CHICAGO – When women with polycystic ovary syndrome (PCOS) took metformin during pregnancy, preterm births and late miscarriages were reduced, but researchers saw no effect on blood glucose levels or other diabetes-related maternal outcomes.

A Nordic study of pregnant women, dubbed PregMet 2, followed the course of 487 women with PCOS who were randomized to take 2,000 mg of metformin or placebo daily during pregnancy.

Kari Oakes/MDedge News

[email protected]

CHICAGO – When women with polycystic ovary syndrome (PCOS) took metformin during pregnancy, preterm births and late miscarriages were reduced, but researchers saw no effect on blood glucose levels or other diabetes-related maternal outcomes.

A Nordic study of pregnant women, dubbed PregMet 2, followed the course of 487 women with PCOS who were randomized to take 2,000 mg of metformin or placebo daily during pregnancy.

Kari Oakes/MDedge News

[email protected]

CHICAGO – When women with polycystic ovary syndrome (PCOS) took metformin during pregnancy, preterm births and late miscarriages were reduced, but researchers saw no effect on blood glucose levels or other diabetes-related maternal outcomes.

A Nordic study of pregnant women, dubbed PregMet 2, followed the course of 487 women with PCOS who were randomized to take 2,000 mg of metformin or placebo daily during pregnancy.

Kari Oakes/MDedge News

[email protected]

Background: The acuity of many patients recently discharged from an acute care facility is high. Some of these patients are being transferred to a SNF upon hospital discharge. Currently existing SNF care systems may not be prepared sufficiently for the challenges that arise with the admission of such patients to the SNFs after hospital discharge, resulting in readmissions.

Study design: Observational, retrospective cohort analysis.

Setting: Collaborative effort among a large, urban, acute care center, interdisciplinary clinical team, 124 community physicians, and eight SNFs.

Synopsis: In addition to standard care, the Enhanced Care Program (ECP) included a team of nurse practitioners participating in the care of SNF patients, a pharmacist-driven medication reconciliation at the time of transfer, and educational in-services for SNF nursing staff. Following introduction of the three ECP interventions, 30-day readmission rates were compared for both ECP and non-ECP patient groups. After adjustment for sociodemographic and clinical characteristics, ECP patients had 29% lower odds of being readmitted within 30 days (P less than .001). Multivariate analyses confirmed similar results. Major caveats include that this was a single-hospital study and that selection of the enrolled patients was not random, but rather, was determined by their primary care providers, potentially leading to some confounding.

Bottom line: For patients discharged to SNFs, an interdisciplinary care approach may reduce 30-day hospital readmissions.

Citation: Rosen BT et al. The Enhanced Care Program: Impact of a care transition program on 30-day hospital readmissions for patients discharged from an acute care facility to skilled nursing facilities. J Hosp Med. 2017 Oct 4:E1-E7. doi: 10.12788/jhm.2852

Dr. Burklin is assistant professor of medicine in the division of hospital medicine, Emory University, Atlanta.

Background: The acuity of many patients recently discharged from an acute care facility is high. Some of these patients are being transferred to a SNF upon hospital discharge. Currently existing SNF care systems may not be prepared sufficiently for the challenges that arise with the admission of such patients to the SNFs after hospital discharge, resulting in readmissions.

Study design: Observational, retrospective cohort analysis.

Setting: Collaborative effort among a large, urban, acute care center, interdisciplinary clinical team, 124 community physicians, and eight SNFs.

Synopsis: In addition to standard care, the Enhanced Care Program (ECP) included a team of nurse practitioners participating in the care of SNF patients, a pharmacist-driven medication reconciliation at the time of transfer, and educational in-services for SNF nursing staff. Following introduction of the three ECP interventions, 30-day readmission rates were compared for both ECP and non-ECP patient groups. After adjustment for sociodemographic and clinical characteristics, ECP patients had 29% lower odds of being readmitted within 30 days (P less than .001). Multivariate analyses confirmed similar results. Major caveats include that this was a single-hospital study and that selection of the enrolled patients was not random, but rather, was determined by their primary care providers, potentially leading to some confounding.

Bottom line: For patients discharged to SNFs, an interdisciplinary care approach may reduce 30-day hospital readmissions.

Citation: Rosen BT et al. The Enhanced Care Program: Impact of a care transition program on 30-day hospital readmissions for patients discharged from an acute care facility to skilled nursing facilities. J Hosp Med. 2017 Oct 4:E1-E7. doi: 10.12788/jhm.2852

Dr. Burklin is assistant professor of medicine in the division of hospital medicine, Emory University, Atlanta.

Background: The acuity of many patients recently discharged from an acute care facility is high. Some of these patients are being transferred to a SNF upon hospital discharge. Currently existing SNF care systems may not be prepared sufficiently for the challenges that arise with the admission of such patients to the SNFs after hospital discharge, resulting in readmissions.

Study design: Observational, retrospective cohort analysis.

Setting: Collaborative effort among a large, urban, acute care center, interdisciplinary clinical team, 124 community physicians, and eight SNFs.

Synopsis: In addition to standard care, the Enhanced Care Program (ECP) included a team of nurse practitioners participating in the care of SNF patients, a pharmacist-driven medication reconciliation at the time of transfer, and educational in-services for SNF nursing staff. Following introduction of the three ECP interventions, 30-day readmission rates were compared for both ECP and non-ECP patient groups. After adjustment for sociodemographic and clinical characteristics, ECP patients had 29% lower odds of being readmitted within 30 days (P less than .001). Multivariate analyses confirmed similar results. Major caveats include that this was a single-hospital study and that selection of the enrolled patients was not random, but rather, was determined by their primary care providers, potentially leading to some confounding.

Bottom line: For patients discharged to SNFs, an interdisciplinary care approach may reduce 30-day hospital readmissions.

Citation: Rosen BT et al. The Enhanced Care Program: Impact of a care transition program on 30-day hospital readmissions for patients discharged from an acute care facility to skilled nursing facilities. J Hosp Med. 2017 Oct 4:E1-E7. doi: 10.12788/jhm.2852

Dr. Burklin is assistant professor of medicine in the division of hospital medicine, Emory University, Atlanta.

The prevalence of gallstones is approximately 10% to 15% of the adult US population.^1,2 Most cases are asymptomatic, as gallstones are usually discovered incidentally during routine imaging for other abdominal conditions, and only about 20% of patients with asymptomatic gallstones develop clinically significant complications.^2,3

Nevertheless, gallstones carry significant healthcare costs. In 2004, the median inpatient cost for any gallstone-related disease was $11,584, with an overall annual cost of $6.2 billion.^4,5

Laparoscopic cholecystectomy is the standard treatment for symptomatic cholelithiasis. For asymptomatic cholelithasis, the usual approach is expectant management (“watch and wait”), but prophylactic cholecystectomy may be an option in certain patients at high risk.

CHEMICAL COMPOSITION

Gallstones can be classified into 2 main categories based on their predominant chemical composition: cholesterol or pigment.

Cholesterol gallstones

About 75% of gallstones are composed of cholesterol.^3,4 In the past, this type of stone was thought to be caused by gallbladder inflammation, bile stasis, and absorption of bile salts from damaged mucosa. However, it is now known that cholesterol gallstones are the result of biliary supersaturation caused by cholesterol hypersecretion into the gallbladder, gallbladder hypomotility, accelerated cholesterol nucleation and crystallization, and mucin gel accumulation.

Pigment gallstones

Black pigment gallstones account for 10% to 15% of all gallstones.⁶ They are caused by chronic hemolysis in association with supersaturation of bile with calcium hydrogen bilirubinate, along with deposition of calcium carbonate, phosphate, and inorganic salts.⁷

Brown pigment stones, accounting for 5% to 10% of all gallstones,⁶ are caused by infection in the obstructed bile ducts, where bacteria that produce beta-glucuronidase, phospholipase, and slime contribute to formation of the stone.^8,9

RISK FACTORS FOR GALLSTONES

Age. After age 40, the risk increases dramatically, with an incidence 4 times higher for those ages 40 to 69 than in younger people.¹⁰

Female sex. Women of reproductive age are 4 times more likely to develop gallstones than men, but this gap narrows after menopause.¹¹ The higher risk is attributed to female sex hormones, pregnancy, and oral contraceptive use. Estrogen decreases secretion of bile salts and increases secretion of cholesterol into the gallbladder, which leads to cholesterol supersaturation. Progesterone acts synergistically by causing hypomobility of the gallbladder, which in turn leads to bile stasis.^12,13

Ethnicity. The risk is higher in Mexican Americans and Native Americans than in other ethnic groups.¹⁴

Rapid weight loss, such as after bariatric surgery, occurs from decreased caloric intake and promotes bile stasis, while lipolysis increases cholesterol mobilization and secretion into the gallbladder. This creates an environment conducive to bile supersaturation with cholesterol, leading to gallstone formation.

Chronic hemolytic disorders carry an increased risk of developing calcium bilirubinate stones due to increased excretion of bilirubin during hemolysis.

Obesity and diabetes mellitus are both attributed to insulin resistance. Obesity also increases bile stasis and cholesterol saturation.

 

 

CLINICAL PRESENTATION OF GALLSTONES (CHOLELITHIASIS)

Most patients with gallstones (cholelithiasis) experience no symptoms. Their gallstones are often discovered incidentally during imaging tests for unrelated or unexplained abdominal symptoms. Most patients with asymptomatic gallstones remain symptom-free, while about 20% develop gallstone-related symptoms.^2,3

Abdominal pain is the most common symptom. The phrase biliary colic—suggesting pain that is fluctuating in nature—appears ubiquitously in the medical literature, but it does not correctly characterize the pain associated with gallstones.

Most patients with gallstone symptoms describe a constant and often severe pain in the right upper abdomen, epigastrium, or both, often persisting for 30 to 120 minutes. Symptoms are frequently reported in the epigastrium when only visceral pain fibers are stimulated due to gallbladder distention. This is usually called midline pain; however, pain occurs in the back and right shoulder in up to 60% of patients, with involvement of somatic fibers.^15,16 Gallstone pain is not relieved by change of position or passage of stool or gas.

Onset of symptoms more than an hour after eating or in the late evening or at night also  very strongly suggests biliary pain. Patients with a history of biliary pain are more likely to experience it again, with a 69% chance of developing recurrent pain within 2 years.¹⁷

GALLSTONE-RELATED COMPLICATIONS

Acute gallbladder inflammation (cholecystitis)

Gallbladder inflammation (cholecystitis) is the most common complication, occurring in up to 10% of symptomatic cases. Many patients with acute cholecystitis present with right upper quadrant pain that may be accompanied by anorexia, nausea, or vomiting. Inspiratory arrest on deep palpation of the right upper quadrant (Murphy sign) has a specificity of 79% to 96% for acute cholecystitis.²⁰ Markers of systemic inflammation such as fever, elevated white blood cell count, and elevated C-reactive protein are highly suggestive of acute cholecystitis.^20,21

Bile duct stones (choledocholithiasis)

Bile duct stones (choledocholithiasis) are detected in 3.4% to 12% of patients with gallstones.^22,23 Most stones in the common bile duct migrate there from the gallbladder via the cystic duct. Less commonly, primary duct stones form in the duct due to biliary stasis. Removing the gallbladder does not completely eliminate the risk of bile duct stones, as stones can remain or recur after surgery.

Bile duct stones can obstruct the common bile duct, which disrupts normal bile flow and leads to jaundice. Other symptoms may include pruritus, right upper quadrant pain, nausea, and vomiting. Serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase (ALT), and alkaline phosphatase are usually high.²⁴

Acute bacterial infection (cholangitis)

Acute bacterial infection of the biliary system (cholangitis) is usually associated with obstruction of the common bile duct. Common symptoms of acute cholangitis include right upper quadrant pain, fever, and jaundice (Charcot triad), and these are present in about 50% to 75% of cases.²¹ In severe cases, patients can develop altered mental status and septicemic shock in addition to the Charcot triad, a condition called the Reynold pentad. White blood cell counts and serum levels of C-reactive protein, bilirubin, aminotransferases, and alkaline phosphatase are usually elevated.²¹

Pancreatitis

Approximately 4% to 8% of patients with gallstones develop inflammation of the pancreas (pancreatitis).²⁵ The diagnosis of acute pancreatitis requires at least 2 of the following:^26,27

• Abdominal pain (typically epigastric, often radiating to the back)
• Amylase or lipase levels at least 3 times above the normal limit
• Imaging findings that suggest acute pancreatitis.

Gallstone-related pancreatitis should be considered if the ALT level is greater than 150 U/mL, which has a 97% specificity for gallstone-related pancreatitis.²⁸

 

 

ABDOMINAL ULTRASONOGRAPHY FOR DIAGNOSIS

Transabdominal ultrasonography, with a sensitivity of 84% to 89% and a specificity of up to 99%, is the test of choice for detecting gallstones.²⁹ The characteristic findings of acute cholecystitis on ultrasonography include enlargement of the gallbladder, thickening of the gallbladder wall, presence of pericholecystic fluid, and tenderness elicited by the ultrasound probe over the gallbladder (sonographic Murphy sign).

Scintigraphy as a second test

Acute cholecystitis is primarily a clinical diagnosis and typically does not require additional imaging beyond ultrasonography. When there is discordance between clinical and ultrasonographic findings, the most accurate second imaging test is scintigraphy of the biliary tract, usually performed with technetium-labeled hydroxy iminodiacetic acid. Given intravenously, the radionuclide is rapidly taken up by the liver and then secreted into the bile. In acute cholecystitis, the cystic duct is functionally occluded and the isotope does not enter the gallbladder, creating an imaging void compared with a normal appearance.

Scintigraphy is more sensitive than abdominal ultrasonography, with a sensitivity of up to 97% vs 81% to 88%, respectively.^29,30 The tests have about equal specificity.

Even though scintigraphy is more sensitive, abdominal ultrasonography is often the initial test for patients with suspected acute cholecystitis because it is more widely available, takes less time, does not involve radiation exposure, and can assess for the presence or absence of gallstones and dilation of the intra- and extrahepatic bile ducts.

Looking for stones in the common bile duct

When acute cholangitis due to choledocholithiasis is suspected, abdominal ultrasonography is a prudent initial test to look for gallstones or biliary dilation suggesting obstruction by stones in the common bile duct. Abdominal ultrasonography has only a 22% to 55% sensitivity for visualizing stones in the common bile duct, but it has a 77% to 87% sensitivity for detecting common bile duct dilation, a surrogate marker of stones.³¹

The normal bile duct diameter ranges from 3 to 6 mm, although mild dilation is often seen in older patients or after cholecystectomy or Roux-en-Y gastric bypass surgery.^32,33 Bile duct dilation of up to 10 mm can be considered normal in patients after cholecystectomy.³⁴ A normal-appearing bile duct on ultrasonography has a negative predictive value of 95% for excluding common bile duct stones.³¹

Endoscopic ultrasonography (EUS), magnetic resonance cholangiopancreatography (MRCP), and endoscopic retrograde cholangiopancreatography (ERCP) have similar sensitivity (89%–94%, 85%–92%, and 89%–93%, respectively) and specificity (94%–95%, 93%–97%, and 100%, respectively) for detecting common bile duct stones.^35–37 EUS is superior to MRCP in detecting stones smaller than 6 mm.³⁸

ERCP should be reserved for managing rather than diagnosing common bile duct stones because of the risk of pancreatitis and perforation. Patients undergoing cholecystectomy who are suspected of having choledocholithiasis may undergo intraoperative cholangiography or laparoscopic common bile duct ultrasonography.

WATCH AND WAIT, OR INTERVENE?

