About 14% of the US general population has chronic kidney disease (CKD).¹ Limited data exist regarding the exact prevalence of CKD-mineral and bone disorder (MBD), but abnormal mineral metabolism is believed to start in stage 3 CKD, implying that 8% of the adult US population could be at risk for, or already have established, CKD-MBD.² Although the disorder has traditionally been managed by nephrologists, this earlier onset suggests that many patients should be screened and treated by their primary care physicians.

Because CKD-MBD can lead to significant morbidity (ie, increased fracture risk) and mortality, identification and treatment are of utmost importance.³ This review provides information from the current literature and the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, and focuses primarily on the non-dialysis CKD population.

CKD-MBD: A broad spectrum of disorders

CKD-MBD is defined as a systemic disorder of mineral and bone metabolism due to CKD. Traditionally referred to as renal osteodystrophy, the term CKD-MBD is meant to indicate and describe a broad clinical spectrum of CKD-associated bone mineral metabolism disorders that manifest from one or a combination of the following:

• Abnormalities of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism
• Abnormalities in bone turnover, mineralization, volume, linear growth, or strength
• Vascular or other soft-tissue calcification.⁴

Renal bone disease can be divided into low bone turnover (adynamic bone disease) and high bone turnover states. Both can lead to a decrease in bone strength and an increase in pathological fractures.⁵

Pathophysiology: Difficult to know where the cascade begins

Understanding the pathophysiology and treatment of bone disease in patients with CKD can be challenging. Because of abnormalities of mineral metabolism and changes in hormones and cytokines, bone remodeling is severely disrupted in patients with CKD, and it remains unclear where this cascade begins.

Aim treatment of CKD-MBD at managing serum phosphate, parathyroid hormone, and calcium levels.

As an adaptive response to decreased kidney function, PTH levels increase. Elevations of both fibroblast growth factor 23 (FGF23) lower blood phosphate levels by inhibiting phosphate reabsorption in the kidneys, thus increasing urinary excretion of phosphorus. Secondary hyperparathyroidism (SHPT), driven by hypocalcemia, responds to normalize serum calcium levels by increasing the number and size of osteoclasts actively breaking down bone matrix. This escalates fracture risk. In addition, the inability of damaged kidneys to convert vitamin D to an active form further deranges calcium and phosphate homeostasis.

Successful management of serum levels begins with monitoring

KDIGO, an independent nonprofit foundation that seeks to improve the care and outcomes of kidney disease patients worldwide, developed guidelines for the diagnosis, evaluation, prevention, and treatment of CKD-MBD in 2009.⁶ These guidelines recommend that treatment of CKD-MBD be aimed at managing serum phosphate, PTH, and calcium levels. The recommended frequency for laboratory monitoring of these levels varies by stage of CKD and is described in TABLE 1.⁶ (For more on chronic kidney disease staging, see KDIGO’s 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease, available at: http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf.)

Because of the interrelated nature of these minerals and hormones, drug therapy aimed at treating one may impact the others. This must be considered when designing treatment regimens.

Hyperphosphatemia: Manage with diet, drugs, dialysis

Observational studies have shown an association between higher serum phosphate levels and mortality.^6-8 KDIGO recommends maintaining serum phosphorus levels within the normal range of the assay in patients with CKD who are not receiving dialysis.⁶ For dialyzed patients, the recommendation is to lower the phosphorus level toward the normal range as much as possible.⁶ Maintaining an appropriate phosphorus level is accomplished through dietary phosphate restriction, the use of phosphate binders, and, in dialyzed patients, dialytic removal of phosphate.⁶

Dietary phosphate restriction is often challenging for patients, in part, because phosphorous content is not always included on food labels in the United States.⁹ Phosphorus is highly absorbed from additives in processed food (approaching 100% absorption), less absorbed from animal sources such as meat and dairy products (40%-60%), and is the least absorbed from plant sources such as beans and nuts (20%-40%).¹⁰ Advise patients to avoid fast food, processed foods, cheese, frozen meals, colas, and certain ready-to-eat cereals and prepared meats, as these products may have additives from which phosphorus is readily absorbed.¹¹ A patient-friendly list of high-phosphorus foods, as well as other dietary advice and recipes, can be found on the National Kidney Foundation Web site at https://www.kidney.org/atoz/content/phosphorus. Tables listing the phosphorus content of common foods are also available in the literature and online.^11,12 Keep in mind that not all resources take into account phosphate bioavailability. Dietician referral may be helpful to assure that patients maintain adequate protein intake while restricting dietary phosphate.

Restrict the dose of calcium-based binders in the setting of persistent or recurrent hypercalcemia, known vascular calcification, or low parathyroid hormone levels.

Phosphate binders are recommended by the KDIGO guidelines for use in patients with kidney disease and hyperphosphatemia.⁶ Most of the data to support the use of phosphate binders was gleaned from the dialysis population. The use of phosphate binders in non-dialyzed patients with CKD has both proponents and opponents, with literature supporting both positions.^13,14 A recent KDIGO conference on controversies in CKD-MBD identified this as an area that should be evaluated further for the next guideline update.¹⁵

Phosphate binders—which bind the phosphorus in food to prevent absorption—should be taken with meals or high-phosphorus snacks. Products and formulations of commonly used phosphate binders are shown in TABLE 2.^16,17 Taste, formulation, adverse effects, pill burden, and cost are issues to discuss with patients when initiating or adjusting phosphate binder therapy. It’s estimated that more than half of all patients receiving dialysis do not adhere to their prescribed phosphate binder regimen, highlighting the need to assess adherence before adjusting dose and to involve the patient in the decision-making process to select a phosphate binder product.¹⁸

Avoid calcium-based binders? The risk of hypercalcemia and the potentially increased risk of vascular calcifications with calcium-based binders have led some nephrologists to favor non-calcium-based products. Two recent meta-analyses found a reduced risk of all-cause mortality with the non-calcium-based binders sevelamer or lanthanum as compared to calcium-based binders.^19,20 Current KDIGO guidelines were published prior to these meta-analyses and do not recommend one phosphate binder over another. They do, however, recommend restricting the dose of calcium-based binders in the setting of persistent or recurrent hypercalcemia, known vascular calcification, or low PTH levels.⁶

Secondary hyperparathyroidism

Due to a lack of data, the goal PTH level in patients not receiving dialysis is unknown.⁶ A reasonable approach in non-dialyzed patients, however, is to correct 25-OH vitamin D (25[OH]D) deficiency, elevations in serum phosphate, and hypocalcemia when the level of intact PTH (iPTH) exceeds the normal range for the assay because correcting these derangements may result in a decline in iPTH.^6,21 If this approach fails and PTH levels continue to rise, use of calcitriol or vitamin D analogues is recommended.⁶ Characteristics of medications used to treat SHPT are presented in TABLE 3.^16,17

In dialysis patients, the target iPTH range suggested by KDIGO is 2 to 9 times the upper limit of normal for the assay.⁶ Elevated PTH levels in the dialysis population may be managed with activated vitamin D and/or cinacalcet.

Native vitamin D (ergocalciferol, cholecalciferol) and activated vitamin D analogs (calcitriol, doxercalciferol, paricalcitol). Native vitamin D products are recommended for non-dialyzed patients with CKD to correct vitamin D deficiencies. Although many approaches may be used clinically to replenish low vitamin D stores, one reasonable recommendation in patients with a 25(OH)D level <30 ng/mL is to prescribe ergocalciferol 50,000 units/week for 8 weeks and then to repeat the serum 25-OH vitamin D test. If the level is still <30 ng/mL, a second 8-week course of weekly ergocalciferol 50,000 IU may be administered.²¹

Following repletion with ergocalciferol, maintenance doses of cholecalciferol (1000-2000 IU/d) or ergocalciferol (50,000 IU/-month) may be initiated.²¹ Discontinue native vitamin D in patients who develop hypercalcemia.

Native vitamin D becomes less effective at reducing PTH levels as kidney disease advances. This is likely due to a decline in renal conversion of 25(OH)D to 1,25-(OH)₂vitamin D (1,25[OH]₂D), the most active form of vitamin D and the form of vitamin D that decreases PTH production. By stage 5 CKD, it is unlikely that native vitamin D will significantly decrease PTH levels; treatment with activated vitamin D products or cinacalcet is generally required.

Because the enzyme responsible for converting 25(OH)D into the most active form can be found in multiple tissues outside of the kidney, and the 1,25(OH)₂D converted for use by these organs may help prevent such conditions/events as hypertension, type 2 diabetes, myocardial infarction, and stroke (in patients with and without kidney disease), some specialists prescribe native vitamin D to patients with CKD for reasons unrelated to PTH suppression. There are no data, however, confirming that 25(OH)D supplementation mitigates these outcomes.²¹

Don’t forget calcium

All of the active vitamin D products can increase serum calcium and phosphate levels. Calcitriol, however, may cause more hypercalcemia than paricalcitol.²² If hypercalcemia develops, you may need to stop, or reduce the dose of, vitamin D analogues. Or you may need to switch patients from calcium-based to non-calcium-based phosphate binders. If hyperphosphatemia develops, intensify phosphate binder therapy or reduce the dose of, or stop, vitamin D analogues. If iPTH levels go below the target range, reduce the dose of the vitamin D analogue to avoid iatrogenic adynamic bone disease.

Avoid this agent in the non-dialyzed patient. Cinacalcet effectively treats SHPT in patients receiving dialysis, but is not recommended for use in undialyzed patients.²³ That’s because unacceptably high rates of hypocalcemia have been observed in non-dialyzed patients who were taking the drug.^23,24 In addition, while cinacalcet neutrally affects, or causes a slight decrease in, serum phosphate in patients receiving dialysis, it increases serum phosphate in patients who are not.^24,25

Drug therapy for osteoporosis

Therapy to prevent and treat fractures in patients with CKD is controversial because patients with CKD stage 3 to 5 with and without MBD were excluded from clinical trials of commercially available treatments. Furthermore, in adynamic bone disease, bones are capable of neither breaking down nor building (ie, reduced resorption). Bisphosphonates and other antiresorptive therapies are more effective at decreasing fractures in patients who are in a state of increased bone resorption, such as menopausal women, so the benefits of these medications in terms of their ability to reduce fractures in CKD patients are questionable, as is their safety.^26,27

In addition, while dual-energy x-ray absorptiometry (DXA) is typically used to identify patients who would benefit from these agents, studies have recently demonstrated that femoral neck bone density measured via DXA may underestimate fracture risk in patients with CKD-MBD (ie, bone density may actually be lower than measured).^26,28

Antiresorptive agents and teriparatide

Osteoporosis treatments include antiresorptive agents (ie, the bisphosphonates, raloxifene, denosumab), and the anabolic bone agent teriparatide.

Evidence supports treating patients with stage 1 to 3 CKD the same as patients without CKD.¹⁵ Bisphosphonates are labeled as contraindicated in patients with a glomerular filtration rate (GFR) <30 mL/min/1.73m², due to concerns arising from animal trials and subsequent human case reports (both with intravenous formulations only) regarding acute kidney injury.²⁷

While raloxifene lacks a warning regarding use in patients with stage 3 to 5 CKD, it has not been shown to prevent hip fractures in any population.²⁹

Denosumab is not contraindicated for use in patients with CKD stage 3 to 5 without MBD, but it can worsen hypocalcemia, particularly in patients receiving dialysis.³⁰

Teriparatide is contraindicated in patients with CKD and SHPT,³¹ and there are no studies of its use in patients with CKD-MBD.

What the guidelines say about antiresorptive treatment

For patients with stage 3 to 5 CKD with manifestations of MBD, 2009 KDIGO guidelines recommend a bone biopsy to evaluate for adynamic bone disease before initiating antiresorptive treatment.⁶ Because few physicians in most communities are trained to conduct and evaluate bone biopsies, this recommendation is infrequently followed. Without a bone biopsy to rule out adynamic bone disease, options to prevent or treat fractures in the setting of CKD-MBD are limited.

CORRESPONDENCE
Karly Pippitt, MD, Department of Family and Preventive Medicine, University of Utah School of Medicine, 375 Chipeta Way, Suite A, Salt Lake City, UT 84108; [email protected].

About 14% of the US general population has chronic kidney disease (CKD).¹ Limited data exist regarding the exact prevalence of CKD-mineral and bone disorder (MBD), but abnormal mineral metabolism is believed to start in stage 3 CKD, implying that 8% of the adult US population could be at risk for, or already have established, CKD-MBD.² Although the disorder has traditionally been managed by nephrologists, this earlier onset suggests that many patients should be screened and treated by their primary care physicians.

Because CKD-MBD can lead to significant morbidity (ie, increased fracture risk) and mortality, identification and treatment are of utmost importance.³ This review provides information from the current literature and the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, and focuses primarily on the non-dialysis CKD population.

CKD-MBD: A broad spectrum of disorders

CKD-MBD is defined as a systemic disorder of mineral and bone metabolism due to CKD. Traditionally referred to as renal osteodystrophy, the term CKD-MBD is meant to indicate and describe a broad clinical spectrum of CKD-associated bone mineral metabolism disorders that manifest from one or a combination of the following:

• Abnormalities of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism
• Abnormalities in bone turnover, mineralization, volume, linear growth, or strength
• Vascular or other soft-tissue calcification.⁴

Renal bone disease can be divided into low bone turnover (adynamic bone disease) and high bone turnover states. Both can lead to a decrease in bone strength and an increase in pathological fractures.⁵

Pathophysiology: Difficult to know where the cascade begins

Understanding the pathophysiology and treatment of bone disease in patients with CKD can be challenging. Because of abnormalities of mineral metabolism and changes in hormones and cytokines, bone remodeling is severely disrupted in patients with CKD, and it remains unclear where this cascade begins.

Aim treatment of CKD-MBD at managing serum phosphate, parathyroid hormone, and calcium levels.

As an adaptive response to decreased kidney function, PTH levels increase. Elevations of both fibroblast growth factor 23 (FGF23) lower blood phosphate levels by inhibiting phosphate reabsorption in the kidneys, thus increasing urinary excretion of phosphorus. Secondary hyperparathyroidism (SHPT), driven by hypocalcemia, responds to normalize serum calcium levels by increasing the number and size of osteoclasts actively breaking down bone matrix. This escalates fracture risk. In addition, the inability of damaged kidneys to convert vitamin D to an active form further deranges calcium and phosphate homeostasis.

Successful management of serum levels begins with monitoring

KDIGO, an independent nonprofit foundation that seeks to improve the care and outcomes of kidney disease patients worldwide, developed guidelines for the diagnosis, evaluation, prevention, and treatment of CKD-MBD in 2009.⁶ These guidelines recommend that treatment of CKD-MBD be aimed at managing serum phosphate, PTH, and calcium levels. The recommended frequency for laboratory monitoring of these levels varies by stage of CKD and is described in TABLE 1.⁶ (For more on chronic kidney disease staging, see KDIGO’s 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease, available at: http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf.)

Because of the interrelated nature of these minerals and hormones, drug therapy aimed at treating one may impact the others. This must be considered when designing treatment regimens.

Hyperphosphatemia: Manage with diet, drugs, dialysis

Observational studies have shown an association between higher serum phosphate levels and mortality.^6-8 KDIGO recommends maintaining serum phosphorus levels within the normal range of the assay in patients with CKD who are not receiving dialysis.⁶ For dialyzed patients, the recommendation is to lower the phosphorus level toward the normal range as much as possible.⁶ Maintaining an appropriate phosphorus level is accomplished through dietary phosphate restriction, the use of phosphate binders, and, in dialyzed patients, dialytic removal of phosphate.⁶

Dietary phosphate restriction is often challenging for patients, in part, because phosphorous content is not always included on food labels in the United States.⁹ Phosphorus is highly absorbed from additives in processed food (approaching 100% absorption), less absorbed from animal sources such as meat and dairy products (40%-60%), and is the least absorbed from plant sources such as beans and nuts (20%-40%).¹⁰ Advise patients to avoid fast food, processed foods, cheese, frozen meals, colas, and certain ready-to-eat cereals and prepared meats, as these products may have additives from which phosphorus is readily absorbed.¹¹ A patient-friendly list of high-phosphorus foods, as well as other dietary advice and recipes, can be found on the National Kidney Foundation Web site at https://www.kidney.org/atoz/content/phosphorus. Tables listing the phosphorus content of common foods are also available in the literature and online.^11,12 Keep in mind that not all resources take into account phosphate bioavailability. Dietician referral may be helpful to assure that patients maintain adequate protein intake while restricting dietary phosphate.

Restrict the dose of calcium-based binders in the setting of persistent or recurrent hypercalcemia, known vascular calcification, or low parathyroid hormone levels.

Phosphate binders are recommended by the KDIGO guidelines for use in patients with kidney disease and hyperphosphatemia.⁶ Most of the data to support the use of phosphate binders was gleaned from the dialysis population. The use of phosphate binders in non-dialyzed patients with CKD has both proponents and opponents, with literature supporting both positions.^13,14 A recent KDIGO conference on controversies in CKD-MBD identified this as an area that should be evaluated further for the next guideline update.¹⁵

Phosphate binders—which bind the phosphorus in food to prevent absorption—should be taken with meals or high-phosphorus snacks. Products and formulations of commonly used phosphate binders are shown in TABLE 2.^16,17 Taste, formulation, adverse effects, pill burden, and cost are issues to discuss with patients when initiating or adjusting phosphate binder therapy. It’s estimated that more than half of all patients receiving dialysis do not adhere to their prescribed phosphate binder regimen, highlighting the need to assess adherence before adjusting dose and to involve the patient in the decision-making process to select a phosphate binder product.¹⁸

Avoid calcium-based binders? The risk of hypercalcemia and the potentially increased risk of vascular calcifications with calcium-based binders have led some nephrologists to favor non-calcium-based products. Two recent meta-analyses found a reduced risk of all-cause mortality with the non-calcium-based binders sevelamer or lanthanum as compared to calcium-based binders.^19,20 Current KDIGO guidelines were published prior to these meta-analyses and do not recommend one phosphate binder over another. They do, however, recommend restricting the dose of calcium-based binders in the setting of persistent or recurrent hypercalcemia, known vascular calcification, or low PTH levels.⁶

Secondary hyperparathyroidism

Due to a lack of data, the goal PTH level in patients not receiving dialysis is unknown.⁶ A reasonable approach in non-dialyzed patients, however, is to correct 25-OH vitamin D (25[OH]D) deficiency, elevations in serum phosphate, and hypocalcemia when the level of intact PTH (iPTH) exceeds the normal range for the assay because correcting these derangements may result in a decline in iPTH.^6,21 If this approach fails and PTH levels continue to rise, use of calcitriol or vitamin D analogues is recommended.⁶ Characteristics of medications used to treat SHPT are presented in TABLE 3.^16,17

In dialysis patients, the target iPTH range suggested by KDIGO is 2 to 9 times the upper limit of normal for the assay.⁶ Elevated PTH levels in the dialysis population may be managed with activated vitamin D and/or cinacalcet.

Native vitamin D (ergocalciferol, cholecalciferol) and activated vitamin D analogs (calcitriol, doxercalciferol, paricalcitol). Native vitamin D products are recommended for non-dialyzed patients with CKD to correct vitamin D deficiencies. Although many approaches may be used clinically to replenish low vitamin D stores, one reasonable recommendation in patients with a 25(OH)D level <30 ng/mL is to prescribe ergocalciferol 50,000 units/week for 8 weeks and then to repeat the serum 25-OH vitamin D test. If the level is still <30 ng/mL, a second 8-week course of weekly ergocalciferol 50,000 IU may be administered.²¹

Following repletion with ergocalciferol, maintenance doses of cholecalciferol (1000-2000 IU/d) or ergocalciferol (50,000 IU/-month) may be initiated.²¹ Discontinue native vitamin D in patients who develop hypercalcemia.

Native vitamin D becomes less effective at reducing PTH levels as kidney disease advances. This is likely due to a decline in renal conversion of 25(OH)D to 1,25-(OH)₂vitamin D (1,25[OH]₂D), the most active form of vitamin D and the form of vitamin D that decreases PTH production. By stage 5 CKD, it is unlikely that native vitamin D will significantly decrease PTH levels; treatment with activated vitamin D products or cinacalcet is generally required.

Because the enzyme responsible for converting 25(OH)D into the most active form can be found in multiple tissues outside of the kidney, and the 1,25(OH)₂D converted for use by these organs may help prevent such conditions/events as hypertension, type 2 diabetes, myocardial infarction, and stroke (in patients with and without kidney disease), some specialists prescribe native vitamin D to patients with CKD for reasons unrelated to PTH suppression. There are no data, however, confirming that 25(OH)D supplementation mitigates these outcomes.²¹

Don’t forget calcium

All of the active vitamin D products can increase serum calcium and phosphate levels. Calcitriol, however, may cause more hypercalcemia than paricalcitol.²² If hypercalcemia develops, you may need to stop, or reduce the dose of, vitamin D analogues. Or you may need to switch patients from calcium-based to non-calcium-based phosphate binders. If hyperphosphatemia develops, intensify phosphate binder therapy or reduce the dose of, or stop, vitamin D analogues. If iPTH levels go below the target range, reduce the dose of the vitamin D analogue to avoid iatrogenic adynamic bone disease.

Avoid this agent in the non-dialyzed patient. Cinacalcet effectively treats SHPT in patients receiving dialysis, but is not recommended for use in undialyzed patients.²³ That’s because unacceptably high rates of hypocalcemia have been observed in non-dialyzed patients who were taking the drug.^23,24 In addition, while cinacalcet neutrally affects, or causes a slight decrease in, serum phosphate in patients receiving dialysis, it increases serum phosphate in patients who are not.^24,25

Drug therapy for osteoporosis

Therapy to prevent and treat fractures in patients with CKD is controversial because patients with CKD stage 3 to 5 with and without MBD were excluded from clinical trials of commercially available treatments. Furthermore, in adynamic bone disease, bones are capable of neither breaking down nor building (ie, reduced resorption). Bisphosphonates and other antiresorptive therapies are more effective at decreasing fractures in patients who are in a state of increased bone resorption, such as menopausal women, so the benefits of these medications in terms of their ability to reduce fractures in CKD patients are questionable, as is their safety.^26,27

In addition, while dual-energy x-ray absorptiometry (DXA) is typically used to identify patients who would benefit from these agents, studies have recently demonstrated that femoral neck bone density measured via DXA may underestimate fracture risk in patients with CKD-MBD (ie, bone density may actually be lower than measured).^26,28

Antiresorptive agents and teriparatide

Osteoporosis treatments include antiresorptive agents (ie, the bisphosphonates, raloxifene, denosumab), and the anabolic bone agent teriparatide.

Evidence supports treating patients with stage 1 to 3 CKD the same as patients without CKD.¹⁵ Bisphosphonates are labeled as contraindicated in patients with a glomerular filtration rate (GFR) <30 mL/min/1.73m², due to concerns arising from animal trials and subsequent human case reports (both with intravenous formulations only) regarding acute kidney injury.²⁷

While raloxifene lacks a warning regarding use in patients with stage 3 to 5 CKD, it has not been shown to prevent hip fractures in any population.²⁹

Denosumab is not contraindicated for use in patients with CKD stage 3 to 5 without MBD, but it can worsen hypocalcemia, particularly in patients receiving dialysis.³⁰

Teriparatide is contraindicated in patients with CKD and SHPT,³¹ and there are no studies of its use in patients with CKD-MBD.

What the guidelines say about antiresorptive treatment

For patients with stage 3 to 5 CKD with manifestations of MBD, 2009 KDIGO guidelines recommend a bone biopsy to evaluate for adynamic bone disease before initiating antiresorptive treatment.⁶ Because few physicians in most communities are trained to conduct and evaluate bone biopsies, this recommendation is infrequently followed. Without a bone biopsy to rule out adynamic bone disease, options to prevent or treat fractures in the setting of CKD-MBD are limited.

CORRESPONDENCE
Karly Pippitt, MD, Department of Family and Preventive Medicine, University of Utah School of Medicine, 375 Chipeta Way, Suite A, Salt Lake City, UT 84108; [email protected].

About 14% of the US general population has chronic kidney disease (CKD).¹ Limited data exist regarding the exact prevalence of CKD-mineral and bone disorder (MBD), but abnormal mineral metabolism is believed to start in stage 3 CKD, implying that 8% of the adult US population could be at risk for, or already have established, CKD-MBD.² Although the disorder has traditionally been managed by nephrologists, this earlier onset suggests that many patients should be screened and treated by their primary care physicians.

Because CKD-MBD can lead to significant morbidity (ie, increased fracture risk) and mortality, identification and treatment are of utmost importance.³ This review provides information from the current literature and the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, and focuses primarily on the non-dialysis CKD population.

CKD-MBD: A broad spectrum of disorders

CKD-MBD is defined as a systemic disorder of mineral and bone metabolism due to CKD. Traditionally referred to as renal osteodystrophy, the term CKD-MBD is meant to indicate and describe a broad clinical spectrum of CKD-associated bone mineral metabolism disorders that manifest from one or a combination of the following:

• Abnormalities of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism
• Abnormalities in bone turnover, mineralization, volume, linear growth, or strength
• Vascular or other soft-tissue calcification.⁴

Renal bone disease can be divided into low bone turnover (adynamic bone disease) and high bone turnover states. Both can lead to a decrease in bone strength and an increase in pathological fractures.⁵

Pathophysiology: Difficult to know where the cascade begins

Understanding the pathophysiology and treatment of bone disease in patients with CKD can be challenging. Because of abnormalities of mineral metabolism and changes in hormones and cytokines, bone remodeling is severely disrupted in patients with CKD, and it remains unclear where this cascade begins.

Aim treatment of CKD-MBD at managing serum phosphate, parathyroid hormone, and calcium levels.

As an adaptive response to decreased kidney function, PTH levels increase. Elevations of both fibroblast growth factor 23 (FGF23) lower blood phosphate levels by inhibiting phosphate reabsorption in the kidneys, thus increasing urinary excretion of phosphorus. Secondary hyperparathyroidism (SHPT), driven by hypocalcemia, responds to normalize serum calcium levels by increasing the number and size of osteoclasts actively breaking down bone matrix. This escalates fracture risk. In addition, the inability of damaged kidneys to convert vitamin D to an active form further deranges calcium and phosphate homeostasis.

Successful management of serum levels begins with monitoring

KDIGO, an independent nonprofit foundation that seeks to improve the care and outcomes of kidney disease patients worldwide, developed guidelines for the diagnosis, evaluation, prevention, and treatment of CKD-MBD in 2009.⁶ These guidelines recommend that treatment of CKD-MBD be aimed at managing serum phosphate, PTH, and calcium levels. The recommended frequency for laboratory monitoring of these levels varies by stage of CKD and is described in TABLE 1.⁶ (For more on chronic kidney disease staging, see KDIGO’s 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease, available at: http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf.)

