When your beloved authors were studying research and statistics, around the time that Methuselah was celebrating his first birthday, we thought we knew the difference between hypothesis testing and hypothesis generating. With the former, you begin with a question, design a study to answer it, carry it out, and then do some statistical mumbo-jumbo on the data to determine if you have reasonable evidence to answer the question. With the latter, usually done after you’ve answered the main questions, you don’t have any preconceived idea of what’s going on, so you analyze anything that moves. We know that’s not really kosher, because the probability of finding something just by chance (a Type I error) increases astronomically as you do more tests.1 So, in the hypothesis generating phase, you don’t come to any conclusions; you just say, “That’s an interesting finding. Now we’ll have to do a real study to see if our observation holds up.”

Click on the PDF icon at the top of this introduction to read the full article.

When your beloved authors were studying research and statistics, around the time that Methuselah was celebrating his first birthday, we thought we knew the difference between hypothesis testing and hypothesis generating. With the former, you begin with a question, design a study to answer it, carry it out, and then do some statistical mumbo-jumbo on the data to determine if you have reasonable evidence to answer the question. With the latter, usually done after you’ve answered the main questions, you don’t have any preconceived idea of what’s going on, so you analyze anything that moves. We know that’s not really kosher, because the probability of finding something just by chance (a Type I error) increases astronomically as you do more tests.1 So, in the hypothesis generating phase, you don’t come to any conclusions; you just say, “That’s an interesting finding. Now we’ll have to do a real study to see if our observation holds up.”

Click on the PDF icon at the top of this introduction to read the full article.

When your beloved authors were studying research and statistics, around the time that Methuselah was celebrating his first birthday, we thought we knew the difference between hypothesis testing and hypothesis generating. With the former, you begin with a question, design a study to answer it, carry it out, and then do some statistical mumbo-jumbo on the data to determine if you have reasonable evidence to answer the question. With the latter, usually done after you’ve answered the main questions, you don’t have any preconceived idea of what’s going on, so you analyze anything that moves. We know that’s not really kosher, because the probability of finding something just by chance (a Type I error) increases astronomically as you do more tests.1 So, in the hypothesis generating phase, you don’t come to any conclusions; you just say, “That’s an interesting finding. Now we’ll have to do a real study to see if our observation holds up.”

Click on the PDF icon at the top of this introduction to read the full article.

An 80-year-old Hawaiian man of Chinese ancestry arrives at the emergency department with diarrhea and dehydration. You are called to admit him for acute renal failure. On entering the patient’s room, you note that he has a diffuse maculopapular rash and is wheezing.

Twenty-one months earlier, the patient suffered his first episode of gout. Since that time, he has been asymptomatic. Two months ago, his primary care physician obtained a uric acid level and found it elevated at 10.6 mg/dL. She started the patient on allopurinol 300 mg PO daily.

Twenty days ago (approximately 6 weeks after initiation of allopurinol), the rash developed along with generalized pruritus. The patient’s primary care physician referred him to a dermatologist for skin biopsy, and he discontinued allopurinol 11 days ago.

Just in the past week, the patient began to experience a metallic taste in his mouth, as well as anorexia, malaise, chills, dysuria, and nonbloody diarrhea. He became nauseous and decreased his oral intake, which led to dehydration and progressive weakness.

Additional medical history

• The patient’s medical history is significant for renal insufficiency, type 2 diabetes mellitus, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, chronic nasal allergies, benign prostatic hypertrophy, osteoarthritis, and gout.
• He is taking the following medications: fluticasone inhalant 110 mcg daily; fluticasone propionate one spray in both nostrils daily; montelukast 10 mg PO daily; irbesartan 300 mg PO daily; amlodipine 5 mg PO daily; glyburide 2.5 mg PO BID; triamterene/hydrochlorothiazide 37.5/25 mg PO QOD; albuterol 90 mcg 2 puffs q6h prn; terazosin 2 mg PO qhs; simvastatin 40 mg PO daily; azelastine 137 mcg 1 spray in both nostrils prn; meclizine 25 mg PO daily prn; fexofenadine 150 mg PO qPM; cyclobenzaprine 10 mg PO qhs prn; and hydrocodone/acetamino- phen 5/500 mg 2 tabs PO daily prn.

Social history

• The patient recently arrived from Hawaii to visit his wife’s family.
• He does not drink alcohol, but he smokes 4 cigarettes a day.

Review of systems

• A review of systems is negative for the following: fever, sick contacts, history of renal calculi, hemoptysis, ocular or ENT symptoms, history of hepatic disease, peripheral neuropathy, and neurologic symptoms.

Physical examination

• The patient is alert and cooperative.
• Temperature is 97.9^oF, blood pressure 110/52 mm Hg, pulse 112 beats per minute, respiratory rate 16 breaths per minute, oxygen saturation 96% on room air.
• Mucous membranes are dry.
• Auscultation of the heart is normal.
• Significant wheezing is present in bilateral lung fields, but requiring no use of accessory muscles during respiration.
• Abdominal exam is remarkable only for obesity.
• Trace pitting edema is present in both lower extremities.
• The maculopapular rash is diffuse and nonblanching. Scaling on the trunk, areas of erythema below the umbilicus, and coalescing macular lesions on bilateral lower extremities are present.
• Joints are not swollen or tender, and there are no tophi.
• There are no focal neurologic deficits, and deep tendon reflexes are normal.

Laboratory studies completed in the ED

• Blood urea nitrogen, 112 mg/dL ; creatinine, 3 mg/dL ; glomerular filtration rate (GFR), 22 mL/min (baseline ratio of blood urea nitrogen/creatinine, 36:1.57; baseline GFR, 43 mL/min)
• White blood cell count, 15 k/uL
• Hemoglobin, 14.3 g/dL ; hematocrit, 43.6%; platelet count, 307/uL
• Alanine aminotransferase and aspartate aminotransferase, 177 and 139 IU/L, respectively
• Direct, indirect, and total bilirubin, 0.60, 1.19, and 1.79 mg/dL, respectively
• Serum eosinophils, 22% (normal <6%)
• Erythrocyte sedimentation rate, 50 mm/h.

Radiology

• Chest radiographs (posterior-anterior, lateral) show a bilateral process consistent with atelectasis or lung scarring.
• Noncontrast computed tomography (CT) of the thorax confirms parenchymal scarring but no acute process.
• Hepatic sonography reveals increased echogenicity of the liver parenchyma consistent with an acute hepatocellular process.
• Magnetic resonance imaging (MRI) of the abdomen shows a diffuse process in the liver with trace parahepatic ascites.
• Renal ultrasound shows bilateral renal cysts with no hydronephrosis or urolithiasis.
• Cardiac echocardiography reveals left ventricular hypertrophy but normal ejection fraction.
• Noncontrast CT (head) and MRI (brain) show an acute right frontoparietal cerebrovascular accident and an old lacunar infarct.

Dermatologist’s report

• A skin biopsy reveals lymphocytic perivascular infiltrate with scattered eosinophils and mild spongiosis consistent with vasculitis.

Follow-up laboratory data

• Acute hepatitis panel is negative
• Uric acid, 13.8 mg/dL
• Urine eosinophils, 31% (normal <1%)
• Anti-neutrophil cytoplasmic antibody IgG, 1:40 mildly elevated (normal<1:20)
• Anti-nuclear antibody (ANA) IgG, none
• Glycosylated hemoglobin, 7.1%
• High-sensitivity C-reactive protein, 207.96 mg/L (>10 mg/L is very high)

In summary, this patient’s erythematous rash is a biopsy-confirmed vasculitis. Additional findings are hepatitis, acute on chronic renal failure, eosinophilia, and leukocytosis.

Q/ What is your presumptive diagnosis?

Allopurinol hypersensitivity syndrome

Allopurinol hypersensitivity syndrome (AHS) is a diffuse vasculitis induced by a type III hypersensitivity reaction, possibly to oxypurinol, allopurinol’s toxic metabolite. The exact pathophysiology is unknown, but oxypurinol levels correlate positively with the risk of AHS.¹ Thiazides may increase oxypurinol levels.²

Signs and symptoms of AHS include fever, erythematous skin rash, eosinophilia, hepatitis, progressive renal insufficiency, and leukocytosis. Case reports have also attributed septic shock, myocardial infarction, and Guillain-Barré syndrome to AHS.^3-6 The incidence of AHS is 0.1% to 0.4% of patients treated with allopurinol; mortality approaches 25%.¹

Q/ What are the diagnostic criteria for AHS?

Singer and Wallace have outlined diagnostic criteria for AHS,⁷ the first being a clear history of exposure to allopurinol.

Second, the clinical profile usually takes one of the following forms:

• The patient exhibits at least 2 of the following major features: worsening renal function, acute hepatocellular injury, or a rash (toxic epidermal necrolysis, erythema multiforme, or diffuse maculopapular or exfoliative dermatitis) or
• The patient exhibits just one of the major features and at least one of the following minor features: fever, eosinophilia, or leukocytosis.

Third, there is no history of exposure to another drug that may cause a similar clinical picture.

Q/ What is the accepted treatment for ahS?

Although there is no well-established treatment plan, the standard of care is to discontinue allopurinol, administer parenteral corticosteroids followed by oral taper, and offer supportive management. Desensitization protocols are difficult and hypersensitivity reactions may recur. Early withdrawal of steroids has been reported to result in recurrence of symptoms. However, no strong data exist for determining an optimal length of corticosteroid therapy, or the number of days that constitutes “early” withdrawal of steroids. Mortality is high, even with seemingly adequate treatment.

Q/ Which patients are most at risk for ahS?

Definite risk factors for AHS include recent onset of allopurinol therapy, the presence of HLA-B5801 allele in patients of Han Chinese and European ancestry, and chronic kidney disease.^1,8,9 Suggested risk factors include concomitant use of thiazide diuretics with allopurinol, treatment of asymptomatic hyperuricemia, and high allopurinol dose relative to renal function.

Q/ What are the indications for allopurinol therapy?

Indications for allopurinol therapy:^1,10

• Failure of uricosuric drugs or contraindications to their use
• Frequent attacks of gouty arthritis (≥3 per year)
• Nephrolithiasis
• Marked overproduction of urate, such as seen in tumor lysis syndrome
• The presence of tophi.

For patients with appropriate indications for allopurinol therapy, treat with the minimum effective dose. Initiation of allopurinol is controversial for a patient with a single lifetime episode of gout. However, most patients with one episode of gout will develop recurrent gout.⁸

In patients with creatinine clearance >60 mL/min, allopurinol is usually started at 100 mg oral daily and titrated every 2 to 3 weeks until reaching the desired effectiveness.⁸ One retrospective study suggests that initiating allopurinol at a dose of 1.5 mg per unit of estimated GFR may reduce the risk of AHS.¹¹

Our patient’s case: Treatment, discharge, readmission

With our patient, we started intravenous normal saline fluid boluses and parenteral methylprednisolone, 60 mg q6h. We discontinued triamterene/hydrochlorothiazide due to his hyperuricemia, and irbesartan and glyburide due to renal failure. Basal and rapid-acting insulins maintained good glycemic control. To control his wheezing and dyspnea, we began albuterol/ipratropium nebulizer treatments and oxygen delivery via nasal cannula. Nephrology, pulmonology, and rheumatology consultants agreed with these management decisions.

Over the next 9 days, the patient’s renal function improved and his rash started to resolve. His wheezing fluctuated but persisted throughout the hospital stay. We stopped nasal oxygen delivery, and his oxygen saturation remained normal (96%-98%) on room air. He was subsequently discharged in stable condition on a 2-week prednisone taper starting at 30 mg bid.

Thirteen days later, he was readmitted with a right frontoparietal cerebrovascular accident (CVA). He developed respiratory distress, which led to respiratory arrest, and was ventilated. He became hypotensive, lapsed into shock, and died a few days later (approximately one month after initial presentation).

The appropriate use of allopurinol—a second look

This case raised many questions for our inpatient team concerning not just AHS, but the appropriate use and dosing of allopurinol. Allopurinol is widely used for hyperuricemia and gout because it is effective for all causes of hyperuricemia and is inexpensive. Given that 3.9%¹² of the general population has gout and that its prevalence has increased with rising rates of obesity, the importance of AHS is not abstract.

Revisiting initial treatment choices. Our patient was at risk for this syndrome due to his Chinese ancestry, recent onset of allopurinol therapy, concomitant use of triamterene/hydrochlorothiazide, and impaired renal function. Although his uric acid level was >10 mg/dL when treatment was started, his risk factors may have precluded initiation of allopurinol. Furthermore, the prescribed dose of allopurinol (300 mg) was too high for his baseline GFR; 100 mg daily would have been more appropriate. It could be argued that hydrochlorothiazide would not be an antihypertensive of choice due to its hyperuricemic effects. Switching the thiazide to a loop diuretic would offer no benefit, because loop diuretics also cause hyperuricemia. (More on which antihypertensive agent would have been appropriate in a bit.)