Asymptomatic gallstones

Standard treatment for these patients is expectant management. Cholecystectomy is not recommended for patients with asymptomatic gallstones.⁴⁷ Nevertheless, some patients may benefit from prophylactic cholecystectomy. We and others⁴⁸ suggest considering cholecystectomy in the following patients.

Patients with chronic hemolytic anemia (including children with sickle cell anemia and spherocytosis). These patients have a higher risk of developing calcium bilirubinate stones, and cholecystectomy has improved outcomes.⁴⁹ It should be noted that most of these data come from pediatric populations and have been extrapolated to adults.

Native Americans, who have a higher risk of gallbladder cancer if they have gallstones.^2,50

Conversely, calcification of the gallbladder wall (“porcelain gallbladder”) is no longer considered an absolute indication for cholecystectomy. This condition was thought to be associated with a high rate of gallbladder carcinoma, but analyses of larger, more recent data sets found much smaller risks.^51,52 Further, cholecystectomy in these patients was found to be associated with high rates of postoperative complications. Thus, prophylactic cholecystectomy is no longer recommended in asymptomatic cases of porcelain gallbladder.

In addition, concomitant cholecystectomy in patients undergoing bariatric surgery is no longer considered the therapeutic standard. Historically, cholecystectomy was performed in these patients because of the increased risk of gallstones associated with rapid weight loss after surgery. However, research now weighs against concomitant cholecystectomy with bariatric surgery and most other abdominal surgeries for asymptomatic gallstones.⁵³

 

 

Laparoscopic surgery for symptomatic gallstones

Based on information in reference 48.

For patients experiencing acute cholecystitis, laparoscopic cholecystectomy within 72 hours is recommended.⁴⁸ There were safety concerns regarding higher rates of morbidity and conversion from laparoscopic to open cholecystectomy in patients who underwent surgery before the acute cholecystitis episode had settled. However, a large meta-analysis found no significant difference between early and delayed laparoscopic cholecystectomy in bile duct injury or conversion rates.⁵⁴ Further, early cholecystectomy—defined as within 1 week of symptom onset—has been found to reduce gallstone-related complications, shorten hospital stays, and lower costs.^55–57 If the patient cannot undergo surgery, percutaneous cholecystotomy or novel endoscopic gallbladder drainage interventions can be used.

Reprinted from ASGE Standards of Practice Committee; Maple JT, Ben-Menachem T, Anderson MA, et al. The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointest Endoscp 2010; 71:1–9 with permission from Elsevier.

Several variables predict the presence of bile duct stones in patients who have symptoms (Table 4). Based on these predictors, the ASGE classifies the probabilities as low (< 10%), intermediate (10% to 50%), and high (> 50%)³¹:

• 
  Low-risk patients require no further evaluation of the common bile duct
• High-risk patients should undergo preoperative ERCP and stone extraction if needed
• Intermediate-risk patients should undergo preoperative imaging with EUS or MRCP or intraoperative bile duct evaluation, depending on the availability, costs, and local expertise.

Patients with associated cholangitis should be given intravenous fluids and broad-spectrum antibiotics. Biliary decompression should be done as early as possible to decrease the risk of morbidity and mortality. For acute cholangitis, ERCP is the treatment of choice.²⁵

Patients with acute gallstone pancreatitis should receive conservative management with intravenous isotonic solutions and pain control, followed by laparoscopic cholecystectomy.⁴⁸

The timing of laparoscopic cholecystectomy in acute gallstone pancreatitis has been debated. Studies conducted during the era of open cholecystectomy reported similar or worse outcomes if cholecystectomy was done sooner rather than later.

However, in 1999, Uhl et al⁵⁸ reported that 48 of 77 patients admitted with acute gallstone pancreatitis were able to undergo laparoscopic cholecystectomy during the same admission. Success rates were 85% (30 of 35 patients) in those with mild disease and 62% (8 of 13 patients) in those with severe disease. They concluded laparoscopic cholecystectomy could be safely performed within 7 days in patients with mild disease, whereas in severe disease at least 3 weeks should elapse because of the risk of infection.

In a randomized trial published in 2010, Aboulian et al⁵⁹ reported that hospital length of stay (the primary end point) was shorter in 25 patients who underwent laparoscopic cholecystectomy early (within 48 hours of admission) than in 25 patients who underwent surgery after abdominal pain had resolved and laboratory enzymes showed a normalizing trend, 3.5 vs 5.8 days (P = .0016). Rates of perioperative complications and need for conversion to open surgery were similar between the 2 groups.

If there is associated cholangitis, patients should also be given broad-spectrum antibiotics and should undergo ERCP within 24 hours of admission.^25–27

SUMMARY

Gallstones are common in US adults. Abdominal ultrasonography is the diagnostic imaging test of choice to detect gallbladder stones and assess for findings suggestive of acute cholecystitis and dilation of the common bile duct. Fortunately, most gallstones are asymptomatic and can usually be managed expectantly. In patients who have symptoms or have gallstone complications, laparoscopic cholecystectomy is the standard of care.

The prevalence of gallstones is approximately 10% to 15% of the adult US population.^1,2 Most cases are asymptomatic, as gallstones are usually discovered incidentally during routine imaging for other abdominal conditions, and only about 20% of patients with asymptomatic gallstones develop clinically significant complications.^2,3

Nevertheless, gallstones carry significant healthcare costs. In 2004, the median inpatient cost for any gallstone-related disease was $11,584, with an overall annual cost of $6.2 billion.^4,5

Laparoscopic cholecystectomy is the standard treatment for symptomatic cholelithiasis. For asymptomatic cholelithasis, the usual approach is expectant management (“watch and wait”), but prophylactic cholecystectomy may be an option in certain patients at high risk.

CHEMICAL COMPOSITION

Gallstones can be classified into 2 main categories based on their predominant chemical composition: cholesterol or pigment.

Cholesterol gallstones

About 75% of gallstones are composed of cholesterol.^3,4 In the past, this type of stone was thought to be caused by gallbladder inflammation, bile stasis, and absorption of bile salts from damaged mucosa. However, it is now known that cholesterol gallstones are the result of biliary supersaturation caused by cholesterol hypersecretion into the gallbladder, gallbladder hypomotility, accelerated cholesterol nucleation and crystallization, and mucin gel accumulation.

Pigment gallstones

Black pigment gallstones account for 10% to 15% of all gallstones.⁶ They are caused by chronic hemolysis in association with supersaturation of bile with calcium hydrogen bilirubinate, along with deposition of calcium carbonate, phosphate, and inorganic salts.⁷

Brown pigment stones, accounting for 5% to 10% of all gallstones,⁶ are caused by infection in the obstructed bile ducts, where bacteria that produce beta-glucuronidase, phospholipase, and slime contribute to formation of the stone.^8,9

RISK FACTORS FOR GALLSTONES

Age. After age 40, the risk increases dramatically, with an incidence 4 times higher for those ages 40 to 69 than in younger people.¹⁰

Female sex. Women of reproductive age are 4 times more likely to develop gallstones than men, but this gap narrows after menopause.¹¹ The higher risk is attributed to female sex hormones, pregnancy, and oral contraceptive use. Estrogen decreases secretion of bile salts and increases secretion of cholesterol into the gallbladder, which leads to cholesterol supersaturation. Progesterone acts synergistically by causing hypomobility of the gallbladder, which in turn leads to bile stasis.^12,13

Ethnicity. The risk is higher in Mexican Americans and Native Americans than in other ethnic groups.¹⁴

Rapid weight loss, such as after bariatric surgery, occurs from decreased caloric intake and promotes bile stasis, while lipolysis increases cholesterol mobilization and secretion into the gallbladder. This creates an environment conducive to bile supersaturation with cholesterol, leading to gallstone formation.

Chronic hemolytic disorders carry an increased risk of developing calcium bilirubinate stones due to increased excretion of bilirubin during hemolysis.

Obesity and diabetes mellitus are both attributed to insulin resistance. Obesity also increases bile stasis and cholesterol saturation.

 

 

CLINICAL PRESENTATION OF GALLSTONES (CHOLELITHIASIS)

Most patients with gallstones (cholelithiasis) experience no symptoms. Their gallstones are often discovered incidentally during imaging tests for unrelated or unexplained abdominal symptoms. Most patients with asymptomatic gallstones remain symptom-free, while about 20% develop gallstone-related symptoms.^2,3

Abdominal pain is the most common symptom. The phrase biliary colic—suggesting pain that is fluctuating in nature—appears ubiquitously in the medical literature, but it does not correctly characterize the pain associated with gallstones.

Most patients with gallstone symptoms describe a constant and often severe pain in the right upper abdomen, epigastrium, or both, often persisting for 30 to 120 minutes. Symptoms are frequently reported in the epigastrium when only visceral pain fibers are stimulated due to gallbladder distention. This is usually called midline pain; however, pain occurs in the back and right shoulder in up to 60% of patients, with involvement of somatic fibers.^15,16 Gallstone pain is not relieved by change of position or passage of stool or gas.

Onset of symptoms more than an hour after eating or in the late evening or at night also  very strongly suggests biliary pain. Patients with a history of biliary pain are more likely to experience it again, with a 69% chance of developing recurrent pain within 2 years.¹⁷

GALLSTONE-RELATED COMPLICATIONS

Acute gallbladder inflammation (cholecystitis)

Gallbladder inflammation (cholecystitis) is the most common complication, occurring in up to 10% of symptomatic cases. Many patients with acute cholecystitis present with right upper quadrant pain that may be accompanied by anorexia, nausea, or vomiting. Inspiratory arrest on deep palpation of the right upper quadrant (Murphy sign) has a specificity of 79% to 96% for acute cholecystitis.²⁰ Markers of systemic inflammation such as fever, elevated white blood cell count, and elevated C-reactive protein are highly suggestive of acute cholecystitis.^20,21

Bile duct stones (choledocholithiasis)

Bile duct stones (choledocholithiasis) are detected in 3.4% to 12% of patients with gallstones.^22,23 Most stones in the common bile duct migrate there from the gallbladder via the cystic duct. Less commonly, primary duct stones form in the duct due to biliary stasis. Removing the gallbladder does not completely eliminate the risk of bile duct stones, as stones can remain or recur after surgery.

Bile duct stones can obstruct the common bile duct, which disrupts normal bile flow and leads to jaundice. Other symptoms may include pruritus, right upper quadrant pain, nausea, and vomiting. Serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase (ALT), and alkaline phosphatase are usually high.²⁴

Acute bacterial infection (cholangitis)

Acute bacterial infection of the biliary system (cholangitis) is usually associated with obstruction of the common bile duct. Common symptoms of acute cholangitis include right upper quadrant pain, fever, and jaundice (Charcot triad), and these are present in about 50% to 75% of cases.²¹ In severe cases, patients can develop altered mental status and septicemic shock in addition to the Charcot triad, a condition called the Reynold pentad. White blood cell counts and serum levels of C-reactive protein, bilirubin, aminotransferases, and alkaline phosphatase are usually elevated.²¹

Pancreatitis

Approximately 4% to 8% of patients with gallstones develop inflammation of the pancreas (pancreatitis).²⁵ The diagnosis of acute pancreatitis requires at least 2 of the following:^26,27

• Abdominal pain (typically epigastric, often radiating to the back)
• Amylase or lipase levels at least 3 times above the normal limit
• Imaging findings that suggest acute pancreatitis.

Gallstone-related pancreatitis should be considered if the ALT level is greater than 150 U/mL, which has a 97% specificity for gallstone-related pancreatitis.²⁸

 

 

ABDOMINAL ULTRASONOGRAPHY FOR DIAGNOSIS

Transabdominal ultrasonography, with a sensitivity of 84% to 89% and a specificity of up to 99%, is the test of choice for detecting gallstones.²⁹ The characteristic findings of acute cholecystitis on ultrasonography include enlargement of the gallbladder, thickening of the gallbladder wall, presence of pericholecystic fluid, and tenderness elicited by the ultrasound probe over the gallbladder (sonographic Murphy sign).

Scintigraphy as a second test

Acute cholecystitis is primarily a clinical diagnosis and typically does not require additional imaging beyond ultrasonography. When there is discordance between clinical and ultrasonographic findings, the most accurate second imaging test is scintigraphy of the biliary tract, usually performed with technetium-labeled hydroxy iminodiacetic acid. Given intravenously, the radionuclide is rapidly taken up by the liver and then secreted into the bile. In acute cholecystitis, the cystic duct is functionally occluded and the isotope does not enter the gallbladder, creating an imaging void compared with a normal appearance.

Scintigraphy is more sensitive than abdominal ultrasonography, with a sensitivity of up to 97% vs 81% to 88%, respectively.^29,30 The tests have about equal specificity.

Even though scintigraphy is more sensitive, abdominal ultrasonography is often the initial test for patients with suspected acute cholecystitis because it is more widely available, takes less time, does not involve radiation exposure, and can assess for the presence or absence of gallstones and dilation of the intra- and extrahepatic bile ducts.

Looking for stones in the common bile duct

When acute cholangitis due to choledocholithiasis is suspected, abdominal ultrasonography is a prudent initial test to look for gallstones or biliary dilation suggesting obstruction by stones in the common bile duct. Abdominal ultrasonography has only a 22% to 55% sensitivity for visualizing stones in the common bile duct, but it has a 77% to 87% sensitivity for detecting common bile duct dilation, a surrogate marker of stones.³¹

The normal bile duct diameter ranges from 3 to 6 mm, although mild dilation is often seen in older patients or after cholecystectomy or Roux-en-Y gastric bypass surgery.^32,33 Bile duct dilation of up to 10 mm can be considered normal in patients after cholecystectomy.³⁴ A normal-appearing bile duct on ultrasonography has a negative predictive value of 95% for excluding common bile duct stones.³¹

Endoscopic ultrasonography (EUS), magnetic resonance cholangiopancreatography (MRCP), and endoscopic retrograde cholangiopancreatography (ERCP) have similar sensitivity (89%–94%, 85%–92%, and 89%–93%, respectively) and specificity (94%–95%, 93%–97%, and 100%, respectively) for detecting common bile duct stones.^35–37 EUS is superior to MRCP in detecting stones smaller than 6 mm.³⁸

ERCP should be reserved for managing rather than diagnosing common bile duct stones because of the risk of pancreatitis and perforation. Patients undergoing cholecystectomy who are suspected of having choledocholithiasis may undergo intraoperative cholangiography or laparoscopic common bile duct ultrasonography.

WATCH AND WAIT, OR INTERVENE?

Asymptomatic gallstones

Standard treatment for these patients is expectant management. Cholecystectomy is not recommended for patients with asymptomatic gallstones.⁴⁷ Nevertheless, some patients may benefit from prophylactic cholecystectomy. We and others⁴⁸ suggest considering cholecystectomy in the following patients.

Patients with chronic hemolytic anemia (including children with sickle cell anemia and spherocytosis). These patients have a higher risk of developing calcium bilirubinate stones, and cholecystectomy has improved outcomes.⁴⁹ It should be noted that most of these data come from pediatric populations and have been extrapolated to adults.

Native Americans, who have a higher risk of gallbladder cancer if they have gallstones.^2,50

Conversely, calcification of the gallbladder wall (“porcelain gallbladder”) is no longer considered an absolute indication for cholecystectomy. This condition was thought to be associated with a high rate of gallbladder carcinoma, but analyses of larger, more recent data sets found much smaller risks.^51,52 Further, cholecystectomy in these patients was found to be associated with high rates of postoperative complications. Thus, prophylactic cholecystectomy is no longer recommended in asymptomatic cases of porcelain gallbladder.

