterization was only remarkable for 40% to 50% obstruction of the mid-left anterior descending artery, which did not explain the patient’s dyspnea or chest pain. Right side pressures were described as follows: right atrial mean, 10 mm Hg; right ventricle, 36/8 mm Hg; pulmonary artery, 33/16 mm Hg; pulmonary artery mean, 23 mm Hg; pulmonary capillary wedge pressure, 12 mm Hg; and a mean arterial pressure of 100 mm Hg. He had a left ventricle ejection fraction of 60%. 

Because images suggested dextroposition of the heart and right lung hypoplasia, a chest computed tomography (CT) and angiography were done (Figure 2). The images showed hypoplasia of the right lung field with an anomalous venous return from the right midlung, having a vertical contour that drained into the supradiaphragmatic IVC. In addition, CT reconstruction demarcated the last mentioned contour draining into the IVC, consistent with scimitar syndrome (Figure 3). The patient was treated conservatively due to age, optimizing therapy for obstructive lung and cardiovascular disease.

Discussion

Partial anomalous pulmonary venous return is a relatively uncommon congenital anomaly, accounting for 0.5% to 1% of congenital heart disease.^4,5 The characteristic abnormality is PAPVR of part of or the entire right lung to the IVC, either below the diaphragm or at the junction of the IVC and the right atrium. The rare combination (3%-5%) of an association of PAPVR, right lung hypoplasia, and dextroposition of the heart is designated scimitar syndrome. The scimitar vein sign is a characteristic chest roentgenographic finding of a crescentlike shadow in the right lower lung field where the curvilinear dimension gives the appearance of a scimitar sword.

Related: Another Reason Not to Smoke: Acute Eosinophilic Pneunomia

Normally, the pulmonary veins from the right and left lung carry oxygenated blood into the left atrium, then to the left ventricle, and then flowing out systemically. The SCV and IVC return the deoxygenated blood from the body system to the right atrium. From the right atrium, blood flows into the right ventricle, and then through pulmonary arteries, reaching the lungs where oxygenation occurs. In this syndrome, a left-to-right shunt is established when the anomalous pulmonary vein drains blood from the right lung into the IVC, resulting in an increased risk of developing right ventricular failure due to long-standing right ventricular volume overload.

Presentation and Diagnosis

There are two clinical presentations of scimitar syndrome: infantile and pediatric/adult. Infantile scimitar syndrome has a clinical presentation of tachypnea and heart failure within the first 2 months of life, with a high mortality rate. The pediatric/adult type is milder and frequently asymptomatic, and the diagnosis is usually incidental after performing an imaging study. Scimitar vein sign appears in 70% of the noninfantile cases, and lung hypoplasia is less severe. A spirometry may reveal mild deficits in vital capacity and FEV₁. An electrocardiogram may show right ventricular hypertrophy.

Cardiac catheterization is required to confirm the diagnosis. Additionally, this procedure can help in the assessment of the pulmonary venous drainage course, pulmonary artery anatomy and pressure, scimitar vein stenosis, and presence of left-to-right shunt or other cardiac anomalies, if present. Other modalities have been suggested as alternative methods for diagnosing this condition, including the use of coronary CT and 3D echocardiography.^6,7 However, these diagnostic tests are not available in all facilities and are very costly.

Treatment and Prognosis

Vida and colleagues conducted a multicentric study for the European Congenital Heart Surgeons Association on scimitar syndrome.⁸ Data were collected from 1997 to 2007 for 68 patients who underwent a surgical procedure. A total of 11 patients were categorized as late onset, and when compared with the infantile category, they had fewer postoperatory complications, hospital mortality, late mortality, and were less likely to develop pulmonary hypertension. Both pulmonary stenosis and pulmonary hypertension were linked with poor outcomes. It seems the younger the patient (infantile), the higher the possibility of complications and mortality. Adults who are incidentally diagnosed have a better outcome if asymptomatic. Findings such as hypoplastic lungs may predispose these patients to developing recurrent pneumonias.^8,9

Related: Prevention of Venous Thromboembolism After Total Joint Replacement: A Rivaroxaban Update

Dusenbery and colleagues documented in a cohort study the relationship between poor survival and other variables. Significant variables included age at presentation, nonatrial septal defect (non-ASD) congenital heart disease, left pulmonary vein stenosis, and pulmonary artery pressure (PAP) at the time of presentation. Predictors of survival for nonsurgical patients were directly related to PAP at presentation and absence of non-ASD congenital heart disease. If the patient’s PAP is less than half of the systemic pressure, the survival is near 100% at 5 years from initial presentation.⁹

Surgery is the definitive treatment for PAPVR. However, asymptomatic patients with PAPVR with small left-to-right shunt do not require intervention, as the defect has no significant clinical impact, and patients have a normal life expectancy without correction.¹⁰

Surgical treatment may be considered in the following circumstances:

Surgical options include redirecting the venous drainage to the left atria, ligation/embolization of vascular supply to the sequestered lobe, and pneumonectomy. The procedure complications may include thrombosis of the scimitar vein, lung infarct, hemoptysis, and pulmonary hypertension, which may lead to resection of the lung.^11,12 Surgical procedures are recommended in cases where the patient has had recurrent lung infections or a significant degree of shunting. Studies have compared both approaches, demonstrating a better outcome after 10 years for those patients who were medically treated considering the aforementioned surgical indications.

Conclusion

Scimitar syndrome is a rare but welldescribed constellation of cardiopulmonary anomalies, accounting for 0.5% to 1% of congenital heart disease. It is a variant of PAPVR, in which part of or even the entire right lung is drained by right pulmonary veins that connect anomalously to the IVC. Although a diagnosis can be made by chest radiograph, further imaging is needed to corroborate the diagnosis and demonstrate other associated abnormalities.

Additional tests have been described in the literature, but these procedures are not available in all facilities and may incur a higher cost. Therefore, CT angiographic reconstruction is an alternative, noninvasive procedure. Surgery is the definitive treatment; however, asymptomatic patients with PAPVR and small left-to-right shunt do not require intervention.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Anatomic variations may result in abnormal return from the pulmonary veins to the right side of the heart. This group of congenital anomalies, also known as partial anomalous pulmonary venous return (PAPVR), may connect oxygenated blood from the pulmonary vein to a systemic vein before reaching the right atrium. The most common PAPVR is derived from the left upper pulmonary vein, which then connects to the left innominate vein and drains into the superior vena cava (SVC).

Scimitar syndrome is a rare PAPVR variant in which part of or the entire right lung is drained by the pulmonary vein into the inferior vena cava (IVC), giving the curvilinear dimension the appearance of a Middle Eastern sword (scimitar). The syndrome is frequently associated with other abnormalities, such as right lung hypoplasia and abnormal right lung lobation, dextroposition of the heart, right pulmonary artery hypoplasia, systemic arterial blood supply to the right lower lung from the infradiaphragmatic aorta, atrial septal defects of the secundum type, right-sided diaphragmatic hernia, and horseshoe lung.^1,2 The syndrome was first described in 1836 by Cooper during an autopsy of an infant, and Dotter diagnosed the first symptomatic patient in 1949.^3,4

Case Report

A 62-year-old man, former smoker (40 pack-year), with a past medical history of arterial hypertension and asthma visited the clinic, reporting exertional dyspnea. He also reported oppressive, retrosternally located exertional chest pain, 6/10 in intensity, of 3 minutes’ duration that radiated to the right chest and ameliorated with rest. Symptoms had occurred every other day for the past year. His physical exam was remarkable for central obesity. Lung auscultation was essentially clear. There was no jugular vein distention. The patient’s heart showed a regular rate and rhythm without evidence of murmurs or gallops. There was no evidence of leg edema or cyanosis. The patient’s resting oxygen saturation of 98% remained unchanged after exercise.

Related: Venous Thromboembolism Prophylaxis in Acutely Ill Veterans With Respiratory Disease

An electrocardiogram showed normal sinus rhythm with no ischemic changes. A pulmonary function test showed a forced expiratory volume (FEV₁) of 1.44 L (61% of predicted), forced vital capacity (FVC) of 1.99 L (68% of predicted), and slow vital capacity (SVC) of 2.09 L (60% of predicted), with an FEV₁/SVC ratio of 68% of predicted. These results suggested moderate-to-severe obstructive ventilatory impairment.

There was no response to bronchodilator therapy. Lung volumes were measured by plethysmography. The residual volume (RV), total lung capacity (TLC), and RV/TLC ratio were 2.57 L (147% of predicted), 4.66 L (88% of predicted), and 55%, respectively, suggesting severe air trapping. Diffusion lung capacity (DLCO) testing revealed 16.95 mL/min/mm Hg (73% of predicted) when corrected by hemoglobin and DLCO/alveolar volume of 4.97 mL/min/mm Hg/L (114% of predicted). This result was consistent with a mild reduction of gas transfer, which normalized when corrected by alveolar volume.

A posteroanterior chest radiograph image was remarkable for mediastinal shifting toward the right side, volume loss of the right lung, and evidence of a previous gunshot on the right chest wall (Figure 1). Previous chest imaging done in October 2009 showed an opacification of the right lower lung with indistinctness of the right cardiac border and partial obliteration of the right hemidiaphragm. The patient was treated with inhaled steroids and long- acting bronchodilators with partial improvement in dyspnea symptoms.

Myocardial perfusion imaging revealed scintigraphic evidence of heart rate-induced ischemia on the inferior and apical wall segments of the left ventricular myocardium. A transthoracic echocardiogram showed a very poor echocardiographic window. Left ventricular function seemed preserved. Transesophageal echocardiography was scheduled, but the patient missed the appointment.

Cardiac catheterization was only remarkable for 40% to 50% obstruction of the mid-left anterior descending artery, which did not explain the patient’s dyspnea or chest pain. Right side pressures were described as follows: right atrial mean, 10 mm Hg; right ventricle, 36/8 mm Hg; pulmonary artery, 33/16 mm Hg; pulmonary artery mean, 23 mm Hg; pulmonary capillary wedge pressure, 12 mm Hg; and a mean arterial pressure of 100 mm Hg. He had a left ventricle ejection fraction of 60%. 

Because images suggested dextroposition of the heart and right lung hypoplasia, a chest computed tomography (CT) and angiography were done (Figure 2). The images showed hypoplasia of the right lung field with an anomalous venous return from the right midlung, having a vertical contour that drained into the supradiaphragmatic IVC. In addition, CT reconstruction demarcated the last mentioned contour draining into the IVC, consistent with scimitar syndrome (Figure 3). The patient was treated conservatively due to age, optimizing therapy for obstructive lung and cardiovascular disease.

Discussion

Partial anomalous pulmonary venous return is a relatively uncommon congenital anomaly, accounting for 0.5% to 1% of congenital heart disease.^4,5 The characteristic abnormality is PAPVR of part of or the entire right lung to the IVC, either below the diaphragm or at the junction of the IVC and the right atrium. The rare combination (3%-5%) of an association of PAPVR, right lung hypoplasia, and dextroposition of the heart is designated scimitar syndrome. The scimitar vein sign is a characteristic chest roentgenographic finding of a crescentlike shadow in the right lower lung field where the curvilinear dimension gives the appearance of a scimitar sword.

Related: Another Reason Not to Smoke: Acute Eosinophilic Pneunomia

Normally, the pulmonary veins from the right and left lung carry oxygenated blood into the left atrium, then to the left ventricle, and then flowing out systemically. The SCV and IVC return the deoxygenated blood from the body system to the right atrium. From the right atrium, blood flows into the right ventricle, and then through pulmonary arteries, reaching the lungs where oxygenation occurs. In this syndrome, a left-to-right shunt is established when the anomalous pulmonary vein drains blood from the right lung into the IVC, resulting in an increased risk of developing right ventricular failure due to long-standing right ventricular volume overload.

Presentation and Diagnosis

There are two clinical presentations of scimitar syndrome: infantile and pediatric/adult. Infantile scimitar syndrome has a clinical presentation of tachypnea and heart failure within the first 2 months of life, with a high mortality rate. The pediatric/adult type is milder and frequently asymptomatic, and the diagnosis is usually incidental after performing an imaging study. Scimitar vein sign appears in 70% of the noninfantile cases, and lung hypoplasia is less severe. A spirometry may reveal mild deficits in vital capacity and FEV₁. An electrocardiogram may show right ventricular hypertrophy.

Cardiac catheterization is required to confirm the diagnosis. Additionally, this procedure can help in the assessment of the pulmonary venous drainage course, pulmonary artery anatomy and pressure, scimitar vein stenosis, and presence of left-to-right shunt or other cardiac anomalies, if present. Other modalities have been suggested as alternative methods for diagnosing this condition, including the use of coronary CT and 3D echocardiography.^6,7 However, these diagnostic tests are not available in all facilities and are very costly.

Treatment and Prognosis

Vida and colleagues conducted a multicentric study for the European Congenital Heart Surgeons Association on scimitar syndrome.⁸ Data were collected from 1997 to 2007 for 68 patients who underwent a surgical procedure. A total of 11 patients were categorized as late onset, and when compared with the infantile category, they had fewer postoperatory complications, hospital mortality, late mortality, and were less likely to develop pulmonary hypertension. Both pulmonary stenosis and pulmonary hypertension were linked with poor outcomes. It seems the younger the patient (infantile), the higher the possibility of complications and mortality. Adults who are incidentally diagnosed have a better outcome if asymptomatic. Findings such as hypoplastic lungs may predispose these patients to developing recurrent pneumonias.^8,9

Related: Prevention of Venous Thromboembolism After Total Joint Replacement: A Rivaroxaban Update

Dusenbery and colleagues documented in a cohort study the relationship between poor survival and other variables. Significant variables included age at presentation, nonatrial septal defect (non-ASD) congenital heart disease, left pulmonary vein stenosis, and pulmonary artery pressure (PAP) at the time of presentation. Predictors of survival for nonsurgical patients were directly related to PAP at presentation and absence of non-ASD congenital heart disease. If the patient’s PAP is less than half of the systemic pressure, the survival is near 100% at 5 years from initial presentation.⁹

Surgery is the definitive treatment for PAPVR. However, asymptomatic patients with PAPVR with small left-to-right shunt do not require intervention, as the defect has no significant clinical impact, and patients have a normal life expectancy without correction.¹⁰

Surgical treatment may be considered in the following circumstances:

Surgical options include redirecting the venous drainage to the left atria, ligation/embolization of vascular supply to the sequestered lobe, and pneumonectomy. The procedure complications may include thrombosis of the scimitar vein, lung infarct, hemoptysis, and pulmonary hypertension, which may lead to resection of the lung.^11,12 Surgical procedures are recommended in cases where the patient has had recurrent lung infections or a significant degree of shunting. Studies have compared both approaches, demonstrating a better outcome after 10 years for those patients who were medically treated considering the aforementioned surgical indications.

Conclusion

Scimitar syndrome is a rare but welldescribed constellation of cardiopulmonary anomalies, accounting for 0.5% to 1% of congenital heart disease. It is a variant of PAPVR, in which part of or even the entire right lung is drained by right pulmonary veins that connect anomalously to the IVC. Although a diagnosis can be made by chest radiograph, further imaging is needed to corroborate the diagnosis and demonstrate other associated abnormalities.

Additional tests have been described in the literature, but these procedures are not available in all facilities and may incur a higher cost. Therefore, CT angiographic reconstruction is an alternative, noninvasive procedure. Surgery is the definitive treatment; however, asymptomatic patients with PAPVR and small left-to-right shunt do not require intervention.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Anatomic variations may result in abnormal return from the pulmonary veins to the right side of the heart. This group of congenital anomalies, also known as partial anomalous pulmonary venous return (PAPVR), may connect oxygenated blood from the pulmonary vein to a systemic vein before reaching the right atrium. The most common PAPVR is derived from the left upper pulmonary vein, which then connects to the left innominate vein and drains into the superior vena cava (SVC).

Scimitar syndrome is a rare PAPVR variant in which part of or the entire right lung is drained by the pulmonary vein into the inferior vena cava (IVC), giving the curvilinear dimension the appearance of a Middle Eastern sword (scimitar). The syndrome is frequently associated with other abnormalities, such as right lung hypoplasia and abnormal right lung lobation, dextroposition of the heart, right pulmonary artery hypoplasia, systemic arterial blood supply to the right lower lung from the infradiaphragmatic aorta, atrial septal defects of the secundum type, right-sided diaphragmatic hernia, and horseshoe lung.^1,2 The syndrome was first described in 1836 by Cooper during an autopsy of an infant, and Dotter diagnosed the first symptomatic patient in 1949.^3,4

Case Report

A 62-year-old man, former smoker (40 pack-year), with a past medical history of arterial hypertension and asthma visited the clinic, reporting exertional dyspnea. He also reported oppressive, retrosternally located exertional chest pain, 6/10 in intensity, of 3 minutes’ duration that radiated to the right chest and ameliorated with rest. Symptoms had occurred every other day for the past year. His physical exam was remarkable for central obesity. Lung auscultation was essentially clear. There was no jugular vein distention. The patient’s heart showed a regular rate and rhythm without evidence of murmurs or gallops. There was no evidence of leg edema or cyanosis. The patient’s resting oxygen saturation of 98% remained unchanged after exercise.

Related: Venous Thromboembolism Prophylaxis in Acutely Ill Veterans With Respiratory Disease

An electrocardiogram showed normal sinus rhythm with no ischemic changes. A pulmonary function test showed a forced expiratory volume (FEV₁) of 1.44 L (61% of predicted), forced vital capacity (FVC) of 1.99 L (68% of predicted), and slow vital capacity (SVC) of 2.09 L (60% of predicted), with an FEV₁/SVC ratio of 68% of predicted. These results suggested moderate-to-severe obstructive ventilatory impairment.

There was no response to bronchodilator therapy. Lung volumes were measured by plethysmography. The residual volume (RV), total lung capacity (TLC), and RV/TLC ratio were 2.57 L (147% of predicted), 4.66 L (88% of predicted), and 55%, respectively, suggesting severe air trapping. Diffusion lung capacity (DLCO) testing revealed 16.95 mL/min/mm Hg (73% of predicted) when corrected by hemoglobin and DLCO/alveolar volume of 4.97 mL/min/mm Hg/L (114% of predicted). This result was consistent with a mild reduction of gas transfer, which normalized when corrected by alveolar volume.

A posteroanterior chest radiograph image was remarkable for mediastinal shifting toward the right side, volume loss of the right lung, and evidence of a previous gunshot on the right chest wall (Figure 1). Previous chest imaging done in October 2009 showed an opacification of the right lower lung with indistinctness of the right cardiac border and partial obliteration of the right hemidiaphragm. The patient was treated with inhaled steroids and long- acting bronchodilators with partial improvement in dyspnea symptoms.

Myocardial perfusion imaging revealed scintigraphic evidence of heart rate-induced ischemia on the inferior and apical wall segments of the left ventricular myocardium. A transthoracic echocardiogram showed a very poor echocardiographic window. Left ventricular function seemed preserved. Transesophageal echocardiography was scheduled, but the patient missed the appointment.

Cardiac catheterization was only remarkable for 40% to 50% obstruction of the mid-left anterior descending artery, which did not explain the patient’s dyspnea or chest pain. Right side pressures were described as follows: right atrial mean, 10 mm Hg; right ventricle, 36/8 mm Hg; pulmonary artery, 33/16 mm Hg; pulmonary artery mean, 23 mm Hg; pulmonary capillary wedge pressure, 12 mm Hg; and a mean arterial pressure of 100 mm Hg. He had a left ventricle ejection fraction of 60%. 

Because images suggested dextroposition of the heart and right lung hypoplasia, a chest computed tomography (CT) and angiography were done (Figure 2). The images showed hypoplasia of the right lung field with an anomalous venous return from the right midlung, having a vertical contour that drained into the supradiaphragmatic IVC. In addition, CT reconstruction demarcated the last mentioned contour draining into the IVC, consistent with scimitar syndrome (Figure 3). The patient was treated conservatively due to age, optimizing therapy for obstructive lung and cardiovascular disease.

Discussion

Partial anomalous pulmonary venous return is a relatively uncommon congenital anomaly, accounting for 0.5% to 1% of congenital heart disease.^4,5 The characteristic abnormality is PAPVR of part of or the entire right lung to the IVC, either below the diaphragm or at the junction of the IVC and the right atrium. The rare combination (3%-5%) of an association of PAPVR, right lung hypoplasia, and dextroposition of the heart is designated scimitar syndrome. The scimitar vein sign is a characteristic chest roentgenographic finding of a crescentlike shadow in the right lower lung field where the curvilinear dimension gives the appearance of a scimitar sword.

Related: Another Reason Not to Smoke: Acute Eosinophilic Pneunomia

Normally, the pulmonary veins from the right and left lung carry oxygenated blood into the left atrium, then to the left ventricle, and then flowing out systemically. The SCV and IVC return the deoxygenated blood from the body system to the right atrium. From the right atrium, blood flows into the right ventricle, and then through pulmonary arteries, reaching the lungs where oxygenation occurs. In this syndrome, a left-to-right shunt is established when the anomalous pulmonary vein drains blood from the right lung into the IVC, resulting in an increased risk of developing right ventricular failure due to long-standing right ventricular volume overload.

Presentation and Diagnosis

There are two clinical presentations of scimitar syndrome: infantile and pediatric/adult. Infantile scimitar syndrome has a clinical presentation of tachypnea and heart failure within the first 2 months of life, with a high mortality rate. The pediatric/adult type is milder and frequently asymptomatic, and the diagnosis is usually incidental after performing an imaging study. Scimitar vein sign appears in 70% of the noninfantile cases, and lung hypoplasia is less severe. A spirometry may reveal mild deficits in vital capacity and FEV₁. An electrocardiogram may show right ventricular hypertrophy.

Cardiac catheterization is required to confirm the diagnosis. Additionally, this procedure can help in the assessment of the pulmonary venous drainage course, pulmonary artery anatomy and pressure, scimitar vein stenosis, and presence of left-to-right shunt or other cardiac anomalies, if present. Other modalities have been suggested as alternative methods for diagnosing this condition, including the use of coronary CT and 3D echocardiography.^6,7 However, these diagnostic tests are not available in all facilities and are very costly.

Treatment and Prognosis

Vida and colleagues conducted a multicentric study for the European Congenital Heart Surgeons Association on scimitar syndrome.⁸ Data were collected from 1997 to 2007 for 68 patients who underwent a surgical procedure. A total of 11 patients were categorized as late onset, and when compared with the infantile category, they had fewer postoperatory complications, hospital mortality, late mortality, and were less likely to develop pulmonary hypertension. Both pulmonary stenosis and pulmonary hypertension were linked with poor outcomes. It seems the younger the patient (infantile), the higher the possibility of complications and mortality. Adults who are incidentally diagnosed have a better outcome if asymptomatic. Findings such as hypoplastic lungs may predispose these patients to developing recurrent pneumonias.^8,9

Related: Prevention of Venous Thromboembolism After Total Joint Replacement: A Rivaroxaban Update

Dusenbery and colleagues documented in a cohort study the relationship between poor survival and other variables. Significant variables included age at presentation, nonatrial septal defect (non-ASD) congenital heart disease, left pulmonary vein stenosis, and pulmonary artery pressure (PAP) at the time of presentation. Predictors of survival for nonsurgical patients were directly related to PAP at presentation and absence of non-ASD congenital heart disease. If the patient’s PAP is less than half of the systemic pressure, the survival is near 100% at 5 years from initial presentation.⁹

Surgery is the definitive treatment for PAPVR. However, asymptomatic patients with PAPVR with small left-to-right shunt do not require intervention, as the defect has no significant clinical impact, and patients have a normal life expectancy without correction.¹⁰

Surgical treatment may be considered in the following circumstances:

Surgical options include redirecting the venous drainage to the left atria, ligation/embolization of vascular supply to the sequestered lobe, and pneumonectomy. The procedure complications may include thrombosis of the scimitar vein, lung infarct, hemoptysis, and pulmonary hypertension, which may lead to resection of the lung.^11,12 Surgical procedures are recommended in cases where the patient has had recurrent lung infections or a significant degree of shunting. Studies have compared both approaches, demonstrating a better outcome after 10 years for those patients who were medically treated considering the aforementioned surgical indications.

Conclusion

Scimitar syndrome is a rare but welldescribed constellation of cardiopulmonary anomalies, accounting for 0.5% to 1% of congenital heart disease. It is a variant of PAPVR, in which part of or even the entire right lung is drained by right pulmonary veins that connect anomalously to the IVC. Although a diagnosis can be made by chest radiograph, further imaging is needed to corroborate the diagnosis and demonstrate other associated abnormalities.

Additional tests have been described in the literature, but these procedures are not available in all facilities and may incur a higher cost. Therefore, CT angiographic reconstruction is an alternative, noninvasive procedure. Surgery is the definitive treatment; however, asymptomatic patients with PAPVR and small left-to-right shunt do not require intervention.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

The objective of this article is to help primary care providers (PCPs) council patients regarding testosterone replacement therapy (TRT). This case will present a patient who initiated TRT at a community-based alternative medicine clinic. The case will be followed by a discussion regarding the standard diagnosis of hypogonadism, the potential benefits and risks of TRT, and a review of the current clinical guideline recommendations. Examples of information being disseminated to the general public by the complementary and alternative medicine (CAM) providers will be briefly reviewed for an increased awareness of the questions patients may pose regarding TRT.

Background

From 2000 to 2011, total testosterone sales increased 12-fold globally.¹ Possible causes for the increase involved the aging population, newer options for TRT administration, and increased direct-to-consumer advertising. A low testosterone level (sometimes referred to as low T in consumer marketing materials) is associated with a variety of medical conditions (ie, low mood, increased body fat, declining athletic performance, and decreased sexual performance) that have become increasingly prevalent among middle aged and older men.² It has also received attention as an intervention to reverse frailty and sarcopenia.³

Testosterone replacement therapy options include injectable solutions, transdermal gels and patches, pellet implants, or buccal tablets. The ease of administration of transdermal testosterone comes at a relatively high cost. Injectable testosterone preparations are generally the least expensive option, and many patients choose injections for this reason.