The role of AHS in the patient’s death is unclear. He was at high risk for stroke considering his age, comorbidities, and evidence of an old lacunar infarct. Myocardial infarctions have been reported as one cause of death in AHS, but we have found no reports of associated stroke. However, the temporal proximity of the CVA suggests a contributing effect of AHS. The adequacy of treatment is also brought into question. Early withdrawal of glucocorticoids can be associated with relapse of AHS; in retrospect, the prednisone dose may have been too low or the taper too short, or both.

Therapeutic alternatives to allopurinol were available. The most appropriate initial option for this patient likely was no pharmacologic intervention at all but a focus on weight loss and diet. The risk of gouty attacks in men increases as body mass index rises above normal (≥25 kg/m2) and decreases with weight loss. Lower calorie diets with decreased saturated fat, higher complex carbohydrates, and allowed proteins (low-fat dairy products) are more palatable and more effective than strict low-purine diets.

A urate-lowering antihypertensive may have been a better option—specifically, losartan rather than irbesartan and triamterene/hydrochlorothiazide.^8,13 Losartan has uricosuric properties at the 50-mg dose.¹⁴ When compared in different studies with irbesartan, enalapril, and candesartan, losartan alone lowered serum urate levels. Increasing losartan to 100 mg could provide better hypertensive control but has not been found to lower urate levels more dramatically than the lower dose.¹³

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been found to blunt the urate-elevating effects of thiazides. Therefore, if the patient’s blood pressure was not adequately controlled on losartan alone, the combination of losartan/hydrochlorothiazide would be a reasonable choice because minimal or no change in serum uric acid levels would be expected.¹⁵

Febuxostat, a nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol in patients with gout. It is a more potent urate-lowering agent than allopurinol and can be used without dosage reduction in mild (creatinine clearance [CrCl], 60-89 mL/min) to moderate (CrCl, 30-59 mL/ min) renal insufficiency. Febuxostat is metabolized primarily in the liver—in contrast to allopurinol, which is excreted by the kidneys—and may increase liver transaminase levels.¹⁰ Although febuxostat was not available at the time our patient developed AHS, it would not have been indicated in asymptomatic hyperuricemia.

This compelling case reminds us to carefully consider the indications and risk factors in using allopurinol, and to be aware of the rare but sometimes devastating consequences of this commonly used drug.

CORRESPONDENCE
Tahirah Tyrell, MD, Rochester General Medical Group, 1425 Portland Avenue, Rochester, NY 14621;
[email protected].

An 80-year-old Hawaiian man of Chinese ancestry arrives at the emergency department with diarrhea and dehydration. You are called to admit him for acute renal failure. On entering the patient’s room, you note that he has a diffuse maculopapular rash and is wheezing.

Twenty-one months earlier, the patient suffered his first episode of gout. Since that time, he has been asymptomatic. Two months ago, his primary care physician obtained a uric acid level and found it elevated at 10.6 mg/dL. She started the patient on allopurinol 300 mg PO daily.

Twenty days ago (approximately 6 weeks after initiation of allopurinol), the rash developed along with generalized pruritus. The patient’s primary care physician referred him to a dermatologist for skin biopsy, and he discontinued allopurinol 11 days ago.

Just in the past week, the patient began to experience a metallic taste in his mouth, as well as anorexia, malaise, chills, dysuria, and nonbloody diarrhea. He became nauseous and decreased his oral intake, which led to dehydration and progressive weakness.

Additional medical history

• The patient’s medical history is significant for renal insufficiency, type 2 diabetes mellitus, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, chronic nasal allergies, benign prostatic hypertrophy, osteoarthritis, and gout.
• He is taking the following medications: fluticasone inhalant 110 mcg daily; fluticasone propionate one spray in both nostrils daily; montelukast 10 mg PO daily; irbesartan 300 mg PO daily; amlodipine 5 mg PO daily; glyburide 2.5 mg PO BID; triamterene/hydrochlorothiazide 37.5/25 mg PO QOD; albuterol 90 mcg 2 puffs q6h prn; terazosin 2 mg PO qhs; simvastatin 40 mg PO daily; azelastine 137 mcg 1 spray in both nostrils prn; meclizine 25 mg PO daily prn; fexofenadine 150 mg PO qPM; cyclobenzaprine 10 mg PO qhs prn; and hydrocodone/acetamino- phen 5/500 mg 2 tabs PO daily prn.

Social history

• The patient recently arrived from Hawaii to visit his wife’s family.
• He does not drink alcohol, but he smokes 4 cigarettes a day.

Review of systems

• A review of systems is negative for the following: fever, sick contacts, history of renal calculi, hemoptysis, ocular or ENT symptoms, history of hepatic disease, peripheral neuropathy, and neurologic symptoms.

Physical examination

• The patient is alert and cooperative.
• Temperature is 97.9^oF, blood pressure 110/52 mm Hg, pulse 112 beats per minute, respiratory rate 16 breaths per minute, oxygen saturation 96% on room air.
• Mucous membranes are dry.
• Auscultation of the heart is normal.
• Significant wheezing is present in bilateral lung fields, but requiring no use of accessory muscles during respiration.
• Abdominal exam is remarkable only for obesity.
• Trace pitting edema is present in both lower extremities.
• The maculopapular rash is diffuse and nonblanching. Scaling on the trunk, areas of erythema below the umbilicus, and coalescing macular lesions on bilateral lower extremities are present.
• Joints are not swollen or tender, and there are no tophi.
• There are no focal neurologic deficits, and deep tendon reflexes are normal.

Laboratory studies completed in the ED

• Blood urea nitrogen, 112 mg/dL ; creatinine, 3 mg/dL ; glomerular filtration rate (GFR), 22 mL/min (baseline ratio of blood urea nitrogen/creatinine, 36:1.57; baseline GFR, 43 mL/min)
• White blood cell count, 15 k/uL
• Hemoglobin, 14.3 g/dL ; hematocrit, 43.6%; platelet count, 307/uL
• Alanine aminotransferase and aspartate aminotransferase, 177 and 139 IU/L, respectively
• Direct, indirect, and total bilirubin, 0.60, 1.19, and 1.79 mg/dL, respectively
• Serum eosinophils, 22% (normal <6%)
• Erythrocyte sedimentation rate, 50 mm/h.

Radiology

• Chest radiographs (posterior-anterior, lateral) show a bilateral process consistent with atelectasis or lung scarring.
• Noncontrast computed tomography (CT) of the thorax confirms parenchymal scarring but no acute process.
• Hepatic sonography reveals increased echogenicity of the liver parenchyma consistent with an acute hepatocellular process.
• Magnetic resonance imaging (MRI) of the abdomen shows a diffuse process in the liver with trace parahepatic ascites.
• Renal ultrasound shows bilateral renal cysts with no hydronephrosis or urolithiasis.
• Cardiac echocardiography reveals left ventricular hypertrophy but normal ejection fraction.
• Noncontrast CT (head) and MRI (brain) show an acute right frontoparietal cerebrovascular accident and an old lacunar infarct.

Dermatologist’s report

• A skin biopsy reveals lymphocytic perivascular infiltrate with scattered eosinophils and mild spongiosis consistent with vasculitis.

Follow-up laboratory data

• Acute hepatitis panel is negative
• Uric acid, 13.8 mg/dL
• Urine eosinophils, 31% (normal <1%)
• Anti-neutrophil cytoplasmic antibody IgG, 1:40 mildly elevated (normal<1:20)
• Anti-nuclear antibody (ANA) IgG, none
• Glycosylated hemoglobin, 7.1%
• High-sensitivity C-reactive protein, 207.96 mg/L (>10 mg/L is very high)

In summary, this patient’s erythematous rash is a biopsy-confirmed vasculitis. Additional findings are hepatitis, acute on chronic renal failure, eosinophilia, and leukocytosis.

Q/ What is your presumptive diagnosis?

Allopurinol hypersensitivity syndrome

Allopurinol hypersensitivity syndrome (AHS) is a diffuse vasculitis induced by a type III hypersensitivity reaction, possibly to oxypurinol, allopurinol’s toxic metabolite. The exact pathophysiology is unknown, but oxypurinol levels correlate positively with the risk of AHS.¹ Thiazides may increase oxypurinol levels.²

Signs and symptoms of AHS include fever, erythematous skin rash, eosinophilia, hepatitis, progressive renal insufficiency, and leukocytosis. Case reports have also attributed septic shock, myocardial infarction, and Guillain-Barré syndrome to AHS.^3-6 The incidence of AHS is 0.1% to 0.4% of patients treated with allopurinol; mortality approaches 25%.¹

Q/ What are the diagnostic criteria for AHS?

Singer and Wallace have outlined diagnostic criteria for AHS,⁷ the first being a clear history of exposure to allopurinol.

Second, the clinical profile usually takes one of the following forms:

• The patient exhibits at least 2 of the following major features: worsening renal function, acute hepatocellular injury, or a rash (toxic epidermal necrolysis, erythema multiforme, or diffuse maculopapular or exfoliative dermatitis) or
• The patient exhibits just one of the major features and at least one of the following minor features: fever, eosinophilia, or leukocytosis.

Third, there is no history of exposure to another drug that may cause a similar clinical picture.

Q/ What is the accepted treatment for ahS?

Although there is no well-established treatment plan, the standard of care is to discontinue allopurinol, administer parenteral corticosteroids followed by oral taper, and offer supportive management. Desensitization protocols are difficult and hypersensitivity reactions may recur. Early withdrawal of steroids has been reported to result in recurrence of symptoms. However, no strong data exist for determining an optimal length of corticosteroid therapy, or the number of days that constitutes “early” withdrawal of steroids. Mortality is high, even with seemingly adequate treatment.

Q/ Which patients are most at risk for ahS?

Definite risk factors for AHS include recent onset of allopurinol therapy, the presence of HLA-B5801 allele in patients of Han Chinese and European ancestry, and chronic kidney disease.^1,8,9 Suggested risk factors include concomitant use of thiazide diuretics with allopurinol, treatment of asymptomatic hyperuricemia, and high allopurinol dose relative to renal function.

Q/ What are the indications for allopurinol therapy?

Indications for allopurinol therapy:^1,10

• Failure of uricosuric drugs or contraindications to their use
• Frequent attacks of gouty arthritis (≥3 per year)
• Nephrolithiasis
• Marked overproduction of urate, such as seen in tumor lysis syndrome
• The presence of tophi.

For patients with appropriate indications for allopurinol therapy, treat with the minimum effective dose. Initiation of allopurinol is controversial for a patient with a single lifetime episode of gout. However, most patients with one episode of gout will develop recurrent gout.⁸

In patients with creatinine clearance >60 mL/min, allopurinol is usually started at 100 mg oral daily and titrated every 2 to 3 weeks until reaching the desired effectiveness.⁸ One retrospective study suggests that initiating allopurinol at a dose of 1.5 mg per unit of estimated GFR may reduce the risk of AHS.¹¹

Our patient’s case: Treatment, discharge, readmission

With our patient, we started intravenous normal saline fluid boluses and parenteral methylprednisolone, 60 mg q6h. We discontinued triamterene/hydrochlorothiazide due to his hyperuricemia, and irbesartan and glyburide due to renal failure. Basal and rapid-acting insulins maintained good glycemic control. To control his wheezing and dyspnea, we began albuterol/ipratropium nebulizer treatments and oxygen delivery via nasal cannula. Nephrology, pulmonology, and rheumatology consultants agreed with these management decisions.

Over the next 9 days, the patient’s renal function improved and his rash started to resolve. His wheezing fluctuated but persisted throughout the hospital stay. We stopped nasal oxygen delivery, and his oxygen saturation remained normal (96%-98%) on room air. He was subsequently discharged in stable condition on a 2-week prednisone taper starting at 30 mg bid.

Thirteen days later, he was readmitted with a right frontoparietal cerebrovascular accident (CVA). He developed respiratory distress, which led to respiratory arrest, and was ventilated. He became hypotensive, lapsed into shock, and died a few days later (approximately one month after initial presentation).

The appropriate use of allopurinol—a second look

This case raised many questions for our inpatient team concerning not just AHS, but the appropriate use and dosing of allopurinol. Allopurinol is widely used for hyperuricemia and gout because it is effective for all causes of hyperuricemia and is inexpensive. Given that 3.9%¹² of the general population has gout and that its prevalence has increased with rising rates of obesity, the importance of AHS is not abstract.

Revisiting initial treatment choices. Our patient was at risk for this syndrome due to his Chinese ancestry, recent onset of allopurinol therapy, concomitant use of triamterene/hydrochlorothiazide, and impaired renal function. Although his uric acid level was >10 mg/dL when treatment was started, his risk factors may have precluded initiation of allopurinol. Furthermore, the prescribed dose of allopurinol (300 mg) was too high for his baseline GFR; 100 mg daily would have been more appropriate. It could be argued that hydrochlorothiazide would not be an antihypertensive of choice due to its hyperuricemic effects. Switching the thiazide to a loop diuretic would offer no benefit, because loop diuretics also cause hyperuricemia. (More on which antihypertensive agent would have been appropriate in a bit.)