In addition, concomitant cholecystectomy in patients undergoing bariatric surgery is no longer considered the therapeutic standard. Historically, cholecystectomy was performed in these patients because of the increased risk of gallstones associated with rapid weight loss after surgery. However, research now weighs against concomitant cholecystectomy with bariatric surgery and most other abdominal surgeries for asymptomatic gallstones.⁵³

 

 

Laparoscopic surgery for symptomatic gallstones

Based on information in reference 48.

For patients experiencing acute cholecystitis, laparoscopic cholecystectomy within 72 hours is recommended.⁴⁸ There were safety concerns regarding higher rates of morbidity and conversion from laparoscopic to open cholecystectomy in patients who underwent surgery before the acute cholecystitis episode had settled. However, a large meta-analysis found no significant difference between early and delayed laparoscopic cholecystectomy in bile duct injury or conversion rates.⁵⁴ Further, early cholecystectomy—defined as within 1 week of symptom onset—has been found to reduce gallstone-related complications, shorten hospital stays, and lower costs.^55–57 If the patient cannot undergo surgery, percutaneous cholecystotomy or novel endoscopic gallbladder drainage interventions can be used.

Reprinted from ASGE Standards of Practice Committee; Maple JT, Ben-Menachem T, Anderson MA, et al. The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointest Endoscp 2010; 71:1–9 with permission from Elsevier.

Several variables predict the presence of bile duct stones in patients who have symptoms (Table 4). Based on these predictors, the ASGE classifies the probabilities as low (< 10%), intermediate (10% to 50%), and high (> 50%)³¹:

• 
  Low-risk patients require no further evaluation of the common bile duct
• High-risk patients should undergo preoperative ERCP and stone extraction if needed
• Intermediate-risk patients should undergo preoperative imaging with EUS or MRCP or intraoperative bile duct evaluation, depending on the availability, costs, and local expertise.

Patients with associated cholangitis should be given intravenous fluids and broad-spectrum antibiotics. Biliary decompression should be done as early as possible to decrease the risk of morbidity and mortality. For acute cholangitis, ERCP is the treatment of choice.²⁵

Patients with acute gallstone pancreatitis should receive conservative management with intravenous isotonic solutions and pain control, followed by laparoscopic cholecystectomy.⁴⁸

The timing of laparoscopic cholecystectomy in acute gallstone pancreatitis has been debated. Studies conducted during the era of open cholecystectomy reported similar or worse outcomes if cholecystectomy was done sooner rather than later.

However, in 1999, Uhl et al⁵⁸ reported that 48 of 77 patients admitted with acute gallstone pancreatitis were able to undergo laparoscopic cholecystectomy during the same admission. Success rates were 85% (30 of 35 patients) in those with mild disease and 62% (8 of 13 patients) in those with severe disease. They concluded laparoscopic cholecystectomy could be safely performed within 7 days in patients with mild disease, whereas in severe disease at least 3 weeks should elapse because of the risk of infection.

In a randomized trial published in 2010, Aboulian et al⁵⁹ reported that hospital length of stay (the primary end point) was shorter in 25 patients who underwent laparoscopic cholecystectomy early (within 48 hours of admission) than in 25 patients who underwent surgery after abdominal pain had resolved and laboratory enzymes showed a normalizing trend, 3.5 vs 5.8 days (P = .0016). Rates of perioperative complications and need for conversion to open surgery were similar between the 2 groups.

If there is associated cholangitis, patients should also be given broad-spectrum antibiotics and should undergo ERCP within 24 hours of admission.^25–27

SUMMARY

Gallstones are common in US adults. Abdominal ultrasonography is the diagnostic imaging test of choice to detect gallbladder stones and assess for findings suggestive of acute cholecystitis and dilation of the common bile duct. Fortunately, most gallstones are asymptomatic and can usually be managed expectantly. In patients who have symptoms or have gallstone complications, laparoscopic cholecystectomy is the standard of care.

The prevalence of gallstones is approximately 10% to 15% of the adult US population.^1,2 Most cases are asymptomatic, as gallstones are usually discovered incidentally during routine imaging for other abdominal conditions, and only about 20% of patients with asymptomatic gallstones develop clinically significant complications.^2,3

Nevertheless, gallstones carry significant healthcare costs. In 2004, the median inpatient cost for any gallstone-related disease was $11,584, with an overall annual cost of $6.2 billion.^4,5

Laparoscopic cholecystectomy is the standard treatment for symptomatic cholelithiasis. For asymptomatic cholelithasis, the usual approach is expectant management (“watch and wait”), but prophylactic cholecystectomy may be an option in certain patients at high risk.

CHEMICAL COMPOSITION

Gallstones can be classified into 2 main categories based on their predominant chemical composition: cholesterol or pigment.

Cholesterol gallstones

About 75% of gallstones are composed of cholesterol.^3,4 In the past, this type of stone was thought to be caused by gallbladder inflammation, bile stasis, and absorption of bile salts from damaged mucosa. However, it is now known that cholesterol gallstones are the result of biliary supersaturation caused by cholesterol hypersecretion into the gallbladder, gallbladder hypomotility, accelerated cholesterol nucleation and crystallization, and mucin gel accumulation.

Pigment gallstones

Black pigment gallstones account for 10% to 15% of all gallstones.⁶ They are caused by chronic hemolysis in association with supersaturation of bile with calcium hydrogen bilirubinate, along with deposition of calcium carbonate, phosphate, and inorganic salts.⁷

Brown pigment stones, accounting for 5% to 10% of all gallstones,⁶ are caused by infection in the obstructed bile ducts, where bacteria that produce beta-glucuronidase, phospholipase, and slime contribute to formation of the stone.^8,9

RISK FACTORS FOR GALLSTONES

Age. After age 40, the risk increases dramatically, with an incidence 4 times higher for those ages 40 to 69 than in younger people.¹⁰

Female sex. Women of reproductive age are 4 times more likely to develop gallstones than men, but this gap narrows after menopause.¹¹ The higher risk is attributed to female sex hormones, pregnancy, and oral contraceptive use. Estrogen decreases secretion of bile salts and increases secretion of cholesterol into the gallbladder, which leads to cholesterol supersaturation. Progesterone acts synergistically by causing hypomobility of the gallbladder, which in turn leads to bile stasis.^12,13

Ethnicity. The risk is higher in Mexican Americans and Native Americans than in other ethnic groups.¹⁴

Rapid weight loss, such as after bariatric surgery, occurs from decreased caloric intake and promotes bile stasis, while lipolysis increases cholesterol mobilization and secretion into the gallbladder. This creates an environment conducive to bile supersaturation with cholesterol, leading to gallstone formation.

Chronic hemolytic disorders carry an increased risk of developing calcium bilirubinate stones due to increased excretion of bilirubin during hemolysis.

Obesity and diabetes mellitus are both attributed to insulin resistance. Obesity also increases bile stasis and cholesterol saturation.

 

 

CLINICAL PRESENTATION OF GALLSTONES (CHOLELITHIASIS)

Most patients with gallstones (cholelithiasis) experience no symptoms. Their gallstones are often discovered incidentally during imaging tests for unrelated or unexplained abdominal symptoms. Most patients with asymptomatic gallstones remain symptom-free, while about 20% develop gallstone-related symptoms.^2,3

Abdominal pain is the most common symptom. The phrase biliary colic—suggesting pain that is fluctuating in nature—appears ubiquitously in the medical literature, but it does not correctly characterize the pain associated with gallstones.

Most patients with gallstone symptoms describe a constant and often severe pain in the right upper abdomen, epigastrium, or both, often persisting for 30 to 120 minutes. Symptoms are frequently reported in the epigastrium when only visceral pain fibers are stimulated due to gallbladder distention. This is usually called midline pain; however, pain occurs in the back and right shoulder in up to 60% of patients, with involvement of somatic fibers.^15,16 Gallstone pain is not relieved by change of position or passage of stool or gas.

Onset of symptoms more than an hour after eating or in the late evening or at night also  very strongly suggests biliary pain. Patients with a history of biliary pain are more likely to experience it again, with a 69% chance of developing recurrent pain within 2 years.¹⁷

GALLSTONE-RELATED COMPLICATIONS

Acute gallbladder inflammation (cholecystitis)

Gallbladder inflammation (cholecystitis) is the most common complication, occurring in up to 10% of symptomatic cases. Many patients with acute cholecystitis present with right upper quadrant pain that may be accompanied by anorexia, nausea, or vomiting. Inspiratory arrest on deep palpation of the right upper quadrant (Murphy sign) has a specificity of 79% to 96% for acute cholecystitis.²⁰ Markers of systemic inflammation such as fever, elevated white blood cell count, and elevated C-reactive protein are highly suggestive of acute cholecystitis.^20,21

Bile duct stones (choledocholithiasis)

Bile duct stones (choledocholithiasis) are detected in 3.4% to 12% of patients with gallstones.^22,23 Most stones in the common bile duct migrate there from the gallbladder via the cystic duct. Less commonly, primary duct stones form in the duct due to biliary stasis. Removing the gallbladder does not completely eliminate the risk of bile duct stones, as stones can remain or recur after surgery.

Bile duct stones can obstruct the common bile duct, which disrupts normal bile flow and leads to jaundice. Other symptoms may include pruritus, right upper quadrant pain, nausea, and vomiting. Serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase (ALT), and alkaline phosphatase are usually high.²⁴

Acute bacterial infection (cholangitis)

Acute bacterial infection of the biliary system (cholangitis) is usually associated with obstruction of the common bile duct. Common symptoms of acute cholangitis include right upper quadrant pain, fever, and jaundice (Charcot triad), and these are present in about 50% to 75% of cases.²¹ In severe cases, patients can develop altered mental status and septicemic shock in addition to the Charcot triad, a condition called the Reynold pentad. White blood cell counts and serum levels of C-reactive protein, bilirubin, aminotransferases, and alkaline phosphatase are usually elevated.²¹

Pancreatitis

Approximately 4% to 8% of patients with gallstones develop inflammation of the pancreas (pancreatitis).²⁵ The diagnosis of acute pancreatitis requires at least 2 of the following:^26,27

• Abdominal pain (typically epigastric, often radiating to the back)
• Amylase or lipase levels at least 3 times above the normal limit
• Imaging findings that suggest acute pancreatitis.

Gallstone-related pancreatitis should be considered if the ALT level is greater than 150 U/mL, which has a 97% specificity for gallstone-related pancreatitis.²⁸

 

 

ABDOMINAL ULTRASONOGRAPHY FOR DIAGNOSIS

Transabdominal ultrasonography, with a sensitivity of 84% to 89% and a specificity of up to 99%, is the test of choice for detecting gallstones.²⁹ The characteristic findings of acute cholecystitis on ultrasonography include enlargement of the gallbladder, thickening of the gallbladder wall, presence of pericholecystic fluid, and tenderness elicited by the ultrasound probe over the gallbladder (sonographic Murphy sign).

Scintigraphy as a second test

Acute cholecystitis is primarily a clinical diagnosis and typically does not require additional imaging beyond ultrasonography. When there is discordance between clinical and ultrasonographic findings, the most accurate second imaging test is scintigraphy of the biliary tract, usually performed with technetium-labeled hydroxy iminodiacetic acid. Given intravenously, the radionuclide is rapidly taken up by the liver and then secreted into the bile. In acute cholecystitis, the cystic duct is functionally occluded and the isotope does not enter the gallbladder, creating an imaging void compared with a normal appearance.

Scintigraphy is more sensitive than abdominal ultrasonography, with a sensitivity of up to 97% vs 81% to 88%, respectively.^29,30 The tests have about equal specificity.

Even though scintigraphy is more sensitive, abdominal ultrasonography is often the initial test for patients with suspected acute cholecystitis because it is more widely available, takes less time, does not involve radiation exposure, and can assess for the presence or absence of gallstones and dilation of the intra- and extrahepatic bile ducts.

Looking for stones in the common bile duct

When acute cholangitis due to choledocholithiasis is suspected, abdominal ultrasonography is a prudent initial test to look for gallstones or biliary dilation suggesting obstruction by stones in the common bile duct. Abdominal ultrasonography has only a 22% to 55% sensitivity for visualizing stones in the common bile duct, but it has a 77% to 87% sensitivity for detecting common bile duct dilation, a surrogate marker of stones.³¹

The normal bile duct diameter ranges from 3 to 6 mm, although mild dilation is often seen in older patients or after cholecystectomy or Roux-en-Y gastric bypass surgery.^32,33 Bile duct dilation of up to 10 mm can be considered normal in patients after cholecystectomy.³⁴ A normal-appearing bile duct on ultrasonography has a negative predictive value of 95% for excluding common bile duct stones.³¹

Endoscopic ultrasonography (EUS), magnetic resonance cholangiopancreatography (MRCP), and endoscopic retrograde cholangiopancreatography (ERCP) have similar sensitivity (89%–94%, 85%–92%, and 89%–93%, respectively) and specificity (94%–95%, 93%–97%, and 100%, respectively) for detecting common bile duct stones.^35–37 EUS is superior to MRCP in detecting stones smaller than 6 mm.³⁸

ERCP should be reserved for managing rather than diagnosing common bile duct stones because of the risk of pancreatitis and perforation. Patients undergoing cholecystectomy who are suspected of having choledocholithiasis may undergo intraoperative cholangiography or laparoscopic common bile duct ultrasonography.

WATCH AND WAIT, OR INTERVENE?

Asymptomatic gallstones

Standard treatment for these patients is expectant management. Cholecystectomy is not recommended for patients with asymptomatic gallstones.⁴⁷ Nevertheless, some patients may benefit from prophylactic cholecystectomy. We and others⁴⁸ suggest considering cholecystectomy in the following patients.

Patients with chronic hemolytic anemia (including children with sickle cell anemia and spherocytosis). These patients have a higher risk of developing calcium bilirubinate stones, and cholecystectomy has improved outcomes.⁴⁹ It should be noted that most of these data come from pediatric populations and have been extrapolated to adults.

Native Americans, who have a higher risk of gallbladder cancer if they have gallstones.^2,50

Conversely, calcification of the gallbladder wall (“porcelain gallbladder”) is no longer considered an absolute indication for cholecystectomy. This condition was thought to be associated with a high rate of gallbladder carcinoma, but analyses of larger, more recent data sets found much smaller risks.^51,52 Further, cholecystectomy in these patients was found to be associated with high rates of postoperative complications. Thus, prophylactic cholecystectomy is no longer recommended in asymptomatic cases of porcelain gallbladder.

In addition, concomitant cholecystectomy in patients undergoing bariatric surgery is no longer considered the therapeutic standard. Historically, cholecystectomy was performed in these patients because of the increased risk of gallstones associated with rapid weight loss after surgery. However, research now weighs against concomitant cholecystectomy with bariatric surgery and most other abdominal surgeries for asymptomatic gallstones.⁵³

 

 

Laparoscopic surgery for symptomatic gallstones

Based on information in reference 48.

For patients experiencing acute cholecystitis, laparoscopic cholecystectomy within 72 hours is recommended.⁴⁸ There were safety concerns regarding higher rates of morbidity and conversion from laparoscopic to open cholecystectomy in patients who underwent surgery before the acute cholecystitis episode had settled. However, a large meta-analysis found no significant difference between early and delayed laparoscopic cholecystectomy in bile duct injury or conversion rates.⁵⁴ Further, early cholecystectomy—defined as within 1 week of symptom onset—has been found to reduce gallstone-related complications, shorten hospital stays, and lower costs.^55–57 If the patient cannot undergo surgery, percutaneous cholecystotomy or novel endoscopic gallbladder drainage interventions can be used.

Reprinted from ASGE Standards of Practice Committee; Maple JT, Ben-Menachem T, Anderson MA, et al. The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointest Endoscp 2010; 71:1–9 with permission from Elsevier.