Because of the interrelated nature of these minerals and hormones, drug therapy aimed at treating one may impact the others. This must be considered when designing treatment regimens.

Hyperphosphatemia: Manage with diet, drugs, dialysis

Observational studies have shown an association between higher serum phosphate levels and mortality.^6-8 KDIGO recommends maintaining serum phosphorus levels within the normal range of the assay in patients with CKD who are not receiving dialysis.⁶ For dialyzed patients, the recommendation is to lower the phosphorus level toward the normal range as much as possible.⁶ Maintaining an appropriate phosphorus level is accomplished through dietary phosphate restriction, the use of phosphate binders, and, in dialyzed patients, dialytic removal of phosphate.⁶

Dietary phosphate restriction is often challenging for patients, in part, because phosphorous content is not always included on food labels in the United States.⁹ Phosphorus is highly absorbed from additives in processed food (approaching 100% absorption), less absorbed from animal sources such as meat and dairy products (40%-60%), and is the least absorbed from plant sources such as beans and nuts (20%-40%).¹⁰ Advise patients to avoid fast food, processed foods, cheese, frozen meals, colas, and certain ready-to-eat cereals and prepared meats, as these products may have additives from which phosphorus is readily absorbed.¹¹ A patient-friendly list of high-phosphorus foods, as well as other dietary advice and recipes, can be found on the National Kidney Foundation Web site at https://www.kidney.org/atoz/content/phosphorus. Tables listing the phosphorus content of common foods are also available in the literature and online.^11,12 Keep in mind that not all resources take into account phosphate bioavailability. Dietician referral may be helpful to assure that patients maintain adequate protein intake while restricting dietary phosphate.

Restrict the dose of calcium-based binders in the setting of persistent or recurrent hypercalcemia, known vascular calcification, or low parathyroid hormone levels.

Phosphate binders are recommended by the KDIGO guidelines for use in patients with kidney disease and hyperphosphatemia.⁶ Most of the data to support the use of phosphate binders was gleaned from the dialysis population. The use of phosphate binders in non-dialyzed patients with CKD has both proponents and opponents, with literature supporting both positions.^13,14 A recent KDIGO conference on controversies in CKD-MBD identified this as an area that should be evaluated further for the next guideline update.¹⁵

Phosphate binders—which bind the phosphorus in food to prevent absorption—should be taken with meals or high-phosphorus snacks. Products and formulations of commonly used phosphate binders are shown in TABLE 2.^16,17 Taste, formulation, adverse effects, pill burden, and cost are issues to discuss with patients when initiating or adjusting phosphate binder therapy. It’s estimated that more than half of all patients receiving dialysis do not adhere to their prescribed phosphate binder regimen, highlighting the need to assess adherence before adjusting dose and to involve the patient in the decision-making process to select a phosphate binder product.¹⁸

Avoid calcium-based binders? The risk of hypercalcemia and the potentially increased risk of vascular calcifications with calcium-based binders have led some nephrologists to favor non-calcium-based products. Two recent meta-analyses found a reduced risk of all-cause mortality with the non-calcium-based binders sevelamer or lanthanum as compared to calcium-based binders.^19,20 Current KDIGO guidelines were published prior to these meta-analyses and do not recommend one phosphate binder over another. They do, however, recommend restricting the dose of calcium-based binders in the setting of persistent or recurrent hypercalcemia, known vascular calcification, or low PTH levels.⁶

Secondary hyperparathyroidism

Due to a lack of data, the goal PTH level in patients not receiving dialysis is unknown.⁶ A reasonable approach in non-dialyzed patients, however, is to correct 25-OH vitamin D (25[OH]D) deficiency, elevations in serum phosphate, and hypocalcemia when the level of intact PTH (iPTH) exceeds the normal range for the assay because correcting these derangements may result in a decline in iPTH.^6,21 If this approach fails and PTH levels continue to rise, use of calcitriol or vitamin D analogues is recommended.⁶ Characteristics of medications used to treat SHPT are presented in TABLE 3.^16,17

In dialysis patients, the target iPTH range suggested by KDIGO is 2 to 9 times the upper limit of normal for the assay.⁶ Elevated PTH levels in the dialysis population may be managed with activated vitamin D and/or cinacalcet.

Native vitamin D (ergocalciferol, cholecalciferol) and activated vitamin D analogs (calcitriol, doxercalciferol, paricalcitol). Native vitamin D products are recommended for non-dialyzed patients with CKD to correct vitamin D deficiencies. Although many approaches may be used clinically to replenish low vitamin D stores, one reasonable recommendation in patients with a 25(OH)D level <30 ng/mL is to prescribe ergocalciferol 50,000 units/week for 8 weeks and then to repeat the serum 25-OH vitamin D test. If the level is still <30 ng/mL, a second 8-week course of weekly ergocalciferol 50,000 IU may be administered.²¹

Following repletion with ergocalciferol, maintenance doses of cholecalciferol (1000-2000 IU/d) or ergocalciferol (50,000 IU/-month) may be initiated.²¹ Discontinue native vitamin D in patients who develop hypercalcemia.

Native vitamin D becomes less effective at reducing PTH levels as kidney disease advances. This is likely due to a decline in renal conversion of 25(OH)D to 1,25-(OH)₂vitamin D (1,25[OH]₂D), the most active form of vitamin D and the form of vitamin D that decreases PTH production. By stage 5 CKD, it is unlikely that native vitamin D will significantly decrease PTH levels; treatment with activated vitamin D products or cinacalcet is generally required.

Because the enzyme responsible for converting 25(OH)D into the most active form can be found in multiple tissues outside of the kidney, and the 1,25(OH)₂D converted for use by these organs may help prevent such conditions/events as hypertension, type 2 diabetes, myocardial infarction, and stroke (in patients with and without kidney disease), some specialists prescribe native vitamin D to patients with CKD for reasons unrelated to PTH suppression. There are no data, however, confirming that 25(OH)D supplementation mitigates these outcomes.²¹

Don’t forget calcium

All of the active vitamin D products can increase serum calcium and phosphate levels. Calcitriol, however, may cause more hypercalcemia than paricalcitol.²² If hypercalcemia develops, you may need to stop, or reduce the dose of, vitamin D analogues. Or you may need to switch patients from calcium-based to non-calcium-based phosphate binders. If hyperphosphatemia develops, intensify phosphate binder therapy or reduce the dose of, or stop, vitamin D analogues. If iPTH levels go below the target range, reduce the dose of the vitamin D analogue to avoid iatrogenic adynamic bone disease.

Avoid this agent in the non-dialyzed patient. Cinacalcet effectively treats SHPT in patients receiving dialysis, but is not recommended for use in undialyzed patients.²³ That’s because unacceptably high rates of hypocalcemia have been observed in non-dialyzed patients who were taking the drug.^23,24 In addition, while cinacalcet neutrally affects, or causes a slight decrease in, serum phosphate in patients receiving dialysis, it increases serum phosphate in patients who are not.^24,25

Drug therapy for osteoporosis

Therapy to prevent and treat fractures in patients with CKD is controversial because patients with CKD stage 3 to 5 with and without MBD were excluded from clinical trials of commercially available treatments. Furthermore, in adynamic bone disease, bones are capable of neither breaking down nor building (ie, reduced resorption). Bisphosphonates and other antiresorptive therapies are more effective at decreasing fractures in patients who are in a state of increased bone resorption, such as menopausal women, so the benefits of these medications in terms of their ability to reduce fractures in CKD patients are questionable, as is their safety.^26,27

In addition, while dual-energy x-ray absorptiometry (DXA) is typically used to identify patients who would benefit from these agents, studies have recently demonstrated that femoral neck bone density measured via DXA may underestimate fracture risk in patients with CKD-MBD (ie, bone density may actually be lower than measured).^26,28

Antiresorptive agents and teriparatide

Osteoporosis treatments include antiresorptive agents (ie, the bisphosphonates, raloxifene, denosumab), and the anabolic bone agent teriparatide.

Evidence supports treating patients with stage 1 to 3 CKD the same as patients without CKD.¹⁵ Bisphosphonates are labeled as contraindicated in patients with a glomerular filtration rate (GFR) <30 mL/min/1.73m², due to concerns arising from animal trials and subsequent human case reports (both with intravenous formulations only) regarding acute kidney injury.²⁷

While raloxifene lacks a warning regarding use in patients with stage 3 to 5 CKD, it has not been shown to prevent hip fractures in any population.²⁹

Denosumab is not contraindicated for use in patients with CKD stage 3 to 5 without MBD, but it can worsen hypocalcemia, particularly in patients receiving dialysis.³⁰

Teriparatide is contraindicated in patients with CKD and SHPT,³¹ and there are no studies of its use in patients with CKD-MBD.

What the guidelines say about antiresorptive treatment

For patients with stage 3 to 5 CKD with manifestations of MBD, 2009 KDIGO guidelines recommend a bone biopsy to evaluate for adynamic bone disease before initiating antiresorptive treatment.⁶ Because few physicians in most communities are trained to conduct and evaluate bone biopsies, this recommendation is infrequently followed. Without a bone biopsy to rule out adynamic bone disease, options to prevent or treat fractures in the setting of CKD-MBD are limited.

CORRESPONDENCE
Karly Pippitt, MD, Department of Family and Preventive Medicine, University of Utah School of Medicine, 375 Chipeta Way, Suite A, Salt Lake City, UT 84108; [email protected].

CASE 1 › Joe S is a 41-year-old African-American man who comes to your clinic after his employee health screening revealed elevated triglycerides. The patient has a 3-year history of type 2 diabetes mellitus (T2DM); he also has a history of hypertension, gastroesophageal reflux disease, and obstructive sleep apnea. Mr. S tells you he takes metformin 1000 mg twice daily, but stopped taking his glipizide because he didn’t think it was helping his blood sugar. His last hemoglobin (Hb) A1c result was 8.8%, and he is very resistant to starting insulin therapy.

The patient’s other medications include enalapril 10 mg/d, atorvastatin 10 mg/d, and omeprazole 20 mg/d. Mr. S weighs 255.6 lbs (body mass index=34.7), his BP is 140/88 mm Hg, and his heart rate is 82 beats per minute. Laboratory values include: serum creatinine, 1.01 mg/dL; estimated glomerular filtration rate (eGFR) >100 mL/min/1.73 m²; potassium (K), 4.3 mmol/L; serum phosphorous (Phos), 2.8 mg/dL; magnesium (Mg), 1.9 mg/dL; total cholesterol, 167 mg/dL; low-density lipoprotein (LDL), 78 mg/dL; high-density lipoprotein (HDL), 38 mg/dL; and triglycerides, 256 mg/dL.

CASE 2  › Susan R, a 68-year-old Caucasian woman, returns to your clinic for a follow-up visit 3 months after you prescribed dapagliflozin 10 mg/d for her T2DM. Her glucose levels have improved, but she complains of vaginal pruritus and is worried that she has a yeast infection.

You diagnose vulvovaginal candidiasis in this patient and prescribe a single dose of fluconazole 150 mg. After reviewing her laboratory test results, you notice that since starting the dapagliflozin, her HbA1c level has improved slightly from 9.8% to 9.3%, but is still not where it needs to be. Her eGFR is 49 mL/min/1.73 m².

What would you recommend to improve control of these patients’ blood glucose levels?

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of agents to enter the T2DM management arena. They act in the proximal renal tubules to decrease the reabsorption of glucose by targeting the SGLT2 transmembrane protein, which reabsorbs about 90% of the body’s glucose.^1,2 The class is currently made up of 3 agents—canagliflozin, dapagliflozin, and empagliflozin—all of which are approved by the US Food and Drug Administration (FDA) for the treatment of T2DM (TABLE 1).²

The American Diabetes Association and the European Association for the Study of Diabetes published updated guidelines for T2DM management in 2015.¹ In addition to lifestyle modifications, the guidelines recommend the use of metformin as first-line therapy unless it is contraindicated or patients are unable to tolerate it (eg, because of gastrointestinal adverse effects). They recommend other pharmacologic therapies as second-line options based on specific patient characteristics. Thus, SGLT2 inhibitors may be used as add-on therapy after metformin, or as a first-line option if metformin is contraindicated or not tolerated. Because the mechanism of action of SGLT2 inhibitors is independent of insulin secretion, these agents may be used at any stage of the diabetes continuum.

SGLT2 agents as monotherapy, or as add-on therapy

All SGLT2 agents have been studied as monotherapy accompanied by diet and exercise and shown to produce HbA1c reductions of 0.34% to 1.11%.^3-6 In trials, the effect was similar regardless of study duration (18-104 weeks); generally, higher doses corresponded with larger HbA1c reductions.^3-6

Used as monotherapy, SGLT2 inhibitors produce HbA1c reductions of as much as 1.11%.

SGLT2 inhibitors have also been studied as add-on therapy to several oral agents including metformin, sulfonylureas, thiazolidinediones (TZDs), and the combination of metformin plus sulfonylureas or TZDs or dipeptidyl peptidase IV (DPP-IV) inhibitors.¹ When used in any of these combinations, each SGLT2 agent demonstrated a consistent HbA1c lowering effect of 0.62% to 1.19%.^7-14

Additionally, SGLT2 inhibitors have been studied in combination with insulin therapy (median or mean daily doses >60 units), which yielded further reductions in HbA1c of 0.58% to 1.02% without significant insulin adjustments or an increase in major hypoglycemia events.^15-17 Patients receiving insulin and an SGLT2 inhibitor had lower insulin doses and more weight loss compared to placebo groups.

SGLT2 inhibitors offer additional benefits

Secondary analyses of most studies of SGLT2 inhibitors include changes in BP and weight from baseline as well as minor changes (some positive, some not) in several lipid parameters.^{3-5,7-9,13-15,17-24} In general, these effects do not appear to be dose-dependent (with the exception of canagliflozin and its associated lipid effects²⁵) and are similar among the 3 medications.^{3-5,7-9,13-15,17-24} (For more on who would benefit from these agents, see “When to consider an SGLT2 inhibitor” above.)

BP reduction. Although the mean baseline BP was controlled in most studies, SGLT2 inhibitors have been shown to significantly reduce BP. Reductions in BP with all 3 SGLT2 medications range from approximately 2 to 5 mm Hg systolic and 0.5 to 2.5 mm Hg diastolic, which may be due to weight loss and diuresis.^{4-8,10-16,20-23} While the reductions were modest at best, one study involving empagliflozin reported that more than one-quarter of patients with uncontrolled BP at baseline achieved a BP <130/80 mm Hg 24 weeks later.⁵ While these agents should not be used solely for their BP lowering effects, they may help a small number of patients with mildly elevated BP achieve their goal without an additional antihypertensive agent.

Weight reduction. Modest weight loss, likely due to the loss of calories through urine, was seen with SGLT2 inhibitors in most studies, with reductions persisting beyond one year of use. In most studies, including those involving obese patients on insulin therapy,^15,17,21 patients’ body weights were reduced by approximately 2 to 4 kg from baseline.^{3-16,18,21-23,26}

Lipid effects. Although the mechanism is unclear, use of SGLT2 inhibitors can have varying effects on lipid panels. In most studies, total and LDL cholesterol levels were increased with elevations ranging from 0.7 to 10 mg/dL.^{3,7,8,18,19,22,23} Conversely, at least one study demonstrated mild reductions in total and LDL cholesterol levels with higher doses of empagliflozin.¹³ Additionally, modest reductions in triglycerides and increases in HDL across all doses of canagliflozin, dapagliflozin, and empagliflozin have been seen.^8,9,13,15,19 While the clinical relevance of these lipid changes is unknown, monitoring is recommended.²

These agents are well tolerated

SGLT2 inhibitors were generally well tolerated in studies. The most common adverse effects include mycotic infections (2.4%-21.6%) and urinary tract infections (UTIs) (4.0%-19.6%) (both with higher incidences in females); volume-related effects such as dizziness and hypotension (0.3%-8.3%); and nasopharyngitis (5.4%-18.3%).^{4-14,16-23,26-28} Hypoglycemia was observed more often when an SGLT2 inhibitor was used in combination with a sulfonylurea or insulin therapy.^{4-14,16-23,26-28} The number of times adverse events led to discontinuation was low and similar to that in control groups.^{4-14,16-23,26-28}

Mycotic and urinary infections should be diagnosed and treated according to current standards of care and do not require discontinuation of the SGLT2 inhibitor. Canagli-flozin therapy was associated with electrolyte abnormalities including hyperkalemia, hypermagnesemia, and hyperphosphatemia.²⁵ Thus, levels should be monitored periodically, especially in patients predisposed to elevations due to other conditions or medications.²⁵

Two additional warnings are worth noting

Diabetic ketoacidosis (DKA) has been reported with all 3 agents, and bone fractures have been reported with canagliflozin.

The FDA issued a warning in May 2015 regarding the increased risk of DKA with the use of SGLT2 inhibitor single and combination products.²⁹ This warning was prompted by several case reports of DKA with uncharacteristically mild to moderate glucose elevations in patients with type 1 diabetes mellitus (T1DM) and T2DM who were taking an SGLT2 inhibitor. The absence of significant hyperglycemia delayed diagnosis in many cases. Therefore, patients should be counseled on the signs and symptoms of DKA, as well as when to seek medical attention.

SGLT2 inhibitors can reduce BP by about 2 to 5 mm Hg, systolic, and 0.5 to 2.5 mm Hg, diastolic.

Patients with diabetes and symptoms of ketoacidosis (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, and fatigue) should be evaluated regardless of current blood glucose levels, and SGLT2 inhibitors should be discontinued if acidosis is confirmed. Identified potential triggers include illness, reduced food and fluid intake, reduced insulin dose, and history of alcohol intake. Use of SGLT2 inhibitors should be avoided in patients with T1DM until safety and efficacy are established in large randomized controlled trials. The European Medicines Agency announced that a thorough review of all currently approved SGLT2 agents is underway to evaluate the risk for DKA.³⁰

In addition, the FDA called for a revision of the label of canagliflozin to reflect a strengthened warning about an increased risk of bone fractures and decreased bone mineral density (BMD).³¹ Fractures can occur as early as 12 weeks after initiating treatment and with only minor trauma.³¹

Over a 2-year period, canagliflozin also significantly decreased BMD in the hip and lower spine compared to placebo.³¹ Patients should be evaluated for additional risk factors for fracture before taking canagliflozin.³¹ The FDA is continuing to evaluate whether the other approved SGLT2 inhibitors are associated with an increased risk for fractures.

Drug interactions: Proceed carefully with diuretics

The number of drugs that interact with SGLT2 inhibitors is minimal. Because these agents can cause volume-related effects such as hypotension, dizziness, and osmotic diuresis, patients—particularly the elderly and those with renal impairment—taking concomitant diuretics, especially loop diuretics, may be at increased risk for these effects and should be monitored accordingly.^2,25

Canagliflozin is primarily metabolized via glucuronidation by the uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes. Therefore, UGT enzyme inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir) decrease canagliflozin’s serum concentration. If a patient has an eGFR >60 mL/min/1.73 m² and is tolerating a dose of 100 mg/d, consider increasing the dose to 300 mg/d during concomitant treatment.

In addition, researchers have found that canagliflozin increases serum levels of digoxin by between 20% and 36%.²⁵ Experts suspect this occurs because canagliflozin inhibits P-glycoprotein efflux of digoxin. Although monitoring of digoxin levels is recommended, this interaction is considered to be minor.²⁵

Cost consideration: SGLT2 inhibitors are more expensive

The SGLT2 inhibitors are available only as brand name products and are more expensive than agents that have generic options (eg, metformin, sulfonylureas, TZDs). The average wholesale cost is approximately $400 for a 30-day supply of all SGLT2 agents.³² When considering an SGLT2 inhibitor, the patient should ideally have medication prescription coverage. Depending on the specific insurance plan, these agents are classified as tier 2 to 4, which is comparable to other oral brand name options.

Research looks at CV outcomes and cancer risk

Cardiovascular (CV) risk reduction. To date, only one study evaluating the effect of SGLT2 inhibitors on CV outcomes is complete.³³ Two large randomized controlled trials involving canagliflozin and dapagliflozin designed to evaluate treatment effects on major CV endpoints are ongoing.^34,35

In the EMPA-REG OUTCOME trial,³³ researchers found that empagliflozin had beneficial effects on CV outcomes, making it one of the only antidiabetic agents on the market to have such benefits. The study, which involved more than 7000 patients with a history of T2DM and existing cardiovascular disease (CVD), found that 10.5% of patients in the empagliflozin group vs 12.1% in the placebo group died from a CV cause or experienced a nonfatal myocardial infarction or stroke over a median of 3.1 years. Results were similar with both doses (10 mg vs 25 mg) of empagliflozin. The mechanisms behind the CV benefits are likely multifactorial and may be related to reductions in weight and BP,³³ but additional research is needed to fully elucidate the role of empagliflozin in this population.

Canagliflozin is being evaluated in the Canagliflozin Cardiovascular Assessment Study (CANVAS) for its effect on major CV events—CV death, nonfatal myocardial infarction, and nonfatal stroke—in patients with either a history of CVD or who are at increased risk of CVD and have uncontrolled diabetes.³⁴ The trial is expected to wrap up in June 2017.

And dapagliflozin is being studied in the DECLARE-TIMI 58 trial (the Effect of Dapagliflozin on the Incidence of Cardiovascular Events) in patients with T2DM and either known CVD or at least 2 risk factors for CVD.³⁵ The study is designed to assess dapagliflozin’s effect on the incidence of CV death, myocardial infarction, and ischemic stroke and has an estimated completion date of April 2019, which will provide a median follow-up of 4.5 years.

Cancer. All 3 agents have been examined for any possible carcinogenic links. In 2011, the FDA issued a request for further investigation surrounding the risk of cancer associated with dapagliflozin.³⁶ As of November 2013, 10 of 6045 patients treated with dapagliflozin developed bladder cancer compared to 1 of 3512 controls.³⁶ Furthermore, 9 of 2223 patients treated with dapagliflozin developed breast cancer compared to 1 of 1053 controls.³⁶

Although the trials were not designed to detect an increase in risk, the number of observed cases warranted further investigation. No official warning for breast cancer exists since the characteristics of the malignancies led the FDA to believe dapagliflozin was unlikely the cause.³⁶

When considering an SGLT2 inhibitor, the patient should ideally have medication prescription coverage.

Given what we know to date, it appears to be prudent to avoid prescribing SGLT2 inhibitors in patients with active bladder cancer, and to use them with caution in those with a history of the disease.²

Other studies. Initially, animal studies suggested an increased risk of various malignancies associated with canagliflozin use in rats,³⁷ but consistent results were not seen in human studies. Similarly, at least one study found that empagliflozin was associated with lung cancer and melanoma, but closer examination found that most patients who developed these cancers had risk factors.³⁸ Large, long-term studies of these agents in various populations are needed to thoroughly investigate possible carcinogenicity.

Additional considerations: Kidney function, age, and pregnancy

Consider avoiding SGLT2 inhibitors in patients with moderate kidney dysfunction (eGFR 30-59 mL/min/1.73 m²). Studies have shown that SGLT2 inhibitors are not as effective at lowering blood glucose in those with reduced eGFR, although adverse events were similar to those in placebo groups.^24,39,40 Dapagliflozin is not recommended in patients with an eGFR <60 mL/min/1.73 m² due to lack of efficacy.^2,24 Empagliflozin does not require dose adjustments if eGFR is ≥45 mL/min/1.73 m². A lower dose of canagliflozin (ie, 100 mg/d) is recommended in those with an eGFR of 45 to 59 mL/min/1.73 m².² All agents are contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²).

Older patients are at higher risk for dehydration, hypotension, and falls; therefore, SGLT2 inhibitors should be used with caution in this population. Similarly, they should not be used in patients with T1DM and should be avoided in those with active, or a history of, DKA.

There are no data on the use of SGLT2 inhibitors in pregnancy; thus, these agents should be avoided unless the potential benefits outweigh the potential risks to the unborn fetus.²

CASE 1 › An SGLT2 inhibitor is an acceptable option for Mr. S. Because he is resistant to starting insulin therapy and his HbA1c is <9%, an additional oral medication is reasonable. Adding an SGLT2 inhibitor may reduce his HbA1c up to ~1%, and education on lifestyle modifications may help bring him to goal. An SGLT2 inhibitor may also benefit his BP and weight, both of which could be improved.

The FDA issued a warning in light of several case reports of DKA with unusually mild glucose elevations in patients taking an SGLT2 inhibitor.

Given the drugs he’s taking, drug interactions should not be an issue, and his renal function and pertinent labs (K, Phos, Mg) are within normal limits. Nevertheless, monitor these labs periodically and monitor Mr. S for adverse effects, such as UTIs, although these are more common in women. Canagliflozin is the preferred SGLT2 inhibitor on his insurance formulary, so you could initiate therapy at 100 mg/d, administered prior to the first meal, and increase to 300 mg/d if needed. As an alternative, consider prescribing the metformin/canagliflozin combination agent.

CASE 2 › Ms. R is likely experiencing a yeast infection as an adverse effect of the dapagliflozin. Although one yeast infection is insufficient grounds for discontinuation of the drug, recurrent infections should prompt a risk-to-benefit analysis to determine whether it’s worth continuing the medication. Her recent eGFR (<60 mL/min/1.73 m²) is, however, a contraindication to dapagliflozin, and therapy should be discontinued. Canagliflozin and empagliflozin may be considered since her eGFR is >45 mL/min/1.73 m², but given her current HbA1c and recent adverse drug event, alternative therapies, such as basal insulin, are more appropriate treatment choices.

CORRESPONDENCE
Katelin M. Lisenby, PharmD, BCPS, University of Alabama College of Community Health Sciences, University Medical Center, Box 870374, Tuscaloosa, AL 35487; [email protected].

CASE 1 › Joe S is a 41-year-old African-American man who comes to your clinic after his employee health screening revealed elevated triglycerides. The patient has a 3-year history of type 2 diabetes mellitus (T2DM); he also has a history of hypertension, gastroesophageal reflux disease, and obstructive sleep apnea. Mr. S tells you he takes metformin 1000 mg twice daily, but stopped taking his glipizide because he didn’t think it was helping his blood sugar. His last hemoglobin (Hb) A1c result was 8.8%, and he is very resistant to starting insulin therapy.