The role of AHS in the patient’s death is unclear. He was at high risk for stroke considering his age, comorbidities, and evidence of an old lacunar infarct. Myocardial infarctions have been reported as one cause of death in AHS, but we have found no reports of associated stroke. However, the temporal proximity of the CVA suggests a contributing effect of AHS. The adequacy of treatment is also brought into question. Early withdrawal of glucocorticoids can be associated with relapse of AHS; in retrospect, the prednisone dose may have been too low or the taper too short, or both.

Therapeutic alternatives to allopurinol were available. The most appropriate initial option for this patient likely was no pharmacologic intervention at all but a focus on weight loss and diet. The risk of gouty attacks in men increases as body mass index rises above normal (≥25 kg/m2) and decreases with weight loss. Lower calorie diets with decreased saturated fat, higher complex carbohydrates, and allowed proteins (low-fat dairy products) are more palatable and more effective than strict low-purine diets.

A urate-lowering antihypertensive may have been a better option—specifically, losartan rather than irbesartan and triamterene/hydrochlorothiazide.^8,13 Losartan has uricosuric properties at the 50-mg dose.¹⁴ When compared in different studies with irbesartan, enalapril, and candesartan, losartan alone lowered serum urate levels. Increasing losartan to 100 mg could provide better hypertensive control but has not been found to lower urate levels more dramatically than the lower dose.¹³

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been found to blunt the urate-elevating effects of thiazides. Therefore, if the patient’s blood pressure was not adequately controlled on losartan alone, the combination of losartan/hydrochlorothiazide would be a reasonable choice because minimal or no change in serum uric acid levels would be expected.¹⁵

Febuxostat, a nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol in patients with gout. It is a more potent urate-lowering agent than allopurinol and can be used without dosage reduction in mild (creatinine clearance [CrCl], 60-89 mL/min) to moderate (CrCl, 30-59 mL/ min) renal insufficiency. Febuxostat is metabolized primarily in the liver—in contrast to allopurinol, which is excreted by the kidneys—and may increase liver transaminase levels.¹⁰ Although febuxostat was not available at the time our patient developed AHS, it would not have been indicated in asymptomatic hyperuricemia.

This compelling case reminds us to carefully consider the indications and risk factors in using allopurinol, and to be aware of the rare but sometimes devastating consequences of this commonly used drug.

CORRESPONDENCE
Tahirah Tyrell, MD, Rochester General Medical Group, 1425 Portland Avenue, Rochester, NY 14621;
[email protected].

An 80-year-old Hawaiian man of Chinese ancestry arrives at the emergency department with diarrhea and dehydration. You are called to admit him for acute renal failure. On entering the patient’s room, you note that he has a diffuse maculopapular rash and is wheezing.

Twenty-one months earlier, the patient suffered his first episode of gout. Since that time, he has been asymptomatic. Two months ago, his primary care physician obtained a uric acid level and found it elevated at 10.6 mg/dL. She started the patient on allopurinol 300 mg PO daily.

Twenty days ago (approximately 6 weeks after initiation of allopurinol), the rash developed along with generalized pruritus. The patient’s primary care physician referred him to a dermatologist for skin biopsy, and he discontinued allopurinol 11 days ago.

Just in the past week, the patient began to experience a metallic taste in his mouth, as well as anorexia, malaise, chills, dysuria, and nonbloody diarrhea. He became nauseous and decreased his oral intake, which led to dehydration and progressive weakness.

Additional medical history

• The patient’s medical history is significant for renal insufficiency, type 2 diabetes mellitus, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, chronic nasal allergies, benign prostatic hypertrophy, osteoarthritis, and gout.
• He is taking the following medications: fluticasone inhalant 110 mcg daily; fluticasone propionate one spray in both nostrils daily; montelukast 10 mg PO daily; irbesartan 300 mg PO daily; amlodipine 5 mg PO daily; glyburide 2.5 mg PO BID; triamterene/hydrochlorothiazide 37.5/25 mg PO QOD; albuterol 90 mcg 2 puffs q6h prn; terazosin 2 mg PO qhs; simvastatin 40 mg PO daily; azelastine 137 mcg 1 spray in both nostrils prn; meclizine 25 mg PO daily prn; fexofenadine 150 mg PO qPM; cyclobenzaprine 10 mg PO qhs prn; and hydrocodone/acetamino- phen 5/500 mg 2 tabs PO daily prn.

Social history

• The patient recently arrived from Hawaii to visit his wife’s family.
• He does not drink alcohol, but he smokes 4 cigarettes a day.

Review of systems

• A review of systems is negative for the following: fever, sick contacts, history of renal calculi, hemoptysis, ocular or ENT symptoms, history of hepatic disease, peripheral neuropathy, and neurologic symptoms.

Physical examination

• The patient is alert and cooperative.
• Temperature is 97.9^oF, blood pressure 110/52 mm Hg, pulse 112 beats per minute, respiratory rate 16 breaths per minute, oxygen saturation 96% on room air.
• Mucous membranes are dry.
• Auscultation of the heart is normal.
• Significant wheezing is present in bilateral lung fields, but requiring no use of accessory muscles during respiration.
• Abdominal exam is remarkable only for obesity.
• Trace pitting edema is present in both lower extremities.
• The maculopapular rash is diffuse and nonblanching. Scaling on the trunk, areas of erythema below the umbilicus, and coalescing macular lesions on bilateral lower extremities are present.
• Joints are not swollen or tender, and there are no tophi.
• There are no focal neurologic deficits, and deep tendon reflexes are normal.

Laboratory studies completed in the ED

• Blood urea nitrogen, 112 mg/dL ; creatinine, 3 mg/dL ; glomerular filtration rate (GFR), 22 mL/min (baseline ratio of blood urea nitrogen/creatinine, 36:1.57; baseline GFR, 43 mL/min)
• White blood cell count, 15 k/uL
• Hemoglobin, 14.3 g/dL ; hematocrit, 43.6%; platelet count, 307/uL
• Alanine aminotransferase and aspartate aminotransferase, 177 and 139 IU/L, respectively
• Direct, indirect, and total bilirubin, 0.60, 1.19, and 1.79 mg/dL, respectively
• Serum eosinophils, 22% (normal <6%)
• Erythrocyte sedimentation rate, 50 mm/h.

Radiology

• Chest radiographs (posterior-anterior, lateral) show a bilateral process consistent with atelectasis or lung scarring.
• Noncontrast computed tomography (CT) of the thorax confirms parenchymal scarring but no acute process.
• Hepatic sonography reveals increased echogenicity of the liver parenchyma consistent with an acute hepatocellular process.
• Magnetic resonance imaging (MRI) of the abdomen shows a diffuse process in the liver with trace parahepatic ascites.
• Renal ultrasound shows bilateral renal cysts with no hydronephrosis or urolithiasis.
• Cardiac echocardiography reveals left ventricular hypertrophy but normal ejection fraction.
• Noncontrast CT (head) and MRI (brain) show an acute right frontoparietal cerebrovascular accident and an old lacunar infarct.

Dermatologist’s report

• A skin biopsy reveals lymphocytic perivascular infiltrate with scattered eosinophils and mild spongiosis consistent with vasculitis.

Follow-up laboratory data

• Acute hepatitis panel is negative
• Uric acid, 13.8 mg/dL
• Urine eosinophils, 31% (normal <1%)
• Anti-neutrophil cytoplasmic antibody IgG, 1:40 mildly elevated (normal<1:20)
• Anti-nuclear antibody (ANA) IgG, none
• Glycosylated hemoglobin, 7.1%
• High-sensitivity C-reactive protein, 207.96 mg/L (>10 mg/L is very high)

In summary, this patient’s erythematous rash is a biopsy-confirmed vasculitis. Additional findings are hepatitis, acute on chronic renal failure, eosinophilia, and leukocytosis.

Q/ What is your presumptive diagnosis?

Allopurinol hypersensitivity syndrome

Allopurinol hypersensitivity syndrome (AHS) is a diffuse vasculitis induced by a type III hypersensitivity reaction, possibly to oxypurinol, allopurinol’s toxic metabolite. The exact pathophysiology is unknown, but oxypurinol levels correlate positively with the risk of AHS.¹ Thiazides may increase oxypurinol levels.²

Signs and symptoms of AHS include fever, erythematous skin rash, eosinophilia, hepatitis, progressive renal insufficiency, and leukocytosis. Case reports have also attributed septic shock, myocardial infarction, and Guillain-Barré syndrome to AHS.^3-6 The incidence of AHS is 0.1% to 0.4% of patients treated with allopurinol; mortality approaches 25%.¹

Q/ What are the diagnostic criteria for AHS?

Singer and Wallace have outlined diagnostic criteria for AHS,⁷ the first being a clear history of exposure to allopurinol.

Second, the clinical profile usually takes one of the following forms:

• The patient exhibits at least 2 of the following major features: worsening renal function, acute hepatocellular injury, or a rash (toxic epidermal necrolysis, erythema multiforme, or diffuse maculopapular or exfoliative dermatitis) or
• The patient exhibits just one of the major features and at least one of the following minor features: fever, eosinophilia, or leukocytosis.

Third, there is no history of exposure to another drug that may cause a similar clinical picture.

Q/ What is the accepted treatment for ahS?

Although there is no well-established treatment plan, the standard of care is to discontinue allopurinol, administer parenteral corticosteroids followed by oral taper, and offer supportive management. Desensitization protocols are difficult and hypersensitivity reactions may recur. Early withdrawal of steroids has been reported to result in recurrence of symptoms. However, no strong data exist for determining an optimal length of corticosteroid therapy, or the number of days that constitutes “early” withdrawal of steroids. Mortality is high, even with seemingly adequate treatment.

Q/ Which patients are most at risk for ahS?

Definite risk factors for AHS include recent onset of allopurinol therapy, the presence of HLA-B5801 allele in patients of Han Chinese and European ancestry, and chronic kidney disease.^1,8,9 Suggested risk factors include concomitant use of thiazide diuretics with allopurinol, treatment of asymptomatic hyperuricemia, and high allopurinol dose relative to renal function.

Q/ What are the indications for allopurinol therapy?

Indications for allopurinol therapy:^1,10

• Failure of uricosuric drugs or contraindications to their use
• Frequent attacks of gouty arthritis (≥3 per year)
• Nephrolithiasis
• Marked overproduction of urate, such as seen in tumor lysis syndrome
• The presence of tophi.

For patients with appropriate indications for allopurinol therapy, treat with the minimum effective dose. Initiation of allopurinol is controversial for a patient with a single lifetime episode of gout. However, most patients with one episode of gout will develop recurrent gout.⁸

In patients with creatinine clearance >60 mL/min, allopurinol is usually started at 100 mg oral daily and titrated every 2 to 3 weeks until reaching the desired effectiveness.⁸ One retrospective study suggests that initiating allopurinol at a dose of 1.5 mg per unit of estimated GFR may reduce the risk of AHS.¹¹

Our patient’s case: Treatment, discharge, readmission

With our patient, we started intravenous normal saline fluid boluses and parenteral methylprednisolone, 60 mg q6h. We discontinued triamterene/hydrochlorothiazide due to his hyperuricemia, and irbesartan and glyburide due to renal failure. Basal and rapid-acting insulins maintained good glycemic control. To control his wheezing and dyspnea, we began albuterol/ipratropium nebulizer treatments and oxygen delivery via nasal cannula. Nephrology, pulmonology, and rheumatology consultants agreed with these management decisions.

Over the next 9 days, the patient’s renal function improved and his rash started to resolve. His wheezing fluctuated but persisted throughout the hospital stay. We stopped nasal oxygen delivery, and his oxygen saturation remained normal (96%-98%) on room air. He was subsequently discharged in stable condition on a 2-week prednisone taper starting at 30 mg bid.

Thirteen days later, he was readmitted with a right frontoparietal cerebrovascular accident (CVA). He developed respiratory distress, which led to respiratory arrest, and was ventilated. He became hypotensive, lapsed into shock, and died a few days later (approximately one month after initial presentation).

The appropriate use of allopurinol—a second look

This case raised many questions for our inpatient team concerning not just AHS, but the appropriate use and dosing of allopurinol. Allopurinol is widely used for hyperuricemia and gout because it is effective for all causes of hyperuricemia and is inexpensive. Given that 3.9%¹² of the general population has gout and that its prevalence has increased with rising rates of obesity, the importance of AHS is not abstract.

