In the current sociopolitical environment in the United States, the slogan “words matter” has become a battle cry for several groups and causes, emphasizing that our choice of words can influence the way we assess a specific person or situation. We are not immune to the subliminal bias of words, even as we evaluate such seemingly objective components of clinical management as laboratory test results.

Several years ago, I was supervising teaching rounds on a general medicine service. It was the first rounds of the month, and the patients were relatively new to the residents and totally unknown to me. One patient was an elderly man with weight loss, fatigue, weakness, and a history of excessive alcohol ingestion. His family had corroborated the last detail, but he had stopped drinking a long time before his admission. He had normal creatinine, minimal anemia, and markedly elevated and unexplained “liver function tests.” Liver biopsy was planned.

As we entered his room, we saw a gaunt man struggle to rise from the bedside chair to get back into bed. He rocked several times and then pushed himself up from the chair using his arms. Then, after a few short steps, he plopped back into bed and greeted us. His breakfast tray was untouched at the bedside. I introduced myself, we chatted for a short while as I examined him in front of our team, and we left.

In the hallway I asked, “Who would like to get an additional blood test before we do a liver biopsy?” Without waiting for a response I asked a second question, “What exactly are liver function tests?”

Words do matter, and they influence the way we analyze clinical scenarios. It could be argued that a complete and careful history would have established that our patient’s fatigue and weakness were due to proximal muscle weakness and not general asthenia, and that detailed questioning would have revealed that his weight loss was mainly from difficulty in swallowing without a sense of choking and coughing. But faced with an elderly man, a likely explanation for liver disease, and markedly elevated aspartate and alanine aminotransferase (AST and ALT) levels, there was premature closure of the diagnosis, and the decision was made to obtain a liver biopsy—which our hepatology consultants surely would not have done. I believe that a major contributor to the premature diagnosis was the choice of the words “liver function tests” and the default assumption that elevated serum levels of these enzymes always reflect liver disease.

Aminotransferases are fairly ubiquitous, likely present in various concentrations in all cells in our body. AST exists in mitochondrial and cytosolic forms, and ALT in the cytosol. The concentration of ALT is higher in the liver than in other organs, and its enzymatic activity is suppressed by hepatic exposure to alcohol. Both enzymes are present in muscle, and although AST is more abundant in cells other than hepatocytes, the longer serum half-life of ALT may result in roughly equal serum levels in the setting of chronic muscle injury such as myositis (the true diagnosis in our weak patient).

While a meticulous history and examination would indeed have led to the diagnosis of muscle disease in this man, they alone could not have determined whether he had coexistent liver and muscle disease. And this is a real challenge when acute muscle toxicity and liver toxicity are equally possible (eg, statin or immune checkpoint autoimmune tissue damage, or after significant trauma).

There are many nuances in the interpretation of even the most common laboratory tests. In this issue of the Journal, Agganis et al discuss liver enzymes (a term slightly more acceptable to me than liver function tests). In future issues, we will address the interpretation of other laboratory tests.

In the current sociopolitical environment in the United States, the slogan “words matter” has become a battle cry for several groups and causes, emphasizing that our choice of words can influence the way we assess a specific person or situation. We are not immune to the subliminal bias of words, even as we evaluate such seemingly objective components of clinical management as laboratory test results.

Several years ago, I was supervising teaching rounds on a general medicine service. It was the first rounds of the month, and the patients were relatively new to the residents and totally unknown to me. One patient was an elderly man with weight loss, fatigue, weakness, and a history of excessive alcohol ingestion. His family had corroborated the last detail, but he had stopped drinking a long time before his admission. He had normal creatinine, minimal anemia, and markedly elevated and unexplained “liver function tests.” Liver biopsy was planned.

As we entered his room, we saw a gaunt man struggle to rise from the bedside chair to get back into bed. He rocked several times and then pushed himself up from the chair using his arms. Then, after a few short steps, he plopped back into bed and greeted us. His breakfast tray was untouched at the bedside. I introduced myself, we chatted for a short while as I examined him in front of our team, and we left.

In the hallway I asked, “Who would like to get an additional blood test before we do a liver biopsy?” Without waiting for a response I asked a second question, “What exactly are liver function tests?”

Words do matter, and they influence the way we analyze clinical scenarios. It could be argued that a complete and careful history would have established that our patient’s fatigue and weakness were due to proximal muscle weakness and not general asthenia, and that detailed questioning would have revealed that his weight loss was mainly from difficulty in swallowing without a sense of choking and coughing. But faced with an elderly man, a likely explanation for liver disease, and markedly elevated aspartate and alanine aminotransferase (AST and ALT) levels, there was premature closure of the diagnosis, and the decision was made to obtain a liver biopsy—which our hepatology consultants surely would not have done. I believe that a major contributor to the premature diagnosis was the choice of the words “liver function tests” and the default assumption that elevated serum levels of these enzymes always reflect liver disease.

Aminotransferases are fairly ubiquitous, likely present in various concentrations in all cells in our body. AST exists in mitochondrial and cytosolic forms, and ALT in the cytosol. The concentration of ALT is higher in the liver than in other organs, and its enzymatic activity is suppressed by hepatic exposure to alcohol. Both enzymes are present in muscle, and although AST is more abundant in cells other than hepatocytes, the longer serum half-life of ALT may result in roughly equal serum levels in the setting of chronic muscle injury such as myositis (the true diagnosis in our weak patient).

While a meticulous history and examination would indeed have led to the diagnosis of muscle disease in this man, they alone could not have determined whether he had coexistent liver and muscle disease. And this is a real challenge when acute muscle toxicity and liver toxicity are equally possible (eg, statin or immune checkpoint autoimmune tissue damage, or after significant trauma).

There are many nuances in the interpretation of even the most common laboratory tests. In this issue of the Journal, Agganis et al discuss liver enzymes (a term slightly more acceptable to me than liver function tests). In future issues, we will address the interpretation of other laboratory tests.

In the current sociopolitical environment in the United States, the slogan “words matter” has become a battle cry for several groups and causes, emphasizing that our choice of words can influence the way we assess a specific person or situation. We are not immune to the subliminal bias of words, even as we evaluate such seemingly objective components of clinical management as laboratory test results.

Several years ago, I was supervising teaching rounds on a general medicine service. It was the first rounds of the month, and the patients were relatively new to the residents and totally unknown to me. One patient was an elderly man with weight loss, fatigue, weakness, and a history of excessive alcohol ingestion. His family had corroborated the last detail, but he had stopped drinking a long time before his admission. He had normal creatinine, minimal anemia, and markedly elevated and unexplained “liver function tests.” Liver biopsy was planned.

As we entered his room, we saw a gaunt man struggle to rise from the bedside chair to get back into bed. He rocked several times and then pushed himself up from the chair using his arms. Then, after a few short steps, he plopped back into bed and greeted us. His breakfast tray was untouched at the bedside. I introduced myself, we chatted for a short while as I examined him in front of our team, and we left.

In the hallway I asked, “Who would like to get an additional blood test before we do a liver biopsy?” Without waiting for a response I asked a second question, “What exactly are liver function tests?”

Words do matter, and they influence the way we analyze clinical scenarios. It could be argued that a complete and careful history would have established that our patient’s fatigue and weakness were due to proximal muscle weakness and not general asthenia, and that detailed questioning would have revealed that his weight loss was mainly from difficulty in swallowing without a sense of choking and coughing. But faced with an elderly man, a likely explanation for liver disease, and markedly elevated aspartate and alanine aminotransferase (AST and ALT) levels, there was premature closure of the diagnosis, and the decision was made to obtain a liver biopsy—which our hepatology consultants surely would not have done. I believe that a major contributor to the premature diagnosis was the choice of the words “liver function tests” and the default assumption that elevated serum levels of these enzymes always reflect liver disease.

Aminotransferases are fairly ubiquitous, likely present in various concentrations in all cells in our body. AST exists in mitochondrial and cytosolic forms, and ALT in the cytosol. The concentration of ALT is higher in the liver than in other organs, and its enzymatic activity is suppressed by hepatic exposure to alcohol. Both enzymes are present in muscle, and although AST is more abundant in cells other than hepatocytes, the longer serum half-life of ALT may result in roughly equal serum levels in the setting of chronic muscle injury such as myositis (the true diagnosis in our weak patient).

While a meticulous history and examination would indeed have led to the diagnosis of muscle disease in this man, they alone could not have determined whether he had coexistent liver and muscle disease. And this is a real challenge when acute muscle toxicity and liver toxicity are equally possible (eg, statin or immune checkpoint autoimmune tissue damage, or after significant trauma).

There are many nuances in the interpretation of even the most common laboratory tests. In this issue of the Journal, Agganis et al discuss liver enzymes (a term slightly more acceptable to me than liver function tests). In future issues, we will address the interpretation of other laboratory tests.

The balance between dietary intake and excretion of phosphorus can be impaired in patients with decreased renal function, leading to hyperphosphatemia. Many patients with end-stage renal disease on dialysis require phosphorus-binding drugs to control their serum phosphorus levels.

See related editorial and article

In this review, we discuss the pathophysiology of hyperphosphatemia in kidney disease, its consequences, and how to control it, focusing on the different classes of phosphorus binders.

ROLE OF THE INTERNIST

With kidney disease common and on the increase,¹ nephrologists and internists need to work together to provide optimal care.

Further, many internists in managed care plans and accountable care organizations now handle many tasks previously left to specialists—including prescribing and managing phosphorus binders in patients with kidney disease.

PATHOPHYSIOLOGY OF HYPERPHOSPHATEMIA

The pathophysiology of bone mineral disorders in kidney disease is complex. To simplify the discussion, we will address it in 3 parts:

• Phosphorus balance
• The interplay of hormones, including fibro­blast growth factor 23 (FGF23)
• The mechanism of hyperphosphatemia in kidney disease.

Phosphorus balance

Phosphorus is a macronutrient essential for a range of cellular functions that include structure, energy production, metabolism, and cell signaling. It exists primarily in the form of inorganic phosphate.

An average Western diet provides 20 mg of phosphorus per kilogram of body weight per day. Of this, 13 mg/kg is absorbed, and the rest is excreted in the feces.²

Absorption of dietary phosphorus occurs mainly in the jejunum. It is mediated by both a paracellular sodium-independent pathway (driven by high intraluminal phosphorus content) and by active sodium-dependent cotransporters. It is also influenced by diet and promoted by active vitamin D (1,25 dihydroxyvitamin D₃, also called calcitriol).³

Absorbed phosphorus enters the extracellular fluid and shifts in and out of the skeleton under the influence of parathyroid hormone.

Phosphorus excretion is handled almost entirely by the kidneys. Phosphorus is freely filtered at the glomerulus and reabsorbed mainly in the proximal tubule by sodium-phosphate cotransporters.

Normally, when phosphorus intake is adequate, most of the filtered phosphorus is reabsorbed and only 10% to 20% is excreted in the urine. However, the threshold for phosphorus reabsorption in the proximal tubule is influenced by parathyroid hormone, FGF23, and dietary phosphorus intake: low serum phosphate levels lead to an increase in the synthesis of sodium-phosphorus cotransporters, resulting in increased (nearly complete) proximal reabsorption and an increase in the serum phosphorus concentration.⁴ Conversely, both parathyroid hormone and FGF23 are phosphaturic and decrease the number of phosphorus transporters, which in turn leads to increased phosphorus excretion and a decrease in serum phosphorus concentration.⁵

Interplay of hormones

FGF23 is a phosphaturic glycoprotein secreted by osteoblasts and osteocytes. It acts by binding to fibroblastic growth receptor 1 in the presence of its coreceptor, the Klotho protein.⁶

FGF23 is regulated by serum phosphorus levels and plays a major role in the response to elevated serum phosphorus. It causes a direct increase in urinary phosphorus excretion, a decrease in intestinal phosphorus absorption (indirectly via inhibition of calcitriol), and decreased bone resorption via a decrease in parathyroid hormone production.⁷

Mechanism of hyperphosphatemia in kidney disease

In chronic kidney disease, phosphorus retention can trigger secondary hyperparathyroidism, as rising phosphorus levels stimulate FGF23. In the early stages of chronic kidney disease, this response can correct the phosphorus levels, but with several consequences:

• Decreased calcitriol due to its inhibition by FGF23⁹
• Hypocalcemia due to decreased calcitriol (leading to decreased intestinal calcium absorption) and calcium binding of retained phosphorus
• Elevated parathyroid hormone due to low calcitriol levels (lack of inhibitory feedback by calcitriol), hyperphosphatemia, and hypocalcemia (direct parathyroid hormone stimulation).

As the elevated phosphorus level is likely to be the triggering event behind secondary renal hyperparathyroidism, it needs to be controlled. This is accomplished by restricting dietary phosphorus and using phosphorus binders.

HYPERPHOSPHATEMIA MAY LEAD TO VASCULAR CALCIFICATION

Elevated serum phosphorus levels (normal range 2.48–4.65 mg/dL in adults¹¹) are associated with cardiovascular calcification and subsequent increases in mortality and morbidity rates. Elevations in serum phosphorus and calcium levels are associated with progression in vascular calcification¹² and likely account for the accelerated vascular calcification that is seen in kidney disease.¹³

Hyperphosphatemia has been identified as an independent risk factor for death in patients with end-stage renal disease,¹⁴ but that relationship is less clear in patients with chronic kidney disease. A study in patients with chronic kidney disease and not on dialysis found a lower mortality rate in those who were prescribed phosphorus binders,¹⁵ but the study was criticized for limitations in its design.

Hyperphosphatemia can also lead to adverse effects on bone health due to complications such as renal osteodystrophy.

However, in its 2017 update, the Kidney Disease: Improving Global Outcomes (KDIGO) program only “suggests” lowering elevated phosphorus levels “toward” the normal range in patients with chronic kidney disease stages G3a through G5D, ie, those with glomerular filtration rates less than 60 mL/min/1.73 m², including those on dialysis. The recommendation is graded 2C, ie, weak, based on low-quality evidence (https://kdigo.org/guidelines/ckd-mbd).

DIETARY RESTRICTION OF PHOSPHORUS

Diet is the major source of phosphorus intake. The average daily phosphorus consumption is  20 mg/kg, or 1,400 mg, and protein is the major source of dietary phosphorus.

In patients with stage 4 or 5 chronic kidney disease, the Kidney Disease Outcomes Quality Initiative recommends limiting protein intake to 0.6 mg/kg/day.¹⁶ However, in patients on hemodialysis, they recommend increasing protein intake to 1.1 mg/kg/day while limiting phosphorus intake to about 800 to 1,000 mg/day. This poses a challenge, as limiting phosphorus intake can reduce protein intake.

Sources of protein can be broadly classified as plant-based or animal-based. Animal protein contains organic phosphorus, which is easily absorbed.¹⁸ Plant protein may not be absorbed as easily.

Moe et al¹⁹ studied the importance of the protein source of phosphorus after 7 days of controlled diets. Despite equivalent protein and phosphorus concentrations in the vegetarian and meat-based diets, participants on the vegetarian diet had lower serum phosphorus levels, a trend toward lower 24-hour urinary phosphorus excretion, and significantly lower FGF23 levels than those on the meat-based diet. This suggests that a vegetarian diet may have advantages in terms of preventing hyperphosphatemia.

Another measure to reduce phosphorus absorption from meat is to boil it, which reduces the phosphorus content by 50%.²⁰

Processed foods containing additives and preservatives are very high in phosphorus²¹ and should be avoided, particularly as there is no mandate to label phosphorus content in food.

PHOSPHORUS AND DIALYSIS

Although hemodialysis removes phosphorus, it does not remove enough to keep levels within normal limits. Indeed, even when patients adhere to a daily phosphorus limit of 1,000 mg, phosphorus accumulates. If 70% of the phosphorus in the diet is absorbed, this is 4,500 to 5,000 mg in a week. A 4-hour hemodialysis session will remove only 1,000 mg of phosphorus, which equals about 3,000 mg for patients undergoing dialysis 3 times a week,²² far less than phosphorus absorption.

In patients on continuous ambulatory peritoneal dialysis, a daily regimen of 4 exchanges of 2 L per exchange removes about 200 mg of phosphorus per day. In a 2012 study, patients on nocturnal dialysis or home dialysis involving longer session length had greater lowering of phosphorus levels than patients undergoing routine hemodialysis.²³

Hence, phosphorus binders are often necessary in patients on routine hemodialysis or peritoneal dialysis.

PHOSPHORUS BINDERS

Phosphorus binders reduce serum phosphorus levels by binding with ingested phosphorus in the gastrointestinal tract and forming insoluble complexes that are not absorbed. For this reason they are much more effective when taken with meals. Phosphorus binders come in different formulations: pills, capsules, chewable tablets, liquids, and even powders that can be sprinkled on food.

The potency of each binder is quantified by its “phosphorus binder equivalent dose,” ie, its binding capacity compared with that of calcium carbonate as a reference.²⁴

Phosphorus binders are broadly divided into those that contain calcium and those that do not.

Calcium-containing binders

The 2 most commonly used preparations are calcium carbonate (eg, Tums) and calcium acetate (eg, Phoslo). While these are relatively safe, some studies suggest that their use can lead to accelerated vascular calcification.²⁵

According to KDIGO,²⁶ calcium-containing binders should be avoided in hypercalcemia and adynamic bone disease. Additionally, the daily elemental calcium intake from binders should be limited to 1,500 mg, with a total daily intake that does not exceed 2,000 mg.

The elemental calcium content of calcium carbonate is about 40% of its weight (eg, 200 mg of elemental calcium in a 500-mg tablet of Tums), while the elemental calcium content of calcium acetate is about 25%. Therefore, a patient who needs 6 g of calcium carbonate for efficacy will be ingesting 2.4 g of elemental calcium per day, and that exceeds the recommended daily maximum. The main advantage of calcium carbonate is its low cost and easy availability. Commonly reported side effects include nausea and constipation.

A less commonly used calcium-based binder is calcium citrate (eg, Calcitrate). It should, however, be avoided in chronic kidney disease because of the risk of aluminum accumulation. Calcium citrate can enhance intestinal absorption of aluminum from dietary sources, as aluminum can form complexes with citrate.²⁷

Calcium-free binders

There are several calcium-free binders. Some are based on metals such as aluminum, magnesium, iron, and lanthanum; others, such as sevelamer, are resin-based.

Aluminum- and magnesium-based binders are generally not used long-term in kidney disease because of the toxicity associated with aluminum and magnesium accumulation. However, aluminum hydroxide has an off-label use as a phosphorus binder in the acute setting, particularly when serum phosphorus levels are above 7 mg/dL.²⁸ The dose is 300 to 600 mg 3 times daily with meals for a maximum of 4 weeks.

Sevelamer. Approved by the US Food and Drug Administration (FDA) in 1998, sevelamer acts by trapping phosphorus through ion exchange and hydrogen binding. It has the advantage of being calcium-free, which makes it particularly desirable in patients with hypercalcemia.

The Renagel in New Dialysis²⁵ and Treat-To-Goal²⁹ studies were randomized controlled trials that looked at the effects of sevelamer vs calcium-based binders on the risk of vascular calcification. The primary end points were serum phosphorus and calcium levels, while the secondary end points were coronary artery calcification on computed tomography and thoracic vertebral bone density. Both studies demonstrated a higher risk of vascular calcification with the calcium-based binders.

Another possible benefit of sevelamer is an improvement in lipid profile. Sevelamer lowers total cholesterol and low-density lipoprotein cholesterol levels without affecting high-density lipoprotein cholesterol or triglyceride levels.³⁰ This is likely due to its bile acid-binding effect.³¹ Sevelamer has also been shown to lower C-reactive protein levels.³² While the cardiovascular profile appears to be improved with the treatment, there are no convincing data to confirm that those properties translate to a proven independent survival benefit.

The Calcium Acetate Renagel Evaluation³³ was a randomized controlled study comparing sevelamer and calcium acetate. The authors attempted to control for the lipid-lowering effects of sevelamer by giving atorvastatin to all patients in both groups who had a low-density lipoprotein level greater than 70 mg/dL. The study found sevelamer to be not inferior to calcium acetate in terms of mortality and coronary calcification.

Further studies such as the Brazilian Renagel and Calcium trial³⁴ and the Dialysis Clinical Outcomes Revisited trial failed to show a significant long-term benefit of sevelamer over calcium-based binders. However, a secondary statistical analysis of the latter study showed possible benefit of sevelamer over calcium acetate among those age 65 and older.³⁵

To understand how sevelamer could affect vascular calcification, Yilmaz et al³⁶ compared the effects of sevelamer vs calcium acetate on FGF23 and fetuin A levels. Fetuin A is an important inhibitor of vascular calcification and is progressively diminished in kidney disease, leading to accelerated calcification.³⁷ Patients on sevelamer had higher levels of fetuin A than their counterparts on calcium acetate.³⁷ The authors proposed increased fetuin A levels as a mechanism for decreased vascular calcification.

In summary, some studies suggest that sevelamer may offer the advantage of decreasing vascular calcification, but the data are mixed and do not provide a solid answer. The main disadvantages of sevelamer are a high pill burden and side effects of nausea and dyspepsia.

Lanthanum, a metallic element, was approved as a phosphorus binder by the FDA in 2008. It comes as a chewable tablet and offers the advantage of requiring the patient to take fewer pills than sevelamer and calcium-based binders.

Sucroferric oxyhydroxide comes as a chewable tablet. It was approved by the FDA in 2013. Although each tablet contains 500 mg of iron, it has not been shown to improve iron markers. In terms of phosphorus-lowering ability, it has been shown to be noninferior to sevelamer.³⁹ Advantages include a significantly lower pill burden. Disadvantages include gastrointestinal side effects such as diarrhea and nausea and the drug’s high cost.

Ferric citrate was approved by the FDA in 2014, and 1 g delivers 210 mg of elemental iron. The main advantage of ferric citrate is its ability to increase iron markers. The phase 3 trial that demonstrated its efficacy as a binder showed an increase in ferritin compared with the active control.⁴⁰ The study also showed a decrease in the need to use intravenous iron and erythropoesis-stimulating agents. This was thought to be due to improved iron stores, leading to decreased erythropoietin resistance.⁴¹

The mean number of ferric citrate tablets needed to achieve the desired phosphorus-lowering effect was 8 per day, containing 1,680 mg of iron. In comparison, oral ferrous sulfate typically provides 210 mg of iron per day.⁴²

Disadvantages of ferric citrate include high pill burden, high cost, and gastrointestinal side effects such as nausea and constipation.

Chitosan binds salivary phosphorus. It can potentially be used, but it is not approved, and its efficacy in lowering serum phosphorus remains unclear.⁴³

CHOOSING THE APPROPRIATE PHOSPHORUS BINDER

The choice of phosphorus binder is based on the patient’s serum calcium level and iron stores and on the drug’s side effect profile, iron pill burden, and cost. Involving patients in the choice after discussing potential side effects, pill burden, and cost is important for shared decision-making and could play a role in improving adherence.

Phosphorus binders are a major portion of the pill burden in patients with end-stage renal disease, possibly affecting patient adherence. The cost of phosphorus binders is estimated at half a billion dollars annually, underlining the significant economic impact of phosphorus control.¹¹

Calcium-based binders should be the first choice when there is secondary hyperparathyroidism without hypercalcemia. There is no clear evidence regarding the benefit of correcting hypocalcemia, but KDIGO recommends keeping the serum calcium level within the reference range. KDIGO also recommends restricting calcium-based binders in persistent hypercalcemia, arterial calcification, and adynamic bone disease. This recommendation is largely based on expert opinion.

Noncalcium-based binders, which in theory might prevent vascular calcification, should be considered for patients with at least 1 of the following⁴⁴:

• Complicated diabetes mellitus
• Vascular or valvular calcification
• Persistent inflammation.

Noncalcium-based binders are also preferred in low bone-turnover states such as adynamic bone disease, as elevated calcium can inhibit parathyroid hormone.

However, the advantage of noncalcium-based binders regarding vascular calcification is largely theoretical and has not been proven clinically. Indeed, there are data comparing long-term outcomes of the different classes of phosphorus binders, but studies were limited by short follow-up, and individual studies have lacked power to detect statistical significance between two classes of binders on long-term outcomes. Meta-analyses have provided conflicting data, with some suggesting better outcomes with sevelamer than with calcium-based binders, and with others failing to show any difference.⁴⁵

Because iron deficiency is common in kidney disease, ferric citrate, which can improve iron markers, may be a suitable option, provided its cost is covered by insurance.

SPECIAL CIRCUMSTANCES FOR THE USE OF PHOSPHORUS BINDERS

Tumor lysis syndrome

Tumor lysis syndrome occurs when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.⁴⁶ Phosphorus binders in conjunction with intravenous hydration are used to treat hyperphosphatemia, but evidence about their efficacy in this setting is limited.

Hypocalcemia in tumor lysis syndrome is usually not treated unless symptomatic, as the calcium-phosphorus product can increase, leading to calcium phosphate crystallization. When the calcium-phosphorus product is greater than 60, there is a higher risk of calcium phosphate deposition in the renal tubules that can lead to acute renal failure in tumor lysis syndrome.⁴⁷ To lower the risk of calcium phosphate crystallization, calcium-based binders should be avoided in tumor lysis syndrome.

Total parenteral nutrition

Since patients on total parenteral nutrition do not eat, phosphorus binders are considered ineffective; there are no concrete data showing that phosphorus binders are effective in these patients.⁴⁸ In patients with kidney disease, the phosphorus content in the parenteral nutrition formulation must be reduced.

Pregnancy

Data on phosphorus binders in pregnancy are limited. Calcium can cross the placenta. Calcium carbonate can be used in pregnancy, and fetal harm is not expected if calcium concentrations are within normal limits.⁴⁹ Calcium acetate, sevelamer, and lanthanum are considered pregnancy category C drugs. Patients with advanced chronic kidney disease and end-stage renal disease who become pregnant must receive specialized obstetric care for high-risk pregnancy.

FUTURE DIRECTIONS

Future therapies may target FGF23 and other inflammatory markers that are up-regulated in renal hyperparathyroidism. However, trials studying these markers are needed to provide a better understanding of their role in bone mineral and cardiovascular health and in overall long-term outcomes. Additionally, randomized controlled trials are needed to study long-term nonsurrogate outcomes such as reduction in cardiovascular disease and rates of overall mortality.

The balance between dietary intake and excretion of phosphorus can be impaired in patients with decreased renal function, leading to hyperphosphatemia. Many patients with end-stage renal disease on dialysis require phosphorus-binding drugs to control their serum phosphorus levels.

See related editorial and article

In this review, we discuss the pathophysiology of hyperphosphatemia in kidney disease, its consequences, and how to control it, focusing on the different classes of phosphorus binders.

ROLE OF THE INTERNIST

With kidney disease common and on the increase,¹ nephrologists and internists need to work together to provide optimal care.

Further, many internists in managed care plans and accountable care organizations now handle many tasks previously left to specialists—including prescribing and managing phosphorus binders in patients with kidney disease.

PATHOPHYSIOLOGY OF HYPERPHOSPHATEMIA

The pathophysiology of bone mineral disorders in kidney disease is complex. To simplify the discussion, we will address it in 3 parts:

• Phosphorus balance
• The interplay of hormones, including fibro­blast growth factor 23 (FGF23)
• The mechanism of hyperphosphatemia in kidney disease.

Phosphorus balance

Phosphorus is a macronutrient essential for a range of cellular functions that include structure, energy production, metabolism, and cell signaling. It exists primarily in the form of inorganic phosphate.

An average Western diet provides 20 mg of phosphorus per kilogram of body weight per day. Of this, 13 mg/kg is absorbed, and the rest is excreted in the feces.²

Absorption of dietary phosphorus occurs mainly in the jejunum. It is mediated by both a paracellular sodium-independent pathway (driven by high intraluminal phosphorus content) and by active sodium-dependent cotransporters. It is also influenced by diet and promoted by active vitamin D (1,25 dihydroxyvitamin D₃, also called calcitriol).³

Absorbed phosphorus enters the extracellular fluid and shifts in and out of the skeleton under the influence of parathyroid hormone.

Phosphorus excretion is handled almost entirely by the kidneys. Phosphorus is freely filtered at the glomerulus and reabsorbed mainly in the proximal tubule by sodium-phosphate cotransporters.

Normally, when phosphorus intake is adequate, most of the filtered phosphorus is reabsorbed and only 10% to 20% is excreted in the urine. However, the threshold for phosphorus reabsorption in the proximal tubule is influenced by parathyroid hormone, FGF23, and dietary phosphorus intake: low serum phosphate levels lead to an increase in the synthesis of sodium-phosphorus cotransporters, resulting in increased (nearly complete) proximal reabsorption and an increase in the serum phosphorus concentration.⁴ Conversely, both parathyroid hormone and FGF23 are phosphaturic and decrease the number of phosphorus transporters, which in turn leads to increased phosphorus excretion and a decrease in serum phosphorus concentration.⁵

Interplay of hormones

FGF23 is a phosphaturic glycoprotein secreted by osteoblasts and osteocytes. It acts by binding to fibroblastic growth receptor 1 in the presence of its coreceptor, the Klotho protein.⁶

FGF23 is regulated by serum phosphorus levels and plays a major role in the response to elevated serum phosphorus. It causes a direct increase in urinary phosphorus excretion, a decrease in intestinal phosphorus absorption (indirectly via inhibition of calcitriol), and decreased bone resorption via a decrease in parathyroid hormone production.⁷

Mechanism of hyperphosphatemia in kidney disease

In chronic kidney disease, phosphorus retention can trigger secondary hyperparathyroidism, as rising phosphorus levels stimulate FGF23. In the early stages of chronic kidney disease, this response can correct the phosphorus levels, but with several consequences:

• Decreased calcitriol due to its inhibition by FGF23⁹
• Hypocalcemia due to decreased calcitriol (leading to decreased intestinal calcium absorption) and calcium binding of retained phosphorus
• Elevated parathyroid hormone due to low calcitriol levels (lack of inhibitory feedback by calcitriol), hyperphosphatemia, and hypocalcemia (direct parathyroid hormone stimulation).

As the elevated phosphorus level is likely to be the triggering event behind secondary renal hyperparathyroidism, it needs to be controlled. This is accomplished by restricting dietary phosphorus and using phosphorus binders.

HYPERPHOSPHATEMIA MAY LEAD TO VASCULAR CALCIFICATION

Elevated serum phosphorus levels (normal range 2.48–4.65 mg/dL in adults¹¹) are associated with cardiovascular calcification and subsequent increases in mortality and morbidity rates. Elevations in serum phosphorus and calcium levels are associated with progression in vascular calcification¹² and likely account for the accelerated vascular calcification that is seen in kidney disease.¹³

Hyperphosphatemia has been identified as an independent risk factor for death in patients with end-stage renal disease,¹⁴ but that relationship is less clear in patients with chronic kidney disease. A study in patients with chronic kidney disease and not on dialysis found a lower mortality rate in those who were prescribed phosphorus binders,¹⁵ but the study was criticized for limitations in its design.

Hyperphosphatemia can also lead to adverse effects on bone health due to complications such as renal osteodystrophy.

However, in its 2017 update, the Kidney Disease: Improving Global Outcomes (KDIGO) program only “suggests” lowering elevated phosphorus levels “toward” the normal range in patients with chronic kidney disease stages G3a through G5D, ie, those with glomerular filtration rates less than 60 mL/min/1.73 m², including those on dialysis. The recommendation is graded 2C, ie, weak, based on low-quality evidence (https://kdigo.org/guidelines/ckd-mbd).

DIETARY RESTRICTION OF PHOSPHORUS

Diet is the major source of phosphorus intake. The average daily phosphorus consumption is  20 mg/kg, or 1,400 mg, and protein is the major source of dietary phosphorus.

In patients with stage 4 or 5 chronic kidney disease, the Kidney Disease Outcomes Quality Initiative recommends limiting protein intake to 0.6 mg/kg/day.¹⁶ However, in patients on hemodialysis, they recommend increasing protein intake to 1.1 mg/kg/day while limiting phosphorus intake to about 800 to 1,000 mg/day. This poses a challenge, as limiting phosphorus intake can reduce protein intake.

Sources of protein can be broadly classified as plant-based or animal-based. Animal protein contains organic phosphorus, which is easily absorbed.¹⁸ Plant protein may not be absorbed as easily.

Moe et al¹⁹ studied the importance of the protein source of phosphorus after 7 days of controlled diets. Despite equivalent protein and phosphorus concentrations in the vegetarian and meat-based diets, participants on the vegetarian diet had lower serum phosphorus levels, a trend toward lower 24-hour urinary phosphorus excretion, and significantly lower FGF23 levels than those on the meat-based diet. This suggests that a vegetarian diet may have advantages in terms of preventing hyperphosphatemia.