Several variables predict the presence of bile duct stones in patients who have symptoms (Table 4). Based on these predictors, the ASGE classifies the probabilities as low (< 10%), intermediate (10% to 50%), and high (> 50%)³¹:

• 
  Low-risk patients require no further evaluation of the common bile duct
• High-risk patients should undergo preoperative ERCP and stone extraction if needed
• Intermediate-risk patients should undergo preoperative imaging with EUS or MRCP or intraoperative bile duct evaluation, depending on the availability, costs, and local expertise.

Patients with associated cholangitis should be given intravenous fluids and broad-spectrum antibiotics. Biliary decompression should be done as early as possible to decrease the risk of morbidity and mortality. For acute cholangitis, ERCP is the treatment of choice.²⁵

Patients with acute gallstone pancreatitis should receive conservative management with intravenous isotonic solutions and pain control, followed by laparoscopic cholecystectomy.⁴⁸

The timing of laparoscopic cholecystectomy in acute gallstone pancreatitis has been debated. Studies conducted during the era of open cholecystectomy reported similar or worse outcomes if cholecystectomy was done sooner rather than later.

However, in 1999, Uhl et al⁵⁸ reported that 48 of 77 patients admitted with acute gallstone pancreatitis were able to undergo laparoscopic cholecystectomy during the same admission. Success rates were 85% (30 of 35 patients) in those with mild disease and 62% (8 of 13 patients) in those with severe disease. They concluded laparoscopic cholecystectomy could be safely performed within 7 days in patients with mild disease, whereas in severe disease at least 3 weeks should elapse because of the risk of infection.

In a randomized trial published in 2010, Aboulian et al⁵⁹ reported that hospital length of stay (the primary end point) was shorter in 25 patients who underwent laparoscopic cholecystectomy early (within 48 hours of admission) than in 25 patients who underwent surgery after abdominal pain had resolved and laboratory enzymes showed a normalizing trend, 3.5 vs 5.8 days (P = .0016). Rates of perioperative complications and need for conversion to open surgery were similar between the 2 groups.

If there is associated cholangitis, patients should also be given broad-spectrum antibiotics and should undergo ERCP within 24 hours of admission.^25–27

SUMMARY

Gallstones are common in US adults. Abdominal ultrasonography is the diagnostic imaging test of choice to detect gallbladder stones and assess for findings suggestive of acute cholecystitis and dilation of the common bile duct. Fortunately, most gallstones are asymptomatic and can usually be managed expectantly. In patients who have symptoms or have gallstone complications, laparoscopic cholecystectomy is the standard of care.

Yes. Sepsis, stroke, chronic kidney disease, pulmonary disease, chemotherapy, heart failure, and stress cardiomyopathy can all raise serum troponin concentrations, and in some cases the elevations are prognostically important. Careful clinical assessment, serial monitoring of troponin levels, and other supportive tests are usually necessary to tell whether troponin elevations are due to acute coronary syndrome or to these other causes.

NOT ONLY A MARKER OF MYOCARDIAL DAMAGE

Troponin, an intracellular protein found in skeletal and cardiac muscle cells, is essential for muscle contraction. Troponin T and troponin I are clinically equivalent, and both are biomarkers of myocardial damage.

A troponin assay is ordered when patients present with sudden onset of symptoms of acute coronary syndrome such as chest pain, dyspnea, diaphoresis, and electrocardiographic abnormalities. The assay is positive when the manufacturer-specified threshold corresponding to a concentration above the 99th percentile is detected.

Serial testing of serum biomarkers of acute myocardial damage is essential to confirm the diagnosis of myocardial infarction. Because of their higher sensitivity and specificity compared with creatine kinase-MB and other markers, troponins are the preferred biomarker in diagnosing acute coronary syndrome.

In 1984, Piper et al¹ reported that free cytosolic pools of cardiac enzymes could be released after reversible myocardial injury as a result of temporary disruption of the cell membrane. This upended the previous assumption that troponin was released only after irreversible myocardial necrosis, and it provided an explanation for troponin elevations observed in conditions with no evidence of epicardial coronary artery disease or permanent myocardial damage.¹

SEPSIS

Studies of patients with sepsis, severe sepsis, and septic shock have shown troponin elevations with no evidence of acute coronary syndrome.² In sepsis, troponin elevations are presumed to be caused by a combination of events. Renal dysfunction leads to decreased clearance of troponin fragments by the kidneys. The massive inflammatory response in septic shock results in cytokine-induced cardiac damage, and increased levels of endogen­ous and exogenous catecholamines damage cardiac myocytes.³

Studies of the prognostic value of these elevations have produced mixed and contradictory results. But a 2013 meta-analysis⁴ showed that patients with a troponin elevation at the time of diagnosis of sepsis had a risk of death almost twice that of patients without a troponin elevation (relative risk 1.91, 95% confidence interval [CI] 1.63–2.24).

STROKE

Acute ischemic stroke can trigger troponin elevations in several ways. Since the risk factors for acute ischemic stroke and coronary stenosis are similar, patients who have an ischemic stroke have a higher risk of coronary atherosclerosis and coronary stenosis than the general population.⁵

Stroke can cause a variety of cardiovascular and respiratory responses (eg, tachyarrhythmia, hypertensive crisis, respiratory failure) that increase the stress on the myocardium. In patients with stroke and concurrent coronary artery stenosis, the increased metabolic demand can exceed the oxygen supply capacity, resulting in myocardial ischemia, which can manifest as increased levels of serum troponin.⁵

Stroke can also cause troponin elevation through neurogenic myocardial damage. Ischemic stroke and intracranial hemorrhage can trigger alterations in autonomic control. Sometimes this results in increased sympathetic activity with concomitant catecholamine surge, leading to contraction band necrosis and other forms of myocardial damage and, as a result, troponin elevation.^5,6 This may explain troponin elevation in patients with acute ischemic stroke in the absence of concomitant coronary artery disease. Recent evidence suggests that patients with acute ischemic stroke and elevated troponin had significantly less angiographic evidence of coronary artery disease than matched patients with non-ST-elevation myocardial infarction.⁷

 

 

CHRONIC KIDNEY DISEASE

Cardiac troponins may be elevated in chronic kidney disease. Explanations for this include the theory that troponin is broken down into fragments that are cleared by the kidney.⁸ Therefore, decreased renal function leads to an increase in troponin fragments measured with troponin assays. Other explanations are chronic volume overload, chronic elevation of proinflammatory cytokines, and associated comorbidities such as hypertension.

Troponin elevations can have prognostic significance in chronic kidney disease. In a meta-analysis of 98 studies of patients with chronic kidney disease and no symptoms of acute coronary syndrome, troponin elevation was associated with 2- to 4-fold higher rates of all-cause mortality, cardiovascular mortality, and major acute coronary events in both dialysis-dependent and nondialysis patients.⁸ Thus, troponin is a unique factor in risk-stratification in patients with chronic kidney disease and could affect how it is managed in the future.

To determine if an acute coronary syndrome is taking place when evaluating patients with chronic kidney disease and elevated troponins, physicians must use other evidence—for example, serial measurements of troponin levels showing continued troponin elevation, elevations in troponin from the patient’s baseline, elevated creatine kinase-MB levels, electrocardiographic changes, and clinical symptoms.

PULMONARY DISEASE

Troponin elevation can signify right heart strain in a variety of pulmonary diseases.

Pulmonary embolism. Troponin elevation is a marker of right ventricular dysfunction in patients with moderate to large pulmonary embolism.

In a study of normotensive patients with acute pulmonary embolism, 52% had elevated serum troponin, and they had a higher risk of an adverse outcome (death, recurrent pulmonary embolism, or major bleeding) within 30 days (odds ratio 4.97, 95% CI 1.71–14.43) and a lower probability of 6-month survival.⁹ Troponin elevation in pulmonary embolism is not helpful in confirming the diagnosis but is primarily useful in prognosis.

Pulmonary arterial hypertension. Cardiac troponin elevations can also indicate severe disease and poor outcomes in patients with pulmonary arterial hypertension. A study by Heresi et al¹⁰ confirmed this, even in patients with only slight elevations in troponin levels. Troponin was detected in 17 (25%) of 68 patients with pulmonary arterial hypertension diagnostic category 1. Further, patients with detectable troponin had more advanced functional class symptoms, a shorter 6-minute walk distance, more pericardial effusions, larger right atrial area, and higher B-type natriuretic peptide and C-reactive protein levels.¹⁰

Measuring troponins in the setting of pulmonary hypertension allows clinicians to identify high-risk patients and may help guide the management of these patients.

Chronic obstructive pulmonary disease. Elevation of serum troponins is also reported in patients with acute exacerbation of chronic obstructive pulmonary disease and has been correlated with increased all-cause mortality rates in these patients.¹¹

CHEMOTHERAPY

Chemotherapy-induced cardiotoxicity may result in troponin elevations. Chemotherapy causes cardiac toxicity by several mechanisms, including production of oxygen free radicals, disturbance of mitochondrial energy metabolism, intracellular calcium overload, and increased lipid peroxidation. Chemotherapeutic agents associated with cardiotoxicity include anthracyclines, trastuzumab, chlormethine, and mitomycin.

Chemotherapy-induced left ventricular deterioration is often irreversible. Monitoring troponin levels can help identify problems before cardiac dysfunction becomes clinically evident during the weeks and months after the start of high-dose chemotherapy.

Cardinale et al¹² found marked myocardial depression 7 months after the start of high-dose chemotherapy. They reported a close relationship between short-term troponin elevation and the greatest reduction in left-ventricular ejection fraction (r = −0.87; P < .0001). Normal troponin values after high-dose chemotherapy also seemed to identify patients at lower risk, with either no cardiac damage or only transient subclinical left-ventricular dysfunction.¹²

HEART FAILURE

Heart failure leads to release of cardiac troponins through myocardial strain and myocardial death. Volume and pressure overload of the ventricles causes excessive wall tension, resulting in myofibrillar damage. Measuring troponins is an effective way to detect cardiac myolysis in heart failure, independent of the presence of coronary artery disease.

In heart failure, elevated troponins correlate with adverse outcome in both hospitalized and stable patients. In addition, elevation of both troponins and B-type natriuretic peptide is associated with worse heart failure outcomes than elevation of either marker alone.

A prospective study¹³ of patients with New York Heart Association class III or IV heart failure showed that an increase in troponin concentration from normal baseline was associated with a risk of death, cardiac transplant, or hospitalization that was 3.4 to 5.09 times higher. Further elevations in B-type natriuretic peptide during the study period were associated with a poor outcome (hazard ratio 5.09; P < .001). Combined elevations of troponin and B-type natriuretic peptide defined the group at highest risk (hazard ratio 8.58; P < .001).

Increased myocardial wall stress may lead to decreased subendocardial perfusion, with resulting troponin elevation and decline in left ventricular systolic function. Further, in vitro experiments with myocytes established a link between myocardial wall stretch and programmed cell death, which may contribute to troponin elevations.¹⁴

 

 

STRESS CARDIOMYOPATHY

Profound reversible myocardial depression and troponin elevation are seen after sudden emotional stress, a condition called stress-induced or takotsubo cardiomyopathy. While the exact mechanism of stress-induced cardiomyopathy remains unclear, it is thought to be due to sudden supraphysiologic elevation of catecholamines and related neuropeptides. Although vasospasm in the epicardial and microvascular circulation has been suggested as the possible mechanism of left ventricular systolic dysfunction and troponin elevation, cardiac myocyte injury from catecholamine- induced cyclic AMP-mediated calcium overload and oxygen-derived free radicals appears to be a more likely mechanism.¹⁵

PSEUDOELEVATIONS OF TROPONIN

In rare cases, endogenous antibodies (eg, heterophilic antibodies) in the blood specimen can interfere with the processing of the troponin immunoassay in the laboratory, causing a false-positive assay. This can occur with samples from patients with a viral infection or autoimmune condition as well as with samples from patients treated with intravenous immunoglobulin (Ig). Heterophilic antibodies can bind to the Fc region of the test antibodies in certain troponin assays, leading to false-positive elevations.¹⁶ Macrotroponin, a molecule found in patients with autoantibodies against troponin I, is composed of troponin I fragments and IgG antibodies and can also cause a false-positive troponin immunoassay.¹⁶

In patients with seropositive rheumatoid arthritis, a false-positive troponin I assay was associated with a high concentration of IgM rheumatoid factor with the use of certain immunoassay techniques.¹⁷ In patients with acute skeletal muscle injury, the first-generation troponin T assay was found to be falsely positive due to the nonspecific binding of skeletal muscle troponin T to the walls of the test tube used for the assay. When the second-generation troponin T assay was used, troponin T levels were found to be slightly more positive than troponin I levels (1.7 vs 1.5 times the upper limit of normal), especially in patients with renal failure.¹⁸

Troponin may also be falsely elevated in hemolyzed blood samples. This has to be taken into consideration in interpreting the results of troponin testing in severely hemolyzed blood samples. However, Puelacher et al¹⁹ suggested that the presence of hemolysis did not appear to interfere with clinical value of the test.

Yes. Sepsis, stroke, chronic kidney disease, pulmonary disease, chemotherapy, heart failure, and stress cardiomyopathy can all raise serum troponin concentrations, and in some cases the elevations are prognostically important. Careful clinical assessment, serial monitoring of troponin levels, and other supportive tests are usually necessary to tell whether troponin elevations are due to acute coronary syndrome or to these other causes.

NOT ONLY A MARKER OF MYOCARDIAL DAMAGE

Troponin, an intracellular protein found in skeletal and cardiac muscle cells, is essential for muscle contraction. Troponin T and troponin I are clinically equivalent, and both are biomarkers of myocardial damage.

A troponin assay is ordered when patients present with sudden onset of symptoms of acute coronary syndrome such as chest pain, dyspnea, diaphoresis, and electrocardiographic abnormalities. The assay is positive when the manufacturer-specified threshold corresponding to a concentration above the 99th percentile is detected.

Serial testing of serum biomarkers of acute myocardial damage is essential to confirm the diagnosis of myocardial infarction. Because of their higher sensitivity and specificity compared with creatine kinase-MB and other markers, troponins are the preferred biomarker in diagnosing acute coronary syndrome.

In 1984, Piper et al¹ reported that free cytosolic pools of cardiac enzymes could be released after reversible myocardial injury as a result of temporary disruption of the cell membrane. This upended the previous assumption that troponin was released only after irreversible myocardial necrosis, and it provided an explanation for troponin elevations observed in conditions with no evidence of epicardial coronary artery disease or permanent myocardial damage.¹

SEPSIS

Studies of patients with sepsis, severe sepsis, and septic shock have shown troponin elevations with no evidence of acute coronary syndrome.² In sepsis, troponin elevations are presumed to be caused by a combination of events. Renal dysfunction leads to decreased clearance of troponin fragments by the kidneys. The massive inflammatory response in septic shock results in cytokine-induced cardiac damage, and increased levels of endogen­ous and exogenous catecholamines damage cardiac myocytes.³

Studies of the prognostic value of these elevations have produced mixed and contradictory results. But a 2013 meta-analysis⁴ showed that patients with a troponin elevation at the time of diagnosis of sepsis had a risk of death almost twice that of patients without a troponin elevation (relative risk 1.91, 95% confidence interval [CI] 1.63–2.24).