Revisiting initial treatment choices. Our patient was at risk for this syndrome due to his Chinese ancestry, recent onset of allopurinol therapy, concomitant use of triamterene/hydrochlorothiazide, and impaired renal function. Although his uric acid level was >10 mg/dL when treatment was started, his risk factors may have precluded initiation of allopurinol. Furthermore, the prescribed dose of allopurinol (300 mg) was too high for his baseline GFR; 100 mg daily would have been more appropriate. It could be argued that hydrochlorothiazide would not be an antihypertensive of choice due to its hyperuricemic effects. Switching the thiazide to a loop diuretic would offer no benefit, because loop diuretics also cause hyperuricemia. (More on which antihypertensive agent would have been appropriate in a bit.)

The role of AHS in the patient’s death is unclear. He was at high risk for stroke considering his age, comorbidities, and evidence of an old lacunar infarct. Myocardial infarctions have been reported as one cause of death in AHS, but we have found no reports of associated stroke. However, the temporal proximity of the CVA suggests a contributing effect of AHS. The adequacy of treatment is also brought into question. Early withdrawal of glucocorticoids can be associated with relapse of AHS; in retrospect, the prednisone dose may have been too low or the taper too short, or both.

Therapeutic alternatives to allopurinol were available. The most appropriate initial option for this patient likely was no pharmacologic intervention at all but a focus on weight loss and diet. The risk of gouty attacks in men increases as body mass index rises above normal (≥25 kg/m2) and decreases with weight loss. Lower calorie diets with decreased saturated fat, higher complex carbohydrates, and allowed proteins (low-fat dairy products) are more palatable and more effective than strict low-purine diets.

A urate-lowering antihypertensive may have been a better option—specifically, losartan rather than irbesartan and triamterene/hydrochlorothiazide.^8,13 Losartan has uricosuric properties at the 50-mg dose.¹⁴ When compared in different studies with irbesartan, enalapril, and candesartan, losartan alone lowered serum urate levels. Increasing losartan to 100 mg could provide better hypertensive control but has not been found to lower urate levels more dramatically than the lower dose.¹³

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been found to blunt the urate-elevating effects of thiazides. Therefore, if the patient’s blood pressure was not adequately controlled on losartan alone, the combination of losartan/hydrochlorothiazide would be a reasonable choice because minimal or no change in serum uric acid levels would be expected.¹⁵

Febuxostat, a nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol in patients with gout. It is a more potent urate-lowering agent than allopurinol and can be used without dosage reduction in mild (creatinine clearance [CrCl], 60-89 mL/min) to moderate (CrCl, 30-59 mL/ min) renal insufficiency. Febuxostat is metabolized primarily in the liver—in contrast to allopurinol, which is excreted by the kidneys—and may increase liver transaminase levels.¹⁰ Although febuxostat was not available at the time our patient developed AHS, it would not have been indicated in asymptomatic hyperuricemia.

This compelling case reminds us to carefully consider the indications and risk factors in using allopurinol, and to be aware of the rare but sometimes devastating consequences of this commonly used drug.

CORRESPONDENCE
Tahirah Tyrell, MD, Rochester General Medical Group, 1425 Portland Avenue, Rochester, NY 14621;
[email protected].

ILLUSTRATED CASE

An 82-year-old patient presents to the emergency department with several episodes of melena over the past week and one episode of hematemesis this morning. He denies any shortness of breath, dizziness, lightheadedness, or fatigue. He is tachycardic but normotensive. Lab results note a hemoglobin level of 8.3 g/dL. Should you order a transfusion of red blood cells?

Acute upper gastrointestinal bleeding (UGIB) commonly requires hospital admission, with approximately 61 cases per 100,000 population in the United States in 2009.² Gastroduodenal peptic ulcer disease accounts for the majority of these cases.³ Although trends indicate an overall decrease in cases requiring hospitalization, UGIB remains a condition associated with a mortality rate of 2.5% and inpatient costs of $2 billion annually.^2,3

Studies have been inconclusive—until now
An RCT published in 1999 showed a restrictive transfusion strategy (hemoglobin threshold of 7 g/dL) to be at least as effective as—and possibly superior to—a liberal strategy (threshold of 10 g/dL) in critically ill patients.⁴ In 2010, an RCT demonstrated that a liberal transfusion strategy (also defined as a transfusion threshold of 10 g/dL) did not reduce the rates of death or in-hospital morbidity in elderly patients after hip surgery.⁵ A recent Cochrane review of transfusion strategies for UGIB included only 3 small studies (N=93), so its authors could not draw any firm conclusions.⁶ The results of a new RCT, detailed below, are more conclusive.

STUDY SUMMARY: Restrictive transfusion policy lowers mortality risk

Villanueva et al conducted a nonblinded RCT comparing outcomes in patients admitted to the hospital with moderate-risk acute UGIB transfused on a liberal vs a restrictive strategy.¹ The restrictive group used a transfusion hemoglobin threshold of 7 g/dL and a posttransfusion target of 7 to 9 g/dL; the liberal group used a threshold of 9 g/dL, with a posttransfusion target of 9 to 11 g/dL. Patients received one unit of red blood cells at a time until their hemoglobin was above the predetermined threshold.

Patients were excluded if they declined blood transfusion; had massive exsanguinating bleeding, acute coronary syndrome, symptomatic peripheral vasculopathy, stroke, lower GI bleeding, or a transient ischemic attack; had received a transfusion within the previous 90 days; or had a recent history of surgery or trauma. Patients at low risk of rebleeding (as defined by the Rockall risk scoring system) were also excluded. Randomization was stratified by the presence or absence of cirrhosis of the liver.

Participants (N=921) had confirmed hematemesis and/or melena on admission. All underwent emergency gastroscopy within 6 hours of admission, with subsequent interventions based on endoscopic findings. In addition to established hemoglobin levels, patients received a transfusion anytime they developed signs or symptoms related to anemia, massive bleeding, or the need for surgery. Staff monitored hemoglobin levels every 8 hours during the first 48 hours, then daily thereafter.

Both groups had similar baseline characteristics, including hemoglobin on admission and source of bleeding. The authors used intention-to-treat analysis to identify the primary outcome: death from any cause at 45 days. Secondary outcomes were further bleeding and in-hospital complications.

During hospitalization, 49% of patients in the restrictive group and 86% of those in the liberal group received a blood transfusion (P<.001). Thirty-two patients (17 from the restrictive group and 15 from the liberal group) withdrew from the study, leaving 889 patients for overall analysis.

At 45 days, overall mortality from any cause was 5% in the restrictive group and 9% in the liberal group (P=.02; number needed to treat [NNT]=25). Sub-group analysis revealed a lower risk of death in patients with cirrhosis and Child-Pugh class A or B disease assigned to the restrictive transfusion group vs the liberal group. The results showed a trend toward a lower risk of death in patients with bleeding from varices or peptic ulcers for the restrictive group, as well.

In addition, the restrictive transfusion group had a significantly lower rate of adverse events (40% vs 48% for the liberal transfusion group; P=.02, NNT=13), with a significant reduction in transfusion reactions (3% vs 9%; P=.001, NNT=17) and cardiac complications (11% vs 16%; P=.04, NNT=20). The restrictive group had a lower rate of further bleeding (10% vs 16% for the liberal transfusion group; P=.01, NNT=17), as well.

WHAT'S NEW: Many reasons to limit transfusions for acute upper GI bleed

This RCT provides evidence that patients with acute UGIB have improved survival rates and fewer adverse events when a restrictive transfusion strategy is used. In addition to improving patient outcomes, a restrictive strategy will likely reduce costs and overall use of blood products. Thus, the study, along with other recent evaluations, adds evidence to support more restrictive transfusion thresholds.

The AABB (formerly named the American Association of Blood Banks) recently
released guidelines calling for restrictive transfusion thresholds (7-8 g/dL) in stable hospitalized patients.⁷ In 2012, the American College of Gastroenterology published a practice guideline with a recommended target hemoglobin level of ≥7 g/dL in the management of patients who have ulcer bleeding but no signs of intravascular depletion or comorbidities such as coronary artery disease.⁸

CAVEATS: Results might differ when endoscopy is delayed

The patients in the study detailed here underwent emergency gastroscopy within 6 hours of admission, and both groups received the same therapies based on endoscopic findings. It remains unclear whether the benefits of a restrictive transfusion strategy would persist in patients who do not undergo endoscopy within that timeframe. And, because the reported baseline characteristics of the patients did not include the prevalence of cardiac disease, caution should be exercised before extrapolating these results to patients with underlying (active or historical) cardiac disease.

CHALLENGES TO IMPLEMENTATION: Changing long-held policies may be difficult

Although RCTs as well as clinical guidelines suggest that restrictive transfusion policies are safe and effective, changing long-held clinical practices is never easy.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATED CASE

An 82-year-old patient presents to the emergency department with several episodes of melena over the past week and one episode of hematemesis this morning. He denies any shortness of breath, dizziness, lightheadedness, or fatigue. He is tachycardic but normotensive. Lab results note a hemoglobin level of 8.3 g/dL. Should you order a transfusion of red blood cells?

Acute upper gastrointestinal bleeding (UGIB) commonly requires hospital admission, with approximately 61 cases per 100,000 population in the United States in 2009.² Gastroduodenal peptic ulcer disease accounts for the majority of these cases.³ Although trends indicate an overall decrease in cases requiring hospitalization, UGIB remains a condition associated with a mortality rate of 2.5% and inpatient costs of $2 billion annually.^2,3

Studies have been inconclusive—until now
An RCT published in 1999 showed a restrictive transfusion strategy (hemoglobin threshold of 7 g/dL) to be at least as effective as—and possibly superior to—a liberal strategy (threshold of 10 g/dL) in critically ill patients.⁴ In 2010, an RCT demonstrated that a liberal transfusion strategy (also defined as a transfusion threshold of 10 g/dL) did not reduce the rates of death or in-hospital morbidity in elderly patients after hip surgery.⁵ A recent Cochrane review of transfusion strategies for UGIB included only 3 small studies (N=93), so its authors could not draw any firm conclusions.⁶ The results of a new RCT, detailed below, are more conclusive.

STUDY SUMMARY: Restrictive transfusion policy lowers mortality risk

Villanueva et al conducted a nonblinded RCT comparing outcomes in patients admitted to the hospital with moderate-risk acute UGIB transfused on a liberal vs a restrictive strategy.¹ The restrictive group used a transfusion hemoglobin threshold of 7 g/dL and a posttransfusion target of 7 to 9 g/dL; the liberal group used a threshold of 9 g/dL, with a posttransfusion target of 9 to 11 g/dL. Patients received one unit of red blood cells at a time until their hemoglobin was above the predetermined threshold.

Patients were excluded if they declined blood transfusion; had massive exsanguinating bleeding, acute coronary syndrome, symptomatic peripheral vasculopathy, stroke, lower GI bleeding, or a transient ischemic attack; had received a transfusion within the previous 90 days; or had a recent history of surgery or trauma. Patients at low risk of rebleeding (as defined by the Rockall risk scoring system) were also excluded. Randomization was stratified by the presence or absence of cirrhosis of the liver.

Participants (N=921) had confirmed hematemesis and/or melena on admission. All underwent emergency gastroscopy within 6 hours of admission, with subsequent interventions based on endoscopic findings. In addition to established hemoglobin levels, patients received a transfusion anytime they developed signs or symptoms related to anemia, massive bleeding, or the need for surgery. Staff monitored hemoglobin levels every 8 hours during the first 48 hours, then daily thereafter.

Both groups had similar baseline characteristics, including hemoglobin on admission and source of bleeding. The authors used intention-to-treat analysis to identify the primary outcome: death from any cause at 45 days. Secondary outcomes were further bleeding and in-hospital complications.

During hospitalization, 49% of patients in the restrictive group and 86% of those in the liberal group received a blood transfusion (P<.001). Thirty-two patients (17 from the restrictive group and 15 from the liberal group) withdrew from the study, leaving 889 patients for overall analysis.

At 45 days, overall mortality from any cause was 5% in the restrictive group and 9% in the liberal group (P=.02; number needed to treat [NNT]=25). Sub-group analysis revealed a lower risk of death in patients with cirrhosis and Child-Pugh class A or B disease assigned to the restrictive transfusion group vs the liberal group. The results showed a trend toward a lower risk of death in patients with bleeding from varices or peptic ulcers for the restrictive group, as well.

In addition, the restrictive transfusion group had a significantly lower rate of adverse events (40% vs 48% for the liberal transfusion group; P=.02, NNT=13), with a significant reduction in transfusion reactions (3% vs 9%; P=.001, NNT=17) and cardiac complications (11% vs 16%; P=.04, NNT=20). The restrictive group had a lower rate of further bleeding (10% vs 16% for the liberal transfusion group; P=.01, NNT=17), as well.

WHAT'S NEW: Many reasons to limit transfusions for acute upper GI bleed

This RCT provides evidence that patients with acute UGIB have improved survival rates and fewer adverse events when a restrictive transfusion strategy is used. In addition to improving patient outcomes, a restrictive strategy will likely reduce costs and overall use of blood products. Thus, the study, along with other recent evaluations, adds evidence to support more restrictive transfusion thresholds.