Another measure to reduce phosphorus absorption from meat is to boil it, which reduces the phosphorus content by 50%.²⁰

Processed foods containing additives and preservatives are very high in phosphorus²¹ and should be avoided, particularly as there is no mandate to label phosphorus content in food.

PHOSPHORUS AND DIALYSIS

Although hemodialysis removes phosphorus, it does not remove enough to keep levels within normal limits. Indeed, even when patients adhere to a daily phosphorus limit of 1,000 mg, phosphorus accumulates. If 70% of the phosphorus in the diet is absorbed, this is 4,500 to 5,000 mg in a week. A 4-hour hemodialysis session will remove only 1,000 mg of phosphorus, which equals about 3,000 mg for patients undergoing dialysis 3 times a week,²² far less than phosphorus absorption.

In patients on continuous ambulatory peritoneal dialysis, a daily regimen of 4 exchanges of 2 L per exchange removes about 200 mg of phosphorus per day. In a 2012 study, patients on nocturnal dialysis or home dialysis involving longer session length had greater lowering of phosphorus levels than patients undergoing routine hemodialysis.²³

Hence, phosphorus binders are often necessary in patients on routine hemodialysis or peritoneal dialysis.

PHOSPHORUS BINDERS

Phosphorus binders reduce serum phosphorus levels by binding with ingested phosphorus in the gastrointestinal tract and forming insoluble complexes that are not absorbed. For this reason they are much more effective when taken with meals. Phosphorus binders come in different formulations: pills, capsules, chewable tablets, liquids, and even powders that can be sprinkled on food.

The potency of each binder is quantified by its “phosphorus binder equivalent dose,” ie, its binding capacity compared with that of calcium carbonate as a reference.²⁴

Phosphorus binders are broadly divided into those that contain calcium and those that do not.

Calcium-containing binders

The 2 most commonly used preparations are calcium carbonate (eg, Tums) and calcium acetate (eg, Phoslo). While these are relatively safe, some studies suggest that their use can lead to accelerated vascular calcification.²⁵

According to KDIGO,²⁶ calcium-containing binders should be avoided in hypercalcemia and adynamic bone disease. Additionally, the daily elemental calcium intake from binders should be limited to 1,500 mg, with a total daily intake that does not exceed 2,000 mg.

The elemental calcium content of calcium carbonate is about 40% of its weight (eg, 200 mg of elemental calcium in a 500-mg tablet of Tums), while the elemental calcium content of calcium acetate is about 25%. Therefore, a patient who needs 6 g of calcium carbonate for efficacy will be ingesting 2.4 g of elemental calcium per day, and that exceeds the recommended daily maximum. The main advantage of calcium carbonate is its low cost and easy availability. Commonly reported side effects include nausea and constipation.

A less commonly used calcium-based binder is calcium citrate (eg, Calcitrate). It should, however, be avoided in chronic kidney disease because of the risk of aluminum accumulation. Calcium citrate can enhance intestinal absorption of aluminum from dietary sources, as aluminum can form complexes with citrate.²⁷

Calcium-free binders

There are several calcium-free binders. Some are based on metals such as aluminum, magnesium, iron, and lanthanum; others, such as sevelamer, are resin-based.

Aluminum- and magnesium-based binders are generally not used long-term in kidney disease because of the toxicity associated with aluminum and magnesium accumulation. However, aluminum hydroxide has an off-label use as a phosphorus binder in the acute setting, particularly when serum phosphorus levels are above 7 mg/dL.²⁸ The dose is 300 to 600 mg 3 times daily with meals for a maximum of 4 weeks.

Sevelamer. Approved by the US Food and Drug Administration (FDA) in 1998, sevelamer acts by trapping phosphorus through ion exchange and hydrogen binding. It has the advantage of being calcium-free, which makes it particularly desirable in patients with hypercalcemia.

The Renagel in New Dialysis²⁵ and Treat-To-Goal²⁹ studies were randomized controlled trials that looked at the effects of sevelamer vs calcium-based binders on the risk of vascular calcification. The primary end points were serum phosphorus and calcium levels, while the secondary end points were coronary artery calcification on computed tomography and thoracic vertebral bone density. Both studies demonstrated a higher risk of vascular calcification with the calcium-based binders.

Another possible benefit of sevelamer is an improvement in lipid profile. Sevelamer lowers total cholesterol and low-density lipoprotein cholesterol levels without affecting high-density lipoprotein cholesterol or triglyceride levels.³⁰ This is likely due to its bile acid-binding effect.³¹ Sevelamer has also been shown to lower C-reactive protein levels.³² While the cardiovascular profile appears to be improved with the treatment, there are no convincing data to confirm that those properties translate to a proven independent survival benefit.

The Calcium Acetate Renagel Evaluation³³ was a randomized controlled study comparing sevelamer and calcium acetate. The authors attempted to control for the lipid-lowering effects of sevelamer by giving atorvastatin to all patients in both groups who had a low-density lipoprotein level greater than 70 mg/dL. The study found sevelamer to be not inferior to calcium acetate in terms of mortality and coronary calcification.

Further studies such as the Brazilian Renagel and Calcium trial³⁴ and the Dialysis Clinical Outcomes Revisited trial failed to show a significant long-term benefit of sevelamer over calcium-based binders. However, a secondary statistical analysis of the latter study showed possible benefit of sevelamer over calcium acetate among those age 65 and older.³⁵

To understand how sevelamer could affect vascular calcification, Yilmaz et al³⁶ compared the effects of sevelamer vs calcium acetate on FGF23 and fetuin A levels. Fetuin A is an important inhibitor of vascular calcification and is progressively diminished in kidney disease, leading to accelerated calcification.³⁷ Patients on sevelamer had higher levels of fetuin A than their counterparts on calcium acetate.³⁷ The authors proposed increased fetuin A levels as a mechanism for decreased vascular calcification.

In summary, some studies suggest that sevelamer may offer the advantage of decreasing vascular calcification, but the data are mixed and do not provide a solid answer. The main disadvantages of sevelamer are a high pill burden and side effects of nausea and dyspepsia.

Lanthanum, a metallic element, was approved as a phosphorus binder by the FDA in 2008. It comes as a chewable tablet and offers the advantage of requiring the patient to take fewer pills than sevelamer and calcium-based binders.

Sucroferric oxyhydroxide comes as a chewable tablet. It was approved by the FDA in 2013. Although each tablet contains 500 mg of iron, it has not been shown to improve iron markers. In terms of phosphorus-lowering ability, it has been shown to be noninferior to sevelamer.³⁹ Advantages include a significantly lower pill burden. Disadvantages include gastrointestinal side effects such as diarrhea and nausea and the drug’s high cost.

Ferric citrate was approved by the FDA in 2014, and 1 g delivers 210 mg of elemental iron. The main advantage of ferric citrate is its ability to increase iron markers. The phase 3 trial that demonstrated its efficacy as a binder showed an increase in ferritin compared with the active control.⁴⁰ The study also showed a decrease in the need to use intravenous iron and erythropoesis-stimulating agents. This was thought to be due to improved iron stores, leading to decreased erythropoietin resistance.⁴¹

The mean number of ferric citrate tablets needed to achieve the desired phosphorus-lowering effect was 8 per day, containing 1,680 mg of iron. In comparison, oral ferrous sulfate typically provides 210 mg of iron per day.⁴²

Disadvantages of ferric citrate include high pill burden, high cost, and gastrointestinal side effects such as nausea and constipation.

Chitosan binds salivary phosphorus. It can potentially be used, but it is not approved, and its efficacy in lowering serum phosphorus remains unclear.⁴³

CHOOSING THE APPROPRIATE PHOSPHORUS BINDER

The choice of phosphorus binder is based on the patient’s serum calcium level and iron stores and on the drug’s side effect profile, iron pill burden, and cost. Involving patients in the choice after discussing potential side effects, pill burden, and cost is important for shared decision-making and could play a role in improving adherence.

Phosphorus binders are a major portion of the pill burden in patients with end-stage renal disease, possibly affecting patient adherence. The cost of phosphorus binders is estimated at half a billion dollars annually, underlining the significant economic impact of phosphorus control.¹¹

Calcium-based binders should be the first choice when there is secondary hyperparathyroidism without hypercalcemia. There is no clear evidence regarding the benefit of correcting hypocalcemia, but KDIGO recommends keeping the serum calcium level within the reference range. KDIGO also recommends restricting calcium-based binders in persistent hypercalcemia, arterial calcification, and adynamic bone disease. This recommendation is largely based on expert opinion.

Noncalcium-based binders, which in theory might prevent vascular calcification, should be considered for patients with at least 1 of the following⁴⁴:

• Complicated diabetes mellitus
• Vascular or valvular calcification
• Persistent inflammation.

Noncalcium-based binders are also preferred in low bone-turnover states such as adynamic bone disease, as elevated calcium can inhibit parathyroid hormone.

However, the advantage of noncalcium-based binders regarding vascular calcification is largely theoretical and has not been proven clinically. Indeed, there are data comparing long-term outcomes of the different classes of phosphorus binders, but studies were limited by short follow-up, and individual studies have lacked power to detect statistical significance between two classes of binders on long-term outcomes. Meta-analyses have provided conflicting data, with some suggesting better outcomes with sevelamer than with calcium-based binders, and with others failing to show any difference.⁴⁵

Because iron deficiency is common in kidney disease, ferric citrate, which can improve iron markers, may be a suitable option, provided its cost is covered by insurance.

SPECIAL CIRCUMSTANCES FOR THE USE OF PHOSPHORUS BINDERS

Tumor lysis syndrome

Tumor lysis syndrome occurs when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.⁴⁶ Phosphorus binders in conjunction with intravenous hydration are used to treat hyperphosphatemia, but evidence about their efficacy in this setting is limited.

Hypocalcemia in tumor lysis syndrome is usually not treated unless symptomatic, as the calcium-phosphorus product can increase, leading to calcium phosphate crystallization. When the calcium-phosphorus product is greater than 60, there is a higher risk of calcium phosphate deposition in the renal tubules that can lead to acute renal failure in tumor lysis syndrome.⁴⁷ To lower the risk of calcium phosphate crystallization, calcium-based binders should be avoided in tumor lysis syndrome.

Total parenteral nutrition

Since patients on total parenteral nutrition do not eat, phosphorus binders are considered ineffective; there are no concrete data showing that phosphorus binders are effective in these patients.⁴⁸ In patients with kidney disease, the phosphorus content in the parenteral nutrition formulation must be reduced.

Pregnancy

Data on phosphorus binders in pregnancy are limited. Calcium can cross the placenta. Calcium carbonate can be used in pregnancy, and fetal harm is not expected if calcium concentrations are within normal limits.⁴⁹ Calcium acetate, sevelamer, and lanthanum are considered pregnancy category C drugs. Patients with advanced chronic kidney disease and end-stage renal disease who become pregnant must receive specialized obstetric care for high-risk pregnancy.

FUTURE DIRECTIONS

Future therapies may target FGF23 and other inflammatory markers that are up-regulated in renal hyperparathyroidism. However, trials studying these markers are needed to provide a better understanding of their role in bone mineral and cardiovascular health and in overall long-term outcomes. Additionally, randomized controlled trials are needed to study long-term nonsurrogate outcomes such as reduction in cardiovascular disease and rates of overall mortality.

The balance between dietary intake and excretion of phosphorus can be impaired in patients with decreased renal function, leading to hyperphosphatemia. Many patients with end-stage renal disease on dialysis require phosphorus-binding drugs to control their serum phosphorus levels.

See related editorial and article

In this review, we discuss the pathophysiology of hyperphosphatemia in kidney disease, its consequences, and how to control it, focusing on the different classes of phosphorus binders.

ROLE OF THE INTERNIST

With kidney disease common and on the increase,¹ nephrologists and internists need to work together to provide optimal care.

Further, many internists in managed care plans and accountable care organizations now handle many tasks previously left to specialists—including prescribing and managing phosphorus binders in patients with kidney disease.

PATHOPHYSIOLOGY OF HYPERPHOSPHATEMIA

The pathophysiology of bone mineral disorders in kidney disease is complex. To simplify the discussion, we will address it in 3 parts:

• Phosphorus balance
• The interplay of hormones, including fibro­blast growth factor 23 (FGF23)
• The mechanism of hyperphosphatemia in kidney disease.

Phosphorus balance

Phosphorus is a macronutrient essential for a range of cellular functions that include structure, energy production, metabolism, and cell signaling. It exists primarily in the form of inorganic phosphate.

An average Western diet provides 20 mg of phosphorus per kilogram of body weight per day. Of this, 13 mg/kg is absorbed, and the rest is excreted in the feces.²

Absorption of dietary phosphorus occurs mainly in the jejunum. It is mediated by both a paracellular sodium-independent pathway (driven by high intraluminal phosphorus content) and by active sodium-dependent cotransporters. It is also influenced by diet and promoted by active vitamin D (1,25 dihydroxyvitamin D₃, also called calcitriol).³

Absorbed phosphorus enters the extracellular fluid and shifts in and out of the skeleton under the influence of parathyroid hormone.

Phosphorus excretion is handled almost entirely by the kidneys. Phosphorus is freely filtered at the glomerulus and reabsorbed mainly in the proximal tubule by sodium-phosphate cotransporters.

Normally, when phosphorus intake is adequate, most of the filtered phosphorus is reabsorbed and only 10% to 20% is excreted in the urine. However, the threshold for phosphorus reabsorption in the proximal tubule is influenced by parathyroid hormone, FGF23, and dietary phosphorus intake: low serum phosphate levels lead to an increase in the synthesis of sodium-phosphorus cotransporters, resulting in increased (nearly complete) proximal reabsorption and an increase in the serum phosphorus concentration.⁴ Conversely, both parathyroid hormone and FGF23 are phosphaturic and decrease the number of phosphorus transporters, which in turn leads to increased phosphorus excretion and a decrease in serum phosphorus concentration.⁵

Interplay of hormones

FGF23 is a phosphaturic glycoprotein secreted by osteoblasts and osteocytes. It acts by binding to fibroblastic growth receptor 1 in the presence of its coreceptor, the Klotho protein.⁶

FGF23 is regulated by serum phosphorus levels and plays a major role in the response to elevated serum phosphorus. It causes a direct increase in urinary phosphorus excretion, a decrease in intestinal phosphorus absorption (indirectly via inhibition of calcitriol), and decreased bone resorption via a decrease in parathyroid hormone production.⁷

Mechanism of hyperphosphatemia in kidney disease

In chronic kidney disease, phosphorus retention can trigger secondary hyperparathyroidism, as rising phosphorus levels stimulate FGF23. In the early stages of chronic kidney disease, this response can correct the phosphorus levels, but with several consequences:

• Decreased calcitriol due to its inhibition by FGF23⁹
• Hypocalcemia due to decreased calcitriol (leading to decreased intestinal calcium absorption) and calcium binding of retained phosphorus
• Elevated parathyroid hormone due to low calcitriol levels (lack of inhibitory feedback by calcitriol), hyperphosphatemia, and hypocalcemia (direct parathyroid hormone stimulation).

As the elevated phosphorus level is likely to be the triggering event behind secondary renal hyperparathyroidism, it needs to be controlled. This is accomplished by restricting dietary phosphorus and using phosphorus binders.

HYPERPHOSPHATEMIA MAY LEAD TO VASCULAR CALCIFICATION

Elevated serum phosphorus levels (normal range 2.48–4.65 mg/dL in adults¹¹) are associated with cardiovascular calcification and subsequent increases in mortality and morbidity rates. Elevations in serum phosphorus and calcium levels are associated with progression in vascular calcification¹² and likely account for the accelerated vascular calcification that is seen in kidney disease.¹³

Hyperphosphatemia has been identified as an independent risk factor for death in patients with end-stage renal disease,¹⁴ but that relationship is less clear in patients with chronic kidney disease. A study in patients with chronic kidney disease and not on dialysis found a lower mortality rate in those who were prescribed phosphorus binders,¹⁵ but the study was criticized for limitations in its design.

Hyperphosphatemia can also lead to adverse effects on bone health due to complications such as renal osteodystrophy.

However, in its 2017 update, the Kidney Disease: Improving Global Outcomes (KDIGO) program only “suggests” lowering elevated phosphorus levels “toward” the normal range in patients with chronic kidney disease stages G3a through G5D, ie, those with glomerular filtration rates less than 60 mL/min/1.73 m², including those on dialysis. The recommendation is graded 2C, ie, weak, based on low-quality evidence (https://kdigo.org/guidelines/ckd-mbd).

DIETARY RESTRICTION OF PHOSPHORUS

Diet is the major source of phosphorus intake. The average daily phosphorus consumption is  20 mg/kg, or 1,400 mg, and protein is the major source of dietary phosphorus.

In patients with stage 4 or 5 chronic kidney disease, the Kidney Disease Outcomes Quality Initiative recommends limiting protein intake to 0.6 mg/kg/day.¹⁶ However, in patients on hemodialysis, they recommend increasing protein intake to 1.1 mg/kg/day while limiting phosphorus intake to about 800 to 1,000 mg/day. This poses a challenge, as limiting phosphorus intake can reduce protein intake.

Sources of protein can be broadly classified as plant-based or animal-based. Animal protein contains organic phosphorus, which is easily absorbed.¹⁸ Plant protein may not be absorbed as easily.

Moe et al¹⁹ studied the importance of the protein source of phosphorus after 7 days of controlled diets. Despite equivalent protein and phosphorus concentrations in the vegetarian and meat-based diets, participants on the vegetarian diet had lower serum phosphorus levels, a trend toward lower 24-hour urinary phosphorus excretion, and significantly lower FGF23 levels than those on the meat-based diet. This suggests that a vegetarian diet may have advantages in terms of preventing hyperphosphatemia.

Another measure to reduce phosphorus absorption from meat is to boil it, which reduces the phosphorus content by 50%.²⁰

Processed foods containing additives and preservatives are very high in phosphorus²¹ and should be avoided, particularly as there is no mandate to label phosphorus content in food.

PHOSPHORUS AND DIALYSIS

Although hemodialysis removes phosphorus, it does not remove enough to keep levels within normal limits. Indeed, even when patients adhere to a daily phosphorus limit of 1,000 mg, phosphorus accumulates. If 70% of the phosphorus in the diet is absorbed, this is 4,500 to 5,000 mg in a week. A 4-hour hemodialysis session will remove only 1,000 mg of phosphorus, which equals about 3,000 mg for patients undergoing dialysis 3 times a week,²² far less than phosphorus absorption.

In patients on continuous ambulatory peritoneal dialysis, a daily regimen of 4 exchanges of 2 L per exchange removes about 200 mg of phosphorus per day. In a 2012 study, patients on nocturnal dialysis or home dialysis involving longer session length had greater lowering of phosphorus levels than patients undergoing routine hemodialysis.²³

Hence, phosphorus binders are often necessary in patients on routine hemodialysis or peritoneal dialysis.

PHOSPHORUS BINDERS

Phosphorus binders reduce serum phosphorus levels by binding with ingested phosphorus in the gastrointestinal tract and forming insoluble complexes that are not absorbed. For this reason they are much more effective when taken with meals. Phosphorus binders come in different formulations: pills, capsules, chewable tablets, liquids, and even powders that can be sprinkled on food.

The potency of each binder is quantified by its “phosphorus binder equivalent dose,” ie, its binding capacity compared with that of calcium carbonate as a reference.²⁴

Phosphorus binders are broadly divided into those that contain calcium and those that do not.

Calcium-containing binders

The 2 most commonly used preparations are calcium carbonate (eg, Tums) and calcium acetate (eg, Phoslo). While these are relatively safe, some studies suggest that their use can lead to accelerated vascular calcification.²⁵

According to KDIGO,²⁶ calcium-containing binders should be avoided in hypercalcemia and adynamic bone disease. Additionally, the daily elemental calcium intake from binders should be limited to 1,500 mg, with a total daily intake that does not exceed 2,000 mg.

The elemental calcium content of calcium carbonate is about 40% of its weight (eg, 200 mg of elemental calcium in a 500-mg tablet of Tums), while the elemental calcium content of calcium acetate is about 25%. Therefore, a patient who needs 6 g of calcium carbonate for efficacy will be ingesting 2.4 g of elemental calcium per day, and that exceeds the recommended daily maximum. The main advantage of calcium carbonate is its low cost and easy availability. Commonly reported side effects include nausea and constipation.

A less commonly used calcium-based binder is calcium citrate (eg, Calcitrate). It should, however, be avoided in chronic kidney disease because of the risk of aluminum accumulation. Calcium citrate can enhance intestinal absorption of aluminum from dietary sources, as aluminum can form complexes with citrate.²⁷

Calcium-free binders

There are several calcium-free binders. Some are based on metals such as aluminum, magnesium, iron, and lanthanum; others, such as sevelamer, are resin-based.

Aluminum- and magnesium-based binders are generally not used long-term in kidney disease because of the toxicity associated with aluminum and magnesium accumulation. However, aluminum hydroxide has an off-label use as a phosphorus binder in the acute setting, particularly when serum phosphorus levels are above 7 mg/dL.²⁸ The dose is 300 to 600 mg 3 times daily with meals for a maximum of 4 weeks.

Sevelamer. Approved by the US Food and Drug Administration (FDA) in 1998, sevelamer acts by trapping phosphorus through ion exchange and hydrogen binding. It has the advantage of being calcium-free, which makes it particularly desirable in patients with hypercalcemia.

The Renagel in New Dialysis²⁵ and Treat-To-Goal²⁹ studies were randomized controlled trials that looked at the effects of sevelamer vs calcium-based binders on the risk of vascular calcification. The primary end points were serum phosphorus and calcium levels, while the secondary end points were coronary artery calcification on computed tomography and thoracic vertebral bone density. Both studies demonstrated a higher risk of vascular calcification with the calcium-based binders.

Another possible benefit of sevelamer is an improvement in lipid profile. Sevelamer lowers total cholesterol and low-density lipoprotein cholesterol levels without affecting high-density lipoprotein cholesterol or triglyceride levels.³⁰ This is likely due to its bile acid-binding effect.³¹ Sevelamer has also been shown to lower C-reactive protein levels.³² While the cardiovascular profile appears to be improved with the treatment, there are no convincing data to confirm that those properties translate to a proven independent survival benefit.

The Calcium Acetate Renagel Evaluation³³ was a randomized controlled study comparing sevelamer and calcium acetate. The authors attempted to control for the lipid-lowering effects of sevelamer by giving atorvastatin to all patients in both groups who had a low-density lipoprotein level greater than 70 mg/dL. The study found sevelamer to be not inferior to calcium acetate in terms of mortality and coronary calcification.

Further studies such as the Brazilian Renagel and Calcium trial³⁴ and the Dialysis Clinical Outcomes Revisited trial failed to show a significant long-term benefit of sevelamer over calcium-based binders. However, a secondary statistical analysis of the latter study showed possible benefit of sevelamer over calcium acetate among those age 65 and older.³⁵

To understand how sevelamer could affect vascular calcification, Yilmaz et al³⁶ compared the effects of sevelamer vs calcium acetate on FGF23 and fetuin A levels. Fetuin A is an important inhibitor of vascular calcification and is progressively diminished in kidney disease, leading to accelerated calcification.³⁷ Patients on sevelamer had higher levels of fetuin A than their counterparts on calcium acetate.³⁷ The authors proposed increased fetuin A levels as a mechanism for decreased vascular calcification.

In summary, some studies suggest that sevelamer may offer the advantage of decreasing vascular calcification, but the data are mixed and do not provide a solid answer. The main disadvantages of sevelamer are a high pill burden and side effects of nausea and dyspepsia.

Lanthanum, a metallic element, was approved as a phosphorus binder by the FDA in 2008. It comes as a chewable tablet and offers the advantage of requiring the patient to take fewer pills than sevelamer and calcium-based binders.

Sucroferric oxyhydroxide comes as a chewable tablet. It was approved by the FDA in 2013. Although each tablet contains 500 mg of iron, it has not been shown to improve iron markers. In terms of phosphorus-lowering ability, it has been shown to be noninferior to sevelamer.³⁹ Advantages include a significantly lower pill burden. Disadvantages include gastrointestinal side effects such as diarrhea and nausea and the drug’s high cost.

Ferric citrate was approved by the FDA in 2014, and 1 g delivers 210 mg of elemental iron. The main advantage of ferric citrate is its ability to increase iron markers. The phase 3 trial that demonstrated its efficacy as a binder showed an increase in ferritin compared with the active control.⁴⁰ The study also showed a decrease in the need to use intravenous iron and erythropoesis-stimulating agents. This was thought to be due to improved iron stores, leading to decreased erythropoietin resistance.⁴¹

The mean number of ferric citrate tablets needed to achieve the desired phosphorus-lowering effect was 8 per day, containing 1,680 mg of iron. In comparison, oral ferrous sulfate typically provides 210 mg of iron per day.⁴²

Disadvantages of ferric citrate include high pill burden, high cost, and gastrointestinal side effects such as nausea and constipation.

Chitosan binds salivary phosphorus. It can potentially be used, but it is not approved, and its efficacy in lowering serum phosphorus remains unclear.⁴³

CHOOSING THE APPROPRIATE PHOSPHORUS BINDER

The choice of phosphorus binder is based on the patient’s serum calcium level and iron stores and on the drug’s side effect profile, iron pill burden, and cost. Involving patients in the choice after discussing potential side effects, pill burden, and cost is important for shared decision-making and could play a role in improving adherence.

Phosphorus binders are a major portion of the pill burden in patients with end-stage renal disease, possibly affecting patient adherence. The cost of phosphorus binders is estimated at half a billion dollars annually, underlining the significant economic impact of phosphorus control.¹¹

Calcium-based binders should be the first choice when there is secondary hyperparathyroidism without hypercalcemia. There is no clear evidence regarding the benefit of correcting hypocalcemia, but KDIGO recommends keeping the serum calcium level within the reference range. KDIGO also recommends restricting calcium-based binders in persistent hypercalcemia, arterial calcification, and adynamic bone disease. This recommendation is largely based on expert opinion.

Noncalcium-based binders, which in theory might prevent vascular calcification, should be considered for patients with at least 1 of the following⁴⁴:

• Complicated diabetes mellitus
• Vascular or valvular calcification
• Persistent inflammation.

Noncalcium-based binders are also preferred in low bone-turnover states such as adynamic bone disease, as elevated calcium can inhibit parathyroid hormone.

However, the advantage of noncalcium-based binders regarding vascular calcification is largely theoretical and has not been proven clinically. Indeed, there are data comparing long-term outcomes of the different classes of phosphorus binders, but studies were limited by short follow-up, and individual studies have lacked power to detect statistical significance between two classes of binders on long-term outcomes. Meta-analyses have provided conflicting data, with some suggesting better outcomes with sevelamer than with calcium-based binders, and with others failing to show any difference.⁴⁵

Because iron deficiency is common in kidney disease, ferric citrate, which can improve iron markers, may be a suitable option, provided its cost is covered by insurance.

SPECIAL CIRCUMSTANCES FOR THE USE OF PHOSPHORUS BINDERS

Tumor lysis syndrome

Tumor lysis syndrome occurs when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.⁴⁶ Phosphorus binders in conjunction with intravenous hydration are used to treat hyperphosphatemia, but evidence about their efficacy in this setting is limited.

Hypocalcemia in tumor lysis syndrome is usually not treated unless symptomatic, as the calcium-phosphorus product can increase, leading to calcium phosphate crystallization. When the calcium-phosphorus product is greater than 60, there is a higher risk of calcium phosphate deposition in the renal tubules that can lead to acute renal failure in tumor lysis syndrome.⁴⁷ To lower the risk of calcium phosphate crystallization, calcium-based binders should be avoided in tumor lysis syndrome.

Total parenteral nutrition

Since patients on total parenteral nutrition do not eat, phosphorus binders are considered ineffective; there are no concrete data showing that phosphorus binders are effective in these patients.⁴⁸ In patients with kidney disease, the phosphorus content in the parenteral nutrition formulation must be reduced.

Pregnancy

Data on phosphorus binders in pregnancy are limited. Calcium can cross the placenta. Calcium carbonate can be used in pregnancy, and fetal harm is not expected if calcium concentrations are within normal limits.⁴⁹ Calcium acetate, sevelamer, and lanthanum are considered pregnancy category C drugs. Patients with advanced chronic kidney disease and end-stage renal disease who become pregnant must receive specialized obstetric care for high-risk pregnancy.

FUTURE DIRECTIONS

Future therapies may target FGF23 and other inflammatory markers that are up-regulated in renal hyperparathyroidism. However, trials studying these markers are needed to provide a better understanding of their role in bone mineral and cardiovascular health and in overall long-term outcomes. Additionally, randomized controlled trials are needed to study long-term nonsurrogate outcomes such as reduction in cardiovascular disease and rates of overall mortality.

Phosphorus is essential for life. However, both low and high levels of phosphorus in the body have consequences, and its concentration in the blood is tightly regulated through dietary absorption, bone flux, and renal excretion and is influenced by calcitriol (1,25 hydroxyvitamin D₃), parathyroid hormone, and fibroblast growth factor 23 (FGF23).

See related articles by M. Shetty and A. Sekar

Sekar et al,¹ in this issue of the Journal, provide an extensive review of the pathophysiology of phosphorus metabolism and strategies to control phosphorus levels in patients with hyperphosphatemia and end-stage kidney disease.

PHOSPHORUS OR PHOSPHATE?

What's in a name? That which we call a rose
By any other word would smell as sweet.
—Shakespeare, Romeo and Juliet

The terms phosphate and phosphorus are often used interchangeably, though most writers still prefer phosphate over phosphorus.

The serum concentrations of phosphate and phosphorus are the same when expressed in millimoles per liter, as every mole of phosphate contains 1 mole of phosphorus, but not the same when expressed in milligrams per deciliter.² The molecular weight of phosphorus is 30.97, whereas the molecular weight of the phosphate ion (PO₄^3–) is 94.97—more than 3 times higher. Therefore, using these terms interchangeably in this context can lead to numerical error.³

Phosphorus, being highly reactive, does not exist by itself in nature and is typically present as phosphates in biologic systems. When describing phosphorus metabolism, the term phosphates should ideally be used because phosphates are the actual participants in the bodily processes. But in the clinical laboratory, all methods that measure serum phosphorus in fact measure inorganic phosphate and are expressed in terms of milligrams of phosphorus per deciliter rather than milligrams of phosphate per deciliter, and using these 2 terms interchangeably in clinical practice should not be of concern.⁴

THE PROBLEM

US adults typically ingest 1,200 mg of phosphorus each day, and about 60% to 70% of the ingested phosphorus is absorbed both by passive paracellular diffusion via tight junctions and by active transcellular transport via sodium-phosphate cotransport. The kidneys must excrete the same amount daily to maintain a steady state. As kidney function declines, phosphorus accumulates in the blood, leading to hyperphosphatemia.

Hyperphosphatemia is often asymptomatic, but it can cause generalized itching, red eyes, and adverse effects on the bone and parathyroid glands. Higher serum phosphorus levels have been shown to be associated with vascular calcification,⁵ cardiovascular events, and higher all-cause mortality rates in the general population,⁶ in patients with diabetes,⁷ and in those with chronic kidney disease.⁸ This association between higher serum phosphorus levels and the all-cause mortality rate led to the assumption that lowering serum phosphorus levels in these patients could reduce the rates of cardiovascular events and death, and to efforts to correct hyperphosphatemia.

Research into FGF23 continues, especially its role in cardiovascular complications of chronic kidney disease, as both phosphorus and FGF23 levels are elevated in chronic kidney disease and are implicated in poor clinical outcomes in these patients. However, both FGF23 and parathyroid hormone levels rise early in the course of kidney disease, long before overt hyperphosphatemia develops. Further, FGF23 rises earlier than parathyroid hormone and has been found to be an independent risk factor for cardiovascular events and death from any cause in end-stage kidney disease.⁹

Whether hyperphosphatemia is the culprit or merely an epiphenomenon of metabolic complications of chronic kidney disease is still unclear, as more molecules are being identified in the complex process of cardiovascular calcification.¹⁰

However, one thing is clear: vascular calcification is not just a simple precipitation of calcium and phosphorus. Instead, it is an active process that involves many regulators of mineral metabolism.¹⁰ The complex nature of this process is likely one of the reasons that evidence is conflicting¹¹ about the benefits of phosphorus binders in terms of cardiovascular events or all-cause mortality in these patients.