STROKE

Acute ischemic stroke can trigger troponin elevations in several ways. Since the risk factors for acute ischemic stroke and coronary stenosis are similar, patients who have an ischemic stroke have a higher risk of coronary atherosclerosis and coronary stenosis than the general population.⁵

Stroke can cause a variety of cardiovascular and respiratory responses (eg, tachyarrhythmia, hypertensive crisis, respiratory failure) that increase the stress on the myocardium. In patients with stroke and concurrent coronary artery stenosis, the increased metabolic demand can exceed the oxygen supply capacity, resulting in myocardial ischemia, which can manifest as increased levels of serum troponin.⁵

Stroke can also cause troponin elevation through neurogenic myocardial damage. Ischemic stroke and intracranial hemorrhage can trigger alterations in autonomic control. Sometimes this results in increased sympathetic activity with concomitant catecholamine surge, leading to contraction band necrosis and other forms of myocardial damage and, as a result, troponin elevation.^5,6 This may explain troponin elevation in patients with acute ischemic stroke in the absence of concomitant coronary artery disease. Recent evidence suggests that patients with acute ischemic stroke and elevated troponin had significantly less angiographic evidence of coronary artery disease than matched patients with non-ST-elevation myocardial infarction.⁷

 

 

CHRONIC KIDNEY DISEASE

Cardiac troponins may be elevated in chronic kidney disease. Explanations for this include the theory that troponin is broken down into fragments that are cleared by the kidney.⁸ Therefore, decreased renal function leads to an increase in troponin fragments measured with troponin assays. Other explanations are chronic volume overload, chronic elevation of proinflammatory cytokines, and associated comorbidities such as hypertension.

Troponin elevations can have prognostic significance in chronic kidney disease. In a meta-analysis of 98 studies of patients with chronic kidney disease and no symptoms of acute coronary syndrome, troponin elevation was associated with 2- to 4-fold higher rates of all-cause mortality, cardiovascular mortality, and major acute coronary events in both dialysis-dependent and nondialysis patients.⁸ Thus, troponin is a unique factor in risk-stratification in patients with chronic kidney disease and could affect how it is managed in the future.

To determine if an acute coronary syndrome is taking place when evaluating patients with chronic kidney disease and elevated troponins, physicians must use other evidence—for example, serial measurements of troponin levels showing continued troponin elevation, elevations in troponin from the patient’s baseline, elevated creatine kinase-MB levels, electrocardiographic changes, and clinical symptoms.

PULMONARY DISEASE

Troponin elevation can signify right heart strain in a variety of pulmonary diseases.

Pulmonary embolism. Troponin elevation is a marker of right ventricular dysfunction in patients with moderate to large pulmonary embolism.

In a study of normotensive patients with acute pulmonary embolism, 52% had elevated serum troponin, and they had a higher risk of an adverse outcome (death, recurrent pulmonary embolism, or major bleeding) within 30 days (odds ratio 4.97, 95% CI 1.71–14.43) and a lower probability of 6-month survival.⁹ Troponin elevation in pulmonary embolism is not helpful in confirming the diagnosis but is primarily useful in prognosis.

Pulmonary arterial hypertension. Cardiac troponin elevations can also indicate severe disease and poor outcomes in patients with pulmonary arterial hypertension. A study by Heresi et al¹⁰ confirmed this, even in patients with only slight elevations in troponin levels. Troponin was detected in 17 (25%) of 68 patients with pulmonary arterial hypertension diagnostic category 1. Further, patients with detectable troponin had more advanced functional class symptoms, a shorter 6-minute walk distance, more pericardial effusions, larger right atrial area, and higher B-type natriuretic peptide and C-reactive protein levels.¹⁰

Measuring troponins in the setting of pulmonary hypertension allows clinicians to identify high-risk patients and may help guide the management of these patients.

Chronic obstructive pulmonary disease. Elevation of serum troponins is also reported in patients with acute exacerbation of chronic obstructive pulmonary disease and has been correlated with increased all-cause mortality rates in these patients.¹¹

CHEMOTHERAPY

Chemotherapy-induced cardiotoxicity may result in troponin elevations. Chemotherapy causes cardiac toxicity by several mechanisms, including production of oxygen free radicals, disturbance of mitochondrial energy metabolism, intracellular calcium overload, and increased lipid peroxidation. Chemotherapeutic agents associated with cardiotoxicity include anthracyclines, trastuzumab, chlormethine, and mitomycin.

Chemotherapy-induced left ventricular deterioration is often irreversible. Monitoring troponin levels can help identify problems before cardiac dysfunction becomes clinically evident during the weeks and months after the start of high-dose chemotherapy.

Cardinale et al¹² found marked myocardial depression 7 months after the start of high-dose chemotherapy. They reported a close relationship between short-term troponin elevation and the greatest reduction in left-ventricular ejection fraction (r = −0.87; P < .0001). Normal troponin values after high-dose chemotherapy also seemed to identify patients at lower risk, with either no cardiac damage or only transient subclinical left-ventricular dysfunction.¹²

HEART FAILURE

Heart failure leads to release of cardiac troponins through myocardial strain and myocardial death. Volume and pressure overload of the ventricles causes excessive wall tension, resulting in myofibrillar damage. Measuring troponins is an effective way to detect cardiac myolysis in heart failure, independent of the presence of coronary artery disease.

In heart failure, elevated troponins correlate with adverse outcome in both hospitalized and stable patients. In addition, elevation of both troponins and B-type natriuretic peptide is associated with worse heart failure outcomes than elevation of either marker alone.

A prospective study¹³ of patients with New York Heart Association class III or IV heart failure showed that an increase in troponin concentration from normal baseline was associated with a risk of death, cardiac transplant, or hospitalization that was 3.4 to 5.09 times higher. Further elevations in B-type natriuretic peptide during the study period were associated with a poor outcome (hazard ratio 5.09; P < .001). Combined elevations of troponin and B-type natriuretic peptide defined the group at highest risk (hazard ratio 8.58; P < .001).

Increased myocardial wall stress may lead to decreased subendocardial perfusion, with resulting troponin elevation and decline in left ventricular systolic function. Further, in vitro experiments with myocytes established a link between myocardial wall stretch and programmed cell death, which may contribute to troponin elevations.¹⁴

 

 

STRESS CARDIOMYOPATHY

Profound reversible myocardial depression and troponin elevation are seen after sudden emotional stress, a condition called stress-induced or takotsubo cardiomyopathy. While the exact mechanism of stress-induced cardiomyopathy remains unclear, it is thought to be due to sudden supraphysiologic elevation of catecholamines and related neuropeptides. Although vasospasm in the epicardial and microvascular circulation has been suggested as the possible mechanism of left ventricular systolic dysfunction and troponin elevation, cardiac myocyte injury from catecholamine- induced cyclic AMP-mediated calcium overload and oxygen-derived free radicals appears to be a more likely mechanism.¹⁵

PSEUDOELEVATIONS OF TROPONIN

In rare cases, endogenous antibodies (eg, heterophilic antibodies) in the blood specimen can interfere with the processing of the troponin immunoassay in the laboratory, causing a false-positive assay. This can occur with samples from patients with a viral infection or autoimmune condition as well as with samples from patients treated with intravenous immunoglobulin (Ig). Heterophilic antibodies can bind to the Fc region of the test antibodies in certain troponin assays, leading to false-positive elevations.¹⁶ Macrotroponin, a molecule found in patients with autoantibodies against troponin I, is composed of troponin I fragments and IgG antibodies and can also cause a false-positive troponin immunoassay.¹⁶

In patients with seropositive rheumatoid arthritis, a false-positive troponin I assay was associated with a high concentration of IgM rheumatoid factor with the use of certain immunoassay techniques.¹⁷ In patients with acute skeletal muscle injury, the first-generation troponin T assay was found to be falsely positive due to the nonspecific binding of skeletal muscle troponin T to the walls of the test tube used for the assay. When the second-generation troponin T assay was used, troponin T levels were found to be slightly more positive than troponin I levels (1.7 vs 1.5 times the upper limit of normal), especially in patients with renal failure.¹⁸

Troponin may also be falsely elevated in hemolyzed blood samples. This has to be taken into consideration in interpreting the results of troponin testing in severely hemolyzed blood samples. However, Puelacher et al¹⁹ suggested that the presence of hemolysis did not appear to interfere with clinical value of the test.

Yes. Sepsis, stroke, chronic kidney disease, pulmonary disease, chemotherapy, heart failure, and stress cardiomyopathy can all raise serum troponin concentrations, and in some cases the elevations are prognostically important. Careful clinical assessment, serial monitoring of troponin levels, and other supportive tests are usually necessary to tell whether troponin elevations are due to acute coronary syndrome or to these other causes.

NOT ONLY A MARKER OF MYOCARDIAL DAMAGE

Troponin, an intracellular protein found in skeletal and cardiac muscle cells, is essential for muscle contraction. Troponin T and troponin I are clinically equivalent, and both are biomarkers of myocardial damage.

A troponin assay is ordered when patients present with sudden onset of symptoms of acute coronary syndrome such as chest pain, dyspnea, diaphoresis, and electrocardiographic abnormalities. The assay is positive when the manufacturer-specified threshold corresponding to a concentration above the 99th percentile is detected.

Serial testing of serum biomarkers of acute myocardial damage is essential to confirm the diagnosis of myocardial infarction. Because of their higher sensitivity and specificity compared with creatine kinase-MB and other markers, troponins are the preferred biomarker in diagnosing acute coronary syndrome.

In 1984, Piper et al¹ reported that free cytosolic pools of cardiac enzymes could be released after reversible myocardial injury as a result of temporary disruption of the cell membrane. This upended the previous assumption that troponin was released only after irreversible myocardial necrosis, and it provided an explanation for troponin elevations observed in conditions with no evidence of epicardial coronary artery disease or permanent myocardial damage.¹

SEPSIS

Studies of patients with sepsis, severe sepsis, and septic shock have shown troponin elevations with no evidence of acute coronary syndrome.² In sepsis, troponin elevations are presumed to be caused by a combination of events. Renal dysfunction leads to decreased clearance of troponin fragments by the kidneys. The massive inflammatory response in septic shock results in cytokine-induced cardiac damage, and increased levels of endogen­ous and exogenous catecholamines damage cardiac myocytes.³

Studies of the prognostic value of these elevations have produced mixed and contradictory results. But a 2013 meta-analysis⁴ showed that patients with a troponin elevation at the time of diagnosis of sepsis had a risk of death almost twice that of patients without a troponin elevation (relative risk 1.91, 95% confidence interval [CI] 1.63–2.24).

STROKE

Acute ischemic stroke can trigger troponin elevations in several ways. Since the risk factors for acute ischemic stroke and coronary stenosis are similar, patients who have an ischemic stroke have a higher risk of coronary atherosclerosis and coronary stenosis than the general population.⁵

Stroke can cause a variety of cardiovascular and respiratory responses (eg, tachyarrhythmia, hypertensive crisis, respiratory failure) that increase the stress on the myocardium. In patients with stroke and concurrent coronary artery stenosis, the increased metabolic demand can exceed the oxygen supply capacity, resulting in myocardial ischemia, which can manifest as increased levels of serum troponin.⁵

Stroke can also cause troponin elevation through neurogenic myocardial damage. Ischemic stroke and intracranial hemorrhage can trigger alterations in autonomic control. Sometimes this results in increased sympathetic activity with concomitant catecholamine surge, leading to contraction band necrosis and other forms of myocardial damage and, as a result, troponin elevation.^5,6 This may explain troponin elevation in patients with acute ischemic stroke in the absence of concomitant coronary artery disease. Recent evidence suggests that patients with acute ischemic stroke and elevated troponin had significantly less angiographic evidence of coronary artery disease than matched patients with non-ST-elevation myocardial infarction.⁷

 

 

CHRONIC KIDNEY DISEASE

Cardiac troponins may be elevated in chronic kidney disease. Explanations for this include the theory that troponin is broken down into fragments that are cleared by the kidney.⁸ Therefore, decreased renal function leads to an increase in troponin fragments measured with troponin assays. Other explanations are chronic volume overload, chronic elevation of proinflammatory cytokines, and associated comorbidities such as hypertension.

Troponin elevations can have prognostic significance in chronic kidney disease. In a meta-analysis of 98 studies of patients with chronic kidney disease and no symptoms of acute coronary syndrome, troponin elevation was associated with 2- to 4-fold higher rates of all-cause mortality, cardiovascular mortality, and major acute coronary events in both dialysis-dependent and nondialysis patients.⁸ Thus, troponin is a unique factor in risk-stratification in patients with chronic kidney disease and could affect how it is managed in the future.

To determine if an acute coronary syndrome is taking place when evaluating patients with chronic kidney disease and elevated troponins, physicians must use other evidence—for example, serial measurements of troponin levels showing continued troponin elevation, elevations in troponin from the patient’s baseline, elevated creatine kinase-MB levels, electrocardiographic changes, and clinical symptoms.

PULMONARY DISEASE

Troponin elevation can signify right heart strain in a variety of pulmonary diseases.

Pulmonary embolism. Troponin elevation is a marker of right ventricular dysfunction in patients with moderate to large pulmonary embolism.

In a study of normotensive patients with acute pulmonary embolism, 52% had elevated serum troponin, and they had a higher risk of an adverse outcome (death, recurrent pulmonary embolism, or major bleeding) within 30 days (odds ratio 4.97, 95% CI 1.71–14.43) and a lower probability of 6-month survival.⁹ Troponin elevation in pulmonary embolism is not helpful in confirming the diagnosis but is primarily useful in prognosis.

Pulmonary arterial hypertension. Cardiac troponin elevations can also indicate severe disease and poor outcomes in patients with pulmonary arterial hypertension. A study by Heresi et al¹⁰ confirmed this, even in patients with only slight elevations in troponin levels. Troponin was detected in 17 (25%) of 68 patients with pulmonary arterial hypertension diagnostic category 1. Further, patients with detectable troponin had more advanced functional class symptoms, a shorter 6-minute walk distance, more pericardial effusions, larger right atrial area, and higher B-type natriuretic peptide and C-reactive protein levels.¹⁰

Measuring troponins in the setting of pulmonary hypertension allows clinicians to identify high-risk patients and may help guide the management of these patients.

Chronic obstructive pulmonary disease. Elevation of serum troponins is also reported in patients with acute exacerbation of chronic obstructive pulmonary disease and has been correlated with increased all-cause mortality rates in these patients.¹¹

CHEMOTHERAPY

Chemotherapy-induced cardiotoxicity may result in troponin elevations. Chemotherapy causes cardiac toxicity by several mechanisms, including production of oxygen free radicals, disturbance of mitochondrial energy metabolism, intracellular calcium overload, and increased lipid peroxidation. Chemotherapeutic agents associated with cardiotoxicity include anthracyclines, trastuzumab, chlormethine, and mitomycin.

Chemotherapy-induced left ventricular deterioration is often irreversible. Monitoring troponin levels can help identify problems before cardiac dysfunction becomes clinically evident during the weeks and months after the start of high-dose chemotherapy.

Cardinale et al¹² found marked myocardial depression 7 months after the start of high-dose chemotherapy. They reported a close relationship between short-term troponin elevation and the greatest reduction in left-ventricular ejection fraction (r = −0.87; P < .0001). Normal troponin values after high-dose chemotherapy also seemed to identify patients at lower risk, with either no cardiac damage or only transient subclinical left-ventricular dysfunction.¹²

HEART FAILURE

Heart failure leads to release of cardiac troponins through myocardial strain and myocardial death. Volume and pressure overload of the ventricles causes excessive wall tension, resulting in myofibrillar damage. Measuring troponins is an effective way to detect cardiac myolysis in heart failure, independent of the presence of coronary artery disease.

In heart failure, elevated troponins correlate with adverse outcome in both hospitalized and stable patients. In addition, elevation of both troponins and B-type natriuretic peptide is associated with worse heart failure outcomes than elevation of either marker alone.