The AABB (formerly named the American Association of Blood Banks) recently
released guidelines calling for restrictive transfusion thresholds (7-8 g/dL) in stable hospitalized patients.⁷ In 2012, the American College of Gastroenterology published a practice guideline with a recommended target hemoglobin level of ≥7 g/dL in the management of patients who have ulcer bleeding but no signs of intravascular depletion or comorbidities such as coronary artery disease.⁸

CAVEATS: Results might differ when endoscopy is delayed

The patients in the study detailed here underwent emergency gastroscopy within 6 hours of admission, and both groups received the same therapies based on endoscopic findings. It remains unclear whether the benefits of a restrictive transfusion strategy would persist in patients who do not undergo endoscopy within that timeframe. And, because the reported baseline characteristics of the patients did not include the prevalence of cardiac disease, caution should be exercised before extrapolating these results to patients with underlying (active or historical) cardiac disease.

CHALLENGES TO IMPLEMENTATION: Changing long-held policies may be difficult

Although RCTs as well as clinical guidelines suggest that restrictive transfusion policies are safe and effective, changing long-held clinical practices is never easy.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATED CASE

An 82-year-old patient presents to the emergency department with several episodes of melena over the past week and one episode of hematemesis this morning. He denies any shortness of breath, dizziness, lightheadedness, or fatigue. He is tachycardic but normotensive. Lab results note a hemoglobin level of 8.3 g/dL. Should you order a transfusion of red blood cells?

Acute upper gastrointestinal bleeding (UGIB) commonly requires hospital admission, with approximately 61 cases per 100,000 population in the United States in 2009.² Gastroduodenal peptic ulcer disease accounts for the majority of these cases.³ Although trends indicate an overall decrease in cases requiring hospitalization, UGIB remains a condition associated with a mortality rate of 2.5% and inpatient costs of $2 billion annually.^2,3

Studies have been inconclusive—until now
An RCT published in 1999 showed a restrictive transfusion strategy (hemoglobin threshold of 7 g/dL) to be at least as effective as—and possibly superior to—a liberal strategy (threshold of 10 g/dL) in critically ill patients.⁴ In 2010, an RCT demonstrated that a liberal transfusion strategy (also defined as a transfusion threshold of 10 g/dL) did not reduce the rates of death or in-hospital morbidity in elderly patients after hip surgery.⁵ A recent Cochrane review of transfusion strategies for UGIB included only 3 small studies (N=93), so its authors could not draw any firm conclusions.⁶ The results of a new RCT, detailed below, are more conclusive.

STUDY SUMMARY: Restrictive transfusion policy lowers mortality risk

Villanueva et al conducted a nonblinded RCT comparing outcomes in patients admitted to the hospital with moderate-risk acute UGIB transfused on a liberal vs a restrictive strategy.¹ The restrictive group used a transfusion hemoglobin threshold of 7 g/dL and a posttransfusion target of 7 to 9 g/dL; the liberal group used a threshold of 9 g/dL, with a posttransfusion target of 9 to 11 g/dL. Patients received one unit of red blood cells at a time until their hemoglobin was above the predetermined threshold.

Patients were excluded if they declined blood transfusion; had massive exsanguinating bleeding, acute coronary syndrome, symptomatic peripheral vasculopathy, stroke, lower GI bleeding, or a transient ischemic attack; had received a transfusion within the previous 90 days; or had a recent history of surgery or trauma. Patients at low risk of rebleeding (as defined by the Rockall risk scoring system) were also excluded. Randomization was stratified by the presence or absence of cirrhosis of the liver.

Participants (N=921) had confirmed hematemesis and/or melena on admission. All underwent emergency gastroscopy within 6 hours of admission, with subsequent interventions based on endoscopic findings. In addition to established hemoglobin levels, patients received a transfusion anytime they developed signs or symptoms related to anemia, massive bleeding, or the need for surgery. Staff monitored hemoglobin levels every 8 hours during the first 48 hours, then daily thereafter.

Both groups had similar baseline characteristics, including hemoglobin on admission and source of bleeding. The authors used intention-to-treat analysis to identify the primary outcome: death from any cause at 45 days. Secondary outcomes were further bleeding and in-hospital complications.

During hospitalization, 49% of patients in the restrictive group and 86% of those in the liberal group received a blood transfusion (P<.001). Thirty-two patients (17 from the restrictive group and 15 from the liberal group) withdrew from the study, leaving 889 patients for overall analysis.

At 45 days, overall mortality from any cause was 5% in the restrictive group and 9% in the liberal group (P=.02; number needed to treat [NNT]=25). Sub-group analysis revealed a lower risk of death in patients with cirrhosis and Child-Pugh class A or B disease assigned to the restrictive transfusion group vs the liberal group. The results showed a trend toward a lower risk of death in patients with bleeding from varices or peptic ulcers for the restrictive group, as well.

In addition, the restrictive transfusion group had a significantly lower rate of adverse events (40% vs 48% for the liberal transfusion group; P=.02, NNT=13), with a significant reduction in transfusion reactions (3% vs 9%; P=.001, NNT=17) and cardiac complications (11% vs 16%; P=.04, NNT=20). The restrictive group had a lower rate of further bleeding (10% vs 16% for the liberal transfusion group; P=.01, NNT=17), as well.

WHAT'S NEW: Many reasons to limit transfusions for acute upper GI bleed

This RCT provides evidence that patients with acute UGIB have improved survival rates and fewer adverse events when a restrictive transfusion strategy is used. In addition to improving patient outcomes, a restrictive strategy will likely reduce costs and overall use of blood products. Thus, the study, along with other recent evaluations, adds evidence to support more restrictive transfusion thresholds.

The AABB (formerly named the American Association of Blood Banks) recently
released guidelines calling for restrictive transfusion thresholds (7-8 g/dL) in stable hospitalized patients.⁷ In 2012, the American College of Gastroenterology published a practice guideline with a recommended target hemoglobin level of ≥7 g/dL in the management of patients who have ulcer bleeding but no signs of intravascular depletion or comorbidities such as coronary artery disease.⁸

CAVEATS: Results might differ when endoscopy is delayed

The patients in the study detailed here underwent emergency gastroscopy within 6 hours of admission, and both groups received the same therapies based on endoscopic findings. It remains unclear whether the benefits of a restrictive transfusion strategy would persist in patients who do not undergo endoscopy within that timeframe. And, because the reported baseline characteristics of the patients did not include the prevalence of cardiac disease, caution should be exercised before extrapolating these results to patients with underlying (active or historical) cardiac disease.

CHALLENGES TO IMPLEMENTATION: Changing long-held policies may be difficult

Although RCTs as well as clinical guidelines suggest that restrictive transfusion policies are safe and effective, changing long-held clinical practices is never easy.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

CASE Jane C, a 76-year-old patient, reports lower abdominal discomfort and increased bowel movements. Her left lower quadrant is tender to palpation, without signs of a surgical abdomen, and vital signs are normal. Laboratory studies are also normal, except for mild anemia and a positive fecal occult blood test. Abdominal and pelvic computed tomography (CT), with and without contrast, are negative for acute pathology, but a 1.7-cm lesion is found in the upper pole of the left kidney. What is your next step?

Renal or adrenal masses may be discovered during imaging studies for complaints unrelated to the kidneys or adrenals. Detection of incidentalomas has increased dramatically, keeping pace with the growing use of ultrasonography, CT, and magnetic resonance imaging (MRI) for abdominal, chest, and back complaints.¹

Family physicians can evaluate most of these masses and determine the need for referral by using clinical judgment, appropriate imaging studies, and screening laboratory tests. In the pages that follow, we present a systematic approach for evaluating these incidentalomas and determining when consultation or referral is needed.

Incidental renal masses are common

Lesions are commonly found in normal kidneys, and the incidence increases with age. Approximately one-third of individuals age 50 and older will have at least one renal cyst on CT.²

Most incidental renal masses are benign cysts requiring no further evaluation. Other possibilities include indeterminate or malignant cysts or solid masses, which may be malignant or benign. Inflammatory renal lesions from infection, infarction, or trauma also occur, but these tend to be symptomatic and are rarely found incidentally.

Classification of renal cysts—not based on size

Cysts are the most common adult renal masses. Typically they are unilocular and located in the renal cortex, frequently extending to the renal surface.³ Renal function is usually preserved, regardless of the cyst’s location or size. Careful examination of adjacent tissue is essential, as secondary cysts may form when solid tumors obstruct tubules of normal parenchyma. Cystic lesions containing enhancing soft tissue unattached to the wall or septa likely are malignant.⁴

The Bosniak classification system, with 5 classes based on CT characteristics
(TABLE 1), is a useful guide for managing renal cystic lesions.⁴ Size is not an important feature in the Bosniak system; small cysts may be malignant and larger ones benign. Small cysts may grow into larger benign lesions, occasionally causing flank or abdominal pain, palpable masses, or hematuria.

Simple cysts. Renal cysts that meet Bosniak class I criteria can be confidently labeled benign and need no further evaluation (FIGURE 1). Simple renal cysts on CT have homogenous low-attenuating fluid and thin nonenhancing walls without septa.⁴

On ultrasound, simple renal cysts show spherical or ovoid shape without internal echoes, a thin smooth wall separate from the surrounding parenchyma, and posterior wall enhancement caused by increased transmission through the water-filled cyst. The likelihood of malignancy is extremely low in a renal cyst that meets these criteria, which have a reported accuracy of 98% to 100%.³ Thus, no further evaluation is required if an obviously benign simple cyst is first noted on an adequate ultrasound. Inadequate ultrasound visualization or evidence of calcifications, septa, or multiple chambers calls for prompt renal CT.

CASE The mass on Ms. C’s left kidney is hypoattenuating and nonenhancing on CT. It meets Bosniak criteria for a benign simple cyst (class I) and requires no further evaluation or follow-up. Colonoscopy detects multiple colonic polyps that are removed, and the patient does well.

Mildly complicated cysts. Less diagnostic certainty characterizes cysts with mild abnormalities that keep them from being labeled as simple. Bosniak classes II and IIF describe mildly abnormal renal cysts. Class II cysts can be dismissed, whereas class IIF cysts require follow-up.

Class II cysts may contain a few hairline septa, fine calcium deposits in walls or septa, or an unmeasurable enhancement of the walls. A hyperattenuating but nonenhancing fluid also is described as category II. Small homogeneous cysts <3 cm, without enhancement but hyperattenuated, are reliably considered benign and need not be evaluated.^2,7

Class IIF cysts may have multiple hairline-thin septa with unmeasurable enhancement or minimal smooth thickening or irregular/nodular calcifications of wall or septa without enhancing soft tissue components. Hyperattenuating cystic lesions >3 cm and intrarenal “noncortical” cysts are included in this category. Class IIF cysts require follow-up at 6 months with CT or MRI, then annually for at least 5 years.⁸

Obviously complicated cysts. Bosniak class III is indeterminate—neither benign nor clearly malignant. Class III cysts may have thickened borders or septa with measurable enhancement, or they may be multilocular, hemorrhagic, or infected. In 5 case series, 29 of 57 class III lesions proved to be malignant.⁵ MRI may characterize these lesions more definitively than CT prior to urologic referral.

Malignant cysts. Bosniak class IV renal lesions are clearly malignant, with large heterogeneous cysts or necrotic components, shaggy thickened walls, or enhancing soft tissue components separate from the wall or septa. Their unequivocal appearance results from solid tumor necrosis and liquefaction. Diagnosis is straightforward, and excision is indicated.²

A closer look at solid renal masses
Solid renal masses usually consist of enhancing tissue with little or no fluid. The goal of evaluation is to exclude malignancies, such as renal cell cancer, lymphomas, sarcomas, or metastasis. Benign solid masses include renal adenomas, angiomyolipomas, and oncocytomas, among others.

Several lesions can be diagnosed by appearance or symptoms:

Angiomyolipomas are recognized by their fat content within a noncalcified mass. Unenhanced CT usually is sufficient for diagnosis, unless the mass is very small or has atypical features.⁹

Vascular lesions can be identified because they enhance to the same degree as the vasculature. With the exception of inflammatory or vascular abnormalities, all enhancing lesions that do not contain fat should be presumed to be malignant.