The patient’s other medications include enalapril 10 mg/d, atorvastatin 10 mg/d, and omeprazole 20 mg/d. Mr. S weighs 255.6 lbs (body mass index=34.7), his BP is 140/88 mm Hg, and his heart rate is 82 beats per minute. Laboratory values include: serum creatinine, 1.01 mg/dL; estimated glomerular filtration rate (eGFR) >100 mL/min/1.73 m²; potassium (K), 4.3 mmol/L; serum phosphorous (Phos), 2.8 mg/dL; magnesium (Mg), 1.9 mg/dL; total cholesterol, 167 mg/dL; low-density lipoprotein (LDL), 78 mg/dL; high-density lipoprotein (HDL), 38 mg/dL; and triglycerides, 256 mg/dL.

CASE 2  › Susan R, a 68-year-old Caucasian woman, returns to your clinic for a follow-up visit 3 months after you prescribed dapagliflozin 10 mg/d for her T2DM. Her glucose levels have improved, but she complains of vaginal pruritus and is worried that she has a yeast infection.

You diagnose vulvovaginal candidiasis in this patient and prescribe a single dose of fluconazole 150 mg. After reviewing her laboratory test results, you notice that since starting the dapagliflozin, her HbA1c level has improved slightly from 9.8% to 9.3%, but is still not where it needs to be. Her eGFR is 49 mL/min/1.73 m².

What would you recommend to improve control of these patients’ blood glucose levels?

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of agents to enter the T2DM management arena. They act in the proximal renal tubules to decrease the reabsorption of glucose by targeting the SGLT2 transmembrane protein, which reabsorbs about 90% of the body’s glucose.^1,2 The class is currently made up of 3 agents—canagliflozin, dapagliflozin, and empagliflozin—all of which are approved by the US Food and Drug Administration (FDA) for the treatment of T2DM (TABLE 1).²

The American Diabetes Association and the European Association for the Study of Diabetes published updated guidelines for T2DM management in 2015.¹ In addition to lifestyle modifications, the guidelines recommend the use of metformin as first-line therapy unless it is contraindicated or patients are unable to tolerate it (eg, because of gastrointestinal adverse effects). They recommend other pharmacologic therapies as second-line options based on specific patient characteristics. Thus, SGLT2 inhibitors may be used as add-on therapy after metformin, or as a first-line option if metformin is contraindicated or not tolerated. Because the mechanism of action of SGLT2 inhibitors is independent of insulin secretion, these agents may be used at any stage of the diabetes continuum.

SGLT2 agents as monotherapy, or as add-on therapy

All SGLT2 agents have been studied as monotherapy accompanied by diet and exercise and shown to produce HbA1c reductions of 0.34% to 1.11%.^3-6 In trials, the effect was similar regardless of study duration (18-104 weeks); generally, higher doses corresponded with larger HbA1c reductions.^3-6

Used as monotherapy, SGLT2 inhibitors produce HbA1c reductions of as much as 1.11%.

SGLT2 inhibitors have also been studied as add-on therapy to several oral agents including metformin, sulfonylureas, thiazolidinediones (TZDs), and the combination of metformin plus sulfonylureas or TZDs or dipeptidyl peptidase IV (DPP-IV) inhibitors.¹ When used in any of these combinations, each SGLT2 agent demonstrated a consistent HbA1c lowering effect of 0.62% to 1.19%.^7-14

Additionally, SGLT2 inhibitors have been studied in combination with insulin therapy (median or mean daily doses >60 units), which yielded further reductions in HbA1c of 0.58% to 1.02% without significant insulin adjustments or an increase in major hypoglycemia events.^15-17 Patients receiving insulin and an SGLT2 inhibitor had lower insulin doses and more weight loss compared to placebo groups.

SGLT2 inhibitors offer additional benefits

Secondary analyses of most studies of SGLT2 inhibitors include changes in BP and weight from baseline as well as minor changes (some positive, some not) in several lipid parameters.^{3-5,7-9,13-15,17-24} In general, these effects do not appear to be dose-dependent (with the exception of canagliflozin and its associated lipid effects²⁵) and are similar among the 3 medications.^{3-5,7-9,13-15,17-24} (For more on who would benefit from these agents, see “When to consider an SGLT2 inhibitor” above.)

BP reduction. Although the mean baseline BP was controlled in most studies, SGLT2 inhibitors have been shown to significantly reduce BP. Reductions in BP with all 3 SGLT2 medications range from approximately 2 to 5 mm Hg systolic and 0.5 to 2.5 mm Hg diastolic, which may be due to weight loss and diuresis.^{4-8,10-16,20-23} While the reductions were modest at best, one study involving empagliflozin reported that more than one-quarter of patients with uncontrolled BP at baseline achieved a BP <130/80 mm Hg 24 weeks later.⁵ While these agents should not be used solely for their BP lowering effects, they may help a small number of patients with mildly elevated BP achieve their goal without an additional antihypertensive agent.

Weight reduction. Modest weight loss, likely due to the loss of calories through urine, was seen with SGLT2 inhibitors in most studies, with reductions persisting beyond one year of use. In most studies, including those involving obese patients on insulin therapy,^15,17,21 patients’ body weights were reduced by approximately 2 to 4 kg from baseline.^{3-16,18,21-23,26}

Lipid effects. Although the mechanism is unclear, use of SGLT2 inhibitors can have varying effects on lipid panels. In most studies, total and LDL cholesterol levels were increased with elevations ranging from 0.7 to 10 mg/dL.^{3,7,8,18,19,22,23} Conversely, at least one study demonstrated mild reductions in total and LDL cholesterol levels with higher doses of empagliflozin.¹³ Additionally, modest reductions in triglycerides and increases in HDL across all doses of canagliflozin, dapagliflozin, and empagliflozin have been seen.^8,9,13,15,19 While the clinical relevance of these lipid changes is unknown, monitoring is recommended.²

These agents are well tolerated

SGLT2 inhibitors were generally well tolerated in studies. The most common adverse effects include mycotic infections (2.4%-21.6%) and urinary tract infections (UTIs) (4.0%-19.6%) (both with higher incidences in females); volume-related effects such as dizziness and hypotension (0.3%-8.3%); and nasopharyngitis (5.4%-18.3%).^{4-14,16-23,26-28} Hypoglycemia was observed more often when an SGLT2 inhibitor was used in combination with a sulfonylurea or insulin therapy.^{4-14,16-23,26-28} The number of times adverse events led to discontinuation was low and similar to that in control groups.^{4-14,16-23,26-28}

Mycotic and urinary infections should be diagnosed and treated according to current standards of care and do not require discontinuation of the SGLT2 inhibitor. Canagli-flozin therapy was associated with electrolyte abnormalities including hyperkalemia, hypermagnesemia, and hyperphosphatemia.²⁵ Thus, levels should be monitored periodically, especially in patients predisposed to elevations due to other conditions or medications.²⁵

Two additional warnings are worth noting

Diabetic ketoacidosis (DKA) has been reported with all 3 agents, and bone fractures have been reported with canagliflozin.

The FDA issued a warning in May 2015 regarding the increased risk of DKA with the use of SGLT2 inhibitor single and combination products.²⁹ This warning was prompted by several case reports of DKA with uncharacteristically mild to moderate glucose elevations in patients with type 1 diabetes mellitus (T1DM) and T2DM who were taking an SGLT2 inhibitor. The absence of significant hyperglycemia delayed diagnosis in many cases. Therefore, patients should be counseled on the signs and symptoms of DKA, as well as when to seek medical attention.

SGLT2 inhibitors can reduce BP by about 2 to 5 mm Hg, systolic, and 0.5 to 2.5 mm Hg, diastolic.

Patients with diabetes and symptoms of ketoacidosis (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, and fatigue) should be evaluated regardless of current blood glucose levels, and SGLT2 inhibitors should be discontinued if acidosis is confirmed. Identified potential triggers include illness, reduced food and fluid intake, reduced insulin dose, and history of alcohol intake. Use of SGLT2 inhibitors should be avoided in patients with T1DM until safety and efficacy are established in large randomized controlled trials. The European Medicines Agency announced that a thorough review of all currently approved SGLT2 agents is underway to evaluate the risk for DKA.³⁰

In addition, the FDA called for a revision of the label of canagliflozin to reflect a strengthened warning about an increased risk of bone fractures and decreased bone mineral density (BMD).³¹ Fractures can occur as early as 12 weeks after initiating treatment and with only minor trauma.³¹

Over a 2-year period, canagliflozin also significantly decreased BMD in the hip and lower spine compared to placebo.³¹ Patients should be evaluated for additional risk factors for fracture before taking canagliflozin.³¹ The FDA is continuing to evaluate whether the other approved SGLT2 inhibitors are associated with an increased risk for fractures.

Drug interactions: Proceed carefully with diuretics

The number of drugs that interact with SGLT2 inhibitors is minimal. Because these agents can cause volume-related effects such as hypotension, dizziness, and osmotic diuresis, patients—particularly the elderly and those with renal impairment—taking concomitant diuretics, especially loop diuretics, may be at increased risk for these effects and should be monitored accordingly.^2,25

Canagliflozin is primarily metabolized via glucuronidation by the uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes. Therefore, UGT enzyme inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir) decrease canagliflozin’s serum concentration. If a patient has an eGFR >60 mL/min/1.73 m² and is tolerating a dose of 100 mg/d, consider increasing the dose to 300 mg/d during concomitant treatment.

In addition, researchers have found that canagliflozin increases serum levels of digoxin by between 20% and 36%.²⁵ Experts suspect this occurs because canagliflozin inhibits P-glycoprotein efflux of digoxin. Although monitoring of digoxin levels is recommended, this interaction is considered to be minor.²⁵

Cost consideration: SGLT2 inhibitors are more expensive

The SGLT2 inhibitors are available only as brand name products and are more expensive than agents that have generic options (eg, metformin, sulfonylureas, TZDs). The average wholesale cost is approximately $400 for a 30-day supply of all SGLT2 agents.³² When considering an SGLT2 inhibitor, the patient should ideally have medication prescription coverage. Depending on the specific insurance plan, these agents are classified as tier 2 to 4, which is comparable to other oral brand name options.

Research looks at CV outcomes and cancer risk

Cardiovascular (CV) risk reduction. To date, only one study evaluating the effect of SGLT2 inhibitors on CV outcomes is complete.³³ Two large randomized controlled trials involving canagliflozin and dapagliflozin designed to evaluate treatment effects on major CV endpoints are ongoing.^34,35

In the EMPA-REG OUTCOME trial,³³ researchers found that empagliflozin had beneficial effects on CV outcomes, making it one of the only antidiabetic agents on the market to have such benefits. The study, which involved more than 7000 patients with a history of T2DM and existing cardiovascular disease (CVD), found that 10.5% of patients in the empagliflozin group vs 12.1% in the placebo group died from a CV cause or experienced a nonfatal myocardial infarction or stroke over a median of 3.1 years. Results were similar with both doses (10 mg vs 25 mg) of empagliflozin. The mechanisms behind the CV benefits are likely multifactorial and may be related to reductions in weight and BP,³³ but additional research is needed to fully elucidate the role of empagliflozin in this population.

Canagliflozin is being evaluated in the Canagliflozin Cardiovascular Assessment Study (CANVAS) for its effect on major CV events—CV death, nonfatal myocardial infarction, and nonfatal stroke—in patients with either a history of CVD or who are at increased risk of CVD and have uncontrolled diabetes.³⁴ The trial is expected to wrap up in June 2017.

And dapagliflozin is being studied in the DECLARE-TIMI 58 trial (the Effect of Dapagliflozin on the Incidence of Cardiovascular Events) in patients with T2DM and either known CVD or at least 2 risk factors for CVD.³⁵ The study is designed to assess dapagliflozin’s effect on the incidence of CV death, myocardial infarction, and ischemic stroke and has an estimated completion date of April 2019, which will provide a median follow-up of 4.5 years.

Cancer. All 3 agents have been examined for any possible carcinogenic links. In 2011, the FDA issued a request for further investigation surrounding the risk of cancer associated with dapagliflozin.³⁶ As of November 2013, 10 of 6045 patients treated with dapagliflozin developed bladder cancer compared to 1 of 3512 controls.³⁶ Furthermore, 9 of 2223 patients treated with dapagliflozin developed breast cancer compared to 1 of 1053 controls.³⁶

Although the trials were not designed to detect an increase in risk, the number of observed cases warranted further investigation. No official warning for breast cancer exists since the characteristics of the malignancies led the FDA to believe dapagliflozin was unlikely the cause.³⁶

When considering an SGLT2 inhibitor, the patient should ideally have medication prescription coverage.

Given what we know to date, it appears to be prudent to avoid prescribing SGLT2 inhibitors in patients with active bladder cancer, and to use them with caution in those with a history of the disease.²

Other studies. Initially, animal studies suggested an increased risk of various malignancies associated with canagliflozin use in rats,³⁷ but consistent results were not seen in human studies. Similarly, at least one study found that empagliflozin was associated with lung cancer and melanoma, but closer examination found that most patients who developed these cancers had risk factors.³⁸ Large, long-term studies of these agents in various populations are needed to thoroughly investigate possible carcinogenicity.

Additional considerations: Kidney function, age, and pregnancy

Consider avoiding SGLT2 inhibitors in patients with moderate kidney dysfunction (eGFR 30-59 mL/min/1.73 m²). Studies have shown that SGLT2 inhibitors are not as effective at lowering blood glucose in those with reduced eGFR, although adverse events were similar to those in placebo groups.^24,39,40 Dapagliflozin is not recommended in patients with an eGFR <60 mL/min/1.73 m² due to lack of efficacy.^2,24 Empagliflozin does not require dose adjustments if eGFR is ≥45 mL/min/1.73 m². A lower dose of canagliflozin (ie, 100 mg/d) is recommended in those with an eGFR of 45 to 59 mL/min/1.73 m².² All agents are contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²).

Older patients are at higher risk for dehydration, hypotension, and falls; therefore, SGLT2 inhibitors should be used with caution in this population. Similarly, they should not be used in patients with T1DM and should be avoided in those with active, or a history of, DKA.

There are no data on the use of SGLT2 inhibitors in pregnancy; thus, these agents should be avoided unless the potential benefits outweigh the potential risks to the unborn fetus.²

CASE 1 › An SGLT2 inhibitor is an acceptable option for Mr. S. Because he is resistant to starting insulin therapy and his HbA1c is <9%, an additional oral medication is reasonable. Adding an SGLT2 inhibitor may reduce his HbA1c up to ~1%, and education on lifestyle modifications may help bring him to goal. An SGLT2 inhibitor may also benefit his BP and weight, both of which could be improved.

The FDA issued a warning in light of several case reports of DKA with unusually mild glucose elevations in patients taking an SGLT2 inhibitor.

Given the drugs he’s taking, drug interactions should not be an issue, and his renal function and pertinent labs (K, Phos, Mg) are within normal limits. Nevertheless, monitor these labs periodically and monitor Mr. S for adverse effects, such as UTIs, although these are more common in women. Canagliflozin is the preferred SGLT2 inhibitor on his insurance formulary, so you could initiate therapy at 100 mg/d, administered prior to the first meal, and increase to 300 mg/d if needed. As an alternative, consider prescribing the metformin/canagliflozin combination agent.

CASE 2 › Ms. R is likely experiencing a yeast infection as an adverse effect of the dapagliflozin. Although one yeast infection is insufficient grounds for discontinuation of the drug, recurrent infections should prompt a risk-to-benefit analysis to determine whether it’s worth continuing the medication. Her recent eGFR (<60 mL/min/1.73 m²) is, however, a contraindication to dapagliflozin, and therapy should be discontinued. Canagliflozin and empagliflozin may be considered since her eGFR is >45 mL/min/1.73 m², but given her current HbA1c and recent adverse drug event, alternative therapies, such as basal insulin, are more appropriate treatment choices.

CORRESPONDENCE
Katelin M. Lisenby, PharmD, BCPS, University of Alabama College of Community Health Sciences, University Medical Center, Box 870374, Tuscaloosa, AL 35487; [email protected].

CASE 1 › Joe S is a 41-year-old African-American man who comes to your clinic after his employee health screening revealed elevated triglycerides. The patient has a 3-year history of type 2 diabetes mellitus (T2DM); he also has a history of hypertension, gastroesophageal reflux disease, and obstructive sleep apnea. Mr. S tells you he takes metformin 1000 mg twice daily, but stopped taking his glipizide because he didn’t think it was helping his blood sugar. His last hemoglobin (Hb) A1c result was 8.8%, and he is very resistant to starting insulin therapy.

The patient’s other medications include enalapril 10 mg/d, atorvastatin 10 mg/d, and omeprazole 20 mg/d. Mr. S weighs 255.6 lbs (body mass index=34.7), his BP is 140/88 mm Hg, and his heart rate is 82 beats per minute. Laboratory values include: serum creatinine, 1.01 mg/dL; estimated glomerular filtration rate (eGFR) >100 mL/min/1.73 m²; potassium (K), 4.3 mmol/L; serum phosphorous (Phos), 2.8 mg/dL; magnesium (Mg), 1.9 mg/dL; total cholesterol, 167 mg/dL; low-density lipoprotein (LDL), 78 mg/dL; high-density lipoprotein (HDL), 38 mg/dL; and triglycerides, 256 mg/dL.

CASE 2  › Susan R, a 68-year-old Caucasian woman, returns to your clinic for a follow-up visit 3 months after you prescribed dapagliflozin 10 mg/d for her T2DM. Her glucose levels have improved, but she complains of vaginal pruritus and is worried that she has a yeast infection.

You diagnose vulvovaginal candidiasis in this patient and prescribe a single dose of fluconazole 150 mg. After reviewing her laboratory test results, you notice that since starting the dapagliflozin, her HbA1c level has improved slightly from 9.8% to 9.3%, but is still not where it needs to be. Her eGFR is 49 mL/min/1.73 m².

What would you recommend to improve control of these patients’ blood glucose levels?

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of agents to enter the T2DM management arena. They act in the proximal renal tubules to decrease the reabsorption of glucose by targeting the SGLT2 transmembrane protein, which reabsorbs about 90% of the body’s glucose.^1,2 The class is currently made up of 3 agents—canagliflozin, dapagliflozin, and empagliflozin—all of which are approved by the US Food and Drug Administration (FDA) for the treatment of T2DM (TABLE 1).²

The American Diabetes Association and the European Association for the Study of Diabetes published updated guidelines for T2DM management in 2015.¹ In addition to lifestyle modifications, the guidelines recommend the use of metformin as first-line therapy unless it is contraindicated or patients are unable to tolerate it (eg, because of gastrointestinal adverse effects). They recommend other pharmacologic therapies as second-line options based on specific patient characteristics. Thus, SGLT2 inhibitors may be used as add-on therapy after metformin, or as a first-line option if metformin is contraindicated or not tolerated. Because the mechanism of action of SGLT2 inhibitors is independent of insulin secretion, these agents may be used at any stage of the diabetes continuum.

SGLT2 agents as monotherapy, or as add-on therapy

All SGLT2 agents have been studied as monotherapy accompanied by diet and exercise and shown to produce HbA1c reductions of 0.34% to 1.11%.^3-6 In trials, the effect was similar regardless of study duration (18-104 weeks); generally, higher doses corresponded with larger HbA1c reductions.^3-6

Used as monotherapy, SGLT2 inhibitors produce HbA1c reductions of as much as 1.11%.

SGLT2 inhibitors have also been studied as add-on therapy to several oral agents including metformin, sulfonylureas, thiazolidinediones (TZDs), and the combination of metformin plus sulfonylureas or TZDs or dipeptidyl peptidase IV (DPP-IV) inhibitors.¹ When used in any of these combinations, each SGLT2 agent demonstrated a consistent HbA1c lowering effect of 0.62% to 1.19%.^7-14

Additionally, SGLT2 inhibitors have been studied in combination with insulin therapy (median or mean daily doses >60 units), which yielded further reductions in HbA1c of 0.58% to 1.02% without significant insulin adjustments or an increase in major hypoglycemia events.^15-17 Patients receiving insulin and an SGLT2 inhibitor had lower insulin doses and more weight loss compared to placebo groups.

SGLT2 inhibitors offer additional benefits

Secondary analyses of most studies of SGLT2 inhibitors include changes in BP and weight from baseline as well as minor changes (some positive, some not) in several lipid parameters.^{3-5,7-9,13-15,17-24} In general, these effects do not appear to be dose-dependent (with the exception of canagliflozin and its associated lipid effects²⁵) and are similar among the 3 medications.^{3-5,7-9,13-15,17-24} (For more on who would benefit from these agents, see “When to consider an SGLT2 inhibitor” above.)

BP reduction. Although the mean baseline BP was controlled in most studies, SGLT2 inhibitors have been shown to significantly reduce BP. Reductions in BP with all 3 SGLT2 medications range from approximately 2 to 5 mm Hg systolic and 0.5 to 2.5 mm Hg diastolic, which may be due to weight loss and diuresis.^{4-8,10-16,20-23} While the reductions were modest at best, one study involving empagliflozin reported that more than one-quarter of patients with uncontrolled BP at baseline achieved a BP <130/80 mm Hg 24 weeks later.⁵ While these agents should not be used solely for their BP lowering effects, they may help a small number of patients with mildly elevated BP achieve their goal without an additional antihypertensive agent.

Weight reduction. Modest weight loss, likely due to the loss of calories through urine, was seen with SGLT2 inhibitors in most studies, with reductions persisting beyond one year of use. In most studies, including those involving obese patients on insulin therapy,^15,17,21 patients’ body weights were reduced by approximately 2 to 4 kg from baseline.^{3-16,18,21-23,26}

Lipid effects. Although the mechanism is unclear, use of SGLT2 inhibitors can have varying effects on lipid panels. In most studies, total and LDL cholesterol levels were increased with elevations ranging from 0.7 to 10 mg/dL.^{3,7,8,18,19,22,23} Conversely, at least one study demonstrated mild reductions in total and LDL cholesterol levels with higher doses of empagliflozin.¹³ Additionally, modest reductions in triglycerides and increases in HDL across all doses of canagliflozin, dapagliflozin, and empagliflozin have been seen.^8,9,13,15,19 While the clinical relevance of these lipid changes is unknown, monitoring is recommended.²

These agents are well tolerated

SGLT2 inhibitors were generally well tolerated in studies. The most common adverse effects include mycotic infections (2.4%-21.6%) and urinary tract infections (UTIs) (4.0%-19.6%) (both with higher incidences in females); volume-related effects such as dizziness and hypotension (0.3%-8.3%); and nasopharyngitis (5.4%-18.3%).^{4-14,16-23,26-28} Hypoglycemia was observed more often when an SGLT2 inhibitor was used in combination with a sulfonylurea or insulin therapy.^{4-14,16-23,26-28} The number of times adverse events led to discontinuation was low and similar to that in control groups.^{4-14,16-23,26-28}

Mycotic and urinary infections should be diagnosed and treated according to current standards of care and do not require discontinuation of the SGLT2 inhibitor. Canagli-flozin therapy was associated with electrolyte abnormalities including hyperkalemia, hypermagnesemia, and hyperphosphatemia.²⁵ Thus, levels should be monitored periodically, especially in patients predisposed to elevations due to other conditions or medications.²⁵

Two additional warnings are worth noting

Diabetic ketoacidosis (DKA) has been reported with all 3 agents, and bone fractures have been reported with canagliflozin.

The FDA issued a warning in May 2015 regarding the increased risk of DKA with the use of SGLT2 inhibitor single and combination products.²⁹ This warning was prompted by several case reports of DKA with uncharacteristically mild to moderate glucose elevations in patients with type 1 diabetes mellitus (T1DM) and T2DM who were taking an SGLT2 inhibitor. The absence of significant hyperglycemia delayed diagnosis in many cases. Therefore, patients should be counseled on the signs and symptoms of DKA, as well as when to seek medical attention.

SGLT2 inhibitors can reduce BP by about 2 to 5 mm Hg, systolic, and 0.5 to 2.5 mm Hg, diastolic.

Patients with diabetes and symptoms of ketoacidosis (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, and fatigue) should be evaluated regardless of current blood glucose levels, and SGLT2 inhibitors should be discontinued if acidosis is confirmed. Identified potential triggers include illness, reduced food and fluid intake, reduced insulin dose, and history of alcohol intake. Use of SGLT2 inhibitors should be avoided in patients with T1DM until safety and efficacy are established in large randomized controlled trials. The European Medicines Agency announced that a thorough review of all currently approved SGLT2 agents is underway to evaluate the risk for DKA.³⁰

In addition, the FDA called for a revision of the label of canagliflozin to reflect a strengthened warning about an increased risk of bone fractures and decreased bone mineral density (BMD).³¹ Fractures can occur as early as 12 weeks after initiating treatment and with only minor trauma.³¹

Over a 2-year period, canagliflozin also significantly decreased BMD in the hip and lower spine compared to placebo.³¹ Patients should be evaluated for additional risk factors for fracture before taking canagliflozin.³¹ The FDA is continuing to evaluate whether the other approved SGLT2 inhibitors are associated with an increased risk for fractures.

Drug interactions: Proceed carefully with diuretics

The number of drugs that interact with SGLT2 inhibitors is minimal. Because these agents can cause volume-related effects such as hypotension, dizziness, and osmotic diuresis, patients—particularly the elderly and those with renal impairment—taking concomitant diuretics, especially loop diuretics, may be at increased risk for these effects and should be monitored accordingly.^2,25

Canagliflozin is primarily metabolized via glucuronidation by the uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes. Therefore, UGT enzyme inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir) decrease canagliflozin’s serum concentration. If a patient has an eGFR >60 mL/min/1.73 m² and is tolerating a dose of 100 mg/d, consider increasing the dose to 300 mg/d during concomitant treatment.

In addition, researchers have found that canagliflozin increases serum levels of digoxin by between 20% and 36%.²⁵ Experts suspect this occurs because canagliflozin inhibits P-glycoprotein efflux of digoxin. Although monitoring of digoxin levels is recommended, this interaction is considered to be minor.²⁵

Cost consideration: SGLT2 inhibitors are more expensive

The SGLT2 inhibitors are available only as brand name products and are more expensive than agents that have generic options (eg, metformin, sulfonylureas, TZDs). The average wholesale cost is approximately $400 for a 30-day supply of all SGLT2 agents.³² When considering an SGLT2 inhibitor, the patient should ideally have medication prescription coverage. Depending on the specific insurance plan, these agents are classified as tier 2 to 4, which is comparable to other oral brand name options.

Research looks at CV outcomes and cancer risk

Cardiovascular (CV) risk reduction. To date, only one study evaluating the effect of SGLT2 inhibitors on CV outcomes is complete.³³ Two large randomized controlled trials involving canagliflozin and dapagliflozin designed to evaluate treatment effects on major CV endpoints are ongoing.^34,35

In the EMPA-REG OUTCOME trial,³³ researchers found that empagliflozin had beneficial effects on CV outcomes, making it one of the only antidiabetic agents on the market to have such benefits. The study, which involved more than 7000 patients with a history of T2DM and existing cardiovascular disease (CVD), found that 10.5% of patients in the empagliflozin group vs 12.1% in the placebo group died from a CV cause or experienced a nonfatal myocardial infarction or stroke over a median of 3.1 years. Results were similar with both doses (10 mg vs 25 mg) of empagliflozin. The mechanisms behind the CV benefits are likely multifactorial and may be related to reductions in weight and BP,³³ but additional research is needed to fully elucidate the role of empagliflozin in this population.