Related: Keeping an Open Mind on HRT

Testosterone prescriptions were most frequently written by PCPs with 36% coming from family practitioners and 20.1% from internal medicine practices, according to a Kaiser Permanente study.⁴ Endocrinologists (13.5%) and urologists (6.6%) were less likely to have written the prescriptions for patients.

Due, in part, to direct-to-consumer advertising and to the availability of online medical information, many men now present to their PCP questioning whether they might have low T. Others may have already started therapy at a CAM, integrative medicine, or anti-aging clinic.

Confusing the issue further, some CAM providers promote a variety of off-label medications and nutritional supplements for the treatment of low T, which seems to have struck a chord in the baby boomer generation. No other age group in history has tried to work so intensely on its physical condition and appearance.⁵ Much of the information marketed to consumers emphasizes that many traditionally trained physicians are not educated in the treatment of low T.

Case Report

Mr. C. is a 65-year-old man who was seen in the primary care clinic for the first time. He was accompanied by his much younger fiancée. She reported that Mr. C.’s energy and sexual interest were declining, and the patient reported his “get up and go had gotten up and left.” They sought medical advice from a CAM provider who ordered blood work and then explained that the symptoms were due to low testosterone. For the past 6 months he had been visiting the clinic weekly for testosterone injections.

Mr. C. reported feeling as good as a “40 year old.” He also reported that he started working with a personal trainer and had given up most junk food and alcohol. He had no symptoms of chest pain, erectile dysfunction, or significant urinary urgency, frequency, or nocturia.

Related: Will Testosterone Therapy Kill Your Patient?

The visits to a CAM provider had been an out-of-pocket expense, and he was hoping to transfer his treatment to the VA so the costs could be covered. Mr. C. failed to bring medical records from the other provider but remembered being told that all his tests were “fine” except for the low testosterone level.

His past history was notable for controlled type 2 diabetes mellitus for 8 years, hypertension, hyperlipidemia, and spinal stenosis. He had no history of benign prostatic hyperplasia or prostate cancer.

In addition to the testosterone (100 mg intramuscular injection weekly), his medication regimen included metoprolol 25 mg twice daily, atorvastatin 20 mg daily, acetaminophen 650 mg 3 times daily as needed, aspirin 81 mg daily, metformin 500 mg twice daily, vitamin D 2,000 IU daily, vitamin B12 1,000 mg daily, and Co-Q10 200 mg daily.

On physical examination, Mr. C.’s vitals were stable and his body mass index was in the overweight range at 29.8 kg/m². His cardiopulmonary examination was normal. There was increased central obesity without palpable organomegaly. There was no gynecomastia, and he had normal amounts of axillary and pubic hair. There was no peripheral edema; his genitourinary examination included normal-sized testicles, and the prostate was smooth without nodules.

The PCP informed Mr. C. that he was familiar with the evaluation and management of testosterone therapy. He was advised that additional evaluation would be needed before determining whether the clinical benefit of TRT outweighed the potential risks.

Andropause

Testosterone levels in men are known to decline at a rate of 1% per year after aged 30 years.⁶ About 20% of men aged ≥ 60 years and 50% of men aged ≥ 80 years have low (hypogonadal) total testosterone levels.⁷ The clinical diagnosis of hypogonadism, however, is made on the basis of signs and symptoms consistent with androgen deficiency and a low serum morning testosterone level measured on serum on multiple occasions.⁸

Specific clinical signs and symptoms (“A” list) consistent with androgen deficiency include low libido and sexual activity; diminished spontaneous erections; gynecomastia; reduced facial, axillary, or pubic hair; small (≤ 5 mL) testes; inability to father children; loss of height, fractures, or other signs of bone loss; and hot flashes and night sweats.⁹

Less specific signs and symptoms (“B” list) of androgen deficiency include a decrease in energy or motivation, feelings of sadness or depression, poor concentration or memory, trouble sleeping, increased sleepiness, mild anemia, reduced muscle bulk or strength, increased body fat, and diminished physical performance.⁹

Making the clinical diagnosis of hypogonadism is challenging, because the clinical symptoms have a high prevalence in the older male population and overlap with many nonendocrine diseases. Testosterone replacement therapy has been associated weakly, but consistently, with improved sexual function,^10-12 bone mineral density,^13,14 fat free mass,^13,14 strength,^15,16 lipid profiles,^17,18 insulin resistance,^17,18 and with an increased time to ST segment depression during stress testing.^19,20

Laboratory Evaluation

Serum total testosterone circulates in 3 forms: free testosterone, sex hormone-binding globulin (SHBG)-bound testosterone, and albumin-bound testosterone. Free testosterone is the most bio-available testosterone but represents only 2% to 3% of total testosterone.²¹ Whether total testosterone or free testosterone measurements most closely correlate with symptomatic androgen deficiency is a matter of debate.²¹ A total testosterone level is an appropriate screening test in young, healthy, and lean men for whom SHBG levels are presumably normal. However, a free or bioavailable testosterone level should be considered for men when there is a high likelihood of conditions that can affect SHBG levels.

Conditions that can decrease SHBG (and may result in a low total testosterone reading even when the free fraction may be normal) include obesity, metabolic syndrome, type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, chronic glucocorticoid use, and the use of progestins and anabolic steroids.²¹ Conditions that can increase SHBG (and may result in a normal total testosterone level in patients with hypogonadism, as they have low levels of free testosterone) include aging, cirrhosis, anticonvulsant use, hyperthyroidism, catabolic conditions, and HIV.²¹

Related: Effect of Statins on Total Testosterone Levels in Male Veterans

Serum testosterone levels generally peak in the early morning, followed by a progressive decline over the course of the day until they reach a nadir in the evening.²¹ Although it has been debated that morning testosterone levels are not necessary in older men due to a blunting of the circadian rhythm, many men aged 65 to 80 years who have low T in the afternoon will have normal testosterone levels when retested in the morning.^22,23 Readings below a reference range of 280 ng/dL to 300 ng/dL on at least 2 different occasions support a diagnosis of hypogonadism.⁹

Follicle stimulating hormone (FSH) and luteinizing hormone (LH) laboratory tests may be ordered following confirmation of a low testosterone level. Prolactin levels and iron saturation can help evaluate for the presence of hyperprolactinemia and hemochromatosis, respectively. Primary hypogonadism due to testicular failure is diagnosed with high FSH, high LH, and low testosterone levels. Secondary hypogonadism due to hypothalamic or pituitary failure is diagnosed with low FSH, low LH, and low testosterone levels.

Hypothalamic or pituitary suppression from a nonendocrine condition may result in functional hypogonadotropic hypogonadism (FHH), which can be identified with low (or normal) FSH; low (or normal) LH; and low testosterone levels. Hypogonadotropic hypogonadism has been associated with depression, obesity, stress, and physical exertion; and FHH may also be associated with the use of multiple drugs and drug classes (spironolactone, anabolic and corticosteroids, ketoconazole, ethanol, anticonvulsants, immunosuppressants, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotics, and opioids).^24,25 Even statin therapy has been associated with FHH.^26,27 Testosterone levels will often recover if or when modifiable factors for FHH are corrected.²⁸

Although there is no consensus on an absolute number that defines a low testosterone level, concern exists that there are economic incentives to raise the bar for normal and thereby increase the potential market for testosterone-raising products.²⁹ Many commercial avenues for the treatment of low T do not follow the standards of the established medical community. Some websites suggest screening for low T with total and free testosterone levels for all men aged > 40 years. Others advise men to consider TRT if they have a total testosterone level of < 500 ng/dL or a free testosterone level that is not in the upper one-third range for men aged 21 to 49 years.³⁰ Of even greater concern, Baillargeon and colleagues reported that 25% of all new androgen users had not had their testosterone levels measured in the 12 months before starting treatment.³¹ In another study, 40% of men who initiated TRT did not have a baseline measurement.³²

Treatments

Before considering TRT, physicians need to emphasize lifestyle modifications as first-line treatment for hypogonadism. The most important modifications include weight loss, tobacco cessation, and moderation in alcohol use.

Patients need to be advised of possible adverse events (AEs) of TRT, which may include gynecomastia, polycythemia, sleep apnea, decreased high-density lipoprotein cholesterol, benign prostatic hypertrophy, infertility, testicular atrophy, and abnormal liver function tests. More recently, several studies have shown an association between TRT and an increase in cardiovascular complications, such as stroke, heart attacks, and death.

Prior to considering TRT, a careful history and physical examination, including a clinical prostate examination, should be performed. Minimum additional tests should include hematocrit, fasting lipid profile (FLP), complete metabolic profile (CMP), and prostate-specific antigen (PSA). Initiation of TRT is not recommended for patients with metastatic prostate cancer; breast cancer; an unevaluated prostate nodule; a PSA > 4 ng/mL (or > 3 ng/mL in African Americans or men with a first-degree relative with prostate cancer); hematocrit > 50%; untreated severe obstructive sleep apnea; uncontrolled or poorly controlled congestive heart failure; or an International Prostate Symptoms Score (IPSS) > 19.⁹

A past history of prostate cancer had previously been a contraindication for the use of TRT. However, more recent studies have shown that TRT can be used in those who have no evidence of active or metastatic disease and who are under the close supervision of a physician.^33-35

Widespread screening is not recommended, and population-based surveys can be unreliable. Fifteen percent of healthy young men, for example, will have a low serum testosterone level in a given 24-hour period.⁹ Thirty percent of men with an initial testosterone level in the mildly hypogonadal range will have a normal testosterone level when retested; moreover the threshold below which AEs occur remains unknown.⁹

The goal of TRT is to achieve a total testosterone level in the 400 ng/mL to 700 ng/mL range with improved clinical signs and symptoms.⁹ Laboratory tests should be conducted at 3 months, 6 months, and then annually. These tests include hematocrit, PSA, and a testosterone level.³² Testing for CMP and FLP should also be considered. If, during therapy, the hematocrit is > 54%, the patient should be assessed for hypoxia and sleep apnea, and treatment should resume at a lower dose only when the hematocrit returns to baseline.⁹ A digital examination of the prostate is recommended for men with a PSA of > 0.6 ng/mL. A urologic consultation should be obtained for an increase in the PSA of > 1.4 ng/mL over 12 months, a PSA velocity of > 0.4 ng/mL per year (using the PSA after 6 months as a reference), or for an IPPS of > 19.⁹

Emerging Cardiovascular Concerns

The Testosterone for Older Men study, a randomized, placebo- controlled clinical trial of testosterone therapy in men with a high prevalence of cardiovascular disease, showed significantly greater improvements in leg-press, chest-press, and stair-climbing exercises while carrying a load compared with that in the placebo group.³⁶ However, the study was stopped early due to an increased risk of cardiovascular AEs in those who received testosterone gel.

The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Vigen and colleagues examined a cohort of veterans who underwent coronary angiography and had a low serum testosterone level.³⁷ The use of TRT in this cohort was also associated with an increased risk of adverse cardiovascular outcomes. This study generated several letters and a recent article in response that vigorously questioned the validity of the methods used and the conclusions reached.^38-44 Prior clinical studies of TRT had not detected cardiac AEs, but these trials were generally of short duration and not powered for clinical endpoints.³⁷

A FDA Safety Announcement as well as a VA National Pharmacy Benefits Management bulletin were based on the results of these studies.⁴⁵ The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Direct-to-Consumer Marketing

Some direct-to-consumer marketing promotes the use of aromatase inhibitors, such as anastrozole. This class of medications prevents the conversion of endogenous and exogenous testosterone to estrogen by the aromatase enzyme, which is found predominately in abdominal adipose tissue. There is no evidence that naturally occurring elevations in estrogen cause low testosterone or that treatment of elevated estrogen with an aromatase inhibitor during TRT has any significant clinical benefit in terms of male sexuality.⁴⁶ Nevertheless, some CAM providers now hypothesize that the increase in cardiovascular AEs with TRT noted in the recent studies may have been due to the increase in estrogen that is associated with TRT.⁴⁶

The off-label use of clomiphene citrate to block the negative feedback of estrogen on the production of LH has been promoted as another potential treatment to increase testosterone levels. Luteinizing hormone is the pituitary analog of human chorionic gonadotropin (HCG). Many CAM providers also prescribe HCG to increase the testicles’ testosterone production.

Some consumer-focused media insist that the use of either clomiphene citrate or HCG will increase testosterone production and does not cause testicular atrophy, a known TRT- associated AE. This seems to increase the motivation of many men to try these off-label medications.

Some sources even posit a “conspiracy theory” that the FDA and pharmaceutical companies conspire to keep the price of transdermal TRT options high. Men are told that testosterone creams made at compounding pharmacies are much less expensive than are the transdermal pharmaceuticals, and they are urged to see a CAM provider to obtain a prescription for the compounded testosterone. In some cases, a sample prescription is included.⁴⁷

Many supplements are available that claim to boost testosterone or suppress estrogen. Chrysin, for example, is a bioflavonoid that is marketed as having the potential to act as a natural aromatase inhibitor. Although studies have suggested the potential for chrysin to work in such a manner, the effectiveness may be attenuated by its low bioavailability in supplements.⁴⁸ Long-term studies have not been conducted.⁴⁹ Nettle root is a plant-derived compound that is stated to increase free testosterone levels by binding to SHBG, in place of testosterone, and by inhibiting the enzyme that converts testosterone to dihydrotestosterone. The clinical evidence of effectiveness is based on many open studies, and the significance and magnitude of the effect still needs more rigorous evaluation.⁵⁰

Conclusions

Patients today are barraged with medical information through television, print advertising, radio, and the Internet. A recent study of online sources of herbal product information found that only 10.5% recommended a consultation with a health care professional and < 3% cited scientific literature to accompany their claims.⁵¹ Many patients present to their PCP with questions about TRT or have already started an intervention for low T. Complementary and alternative medicine providers of TRT have been able to capture a segment of the population that often has the motivation and disposable income to pursue nontraditional therapies.

All nutritional supplements contain a standard warning from the FDA: “The above statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease.” Providers should remind patients of the statement and point out the contradictions between the statement and the benefits touted by the supplement marketing literature.

Finally, despite the well- established role of testosterone in enhancing libido, its definitive role in erectile function had been controversial until evidence substantiated a key function for this hormone.⁵² Testosterone may facilitate erection by acting as a vasodilator of the penile arterioles and cavernous sinusoids and may ameliorate the response to the phosphodiesterase-5 inhibitors in hypogonadal men.⁵³ Testosterone replacement alone in hypogonadal men can restore erectile dysfunction.⁵¹ However, hypogonadism is not a common finding in those with erectile dysfunction, only occurring in about 5% of cases.⁵³

Allopathic providers are concerned about the vitality and sexual health of their aging male patients, but their enthusiasm for anti-aging treatments is often tempered by evidence-based studies that have shown a lack of efficacy or potentially serious health care risks. Unfortunately, many patients remain unaware of the controversies regarding TRT. For those patients who receive treatment through CAM providers and are convinced of the efficacy of their low-T treatment regimen, it is important to keep lines of communication open.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

The objective of this article is to help primary care providers (PCPs) council patients regarding testosterone replacement therapy (TRT). This case will present a patient who initiated TRT at a community-based alternative medicine clinic. The case will be followed by a discussion regarding the standard diagnosis of hypogonadism, the potential benefits and risks of TRT, and a review of the current clinical guideline recommendations. Examples of information being disseminated to the general public by the complementary and alternative medicine (CAM) providers will be briefly reviewed for an increased awareness of the questions patients may pose regarding TRT.

Background

From 2000 to 2011, total testosterone sales increased 12-fold globally.¹ Possible causes for the increase involved the aging population, newer options for TRT administration, and increased direct-to-consumer advertising. A low testosterone level (sometimes referred to as low T in consumer marketing materials) is associated with a variety of medical conditions (ie, low mood, increased body fat, declining athletic performance, and decreased sexual performance) that have become increasingly prevalent among middle aged and older men.² It has also received attention as an intervention to reverse frailty and sarcopenia.³

Testosterone replacement therapy options include injectable solutions, transdermal gels and patches, pellet implants, or buccal tablets. The ease of administration of transdermal testosterone comes at a relatively high cost. Injectable testosterone preparations are generally the least expensive option, and many patients choose injections for this reason.

Related: Keeping an Open Mind on HRT

Testosterone prescriptions were most frequently written by PCPs with 36% coming from family practitioners and 20.1% from internal medicine practices, according to a Kaiser Permanente study.⁴ Endocrinologists (13.5%) and urologists (6.6%) were less likely to have written the prescriptions for patients.

Due, in part, to direct-to-consumer advertising and to the availability of online medical information, many men now present to their PCP questioning whether they might have low T. Others may have already started therapy at a CAM, integrative medicine, or anti-aging clinic.

Confusing the issue further, some CAM providers promote a variety of off-label medications and nutritional supplements for the treatment of low T, which seems to have struck a chord in the baby boomer generation. No other age group in history has tried to work so intensely on its physical condition and appearance.⁵ Much of the information marketed to consumers emphasizes that many traditionally trained physicians are not educated in the treatment of low T.

Case Report

Mr. C. is a 65-year-old man who was seen in the primary care clinic for the first time. He was accompanied by his much younger fiancée. She reported that Mr. C.’s energy and sexual interest were declining, and the patient reported his “get up and go had gotten up and left.” They sought medical advice from a CAM provider who ordered blood work and then explained that the symptoms were due to low testosterone. For the past 6 months he had been visiting the clinic weekly for testosterone injections.

Mr. C. reported feeling as good as a “40 year old.” He also reported that he started working with a personal trainer and had given up most junk food and alcohol. He had no symptoms of chest pain, erectile dysfunction, or significant urinary urgency, frequency, or nocturia.

Related: Will Testosterone Therapy Kill Your Patient?

The visits to a CAM provider had been an out-of-pocket expense, and he was hoping to transfer his treatment to the VA so the costs could be covered. Mr. C. failed to bring medical records from the other provider but remembered being told that all his tests were “fine” except for the low testosterone level.

His past history was notable for controlled type 2 diabetes mellitus for 8 years, hypertension, hyperlipidemia, and spinal stenosis. He had no history of benign prostatic hyperplasia or prostate cancer.

In addition to the testosterone (100 mg intramuscular injection weekly), his medication regimen included metoprolol 25 mg twice daily, atorvastatin 20 mg daily, acetaminophen 650 mg 3 times daily as needed, aspirin 81 mg daily, metformin 500 mg twice daily, vitamin D 2,000 IU daily, vitamin B12 1,000 mg daily, and Co-Q10 200 mg daily.

On physical examination, Mr. C.’s vitals were stable and his body mass index was in the overweight range at 29.8 kg/m². His cardiopulmonary examination was normal. There was increased central obesity without palpable organomegaly. There was no gynecomastia, and he had normal amounts of axillary and pubic hair. There was no peripheral edema; his genitourinary examination included normal-sized testicles, and the prostate was smooth without nodules.

The PCP informed Mr. C. that he was familiar with the evaluation and management of testosterone therapy. He was advised that additional evaluation would be needed before determining whether the clinical benefit of TRT outweighed the potential risks.

Andropause

Testosterone levels in men are known to decline at a rate of 1% per year after aged 30 years.⁶ About 20% of men aged ≥ 60 years and 50% of men aged ≥ 80 years have low (hypogonadal) total testosterone levels.⁷ The clinical diagnosis of hypogonadism, however, is made on the basis of signs and symptoms consistent with androgen deficiency and a low serum morning testosterone level measured on serum on multiple occasions.⁸

Specific clinical signs and symptoms (“A” list) consistent with androgen deficiency include low libido and sexual activity; diminished spontaneous erections; gynecomastia; reduced facial, axillary, or pubic hair; small (≤ 5 mL) testes; inability to father children; loss of height, fractures, or other signs of bone loss; and hot flashes and night sweats.⁹

Less specific signs and symptoms (“B” list) of androgen deficiency include a decrease in energy or motivation, feelings of sadness or depression, poor concentration or memory, trouble sleeping, increased sleepiness, mild anemia, reduced muscle bulk or strength, increased body fat, and diminished physical performance.⁹

Making the clinical diagnosis of hypogonadism is challenging, because the clinical symptoms have a high prevalence in the older male population and overlap with many nonendocrine diseases. Testosterone replacement therapy has been associated weakly, but consistently, with improved sexual function,^10-12 bone mineral density,^13,14 fat free mass,^13,14 strength,^15,16 lipid profiles,^17,18 insulin resistance,^17,18 and with an increased time to ST segment depression during stress testing.^19,20

Laboratory Evaluation

Serum total testosterone circulates in 3 forms: free testosterone, sex hormone-binding globulin (SHBG)-bound testosterone, and albumin-bound testosterone. Free testosterone is the most bio-available testosterone but represents only 2% to 3% of total testosterone.²¹ Whether total testosterone or free testosterone measurements most closely correlate with symptomatic androgen deficiency is a matter of debate.²¹ A total testosterone level is an appropriate screening test in young, healthy, and lean men for whom SHBG levels are presumably normal. However, a free or bioavailable testosterone level should be considered for men when there is a high likelihood of conditions that can affect SHBG levels.

Conditions that can decrease SHBG (and may result in a low total testosterone reading even when the free fraction may be normal) include obesity, metabolic syndrome, type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, chronic glucocorticoid use, and the use of progestins and anabolic steroids.²¹ Conditions that can increase SHBG (and may result in a normal total testosterone level in patients with hypogonadism, as they have low levels of free testosterone) include aging, cirrhosis, anticonvulsant use, hyperthyroidism, catabolic conditions, and HIV.²¹

Related: Effect of Statins on Total Testosterone Levels in Male Veterans

Serum testosterone levels generally peak in the early morning, followed by a progressive decline over the course of the day until they reach a nadir in the evening.²¹ Although it has been debated that morning testosterone levels are not necessary in older men due to a blunting of the circadian rhythm, many men aged 65 to 80 years who have low T in the afternoon will have normal testosterone levels when retested in the morning.^22,23 Readings below a reference range of 280 ng/dL to 300 ng/dL on at least 2 different occasions support a diagnosis of hypogonadism.⁹

Follicle stimulating hormone (FSH) and luteinizing hormone (LH) laboratory tests may be ordered following confirmation of a low testosterone level. Prolactin levels and iron saturation can help evaluate for the presence of hyperprolactinemia and hemochromatosis, respectively. Primary hypogonadism due to testicular failure is diagnosed with high FSH, high LH, and low testosterone levels. Secondary hypogonadism due to hypothalamic or pituitary failure is diagnosed with low FSH, low LH, and low testosterone levels.

Hypothalamic or pituitary suppression from a nonendocrine condition may result in functional hypogonadotropic hypogonadism (FHH), which can be identified with low (or normal) FSH; low (or normal) LH; and low testosterone levels. Hypogonadotropic hypogonadism has been associated with depression, obesity, stress, and physical exertion; and FHH may also be associated with the use of multiple drugs and drug classes (spironolactone, anabolic and corticosteroids, ketoconazole, ethanol, anticonvulsants, immunosuppressants, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotics, and opioids).^24,25 Even statin therapy has been associated with FHH.^26,27 Testosterone levels will often recover if or when modifiable factors for FHH are corrected.²⁸

Although there is no consensus on an absolute number that defines a low testosterone level, concern exists that there are economic incentives to raise the bar for normal and thereby increase the potential market for testosterone-raising products.²⁹ Many commercial avenues for the treatment of low T do not follow the standards of the established medical community. Some websites suggest screening for low T with total and free testosterone levels for all men aged > 40 years. Others advise men to consider TRT if they have a total testosterone level of < 500 ng/dL or a free testosterone level that is not in the upper one-third range for men aged 21 to 49 years.³⁰ Of even greater concern, Baillargeon and colleagues reported that 25% of all new androgen users had not had their testosterone levels measured in the 12 months before starting treatment.³¹ In another study, 40% of men who initiated TRT did not have a baseline measurement.³²

Treatments

Before considering TRT, physicians need to emphasize lifestyle modifications as first-line treatment for hypogonadism. The most important modifications include weight loss, tobacco cessation, and moderation in alcohol use.

Patients need to be advised of possible adverse events (AEs) of TRT, which may include gynecomastia, polycythemia, sleep apnea, decreased high-density lipoprotein cholesterol, benign prostatic hypertrophy, infertility, testicular atrophy, and abnormal liver function tests. More recently, several studies have shown an association between TRT and an increase in cardiovascular complications, such as stroke, heart attacks, and death.

Prior to considering TRT, a careful history and physical examination, including a clinical prostate examination, should be performed. Minimum additional tests should include hematocrit, fasting lipid profile (FLP), complete metabolic profile (CMP), and prostate-specific antigen (PSA). Initiation of TRT is not recommended for patients with metastatic prostate cancer; breast cancer; an unevaluated prostate nodule; a PSA > 4 ng/mL (or > 3 ng/mL in African Americans or men with a first-degree relative with prostate cancer); hematocrit > 50%; untreated severe obstructive sleep apnea; uncontrolled or poorly controlled congestive heart failure; or an International Prostate Symptoms Score (IPSS) > 19.⁹

A past history of prostate cancer had previously been a contraindication for the use of TRT. However, more recent studies have shown that TRT can be used in those who have no evidence of active or metastatic disease and who are under the close supervision of a physician.^33-35

Widespread screening is not recommended, and population-based surveys can be unreliable. Fifteen percent of healthy young men, for example, will have a low serum testosterone level in a given 24-hour period.⁹ Thirty percent of men with an initial testosterone level in the mildly hypogonadal range will have a normal testosterone level when retested; moreover the threshold below which AEs occur remains unknown.⁹

The goal of TRT is to achieve a total testosterone level in the 400 ng/mL to 700 ng/mL range with improved clinical signs and symptoms.⁹ Laboratory tests should be conducted at 3 months, 6 months, and then annually. These tests include hematocrit, PSA, and a testosterone level.³² Testing for CMP and FLP should also be considered. If, during therapy, the hematocrit is > 54%, the patient should be assessed for hypoxia and sleep apnea, and treatment should resume at a lower dose only when the hematocrit returns to baseline.⁹ A digital examination of the prostate is recommended for men with a PSA of > 0.6 ng/mL. A urologic consultation should be obtained for an increase in the PSA of > 1.4 ng/mL over 12 months, a PSA velocity of > 0.4 ng/mL per year (using the PSA after 6 months as a reference), or for an IPPS of > 19.⁹

Emerging Cardiovascular Concerns

The Testosterone for Older Men study, a randomized, placebo- controlled clinical trial of testosterone therapy in men with a high prevalence of cardiovascular disease, showed significantly greater improvements in leg-press, chest-press, and stair-climbing exercises while carrying a load compared with that in the placebo group.³⁶ However, the study was stopped early due to an increased risk of cardiovascular AEs in those who received testosterone gel.