In patients with a known extrarenal primary malignancy, 50% to 85% of incidental solid renal masses will represent metastatic disease.¹⁰ Percutaneous biopsy may be warranted to differentiate metastatic lesions from a secondary, primary (ie, renal cell carcinoma), or benign process.¹¹

A study of 2770 solid renal mass excisions revealed that 12.8% were benign, with a direct relationship between malignancy and size. Masses <1 cm were benign 44% of the time.¹² Early identification of small renal carcinomas may improve survival rates. Although renal cell carcinomas <3 cm in diameter have low metastatic potential, a solid, nonfat-containing mass should be evaluated for aggressive nephron-sparing surgery.^6,13

Incidental adrenal masses occur infrequently

Adrenal incidentalomas are defined as radiographically identified masses >1 cm in diameter.¹⁴ They are much less common than their renal counterparts, with a reported prevalence of 0.35% to 5% on CT.¹⁵ Because the adrenal glands are hormonally active and receive substantial blood flow, metastatic, hormonally active, and nonfunctional causes for adrenal masses need to be considered.¹⁶

Adrenal pathology
Adrenal masses may be characterized by increased or normal adrenal function. Hyperfunctioning syndromes include hypercortisolism, hyperaldosteronism, adrenogenital hypersecretion of adrenocortical origin, and pheochromocytomas of the medulla. Symptom evaluation of these syndromes is important, but not sufficient to rule out a hyperfunctioning syndrome.

In a retrospective review of inapparent adrenal masses, ≤13% of pheochromocytomas were clinically silent.¹⁷ Therefore, laboratory testing is necessary for an incidental adrenal mass.

Nonfunctional lesions include adenomas, metastases, cysts, myelolipomas, hemorrhage, and adrenal carcinomas. These masses require evaluation for the possibility of cancer, the most common of which is metastasis. In patients with an extra-adrenal malignancy, the likelihood of malignancy in an incidental adrenal mass is at least 50%.¹⁸ An adrenal mass representing metastasis of a previously unrecognized cancer is exceedingly rare.¹⁹

Primary adrenal carcinoma is also rare, with an estimated incidence of 2 cases per one million in the general population. For patients with adrenal masses, the prevalence of carcinoma increases with lesion size (2% for tumors <4 cm, 6% for tumors 4-6 cm, and 25% for tumors >6 cm in diameter). 17 For this reason, tumors >4 cm in diameter are usually surgically resected in patients with no previous cancer history, unless radiologic criteria demonstrate clearly benign characteristics.

Although adrenal carcinomas are considered nonfunctioning, some evidence suggests they produce low levels of cortisol that may be associated with clinical features of metabolic syndrome.²⁰

CT is first choice for adrenal mass evaluation
Dedicated adrenal CT with both unenhanced and delayed contrast-enhanced images is the most reliable study to evaluate an adrenal mass, according to the American College of Radiology. Consider another study only in patients with contrast allergy, renal compromise, or cancer history.²¹

Unenhanced CT can diagnose the approximately 70% of adenomas that are small, well-defined round masses with homogenous low-density lipid deposition.²² Delayed contrast enhancement can characterize most of the remaining 30%.²³ Unenhanced CT with attenuation values of <10 Hounsfield units (HU) can diagnose adenomas with 71% specificity and 98% sensitivity,²⁴ and can often diagnose simple cysts and myelolipomas, as well.

Other imaging options. MRI is an alternative to CT for patients with contraindications for contrast or radiation exposure. MRI provides less spatial resolution than CT, but chemical shift imaging can measure cytoplasmic lipid content similar to unenhanced CT. A small study found chemical shift MRI more reliable than unenhanced CT, but less reliable than CT with delayed contrast enhancement.²⁵

Positron emission tomography (PET) is useful to noninvasively evaluate biochemical and physiologic processes. PET-CT incorporates unenhanced CT density measurements to improve PET accuracy. In a patient with a history of cancer, PET-CT has a sensitivity of 93% to 100% and a specificity of 95% in differentiating benign from malignant adrenal tumors.²⁶

When to order a biopsy
The need for biopsy has decreased as imaging has improved, but biopsy is required whenever diagnostic imaging fails to differentiatea lesion as benign or malignant. CT guided biopsy provides diagnostic accuracy of 85% to 95%.²⁷ Complications such as pneumothorax, hemorrhage, and bacteremia occur in 3% to 9% of biopsies. Before any adrenal biopsy, measure plasma-free metanephrines to exclude undiagnosed pheochromocytoma, which could precipitate a hypertensive crisis if untreated.²²

These 3 laboratory screening tests are critical

Family physicians can perform the initial biochemical evaluation of an adrenal incidentaloma. Guidance is available from the National Institutes of Health (NIH)²⁸ and the American Academy of Clinical Endocrinologists (AACE) (FIGURE 2).²⁹

Regardless of signs or symptoms, perform screening laboratory tests for 3 types of adrenal hyperfunction: hypercortisolism, hyperaldosteronism, and hypersecretion of catecholamines (pheochromocytoma). Screening tests are not recommended for androgen hypersecretion, which is extremely rare and causes recognizable symptoms such as hirsutism (Table 2).²⁹

Hypercortisolism occurs in approximately 5% of adrenal incidentalomas.³⁰ An overnight dexamethasone suppression test (DST) is most reliable for screening, with sensitivity >95% for Cushing syndrome.³¹ The patient takes a 1-mg dose of oral dexamethasone at 11 pm, and a fasting plasma cortisol sample is drawn the next day at 8 am.

Dexamethasone binds to glucocorticoid receptors in the pituitary gland, suppressing adrenocorticotropic hormone secretion. Cortisol will be depressed the next morning unless the adrenal mass produces cortisol autonomously. Patients with a DST >5 mcg/dL—highly suggestive of Cushing syndrome—require further evaluation, and we suggest referral to an endocrinologist.

Hyperaldosteronism is seen in 1% to 2% of adrenal incidentalomas.³² The aldosterone- to-renin ratio (ARR) is recommended as a screening test for hyperaldosteronism, with an ARR >20 requiring further testing.³³ Medications that may affect the ARR include beta-blockers, spironolactone, clonidine, diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers.²⁹

Refer a patient with evidence of hyperaldosteronism to an endocrinologist and a surgeon with experience in managing these lesions. If the ARR test result suggests an aldosterone excess, a salt-loading test is used to verify failure of aldosterone suppression. Adrenal venous sampling is often performed prior to surgical removal to confirm that an incidentaloma is the source of hyperaldosteronism.

Pheochromocytoma. Approximately 5% of incidental adrenal lesions are pheochromocytomas.³⁰ Many patients with these epinephrine/norepinephrine secreting tumors do not show the classic symptom triad of headache, palpitations, and diaphoresis, and approximately half have normal blood pressure.³⁴

Identifying a pheochromocytoma is important in any patient requiring surgery or biopsy, as surgical manipulation can cause a potentially fatal intraoperative catecholamine surge. Presurgical medical management can mitigate this reaction.

A plasma-free metanephrines test, which has 95% sensitivity, is the most reliable test for pheochromocytoma.³⁵ Medications, including tricyclic antidepressants, decongestants, amphetamines, reserpine, and phenoxybenzamine, can cause falsepositive results.²⁹ Confirm a positive plasma-free metanephrines test with a 24-hour fractionated urine metanephrines test, and refer the patient to an endocrinologist.

Managing adrenal incidentalomas

Refer all patients with adrenal masses >4 cm for surgical evaluation because of the risk of malignancy; all patients who have a history of malignancy and an adrenal mass of any size require a referral to an oncologist. Perform the AACE-recommended 3-element biochemical workup for all masses, with the exception of definitively diagnosed cysts or myelolipomas.

Refer to an endocrinologist all patients with abnormal screening laboratory results, regardless of adrenal mass size, as well as patients with concerning clinical findings. Initiate cardiovascular, diabetes, and bone density evaluation and management for metabolic syndrome.²⁰

Monitoring after a negative workup
Little evidence exists to guide monitoring of small adrenal incidentalomas (<4 cm) with a negative workup. The 2002 NIH report recommended annual radiologic follow-up for 5 years,²⁸ whereas the 2009 AACE guidelines recommend radiographic follow-up at 3 to 6 months, then at one and 2 years.²⁹

Evidence indicates that 14% of lesions will enlarge in 2 years, although the clinical significance of enlargement is unknown. Some authors argue against CT monitoring because the risk of adrenal mass progression is similar to the malignancy risk posed by 3 years of radiation exposure with CT.²⁰

Some guidelines recommend repeat biochemical screening every 3 to 4 years.^28,29 AACE guidelines quote a 47% rate of progression over 3 years, but most adrenal masses progress to subclinical Cushing syndrome— a condition of uncertain significance. Subclinical Cushing’s has not been reported to progress to the overt syndrome, and new catecholamine or aldosterone secretion is rare.

Many endocrinologists reduce the frequency of follow-up, depending on the type of adrenal mass (cyst or solid) and its size. AACE suggests CT for adenomas one to 4 cm at 12 months. AACE and NIH recommend hormonal evaluation annually for 4 years. Adrenal cysts or myelolipoma in patients without cancer need no follow-up.²⁹

CORRESPONDENCE
James C. Higgins, DO, CAPT, MC, USN, Ret., Naval Hospital Jacksonville, Family Medicine Department, 2080 Child Street, Box 1000, Jacksonville, FL 32214;
[email protected]

CASE Jane C, a 76-year-old patient, reports lower abdominal discomfort and increased bowel movements. Her left lower quadrant is tender to palpation, without signs of a surgical abdomen, and vital signs are normal. Laboratory studies are also normal, except for mild anemia and a positive fecal occult blood test. Abdominal and pelvic computed tomography (CT), with and without contrast, are negative for acute pathology, but a 1.7-cm lesion is found in the upper pole of the left kidney. What is your next step?

Renal or adrenal masses may be discovered during imaging studies for complaints unrelated to the kidneys or adrenals. Detection of incidentalomas has increased dramatically, keeping pace with the growing use of ultrasonography, CT, and magnetic resonance imaging (MRI) for abdominal, chest, and back complaints.¹

Family physicians can evaluate most of these masses and determine the need for referral by using clinical judgment, appropriate imaging studies, and screening laboratory tests. In the pages that follow, we present a systematic approach for evaluating these incidentalomas and determining when consultation or referral is needed.

Incidental renal masses are common

Lesions are commonly found in normal kidneys, and the incidence increases with age. Approximately one-third of individuals age 50 and older will have at least one renal cyst on CT.²

Most incidental renal masses are benign cysts requiring no further evaluation. Other possibilities include indeterminate or malignant cysts or solid masses, which may be malignant or benign. Inflammatory renal lesions from infection, infarction, or trauma also occur, but these tend to be symptomatic and are rarely found incidentally.

Classification of renal cysts—not based on size

Cysts are the most common adult renal masses. Typically they are unilocular and located in the renal cortex, frequently extending to the renal surface.³ Renal function is usually preserved, regardless of the cyst’s location or size. Careful examination of adjacent tissue is essential, as secondary cysts may form when solid tumors obstruct tubules of normal parenchyma. Cystic lesions containing enhancing soft tissue unattached to the wall or septa likely are malignant.⁴

The Bosniak classification system, with 5 classes based on CT characteristics
(TABLE 1), is a useful guide for managing renal cystic lesions.⁴ Size is not an important feature in the Bosniak system; small cysts may be malignant and larger ones benign. Small cysts may grow into larger benign lesions, occasionally causing flank or abdominal pain, palpable masses, or hematuria.

Simple cysts. Renal cysts that meet Bosniak class I criteria can be confidently labeled benign and need no further evaluation (FIGURE 1). Simple renal cysts on CT have homogenous low-attenuating fluid and thin nonenhancing walls without septa.⁴

On ultrasound, simple renal cysts show spherical or ovoid shape without internal echoes, a thin smooth wall separate from the surrounding parenchyma, and posterior wall enhancement caused by increased transmission through the water-filled cyst. The likelihood of malignancy is extremely low in a renal cyst that meets these criteria, which have a reported accuracy of 98% to 100%.³ Thus, no further evaluation is required if an obviously benign simple cyst is first noted on an adequate ultrasound. Inadequate ultrasound visualization or evidence of calcifications, septa, or multiple chambers calls for prompt renal CT.

CASE The mass on Ms. C’s left kidney is hypoattenuating and nonenhancing on CT. It meets Bosniak criteria for a benign simple cyst (class I) and requires no further evaluation or follow-up. Colonoscopy detects multiple colonic polyps that are removed, and the patient does well.

Mildly complicated cysts. Less diagnostic certainty characterizes cysts with mild abnormalities that keep them from being labeled as simple. Bosniak classes II and IIF describe mildly abnormal renal cysts. Class II cysts can be dismissed, whereas class IIF cysts require follow-up.

Class II cysts may contain a few hairline septa, fine calcium deposits in walls or septa, or an unmeasurable enhancement of the walls. A hyperattenuating but nonenhancing fluid also is described as category II. Small homogeneous cysts <3 cm, without enhancement but hyperattenuated, are reliably considered benign and need not be evaluated.^2,7

Class IIF cysts may have multiple hairline-thin septa with unmeasurable enhancement or minimal smooth thickening or irregular/nodular calcifications of wall or septa without enhancing soft tissue components. Hyperattenuating cystic lesions >3 cm and intrarenal “noncortical” cysts are included in this category. Class IIF cysts require follow-up at 6 months with CT or MRI, then annually for at least 5 years.⁸

Obviously complicated cysts. Bosniak class III is indeterminate—neither benign nor clearly malignant. Class III cysts may have thickened borders or septa with measurable enhancement, or they may be multilocular, hemorrhagic, or infected. In 5 case series, 29 of 57 class III lesions proved to be malignant.⁵ MRI may characterize these lesions more definitively than CT prior to urologic referral.