Canagliflozin is being evaluated in the Canagliflozin Cardiovascular Assessment Study (CANVAS) for its effect on major CV events—CV death, nonfatal myocardial infarction, and nonfatal stroke—in patients with either a history of CVD or who are at increased risk of CVD and have uncontrolled diabetes.³⁴ The trial is expected to wrap up in June 2017.

And dapagliflozin is being studied in the DECLARE-TIMI 58 trial (the Effect of Dapagliflozin on the Incidence of Cardiovascular Events) in patients with T2DM and either known CVD or at least 2 risk factors for CVD.³⁵ The study is designed to assess dapagliflozin’s effect on the incidence of CV death, myocardial infarction, and ischemic stroke and has an estimated completion date of April 2019, which will provide a median follow-up of 4.5 years.

Cancer. All 3 agents have been examined for any possible carcinogenic links. In 2011, the FDA issued a request for further investigation surrounding the risk of cancer associated with dapagliflozin.³⁶ As of November 2013, 10 of 6045 patients treated with dapagliflozin developed bladder cancer compared to 1 of 3512 controls.³⁶ Furthermore, 9 of 2223 patients treated with dapagliflozin developed breast cancer compared to 1 of 1053 controls.³⁶

Although the trials were not designed to detect an increase in risk, the number of observed cases warranted further investigation. No official warning for breast cancer exists since the characteristics of the malignancies led the FDA to believe dapagliflozin was unlikely the cause.³⁶

When considering an SGLT2 inhibitor, the patient should ideally have medication prescription coverage.

Given what we know to date, it appears to be prudent to avoid prescribing SGLT2 inhibitors in patients with active bladder cancer, and to use them with caution in those with a history of the disease.²

Other studies. Initially, animal studies suggested an increased risk of various malignancies associated with canagliflozin use in rats,³⁷ but consistent results were not seen in human studies. Similarly, at least one study found that empagliflozin was associated with lung cancer and melanoma, but closer examination found that most patients who developed these cancers had risk factors.³⁸ Large, long-term studies of these agents in various populations are needed to thoroughly investigate possible carcinogenicity.

Additional considerations: Kidney function, age, and pregnancy

Consider avoiding SGLT2 inhibitors in patients with moderate kidney dysfunction (eGFR 30-59 mL/min/1.73 m²). Studies have shown that SGLT2 inhibitors are not as effective at lowering blood glucose in those with reduced eGFR, although adverse events were similar to those in placebo groups.^24,39,40 Dapagliflozin is not recommended in patients with an eGFR <60 mL/min/1.73 m² due to lack of efficacy.^2,24 Empagliflozin does not require dose adjustments if eGFR is ≥45 mL/min/1.73 m². A lower dose of canagliflozin (ie, 100 mg/d) is recommended in those with an eGFR of 45 to 59 mL/min/1.73 m².² All agents are contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²).

Older patients are at higher risk for dehydration, hypotension, and falls; therefore, SGLT2 inhibitors should be used with caution in this population. Similarly, they should not be used in patients with T1DM and should be avoided in those with active, or a history of, DKA.

There are no data on the use of SGLT2 inhibitors in pregnancy; thus, these agents should be avoided unless the potential benefits outweigh the potential risks to the unborn fetus.²

CASE 1 › An SGLT2 inhibitor is an acceptable option for Mr. S. Because he is resistant to starting insulin therapy and his HbA1c is <9%, an additional oral medication is reasonable. Adding an SGLT2 inhibitor may reduce his HbA1c up to ~1%, and education on lifestyle modifications may help bring him to goal. An SGLT2 inhibitor may also benefit his BP and weight, both of which could be improved.

The FDA issued a warning in light of several case reports of DKA with unusually mild glucose elevations in patients taking an SGLT2 inhibitor.

Given the drugs he’s taking, drug interactions should not be an issue, and his renal function and pertinent labs (K, Phos, Mg) are within normal limits. Nevertheless, monitor these labs periodically and monitor Mr. S for adverse effects, such as UTIs, although these are more common in women. Canagliflozin is the preferred SGLT2 inhibitor on his insurance formulary, so you could initiate therapy at 100 mg/d, administered prior to the first meal, and increase to 300 mg/d if needed. As an alternative, consider prescribing the metformin/canagliflozin combination agent.

CASE 2 › Ms. R is likely experiencing a yeast infection as an adverse effect of the dapagliflozin. Although one yeast infection is insufficient grounds for discontinuation of the drug, recurrent infections should prompt a risk-to-benefit analysis to determine whether it’s worth continuing the medication. Her recent eGFR (<60 mL/min/1.73 m²) is, however, a contraindication to dapagliflozin, and therapy should be discontinued. Canagliflozin and empagliflozin may be considered since her eGFR is >45 mL/min/1.73 m², but given her current HbA1c and recent adverse drug event, alternative therapies, such as basal insulin, are more appropriate treatment choices.

CORRESPONDENCE
Katelin M. Lisenby, PharmD, BCPS, University of Alabama College of Community Health Sciences, University Medical Center, Box 870374, Tuscaloosa, AL 35487; [email protected].

The care of people with pain has been wrought with ineffective and unnecessary treatment, including the misuse of opioids, largely because we do not have an accurate conceptualization of pain. The absence of animal and human models of central nervous system (CNS) pain processing ensures that our understanding of pain will remain incomplete for the foreseeable future, but enough evidence exists to help family physicians develop an understanding of pain that goes beyond what we learned in medical school and that can help us more effectively treat patients with pain.

In this review, we will briefly discuss the established concepts of nociceptive and neuropathic pain. And then, with those concepts in mind, we will explore a third type of pain that for lack of a better term, we will call “pain for psychological reasons.” We hypothesize that this pain may be the consequence of changes in nervous system function that arise from developmental trauma, other traumatic experiences in a patient’s life, or mental health disorders. It is this third type of pain that may offer us insights into conditions such as fibromyalgia.

While we do not yet have validated diagnostic criteria for this third type of pain, we believe that there is enough information to present initial criteria so that one may distinguish it from nociceptive and neuropathic pain.

Nociceptive and neuropathic pain: The current paradigm

Nociceptive pain. The sensory pain experience, or nociceptive pain, is produced by noxious stimuli that either damage, or are capable of damaging, tissues (eg, burns, cuts, fractures, inflammation, and increased pressure in a hollow viscus). Noxious stimuli are detected at the molecular level by specific pain sensory receptors embedded in our tissues called nociceptors.

The process by which noxious stimuli lead to the experience of sensory pain consists of 4 steps—transduction, transmission, modulation, and perception—which are described in “From periphery to brain: The process of nociceptive pain.”^1-4

Neuropathic pain. While nociceptive pain can be easily traced from a peripheral nociceptive fiber to the brain and typically resolves when the nociceptive stimulus stops, neuropathic pain (NPP) results from changes to the function of the nervous system and is typically caused by injury to the nerves. Such changes, referred to as neuronal sensitization, may not quickly resolve, as is the case with postherpetic neuralgia. In fact, the changes can become permanent. NPP fundamentally differs from nociceptive pain because it results from changes in the central processing of pain that can lead a person to perceive pain sensations even in the absence of tissue pathology.

This third type of pain may be the consequence of changes in nervous system function that arise from developmental trauma, other traumatic experiences in a patient's life, or mental health disorders.

Common causes of NPP that persists even after tissue damage has healed include trauma (eg, amputation of a limb), ischemia (eg, pressure palsy), disease (eg, the metabolic injury of diabetes or the injury caused by a shingles infection), and drug treatment (eg, chemotherapy). The underlying mechanisms of NPP and the neuronal plasticity (the ability of the nervous system to rewire itself) that initiate and then maintain NPP are important areas of active research that may eventually lead to the development of more effective treatments.

Timing is critical. Neuroplastic changes in the nervous system following nerve injury are time-dependent. Synaptic plasticity can occur within seconds to minutes, while cellular plasticity occurs within hours to days. Synaptic and cellular plasticity happen relatively fast and may be reversible.

In contrast, systems plasticity (when new CNS neuronal connections are formed in response to nerve injury) takes place over the months and years following nerve injury and is often irreversible. When we recognize NPP and intervene before system neuroplastic changes occur, it may be possible to prevent pain from becoming chronic (TABLE 1⁵). In cases of nerve injury, researchers have long suspected that early and aggressive pain treatment within the first few months that may include sympathetic and peripheral neural blockade reduces the likelihood that the patient will have chronic pain.^6,7

It’s time to update our understanding of pain

The International Association for the Study of Pain (IASP)—a group of health care providers, scientists, and policymakers seeking to improve pain relief worldwide—notes in its definition of pain that the complaint, “I hurt” does not necessarily imply that there is a painful stimulus in the form of tissue injury.⁸ Yet most of us have been taught to think of pain solely as the result of tissue pathology, and we assume that emotional factors merely modify how the physical damage is perceived. This traditional concept of pain is incomplete. It leads clinicians to misdiagnose the cause of pain, initiate expensive and unnecessary treatment, engage in well-meaning but misguided prescribing behavior, and miss opportunities to help patients.

Pain in the absence of any pathophysiologic cause or injury

The clinician’s search for a pain diagnosis is typically predicated on the notion that there must be an underlying tissue injury of severity equal to the severity of the patient’s pain complaints. This approach to a pain evaluation rests on 2 assumptions that are not true for all patients:

1. Pain is simply a sensory experience that is always caused by tissue damage of some type.
2. The severity of the pain experienced by a patient should be tightly bound to the severity of the pain stimulus (ie, tissue damage).

These assumptions are true of acute nociceptive pain, they may or may not be true for NPP, but they do not apply to the third type of pain—pain for psychological reasons. While tissue pathology in humans and animals with nociceptive pain is usually visible, measurable, and correlates with observed pain behaviors, the damage to nerve tissue and the ensuing changes in nervous system function with NPP are not always visible or able to be imaged. These changes produce pain that can appear more severe than expected based on a brief exam. Some of the time, however, characteristic symptoms and physical signs of NPP will be present, and perhaps electrodiagnostic or other tests will be abnormal, thus providing some objective sense of changes in nervous system function.

In contrast, pain behavior due to the third type of pain usually appears very much out of proportion, and unbound to, tissue pathology. Furthermore, the patient’s pain behaviors often reflect heightened emotional pain processing (TABLE 2⁹). The resulting emotionally charged presentation can be alarming and suggestive of extreme tissue injury, but there may be absolutely no evidence of tissue injury or pathology.

Functional change in the CNS

There is evidence from experimental studies that psychologic factors change nervous system function. In one review, the authors concluded, “Pain…can vary widely between people and even within an individual depending on…the psychological state of the person.”¹⁰ In a second review, the authors concluded that our emotional state has an enormous influence on pain; a negative emotional state increases pain, whereas a positive state lowers pain.¹¹

But can psychological factors induce long-term changes in nervous system function analogous to the systems neuroplasticity responsible for irreversible changes in NPP? And can psychologically induced changes in nervous system sensory processing lead to pain without any tissue or nerve damage?

We theorize that a functional change in the CNS can occur in response to certain emotional states or traumatic experiences (eg, child abuse, assault, accidents). (More on this in a bit.) When such changes occur, mildly painful stimuli are amplified and processed through overly sensitized, dysregulated, ramped-up emotional and somatosensory pain circuits in the brain. This is analogous to the functional changes in the nervous system that occur with NPP; however, when the nervous system changes are due to psychological factors, there may be no tissue or nerve injury.

Childhood trauma influences adult pain. One of the more compelling narratives emerging in health care has to do with the influence that childhood developmental trauma can have on health, including pain. In his chapter on the impact of early life trauma on health and disease, Lanius states:¹²

“Women were 50% more likely than men to have experienced 5 or more categories of adverse childhood experiences. We believe that here is a key to what in mainstream epidemiology appears as women’s natural proneness to ill-defined health problems like fibromyalgia, chronic fatigue syndrome, obesity, irritable bowel syndrome, and chronic non-malignant pain syndromes. In light of our findings, we now see these as medical constructs, artifacts resulting from medical blindness to social realities and ignorance of the impact of gender.”

Brain activity in response to emotional insult mimics physical pain, and it is difficult to tell from images of brain activity whether a person is experiencing one or the other.

Lanius¹² suggests that adverse childhood experiences¹³ (trauma such as abuse and sexual assault) can lead to long-term changes within the nervous system, including areas of pain processing. My coauthor and I describe these changes here in terms of nervous system sensitization or dysregulation, and we believe that these changes lead to a bias toward hyperactivation of emotional pain circuits, which leads to the emotionally laden pain behaviors that often seem out of proportion to tissue pathology.

The care of people with pain has been wrought with ineffective and unnecessary treatment, including the misuse of opioids, largely because we do not have an accurate conceptualization of pain. The absence of animal and human models of central nervous system (CNS) pain processing ensures that our understanding of pain will remain incomplete for the foreseeable future, but enough evidence exists to help family physicians develop an understanding of pain that goes beyond what we learned in medical school and that can help us more effectively treat patients with pain.

In this review, we will briefly discuss the established concepts of nociceptive and neuropathic pain. And then, with those concepts in mind, we will explore a third type of pain that for lack of a better term, we will call “pain for psychological reasons.” We hypothesize that this pain may be the consequence of changes in nervous system function that arise from developmental trauma, other traumatic experiences in a patient’s life, or mental health disorders. It is this third type of pain that may offer us insights into conditions such as fibromyalgia.

While we do not yet have validated diagnostic criteria for this third type of pain, we believe that there is enough information to present initial criteria so that one may distinguish it from nociceptive and neuropathic pain.

Nociceptive and neuropathic pain: The current paradigm

Nociceptive pain. The sensory pain experience, or nociceptive pain, is produced by noxious stimuli that either damage, or are capable of damaging, tissues (eg, burns, cuts, fractures, inflammation, and increased pressure in a hollow viscus). Noxious stimuli are detected at the molecular level by specific pain sensory receptors embedded in our tissues called nociceptors.

The process by which noxious stimuli lead to the experience of sensory pain consists of 4 steps—transduction, transmission, modulation, and perception—which are described in “From periphery to brain: The process of nociceptive pain.”^1-4

Neuropathic pain. While nociceptive pain can be easily traced from a peripheral nociceptive fiber to the brain and typically resolves when the nociceptive stimulus stops, neuropathic pain (NPP) results from changes to the function of the nervous system and is typically caused by injury to the nerves. Such changes, referred to as neuronal sensitization, may not quickly resolve, as is the case with postherpetic neuralgia. In fact, the changes can become permanent. NPP fundamentally differs from nociceptive pain because it results from changes in the central processing of pain that can lead a person to perceive pain sensations even in the absence of tissue pathology.

This third type of pain may be the consequence of changes in nervous system function that arise from developmental trauma, other traumatic experiences in a patient's life, or mental health disorders.

Common causes of NPP that persists even after tissue damage has healed include trauma (eg, amputation of a limb), ischemia (eg, pressure palsy), disease (eg, the metabolic injury of diabetes or the injury caused by a shingles infection), and drug treatment (eg, chemotherapy). The underlying mechanisms of NPP and the neuronal plasticity (the ability of the nervous system to rewire itself) that initiate and then maintain NPP are important areas of active research that may eventually lead to the development of more effective treatments.

Timing is critical. Neuroplastic changes in the nervous system following nerve injury are time-dependent. Synaptic plasticity can occur within seconds to minutes, while cellular plasticity occurs within hours to days. Synaptic and cellular plasticity happen relatively fast and may be reversible.

In contrast, systems plasticity (when new CNS neuronal connections are formed in response to nerve injury) takes place over the months and years following nerve injury and is often irreversible. When we recognize NPP and intervene before system neuroplastic changes occur, it may be possible to prevent pain from becoming chronic (TABLE 1⁵). In cases of nerve injury, researchers have long suspected that early and aggressive pain treatment within the first few months that may include sympathetic and peripheral neural blockade reduces the likelihood that the patient will have chronic pain.^6,7

It’s time to update our understanding of pain

The International Association for the Study of Pain (IASP)—a group of health care providers, scientists, and policymakers seeking to improve pain relief worldwide—notes in its definition of pain that the complaint, “I hurt” does not necessarily imply that there is a painful stimulus in the form of tissue injury.⁸ Yet most of us have been taught to think of pain solely as the result of tissue pathology, and we assume that emotional factors merely modify how the physical damage is perceived. This traditional concept of pain is incomplete. It leads clinicians to misdiagnose the cause of pain, initiate expensive and unnecessary treatment, engage in well-meaning but misguided prescribing behavior, and miss opportunities to help patients.

Pain in the absence of any pathophysiologic cause or injury

The clinician’s search for a pain diagnosis is typically predicated on the notion that there must be an underlying tissue injury of severity equal to the severity of the patient’s pain complaints. This approach to a pain evaluation rests on 2 assumptions that are not true for all patients:

1. Pain is simply a sensory experience that is always caused by tissue damage of some type.
2. The severity of the pain experienced by a patient should be tightly bound to the severity of the pain stimulus (ie, tissue damage).

These assumptions are true of acute nociceptive pain, they may or may not be true for NPP, but they do not apply to the third type of pain—pain for psychological reasons. While tissue pathology in humans and animals with nociceptive pain is usually visible, measurable, and correlates with observed pain behaviors, the damage to nerve tissue and the ensuing changes in nervous system function with NPP are not always visible or able to be imaged. These changes produce pain that can appear more severe than expected based on a brief exam. Some of the time, however, characteristic symptoms and physical signs of NPP will be present, and perhaps electrodiagnostic or other tests will be abnormal, thus providing some objective sense of changes in nervous system function.

In contrast, pain behavior due to the third type of pain usually appears very much out of proportion, and unbound to, tissue pathology. Furthermore, the patient’s pain behaviors often reflect heightened emotional pain processing (TABLE 2⁹). The resulting emotionally charged presentation can be alarming and suggestive of extreme tissue injury, but there may be absolutely no evidence of tissue injury or pathology.

Functional change in the CNS

There is evidence from experimental studies that psychologic factors change nervous system function. In one review, the authors concluded, “Pain…can vary widely between people and even within an individual depending on…the psychological state of the person.”¹⁰ In a second review, the authors concluded that our emotional state has an enormous influence on pain; a negative emotional state increases pain, whereas a positive state lowers pain.¹¹

But can psychological factors induce long-term changes in nervous system function analogous to the systems neuroplasticity responsible for irreversible changes in NPP? And can psychologically induced changes in nervous system sensory processing lead to pain without any tissue or nerve damage?

We theorize that a functional change in the CNS can occur in response to certain emotional states or traumatic experiences (eg, child abuse, assault, accidents). (More on this in a bit.) When such changes occur, mildly painful stimuli are amplified and processed through overly sensitized, dysregulated, ramped-up emotional and somatosensory pain circuits in the brain. This is analogous to the functional changes in the nervous system that occur with NPP; however, when the nervous system changes are due to psychological factors, there may be no tissue or nerve injury.

Childhood trauma influences adult pain. One of the more compelling narratives emerging in health care has to do with the influence that childhood developmental trauma can have on health, including pain. In his chapter on the impact of early life trauma on health and disease, Lanius states:¹²

“Women were 50% more likely than men to have experienced 5 or more categories of adverse childhood experiences. We believe that here is a key to what in mainstream epidemiology appears as women’s natural proneness to ill-defined health problems like fibromyalgia, chronic fatigue syndrome, obesity, irritable bowel syndrome, and chronic non-malignant pain syndromes. In light of our findings, we now see these as medical constructs, artifacts resulting from medical blindness to social realities and ignorance of the impact of gender.”

Brain activity in response to emotional insult mimics physical pain, and it is difficult to tell from images of brain activity whether a person is experiencing one or the other.

Lanius¹² suggests that adverse childhood experiences¹³ (trauma such as abuse and sexual assault) can lead to long-term changes within the nervous system, including areas of pain processing. My coauthor and I describe these changes here in terms of nervous system sensitization or dysregulation, and we believe that these changes lead to a bias toward hyperactivation of emotional pain circuits, which leads to the emotionally laden pain behaviors that often seem out of proportion to tissue pathology.

The care of people with pain has been wrought with ineffective and unnecessary treatment, including the misuse of opioids, largely because we do not have an accurate conceptualization of pain. The absence of animal and human models of central nervous system (CNS) pain processing ensures that our understanding of pain will remain incomplete for the foreseeable future, but enough evidence exists to help family physicians develop an understanding of pain that goes beyond what we learned in medical school and that can help us more effectively treat patients with pain.

In this review, we will briefly discuss the established concepts of nociceptive and neuropathic pain. And then, with those concepts in mind, we will explore a third type of pain that for lack of a better term, we will call “pain for psychological reasons.” We hypothesize that this pain may be the consequence of changes in nervous system function that arise from developmental trauma, other traumatic experiences in a patient’s life, or mental health disorders. It is this third type of pain that may offer us insights into conditions such as fibromyalgia.

While we do not yet have validated diagnostic criteria for this third type of pain, we believe that there is enough information to present initial criteria so that one may distinguish it from nociceptive and neuropathic pain.

Nociceptive and neuropathic pain: The current paradigm

Nociceptive pain. The sensory pain experience, or nociceptive pain, is produced by noxious stimuli that either damage, or are capable of damaging, tissues (eg, burns, cuts, fractures, inflammation, and increased pressure in a hollow viscus). Noxious stimuli are detected at the molecular level by specific pain sensory receptors embedded in our tissues called nociceptors.

The process by which noxious stimuli lead to the experience of sensory pain consists of 4 steps—transduction, transmission, modulation, and perception—which are described in “From periphery to brain: The process of nociceptive pain.”^1-4

Neuropathic pain. While nociceptive pain can be easily traced from a peripheral nociceptive fiber to the brain and typically resolves when the nociceptive stimulus stops, neuropathic pain (NPP) results from changes to the function of the nervous system and is typically caused by injury to the nerves. Such changes, referred to as neuronal sensitization, may not quickly resolve, as is the case with postherpetic neuralgia. In fact, the changes can become permanent. NPP fundamentally differs from nociceptive pain because it results from changes in the central processing of pain that can lead a person to perceive pain sensations even in the absence of tissue pathology.

This third type of pain may be the consequence of changes in nervous system function that arise from developmental trauma, other traumatic experiences in a patient's life, or mental health disorders.

Common causes of NPP that persists even after tissue damage has healed include trauma (eg, amputation of a limb), ischemia (eg, pressure palsy), disease (eg, the metabolic injury of diabetes or the injury caused by a shingles infection), and drug treatment (eg, chemotherapy). The underlying mechanisms of NPP and the neuronal plasticity (the ability of the nervous system to rewire itself) that initiate and then maintain NPP are important areas of active research that may eventually lead to the development of more effective treatments.

Timing is critical. Neuroplastic changes in the nervous system following nerve injury are time-dependent. Synaptic plasticity can occur within seconds to minutes, while cellular plasticity occurs within hours to days. Synaptic and cellular plasticity happen relatively fast and may be reversible.

In contrast, systems plasticity (when new CNS neuronal connections are formed in response to nerve injury) takes place over the months and years following nerve injury and is often irreversible. When we recognize NPP and intervene before system neuroplastic changes occur, it may be possible to prevent pain from becoming chronic (TABLE 1⁵). In cases of nerve injury, researchers have long suspected that early and aggressive pain treatment within the first few months that may include sympathetic and peripheral neural blockade reduces the likelihood that the patient will have chronic pain.^6,7

It’s time to update our understanding of pain

The International Association for the Study of Pain (IASP)—a group of health care providers, scientists, and policymakers seeking to improve pain relief worldwide—notes in its definition of pain that the complaint, “I hurt” does not necessarily imply that there is a painful stimulus in the form of tissue injury.⁸ Yet most of us have been taught to think of pain solely as the result of tissue pathology, and we assume that emotional factors merely modify how the physical damage is perceived. This traditional concept of pain is incomplete. It leads clinicians to misdiagnose the cause of pain, initiate expensive and unnecessary treatment, engage in well-meaning but misguided prescribing behavior, and miss opportunities to help patients.

Pain in the absence of any pathophysiologic cause or injury

The clinician’s search for a pain diagnosis is typically predicated on the notion that there must be an underlying tissue injury of severity equal to the severity of the patient’s pain complaints. This approach to a pain evaluation rests on 2 assumptions that are not true for all patients:

1. Pain is simply a sensory experience that is always caused by tissue damage of some type.
2. The severity of the pain experienced by a patient should be tightly bound to the severity of the pain stimulus (ie, tissue damage).

These assumptions are true of acute nociceptive pain, they may or may not be true for NPP, but they do not apply to the third type of pain—pain for psychological reasons. While tissue pathology in humans and animals with nociceptive pain is usually visible, measurable, and correlates with observed pain behaviors, the damage to nerve tissue and the ensuing changes in nervous system function with NPP are not always visible or able to be imaged. These changes produce pain that can appear more severe than expected based on a brief exam. Some of the time, however, characteristic symptoms and physical signs of NPP will be present, and perhaps electrodiagnostic or other tests will be abnormal, thus providing some objective sense of changes in nervous system function.

In contrast, pain behavior due to the third type of pain usually appears very much out of proportion, and unbound to, tissue pathology. Furthermore, the patient’s pain behaviors often reflect heightened emotional pain processing (TABLE 2⁹). The resulting emotionally charged presentation can be alarming and suggestive of extreme tissue injury, but there may be absolutely no evidence of tissue injury or pathology.

Functional change in the CNS

There is evidence from experimental studies that psychologic factors change nervous system function. In one review, the authors concluded, “Pain…can vary widely between people and even within an individual depending on…the psychological state of the person.”¹⁰ In a second review, the authors concluded that our emotional state has an enormous influence on pain; a negative emotional state increases pain, whereas a positive state lowers pain.¹¹

But can psychological factors induce long-term changes in nervous system function analogous to the systems neuroplasticity responsible for irreversible changes in NPP? And can psychologically induced changes in nervous system sensory processing lead to pain without any tissue or nerve damage?

We theorize that a functional change in the CNS can occur in response to certain emotional states or traumatic experiences (eg, child abuse, assault, accidents). (More on this in a bit.) When such changes occur, mildly painful stimuli are amplified and processed through overly sensitized, dysregulated, ramped-up emotional and somatosensory pain circuits in the brain. This is analogous to the functional changes in the nervous system that occur with NPP; however, when the nervous system changes are due to psychological factors, there may be no tissue or nerve injury.