A prospective study¹³ of patients with New York Heart Association class III or IV heart failure showed that an increase in troponin concentration from normal baseline was associated with a risk of death, cardiac transplant, or hospitalization that was 3.4 to 5.09 times higher. Further elevations in B-type natriuretic peptide during the study period were associated with a poor outcome (hazard ratio 5.09; P < .001). Combined elevations of troponin and B-type natriuretic peptide defined the group at highest risk (hazard ratio 8.58; P < .001).

Increased myocardial wall stress may lead to decreased subendocardial perfusion, with resulting troponin elevation and decline in left ventricular systolic function. Further, in vitro experiments with myocytes established a link between myocardial wall stretch and programmed cell death, which may contribute to troponin elevations.¹⁴

 

 

STRESS CARDIOMYOPATHY

Profound reversible myocardial depression and troponin elevation are seen after sudden emotional stress, a condition called stress-induced or takotsubo cardiomyopathy. While the exact mechanism of stress-induced cardiomyopathy remains unclear, it is thought to be due to sudden supraphysiologic elevation of catecholamines and related neuropeptides. Although vasospasm in the epicardial and microvascular circulation has been suggested as the possible mechanism of left ventricular systolic dysfunction and troponin elevation, cardiac myocyte injury from catecholamine- induced cyclic AMP-mediated calcium overload and oxygen-derived free radicals appears to be a more likely mechanism.¹⁵

PSEUDOELEVATIONS OF TROPONIN

In rare cases, endogenous antibodies (eg, heterophilic antibodies) in the blood specimen can interfere with the processing of the troponin immunoassay in the laboratory, causing a false-positive assay. This can occur with samples from patients with a viral infection or autoimmune condition as well as with samples from patients treated with intravenous immunoglobulin (Ig). Heterophilic antibodies can bind to the Fc region of the test antibodies in certain troponin assays, leading to false-positive elevations.¹⁶ Macrotroponin, a molecule found in patients with autoantibodies against troponin I, is composed of troponin I fragments and IgG antibodies and can also cause a false-positive troponin immunoassay.¹⁶

In patients with seropositive rheumatoid arthritis, a false-positive troponin I assay was associated with a high concentration of IgM rheumatoid factor with the use of certain immunoassay techniques.¹⁷ In patients with acute skeletal muscle injury, the first-generation troponin T assay was found to be falsely positive due to the nonspecific binding of skeletal muscle troponin T to the walls of the test tube used for the assay. When the second-generation troponin T assay was used, troponin T levels were found to be slightly more positive than troponin I levels (1.7 vs 1.5 times the upper limit of normal), especially in patients with renal failure.¹⁸

Troponin may also be falsely elevated in hemolyzed blood samples. This has to be taken into consideration in interpreting the results of troponin testing in severely hemolyzed blood samples. However, Puelacher et al¹⁹ suggested that the presence of hemolysis did not appear to interfere with clinical value of the test.

New laboratory tests seem to go through a life cycle. At first, some are used mainly by subspecialists, who became aware of them through early clinical trials or studies presented at specialty meetings. The general medical community adopts their use after noting that they are being ordered by consultants or were used in important published studies.

Sometimes, a new test is significantly better than the older ones, and clinical pathologists and subspecialists encourage us to use it. Sometimes, a new test may represent a breakthrough in the understanding of the pathophysiology of a disease, and its use is promoted by clinicians with special interest in that disease. Testing for serum troponin, as discussed by Sebastian et al in this issue of the Journal, is an example primarily of the first situation, while testing for antineutrophil cytoplasmic antibodies (ANCA) and immunoglobulin G4 are two of many examples of the second.

Once a test comes into widespread use, its accuracy and reproducibility can be problematic. The assay itself may have inherent weaknesses, or techniques may not be standardized among different laboratories; think about diagnosis of the antiphospholipid antibody syndrome. Standardization of laboratory techniques can often be achieved. For troponin, this remains a problem, though small, for patients whose serum is tested in different laboratories or for clinicians trying to directly compare different clinical trial results; but it doesn’t affect clinical decision-making when longitudinally following a specific patient through a single hospitalization.

In its mature years, as a useful novel test becomes widely used, it may alter how we view the management and pathophysiology of a disease. For example, in the days when postoperative myocardial infarction (MI) was diagnosed by electrocardiographic changes and then by elevations in creatine kinase (CK) and alterations in the ratio of  aspartate aminotransferase (AST) to alanine aminotransferase (ALT), the peak in MI incidence was thought to occur several days after surgery. With the advent of CK isoenzymes and then cardiac myocyte-derived troponin, it became apparent that perioperative myocardial injury occurs more in a time frame of hours after surgery. Laboratory data dovetailed with pathologic and angiographic data indicating that the mechanism of MI in the perioperative setting for many patients is different than in “native” MI. As newer, highly sensitive troponin assays are introduced, they may further our understanding of mechanisms of cardiac myocyte membrane injury and tissue necrosis, and may further clarify (or blur) the distinction between the two.

Often, a widely used test is ordered in clinical situations that were not specifically evaluated during initial studies of the test and early use by specialists. Case reports of unexpected results then appear in the literature. Intrinsic test performance may occasionally be influenced in unanticipated ways (eg, rheumatoid factor can affect test results of some troponin and cryptococcal antigen assays), but more frequently it is the definition of “normal” and interpretation of the test results in specific clinical conditions that are affected. For example, troponin levels are higher in patients with chronic kidney disease and severe sepsis. These elevations may be explained by decreased renal clearance of detected fragments of troponin but may also reflect subclinical myocardial injury related to circulating cytokines or other factors. Elevation of troponins in patients with these and other conditions has correlated with poorer outcomes. Thus, in some settings, elevated circulating troponin has greater prognostic than diagnostic significance.

Recognizing imperfect test specificity (false-positive results) is critical when using a test in complex clinical situations. This can be especially challenging when using indirect serologic tests: consider the many reasons for “false-positive” antinuclear antibody, ANCA, and rheumatoid factor test results. But it can also be a challenge when trying to use a targeted test like troponin to distinguish between MI, sepsis, and pulmonary embolism as the cause of acute hypotension.

Many routinely ordered tests require more nuanced interpretation than simply checking the value against the defined laboratory “normal.” These nuances may be well known to those who order the test often or to specialists, but not to all. Familiarity with tests can also result in a subliminal assumption that we fully understand their characteristics and can lead to misinterpretation of results. There are forgotten critical concepts about tests that are ordered extremely commonly: eg, AST and ALT do not come only from the liver and do not reflect “liver function.” Liver biopsy is unlikely to provide the explanation for a myositis patient’s sense of weakness, even if the aminotransferase levels are elevated in the several-hundred range.

A CALL FOR MANUSCRIPTS

I invite you to draw on your personal experience and the literature and submit short manuscripts that address the nuanced interpretation, limitations, and cost of specific laboratory tests. As with all submissions, these will undergo peer review for content accuracy, as well as relevancy and utility for our core readership before being considered for publication.

New laboratory tests seem to go through a life cycle. At first, some are used mainly by subspecialists, who became aware of them through early clinical trials or studies presented at specialty meetings. The general medical community adopts their use after noting that they are being ordered by consultants or were used in important published studies.

Sometimes, a new test is significantly better than the older ones, and clinical pathologists and subspecialists encourage us to use it. Sometimes, a new test may represent a breakthrough in the understanding of the pathophysiology of a disease, and its use is promoted by clinicians with special interest in that disease. Testing for serum troponin, as discussed by Sebastian et al in this issue of the Journal, is an example primarily of the first situation, while testing for antineutrophil cytoplasmic antibodies (ANCA) and immunoglobulin G4 are two of many examples of the second.

Once a test comes into widespread use, its accuracy and reproducibility can be problematic. The assay itself may have inherent weaknesses, or techniques may not be standardized among different laboratories; think about diagnosis of the antiphospholipid antibody syndrome. Standardization of laboratory techniques can often be achieved. For troponin, this remains a problem, though small, for patients whose serum is tested in different laboratories or for clinicians trying to directly compare different clinical trial results; but it doesn’t affect clinical decision-making when longitudinally following a specific patient through a single hospitalization.

In its mature years, as a useful novel test becomes widely used, it may alter how we view the management and pathophysiology of a disease. For example, in the days when postoperative myocardial infarction (MI) was diagnosed by electrocardiographic changes and then by elevations in creatine kinase (CK) and alterations in the ratio of  aspartate aminotransferase (AST) to alanine aminotransferase (ALT), the peak in MI incidence was thought to occur several days after surgery. With the advent of CK isoenzymes and then cardiac myocyte-derived troponin, it became apparent that perioperative myocardial injury occurs more in a time frame of hours after surgery. Laboratory data dovetailed with pathologic and angiographic data indicating that the mechanism of MI in the perioperative setting for many patients is different than in “native” MI. As newer, highly sensitive troponin assays are introduced, they may further our understanding of mechanisms of cardiac myocyte membrane injury and tissue necrosis, and may further clarify (or blur) the distinction between the two.

Often, a widely used test is ordered in clinical situations that were not specifically evaluated during initial studies of the test and early use by specialists. Case reports of unexpected results then appear in the literature. Intrinsic test performance may occasionally be influenced in unanticipated ways (eg, rheumatoid factor can affect test results of some troponin and cryptococcal antigen assays), but more frequently it is the definition of “normal” and interpretation of the test results in specific clinical conditions that are affected. For example, troponin levels are higher in patients with chronic kidney disease and severe sepsis. These elevations may be explained by decreased renal clearance of detected fragments of troponin but may also reflect subclinical myocardial injury related to circulating cytokines or other factors. Elevation of troponins in patients with these and other conditions has correlated with poorer outcomes. Thus, in some settings, elevated circulating troponin has greater prognostic than diagnostic significance.

Recognizing imperfect test specificity (false-positive results) is critical when using a test in complex clinical situations. This can be especially challenging when using indirect serologic tests: consider the many reasons for “false-positive” antinuclear antibody, ANCA, and rheumatoid factor test results. But it can also be a challenge when trying to use a targeted test like troponin to distinguish between MI, sepsis, and pulmonary embolism as the cause of acute hypotension.

Many routinely ordered tests require more nuanced interpretation than simply checking the value against the defined laboratory “normal.” These nuances may be well known to those who order the test often or to specialists, but not to all. Familiarity with tests can also result in a subliminal assumption that we fully understand their characteristics and can lead to misinterpretation of results. There are forgotten critical concepts about tests that are ordered extremely commonly: eg, AST and ALT do not come only from the liver and do not reflect “liver function.” Liver biopsy is unlikely to provide the explanation for a myositis patient’s sense of weakness, even if the aminotransferase levels are elevated in the several-hundred range.

A CALL FOR MANUSCRIPTS

I invite you to draw on your personal experience and the literature and submit short manuscripts that address the nuanced interpretation, limitations, and cost of specific laboratory tests. As with all submissions, these will undergo peer review for content accuracy, as well as relevancy and utility for our core readership before being considered for publication.

New laboratory tests seem to go through a life cycle. At first, some are used mainly by subspecialists, who became aware of them through early clinical trials or studies presented at specialty meetings. The general medical community adopts their use after noting that they are being ordered by consultants or were used in important published studies.

Sometimes, a new test is significantly better than the older ones, and clinical pathologists and subspecialists encourage us to use it. Sometimes, a new test may represent a breakthrough in the understanding of the pathophysiology of a disease, and its use is promoted by clinicians with special interest in that disease. Testing for serum troponin, as discussed by Sebastian et al in this issue of the Journal, is an example primarily of the first situation, while testing for antineutrophil cytoplasmic antibodies (ANCA) and immunoglobulin G4 are two of many examples of the second.

Once a test comes into widespread use, its accuracy and reproducibility can be problematic. The assay itself may have inherent weaknesses, or techniques may not be standardized among different laboratories; think about diagnosis of the antiphospholipid antibody syndrome. Standardization of laboratory techniques can often be achieved. For troponin, this remains a problem, though small, for patients whose serum is tested in different laboratories or for clinicians trying to directly compare different clinical trial results; but it doesn’t affect clinical decision-making when longitudinally following a specific patient through a single hospitalization.

In its mature years, as a useful novel test becomes widely used, it may alter how we view the management and pathophysiology of a disease. For example, in the days when postoperative myocardial infarction (MI) was diagnosed by electrocardiographic changes and then by elevations in creatine kinase (CK) and alterations in the ratio of  aspartate aminotransferase (AST) to alanine aminotransferase (ALT), the peak in MI incidence was thought to occur several days after surgery. With the advent of CK isoenzymes and then cardiac myocyte-derived troponin, it became apparent that perioperative myocardial injury occurs more in a time frame of hours after surgery. Laboratory data dovetailed with pathologic and angiographic data indicating that the mechanism of MI in the perioperative setting for many patients is different than in “native” MI. As newer, highly sensitive troponin assays are introduced, they may further our understanding of mechanisms of cardiac myocyte membrane injury and tissue necrosis, and may further clarify (or blur) the distinction between the two.

Often, a widely used test is ordered in clinical situations that were not specifically evaluated during initial studies of the test and early use by specialists. Case reports of unexpected results then appear in the literature. Intrinsic test performance may occasionally be influenced in unanticipated ways (eg, rheumatoid factor can affect test results of some troponin and cryptococcal antigen assays), but more frequently it is the definition of “normal” and interpretation of the test results in specific clinical conditions that are affected. For example, troponin levels are higher in patients with chronic kidney disease and severe sepsis. These elevations may be explained by decreased renal clearance of detected fragments of troponin but may also reflect subclinical myocardial injury related to circulating cytokines or other factors. Elevation of troponins in patients with these and other conditions has correlated with poorer outcomes. Thus, in some settings, elevated circulating troponin has greater prognostic than diagnostic significance.

Recognizing imperfect test specificity (false-positive results) is critical when using a test in complex clinical situations. This can be especially challenging when using indirect serologic tests: consider the many reasons for “false-positive” antinuclear antibody, ANCA, and rheumatoid factor test results. But it can also be a challenge when trying to use a targeted test like troponin to distinguish between MI, sepsis, and pulmonary embolism as the cause of acute hypotension.

Many routinely ordered tests require more nuanced interpretation than simply checking the value against the defined laboratory “normal.” These nuances may be well known to those who order the test often or to specialists, but not to all. Familiarity with tests can also result in a subliminal assumption that we fully understand their characteristics and can lead to misinterpretation of results. There are forgotten critical concepts about tests that are ordered extremely commonly: eg, AST and ALT do not come only from the liver and do not reflect “liver function.” Liver biopsy is unlikely to provide the explanation for a myositis patient’s sense of weakness, even if the aminotransferase levels are elevated in the several-hundred range.

A CALL FOR MANUSCRIPTS

I invite you to draw on your personal experience and the literature and submit short manuscripts that address the nuanced interpretation, limitations, and cost of specific laboratory tests. As with all submissions, these will undergo peer review for content accuracy, as well as relevancy and utility for our core readership before being considered for publication.

A 46-year-old man with poorly controlled hypertension presented with the sudden onset of chest pain and shortness of breath. His blood pressure was 158/96 mm Hg and his left ventricular ejection fraction was less than 20%. He was admitted to the hospital for newly diagnosed heart failure.

SACCULAR AORTIC ANEURYSMS

This case shows the value of carefully examining the chest radiograph, especially behind the heart.