Malignant cysts. Bosniak class IV renal lesions are clearly malignant, with large heterogeneous cysts or necrotic components, shaggy thickened walls, or enhancing soft tissue components separate from the wall or septa. Their unequivocal appearance results from solid tumor necrosis and liquefaction. Diagnosis is straightforward, and excision is indicated.²

A closer look at solid renal masses
Solid renal masses usually consist of enhancing tissue with little or no fluid. The goal of evaluation is to exclude malignancies, such as renal cell cancer, lymphomas, sarcomas, or metastasis. Benign solid masses include renal adenomas, angiomyolipomas, and oncocytomas, among others.

Several lesions can be diagnosed by appearance or symptoms:

Angiomyolipomas are recognized by their fat content within a noncalcified mass. Unenhanced CT usually is sufficient for diagnosis, unless the mass is very small or has atypical features.⁹

Vascular lesions can be identified because they enhance to the same degree as the vasculature. With the exception of inflammatory or vascular abnormalities, all enhancing lesions that do not contain fat should be presumed to be malignant.

In patients with a known extrarenal primary malignancy, 50% to 85% of incidental solid renal masses will represent metastatic disease.¹⁰ Percutaneous biopsy may be warranted to differentiate metastatic lesions from a secondary, primary (ie, renal cell carcinoma), or benign process.¹¹

A study of 2770 solid renal mass excisions revealed that 12.8% were benign, with a direct relationship between malignancy and size. Masses <1 cm were benign 44% of the time.¹² Early identification of small renal carcinomas may improve survival rates. Although renal cell carcinomas <3 cm in diameter have low metastatic potential, a solid, nonfat-containing mass should be evaluated for aggressive nephron-sparing surgery.^6,13

Incidental adrenal masses occur infrequently

Adrenal incidentalomas are defined as radiographically identified masses >1 cm in diameter.¹⁴ They are much less common than their renal counterparts, with a reported prevalence of 0.35% to 5% on CT.¹⁵ Because the adrenal glands are hormonally active and receive substantial blood flow, metastatic, hormonally active, and nonfunctional causes for adrenal masses need to be considered.¹⁶

Adrenal pathology
Adrenal masses may be characterized by increased or normal adrenal function. Hyperfunctioning syndromes include hypercortisolism, hyperaldosteronism, adrenogenital hypersecretion of adrenocortical origin, and pheochromocytomas of the medulla. Symptom evaluation of these syndromes is important, but not sufficient to rule out a hyperfunctioning syndrome.

In a retrospective review of inapparent adrenal masses, ≤13% of pheochromocytomas were clinically silent.¹⁷ Therefore, laboratory testing is necessary for an incidental adrenal mass.

Nonfunctional lesions include adenomas, metastases, cysts, myelolipomas, hemorrhage, and adrenal carcinomas. These masses require evaluation for the possibility of cancer, the most common of which is metastasis. In patients with an extra-adrenal malignancy, the likelihood of malignancy in an incidental adrenal mass is at least 50%.¹⁸ An adrenal mass representing metastasis of a previously unrecognized cancer is exceedingly rare.¹⁹

Primary adrenal carcinoma is also rare, with an estimated incidence of 2 cases per one million in the general population. For patients with adrenal masses, the prevalence of carcinoma increases with lesion size (2% for tumors <4 cm, 6% for tumors 4-6 cm, and 25% for tumors >6 cm in diameter). 17 For this reason, tumors >4 cm in diameter are usually surgically resected in patients with no previous cancer history, unless radiologic criteria demonstrate clearly benign characteristics.

Although adrenal carcinomas are considered nonfunctioning, some evidence suggests they produce low levels of cortisol that may be associated with clinical features of metabolic syndrome.²⁰

CT is first choice for adrenal mass evaluation
Dedicated adrenal CT with both unenhanced and delayed contrast-enhanced images is the most reliable study to evaluate an adrenal mass, according to the American College of Radiology. Consider another study only in patients with contrast allergy, renal compromise, or cancer history.²¹

Unenhanced CT can diagnose the approximately 70% of adenomas that are small, well-defined round masses with homogenous low-density lipid deposition.²² Delayed contrast enhancement can characterize most of the remaining 30%.²³ Unenhanced CT with attenuation values of <10 Hounsfield units (HU) can diagnose adenomas with 71% specificity and 98% sensitivity,²⁴ and can often diagnose simple cysts and myelolipomas, as well.

Other imaging options. MRI is an alternative to CT for patients with contraindications for contrast or radiation exposure. MRI provides less spatial resolution than CT, but chemical shift imaging can measure cytoplasmic lipid content similar to unenhanced CT. A small study found chemical shift MRI more reliable than unenhanced CT, but less reliable than CT with delayed contrast enhancement.²⁵

Positron emission tomography (PET) is useful to noninvasively evaluate biochemical and physiologic processes. PET-CT incorporates unenhanced CT density measurements to improve PET accuracy. In a patient with a history of cancer, PET-CT has a sensitivity of 93% to 100% and a specificity of 95% in differentiating benign from malignant adrenal tumors.²⁶

When to order a biopsy
The need for biopsy has decreased as imaging has improved, but biopsy is required whenever diagnostic imaging fails to differentiatea lesion as benign or malignant. CT guided biopsy provides diagnostic accuracy of 85% to 95%.²⁷ Complications such as pneumothorax, hemorrhage, and bacteremia occur in 3% to 9% of biopsies. Before any adrenal biopsy, measure plasma-free metanephrines to exclude undiagnosed pheochromocytoma, which could precipitate a hypertensive crisis if untreated.²²

These 3 laboratory screening tests are critical

Family physicians can perform the initial biochemical evaluation of an adrenal incidentaloma. Guidance is available from the National Institutes of Health (NIH)²⁸ and the American Academy of Clinical Endocrinologists (AACE) (FIGURE 2).²⁹

Regardless of signs or symptoms, perform screening laboratory tests for 3 types of adrenal hyperfunction: hypercortisolism, hyperaldosteronism, and hypersecretion of catecholamines (pheochromocytoma). Screening tests are not recommended for androgen hypersecretion, which is extremely rare and causes recognizable symptoms such as hirsutism (Table 2).²⁹

Hypercortisolism occurs in approximately 5% of adrenal incidentalomas.³⁰ An overnight dexamethasone suppression test (DST) is most reliable for screening, with sensitivity >95% for Cushing syndrome.³¹ The patient takes a 1-mg dose of oral dexamethasone at 11 pm, and a fasting plasma cortisol sample is drawn the next day at 8 am.

Dexamethasone binds to glucocorticoid receptors in the pituitary gland, suppressing adrenocorticotropic hormone secretion. Cortisol will be depressed the next morning unless the adrenal mass produces cortisol autonomously. Patients with a DST >5 mcg/dL—highly suggestive of Cushing syndrome—require further evaluation, and we suggest referral to an endocrinologist.

Hyperaldosteronism is seen in 1% to 2% of adrenal incidentalomas.³² The aldosterone- to-renin ratio (ARR) is recommended as a screening test for hyperaldosteronism, with an ARR >20 requiring further testing.³³ Medications that may affect the ARR include beta-blockers, spironolactone, clonidine, diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers.²⁹

Refer a patient with evidence of hyperaldosteronism to an endocrinologist and a surgeon with experience in managing these lesions. If the ARR test result suggests an aldosterone excess, a salt-loading test is used to verify failure of aldosterone suppression. Adrenal venous sampling is often performed prior to surgical removal to confirm that an incidentaloma is the source of hyperaldosteronism.

Pheochromocytoma. Approximately 5% of incidental adrenal lesions are pheochromocytomas.³⁰ Many patients with these epinephrine/norepinephrine secreting tumors do not show the classic symptom triad of headache, palpitations, and diaphoresis, and approximately half have normal blood pressure.³⁴

Identifying a pheochromocytoma is important in any patient requiring surgery or biopsy, as surgical manipulation can cause a potentially fatal intraoperative catecholamine surge. Presurgical medical management can mitigate this reaction.

A plasma-free metanephrines test, which has 95% sensitivity, is the most reliable test for pheochromocytoma.³⁵ Medications, including tricyclic antidepressants, decongestants, amphetamines, reserpine, and phenoxybenzamine, can cause falsepositive results.²⁹ Confirm a positive plasma-free metanephrines test with a 24-hour fractionated urine metanephrines test, and refer the patient to an endocrinologist.

Managing adrenal incidentalomas

Refer all patients with adrenal masses >4 cm for surgical evaluation because of the risk of malignancy; all patients who have a history of malignancy and an adrenal mass of any size require a referral to an oncologist. Perform the AACE-recommended 3-element biochemical workup for all masses, with the exception of definitively diagnosed cysts or myelolipomas.

Refer to an endocrinologist all patients with abnormal screening laboratory results, regardless of adrenal mass size, as well as patients with concerning clinical findings. Initiate cardiovascular, diabetes, and bone density evaluation and management for metabolic syndrome.²⁰

Monitoring after a negative workup
Little evidence exists to guide monitoring of small adrenal incidentalomas (<4 cm) with a negative workup. The 2002 NIH report recommended annual radiologic follow-up for 5 years,²⁸ whereas the 2009 AACE guidelines recommend radiographic follow-up at 3 to 6 months, then at one and 2 years.²⁹

Evidence indicates that 14% of lesions will enlarge in 2 years, although the clinical significance of enlargement is unknown. Some authors argue against CT monitoring because the risk of adrenal mass progression is similar to the malignancy risk posed by 3 years of radiation exposure with CT.²⁰

Some guidelines recommend repeat biochemical screening every 3 to 4 years.^28,29 AACE guidelines quote a 47% rate of progression over 3 years, but most adrenal masses progress to subclinical Cushing syndrome— a condition of uncertain significance. Subclinical Cushing’s has not been reported to progress to the overt syndrome, and new catecholamine or aldosterone secretion is rare.

Many endocrinologists reduce the frequency of follow-up, depending on the type of adrenal mass (cyst or solid) and its size. AACE suggests CT for adenomas one to 4 cm at 12 months. AACE and NIH recommend hormonal evaluation annually for 4 years. Adrenal cysts or myelolipoma in patients without cancer need no follow-up.²⁹

CORRESPONDENCE
James C. Higgins, DO, CAPT, MC, USN, Ret., Naval Hospital Jacksonville, Family Medicine Department, 2080 Child Street, Box 1000, Jacksonville, FL 32214;
[email protected]

CASE Jane C, a 76-year-old patient, reports lower abdominal discomfort and increased bowel movements. Her left lower quadrant is tender to palpation, without signs of a surgical abdomen, and vital signs are normal. Laboratory studies are also normal, except for mild anemia and a positive fecal occult blood test. Abdominal and pelvic computed tomography (CT), with and without contrast, are negative for acute pathology, but a 1.7-cm lesion is found in the upper pole of the left kidney. What is your next step?

Renal or adrenal masses may be discovered during imaging studies for complaints unrelated to the kidneys or adrenals. Detection of incidentalomas has increased dramatically, keeping pace with the growing use of ultrasonography, CT, and magnetic resonance imaging (MRI) for abdominal, chest, and back complaints.¹

Family physicians can evaluate most of these masses and determine the need for referral by using clinical judgment, appropriate imaging studies, and screening laboratory tests. In the pages that follow, we present a systematic approach for evaluating these incidentalomas and determining when consultation or referral is needed.

Incidental renal masses are common

Lesions are commonly found in normal kidneys, and the incidence increases with age. Approximately one-third of individuals age 50 and older will have at least one renal cyst on CT.²

Most incidental renal masses are benign cysts requiring no further evaluation. Other possibilities include indeterminate or malignant cysts or solid masses, which may be malignant or benign. Inflammatory renal lesions from infection, infarction, or trauma also occur, but these tend to be symptomatic and are rarely found incidentally.

Classification of renal cysts—not based on size

Cysts are the most common adult renal masses. Typically they are unilocular and located in the renal cortex, frequently extending to the renal surface.³ Renal function is usually preserved, regardless of the cyst’s location or size. Careful examination of adjacent tissue is essential, as secondary cysts may form when solid tumors obstruct tubules of normal parenchyma. Cystic lesions containing enhancing soft tissue unattached to the wall or septa likely are malignant.⁴

The Bosniak classification system, with 5 classes based on CT characteristics
(TABLE 1), is a useful guide for managing renal cystic lesions.⁴ Size is not an important feature in the Bosniak system; small cysts may be malignant and larger ones benign. Small cysts may grow into larger benign lesions, occasionally causing flank or abdominal pain, palpable masses, or hematuria.