Reducing intake

Dietary phosphorus restriction is the first step in controlling serum phosphorus. But reducing phosphorus intake while otherwise trying to optimize the nutritional status can be challenging.

The recommended daily protein intake is 1.0 to 1.2 g/kg. But phosphorus is typically found in foods rich in proteins, and restricting protein severely can compromise nutritional status and may be as bad as elevated phosphate levels in terms of outcomes.

Although plant-based foods contain more phosphate per gram of protein (ie, they have a higher ratio of phosphorus to protein) than animal-based foods, the bioavailability of phosphorus from plant foods is lower. Phosphorus in plant-based foods is mainly in the form of phytate. Humans cannot hydrolyze phytate because we lack the phytase enzyme; hence, the phosphorus in plant-based foods is not well absorbed. Therefore, a vegetarian diet may be preferable and beneficial in patients with chronic kidney disease. A small study in humans showed that a vegetarian diet resulted in lower serum phosphorus and FGF23 levels, but the study was limited by its small sample size.¹²

Patients should be advised to avoid foods that have a high phosphate content, such as processed foods, fast foods, and cola beverages, which often have phosphate-based food additives.

Further, one should be cautious about using supplements with healthy-sounding names. A case in point is “vitamin water”: 12 oz of this fruit punch-flavored beverage contains 392 mg of phosphorus,¹³ and this alone would require 12 to 15 phosphate binder tablets to bind its phosphorus content.

In addition, many prescription drugs have significant amounts of phosphorus, and this is often unrecognized.

Sherman et al¹⁴ reviewed 200 of the most commonly prescribed drugs in dialysis patients and found that 23 (11.5%) of the drug labels listed phosphorus-containing ingredients, but the actual amount of phosphorus was not listed. The phosphorus content ranged from 1.4 mg (clonidine 0.2 mg, Blue Point Laboratories, Dublin, Ireland) to 111.5 mg (paroxetine 40 mg, GlaxoSmith Kline, Philadelphia, PA). The phosphorus content was inconsistent and varied with the dose of the agent, type of formulation (tablet or syrup), branded or generic formulation, and manufacturer.

Branded lisinopril (Merck, Kenilworth, NJ) had 21.4 mg of phosphorus per 10-mg dose, while a generic product (Blue Point Laboratories, Dublin, Ireland) had 32.6 mg. Different brands of generic amlodipine 10 mg varied in their phosphorus content from 8.6 mg (Lupin Pharmaceuticals, Mumbai, India) to 27.8 mg (Greenstone LLC, Peapack, NJ) to 40.1 mg (Qualitest Pharmaceuticals, Huntsville, AL. Rena-Vite (Cypress Pharmaceuticals, Madison, MS), a multivitamin marketed to patients with kidney disease, had 37.7 mg of phosphorus per tablet. Thus, just to bind the phosphorus content of these 3 tablets (lisinopril, amlodipine, and Rena-Vite), a patient could need at least 3 to 4 extra doses of phosphate binder.

The phosphate content of medications should be considered when prescribing. For example, Reno Caps (Nnodum Pharmaceuticals, Cincinnati, OH), another vitamin supplement, has only 1.7 mg of phosphorus per tablet and should be considered, especially in patients with poorly controlled serum phosphorus levels. However, the challenge is that medication labels do not provide the phosphorus content.

Reducing phosphorus absorption

Although these agents reduce serum phosphorus and help reduce symptoms, an important quality-of-life measure, it is uncertain whether they improve clinical outcomes.¹¹ To date, no specific phosphorus binder offers a survival benefit over placebo.¹¹

Based on the limited and conflicting evidence, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, recently updated, suggest that oral phosphorus binders should be used in patients with hyperphosphatemia to lower serum phosphorus levels toward the normal range.¹⁵ They further recommend not exceeding 1,500 mg of elemental calcium per day if a calcium-based binder is used, and they recommend avoiding calcium-based binders in patients with hypercalcemia, adynamic bone disease, or vascular calcification.

Phosphorus binders may account for up to 50% of the daily pill burden and may contribute to poor medication adherence.¹⁶ Dialysis patients need to take a lot of these drugs: by weight, 5 to 6 pounds per year.

These drugs can bind and interfere with the absorption of other vital medications and so should be taken with meals and separately from other medications.

Removing phosphorus

Removal of phosphorus by adequate dialysis or kidney transplant is the final strategy.

New agents under study

To improve phosphorus control, other agents that inhibit absorption of phosphate are being investigated.

Nicotinamide reduces expression of the sodium-phosphorus cotransporter NTP2b. Its use in combination with a low-phosphorus diet and phosphorus binders may maximize reductions in phosphorus absorption and is being studied in the CKD Optimal Management With Binders and Nicotinamide (COMBINE) study.

Tenapanor, an inhibitor of the sodium-hydrogen transporter NHE3, has been shown in animal studies to increase fecal phosphate excretion and decrease urinary phosphate excretion17 but requires further evaluation.

Phosphorus is essential for life. However, both low and high levels of phosphorus in the body have consequences, and its concentration in the blood is tightly regulated through dietary absorption, bone flux, and renal excretion and is influenced by calcitriol (1,25 hydroxyvitamin D₃), parathyroid hormone, and fibroblast growth factor 23 (FGF23).

See related articles by M. Shetty and A. Sekar

Sekar et al,¹ in this issue of the Journal, provide an extensive review of the pathophysiology of phosphorus metabolism and strategies to control phosphorus levels in patients with hyperphosphatemia and end-stage kidney disease.

PHOSPHORUS OR PHOSPHATE?

What's in a name? That which we call a rose
By any other word would smell as sweet.
—Shakespeare, Romeo and Juliet

The terms phosphate and phosphorus are often used interchangeably, though most writers still prefer phosphate over phosphorus.

The serum concentrations of phosphate and phosphorus are the same when expressed in millimoles per liter, as every mole of phosphate contains 1 mole of phosphorus, but not the same when expressed in milligrams per deciliter.² The molecular weight of phosphorus is 30.97, whereas the molecular weight of the phosphate ion (PO₄^3–) is 94.97—more than 3 times higher. Therefore, using these terms interchangeably in this context can lead to numerical error.³

Phosphorus, being highly reactive, does not exist by itself in nature and is typically present as phosphates in biologic systems. When describing phosphorus metabolism, the term phosphates should ideally be used because phosphates are the actual participants in the bodily processes. But in the clinical laboratory, all methods that measure serum phosphorus in fact measure inorganic phosphate and are expressed in terms of milligrams of phosphorus per deciliter rather than milligrams of phosphate per deciliter, and using these 2 terms interchangeably in clinical practice should not be of concern.⁴

THE PROBLEM

US adults typically ingest 1,200 mg of phosphorus each day, and about 60% to 70% of the ingested phosphorus is absorbed both by passive paracellular diffusion via tight junctions and by active transcellular transport via sodium-phosphate cotransport. The kidneys must excrete the same amount daily to maintain a steady state. As kidney function declines, phosphorus accumulates in the blood, leading to hyperphosphatemia.

Hyperphosphatemia is often asymptomatic, but it can cause generalized itching, red eyes, and adverse effects on the bone and parathyroid glands. Higher serum phosphorus levels have been shown to be associated with vascular calcification,⁵ cardiovascular events, and higher all-cause mortality rates in the general population,⁶ in patients with diabetes,⁷ and in those with chronic kidney disease.⁸ This association between higher serum phosphorus levels and the all-cause mortality rate led to the assumption that lowering serum phosphorus levels in these patients could reduce the rates of cardiovascular events and death, and to efforts to correct hyperphosphatemia.

Research into FGF23 continues, especially its role in cardiovascular complications of chronic kidney disease, as both phosphorus and FGF23 levels are elevated in chronic kidney disease and are implicated in poor clinical outcomes in these patients. However, both FGF23 and parathyroid hormone levels rise early in the course of kidney disease, long before overt hyperphosphatemia develops. Further, FGF23 rises earlier than parathyroid hormone and has been found to be an independent risk factor for cardiovascular events and death from any cause in end-stage kidney disease.⁹

Whether hyperphosphatemia is the culprit or merely an epiphenomenon of metabolic complications of chronic kidney disease is still unclear, as more molecules are being identified in the complex process of cardiovascular calcification.¹⁰

However, one thing is clear: vascular calcification is not just a simple precipitation of calcium and phosphorus. Instead, it is an active process that involves many regulators of mineral metabolism.¹⁰ The complex nature of this process is likely one of the reasons that evidence is conflicting¹¹ about the benefits of phosphorus binders in terms of cardiovascular events or all-cause mortality in these patients.

Reducing intake

Dietary phosphorus restriction is the first step in controlling serum phosphorus. But reducing phosphorus intake while otherwise trying to optimize the nutritional status can be challenging.

The recommended daily protein intake is 1.0 to 1.2 g/kg. But phosphorus is typically found in foods rich in proteins, and restricting protein severely can compromise nutritional status and may be as bad as elevated phosphate levels in terms of outcomes.

Although plant-based foods contain more phosphate per gram of protein (ie, they have a higher ratio of phosphorus to protein) than animal-based foods, the bioavailability of phosphorus from plant foods is lower. Phosphorus in plant-based foods is mainly in the form of phytate. Humans cannot hydrolyze phytate because we lack the phytase enzyme; hence, the phosphorus in plant-based foods is not well absorbed. Therefore, a vegetarian diet may be preferable and beneficial in patients with chronic kidney disease. A small study in humans showed that a vegetarian diet resulted in lower serum phosphorus and FGF23 levels, but the study was limited by its small sample size.¹²

Patients should be advised to avoid foods that have a high phosphate content, such as processed foods, fast foods, and cola beverages, which often have phosphate-based food additives.

Further, one should be cautious about using supplements with healthy-sounding names. A case in point is “vitamin water”: 12 oz of this fruit punch-flavored beverage contains 392 mg of phosphorus,¹³ and this alone would require 12 to 15 phosphate binder tablets to bind its phosphorus content.

In addition, many prescription drugs have significant amounts of phosphorus, and this is often unrecognized.

Sherman et al¹⁴ reviewed 200 of the most commonly prescribed drugs in dialysis patients and found that 23 (11.5%) of the drug labels listed phosphorus-containing ingredients, but the actual amount of phosphorus was not listed. The phosphorus content ranged from 1.4 mg (clonidine 0.2 mg, Blue Point Laboratories, Dublin, Ireland) to 111.5 mg (paroxetine 40 mg, GlaxoSmith Kline, Philadelphia, PA). The phosphorus content was inconsistent and varied with the dose of the agent, type of formulation (tablet or syrup), branded or generic formulation, and manufacturer.

Branded lisinopril (Merck, Kenilworth, NJ) had 21.4 mg of phosphorus per 10-mg dose, while a generic product (Blue Point Laboratories, Dublin, Ireland) had 32.6 mg. Different brands of generic amlodipine 10 mg varied in their phosphorus content from 8.6 mg (Lupin Pharmaceuticals, Mumbai, India) to 27.8 mg (Greenstone LLC, Peapack, NJ) to 40.1 mg (Qualitest Pharmaceuticals, Huntsville, AL. Rena-Vite (Cypress Pharmaceuticals, Madison, MS), a multivitamin marketed to patients with kidney disease, had 37.7 mg of phosphorus per tablet. Thus, just to bind the phosphorus content of these 3 tablets (lisinopril, amlodipine, and Rena-Vite), a patient could need at least 3 to 4 extra doses of phosphate binder.

The phosphate content of medications should be considered when prescribing. For example, Reno Caps (Nnodum Pharmaceuticals, Cincinnati, OH), another vitamin supplement, has only 1.7 mg of phosphorus per tablet and should be considered, especially in patients with poorly controlled serum phosphorus levels. However, the challenge is that medication labels do not provide the phosphorus content.

Reducing phosphorus absorption

Although these agents reduce serum phosphorus and help reduce symptoms, an important quality-of-life measure, it is uncertain whether they improve clinical outcomes.¹¹ To date, no specific phosphorus binder offers a survival benefit over placebo.¹¹

Based on the limited and conflicting evidence, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, recently updated, suggest that oral phosphorus binders should be used in patients with hyperphosphatemia to lower serum phosphorus levels toward the normal range.¹⁵ They further recommend not exceeding 1,500 mg of elemental calcium per day if a calcium-based binder is used, and they recommend avoiding calcium-based binders in patients with hypercalcemia, adynamic bone disease, or vascular calcification.

Phosphorus binders may account for up to 50% of the daily pill burden and may contribute to poor medication adherence.¹⁶ Dialysis patients need to take a lot of these drugs: by weight, 5 to 6 pounds per year.

These drugs can bind and interfere with the absorption of other vital medications and so should be taken with meals and separately from other medications.

Removing phosphorus

Removal of phosphorus by adequate dialysis or kidney transplant is the final strategy.

New agents under study

To improve phosphorus control, other agents that inhibit absorption of phosphate are being investigated.

Nicotinamide reduces expression of the sodium-phosphorus cotransporter NTP2b. Its use in combination with a low-phosphorus diet and phosphorus binders may maximize reductions in phosphorus absorption and is being studied in the CKD Optimal Management With Binders and Nicotinamide (COMBINE) study.

Tenapanor, an inhibitor of the sodium-hydrogen transporter NHE3, has been shown in animal studies to increase fecal phosphate excretion and decrease urinary phosphate excretion17 but requires further evaluation.

Phosphorus is essential for life. However, both low and high levels of phosphorus in the body have consequences, and its concentration in the blood is tightly regulated through dietary absorption, bone flux, and renal excretion and is influenced by calcitriol (1,25 hydroxyvitamin D₃), parathyroid hormone, and fibroblast growth factor 23 (FGF23).

See related articles by M. Shetty and A. Sekar

Sekar et al,¹ in this issue of the Journal, provide an extensive review of the pathophysiology of phosphorus metabolism and strategies to control phosphorus levels in patients with hyperphosphatemia and end-stage kidney disease.

PHOSPHORUS OR PHOSPHATE?

What's in a name? That which we call a rose
By any other word would smell as sweet.
—Shakespeare, Romeo and Juliet

The terms phosphate and phosphorus are often used interchangeably, though most writers still prefer phosphate over phosphorus.

The serum concentrations of phosphate and phosphorus are the same when expressed in millimoles per liter, as every mole of phosphate contains 1 mole of phosphorus, but not the same when expressed in milligrams per deciliter.² The molecular weight of phosphorus is 30.97, whereas the molecular weight of the phosphate ion (PO₄^3–) is 94.97—more than 3 times higher. Therefore, using these terms interchangeably in this context can lead to numerical error.³

Phosphorus, being highly reactive, does not exist by itself in nature and is typically present as phosphates in biologic systems. When describing phosphorus metabolism, the term phosphates should ideally be used because phosphates are the actual participants in the bodily processes. But in the clinical laboratory, all methods that measure serum phosphorus in fact measure inorganic phosphate and are expressed in terms of milligrams of phosphorus per deciliter rather than milligrams of phosphate per deciliter, and using these 2 terms interchangeably in clinical practice should not be of concern.⁴

THE PROBLEM

US adults typically ingest 1,200 mg of phosphorus each day, and about 60% to 70% of the ingested phosphorus is absorbed both by passive paracellular diffusion via tight junctions and by active transcellular transport via sodium-phosphate cotransport. The kidneys must excrete the same amount daily to maintain a steady state. As kidney function declines, phosphorus accumulates in the blood, leading to hyperphosphatemia.

Hyperphosphatemia is often asymptomatic, but it can cause generalized itching, red eyes, and adverse effects on the bone and parathyroid glands. Higher serum phosphorus levels have been shown to be associated with vascular calcification,⁵ cardiovascular events, and higher all-cause mortality rates in the general population,⁶ in patients with diabetes,⁷ and in those with chronic kidney disease.⁸ This association between higher serum phosphorus levels and the all-cause mortality rate led to the assumption that lowering serum phosphorus levels in these patients could reduce the rates of cardiovascular events and death, and to efforts to correct hyperphosphatemia.

Research into FGF23 continues, especially its role in cardiovascular complications of chronic kidney disease, as both phosphorus and FGF23 levels are elevated in chronic kidney disease and are implicated in poor clinical outcomes in these patients. However, both FGF23 and parathyroid hormone levels rise early in the course of kidney disease, long before overt hyperphosphatemia develops. Further, FGF23 rises earlier than parathyroid hormone and has been found to be an independent risk factor for cardiovascular events and death from any cause in end-stage kidney disease.⁹

Whether hyperphosphatemia is the culprit or merely an epiphenomenon of metabolic complications of chronic kidney disease is still unclear, as more molecules are being identified in the complex process of cardiovascular calcification.¹⁰

However, one thing is clear: vascular calcification is not just a simple precipitation of calcium and phosphorus. Instead, it is an active process that involves many regulators of mineral metabolism.¹⁰ The complex nature of this process is likely one of the reasons that evidence is conflicting¹¹ about the benefits of phosphorus binders in terms of cardiovascular events or all-cause mortality in these patients.

Reducing intake

Dietary phosphorus restriction is the first step in controlling serum phosphorus. But reducing phosphorus intake while otherwise trying to optimize the nutritional status can be challenging.

The recommended daily protein intake is 1.0 to 1.2 g/kg. But phosphorus is typically found in foods rich in proteins, and restricting protein severely can compromise nutritional status and may be as bad as elevated phosphate levels in terms of outcomes.

Although plant-based foods contain more phosphate per gram of protein (ie, they have a higher ratio of phosphorus to protein) than animal-based foods, the bioavailability of phosphorus from plant foods is lower. Phosphorus in plant-based foods is mainly in the form of phytate. Humans cannot hydrolyze phytate because we lack the phytase enzyme; hence, the phosphorus in plant-based foods is not well absorbed. Therefore, a vegetarian diet may be preferable and beneficial in patients with chronic kidney disease. A small study in humans showed that a vegetarian diet resulted in lower serum phosphorus and FGF23 levels, but the study was limited by its small sample size.¹²

Patients should be advised to avoid foods that have a high phosphate content, such as processed foods, fast foods, and cola beverages, which often have phosphate-based food additives.

Further, one should be cautious about using supplements with healthy-sounding names. A case in point is “vitamin water”: 12 oz of this fruit punch-flavored beverage contains 392 mg of phosphorus,¹³ and this alone would require 12 to 15 phosphate binder tablets to bind its phosphorus content.

In addition, many prescription drugs have significant amounts of phosphorus, and this is often unrecognized.

Sherman et al¹⁴ reviewed 200 of the most commonly prescribed drugs in dialysis patients and found that 23 (11.5%) of the drug labels listed phosphorus-containing ingredients, but the actual amount of phosphorus was not listed. The phosphorus content ranged from 1.4 mg (clonidine 0.2 mg, Blue Point Laboratories, Dublin, Ireland) to 111.5 mg (paroxetine 40 mg, GlaxoSmith Kline, Philadelphia, PA). The phosphorus content was inconsistent and varied with the dose of the agent, type of formulation (tablet or syrup), branded or generic formulation, and manufacturer.

Branded lisinopril (Merck, Kenilworth, NJ) had 21.4 mg of phosphorus per 10-mg dose, while a generic product (Blue Point Laboratories, Dublin, Ireland) had 32.6 mg. Different brands of generic amlodipine 10 mg varied in their phosphorus content from 8.6 mg (Lupin Pharmaceuticals, Mumbai, India) to 27.8 mg (Greenstone LLC, Peapack, NJ) to 40.1 mg (Qualitest Pharmaceuticals, Huntsville, AL. Rena-Vite (Cypress Pharmaceuticals, Madison, MS), a multivitamin marketed to patients with kidney disease, had 37.7 mg of phosphorus per tablet. Thus, just to bind the phosphorus content of these 3 tablets (lisinopril, amlodipine, and Rena-Vite), a patient could need at least 3 to 4 extra doses of phosphate binder.

The phosphate content of medications should be considered when prescribing. For example, Reno Caps (Nnodum Pharmaceuticals, Cincinnati, OH), another vitamin supplement, has only 1.7 mg of phosphorus per tablet and should be considered, especially in patients with poorly controlled serum phosphorus levels. However, the challenge is that medication labels do not provide the phosphorus content.

Reducing phosphorus absorption

Although these agents reduce serum phosphorus and help reduce symptoms, an important quality-of-life measure, it is uncertain whether they improve clinical outcomes.¹¹ To date, no specific phosphorus binder offers a survival benefit over placebo.¹¹

Based on the limited and conflicting evidence, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, recently updated, suggest that oral phosphorus binders should be used in patients with hyperphosphatemia to lower serum phosphorus levels toward the normal range.¹⁵ They further recommend not exceeding 1,500 mg of elemental calcium per day if a calcium-based binder is used, and they recommend avoiding calcium-based binders in patients with hypercalcemia, adynamic bone disease, or vascular calcification.

Phosphorus binders may account for up to 50% of the daily pill burden and may contribute to poor medication adherence.¹⁶ Dialysis patients need to take a lot of these drugs: by weight, 5 to 6 pounds per year.

These drugs can bind and interfere with the absorption of other vital medications and so should be taken with meals and separately from other medications.

Removing phosphorus

Removal of phosphorus by adequate dialysis or kidney transplant is the final strategy.

New agents under study

To improve phosphorus control, other agents that inhibit absorption of phosphate are being investigated.

Nicotinamide reduces expression of the sodium-phosphorus cotransporter NTP2b. Its use in combination with a low-phosphorus diet and phosphorus binders may maximize reductions in phosphorus absorption and is being studied in the CKD Optimal Management With Binders and Nicotinamide (COMBINE) study.

Tenapanor, an inhibitor of the sodium-hydrogen transporter NHE3, has been shown in animal studies to increase fecal phosphate excretion and decrease urinary phosphate excretion17 but requires further evaluation.

A 51-year-old man with end-stage renal disease, on peritoneal dialysis for the past 4 years, presented to the emergency department with severe pain in both legs. The pain had started 2 months previously and had progressively worsened. After multiple admissions in the past for hyperkalemia and volume overload due to noncompliance, he had been advised to switch to hemodialysis.

See related article and editorial

Laboratory analysis revealed the following values:

• Serum creatinine 12.62 mg/dL (reference range 0.73–1.22)
• Blood urea nitrogen 159 mg/dL (9–24)
• Serum calcium corrected for serum albumin 8.1 mg/dL (8.4–10.0)
• Serum phosphorus 10.6 mg/dL (2.7–4.8).

His history of end-stage renal disease, failure of peritoneal dialysis, high calcium-phosphorus product (8.1 mg/dL × 10.6 mg/dL = 85.9 mg²/dL ², reference range ≤ 55), and characteristic physical findings led to the diagnosis of calcific uremic arteriolopathy.

CALCIFIC UREMIC ARTERIOLOPATHY

Calcific uremic arteriolopathy or “calciphylaxis,” seen most often in patients with end-stage renal disease, is caused by calcium deposition in the media of the dermo-hypodermic arterioles, leading to infarction of adjacent tissue.^1–3 A high calcium-phosphorus product (> 55) has been implicated in its development; however, the calcium-phosphorus product can be normal despite hyperphosphatemia, which itself may promote ectopic calcification.

Early ischemic manifestations include livedo reticularis and painful retiform purpura on the thighs and other areas of high adiposity. Lesions evolve into violaceous plaquelike subcutaneous nodules that can infarct, become necrotic, ulcerate, and become infected. Punch biopsy demonstrating arteriolar calcification, subintimal fibrosis, and thrombosis confirms the diagnosis.

Differential diagnosis

Warfarin necrosis can cause large, irregular, bloody bullae that ulcerate and turn into eschar that may resemble lesions of calcific uremic arteriolopathy. Our patient, however, had no exposure to warfarin.

Pemphigus foliaceus, an immunoglobulin G4-mediated autoimmune disorder targeted against desmoglein-1, leads to the formation of fragile blisters that easily rupture when rubbed (Nikolsky sign). Lesions evolve into scaling, crusty erosions on an erythematous base. With tender blisters and lack of mucous membrane involvement, pemphigus foliaceus shares similarities with calcific uremic arteriolopathy, but the presence of necrotic eschar surrounded by violaceous plaques in our patient made it an unlikely diagnosis.

Cryofibrinogenemia. In the right clinical scenario, ie, in a patient with vasculitis, malignancy, infection, cryoglobulinemia, or collagen diseases, cryofibrinogen-mediated cold-induced occlusive lesions may mimic calcific uremic arteriolopathy, with painful or pruritic erythema, purpura, livedo reticularis, necrosis, and ulceration.⁴ Our patient had no color changes with exposure to cold, nor any history of Raynaud phenomenon or joint pain, making the diagnosis of cryofibrinogenemia less likely.

Nephrogenic systemic fibrosis. Gadolinium contrast medium in magnetic resonance imaging can cause nephrogenic systemic fibrosis, characterized by erythematous papules that coalesce into brawny plaques with surrounding woody induration, which may resemble lesions of calcific uremic arteriolopathy.⁵ However, our patient had not been exposed to gadolinium.

Management

Management is multidisciplinary and includes the following¹:

• Hemodialysis, modified to optimize calcium balance²
• Intravenous sodium thiosulfate: the exact mechanism of action remains unclear, but it is thought to play a role in chelating calcium from tissue deposits, thus decreasing pain and promoting regression of skin lesions³
• Wound care, including chemical debridement agents, negative-pressure wound therapy, and surgical debridement for infected wounds⁶
• Pain management with opioid analgesics.

The patient was treated with all these measures. However, he died of sudden cardiac arrest during the same admission.

A 51-year-old man with end-stage renal disease, on peritoneal dialysis for the past 4 years, presented to the emergency department with severe pain in both legs. The pain had started 2 months previously and had progressively worsened. After multiple admissions in the past for hyperkalemia and volume overload due to noncompliance, he had been advised to switch to hemodialysis.

See related article and editorial

Laboratory analysis revealed the following values:

• Serum creatinine 12.62 mg/dL (reference range 0.73–1.22)
• Blood urea nitrogen 159 mg/dL (9–24)
• Serum calcium corrected for serum albumin 8.1 mg/dL (8.4–10.0)
• Serum phosphorus 10.6 mg/dL (2.7–4.8).

His history of end-stage renal disease, failure of peritoneal dialysis, high calcium-phosphorus product (8.1 mg/dL × 10.6 mg/dL = 85.9 mg²/dL ², reference range ≤ 55), and characteristic physical findings led to the diagnosis of calcific uremic arteriolopathy.

CALCIFIC UREMIC ARTERIOLOPATHY

Calcific uremic arteriolopathy or “calciphylaxis,” seen most often in patients with end-stage renal disease, is caused by calcium deposition in the media of the dermo-hypodermic arterioles, leading to infarction of adjacent tissue.^1–3 A high calcium-phosphorus product (> 55) has been implicated in its development; however, the calcium-phosphorus product can be normal despite hyperphosphatemia, which itself may promote ectopic calcification.

Early ischemic manifestations include livedo reticularis and painful retiform purpura on the thighs and other areas of high adiposity. Lesions evolve into violaceous plaquelike subcutaneous nodules that can infarct, become necrotic, ulcerate, and become infected. Punch biopsy demonstrating arteriolar calcification, subintimal fibrosis, and thrombosis confirms the diagnosis.

Differential diagnosis

Warfarin necrosis can cause large, irregular, bloody bullae that ulcerate and turn into eschar that may resemble lesions of calcific uremic arteriolopathy. Our patient, however, had no exposure to warfarin.

Pemphigus foliaceus, an immunoglobulin G4-mediated autoimmune disorder targeted against desmoglein-1, leads to the formation of fragile blisters that easily rupture when rubbed (Nikolsky sign). Lesions evolve into scaling, crusty erosions on an erythematous base. With tender blisters and lack of mucous membrane involvement, pemphigus foliaceus shares similarities with calcific uremic arteriolopathy, but the presence of necrotic eschar surrounded by violaceous plaques in our patient made it an unlikely diagnosis.

Cryofibrinogenemia. In the right clinical scenario, ie, in a patient with vasculitis, malignancy, infection, cryoglobulinemia, or collagen diseases, cryofibrinogen-mediated cold-induced occlusive lesions may mimic calcific uremic arteriolopathy, with painful or pruritic erythema, purpura, livedo reticularis, necrosis, and ulceration.⁴ Our patient had no color changes with exposure to cold, nor any history of Raynaud phenomenon or joint pain, making the diagnosis of cryofibrinogenemia less likely.

Nephrogenic systemic fibrosis. Gadolinium contrast medium in magnetic resonance imaging can cause nephrogenic systemic fibrosis, characterized by erythematous papules that coalesce into brawny plaques with surrounding woody induration, which may resemble lesions of calcific uremic arteriolopathy.⁵ However, our patient had not been exposed to gadolinium.

Management

Management is multidisciplinary and includes the following¹:

• Hemodialysis, modified to optimize calcium balance²
• Intravenous sodium thiosulfate: the exact mechanism of action remains unclear, but it is thought to play a role in chelating calcium from tissue deposits, thus decreasing pain and promoting regression of skin lesions³
• Wound care, including chemical debridement agents, negative-pressure wound therapy, and surgical debridement for infected wounds⁶
• Pain management with opioid analgesics.

The patient was treated with all these measures. However, he died of sudden cardiac arrest during the same admission.

A 51-year-old man with end-stage renal disease, on peritoneal dialysis for the past 4 years, presented to the emergency department with severe pain in both legs. The pain had started 2 months previously and had progressively worsened. After multiple admissions in the past for hyperkalemia and volume overload due to noncompliance, he had been advised to switch to hemodialysis.

See related article and editorial

Laboratory analysis revealed the following values:

• Serum creatinine 12.62 mg/dL (reference range 0.73–1.22)
• Blood urea nitrogen 159 mg/dL (9–24)
• Serum calcium corrected for serum albumin 8.1 mg/dL (8.4–10.0)
• Serum phosphorus 10.6 mg/dL (2.7–4.8).

His history of end-stage renal disease, failure of peritoneal dialysis, high calcium-phosphorus product (8.1 mg/dL × 10.6 mg/dL = 85.9 mg²/dL ², reference range ≤ 55), and characteristic physical findings led to the diagnosis of calcific uremic arteriolopathy.

CALCIFIC UREMIC ARTERIOLOPATHY

Calcific uremic arteriolopathy or “calciphylaxis,” seen most often in patients with end-stage renal disease, is caused by calcium deposition in the media of the dermo-hypodermic arterioles, leading to infarction of adjacent tissue.^1–3 A high calcium-phosphorus product (> 55) has been implicated in its development; however, the calcium-phosphorus product can be normal despite hyperphosphatemia, which itself may promote ectopic calcification.

Early ischemic manifestations include livedo reticularis and painful retiform purpura on the thighs and other areas of high adiposity. Lesions evolve into violaceous plaquelike subcutaneous nodules that can infarct, become necrotic, ulcerate, and become infected. Punch biopsy demonstrating arteriolar calcification, subintimal fibrosis, and thrombosis confirms the diagnosis.

Differential diagnosis

Warfarin necrosis can cause large, irregular, bloody bullae that ulcerate and turn into eschar that may resemble lesions of calcific uremic arteriolopathy. Our patient, however, had no exposure to warfarin.

Pemphigus foliaceus, an immunoglobulin G4-mediated autoimmune disorder targeted against desmoglein-1, leads to the formation of fragile blisters that easily rupture when rubbed (Nikolsky sign). Lesions evolve into scaling, crusty erosions on an erythematous base. With tender blisters and lack of mucous membrane involvement, pemphigus foliaceus shares similarities with calcific uremic arteriolopathy, but the presence of necrotic eschar surrounded by violaceous plaques in our patient made it an unlikely diagnosis.

Cryofibrinogenemia. In the right clinical scenario, ie, in a patient with vasculitis, malignancy, infection, cryoglobulinemia, or collagen diseases, cryofibrinogen-mediated cold-induced occlusive lesions may mimic calcific uremic arteriolopathy, with painful or pruritic erythema, purpura, livedo reticularis, necrosis, and ulceration.⁴ Our patient had no color changes with exposure to cold, nor any history of Raynaud phenomenon or joint pain, making the diagnosis of cryofibrinogenemia less likely.

Nephrogenic systemic fibrosis. Gadolinium contrast medium in magnetic resonance imaging can cause nephrogenic systemic fibrosis, characterized by erythematous papules that coalesce into brawny plaques with surrounding woody induration, which may resemble lesions of calcific uremic arteriolopathy.⁵ However, our patient had not been exposed to gadolinium.