Childhood trauma influences adult pain. One of the more compelling narratives emerging in health care has to do with the influence that childhood developmental trauma can have on health, including pain. In his chapter on the impact of early life trauma on health and disease, Lanius states:¹²

“Women were 50% more likely than men to have experienced 5 or more categories of adverse childhood experiences. We believe that here is a key to what in mainstream epidemiology appears as women’s natural proneness to ill-defined health problems like fibromyalgia, chronic fatigue syndrome, obesity, irritable bowel syndrome, and chronic non-malignant pain syndromes. In light of our findings, we now see these as medical constructs, artifacts resulting from medical blindness to social realities and ignorance of the impact of gender.”

Brain activity in response to emotional insult mimics physical pain, and it is difficult to tell from images of brain activity whether a person is experiencing one or the other.

Lanius¹² suggests that adverse childhood experiences¹³ (trauma such as abuse and sexual assault) can lead to long-term changes within the nervous system, including areas of pain processing. My coauthor and I describe these changes here in terms of nervous system sensitization or dysregulation, and we believe that these changes lead to a bias toward hyperactivation of emotional pain circuits, which leads to the emotionally laden pain behaviors that often seem out of proportion to tissue pathology.

A 40-year-old woman with hypertrophic   obstructive cardiomyopathy presents to the hematology clinic for a second opinion regarding a history of headaches and fatigue for the past 10 years. She has been diagnosed with idiopathic erythrocytosis, presumed to be due to polycythemia vera. She periodically undergoes phlebotomy to keep her hematocrit below 41%, and this markedly improves her headaches. She denies shortness of breath, cough, fever, weight loss, joint pain, and visual or other neurologic symptoms. She has never reported pruritus related to bathing or exposure to water.

She does not smoke, drink alcohol, or use illicit drugs. She works as a pharmacy technician. She says her father died of cancer (no further details available) and describes a family history of gastrointestinal malignancy in her grandfather and paternal aunt. She takes aspirin, metoprolol, and spironolactone for her cardiomyopathy.

Physical examination reveals generalized plethora, more marked on her cheeks and face, and mild bilateral pitting pedal edema. No lymphadenopathy or hepatosplenomegaly can be palpated. Other systems, including the cardiac, respiratory, and nervous systems, are normal.

ERYTHROCYTOSIS AND POLYCYTHEMIA VERA

1. In patients with erythrocytosis, which of the following is not characteristic of polycythemia vera?

• Erythromelalgia and postbathing pruritus
• Splenomegaly
• History of thrombosis
• Gout
• Hematuria

Erythrocytosis—an abnormally high concentration of red blood cells in the peripheral blood—is a laboratory finding. It often reflects an increase in the total quantity or mass of red blood cells in the body (polycythemia) but can sometimes be due to decreased plasma volume (spurious polycythemia).¹ Erythrocytosis can be caused by a number of diseases, hereditary and acquired, and can be classified as primary or secondary (Table 1).

Symptoms arise from an increase in the total blood volume and red blood cell mass, often leading to dilated capillaries and other blood vessels. Symptoms can occur regardless of the cause and classically include headache (often described as diffuse heaviness), dizziness, and a tendency for bleeding or thrombosis.² Symptoms are relieved when the hematocrit is lowered.

Several features in the history and physical examination of a patient being evaluated for erythrocytosis can suggest an underlying cause. Smoking, chronic respiratory insufficiency, and congenital cyanotic heart disease point to secondary erythrocytosis and can usually be identified at the outset. A history of occupational exposure to carbon monoxide (such as engine exhaust) should be elicited carefully. A family history of erythrocytosis should raise suspicion of a heritable condition such as a hemoglobinopathy associated with increased oxygen affinity or rare forms of primary erythrocytosis associated with endogenous overproduction of erythropoietin or activating mutations of the erythropoietin receptor.³ Iatrogenic causes such as androgen supplementation, erythropoietin abuse, and postrenal-transplant erythrocytosis should also be considered.

Secretion of erythropoietin or erythropoietinlike proteins by a malignant neoplasm is a rare but important cause of erythrocytosis. For example, renal cell carcinoma may present with erythrocytosis secondary to excessive erythropoietin production, and hematuria can be an early symptom.

Polycythemia vera

Polycythemia vera, a myeloproliferative neoplasm, is characterized by increased red blood cell production independent of the mechanisms that normally regulate erythropoiesis. The bone marrow shows a panmyelosis that is often accompanied by leukocytosis or thrombocytosis, or both, in the peripheral blood.

Symptoms such as severe itching after exposure to hot water (aquagenic pruritus) and periodic attacks of redness, swelling, and pain in the hands or feet, or both (erythromelalgia), have been described in patients with polycythemia vera. Splenomegaly is relatively common, seen in approximately two-thirds of patients.⁴ Hyperuricemia (from increased cell turnover) and gout are also associated with polycythemia vera, as is a history of arterial and venous thrombosis.⁵

Hematuria is not commonly seen in polycythemia vera, although bleeding from the bladder, vagina, or uterus has been described.

CASE RESUMED: INITIAL LABORATORY TESTS

Results of our patient’s initial laboratory tests are:

• Hemoglobin 16.9 g/dL (reference range 11.5–15.5)
• Hematocrit 48.8% (36.0–46.0)
• Mean corpuscular volume 85.2 fL (80–100)
• Platelet count 328 × 10⁹/L (150–400)
• White blood cell count 9.14 × 10⁹/L (3.7–11.0)
• Absolute neutrophil count 5.95 × 10⁹/L (1.45–7.5)
• Blood urea nitrogen 12 mg/dL (8–25)
• Creatinine 0.5 mg/dL (0.7–1.4)
• Lactate dehydrogenase 180 U/L (100–220)
• Uric acid 3.0 mg/dL (2.0–7.0)
• Thyroid-stimulating hormone 2.2 µU/mL (0.4–5.5).

The patient undergoes additional tests, including a serum erythropoietin level and hemoglobinopathy screen. Bone marrow aspiration and biopsy are performed, with cytogenetic analysis, chromosomal microarray analysis, and molecular testing for mutation of the Janus kinase 2 (JAK2) gene.

CONFIRMING SUSPECTED POLYCYTHEMIA VERA

2. In patients with suspected polycythemia vera, which of the following laboratory tests is most useful in making the diagnosis?

• Hemoglobin, hematocrit, and red blood cell mass
• Serum erythropoietin level
• Arterial blood gases with co-oximetry
• Testing for the JAK2 mutation
• Bone marrow aspiration and biopsy

The aim of the initial workup of erythrocytosis is to differentiate polycythemia vera from secondary causes of erythrocytosis.

Hemoglobin, hematocrit, red cell mass

Erythrocytosis is defined by an abnormal elevation in the hematocrit (> 48% in women or > 49% in men), hemoglobin concentration (> 16.0 g/dL in women or > 16.5 g/dL in men), or red blood cell mass. The red blood cell count should not be used as a surrogate for red blood cell mass, since some anemias (especially thalassemia minor) can be associated with an increase in the number of red blood cells but a low hemoglobin concentration.

Isotope dilution techniques to determine the red cell mass and plasma volume can differentiate true erythrocytosis from a spurious elevation due to a decrease in plasma volume.^6,7 However, this is an expensive, time-consuming test that is not widely available and so is rarely performed.⁸

JAK2 mutation testing

The initial evaluation of a patient with erythrocytosis has changed significantly in the past 10 years with the discovery of the JAK2 gene and its role in the pathogenesis of polycythemia vera and other myeloproliferative neoplasms.

JAK2, located at 9p24, codes for a tyrosine kinase important for signal transduction in hematopoietic cells. Mutations in this gene have been shown to promote hypersensitivity to cytokines, including erythropoietin.⁹ The most common somatic mutation occurs within exon 14 at base pair 1849 and results in a phenylalanine-for-valine amino acid substitution in the JAK2 protein, designated V617F. Less commonly, mutations occur elsewhere in exons 12 to 15, with more than 50 different mutations described; nonpolymorphic mutations are assumed to have biologic effects similar to those of V617F.

Taken together, the JAK2 V617F and non-V617F mutations have a diagnostic sensitivity of 98% to 100% for polycythemia vera. For practical purposes, this means that the presence of a JAK2 mutation can be used as a clonal marker to distinguish polycythemia vera from reactive secondary causes of erythrocytosis. A JAK2 mutation is one of three major diagnostic criteria for polycythemia vera in the 2016 revision to the 2008 World Health Organization criteria (Table 2).¹⁰ Of note, this mutation is not specific for polycythemia vera and can also be found in other myeloproliferative neoplasms, including primary myelofibrosis and essential thrombocythemia.

Absence of a JAK2 mutation makes polycythemia vera unlikely, so this test is most useful in making the diagnosis.

Serum erythropoietin

Serum erythropoietin testing can be very useful to distinguish polycythemia vera from secondary erythrocytosis. Low levels suggest polycythemia vera, while high levels are seen in secondary processes.¹¹

This test is best used along with JAK2 V617F mutation analysis as an initial step in evaluating patients with erythrocytosis. When JAK2 V617F mutation analysis is negative, a low serum erythropoietin level should prompt further testing for non-V617F JAK2 mutations, whereas a normal or elevated erythropoietin level should be evaluated further with tests to distinguish hereditary from acquired secondary causes of erythrocytosis.

Arterial blood gas analysis and co-oximetry

Arterial blood gas analysis can reveal hypoxemia, pointing to a cardiorespiratory process driving the erythrocytosis, whereas co-oximetry can be used to identify the presence and amount of carboxyhemoglobin in the blood.

Bone marrow biopsy

An increase in pleomorphic megakaryocytes in the bone marrow without stainable iron is often described as characteristic in polycythemia vera patients, but it is not diagnostic. Panmyelosis with increased cellularity is the norm but can be seen in other myeloproliferative neoplasms. The morphologic features of bone marrow are now included as one of the major diagnostic criteria for polycythemia vera (Table 2).

OUR PATIENT’S FURTHER WORKUP

Our patient’s erythropoietin level is 34.2 mIU/mL (reference range 4.7–28.6). Her oxygen saturation is 96%, and her carboxyhemoglobin level is 1.1% (0–5).

She undergoes bone marrow biopsy. Analysis finds that the marrow is normocellular (60%) with trilineage hematopoiesis and decreased stainable iron.

Cytogenetic analysis shows a 46,XX[20] karyotype. Chromosomal microarray analysis shows no pathogenic copy-number changes. There is no detectable JAK2 V617F or exon 12-to-15 mutation.

The patient’s erythrocytosis and abnormal hemoglobin electrophoresis study raise suspicion for a variant type of hemoglobin that has a higher affinity for oxygen than normal.

3. What is the next best step to evaluate this patient?

• Red-cell oxygen equilibrium curve to calculate the P50 (the partial pressure of oxygen that is required to saturate 50% of the hemoglobin.)
• High-performance liquid chromatography
• Globin gene DNA sequencing
• Testing 2,3-bisphosphoglycerate mutase (BPGM) activity

Nearly 200 mutational variants in alpha and beta globin chains that lead to an increased affinity of hemoglobin for oxygen have been reported.¹² While not all mutations are clinically significant, increased oxygen affinity variants can lead to impaired oxygen delivery to tissues, especially the kidneys, resulting in a physiologic increase in erythropoietin and erythrocytosis.

In patients being evaluated for a high-oxygen-affinity hemoglobinopathy, a two-step approach has been outlined.¹³ The first involves measuring the oxygen-binding properties of a freshly collected sample of blood by directly measuring the oxygen saturation of the hemoglobin and pO₂ using a co-oximeter. This information is used to create a red cell oxygen equilibrium curve and to calculate the P50. A low P50 correlates with an abnormally high affinity of hemoglobin for oxygen.

The second step is to identify the abnormal hemoglobin. High-performance liquid chromatography is now widely available as a screening test but does not detect all variants. For many years, sequencing of globin chain DNA has been a gold standard for identifying specific mutations. Subsequent to analyzing a catalog of known hemoglobin variants, mass spectrometry can serve as a screening and identification technique. Mass spectroscopy can also detect known rare variants with posttranslational modifications¹⁴ that are not recognized by DNA analysis. Mass spectroscopy and DNA sequencing are complementary techniques available only in specialized reference laboratories.

Erythrocytosis due to BPGM deficiency is very rare. Clinical and laboratory features mimic those of high-oxygen-affinity hemoglobin, but patients do not have a demonstrable mutation in alpha or beta globin genes. The level of BPGM is low, and the diagnosis is established by measuring BPGM levels and sequencing the BPGM gene.¹⁵

RESULTS OF THE ADDITIONAL WORKUP

In our patient, hemoglobin electrophoresis reveals an abnormal hemoglobin variant. High-performance liquid chromatography reveals an abnormal peak that comprises approximately 23.7% of the total hemoglobin, consistent with an alpha globin variant. Further characterization (using a sample of venous blood) shows an oxygen dissociation P50 of 22 mm Hg (normal 24–30 mm Hg) (Figure 1).

Mass spectrometry identifies the variant as hemoglobin Tarrant. This variant is characterized by a substitution of asparagine for aspartic acid at position 126 of the alpha globin chain, a known site of contact between the alpha 1 and beta 1 chains.¹⁶ It has been seen in patients of Hispanic heritage and clinically correlates with mild erythrocytosis. Indeed, this woman’s mother was from Mexico.

EDUCATING PATIENTS

4. What should patients know about their high-oxygen-affinity hemoglobinopathy?

• High altitudes and air travel can be risky
• Pregnancy may have adverse outcomes
• Systemic anticoagulation may lower the risk of venous thromboembolism
• Periodic phlebotomy may help control symptoms

Most patients with high-oxygen-affinity hemoglobin do not require specific clinical management but only counseling and education about their condition. Establishing an accurate diagnosis is important in order to avoid further inappropriate, invasive, and expensive testing.

Although exposure to high altitudes may be associated with decreased ambient oxygen levels, hypoxia is usually not a problem because of hemoglobin’s high affinity for oxygen.

Impaired delivery of oxygen across the placenta may be anticipated in a mother with high-oxygen-affinity hemoglobin, but this has not been observed clinically.¹⁷

Compared with patients with polycythemia vera, patients with high-oxygen-affinity hemoglobin have fewer complications from hyperviscosity and thrombosis, even with comparable degrees of erythrocytosis.

Although patients usually do not require treatment, phlebotomy may be helpful for symptoms that can be attributed to the higher hemoglobin concentration.

Our patient continues to be seen in clinic for periodic blood counts and phlebotomy for her headaches, as required.

HEMOGLOBIN: RELAXED OR TENSE

Normal adult hemoglobin is a tetramer composed of two pairs of globin polypeptide chains: alpha and beta (Figure 2). The intrinsic properties of the constituent globin chains and their allosteric conformation—as well as extrinsic factors including temperature, pH, and the binding of hydrogen ion and 2,3-BPG—play important roles in modifying the affinity of hemoglobin for oxygen. The major modulator of hemoglobin-oxygen affinity in human erythrocytes is 2,3-BPG.

The hemoglobin tetramer, consisting of two identical halves, alpha 1-beta 1 and alpha 2-beta 2, oscillates between two quaternary conformations, “relaxed” (fully oxygenated) and “tense” (fully deoxygenated).¹⁸ High-oxygen-affinity hemoglobins can result from factors that enhance the relaxed state, either by stabilizing the relaxed state or by destabilizing the tense state. Structural modifications in hemoglobin typically affect the main contacts involved in the transition from the deoxygenated to the oxygenated state, the 2,3-BPG binding sites, the heme pocket, or elongation of globin chains by various mutations. In hemoglobin Tarrant, the mutation prevents formation of noncovalent salt bridges in the alpha 1-beta 1 contact that normally stabilize the deoxygenated conformation of hemoglobin. As a result, the deoxygenated (tense) state is destabilized, shifting the allosteric equilibrium in favor of the oxygenated (relaxed) state with consequent high oxygen affinity.¹⁶

MORE ABOUT HIGH-OXYGEN-AFFINITY HEMOGLOBINS

The first case of erythrocytosis due to an abnormal hemoglobin was identified in 1966. This was an alpha chain variant with an arginine-to-leucine substitution at position 92, named hemoglobin Chesapeake.¹⁹

High-oxygen-affinity hemoglobin variants are usually transmitted as autosomal dominant traits. Patients are most often identified because of unexplained erythrocytosis detected on a routine blood cell count, as in our patient.

Not all high-oxygen-affinity hemoglobinopathies are associated with erythrocytosis. The degree of increased oxygen affinity may only be mild or the abnormal hemoglobin may be slightly unstable, thereby masking the usual clinical signs and symptoms.

Therapeutic phlebotomy should be used cautiously since it can decrease delivery of oxygen to tissues. A subset of patients whose symptoms are related to an elevated red cell mass may experience some relief, as did our patient.

A 40-year-old woman with hypertrophic   obstructive cardiomyopathy presents to the hematology clinic for a second opinion regarding a history of headaches and fatigue for the past 10 years. She has been diagnosed with idiopathic erythrocytosis, presumed to be due to polycythemia vera. She periodically undergoes phlebotomy to keep her hematocrit below 41%, and this markedly improves her headaches. She denies shortness of breath, cough, fever, weight loss, joint pain, and visual or other neurologic symptoms. She has never reported pruritus related to bathing or exposure to water.

She does not smoke, drink alcohol, or use illicit drugs. She works as a pharmacy technician. She says her father died of cancer (no further details available) and describes a family history of gastrointestinal malignancy in her grandfather and paternal aunt. She takes aspirin, metoprolol, and spironolactone for her cardiomyopathy.

Physical examination reveals generalized plethora, more marked on her cheeks and face, and mild bilateral pitting pedal edema. No lymphadenopathy or hepatosplenomegaly can be palpated. Other systems, including the cardiac, respiratory, and nervous systems, are normal.

ERYTHROCYTOSIS AND POLYCYTHEMIA VERA

1. In patients with erythrocytosis, which of the following is not characteristic of polycythemia vera?

• Erythromelalgia and postbathing pruritus
• Splenomegaly
• History of thrombosis
• Gout
• Hematuria

Erythrocytosis—an abnormally high concentration of red blood cells in the peripheral blood—is a laboratory finding. It often reflects an increase in the total quantity or mass of red blood cells in the body (polycythemia) but can sometimes be due to decreased plasma volume (spurious polycythemia).¹ Erythrocytosis can be caused by a number of diseases, hereditary and acquired, and can be classified as primary or secondary (Table 1).

Symptoms arise from an increase in the total blood volume and red blood cell mass, often leading to dilated capillaries and other blood vessels. Symptoms can occur regardless of the cause and classically include headache (often described as diffuse heaviness), dizziness, and a tendency for bleeding or thrombosis.² Symptoms are relieved when the hematocrit is lowered.

Several features in the history and physical examination of a patient being evaluated for erythrocytosis can suggest an underlying cause. Smoking, chronic respiratory insufficiency, and congenital cyanotic heart disease point to secondary erythrocytosis and can usually be identified at the outset. A history of occupational exposure to carbon monoxide (such as engine exhaust) should be elicited carefully. A family history of erythrocytosis should raise suspicion of a heritable condition such as a hemoglobinopathy associated with increased oxygen affinity or rare forms of primary erythrocytosis associated with endogenous overproduction of erythropoietin or activating mutations of the erythropoietin receptor.³ Iatrogenic causes such as androgen supplementation, erythropoietin abuse, and postrenal-transplant erythrocytosis should also be considered.

Secretion of erythropoietin or erythropoietinlike proteins by a malignant neoplasm is a rare but important cause of erythrocytosis. For example, renal cell carcinoma may present with erythrocytosis secondary to excessive erythropoietin production, and hematuria can be an early symptom.

Polycythemia vera

Polycythemia vera, a myeloproliferative neoplasm, is characterized by increased red blood cell production independent of the mechanisms that normally regulate erythropoiesis. The bone marrow shows a panmyelosis that is often accompanied by leukocytosis or thrombocytosis, or both, in the peripheral blood.

Symptoms such as severe itching after exposure to hot water (aquagenic pruritus) and periodic attacks of redness, swelling, and pain in the hands or feet, or both (erythromelalgia), have been described in patients with polycythemia vera. Splenomegaly is relatively common, seen in approximately two-thirds of patients.⁴ Hyperuricemia (from increased cell turnover) and gout are also associated with polycythemia vera, as is a history of arterial and venous thrombosis.⁵

Hematuria is not commonly seen in polycythemia vera, although bleeding from the bladder, vagina, or uterus has been described.

CASE RESUMED: INITIAL LABORATORY TESTS

Results of our patient’s initial laboratory tests are:

• Hemoglobin 16.9 g/dL (reference range 11.5–15.5)
• Hematocrit 48.8% (36.0–46.0)
• Mean corpuscular volume 85.2 fL (80–100)
• Platelet count 328 × 10⁹/L (150–400)
• White blood cell count 9.14 × 10⁹/L (3.7–11.0)
• Absolute neutrophil count 5.95 × 10⁹/L (1.45–7.5)
• Blood urea nitrogen 12 mg/dL (8–25)
• Creatinine 0.5 mg/dL (0.7–1.4)
• Lactate dehydrogenase 180 U/L (100–220)
• Uric acid 3.0 mg/dL (2.0–7.0)
• Thyroid-stimulating hormone 2.2 µU/mL (0.4–5.5).

The patient undergoes additional tests, including a serum erythropoietin level and hemoglobinopathy screen. Bone marrow aspiration and biopsy are performed, with cytogenetic analysis, chromosomal microarray analysis, and molecular testing for mutation of the Janus kinase 2 (JAK2) gene.

CONFIRMING SUSPECTED POLYCYTHEMIA VERA

2. In patients with suspected polycythemia vera, which of the following laboratory tests is most useful in making the diagnosis?

• Hemoglobin, hematocrit, and red blood cell mass
• Serum erythropoietin level
• Arterial blood gases with co-oximetry
• Testing for the JAK2 mutation
• Bone marrow aspiration and biopsy

The aim of the initial workup of erythrocytosis is to differentiate polycythemia vera from secondary causes of erythrocytosis.

Hemoglobin, hematocrit, red cell mass

Erythrocytosis is defined by an abnormal elevation in the hematocrit (> 48% in women or > 49% in men), hemoglobin concentration (> 16.0 g/dL in women or > 16.5 g/dL in men), or red blood cell mass. The red blood cell count should not be used as a surrogate for red blood cell mass, since some anemias (especially thalassemia minor) can be associated with an increase in the number of red blood cells but a low hemoglobin concentration.

Isotope dilution techniques to determine the red cell mass and plasma volume can differentiate true erythrocytosis from a spurious elevation due to a decrease in plasma volume.^6,7 However, this is an expensive, time-consuming test that is not widely available and so is rarely performed.⁸

JAK2 mutation testing

The initial evaluation of a patient with erythrocytosis has changed significantly in the past 10 years with the discovery of the JAK2 gene and its role in the pathogenesis of polycythemia vera and other myeloproliferative neoplasms.

JAK2, located at 9p24, codes for a tyrosine kinase important for signal transduction in hematopoietic cells. Mutations in this gene have been shown to promote hypersensitivity to cytokines, including erythropoietin.⁹ The most common somatic mutation occurs within exon 14 at base pair 1849 and results in a phenylalanine-for-valine amino acid substitution in the JAK2 protein, designated V617F. Less commonly, mutations occur elsewhere in exons 12 to 15, with more than 50 different mutations described; nonpolymorphic mutations are assumed to have biologic effects similar to those of V617F.

Taken together, the JAK2 V617F and non-V617F mutations have a diagnostic sensitivity of 98% to 100% for polycythemia vera. For practical purposes, this means that the presence of a JAK2 mutation can be used as a clonal marker to distinguish polycythemia vera from reactive secondary causes of erythrocytosis. A JAK2 mutation is one of three major diagnostic criteria for polycythemia vera in the 2016 revision to the 2008 World Health Organization criteria (Table 2).¹⁰ Of note, this mutation is not specific for polycythemia vera and can also be found in other myeloproliferative neoplasms, including primary myelofibrosis and essential thrombocythemia.

Absence of a JAK2 mutation makes polycythemia vera unlikely, so this test is most useful in making the diagnosis.

Serum erythropoietin

Serum erythropoietin testing can be very useful to distinguish polycythemia vera from secondary erythrocytosis. Low levels suggest polycythemia vera, while high levels are seen in secondary processes.¹¹

This test is best used along with JAK2 V617F mutation analysis as an initial step in evaluating patients with erythrocytosis. When JAK2 V617F mutation analysis is negative, a low serum erythropoietin level should prompt further testing for non-V617F JAK2 mutations, whereas a normal or elevated erythropoietin level should be evaluated further with tests to distinguish hereditary from acquired secondary causes of erythrocytosis.

Arterial blood gas analysis and co-oximetry

Arterial blood gas analysis can reveal hypoxemia, pointing to a cardiorespiratory process driving the erythrocytosis, whereas co-oximetry can be used to identify the presence and amount of carboxyhemoglobin in the blood.

Bone marrow biopsy

An increase in pleomorphic megakaryocytes in the bone marrow without stainable iron is often described as characteristic in polycythemia vera patients, but it is not diagnostic. Panmyelosis with increased cellularity is the norm but can be seen in other myeloproliferative neoplasms. The morphologic features of bone marrow are now included as one of the major diagnostic criteria for polycythemia vera (Table 2).

OUR PATIENT’S FURTHER WORKUP

Our patient’s erythropoietin level is 34.2 mIU/mL (reference range 4.7–28.6). Her oxygen saturation is 96%, and her carboxyhemoglobin level is 1.1% (0–5).

She undergoes bone marrow biopsy. Analysis finds that the marrow is normocellular (60%) with trilineage hematopoiesis and decreased stainable iron.

Cytogenetic analysis shows a 46,XX[20] karyotype. Chromosomal microarray analysis shows no pathogenic copy-number changes. There is no detectable JAK2 V617F or exon 12-to-15 mutation.

The patient’s erythrocytosis and abnormal hemoglobin electrophoresis study raise suspicion for a variant type of hemoglobin that has a higher affinity for oxygen than normal.

3. What is the next best step to evaluate this patient?

• Red-cell oxygen equilibrium curve to calculate the P50 (the partial pressure of oxygen that is required to saturate 50% of the hemoglobin.)
• High-performance liquid chromatography
• Globin gene DNA sequencing
• Testing 2,3-bisphosphoglycerate mutase (BPGM) activity

Nearly 200 mutational variants in alpha and beta globin chains that lead to an increased affinity of hemoglobin for oxygen have been reported.¹² While not all mutations are clinically significant, increased oxygen affinity variants can lead to impaired oxygen delivery to tissues, especially the kidneys, resulting in a physiologic increase in erythropoietin and erythrocytosis.