Simple cysts. Renal cysts that meet Bosniak class I criteria can be confidently labeled benign and need no further evaluation (FIGURE 1). Simple renal cysts on CT have homogenous low-attenuating fluid and thin nonenhancing walls without septa.⁴

On ultrasound, simple renal cysts show spherical or ovoid shape without internal echoes, a thin smooth wall separate from the surrounding parenchyma, and posterior wall enhancement caused by increased transmission through the water-filled cyst. The likelihood of malignancy is extremely low in a renal cyst that meets these criteria, which have a reported accuracy of 98% to 100%.³ Thus, no further evaluation is required if an obviously benign simple cyst is first noted on an adequate ultrasound. Inadequate ultrasound visualization or evidence of calcifications, septa, or multiple chambers calls for prompt renal CT.

CASE The mass on Ms. C’s left kidney is hypoattenuating and nonenhancing on CT. It meets Bosniak criteria for a benign simple cyst (class I) and requires no further evaluation or follow-up. Colonoscopy detects multiple colonic polyps that are removed, and the patient does well.

Mildly complicated cysts. Less diagnostic certainty characterizes cysts with mild abnormalities that keep them from being labeled as simple. Bosniak classes II and IIF describe mildly abnormal renal cysts. Class II cysts can be dismissed, whereas class IIF cysts require follow-up.

Class II cysts may contain a few hairline septa, fine calcium deposits in walls or septa, or an unmeasurable enhancement of the walls. A hyperattenuating but nonenhancing fluid also is described as category II. Small homogeneous cysts <3 cm, without enhancement but hyperattenuated, are reliably considered benign and need not be evaluated.^2,7

Class IIF cysts may have multiple hairline-thin septa with unmeasurable enhancement or minimal smooth thickening or irregular/nodular calcifications of wall or septa without enhancing soft tissue components. Hyperattenuating cystic lesions >3 cm and intrarenal “noncortical” cysts are included in this category. Class IIF cysts require follow-up at 6 months with CT or MRI, then annually for at least 5 years.⁸

Obviously complicated cysts. Bosniak class III is indeterminate—neither benign nor clearly malignant. Class III cysts may have thickened borders or septa with measurable enhancement, or they may be multilocular, hemorrhagic, or infected. In 5 case series, 29 of 57 class III lesions proved to be malignant.⁵ MRI may characterize these lesions more definitively than CT prior to urologic referral.

Malignant cysts. Bosniak class IV renal lesions are clearly malignant, with large heterogeneous cysts or necrotic components, shaggy thickened walls, or enhancing soft tissue components separate from the wall or septa. Their unequivocal appearance results from solid tumor necrosis and liquefaction. Diagnosis is straightforward, and excision is indicated.²

A closer look at solid renal masses
Solid renal masses usually consist of enhancing tissue with little or no fluid. The goal of evaluation is to exclude malignancies, such as renal cell cancer, lymphomas, sarcomas, or metastasis. Benign solid masses include renal adenomas, angiomyolipomas, and oncocytomas, among others.

Several lesions can be diagnosed by appearance or symptoms:

Angiomyolipomas are recognized by their fat content within a noncalcified mass. Unenhanced CT usually is sufficient for diagnosis, unless the mass is very small or has atypical features.⁹

Vascular lesions can be identified because they enhance to the same degree as the vasculature. With the exception of inflammatory or vascular abnormalities, all enhancing lesions that do not contain fat should be presumed to be malignant.

In patients with a known extrarenal primary malignancy, 50% to 85% of incidental solid renal masses will represent metastatic disease.¹⁰ Percutaneous biopsy may be warranted to differentiate metastatic lesions from a secondary, primary (ie, renal cell carcinoma), or benign process.¹¹

A study of 2770 solid renal mass excisions revealed that 12.8% were benign, with a direct relationship between malignancy and size. Masses <1 cm were benign 44% of the time.¹² Early identification of small renal carcinomas may improve survival rates. Although renal cell carcinomas <3 cm in diameter have low metastatic potential, a solid, nonfat-containing mass should be evaluated for aggressive nephron-sparing surgery.^6,13

Incidental adrenal masses occur infrequently

Adrenal incidentalomas are defined as radiographically identified masses >1 cm in diameter.¹⁴ They are much less common than their renal counterparts, with a reported prevalence of 0.35% to 5% on CT.¹⁵ Because the adrenal glands are hormonally active and receive substantial blood flow, metastatic, hormonally active, and nonfunctional causes for adrenal masses need to be considered.¹⁶

Adrenal pathology
Adrenal masses may be characterized by increased or normal adrenal function. Hyperfunctioning syndromes include hypercortisolism, hyperaldosteronism, adrenogenital hypersecretion of adrenocortical origin, and pheochromocytomas of the medulla. Symptom evaluation of these syndromes is important, but not sufficient to rule out a hyperfunctioning syndrome.

In a retrospective review of inapparent adrenal masses, ≤13% of pheochromocytomas were clinically silent.¹⁷ Therefore, laboratory testing is necessary for an incidental adrenal mass.

Nonfunctional lesions include adenomas, metastases, cysts, myelolipomas, hemorrhage, and adrenal carcinomas. These masses require evaluation for the possibility of cancer, the most common of which is metastasis. In patients with an extra-adrenal malignancy, the likelihood of malignancy in an incidental adrenal mass is at least 50%.¹⁸ An adrenal mass representing metastasis of a previously unrecognized cancer is exceedingly rare.¹⁹

Primary adrenal carcinoma is also rare, with an estimated incidence of 2 cases per one million in the general population. For patients with adrenal masses, the prevalence of carcinoma increases with lesion size (2% for tumors <4 cm, 6% for tumors 4-6 cm, and 25% for tumors >6 cm in diameter). 17 For this reason, tumors >4 cm in diameter are usually surgically resected in patients with no previous cancer history, unless radiologic criteria demonstrate clearly benign characteristics.

Although adrenal carcinomas are considered nonfunctioning, some evidence suggests they produce low levels of cortisol that may be associated with clinical features of metabolic syndrome.²⁰

CT is first choice for adrenal mass evaluation
Dedicated adrenal CT with both unenhanced and delayed contrast-enhanced images is the most reliable study to evaluate an adrenal mass, according to the American College of Radiology. Consider another study only in patients with contrast allergy, renal compromise, or cancer history.²¹

Unenhanced CT can diagnose the approximately 70% of adenomas that are small, well-defined round masses with homogenous low-density lipid deposition.²² Delayed contrast enhancement can characterize most of the remaining 30%.²³ Unenhanced CT with attenuation values of <10 Hounsfield units (HU) can diagnose adenomas with 71% specificity and 98% sensitivity,²⁴ and can often diagnose simple cysts and myelolipomas, as well.

Other imaging options. MRI is an alternative to CT for patients with contraindications for contrast or radiation exposure. MRI provides less spatial resolution than CT, but chemical shift imaging can measure cytoplasmic lipid content similar to unenhanced CT. A small study found chemical shift MRI more reliable than unenhanced CT, but less reliable than CT with delayed contrast enhancement.²⁵

Positron emission tomography (PET) is useful to noninvasively evaluate biochemical and physiologic processes. PET-CT incorporates unenhanced CT density measurements to improve PET accuracy. In a patient with a history of cancer, PET-CT has a sensitivity of 93% to 100% and a specificity of 95% in differentiating benign from malignant adrenal tumors.²⁶

When to order a biopsy
The need for biopsy has decreased as imaging has improved, but biopsy is required whenever diagnostic imaging fails to differentiatea lesion as benign or malignant. CT guided biopsy provides diagnostic accuracy of 85% to 95%.²⁷ Complications such as pneumothorax, hemorrhage, and bacteremia occur in 3% to 9% of biopsies. Before any adrenal biopsy, measure plasma-free metanephrines to exclude undiagnosed pheochromocytoma, which could precipitate a hypertensive crisis if untreated.²²

These 3 laboratory screening tests are critical

Family physicians can perform the initial biochemical evaluation of an adrenal incidentaloma. Guidance is available from the National Institutes of Health (NIH)²⁸ and the American Academy of Clinical Endocrinologists (AACE) (FIGURE 2).²⁹

Regardless of signs or symptoms, perform screening laboratory tests for 3 types of adrenal hyperfunction: hypercortisolism, hyperaldosteronism, and hypersecretion of catecholamines (pheochromocytoma). Screening tests are not recommended for androgen hypersecretion, which is extremely rare and causes recognizable symptoms such as hirsutism (Table 2).²⁹

Hypercortisolism occurs in approximately 5% of adrenal incidentalomas.³⁰ An overnight dexamethasone suppression test (DST) is most reliable for screening, with sensitivity >95% for Cushing syndrome.³¹ The patient takes a 1-mg dose of oral dexamethasone at 11 pm, and a fasting plasma cortisol sample is drawn the next day at 8 am.

Dexamethasone binds to glucocorticoid receptors in the pituitary gland, suppressing adrenocorticotropic hormone secretion. Cortisol will be depressed the next morning unless the adrenal mass produces cortisol autonomously. Patients with a DST >5 mcg/dL—highly suggestive of Cushing syndrome—require further evaluation, and we suggest referral to an endocrinologist.

Hyperaldosteronism is seen in 1% to 2% of adrenal incidentalomas.³² The aldosterone- to-renin ratio (ARR) is recommended as a screening test for hyperaldosteronism, with an ARR >20 requiring further testing.³³ Medications that may affect the ARR include beta-blockers, spironolactone, clonidine, diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers.²⁹

Refer a patient with evidence of hyperaldosteronism to an endocrinologist and a surgeon with experience in managing these lesions. If the ARR test result suggests an aldosterone excess, a salt-loading test is used to verify failure of aldosterone suppression. Adrenal venous sampling is often performed prior to surgical removal to confirm that an incidentaloma is the source of hyperaldosteronism.

Pheochromocytoma. Approximately 5% of incidental adrenal lesions are pheochromocytomas.³⁰ Many patients with these epinephrine/norepinephrine secreting tumors do not show the classic symptom triad of headache, palpitations, and diaphoresis, and approximately half have normal blood pressure.³⁴

Identifying a pheochromocytoma is important in any patient requiring surgery or biopsy, as surgical manipulation can cause a potentially fatal intraoperative catecholamine surge. Presurgical medical management can mitigate this reaction.

A plasma-free metanephrines test, which has 95% sensitivity, is the most reliable test for pheochromocytoma.³⁵ Medications, including tricyclic antidepressants, decongestants, amphetamines, reserpine, and phenoxybenzamine, can cause falsepositive results.²⁹ Confirm a positive plasma-free metanephrines test with a 24-hour fractionated urine metanephrines test, and refer the patient to an endocrinologist.

Managing adrenal incidentalomas

Refer all patients with adrenal masses >4 cm for surgical evaluation because of the risk of malignancy; all patients who have a history of malignancy and an adrenal mass of any size require a referral to an oncologist. Perform the AACE-recommended 3-element biochemical workup for all masses, with the exception of definitively diagnosed cysts or myelolipomas.

Refer to an endocrinologist all patients with abnormal screening laboratory results, regardless of adrenal mass size, as well as patients with concerning clinical findings. Initiate cardiovascular, diabetes, and bone density evaluation and management for metabolic syndrome.²⁰

Monitoring after a negative workup
Little evidence exists to guide monitoring of small adrenal incidentalomas (<4 cm) with a negative workup. The 2002 NIH report recommended annual radiologic follow-up for 5 years,²⁸ whereas the 2009 AACE guidelines recommend radiographic follow-up at 3 to 6 months, then at one and 2 years.²⁹

Evidence indicates that 14% of lesions will enlarge in 2 years, although the clinical significance of enlargement is unknown. Some authors argue against CT monitoring because the risk of adrenal mass progression is similar to the malignancy risk posed by 3 years of radiation exposure with CT.²⁰

Some guidelines recommend repeat biochemical screening every 3 to 4 years.^28,29 AACE guidelines quote a 47% rate of progression over 3 years, but most adrenal masses progress to subclinical Cushing syndrome— a condition of uncertain significance. Subclinical Cushing’s has not been reported to progress to the overt syndrome, and new catecholamine or aldosterone secretion is rare.

Many endocrinologists reduce the frequency of follow-up, depending on the type of adrenal mass (cyst or solid) and its size. AACE suggests CT for adenomas one to 4 cm at 12 months. AACE and NIH recommend hormonal evaluation annually for 4 years. Adrenal cysts or myelolipoma in patients without cancer need no follow-up.²⁹

CORRESPONDENCE
James C. Higgins, DO, CAPT, MC, USN, Ret., Naval Hospital Jacksonville, Family Medicine Department, 2080 Child Street, Box 1000, Jacksonville, FL 32214;
[email protected]