Management

Management is multidisciplinary and includes the following¹:

• Hemodialysis, modified to optimize calcium balance²
• Intravenous sodium thiosulfate: the exact mechanism of action remains unclear, but it is thought to play a role in chelating calcium from tissue deposits, thus decreasing pain and promoting regression of skin lesions³
• Wound care, including chemical debridement agents, negative-pressure wound therapy, and surgical debridement for infected wounds⁶
• Pain management with opioid analgesics.

The patient was treated with all these measures. However, he died of sudden cardiac arrest during the same admission.

Patients presenting with depression commonly have undiagnosed bipolar depression,^1–7 that is, depression with shifts to periods of mania. During manic or hypomanic episodes, people feel energetic, need little sleep, and are often happy and charming.⁸ But too much of a good thing can also wreak havoc on their life.

Bipolar depression (ie, depression in patients with a diagnosis of bipolar disorder) is treated differently from unipolar depression,^3,9–13 making it especially important that clinicians recognize if a patient who presents with depression has a history of (hypo)manic symptoms.

CASE 1: THE IMPULSIVE NURSE

A 32-year-old nurse presents to her primary care provider with depressed mood. She reports having had a single depressive episode when she was a college freshman. Her family history includes depression, bipolar disorder, and schizophrenia, and her paternal grandfather and a maternal aunt committed suicide. Upon questioning, she reveals that in the past, she has had 3 episodes lasting several weeks and characterized by insubordinate behavior at work, irritability, high energy, and decreased need for sleep. She regrets impulsive sexual and financial decisions that she made during these episodes and recently filed for personal bankruptcy. For the past month, her mood has been persistently low, with reduced sleep, appetite, energy, and concentration, and with passive thoughts of suicide.

A CAREFUL HISTORY IS CRITICAL

This case illustrates many typical features of bipolar depression that are revealed only by taking a thorough history. Although the patient is high-functioning, having attained a professional career, she has serious problems with sexual and financial impulsivity and at her job. She has a strong family history of mood disorder. And she describes episodes of depression and mania in the past.

Starts in young adulthood, strong heritability

Bipolar disorder can be a devastating condition with lifelong consequences,^14–20 especially as it typically starts when patients are getting an education or embarking on a career. It usually first manifests in the late teenage years and progresses in the patient’s early 20s.^21,22 The first hospitalization can occur soon thereafter.^23,24

Bipolar disorder is one of the most heritable conditions in psychiatry, and about 13% of children who have an afflicted parent develop it.²⁵ In identical twins, the concordance is about 50% to 75%, indicating the importance of genetics and environmental factors.^26,27

Associated with migraine, other conditions

The disorder is associated with a variety of conditions (Table 1).^28,29 Some conditions (eg, thyroid disease) can cause mood cycling, and some (eg, sexually transmitted infections, accidents) are the consequences of the lifestyle that may accompany mania. For unknown reasons, migraine is highly associated with bipolar disorder.

DEPRESSION AND MANIA: TWO SIDES OF THE SAME COIN

Symptoms of depression and mania are frequently viewed as opposite mood states, though many times patients report a mixture of them.^17,30–35 For both states, the features of a distinct change from the patient’s normal condition and the sustained nature of the symptoms are important diagnostically and indicate a likely underlying biological cause.

Major depressive disorder: Slowing down

The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),⁸ defines major depressive disorder as having either depressed mood or markedly diminished pleasure in most activities for most days during at least 2 weeks.

In addition, at least 4 of the following must be present during the same period:

• Appetite disturbance
• Sleep disturbance
• Motor retardation or agitation
• Lack of energy
• Feelings of worthlessness or excessive guilt
• Decreased concentration
• Recurrent thoughts of death or suicide.

An estimated 20% of the population experience a major depressive episode over their lifetime. A surprisingly high proportion of people with depression—30% to 40%—also have had subthreshold symptoms of mania (symptoms not meeting the criteria for hypomania or mania in terms of number of symptoms or duration).^21,22 Because of these odds, it is important to suspect bipolar disorder even in patients who present with depression but who may not yet have manifested episodes of mania or hypomania.

Mood disorders can be regarded as falling into a spectrum, ranging from unipolar or “pure” major depression without any features of hypomania to major depression and severe mania.^17,31–36

Mania: Speeding up

The DSM-5 defines mania as the presence of persistently elevated, expansive, or irritable mood with increased activity for more than 1 week. In addition, at least 3 of the following features must be present, with impaired functioning (4 features are required if mood is only irritable)⁸:

• Inflated self-esteem or grandiosity
• Decreased need for sleep
• Pressured speech
• Racing thoughts
• Distractibility
• Excessive involvement in pleasurable, high-risk activities.

Hypomania: No functional impairment

Hypomania is a less severe condition, in which the abnormally elevated mood is of shorter duration (4–7 days) and meets the other criteria for mania but without significant functional impairment. People may, in fact, be very functional and productive during hypomanic episodes.⁸

CLASSIFYING BIPOLAR DISORDER

Bipolar disorder is categorized according to severity.^24,37,38 The most severe form, bipolar I disorder, is marked by major depression and manic episodes. It affects up to 1.5% of the US population, with equal proportions of men and women.³⁹ Bipolar II disorder is less severe. It affects 0.8% to 1.6% of the US population, predominantly women.^21,40 In bipolar II disorder, depression is more prominent, with episodes of hypomania.

Subthreshold bipolar disorders are characterized by episodic symptoms that do not meet the threshold for depression or hypomania; the symptoms are fewer or of shorter duration. These minor types of bipolar disorder affect up to 6% of the US population.¹⁷

Other conditions within the spectrum of bipolar and depressive disorders include medication- and substance-induced mania, agitated or anxious depression, and mixed states.^31,34–36

DISTINGUISHING UNIPOLAR FROM BIPOLAR DEPRESSION

Considerable research has focused on finding a clear-cut clinical or biological feature to differentiate unipolar from bipolar depression, but so far none has been discovered. Distinguishing the two conditions still depends on clinical judgment. There are important reasons to identify the distinction between unipolar depression and bipolar disorder.

Prognosis differs. Bipolar disorder tends to be a more severe condition. Young people, who may initially present with only mild symptoms of mania, may develop serious episodes over the years. People may lose their savings, their marriage, and their career during a manic episode. The more critical the occupation (eg, doctor, pilot), the greater the potential consequences of impaired judgment brought on by even mild hypomania.^14–20

Treatment differs. Typical antidepressants given for depression can trigger a manic episode in patients with bipolar depression, with devastating consequences. Atypical neuroleptic drugs used to treat bipolar disorder can also have serious effects (eg, metabolic and neurologic effects, including irreversible tardive dyskinesia).^3,13,40–43

Despite the good reasons to do so, many doctors (including some psychiatrists) do not ask their patients about a propensity to mania or hypomania.^4–6 More stigma is attached to the diagnosis of bipolar disorder than to depression^44–47; once it is in the medical record, the patient may have problems with employment and obtaining medical insurance.^17,44 The old term “manic-depressive” is often associated in the public mind with a person on the streets displaying severely psychotic behavior; the condition is now understood to consist of a spectrum from mild to more severe illness.

Clinical indicators of bipolarity

There are many indicators that a person who presents with depression may be on the bipolar spectrum, but this is not always easily identified.^48–53

History of hypomanic symptoms or subthreshold manic symptoms. Although directly asking the patient about the defining symptoms (eg, “Have you ever had episodes of being ‘hyper’ or too happy?”) may help elicit the diagnosis, many patients with bipolar disorder only report depression, as it is psychically painful. In contrast, hypomania and even mania can be perceived as positive, as patients may have less insight into the abnormality of the condition and feel that they are functioning extremely well.

Early age of onset of a mood disorder, such as severe depression in childhood or early adulthood, points toward bipolar disorder. Diagnosing mood disorders in childhood is difficult, as children are less able to recognize or verbalize many of their symptoms.

Postpartum mood disorder, particularly with psychotic symptoms, indicates a strong possibility of a diagnosis of bipolar disorder.

Drug-induced mania, hypomania, and periods of hyperactivity are key features of bipolar disorder. If asked, patients may report feeling a “buzz” when taking an antidepressant.

Erratic patterns in work and relationships are a red flag and are viewed as “soft signs” of bipolar depression. Akiskal⁵⁴ described the “rule of three” that should make one consider bipolar disorder: for example, three failed marriages, three current jobs or frequent job changes, three distinct professions practiced at the same time, and simultaneously dating three people. Such features indicate both the hyperfunctioning and the disruptive aspects of mania.

Family history of bipolar disorder or severe psychiatric illness is a very important clue. A more subtle clue described by Akiskal⁵⁴ may be that several members of the family are very high-functioning in several different fields: eg, one may be a highly accomplished doctor, another a famous lawyer, and another a prominent politician. Or several members of the family may have erratic patterns of work and relationships. However, these subtle clues have been derived from clinical experiences and have not been validated in large-scale studies.

Dr. Z is a prominent surgical subspecialist who is part of a small group practice. His wife has become increasingly worried about his behavior changes at home, including sleeping only a few hours a night, spending sprees, and binge drinking. He reluctantly agrees to an outpatient psychiatric evaluation if she attends with him. He creates a disturbance in the waiting room by shaking everyone’s hands and trying to hug all the women. During his examination, he is loud and expansive, denying he has any problems and describing himself as “the greatest doctor in the world.” The psychiatrist recommends hospitalization, but Dr. Z refuses and becomes belligerent. He announces that he just needs a career change and that he will fly to Mexico to open a bar.

This case, from the Texas Medical Association Archives,⁵⁵ is not unusual. In addition to many characteristics discussed above, this case is typical in that the spouse brought the patient in, reflecting that the patient lacked insight that his behavior was abnormal. The disinhibition (hugging women), grandiosity, and unrealistic plans are also typical.

DIFFERENTIAL DIAGNOSIS OF BIPOLAR DEPRESSION

Anxiety disorders may be associated with dissociative speech or racing thoughts, which can be confused with bipolar illness. Personality disorders (eg, borderline, narcissistic, sociopathic) can involve a tumultuous and impulsive lifestyle resembling episodes of depression and mania. Schizoaffective illness has features of schizophrenia and bipolar disorder.

It is also possible that, despite what may look like mild features of bipolar disorder, there is no psychiatric condition. Some people with mild mania—often successful professionals or politicians—have high energy and can function very well with only a few hours of sleep. Similarly, depressive symptoms for short periods of time can be adaptive, such as in the face of a serious setback when extreme reflection and a period of inactivity can be useful, leading to subsequent reorganization.

A psychiatric diagnosis is usually made only when there is an abnormality, ie, the behavior is beyond normal limits, the person cannot control his or her symptoms, or social or occupational functioning is impaired.

SCREENING INSTRUMENTS

A few tools help determine the likelihood of bipolar disorder.

The Patient Health Questionnaire (PHQ-9)^59,60 is a good 9-item screening tool for depression.

The Mood Disorder Questionnaire⁶⁰ is specific for bipolar disorder, and like the PHQ-9, it is a patient-reported, short questionnaire that is available free online. The Mood Disorder Questionnaire asks about the symptoms of mania in a yes-no format. The result is positive if all of the following are present:

• A “yes” response to 7 of the 13 features
• Several features occur simultaneously
• The features are a moderate or serious problem.

Unlike most screening instruments, the Mood Disorder Questionnaire is more specific than sensitive. It is 93% specific for bipolar disorder in patients treated for depression in a primary care setting, but only 58% sensitive.^61–63

WHEN TO REFER TO PSYCHIATRY

Patients suspected of having bipolar disorder or who have been previously diagnosed with it should be referred to a psychiatrist if they have certain features, including:

• Bipolar I disorder
• Psychotic symptoms
• Suicide risk or in danger of harming others
• Significantly impaired functioning
• Unclear diagnosis.

CASE 3: A TELEVISION ANCHOR’S DREAM TURNS TO NIGHTMARE

According to a famous news anchor’s autobiography,⁶⁴ the steroids prescribed for her hives “revved her up.” The next course left her depressed. Antidepressant medications propelled her into a manic state, and she was soon planning a book, a television show, and a magazine all at once. During that time, she bought a cottage online. Her shyness evaporated at parties. “I was suddenly the equal of my high-energy friends who move fast and talk fast and loud,” she wrote. “I told everyone that I could understand why men felt like they could run the world, because I felt like that. This was a new me, and I liked her!”⁶⁴ She was soon diagnosed with bipolar disorder and admitted to a psychiatric clinic.

In general, acute bipolar disorder should be treated with a combination of an antidepressant and a mood stabilizer, and possibly an antipsychotic drug. An antidepressant should not be used alone, particularly with patients with a diagnosis of bipolar I disorder, because of the risk of triggering mania or the risk of faster cycling between mania and depression.¹³

Mood stabilizers include lithium, lamotrigine, and valproate. Each can prevent episodes of depression and mania. Lithium, which has been used as a mood stabilizer for 60 years, is specific for bipolar disorder, and it remains the best mood stabilizer treatment.

Antidepressants. The first-line antidepressant medication is bupropion, which is thought to be less likely to precipitate a manic episode,⁶⁵ though all antidepressants have been associated with this side effect in patients with bipolar disorder. Other antidepressants—for example, selective serotonin reuptake inhibitors such as fluoxetine and dual reuptake inhibitors such as venlafaxine and duloxetine—can also be used. The precipitation of mania and possible increased mood cycling was first described with tricylic antidepressants, so drugs of this class should be used with caution.

Neuroleptic drugs such as aripiprazole, quetiapine, and lurasidone may be the easiest drugs to use, as they have antidepressant effects and can also prevent the occurrence of mania. These medications are frequently classified as mood stabilizers. However, they may not have true mood stabilizing properties such as that of lithium. Importantly, their use tends to entail significant metabolic problems and can lead to hyperlipidemia and diabetes. In addition, Parkinson disease-like symptoms— and in some cases irreversible involuntary movements of the mouth and tongue, as well as the body (tardive dyskinesia)—are important possible side effects.

All psychiatric medications have potential side effects (Table 3). Newer antidepressants and neuroleptics may have fewer side effects than older medications but are not more effective.

Should milder forms of bipolar depression be treated?

A dilemma is whether we should treat milder forms of bipolar depression, such as bipolar II depression, depression with subthreshold hypomania symptoms, or depression in persons with a strong family history of bipolar disorder.

Many doctors are justifiably reluctant to prescribe antidepressants for depression because of the risk of triggering mania. Although mood stabilizers such as lithium would counteract possible mania emergence, physicians often do not prescribe them because of inexperience and fear of risks and possible side effects. Patients are likewise resistant because they feel that use of mood stabilizers is tantamount to being told they are “manic-depressive,” with its associated stigma.

Overuse of atypical neuroleptics such as aripiprazole, quetiapine, and olanzapine has led to an awareness of metabolic syndrome and tardive dyskinesia, also making doctors cautious about using these drugs.

Answer: Yes, but treat with caution

Not treating depression consigns a patient to suffer with untreated depression, sometimes for years. Outcomes for patients with depression and bipolar disorder are often poor because the conditions are not recognized, and even when the conditions are recognized, doctors and patients may be reluctant to medicate appropriately. Medications should be used as needed to treat depression, but with an awareness of the possible side effects and with close patient monitoring.

A truly sustained manic state (unlike the brief euphoria brought on by some drugs) is not actually so easy to induce. In an unpublished Cleveland Clinic study, we monitored peaks of hypomanic symptoms in young patients (ages 15–30) during antidepressant treatment without mood stabilizers. About 30% to 40% of patients had subthreshold manic symptoms or a family history of bipolar disorder; 3 patients out of 51 developed hypomania leading to a change of diagnosis to bipolar disorder. Even in patients who had no risk factors for bipolar disorder, 2 out of 53 converted to a bipolar diagnosis. So conversion rates in patients with subthreshold bipolar disorder seem to be low, and the disorder can be identified early by monitoring the patient closely.

NONPHARMACOLOGIC TREATMENTS FOR DEPRESSION

Psychotherapy is indicated for all patients on medications for depression, as both pharmacologic and nonpharmacologic treatments are more effective when combined.⁶⁶ Other treatments include trans­cranial magnetic stimulation, electroconvulsive therapy, light therapy, and exercise. Having a consistent daily routine, particularly regarding the sleep-wake schedule, is also helpful, and patients should be educated about its importance.

Patients presenting with depression commonly have undiagnosed bipolar depression,^1–7 that is, depression with shifts to periods of mania. During manic or hypomanic episodes, people feel energetic, need little sleep, and are often happy and charming.⁸ But too much of a good thing can also wreak havoc on their life.

Bipolar depression (ie, depression in patients with a diagnosis of bipolar disorder) is treated differently from unipolar depression,^3,9–13 making it especially important that clinicians recognize if a patient who presents with depression has a history of (hypo)manic symptoms.

CASE 1: THE IMPULSIVE NURSE

A 32-year-old nurse presents to her primary care provider with depressed mood. She reports having had a single depressive episode when she was a college freshman. Her family history includes depression, bipolar disorder, and schizophrenia, and her paternal grandfather and a maternal aunt committed suicide. Upon questioning, she reveals that in the past, she has had 3 episodes lasting several weeks and characterized by insubordinate behavior at work, irritability, high energy, and decreased need for sleep. She regrets impulsive sexual and financial decisions that she made during these episodes and recently filed for personal bankruptcy. For the past month, her mood has been persistently low, with reduced sleep, appetite, energy, and concentration, and with passive thoughts of suicide.

A CAREFUL HISTORY IS CRITICAL

This case illustrates many typical features of bipolar depression that are revealed only by taking a thorough history. Although the patient is high-functioning, having attained a professional career, she has serious problems with sexual and financial impulsivity and at her job. She has a strong family history of mood disorder. And she describes episodes of depression and mania in the past.

Starts in young adulthood, strong heritability

Bipolar disorder can be a devastating condition with lifelong consequences,^14–20 especially as it typically starts when patients are getting an education or embarking on a career. It usually first manifests in the late teenage years and progresses in the patient’s early 20s.^21,22 The first hospitalization can occur soon thereafter.^23,24

Bipolar disorder is one of the most heritable conditions in psychiatry, and about 13% of children who have an afflicted parent develop it.²⁵ In identical twins, the concordance is about 50% to 75%, indicating the importance of genetics and environmental factors.^26,27

Associated with migraine, other conditions

The disorder is associated with a variety of conditions (Table 1).^28,29 Some conditions (eg, thyroid disease) can cause mood cycling, and some (eg, sexually transmitted infections, accidents) are the consequences of the lifestyle that may accompany mania. For unknown reasons, migraine is highly associated with bipolar disorder.

DEPRESSION AND MANIA: TWO SIDES OF THE SAME COIN

Symptoms of depression and mania are frequently viewed as opposite mood states, though many times patients report a mixture of them.^17,30–35 For both states, the features of a distinct change from the patient’s normal condition and the sustained nature of the symptoms are important diagnostically and indicate a likely underlying biological cause.

Major depressive disorder: Slowing down

The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),⁸ defines major depressive disorder as having either depressed mood or markedly diminished pleasure in most activities for most days during at least 2 weeks.

In addition, at least 4 of the following must be present during the same period:

• Appetite disturbance
• Sleep disturbance
• Motor retardation or agitation
• Lack of energy
• Feelings of worthlessness or excessive guilt
• Decreased concentration
• Recurrent thoughts of death or suicide.

An estimated 20% of the population experience a major depressive episode over their lifetime. A surprisingly high proportion of people with depression—30% to 40%—also have had subthreshold symptoms of mania (symptoms not meeting the criteria for hypomania or mania in terms of number of symptoms or duration).^21,22 Because of these odds, it is important to suspect bipolar disorder even in patients who present with depression but who may not yet have manifested episodes of mania or hypomania.

Mood disorders can be regarded as falling into a spectrum, ranging from unipolar or “pure” major depression without any features of hypomania to major depression and severe mania.^17,31–36

Mania: Speeding up

The DSM-5 defines mania as the presence of persistently elevated, expansive, or irritable mood with increased activity for more than 1 week. In addition, at least 3 of the following features must be present, with impaired functioning (4 features are required if mood is only irritable)⁸:

• Inflated self-esteem or grandiosity
• Decreased need for sleep
• Pressured speech
• Racing thoughts
• Distractibility
• Excessive involvement in pleasurable, high-risk activities.

Hypomania: No functional impairment

Hypomania is a less severe condition, in which the abnormally elevated mood is of shorter duration (4–7 days) and meets the other criteria for mania but without significant functional impairment. People may, in fact, be very functional and productive during hypomanic episodes.⁸

CLASSIFYING BIPOLAR DISORDER

Bipolar disorder is categorized according to severity.^24,37,38 The most severe form, bipolar I disorder, is marked by major depression and manic episodes. It affects up to 1.5% of the US population, with equal proportions of men and women.³⁹ Bipolar II disorder is less severe. It affects 0.8% to 1.6% of the US population, predominantly women.^21,40 In bipolar II disorder, depression is more prominent, with episodes of hypomania.

Subthreshold bipolar disorders are characterized by episodic symptoms that do not meet the threshold for depression or hypomania; the symptoms are fewer or of shorter duration. These minor types of bipolar disorder affect up to 6% of the US population.¹⁷

Other conditions within the spectrum of bipolar and depressive disorders include medication- and substance-induced mania, agitated or anxious depression, and mixed states.^31,34–36

DISTINGUISHING UNIPOLAR FROM BIPOLAR DEPRESSION

Considerable research has focused on finding a clear-cut clinical or biological feature to differentiate unipolar from bipolar depression, but so far none has been discovered. Distinguishing the two conditions still depends on clinical judgment. There are important reasons to identify the distinction between unipolar depression and bipolar disorder.

Prognosis differs. Bipolar disorder tends to be a more severe condition. Young people, who may initially present with only mild symptoms of mania, may develop serious episodes over the years. People may lose their savings, their marriage, and their career during a manic episode. The more critical the occupation (eg, doctor, pilot), the greater the potential consequences of impaired judgment brought on by even mild hypomania.^14–20

Treatment differs. Typical antidepressants given for depression can trigger a manic episode in patients with bipolar depression, with devastating consequences. Atypical neuroleptic drugs used to treat bipolar disorder can also have serious effects (eg, metabolic and neurologic effects, including irreversible tardive dyskinesia).^3,13,40–43

Despite the good reasons to do so, many doctors (including some psychiatrists) do not ask their patients about a propensity to mania or hypomania.^4–6 More stigma is attached to the diagnosis of bipolar disorder than to depression^44–47; once it is in the medical record, the patient may have problems with employment and obtaining medical insurance.^17,44 The old term “manic-depressive” is often associated in the public mind with a person on the streets displaying severely psychotic behavior; the condition is now understood to consist of a spectrum from mild to more severe illness.

Clinical indicators of bipolarity

There are many indicators that a person who presents with depression may be on the bipolar spectrum, but this is not always easily identified.^48–53

History of hypomanic symptoms or subthreshold manic symptoms. Although directly asking the patient about the defining symptoms (eg, “Have you ever had episodes of being ‘hyper’ or too happy?”) may help elicit the diagnosis, many patients with bipolar disorder only report depression, as it is psychically painful. In contrast, hypomania and even mania can be perceived as positive, as patients may have less insight into the abnormality of the condition and feel that they are functioning extremely well.

Early age of onset of a mood disorder, such as severe depression in childhood or early adulthood, points toward bipolar disorder. Diagnosing mood disorders in childhood is difficult, as children are less able to recognize or verbalize many of their symptoms.

Postpartum mood disorder, particularly with psychotic symptoms, indicates a strong possibility of a diagnosis of bipolar disorder.

Drug-induced mania, hypomania, and periods of hyperactivity are key features of bipolar disorder. If asked, patients may report feeling a “buzz” when taking an antidepressant.

Erratic patterns in work and relationships are a red flag and are viewed as “soft signs” of bipolar depression. Akiskal⁵⁴ described the “rule of three” that should make one consider bipolar disorder: for example, three failed marriages, three current jobs or frequent job changes, three distinct professions practiced at the same time, and simultaneously dating three people. Such features indicate both the hyperfunctioning and the disruptive aspects of mania.

Family history of bipolar disorder or severe psychiatric illness is a very important clue. A more subtle clue described by Akiskal⁵⁴ may be that several members of the family are very high-functioning in several different fields: eg, one may be a highly accomplished doctor, another a famous lawyer, and another a prominent politician. Or several members of the family may have erratic patterns of work and relationships. However, these subtle clues have been derived from clinical experiences and have not been validated in large-scale studies.

Dr. Z is a prominent surgical subspecialist who is part of a small group practice. His wife has become increasingly worried about his behavior changes at home, including sleeping only a few hours a night, spending sprees, and binge drinking. He reluctantly agrees to an outpatient psychiatric evaluation if she attends with him. He creates a disturbance in the waiting room by shaking everyone’s hands and trying to hug all the women. During his examination, he is loud and expansive, denying he has any problems and describing himself as “the greatest doctor in the world.” The psychiatrist recommends hospitalization, but Dr. Z refuses and becomes belligerent. He announces that he just needs a career change and that he will fly to Mexico to open a bar.

This case, from the Texas Medical Association Archives,⁵⁵ is not unusual. In addition to many characteristics discussed above, this case is typical in that the spouse brought the patient in, reflecting that the patient lacked insight that his behavior was abnormal. The disinhibition (hugging women), grandiosity, and unrealistic plans are also typical.

DIFFERENTIAL DIAGNOSIS OF BIPOLAR DEPRESSION

Anxiety disorders may be associated with dissociative speech or racing thoughts, which can be confused with bipolar illness. Personality disorders (eg, borderline, narcissistic, sociopathic) can involve a tumultuous and impulsive lifestyle resembling episodes of depression and mania. Schizoaffective illness has features of schizophrenia and bipolar disorder.

It is also possible that, despite what may look like mild features of bipolar disorder, there is no psychiatric condition. Some people with mild mania—often successful professionals or politicians—have high energy and can function very well with only a few hours of sleep. Similarly, depressive symptoms for short periods of time can be adaptive, such as in the face of a serious setback when extreme reflection and a period of inactivity can be useful, leading to subsequent reorganization.

A psychiatric diagnosis is usually made only when there is an abnormality, ie, the behavior is beyond normal limits, the person cannot control his or her symptoms, or social or occupational functioning is impaired.

SCREENING INSTRUMENTS

A few tools help determine the likelihood of bipolar disorder.

The Patient Health Questionnaire (PHQ-9)^59,60 is a good 9-item screening tool for depression.

The Mood Disorder Questionnaire⁶⁰ is specific for bipolar disorder, and like the PHQ-9, it is a patient-reported, short questionnaire that is available free online. The Mood Disorder Questionnaire asks about the symptoms of mania in a yes-no format. The result is positive if all of the following are present:

• A “yes” response to 7 of the 13 features
• Several features occur simultaneously
• The features are a moderate or serious problem.

Unlike most screening instruments, the Mood Disorder Questionnaire is more specific than sensitive. It is 93% specific for bipolar disorder in patients treated for depression in a primary care setting, but only 58% sensitive.^61–63

WHEN TO REFER TO PSYCHIATRY

Patients suspected of having bipolar disorder or who have been previously diagnosed with it should be referred to a psychiatrist if they have certain features, including:

• Bipolar I disorder
• Psychotic symptoms
• Suicide risk or in danger of harming others
• Significantly impaired functioning
• Unclear diagnosis.

CASE 3: A TELEVISION ANCHOR’S DREAM TURNS TO NIGHTMARE

According to a famous news anchor’s autobiography,⁶⁴ the steroids prescribed for her hives “revved her up.” The next course left her depressed. Antidepressant medications propelled her into a manic state, and she was soon planning a book, a television show, and a magazine all at once. During that time, she bought a cottage online. Her shyness evaporated at parties. “I was suddenly the equal of my high-energy friends who move fast and talk fast and loud,” she wrote. “I told everyone that I could understand why men felt like they could run the world, because I felt like that. This was a new me, and I liked her!”⁶⁴ She was soon diagnosed with bipolar disorder and admitted to a psychiatric clinic.

In general, acute bipolar disorder should be treated with a combination of an antidepressant and a mood stabilizer, and possibly an antipsychotic drug. An antidepressant should not be used alone, particularly with patients with a diagnosis of bipolar I disorder, because of the risk of triggering mania or the risk of faster cycling between mania and depression.¹³

Mood stabilizers include lithium, lamotrigine, and valproate. Each can prevent episodes of depression and mania. Lithium, which has been used as a mood stabilizer for 60 years, is specific for bipolar disorder, and it remains the best mood stabilizer treatment.

Antidepressants. The first-line antidepressant medication is bupropion, which is thought to be less likely to precipitate a manic episode,⁶⁵ though all antidepressants have been associated with this side effect in patients with bipolar disorder. Other antidepressants—for example, selective serotonin reuptake inhibitors such as fluoxetine and dual reuptake inhibitors such as venlafaxine and duloxetine—can also be used. The precipitation of mania and possible increased mood cycling was first described with tricylic antidepressants, so drugs of this class should be used with caution.

Neuroleptic drugs such as aripiprazole, quetiapine, and lurasidone may be the easiest drugs to use, as they have antidepressant effects and can also prevent the occurrence of mania. These medications are frequently classified as mood stabilizers. However, they may not have true mood stabilizing properties such as that of lithium. Importantly, their use tends to entail significant metabolic problems and can lead to hyperlipidemia and diabetes. In addition, Parkinson disease-like symptoms— and in some cases irreversible involuntary movements of the mouth and tongue, as well as the body (tardive dyskinesia)—are important possible side effects.

All psychiatric medications have potential side effects (Table 3). Newer antidepressants and neuroleptics may have fewer side effects than older medications but are not more effective.

Should milder forms of bipolar depression be treated?

A dilemma is whether we should treat milder forms of bipolar depression, such as bipolar II depression, depression with subthreshold hypomania symptoms, or depression in persons with a strong family history of bipolar disorder.

Many doctors are justifiably reluctant to prescribe antidepressants for depression because of the risk of triggering mania. Although mood stabilizers such as lithium would counteract possible mania emergence, physicians often do not prescribe them because of inexperience and fear of risks and possible side effects. Patients are likewise resistant because they feel that use of mood stabilizers is tantamount to being told they are “manic-depressive,” with its associated stigma.

Overuse of atypical neuroleptics such as aripiprazole, quetiapine, and olanzapine has led to an awareness of metabolic syndrome and tardive dyskinesia, also making doctors cautious about using these drugs.

Answer: Yes, but treat with caution

Not treating depression consigns a patient to suffer with untreated depression, sometimes for years. Outcomes for patients with depression and bipolar disorder are often poor because the conditions are not recognized, and even when the conditions are recognized, doctors and patients may be reluctant to medicate appropriately. Medications should be used as needed to treat depression, but with an awareness of the possible side effects and with close patient monitoring.

A truly sustained manic state (unlike the brief euphoria brought on by some drugs) is not actually so easy to induce. In an unpublished Cleveland Clinic study, we monitored peaks of hypomanic symptoms in young patients (ages 15–30) during antidepressant treatment without mood stabilizers. About 30% to 40% of patients had subthreshold manic symptoms or a family history of bipolar disorder; 3 patients out of 51 developed hypomania leading to a change of diagnosis to bipolar disorder. Even in patients who had no risk factors for bipolar disorder, 2 out of 53 converted to a bipolar diagnosis. So conversion rates in patients with subthreshold bipolar disorder seem to be low, and the disorder can be identified early by monitoring the patient closely.

NONPHARMACOLOGIC TREATMENTS FOR DEPRESSION

Psychotherapy is indicated for all patients on medications for depression, as both pharmacologic and nonpharmacologic treatments are more effective when combined.⁶⁶ Other treatments include trans­cranial magnetic stimulation, electroconvulsive therapy, light therapy, and exercise. Having a consistent daily routine, particularly regarding the sleep-wake schedule, is also helpful, and patients should be educated about its importance.

Patients presenting with depression commonly have undiagnosed bipolar depression,^1–7 that is, depression with shifts to periods of mania. During manic or hypomanic episodes, people feel energetic, need little sleep, and are often happy and charming.⁸ But too much of a good thing can also wreak havoc on their life.

Bipolar depression (ie, depression in patients with a diagnosis of bipolar disorder) is treated differently from unipolar depression,^3,9–13 making it especially important that clinicians recognize if a patient who presents with depression has a history of (hypo)manic symptoms.

CASE 1: THE IMPULSIVE NURSE

A 32-year-old nurse presents to her primary care provider with depressed mood. She reports having had a single depressive episode when she was a college freshman. Her family history includes depression, bipolar disorder, and schizophrenia, and her paternal grandfather and a maternal aunt committed suicide. Upon questioning, she reveals that in the past, she has had 3 episodes lasting several weeks and characterized by insubordinate behavior at work, irritability, high energy, and decreased need for sleep. She regrets impulsive sexual and financial decisions that she made during these episodes and recently filed for personal bankruptcy. For the past month, her mood has been persistently low, with reduced sleep, appetite, energy, and concentration, and with passive thoughts of suicide.