In patients being evaluated for a high-oxygen-affinity hemoglobinopathy, a two-step approach has been outlined.¹³ The first involves measuring the oxygen-binding properties of a freshly collected sample of blood by directly measuring the oxygen saturation of the hemoglobin and pO₂ using a co-oximeter. This information is used to create a red cell oxygen equilibrium curve and to calculate the P50. A low P50 correlates with an abnormally high affinity of hemoglobin for oxygen.

The second step is to identify the abnormal hemoglobin. High-performance liquid chromatography is now widely available as a screening test but does not detect all variants. For many years, sequencing of globin chain DNA has been a gold standard for identifying specific mutations. Subsequent to analyzing a catalog of known hemoglobin variants, mass spectrometry can serve as a screening and identification technique. Mass spectroscopy can also detect known rare variants with posttranslational modifications¹⁴ that are not recognized by DNA analysis. Mass spectroscopy and DNA sequencing are complementary techniques available only in specialized reference laboratories.

Erythrocytosis due to BPGM deficiency is very rare. Clinical and laboratory features mimic those of high-oxygen-affinity hemoglobin, but patients do not have a demonstrable mutation in alpha or beta globin genes. The level of BPGM is low, and the diagnosis is established by measuring BPGM levels and sequencing the BPGM gene.¹⁵

RESULTS OF THE ADDITIONAL WORKUP

In our patient, hemoglobin electrophoresis reveals an abnormal hemoglobin variant. High-performance liquid chromatography reveals an abnormal peak that comprises approximately 23.7% of the total hemoglobin, consistent with an alpha globin variant. Further characterization (using a sample of venous blood) shows an oxygen dissociation P50 of 22 mm Hg (normal 24–30 mm Hg) (Figure 1).

Mass spectrometry identifies the variant as hemoglobin Tarrant. This variant is characterized by a substitution of asparagine for aspartic acid at position 126 of the alpha globin chain, a known site of contact between the alpha 1 and beta 1 chains.¹⁶ It has been seen in patients of Hispanic heritage and clinically correlates with mild erythrocytosis. Indeed, this woman’s mother was from Mexico.

EDUCATING PATIENTS

4. What should patients know about their high-oxygen-affinity hemoglobinopathy?

• High altitudes and air travel can be risky
• Pregnancy may have adverse outcomes
• Systemic anticoagulation may lower the risk of venous thromboembolism
• Periodic phlebotomy may help control symptoms

Most patients with high-oxygen-affinity hemoglobin do not require specific clinical management but only counseling and education about their condition. Establishing an accurate diagnosis is important in order to avoid further inappropriate, invasive, and expensive testing.

Although exposure to high altitudes may be associated with decreased ambient oxygen levels, hypoxia is usually not a problem because of hemoglobin’s high affinity for oxygen.

Impaired delivery of oxygen across the placenta may be anticipated in a mother with high-oxygen-affinity hemoglobin, but this has not been observed clinically.¹⁷

Compared with patients with polycythemia vera, patients with high-oxygen-affinity hemoglobin have fewer complications from hyperviscosity and thrombosis, even with comparable degrees of erythrocytosis.

Although patients usually do not require treatment, phlebotomy may be helpful for symptoms that can be attributed to the higher hemoglobin concentration.

Our patient continues to be seen in clinic for periodic blood counts and phlebotomy for her headaches, as required.

HEMOGLOBIN: RELAXED OR TENSE

Normal adult hemoglobin is a tetramer composed of two pairs of globin polypeptide chains: alpha and beta (Figure 2). The intrinsic properties of the constituent globin chains and their allosteric conformation—as well as extrinsic factors including temperature, pH, and the binding of hydrogen ion and 2,3-BPG—play important roles in modifying the affinity of hemoglobin for oxygen. The major modulator of hemoglobin-oxygen affinity in human erythrocytes is 2,3-BPG.

The hemoglobin tetramer, consisting of two identical halves, alpha 1-beta 1 and alpha 2-beta 2, oscillates between two quaternary conformations, “relaxed” (fully oxygenated) and “tense” (fully deoxygenated).¹⁸ High-oxygen-affinity hemoglobins can result from factors that enhance the relaxed state, either by stabilizing the relaxed state or by destabilizing the tense state. Structural modifications in hemoglobin typically affect the main contacts involved in the transition from the deoxygenated to the oxygenated state, the 2,3-BPG binding sites, the heme pocket, or elongation of globin chains by various mutations. In hemoglobin Tarrant, the mutation prevents formation of noncovalent salt bridges in the alpha 1-beta 1 contact that normally stabilize the deoxygenated conformation of hemoglobin. As a result, the deoxygenated (tense) state is destabilized, shifting the allosteric equilibrium in favor of the oxygenated (relaxed) state with consequent high oxygen affinity.¹⁶

MORE ABOUT HIGH-OXYGEN-AFFINITY HEMOGLOBINS

The first case of erythrocytosis due to an abnormal hemoglobin was identified in 1966. This was an alpha chain variant with an arginine-to-leucine substitution at position 92, named hemoglobin Chesapeake.¹⁹

High-oxygen-affinity hemoglobin variants are usually transmitted as autosomal dominant traits. Patients are most often identified because of unexplained erythrocytosis detected on a routine blood cell count, as in our patient.

Not all high-oxygen-affinity hemoglobinopathies are associated with erythrocytosis. The degree of increased oxygen affinity may only be mild or the abnormal hemoglobin may be slightly unstable, thereby masking the usual clinical signs and symptoms.

Therapeutic phlebotomy should be used cautiously since it can decrease delivery of oxygen to tissues. A subset of patients whose symptoms are related to an elevated red cell mass may experience some relief, as did our patient.

A 40-year-old woman with hypertrophic   obstructive cardiomyopathy presents to the hematology clinic for a second opinion regarding a history of headaches and fatigue for the past 10 years. She has been diagnosed with idiopathic erythrocytosis, presumed to be due to polycythemia vera. She periodically undergoes phlebotomy to keep her hematocrit below 41%, and this markedly improves her headaches. She denies shortness of breath, cough, fever, weight loss, joint pain, and visual or other neurologic symptoms. She has never reported pruritus related to bathing or exposure to water.

She does not smoke, drink alcohol, or use illicit drugs. She works as a pharmacy technician. She says her father died of cancer (no further details available) and describes a family history of gastrointestinal malignancy in her grandfather and paternal aunt. She takes aspirin, metoprolol, and spironolactone for her cardiomyopathy.

Physical examination reveals generalized plethora, more marked on her cheeks and face, and mild bilateral pitting pedal edema. No lymphadenopathy or hepatosplenomegaly can be palpated. Other systems, including the cardiac, respiratory, and nervous systems, are normal.

ERYTHROCYTOSIS AND POLYCYTHEMIA VERA

1. In patients with erythrocytosis, which of the following is not characteristic of polycythemia vera?

• Erythromelalgia and postbathing pruritus
• Splenomegaly
• History of thrombosis
• Gout
• Hematuria

Erythrocytosis—an abnormally high concentration of red blood cells in the peripheral blood—is a laboratory finding. It often reflects an increase in the total quantity or mass of red blood cells in the body (polycythemia) but can sometimes be due to decreased plasma volume (spurious polycythemia).¹ Erythrocytosis can be caused by a number of diseases, hereditary and acquired, and can be classified as primary or secondary (Table 1).

Symptoms arise from an increase in the total blood volume and red blood cell mass, often leading to dilated capillaries and other blood vessels. Symptoms can occur regardless of the cause and classically include headache (often described as diffuse heaviness), dizziness, and a tendency for bleeding or thrombosis.² Symptoms are relieved when the hematocrit is lowered.

Several features in the history and physical examination of a patient being evaluated for erythrocytosis can suggest an underlying cause. Smoking, chronic respiratory insufficiency, and congenital cyanotic heart disease point to secondary erythrocytosis and can usually be identified at the outset. A history of occupational exposure to carbon monoxide (such as engine exhaust) should be elicited carefully. A family history of erythrocytosis should raise suspicion of a heritable condition such as a hemoglobinopathy associated with increased oxygen affinity or rare forms of primary erythrocytosis associated with endogenous overproduction of erythropoietin or activating mutations of the erythropoietin receptor.³ Iatrogenic causes such as androgen supplementation, erythropoietin abuse, and postrenal-transplant erythrocytosis should also be considered.

Secretion of erythropoietin or erythropoietinlike proteins by a malignant neoplasm is a rare but important cause of erythrocytosis. For example, renal cell carcinoma may present with erythrocytosis secondary to excessive erythropoietin production, and hematuria can be an early symptom.

Polycythemia vera

Polycythemia vera, a myeloproliferative neoplasm, is characterized by increased red blood cell production independent of the mechanisms that normally regulate erythropoiesis. The bone marrow shows a panmyelosis that is often accompanied by leukocytosis or thrombocytosis, or both, in the peripheral blood.

Symptoms such as severe itching after exposure to hot water (aquagenic pruritus) and periodic attacks of redness, swelling, and pain in the hands or feet, or both (erythromelalgia), have been described in patients with polycythemia vera. Splenomegaly is relatively common, seen in approximately two-thirds of patients.⁴ Hyperuricemia (from increased cell turnover) and gout are also associated with polycythemia vera, as is a history of arterial and venous thrombosis.⁵

Hematuria is not commonly seen in polycythemia vera, although bleeding from the bladder, vagina, or uterus has been described.

CASE RESUMED: INITIAL LABORATORY TESTS

Results of our patient’s initial laboratory tests are:

• Hemoglobin 16.9 g/dL (reference range 11.5–15.5)
• Hematocrit 48.8% (36.0–46.0)
• Mean corpuscular volume 85.2 fL (80–100)
• Platelet count 328 × 10⁹/L (150–400)
• White blood cell count 9.14 × 10⁹/L (3.7–11.0)
• Absolute neutrophil count 5.95 × 10⁹/L (1.45–7.5)
• Blood urea nitrogen 12 mg/dL (8–25)
• Creatinine 0.5 mg/dL (0.7–1.4)
• Lactate dehydrogenase 180 U/L (100–220)
• Uric acid 3.0 mg/dL (2.0–7.0)
• Thyroid-stimulating hormone 2.2 µU/mL (0.4–5.5).

The patient undergoes additional tests, including a serum erythropoietin level and hemoglobinopathy screen. Bone marrow aspiration and biopsy are performed, with cytogenetic analysis, chromosomal microarray analysis, and molecular testing for mutation of the Janus kinase 2 (JAK2) gene.

CONFIRMING SUSPECTED POLYCYTHEMIA VERA

2. In patients with suspected polycythemia vera, which of the following laboratory tests is most useful in making the diagnosis?

• Hemoglobin, hematocrit, and red blood cell mass
• Serum erythropoietin level
• Arterial blood gases with co-oximetry
• Testing for the JAK2 mutation
• Bone marrow aspiration and biopsy

The aim of the initial workup of erythrocytosis is to differentiate polycythemia vera from secondary causes of erythrocytosis.

Hemoglobin, hematocrit, red cell mass

Erythrocytosis is defined by an abnormal elevation in the hematocrit (> 48% in women or > 49% in men), hemoglobin concentration (> 16.0 g/dL in women or > 16.5 g/dL in men), or red blood cell mass. The red blood cell count should not be used as a surrogate for red blood cell mass, since some anemias (especially thalassemia minor) can be associated with an increase in the number of red blood cells but a low hemoglobin concentration.

Isotope dilution techniques to determine the red cell mass and plasma volume can differentiate true erythrocytosis from a spurious elevation due to a decrease in plasma volume.^6,7 However, this is an expensive, time-consuming test that is not widely available and so is rarely performed.⁸

JAK2 mutation testing

The initial evaluation of a patient with erythrocytosis has changed significantly in the past 10 years with the discovery of the JAK2 gene and its role in the pathogenesis of polycythemia vera and other myeloproliferative neoplasms.

JAK2, located at 9p24, codes for a tyrosine kinase important for signal transduction in hematopoietic cells. Mutations in this gene have been shown to promote hypersensitivity to cytokines, including erythropoietin.⁹ The most common somatic mutation occurs within exon 14 at base pair 1849 and results in a phenylalanine-for-valine amino acid substitution in the JAK2 protein, designated V617F. Less commonly, mutations occur elsewhere in exons 12 to 15, with more than 50 different mutations described; nonpolymorphic mutations are assumed to have biologic effects similar to those of V617F.

Taken together, the JAK2 V617F and non-V617F mutations have a diagnostic sensitivity of 98% to 100% for polycythemia vera. For practical purposes, this means that the presence of a JAK2 mutation can be used as a clonal marker to distinguish polycythemia vera from reactive secondary causes of erythrocytosis. A JAK2 mutation is one of three major diagnostic criteria for polycythemia vera in the 2016 revision to the 2008 World Health Organization criteria (Table 2).¹⁰ Of note, this mutation is not specific for polycythemia vera and can also be found in other myeloproliferative neoplasms, including primary myelofibrosis and essential thrombocythemia.

Absence of a JAK2 mutation makes polycythemia vera unlikely, so this test is most useful in making the diagnosis.

Serum erythropoietin

Serum erythropoietin testing can be very useful to distinguish polycythemia vera from secondary erythrocytosis. Low levels suggest polycythemia vera, while high levels are seen in secondary processes.¹¹

This test is best used along with JAK2 V617F mutation analysis as an initial step in evaluating patients with erythrocytosis. When JAK2 V617F mutation analysis is negative, a low serum erythropoietin level should prompt further testing for non-V617F JAK2 mutations, whereas a normal or elevated erythropoietin level should be evaluated further with tests to distinguish hereditary from acquired secondary causes of erythrocytosis.

Arterial blood gas analysis and co-oximetry

Arterial blood gas analysis can reveal hypoxemia, pointing to a cardiorespiratory process driving the erythrocytosis, whereas co-oximetry can be used to identify the presence and amount of carboxyhemoglobin in the blood.

Bone marrow biopsy

An increase in pleomorphic megakaryocytes in the bone marrow without stainable iron is often described as characteristic in polycythemia vera patients, but it is not diagnostic. Panmyelosis with increased cellularity is the norm but can be seen in other myeloproliferative neoplasms. The morphologic features of bone marrow are now included as one of the major diagnostic criteria for polycythemia vera (Table 2).

OUR PATIENT’S FURTHER WORKUP

Our patient’s erythropoietin level is 34.2 mIU/mL (reference range 4.7–28.6). Her oxygen saturation is 96%, and her carboxyhemoglobin level is 1.1% (0–5).

She undergoes bone marrow biopsy. Analysis finds that the marrow is normocellular (60%) with trilineage hematopoiesis and decreased stainable iron.

Cytogenetic analysis shows a 46,XX[20] karyotype. Chromosomal microarray analysis shows no pathogenic copy-number changes. There is no detectable JAK2 V617F or exon 12-to-15 mutation.

The patient’s erythrocytosis and abnormal hemoglobin electrophoresis study raise suspicion for a variant type of hemoglobin that has a higher affinity for oxygen than normal.

3. What is the next best step to evaluate this patient?

• Red-cell oxygen equilibrium curve to calculate the P50 (the partial pressure of oxygen that is required to saturate 50% of the hemoglobin.)
• High-performance liquid chromatography
• Globin gene DNA sequencing
• Testing 2,3-bisphosphoglycerate mutase (BPGM) activity

Nearly 200 mutational variants in alpha and beta globin chains that lead to an increased affinity of hemoglobin for oxygen have been reported.¹² While not all mutations are clinically significant, increased oxygen affinity variants can lead to impaired oxygen delivery to tissues, especially the kidneys, resulting in a physiologic increase in erythropoietin and erythrocytosis.

In patients being evaluated for a high-oxygen-affinity hemoglobinopathy, a two-step approach has been outlined.¹³ The first involves measuring the oxygen-binding properties of a freshly collected sample of blood by directly measuring the oxygen saturation of the hemoglobin and pO₂ using a co-oximeter. This information is used to create a red cell oxygen equilibrium curve and to calculate the P50. A low P50 correlates with an abnormally high affinity of hemoglobin for oxygen.

The second step is to identify the abnormal hemoglobin. High-performance liquid chromatography is now widely available as a screening test but does not detect all variants. For many years, sequencing of globin chain DNA has been a gold standard for identifying specific mutations. Subsequent to analyzing a catalog of known hemoglobin variants, mass spectrometry can serve as a screening and identification technique. Mass spectroscopy can also detect known rare variants with posttranslational modifications¹⁴ that are not recognized by DNA analysis. Mass spectroscopy and DNA sequencing are complementary techniques available only in specialized reference laboratories.

Erythrocytosis due to BPGM deficiency is very rare. Clinical and laboratory features mimic those of high-oxygen-affinity hemoglobin, but patients do not have a demonstrable mutation in alpha or beta globin genes. The level of BPGM is low, and the diagnosis is established by measuring BPGM levels and sequencing the BPGM gene.¹⁵

RESULTS OF THE ADDITIONAL WORKUP

In our patient, hemoglobin electrophoresis reveals an abnormal hemoglobin variant. High-performance liquid chromatography reveals an abnormal peak that comprises approximately 23.7% of the total hemoglobin, consistent with an alpha globin variant. Further characterization (using a sample of venous blood) shows an oxygen dissociation P50 of 22 mm Hg (normal 24–30 mm Hg) (Figure 1).

Mass spectrometry identifies the variant as hemoglobin Tarrant. This variant is characterized by a substitution of asparagine for aspartic acid at position 126 of the alpha globin chain, a known site of contact between the alpha 1 and beta 1 chains.¹⁶ It has been seen in patients of Hispanic heritage and clinically correlates with mild erythrocytosis. Indeed, this woman’s mother was from Mexico.

EDUCATING PATIENTS

4. What should patients know about their high-oxygen-affinity hemoglobinopathy?

• High altitudes and air travel can be risky
• Pregnancy may have adverse outcomes
• Systemic anticoagulation may lower the risk of venous thromboembolism
• Periodic phlebotomy may help control symptoms

Most patients with high-oxygen-affinity hemoglobin do not require specific clinical management but only counseling and education about their condition. Establishing an accurate diagnosis is important in order to avoid further inappropriate, invasive, and expensive testing.

Although exposure to high altitudes may be associated with decreased ambient oxygen levels, hypoxia is usually not a problem because of hemoglobin’s high affinity for oxygen.

Impaired delivery of oxygen across the placenta may be anticipated in a mother with high-oxygen-affinity hemoglobin, but this has not been observed clinically.¹⁷

Compared with patients with polycythemia vera, patients with high-oxygen-affinity hemoglobin have fewer complications from hyperviscosity and thrombosis, even with comparable degrees of erythrocytosis.

Although patients usually do not require treatment, phlebotomy may be helpful for symptoms that can be attributed to the higher hemoglobin concentration.

Our patient continues to be seen in clinic for periodic blood counts and phlebotomy for her headaches, as required.

HEMOGLOBIN: RELAXED OR TENSE

Normal adult hemoglobin is a tetramer composed of two pairs of globin polypeptide chains: alpha and beta (Figure 2). The intrinsic properties of the constituent globin chains and their allosteric conformation—as well as extrinsic factors including temperature, pH, and the binding of hydrogen ion and 2,3-BPG—play important roles in modifying the affinity of hemoglobin for oxygen. The major modulator of hemoglobin-oxygen affinity in human erythrocytes is 2,3-BPG.

The hemoglobin tetramer, consisting of two identical halves, alpha 1-beta 1 and alpha 2-beta 2, oscillates between two quaternary conformations, “relaxed” (fully oxygenated) and “tense” (fully deoxygenated).¹⁸ High-oxygen-affinity hemoglobins can result from factors that enhance the relaxed state, either by stabilizing the relaxed state or by destabilizing the tense state. Structural modifications in hemoglobin typically affect the main contacts involved in the transition from the deoxygenated to the oxygenated state, the 2,3-BPG binding sites, the heme pocket, or elongation of globin chains by various mutations. In hemoglobin Tarrant, the mutation prevents formation of noncovalent salt bridges in the alpha 1-beta 1 contact that normally stabilize the deoxygenated conformation of hemoglobin. As a result, the deoxygenated (tense) state is destabilized, shifting the allosteric equilibrium in favor of the oxygenated (relaxed) state with consequent high oxygen affinity.¹⁶

MORE ABOUT HIGH-OXYGEN-AFFINITY HEMOGLOBINS

The first case of erythrocytosis due to an abnormal hemoglobin was identified in 1966. This was an alpha chain variant with an arginine-to-leucine substitution at position 92, named hemoglobin Chesapeake.¹⁹

High-oxygen-affinity hemoglobin variants are usually transmitted as autosomal dominant traits. Patients are most often identified because of unexplained erythrocytosis detected on a routine blood cell count, as in our patient.

Not all high-oxygen-affinity hemoglobinopathies are associated with erythrocytosis. The degree of increased oxygen affinity may only be mild or the abnormal hemoglobin may be slightly unstable, thereby masking the usual clinical signs and symptoms.

Therapeutic phlebotomy should be used cautiously since it can decrease delivery of oxygen to tissues. A subset of patients whose symptoms are related to an elevated red cell mass may experience some relief, as did our patient.

Conventional treatment for a large symptomatic Zenker diverticulum is to surgically either remove it (diverticulectomy) or obliterate it by repositioning and securing it after cutting into the cricopharyngeus muscle (diverticulopexy with cricopharyngeal myotomy). But high rates of complications with these procedures in elderly patients have led to the development of endoscopic procedures that are safer and have similar or higher success rates.

ESOPHAGEAL POUCH IN SPACE BETWEEN MUSCLES

Zenker diverticulum is an outpouching of the esophageal mucosa into the potential space of the Killian triangle, the area between the inferior pharyngeal constrictor and the cricopharyngeus muscle. Increased cricopharyngeal tone coupled with insufficient relaxation results in a pressure gradient that eventually causes esophageal outpouchings. The problem is induced by age-related fibrosis and atrophy, esophageal spasms related to gastroesophageal reflux disease, and idiopathic cricopharyngeal spasms.¹

USUALLY PRESENTS WITH DYSPHAGIA

Zenker diverticulum has an estimated incidence of about 2 per 100,000 per year, but this is likely low because many cases are asymptomatic. It occurs mostly in men and people of Northern European descent in their 60s and 70s and rarely before age 40.²

About 80% to 90% of patients present with dysphagia. Other signs and symptoms include regurgitation of undigested foods and medications, halitosis, hoarseness, chronic cough, and aspiration.

Rare complications of Zenker diverticulum include recurrent pulmonary infection, tracheal fistula, ulceration, hemorrhage, squamous cell carcinoma (incidence 0.4% to 1.5%), vocal cord paralysis, and fistula to the prevertebral ligament with cervical osteomyelitis.¹

The diagnosis is suspected based on symptoms but should be confirmed with a barium esophagram that shows an outpouching of contrast from the main contrast column.

A watch-and-wait approach should be used for patients with mild symptoms (ie, mild or intermittent dysphagia) and minor functional limitations. Patients should be counseled to eat small amounts of food at a time, to chew thoroughly, and to sip liquids between bites.

TREATMENT IS SURGERY OR ENDOSCOPY

Patients with more than mild symptoms who are candidates for intervention should be offered treatment. The goal is to open the septum between the diverticulum and the main esophageal lumen so that food can be propelled from the hypopharynx to the main esophageal lumen without obstruction. Because increased cricopharyngeal tone plays a large role in the development and propagation of a diverticulum, most experts recommend cricopharyngomyotomy in addition to any treatment strategy.

Open surgery

In centers that do not offer flexible endoscopy, and for patients with a large diverticulum, open surgery is the sole option. It is done under general anesthesia with a left cervical approach. The length of the cricopharyngeal myotomy can vary from 2 to 6 cm.^3,4 This is followed by one of three options:

• Diverticulectomy
• Diverticulopexy, in which the diverticulum is repositioned and sutured against the prevertebral fascia
• Diverticular inversion, in which the diverticulum is inverted into the esophageal lumen and then oversewn.⁴

Success rates for open surgery vary from study to study but are usually around 90%.⁴ Complications are reported in 10% to 30% of cases and include mediastinitis, severe recurrent laryngeal nerve injury, and a 1% to 2% chance of death. These rates seem high, but the older age of most of these patients puts them at high risk.⁵

Endoscopic procedures

All endoscopic procedures involve incision of the wall separating the diverticulum from the esophageal lumen to relieve the obstruction.

Rigid endoscopy is used in centers that do not offer flexible endoscopy for patients who are not candidates for surgery. It is done under general anesthesia. With the patient’s neck completely hyperextended, a rigid endoscope is passed into the oral cavity, and diverticulotomy and cricopharyngeal myotomy are performed.

This technique has been extensively evaluated and, although effective, carries up to an 8% risk of complications, including perforation. It is not recommended for patients with a small diverticulum, a high body mass index, or difficulty with neck extension.⁶

Flexible endoscopy is the first-line therapy for most patients in many centers. With the flexible endoscope, the diverticulotomy and the cricopharyngeal myotomy can be performed in an outpatient endoscopy suite, and general anesthesia is not required.³

Initial studies of outcomes using these approaches have been promising,^3,7–9 with substantial reduction in dysphagia, regurgitation, and chronic cough. Unfortunately, this technique is associated with a recurrence rate as high as 25%. However, repeat endoscopic therapy in patients with recurrence results in success rates similar to those for first-time treatment.

Complication rates are low. In a series of 150 patients, four adverse events occurred—three cases of fever and one of pneumonia. In addition, one patient had subcutaneous emphysema that resolved spontaneously.⁷

Improved device on horizon

A potentially major advance in the endoscopic treatment of Zenker diverticulum is the development of a diverticuloscope, a soft tube with a V-shaped end. This tube is inserted through the mouth with one leg of the “V” protecting the anterior esophageal wall and the other leg protecting the posterior diverticular lumen. The endoscope is passed through this tube to perform the diverticulotomy. In one report,¹⁰ diverticuloscope-guided diverticulotomy led to fewer complications, shorter procedural time, and higher success rates compared with the standard technique.¹⁰ This device is not yet available in the United States.

No head-to-head comparison of outcomes with various flexible endoscopic techniques for treating Zenker diverticulum has been published, nor are there data yet on the success of surgery if endoscopic therapy fails.

We recommend flexible endoscopy for the initial treatment of Zenker diverticulum in most patients, but its availability is limited in the United States, as many practitioners do not have adequate experience with the technique.

TAKE-HOME POINTS

• Zenker diverticulum is an outpouching of the esophageal mucosa. It is often asymptomatic. Patients with minimal symptoms and with no functional impairment can be followed conservatively.
• A head-to-head comparison of surgical and endoscopic therapy has not yet been done, and optimal patient selection criteria are lacking. Therefore, treatment recommendations are based primarily on expert opinion.
• We recommend flexible endoscopic therapy as initial treatment in patients with a small diverticulum, but this may be limited by the unavailability of a surgeon experienced in this technique.
• For a large diverticulum, we recommend an open cervical procedure involving excision of the diverticulum or a diverticulopexy for patients who are good surgical candidates.