The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Vigen and colleagues examined a cohort of veterans who underwent coronary angiography and had a low serum testosterone level.³⁷ The use of TRT in this cohort was also associated with an increased risk of adverse cardiovascular outcomes. This study generated several letters and a recent article in response that vigorously questioned the validity of the methods used and the conclusions reached.^38-44 Prior clinical studies of TRT had not detected cardiac AEs, but these trials were generally of short duration and not powered for clinical endpoints.³⁷

A FDA Safety Announcement as well as a VA National Pharmacy Benefits Management bulletin were based on the results of these studies.⁴⁵ The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Direct-to-Consumer Marketing

Some direct-to-consumer marketing promotes the use of aromatase inhibitors, such as anastrozole. This class of medications prevents the conversion of endogenous and exogenous testosterone to estrogen by the aromatase enzyme, which is found predominately in abdominal adipose tissue. There is no evidence that naturally occurring elevations in estrogen cause low testosterone or that treatment of elevated estrogen with an aromatase inhibitor during TRT has any significant clinical benefit in terms of male sexuality.⁴⁶ Nevertheless, some CAM providers now hypothesize that the increase in cardiovascular AEs with TRT noted in the recent studies may have been due to the increase in estrogen that is associated with TRT.⁴⁶

The off-label use of clomiphene citrate to block the negative feedback of estrogen on the production of LH has been promoted as another potential treatment to increase testosterone levels. Luteinizing hormone is the pituitary analog of human chorionic gonadotropin (HCG). Many CAM providers also prescribe HCG to increase the testicles’ testosterone production.

Some consumer-focused media insist that the use of either clomiphene citrate or HCG will increase testosterone production and does not cause testicular atrophy, a known TRT- associated AE. This seems to increase the motivation of many men to try these off-label medications.

Some sources even posit a “conspiracy theory” that the FDA and pharmaceutical companies conspire to keep the price of transdermal TRT options high. Men are told that testosterone creams made at compounding pharmacies are much less expensive than are the transdermal pharmaceuticals, and they are urged to see a CAM provider to obtain a prescription for the compounded testosterone. In some cases, a sample prescription is included.⁴⁷

Many supplements are available that claim to boost testosterone or suppress estrogen. Chrysin, for example, is a bioflavonoid that is marketed as having the potential to act as a natural aromatase inhibitor. Although studies have suggested the potential for chrysin to work in such a manner, the effectiveness may be attenuated by its low bioavailability in supplements.⁴⁸ Long-term studies have not been conducted.⁴⁹ Nettle root is a plant-derived compound that is stated to increase free testosterone levels by binding to SHBG, in place of testosterone, and by inhibiting the enzyme that converts testosterone to dihydrotestosterone. The clinical evidence of effectiveness is based on many open studies, and the significance and magnitude of the effect still needs more rigorous evaluation.⁵⁰

Conclusions

Patients today are barraged with medical information through television, print advertising, radio, and the Internet. A recent study of online sources of herbal product information found that only 10.5% recommended a consultation with a health care professional and < 3% cited scientific literature to accompany their claims.⁵¹ Many patients present to their PCP with questions about TRT or have already started an intervention for low T. Complementary and alternative medicine providers of TRT have been able to capture a segment of the population that often has the motivation and disposable income to pursue nontraditional therapies.

All nutritional supplements contain a standard warning from the FDA: “The above statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease.” Providers should remind patients of the statement and point out the contradictions between the statement and the benefits touted by the supplement marketing literature.

Finally, despite the well- established role of testosterone in enhancing libido, its definitive role in erectile function had been controversial until evidence substantiated a key function for this hormone.⁵² Testosterone may facilitate erection by acting as a vasodilator of the penile arterioles and cavernous sinusoids and may ameliorate the response to the phosphodiesterase-5 inhibitors in hypogonadal men.⁵³ Testosterone replacement alone in hypogonadal men can restore erectile dysfunction.⁵¹ However, hypogonadism is not a common finding in those with erectile dysfunction, only occurring in about 5% of cases.⁵³

Allopathic providers are concerned about the vitality and sexual health of their aging male patients, but their enthusiasm for anti-aging treatments is often tempered by evidence-based studies that have shown a lack of efficacy or potentially serious health care risks. Unfortunately, many patients remain unaware of the controversies regarding TRT. For those patients who receive treatment through CAM providers and are convinced of the efficacy of their low-T treatment regimen, it is important to keep lines of communication open.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

The objective of this article is to help primary care providers (PCPs) council patients regarding testosterone replacement therapy (TRT). This case will present a patient who initiated TRT at a community-based alternative medicine clinic. The case will be followed by a discussion regarding the standard diagnosis of hypogonadism, the potential benefits and risks of TRT, and a review of the current clinical guideline recommendations. Examples of information being disseminated to the general public by the complementary and alternative medicine (CAM) providers will be briefly reviewed for an increased awareness of the questions patients may pose regarding TRT.

Background

From 2000 to 2011, total testosterone sales increased 12-fold globally.¹ Possible causes for the increase involved the aging population, newer options for TRT administration, and increased direct-to-consumer advertising. A low testosterone level (sometimes referred to as low T in consumer marketing materials) is associated with a variety of medical conditions (ie, low mood, increased body fat, declining athletic performance, and decreased sexual performance) that have become increasingly prevalent among middle aged and older men.² It has also received attention as an intervention to reverse frailty and sarcopenia.³

Testosterone replacement therapy options include injectable solutions, transdermal gels and patches, pellet implants, or buccal tablets. The ease of administration of transdermal testosterone comes at a relatively high cost. Injectable testosterone preparations are generally the least expensive option, and many patients choose injections for this reason.

Related: Keeping an Open Mind on HRT

Testosterone prescriptions were most frequently written by PCPs with 36% coming from family practitioners and 20.1% from internal medicine practices, according to a Kaiser Permanente study.⁴ Endocrinologists (13.5%) and urologists (6.6%) were less likely to have written the prescriptions for patients.

Due, in part, to direct-to-consumer advertising and to the availability of online medical information, many men now present to their PCP questioning whether they might have low T. Others may have already started therapy at a CAM, integrative medicine, or anti-aging clinic.

Confusing the issue further, some CAM providers promote a variety of off-label medications and nutritional supplements for the treatment of low T, which seems to have struck a chord in the baby boomer generation. No other age group in history has tried to work so intensely on its physical condition and appearance.⁵ Much of the information marketed to consumers emphasizes that many traditionally trained physicians are not educated in the treatment of low T.

Case Report

Mr. C. is a 65-year-old man who was seen in the primary care clinic for the first time. He was accompanied by his much younger fiancée. She reported that Mr. C.’s energy and sexual interest were declining, and the patient reported his “get up and go had gotten up and left.” They sought medical advice from a CAM provider who ordered blood work and then explained that the symptoms were due to low testosterone. For the past 6 months he had been visiting the clinic weekly for testosterone injections.

Mr. C. reported feeling as good as a “40 year old.” He also reported that he started working with a personal trainer and had given up most junk food and alcohol. He had no symptoms of chest pain, erectile dysfunction, or significant urinary urgency, frequency, or nocturia.

Related: Will Testosterone Therapy Kill Your Patient?

The visits to a CAM provider had been an out-of-pocket expense, and he was hoping to transfer his treatment to the VA so the costs could be covered. Mr. C. failed to bring medical records from the other provider but remembered being told that all his tests were “fine” except for the low testosterone level.

His past history was notable for controlled type 2 diabetes mellitus for 8 years, hypertension, hyperlipidemia, and spinal stenosis. He had no history of benign prostatic hyperplasia or prostate cancer.

In addition to the testosterone (100 mg intramuscular injection weekly), his medication regimen included metoprolol 25 mg twice daily, atorvastatin 20 mg daily, acetaminophen 650 mg 3 times daily as needed, aspirin 81 mg daily, metformin 500 mg twice daily, vitamin D 2,000 IU daily, vitamin B12 1,000 mg daily, and Co-Q10 200 mg daily.

On physical examination, Mr. C.’s vitals were stable and his body mass index was in the overweight range at 29.8 kg/m². His cardiopulmonary examination was normal. There was increased central obesity without palpable organomegaly. There was no gynecomastia, and he had normal amounts of axillary and pubic hair. There was no peripheral edema; his genitourinary examination included normal-sized testicles, and the prostate was smooth without nodules.

The PCP informed Mr. C. that he was familiar with the evaluation and management of testosterone therapy. He was advised that additional evaluation would be needed before determining whether the clinical benefit of TRT outweighed the potential risks.

Andropause

Testosterone levels in men are known to decline at a rate of 1% per year after aged 30 years.⁶ About 20% of men aged ≥ 60 years and 50% of men aged ≥ 80 years have low (hypogonadal) total testosterone levels.⁷ The clinical diagnosis of hypogonadism, however, is made on the basis of signs and symptoms consistent with androgen deficiency and a low serum morning testosterone level measured on serum on multiple occasions.⁸

Specific clinical signs and symptoms (“A” list) consistent with androgen deficiency include low libido and sexual activity; diminished spontaneous erections; gynecomastia; reduced facial, axillary, or pubic hair; small (≤ 5 mL) testes; inability to father children; loss of height, fractures, or other signs of bone loss; and hot flashes and night sweats.⁹

Less specific signs and symptoms (“B” list) of androgen deficiency include a decrease in energy or motivation, feelings of sadness or depression, poor concentration or memory, trouble sleeping, increased sleepiness, mild anemia, reduced muscle bulk or strength, increased body fat, and diminished physical performance.⁹

Making the clinical diagnosis of hypogonadism is challenging, because the clinical symptoms have a high prevalence in the older male population and overlap with many nonendocrine diseases. Testosterone replacement therapy has been associated weakly, but consistently, with improved sexual function,^10-12 bone mineral density,^13,14 fat free mass,^13,14 strength,^15,16 lipid profiles,^17,18 insulin resistance,^17,18 and with an increased time to ST segment depression during stress testing.^19,20

Laboratory Evaluation

Serum total testosterone circulates in 3 forms: free testosterone, sex hormone-binding globulin (SHBG)-bound testosterone, and albumin-bound testosterone. Free testosterone is the most bio-available testosterone but represents only 2% to 3% of total testosterone.²¹ Whether total testosterone or free testosterone measurements most closely correlate with symptomatic androgen deficiency is a matter of debate.²¹ A total testosterone level is an appropriate screening test in young, healthy, and lean men for whom SHBG levels are presumably normal. However, a free or bioavailable testosterone level should be considered for men when there is a high likelihood of conditions that can affect SHBG levels.

Conditions that can decrease SHBG (and may result in a low total testosterone reading even when the free fraction may be normal) include obesity, metabolic syndrome, type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, chronic glucocorticoid use, and the use of progestins and anabolic steroids.²¹ Conditions that can increase SHBG (and may result in a normal total testosterone level in patients with hypogonadism, as they have low levels of free testosterone) include aging, cirrhosis, anticonvulsant use, hyperthyroidism, catabolic conditions, and HIV.²¹

Related: Effect of Statins on Total Testosterone Levels in Male Veterans

Serum testosterone levels generally peak in the early morning, followed by a progressive decline over the course of the day until they reach a nadir in the evening.²¹ Although it has been debated that morning testosterone levels are not necessary in older men due to a blunting of the circadian rhythm, many men aged 65 to 80 years who have low T in the afternoon will have normal testosterone levels when retested in the morning.^22,23 Readings below a reference range of 280 ng/dL to 300 ng/dL on at least 2 different occasions support a diagnosis of hypogonadism.⁹

Follicle stimulating hormone (FSH) and luteinizing hormone (LH) laboratory tests may be ordered following confirmation of a low testosterone level. Prolactin levels and iron saturation can help evaluate for the presence of hyperprolactinemia and hemochromatosis, respectively. Primary hypogonadism due to testicular failure is diagnosed with high FSH, high LH, and low testosterone levels. Secondary hypogonadism due to hypothalamic or pituitary failure is diagnosed with low FSH, low LH, and low testosterone levels.

Hypothalamic or pituitary suppression from a nonendocrine condition may result in functional hypogonadotropic hypogonadism (FHH), which can be identified with low (or normal) FSH; low (or normal) LH; and low testosterone levels. Hypogonadotropic hypogonadism has been associated with depression, obesity, stress, and physical exertion; and FHH may also be associated with the use of multiple drugs and drug classes (spironolactone, anabolic and corticosteroids, ketoconazole, ethanol, anticonvulsants, immunosuppressants, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotics, and opioids).^24,25 Even statin therapy has been associated with FHH.^26,27 Testosterone levels will often recover if or when modifiable factors for FHH are corrected.²⁸

Although there is no consensus on an absolute number that defines a low testosterone level, concern exists that there are economic incentives to raise the bar for normal and thereby increase the potential market for testosterone-raising products.²⁹ Many commercial avenues for the treatment of low T do not follow the standards of the established medical community. Some websites suggest screening for low T with total and free testosterone levels for all men aged > 40 years. Others advise men to consider TRT if they have a total testosterone level of < 500 ng/dL or a free testosterone level that is not in the upper one-third range for men aged 21 to 49 years.³⁰ Of even greater concern, Baillargeon and colleagues reported that 25% of all new androgen users had not had their testosterone levels measured in the 12 months before starting treatment.³¹ In another study, 40% of men who initiated TRT did not have a baseline measurement.³²

Treatments

Before considering TRT, physicians need to emphasize lifestyle modifications as first-line treatment for hypogonadism. The most important modifications include weight loss, tobacco cessation, and moderation in alcohol use.

Patients need to be advised of possible adverse events (AEs) of TRT, which may include gynecomastia, polycythemia, sleep apnea, decreased high-density lipoprotein cholesterol, benign prostatic hypertrophy, infertility, testicular atrophy, and abnormal liver function tests. More recently, several studies have shown an association between TRT and an increase in cardiovascular complications, such as stroke, heart attacks, and death.

Prior to considering TRT, a careful history and physical examination, including a clinical prostate examination, should be performed. Minimum additional tests should include hematocrit, fasting lipid profile (FLP), complete metabolic profile (CMP), and prostate-specific antigen (PSA). Initiation of TRT is not recommended for patients with metastatic prostate cancer; breast cancer; an unevaluated prostate nodule; a PSA > 4 ng/mL (or > 3 ng/mL in African Americans or men with a first-degree relative with prostate cancer); hematocrit > 50%; untreated severe obstructive sleep apnea; uncontrolled or poorly controlled congestive heart failure; or an International Prostate Symptoms Score (IPSS) > 19.⁹

A past history of prostate cancer had previously been a contraindication for the use of TRT. However, more recent studies have shown that TRT can be used in those who have no evidence of active or metastatic disease and who are under the close supervision of a physician.^33-35

Widespread screening is not recommended, and population-based surveys can be unreliable. Fifteen percent of healthy young men, for example, will have a low serum testosterone level in a given 24-hour period.⁹ Thirty percent of men with an initial testosterone level in the mildly hypogonadal range will have a normal testosterone level when retested; moreover the threshold below which AEs occur remains unknown.⁹

The goal of TRT is to achieve a total testosterone level in the 400 ng/mL to 700 ng/mL range with improved clinical signs and symptoms.⁹ Laboratory tests should be conducted at 3 months, 6 months, and then annually. These tests include hematocrit, PSA, and a testosterone level.³² Testing for CMP and FLP should also be considered. If, during therapy, the hematocrit is > 54%, the patient should be assessed for hypoxia and sleep apnea, and treatment should resume at a lower dose only when the hematocrit returns to baseline.⁹ A digital examination of the prostate is recommended for men with a PSA of > 0.6 ng/mL. A urologic consultation should be obtained for an increase in the PSA of > 1.4 ng/mL over 12 months, a PSA velocity of > 0.4 ng/mL per year (using the PSA after 6 months as a reference), or for an IPPS of > 19.⁹

Emerging Cardiovascular Concerns

The Testosterone for Older Men study, a randomized, placebo- controlled clinical trial of testosterone therapy in men with a high prevalence of cardiovascular disease, showed significantly greater improvements in leg-press, chest-press, and stair-climbing exercises while carrying a load compared with that in the placebo group.³⁶ However, the study was stopped early due to an increased risk of cardiovascular AEs in those who received testosterone gel.

The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Vigen and colleagues examined a cohort of veterans who underwent coronary angiography and had a low serum testosterone level.³⁷ The use of TRT in this cohort was also associated with an increased risk of adverse cardiovascular outcomes. This study generated several letters and a recent article in response that vigorously questioned the validity of the methods used and the conclusions reached.^38-44 Prior clinical studies of TRT had not detected cardiac AEs, but these trials were generally of short duration and not powered for clinical endpoints.³⁷

A FDA Safety Announcement as well as a VA National Pharmacy Benefits Management bulletin were based on the results of these studies.⁴⁵ The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.

Direct-to-Consumer Marketing

Some direct-to-consumer marketing promotes the use of aromatase inhibitors, such as anastrozole. This class of medications prevents the conversion of endogenous and exogenous testosterone to estrogen by the aromatase enzyme, which is found predominately in abdominal adipose tissue. There is no evidence that naturally occurring elevations in estrogen cause low testosterone or that treatment of elevated estrogen with an aromatase inhibitor during TRT has any significant clinical benefit in terms of male sexuality.⁴⁶ Nevertheless, some CAM providers now hypothesize that the increase in cardiovascular AEs with TRT noted in the recent studies may have been due to the increase in estrogen that is associated with TRT.⁴⁶

The off-label use of clomiphene citrate to block the negative feedback of estrogen on the production of LH has been promoted as another potential treatment to increase testosterone levels. Luteinizing hormone is the pituitary analog of human chorionic gonadotropin (HCG). Many CAM providers also prescribe HCG to increase the testicles’ testosterone production.

Some consumer-focused media insist that the use of either clomiphene citrate or HCG will increase testosterone production and does not cause testicular atrophy, a known TRT- associated AE. This seems to increase the motivation of many men to try these off-label medications.

Some sources even posit a “conspiracy theory” that the FDA and pharmaceutical companies conspire to keep the price of transdermal TRT options high. Men are told that testosterone creams made at compounding pharmacies are much less expensive than are the transdermal pharmaceuticals, and they are urged to see a CAM provider to obtain a prescription for the compounded testosterone. In some cases, a sample prescription is included.⁴⁷

Many supplements are available that claim to boost testosterone or suppress estrogen. Chrysin, for example, is a bioflavonoid that is marketed as having the potential to act as a natural aromatase inhibitor. Although studies have suggested the potential for chrysin to work in such a manner, the effectiveness may be attenuated by its low bioavailability in supplements.⁴⁸ Long-term studies have not been conducted.⁴⁹ Nettle root is a plant-derived compound that is stated to increase free testosterone levels by binding to SHBG, in place of testosterone, and by inhibiting the enzyme that converts testosterone to dihydrotestosterone. The clinical evidence of effectiveness is based on many open studies, and the significance and magnitude of the effect still needs more rigorous evaluation.⁵⁰

Conclusions

Patients today are barraged with medical information through television, print advertising, radio, and the Internet. A recent study of online sources of herbal product information found that only 10.5% recommended a consultation with a health care professional and < 3% cited scientific literature to accompany their claims.⁵¹ Many patients present to their PCP with questions about TRT or have already started an intervention for low T. Complementary and alternative medicine providers of TRT have been able to capture a segment of the population that often has the motivation and disposable income to pursue nontraditional therapies.

All nutritional supplements contain a standard warning from the FDA: “The above statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease.” Providers should remind patients of the statement and point out the contradictions between the statement and the benefits touted by the supplement marketing literature.

Finally, despite the well- established role of testosterone in enhancing libido, its definitive role in erectile function had been controversial until evidence substantiated a key function for this hormone.⁵² Testosterone may facilitate erection by acting as a vasodilator of the penile arterioles and cavernous sinusoids and may ameliorate the response to the phosphodiesterase-5 inhibitors in hypogonadal men.⁵³ Testosterone replacement alone in hypogonadal men can restore erectile dysfunction.⁵¹ However, hypogonadism is not a common finding in those with erectile dysfunction, only occurring in about 5% of cases.⁵³

Allopathic providers are concerned about the vitality and sexual health of their aging male patients, but their enthusiasm for anti-aging treatments is often tempered by evidence-based studies that have shown a lack of efficacy or potentially serious health care risks. Unfortunately, many patients remain unaware of the controversies regarding TRT. For those patients who receive treatment through CAM providers and are convinced of the efficacy of their low-T treatment regimen, it is important to keep lines of communication open.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Military deployed from World War II through the Vietnam War have had enough time for respiratory disorders with both short and long latencies to manifest. More recent deployments over the past 13 years to Iraq, Kuwait, Afghanistan, and other regions in southwest Asia (SWA) have been associated with a unique spectrum of respiratory disorders. The long-term respiratory effects of SWA deployments are unknown. This review will discuss deployment-related lung cancer and then focus primarily on the emerging respiratory disorders related to SWA deployment and case examples of deployment-related lung disease.

As the number of recent veterans in the VA health care system increases, primary care providers (PCPs) and specialists are increasingly faced with questions about potential hazards of deployment, referring patients to the VA Airborne Hazards and Open Burn Pit Registry, and evaluating patients with new-onset respiratory symptoms following deployment. Previous reviews and white papers have offered recommendations for evaluation and management; however, little has been reported in the form of case examples of patients with deployment-related lung disorders and their clinical course.^1,2

Deployment-Associated Lung Cancer

Lung cancer is the leading cause of cancer death in the U.S. and around the world.³ Lung cancer in the U.S. causes more deaths than does the combination of breast, prostate, colon, and rectal cancers. Lung cancer is the second most common cancer and causes more deaths than does any other cancer in the VHA.⁴ Most cancers with an environmental cause have a significant latent period of decades between the exposure and cancer incidence. Thus, although lung cancer risk is relatively low in active-duty military personnel, the rate of lung cancer in VA patients is nearly double that of the general population, suggesting causes associated with military service.⁵

Tobacco

The main cause of lung cancer is tobacco smoking, which accounts for 85% to 90% of lung cancer in the U.S. The latent period between initiation of tobacco smoking and lung cancer incidence is typically ≥ 30 years. Military service has long been associated with tobacco smoking, due to past practices that included the provision of free cigarettes, the availability of cigarettes at reduced cost, smoking breaks, perceived relief from both stress and boredom, and social factors.⁶ More recently, the adverse effects (AEs) of smoking on health and readiness have been appreciated, and many incentives encouraging tobacco smoking have been eliminated. In 2009, the Institute of Medicine called for a tobacco-free military, and both the Secretary of the Navy and Secretary of Defense have seriously considered this change.⁷

The additional effect of deployment on smoking has been reported.⁸ The longitudinal Millennium Cohort study compared several smoking measures between 55,021 deployers and nondeployers who completed both baseline (acquired July 2001-June 2003) and follow-up questionnaires (acquired June 2004-January 2006). Smoking initiation affected 2.3% of deployers and 1.3% of nondeployers; smoking resumption showed a similar pattern with an increase of 39.4% compared with 28.7%. The overall prevalence of smoking increased 44% among nondeployers and 57% among deployers. Those never smokers exposed to combat were 60% more likely to initiate smoking compared with noncombat deployers. Thus, it is clear that tobacco smoking should be considered a deployment-related exposure that contributes to lung cancer risk.

Asbestos

In 1955, Doll published an analysis associating asbestos exposure with risk for lung cancer.⁹ Many naval veterans and shipyard workers had asbestos exposure, resulting in a spectrum of asbestos-related diseases, including bronchogenic cancer.¹⁰

Depleted Uranium

Depleted uranium was used in munitions during the first Gulf War and more recently during military operations in SWA as a part of Operation New Dawn (OND), Operation Iraqi Freedom (OIF), and Operation Enduring Freedom (OEF). Because of concerns of military personnel having complex exposure to depleted uranium, including via inhalation, the VA established the Depleted Uranium Surveillance Program, which has followed a cohort of service members exposed to inhaled depleted uranium during friendly fire in 1991. No significant differences between individuals with high urinary uranium levels and low urinary uranium levels were found in self-reported respiratory symptoms and pulmonary function testing (PFT). Additionally, 20 years after exposure to depleted uranium, there was no statistically significant difference of low-dose chest computed tomography (CT) evidence of lung cancer in these 2 groups.¹¹

Mustard Gas

Mustard gas is considered a definite lung carcinogen.^12,13 Both long-term, low-dose and short-term, high- intensity exposures are known to cause human lung cancer.¹⁴ Mustard gas was first widely used in warfare in World War I. Mustard gas was used in training for World War II; training accidents resulted in acute toxicity even in lower exposures. It was later used as a chemical warfare agent in the Iran-Iraq conflict in the late 1980s and early 1990s. It is estimated that about 4,000 U.S. service members have been acutely exposed to high concentrations of mustard gas. Sulfur mustard may be incorporated into improvised explosive devices, and there is concern that troops in Iraq have been exposed to this agent in sites previously used for manufacturing and storage.¹⁵

Agent Orange

The herbicide Agent Orange is commonly contaminated with dioxin, which has been demonstrated to be a tumor promoter in animal studies. Agent Orange was used widely in the Vietnam War. The National Academy of Sciences issued a report in 2001 reviewing evidence for a link between Agent Orange and various neoplasms. Evidence was strongest for Hodgkin lymphoma and soft tissue sarcoma. The evidence of an association between Agent Orange exposure and lung cancer was deemed only suggestive.¹⁶

Respiratory Disease Associated With Southwest Asia Deployment

Over the past 14 years, > 2.5 million U.S. military personnel and civilian contractors have been deployed as part of 3 major military operations: OEF in Afghanistan (2001 to present), OIF in Iraq (2003 to 2010), and OND in Iraq (2010 to present).^17,18 Deployed personnel encounter a wide variety of inhalational exposures that include desert dust particulate matter, burn pit combustion products, environmental tobacco smoke, vehicular diesel exhaust, debris from detonations and explosions, and other unique or specific job-related exposures (Table 1).^19,20

A number of recent studies have helped identify and characterize an emerging spectrum of deployment-related lung disorders, including asthma, rhinosinusitis, emphysema, bronchiolitis, granulomatous pneumonitis, and less common conditions such as acute eosinophilic pneumonia and rapidly progressive pulmonary fibrosis (Table 2).^20-30 Still, diagnosis of these conditions is often challenging, and traditional diagnostic tools such as PFT and chest radiography may be normal or mildly abnormal despite significant histopathologic abnormalities on surgical lung biopsy.^24,30,31

Deployment-Related Exposures

As listed in Table 1, there are a number of other exposures that may be encountered during deployment. Environmental air sampling was conducted in several locations in Iraq, Afghanistan, and sites in SWA as part of the Enhanced Particulate Matter Survey. All sites were notable for air pollutant levels that exceeded 15 μg/m³, the military exposure guideline for fine particulate matter (PM2.5). The PM2.5 fraction comprised geologic dust, burn pit emissions, and the heavy metals aluminum, cadmium, and lead.^32,33

Respiratory Disorders

Reports of deployers with respiratory symptoms during and after deployment surfaced as early as 2004.³⁴ The Millennium Cohort study reported a 1.7-fold higher rate of new-onset respiratory symptoms that was independent of smoking status, such as cough and shortness of breath, in deployers compared with nondeployers. These increased symptom rates were associated with land-based deployment and longer deployment duration.³⁵ A number of epidemiologic studies also demonstrated an association between respiratory symptoms and environmental exposures encountered during deployment.^36-39

Respiratory diseases such as asthma, acute eosinophilic pneumonia, and constrictive bronchiolitis have been reported following deployment to SWA, but a review of the literature supports a more expansive list of deployment-related respiratory diseases (Table 2).^20-30 The following case examples describe findings in veterans referred to the authors’ clinic for evaluation of chest symptoms associated with deployment.