A CAREFUL HISTORY IS CRITICAL

This case illustrates many typical features of bipolar depression that are revealed only by taking a thorough history. Although the patient is high-functioning, having attained a professional career, she has serious problems with sexual and financial impulsivity and at her job. She has a strong family history of mood disorder. And she describes episodes of depression and mania in the past.

Starts in young adulthood, strong heritability

Bipolar disorder can be a devastating condition with lifelong consequences,^14–20 especially as it typically starts when patients are getting an education or embarking on a career. It usually first manifests in the late teenage years and progresses in the patient’s early 20s.^21,22 The first hospitalization can occur soon thereafter.^23,24

Bipolar disorder is one of the most heritable conditions in psychiatry, and about 13% of children who have an afflicted parent develop it.²⁵ In identical twins, the concordance is about 50% to 75%, indicating the importance of genetics and environmental factors.^26,27

Associated with migraine, other conditions

The disorder is associated with a variety of conditions (Table 1).^28,29 Some conditions (eg, thyroid disease) can cause mood cycling, and some (eg, sexually transmitted infections, accidents) are the consequences of the lifestyle that may accompany mania. For unknown reasons, migraine is highly associated with bipolar disorder.

DEPRESSION AND MANIA: TWO SIDES OF THE SAME COIN

Symptoms of depression and mania are frequently viewed as opposite mood states, though many times patients report a mixture of them.^17,30–35 For both states, the features of a distinct change from the patient’s normal condition and the sustained nature of the symptoms are important diagnostically and indicate a likely underlying biological cause.

Major depressive disorder: Slowing down

The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),⁸ defines major depressive disorder as having either depressed mood or markedly diminished pleasure in most activities for most days during at least 2 weeks.

In addition, at least 4 of the following must be present during the same period:

• Appetite disturbance
• Sleep disturbance
• Motor retardation or agitation
• Lack of energy
• Feelings of worthlessness or excessive guilt
• Decreased concentration
• Recurrent thoughts of death or suicide.

An estimated 20% of the population experience a major depressive episode over their lifetime. A surprisingly high proportion of people with depression—30% to 40%—also have had subthreshold symptoms of mania (symptoms not meeting the criteria for hypomania or mania in terms of number of symptoms or duration).^21,22 Because of these odds, it is important to suspect bipolar disorder even in patients who present with depression but who may not yet have manifested episodes of mania or hypomania.

Mood disorders can be regarded as falling into a spectrum, ranging from unipolar or “pure” major depression without any features of hypomania to major depression and severe mania.^17,31–36

Mania: Speeding up

The DSM-5 defines mania as the presence of persistently elevated, expansive, or irritable mood with increased activity for more than 1 week. In addition, at least 3 of the following features must be present, with impaired functioning (4 features are required if mood is only irritable)⁸:

• Inflated self-esteem or grandiosity
• Decreased need for sleep
• Pressured speech
• Racing thoughts
• Distractibility
• Excessive involvement in pleasurable, high-risk activities.

Hypomania: No functional impairment

Hypomania is a less severe condition, in which the abnormally elevated mood is of shorter duration (4–7 days) and meets the other criteria for mania but without significant functional impairment. People may, in fact, be very functional and productive during hypomanic episodes.⁸

CLASSIFYING BIPOLAR DISORDER

Bipolar disorder is categorized according to severity.^24,37,38 The most severe form, bipolar I disorder, is marked by major depression and manic episodes. It affects up to 1.5% of the US population, with equal proportions of men and women.³⁹ Bipolar II disorder is less severe. It affects 0.8% to 1.6% of the US population, predominantly women.^21,40 In bipolar II disorder, depression is more prominent, with episodes of hypomania.

Subthreshold bipolar disorders are characterized by episodic symptoms that do not meet the threshold for depression or hypomania; the symptoms are fewer or of shorter duration. These minor types of bipolar disorder affect up to 6% of the US population.¹⁷

Other conditions within the spectrum of bipolar and depressive disorders include medication- and substance-induced mania, agitated or anxious depression, and mixed states.^31,34–36

DISTINGUISHING UNIPOLAR FROM BIPOLAR DEPRESSION

Considerable research has focused on finding a clear-cut clinical or biological feature to differentiate unipolar from bipolar depression, but so far none has been discovered. Distinguishing the two conditions still depends on clinical judgment. There are important reasons to identify the distinction between unipolar depression and bipolar disorder.

Prognosis differs. Bipolar disorder tends to be a more severe condition. Young people, who may initially present with only mild symptoms of mania, may develop serious episodes over the years. People may lose their savings, their marriage, and their career during a manic episode. The more critical the occupation (eg, doctor, pilot), the greater the potential consequences of impaired judgment brought on by even mild hypomania.^14–20

Treatment differs. Typical antidepressants given for depression can trigger a manic episode in patients with bipolar depression, with devastating consequences. Atypical neuroleptic drugs used to treat bipolar disorder can also have serious effects (eg, metabolic and neurologic effects, including irreversible tardive dyskinesia).^3,13,40–43

Despite the good reasons to do so, many doctors (including some psychiatrists) do not ask their patients about a propensity to mania or hypomania.^4–6 More stigma is attached to the diagnosis of bipolar disorder than to depression^44–47; once it is in the medical record, the patient may have problems with employment and obtaining medical insurance.^17,44 The old term “manic-depressive” is often associated in the public mind with a person on the streets displaying severely psychotic behavior; the condition is now understood to consist of a spectrum from mild to more severe illness.

Clinical indicators of bipolarity

There are many indicators that a person who presents with depression may be on the bipolar spectrum, but this is not always easily identified.^48–53

History of hypomanic symptoms or subthreshold manic symptoms. Although directly asking the patient about the defining symptoms (eg, “Have you ever had episodes of being ‘hyper’ or too happy?”) may help elicit the diagnosis, many patients with bipolar disorder only report depression, as it is psychically painful. In contrast, hypomania and even mania can be perceived as positive, as patients may have less insight into the abnormality of the condition and feel that they are functioning extremely well.

Early age of onset of a mood disorder, such as severe depression in childhood or early adulthood, points toward bipolar disorder. Diagnosing mood disorders in childhood is difficult, as children are less able to recognize or verbalize many of their symptoms.

Postpartum mood disorder, particularly with psychotic symptoms, indicates a strong possibility of a diagnosis of bipolar disorder.

Drug-induced mania, hypomania, and periods of hyperactivity are key features of bipolar disorder. If asked, patients may report feeling a “buzz” when taking an antidepressant.

Erratic patterns in work and relationships are a red flag and are viewed as “soft signs” of bipolar depression. Akiskal⁵⁴ described the “rule of three” that should make one consider bipolar disorder: for example, three failed marriages, three current jobs or frequent job changes, three distinct professions practiced at the same time, and simultaneously dating three people. Such features indicate both the hyperfunctioning and the disruptive aspects of mania.

Family history of bipolar disorder or severe psychiatric illness is a very important clue. A more subtle clue described by Akiskal⁵⁴ may be that several members of the family are very high-functioning in several different fields: eg, one may be a highly accomplished doctor, another a famous lawyer, and another a prominent politician. Or several members of the family may have erratic patterns of work and relationships. However, these subtle clues have been derived from clinical experiences and have not been validated in large-scale studies.

Dr. Z is a prominent surgical subspecialist who is part of a small group practice. His wife has become increasingly worried about his behavior changes at home, including sleeping only a few hours a night, spending sprees, and binge drinking. He reluctantly agrees to an outpatient psychiatric evaluation if she attends with him. He creates a disturbance in the waiting room by shaking everyone’s hands and trying to hug all the women. During his examination, he is loud and expansive, denying he has any problems and describing himself as “the greatest doctor in the world.” The psychiatrist recommends hospitalization, but Dr. Z refuses and becomes belligerent. He announces that he just needs a career change and that he will fly to Mexico to open a bar.

This case, from the Texas Medical Association Archives,⁵⁵ is not unusual. In addition to many characteristics discussed above, this case is typical in that the spouse brought the patient in, reflecting that the patient lacked insight that his behavior was abnormal. The disinhibition (hugging women), grandiosity, and unrealistic plans are also typical.

DIFFERENTIAL DIAGNOSIS OF BIPOLAR DEPRESSION

Anxiety disorders may be associated with dissociative speech or racing thoughts, which can be confused with bipolar illness. Personality disorders (eg, borderline, narcissistic, sociopathic) can involve a tumultuous and impulsive lifestyle resembling episodes of depression and mania. Schizoaffective illness has features of schizophrenia and bipolar disorder.

It is also possible that, despite what may look like mild features of bipolar disorder, there is no psychiatric condition. Some people with mild mania—often successful professionals or politicians—have high energy and can function very well with only a few hours of sleep. Similarly, depressive symptoms for short periods of time can be adaptive, such as in the face of a serious setback when extreme reflection and a period of inactivity can be useful, leading to subsequent reorganization.

A psychiatric diagnosis is usually made only when there is an abnormality, ie, the behavior is beyond normal limits, the person cannot control his or her symptoms, or social or occupational functioning is impaired.

SCREENING INSTRUMENTS

A few tools help determine the likelihood of bipolar disorder.

The Patient Health Questionnaire (PHQ-9)^59,60 is a good 9-item screening tool for depression.

The Mood Disorder Questionnaire⁶⁰ is specific for bipolar disorder, and like the PHQ-9, it is a patient-reported, short questionnaire that is available free online. The Mood Disorder Questionnaire asks about the symptoms of mania in a yes-no format. The result is positive if all of the following are present:

• A “yes” response to 7 of the 13 features
• Several features occur simultaneously
• The features are a moderate or serious problem.

Unlike most screening instruments, the Mood Disorder Questionnaire is more specific than sensitive. It is 93% specific for bipolar disorder in patients treated for depression in a primary care setting, but only 58% sensitive.^61–63

WHEN TO REFER TO PSYCHIATRY

Patients suspected of having bipolar disorder or who have been previously diagnosed with it should be referred to a psychiatrist if they have certain features, including:

• Bipolar I disorder
• Psychotic symptoms
• Suicide risk or in danger of harming others
• Significantly impaired functioning
• Unclear diagnosis.

CASE 3: A TELEVISION ANCHOR’S DREAM TURNS TO NIGHTMARE

According to a famous news anchor’s autobiography,⁶⁴ the steroids prescribed for her hives “revved her up.” The next course left her depressed. Antidepressant medications propelled her into a manic state, and she was soon planning a book, a television show, and a magazine all at once. During that time, she bought a cottage online. Her shyness evaporated at parties. “I was suddenly the equal of my high-energy friends who move fast and talk fast and loud,” she wrote. “I told everyone that I could understand why men felt like they could run the world, because I felt like that. This was a new me, and I liked her!”⁶⁴ She was soon diagnosed with bipolar disorder and admitted to a psychiatric clinic.

In general, acute bipolar disorder should be treated with a combination of an antidepressant and a mood stabilizer, and possibly an antipsychotic drug. An antidepressant should not be used alone, particularly with patients with a diagnosis of bipolar I disorder, because of the risk of triggering mania or the risk of faster cycling between mania and depression.¹³

Mood stabilizers include lithium, lamotrigine, and valproate. Each can prevent episodes of depression and mania. Lithium, which has been used as a mood stabilizer for 60 years, is specific for bipolar disorder, and it remains the best mood stabilizer treatment.

Antidepressants. The first-line antidepressant medication is bupropion, which is thought to be less likely to precipitate a manic episode,⁶⁵ though all antidepressants have been associated with this side effect in patients with bipolar disorder. Other antidepressants—for example, selective serotonin reuptake inhibitors such as fluoxetine and dual reuptake inhibitors such as venlafaxine and duloxetine—can also be used. The precipitation of mania and possible increased mood cycling was first described with tricylic antidepressants, so drugs of this class should be used with caution.

Neuroleptic drugs such as aripiprazole, quetiapine, and lurasidone may be the easiest drugs to use, as they have antidepressant effects and can also prevent the occurrence of mania. These medications are frequently classified as mood stabilizers. However, they may not have true mood stabilizing properties such as that of lithium. Importantly, their use tends to entail significant metabolic problems and can lead to hyperlipidemia and diabetes. In addition, Parkinson disease-like symptoms— and in some cases irreversible involuntary movements of the mouth and tongue, as well as the body (tardive dyskinesia)—are important possible side effects.

All psychiatric medications have potential side effects (Table 3). Newer antidepressants and neuroleptics may have fewer side effects than older medications but are not more effective.

Should milder forms of bipolar depression be treated?

A dilemma is whether we should treat milder forms of bipolar depression, such as bipolar II depression, depression with subthreshold hypomania symptoms, or depression in persons with a strong family history of bipolar disorder.

Many doctors are justifiably reluctant to prescribe antidepressants for depression because of the risk of triggering mania. Although mood stabilizers such as lithium would counteract possible mania emergence, physicians often do not prescribe them because of inexperience and fear of risks and possible side effects. Patients are likewise resistant because they feel that use of mood stabilizers is tantamount to being told they are “manic-depressive,” with its associated stigma.

Overuse of atypical neuroleptics such as aripiprazole, quetiapine, and olanzapine has led to an awareness of metabolic syndrome and tardive dyskinesia, also making doctors cautious about using these drugs.

Answer: Yes, but treat with caution

Not treating depression consigns a patient to suffer with untreated depression, sometimes for years. Outcomes for patients with depression and bipolar disorder are often poor because the conditions are not recognized, and even when the conditions are recognized, doctors and patients may be reluctant to medicate appropriately. Medications should be used as needed to treat depression, but with an awareness of the possible side effects and with close patient monitoring.

A truly sustained manic state (unlike the brief euphoria brought on by some drugs) is not actually so easy to induce. In an unpublished Cleveland Clinic study, we monitored peaks of hypomanic symptoms in young patients (ages 15–30) during antidepressant treatment without mood stabilizers. About 30% to 40% of patients had subthreshold manic symptoms or a family history of bipolar disorder; 3 patients out of 51 developed hypomania leading to a change of diagnosis to bipolar disorder. Even in patients who had no risk factors for bipolar disorder, 2 out of 53 converted to a bipolar diagnosis. So conversion rates in patients with subthreshold bipolar disorder seem to be low, and the disorder can be identified early by monitoring the patient closely.

NONPHARMACOLOGIC TREATMENTS FOR DEPRESSION

Psychotherapy is indicated for all patients on medications for depression, as both pharmacologic and nonpharmacologic treatments are more effective when combined.⁶⁶ Other treatments include trans­cranial magnetic stimulation, electroconvulsive therapy, light therapy, and exercise. Having a consistent daily routine, particularly regarding the sleep-wake schedule, is also helpful, and patients should be educated about its importance.

Hospitalized patients with pneumonia who develop a complicated parapneumonic effusion or empyema need to undergo chest tube placement.

WHAT IS PARAPNEUMONIC EFFUSION?

Parapneumonic effusion is a pleural effusion that forms concurrently with bacterial or viral pneumonia. Up to 40% of patients hospitalized with pneumonia develop a parapneumonic effusion.¹ The effusion progresses through a continuum of 3 stages: uncomplicated, complicated, and empyema.

Uncomplicated parapneumonic effusion is an exudative effusion without bacteria or pus that is caused by movement of fluid and neutrophils into the pleural space. Pneumonia itself causes an increase in interstitial fluid and capillary leakage. The effusion becomes complicated as a result of bacteria invading the pleural space, causing a further increase in neutrophils in the pleural fluid. Empyema is defined as the presence of frank pus in the pleural space.

CLINICAL SIGNIFICANCE

According to the US Centers for Disease Control and Prevention, pneumonia accounts for 674,000 emergency department visits each year; of the patients hospitalized, up to 40% develop a parapneumonic effusion.² The only study done on rates of death associated with parapneumonic effusion showed that, compared with patients with no effusion, the risk of death was 3.7 times higher with a unilateral effusion and 6.5 times higher with bilateral effusions.³

INITIAL EVALUATION

The initial evaluation of suspected parapneumonic effusion should include chest radiography with lateral or decubitus views, followed by thoracentesis if indicated. If thoracentesis is performed, the fluid should be tested as follows:

• Gram stain
• Appropriate cultures based on clinical scenario (eg, aerobic, anaerobic, fungal)
• Total protein in pleural fluid and serum
• Lactate dehydrogenase (LDH) in pleural fluid and serum
• Glucose
• pH.

CLASSIFICATION OF EFFUSIONS

When pleural fluid is obtained, the total protein and LDH levels are used to categorize the effusion as either transudative or exudative based on the Light criteria.⁴ An effusion is confirmed as exudative when 1 of the following 3 criteria is met:

• The ratio of pleural fluid protein to serum protein is greater than 0.5
• The ratio of pleural fluid LDH to serum LDH is greater than 0.6
• The pleural fluid LDH is greater than two-thirds the upper limit of normal for the serum LDH.

Category 1 effusions are defined as free- flowing fluid with a thickness of less than 10 mm on any imaging modality. Thoracentesis for pleural fluid analysis is not required. The prognosis is very good.

Category 2 effusions are defined as free- flowing fluid with a thickness greater than 10 mm and less than 50% of the hemithorax. Thoracentesis is typically done because of the size of the effusion, but Gram stain and culture of the pleural fluid are usually negative, and the pH is at least 7.2. The prognosis is good.

Category 3 effusions are considered complicated because the anatomy of the pleural space becomes altered or because bacteria have invaded the pleural space. The effusion is larger than 50% of the hemithorax or is loculated, or the parietal pleura is thickened. Since the bacteria have invaded the pleural space, Gram stain or culture of pleural fluid may be positive, the pleural fluid pH may be less than 7.2, or the glucose level of the fluid may be less than 60 mg/dL. The prognosis for category 3 is poor.

Category 4 effusions are defined as empyema. The only characteristic that separates this from category 3 is frank pus in the pleural space. The prognosis is very poor.

For category 1 or 2 effusions, treatment with antibiotics alone is typically enough. Category 3 effusions usually do not respond to antibiotics alone and may require complete drainage of the fluid with or without a chest tube depending on whether loculations are present, as loculations are difficult to drain with a chest tube. Category 4 effusions require both antibiotics and chest tube placement.

WHAT TYPE OF CHEST TUBE?

Studies have shown that small-bore chest tubes (< 20 F) are as efficacious as larger tubes (≥ 20 F) for the treatment of complicated parapneumonic effusion and empyema.^6,7 Studies have also shown that the size of the tube makes no difference in the time needed to drain the effusion, the length of hospital stay, or the complication rate.^8,9 Based on these studies, a small-bore chest tube should be placed first when clinically appropriate. When a chest tube is placed for empyema, computed tomography should be performed within 24 hours to confirm proper tube placement.

ADVANCED THERAPIES FOR EMPYEMA

Empyema treatment fails when antibiotic coverage is inadequate or when a loculation is not drained appropriately. Options if treatment fails include instillation of fibrinolytics into the pleural space, video-assisted thora­scopic surgery, and decortication.

The role of fibrinolytics has not been well-established, but fibrinolytics should be considered in loculated effusions or empyema, or if drainage of the effusion slows.¹⁰ Video-assisted thora­scopic surgery is reserved for effusions that are incompletely drained with a chest tube with or without fibrinolytics; studies have shown shorter hospital length of stay and higher treatment efficacy when this is performed earlier for loculated effusions.¹¹ Decortication is reserved for symptomatic patients who have a thickened pleura more than 6 months after the initial infection.¹² Timing for each of these procedures is not clearly defined and so must be individualized.

TAKE-AWAY POINTS

• Parapneumonic effusion occurs concurrently with pneumonia and with a high frequency.¹
• Effusions are associated with an increased risk of death.³
• Categorizing the effusion helps guide treatment.
• Chest tubes should be placed for some cases of complicated effusion and for all cases of empyema.
• A small-bore chest tube (< 20 F) should be tried first.

Hospitalized patients with pneumonia who develop a complicated parapneumonic effusion or empyema need to undergo chest tube placement.

WHAT IS PARAPNEUMONIC EFFUSION?

Parapneumonic effusion is a pleural effusion that forms concurrently with bacterial or viral pneumonia. Up to 40% of patients hospitalized with pneumonia develop a parapneumonic effusion.¹ The effusion progresses through a continuum of 3 stages: uncomplicated, complicated, and empyema.

Uncomplicated parapneumonic effusion is an exudative effusion without bacteria or pus that is caused by movement of fluid and neutrophils into the pleural space. Pneumonia itself causes an increase in interstitial fluid and capillary leakage. The effusion becomes complicated as a result of bacteria invading the pleural space, causing a further increase in neutrophils in the pleural fluid. Empyema is defined as the presence of frank pus in the pleural space.

CLINICAL SIGNIFICANCE

According to the US Centers for Disease Control and Prevention, pneumonia accounts for 674,000 emergency department visits each year; of the patients hospitalized, up to 40% develop a parapneumonic effusion.² The only study done on rates of death associated with parapneumonic effusion showed that, compared with patients with no effusion, the risk of death was 3.7 times higher with a unilateral effusion and 6.5 times higher with bilateral effusions.³

INITIAL EVALUATION

The initial evaluation of suspected parapneumonic effusion should include chest radiography with lateral or decubitus views, followed by thoracentesis if indicated. If thoracentesis is performed, the fluid should be tested as follows:

• Gram stain
• Appropriate cultures based on clinical scenario (eg, aerobic, anaerobic, fungal)
• Total protein in pleural fluid and serum
• Lactate dehydrogenase (LDH) in pleural fluid and serum
• Glucose
• pH.

CLASSIFICATION OF EFFUSIONS

When pleural fluid is obtained, the total protein and LDH levels are used to categorize the effusion as either transudative or exudative based on the Light criteria.⁴ An effusion is confirmed as exudative when 1 of the following 3 criteria is met:

• The ratio of pleural fluid protein to serum protein is greater than 0.5
• The ratio of pleural fluid LDH to serum LDH is greater than 0.6
• The pleural fluid LDH is greater than two-thirds the upper limit of normal for the serum LDH.

Category 1 effusions are defined as free- flowing fluid with a thickness of less than 10 mm on any imaging modality. Thoracentesis for pleural fluid analysis is not required. The prognosis is very good.

Category 2 effusions are defined as free- flowing fluid with a thickness greater than 10 mm and less than 50% of the hemithorax. Thoracentesis is typically done because of the size of the effusion, but Gram stain and culture of the pleural fluid are usually negative, and the pH is at least 7.2. The prognosis is good.

Category 3 effusions are considered complicated because the anatomy of the pleural space becomes altered or because bacteria have invaded the pleural space. The effusion is larger than 50% of the hemithorax or is loculated, or the parietal pleura is thickened. Since the bacteria have invaded the pleural space, Gram stain or culture of pleural fluid may be positive, the pleural fluid pH may be less than 7.2, or the glucose level of the fluid may be less than 60 mg/dL. The prognosis for category 3 is poor.

Category 4 effusions are defined as empyema. The only characteristic that separates this from category 3 is frank pus in the pleural space. The prognosis is very poor.

For category 1 or 2 effusions, treatment with antibiotics alone is typically enough. Category 3 effusions usually do not respond to antibiotics alone and may require complete drainage of the fluid with or without a chest tube depending on whether loculations are present, as loculations are difficult to drain with a chest tube. Category 4 effusions require both antibiotics and chest tube placement.

WHAT TYPE OF CHEST TUBE?

Studies have shown that small-bore chest tubes (< 20 F) are as efficacious as larger tubes (≥ 20 F) for the treatment of complicated parapneumonic effusion and empyema.^6,7 Studies have also shown that the size of the tube makes no difference in the time needed to drain the effusion, the length of hospital stay, or the complication rate.^8,9 Based on these studies, a small-bore chest tube should be placed first when clinically appropriate. When a chest tube is placed for empyema, computed tomography should be performed within 24 hours to confirm proper tube placement.

ADVANCED THERAPIES FOR EMPYEMA

Empyema treatment fails when antibiotic coverage is inadequate or when a loculation is not drained appropriately. Options if treatment fails include instillation of fibrinolytics into the pleural space, video-assisted thora­scopic surgery, and decortication.

The role of fibrinolytics has not been well-established, but fibrinolytics should be considered in loculated effusions or empyema, or if drainage of the effusion slows.¹⁰ Video-assisted thora­scopic surgery is reserved for effusions that are incompletely drained with a chest tube with or without fibrinolytics; studies have shown shorter hospital length of stay and higher treatment efficacy when this is performed earlier for loculated effusions.¹¹ Decortication is reserved for symptomatic patients who have a thickened pleura more than 6 months after the initial infection.¹² Timing for each of these procedures is not clearly defined and so must be individualized.

TAKE-AWAY POINTS

• Parapneumonic effusion occurs concurrently with pneumonia and with a high frequency.¹
• Effusions are associated with an increased risk of death.³
• Categorizing the effusion helps guide treatment.
• Chest tubes should be placed for some cases of complicated effusion and for all cases of empyema.
• A small-bore chest tube (< 20 F) should be tried first.

Hospitalized patients with pneumonia who develop a complicated parapneumonic effusion or empyema need to undergo chest tube placement.

WHAT IS PARAPNEUMONIC EFFUSION?

Parapneumonic effusion is a pleural effusion that forms concurrently with bacterial or viral pneumonia. Up to 40% of patients hospitalized with pneumonia develop a parapneumonic effusion.¹ The effusion progresses through a continuum of 3 stages: uncomplicated, complicated, and empyema.

Uncomplicated parapneumonic effusion is an exudative effusion without bacteria or pus that is caused by movement of fluid and neutrophils into the pleural space. Pneumonia itself causes an increase in interstitial fluid and capillary leakage. The effusion becomes complicated as a result of bacteria invading the pleural space, causing a further increase in neutrophils in the pleural fluid. Empyema is defined as the presence of frank pus in the pleural space.

CLINICAL SIGNIFICANCE

According to the US Centers for Disease Control and Prevention, pneumonia accounts for 674,000 emergency department visits each year; of the patients hospitalized, up to 40% develop a parapneumonic effusion.² The only study done on rates of death associated with parapneumonic effusion showed that, compared with patients with no effusion, the risk of death was 3.7 times higher with a unilateral effusion and 6.5 times higher with bilateral effusions.³

INITIAL EVALUATION

The initial evaluation of suspected parapneumonic effusion should include chest radiography with lateral or decubitus views, followed by thoracentesis if indicated. If thoracentesis is performed, the fluid should be tested as follows:

• Gram stain
• Appropriate cultures based on clinical scenario (eg, aerobic, anaerobic, fungal)
• Total protein in pleural fluid and serum
• Lactate dehydrogenase (LDH) in pleural fluid and serum
• Glucose
• pH.

CLASSIFICATION OF EFFUSIONS

When pleural fluid is obtained, the total protein and LDH levels are used to categorize the effusion as either transudative or exudative based on the Light criteria.⁴ An effusion is confirmed as exudative when 1 of the following 3 criteria is met:

• The ratio of pleural fluid protein to serum protein is greater than 0.5
• The ratio of pleural fluid LDH to serum LDH is greater than 0.6
• The pleural fluid LDH is greater than two-thirds the upper limit of normal for the serum LDH.

Category 1 effusions are defined as free- flowing fluid with a thickness of less than 10 mm on any imaging modality. Thoracentesis for pleural fluid analysis is not required. The prognosis is very good.

Category 2 effusions are defined as free- flowing fluid with a thickness greater than 10 mm and less than 50% of the hemithorax. Thoracentesis is typically done because of the size of the effusion, but Gram stain and culture of the pleural fluid are usually negative, and the pH is at least 7.2. The prognosis is good.

Category 3 effusions are considered complicated because the anatomy of the pleural space becomes altered or because bacteria have invaded the pleural space. The effusion is larger than 50% of the hemithorax or is loculated, or the parietal pleura is thickened. Since the bacteria have invaded the pleural space, Gram stain or culture of pleural fluid may be positive, the pleural fluid pH may be less than 7.2, or the glucose level of the fluid may be less than 60 mg/dL. The prognosis for category 3 is poor.

Category 4 effusions are defined as empyema. The only characteristic that separates this from category 3 is frank pus in the pleural space. The prognosis is very poor.

For category 1 or 2 effusions, treatment with antibiotics alone is typically enough. Category 3 effusions usually do not respond to antibiotics alone and may require complete drainage of the fluid with or without a chest tube depending on whether loculations are present, as loculations are difficult to drain with a chest tube. Category 4 effusions require both antibiotics and chest tube placement.

WHAT TYPE OF CHEST TUBE?

Studies have shown that small-bore chest tubes (< 20 F) are as efficacious as larger tubes (≥ 20 F) for the treatment of complicated parapneumonic effusion and empyema.^6,7 Studies have also shown that the size of the tube makes no difference in the time needed to drain the effusion, the length of hospital stay, or the complication rate.^8,9 Based on these studies, a small-bore chest tube should be placed first when clinically appropriate. When a chest tube is placed for empyema, computed tomography should be performed within 24 hours to confirm proper tube placement.

ADVANCED THERAPIES FOR EMPYEMA

Empyema treatment fails when antibiotic coverage is inadequate or when a loculation is not drained appropriately. Options if treatment fails include instillation of fibrinolytics into the pleural space, video-assisted thora­scopic surgery, and decortication.

The role of fibrinolytics has not been well-established, but fibrinolytics should be considered in loculated effusions or empyema, or if drainage of the effusion slows.¹⁰ Video-assisted thora­scopic surgery is reserved for effusions that are incompletely drained with a chest tube with or without fibrinolytics; studies have shown shorter hospital length of stay and higher treatment efficacy when this is performed earlier for loculated effusions.¹¹ Decortication is reserved for symptomatic patients who have a thickened pleura more than 6 months after the initial infection.¹² Timing for each of these procedures is not clearly defined and so must be individualized.

TAKE-AWAY POINTS

• Parapneumonic effusion occurs concurrently with pneumonia and with a high frequency.¹
• Effusions are associated with an increased risk of death.³
• Categorizing the effusion helps guide treatment.
• Chest tubes should be placed for some cases of complicated effusion and for all cases of empyema.
• A small-bore chest tube (< 20 F) should be tried first.

A 51-year-old man with type 2 diabetes was referred to our hospital because of liver dysfunction and nonpruritic exanthema, with papulosquamous, scaly, papular and macular lesions on his trunk and extremities, including his palms (Figure 1) and soles. Also noted were tiny grayish mucus patches on the oral mucosa. Axillary and inguinal superficial lymph nodes were palpable.

Laboratory testing revealed elevated serum levels of markers of liver disease, ie:

• Total bilirubin 9.8 mg/dL (reference range 0.2–1.3)
• Direct bilirubin 8.0 mg/dL (< 0.2)
• Aspartate aminotransferase 57 IU/L (13–35)
• Alanine aminotransferase 90 IU/L (10–54)
• Alkaline phosphatase 4,446 IU/L (36–108).

Possible causes of liver dysfunction such as legal and illicit drugs, alcohol abuse, obstructive biliary tract or liver disease, viral hepatitis, and primary biliary cirrhosis were ruled out by history, serologic testing, abdominal ultrasonography, and computed tomography.

Secondary syphilis was suspected in view of the characteristic distribution of exanthema involving the trunk and extremities, especially the palms and soles. On questioning, the patient admitted to having had unprotected sex with a female sex worker, which also raised the probability of syphilis infection.

The rapid plasma reagin test was positive at a titer of 1:16, and the Treponema pallidum agglutination test was positive at a signal-to-cutoff ratio of 27.02. Antibody testing for human immunodeficiency virus (HIV) was negative.

The patient was started on penicillin G, but 4 hours later, he developed a fever with a temperature of 100.2°F (37.9°C), which was assumed to be a Jarisch-Herxheimer reaction. The fever resolved by the next morning without further treatment.

His course was otherwise uneventful. The exanthema resolved within 3 months, and his liver function returned to normal. Five months later, the rapid plasma reagin test was repeated on an outpatient basis, and the result was normal.