Conventional treatment for a large symptomatic Zenker diverticulum is to surgically either remove it (diverticulectomy) or obliterate it by repositioning and securing it after cutting into the cricopharyngeus muscle (diverticulopexy with cricopharyngeal myotomy). But high rates of complications with these procedures in elderly patients have led to the development of endoscopic procedures that are safer and have similar or higher success rates.

ESOPHAGEAL POUCH IN SPACE BETWEEN MUSCLES

Zenker diverticulum is an outpouching of the esophageal mucosa into the potential space of the Killian triangle, the area between the inferior pharyngeal constrictor and the cricopharyngeus muscle. Increased cricopharyngeal tone coupled with insufficient relaxation results in a pressure gradient that eventually causes esophageal outpouchings. The problem is induced by age-related fibrosis and atrophy, esophageal spasms related to gastroesophageal reflux disease, and idiopathic cricopharyngeal spasms.¹

USUALLY PRESENTS WITH DYSPHAGIA

Zenker diverticulum has an estimated incidence of about 2 per 100,000 per year, but this is likely low because many cases are asymptomatic. It occurs mostly in men and people of Northern European descent in their 60s and 70s and rarely before age 40.²

About 80% to 90% of patients present with dysphagia. Other signs and symptoms include regurgitation of undigested foods and medications, halitosis, hoarseness, chronic cough, and aspiration.

Rare complications of Zenker diverticulum include recurrent pulmonary infection, tracheal fistula, ulceration, hemorrhage, squamous cell carcinoma (incidence 0.4% to 1.5%), vocal cord paralysis, and fistula to the prevertebral ligament with cervical osteomyelitis.¹

The diagnosis is suspected based on symptoms but should be confirmed with a barium esophagram that shows an outpouching of contrast from the main contrast column.

A watch-and-wait approach should be used for patients with mild symptoms (ie, mild or intermittent dysphagia) and minor functional limitations. Patients should be counseled to eat small amounts of food at a time, to chew thoroughly, and to sip liquids between bites.

TREATMENT IS SURGERY OR ENDOSCOPY

Patients with more than mild symptoms who are candidates for intervention should be offered treatment. The goal is to open the septum between the diverticulum and the main esophageal lumen so that food can be propelled from the hypopharynx to the main esophageal lumen without obstruction. Because increased cricopharyngeal tone plays a large role in the development and propagation of a diverticulum, most experts recommend cricopharyngomyotomy in addition to any treatment strategy.

Open surgery

In centers that do not offer flexible endoscopy, and for patients with a large diverticulum, open surgery is the sole option. It is done under general anesthesia with a left cervical approach. The length of the cricopharyngeal myotomy can vary from 2 to 6 cm.^3,4 This is followed by one of three options:

• Diverticulectomy
• Diverticulopexy, in which the diverticulum is repositioned and sutured against the prevertebral fascia
• Diverticular inversion, in which the diverticulum is inverted into the esophageal lumen and then oversewn.⁴

Success rates for open surgery vary from study to study but are usually around 90%.⁴ Complications are reported in 10% to 30% of cases and include mediastinitis, severe recurrent laryngeal nerve injury, and a 1% to 2% chance of death. These rates seem high, but the older age of most of these patients puts them at high risk.⁵

Endoscopic procedures

All endoscopic procedures involve incision of the wall separating the diverticulum from the esophageal lumen to relieve the obstruction.

Rigid endoscopy is used in centers that do not offer flexible endoscopy for patients who are not candidates for surgery. It is done under general anesthesia. With the patient’s neck completely hyperextended, a rigid endoscope is passed into the oral cavity, and diverticulotomy and cricopharyngeal myotomy are performed.

This technique has been extensively evaluated and, although effective, carries up to an 8% risk of complications, including perforation. It is not recommended for patients with a small diverticulum, a high body mass index, or difficulty with neck extension.⁶

Flexible endoscopy is the first-line therapy for most patients in many centers. With the flexible endoscope, the diverticulotomy and the cricopharyngeal myotomy can be performed in an outpatient endoscopy suite, and general anesthesia is not required.³

Initial studies of outcomes using these approaches have been promising,^3,7–9 with substantial reduction in dysphagia, regurgitation, and chronic cough. Unfortunately, this technique is associated with a recurrence rate as high as 25%. However, repeat endoscopic therapy in patients with recurrence results in success rates similar to those for first-time treatment.

Complication rates are low. In a series of 150 patients, four adverse events occurred—three cases of fever and one of pneumonia. In addition, one patient had subcutaneous emphysema that resolved spontaneously.⁷

Improved device on horizon

A potentially major advance in the endoscopic treatment of Zenker diverticulum is the development of a diverticuloscope, a soft tube with a V-shaped end. This tube is inserted through the mouth with one leg of the “V” protecting the anterior esophageal wall and the other leg protecting the posterior diverticular lumen. The endoscope is passed through this tube to perform the diverticulotomy. In one report,¹⁰ diverticuloscope-guided diverticulotomy led to fewer complications, shorter procedural time, and higher success rates compared with the standard technique.¹⁰ This device is not yet available in the United States.

No head-to-head comparison of outcomes with various flexible endoscopic techniques for treating Zenker diverticulum has been published, nor are there data yet on the success of surgery if endoscopic therapy fails.

We recommend flexible endoscopy for the initial treatment of Zenker diverticulum in most patients, but its availability is limited in the United States, as many practitioners do not have adequate experience with the technique.

TAKE-HOME POINTS

• Zenker diverticulum is an outpouching of the esophageal mucosa. It is often asymptomatic. Patients with minimal symptoms and with no functional impairment can be followed conservatively.
• A head-to-head comparison of surgical and endoscopic therapy has not yet been done, and optimal patient selection criteria are lacking. Therefore, treatment recommendations are based primarily on expert opinion.
• We recommend flexible endoscopic therapy as initial treatment in patients with a small diverticulum, but this may be limited by the unavailability of a surgeon experienced in this technique.
• For a large diverticulum, we recommend an open cervical procedure involving excision of the diverticulum or a diverticulopexy for patients who are good surgical candidates.

Conventional treatment for a large symptomatic Zenker diverticulum is to surgically either remove it (diverticulectomy) or obliterate it by repositioning and securing it after cutting into the cricopharyngeus muscle (diverticulopexy with cricopharyngeal myotomy). But high rates of complications with these procedures in elderly patients have led to the development of endoscopic procedures that are safer and have similar or higher success rates.

ESOPHAGEAL POUCH IN SPACE BETWEEN MUSCLES

Zenker diverticulum is an outpouching of the esophageal mucosa into the potential space of the Killian triangle, the area between the inferior pharyngeal constrictor and the cricopharyngeus muscle. Increased cricopharyngeal tone coupled with insufficient relaxation results in a pressure gradient that eventually causes esophageal outpouchings. The problem is induced by age-related fibrosis and atrophy, esophageal spasms related to gastroesophageal reflux disease, and idiopathic cricopharyngeal spasms.¹

USUALLY PRESENTS WITH DYSPHAGIA

Zenker diverticulum has an estimated incidence of about 2 per 100,000 per year, but this is likely low because many cases are asymptomatic. It occurs mostly in men and people of Northern European descent in their 60s and 70s and rarely before age 40.²

About 80% to 90% of patients present with dysphagia. Other signs and symptoms include regurgitation of undigested foods and medications, halitosis, hoarseness, chronic cough, and aspiration.

Rare complications of Zenker diverticulum include recurrent pulmonary infection, tracheal fistula, ulceration, hemorrhage, squamous cell carcinoma (incidence 0.4% to 1.5%), vocal cord paralysis, and fistula to the prevertebral ligament with cervical osteomyelitis.¹

The diagnosis is suspected based on symptoms but should be confirmed with a barium esophagram that shows an outpouching of contrast from the main contrast column.

A watch-and-wait approach should be used for patients with mild symptoms (ie, mild or intermittent dysphagia) and minor functional limitations. Patients should be counseled to eat small amounts of food at a time, to chew thoroughly, and to sip liquids between bites.

TREATMENT IS SURGERY OR ENDOSCOPY

Patients with more than mild symptoms who are candidates for intervention should be offered treatment. The goal is to open the septum between the diverticulum and the main esophageal lumen so that food can be propelled from the hypopharynx to the main esophageal lumen without obstruction. Because increased cricopharyngeal tone plays a large role in the development and propagation of a diverticulum, most experts recommend cricopharyngomyotomy in addition to any treatment strategy.

Open surgery

In centers that do not offer flexible endoscopy, and for patients with a large diverticulum, open surgery is the sole option. It is done under general anesthesia with a left cervical approach. The length of the cricopharyngeal myotomy can vary from 2 to 6 cm.^3,4 This is followed by one of three options:

• Diverticulectomy
• Diverticulopexy, in which the diverticulum is repositioned and sutured against the prevertebral fascia
• Diverticular inversion, in which the diverticulum is inverted into the esophageal lumen and then oversewn.⁴

Success rates for open surgery vary from study to study but are usually around 90%.⁴ Complications are reported in 10% to 30% of cases and include mediastinitis, severe recurrent laryngeal nerve injury, and a 1% to 2% chance of death. These rates seem high, but the older age of most of these patients puts them at high risk.⁵

Endoscopic procedures

All endoscopic procedures involve incision of the wall separating the diverticulum from the esophageal lumen to relieve the obstruction.

Rigid endoscopy is used in centers that do not offer flexible endoscopy for patients who are not candidates for surgery. It is done under general anesthesia. With the patient’s neck completely hyperextended, a rigid endoscope is passed into the oral cavity, and diverticulotomy and cricopharyngeal myotomy are performed.

This technique has been extensively evaluated and, although effective, carries up to an 8% risk of complications, including perforation. It is not recommended for patients with a small diverticulum, a high body mass index, or difficulty with neck extension.⁶

Flexible endoscopy is the first-line therapy for most patients in many centers. With the flexible endoscope, the diverticulotomy and the cricopharyngeal myotomy can be performed in an outpatient endoscopy suite, and general anesthesia is not required.³

Initial studies of outcomes using these approaches have been promising,^3,7–9 with substantial reduction in dysphagia, regurgitation, and chronic cough. Unfortunately, this technique is associated with a recurrence rate as high as 25%. However, repeat endoscopic therapy in patients with recurrence results in success rates similar to those for first-time treatment.

Complication rates are low. In a series of 150 patients, four adverse events occurred—three cases of fever and one of pneumonia. In addition, one patient had subcutaneous emphysema that resolved spontaneously.⁷

Improved device on horizon

A potentially major advance in the endoscopic treatment of Zenker diverticulum is the development of a diverticuloscope, a soft tube with a V-shaped end. This tube is inserted through the mouth with one leg of the “V” protecting the anterior esophageal wall and the other leg protecting the posterior diverticular lumen. The endoscope is passed through this tube to perform the diverticulotomy. In one report,¹⁰ diverticuloscope-guided diverticulotomy led to fewer complications, shorter procedural time, and higher success rates compared with the standard technique.¹⁰ This device is not yet available in the United States.

No head-to-head comparison of outcomes with various flexible endoscopic techniques for treating Zenker diverticulum has been published, nor are there data yet on the success of surgery if endoscopic therapy fails.

We recommend flexible endoscopy for the initial treatment of Zenker diverticulum in most patients, but its availability is limited in the United States, as many practitioners do not have adequate experience with the technique.

TAKE-HOME POINTS

• Zenker diverticulum is an outpouching of the esophageal mucosa. It is often asymptomatic. Patients with minimal symptoms and with no functional impairment can be followed conservatively.
• A head-to-head comparison of surgical and endoscopic therapy has not yet been done, and optimal patient selection criteria are lacking. Therefore, treatment recommendations are based primarily on expert opinion.
• We recommend flexible endoscopic therapy as initial treatment in patients with a small diverticulum, but this may be limited by the unavailability of a surgeon experienced in this technique.
• For a large diverticulum, we recommend an open cervical procedure involving excision of the diverticulum or a diverticulopexy for patients who are good surgical candidates.

The article “Total pancreatectomy and islet cell autotransplantation: Definitive treatment for chronic pancreatitis” (Arce KM, Lin YK, Stevens T, Walsh RM, Hatipoglu BA. Cleve Clin J Med 2016; 83:435–442) incorrectly stated that Paul Lacy and David Scharp performed research at the University of Washington at Seattle. They did their work at Washington University in St. Louis, Missouri.

The article “Total pancreatectomy and islet cell autotransplantation: Definitive treatment for chronic pancreatitis” (Arce KM, Lin YK, Stevens T, Walsh RM, Hatipoglu BA. Cleve Clin J Med 2016; 83:435–442) incorrectly stated that Paul Lacy and David Scharp performed research at the University of Washington at Seattle. They did their work at Washington University in St. Louis, Missouri.

The article “Total pancreatectomy and islet cell autotransplantation: Definitive treatment for chronic pancreatitis” (Arce KM, Lin YK, Stevens T, Walsh RM, Hatipoglu BA. Cleve Clin J Med 2016; 83:435–442) incorrectly stated that Paul Lacy and David Scharp performed research at the University of Washington at Seattle. They did their work at Washington University in St. Louis, Missouri.

A 72-year-old woman with type 2 diabetes mellitus, hypertension, and atrial fibrillation on anticoagulation was brought to the emergency department by her husband after 1 day of altered mental status with acute onset. Her husband reported that she had been minimally arousable, and the physical examination revealed that she was stuporous and withdrew extremities only from noxious stimuli.

Results of initial laboratory tests revealed a creatinine level of 2.4 mg/dL (reference range 0.7–1.4), hemoglobin 12.1 g/dL (12–16), platelet count 16 × 10⁹/L (150–400), white blood cell count of 7.7 × 10⁹/L (3.7–11), and international normalized ratio of 2.1. A peripheral blood smear is shown in Figure 1.

Computed tomography showed evidence of chronic small vascular ischemia. Magnetic resonance imaging of the brain showed numerous foci of restricted diffusion within the supratentorial and infratentorial areas, suggesting microembolic phenomena.

The peripheral blood smear was compatible with microangiopathic hemolytic anemia, which can occur in thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, malignant hypertension, scleroderma, antiphospholipid antibody syndrome, systemic lupus erythematosus, eclampsia, renal allograft rejection, hematopoietic stem cell transplant, and severe sepsis.^1,2

In addition to hemolytic anemia, the patient also had neurologic abnormalities, renal involvement, and thrombocytopenia. The hemolytic anemia and thrombocytopenia were sufficient to raise our suspicion of TTP and to consider initiation of plasma exchange. Only 5% of patients with TTP demonstrate the classic pentad of clinical features,¹ ie, thrombocytopenia, microangiopathic hemolytic anemia, fluctuating neurologic signs, renal impairment, and fever.

In 1991, when plasma exchange was introduced for TTP, the survival rate of patients increased from 10% to 78%.^1,3 Thus, the diagnosis of TTP is an urgent indication for plasma exchange. We normally do plasma exchange daily until the platelet levels improve.

Our patient received methylprednisone 125 mg intravenously every 12 hours and plasma exchange daily. After three cycles of plasma exchange, she regained normal consciousness, and her platelet count had increased to 20.5 × 10⁹/L on the day of discharge from our hospital.

TTP is a life-threatening hematologic disorder. Evidence of microangiopathic hemolytic anemia on a peripheral blood smear is vital to the suspicion of TTP. The diagnosis should be confirmed by ADAMTS13 testing, which should show decreased activity (< 10%) or increased inhibition, or both. Rapid management with plasma exchange and steroids can lead to a satisfactory outcome.

Acknowledgment: We are particularly grateful to Dr. Vivian Arguello (Director of Flow Cytometry, Department of Pathology, Einstein Medical Center, Philadelphia) for her kind support with the blood smear image.

A 72-year-old woman with type 2 diabetes mellitus, hypertension, and atrial fibrillation on anticoagulation was brought to the emergency department by her husband after 1 day of altered mental status with acute onset. Her husband reported that she had been minimally arousable, and the physical examination revealed that she was stuporous and withdrew extremities only from noxious stimuli.

Results of initial laboratory tests revealed a creatinine level of 2.4 mg/dL (reference range 0.7–1.4), hemoglobin 12.1 g/dL (12–16), platelet count 16 × 10⁹/L (150–400), white blood cell count of 7.7 × 10⁹/L (3.7–11), and international normalized ratio of 2.1. A peripheral blood smear is shown in Figure 1.

Computed tomography showed evidence of chronic small vascular ischemia. Magnetic resonance imaging of the brain showed numerous foci of restricted diffusion within the supratentorial and infratentorial areas, suggesting microembolic phenomena.

The peripheral blood smear was compatible with microangiopathic hemolytic anemia, which can occur in thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, malignant hypertension, scleroderma, antiphospholipid antibody syndrome, systemic lupus erythematosus, eclampsia, renal allograft rejection, hematopoietic stem cell transplant, and severe sepsis.^1,2

In addition to hemolytic anemia, the patient also had neurologic abnormalities, renal involvement, and thrombocytopenia. The hemolytic anemia and thrombocytopenia were sufficient to raise our suspicion of TTP and to consider initiation of plasma exchange. Only 5% of patients with TTP demonstrate the classic pentad of clinical features,¹ ie, thrombocytopenia, microangiopathic hemolytic anemia, fluctuating neurologic signs, renal impairment, and fever.

In 1991, when plasma exchange was introduced for TTP, the survival rate of patients increased from 10% to 78%.^1,3 Thus, the diagnosis of TTP is an urgent indication for plasma exchange. We normally do plasma exchange daily until the platelet levels improve.

Our patient received methylprednisone 125 mg intravenously every 12 hours and plasma exchange daily. After three cycles of plasma exchange, she regained normal consciousness, and her platelet count had increased to 20.5 × 10⁹/L on the day of discharge from our hospital.

TTP is a life-threatening hematologic disorder. Evidence of microangiopathic hemolytic anemia on a peripheral blood smear is vital to the suspicion of TTP. The diagnosis should be confirmed by ADAMTS13 testing, which should show decreased activity (< 10%) or increased inhibition, or both. Rapid management with plasma exchange and steroids can lead to a satisfactory outcome.

Acknowledgment: We are particularly grateful to Dr. Vivian Arguello (Director of Flow Cytometry, Department of Pathology, Einstein Medical Center, Philadelphia) for her kind support with the blood smear image.

A 72-year-old woman with type 2 diabetes mellitus, hypertension, and atrial fibrillation on anticoagulation was brought to the emergency department by her husband after 1 day of altered mental status with acute onset. Her husband reported that she had been minimally arousable, and the physical examination revealed that she was stuporous and withdrew extremities only from noxious stimuli.

Results of initial laboratory tests revealed a creatinine level of 2.4 mg/dL (reference range 0.7–1.4), hemoglobin 12.1 g/dL (12–16), platelet count 16 × 10⁹/L (150–400), white blood cell count of 7.7 × 10⁹/L (3.7–11), and international normalized ratio of 2.1. A peripheral blood smear is shown in Figure 1.

Computed tomography showed evidence of chronic small vascular ischemia. Magnetic resonance imaging of the brain showed numerous foci of restricted diffusion within the supratentorial and infratentorial areas, suggesting microembolic phenomena.

The peripheral blood smear was compatible with microangiopathic hemolytic anemia, which can occur in thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, malignant hypertension, scleroderma, antiphospholipid antibody syndrome, systemic lupus erythematosus, eclampsia, renal allograft rejection, hematopoietic stem cell transplant, and severe sepsis.^1,2

In addition to hemolytic anemia, the patient also had neurologic abnormalities, renal involvement, and thrombocytopenia. The hemolytic anemia and thrombocytopenia were sufficient to raise our suspicion of TTP and to consider initiation of plasma exchange. Only 5% of patients with TTP demonstrate the classic pentad of clinical features,¹ ie, thrombocytopenia, microangiopathic hemolytic anemia, fluctuating neurologic signs, renal impairment, and fever.

In 1991, when plasma exchange was introduced for TTP, the survival rate of patients increased from 10% to 78%.^1,3 Thus, the diagnosis of TTP is an urgent indication for plasma exchange. We normally do plasma exchange daily until the platelet levels improve.

Our patient received methylprednisone 125 mg intravenously every 12 hours and plasma exchange daily. After three cycles of plasma exchange, she regained normal consciousness, and her platelet count had increased to 20.5 × 10⁹/L on the day of discharge from our hospital.

TTP is a life-threatening hematologic disorder. Evidence of microangiopathic hemolytic anemia on a peripheral blood smear is vital to the suspicion of TTP. The diagnosis should be confirmed by ADAMTS13 testing, which should show decreased activity (< 10%) or increased inhibition, or both. Rapid management with plasma exchange and steroids can lead to a satisfactory outcome.

Acknowledgment: We are particularly grateful to Dr. Vivian Arguello (Director of Flow Cytometry, Department of Pathology, Einstein Medical Center, Philadelphia) for her kind support with the blood smear image.

A 39-year-old man with human immunodeficiency virus (HIV) infection and a CD4 cell count of 528 × 10⁶/L without treatment was referred for evaluation of periarticular, indurated, erythematous papules and nodules on the knees and elbows and purpuric lesions on the ankles (Figure 1). He has had recurrent fever, arthralgia, and mild constitutional symptoms during the past month. He also reported a diagnosis of polyclonal immunoglobulin A gammopathy.

Punch biopsy of the purpuric lesions was performed, and histologic study showed leukocytoclastic vasculitis with eosinophilic necrosis of the epithelium.

Treatment with a systemic corticosteroid was started. The purpuric lesions disappeared after 3 weeks of therapy, but the nodules over the extensor surface of both knees showed no improvement (Figure 2). Subsequent biopsy of late-stage lesions (3 months after the start of therapy) demonstrated perivascular fibrosis with small, persistent foci of vasculitis, and confirmed the diagnosis of HIV-associated nodular erythema elevatum diutinum (EED). Antiretroviral therapy was started in addition to intralesional corticosteroids and topical dapsone 5% gel, with resolution of the lesions 1 month later.

ERYTHEMA ELEVATUM DIUTINUM

EED is an uncommon chronic dermatosis, classified as a fibrosing form of leukocytoclastic vasculitis and characterized clinically by violaceous papules, plaques, and nodules, usually distributed acrally and symmetrically over extensor surfaces. The histopathologic picture depends on the stage of the lesion. Features of leukocytoclastic vasculitis are found in early-stage lesions, while a fibrotic replacement of the dermis with small persistent foci of vasculitis is typical of late-stage lesions.

EED has clinical and histopathologic similarities to Sweet syndrome, but EED is distinguished from neutrophilic dermatosis by vasculitis.

In HIV-infected patients, it is important to include pruritic papular eruption in the differential diagnosis. It is characterized by chronic bilaterally symmetric pruritic papules on the trunk and extremities and is the most common cutaneous noninfectious manifestation of HIV.

The clinical presentation of EED may also be easily confused with Kaposi sarcoma and bacillary angiomatosis.²

AN EMERGING HIV-RELATED DERMATOSIS

EED is emerging as a specific HIV-associated dermatosis, with 20 cases reported in the medical literature as of this writing.³

The cause of EED is not known, but it is often associated with streptococcal infection, monoclonal IgA gammopathy, hematologic malignancy, cryoglobulinemia, rheumatoid arthritis, and autoimmune disease.³ The stimulus could be immune-complex deposition in blood vessels triggered by HIV infection, or by another infection acting as an antigenic stimulus.⁴ The nodular variant of EED is even rarer, but it evolves most often in HIV-positive individuals.^5,6

Oral dapsone is the treatment of choice but is less effective in late-stage fibrotic lesions.⁷ Treatment courses tend to be long and recurrence is common.⁸ Intralesional, topical, and oral corticosteroids, topical dapsone 5% gel,⁹ tetracycline and nicotinamide, sulfonamides, colchicine, chloroquine, and surgical excision are other options.

Our patient’s presentation reminds us to consider EED in HIV-infected patients and illustrates the importance of histologic diagnosis to differentiate EED from assumed Kaposi sarcoma in patients with HIV. EED can also be the first clinical sign of HIV infection. It is important to rule out underlying disorders such as HIV infection, because directed therapy is often the best management.

A 39-year-old man with human immunodeficiency virus (HIV) infection and a CD4 cell count of 528 × 10⁶/L without treatment was referred for evaluation of periarticular, indurated, erythematous papules and nodules on the knees and elbows and purpuric lesions on the ankles (Figure 1). He has had recurrent fever, arthralgia, and mild constitutional symptoms during the past month. He also reported a diagnosis of polyclonal immunoglobulin A gammopathy.

Punch biopsy of the purpuric lesions was performed, and histologic study showed leukocytoclastic vasculitis with eosinophilic necrosis of the epithelium.

Treatment with a systemic corticosteroid was started. The purpuric lesions disappeared after 3 weeks of therapy, but the nodules over the extensor surface of both knees showed no improvement (Figure 2). Subsequent biopsy of late-stage lesions (3 months after the start of therapy) demonstrated perivascular fibrosis with small, persistent foci of vasculitis, and confirmed the diagnosis of HIV-associated nodular erythema elevatum diutinum (EED). Antiretroviral therapy was started in addition to intralesional corticosteroids and topical dapsone 5% gel, with resolution of the lesions 1 month later.

ERYTHEMA ELEVATUM DIUTINUM

EED is an uncommon chronic dermatosis, classified as a fibrosing form of leukocytoclastic vasculitis and characterized clinically by violaceous papules, plaques, and nodules, usually distributed acrally and symmetrically over extensor surfaces. The histopathologic picture depends on the stage of the lesion. Features of leukocytoclastic vasculitis are found in early-stage lesions, while a fibrotic replacement of the dermis with small persistent foci of vasculitis is typical of late-stage lesions.

EED has clinical and histopathologic similarities to Sweet syndrome, but EED is distinguished from neutrophilic dermatosis by vasculitis.

In HIV-infected patients, it is important to include pruritic papular eruption in the differential diagnosis. It is characterized by chronic bilaterally symmetric pruritic papules on the trunk and extremities and is the most common cutaneous noninfectious manifestation of HIV.