OEF/OIF/OND Case Studies

Case Study 1

A 42-year-old male never smoker presented to his VA PCP for evaluation of nonproductive cough, dyspnea on exertion, chest tightness, and recurrent episodes of bronchitis since 2004 when he was deployed to Afghanistan. He had no history of asthma or other chronic respiratory disease in childhood or adolescence.

The patient served as a Civil Affairs officer in the U.S. Army and was deployed to Bosnia in 1997, Afghanistan in 2004, and Camp Arif-Jan in Kuwait as well as Mosul, Iraq, in 2005. He was exposed to depleted uranium while serving in Bosnia. He also had exposures to sandstorms, desert dust, and burn pit combustion products while deployed to Afghanistan and Iraq. He developed symptoms of chest tightness and dyspnea on exertion during his 2004 deployment, with these symptoms persisting after returning home from deployment. His symptoms occurred frequently while running and limited his ability to pass his military physical fitness test requirements and train for marathons as he had done previously. He also had symptoms of chest tightness and excessive coughing at rest, which were treated with antibiotics by his medical provider as recurrent acute infectious/viral bronchitis.

The patient was medically discharged from the U.S. Army in July 2005, primarily due to musculoskeletal injuries. His past medical history was notable for PTSD, recurrent allergic rhinosinusitis, and lumbosacral back pain. Given persistent respiratory symptoms of dyspnea after walking 1 block, the patient presented to his VA PCP in early 2006.

The patient’s vital signs and physical examination were normal. Spirometry showed a mixed restrictive and obstructive pattern, prompting referral for pulmonary consultation. Full PFT demonstrated an abnormally increased residual volume and mildly decreased diffusion capacity (Table 3). Laryngoscopy was negative for vocal cord dysfunction. A chest X-ray showed mild airway wall thickening bilaterally in the lower lung fields. Subsequent high-resolution CT of the chest demonstrated diffuse centrilobular nodularity (Figure 1). Serial spirometry measurements over 8 months showed severe and worsening airflow limitation despite treatment with inhaled bronchodilator and corticosteroid therapy. Seeking diagnostic clarity, the patient was referred for surgical lung biopsy via video-assisted thorascopic surgery (VATS) within 6 months of initial consultation.

The patient’s lung biopsy demonstrated constrictive changes in bronchioles, hyperinflation, and multiple chemodectomas in all 3 lobes of the right lung (Figures 2 and 3). Three pulmonary pathologists reviewed the biopsy and confirmed findings of constrictive bronchiolitis. Serologies for connective tissue disease were negative, indicating no autoimmune cause of bronchiolitis.

As no specific etiology was identified, the patient was referred for a second opinion with a pulmonologist with expertise in interstitial lung disease. Finding no evidence of post- infectious or autoimmune bronchiolitis, the patient’s diagnosis of constrictive bronchiolitis was deemed to be idiopathic. A number of years later, following publication of a case series of 38 OEF/OIF deployers with biopsy-proven constrictive bronchiolitis, the patient was referred for consultation to an occupational lung disease clinic.²⁴ He subsequently was diagnosed with deployment-related lung disease, as his constrictive bronchiolitis was thought to be related to exposures encountered during his OEF/OIF deployments from 2003 to 2005.

The patient was monitored with spirometry over the next few months. After observing a 10% decline in forced expiratory volume in 1 second (FEV₁) over 9 months despite stable lung volumes and diffusion capacity, the patient was started on macrolide therapy with erythromycin 500 mg daily. He was switched to azithromycin 250 mg daily due to gastrointestinal AEs of nausea and diarrhea while taking erythromycin. He continued use of an inhaled corticosteroid (ICS), as well as bronchodilator therapy with albuterol and formoterol and had stable dyspnea.

The patient was treated briefly with prednisone 40 mg, but he discontinued this medication after 5 days due to worsening anxiety and PTSD symptoms. Azithromycin therapy was discontinued after 4 years, because no significant improvement was noted in the patient’s lung function. Spirometry, lung volumes, and diffusion testing were unchanged for 2 years following discontinuation of azithromycin and continuing therapy with an ICS, long-acting beta-agonist, and albuterol. The patient has stable dyspnea on exertion but exercises regularly and recently was able to complete a marathon.

Case Study 2

A 43-year-old female ex-smoker presented to a VA chest clinic for evaluation of cough that started during a 2003 deployment to Iraq as well as dyspnea on exertion and chest tightness that had been present since her 2010 to 2011 deployment to Afghanistan. The patient had no history of asthma or other chronic respiratory disease during childhood.

She enlisted in the U.S. Navy in 1987 and later served as a medic while in the Navy Reserves. When she joined the U.S. Navy, she easily passed a 1.5-mile physical fitness readiness test run-time requirement with an 8.5-minute run time. She had no respiratory symptoms and ran in several marathons until her first SWA deployment in 2003.

In April 2003, she was deployed for 3 months to work as a combat medic near the Kuwait and Iraq border. She had frequent exposure to desert dust and recalled 5 sandstorms that appeared like a “wall of sand” coming toward the base. A few weeks into this deployment, the patient developed a nonproductive cough that persisted after returning to the U.S. She stopped smoking for a few months after returning home but continued to have a nonproductive cough. She did not seek further medical attention, because she had no exercise-limiting symptoms.

The patient joined the Army National Guard in 2006 and was activated in 2009 to deploy to Afghanistan from January 2010 through January 2011. She was stationed at Bagram Airbase for the entire deployment and worked as a military police officer in the prison. She had exposure to sandstorms and burn pit combustion products. The prison was about 2 miles downwind from a large burn pit.

In October 2010, she quit smoking again because of new-onset chest tightness and dyspnea on exertion. However, her symptoms did not abate, and she noted increased chest tightness and difficulty catching her breath when running near the burn pit. While she tried to avoid the burn pit, she participated in competitive races and a 10-mile run along paths that were near the burn pit.

After returning from deployment, the patient presented to her VA PCP for evaluation of persistent nonproductive cough, chest tightness, and dyspnea on exertion. She was not taking any respiratory or allergy medications at the time of evaluation. Initial chest X-ray and spirometry were normal, and she was referred to the chest clinic for consultation. At the time of pulmonary consultation, the patient had a total smoking history of 15 pack-years but had now abstained from smoking for about 2 years. She reported residential exposure to pet birds for > 20 years. High-resolution chest imaging and full PFT with lung volumes and diffusion capacity were performed to evaluate for hypersensitivity pneumonitis.

Her vital signs, physical examination pulmonary function testing with spirometry, lung volumes, and diffusion testing were all normal (Table 4). Bronchial challenge to methacholine demonstrated airways hyperresponsiveness at a PC[-20] FEV₁ of 1.25 mg/mL. High-resolution chest CT did not demonstrate air trapping, centrilobular nodules, or other evidence of chronic interstitial lung disease. A cardiopulmonary maximum multistage exercise test with arterial line placement showed normal exercise tolerance with the patient achieving 109% of the maximum predicted workload and 90% of predicted VO₂ max.

The patient was diagnosed with deployment-related asthma based on the finding of airways hyperresponsiveness after bronchial challenge testing. Her asthma was considered deployment-related based on the temporal onset of cough and later chest tightness and dyspnea on exertion that occurred during deployment. Ongoing smoking cessation was emphasized.

The patient was started on bronchodilator therapy with albuterol prior to exercise and as needed, but she continued to have symptoms of chest tightness while exercising. Eventually, a low-dose ICS was initiated in conjunction with albuterol as needed. Her symptoms did not resolve with this regimen, but she did experience improvement in exertional chest tightness. This patient was not referred for biopsy given clinical findings of asthma. She will continue pulmonary monitoring every 6 months. However, if her symptoms worsen, she will undergo full PFT, which includes lung volumes and diffusion testing and possible repeat chest imaging.

Conclusion

These 2 cases are representative of the spectrum of deployment-related lung disease. This assessment requires a detailed chronologic occupational and environmental history, establishing a temporal link between respiratory symptoms and deployment exposures and evidence of lung disease on noninvasive testing (or confirmation by surgical lung biopsy in select cases) in which noninvasive testing is nondiagnostic.

Referral for surgical lung biopsy was particularly helpful in the first case, because it ruled out other lung diseases that are more responsive to systemic therapy. However, referral for surgical lung biopsy is not recommended in all patients, and in-depth discussion of the risks and benefits associated with surgery is recommended. Although diagnostic clarity is a benefit of surgical lung biopsy, the authors also discuss with patients that there is no currently available therapy for deployment-related lung disease and thus management is unlikely to change after biopsy. The recommended approach to diagnostic evaluation is shown in Figure 4.

In the authors’ experience, treatment of deployment-related asthma with standard asthma treatment usually improves or stabilizes respiratory symptoms but often does not result in complete resolution of symptoms. Improvement in lung function with systemic pharmacotherapy in the management of deployment-related lung diseases, such as constrictive bronchiolitis, respiratory bronchiolitis, emphysema, or granulomatous pneumonitis has not been observed. Although little is currently known about prognosis, utilization of data collected from the VA Airborne Hazards and Open Burn Pit Registry may contribute to the understanding of deployment exposures and long-term respiratory health effects.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Military deployed from World War II through the Vietnam War have had enough time for respiratory disorders with both short and long latencies to manifest. More recent deployments over the past 13 years to Iraq, Kuwait, Afghanistan, and other regions in southwest Asia (SWA) have been associated with a unique spectrum of respiratory disorders. The long-term respiratory effects of SWA deployments are unknown. This review will discuss deployment-related lung cancer and then focus primarily on the emerging respiratory disorders related to SWA deployment and case examples of deployment-related lung disease.

As the number of recent veterans in the VA health care system increases, primary care providers (PCPs) and specialists are increasingly faced with questions about potential hazards of deployment, referring patients to the VA Airborne Hazards and Open Burn Pit Registry, and evaluating patients with new-onset respiratory symptoms following deployment. Previous reviews and white papers have offered recommendations for evaluation and management; however, little has been reported in the form of case examples of patients with deployment-related lung disorders and their clinical course.^1,2

Deployment-Associated Lung Cancer

Lung cancer is the leading cause of cancer death in the U.S. and around the world.³ Lung cancer in the U.S. causes more deaths than does the combination of breast, prostate, colon, and rectal cancers. Lung cancer is the second most common cancer and causes more deaths than does any other cancer in the VHA.⁴ Most cancers with an environmental cause have a significant latent period of decades between the exposure and cancer incidence. Thus, although lung cancer risk is relatively low in active-duty military personnel, the rate of lung cancer in VA patients is nearly double that of the general population, suggesting causes associated with military service.⁵

Tobacco

The main cause of lung cancer is tobacco smoking, which accounts for 85% to 90% of lung cancer in the U.S. The latent period between initiation of tobacco smoking and lung cancer incidence is typically ≥ 30 years. Military service has long been associated with tobacco smoking, due to past practices that included the provision of free cigarettes, the availability of cigarettes at reduced cost, smoking breaks, perceived relief from both stress and boredom, and social factors.⁶ More recently, the adverse effects (AEs) of smoking on health and readiness have been appreciated, and many incentives encouraging tobacco smoking have been eliminated. In 2009, the Institute of Medicine called for a tobacco-free military, and both the Secretary of the Navy and Secretary of Defense have seriously considered this change.⁷

The additional effect of deployment on smoking has been reported.⁸ The longitudinal Millennium Cohort study compared several smoking measures between 55,021 deployers and nondeployers who completed both baseline (acquired July 2001-June 2003) and follow-up questionnaires (acquired June 2004-January 2006). Smoking initiation affected 2.3% of deployers and 1.3% of nondeployers; smoking resumption showed a similar pattern with an increase of 39.4% compared with 28.7%. The overall prevalence of smoking increased 44% among nondeployers and 57% among deployers. Those never smokers exposed to combat were 60% more likely to initiate smoking compared with noncombat deployers. Thus, it is clear that tobacco smoking should be considered a deployment-related exposure that contributes to lung cancer risk.

Asbestos

In 1955, Doll published an analysis associating asbestos exposure with risk for lung cancer.⁹ Many naval veterans and shipyard workers had asbestos exposure, resulting in a spectrum of asbestos-related diseases, including bronchogenic cancer.¹⁰

Depleted Uranium

Depleted uranium was used in munitions during the first Gulf War and more recently during military operations in SWA as a part of Operation New Dawn (OND), Operation Iraqi Freedom (OIF), and Operation Enduring Freedom (OEF). Because of concerns of military personnel having complex exposure to depleted uranium, including via inhalation, the VA established the Depleted Uranium Surveillance Program, which has followed a cohort of service members exposed to inhaled depleted uranium during friendly fire in 1991. No significant differences between individuals with high urinary uranium levels and low urinary uranium levels were found in self-reported respiratory symptoms and pulmonary function testing (PFT). Additionally, 20 years after exposure to depleted uranium, there was no statistically significant difference of low-dose chest computed tomography (CT) evidence of lung cancer in these 2 groups.¹¹

Mustard Gas

Mustard gas is considered a definite lung carcinogen.^12,13 Both long-term, low-dose and short-term, high- intensity exposures are known to cause human lung cancer.¹⁴ Mustard gas was first widely used in warfare in World War I. Mustard gas was used in training for World War II; training accidents resulted in acute toxicity even in lower exposures. It was later used as a chemical warfare agent in the Iran-Iraq conflict in the late 1980s and early 1990s. It is estimated that about 4,000 U.S. service members have been acutely exposed to high concentrations of mustard gas. Sulfur mustard may be incorporated into improvised explosive devices, and there is concern that troops in Iraq have been exposed to this agent in sites previously used for manufacturing and storage.¹⁵

Agent Orange

The herbicide Agent Orange is commonly contaminated with dioxin, which has been demonstrated to be a tumor promoter in animal studies. Agent Orange was used widely in the Vietnam War. The National Academy of Sciences issued a report in 2001 reviewing evidence for a link between Agent Orange and various neoplasms. Evidence was strongest for Hodgkin lymphoma and soft tissue sarcoma. The evidence of an association between Agent Orange exposure and lung cancer was deemed only suggestive.¹⁶

Respiratory Disease Associated With Southwest Asia Deployment

Over the past 14 years, > 2.5 million U.S. military personnel and civilian contractors have been deployed as part of 3 major military operations: OEF in Afghanistan (2001 to present), OIF in Iraq (2003 to 2010), and OND in Iraq (2010 to present).^17,18 Deployed personnel encounter a wide variety of inhalational exposures that include desert dust particulate matter, burn pit combustion products, environmental tobacco smoke, vehicular diesel exhaust, debris from detonations and explosions, and other unique or specific job-related exposures (Table 1).^19,20

A number of recent studies have helped identify and characterize an emerging spectrum of deployment-related lung disorders, including asthma, rhinosinusitis, emphysema, bronchiolitis, granulomatous pneumonitis, and less common conditions such as acute eosinophilic pneumonia and rapidly progressive pulmonary fibrosis (Table 2).^20-30 Still, diagnosis of these conditions is often challenging, and traditional diagnostic tools such as PFT and chest radiography may be normal or mildly abnormal despite significant histopathologic abnormalities on surgical lung biopsy.^24,30,31

Deployment-Related Exposures

As listed in Table 1, there are a number of other exposures that may be encountered during deployment. Environmental air sampling was conducted in several locations in Iraq, Afghanistan, and sites in SWA as part of the Enhanced Particulate Matter Survey. All sites were notable for air pollutant levels that exceeded 15 μg/m³, the military exposure guideline for fine particulate matter (PM2.5). The PM2.5 fraction comprised geologic dust, burn pit emissions, and the heavy metals aluminum, cadmium, and lead.^32,33

Respiratory Disorders

Reports of deployers with respiratory symptoms during and after deployment surfaced as early as 2004.³⁴ The Millennium Cohort study reported a 1.7-fold higher rate of new-onset respiratory symptoms that was independent of smoking status, such as cough and shortness of breath, in deployers compared with nondeployers. These increased symptom rates were associated with land-based deployment and longer deployment duration.³⁵ A number of epidemiologic studies also demonstrated an association between respiratory symptoms and environmental exposures encountered during deployment.^36-39

Respiratory diseases such as asthma, acute eosinophilic pneumonia, and constrictive bronchiolitis have been reported following deployment to SWA, but a review of the literature supports a more expansive list of deployment-related respiratory diseases (Table 2).^20-30 The following case examples describe findings in veterans referred to the authors’ clinic for evaluation of chest symptoms associated with deployment.

OEF/OIF/OND Case Studies

Case Study 1

A 42-year-old male never smoker presented to his VA PCP for evaluation of nonproductive cough, dyspnea on exertion, chest tightness, and recurrent episodes of bronchitis since 2004 when he was deployed to Afghanistan. He had no history of asthma or other chronic respiratory disease in childhood or adolescence.

The patient served as a Civil Affairs officer in the U.S. Army and was deployed to Bosnia in 1997, Afghanistan in 2004, and Camp Arif-Jan in Kuwait as well as Mosul, Iraq, in 2005. He was exposed to depleted uranium while serving in Bosnia. He also had exposures to sandstorms, desert dust, and burn pit combustion products while deployed to Afghanistan and Iraq. He developed symptoms of chest tightness and dyspnea on exertion during his 2004 deployment, with these symptoms persisting after returning home from deployment. His symptoms occurred frequently while running and limited his ability to pass his military physical fitness test requirements and train for marathons as he had done previously. He also had symptoms of chest tightness and excessive coughing at rest, which were treated with antibiotics by his medical provider as recurrent acute infectious/viral bronchitis.

The patient was medically discharged from the U.S. Army in July 2005, primarily due to musculoskeletal injuries. His past medical history was notable for PTSD, recurrent allergic rhinosinusitis, and lumbosacral back pain. Given persistent respiratory symptoms of dyspnea after walking 1 block, the patient presented to his VA PCP in early 2006.

The patient’s vital signs and physical examination were normal. Spirometry showed a mixed restrictive and obstructive pattern, prompting referral for pulmonary consultation. Full PFT demonstrated an abnormally increased residual volume and mildly decreased diffusion capacity (Table 3). Laryngoscopy was negative for vocal cord dysfunction. A chest X-ray showed mild airway wall thickening bilaterally in the lower lung fields. Subsequent high-resolution CT of the chest demonstrated diffuse centrilobular nodularity (Figure 1). Serial spirometry measurements over 8 months showed severe and worsening airflow limitation despite treatment with inhaled bronchodilator and corticosteroid therapy. Seeking diagnostic clarity, the patient was referred for surgical lung biopsy via video-assisted thorascopic surgery (VATS) within 6 months of initial consultation.

The patient’s lung biopsy demonstrated constrictive changes in bronchioles, hyperinflation, and multiple chemodectomas in all 3 lobes of the right lung (Figures 2 and 3). Three pulmonary pathologists reviewed the biopsy and confirmed findings of constrictive bronchiolitis. Serologies for connective tissue disease were negative, indicating no autoimmune cause of bronchiolitis.

As no specific etiology was identified, the patient was referred for a second opinion with a pulmonologist with expertise in interstitial lung disease. Finding no evidence of post- infectious or autoimmune bronchiolitis, the patient’s diagnosis of constrictive bronchiolitis was deemed to be idiopathic. A number of years later, following publication of a case series of 38 OEF/OIF deployers with biopsy-proven constrictive bronchiolitis, the patient was referred for consultation to an occupational lung disease clinic.²⁴ He subsequently was diagnosed with deployment-related lung disease, as his constrictive bronchiolitis was thought to be related to exposures encountered during his OEF/OIF deployments from 2003 to 2005.

The patient was monitored with spirometry over the next few months. After observing a 10% decline in forced expiratory volume in 1 second (FEV₁) over 9 months despite stable lung volumes and diffusion capacity, the patient was started on macrolide therapy with erythromycin 500 mg daily. He was switched to azithromycin 250 mg daily due to gastrointestinal AEs of nausea and diarrhea while taking erythromycin. He continued use of an inhaled corticosteroid (ICS), as well as bronchodilator therapy with albuterol and formoterol and had stable dyspnea.

The patient was treated briefly with prednisone 40 mg, but he discontinued this medication after 5 days due to worsening anxiety and PTSD symptoms. Azithromycin therapy was discontinued after 4 years, because no significant improvement was noted in the patient’s lung function. Spirometry, lung volumes, and diffusion testing were unchanged for 2 years following discontinuation of azithromycin and continuing therapy with an ICS, long-acting beta-agonist, and albuterol. The patient has stable dyspnea on exertion but exercises regularly and recently was able to complete a marathon.

Case Study 2

A 43-year-old female ex-smoker presented to a VA chest clinic for evaluation of cough that started during a 2003 deployment to Iraq as well as dyspnea on exertion and chest tightness that had been present since her 2010 to 2011 deployment to Afghanistan. The patient had no history of asthma or other chronic respiratory disease during childhood.

She enlisted in the U.S. Navy in 1987 and later served as a medic while in the Navy Reserves. When she joined the U.S. Navy, she easily passed a 1.5-mile physical fitness readiness test run-time requirement with an 8.5-minute run time. She had no respiratory symptoms and ran in several marathons until her first SWA deployment in 2003.

In April 2003, she was deployed for 3 months to work as a combat medic near the Kuwait and Iraq border. She had frequent exposure to desert dust and recalled 5 sandstorms that appeared like a “wall of sand” coming toward the base. A few weeks into this deployment, the patient developed a nonproductive cough that persisted after returning to the U.S. She stopped smoking for a few months after returning home but continued to have a nonproductive cough. She did not seek further medical attention, because she had no exercise-limiting symptoms.

The patient joined the Army National Guard in 2006 and was activated in 2009 to deploy to Afghanistan from January 2010 through January 2011. She was stationed at Bagram Airbase for the entire deployment and worked as a military police officer in the prison. She had exposure to sandstorms and burn pit combustion products. The prison was about 2 miles downwind from a large burn pit.

In October 2010, she quit smoking again because of new-onset chest tightness and dyspnea on exertion. However, her symptoms did not abate, and she noted increased chest tightness and difficulty catching her breath when running near the burn pit. While she tried to avoid the burn pit, she participated in competitive races and a 10-mile run along paths that were near the burn pit.

After returning from deployment, the patient presented to her VA PCP for evaluation of persistent nonproductive cough, chest tightness, and dyspnea on exertion. She was not taking any respiratory or allergy medications at the time of evaluation. Initial chest X-ray and spirometry were normal, and she was referred to the chest clinic for consultation. At the time of pulmonary consultation, the patient had a total smoking history of 15 pack-years but had now abstained from smoking for about 2 years. She reported residential exposure to pet birds for > 20 years. High-resolution chest imaging and full PFT with lung volumes and diffusion capacity were performed to evaluate for hypersensitivity pneumonitis.

Her vital signs, physical examination pulmonary function testing with spirometry, lung volumes, and diffusion testing were all normal (Table 4). Bronchial challenge to methacholine demonstrated airways hyperresponsiveness at a PC[-20] FEV₁ of 1.25 mg/mL. High-resolution chest CT did not demonstrate air trapping, centrilobular nodules, or other evidence of chronic interstitial lung disease. A cardiopulmonary maximum multistage exercise test with arterial line placement showed normal exercise tolerance with the patient achieving 109% of the maximum predicted workload and 90% of predicted VO₂ max.

The patient was diagnosed with deployment-related asthma based on the finding of airways hyperresponsiveness after bronchial challenge testing. Her asthma was considered deployment-related based on the temporal onset of cough and later chest tightness and dyspnea on exertion that occurred during deployment. Ongoing smoking cessation was emphasized.

The patient was started on bronchodilator therapy with albuterol prior to exercise and as needed, but she continued to have symptoms of chest tightness while exercising. Eventually, a low-dose ICS was initiated in conjunction with albuterol as needed. Her symptoms did not resolve with this regimen, but she did experience improvement in exertional chest tightness. This patient was not referred for biopsy given clinical findings of asthma. She will continue pulmonary monitoring every 6 months. However, if her symptoms worsen, she will undergo full PFT, which includes lung volumes and diffusion testing and possible repeat chest imaging.

Conclusion

These 2 cases are representative of the spectrum of deployment-related lung disease. This assessment requires a detailed chronologic occupational and environmental history, establishing a temporal link between respiratory symptoms and deployment exposures and evidence of lung disease on noninvasive testing (or confirmation by surgical lung biopsy in select cases) in which noninvasive testing is nondiagnostic.