SYPHILIS IS NOT A DISEASE OF THE PAST

Syphilis is caused by T pallidum and is mainly transmitted by sexual contact.¹

The incidence of syphilis has substantially increased in recent years in Japan^2,3 and worldwide.⁴ The typical patient is a young man who has sex with men, is infected with HIV, and has a history of syphilis infection.³ However, the rapid increase in syphilis infections in Japan in recent years is largely because of an increase in heterosexual transmission.³

Infectious in its early stages

Syphilis is potentially infectious in its early (primary, secondary, and early latent) stages.^1,5 The secondary stage generally begins 6 to 8 weeks after the primary infection¹ and presents with diverse symptoms, including arthralgia, condylomata lata, generalized lymphaden­opathy, maculopapular and papulosquamous exanthema, myalgia, and pharyngitis.¹

Liver dysfunction in secondary syphilis

Liver dysfunction is common in secondary syphilis, occurring in 25% to 50% of cases.⁵ The liver enzyme pattern in most cases is a disproportionate increase in the alkaline phosphatase level compared with modest elevations of aminotransferases and bilirubin.^2,5 However, some cases may show predominant hepatocellular damage (with prominent elevations in aminotransferase levels), and others may present with severe cholestasis (with prominent elevations in alkaline phosphatase and bilirubin) or even fulminant hepatic failure.^2,5

The diagnostic criteria for syphilitic hepatitis are abnormal liver enzyme levels, serologic evidence of syphilis in conjunction with acute clinical presentation of secondary syphilis, exclusion of alternative causes of liver dysfunction, and prompt recovery of liver function after antimicrobial therapy.^2,5

Pathogenic mechanisms in syphilitic hepatitis include direct portal venous inoculation and immune complex-mediated disease.² However, direct hepatotoxicity of the microorganism seems unlikely, as spirochetes are rarely detected in liver specimens.^2,5

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction is an acute febrile illness during the first 24 hours of antimicrobial treatment.^1,6 It is assumed to be due to lysis of large numbers of spirochetes, releasing lipopolysaccharides (endotoxins) that further incite the release of a range of cytokines, resulting in symptoms such as fever, chills, myalgias, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension.^6,7

The frequency of Jarisch-Herxheimer reaction in syphilis and other spirochetal infections has varied widely in different reports.⁸ It is common in primary and secondary syphilis but usually does not occur in latent syphilis.⁶

Consider the diagnosis

Physicians should consider secondary syphilis in patients who present with characteristic generalized reddish macules and papules with papulosquamous lesions, including on the palms and soles as in our patient, and also in patients who have had unprotected sexual contact. Syphilis is not a disease of the past.

Acknowledgment: The authors thank Dr. Joel Branch, Shonan Kamakura General Hospital, Japan, for his editorial assistance.

A 51-year-old man with type 2 diabetes was referred to our hospital because of liver dysfunction and nonpruritic exanthema, with papulosquamous, scaly, papular and macular lesions on his trunk and extremities, including his palms (Figure 1) and soles. Also noted were tiny grayish mucus patches on the oral mucosa. Axillary and inguinal superficial lymph nodes were palpable.

Laboratory testing revealed elevated serum levels of markers of liver disease, ie:

• Total bilirubin 9.8 mg/dL (reference range 0.2–1.3)
• Direct bilirubin 8.0 mg/dL (< 0.2)
• Aspartate aminotransferase 57 IU/L (13–35)
• Alanine aminotransferase 90 IU/L (10–54)
• Alkaline phosphatase 4,446 IU/L (36–108).

Possible causes of liver dysfunction such as legal and illicit drugs, alcohol abuse, obstructive biliary tract or liver disease, viral hepatitis, and primary biliary cirrhosis were ruled out by history, serologic testing, abdominal ultrasonography, and computed tomography.

Secondary syphilis was suspected in view of the characteristic distribution of exanthema involving the trunk and extremities, especially the palms and soles. On questioning, the patient admitted to having had unprotected sex with a female sex worker, which also raised the probability of syphilis infection.

The rapid plasma reagin test was positive at a titer of 1:16, and the Treponema pallidum agglutination test was positive at a signal-to-cutoff ratio of 27.02. Antibody testing for human immunodeficiency virus (HIV) was negative.

The patient was started on penicillin G, but 4 hours later, he developed a fever with a temperature of 100.2°F (37.9°C), which was assumed to be a Jarisch-Herxheimer reaction. The fever resolved by the next morning without further treatment.

His course was otherwise uneventful. The exanthema resolved within 3 months, and his liver function returned to normal. Five months later, the rapid plasma reagin test was repeated on an outpatient basis, and the result was normal.

SYPHILIS IS NOT A DISEASE OF THE PAST

Syphilis is caused by T pallidum and is mainly transmitted by sexual contact.¹

The incidence of syphilis has substantially increased in recent years in Japan^2,3 and worldwide.⁴ The typical patient is a young man who has sex with men, is infected with HIV, and has a history of syphilis infection.³ However, the rapid increase in syphilis infections in Japan in recent years is largely because of an increase in heterosexual transmission.³

Infectious in its early stages

Syphilis is potentially infectious in its early (primary, secondary, and early latent) stages.^1,5 The secondary stage generally begins 6 to 8 weeks after the primary infection¹ and presents with diverse symptoms, including arthralgia, condylomata lata, generalized lymphaden­opathy, maculopapular and papulosquamous exanthema, myalgia, and pharyngitis.¹

Liver dysfunction in secondary syphilis

Liver dysfunction is common in secondary syphilis, occurring in 25% to 50% of cases.⁵ The liver enzyme pattern in most cases is a disproportionate increase in the alkaline phosphatase level compared with modest elevations of aminotransferases and bilirubin.^2,5 However, some cases may show predominant hepatocellular damage (with prominent elevations in aminotransferase levels), and others may present with severe cholestasis (with prominent elevations in alkaline phosphatase and bilirubin) or even fulminant hepatic failure.^2,5

The diagnostic criteria for syphilitic hepatitis are abnormal liver enzyme levels, serologic evidence of syphilis in conjunction with acute clinical presentation of secondary syphilis, exclusion of alternative causes of liver dysfunction, and prompt recovery of liver function after antimicrobial therapy.^2,5

Pathogenic mechanisms in syphilitic hepatitis include direct portal venous inoculation and immune complex-mediated disease.² However, direct hepatotoxicity of the microorganism seems unlikely, as spirochetes are rarely detected in liver specimens.^2,5

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction is an acute febrile illness during the first 24 hours of antimicrobial treatment.^1,6 It is assumed to be due to lysis of large numbers of spirochetes, releasing lipopolysaccharides (endotoxins) that further incite the release of a range of cytokines, resulting in symptoms such as fever, chills, myalgias, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension.^6,7

The frequency of Jarisch-Herxheimer reaction in syphilis and other spirochetal infections has varied widely in different reports.⁸ It is common in primary and secondary syphilis but usually does not occur in latent syphilis.⁶

Consider the diagnosis

Physicians should consider secondary syphilis in patients who present with characteristic generalized reddish macules and papules with papulosquamous lesions, including on the palms and soles as in our patient, and also in patients who have had unprotected sexual contact. Syphilis is not a disease of the past.

Acknowledgment: The authors thank Dr. Joel Branch, Shonan Kamakura General Hospital, Japan, for his editorial assistance.

A 51-year-old man with type 2 diabetes was referred to our hospital because of liver dysfunction and nonpruritic exanthema, with papulosquamous, scaly, papular and macular lesions on his trunk and extremities, including his palms (Figure 1) and soles. Also noted were tiny grayish mucus patches on the oral mucosa. Axillary and inguinal superficial lymph nodes were palpable.

Laboratory testing revealed elevated serum levels of markers of liver disease, ie:

• Total bilirubin 9.8 mg/dL (reference range 0.2–1.3)
• Direct bilirubin 8.0 mg/dL (< 0.2)
• Aspartate aminotransferase 57 IU/L (13–35)
• Alanine aminotransferase 90 IU/L (10–54)
• Alkaline phosphatase 4,446 IU/L (36–108).

Possible causes of liver dysfunction such as legal and illicit drugs, alcohol abuse, obstructive biliary tract or liver disease, viral hepatitis, and primary biliary cirrhosis were ruled out by history, serologic testing, abdominal ultrasonography, and computed tomography.

Secondary syphilis was suspected in view of the characteristic distribution of exanthema involving the trunk and extremities, especially the palms and soles. On questioning, the patient admitted to having had unprotected sex with a female sex worker, which also raised the probability of syphilis infection.

The rapid plasma reagin test was positive at a titer of 1:16, and the Treponema pallidum agglutination test was positive at a signal-to-cutoff ratio of 27.02. Antibody testing for human immunodeficiency virus (HIV) was negative.

The patient was started on penicillin G, but 4 hours later, he developed a fever with a temperature of 100.2°F (37.9°C), which was assumed to be a Jarisch-Herxheimer reaction. The fever resolved by the next morning without further treatment.

His course was otherwise uneventful. The exanthema resolved within 3 months, and his liver function returned to normal. Five months later, the rapid plasma reagin test was repeated on an outpatient basis, and the result was normal.

SYPHILIS IS NOT A DISEASE OF THE PAST

Syphilis is caused by T pallidum and is mainly transmitted by sexual contact.¹

The incidence of syphilis has substantially increased in recent years in Japan^2,3 and worldwide.⁴ The typical patient is a young man who has sex with men, is infected with HIV, and has a history of syphilis infection.³ However, the rapid increase in syphilis infections in Japan in recent years is largely because of an increase in heterosexual transmission.³

Infectious in its early stages

Syphilis is potentially infectious in its early (primary, secondary, and early latent) stages.^1,5 The secondary stage generally begins 6 to 8 weeks after the primary infection¹ and presents with diverse symptoms, including arthralgia, condylomata lata, generalized lymphaden­opathy, maculopapular and papulosquamous exanthema, myalgia, and pharyngitis.¹

Liver dysfunction in secondary syphilis

Liver dysfunction is common in secondary syphilis, occurring in 25% to 50% of cases.⁵ The liver enzyme pattern in most cases is a disproportionate increase in the alkaline phosphatase level compared with modest elevations of aminotransferases and bilirubin.^2,5 However, some cases may show predominant hepatocellular damage (with prominent elevations in aminotransferase levels), and others may present with severe cholestasis (with prominent elevations in alkaline phosphatase and bilirubin) or even fulminant hepatic failure.^2,5

The diagnostic criteria for syphilitic hepatitis are abnormal liver enzyme levels, serologic evidence of syphilis in conjunction with acute clinical presentation of secondary syphilis, exclusion of alternative causes of liver dysfunction, and prompt recovery of liver function after antimicrobial therapy.^2,5

Pathogenic mechanisms in syphilitic hepatitis include direct portal venous inoculation and immune complex-mediated disease.² However, direct hepatotoxicity of the microorganism seems unlikely, as spirochetes are rarely detected in liver specimens.^2,5

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction is an acute febrile illness during the first 24 hours of antimicrobial treatment.^1,6 It is assumed to be due to lysis of large numbers of spirochetes, releasing lipopolysaccharides (endotoxins) that further incite the release of a range of cytokines, resulting in symptoms such as fever, chills, myalgias, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension.^6,7

The frequency of Jarisch-Herxheimer reaction in syphilis and other spirochetal infections has varied widely in different reports.⁸ It is common in primary and secondary syphilis but usually does not occur in latent syphilis.⁶

Consider the diagnosis

Physicians should consider secondary syphilis in patients who present with characteristic generalized reddish macules and papules with papulosquamous lesions, including on the palms and soles as in our patient, and also in patients who have had unprotected sexual contact. Syphilis is not a disease of the past.

Acknowledgment: The authors thank Dr. Joel Branch, Shonan Kamakura General Hospital, Japan, for his editorial assistance.

A 20-year-old woman had a 4-month history of painful red erosions around the mouth. She had no dysphagia or fatigue and no history of diarrhea, gluten intolerance, or diabetes mellitus. An antifungal-antibacterial ointment prescribed by her dentist had provided no relief.

• Hemoglobin 8.0 g/dL (reference range for females 12.3–15.3)
• Mean corpuscular volume 62 fL (80–100)
• Serum ferritin 1.3 ng/mL (15–200)
• Reticulocyte count 0.86% (0.5–1.5)
• White blood cell count 9.8 × 10⁹/L (4.5–11.0)
• Platelet count 450 × 10⁹/L (150–400).

Vitamin B₁₂ and folate levels were normal, and tests for antitissue transglutaminase and antinuclear antibodies were negative.

Based on these results, the diagnosis was angular cheilitis from iron deficiency anemia. Treatment with oral ferrous gluconate 300 mg twice daily cleared the cheilitis, and after 4 weeks of this treatment, the hemoglobin level increased to 9.8 g/dL, the serum ferritin increased to 7 ng/mL, and the reticulocyte count increased to 2.6%. She was advised to continue taking oral iron tablets for another 3 months until the hemoglobin level reached 12.0 g/dL.

During 2 years of follow-up, she had no recurrence of angular cheilitis, and her hemoglobin and serum ferritin levels remained normal. Ferrous gluconate was her only medication from the time of her diagnosis.

A BROAD DIFFERENTIAL DIAGNOSIS

Angular cheilitis (perlèche) is an inflammatory condition characterized by erosive inflammation at one or both angles of the mouth. It typically presents as erythema, scaling, fissuring, and ulceration. A wide variety of factors, including nutritional deficiencies, local and systemic factors, and drug side effects, may produce cheilitis.^1,2

Nutritional deficiencies account for 25% of all cases of angular cheilitis³ and include iron deficiency and deficiencies of the B vitamins riboflavin (B₂), niacin (B₃), pyridoxine (B₆), and cyanocobalamin (B₁₂).¹

Local causes include infection with Candida albicans or Staphylococcus aureus and allergic contact dermatitis. Common causes of allergic contact dermatitis include lipstick, toothpaste, mouthwash, cosmetics, sunscreen, fragrance, metals such as nickel, and dental appliances.¹

Systemic diseases associated with angular cheilitis include xerostomia, inflammatory bowel disease, Sjögren syndrome, glucagonoma, and human immunodeficiency virus.¹

Drugs that cause angular cheilitis include isotretinoin, sorafenib (antineoplastic kinase inhibitor), and ointments or creams such as neomycin sulfate–polymyxin B sulfate, bacitracin, idoxuridine, and steroids.^1,4

Conditions that mimic angular cheilitis include herpes simplex type 1 (herpes labialis) and actinic cheilitis. Herpes labialis, characterized by burning sensation, itching, or paresthesia, usually precedes a recurrence of vesicles that eventually ulcerate or form a crust and heal without a crust. Herpes labialis often recurs, affecting the vermilion border and lasting approximately 1 week.

Actinic cheilitis, a premalignant condition that commonly involves the lower lip with sparing of the corners of the mouth, is caused by excessive sun exposure. Patients often have persistent dryness and cracking of the lips.

In our patient, angular cheilitis was the main clinical manifestation of iron deficiency anemia, highlighting the importance of looking for iron deficiency in affected patients without a more obvious cause.

A 20-year-old woman had a 4-month history of painful red erosions around the mouth. She had no dysphagia or fatigue and no history of diarrhea, gluten intolerance, or diabetes mellitus. An antifungal-antibacterial ointment prescribed by her dentist had provided no relief.

• Hemoglobin 8.0 g/dL (reference range for females 12.3–15.3)
• Mean corpuscular volume 62 fL (80–100)
• Serum ferritin 1.3 ng/mL (15–200)
• Reticulocyte count 0.86% (0.5–1.5)
• White blood cell count 9.8 × 10⁹/L (4.5–11.0)
• Platelet count 450 × 10⁹/L (150–400).

Vitamin B₁₂ and folate levels were normal, and tests for antitissue transglutaminase and antinuclear antibodies were negative.

Based on these results, the diagnosis was angular cheilitis from iron deficiency anemia. Treatment with oral ferrous gluconate 300 mg twice daily cleared the cheilitis, and after 4 weeks of this treatment, the hemoglobin level increased to 9.8 g/dL, the serum ferritin increased to 7 ng/mL, and the reticulocyte count increased to 2.6%. She was advised to continue taking oral iron tablets for another 3 months until the hemoglobin level reached 12.0 g/dL.

During 2 years of follow-up, she had no recurrence of angular cheilitis, and her hemoglobin and serum ferritin levels remained normal. Ferrous gluconate was her only medication from the time of her diagnosis.

A BROAD DIFFERENTIAL DIAGNOSIS

Angular cheilitis (perlèche) is an inflammatory condition characterized by erosive inflammation at one or both angles of the mouth. It typically presents as erythema, scaling, fissuring, and ulceration. A wide variety of factors, including nutritional deficiencies, local and systemic factors, and drug side effects, may produce cheilitis.^1,2

Nutritional deficiencies account for 25% of all cases of angular cheilitis³ and include iron deficiency and deficiencies of the B vitamins riboflavin (B₂), niacin (B₃), pyridoxine (B₆), and cyanocobalamin (B₁₂).¹

Local causes include infection with Candida albicans or Staphylococcus aureus and allergic contact dermatitis. Common causes of allergic contact dermatitis include lipstick, toothpaste, mouthwash, cosmetics, sunscreen, fragrance, metals such as nickel, and dental appliances.¹

Systemic diseases associated with angular cheilitis include xerostomia, inflammatory bowel disease, Sjögren syndrome, glucagonoma, and human immunodeficiency virus.¹

Drugs that cause angular cheilitis include isotretinoin, sorafenib (antineoplastic kinase inhibitor), and ointments or creams such as neomycin sulfate–polymyxin B sulfate, bacitracin, idoxuridine, and steroids.^1,4

Conditions that mimic angular cheilitis include herpes simplex type 1 (herpes labialis) and actinic cheilitis. Herpes labialis, characterized by burning sensation, itching, or paresthesia, usually precedes a recurrence of vesicles that eventually ulcerate or form a crust and heal without a crust. Herpes labialis often recurs, affecting the vermilion border and lasting approximately 1 week.

Actinic cheilitis, a premalignant condition that commonly involves the lower lip with sparing of the corners of the mouth, is caused by excessive sun exposure. Patients often have persistent dryness and cracking of the lips.

In our patient, angular cheilitis was the main clinical manifestation of iron deficiency anemia, highlighting the importance of looking for iron deficiency in affected patients without a more obvious cause.

A 20-year-old woman had a 4-month history of painful red erosions around the mouth. She had no dysphagia or fatigue and no history of diarrhea, gluten intolerance, or diabetes mellitus. An antifungal-antibacterial ointment prescribed by her dentist had provided no relief.

• Hemoglobin 8.0 g/dL (reference range for females 12.3–15.3)
• Mean corpuscular volume 62 fL (80–100)
• Serum ferritin 1.3 ng/mL (15–200)
• Reticulocyte count 0.86% (0.5–1.5)
• White blood cell count 9.8 × 10⁹/L (4.5–11.0)
• Platelet count 450 × 10⁹/L (150–400).

Vitamin B₁₂ and folate levels were normal, and tests for antitissue transglutaminase and antinuclear antibodies were negative.

Based on these results, the diagnosis was angular cheilitis from iron deficiency anemia. Treatment with oral ferrous gluconate 300 mg twice daily cleared the cheilitis, and after 4 weeks of this treatment, the hemoglobin level increased to 9.8 g/dL, the serum ferritin increased to 7 ng/mL, and the reticulocyte count increased to 2.6%. She was advised to continue taking oral iron tablets for another 3 months until the hemoglobin level reached 12.0 g/dL.

During 2 years of follow-up, she had no recurrence of angular cheilitis, and her hemoglobin and serum ferritin levels remained normal. Ferrous gluconate was her only medication from the time of her diagnosis.

A BROAD DIFFERENTIAL DIAGNOSIS

Angular cheilitis (perlèche) is an inflammatory condition characterized by erosive inflammation at one or both angles of the mouth. It typically presents as erythema, scaling, fissuring, and ulceration. A wide variety of factors, including nutritional deficiencies, local and systemic factors, and drug side effects, may produce cheilitis.^1,2

Nutritional deficiencies account for 25% of all cases of angular cheilitis³ and include iron deficiency and deficiencies of the B vitamins riboflavin (B₂), niacin (B₃), pyridoxine (B₆), and cyanocobalamin (B₁₂).¹

Local causes include infection with Candida albicans or Staphylococcus aureus and allergic contact dermatitis. Common causes of allergic contact dermatitis include lipstick, toothpaste, mouthwash, cosmetics, sunscreen, fragrance, metals such as nickel, and dental appliances.¹

Systemic diseases associated with angular cheilitis include xerostomia, inflammatory bowel disease, Sjögren syndrome, glucagonoma, and human immunodeficiency virus.¹

Drugs that cause angular cheilitis include isotretinoin, sorafenib (antineoplastic kinase inhibitor), and ointments or creams such as neomycin sulfate–polymyxin B sulfate, bacitracin, idoxuridine, and steroids.^1,4

Conditions that mimic angular cheilitis include herpes simplex type 1 (herpes labialis) and actinic cheilitis. Herpes labialis, characterized by burning sensation, itching, or paresthesia, usually precedes a recurrence of vesicles that eventually ulcerate or form a crust and heal without a crust. Herpes labialis often recurs, affecting the vermilion border and lasting approximately 1 week.

Actinic cheilitis, a premalignant condition that commonly involves the lower lip with sparing of the corners of the mouth, is caused by excessive sun exposure. Patients often have persistent dryness and cracking of the lips.

In our patient, angular cheilitis was the main clinical manifestation of iron deficiency anemia, highlighting the importance of looking for iron deficiency in affected patients without a more obvious cause.

A 29-year-old nulliparous woman presents for a routine checkup. She has hypertension and type 2 diabetes mellitus. Her current medications are chlorpropamide 500 mg daily, metformin 500 mg twice a day, lisinopril 40 mg daily, simvastatin 40 mg daily, and aspirin 81 mg daily. Her body mass index is 37 kg/m² and her blood pressure is 130/80 mm Hg. Her hemoglobin A_1c level is 7.8% and her low-density lipoprotein cholesterol 90 mg/dL.

She is considering pregnancy. How would you counsel her?

DEFINING DIABETES IN PREGNANCY

Diabetes in pregnant women, both gestational and pregestational, is the most common medical complication associated with pregnancy.¹

• Gestational diabetes is defined as diabetes that is diagnosed during the second or third trimester of pregnancy and that is not clearly pregestational.²
• Pregestational diabetes exists before pregnancy and can be either type 1 or type 2.

Most cases of diabetes diagnosed during the first trimester reflect pregestational diabetes, as gestational diabetes occurs when insulin resistance increases in the later trimesters.

Type 1 diabetes involves autoimmune destruction of pancreatic islet cells, leading to insulin deficiency and the need for insulin therapy. Type 2 diabetes is characterized by insulin resistance rather than overall insulin deficiency. Type 2 diabetes tends to be associated with comorbidities such as obesity and hypertension, which are independent risk factors for adverse perinatal outcomes.^3,4

Gestational diabetes accounts for most cases of diabetes during pregnancy. Although both pregestational and gestational diabetes increase the risk of maternal and fetal complications, pregestational diabetes is associated with significantly greater risks.¹

IMPACT OF DIABETES ON THE MOTHER

Pregnancy increases the risk of maternal hypoglycemia, especially during the first trimester in patients with type 1 diabetes, as insulin sensitivity increases in early pregnancy.¹ Pregnant women with diabetes may also have an altered counterregulatory response and less hypoglycemic awareness.¹ Insulin resistance rises during the second and early third trimesters, increasing the risk of hyperglycemia in women with diabetes.¹

Glycemic control during pregnancy is usually easier to achieve in patients with type 2 diabetes than with type 1, but it may require much higher insulin doses.

Because pregnancy is inherently a ketogenic state, women with type 1 diabetes are at higher risk of diabetic ketoacidosis, particularly during the second and third trimesters.¹ There are reports of euglycemic diabetic ketoacidosis in pregnant women with either gestational or pregestational diabetes.⁵

Diabetes is associated with a risk of preeclampsia 4 times higher than in nondiabetic women.⁶ Other potential pregnancy-related complications include infections, polyhydram­nios, spontaneous abortion, and cesarean delivery.^1,7 The risk of pregnancy loss is similar in women with either type 1 or type 2 diabetes (2.6% and 3.7%, respectively), but the causes are different.⁸ Although preexisting diabetic complications such as retinopathy, nephropathy, and gastroparesis can be exacerbated during pregnancy,¹ only severe gastroparesis and advanced renal disease are considered relative contraindications to pregnancy.

IMPACT OF DIABETES ON THE FETUS

Fetal complications of maternal diabetes include embryopathy (fetal malformations) and fetopathy (overgrowth, ie, fetus large for gestational age, and increased risk of fetal death or distress). Maternal hyperglycemia is associated with diabetic embryopathy, resulting in major birth defects in 5% to 25% of pregnancies and spontaneous abortions in 15% to 20%.^9,10 There is a 2- to 6-fold increase in risk of congenital malformations.6

The most common diabetes-associated congenital malformations affect the cardiovascular system. Congenital heart disease includes tetralogy of Fallot, transposition of the great vessels, septal defects, and anomalous pulmonary venous return. Other relatively common defects involve the fetal central nervous system, spine, orofacial system, kidneys, urogenital system, gastrointestinal tract, and skeleton.¹¹

The risk of fetopathy is proportional to the degree of maternal hyperglycemia. Excess maternal glucose and fatty acid levels can lead to fetal hyperglycemia and overgrowth, which increases fetal oxygen requirements. Erythro­poietin levels rise, causing an increase in red cell mass, with subsequent hyperviscosity within the placenta and higher risk of fetal death.

Other complications include intrauterine growth restriction, prematurity, and preterm delivery. Fetal macrosomia (birth weight > 90th percentile or 4 kg, approximately 8 lb, 13 oz) occurs in 27% to 62% of children born to mothers with diabetes, a rate 10 times higher than in patients without diabetes. It contributes to shoulder dystocia (risk 2 to 4 times higher in diabetic pregnancies) and cesarean delivery.⁶ Infants born to mothers with diabetes also have higher risks of neonatal hypoglycemia, erythrocytosis, hyperbilirubinemia, hypocalcemia, respiratory distress, cardiomyopathy, and death, as well as for developing diabetes, obesity, and other adverse cardiometabolic outcomes later in life.¹¹

Nearly half of pregnancies in the general population are unplanned,¹⁵ so preconception diabetes assessment needs to be part of routine medical care for all reproductive-age women. Because most organogenesis occurs during the first 5 to 8 weeks after fertilization—potentially before a woman realizes she is pregnant—achieving optimal glycemic control before conception is necessary to improve pregnancy outcomes.¹

EVERY VISIT IS AN OPPORTUNITY

Every medical visit with a reproductive-age woman with diabetes is an opportunity for counseling about pregnancy. Topics that need to be discussed include the risks of unplanned pregnancy and of poor metabolic control, and the benefits of improved maternal and fetal outcomes with appropriate pregnancy planning and diabetes management.

Referral to a registered dietitian for individualized counseling about proper nutrition, particularly during pregnancy, has been associated with positive outcomes.¹⁶ Patients with diabetes and at high risk of pregnancy complications should be referred to a clinic that specializes in high-risk pregnancies.

Practitioners also should emphasize the importance of regular exercise and encourage patients to maintain or achieve a medically optimal weight before conception. Ideally, this would be a normal body mass index; however, this is not always possible.

In women who are planning pregnancy or are not on effective contraception, medications should be reviewed for potential teratogenicity. If needed, discuss alternative medications or switch to safer ones. However, these changes should not interrupt diabetes treatment.

In addition, ensure that the patient is up to date on age- and disease-appropriate preventive care (eg, immunizations, screening for sexually transmitted disease and malignancy). Counseling and intervention for use of tobacco, alcohol, and recreational drugs are also important. As with any preconception counseling, the patient (and her partner, if possible) should be advised to avoid travel to areas where Zika virus is endemic, and informed about the availability of expanded carrier genetic screening through her obstetric provider.

Finally, pregnant women with diabetes benefit from screening for diabetic complications including hypertension, retinopathy, cardiovascular disease, neuropathy, and nephropathy.

ASSESSING RISKS

Blood pressure

Chronic (preexisting) hypertension is defined as a systolic pressure 140 mm Hg or higher or a diastolic pressure 90 mm Hg or higher, or both, that antedates pregnancy or is present before the 20th week of pregnancy.³ Chronic hypertension has been reported in up to 5% of pregnant women and is associated with increased risk of preterm delivery, superimposed preeclampsia, low birth weight, and perinatal death.³

Reproductive-age women with diabetes and high blood pressure benefit from lifestyle and behavioral modifications.¹⁷ If drug therapy is needed, antihypertensive drugs that are safe for the fetus should be used. Treatment of mild or moderate hypertension during pregnancy reduces the risk of progression to severe hypertension but may not improve obstetric outcomes.

Diabetic retinopathy

Diabetic retinopathy can significantly worsen during pregnancy: the risk of progression is double that in the nonpregnant state.¹⁸ Women with diabetes who are contemplating pregnancy should have a comprehensive eye examination before conception, and any active proliferative retinopathy needs to be treated. These patients may require ophthalmologic monitoring and treatment during pregnancy. (Note: laser photocoagulation is not contraindicated during pregnancy.)

Cardiovascular disease

Cardiovascular physiology changes dramatically during pregnancy. Cardiovascular disease, especially when superimposed on diabetes, can increase the risk of maternal death. Thus, evaluation for cardiovascular risk factors as well as cardiovascular system integrity before conception is important. Listen for arterial bruits and murmurs, and assess peripheral pulses. Consideration should be given to obtaining a preconception resting electrocardiogram in women with diabetes who are over age 35 or who are suspected of having cardiovascular disease.¹⁶

Neurologic disorders

Peripheral neuropathy, the most common neurologic complication of diabetes, is associated with injury and infection.¹⁹

Autonomic neuropathy is associated with decreased cardiac responsiveness and orthostatic hypotension.¹⁹ Diabetic gastroparesis alone can precipitate serious complications during pregnancy, including extreme hypoglycemia and hyperglycemia, increased risk of diabetic ketoacidosis, weight loss, malnutrition, frequent hospitalizations, and increased requirement for parenteral nutrition.²⁰

Although diabetic neuropathy does not significantly worsen during pregnancy, women with preexisting gastroparesis should be counseled on the substantial risks associated with pregnancy. Screening for neuropathy should be part of all diabetic preconception examinations.

Renal complications

Pregnancy in women with diabetes and preexisting renal dysfunction increases their risk of accelerated progression of diabetic kidney disease.²¹ Preexisting renal dysfunction also increases the risk of pregnancy-related complications, such as stillbirth, intrauterine growth restriction, gestational hypertension, preeclampsia, and preterm delivery.^19,21,22 Further, the risk of pregnancy complications correlates directly with the severity of renal dysfunction.²²

Psychiatric disorders

Emotional wellness is essential for optimal diabetes management. It is important to recognize the emotional impact of diabetes in pregnant women and to conduct routine screening for depression, anxiety, stress, and eating disorders.¹⁶

Hemoglobin A_1c. The general consensus is to achieve the lowest hemoglobin A_1c level possible that does not increase the risk of hypoglycemia. The American Diabetes Association (ADA) recommends that, before attempting to conceive, women should lower their hemoglobin A_1c to below 6.5%.¹

Thyroid measures. Autoimmune thyroid disease is the most common autoimmune disorder associated with diabetes and has been reported in 35% to 40% of women with type 1 diabetes.²³ Recommendations are to check thyroid-stimulating hormone and thyroid peroxidase antibody levels before conception or early in pregnancy in all women with diabetes.^1,24 Overt hypothyroidism should be treated before conception, given that early fetal brain development depends on maternal thyroxine.

Renal function testing. Preconception assessment of renal function is important for counseling and risk stratification. This assessment should include serum creatinine level, estimated glomerular filtration rate, and urinary albumin excretion.²¹

Celiac screening. Because women with type 1 diabetes are more susceptible to autoimmune diseases, they should be screened for celiac disease before conception, with testing for  immunoglobulin A (IgA) and tissue transglutaminase antibodies, with or without IgA endomysial antibodies.^16,25,26 An estimated 6% of patients with type 1 diabetes have celiac disease vs 1% of the general population.²⁵ Celiac disease is 2 to 3 times more common in women, and asymptomatic people with type 1 diabetes are considered at increased risk for celiac disease.²⁶

The association between type 1 diabetes and celiac disease most likely relates to the overlap in human leukocyte antigens of the diseases. There is no established link between type 2 diabetes and celiac disease.²⁵

Undiagnosed celiac disease increases a woman’s risk of obstetric complications such as preterm birth, low birth weight, and stillbirth.²⁶ The most likely explanation for these adverse effects is nutrient malabsorption, which is characteristic of celiac disease. Adherence to a gluten-free diet before and during gestation may reduce the risk of preterm delivery by as much as 20%.²⁶

Vitamin B₁₂ level. Celiac disease interferes with the absorption of vitamin B₁₂-instrinsic factor in the ileum, which can lead to vitamin B₁₂ deficiency. Therefore, baseline vitamin B₁₂ levels should be checked before conception in women with celiac disease. Levels should also be checked in women taking metformin, which also decreases vitamin B₁₂ absorption. Of note, increased folate levels due to taking supplements can potentially mask vitamin B₁₂ deficiency.