Saccular aneurysms of the descending thoracic aorta are rare and can be easily missed if asymptomatic. They are less common than fusiform aneurysms and may be more prone to rupture. Shang et al¹ identified atherosclerosis as the most frequent cause of saccular aneurysms of the thoracic aorta. However, they can be caused by other inflammatory conditions and infections.¹

Without surgical repair, thoracic aortic aneurysms larger than 6 cm have higher rates of expansion and rupture (a 20% 6-year cumulative risk) than smaller ones.² Mid-descending aortic aneurysms expand faster than those of the ascending aorta.³

Indications for surgery include rupture, severe chest pain, compressive symptoms, large size (eg, ≥ 5.5 cm for asymptomatic descending thoracic aneurysms), and rapid growth rate (≥ 10 mm per year), all of which are associated with a higher mortality rate.⁴

Endovascular grafting should be strongly considered in patients who have significant comorbidities, but this approach may have poorer long-term outcomes compared with open surgery. Blood pressure should be lowered as far as the patient can tolerate without adverse effects, usually with a beta-blocker along with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.⁴

Statin therapy to lower the low-density lipoprotein cholesterol level to less than 70 mg/dL is also needed to reduce the risk of complications and cardiovascular disease.

All patients with saccular aortic aneurysm should be followed closely and be evaluated for surgery.

A 46-year-old man with poorly controlled hypertension presented with the sudden onset of chest pain and shortness of breath. His blood pressure was 158/96 mm Hg and his left ventricular ejection fraction was less than 20%. He was admitted to the hospital for newly diagnosed heart failure.

SACCULAR AORTIC ANEURYSMS

This case shows the value of carefully examining the chest radiograph, especially behind the heart.

Saccular aneurysms of the descending thoracic aorta are rare and can be easily missed if asymptomatic. They are less common than fusiform aneurysms and may be more prone to rupture. Shang et al¹ identified atherosclerosis as the most frequent cause of saccular aneurysms of the thoracic aorta. However, they can be caused by other inflammatory conditions and infections.¹

Without surgical repair, thoracic aortic aneurysms larger than 6 cm have higher rates of expansion and rupture (a 20% 6-year cumulative risk) than smaller ones.² Mid-descending aortic aneurysms expand faster than those of the ascending aorta.³

Indications for surgery include rupture, severe chest pain, compressive symptoms, large size (eg, ≥ 5.5 cm for asymptomatic descending thoracic aneurysms), and rapid growth rate (≥ 10 mm per year), all of which are associated with a higher mortality rate.⁴

Endovascular grafting should be strongly considered in patients who have significant comorbidities, but this approach may have poorer long-term outcomes compared with open surgery. Blood pressure should be lowered as far as the patient can tolerate without adverse effects, usually with a beta-blocker along with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.⁴

Statin therapy to lower the low-density lipoprotein cholesterol level to less than 70 mg/dL is also needed to reduce the risk of complications and cardiovascular disease.

All patients with saccular aortic aneurysm should be followed closely and be evaluated for surgery.

A 46-year-old man with poorly controlled hypertension presented with the sudden onset of chest pain and shortness of breath. His blood pressure was 158/96 mm Hg and his left ventricular ejection fraction was less than 20%. He was admitted to the hospital for newly diagnosed heart failure.

SACCULAR AORTIC ANEURYSMS

This case shows the value of carefully examining the chest radiograph, especially behind the heart.

Saccular aneurysms of the descending thoracic aorta are rare and can be easily missed if asymptomatic. They are less common than fusiform aneurysms and may be more prone to rupture. Shang et al¹ identified atherosclerosis as the most frequent cause of saccular aneurysms of the thoracic aorta. However, they can be caused by other inflammatory conditions and infections.¹

Without surgical repair, thoracic aortic aneurysms larger than 6 cm have higher rates of expansion and rupture (a 20% 6-year cumulative risk) than smaller ones.² Mid-descending aortic aneurysms expand faster than those of the ascending aorta.³

Indications for surgery include rupture, severe chest pain, compressive symptoms, large size (eg, ≥ 5.5 cm for asymptomatic descending thoracic aneurysms), and rapid growth rate (≥ 10 mm per year), all of which are associated with a higher mortality rate.⁴

Endovascular grafting should be strongly considered in patients who have significant comorbidities, but this approach may have poorer long-term outcomes compared with open surgery. Blood pressure should be lowered as far as the patient can tolerate without adverse effects, usually with a beta-blocker along with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.⁴

Statin therapy to lower the low-density lipoprotein cholesterol level to less than 70 mg/dL is also needed to reduce the risk of complications and cardiovascular disease.

All patients with saccular aortic aneurysm should be followed closely and be evaluated for surgery.

Ultrasonography has been used to evaluate musculoskeletal problems for decades but has only recently become more widely available in the United States. Advances in technology and physician familiarity are increasing its role in orthopedic imaging.

See related editorial

No single imaging method can yield all musculoskeletal diagnoses. Like any imaging technique, ultrasonography has strengths and weaknesses specific to orthopedics. Radiography, computed tomography (CT), and magnetic resonance imaging (MRI) play important roles for investigating musculoskeletal problems and are complementary to each other and to ultrasonography.

To help clinicians make informed decisions about ordering musculoskeletal ultrasonography, this article reviews the basic physics underlying ultrasonography, its advantages and disadvantages compared with other imaging methods, and common clinical applications.

CLASSIC TECHNOLOGY MAKING A RESURGENCE

The first reports of the use of musculoskeletal ultrasonography appeared in the 1970s for investigating the rotator cuff,^1–3 actually preceding reports of its use in obstetrics and gynecology.⁴ In the 1980s, reports emerged for evaluating the Achilles tendon.^5,6 After that, its popularity in the United States plateaued, likely because of the advent of MRI, lower reimbursement and greater variability in interpretation compared with MRI, as well as a lack of physicians and sonographers trained in its use.^7,8

Musculoskeletal ultrasonography is currently experiencing a resurgence. Although it remains a specialized service more commonly available in large hospitals, its use is increasing rapidly, and it will likely become more widely available.

SPECIAL TRAINING REQUIRED

Musculoskeletal ultrasonography is simply an ultrasonographic examination of part of the musculoskeletal system. But because not all ultrasonographic transducers offer sufficient resolution for musculoskeletal evaluation and not all sonographers and imaging physicians are familiar with the specialized techniques, musculoskeletal ultrasonography often has a separate designation (eg, “MSKUS,” “MSUS”). At Cleveland Clinic, it is offered through the department of musculoskeletal imaging by subspecialty-trained musculoskeletal radiologists and specially trained musculoskeletal ultrasonographers with 4 to 5 years of training in the technique.

Musculoskeletal ultrasonography is also performed by physician groups with specialized training, including sports medicine physicians, rheumatologists, physiatrists, neurologists, and orthopedic surgeons. The American Institute of Ultrasound in Medicine offers voluntary accreditation for practice groups using musculoskeletal ultrasonography. Certification in musculoskeletal radiology is offered to sonographers through the American Registry for Diagnostic Medical Sonography.

SONOGRAPHY HAS UNIQUE QUALITIES

Ultrasonography uses high-frequency sound waves to generate images. The transducer (or probe) emits sound from the many piezoelectric elements at its surface, and the sound waves travel through and react with tissues. Sound reflected by tissues is detected by the transducer and converted to an image. Objects that reflect sound appear hyperechoic (brighter), whereas tissues that reflect little or no sound appear hypoechoic.

High-resolution imaging of superficial structures

Ultrasonography involves a fundamental trade-off between image resolution and imaging depth. Higher-frequency sound waves do not penetrate far into tissues but generate a higher-resolution image; lower-frequency sound waves can penetrate much further but yield a lower-resolution image. Although high-resolution imaging of deep structures with ultrasonography is not possible (Figure 1), many musculoskeletal structures are located superficially and are amenable to ultrasonographic evaluation.

Be aware of artifacts

Some materials attenuate sound very little, such as simple fluid. Low attenuation results in artifacts on ultrasonography, making tissues behind the simple fluid appear brighter than neighboring tissues. These artifacts may be reported as “increased through transmission” or “posterior acoustic enhancement.” Conversely, metal and bone reflect all sound waves that reach them, rendering any structures beyond them invisible. This “shadowing” creates a problem for imaging of structures in or near bone. Subcutaneous fat also attenuates sound waves, limiting the use of ultrasonography for patients with obesity (Figure 2).

High-frequency linear transducer sharpens images

High-frequency linear transducers reduce anisotropy because their flat surface keeps sound waves more uniformly perpendicular to the structure of interest.^4,7 Their development has allowed imaging of superficial structures that is superior to that of MRI. A high-frequency linear transducer offers more than twice the spatial resolution of a typical 1.5T MRI examination of superficial tissue.^12,13

Operator experience is critical

Ultrasonography examinations, more than other imaging tests, are dependent on operator experience. A solid understanding of musculoskeletal anatomy is imperative. Because the probe images only a thin section of tissue (about the thickness of a credit card), referencing adjacent structures for orientation is more difficult with ultrasonography than with CT or MRI.

The accuracy of ultrasonography is highly dependent on acquiring and interpreting images, whereas the accuracy of MRI is dependent primarily on image interpretation.⁷ Interpreting physicians must check that sonographers capture relevant targets.

 

 

STRENGTHS OF MUSCULOSKELETAL ULTRASONOGRAPHY

Ultrasonography has multiple advantages:

No ionizing radiation exposure.

Portability. Unlike CT or MRI, ultrasonography equipment is portable.

Increased patient comfort. Patient positioning for an ultrasonography examination is more flexible than for MRI or CT,¹⁴ and the examination does not induce claustrophobia.⁸

High-resolution imaging. Ultrasonography provides very-high-resolution imaging of superficial soft tissues—in some cases, higher than MRI or CT.

Real-time dynamic examinations are possible with ultrasonography, unlike with CT or MRI, and may increase test sensitivity.^4,15–18

Implanted hardware is less of a problem. Although ultrasonography cannot image beyond implanted orthopedic metallic hardware, the hardware does not obscure surrounding soft tissues as it does on CT and MRI.^6,19,20 Also, ultrasonography is safe for patients with a pacemaker.⁸

WEAKNESSES

The main disadvantages of musculoskeletal ultrasonography are inherent to its limited field of view, making it inappropriate for a survey examination (eg, for ankle pain, knee pain,  hip pain).⁴ Unlike CT and MRI, ultrasonography does not provide a “bird’s-eye view,” and important abnormalities can be missed during evaluation of large areas (Figure 4).

Ultrasonography also cannot evaluate bone or intra-articular structures such as cartilage, bone marrow, labrum, and intra-articular ligaments; MRI is the standard for evaluating these structures.²¹

Ultrasonography is time-consuming. To perform a detailed examination of the anterior, posterior, medial, and lateral aspects of the hip, knee, or ankle would require 1.5 to 2 hours of scanning time and an additional 10 to 25 minutes of image checking and interpretation.

CURRENT CLINICAL INDICATIONS

Musculoskeletal ultrasonography is best used for clinical questions regarding limited, superficial musculoskeletal problems.

Fluid collections

Ultrasonography can help evaluate small fluid collections in soft tissue. As is true for a lung opacity on chest radiography, soft-tissue fluid detected on ultrasonography is nonspecific, and results must be correlated with the clinical picture to narrow the differential diagnosis.

Fluid collections can be classified as loculated or nonloculated.

Nonloculated fluid involves more fluid than is simply interposed between tissue planes and has no wall or defined margins. It can be simple or complex in appearance: simple fluid is anechoic, and complex fluid appears more heterogeneous and may contain septations or debris.

Subcutaneous edema, which may occur postoperatively or from trauma, venous insufficiency, or inflammatory or infectious processes, appears on ultrasonography as nonloculated fluid interspersed between subcutaneous fat lobules.

Loculated fluid collections have well-defined margins or a discrete wall that does not follow normal tissue planes. They can also be simple or complex and can be caused by hematoma, abscess, or ganglion. Less commonly, neoplasms can mimic a loculated fluid collection (Figure 4).

A ganglion is a specific type of loculated fluid collection containing synovial fluid arising from a joint or tendon sheath. It tends to occur in specific locations, most commonly around the wrist, most often arising from the dorsal scapholunate ligament and volar wrist between the radial artery and flexor carpi radialis.²² On MRI, it can be difficult to distinguish between small vascular structures and a small ganglion, especially in the hands and feet.²³

Ultrasonography can also help identify a  Baker cyst, a specific fluid collection arising from the semimembranosus bursa between the medial head of the gastrocnemius tendon and the semimembranosus tendon. Ultrasonography can also detect inflammation, rupture, or leaking associated with a Baker cyst.²⁴

Power Doppler is an ultrasonographic examination that can detect increased blood flow surrounding a fluid collection and determine the likelihood of an acute inflammatory or infectious cause.²⁵

Joint effusion and synovitis

Musculoskeletal ultrasonography can help evaluate joints for effusion and synovitis. It is highly sensitive (94%) and specific (95%) for synovitis, making it superior to contrast-enhanced MRI.^26,27 The area of concern should be limited to 1 quadrant of a joint (anterior, posterior, medial, or lateral); for problems beyond that, MRI should be considered.

A joint effusion appears as a distended joint capsule containing hypoechoic (complex) or anechoic (simple) joint fluid.

Complex joint fluid may contain debris and occurs with hemarthrosis, infection, and inflammation.²³ Hypertrophied synovium is hypoechoic and can mimic complex joint fluid.

Power Doppler evaluation can help distinguish synovitis from joint fluid by demonstrating blood flow, a feature of synovitis but not of simple joint fluid. Power Doppler is the most sensitive means of detecting blood flow, although it does not show direction of flow.²⁸

Using ultrasonography can help to improve disease control and minimize disabling changes by monitoring synovitis therapy. In addition, subclinical synovitis and enthesitis (inflammation of insertion sites of tendons or ligaments into bone) detected by ultrasonography may predict future disease and disease flares.^29–31

Ultrasonographic guidance for a wide range of procedures is increasing rapidly.^32–36 Multiple studies have shown the advantage of ultrasonography-guided aspiration and injection compared with techniques without imaging guidance.^37,38

Soft-tissue masses

Accurately diagnosing soft-tissue masses can be difficult. A mass may remain indeterminate even after multiple imaging studies, requiring biopsy or surgical referral. However, for a few specific masses, ultrasonography is highly accurate and can eliminate the need for further imaging.

Ultrasonography can help evaluate soft- tissue masses no larger than 5 cm in diameter and no deeper than superficial muscular fascia. If the mass is larger or deeper than that, ultrasonography is less reliable for showing the margins of the mass and its relationship to adjacent structures (Figure 5). Further imaging by MRI may be recommended in such cases.

Fortunately, many of the most common soft-tissue masses can be accurately diagnosed with ultrasonography, including lipomas, ganglion cysts, foreign bodies, and simple fluid collections.^4,39 Nerve-sheath tumors can also be diagnosed with ultrasonography if the lesion clearly arises from a nerve. Other soft-tissue masses are likely to be indeterminate with ultrasonography, requiring follow-up with MRI with contrast.

 

 

Tendons

Musculoskeletal ultrasonography can be effective for evaluating tendons around joints, especially 1 or a small number of nearby superficial tendons. Tendons particularly well suited for ultrasonographic examination include:

• Upper-extremity tendons located in the rotator cuff or around the elbow, and flexor and extensor tendons of the hands; ultrasonographic evaluation of the rotator cuff is highly accurate, equivalent to that of MRI for partial-thickness and full-thickness tearing^40–43
• Lower-extremity tendons of the extensor mechanism of the knee, distal hamstring tendons, tendons around the ankle,^44–46 and flexor and extensor tendons of the foot.

Ultrasonography can help diagnose a variety of tendon abnormalities (Table 1),^48,49 including tearing, for which a dynamic examination can be performed.