Referral for surgical lung biopsy was particularly helpful in the first case, because it ruled out other lung diseases that are more responsive to systemic therapy. However, referral for surgical lung biopsy is not recommended in all patients, and in-depth discussion of the risks and benefits associated with surgery is recommended. Although diagnostic clarity is a benefit of surgical lung biopsy, the authors also discuss with patients that there is no currently available therapy for deployment-related lung disease and thus management is unlikely to change after biopsy. The recommended approach to diagnostic evaluation is shown in Figure 4.

In the authors’ experience, treatment of deployment-related asthma with standard asthma treatment usually improves or stabilizes respiratory symptoms but often does not result in complete resolution of symptoms. Improvement in lung function with systemic pharmacotherapy in the management of deployment-related lung diseases, such as constrictive bronchiolitis, respiratory bronchiolitis, emphysema, or granulomatous pneumonitis has not been observed. Although little is currently known about prognosis, utilization of data collected from the VA Airborne Hazards and Open Burn Pit Registry may contribute to the understanding of deployment exposures and long-term respiratory health effects.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Military deployed from World War II through the Vietnam War have had enough time for respiratory disorders with both short and long latencies to manifest. More recent deployments over the past 13 years to Iraq, Kuwait, Afghanistan, and other regions in southwest Asia (SWA) have been associated with a unique spectrum of respiratory disorders. The long-term respiratory effects of SWA deployments are unknown. This review will discuss deployment-related lung cancer and then focus primarily on the emerging respiratory disorders related to SWA deployment and case examples of deployment-related lung disease.

As the number of recent veterans in the VA health care system increases, primary care providers (PCPs) and specialists are increasingly faced with questions about potential hazards of deployment, referring patients to the VA Airborne Hazards and Open Burn Pit Registry, and evaluating patients with new-onset respiratory symptoms following deployment. Previous reviews and white papers have offered recommendations for evaluation and management; however, little has been reported in the form of case examples of patients with deployment-related lung disorders and their clinical course.^1,2

Deployment-Associated Lung Cancer

Lung cancer is the leading cause of cancer death in the U.S. and around the world.³ Lung cancer in the U.S. causes more deaths than does the combination of breast, prostate, colon, and rectal cancers. Lung cancer is the second most common cancer and causes more deaths than does any other cancer in the VHA.⁴ Most cancers with an environmental cause have a significant latent period of decades between the exposure and cancer incidence. Thus, although lung cancer risk is relatively low in active-duty military personnel, the rate of lung cancer in VA patients is nearly double that of the general population, suggesting causes associated with military service.⁵

Tobacco

The main cause of lung cancer is tobacco smoking, which accounts for 85% to 90% of lung cancer in the U.S. The latent period between initiation of tobacco smoking and lung cancer incidence is typically ≥ 30 years. Military service has long been associated with tobacco smoking, due to past practices that included the provision of free cigarettes, the availability of cigarettes at reduced cost, smoking breaks, perceived relief from both stress and boredom, and social factors.⁶ More recently, the adverse effects (AEs) of smoking on health and readiness have been appreciated, and many incentives encouraging tobacco smoking have been eliminated. In 2009, the Institute of Medicine called for a tobacco-free military, and both the Secretary of the Navy and Secretary of Defense have seriously considered this change.⁷

The additional effect of deployment on smoking has been reported.⁸ The longitudinal Millennium Cohort study compared several smoking measures between 55,021 deployers and nondeployers who completed both baseline (acquired July 2001-June 2003) and follow-up questionnaires (acquired June 2004-January 2006). Smoking initiation affected 2.3% of deployers and 1.3% of nondeployers; smoking resumption showed a similar pattern with an increase of 39.4% compared with 28.7%. The overall prevalence of smoking increased 44% among nondeployers and 57% among deployers. Those never smokers exposed to combat were 60% more likely to initiate smoking compared with noncombat deployers. Thus, it is clear that tobacco smoking should be considered a deployment-related exposure that contributes to lung cancer risk.

Asbestos

In 1955, Doll published an analysis associating asbestos exposure with risk for lung cancer.⁹ Many naval veterans and shipyard workers had asbestos exposure, resulting in a spectrum of asbestos-related diseases, including bronchogenic cancer.¹⁰

Depleted Uranium

Depleted uranium was used in munitions during the first Gulf War and more recently during military operations in SWA as a part of Operation New Dawn (OND), Operation Iraqi Freedom (OIF), and Operation Enduring Freedom (OEF). Because of concerns of military personnel having complex exposure to depleted uranium, including via inhalation, the VA established the Depleted Uranium Surveillance Program, which has followed a cohort of service members exposed to inhaled depleted uranium during friendly fire in 1991. No significant differences between individuals with high urinary uranium levels and low urinary uranium levels were found in self-reported respiratory symptoms and pulmonary function testing (PFT). Additionally, 20 years after exposure to depleted uranium, there was no statistically significant difference of low-dose chest computed tomography (CT) evidence of lung cancer in these 2 groups.¹¹

Mustard Gas

Mustard gas is considered a definite lung carcinogen.^12,13 Both long-term, low-dose and short-term, high- intensity exposures are known to cause human lung cancer.¹⁴ Mustard gas was first widely used in warfare in World War I. Mustard gas was used in training for World War II; training accidents resulted in acute toxicity even in lower exposures. It was later used as a chemical warfare agent in the Iran-Iraq conflict in the late 1980s and early 1990s. It is estimated that about 4,000 U.S. service members have been acutely exposed to high concentrations of mustard gas. Sulfur mustard may be incorporated into improvised explosive devices, and there is concern that troops in Iraq have been exposed to this agent in sites previously used for manufacturing and storage.¹⁵

Agent Orange

The herbicide Agent Orange is commonly contaminated with dioxin, which has been demonstrated to be a tumor promoter in animal studies. Agent Orange was used widely in the Vietnam War. The National Academy of Sciences issued a report in 2001 reviewing evidence for a link between Agent Orange and various neoplasms. Evidence was strongest for Hodgkin lymphoma and soft tissue sarcoma. The evidence of an association between Agent Orange exposure and lung cancer was deemed only suggestive.¹⁶

Respiratory Disease Associated With Southwest Asia Deployment

Over the past 14 years, > 2.5 million U.S. military personnel and civilian contractors have been deployed as part of 3 major military operations: OEF in Afghanistan (2001 to present), OIF in Iraq (2003 to 2010), and OND in Iraq (2010 to present).^17,18 Deployed personnel encounter a wide variety of inhalational exposures that include desert dust particulate matter, burn pit combustion products, environmental tobacco smoke, vehicular diesel exhaust, debris from detonations and explosions, and other unique or specific job-related exposures (Table 1).^19,20

A number of recent studies have helped identify and characterize an emerging spectrum of deployment-related lung disorders, including asthma, rhinosinusitis, emphysema, bronchiolitis, granulomatous pneumonitis, and less common conditions such as acute eosinophilic pneumonia and rapidly progressive pulmonary fibrosis (Table 2).^20-30 Still, diagnosis of these conditions is often challenging, and traditional diagnostic tools such as PFT and chest radiography may be normal or mildly abnormal despite significant histopathologic abnormalities on surgical lung biopsy.^24,30,31

Deployment-Related Exposures

As listed in Table 1, there are a number of other exposures that may be encountered during deployment. Environmental air sampling was conducted in several locations in Iraq, Afghanistan, and sites in SWA as part of the Enhanced Particulate Matter Survey. All sites were notable for air pollutant levels that exceeded 15 μg/m³, the military exposure guideline for fine particulate matter (PM2.5). The PM2.5 fraction comprised geologic dust, burn pit emissions, and the heavy metals aluminum, cadmium, and lead.^32,33

Respiratory Disorders

Reports of deployers with respiratory symptoms during and after deployment surfaced as early as 2004.³⁴ The Millennium Cohort study reported a 1.7-fold higher rate of new-onset respiratory symptoms that was independent of smoking status, such as cough and shortness of breath, in deployers compared with nondeployers. These increased symptom rates were associated with land-based deployment and longer deployment duration.³⁵ A number of epidemiologic studies also demonstrated an association between respiratory symptoms and environmental exposures encountered during deployment.^36-39

Respiratory diseases such as asthma, acute eosinophilic pneumonia, and constrictive bronchiolitis have been reported following deployment to SWA, but a review of the literature supports a more expansive list of deployment-related respiratory diseases (Table 2).^20-30 The following case examples describe findings in veterans referred to the authors’ clinic for evaluation of chest symptoms associated with deployment.

OEF/OIF/OND Case Studies

Case Study 1

A 42-year-old male never smoker presented to his VA PCP for evaluation of nonproductive cough, dyspnea on exertion, chest tightness, and recurrent episodes of bronchitis since 2004 when he was deployed to Afghanistan. He had no history of asthma or other chronic respiratory disease in childhood or adolescence.

The patient served as a Civil Affairs officer in the U.S. Army and was deployed to Bosnia in 1997, Afghanistan in 2004, and Camp Arif-Jan in Kuwait as well as Mosul, Iraq, in 2005. He was exposed to depleted uranium while serving in Bosnia. He also had exposures to sandstorms, desert dust, and burn pit combustion products while deployed to Afghanistan and Iraq. He developed symptoms of chest tightness and dyspnea on exertion during his 2004 deployment, with these symptoms persisting after returning home from deployment. His symptoms occurred frequently while running and limited his ability to pass his military physical fitness test requirements and train for marathons as he had done previously. He also had symptoms of chest tightness and excessive coughing at rest, which were treated with antibiotics by his medical provider as recurrent acute infectious/viral bronchitis.

The patient was medically discharged from the U.S. Army in July 2005, primarily due to musculoskeletal injuries. His past medical history was notable for PTSD, recurrent allergic rhinosinusitis, and lumbosacral back pain. Given persistent respiratory symptoms of dyspnea after walking 1 block, the patient presented to his VA PCP in early 2006.

The patient’s vital signs and physical examination were normal. Spirometry showed a mixed restrictive and obstructive pattern, prompting referral for pulmonary consultation. Full PFT demonstrated an abnormally increased residual volume and mildly decreased diffusion capacity (Table 3). Laryngoscopy was negative for vocal cord dysfunction. A chest X-ray showed mild airway wall thickening bilaterally in the lower lung fields. Subsequent high-resolution CT of the chest demonstrated diffuse centrilobular nodularity (Figure 1). Serial spirometry measurements over 8 months showed severe and worsening airflow limitation despite treatment with inhaled bronchodilator and corticosteroid therapy. Seeking diagnostic clarity, the patient was referred for surgical lung biopsy via video-assisted thorascopic surgery (VATS) within 6 months of initial consultation.

The patient’s lung biopsy demonstrated constrictive changes in bronchioles, hyperinflation, and multiple chemodectomas in all 3 lobes of the right lung (Figures 2 and 3). Three pulmonary pathologists reviewed the biopsy and confirmed findings of constrictive bronchiolitis. Serologies for connective tissue disease were negative, indicating no autoimmune cause of bronchiolitis.

As no specific etiology was identified, the patient was referred for a second opinion with a pulmonologist with expertise in interstitial lung disease. Finding no evidence of post- infectious or autoimmune bronchiolitis, the patient’s diagnosis of constrictive bronchiolitis was deemed to be idiopathic. A number of years later, following publication of a case series of 38 OEF/OIF deployers with biopsy-proven constrictive bronchiolitis, the patient was referred for consultation to an occupational lung disease clinic.²⁴ He subsequently was diagnosed with deployment-related lung disease, as his constrictive bronchiolitis was thought to be related to exposures encountered during his OEF/OIF deployments from 2003 to 2005.

The patient was monitored with spirometry over the next few months. After observing a 10% decline in forced expiratory volume in 1 second (FEV₁) over 9 months despite stable lung volumes and diffusion capacity, the patient was started on macrolide therapy with erythromycin 500 mg daily. He was switched to azithromycin 250 mg daily due to gastrointestinal AEs of nausea and diarrhea while taking erythromycin. He continued use of an inhaled corticosteroid (ICS), as well as bronchodilator therapy with albuterol and formoterol and had stable dyspnea.

The patient was treated briefly with prednisone 40 mg, but he discontinued this medication after 5 days due to worsening anxiety and PTSD symptoms. Azithromycin therapy was discontinued after 4 years, because no significant improvement was noted in the patient’s lung function. Spirometry, lung volumes, and diffusion testing were unchanged for 2 years following discontinuation of azithromycin and continuing therapy with an ICS, long-acting beta-agonist, and albuterol. The patient has stable dyspnea on exertion but exercises regularly and recently was able to complete a marathon.

Case Study 2

A 43-year-old female ex-smoker presented to a VA chest clinic for evaluation of cough that started during a 2003 deployment to Iraq as well as dyspnea on exertion and chest tightness that had been present since her 2010 to 2011 deployment to Afghanistan. The patient had no history of asthma or other chronic respiratory disease during childhood.

She enlisted in the U.S. Navy in 1987 and later served as a medic while in the Navy Reserves. When she joined the U.S. Navy, she easily passed a 1.5-mile physical fitness readiness test run-time requirement with an 8.5-minute run time. She had no respiratory symptoms and ran in several marathons until her first SWA deployment in 2003.

In April 2003, she was deployed for 3 months to work as a combat medic near the Kuwait and Iraq border. She had frequent exposure to desert dust and recalled 5 sandstorms that appeared like a “wall of sand” coming toward the base. A few weeks into this deployment, the patient developed a nonproductive cough that persisted after returning to the U.S. She stopped smoking for a few months after returning home but continued to have a nonproductive cough. She did not seek further medical attention, because she had no exercise-limiting symptoms.

The patient joined the Army National Guard in 2006 and was activated in 2009 to deploy to Afghanistan from January 2010 through January 2011. She was stationed at Bagram Airbase for the entire deployment and worked as a military police officer in the prison. She had exposure to sandstorms and burn pit combustion products. The prison was about 2 miles downwind from a large burn pit.

In October 2010, she quit smoking again because of new-onset chest tightness and dyspnea on exertion. However, her symptoms did not abate, and she noted increased chest tightness and difficulty catching her breath when running near the burn pit. While she tried to avoid the burn pit, she participated in competitive races and a 10-mile run along paths that were near the burn pit.

After returning from deployment, the patient presented to her VA PCP for evaluation of persistent nonproductive cough, chest tightness, and dyspnea on exertion. She was not taking any respiratory or allergy medications at the time of evaluation. Initial chest X-ray and spirometry were normal, and she was referred to the chest clinic for consultation. At the time of pulmonary consultation, the patient had a total smoking history of 15 pack-years but had now abstained from smoking for about 2 years. She reported residential exposure to pet birds for > 20 years. High-resolution chest imaging and full PFT with lung volumes and diffusion capacity were performed to evaluate for hypersensitivity pneumonitis.

Her vital signs, physical examination pulmonary function testing with spirometry, lung volumes, and diffusion testing were all normal (Table 4). Bronchial challenge to methacholine demonstrated airways hyperresponsiveness at a PC[-20] FEV₁ of 1.25 mg/mL. High-resolution chest CT did not demonstrate air trapping, centrilobular nodules, or other evidence of chronic interstitial lung disease. A cardiopulmonary maximum multistage exercise test with arterial line placement showed normal exercise tolerance with the patient achieving 109% of the maximum predicted workload and 90% of predicted VO₂ max.

The patient was diagnosed with deployment-related asthma based on the finding of airways hyperresponsiveness after bronchial challenge testing. Her asthma was considered deployment-related based on the temporal onset of cough and later chest tightness and dyspnea on exertion that occurred during deployment. Ongoing smoking cessation was emphasized.

The patient was started on bronchodilator therapy with albuterol prior to exercise and as needed, but she continued to have symptoms of chest tightness while exercising. Eventually, a low-dose ICS was initiated in conjunction with albuterol as needed. Her symptoms did not resolve with this regimen, but she did experience improvement in exertional chest tightness. This patient was not referred for biopsy given clinical findings of asthma. She will continue pulmonary monitoring every 6 months. However, if her symptoms worsen, she will undergo full PFT, which includes lung volumes and diffusion testing and possible repeat chest imaging.

Conclusion

These 2 cases are representative of the spectrum of deployment-related lung disease. This assessment requires a detailed chronologic occupational and environmental history, establishing a temporal link between respiratory symptoms and deployment exposures and evidence of lung disease on noninvasive testing (or confirmation by surgical lung biopsy in select cases) in which noninvasive testing is nondiagnostic.

Referral for surgical lung biopsy was particularly helpful in the first case, because it ruled out other lung diseases that are more responsive to systemic therapy. However, referral for surgical lung biopsy is not recommended in all patients, and in-depth discussion of the risks and benefits associated with surgery is recommended. Although diagnostic clarity is a benefit of surgical lung biopsy, the authors also discuss with patients that there is no currently available therapy for deployment-related lung disease and thus management is unlikely to change after biopsy. The recommended approach to diagnostic evaluation is shown in Figure 4.

In the authors’ experience, treatment of deployment-related asthma with standard asthma treatment usually improves or stabilizes respiratory symptoms but often does not result in complete resolution of symptoms. Improvement in lung function with systemic pharmacotherapy in the management of deployment-related lung diseases, such as constrictive bronchiolitis, respiratory bronchiolitis, emphysema, or granulomatous pneumonitis has not been observed. Although little is currently known about prognosis, utilization of data collected from the VA Airborne Hazards and Open Burn Pit Registry may contribute to the understanding of deployment exposures and long-term respiratory health effects.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Carpal tunnel release is one of the most common hand surgeries performed at the North Florida/South Georgia Veterans Health System (NFSGVHS). Depending on surgeon experience and comfort level, surgeries are performed through either the traditional open method or the endoscopic method, single or double port (Figures 1 and 2). The advantage of the endoscopic method is faster recovery and return to work; however, the endoscopic method requires more expensive equipment and a steeper learning curve for surgeons. Complications are uncommon but can create unsatisfactory patient experiences because of costly lost workdays and long travel distances to the medical facility.

The purpose of this study was to compare the endoscopic method with the open carpal tunnel release method to determine whether there was an increased complication risk. Researchers anticipated that this information would help surgeons better inform patients of operative risks and prompt changes in NFSGVHS treatment plans to improve the quality of veteran care.

Methods

An Institutional Review Board- approved (#647-2011) retrospective review was done of patients who had carpal tunnel surgery performed by the NFSGVHS plastic surgery service from January 1, 2005, to December 31, 2010. Surgeries included in the review took place at the Malcom Randall VAMC in Gainesville and at the Lake City VAMC, both in Florida. Most of the surgeries included in the study were performed by a resident or fellow under the supervision of an attending physician. Eight different attending surgeons staffed the operations. Seven were board-certified or board-eligible plastic surgeons, 2 had advanced hand fellowship training, and 1 was a general surgeon with hand fellowship training. All hand fellowship-trained surgeons were in their first year of practice at the time of the study.

Only primary carpal tunnel releases were included in the study. Exclusion criteria included patients who were operated on by a service section other than the plastic surgery service (orthopedics or neurosurgery) and hands on which other procedures were performed during the same operation. Charts were reviewed for up to 1 year post surgery. Complications that required intervention were recorded. Researchers did not include pillar tenderness or an increase in occupational therapy visits as complications, due to the wide variety of patient tolerance to postoperative pain and varying motivation to return to work and daily routine.

Methods of release were endoscopic, open, or endoscopic converted to open. All but 6 of the completed endoscopic surgeries were performed using the double port Chow technique. The other 6 endoscopic surgeries were performed using the single port Agee technique at the distal wrist crease. There were 3 endoscopic converted to open cases that were performed using a single port, proximally-based technique in the midpalm. This method was abandoned after 3 unsuccessful endoscopic attempts, 1 resulting in digital nerve injury despite interactive cadaver labs prior to operative experience.

Endoscopic surgeries converted to open were recorded as open surgeries, because the patients had the full invasive experience. Researchers used the chi-square test and P value < .05 to compare the different methods of carpal tunnel release with identified complications.

Results and Complications

A total of 584 hands belonging to 452 patients were included in the study. Patients included 395 men and 57 women aged from 33 to 91 years. There were 271 endoscopic releases, 228 open releases, and 85 endoscopic converted to open releases. The NFSGVHS conversion rate was 23.7%. Complications in the converted cases (n = 4) were included in the open release results.

There were 40 complications in 38 hands. The overall complication rate was 6.5%. Complications noted were tendonitis presenting as De Quervain disease or trigger finger (9 endoscopic surgeries; 6 open surgeries), infection (2 endoscopic surgeries; 6 open surgeries), wound dehiscence (5 open surgeries), nerve injury (1 open surgery), respiratory distress (1 endoscopic), complex regional pain syndrome (1 open surgery), and scheduled returns to the operating room (OR) for recurrent, ongoing, or worsening symptoms (5 endoscopic surgeries; 5 open surgeries). Complications with an n > 1 were evaluated for statistical significance with P value < .05 (Table 1).

The NFSGVHS study had 10 patients return to the OR for open exploration (Table 2). Nine of these patients went back to the OR based on symptoms consistent with nerve conduction studies that had deteriorated compared with their preoperative studies. One endoscopic case was brought back to the OR for a suspected nerve injury without nerve conduction studies. Findings during reoperation included scar adhesions, incomplete release of ligaments, digital nerve injury, and negative explorations.

Two hypothenar fat transfers were performed to prevent scar adhesions in cases that had originally been open releases.¹ Two of the open cases were endoscopic converted to open cases. One went back to the OR with a suspected nerve injury. Dense adhesions and an injured common digital nerve were identified and repaired. The second converted case that went back to the OR had a suspected, but unconfirmed, nerve injury to the motor branch. The diagnosis and treatment were delayed for more than a year due to the patient having other pressing medical and family concerns. An exploration found significant scar adhesions, and an opponensplasty was performed.

One patient had respiratory insufficiency secondary to chemical pneumonitis. The patient was sedated during an endoscopic carpal tunnel release, aspirated, and kept intubated in the intensive care unit until the morning after surgery.

An early complex regional pain syndrome diagnosis was made in a patient with underlying neuropathy and a preoperative “profound” median neuropathies diagnosis at the wrist with underlying peripheral neuropathy found on nerve conduction studies. The patient experienced an unusual amount of postoperative pain and edema after an uncomplicated open carpal tunnel release. This was treated with rapid intervention using anti- inflammatories and hand therapy. The patient also started a regimen of skin care, edema management, neuroreeducation, and contrast baths. Symptoms responded within a week.

There were 12 wound complications: 10 in open and 2 in endoscopic surgeries. Total wound complications were equally split between patients with and without diabetes. Infection and dehiscence were noted. Sutures were removed an average of 9.6 days after surgery in the patients whose wounds broke down. A statistically significant relationship was found only between the open method of release and wound dehiscence (P < .05).

There was no statistically significant difference in the overall complication rate in the NFSGVHS population when comparing endoscopic with open carpal tunnel release or when comparing the risk of postoperative tendonitis, wound infection, or return to the OR.

Discussion

Carpal tunnel syndrome was documented by James Paget in mid-19th century in reference to a distal radius fracture.² It is the most common peripheral nerve compression, with an incidence ranging from 1 to 3 cases per 1,000 subjects per year and a prevalence of 50 cases per 1,000 subjects per year.³ In an active-duty U.S. military population, the incidence of carpal tunnel syndrome is 3.98 per 1,000 person years.⁴

Related: Risk Factors for Postoperative Complications in Trigger Finger Release

The endoscopic method of release was first introduced in 1989 by Okutsu and colleagues.⁵ About 500,000 carpal tunnel releases are now performed in the U.S. every year, with 50,000 performed endoscopically.³ There were 185 carpal tunnel releases (56 endoscopic and 129 open) performed at the NFSGVHS in 2012.⁶ The minimally invasive procedure was designed to preserve the overlying skin and fascia, promoting an earlier return to work and daily activities. This is particularly relevant for manual workers who desire rapid return of grip strength. Multiple published reports have found more rapid recovery based on a reduction in scar tenderness, increase in grip strength, or return to work.^7-13 Patients seem to have equivalent results over the long term, ranging from 3 months to 1 year.^7,8,13-15 Return to work was not evaluated in this study, because many patients were either retired or not working steadily.

The endoscopic method was criticized after its introduction due to its potential increase in major structural injury to the median nerve, ulnar nerve, palmar arch, ulnar artery, or flexor tendons.¹⁶ A meta-analysis found improved outcomes but a statistically significant higher complication rate in endoscopic, compared with open release (2.2% in endoscopic vs 1.2% in open).¹⁶ Referral patterns have found iatrogenic nerve injury in patients referred by surgeons without formal hand fellowship training.¹⁷ There is a wide variety of background training for surgeons who may offer carpal tunnel release, including plastic surgery, orthopedics, general surgery, and neurosurgery.

Related: Arthritis, Infectious Tenosynovitis, and Tendon Rupture in a Patient With Rheumatoid Arthritis and Psoriasis

Major structural injuries were reported by hand surgeons using both open and endoscopic methods in a questionnaire sent to members of the American Society for Surgery of the Hand, indicating that either approach demands respect.¹⁸ A large review of the literature from 1966 to 2001 by Benson and colleagues found that the endoscopic approach was not more likely to produce injury to tendons, arteries, or nerves compared with the open approach and actually had a lower rate of structural damage (0.49% vs 0.19%).¹⁹ Researchers who conducted this study confirmed one common digital nerve injury in an endoscopic converted to open technique, using a distally-based port with the blade not being deployed via the endoscopic method. The endoscopic method has been found to have a higher rate of reversible nerve injury (neuropraxia) compared with the open technique.^7,10,19

The NFSGVHS results found a higher rate of wound dehiscence. More frequent wound site complications, particularly infection, hypertrophic scar, and scar tenderness have been noted using the open method.^3,8,20 This is probably due to the deeper and slightly larger incision used for the open method compared with the smaller and shallower incisions used for the endoscopic release.