The clinical presentation of EED may also be easily confused with Kaposi sarcoma and bacillary angiomatosis.²

AN EMERGING HIV-RELATED DERMATOSIS

EED is emerging as a specific HIV-associated dermatosis, with 20 cases reported in the medical literature as of this writing.³

The cause of EED is not known, but it is often associated with streptococcal infection, monoclonal IgA gammopathy, hematologic malignancy, cryoglobulinemia, rheumatoid arthritis, and autoimmune disease.³ The stimulus could be immune-complex deposition in blood vessels triggered by HIV infection, or by another infection acting as an antigenic stimulus.⁴ The nodular variant of EED is even rarer, but it evolves most often in HIV-positive individuals.^5,6

Oral dapsone is the treatment of choice but is less effective in late-stage fibrotic lesions.⁷ Treatment courses tend to be long and recurrence is common.⁸ Intralesional, topical, and oral corticosteroids, topical dapsone 5% gel,⁹ tetracycline and nicotinamide, sulfonamides, colchicine, chloroquine, and surgical excision are other options.

Our patient’s presentation reminds us to consider EED in HIV-infected patients and illustrates the importance of histologic diagnosis to differentiate EED from assumed Kaposi sarcoma in patients with HIV. EED can also be the first clinical sign of HIV infection. It is important to rule out underlying disorders such as HIV infection, because directed therapy is often the best management.

A 39-year-old man with human immunodeficiency virus (HIV) infection and a CD4 cell count of 528 × 10⁶/L without treatment was referred for evaluation of periarticular, indurated, erythematous papules and nodules on the knees and elbows and purpuric lesions on the ankles (Figure 1). He has had recurrent fever, arthralgia, and mild constitutional symptoms during the past month. He also reported a diagnosis of polyclonal immunoglobulin A gammopathy.

Punch biopsy of the purpuric lesions was performed, and histologic study showed leukocytoclastic vasculitis with eosinophilic necrosis of the epithelium.

Treatment with a systemic corticosteroid was started. The purpuric lesions disappeared after 3 weeks of therapy, but the nodules over the extensor surface of both knees showed no improvement (Figure 2). Subsequent biopsy of late-stage lesions (3 months after the start of therapy) demonstrated perivascular fibrosis with small, persistent foci of vasculitis, and confirmed the diagnosis of HIV-associated nodular erythema elevatum diutinum (EED). Antiretroviral therapy was started in addition to intralesional corticosteroids and topical dapsone 5% gel, with resolution of the lesions 1 month later.

ERYTHEMA ELEVATUM DIUTINUM

EED is an uncommon chronic dermatosis, classified as a fibrosing form of leukocytoclastic vasculitis and characterized clinically by violaceous papules, plaques, and nodules, usually distributed acrally and symmetrically over extensor surfaces. The histopathologic picture depends on the stage of the lesion. Features of leukocytoclastic vasculitis are found in early-stage lesions, while a fibrotic replacement of the dermis with small persistent foci of vasculitis is typical of late-stage lesions.

EED has clinical and histopathologic similarities to Sweet syndrome, but EED is distinguished from neutrophilic dermatosis by vasculitis.

In HIV-infected patients, it is important to include pruritic papular eruption in the differential diagnosis. It is characterized by chronic bilaterally symmetric pruritic papules on the trunk and extremities and is the most common cutaneous noninfectious manifestation of HIV.

The clinical presentation of EED may also be easily confused with Kaposi sarcoma and bacillary angiomatosis.²

AN EMERGING HIV-RELATED DERMATOSIS

EED is emerging as a specific HIV-associated dermatosis, with 20 cases reported in the medical literature as of this writing.³

The cause of EED is not known, but it is often associated with streptococcal infection, monoclonal IgA gammopathy, hematologic malignancy, cryoglobulinemia, rheumatoid arthritis, and autoimmune disease.³ The stimulus could be immune-complex deposition in blood vessels triggered by HIV infection, or by another infection acting as an antigenic stimulus.⁴ The nodular variant of EED is even rarer, but it evolves most often in HIV-positive individuals.^5,6

Oral dapsone is the treatment of choice but is less effective in late-stage fibrotic lesions.⁷ Treatment courses tend to be long and recurrence is common.⁸ Intralesional, topical, and oral corticosteroids, topical dapsone 5% gel,⁹ tetracycline and nicotinamide, sulfonamides, colchicine, chloroquine, and surgical excision are other options.

Our patient’s presentation reminds us to consider EED in HIV-infected patients and illustrates the importance of histologic diagnosis to differentiate EED from assumed Kaposi sarcoma in patients with HIV. EED can also be the first clinical sign of HIV infection. It is important to rule out underlying disorders such as HIV infection, because directed therapy is often the best management.

A 39-year-old Filipino man presented with nausea, vomiting, and abdominal pain of 2 weeks’ duration. He did not report trauma, and he had no history of medical illness or surgery.

On arrival, his blood pressure was 123/83 mm Hg, pulse 122 beats per minute, respiratory rate 18 breaths per minute, and temperature 100.7°F (38.1°C). On physical examination, he exhibited marked tenderness of the right upper quadrant on palpation. The abdomen was otherwise soft with no guarding or rebound tenderness.

Results of initial laboratory testing were as follows:

• Leukocyte count 17.0 × 10⁹/L (reference range 4.5–11.0)
• Serum glucose 558 mg/dL without ketoacidosis
• Aspartate aminotransferase 109 U/L (2–40)
• Alanine aminotranferase 28 U/L (2–50)
• Total serum bilirubin 4.0 mg/dL (0.0–1.5).

Plain chest radiography showed dramatic elevation of the right hemidiaphragm with a large subphrenic air-fluid level (Figure 1). Abdominal computed tomography (CT) demonstrated a multiloculated hepatic abscess 18 × 13.5 cm subjacent to the diaphragm (Figure 2). Cultures of blood and the abscess yielded Klebsiella pneumoniae. The patient recovered after percutaneous drainage and a course of ceftriaxone.

PRIMARY KLEBSIELLA LIVER ABSCESS

K pneumoniae, a gram-negative aerobic encapsulated bacillus of the normal human intestinal flora, is closely related to Escherichia coli, historically the most frequent bacterial cause of pyogenic liver abscess.¹ Over the last 30 years, K pneumoniae has eclipsed E coli as the most common causative agent, with the epicenter of this trend being located in Taiwan and South Korea, perhaps because rates of fecal Klebsiella carriage in that region are particularly high.^1,2

Concurrently, there has been increasing recognition—initially across Asia, but lately in Europe and the Western Hemisphere—of the so-called invasive Klebsiella liver abscess (KLA) syndrome, virtually unique to the hypervirulent K1 and K2 capsular serotypes of K pneumoniae prevalent in Asia.^3–6 This community-acquired syndrome is characterized by hematogenous deposition of the organism at distant sites, such as the lung, soft tissues, central nervous system, and eyes. Impairment of phagocytic function, as occurs in diabetes mellitus, and the resistance to phagocytosis conferred by the K1 and K2 serotypes have been identified as predisposing factors for dissemination.^7,8 The mucoid phenotype of K pneumoniae, very common in Asian isolates of the K1 and K2 serotypes, is also associated with hypervirulence and extrahepatic spread, presumably through evasion of phagocytosis and complement-mediated opsonization.^2,9

Our patient’s risk factors for KLA were his Asian origin and uncontrolled diabetes. No evidence of remote infection was detected during his hospitalization.

HEMIDIAPHRAGM ELEVATION

Acquired hemidiaphragm elevation is most commonly unilateral and typically represents an incidental radiologic finding attributable to paralysis of the corresponding diaphragm after phrenic nerve injury caused by trauma, surgery, or infection. Unilateral diaphragmatic paralysis is classically confirmed by performing a fluoroscopic sniff test, which is positive if the affected hemidiaphragm is observed in real time to paradoxically move upward during forced inhalation.¹⁰ This condition is usually asymptomatic at rest but could cause exertional dyspnea and contribute to ventilatory failure when pulmonary disease coexists.¹¹

Occasionally, as in our patient, hemidiaphragm elevation is part of the presentation of active abdominal pathology that displaces the corresponding hemidiaphragm cephalad by mass effect. Examples of such space-occupying abdominal lesions include infections, malignancy, hepatosplenomegaly, and pneumoperitoneum from a ruptured viscus. Pneumoperitoneum is suggested by the presence of an air crescent immediately subjacent to the affected hemidiaphragm on an upright radiograph accompanied by peritoneal signs.

Although there was subphrenic air on this patient’s initial chest radiograph, it was actually part of an air-fluid level without associated peritoneal signs. An air-fluid level is characterized by a sharp horizontal demarcation between the lighter gas component floating at the top and the heavier fluid component settling on the bottom (Figure 1). The subsequent CT excluded free intra-abdominal air while identifying a large hepatic abscess as the cause of hemidiaphragm elevation. In trauma victims, CT is also helpful in ruling out diaphragmatic rupture, which can have a similar radiographic appearance.¹²

Our patient’s presentation was a reminder that an elevated hemidiaphragm may reflect abdominal pathology and that subphrenic air in this context need not be either “free” or a surgical emergency. Drainage of the abscess restored the normal position of our patient’s right hemidiaphragm (Figure 3).

A 39-year-old Filipino man presented with nausea, vomiting, and abdominal pain of 2 weeks’ duration. He did not report trauma, and he had no history of medical illness or surgery.

On arrival, his blood pressure was 123/83 mm Hg, pulse 122 beats per minute, respiratory rate 18 breaths per minute, and temperature 100.7°F (38.1°C). On physical examination, he exhibited marked tenderness of the right upper quadrant on palpation. The abdomen was otherwise soft with no guarding or rebound tenderness.

Results of initial laboratory testing were as follows:

• Leukocyte count 17.0 × 10⁹/L (reference range 4.5–11.0)
• Serum glucose 558 mg/dL without ketoacidosis
• Aspartate aminotransferase 109 U/L (2–40)
• Alanine aminotranferase 28 U/L (2–50)
• Total serum bilirubin 4.0 mg/dL (0.0–1.5).

Plain chest radiography showed dramatic elevation of the right hemidiaphragm with a large subphrenic air-fluid level (Figure 1). Abdominal computed tomography (CT) demonstrated a multiloculated hepatic abscess 18 × 13.5 cm subjacent to the diaphragm (Figure 2). Cultures of blood and the abscess yielded Klebsiella pneumoniae. The patient recovered after percutaneous drainage and a course of ceftriaxone.

PRIMARY KLEBSIELLA LIVER ABSCESS

K pneumoniae, a gram-negative aerobic encapsulated bacillus of the normal human intestinal flora, is closely related to Escherichia coli, historically the most frequent bacterial cause of pyogenic liver abscess.¹ Over the last 30 years, K pneumoniae has eclipsed E coli as the most common causative agent, with the epicenter of this trend being located in Taiwan and South Korea, perhaps because rates of fecal Klebsiella carriage in that region are particularly high.^1,2

Concurrently, there has been increasing recognition—initially across Asia, but lately in Europe and the Western Hemisphere—of the so-called invasive Klebsiella liver abscess (KLA) syndrome, virtually unique to the hypervirulent K1 and K2 capsular serotypes of K pneumoniae prevalent in Asia.^3–6 This community-acquired syndrome is characterized by hematogenous deposition of the organism at distant sites, such as the lung, soft tissues, central nervous system, and eyes. Impairment of phagocytic function, as occurs in diabetes mellitus, and the resistance to phagocytosis conferred by the K1 and K2 serotypes have been identified as predisposing factors for dissemination.^7,8 The mucoid phenotype of K pneumoniae, very common in Asian isolates of the K1 and K2 serotypes, is also associated with hypervirulence and extrahepatic spread, presumably through evasion of phagocytosis and complement-mediated opsonization.^2,9

Our patient’s risk factors for KLA were his Asian origin and uncontrolled diabetes. No evidence of remote infection was detected during his hospitalization.

HEMIDIAPHRAGM ELEVATION

Acquired hemidiaphragm elevation is most commonly unilateral and typically represents an incidental radiologic finding attributable to paralysis of the corresponding diaphragm after phrenic nerve injury caused by trauma, surgery, or infection. Unilateral diaphragmatic paralysis is classically confirmed by performing a fluoroscopic sniff test, which is positive if the affected hemidiaphragm is observed in real time to paradoxically move upward during forced inhalation.¹⁰ This condition is usually asymptomatic at rest but could cause exertional dyspnea and contribute to ventilatory failure when pulmonary disease coexists.¹¹

Occasionally, as in our patient, hemidiaphragm elevation is part of the presentation of active abdominal pathology that displaces the corresponding hemidiaphragm cephalad by mass effect. Examples of such space-occupying abdominal lesions include infections, malignancy, hepatosplenomegaly, and pneumoperitoneum from a ruptured viscus. Pneumoperitoneum is suggested by the presence of an air crescent immediately subjacent to the affected hemidiaphragm on an upright radiograph accompanied by peritoneal signs.

Although there was subphrenic air on this patient’s initial chest radiograph, it was actually part of an air-fluid level without associated peritoneal signs. An air-fluid level is characterized by a sharp horizontal demarcation between the lighter gas component floating at the top and the heavier fluid component settling on the bottom (Figure 1). The subsequent CT excluded free intra-abdominal air while identifying a large hepatic abscess as the cause of hemidiaphragm elevation. In trauma victims, CT is also helpful in ruling out diaphragmatic rupture, which can have a similar radiographic appearance.¹²

Our patient’s presentation was a reminder that an elevated hemidiaphragm may reflect abdominal pathology and that subphrenic air in this context need not be either “free” or a surgical emergency. Drainage of the abscess restored the normal position of our patient’s right hemidiaphragm (Figure 3).

A 39-year-old Filipino man presented with nausea, vomiting, and abdominal pain of 2 weeks’ duration. He did not report trauma, and he had no history of medical illness or surgery.

On arrival, his blood pressure was 123/83 mm Hg, pulse 122 beats per minute, respiratory rate 18 breaths per minute, and temperature 100.7°F (38.1°C). On physical examination, he exhibited marked tenderness of the right upper quadrant on palpation. The abdomen was otherwise soft with no guarding or rebound tenderness.

Results of initial laboratory testing were as follows:

• Leukocyte count 17.0 × 10⁹/L (reference range 4.5–11.0)
• Serum glucose 558 mg/dL without ketoacidosis
• Aspartate aminotransferase 109 U/L (2–40)
• Alanine aminotranferase 28 U/L (2–50)
• Total serum bilirubin 4.0 mg/dL (0.0–1.5).

Plain chest radiography showed dramatic elevation of the right hemidiaphragm with a large subphrenic air-fluid level (Figure 1). Abdominal computed tomography (CT) demonstrated a multiloculated hepatic abscess 18 × 13.5 cm subjacent to the diaphragm (Figure 2). Cultures of blood and the abscess yielded Klebsiella pneumoniae. The patient recovered after percutaneous drainage and a course of ceftriaxone.

PRIMARY KLEBSIELLA LIVER ABSCESS

K pneumoniae, a gram-negative aerobic encapsulated bacillus of the normal human intestinal flora, is closely related to Escherichia coli, historically the most frequent bacterial cause of pyogenic liver abscess.¹ Over the last 30 years, K pneumoniae has eclipsed E coli as the most common causative agent, with the epicenter of this trend being located in Taiwan and South Korea, perhaps because rates of fecal Klebsiella carriage in that region are particularly high.^1,2

Concurrently, there has been increasing recognition—initially across Asia, but lately in Europe and the Western Hemisphere—of the so-called invasive Klebsiella liver abscess (KLA) syndrome, virtually unique to the hypervirulent K1 and K2 capsular serotypes of K pneumoniae prevalent in Asia.^3–6 This community-acquired syndrome is characterized by hematogenous deposition of the organism at distant sites, such as the lung, soft tissues, central nervous system, and eyes. Impairment of phagocytic function, as occurs in diabetes mellitus, and the resistance to phagocytosis conferred by the K1 and K2 serotypes have been identified as predisposing factors for dissemination.^7,8 The mucoid phenotype of K pneumoniae, very common in Asian isolates of the K1 and K2 serotypes, is also associated with hypervirulence and extrahepatic spread, presumably through evasion of phagocytosis and complement-mediated opsonization.^2,9

Our patient’s risk factors for KLA were his Asian origin and uncontrolled diabetes. No evidence of remote infection was detected during his hospitalization.

HEMIDIAPHRAGM ELEVATION

Acquired hemidiaphragm elevation is most commonly unilateral and typically represents an incidental radiologic finding attributable to paralysis of the corresponding diaphragm after phrenic nerve injury caused by trauma, surgery, or infection. Unilateral diaphragmatic paralysis is classically confirmed by performing a fluoroscopic sniff test, which is positive if the affected hemidiaphragm is observed in real time to paradoxically move upward during forced inhalation.¹⁰ This condition is usually asymptomatic at rest but could cause exertional dyspnea and contribute to ventilatory failure when pulmonary disease coexists.¹¹

Occasionally, as in our patient, hemidiaphragm elevation is part of the presentation of active abdominal pathology that displaces the corresponding hemidiaphragm cephalad by mass effect. Examples of such space-occupying abdominal lesions include infections, malignancy, hepatosplenomegaly, and pneumoperitoneum from a ruptured viscus. Pneumoperitoneum is suggested by the presence of an air crescent immediately subjacent to the affected hemidiaphragm on an upright radiograph accompanied by peritoneal signs.

Although there was subphrenic air on this patient’s initial chest radiograph, it was actually part of an air-fluid level without associated peritoneal signs. An air-fluid level is characterized by a sharp horizontal demarcation between the lighter gas component floating at the top and the heavier fluid component settling on the bottom (Figure 1). The subsequent CT excluded free intra-abdominal air while identifying a large hepatic abscess as the cause of hemidiaphragm elevation. In trauma victims, CT is also helpful in ruling out diaphragmatic rupture, which can have a similar radiographic appearance.¹²

Our patient’s presentation was a reminder that an elevated hemidiaphragm may reflect abdominal pathology and that subphrenic air in this context need not be either “free” or a surgical emergency. Drainage of the abscess restored the normal position of our patient’s right hemidiaphragm (Figure 3).

Our goal at the Cleveland Clinic Journal of Medicine is to provide timely, readily digestible, and useful clinical information to our readers. To do so, we need authors who buy into our educational mission, but we also need conscientious peer reviewers and an editorial staff capable of turning “doctorese” into readily understood English.

Our physician deputy editors Pelin Batur and James Pile solicit articles, guide authors, draft and revise CME questions, and assist greatly in the peer review process. Our nonphysician editors edit manuscripts to achieve a consistent editorial style in all of our published papers, but they serve many other key functions. They  manage the business of publishing a monthly journal at a time of drastically shrinking advertising revenue, they ensure that Journal content complies with rules for CME material published in print and online, and they keep up with continuous changes in online publishing. The Journal receives significant funding from Cleveland Clinic’s Education Institute, funding we need to pursue our role as an independent, peer-reviewed conveyer of clinical information.

I write this to emphasize that real people manage all of these tasks, and to gratefully acknowledge two people who are leaving the Journal: Mr. Joseph Dennehy and Dr. James Pile.

Long-time sales and marketing director Joe Dennehy played a key role in the Journal’s rise from relative obscurity about 20 years ago. This period was marked by many hospital-based journals closing up shop. Published since 1931, the Journal was relaunched in 1995 as a resource for postgraduate medical education with a national and international reach. Joe was brought in to guide and implement the marketing of the Journal as an independent, high-quality, clinical educational journal to increase its attractiveness as an advertising medium for the pharmaceutical industry so we could at least partly defray the significant expenses of publishing.

Joe is well known to medical publishers and media buyers, and over the past 20 years he became the face of the Journal in sales and marketing circles. In 2010, the Association of Medical Media recognized Joe’s achievements at its 18th Annual Nexus Representatives of the Year Awards, which acknowledge outstanding sales and marketing directors for their superior service, professionalism, and communication of ideas. Joe exemplifies these qualities and has been an inspiration to those of us who know and work with him. He has fully understood the sincerity of our mission and has never asked us to stray from it. Although Joe and his wife Holly live in New York, they are part of the Cleveland-based Journal family, and we will miss them. We wish them happiness and good health.

Dr. James Pile is an internal medicine hospitalist, an infectious disease specialist, and a superior medical educator. His work with us for the past several years has enhanced the Journal’s educational value for practicing hospitalists. His working familiarity with clinical leaders in the Society of Hospital Medicine has provided us with willing and skilled peer reviewers. Jim is now transitioning to a role as director of the internal medicine residency program at MetroHealth Medical Center, also here in Cleveland. He will continue to be a clinical resource for us as author and reviewer, but his ever-calm demeanor and clinical common sense will be hard to replace.

The Journal continues to evolve with the publishing times. We are assuming a greater presence in the digital world and adjusting to an environment of ever-diminishing advertising revenue. But with the work of our editorial team (I invite you to periodically glance at our masthead to note our team of writers, managers, and production staff), we intend to stay true to our educational mission. Our personal thanks to Joe and Jim for their contributions of the past, and to our current team in Scientific Publications for their ongoing and very personal commitment to providing the highest quality medical education that we can.

Our goal at the Cleveland Clinic Journal of Medicine is to provide timely, readily digestible, and useful clinical information to our readers. To do so, we need authors who buy into our educational mission, but we also need conscientious peer reviewers and an editorial staff capable of turning “doctorese” into readily understood English.

Our physician deputy editors Pelin Batur and James Pile solicit articles, guide authors, draft and revise CME questions, and assist greatly in the peer review process. Our nonphysician editors edit manuscripts to achieve a consistent editorial style in all of our published papers, but they serve many other key functions. They  manage the business of publishing a monthly journal at a time of drastically shrinking advertising revenue, they ensure that Journal content complies with rules for CME material published in print and online, and they keep up with continuous changes in online publishing. The Journal receives significant funding from Cleveland Clinic’s Education Institute, funding we need to pursue our role as an independent, peer-reviewed conveyer of clinical information.

I write this to emphasize that real people manage all of these tasks, and to gratefully acknowledge two people who are leaving the Journal: Mr. Joseph Dennehy and Dr. James Pile.

Long-time sales and marketing director Joe Dennehy played a key role in the Journal’s rise from relative obscurity about 20 years ago. This period was marked by many hospital-based journals closing up shop. Published since 1931, the Journal was relaunched in 1995 as a resource for postgraduate medical education with a national and international reach. Joe was brought in to guide and implement the marketing of the Journal as an independent, high-quality, clinical educational journal to increase its attractiveness as an advertising medium for the pharmaceutical industry so we could at least partly defray the significant expenses of publishing.

Joe is well known to medical publishers and media buyers, and over the past 20 years he became the face of the Journal in sales and marketing circles. In 2010, the Association of Medical Media recognized Joe’s achievements at its 18th Annual Nexus Representatives of the Year Awards, which acknowledge outstanding sales and marketing directors for their superior service, professionalism, and communication of ideas. Joe exemplifies these qualities and has been an inspiration to those of us who know and work with him. He has fully understood the sincerity of our mission and has never asked us to stray from it. Although Joe and his wife Holly live in New York, they are part of the Cleveland-based Journal family, and we will miss them. We wish them happiness and good health.

Dr. James Pile is an internal medicine hospitalist, an infectious disease specialist, and a superior medical educator. His work with us for the past several years has enhanced the Journal’s educational value for practicing hospitalists. His working familiarity with clinical leaders in the Society of Hospital Medicine has provided us with willing and skilled peer reviewers. Jim is now transitioning to a role as director of the internal medicine residency program at MetroHealth Medical Center, also here in Cleveland. He will continue to be a clinical resource for us as author and reviewer, but his ever-calm demeanor and clinical common sense will be hard to replace.

The Journal continues to evolve with the publishing times. We are assuming a greater presence in the digital world and adjusting to an environment of ever-diminishing advertising revenue. But with the work of our editorial team (I invite you to periodically glance at our masthead to note our team of writers, managers, and production staff), we intend to stay true to our educational mission. Our personal thanks to Joe and Jim for their contributions of the past, and to our current team in Scientific Publications for their ongoing and very personal commitment to providing the highest quality medical education that we can.

Our goal at the Cleveland Clinic Journal of Medicine is to provide timely, readily digestible, and useful clinical information to our readers. To do so, we need authors who buy into our educational mission, but we also need conscientious peer reviewers and an editorial staff capable of turning “doctorese” into readily understood English.

Our physician deputy editors Pelin Batur and James Pile solicit articles, guide authors, draft and revise CME questions, and assist greatly in the peer review process. Our nonphysician editors edit manuscripts to achieve a consistent editorial style in all of our published papers, but they serve many other key functions. They  manage the business of publishing a monthly journal at a time of drastically shrinking advertising revenue, they ensure that Journal content complies with rules for CME material published in print and online, and they keep up with continuous changes in online publishing. The Journal receives significant funding from Cleveland Clinic’s Education Institute, funding we need to pursue our role as an independent, peer-reviewed conveyer of clinical information.

I write this to emphasize that real people manage all of these tasks, and to gratefully acknowledge two people who are leaving the Journal: Mr. Joseph Dennehy and Dr. James Pile.

Long-time sales and marketing director Joe Dennehy played a key role in the Journal’s rise from relative obscurity about 20 years ago. This period was marked by many hospital-based journals closing up shop. Published since 1931, the Journal was relaunched in 1995 as a resource for postgraduate medical education with a national and international reach. Joe was brought in to guide and implement the marketing of the Journal as an independent, high-quality, clinical educational journal to increase its attractiveness as an advertising medium for the pharmaceutical industry so we could at least partly defray the significant expenses of publishing.

Joe is well known to medical publishers and media buyers, and over the past 20 years he became the face of the Journal in sales and marketing circles. In 2010, the Association of Medical Media recognized Joe’s achievements at its 18th Annual Nexus Representatives of the Year Awards, which acknowledge outstanding sales and marketing directors for their superior service, professionalism, and communication of ideas. Joe exemplifies these qualities and has been an inspiration to those of us who know and work with him. He has fully understood the sincerity of our mission and has never asked us to stray from it. Although Joe and his wife Holly live in New York, they are part of the Cleveland-based Journal family, and we will miss them. We wish them happiness and good health.

Dr. James Pile is an internal medicine hospitalist, an infectious disease specialist, and a superior medical educator. His work with us for the past several years has enhanced the Journal’s educational value for practicing hospitalists. His working familiarity with clinical leaders in the Society of Hospital Medicine has provided us with willing and skilled peer reviewers. Jim is now transitioning to a role as director of the internal medicine residency program at MetroHealth Medical Center, also here in Cleveland. He will continue to be a clinical resource for us as author and reviewer, but his ever-calm demeanor and clinical common sense will be hard to replace.

The Journal continues to evolve with the publishing times. We are assuming a greater presence in the digital world and adjusting to an environment of ever-diminishing advertising revenue. But with the work of our editorial team (I invite you to periodically glance at our masthead to note our team of writers, managers, and production staff), we intend to stay true to our educational mission. Our personal thanks to Joe and Jim for their contributions of the past, and to our current team in Scientific Publications for their ongoing and very personal commitment to providing the highest quality medical education that we can.