MEDICATIONS TO REVIEW FOR PREGNANCY INTERACTIONS

Diabetic medications

Insulin is the first-line pharmacotherapy for pregnant patients with type 1, type 2, or gestational diabetes. Insulin does not cross the placenta to a measurable extent, and most insulin preparations have been classified as category B,¹ meaning no risks to the fetus have been found in humans.

Insulin dosing during pregnancy is not static. Beginning around mid-gestation, insulin requirements increase,^28,29 but after 32 weeks the need may decrease. These changes require practitioners to closely monitor blood glucose throughout pregnancy.

Both basal-bolus injections and continuous subcutaneous infusion are reasonable options during pregnancy.³⁰ However, the need for multiple and potentially painful insulin injections daily can lead to poor compliance. This inconvenience has led to studies using oral hypoglycemic medications instead of insulin for patients with gestational and type 2 diabetes.

Metformin is an oral biguanide that decreases hepatic gluconeogenesis and intestinal glucose absorption while peripherally increasing glucose utilization and uptake. Metformin does not pose a risk of hypoglycemia because its mechanism of action does not involve increased insulin production.⁷

Metformin does cross the placenta, resulting in umbilical cord blood levels higher than maternal levels. Nevertheless, studies support the efficacy and short-term safety of metformin use during a pregnancy complicated by gestational or type 2 diabetes.^7,31 Moreover, metformin has been associated with a lower risk of neonatal hypoglycemia and maternal weight gain than insulin.³² However, this agent should be used with caution, as long-term data are not yet available, and it may slightly increase the risk of premature delivery.

Glyburide is another oral hypoglycemic medication that has been used during pregnancy. This second-generation sulfonylurea enhances the release of insulin from the pancreas by binding beta islet cell ATP-calcium channel receptors. Compared with other sulfonylureas, glyburide has the lowest rate of maternal-to-fetal transfer, with umbilical cord plasma concentrations 70% of maternal levels.³³ Although some trials support the efficacy and short-term safety of glyburide treatment for gestational diabetes,³⁴ recent studies have associated glyburide use during pregnancy with a higher rate of neonatal hypoglycemia, neonatal respiratory distress, macrosomia, and neonatal intensive care unit admissions than insulin and metformin.^1,35

Patients treated with oral agents should be informed that these drugs cross the placenta, and that although no adverse effects on the fetus have been demonstrated, long-term safety data are lacking. In addition, oral agents are ineffective in type 1 diabetes and may be insufficient to overcome the insulin resistance in type 2 diabetes.

Antihypertensive drugs

All antihypertensive drugs cross the placenta, but several have an acceptable safety profile in pregnancy, including methyldopa, labeta­lol, clonidine, prazosin, and nifedipine. Hydralazine and labetalol are short-acting, come in intravenous formulations, and can be used for urgent blood pressure control during pregnancy. Diltiazem may be used for heart rate control during pregnancy, and it has been shown to lower blood pressure and proteinuria in pregnant patients with underlying renal disease.^36,37 The ADA recommends against chronic use of diuretics during pregnancy because of potential reductions in maternal plasma volume and uteroplacental perfusion.¹

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors are contraindicated during pregnancy because of the risk of fetal defects, particularly in the renal system.^21,38 Although there is evidence to question the association between first semester exposure and fetotoxicity,³⁹ we avoid these drugs during pregnancy and switch to a different agent in women planning pregnancy.

Other drugs

Statins are contraindicated in pregnancy because they interfere with the development of the fetal nervous system.²¹ Although preliminary data from a small study did not identify safety risks associated with pravastatin use after 12 weeks of gestation,⁴⁰ we recommend discontinuing statins in women attempting pregnancy.

Aspirin. The US Preventive Services Task Force41 recommends low-dose aspirin (81 mg/day) after 12 weeks of gestation for women with type 1 or type 2 diabetes, as well as those with renal disease or chronic hypertension, to prevent preeclampsia. Of note, higher doses need to be used with caution during pregnancy because fetal abnormalities have been reported, such as disruption of fetal vasculature (mesenteric vessels), gastroschisis, and small intestinal atresia.¹⁶

Folate supplementation (0.6–4 mg/day) is recommended in women with celiac disease to prevent neural tube defects in the offspring, and the US Preventive Services Task Force recommends 0.4 mg daily of folic acid supplementation for all women planning or capable of pregnancy.^42–44 Higher doses, ranging from 0.6 to 5 mg/day, have been proposed for patients with diabetes,¹³ and we recommend at least 1 mg for this group, based on data suggesting that higher doses further reduce the risk of neural tube defects.⁴³

Maternal diabetes, insulin therapy, and oral hypoglycemic agents are not contraindications to breastfeeding. The US Preventive Services Task Force recommends interventions by primary care physicians to promote and support breastfeeding.⁴⁵ Breastfeeding is encouraged based on various short- and long-term health benefits for both breastfed infants and breastfeeding mothers. Breastfeeding decreases a woman’s insulin requirements and increases the risk for hypoglycemia, especially in patients with insulin-dependent type 1 diabetes.¹

Additionally, insulin sensitivity increases immediately following delivery of the placenta.¹ Therefore, it is prudent to adjust insulin doses postpartum, especially while a patient is breastfeeding, or to suggest high-carbohydrate snacks before feeds.^9,29

Antihypertensive drugs considered safe to use during lactation include captopril, enalapril, quinapril, labetalol, propranolol, nifedipine, and hydralazine.^21,46 Methyldopa is not contraindicated, but it causes fatigue and worsened postpartum depression and should not be used as first-line therapy. Diuretics and ARBs are not recommended during lactation.²¹ Both metformin and glyburide enter breast milk in small enough amounts that they are not contraindicated during breastfeeding.¹⁶ The Lactmed database (www.toxnet.nlm.nih.gov) provides information about drugs and breastfeeding.

WHAT ABOUT CONTRACEPTIVES?

The ADA recommends contraception for women with diabetes because, just as in women without diabetes, the risks of unplanned pregnancy outweigh those of contraceptives.¹

We recommend low-dose combination estrogen-progestin oral contraceptives to normotensive women under age 35 with diabetes but without underlying microvascular disease. For women over age 35 or for those with microvascular disease, additional options include intrauterine devices or progestin implants. We prefer not to use injectable depot medroxyprogesterone acetate because of its side effects of insulin resistance and weight gain.⁴⁷

CASE DISCUSSION: NEXT STEPS

Our patient’s interest in family planning presents an opportunity for preconception counseling. We recommend a prenatal folic acid supplement, diet and regular exercise for weight loss, and screening tests including a comprehensive metabolic panel, hemoglobin A_1c, thyroid-stimulating hormone, and dilated eye examination. We make sure she is up to date on her indicated health maintenance (eg, immunizations, disease screening), and we review her medications for potential teratogens. She denies any recreational drug use. Also, she has no plans for long-distance travel.

Our counseling includes discussions of pregnancy risks associated with pregestational diabetes and suboptimal glycemic control. We encourage her to use effective contraception until she is “medically optimized” for pregnancy—ie, until her hemoglobin A_1c is lower than 6.5% and she has achieved a medically optimal weight. If feasible, a reduction of weight (7% or so) through lifestyle modification should be attempted, and if her hemoglobin A_1c remains elevated, adding insulin would be recommended.

Pregnant patients or patients contemplating pregnancy are usually motivated to modify their behavior, making this a good time to reinforce lifestyle modifications. Many patients benefit from individualized counseling by a registered dietitian to help achieve the recommended weight and glycemic control.

Our physical examination in this patient includes screening for micro- and macrovascular complications of diabetes, and the test results are negative. Patients with active proliferative retinopathy should be referred to an ophthalmologist for assessment and treatment.

We review her medications for potential teratogenic effects and stop her ACE inhibitor (lisinopril) and statin (simvastatin). We switch her from a first-generation sulfonylurea (chlorpropamide) to glyburide, a second-generation sulfonylurea. Second-generation sulfonylureas are considered more “fetus-friendly” because first-generation sulfonylureas cross the placenta more easily and can cause fetal hyperinsulinemia, leading to macrosomia and neonatal hypoglycemia.⁷

The management of diabetes during pregnancy leans toward insulin use, given the lack of information regarding long-term outcomes with oral agents. If insulin is needed, it is best to initiate it before the patient conceives, and then to stop other diabetes medications. We would not make any changes to her aspirin or metformin use.

Educating the patient and her family about prevention, recognition, and treatment of hypoglycemia is important to prevent and manage the increased risk of hypoglycemia with insulin therapy and in early pregnancy.¹ Consideration should be given to providing ketone strips as well as education on diabetic ketoacidosis prevention and detection.¹ If the patient conceives, begin prenatal care early to allow adequate planning for care of her disease and evaluation of the fetus. Because of the complexity of insulin management in pregnancy, the ADA recommends referral, if possible, to a center offering team-based care, including an obstetrician specialized in high-risk pregnancies, an endocrinologist, and a dietitian.¹

A 29-year-old nulliparous woman presents for a routine checkup. She has hypertension and type 2 diabetes mellitus. Her current medications are chlorpropamide 500 mg daily, metformin 500 mg twice a day, lisinopril 40 mg daily, simvastatin 40 mg daily, and aspirin 81 mg daily. Her body mass index is 37 kg/m² and her blood pressure is 130/80 mm Hg. Her hemoglobin A_1c level is 7.8% and her low-density lipoprotein cholesterol 90 mg/dL.

She is considering pregnancy. How would you counsel her?

DEFINING DIABETES IN PREGNANCY

Diabetes in pregnant women, both gestational and pregestational, is the most common medical complication associated with pregnancy.¹

• Gestational diabetes is defined as diabetes that is diagnosed during the second or third trimester of pregnancy and that is not clearly pregestational.²
• Pregestational diabetes exists before pregnancy and can be either type 1 or type 2.

Most cases of diabetes diagnosed during the first trimester reflect pregestational diabetes, as gestational diabetes occurs when insulin resistance increases in the later trimesters.

Type 1 diabetes involves autoimmune destruction of pancreatic islet cells, leading to insulin deficiency and the need for insulin therapy. Type 2 diabetes is characterized by insulin resistance rather than overall insulin deficiency. Type 2 diabetes tends to be associated with comorbidities such as obesity and hypertension, which are independent risk factors for adverse perinatal outcomes.^3,4

Gestational diabetes accounts for most cases of diabetes during pregnancy. Although both pregestational and gestational diabetes increase the risk of maternal and fetal complications, pregestational diabetes is associated with significantly greater risks.¹

IMPACT OF DIABETES ON THE MOTHER

Pregnancy increases the risk of maternal hypoglycemia, especially during the first trimester in patients with type 1 diabetes, as insulin sensitivity increases in early pregnancy.¹ Pregnant women with diabetes may also have an altered counterregulatory response and less hypoglycemic awareness.¹ Insulin resistance rises during the second and early third trimesters, increasing the risk of hyperglycemia in women with diabetes.¹

Glycemic control during pregnancy is usually easier to achieve in patients with type 2 diabetes than with type 1, but it may require much higher insulin doses.

Because pregnancy is inherently a ketogenic state, women with type 1 diabetes are at higher risk of diabetic ketoacidosis, particularly during the second and third trimesters.¹ There are reports of euglycemic diabetic ketoacidosis in pregnant women with either gestational or pregestational diabetes.⁵

Diabetes is associated with a risk of preeclampsia 4 times higher than in nondiabetic women.⁶ Other potential pregnancy-related complications include infections, polyhydram­nios, spontaneous abortion, and cesarean delivery.^1,7 The risk of pregnancy loss is similar in women with either type 1 or type 2 diabetes (2.6% and 3.7%, respectively), but the causes are different.⁸ Although preexisting diabetic complications such as retinopathy, nephropathy, and gastroparesis can be exacerbated during pregnancy,¹ only severe gastroparesis and advanced renal disease are considered relative contraindications to pregnancy.

IMPACT OF DIABETES ON THE FETUS

Fetal complications of maternal diabetes include embryopathy (fetal malformations) and fetopathy (overgrowth, ie, fetus large for gestational age, and increased risk of fetal death or distress). Maternal hyperglycemia is associated with diabetic embryopathy, resulting in major birth defects in 5% to 25% of pregnancies and spontaneous abortions in 15% to 20%.^9,10 There is a 2- to 6-fold increase in risk of congenital malformations.6

The most common diabetes-associated congenital malformations affect the cardiovascular system. Congenital heart disease includes tetralogy of Fallot, transposition of the great vessels, septal defects, and anomalous pulmonary venous return. Other relatively common defects involve the fetal central nervous system, spine, orofacial system, kidneys, urogenital system, gastrointestinal tract, and skeleton.¹¹

The risk of fetopathy is proportional to the degree of maternal hyperglycemia. Excess maternal glucose and fatty acid levels can lead to fetal hyperglycemia and overgrowth, which increases fetal oxygen requirements. Erythro­poietin levels rise, causing an increase in red cell mass, with subsequent hyperviscosity within the placenta and higher risk of fetal death.

Other complications include intrauterine growth restriction, prematurity, and preterm delivery. Fetal macrosomia (birth weight > 90th percentile or 4 kg, approximately 8 lb, 13 oz) occurs in 27% to 62% of children born to mothers with diabetes, a rate 10 times higher than in patients without diabetes. It contributes to shoulder dystocia (risk 2 to 4 times higher in diabetic pregnancies) and cesarean delivery.⁶ Infants born to mothers with diabetes also have higher risks of neonatal hypoglycemia, erythrocytosis, hyperbilirubinemia, hypocalcemia, respiratory distress, cardiomyopathy, and death, as well as for developing diabetes, obesity, and other adverse cardiometabolic outcomes later in life.¹¹

Nearly half of pregnancies in the general population are unplanned,¹⁵ so preconception diabetes assessment needs to be part of routine medical care for all reproductive-age women. Because most organogenesis occurs during the first 5 to 8 weeks after fertilization—potentially before a woman realizes she is pregnant—achieving optimal glycemic control before conception is necessary to improve pregnancy outcomes.¹

EVERY VISIT IS AN OPPORTUNITY

Every medical visit with a reproductive-age woman with diabetes is an opportunity for counseling about pregnancy. Topics that need to be discussed include the risks of unplanned pregnancy and of poor metabolic control, and the benefits of improved maternal and fetal outcomes with appropriate pregnancy planning and diabetes management.

Referral to a registered dietitian for individualized counseling about proper nutrition, particularly during pregnancy, has been associated with positive outcomes.¹⁶ Patients with diabetes and at high risk of pregnancy complications should be referred to a clinic that specializes in high-risk pregnancies.

Practitioners also should emphasize the importance of regular exercise and encourage patients to maintain or achieve a medically optimal weight before conception. Ideally, this would be a normal body mass index; however, this is not always possible.

In women who are planning pregnancy or are not on effective contraception, medications should be reviewed for potential teratogenicity. If needed, discuss alternative medications or switch to safer ones. However, these changes should not interrupt diabetes treatment.

In addition, ensure that the patient is up to date on age- and disease-appropriate preventive care (eg, immunizations, screening for sexually transmitted disease and malignancy). Counseling and intervention for use of tobacco, alcohol, and recreational drugs are also important. As with any preconception counseling, the patient (and her partner, if possible) should be advised to avoid travel to areas where Zika virus is endemic, and informed about the availability of expanded carrier genetic screening through her obstetric provider.

Finally, pregnant women with diabetes benefit from screening for diabetic complications including hypertension, retinopathy, cardiovascular disease, neuropathy, and nephropathy.

ASSESSING RISKS

Blood pressure

Chronic (preexisting) hypertension is defined as a systolic pressure 140 mm Hg or higher or a diastolic pressure 90 mm Hg or higher, or both, that antedates pregnancy or is present before the 20th week of pregnancy.³ Chronic hypertension has been reported in up to 5% of pregnant women and is associated with increased risk of preterm delivery, superimposed preeclampsia, low birth weight, and perinatal death.³

Reproductive-age women with diabetes and high blood pressure benefit from lifestyle and behavioral modifications.¹⁷ If drug therapy is needed, antihypertensive drugs that are safe for the fetus should be used. Treatment of mild or moderate hypertension during pregnancy reduces the risk of progression to severe hypertension but may not improve obstetric outcomes.

Diabetic retinopathy

Diabetic retinopathy can significantly worsen during pregnancy: the risk of progression is double that in the nonpregnant state.¹⁸ Women with diabetes who are contemplating pregnancy should have a comprehensive eye examination before conception, and any active proliferative retinopathy needs to be treated. These patients may require ophthalmologic monitoring and treatment during pregnancy. (Note: laser photocoagulation is not contraindicated during pregnancy.)

Cardiovascular disease

Cardiovascular physiology changes dramatically during pregnancy. Cardiovascular disease, especially when superimposed on diabetes, can increase the risk of maternal death. Thus, evaluation for cardiovascular risk factors as well as cardiovascular system integrity before conception is important. Listen for arterial bruits and murmurs, and assess peripheral pulses. Consideration should be given to obtaining a preconception resting electrocardiogram in women with diabetes who are over age 35 or who are suspected of having cardiovascular disease.¹⁶

Neurologic disorders

Peripheral neuropathy, the most common neurologic complication of diabetes, is associated with injury and infection.¹⁹

Autonomic neuropathy is associated with decreased cardiac responsiveness and orthostatic hypotension.¹⁹ Diabetic gastroparesis alone can precipitate serious complications during pregnancy, including extreme hypoglycemia and hyperglycemia, increased risk of diabetic ketoacidosis, weight loss, malnutrition, frequent hospitalizations, and increased requirement for parenteral nutrition.²⁰

Although diabetic neuropathy does not significantly worsen during pregnancy, women with preexisting gastroparesis should be counseled on the substantial risks associated with pregnancy. Screening for neuropathy should be part of all diabetic preconception examinations.

Renal complications

Pregnancy in women with diabetes and preexisting renal dysfunction increases their risk of accelerated progression of diabetic kidney disease.²¹ Preexisting renal dysfunction also increases the risk of pregnancy-related complications, such as stillbirth, intrauterine growth restriction, gestational hypertension, preeclampsia, and preterm delivery.^19,21,22 Further, the risk of pregnancy complications correlates directly with the severity of renal dysfunction.²²

Psychiatric disorders

Emotional wellness is essential for optimal diabetes management. It is important to recognize the emotional impact of diabetes in pregnant women and to conduct routine screening for depression, anxiety, stress, and eating disorders.¹⁶

Hemoglobin A_1c. The general consensus is to achieve the lowest hemoglobin A_1c level possible that does not increase the risk of hypoglycemia. The American Diabetes Association (ADA) recommends that, before attempting to conceive, women should lower their hemoglobin A_1c to below 6.5%.¹

Thyroid measures. Autoimmune thyroid disease is the most common autoimmune disorder associated with diabetes and has been reported in 35% to 40% of women with type 1 diabetes.²³ Recommendations are to check thyroid-stimulating hormone and thyroid peroxidase antibody levels before conception or early in pregnancy in all women with diabetes.^1,24 Overt hypothyroidism should be treated before conception, given that early fetal brain development depends on maternal thyroxine.

Renal function testing. Preconception assessment of renal function is important for counseling and risk stratification. This assessment should include serum creatinine level, estimated glomerular filtration rate, and urinary albumin excretion.²¹

Celiac screening. Because women with type 1 diabetes are more susceptible to autoimmune diseases, they should be screened for celiac disease before conception, with testing for  immunoglobulin A (IgA) and tissue transglutaminase antibodies, with or without IgA endomysial antibodies.^16,25,26 An estimated 6% of patients with type 1 diabetes have celiac disease vs 1% of the general population.²⁵ Celiac disease is 2 to 3 times more common in women, and asymptomatic people with type 1 diabetes are considered at increased risk for celiac disease.²⁶

The association between type 1 diabetes and celiac disease most likely relates to the overlap in human leukocyte antigens of the diseases. There is no established link between type 2 diabetes and celiac disease.²⁵

Undiagnosed celiac disease increases a woman’s risk of obstetric complications such as preterm birth, low birth weight, and stillbirth.²⁶ The most likely explanation for these adverse effects is nutrient malabsorption, which is characteristic of celiac disease. Adherence to a gluten-free diet before and during gestation may reduce the risk of preterm delivery by as much as 20%.²⁶

Vitamin B₁₂ level. Celiac disease interferes with the absorption of vitamin B₁₂-instrinsic factor in the ileum, which can lead to vitamin B₁₂ deficiency. Therefore, baseline vitamin B₁₂ levels should be checked before conception in women with celiac disease. Levels should also be checked in women taking metformin, which also decreases vitamin B₁₂ absorption. Of note, increased folate levels due to taking supplements can potentially mask vitamin B₁₂ deficiency.

MEDICATIONS TO REVIEW FOR PREGNANCY INTERACTIONS

Diabetic medications

Insulin is the first-line pharmacotherapy for pregnant patients with type 1, type 2, or gestational diabetes. Insulin does not cross the placenta to a measurable extent, and most insulin preparations have been classified as category B,¹ meaning no risks to the fetus have been found in humans.

Insulin dosing during pregnancy is not static. Beginning around mid-gestation, insulin requirements increase,^28,29 but after 32 weeks the need may decrease. These changes require practitioners to closely monitor blood glucose throughout pregnancy.

Both basal-bolus injections and continuous subcutaneous infusion are reasonable options during pregnancy.³⁰ However, the need for multiple and potentially painful insulin injections daily can lead to poor compliance. This inconvenience has led to studies using oral hypoglycemic medications instead of insulin for patients with gestational and type 2 diabetes.

Metformin is an oral biguanide that decreases hepatic gluconeogenesis and intestinal glucose absorption while peripherally increasing glucose utilization and uptake. Metformin does not pose a risk of hypoglycemia because its mechanism of action does not involve increased insulin production.⁷

Metformin does cross the placenta, resulting in umbilical cord blood levels higher than maternal levels. Nevertheless, studies support the efficacy and short-term safety of metformin use during a pregnancy complicated by gestational or type 2 diabetes.^7,31 Moreover, metformin has been associated with a lower risk of neonatal hypoglycemia and maternal weight gain than insulin.³² However, this agent should be used with caution, as long-term data are not yet available, and it may slightly increase the risk of premature delivery.

Glyburide is another oral hypoglycemic medication that has been used during pregnancy. This second-generation sulfonylurea enhances the release of insulin from the pancreas by binding beta islet cell ATP-calcium channel receptors. Compared with other sulfonylureas, glyburide has the lowest rate of maternal-to-fetal transfer, with umbilical cord plasma concentrations 70% of maternal levels.³³ Although some trials support the efficacy and short-term safety of glyburide treatment for gestational diabetes,³⁴ recent studies have associated glyburide use during pregnancy with a higher rate of neonatal hypoglycemia, neonatal respiratory distress, macrosomia, and neonatal intensive care unit admissions than insulin and metformin.^1,35

Patients treated with oral agents should be informed that these drugs cross the placenta, and that although no adverse effects on the fetus have been demonstrated, long-term safety data are lacking. In addition, oral agents are ineffective in type 1 diabetes and may be insufficient to overcome the insulin resistance in type 2 diabetes.

Antihypertensive drugs

All antihypertensive drugs cross the placenta, but several have an acceptable safety profile in pregnancy, including methyldopa, labeta­lol, clonidine, prazosin, and nifedipine. Hydralazine and labetalol are short-acting, come in intravenous formulations, and can be used for urgent blood pressure control during pregnancy. Diltiazem may be used for heart rate control during pregnancy, and it has been shown to lower blood pressure and proteinuria in pregnant patients with underlying renal disease.^36,37 The ADA recommends against chronic use of diuretics during pregnancy because of potential reductions in maternal plasma volume and uteroplacental perfusion.¹

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors are contraindicated during pregnancy because of the risk of fetal defects, particularly in the renal system.^21,38 Although there is evidence to question the association between first semester exposure and fetotoxicity,³⁹ we avoid these drugs during pregnancy and switch to a different agent in women planning pregnancy.

Other drugs

Statins are contraindicated in pregnancy because they interfere with the development of the fetal nervous system.²¹ Although preliminary data from a small study did not identify safety risks associated with pravastatin use after 12 weeks of gestation,⁴⁰ we recommend discontinuing statins in women attempting pregnancy.

Aspirin. The US Preventive Services Task Force41 recommends low-dose aspirin (81 mg/day) after 12 weeks of gestation for women with type 1 or type 2 diabetes, as well as those with renal disease or chronic hypertension, to prevent preeclampsia. Of note, higher doses need to be used with caution during pregnancy because fetal abnormalities have been reported, such as disruption of fetal vasculature (mesenteric vessels), gastroschisis, and small intestinal atresia.¹⁶

Folate supplementation (0.6–4 mg/day) is recommended in women with celiac disease to prevent neural tube defects in the offspring, and the US Preventive Services Task Force recommends 0.4 mg daily of folic acid supplementation for all women planning or capable of pregnancy.^42–44 Higher doses, ranging from 0.6 to 5 mg/day, have been proposed for patients with diabetes,¹³ and we recommend at least 1 mg for this group, based on data suggesting that higher doses further reduce the risk of neural tube defects.⁴³

Maternal diabetes, insulin therapy, and oral hypoglycemic agents are not contraindications to breastfeeding. The US Preventive Services Task Force recommends interventions by primary care physicians to promote and support breastfeeding.⁴⁵ Breastfeeding is encouraged based on various short- and long-term health benefits for both breastfed infants and breastfeeding mothers. Breastfeeding decreases a woman’s insulin requirements and increases the risk for hypoglycemia, especially in patients with insulin-dependent type 1 diabetes.¹

Additionally, insulin sensitivity increases immediately following delivery of the placenta.¹ Therefore, it is prudent to adjust insulin doses postpartum, especially while a patient is breastfeeding, or to suggest high-carbohydrate snacks before feeds.^9,29

Antihypertensive drugs considered safe to use during lactation include captopril, enalapril, quinapril, labetalol, propranolol, nifedipine, and hydralazine.^21,46 Methyldopa is not contraindicated, but it causes fatigue and worsened postpartum depression and should not be used as first-line therapy. Diuretics and ARBs are not recommended during lactation.²¹ Both metformin and glyburide enter breast milk in small enough amounts that they are not contraindicated during breastfeeding.¹⁶ The Lactmed database (www.toxnet.nlm.nih.gov) provides information about drugs and breastfeeding.

WHAT ABOUT CONTRACEPTIVES?

The ADA recommends contraception for women with diabetes because, just as in women without diabetes, the risks of unplanned pregnancy outweigh those of contraceptives.¹

We recommend low-dose combination estrogen-progestin oral contraceptives to normotensive women under age 35 with diabetes but without underlying microvascular disease. For women over age 35 or for those with microvascular disease, additional options include intrauterine devices or progestin implants. We prefer not to use injectable depot medroxyprogesterone acetate because of its side effects of insulin resistance and weight gain.⁴⁷

CASE DISCUSSION: NEXT STEPS

Our patient’s interest in family planning presents an opportunity for preconception counseling. We recommend a prenatal folic acid supplement, diet and regular exercise for weight loss, and screening tests including a comprehensive metabolic panel, hemoglobin A_1c, thyroid-stimulating hormone, and dilated eye examination. We make sure she is up to date on her indicated health maintenance (eg, immunizations, disease screening), and we review her medications for potential teratogens. She denies any recreational drug use. Also, she has no plans for long-distance travel.

Our counseling includes discussions of pregnancy risks associated with pregestational diabetes and suboptimal glycemic control. We encourage her to use effective contraception until she is “medically optimized” for pregnancy—ie, until her hemoglobin A_1c is lower than 6.5% and she has achieved a medically optimal weight. If feasible, a reduction of weight (7% or so) through lifestyle modification should be attempted, and if her hemoglobin A_1c remains elevated, adding insulin would be recommended.

Pregnant patients or patients contemplating pregnancy are usually motivated to modify their behavior, making this a good time to reinforce lifestyle modifications. Many patients benefit from individualized counseling by a registered dietitian to help achieve the recommended weight and glycemic control.

Our physical examination in this patient includes screening for micro- and macrovascular complications of diabetes, and the test results are negative. Patients with active proliferative retinopathy should be referred to an ophthalmologist for assessment and treatment.

We review her medications for potential teratogenic effects and stop her ACE inhibitor (lisinopril) and statin (simvastatin). We switch her from a first-generation sulfonylurea (chlorpropamide) to glyburide, a second-generation sulfonylurea. Second-generation sulfonylureas are considered more “fetus-friendly” because first-generation sulfonylureas cross the placenta more easily and can cause fetal hyperinsulinemia, leading to macrosomia and neonatal hypoglycemia.⁷

The management of diabetes during pregnancy leans toward insulin use, given the lack of information regarding long-term outcomes with oral agents. If insulin is needed, it is best to initiate it before the patient conceives, and then to stop other diabetes medications. We would not make any changes to her aspirin or metformin use.

Educating the patient and her family about prevention, recognition, and treatment of hypoglycemia is important to prevent and manage the increased risk of hypoglycemia with insulin therapy and in early pregnancy.¹ Consideration should be given to providing ketone strips as well as education on diabetic ketoacidosis prevention and detection.¹ If the patient conceives, begin prenatal care early to allow adequate planning for care of her disease and evaluation of the fetus. Because of the complexity of insulin management in pregnancy, the ADA recommends referral, if possible, to a center offering team-based care, including an obstetrician specialized in high-risk pregnancies, an endocrinologist, and a dietitian.¹

A 29-year-old nulliparous woman presents for a routine checkup. She has hypertension and type 2 diabetes mellitus. Her current medications are chlorpropamide 500 mg daily, metformin 500 mg twice a day, lisinopril 40 mg daily, simvastatin 40 mg daily, and aspirin 81 mg daily. Her body mass index is 37 kg/m² and her blood pressure is 130/80 mm Hg. Her hemoglobin A_1c level is 7.8% and her low-density lipoprotein cholesterol 90 mg/dL.

She is considering pregnancy. How would you counsel her?

DEFINING DIABETES IN PREGNANCY

Diabetes in pregnant women, both gestational and pregestational, is the most common medical complication associated with pregnancy.¹

• Gestational diabetes is defined as diabetes that is diagnosed during the second or third trimester of pregnancy and that is not clearly pregestational.²
• Pregestational diabetes exists before pregnancy and can be either type 1 or type 2.

Most cases of diabetes diagnosed during the first trimester reflect pregestational diabetes, as gestational diabetes occurs when insulin resistance increases in the later trimesters.

Type 1 diabetes involves autoimmune destruction of pancreatic islet cells, leading to insulin deficiency and the need for insulin therapy. Type 2 diabetes is characterized by insulin resistance rather than overall insulin deficiency. Type 2 diabetes tends to be associated with comorbidities such as obesity and hypertension, which are independent risk factors for adverse perinatal outcomes.^3,4

Gestational diabetes accounts for most cases of diabetes during pregnancy. Although both pregestational and gestational diabetes increase the risk of maternal and fetal complications, pregestational diabetes is associated with significantly greater risks.¹

IMPACT OF DIABETES ON THE MOTHER

Pregnancy increases the risk of maternal hypoglycemia, especially during the first trimester in patients with type 1 diabetes, as insulin sensitivity increases in early pregnancy.¹ Pregnant women with diabetes may also have an altered counterregulatory response and less hypoglycemic awareness.¹ Insulin resistance rises during the second and early third trimesters, increasing the risk of hyperglycemia in women with diabetes.¹

Glycemic control during pregnancy is usually easier to achieve in patients with type 2 diabetes than with type 1, but it may require much higher insulin doses.

Because pregnancy is inherently a ketogenic state, women with type 1 diabetes are at higher risk of diabetic ketoacidosis, particularly during the second and third trimesters.¹ There are reports of euglycemic diabetic ketoacidosis in pregnant women with either gestational or pregestational diabetes.⁵

Diabetes is associated with a risk of preeclampsia 4 times higher than in nondiabetic women.⁶ Other potential pregnancy-related complications include infections, polyhydram­nios, spontaneous abortion, and cesarean delivery.^1,7 The risk of pregnancy loss is similar in women with either type 1 or type 2 diabetes (2.6% and 3.7%, respectively), but the causes are different.⁸ Although preexisting diabetic complications such as retinopathy, nephropathy, and gastroparesis can be exacerbated during pregnancy,¹ only severe gastroparesis and advanced renal disease are considered relative contraindications to pregnancy.