There is the inevitable learning curve for the endoscopic release due to the more complicated nature of the procedure. The NFSGVHS conversion rate was 23.7% over the 5-year period from 2005 to 2010. All 3 fellowship- trained hand surgeons were in their first year of practice at the time of the study, so the authors anticipate a lower conversion rate in forthcoming studies. The NFSGVHS researchers did not consider converting to an open technique to be a complication and believe it is appropriate to teach plastic surgery residents and fellows to have a low threshold to convert when visualization is not optimal and the potential for significant injury exists. The learning curve and a higher conversion rate have been acknowledged by Beck and colleagues with no increase in morbidity.²¹

The authors anticipated finding an increased rate of tendonitis in the endoscopic method, as found by Goshtasby and colleagues, where trigger finger was found more frequently in the endoscopic patients.²² The NFSGVHS study found that the number of patients presenting for steroid injections to treat postoperative tendonitis in the hand and wrist was not statistically significant when comparing the 2 surgical methods of release (3.3% in endoscopic vs 1.9% in open; P = .28).

The NFSGVHS rate of return to the OR within a year of surgery was 1.7%. The researchers from NFSGHVS anticipated a higher rate of return to the OR for ongoing symptoms secondary to incomplete release of the transverse carpal ligament. Published studies have found an intact retinaculum to be a cause of persistent symptoms when smaller incisions are used.^23,24 Five endoscopic cases and 5 open cases eventually returned to the OR for carpal tunnel exploration. Two of the patients were classified as recurrent, because they had improvement of symptoms initially but presented > 6 months later with new symptoms. Eight of the patients were classified as persistent, because they did not have an extended period of relief of preoperative symptoms (Table 2).²⁵ There was no statistically significant difference in return to the OR in the 2 study groups. The NFSGVHS researchers did note a trend in more incomplete nerve releases in the endoscopic group and more scar adhesions as the etiology of symptoms in the open group who went back to surgery.

Published studies have found no difference in overall complication rates when comparing the open with the endoscopic method of release, which is consistent with NFSGVHS data.^8,11,12,26

A limitation of the current retrospective study is the large number of providers who both operated on the patients and documented their postoperative findings. The strength of the study is that VA patients tend to stay within the VISN for their health care so postoperative problems will be identified and routed to the plastic surgery service for evaluation and treatment.

Clinical implications for the NFSGVHS practice are that surgeons can confidently offer both the open and endoscopic surgeries without an overall risk of increased complications to patients. Patients who are identified as higher risk for wound dehiscence, such as those who place an unusual amount of pressure on their palms due to assisted walking devices or are at a higher risk of falling onto the surgical site, will be steered toward an endoscopic surgery. The NFSGVHS began a splinting protocol in the early postoperative period that was not previously used on those select patients who have open carpal tunnel releases.

Conclusion

Wound dehiscence was the only statistically significant complication found in the NFSGVHS veteran population when comparing open with endoscopic carpal tunnel release. This can potentially be prevented in future patients by delaying the removal of sutures and prolonging the use of a protective dressing in patients who undergo open release. There was not a statistically significant increase in overall complications when using the minimally invasive method of release, which is consistent with existing literature.

Acknowledgement
This material is the result of work supported with resources and the use of facilities at the Malcom Randall VAMC.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Carpal tunnel release is one of the most common hand surgeries performed at the North Florida/South Georgia Veterans Health System (NFSGVHS). Depending on surgeon experience and comfort level, surgeries are performed through either the traditional open method or the endoscopic method, single or double port (Figures 1 and 2). The advantage of the endoscopic method is faster recovery and return to work; however, the endoscopic method requires more expensive equipment and a steeper learning curve for surgeons. Complications are uncommon but can create unsatisfactory patient experiences because of costly lost workdays and long travel distances to the medical facility.

The purpose of this study was to compare the endoscopic method with the open carpal tunnel release method to determine whether there was an increased complication risk. Researchers anticipated that this information would help surgeons better inform patients of operative risks and prompt changes in NFSGVHS treatment plans to improve the quality of veteran care.

Methods

An Institutional Review Board- approved (#647-2011) retrospective review was done of patients who had carpal tunnel surgery performed by the NFSGVHS plastic surgery service from January 1, 2005, to December 31, 2010. Surgeries included in the review took place at the Malcom Randall VAMC in Gainesville and at the Lake City VAMC, both in Florida. Most of the surgeries included in the study were performed by a resident or fellow under the supervision of an attending physician. Eight different attending surgeons staffed the operations. Seven were board-certified or board-eligible plastic surgeons, 2 had advanced hand fellowship training, and 1 was a general surgeon with hand fellowship training. All hand fellowship-trained surgeons were in their first year of practice at the time of the study.

Only primary carpal tunnel releases were included in the study. Exclusion criteria included patients who were operated on by a service section other than the plastic surgery service (orthopedics or neurosurgery) and hands on which other procedures were performed during the same operation. Charts were reviewed for up to 1 year post surgery. Complications that required intervention were recorded. Researchers did not include pillar tenderness or an increase in occupational therapy visits as complications, due to the wide variety of patient tolerance to postoperative pain and varying motivation to return to work and daily routine.

Methods of release were endoscopic, open, or endoscopic converted to open. All but 6 of the completed endoscopic surgeries were performed using the double port Chow technique. The other 6 endoscopic surgeries were performed using the single port Agee technique at the distal wrist crease. There were 3 endoscopic converted to open cases that were performed using a single port, proximally-based technique in the midpalm. This method was abandoned after 3 unsuccessful endoscopic attempts, 1 resulting in digital nerve injury despite interactive cadaver labs prior to operative experience.

Endoscopic surgeries converted to open were recorded as open surgeries, because the patients had the full invasive experience. Researchers used the chi-square test and P value < .05 to compare the different methods of carpal tunnel release with identified complications.

Results and Complications

A total of 584 hands belonging to 452 patients were included in the study. Patients included 395 men and 57 women aged from 33 to 91 years. There were 271 endoscopic releases, 228 open releases, and 85 endoscopic converted to open releases. The NFSGVHS conversion rate was 23.7%. Complications in the converted cases (n = 4) were included in the open release results.

There were 40 complications in 38 hands. The overall complication rate was 6.5%. Complications noted were tendonitis presenting as De Quervain disease or trigger finger (9 endoscopic surgeries; 6 open surgeries), infection (2 endoscopic surgeries; 6 open surgeries), wound dehiscence (5 open surgeries), nerve injury (1 open surgery), respiratory distress (1 endoscopic), complex regional pain syndrome (1 open surgery), and scheduled returns to the operating room (OR) for recurrent, ongoing, or worsening symptoms (5 endoscopic surgeries; 5 open surgeries). Complications with an n > 1 were evaluated for statistical significance with P value < .05 (Table 1).

The NFSGVHS study had 10 patients return to the OR for open exploration (Table 2). Nine of these patients went back to the OR based on symptoms consistent with nerve conduction studies that had deteriorated compared with their preoperative studies. One endoscopic case was brought back to the OR for a suspected nerve injury without nerve conduction studies. Findings during reoperation included scar adhesions, incomplete release of ligaments, digital nerve injury, and negative explorations.

Two hypothenar fat transfers were performed to prevent scar adhesions in cases that had originally been open releases.¹ Two of the open cases were endoscopic converted to open cases. One went back to the OR with a suspected nerve injury. Dense adhesions and an injured common digital nerve were identified and repaired. The second converted case that went back to the OR had a suspected, but unconfirmed, nerve injury to the motor branch. The diagnosis and treatment were delayed for more than a year due to the patient having other pressing medical and family concerns. An exploration found significant scar adhesions, and an opponensplasty was performed.

One patient had respiratory insufficiency secondary to chemical pneumonitis. The patient was sedated during an endoscopic carpal tunnel release, aspirated, and kept intubated in the intensive care unit until the morning after surgery.

An early complex regional pain syndrome diagnosis was made in a patient with underlying neuropathy and a preoperative “profound” median neuropathies diagnosis at the wrist with underlying peripheral neuropathy found on nerve conduction studies. The patient experienced an unusual amount of postoperative pain and edema after an uncomplicated open carpal tunnel release. This was treated with rapid intervention using anti- inflammatories and hand therapy. The patient also started a regimen of skin care, edema management, neuroreeducation, and contrast baths. Symptoms responded within a week.

There were 12 wound complications: 10 in open and 2 in endoscopic surgeries. Total wound complications were equally split between patients with and without diabetes. Infection and dehiscence were noted. Sutures were removed an average of 9.6 days after surgery in the patients whose wounds broke down. A statistically significant relationship was found only between the open method of release and wound dehiscence (P < .05).

There was no statistically significant difference in the overall complication rate in the NFSGVHS population when comparing endoscopic with open carpal tunnel release or when comparing the risk of postoperative tendonitis, wound infection, or return to the OR.

Discussion

Carpal tunnel syndrome was documented by James Paget in mid-19th century in reference to a distal radius fracture.² It is the most common peripheral nerve compression, with an incidence ranging from 1 to 3 cases per 1,000 subjects per year and a prevalence of 50 cases per 1,000 subjects per year.³ In an active-duty U.S. military population, the incidence of carpal tunnel syndrome is 3.98 per 1,000 person years.⁴

Related: Risk Factors for Postoperative Complications in Trigger Finger Release

The endoscopic method of release was first introduced in 1989 by Okutsu and colleagues.⁵ About 500,000 carpal tunnel releases are now performed in the U.S. every year, with 50,000 performed endoscopically.³ There were 185 carpal tunnel releases (56 endoscopic and 129 open) performed at the NFSGVHS in 2012.⁶ The minimally invasive procedure was designed to preserve the overlying skin and fascia, promoting an earlier return to work and daily activities. This is particularly relevant for manual workers who desire rapid return of grip strength. Multiple published reports have found more rapid recovery based on a reduction in scar tenderness, increase in grip strength, or return to work.^7-13 Patients seem to have equivalent results over the long term, ranging from 3 months to 1 year.^7,8,13-15 Return to work was not evaluated in this study, because many patients were either retired or not working steadily.

The endoscopic method was criticized after its introduction due to its potential increase in major structural injury to the median nerve, ulnar nerve, palmar arch, ulnar artery, or flexor tendons.¹⁶ A meta-analysis found improved outcomes but a statistically significant higher complication rate in endoscopic, compared with open release (2.2% in endoscopic vs 1.2% in open).¹⁶ Referral patterns have found iatrogenic nerve injury in patients referred by surgeons without formal hand fellowship training.¹⁷ There is a wide variety of background training for surgeons who may offer carpal tunnel release, including plastic surgery, orthopedics, general surgery, and neurosurgery.

Related: Arthritis, Infectious Tenosynovitis, and Tendon Rupture in a Patient With Rheumatoid Arthritis and Psoriasis

Major structural injuries were reported by hand surgeons using both open and endoscopic methods in a questionnaire sent to members of the American Society for Surgery of the Hand, indicating that either approach demands respect.¹⁸ A large review of the literature from 1966 to 2001 by Benson and colleagues found that the endoscopic approach was not more likely to produce injury to tendons, arteries, or nerves compared with the open approach and actually had a lower rate of structural damage (0.49% vs 0.19%).¹⁹ Researchers who conducted this study confirmed one common digital nerve injury in an endoscopic converted to open technique, using a distally-based port with the blade not being deployed via the endoscopic method. The endoscopic method has been found to have a higher rate of reversible nerve injury (neuropraxia) compared with the open technique.^7,10,19

The NFSGVHS results found a higher rate of wound dehiscence. More frequent wound site complications, particularly infection, hypertrophic scar, and scar tenderness have been noted using the open method.^3,8,20 This is probably due to the deeper and slightly larger incision used for the open method compared with the smaller and shallower incisions used for the endoscopic release.

There is the inevitable learning curve for the endoscopic release due to the more complicated nature of the procedure. The NFSGVHS conversion rate was 23.7% over the 5-year period from 2005 to 2010. All 3 fellowship- trained hand surgeons were in their first year of practice at the time of the study, so the authors anticipate a lower conversion rate in forthcoming studies. The NFSGVHS researchers did not consider converting to an open technique to be a complication and believe it is appropriate to teach plastic surgery residents and fellows to have a low threshold to convert when visualization is not optimal and the potential for significant injury exists. The learning curve and a higher conversion rate have been acknowledged by Beck and colleagues with no increase in morbidity.²¹

The authors anticipated finding an increased rate of tendonitis in the endoscopic method, as found by Goshtasby and colleagues, where trigger finger was found more frequently in the endoscopic patients.²² The NFSGVHS study found that the number of patients presenting for steroid injections to treat postoperative tendonitis in the hand and wrist was not statistically significant when comparing the 2 surgical methods of release (3.3% in endoscopic vs 1.9% in open; P = .28).

The NFSGVHS rate of return to the OR within a year of surgery was 1.7%. The researchers from NFSGHVS anticipated a higher rate of return to the OR for ongoing symptoms secondary to incomplete release of the transverse carpal ligament. Published studies have found an intact retinaculum to be a cause of persistent symptoms when smaller incisions are used.^23,24 Five endoscopic cases and 5 open cases eventually returned to the OR for carpal tunnel exploration. Two of the patients were classified as recurrent, because they had improvement of symptoms initially but presented > 6 months later with new symptoms. Eight of the patients were classified as persistent, because they did not have an extended period of relief of preoperative symptoms (Table 2).²⁵ There was no statistically significant difference in return to the OR in the 2 study groups. The NFSGVHS researchers did note a trend in more incomplete nerve releases in the endoscopic group and more scar adhesions as the etiology of symptoms in the open group who went back to surgery.

Published studies have found no difference in overall complication rates when comparing the open with the endoscopic method of release, which is consistent with NFSGVHS data.^8,11,12,26

A limitation of the current retrospective study is the large number of providers who both operated on the patients and documented their postoperative findings. The strength of the study is that VA patients tend to stay within the VISN for their health care so postoperative problems will be identified and routed to the plastic surgery service for evaluation and treatment.

Clinical implications for the NFSGVHS practice are that surgeons can confidently offer both the open and endoscopic surgeries without an overall risk of increased complications to patients. Patients who are identified as higher risk for wound dehiscence, such as those who place an unusual amount of pressure on their palms due to assisted walking devices or are at a higher risk of falling onto the surgical site, will be steered toward an endoscopic surgery. The NFSGVHS began a splinting protocol in the early postoperative period that was not previously used on those select patients who have open carpal tunnel releases.

Conclusion

Wound dehiscence was the only statistically significant complication found in the NFSGVHS veteran population when comparing open with endoscopic carpal tunnel release. This can potentially be prevented in future patients by delaying the removal of sutures and prolonging the use of a protective dressing in patients who undergo open release. There was not a statistically significant increase in overall complications when using the minimally invasive method of release, which is consistent with existing literature.

Acknowledgement
This material is the result of work supported with resources and the use of facilities at the Malcom Randall VAMC.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Carpal tunnel release is one of the most common hand surgeries performed at the North Florida/South Georgia Veterans Health System (NFSGVHS). Depending on surgeon experience and comfort level, surgeries are performed through either the traditional open method or the endoscopic method, single or double port (Figures 1 and 2). The advantage of the endoscopic method is faster recovery and return to work; however, the endoscopic method requires more expensive equipment and a steeper learning curve for surgeons. Complications are uncommon but can create unsatisfactory patient experiences because of costly lost workdays and long travel distances to the medical facility.

The purpose of this study was to compare the endoscopic method with the open carpal tunnel release method to determine whether there was an increased complication risk. Researchers anticipated that this information would help surgeons better inform patients of operative risks and prompt changes in NFSGVHS treatment plans to improve the quality of veteran care.

Methods

An Institutional Review Board- approved (#647-2011) retrospective review was done of patients who had carpal tunnel surgery performed by the NFSGVHS plastic surgery service from January 1, 2005, to December 31, 2010. Surgeries included in the review took place at the Malcom Randall VAMC in Gainesville and at the Lake City VAMC, both in Florida. Most of the surgeries included in the study were performed by a resident or fellow under the supervision of an attending physician. Eight different attending surgeons staffed the operations. Seven were board-certified or board-eligible plastic surgeons, 2 had advanced hand fellowship training, and 1 was a general surgeon with hand fellowship training. All hand fellowship-trained surgeons were in their first year of practice at the time of the study.

Only primary carpal tunnel releases were included in the study. Exclusion criteria included patients who were operated on by a service section other than the plastic surgery service (orthopedics or neurosurgery) and hands on which other procedures were performed during the same operation. Charts were reviewed for up to 1 year post surgery. Complications that required intervention were recorded. Researchers did not include pillar tenderness or an increase in occupational therapy visits as complications, due to the wide variety of patient tolerance to postoperative pain and varying motivation to return to work and daily routine.

Methods of release were endoscopic, open, or endoscopic converted to open. All but 6 of the completed endoscopic surgeries were performed using the double port Chow technique. The other 6 endoscopic surgeries were performed using the single port Agee technique at the distal wrist crease. There were 3 endoscopic converted to open cases that were performed using a single port, proximally-based technique in the midpalm. This method was abandoned after 3 unsuccessful endoscopic attempts, 1 resulting in digital nerve injury despite interactive cadaver labs prior to operative experience.

Endoscopic surgeries converted to open were recorded as open surgeries, because the patients had the full invasive experience. Researchers used the chi-square test and P value < .05 to compare the different methods of carpal tunnel release with identified complications.

Results and Complications

A total of 584 hands belonging to 452 patients were included in the study. Patients included 395 men and 57 women aged from 33 to 91 years. There were 271 endoscopic releases, 228 open releases, and 85 endoscopic converted to open releases. The NFSGVHS conversion rate was 23.7%. Complications in the converted cases (n = 4) were included in the open release results.

There were 40 complications in 38 hands. The overall complication rate was 6.5%. Complications noted were tendonitis presenting as De Quervain disease or trigger finger (9 endoscopic surgeries; 6 open surgeries), infection (2 endoscopic surgeries; 6 open surgeries), wound dehiscence (5 open surgeries), nerve injury (1 open surgery), respiratory distress (1 endoscopic), complex regional pain syndrome (1 open surgery), and scheduled returns to the operating room (OR) for recurrent, ongoing, or worsening symptoms (5 endoscopic surgeries; 5 open surgeries). Complications with an n > 1 were evaluated for statistical significance with P value < .05 (Table 1).

The NFSGVHS study had 10 patients return to the OR for open exploration (Table 2). Nine of these patients went back to the OR based on symptoms consistent with nerve conduction studies that had deteriorated compared with their preoperative studies. One endoscopic case was brought back to the OR for a suspected nerve injury without nerve conduction studies. Findings during reoperation included scar adhesions, incomplete release of ligaments, digital nerve injury, and negative explorations.

Two hypothenar fat transfers were performed to prevent scar adhesions in cases that had originally been open releases.¹ Two of the open cases were endoscopic converted to open cases. One went back to the OR with a suspected nerve injury. Dense adhesions and an injured common digital nerve were identified and repaired. The second converted case that went back to the OR had a suspected, but unconfirmed, nerve injury to the motor branch. The diagnosis and treatment were delayed for more than a year due to the patient having other pressing medical and family concerns. An exploration found significant scar adhesions, and an opponensplasty was performed.

One patient had respiratory insufficiency secondary to chemical pneumonitis. The patient was sedated during an endoscopic carpal tunnel release, aspirated, and kept intubated in the intensive care unit until the morning after surgery.

An early complex regional pain syndrome diagnosis was made in a patient with underlying neuropathy and a preoperative “profound” median neuropathies diagnosis at the wrist with underlying peripheral neuropathy found on nerve conduction studies. The patient experienced an unusual amount of postoperative pain and edema after an uncomplicated open carpal tunnel release. This was treated with rapid intervention using anti- inflammatories and hand therapy. The patient also started a regimen of skin care, edema management, neuroreeducation, and contrast baths. Symptoms responded within a week.

There were 12 wound complications: 10 in open and 2 in endoscopic surgeries. Total wound complications were equally split between patients with and without diabetes. Infection and dehiscence were noted. Sutures were removed an average of 9.6 days after surgery in the patients whose wounds broke down. A statistically significant relationship was found only between the open method of release and wound dehiscence (P < .05).

There was no statistically significant difference in the overall complication rate in the NFSGVHS population when comparing endoscopic with open carpal tunnel release or when comparing the risk of postoperative tendonitis, wound infection, or return to the OR.

Discussion

Carpal tunnel syndrome was documented by James Paget in mid-19th century in reference to a distal radius fracture.² It is the most common peripheral nerve compression, with an incidence ranging from 1 to 3 cases per 1,000 subjects per year and a prevalence of 50 cases per 1,000 subjects per year.³ In an active-duty U.S. military population, the incidence of carpal tunnel syndrome is 3.98 per 1,000 person years.⁴

Related: Risk Factors for Postoperative Complications in Trigger Finger Release

The endoscopic method of release was first introduced in 1989 by Okutsu and colleagues.⁵ About 500,000 carpal tunnel releases are now performed in the U.S. every year, with 50,000 performed endoscopically.³ There were 185 carpal tunnel releases (56 endoscopic and 129 open) performed at the NFSGVHS in 2012.⁶ The minimally invasive procedure was designed to preserve the overlying skin and fascia, promoting an earlier return to work and daily activities. This is particularly relevant for manual workers who desire rapid return of grip strength. Multiple published reports have found more rapid recovery based on a reduction in scar tenderness, increase in grip strength, or return to work.^7-13 Patients seem to have equivalent results over the long term, ranging from 3 months to 1 year.^7,8,13-15 Return to work was not evaluated in this study, because many patients were either retired or not working steadily.

The endoscopic method was criticized after its introduction due to its potential increase in major structural injury to the median nerve, ulnar nerve, palmar arch, ulnar artery, or flexor tendons.¹⁶ A meta-analysis found improved outcomes but a statistically significant higher complication rate in endoscopic, compared with open release (2.2% in endoscopic vs 1.2% in open).¹⁶ Referral patterns have found iatrogenic nerve injury in patients referred by surgeons without formal hand fellowship training.¹⁷ There is a wide variety of background training for surgeons who may offer carpal tunnel release, including plastic surgery, orthopedics, general surgery, and neurosurgery.

Related: Arthritis, Infectious Tenosynovitis, and Tendon Rupture in a Patient With Rheumatoid Arthritis and Psoriasis

Major structural injuries were reported by hand surgeons using both open and endoscopic methods in a questionnaire sent to members of the American Society for Surgery of the Hand, indicating that either approach demands respect.¹⁸ A large review of the literature from 1966 to 2001 by Benson and colleagues found that the endoscopic approach was not more likely to produce injury to tendons, arteries, or nerves compared with the open approach and actually had a lower rate of structural damage (0.49% vs 0.19%).¹⁹ Researchers who conducted this study confirmed one common digital nerve injury in an endoscopic converted to open technique, using a distally-based port with the blade not being deployed via the endoscopic method. The endoscopic method has been found to have a higher rate of reversible nerve injury (neuropraxia) compared with the open technique.^7,10,19

The NFSGVHS results found a higher rate of wound dehiscence. More frequent wound site complications, particularly infection, hypertrophic scar, and scar tenderness have been noted using the open method.^3,8,20 This is probably due to the deeper and slightly larger incision used for the open method compared with the smaller and shallower incisions used for the endoscopic release.

There is the inevitable learning curve for the endoscopic release due to the more complicated nature of the procedure. The NFSGVHS conversion rate was 23.7% over the 5-year period from 2005 to 2010. All 3 fellowship- trained hand surgeons were in their first year of practice at the time of the study, so the authors anticipate a lower conversion rate in forthcoming studies. The NFSGVHS researchers did not consider converting to an open technique to be a complication and believe it is appropriate to teach plastic surgery residents and fellows to have a low threshold to convert when visualization is not optimal and the potential for significant injury exists. The learning curve and a higher conversion rate have been acknowledged by Beck and colleagues with no increase in morbidity.²¹

The authors anticipated finding an increased rate of tendonitis in the endoscopic method, as found by Goshtasby and colleagues, where trigger finger was found more frequently in the endoscopic patients.²² The NFSGVHS study found that the number of patients presenting for steroid injections to treat postoperative tendonitis in the hand and wrist was not statistically significant when comparing the 2 surgical methods of release (3.3% in endoscopic vs 1.9% in open; P = .28).

The NFSGVHS rate of return to the OR within a year of surgery was 1.7%. The researchers from NFSGHVS anticipated a higher rate of return to the OR for ongoing symptoms secondary to incomplete release of the transverse carpal ligament. Published studies have found an intact retinaculum to be a cause of persistent symptoms when smaller incisions are used.^23,24 Five endoscopic cases and 5 open cases eventually returned to the OR for carpal tunnel exploration. Two of the patients were classified as recurrent, because they had improvement of symptoms initially but presented > 6 months later with new symptoms. Eight of the patients were classified as persistent, because they did not have an extended period of relief of preoperative symptoms (Table 2).²⁵ There was no statistically significant difference in return to the OR in the 2 study groups. The NFSGVHS researchers did note a trend in more incomplete nerve releases in the endoscopic group and more scar adhesions as the etiology of symptoms in the open group who went back to surgery.

Published studies have found no difference in overall complication rates when comparing the open with the endoscopic method of release, which is consistent with NFSGVHS data.^8,11,12,26

A limitation of the current retrospective study is the large number of providers who both operated on the patients and documented their postoperative findings. The strength of the study is that VA patients tend to stay within the VISN for their health care so postoperative problems will be identified and routed to the plastic surgery service for evaluation and treatment.

Clinical implications for the NFSGVHS practice are that surgeons can confidently offer both the open and endoscopic surgeries without an overall risk of increased complications to patients. Patients who are identified as higher risk for wound dehiscence, such as those who place an unusual amount of pressure on their palms due to assisted walking devices or are at a higher risk of falling onto the surgical site, will be steered toward an endoscopic surgery. The NFSGVHS began a splinting protocol in the early postoperative period that was not previously used on those select patients who have open carpal tunnel releases.

Conclusion

Wound dehiscence was the only statistically significant complication found in the NFSGVHS veteran population when comparing open with endoscopic carpal tunnel release. This can potentially be prevented in future patients by delaying the removal of sutures and prolonging the use of a protective dressing in patients who undergo open release. There was not a statistically significant increase in overall complications when using the minimally invasive method of release, which is consistent with existing literature.

Acknowledgement
This material is the result of work supported with resources and the use of facilities at the Malcom Randall VAMC.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

When follicular mucinosis (FM) is defined as an epithelial reaction pattern characterized by intrafollicular and perifollicular mucin accumulation, it cannot be considered a distinct disease entity, as this pattern is ubiquitously present in various inflammatory and neoplastic skin conditions.^1,2 The distinction between idiopathic FM and lymphoma-associated follicular mucinosis (LAFM) was made several years ago by authors who evaluated the differences in the clinical presentation of these entities, including patient age at onset, number of lesions, pattern of distribution, and most importantly clinical progression.¹ In this article, we discuss the importance of close clinical follow-up in patients with FM or patch-stage mycosis fungoides (MF) in whom histopathologic evaluation is ambiguous or nondiagnostic. We also highlight the value of ancillary testing, including T-cell receptor gene rearrangement, flow cytometry, and immunohistochemistry, as a component in the diagnostic process rather than the sole diagnostic moiety. A review of the pertinent literature also is performed.

History of FM and MF
Pinkus³ first described an entity he termed alopecia mucinosa in 1957. Pinkus noted 3 distinct patterns: an idiopathic form of alopecia mucinosa, lymphoblastoma with associated FM, and alopecia mucinosa that later transformed into lymphoblastoma.⁴ In 1983, however, Pinkus⁴ described uncertainty if alopecia mucinosa represented the first stage of MF or if patients with alopecia mucinosa were simply at an increased risk for developing lymphoma. He believed there were too many cases of lymphoma following a diagnosis of alopecia mucinosa for the relation to be coincidental, yet he noted that many of the cases resolved either spontaneously or following treatment with x-rays or topical steroids. He concluded his report with a sentiment that is echoed in many current studies regarding this entity: “Many questions surrounding this entity are as unanswerable today as they were 25 years ago.”⁴

Jablonska et al⁵ were the first to coin the term mucinosis follicularis, now known as FM, to replace alopecia mucinosa because they felt the description was more accurate, as lesions also arise on non–hair-bearing skin. Although there is general agreement that there is a form of MF that has associated FM, this is where the agreement ends with regard to the diagnosis of MF versus FM. Böer et al⁶ discussed the historic evolution of these terms, mostly to highlight the origins of the confusion. The investigators proposed that FM should only be used as a descriptive term and that all cases of alopecia mucinosa represent MF. They also concluded that many benign dermatoses associated with a risk for evolution to MF (eg, small and large plaque psoriasis [LPP]) should simply be diagnosed as MF.⁶ Subsequently, the proposal that idiopathic FM and LAFM are not 2 distinct entities but rather a clinicopathologic continuum and that idiopathic FM is simply a variant of MF along this spectrum has gained some approval.^6,7 However, this belief is not shared among all authorities in the field, and attempts to define diagnostic criteria that distinguish between a benign clinical course and a course that is more progressive and fatal continue. Currently, it is agreed upon that when distinguishing between these 2 clinical courses, primary (idiopathic) follicular mucinosis refers to a benign course with no overt sign of malignancy, and lymphoma-associated follicular mucinosis refers to a diagnostic malignant condition. Lymphoma-associated follicular mucinosis refers to FM associated with cutaneous T-cell lymphoma, the most common form of which is FM. Many authors^8-15 have sought ancillary methodologies in addition to clinical parameters to assist in the evaluation between both disease courses. Methodologies have included assessment of T-cell receptor gene rearrangements, flow cytometry, and immunohistochemical staining, mostly as an effort to establish monoclonality as a defining characteristic of LAFM; however, monoclonality in cutaneous T-cell infiltrates should be interpreted with caution and should not be considered as a confirmation of malignancy due to recent findings of monoclonality in benign inflammatory dermatoses such as lichen planus. The Table outlines several of the most common benign inflammatory dermatoses that demonstrate monoclonality, but this list should not be considered exhaustive, as there are many others in which monoclonality is sometimes seen.^8-15 The lack of definitive criteria to distinguish between the 2 groups has led to confusion and consternation regarding the diagnosis of idiopathic FM versus LAFM and has led many in the field to consider the 2 conditions to be one and the same.

Diagnosis of FM and MF: Clinicopathologic Features
The World Health Organization (WHO) defined MF as an epidermotropic primary cutaneous T-cell lymphoma (CTCL) characterized by infiltrates of small- to medium-sized T lymphocytes with cerebriform nuclei. Further, the WHO stated that the term mycosis fungoides should be exclusively reserved for classical cases typified by the evolution of cutaneous patches, plaques, and tumors, or for variants that show a similar clinical course.¹⁶ Mycosis fungoides is divided into 3 stages—patch, plaque, and tumor—which are solely clinical descriptors.¹⁷ The WHO also described a clinical staging system with pathologic emphasis placed only on lymph node involvement and identification of Sézary cells.¹⁶ It lists folliculotropic MF as a variant, with only some cases presenting with mucinous degeneration of hair follicles. A lack of consensus among pathologists regarding criteria for diagnosis in patch-stage MF remains, but diagnosis of plaque-stage disease is not regularly debated due to its more reliably present, well-developed histologic features (eg, haloed lymphocytes, epidermotropism of lymphocytes, lymphocytes with convoluted nuceli, Pautrier microabscesses).¹⁸ Although there have been specific histologic findings reported to be associated with patch-stage MF, they have only been present in a few cases and are therefore of limited usefulness in practice.^1,19 The categorization of patients with subtle histologic features common to both MF and inflammatory conditions such as parapsoriasis en plaques (the term plaque in this case is a misnomer because the word plaque means patch in French) continues to be elusive. A lack of agreement regarding LPP persists in the current literature in the same manner as FM. Some researchers have contended for many years that LPP is a type of MF, while others remain unconvinced, mainly due to the lack of evidence that lumping a benign condition (LPP) with an increased risk for malignant transformation and a known malignancy (MF) together is of any benefit to the patient. Assessment of clinicopathologic correlation, immunohistochemistry, clonality, and T-cell gene rearrangement have failed to positively identify patients who are at risk for disease progression, whether the diagnosis is called LPP or early patch-stage MF.²⁰

Mycosis fungoides is more common in males and its incidence increases with age; however, diagnosis should not be ruled out based on age or gender. Typical presentation of early-stage disease includes erythematous patches or plaques, often with light scaling.¹⁹ Lesions routinely are of long-standing duration (months to years), are located in areas that are infrequently exposed to sunlight, and often are 5 cm in diameter or larger with irregular borders.²¹ Associated poikiloderma is relatively specific to MF but rarely is seen in other CTCLs, connective-tissue diseases, and some genodermatoses. Poikiloderma commonly is identified in LPP, which shows the same telangiectasia, mottled pigmentation, and epidermal atrophy as MF-associated poikiloderma, leading some to believe that there is no separation between the 2 conditions. In all stages of MF, lesions frequently are numerous and occur on multiple sites. Plaques and tumors can show spontaneous ulceration. When lesions are folliculotropic, they can cause localized alopecia, follicular-based papules, and fungating pseudotumors in more advanced stages.¹ The clinical presentation of FM substantially overlaps with folliculotropic MF, and although FM lesions often are solitary and are located on the face or scalp, they also can present as multiple lesions located elsewhere on the body. It also has been proposed that folliculotropic MF should not be separated from FM-associated MF (or LAFM).²²

The characteristic histologic picture of LAFM in patch or plaque stage shows mucin deposition within hair follicles, similar to idiopathic FM. On histology, both conditions demonstrate dense lymphoid infiltrates around and within hair follicles as well as in the dermis (Figure). Most cases of LAFM show epidermotropism of lymphocytes between follicles, but this finding is not present in every case and often disappears when the disease advances to the tumor stage.^1,19 Although Pautrier microabscesses (collections of lymphocytes within the superficial epidermis) are considered to be somewhat specific to MF, they are only present in a minority of cases.²⁰ In a study by the International Society for Cutaneous Lymphomas,²¹ the only histopathologic criteria that showed any appreciable sensitivity or specificity in the diagnosis of MF were the presence of lymphoid cells with variable nuclear and cytoplasmic features and/or strikingly irregular nuclear contours with the presence of lymphocytes larger than those usually seen in inflammatory dermatoses. Despite these criteria, the study reported a high misclassification rate. A complicated scoring system for diagnosis of MF in patch- or early plaque-stage disease was proposed by the International Society for Cutaneous Lymphomas,²¹ which integrates clinical, histopathologic, molecular, and immunophenotypic criteria. However, these criteria have been continually debated in the literature and are only discussed in this article in relation to the association between MF and FM. Diagnosis of tumor-stage MF is not addressed in this article, as it is readily identified as lymphoma and is not easily confused with idiopathic FM.

Histopathology of 2 separate cases, both diagnosed as follicular mucinosis pending further follow-up. After close clinical follow-up, one case was diagnosed as mycosis fungoides (A) and the other as follicular mucinosis (B)(both H&E, original magnification ×2). Immunohistochemical stains were noncontributory, and T-cell gene rearrangement was positive only in the case of mycosis fungoides. Histopathology revealed mucin deposition in the hair follicles and a dense lymphoid infiltrate around and within the follicles in both cases. Pautrier microabscesses, cerebriform nuclei, and epidermotropism of lymphocytes between follicles were absent in the case of mycosis fungoides.

Clinical assessment of a patient’s medical history to identify persistent and progressive disease is paramount to the diagnosis of MF. Although MF lesions tend to increase in size and number over time, this presentation is not without exception.²¹ In early patch-stage disease, eliminating some of the patient’s current medications may be sufficient in clearing cutaneous patches that cannot be conclusively identified as either MF or a benign inflammatory lymphoid infiltrate, which further emphasizes the importance of clinical assessment of the patient’s medical history in the diagnosis of MF. The shape of the lesions also is helpful in distinguishing between MF and other skin disorders, such as digitate dermatosis or LPP; unlike the latter, the waxing and waning nature of MF lesions often produces irregularly shaped patches with little coalescence. Again, there are some investigators who believe that these lesions represent varying presentations of MF.⁶

In a study by Cerroni et al,¹ 44 patients with FM were divided into 2 groups: (1) a cohort of 16 patients with no history or clinical evidence of MF or Sézary syndrome (ie, LAFM), and (2) a cohort of 28 patients with clinicopathologic evidence of CTCL. Patients in both groups were followed for a maximum of 20 years. Results indicated that that the presence of perifollicular or intrafollicular mucin, epidermotropism of lymphocytes, monoclonality, and epidemiologic characteristics (eg, age, sex, race) cannot reliably distinguish the 2 disease forms. Furthermore, it was suggested that these conditions are not mutually exclusive entities and are actually variants of CTCL. The observation that the 2 diseases share prognostic overlap adds further credence to the already puzzling conundrum. Nineteen of 28 patients with MF were alive and well at follow-up, and all patients in the idiopathic FM group were alive, with only 9 of 16 patients showing residual disease and none with CTCL.¹

Other clinical factors that may be helpful in the diagnosis of MF are the presentation of lesions in non–sun-exposed areas of the skin and multiple lesions, as unilesional MF is exceedingly uncommon.²¹ No histologic features have been proven to predict which early patch- or plaque-stage MFs will progress to full-blown CTCL versus benign idiopathic FM; thus, great caution should be taken in patients with early-stage disease to ensure they are not prematurely and/or incorrectly classified as CTCL. Such a diagnosis has medical, social, and economical ramifications that should not be overlooked.

If idiopathic FM and LAFM were considered distinct disease processes, the ambiguity in making a definitive diagnosis should give the physician pause, and a diagnosis of LAFM may only be appropriate when there is unequivocal clinicopathologic evidence. Otherwise, a lymphoma diagnosis is somewhat superfluous and potentially harmful. Definitive diagnosis of LAFM also is complicated by reports of other hematologic malignancies presenting with FM-like histopathologic findings, such as chronic myelogenous leukemia, leukemia-associated eosinophilic folliculitis, and acute myeloblastic leukemia.^23,24 Although MF is the most common malignancy associated with FM, it is important to consider other less common malignancies that also may be present.

Diagnosis: Patient Consequences
Accurate diagnosis of idiopathic FM versus LAFM is critical, as the ramifications of a cancer diagnosis can have broad implications. For example, patients who receive cancer diagnoses often experience emotional trauma and social stigma, even when adequate patient education has been provided. The incidence of depression and anxiety also can increase following a cancer diagnosis and can be complicated by medical treatments (eg, systemic steroids, interferon),²⁵ which are known to increase the frequency of these psychological disturbances. Health insurance premiums likely will be higher if a patient is diagnosed with cancer versus a benign inflammatory condition. Hesitation of the pathologist to assign a cancer diagnosis when unequivocal evidence is not present should not be regarded as trickery, malpractice, or deceit of the health care bylaws, as benign language with suggestion of close clinical follow-up in the setting of diagnostic uncertainty will “first, do no harm” and secondly, serve as a vehicle for patient advocacy.

If there is a definitive distinction between idiopathic FM and LAFM, it requires further research before it can be fully understood. Currently, the WHO does not recognize a diagnosis of FM-associated MF (or LAFM) and acknowledges that folliculotropic MF is not always associated with FM.^16,26 Given uncertainty and repercussions associated with a cancer diagnosis, however indolent, it may be morally responsible and medically favorable for physicians to consider FM in the differential diagnosis when applicable rather than making a diagnosis of MF outright. Given the importance of both clinical and histologic factors, it may be beneficial for definitive diagnosis of FM versus MF to lie with the clinician, while the pathologist serves as an adjunct in the diagnostic process. Because the prognosis of idiopathic FM often is marred by possible transformation into MF or other CTCLs, therapeutic decisions should be dictated by close clinical follow-up. Additionally, stage of disease, patient age, treatment compliance, comorbidities, and possible side effects of medications should all be considered when evaluating potential therapeutic regimens.²⁷

Conclusion
Research is underway to more accurately identify patients with FM who are at risk for progression to LAFM versus those with benign remitting FM. Once the required diagnostic criteria are established to accurately classify these patients, with an emphasis on prognosis and suggested treatments, it might be necessary to establish new, less debated terminology so pathologists and clinicians alike can improve patient care. Continued histopathologic scrutiny, use of sophisticated molecular techniques, and knowledge of other currently undiscovered modalities will shed light on this important disease process and aid in proper disease management, which may be advantageous to both patients and physicians.

When follicular mucinosis (FM) is defined as an epithelial reaction pattern characterized by intrafollicular and perifollicular mucin accumulation, it cannot be considered a distinct disease entity, as this pattern is ubiquitously present in various inflammatory and neoplastic skin conditions.^1,2 The distinction between idiopathic FM and lymphoma-associated follicular mucinosis (LAFM) was made several years ago by authors who evaluated the differences in the clinical presentation of these entities, including patient age at onset, number of lesions, pattern of distribution, and most importantly clinical progression.¹ In this article, we discuss the importance of close clinical follow-up in patients with FM or patch-stage mycosis fungoides (MF) in whom histopathologic evaluation is ambiguous or nondiagnostic. We also highlight the value of ancillary testing, including T-cell receptor gene rearrangement, flow cytometry, and immunohistochemistry, as a component in the diagnostic process rather than the sole diagnostic moiety. A review of the pertinent literature also is performed.

History of FM and MF
Pinkus³ first described an entity he termed alopecia mucinosa in 1957. Pinkus noted 3 distinct patterns: an idiopathic form of alopecia mucinosa, lymphoblastoma with associated FM, and alopecia mucinosa that later transformed into lymphoblastoma.⁴ In 1983, however, Pinkus⁴ described uncertainty if alopecia mucinosa represented the first stage of MF or if patients with alopecia mucinosa were simply at an increased risk for developing lymphoma. He believed there were too many cases of lymphoma following a diagnosis of alopecia mucinosa for the relation to be coincidental, yet he noted that many of the cases resolved either spontaneously or following treatment with x-rays or topical steroids. He concluded his report with a sentiment that is echoed in many current studies regarding this entity: “Many questions surrounding this entity are as unanswerable today as they were 25 years ago.”⁴

Jablonska et al⁵ were the first to coin the term mucinosis follicularis, now known as FM, to replace alopecia mucinosa because they felt the description was more accurate, as lesions also arise on non–hair-bearing skin. Although there is general agreement that there is a form of MF that has associated FM, this is where the agreement ends with regard to the diagnosis of MF versus FM. Böer et al⁶ discussed the historic evolution of these terms, mostly to highlight the origins of the confusion. The investigators proposed that FM should only be used as a descriptive term and that all cases of alopecia mucinosa represent MF. They also concluded that many benign dermatoses associated with a risk for evolution to MF (eg, small and large plaque psoriasis [LPP]) should simply be diagnosed as MF.⁶ Subsequently, the proposal that idiopathic FM and LAFM are not 2 distinct entities but rather a clinicopathologic continuum and that idiopathic FM is simply a variant of MF along this spectrum has gained some approval.^6,7 However, this belief is not shared among all authorities in the field, and attempts to define diagnostic criteria that distinguish between a benign clinical course and a course that is more progressive and fatal continue. Currently, it is agreed upon that when distinguishing between these 2 clinical courses, primary (idiopathic) follicular mucinosis refers to a benign course with no overt sign of malignancy, and lymphoma-associated follicular mucinosis refers to a diagnostic malignant condition. Lymphoma-associated follicular mucinosis refers to FM associated with cutaneous T-cell lymphoma, the most common form of which is FM. Many authors^8-15 have sought ancillary methodologies in addition to clinical parameters to assist in the evaluation between both disease courses. Methodologies have included assessment of T-cell receptor gene rearrangements, flow cytometry, and immunohistochemical staining, mostly as an effort to establish monoclonality as a defining characteristic of LAFM; however, monoclonality in cutaneous T-cell infiltrates should be interpreted with caution and should not be considered as a confirmation of malignancy due to recent findings of monoclonality in benign inflammatory dermatoses such as lichen planus. The Table outlines several of the most common benign inflammatory dermatoses that demonstrate monoclonality, but this list should not be considered exhaustive, as there are many others in which monoclonality is sometimes seen.^8-15 The lack of definitive criteria to distinguish between the 2 groups has led to confusion and consternation regarding the diagnosis of idiopathic FM versus LAFM and has led many in the field to consider the 2 conditions to be one and the same.

Diagnosis of FM and MF: Clinicopathologic Features
The World Health Organization (WHO) defined MF as an epidermotropic primary cutaneous T-cell lymphoma (CTCL) characterized by infiltrates of small- to medium-sized T lymphocytes with cerebriform nuclei. Further, the WHO stated that the term mycosis fungoides should be exclusively reserved for classical cases typified by the evolution of cutaneous patches, plaques, and tumors, or for variants that show a similar clinical course.¹⁶ Mycosis fungoides is divided into 3 stages—patch, plaque, and tumor—which are solely clinical descriptors.¹⁷ The WHO also described a clinical staging system with pathologic emphasis placed only on lymph node involvement and identification of Sézary cells.¹⁶ It lists folliculotropic MF as a variant, with only some cases presenting with mucinous degeneration of hair follicles. A lack of consensus among pathologists regarding criteria for diagnosis in patch-stage MF remains, but diagnosis of plaque-stage disease is not regularly debated due to its more reliably present, well-developed histologic features (eg, haloed lymphocytes, epidermotropism of lymphocytes, lymphocytes with convoluted nuceli, Pautrier microabscesses).¹⁸ Although there have been specific histologic findings reported to be associated with patch-stage MF, they have only been present in a few cases and are therefore of limited usefulness in practice.^1,19 The categorization of patients with subtle histologic features common to both MF and inflammatory conditions such as parapsoriasis en plaques (the term plaque in this case is a misnomer because the word plaque means patch in French) continues to be elusive. A lack of agreement regarding LPP persists in the current literature in the same manner as FM. Some researchers have contended for many years that LPP is a type of MF, while others remain unconvinced, mainly due to the lack of evidence that lumping a benign condition (LPP) with an increased risk for malignant transformation and a known malignancy (MF) together is of any benefit to the patient. Assessment of clinicopathologic correlation, immunohistochemistry, clonality, and T-cell gene rearrangement have failed to positively identify patients who are at risk for disease progression, whether the diagnosis is called LPP or early patch-stage MF.²⁰

Mycosis fungoides is more common in males and its incidence increases with age; however, diagnosis should not be ruled out based on age or gender. Typical presentation of early-stage disease includes erythematous patches or plaques, often with light scaling.¹⁹ Lesions routinely are of long-standing duration (months to years), are located in areas that are infrequently exposed to sunlight, and often are 5 cm in diameter or larger with irregular borders.²¹ Associated poikiloderma is relatively specific to MF but rarely is seen in other CTCLs, connective-tissue diseases, and some genodermatoses. Poikiloderma commonly is identified in LPP, which shows the same telangiectasia, mottled pigmentation, and epidermal atrophy as MF-associated poikiloderma, leading some to believe that there is no separation between the 2 conditions. In all stages of MF, lesions frequently are numerous and occur on multiple sites. Plaques and tumors can show spontaneous ulceration. When lesions are folliculotropic, they can cause localized alopecia, follicular-based papules, and fungating pseudotumors in more advanced stages.¹ The clinical presentation of FM substantially overlaps with folliculotropic MF, and although FM lesions often are solitary and are located on the face or scalp, they also can present as multiple lesions located elsewhere on the body. It also has been proposed that folliculotropic MF should not be separated from FM-associated MF (or LAFM).²²

The characteristic histologic picture of LAFM in patch or plaque stage shows mucin deposition within hair follicles, similar to idiopathic FM. On histology, both conditions demonstrate dense lymphoid infiltrates around and within hair follicles as well as in the dermis (Figure). Most cases of LAFM show epidermotropism of lymphocytes between follicles, but this finding is not present in every case and often disappears when the disease advances to the tumor stage.^1,19 Although Pautrier microabscesses (collections of lymphocytes within the superficial epidermis) are considered to be somewhat specific to MF, they are only present in a minority of cases.²⁰ In a study by the International Society for Cutaneous Lymphomas,²¹ the only histopathologic criteria that showed any appreciable sensitivity or specificity in the diagnosis of MF were the presence of lymphoid cells with variable nuclear and cytoplasmic features and/or strikingly irregular nuclear contours with the presence of lymphocytes larger than those usually seen in inflammatory dermatoses. Despite these criteria, the study reported a high misclassification rate. A complicated scoring system for diagnosis of MF in patch- or early plaque-stage disease was proposed by the International Society for Cutaneous Lymphomas,²¹ which integrates clinical, histopathologic, molecular, and immunophenotypic criteria. However, these criteria have been continually debated in the literature and are only discussed in this article in relation to the association between MF and FM. Diagnosis of tumor-stage MF is not addressed in this article, as it is readily identified as lymphoma and is not easily confused with idiopathic FM.

Histopathology of 2 separate cases, both diagnosed as follicular mucinosis pending further follow-up. After close clinical follow-up, one case was diagnosed as mycosis fungoides (A) and the other as follicular mucinosis (B)(both H&E, original magnification ×2). Immunohistochemical stains were noncontributory, and T-cell gene rearrangement was positive only in the case of mycosis fungoides. Histopathology revealed mucin deposition in the hair follicles and a dense lymphoid infiltrate around and within the follicles in both cases. Pautrier microabscesses, cerebriform nuclei, and epidermotropism of lymphocytes between follicles were absent in the case of mycosis fungoides.

Clinical assessment of a patient’s medical history to identify persistent and progressive disease is paramount to the diagnosis of MF. Although MF lesions tend to increase in size and number over time, this presentation is not without exception.²¹ In early patch-stage disease, eliminating some of the patient’s current medications may be sufficient in clearing cutaneous patches that cannot be conclusively identified as either MF or a benign inflammatory lymphoid infiltrate, which further emphasizes the importance of clinical assessment of the patient’s medical history in the diagnosis of MF. The shape of the lesions also is helpful in distinguishing between MF and other skin disorders, such as digitate dermatosis or LPP; unlike the latter, the waxing and waning nature of MF lesions often produces irregularly shaped patches with little coalescence. Again, there are some investigators who believe that these lesions represent varying presentations of MF.⁶

In a study by Cerroni et al,¹ 44 patients with FM were divided into 2 groups: (1) a cohort of 16 patients with no history or clinical evidence of MF or Sézary syndrome (ie, LAFM), and (2) a cohort of 28 patients with clinicopathologic evidence of CTCL. Patients in both groups were followed for a maximum of 20 years. Results indicated that that the presence of perifollicular or intrafollicular mucin, epidermotropism of lymphocytes, monoclonality, and epidemiologic characteristics (eg, age, sex, race) cannot reliably distinguish the 2 disease forms. Furthermore, it was suggested that these conditions are not mutually exclusive entities and are actually variants of CTCL. The observation that the 2 diseases share prognostic overlap adds further credence to the already puzzling conundrum. Nineteen of 28 patients with MF were alive and well at follow-up, and all patients in the idiopathic FM group were alive, with only 9 of 16 patients showing residual disease and none with CTCL.¹

Other clinical factors that may be helpful in the diagnosis of MF are the presentation of lesions in non–sun-exposed areas of the skin and multiple lesions, as unilesional MF is exceedingly uncommon.²¹ No histologic features have been proven to predict which early patch- or plaque-stage MFs will progress to full-blown CTCL versus benign idiopathic FM; thus, great caution should be taken in patients with early-stage disease to ensure they are not prematurely and/or incorrectly classified as CTCL. Such a diagnosis has medical, social, and economical ramifications that should not be overlooked.

If idiopathic FM and LAFM were considered distinct disease processes, the ambiguity in making a definitive diagnosis should give the physician pause, and a diagnosis of LAFM may only be appropriate when there is unequivocal clinicopathologic evidence. Otherwise, a lymphoma diagnosis is somewhat superfluous and potentially harmful. Definitive diagnosis of LAFM also is complicated by reports of other hematologic malignancies presenting with FM-like histopathologic findings, such as chronic myelogenous leukemia, leukemia-associated eosinophilic folliculitis, and acute myeloblastic leukemia.^23,24 Although MF is the most common malignancy associated with FM, it is important to consider other less common malignancies that also may be present.