IMPACT OF DIABETES ON THE FETUS

Fetal complications of maternal diabetes include embryopathy (fetal malformations) and fetopathy (overgrowth, ie, fetus large for gestational age, and increased risk of fetal death or distress). Maternal hyperglycemia is associated with diabetic embryopathy, resulting in major birth defects in 5% to 25% of pregnancies and spontaneous abortions in 15% to 20%.^9,10 There is a 2- to 6-fold increase in risk of congenital malformations.6

The most common diabetes-associated congenital malformations affect the cardiovascular system. Congenital heart disease includes tetralogy of Fallot, transposition of the great vessels, septal defects, and anomalous pulmonary venous return. Other relatively common defects involve the fetal central nervous system, spine, orofacial system, kidneys, urogenital system, gastrointestinal tract, and skeleton.¹¹

The risk of fetopathy is proportional to the degree of maternal hyperglycemia. Excess maternal glucose and fatty acid levels can lead to fetal hyperglycemia and overgrowth, which increases fetal oxygen requirements. Erythro­poietin levels rise, causing an increase in red cell mass, with subsequent hyperviscosity within the placenta and higher risk of fetal death.

Other complications include intrauterine growth restriction, prematurity, and preterm delivery. Fetal macrosomia (birth weight > 90th percentile or 4 kg, approximately 8 lb, 13 oz) occurs in 27% to 62% of children born to mothers with diabetes, a rate 10 times higher than in patients without diabetes. It contributes to shoulder dystocia (risk 2 to 4 times higher in diabetic pregnancies) and cesarean delivery.⁶ Infants born to mothers with diabetes also have higher risks of neonatal hypoglycemia, erythrocytosis, hyperbilirubinemia, hypocalcemia, respiratory distress, cardiomyopathy, and death, as well as for developing diabetes, obesity, and other adverse cardiometabolic outcomes later in life.¹¹

Nearly half of pregnancies in the general population are unplanned,¹⁵ so preconception diabetes assessment needs to be part of routine medical care for all reproductive-age women. Because most organogenesis occurs during the first 5 to 8 weeks after fertilization—potentially before a woman realizes she is pregnant—achieving optimal glycemic control before conception is necessary to improve pregnancy outcomes.¹

EVERY VISIT IS AN OPPORTUNITY

Every medical visit with a reproductive-age woman with diabetes is an opportunity for counseling about pregnancy. Topics that need to be discussed include the risks of unplanned pregnancy and of poor metabolic control, and the benefits of improved maternal and fetal outcomes with appropriate pregnancy planning and diabetes management.

Referral to a registered dietitian for individualized counseling about proper nutrition, particularly during pregnancy, has been associated with positive outcomes.¹⁶ Patients with diabetes and at high risk of pregnancy complications should be referred to a clinic that specializes in high-risk pregnancies.

Practitioners also should emphasize the importance of regular exercise and encourage patients to maintain or achieve a medically optimal weight before conception. Ideally, this would be a normal body mass index; however, this is not always possible.

In women who are planning pregnancy or are not on effective contraception, medications should be reviewed for potential teratogenicity. If needed, discuss alternative medications or switch to safer ones. However, these changes should not interrupt diabetes treatment.

In addition, ensure that the patient is up to date on age- and disease-appropriate preventive care (eg, immunizations, screening for sexually transmitted disease and malignancy). Counseling and intervention for use of tobacco, alcohol, and recreational drugs are also important. As with any preconception counseling, the patient (and her partner, if possible) should be advised to avoid travel to areas where Zika virus is endemic, and informed about the availability of expanded carrier genetic screening through her obstetric provider.

Finally, pregnant women with diabetes benefit from screening for diabetic complications including hypertension, retinopathy, cardiovascular disease, neuropathy, and nephropathy.

ASSESSING RISKS

Blood pressure

Chronic (preexisting) hypertension is defined as a systolic pressure 140 mm Hg or higher or a diastolic pressure 90 mm Hg or higher, or both, that antedates pregnancy or is present before the 20th week of pregnancy.³ Chronic hypertension has been reported in up to 5% of pregnant women and is associated with increased risk of preterm delivery, superimposed preeclampsia, low birth weight, and perinatal death.³

Reproductive-age women with diabetes and high blood pressure benefit from lifestyle and behavioral modifications.¹⁷ If drug therapy is needed, antihypertensive drugs that are safe for the fetus should be used. Treatment of mild or moderate hypertension during pregnancy reduces the risk of progression to severe hypertension but may not improve obstetric outcomes.

Diabetic retinopathy

Diabetic retinopathy can significantly worsen during pregnancy: the risk of progression is double that in the nonpregnant state.¹⁸ Women with diabetes who are contemplating pregnancy should have a comprehensive eye examination before conception, and any active proliferative retinopathy needs to be treated. These patients may require ophthalmologic monitoring and treatment during pregnancy. (Note: laser photocoagulation is not contraindicated during pregnancy.)

Cardiovascular disease

Cardiovascular physiology changes dramatically during pregnancy. Cardiovascular disease, especially when superimposed on diabetes, can increase the risk of maternal death. Thus, evaluation for cardiovascular risk factors as well as cardiovascular system integrity before conception is important. Listen for arterial bruits and murmurs, and assess peripheral pulses. Consideration should be given to obtaining a preconception resting electrocardiogram in women with diabetes who are over age 35 or who are suspected of having cardiovascular disease.¹⁶

Neurologic disorders

Peripheral neuropathy, the most common neurologic complication of diabetes, is associated with injury and infection.¹⁹

Autonomic neuropathy is associated with decreased cardiac responsiveness and orthostatic hypotension.¹⁹ Diabetic gastroparesis alone can precipitate serious complications during pregnancy, including extreme hypoglycemia and hyperglycemia, increased risk of diabetic ketoacidosis, weight loss, malnutrition, frequent hospitalizations, and increased requirement for parenteral nutrition.²⁰

Although diabetic neuropathy does not significantly worsen during pregnancy, women with preexisting gastroparesis should be counseled on the substantial risks associated with pregnancy. Screening for neuropathy should be part of all diabetic preconception examinations.

Renal complications

Pregnancy in women with diabetes and preexisting renal dysfunction increases their risk of accelerated progression of diabetic kidney disease.²¹ Preexisting renal dysfunction also increases the risk of pregnancy-related complications, such as stillbirth, intrauterine growth restriction, gestational hypertension, preeclampsia, and preterm delivery.^19,21,22 Further, the risk of pregnancy complications correlates directly with the severity of renal dysfunction.²²

Psychiatric disorders

Emotional wellness is essential for optimal diabetes management. It is important to recognize the emotional impact of diabetes in pregnant women and to conduct routine screening for depression, anxiety, stress, and eating disorders.¹⁶

Hemoglobin A_1c. The general consensus is to achieve the lowest hemoglobin A_1c level possible that does not increase the risk of hypoglycemia. The American Diabetes Association (ADA) recommends that, before attempting to conceive, women should lower their hemoglobin A_1c to below 6.5%.¹

Thyroid measures. Autoimmune thyroid disease is the most common autoimmune disorder associated with diabetes and has been reported in 35% to 40% of women with type 1 diabetes.²³ Recommendations are to check thyroid-stimulating hormone and thyroid peroxidase antibody levels before conception or early in pregnancy in all women with diabetes.^1,24 Overt hypothyroidism should be treated before conception, given that early fetal brain development depends on maternal thyroxine.

Renal function testing. Preconception assessment of renal function is important for counseling and risk stratification. This assessment should include serum creatinine level, estimated glomerular filtration rate, and urinary albumin excretion.²¹

Celiac screening. Because women with type 1 diabetes are more susceptible to autoimmune diseases, they should be screened for celiac disease before conception, with testing for  immunoglobulin A (IgA) and tissue transglutaminase antibodies, with or without IgA endomysial antibodies.^16,25,26 An estimated 6% of patients with type 1 diabetes have celiac disease vs 1% of the general population.²⁵ Celiac disease is 2 to 3 times more common in women, and asymptomatic people with type 1 diabetes are considered at increased risk for celiac disease.²⁶

The association between type 1 diabetes and celiac disease most likely relates to the overlap in human leukocyte antigens of the diseases. There is no established link between type 2 diabetes and celiac disease.²⁵

Undiagnosed celiac disease increases a woman’s risk of obstetric complications such as preterm birth, low birth weight, and stillbirth.²⁶ The most likely explanation for these adverse effects is nutrient malabsorption, which is characteristic of celiac disease. Adherence to a gluten-free diet before and during gestation may reduce the risk of preterm delivery by as much as 20%.²⁶

Vitamin B₁₂ level. Celiac disease interferes with the absorption of vitamin B₁₂-instrinsic factor in the ileum, which can lead to vitamin B₁₂ deficiency. Therefore, baseline vitamin B₁₂ levels should be checked before conception in women with celiac disease. Levels should also be checked in women taking metformin, which also decreases vitamin B₁₂ absorption. Of note, increased folate levels due to taking supplements can potentially mask vitamin B₁₂ deficiency.

MEDICATIONS TO REVIEW FOR PREGNANCY INTERACTIONS

Diabetic medications

Insulin is the first-line pharmacotherapy for pregnant patients with type 1, type 2, or gestational diabetes. Insulin does not cross the placenta to a measurable extent, and most insulin preparations have been classified as category B,¹ meaning no risks to the fetus have been found in humans.

Insulin dosing during pregnancy is not static. Beginning around mid-gestation, insulin requirements increase,^28,29 but after 32 weeks the need may decrease. These changes require practitioners to closely monitor blood glucose throughout pregnancy.

Both basal-bolus injections and continuous subcutaneous infusion are reasonable options during pregnancy.³⁰ However, the need for multiple and potentially painful insulin injections daily can lead to poor compliance. This inconvenience has led to studies using oral hypoglycemic medications instead of insulin for patients with gestational and type 2 diabetes.

Metformin is an oral biguanide that decreases hepatic gluconeogenesis and intestinal glucose absorption while peripherally increasing glucose utilization and uptake. Metformin does not pose a risk of hypoglycemia because its mechanism of action does not involve increased insulin production.⁷

Metformin does cross the placenta, resulting in umbilical cord blood levels higher than maternal levels. Nevertheless, studies support the efficacy and short-term safety of metformin use during a pregnancy complicated by gestational or type 2 diabetes.^7,31 Moreover, metformin has been associated with a lower risk of neonatal hypoglycemia and maternal weight gain than insulin.³² However, this agent should be used with caution, as long-term data are not yet available, and it may slightly increase the risk of premature delivery.

Glyburide is another oral hypoglycemic medication that has been used during pregnancy. This second-generation sulfonylurea enhances the release of insulin from the pancreas by binding beta islet cell ATP-calcium channel receptors. Compared with other sulfonylureas, glyburide has the lowest rate of maternal-to-fetal transfer, with umbilical cord plasma concentrations 70% of maternal levels.³³ Although some trials support the efficacy and short-term safety of glyburide treatment for gestational diabetes,³⁴ recent studies have associated glyburide use during pregnancy with a higher rate of neonatal hypoglycemia, neonatal respiratory distress, macrosomia, and neonatal intensive care unit admissions than insulin and metformin.^1,35

Patients treated with oral agents should be informed that these drugs cross the placenta, and that although no adverse effects on the fetus have been demonstrated, long-term safety data are lacking. In addition, oral agents are ineffective in type 1 diabetes and may be insufficient to overcome the insulin resistance in type 2 diabetes.

Antihypertensive drugs

All antihypertensive drugs cross the placenta, but several have an acceptable safety profile in pregnancy, including methyldopa, labeta­lol, clonidine, prazosin, and nifedipine. Hydralazine and labetalol are short-acting, come in intravenous formulations, and can be used for urgent blood pressure control during pregnancy. Diltiazem may be used for heart rate control during pregnancy, and it has been shown to lower blood pressure and proteinuria in pregnant patients with underlying renal disease.^36,37 The ADA recommends against chronic use of diuretics during pregnancy because of potential reductions in maternal plasma volume and uteroplacental perfusion.¹

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors are contraindicated during pregnancy because of the risk of fetal defects, particularly in the renal system.^21,38 Although there is evidence to question the association between first semester exposure and fetotoxicity,³⁹ we avoid these drugs during pregnancy and switch to a different agent in women planning pregnancy.

Other drugs

Statins are contraindicated in pregnancy because they interfere with the development of the fetal nervous system.²¹ Although preliminary data from a small study did not identify safety risks associated with pravastatin use after 12 weeks of gestation,⁴⁰ we recommend discontinuing statins in women attempting pregnancy.

Aspirin. The US Preventive Services Task Force41 recommends low-dose aspirin (81 mg/day) after 12 weeks of gestation for women with type 1 or type 2 diabetes, as well as those with renal disease or chronic hypertension, to prevent preeclampsia. Of note, higher doses need to be used with caution during pregnancy because fetal abnormalities have been reported, such as disruption of fetal vasculature (mesenteric vessels), gastroschisis, and small intestinal atresia.¹⁶

Folate supplementation (0.6–4 mg/day) is recommended in women with celiac disease to prevent neural tube defects in the offspring, and the US Preventive Services Task Force recommends 0.4 mg daily of folic acid supplementation for all women planning or capable of pregnancy.^42–44 Higher doses, ranging from 0.6 to 5 mg/day, have been proposed for patients with diabetes,¹³ and we recommend at least 1 mg for this group, based on data suggesting that higher doses further reduce the risk of neural tube defects.⁴³

Maternal diabetes, insulin therapy, and oral hypoglycemic agents are not contraindications to breastfeeding. The US Preventive Services Task Force recommends interventions by primary care physicians to promote and support breastfeeding.⁴⁵ Breastfeeding is encouraged based on various short- and long-term health benefits for both breastfed infants and breastfeeding mothers. Breastfeeding decreases a woman’s insulin requirements and increases the risk for hypoglycemia, especially in patients with insulin-dependent type 1 diabetes.¹

Additionally, insulin sensitivity increases immediately following delivery of the placenta.¹ Therefore, it is prudent to adjust insulin doses postpartum, especially while a patient is breastfeeding, or to suggest high-carbohydrate snacks before feeds.^9,29

Antihypertensive drugs considered safe to use during lactation include captopril, enalapril, quinapril, labetalol, propranolol, nifedipine, and hydralazine.^21,46 Methyldopa is not contraindicated, but it causes fatigue and worsened postpartum depression and should not be used as first-line therapy. Diuretics and ARBs are not recommended during lactation.²¹ Both metformin and glyburide enter breast milk in small enough amounts that they are not contraindicated during breastfeeding.¹⁶ The Lactmed database (www.toxnet.nlm.nih.gov) provides information about drugs and breastfeeding.

WHAT ABOUT CONTRACEPTIVES?

The ADA recommends contraception for women with diabetes because, just as in women without diabetes, the risks of unplanned pregnancy outweigh those of contraceptives.¹

We recommend low-dose combination estrogen-progestin oral contraceptives to normotensive women under age 35 with diabetes but without underlying microvascular disease. For women over age 35 or for those with microvascular disease, additional options include intrauterine devices or progestin implants. We prefer not to use injectable depot medroxyprogesterone acetate because of its side effects of insulin resistance and weight gain.⁴⁷

CASE DISCUSSION: NEXT STEPS

Our patient’s interest in family planning presents an opportunity for preconception counseling. We recommend a prenatal folic acid supplement, diet and regular exercise for weight loss, and screening tests including a comprehensive metabolic panel, hemoglobin A_1c, thyroid-stimulating hormone, and dilated eye examination. We make sure she is up to date on her indicated health maintenance (eg, immunizations, disease screening), and we review her medications for potential teratogens. She denies any recreational drug use. Also, she has no plans for long-distance travel.

Our counseling includes discussions of pregnancy risks associated with pregestational diabetes and suboptimal glycemic control. We encourage her to use effective contraception until she is “medically optimized” for pregnancy—ie, until her hemoglobin A_1c is lower than 6.5% and she has achieved a medically optimal weight. If feasible, a reduction of weight (7% or so) through lifestyle modification should be attempted, and if her hemoglobin A_1c remains elevated, adding insulin would be recommended.

Pregnant patients or patients contemplating pregnancy are usually motivated to modify their behavior, making this a good time to reinforce lifestyle modifications. Many patients benefit from individualized counseling by a registered dietitian to help achieve the recommended weight and glycemic control.

Our physical examination in this patient includes screening for micro- and macrovascular complications of diabetes, and the test results are negative. Patients with active proliferative retinopathy should be referred to an ophthalmologist for assessment and treatment.

We review her medications for potential teratogenic effects and stop her ACE inhibitor (lisinopril) and statin (simvastatin). We switch her from a first-generation sulfonylurea (chlorpropamide) to glyburide, a second-generation sulfonylurea. Second-generation sulfonylureas are considered more “fetus-friendly” because first-generation sulfonylureas cross the placenta more easily and can cause fetal hyperinsulinemia, leading to macrosomia and neonatal hypoglycemia.⁷

The management of diabetes during pregnancy leans toward insulin use, given the lack of information regarding long-term outcomes with oral agents. If insulin is needed, it is best to initiate it before the patient conceives, and then to stop other diabetes medications. We would not make any changes to her aspirin or metformin use.

Educating the patient and her family about prevention, recognition, and treatment of hypoglycemia is important to prevent and manage the increased risk of hypoglycemia with insulin therapy and in early pregnancy.¹ Consideration should be given to providing ketone strips as well as education on diabetic ketoacidosis prevention and detection.¹ If the patient conceives, begin prenatal care early to allow adequate planning for care of her disease and evaluation of the fetus. Because of the complexity of insulin management in pregnancy, the ADA recommends referral, if possible, to a center offering team-based care, including an obstetrician specialized in high-risk pregnancies, an endocrinologist, and a dietitian.¹

EXPERT COMMENTARY

GSM encompasses a constellation of symptoms involving the vulva, vagina, urethra, and bladder, and it can affect quality of life in more than half of women by 3 years past menopause.^1,2 Local estrogen creams, tablets, and rings are considered the gold standard treatment for GSM.³ The rising cost of many of these pharmacologic treatments has created headlines and concerns over price gouging for drugs used to treat female sexual dysfunction.⁴ Recent alternatives to local estrogens include vaginal moisturizers and lubricants, vaginal dehydroepiandrosterone (DHEA) suppositories, oral ospemifene, and vaginal laser therapy.

Laser treatment (with fractionated CO2, erbium, and hybrid lasers) activates heat shock proteins and tissue growth factors to stimulateneocollagenesis and neovascularization within the vaginal epithelium,but it is expensive and not covered by insurance because it is considered a cosmetic procedure.⁵Most evidence on laser therapy for GSM comes from prospective case series with small numbers and short-term follow-up with no comparison arms.^6,7 A recent trial by Cruz and colleagues, however, is notable because it is one of the first published studies that compared vaginal laser with vaginal estrogen alone and with a combination laser plus estrogen arm. We need level 1 comparative data from studies such as this to help us counsel the millions of US women with GSM.

Details of the study

In this single-site randomized, double-blind, placebo-controlled trial conducted in Brazil, postmenopausal women were assigned to 1 of 3 treatment groups (15 per group):

• CO2 laser (MonaLisa Touch, SmartXide 2 system; DEKA Laser; Florence, Italy): 2 treatments total, 1 month apart, plus placebo cream (laser arm)
• estriol cream (1 mg estriol 3 times per week for 20 weeks) plus sham laser (estriol arm)
• CO2 laser plus estriol cream 3 times per week (laser plus estriol combination arm).

The primary outcome included a change in visual analog scale (VAS) score for symptoms related to vulvovaginal atrophy (VVA), including dyspareunia, dryness, and burning (0–10 scale with 0 = no symptoms and 10 = most severe symptoms), and change in the objective Vaginal Health Index (VHI). Assessments were made at baseline and at 8 and 20 weeks. Participants were included if they were menopausal for at least 2 years and had at least 1 moderately bothersome VVA symptom (based on a VAS score of 4 or greater).

Secondary outcomes included the objective FSFI questionnaire evaluating desire, arousal, lubrication, orgasm, satisfaction, and pain. FSFI scores can range from 2 (severe dysfunction) to 36 (no dysfunction). A total FSFI score less than 26 was deemed equivalent to dysfunction. Cytologic smear evaluation using a vaginal maturation index was included in all 3 treatment arms. Sample size calculation of 45 patients (15 per arm) for this trial was based on a 3-point difference in the VHI.

The baseline characteristics for participants in each treatment arm were similar, except that participants in the vaginal estriol group were less symptomatic at baseline. This group had less burning at baseline based on the FSFI and less dyspareunia based on the VAS.

Laser treatment improved dryness, burning, and dyspareunia but caused more pain

All 3 treatment groups showed statistically significant improvement in vaginal dryness at 20 weeks, but only the laser-alone arm and the laser plus estriol arms showed improvement in dyspareunia and burning. The total FSFI scores improved significantly only in the laser plus estriol arm (TABLE). No difference in the vaginal maturation index was noted between groups; however, improved numbers of parabasal cells were found in participants in the laser treatment arms.

While participants in the laser treatment arms (alone and in combination with estriol) showed significant improvement in the VAS domains of dyspareunia and burning compared with those treated with estriol alone, there was a contradictory finding of more pain in both laser arms at 20 weeks compared with the estriol-alone group, based on the FSFI. The FSFI is a validated, objective quality-of-life questionnaire, and the finding of more pain with laser treatment is a concern.

Study strengths and weaknesses

This study is one of the first of its kind to compare laser therapy alone and in combination with local estriol to vaginal estriol alone for the treatment of GSM. The trial’s strength is in its design as a double-blind, placebo-controlled block randomized trial, which adds to the prospective cohort trials that generally show favorable outcomes for fractionated laser for the treatment of GSM.

The study’s weaknesses include its small sample size, single trial site, and short-term follow-up. Findings from this trial should be considered preliminary and not generalizable. Other weaknesses are the 3 of 45 participants lost to follow-up and the significant baseline differences among the women, with lower bothersome baseline VAS scores in the estriol arm.

Furthermore, this study was not powered for multiple comparisons, and conclusions favoring laser therapy cannot be overinflated. Lasers such as CO2 target the chromophore water, and indiscriminate use in severely dry vaginal epithelium may cause more pain or scarring. Longer-term follow-up is needed.

More research also is needed to develop guidelines related to pre-laser treatment to achieve optimal vaginal pH and ideal vaginal maturation, including, for example, vaginal priming with estrogen, DHEA, or other moisturizers.

This study also suggests the use of vaginal laser therapy as a drug delivery mechanism for combination therapy. Many vaginal estrogen treatments are expensive (despite prescription drug coverage), and laser treatments are very expensive (and not covered by insurance), so research to optimize outcomes and minimize patient expense is needed.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

GSM encompasses a constellation of symptoms involving the vulva, vagina, urethra, and bladder, and it can affect quality of life in more than half of women by 3 years past menopause.^1,2 Local estrogen creams, tablets, and rings are considered the gold standard treatment for GSM.³ The rising cost of many of these pharmacologic treatments has created headlines and concerns over price gouging for drugs used to treat female sexual dysfunction.⁴ Recent alternatives to local estrogens include vaginal moisturizers and lubricants, vaginal dehydroepiandrosterone (DHEA) suppositories, oral ospemifene, and vaginal laser therapy.

Laser treatment (with fractionated CO2, erbium, and hybrid lasers) activates heat shock proteins and tissue growth factors to stimulateneocollagenesis and neovascularization within the vaginal epithelium,but it is expensive and not covered by insurance because it is considered a cosmetic procedure.⁵Most evidence on laser therapy for GSM comes from prospective case series with small numbers and short-term follow-up with no comparison arms.^6,7 A recent trial by Cruz and colleagues, however, is notable because it is one of the first published studies that compared vaginal laser with vaginal estrogen alone and with a combination laser plus estrogen arm. We need level 1 comparative data from studies such as this to help us counsel the millions of US women with GSM.

Details of the study

In this single-site randomized, double-blind, placebo-controlled trial conducted in Brazil, postmenopausal women were assigned to 1 of 3 treatment groups (15 per group):

• CO2 laser (MonaLisa Touch, SmartXide 2 system; DEKA Laser; Florence, Italy): 2 treatments total, 1 month apart, plus placebo cream (laser arm)
• estriol cream (1 mg estriol 3 times per week for 20 weeks) plus sham laser (estriol arm)
• CO2 laser plus estriol cream 3 times per week (laser plus estriol combination arm).

The primary outcome included a change in visual analog scale (VAS) score for symptoms related to vulvovaginal atrophy (VVA), including dyspareunia, dryness, and burning (0–10 scale with 0 = no symptoms and 10 = most severe symptoms), and change in the objective Vaginal Health Index (VHI). Assessments were made at baseline and at 8 and 20 weeks. Participants were included if they were menopausal for at least 2 years and had at least 1 moderately bothersome VVA symptom (based on a VAS score of 4 or greater).

Secondary outcomes included the objective FSFI questionnaire evaluating desire, arousal, lubrication, orgasm, satisfaction, and pain. FSFI scores can range from 2 (severe dysfunction) to 36 (no dysfunction). A total FSFI score less than 26 was deemed equivalent to dysfunction. Cytologic smear evaluation using a vaginal maturation index was included in all 3 treatment arms. Sample size calculation of 45 patients (15 per arm) for this trial was based on a 3-point difference in the VHI.

The baseline characteristics for participants in each treatment arm were similar, except that participants in the vaginal estriol group were less symptomatic at baseline. This group had less burning at baseline based on the FSFI and less dyspareunia based on the VAS.

Laser treatment improved dryness, burning, and dyspareunia but caused more pain

All 3 treatment groups showed statistically significant improvement in vaginal dryness at 20 weeks, but only the laser-alone arm and the laser plus estriol arms showed improvement in dyspareunia and burning. The total FSFI scores improved significantly only in the laser plus estriol arm (TABLE). No difference in the vaginal maturation index was noted between groups; however, improved numbers of parabasal cells were found in participants in the laser treatment arms.

While participants in the laser treatment arms (alone and in combination with estriol) showed significant improvement in the VAS domains of dyspareunia and burning compared with those treated with estriol alone, there was a contradictory finding of more pain in both laser arms at 20 weeks compared with the estriol-alone group, based on the FSFI. The FSFI is a validated, objective quality-of-life questionnaire, and the finding of more pain with laser treatment is a concern.

Study strengths and weaknesses

This study is one of the first of its kind to compare laser therapy alone and in combination with local estriol to vaginal estriol alone for the treatment of GSM. The trial’s strength is in its design as a double-blind, placebo-controlled block randomized trial, which adds to the prospective cohort trials that generally show favorable outcomes for fractionated laser for the treatment of GSM.

The study’s weaknesses include its small sample size, single trial site, and short-term follow-up. Findings from this trial should be considered preliminary and not generalizable. Other weaknesses are the 3 of 45 participants lost to follow-up and the significant baseline differences among the women, with lower bothersome baseline VAS scores in the estriol arm.

Furthermore, this study was not powered for multiple comparisons, and conclusions favoring laser therapy cannot be overinflated. Lasers such as CO2 target the chromophore water, and indiscriminate use in severely dry vaginal epithelium may cause more pain or scarring. Longer-term follow-up is needed.

More research also is needed to develop guidelines related to pre-laser treatment to achieve optimal vaginal pH and ideal vaginal maturation, including, for example, vaginal priming with estrogen, DHEA, or other moisturizers.

This study also suggests the use of vaginal laser therapy as a drug delivery mechanism for combination therapy. Many vaginal estrogen treatments are expensive (despite prescription drug coverage), and laser treatments are very expensive (and not covered by insurance), so research to optimize outcomes and minimize patient expense is needed.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

GSM encompasses a constellation of symptoms involving the vulva, vagina, urethra, and bladder, and it can affect quality of life in more than half of women by 3 years past menopause.^1,2 Local estrogen creams, tablets, and rings are considered the gold standard treatment for GSM.³ The rising cost of many of these pharmacologic treatments has created headlines and concerns over price gouging for drugs used to treat female sexual dysfunction.⁴ Recent alternatives to local estrogens include vaginal moisturizers and lubricants, vaginal dehydroepiandrosterone (DHEA) suppositories, oral ospemifene, and vaginal laser therapy.

Laser treatment (with fractionated CO2, erbium, and hybrid lasers) activates heat shock proteins and tissue growth factors to stimulateneocollagenesis and neovascularization within the vaginal epithelium,but it is expensive and not covered by insurance because it is considered a cosmetic procedure.⁵Most evidence on laser therapy for GSM comes from prospective case series with small numbers and short-term follow-up with no comparison arms.^6,7 A recent trial by Cruz and colleagues, however, is notable because it is one of the first published studies that compared vaginal laser with vaginal estrogen alone and with a combination laser plus estrogen arm. We need level 1 comparative data from studies such as this to help us counsel the millions of US women with GSM.

Details of the study

In this single-site randomized, double-blind, placebo-controlled trial conducted in Brazil, postmenopausal women were assigned to 1 of 3 treatment groups (15 per group):

• CO2 laser (MonaLisa Touch, SmartXide 2 system; DEKA Laser; Florence, Italy): 2 treatments total, 1 month apart, plus placebo cream (laser arm)
• estriol cream (1 mg estriol 3 times per week for 20 weeks) plus sham laser (estriol arm)
• CO2 laser plus estriol cream 3 times per week (laser plus estriol combination arm).

The primary outcome included a change in visual analog scale (VAS) score for symptoms related to vulvovaginal atrophy (VVA), including dyspareunia, dryness, and burning (0–10 scale with 0 = no symptoms and 10 = most severe symptoms), and change in the objective Vaginal Health Index (VHI). Assessments were made at baseline and at 8 and 20 weeks. Participants were included if they were menopausal for at least 2 years and had at least 1 moderately bothersome VVA symptom (based on a VAS score of 4 or greater).

Secondary outcomes included the objective FSFI questionnaire evaluating desire, arousal, lubrication, orgasm, satisfaction, and pain. FSFI scores can range from 2 (severe dysfunction) to 36 (no dysfunction). A total FSFI score less than 26 was deemed equivalent to dysfunction. Cytologic smear evaluation using a vaginal maturation index was included in all 3 treatment arms. Sample size calculation of 45 patients (15 per arm) for this trial was based on a 3-point difference in the VHI.

The baseline characteristics for participants in each treatment arm were similar, except that participants in the vaginal estriol group were less symptomatic at baseline. This group had less burning at baseline based on the FSFI and less dyspareunia based on the VAS.

Laser treatment improved dryness, burning, and dyspareunia but caused more pain

All 3 treatment groups showed statistically significant improvement in vaginal dryness at 20 weeks, but only the laser-alone arm and the laser plus estriol arms showed improvement in dyspareunia and burning. The total FSFI scores improved significantly only in the laser plus estriol arm (TABLE). No difference in the vaginal maturation index was noted between groups; however, improved numbers of parabasal cells were found in participants in the laser treatment arms.

While participants in the laser treatment arms (alone and in combination with estriol) showed significant improvement in the VAS domains of dyspareunia and burning compared with those treated with estriol alone, there was a contradictory finding of more pain in both laser arms at 20 weeks compared with the estriol-alone group, based on the FSFI. The FSFI is a validated, objective quality-of-life questionnaire, and the finding of more pain with laser treatment is a concern.

Study strengths and weaknesses

This study is one of the first of its kind to compare laser therapy alone and in combination with local estriol to vaginal estriol alone for the treatment of GSM. The trial’s strength is in its design as a double-blind, placebo-controlled block randomized trial, which adds to the prospective cohort trials that generally show favorable outcomes for fractionated laser for the treatment of GSM.

The study’s weaknesses include its small sample size, single trial site, and short-term follow-up. Findings from this trial should be considered preliminary and not generalizable. Other weaknesses are the 3 of 45 participants lost to follow-up and the significant baseline differences among the women, with lower bothersome baseline VAS scores in the estriol arm.

Furthermore, this study was not powered for multiple comparisons, and conclusions favoring laser therapy cannot be overinflated. Lasers such as CO2 target the chromophore water, and indiscriminate use in severely dry vaginal epithelium may cause more pain or scarring. Longer-term follow-up is needed.

More research also is needed to develop guidelines related to pre-laser treatment to achieve optimal vaginal pH and ideal vaginal maturation, including, for example, vaginal priming with estrogen, DHEA, or other moisturizers.

This study also suggests the use of vaginal laser therapy as a drug delivery mechanism for combination therapy. Many vaginal estrogen treatments are expensive (despite prescription drug coverage), and laser treatments are very expensive (and not covered by insurance), so research to optimize outcomes and minimize patient expense is needed.

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