Diagnosis: Patient Consequences
Accurate diagnosis of idiopathic FM versus LAFM is critical, as the ramifications of a cancer diagnosis can have broad implications. For example, patients who receive cancer diagnoses often experience emotional trauma and social stigma, even when adequate patient education has been provided. The incidence of depression and anxiety also can increase following a cancer diagnosis and can be complicated by medical treatments (eg, systemic steroids, interferon),²⁵ which are known to increase the frequency of these psychological disturbances. Health insurance premiums likely will be higher if a patient is diagnosed with cancer versus a benign inflammatory condition. Hesitation of the pathologist to assign a cancer diagnosis when unequivocal evidence is not present should not be regarded as trickery, malpractice, or deceit of the health care bylaws, as benign language with suggestion of close clinical follow-up in the setting of diagnostic uncertainty will “first, do no harm” and secondly, serve as a vehicle for patient advocacy.

If there is a definitive distinction between idiopathic FM and LAFM, it requires further research before it can be fully understood. Currently, the WHO does not recognize a diagnosis of FM-associated MF (or LAFM) and acknowledges that folliculotropic MF is not always associated with FM.^16,26 Given uncertainty and repercussions associated with a cancer diagnosis, however indolent, it may be morally responsible and medically favorable for physicians to consider FM in the differential diagnosis when applicable rather than making a diagnosis of MF outright. Given the importance of both clinical and histologic factors, it may be beneficial for definitive diagnosis of FM versus MF to lie with the clinician, while the pathologist serves as an adjunct in the diagnostic process. Because the prognosis of idiopathic FM often is marred by possible transformation into MF or other CTCLs, therapeutic decisions should be dictated by close clinical follow-up. Additionally, stage of disease, patient age, treatment compliance, comorbidities, and possible side effects of medications should all be considered when evaluating potential therapeutic regimens.²⁷

Conclusion
Research is underway to more accurately identify patients with FM who are at risk for progression to LAFM versus those with benign remitting FM. Once the required diagnostic criteria are established to accurately classify these patients, with an emphasis on prognosis and suggested treatments, it might be necessary to establish new, less debated terminology so pathologists and clinicians alike can improve patient care. Continued histopathologic scrutiny, use of sophisticated molecular techniques, and knowledge of other currently undiscovered modalities will shed light on this important disease process and aid in proper disease management, which may be advantageous to both patients and physicians.

When follicular mucinosis (FM) is defined as an epithelial reaction pattern characterized by intrafollicular and perifollicular mucin accumulation, it cannot be considered a distinct disease entity, as this pattern is ubiquitously present in various inflammatory and neoplastic skin conditions.^1,2 The distinction between idiopathic FM and lymphoma-associated follicular mucinosis (LAFM) was made several years ago by authors who evaluated the differences in the clinical presentation of these entities, including patient age at onset, number of lesions, pattern of distribution, and most importantly clinical progression.¹ In this article, we discuss the importance of close clinical follow-up in patients with FM or patch-stage mycosis fungoides (MF) in whom histopathologic evaluation is ambiguous or nondiagnostic. We also highlight the value of ancillary testing, including T-cell receptor gene rearrangement, flow cytometry, and immunohistochemistry, as a component in the diagnostic process rather than the sole diagnostic moiety. A review of the pertinent literature also is performed.

History of FM and MF
Pinkus³ first described an entity he termed alopecia mucinosa in 1957. Pinkus noted 3 distinct patterns: an idiopathic form of alopecia mucinosa, lymphoblastoma with associated FM, and alopecia mucinosa that later transformed into lymphoblastoma.⁴ In 1983, however, Pinkus⁴ described uncertainty if alopecia mucinosa represented the first stage of MF or if patients with alopecia mucinosa were simply at an increased risk for developing lymphoma. He believed there were too many cases of lymphoma following a diagnosis of alopecia mucinosa for the relation to be coincidental, yet he noted that many of the cases resolved either spontaneously or following treatment with x-rays or topical steroids. He concluded his report with a sentiment that is echoed in many current studies regarding this entity: “Many questions surrounding this entity are as unanswerable today as they were 25 years ago.”⁴

Jablonska et al⁵ were the first to coin the term mucinosis follicularis, now known as FM, to replace alopecia mucinosa because they felt the description was more accurate, as lesions also arise on non–hair-bearing skin. Although there is general agreement that there is a form of MF that has associated FM, this is where the agreement ends with regard to the diagnosis of MF versus FM. Böer et al⁶ discussed the historic evolution of these terms, mostly to highlight the origins of the confusion. The investigators proposed that FM should only be used as a descriptive term and that all cases of alopecia mucinosa represent MF. They also concluded that many benign dermatoses associated with a risk for evolution to MF (eg, small and large plaque psoriasis [LPP]) should simply be diagnosed as MF.⁶ Subsequently, the proposal that idiopathic FM and LAFM are not 2 distinct entities but rather a clinicopathologic continuum and that idiopathic FM is simply a variant of MF along this spectrum has gained some approval.^6,7 However, this belief is not shared among all authorities in the field, and attempts to define diagnostic criteria that distinguish between a benign clinical course and a course that is more progressive and fatal continue. Currently, it is agreed upon that when distinguishing between these 2 clinical courses, primary (idiopathic) follicular mucinosis refers to a benign course with no overt sign of malignancy, and lymphoma-associated follicular mucinosis refers to a diagnostic malignant condition. Lymphoma-associated follicular mucinosis refers to FM associated with cutaneous T-cell lymphoma, the most common form of which is FM. Many authors^8-15 have sought ancillary methodologies in addition to clinical parameters to assist in the evaluation between both disease courses. Methodologies have included assessment of T-cell receptor gene rearrangements, flow cytometry, and immunohistochemical staining, mostly as an effort to establish monoclonality as a defining characteristic of LAFM; however, monoclonality in cutaneous T-cell infiltrates should be interpreted with caution and should not be considered as a confirmation of malignancy due to recent findings of monoclonality in benign inflammatory dermatoses such as lichen planus. The Table outlines several of the most common benign inflammatory dermatoses that demonstrate monoclonality, but this list should not be considered exhaustive, as there are many others in which monoclonality is sometimes seen.^8-15 The lack of definitive criteria to distinguish between the 2 groups has led to confusion and consternation regarding the diagnosis of idiopathic FM versus LAFM and has led many in the field to consider the 2 conditions to be one and the same.

Diagnosis of FM and MF: Clinicopathologic Features
The World Health Organization (WHO) defined MF as an epidermotropic primary cutaneous T-cell lymphoma (CTCL) characterized by infiltrates of small- to medium-sized T lymphocytes with cerebriform nuclei. Further, the WHO stated that the term mycosis fungoides should be exclusively reserved for classical cases typified by the evolution of cutaneous patches, plaques, and tumors, or for variants that show a similar clinical course.¹⁶ Mycosis fungoides is divided into 3 stages—patch, plaque, and tumor—which are solely clinical descriptors.¹⁷ The WHO also described a clinical staging system with pathologic emphasis placed only on lymph node involvement and identification of Sézary cells.¹⁶ It lists folliculotropic MF as a variant, with only some cases presenting with mucinous degeneration of hair follicles. A lack of consensus among pathologists regarding criteria for diagnosis in patch-stage MF remains, but diagnosis of plaque-stage disease is not regularly debated due to its more reliably present, well-developed histologic features (eg, haloed lymphocytes, epidermotropism of lymphocytes, lymphocytes with convoluted nuceli, Pautrier microabscesses).¹⁸ Although there have been specific histologic findings reported to be associated with patch-stage MF, they have only been present in a few cases and are therefore of limited usefulness in practice.^1,19 The categorization of patients with subtle histologic features common to both MF and inflammatory conditions such as parapsoriasis en plaques (the term plaque in this case is a misnomer because the word plaque means patch in French) continues to be elusive. A lack of agreement regarding LPP persists in the current literature in the same manner as FM. Some researchers have contended for many years that LPP is a type of MF, while others remain unconvinced, mainly due to the lack of evidence that lumping a benign condition (LPP) with an increased risk for malignant transformation and a known malignancy (MF) together is of any benefit to the patient. Assessment of clinicopathologic correlation, immunohistochemistry, clonality, and T-cell gene rearrangement have failed to positively identify patients who are at risk for disease progression, whether the diagnosis is called LPP or early patch-stage MF.²⁰

Mycosis fungoides is more common in males and its incidence increases with age; however, diagnosis should not be ruled out based on age or gender. Typical presentation of early-stage disease includes erythematous patches or plaques, often with light scaling.¹⁹ Lesions routinely are of long-standing duration (months to years), are located in areas that are infrequently exposed to sunlight, and often are 5 cm in diameter or larger with irregular borders.²¹ Associated poikiloderma is relatively specific to MF but rarely is seen in other CTCLs, connective-tissue diseases, and some genodermatoses. Poikiloderma commonly is identified in LPP, which shows the same telangiectasia, mottled pigmentation, and epidermal atrophy as MF-associated poikiloderma, leading some to believe that there is no separation between the 2 conditions. In all stages of MF, lesions frequently are numerous and occur on multiple sites. Plaques and tumors can show spontaneous ulceration. When lesions are folliculotropic, they can cause localized alopecia, follicular-based papules, and fungating pseudotumors in more advanced stages.¹ The clinical presentation of FM substantially overlaps with folliculotropic MF, and although FM lesions often are solitary and are located on the face or scalp, they also can present as multiple lesions located elsewhere on the body. It also has been proposed that folliculotropic MF should not be separated from FM-associated MF (or LAFM).²²

The characteristic histologic picture of LAFM in patch or plaque stage shows mucin deposition within hair follicles, similar to idiopathic FM. On histology, both conditions demonstrate dense lymphoid infiltrates around and within hair follicles as well as in the dermis (Figure). Most cases of LAFM show epidermotropism of lymphocytes between follicles, but this finding is not present in every case and often disappears when the disease advances to the tumor stage.^1,19 Although Pautrier microabscesses (collections of lymphocytes within the superficial epidermis) are considered to be somewhat specific to MF, they are only present in a minority of cases.²⁰ In a study by the International Society for Cutaneous Lymphomas,²¹ the only histopathologic criteria that showed any appreciable sensitivity or specificity in the diagnosis of MF were the presence of lymphoid cells with variable nuclear and cytoplasmic features and/or strikingly irregular nuclear contours with the presence of lymphocytes larger than those usually seen in inflammatory dermatoses. Despite these criteria, the study reported a high misclassification rate. A complicated scoring system for diagnosis of MF in patch- or early plaque-stage disease was proposed by the International Society for Cutaneous Lymphomas,²¹ which integrates clinical, histopathologic, molecular, and immunophenotypic criteria. However, these criteria have been continually debated in the literature and are only discussed in this article in relation to the association between MF and FM. Diagnosis of tumor-stage MF is not addressed in this article, as it is readily identified as lymphoma and is not easily confused with idiopathic FM.

Histopathology of 2 separate cases, both diagnosed as follicular mucinosis pending further follow-up. After close clinical follow-up, one case was diagnosed as mycosis fungoides (A) and the other as follicular mucinosis (B)(both H&E, original magnification ×2). Immunohistochemical stains were noncontributory, and T-cell gene rearrangement was positive only in the case of mycosis fungoides. Histopathology revealed mucin deposition in the hair follicles and a dense lymphoid infiltrate around and within the follicles in both cases. Pautrier microabscesses, cerebriform nuclei, and epidermotropism of lymphocytes between follicles were absent in the case of mycosis fungoides.

Clinical assessment of a patient’s medical history to identify persistent and progressive disease is paramount to the diagnosis of MF. Although MF lesions tend to increase in size and number over time, this presentation is not without exception.²¹ In early patch-stage disease, eliminating some of the patient’s current medications may be sufficient in clearing cutaneous patches that cannot be conclusively identified as either MF or a benign inflammatory lymphoid infiltrate, which further emphasizes the importance of clinical assessment of the patient’s medical history in the diagnosis of MF. The shape of the lesions also is helpful in distinguishing between MF and other skin disorders, such as digitate dermatosis or LPP; unlike the latter, the waxing and waning nature of MF lesions often produces irregularly shaped patches with little coalescence. Again, there are some investigators who believe that these lesions represent varying presentations of MF.⁶

In a study by Cerroni et al,¹ 44 patients with FM were divided into 2 groups: (1) a cohort of 16 patients with no history or clinical evidence of MF or Sézary syndrome (ie, LAFM), and (2) a cohort of 28 patients with clinicopathologic evidence of CTCL. Patients in both groups were followed for a maximum of 20 years. Results indicated that that the presence of perifollicular or intrafollicular mucin, epidermotropism of lymphocytes, monoclonality, and epidemiologic characteristics (eg, age, sex, race) cannot reliably distinguish the 2 disease forms. Furthermore, it was suggested that these conditions are not mutually exclusive entities and are actually variants of CTCL. The observation that the 2 diseases share prognostic overlap adds further credence to the already puzzling conundrum. Nineteen of 28 patients with MF were alive and well at follow-up, and all patients in the idiopathic FM group were alive, with only 9 of 16 patients showing residual disease and none with CTCL.¹

Other clinical factors that may be helpful in the diagnosis of MF are the presentation of lesions in non–sun-exposed areas of the skin and multiple lesions, as unilesional MF is exceedingly uncommon.²¹ No histologic features have been proven to predict which early patch- or plaque-stage MFs will progress to full-blown CTCL versus benign idiopathic FM; thus, great caution should be taken in patients with early-stage disease to ensure they are not prematurely and/or incorrectly classified as CTCL. Such a diagnosis has medical, social, and economical ramifications that should not be overlooked.

If idiopathic FM and LAFM were considered distinct disease processes, the ambiguity in making a definitive diagnosis should give the physician pause, and a diagnosis of LAFM may only be appropriate when there is unequivocal clinicopathologic evidence. Otherwise, a lymphoma diagnosis is somewhat superfluous and potentially harmful. Definitive diagnosis of LAFM also is complicated by reports of other hematologic malignancies presenting with FM-like histopathologic findings, such as chronic myelogenous leukemia, leukemia-associated eosinophilic folliculitis, and acute myeloblastic leukemia.^23,24 Although MF is the most common malignancy associated with FM, it is important to consider other less common malignancies that also may be present.

Diagnosis: Patient Consequences
Accurate diagnosis of idiopathic FM versus LAFM is critical, as the ramifications of a cancer diagnosis can have broad implications. For example, patients who receive cancer diagnoses often experience emotional trauma and social stigma, even when adequate patient education has been provided. The incidence of depression and anxiety also can increase following a cancer diagnosis and can be complicated by medical treatments (eg, systemic steroids, interferon),²⁵ which are known to increase the frequency of these psychological disturbances. Health insurance premiums likely will be higher if a patient is diagnosed with cancer versus a benign inflammatory condition. Hesitation of the pathologist to assign a cancer diagnosis when unequivocal evidence is not present should not be regarded as trickery, malpractice, or deceit of the health care bylaws, as benign language with suggestion of close clinical follow-up in the setting of diagnostic uncertainty will “first, do no harm” and secondly, serve as a vehicle for patient advocacy.

If there is a definitive distinction between idiopathic FM and LAFM, it requires further research before it can be fully understood. Currently, the WHO does not recognize a diagnosis of FM-associated MF (or LAFM) and acknowledges that folliculotropic MF is not always associated with FM.^16,26 Given uncertainty and repercussions associated with a cancer diagnosis, however indolent, it may be morally responsible and medically favorable for physicians to consider FM in the differential diagnosis when applicable rather than making a diagnosis of MF outright. Given the importance of both clinical and histologic factors, it may be beneficial for definitive diagnosis of FM versus MF to lie with the clinician, while the pathologist serves as an adjunct in the diagnostic process. Because the prognosis of idiopathic FM often is marred by possible transformation into MF or other CTCLs, therapeutic decisions should be dictated by close clinical follow-up. Additionally, stage of disease, patient age, treatment compliance, comorbidities, and possible side effects of medications should all be considered when evaluating potential therapeutic regimens.²⁷

Conclusion
Research is underway to more accurately identify patients with FM who are at risk for progression to LAFM versus those with benign remitting FM. Once the required diagnostic criteria are established to accurately classify these patients, with an emphasis on prognosis and suggested treatments, it might be necessary to establish new, less debated terminology so pathologists and clinicians alike can improve patient care. Continued histopathologic scrutiny, use of sophisticated molecular techniques, and knowledge of other currently undiscovered modalities will shed light on this important disease process and aid in proper disease management, which may be advantageous to both patients and physicians.

SEDENTARY TIME INCREASES HEALTH RISKS
Biswas A, Oh PI, Faulkner GE, et al. Sedentary time and its association with risk for disease incidence, mortality, and hospitalization in adults: a systematic review and meta-analysis. Ann Intern Med. 2015;162(2):123-132. doi: 10.7326/M14-1651.

The more time a person spends sedentary, regardless of physical activity, the greater the risk for deleterious health outcomes, a systematic review and meta-analysis of more than 1.5 million patients found.

Researchers reviewed 47 studies on the association between sedentary time and hospitalizations, all-cause mortality, cardiovascular disease, diabetes, and cancer in adults, and found that sedentary time was independently associated with the following negative health outcomes:
• All-cause mortality (hazard ratio [HR], 1.24)
• Cardiovascular disease mortality (HR, 1.18)
• Cardiovascular disease incidence (HR, 1.14)
• Cancer mortality (HR, 1.17)
• Cancer incidence (HR, 1.13)
• Type 2 diabetes incidence (HR, 1.91)

Sedentary time was assessed as either daily overall sedentary time, sitting time, television or screen time, or leisure time spent sitting. High sedentary time was defined as a range from five or more hours per day watching television to 11 hours a day total sedentary time, depending on the study.

DOES EXERCISE INTENSITY IMPACT ABDOMINAL OBESITY?
Ross R, Hudson R, Stotz PJ, Lam M. Effects of exercise amount and intensity on abdominal obesity and glucose tolerance in obese adults: a randomized trial. Ann Intern Med. 2015;162(5):325-334. doi: 10.7326/M14-1189.

Exercise, regardless of the amount or intensity, produces similar reductions in abdominal obesity, but only high-amount, high-intensity exercise showed improvements in two-hour glucose readings, according to a 24-week trial of 300 abdominally obese adults.

Subjects were split into a control group and three groups told to exercise five times per week at varying amounts and intensity based on maximum oxygen capacity (VO2 peak)—low-amount, low-intensity (LALI); high-amount, low-intensity (HALI); and high-amount, high-intensity (HAHI)—with the following results (see Table).

CHOOSE FRUITS AND VEGETABLES FOR LONGEVITY
Wang X, Ouyang Y, Liu J, et al. Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ. 2014;349:g4490.

Eating at least five servings of fruits and vegetables daily is associated with a reduced risk for mortality from all causes and cardiovascular disease, but not cancer, a meta-analysis of studies published in BMJ reports.

Researchers analyzed 16 prospective cohort studies from the United States, Europe, and Asia that reviewed the effects of fruit and vegetable consumption on mortality from all causes, cardiovascular disease, and cancer. The studies involved a combined total of 833,234 subjects and a follow-up period ranging from 4.6 to 26 years and showed
• Risk for all-cause mortality decreased by 5% per serving per day, up to five servings a day.
• Risk for cardiovascular mortality decreased by 4% per serving, per day, up to five servings a day.
• Risk for cancer mortality was not appreciably ­associated with increased fruit or vegetable consumption.
• Fruit provided the greatest reduction in risk for all-cause mortality at 6% per serving and cardiovascular mortality at 5% per serving. Vegetables reduced risks by 5% and 4%, respectively.

“This meta-analysis provides further evidence that higher consumption of fruits and vegetables is associated with a lower risk for mortality from all causes, particularly from cardiovascular diseases,” the authors conclude. “The results support current recommendations to increase consumption to promote health and overall longevity.”  

SEDENTARY TIME INCREASES HEALTH RISKS
Biswas A, Oh PI, Faulkner GE, et al. Sedentary time and its association with risk for disease incidence, mortality, and hospitalization in adults: a systematic review and meta-analysis. Ann Intern Med. 2015;162(2):123-132. doi: 10.7326/M14-1651.

The more time a person spends sedentary, regardless of physical activity, the greater the risk for deleterious health outcomes, a systematic review and meta-analysis of more than 1.5 million patients found.

Researchers reviewed 47 studies on the association between sedentary time and hospitalizations, all-cause mortality, cardiovascular disease, diabetes, and cancer in adults, and found that sedentary time was independently associated with the following negative health outcomes:
• All-cause mortality (hazard ratio [HR], 1.24)
• Cardiovascular disease mortality (HR, 1.18)
• Cardiovascular disease incidence (HR, 1.14)
• Cancer mortality (HR, 1.17)
• Cancer incidence (HR, 1.13)
• Type 2 diabetes incidence (HR, 1.91)

Sedentary time was assessed as either daily overall sedentary time, sitting time, television or screen time, or leisure time spent sitting. High sedentary time was defined as a range from five or more hours per day watching television to 11 hours a day total sedentary time, depending on the study.

DOES EXERCISE INTENSITY IMPACT ABDOMINAL OBESITY?
Ross R, Hudson R, Stotz PJ, Lam M. Effects of exercise amount and intensity on abdominal obesity and glucose tolerance in obese adults: a randomized trial. Ann Intern Med. 2015;162(5):325-334. doi: 10.7326/M14-1189.

Exercise, regardless of the amount or intensity, produces similar reductions in abdominal obesity, but only high-amount, high-intensity exercise showed improvements in two-hour glucose readings, according to a 24-week trial of 300 abdominally obese adults.

Subjects were split into a control group and three groups told to exercise five times per week at varying amounts and intensity based on maximum oxygen capacity (VO2 peak)—low-amount, low-intensity (LALI); high-amount, low-intensity (HALI); and high-amount, high-intensity (HAHI)—with the following results (see Table).

CHOOSE FRUITS AND VEGETABLES FOR LONGEVITY
Wang X, Ouyang Y, Liu J, et al. Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ. 2014;349:g4490.

Eating at least five servings of fruits and vegetables daily is associated with a reduced risk for mortality from all causes and cardiovascular disease, but not cancer, a meta-analysis of studies published in BMJ reports.

Researchers analyzed 16 prospective cohort studies from the United States, Europe, and Asia that reviewed the effects of fruit and vegetable consumption on mortality from all causes, cardiovascular disease, and cancer. The studies involved a combined total of 833,234 subjects and a follow-up period ranging from 4.6 to 26 years and showed
• Risk for all-cause mortality decreased by 5% per serving per day, up to five servings a day.
• Risk for cardiovascular mortality decreased by 4% per serving, per day, up to five servings a day.
• Risk for cancer mortality was not appreciably ­associated with increased fruit or vegetable consumption.
• Fruit provided the greatest reduction in risk for all-cause mortality at 6% per serving and cardiovascular mortality at 5% per serving. Vegetables reduced risks by 5% and 4%, respectively.

“This meta-analysis provides further evidence that higher consumption of fruits and vegetables is associated with a lower risk for mortality from all causes, particularly from cardiovascular diseases,” the authors conclude. “The results support current recommendations to increase consumption to promote health and overall longevity.”  

SEDENTARY TIME INCREASES HEALTH RISKS
Biswas A, Oh PI, Faulkner GE, et al. Sedentary time and its association with risk for disease incidence, mortality, and hospitalization in adults: a systematic review and meta-analysis. Ann Intern Med. 2015;162(2):123-132. doi: 10.7326/M14-1651.

The more time a person spends sedentary, regardless of physical activity, the greater the risk for deleterious health outcomes, a systematic review and meta-analysis of more than 1.5 million patients found.

Researchers reviewed 47 studies on the association between sedentary time and hospitalizations, all-cause mortality, cardiovascular disease, diabetes, and cancer in adults, and found that sedentary time was independently associated with the following negative health outcomes:
• All-cause mortality (hazard ratio [HR], 1.24)
• Cardiovascular disease mortality (HR, 1.18)
• Cardiovascular disease incidence (HR, 1.14)
• Cancer mortality (HR, 1.17)
• Cancer incidence (HR, 1.13)
• Type 2 diabetes incidence (HR, 1.91)

Sedentary time was assessed as either daily overall sedentary time, sitting time, television or screen time, or leisure time spent sitting. High sedentary time was defined as a range from five or more hours per day watching television to 11 hours a day total sedentary time, depending on the study.

DOES EXERCISE INTENSITY IMPACT ABDOMINAL OBESITY?
Ross R, Hudson R, Stotz PJ, Lam M. Effects of exercise amount and intensity on abdominal obesity and glucose tolerance in obese adults: a randomized trial. Ann Intern Med. 2015;162(5):325-334. doi: 10.7326/M14-1189.

Exercise, regardless of the amount or intensity, produces similar reductions in abdominal obesity, but only high-amount, high-intensity exercise showed improvements in two-hour glucose readings, according to a 24-week trial of 300 abdominally obese adults.

Subjects were split into a control group and three groups told to exercise five times per week at varying amounts and intensity based on maximum oxygen capacity (VO2 peak)—low-amount, low-intensity (LALI); high-amount, low-intensity (HALI); and high-amount, high-intensity (HAHI)—with the following results (see Table).

CHOOSE FRUITS AND VEGETABLES FOR LONGEVITY
Wang X, Ouyang Y, Liu J, et al. Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ. 2014;349:g4490.

Eating at least five servings of fruits and vegetables daily is associated with a reduced risk for mortality from all causes and cardiovascular disease, but not cancer, a meta-analysis of studies published in BMJ reports.

Researchers analyzed 16 prospective cohort studies from the United States, Europe, and Asia that reviewed the effects of fruit and vegetable consumption on mortality from all causes, cardiovascular disease, and cancer. The studies involved a combined total of 833,234 subjects and a follow-up period ranging from 4.6 to 26 years and showed
• Risk for all-cause mortality decreased by 5% per serving per day, up to five servings a day.
• Risk for cardiovascular mortality decreased by 4% per serving, per day, up to five servings a day.
• Risk for cancer mortality was not appreciably ­associated with increased fruit or vegetable consumption.
• Fruit provided the greatest reduction in risk for all-cause mortality at 6% per serving and cardiovascular mortality at 5% per serving. Vegetables reduced risks by 5% and 4%, respectively.

“This meta-analysis provides further evidence that higher consumption of fruits and vegetables is associated with a lower risk for mortality from all causes, particularly from cardiovascular diseases,” the authors conclude. “The results support current recommendations to increase consumption to promote health and overall longevity.”