Many tendons have a tendon sheath containing tenosynovium, while others have surrounding peritenon only; either can become thickened and inflamed. Tenosynovitis is a nonspecific finding and may be inflammatory, infectious, or posttraumatic. The presence of tendon sheath fluid alone on ultrasonography can be a normal finding, and some tendon sheaths that communicate with adjacent joints (eg, the long head biceps tendon, the flexor hallucis longus tendon) commonly contain simple fluid.⁶ A dynamic examination with ultrasonography can help diagnose snapping related to abnormal tendon movement, for example, in the case of intra-sheath and extra-sheath subluxation of the peroneal tendons.^45,50,51

Ligaments

Ultrasonography can detect abnormalities in many superficial ligaments (Table 1).

Ankle. Ankle ligaments are superficial and can be clearly visualized. The diagnostic accuracy of ultrasonography for tearing of the anterior talofibular ligament may be as high as 100%.^50,52,53

Elbow and thumb. The larger of the collateral ligaments of the elbow, especially the ulnar collateral ligament, and the ulnar collateral ligament of the thumb can be effectively evaluated with ultrasonography.^54,55

Knee. The collateral ligaments of the knee can be seen with ultrasonography, but injuries of the external ligaments of the knee are often associated with intrinsic derangements that cannot be evaluated with ultrasonography.^56,57 Intra-articular ligaments such as the anterior cruciate ligament are also not amenable to ultrasonography.

Dynamic examination of a ligament with ultrasonography can help determine the grade of the injury.

Deeply located ligaments (eg, around the hip) and ligaments surrounded by bone, such as the Lisfranc ligament, cannot be completely seen on ultrasonography.

Muscle

Musculoskeletal ultrasonography is useful for small areas of concern within a muscle (Table 1). It can detect muscle strains and tears, intramuscular collections or lesions, and fascial scarring or fascial injuries such as superficial muscle herniation. Although ultrasonography may yield a definitive diagnosis for a muscle problem, further imaging may be needed.

Nerves

Ultrasonography is useful for peripheral nerve investigation but requires a steep learning curve for sonographers and interpreting physicians.^58,59 It is best suited for directed questions regarding focal abnormal nerve findings on physical examination.

Ultrasonography can help identify areas of nerve entrapment caused by a mass or dynamic compression. It can detect neuritis (Table 1), lesions of peripheral nerves (eg, nerve-sheath tumors), and neuromas (eg, Morton neuroma of the intermetatarsal space). In a large meta-analysis, ultrasonography and MRI were found to be equally accurate for detecting Morton neuroma.⁶⁰ Even for nerve-sheath tumors located deep to the muscular fascia, ultrasonography can confirm the diagnosis because of the characteristic appearance of the nerves. Ultrasonography can also demonstrate a large extent of the course of superficial peripheral nerves while keeping the imaging plane appropriately oriented to the nerves.

Acknowledgment: We would like to sincerely thank Megan Griffiths, MA, for her help in the preparation and submission of this manuscript.

Ultrasonography has been used to evaluate musculoskeletal problems for decades but has only recently become more widely available in the United States. Advances in technology and physician familiarity are increasing its role in orthopedic imaging.

See related editorial

No single imaging method can yield all musculoskeletal diagnoses. Like any imaging technique, ultrasonography has strengths and weaknesses specific to orthopedics. Radiography, computed tomography (CT), and magnetic resonance imaging (MRI) play important roles for investigating musculoskeletal problems and are complementary to each other and to ultrasonography.

To help clinicians make informed decisions about ordering musculoskeletal ultrasonography, this article reviews the basic physics underlying ultrasonography, its advantages and disadvantages compared with other imaging methods, and common clinical applications.

CLASSIC TECHNOLOGY MAKING A RESURGENCE

The first reports of the use of musculoskeletal ultrasonography appeared in the 1970s for investigating the rotator cuff,^1–3 actually preceding reports of its use in obstetrics and gynecology.⁴ In the 1980s, reports emerged for evaluating the Achilles tendon.^5,6 After that, its popularity in the United States plateaued, likely because of the advent of MRI, lower reimbursement and greater variability in interpretation compared with MRI, as well as a lack of physicians and sonographers trained in its use.^7,8

Musculoskeletal ultrasonography is currently experiencing a resurgence. Although it remains a specialized service more commonly available in large hospitals, its use is increasing rapidly, and it will likely become more widely available.

SPECIAL TRAINING REQUIRED

Musculoskeletal ultrasonography is simply an ultrasonographic examination of part of the musculoskeletal system. But because not all ultrasonographic transducers offer sufficient resolution for musculoskeletal evaluation and not all sonographers and imaging physicians are familiar with the specialized techniques, musculoskeletal ultrasonography often has a separate designation (eg, “MSKUS,” “MSUS”). At Cleveland Clinic, it is offered through the department of musculoskeletal imaging by subspecialty-trained musculoskeletal radiologists and specially trained musculoskeletal ultrasonographers with 4 to 5 years of training in the technique.

Musculoskeletal ultrasonography is also performed by physician groups with specialized training, including sports medicine physicians, rheumatologists, physiatrists, neurologists, and orthopedic surgeons. The American Institute of Ultrasound in Medicine offers voluntary accreditation for practice groups using musculoskeletal ultrasonography. Certification in musculoskeletal radiology is offered to sonographers through the American Registry for Diagnostic Medical Sonography.

SONOGRAPHY HAS UNIQUE QUALITIES

Ultrasonography uses high-frequency sound waves to generate images. The transducer (or probe) emits sound from the many piezoelectric elements at its surface, and the sound waves travel through and react with tissues. Sound reflected by tissues is detected by the transducer and converted to an image. Objects that reflect sound appear hyperechoic (brighter), whereas tissues that reflect little or no sound appear hypoechoic.

High-resolution imaging of superficial structures

Ultrasonography involves a fundamental trade-off between image resolution and imaging depth. Higher-frequency sound waves do not penetrate far into tissues but generate a higher-resolution image; lower-frequency sound waves can penetrate much further but yield a lower-resolution image. Although high-resolution imaging of deep structures with ultrasonography is not possible (Figure 1), many musculoskeletal structures are located superficially and are amenable to ultrasonographic evaluation.

Be aware of artifacts

Some materials attenuate sound very little, such as simple fluid. Low attenuation results in artifacts on ultrasonography, making tissues behind the simple fluid appear brighter than neighboring tissues. These artifacts may be reported as “increased through transmission” or “posterior acoustic enhancement.” Conversely, metal and bone reflect all sound waves that reach them, rendering any structures beyond them invisible. This “shadowing” creates a problem for imaging of structures in or near bone. Subcutaneous fat also attenuates sound waves, limiting the use of ultrasonography for patients with obesity (Figure 2).

High-frequency linear transducer sharpens images

High-frequency linear transducers reduce anisotropy because their flat surface keeps sound waves more uniformly perpendicular to the structure of interest.^4,7 Their development has allowed imaging of superficial structures that is superior to that of MRI. A high-frequency linear transducer offers more than twice the spatial resolution of a typical 1.5T MRI examination of superficial tissue.^12,13

Operator experience is critical

Ultrasonography examinations, more than other imaging tests, are dependent on operator experience. A solid understanding of musculoskeletal anatomy is imperative. Because the probe images only a thin section of tissue (about the thickness of a credit card), referencing adjacent structures for orientation is more difficult with ultrasonography than with CT or MRI.

The accuracy of ultrasonography is highly dependent on acquiring and interpreting images, whereas the accuracy of MRI is dependent primarily on image interpretation.⁷ Interpreting physicians must check that sonographers capture relevant targets.

 

 

STRENGTHS OF MUSCULOSKELETAL ULTRASONOGRAPHY

Ultrasonography has multiple advantages:

No ionizing radiation exposure.

Portability. Unlike CT or MRI, ultrasonography equipment is portable.

Increased patient comfort. Patient positioning for an ultrasonography examination is more flexible than for MRI or CT,¹⁴ and the examination does not induce claustrophobia.⁸

High-resolution imaging. Ultrasonography provides very-high-resolution imaging of superficial soft tissues—in some cases, higher than MRI or CT.

Real-time dynamic examinations are possible with ultrasonography, unlike with CT or MRI, and may increase test sensitivity.^4,15–18

Implanted hardware is less of a problem. Although ultrasonography cannot image beyond implanted orthopedic metallic hardware, the hardware does not obscure surrounding soft tissues as it does on CT and MRI.^6,19,20 Also, ultrasonography is safe for patients with a pacemaker.⁸

WEAKNESSES

The main disadvantages of musculoskeletal ultrasonography are inherent to its limited field of view, making it inappropriate for a survey examination (eg, for ankle pain, knee pain,  hip pain).⁴ Unlike CT and MRI, ultrasonography does not provide a “bird’s-eye view,” and important abnormalities can be missed during evaluation of large areas (Figure 4).

Ultrasonography also cannot evaluate bone or intra-articular structures such as cartilage, bone marrow, labrum, and intra-articular ligaments; MRI is the standard for evaluating these structures.²¹

Ultrasonography is time-consuming. To perform a detailed examination of the anterior, posterior, medial, and lateral aspects of the hip, knee, or ankle would require 1.5 to 2 hours of scanning time and an additional 10 to 25 minutes of image checking and interpretation.

CURRENT CLINICAL INDICATIONS

Musculoskeletal ultrasonography is best used for clinical questions regarding limited, superficial musculoskeletal problems.

Fluid collections

Ultrasonography can help evaluate small fluid collections in soft tissue. As is true for a lung opacity on chest radiography, soft-tissue fluid detected on ultrasonography is nonspecific, and results must be correlated with the clinical picture to narrow the differential diagnosis.

Fluid collections can be classified as loculated or nonloculated.

Nonloculated fluid involves more fluid than is simply interposed between tissue planes and has no wall or defined margins. It can be simple or complex in appearance: simple fluid is anechoic, and complex fluid appears more heterogeneous and may contain septations or debris.

Subcutaneous edema, which may occur postoperatively or from trauma, venous insufficiency, or inflammatory or infectious processes, appears on ultrasonography as nonloculated fluid interspersed between subcutaneous fat lobules.

Loculated fluid collections have well-defined margins or a discrete wall that does not follow normal tissue planes. They can also be simple or complex and can be caused by hematoma, abscess, or ganglion. Less commonly, neoplasms can mimic a loculated fluid collection (Figure 4).

A ganglion is a specific type of loculated fluid collection containing synovial fluid arising from a joint or tendon sheath. It tends to occur in specific locations, most commonly around the wrist, most often arising from the dorsal scapholunate ligament and volar wrist between the radial artery and flexor carpi radialis.²² On MRI, it can be difficult to distinguish between small vascular structures and a small ganglion, especially in the hands and feet.²³

Ultrasonography can also help identify a  Baker cyst, a specific fluid collection arising from the semimembranosus bursa between the medial head of the gastrocnemius tendon and the semimembranosus tendon. Ultrasonography can also detect inflammation, rupture, or leaking associated with a Baker cyst.²⁴

Power Doppler is an ultrasonographic examination that can detect increased blood flow surrounding a fluid collection and determine the likelihood of an acute inflammatory or infectious cause.²⁵

Joint effusion and synovitis

Musculoskeletal ultrasonography can help evaluate joints for effusion and synovitis. It is highly sensitive (94%) and specific (95%) for synovitis, making it superior to contrast-enhanced MRI.^26,27 The area of concern should be limited to 1 quadrant of a joint (anterior, posterior, medial, or lateral); for problems beyond that, MRI should be considered.

A joint effusion appears as a distended joint capsule containing hypoechoic (complex) or anechoic (simple) joint fluid.

Complex joint fluid may contain debris and occurs with hemarthrosis, infection, and inflammation.²³ Hypertrophied synovium is hypoechoic and can mimic complex joint fluid.

Power Doppler evaluation can help distinguish synovitis from joint fluid by demonstrating blood flow, a feature of synovitis but not of simple joint fluid. Power Doppler is the most sensitive means of detecting blood flow, although it does not show direction of flow.²⁸

Using ultrasonography can help to improve disease control and minimize disabling changes by monitoring synovitis therapy. In addition, subclinical synovitis and enthesitis (inflammation of insertion sites of tendons or ligaments into bone) detected by ultrasonography may predict future disease and disease flares.^29–31

Ultrasonographic guidance for a wide range of procedures is increasing rapidly.^32–36 Multiple studies have shown the advantage of ultrasonography-guided aspiration and injection compared with techniques without imaging guidance.^37,38

Soft-tissue masses

Accurately diagnosing soft-tissue masses can be difficult. A mass may remain indeterminate even after multiple imaging studies, requiring biopsy or surgical referral. However, for a few specific masses, ultrasonography is highly accurate and can eliminate the need for further imaging.

Ultrasonography can help evaluate soft- tissue masses no larger than 5 cm in diameter and no deeper than superficial muscular fascia. If the mass is larger or deeper than that, ultrasonography is less reliable for showing the margins of the mass and its relationship to adjacent structures (Figure 5). Further imaging by MRI may be recommended in such cases.

Fortunately, many of the most common soft-tissue masses can be accurately diagnosed with ultrasonography, including lipomas, ganglion cysts, foreign bodies, and simple fluid collections.^4,39 Nerve-sheath tumors can also be diagnosed with ultrasonography if the lesion clearly arises from a nerve. Other soft-tissue masses are likely to be indeterminate with ultrasonography, requiring follow-up with MRI with contrast.

 

 

Tendons

Musculoskeletal ultrasonography can be effective for evaluating tendons around joints, especially 1 or a small number of nearby superficial tendons. Tendons particularly well suited for ultrasonographic examination include:

• Upper-extremity tendons located in the rotator cuff or around the elbow, and flexor and extensor tendons of the hands; ultrasonographic evaluation of the rotator cuff is highly accurate, equivalent to that of MRI for partial-thickness and full-thickness tearing^40–43
• Lower-extremity tendons of the extensor mechanism of the knee, distal hamstring tendons, tendons around the ankle,^44–46 and flexor and extensor tendons of the foot.

Ultrasonography can help diagnose a variety of tendon abnormalities (Table 1),^48,49 including tearing, for which a dynamic examination can be performed.

Many tendons have a tendon sheath containing tenosynovium, while others have surrounding peritenon only; either can become thickened and inflamed. Tenosynovitis is a nonspecific finding and may be inflammatory, infectious, or posttraumatic. The presence of tendon sheath fluid alone on ultrasonography can be a normal finding, and some tendon sheaths that communicate with adjacent joints (eg, the long head biceps tendon, the flexor hallucis longus tendon) commonly contain simple fluid.⁶ A dynamic examination with ultrasonography can help diagnose snapping related to abnormal tendon movement, for example, in the case of intra-sheath and extra-sheath subluxation of the peroneal tendons.^45,50,51

Ligaments

Ultrasonography can detect abnormalities in many superficial ligaments (Table 1).

Ankle. Ankle ligaments are superficial and can be clearly visualized. The diagnostic accuracy of ultrasonography for tearing of the anterior talofibular ligament may be as high as 100%.^50,52,53

Elbow and thumb. The larger of the collateral ligaments of the elbow, especially the ulnar collateral ligament, and the ulnar collateral ligament of the thumb can be effectively evaluated with ultrasonography.^54,55

Knee. The collateral ligaments of the knee can be seen with ultrasonography, but injuries of the external ligaments of the knee are often associated with intrinsic derangements that cannot be evaluated with ultrasonography.^56,57 Intra-articular ligaments such as the anterior cruciate ligament are also not amenable to ultrasonography.

Dynamic examination of a ligament with ultrasonography can help determine the grade of the injury.

Deeply located ligaments (eg, around the hip) and ligaments surrounded by bone, such as the Lisfranc ligament, cannot be completely seen on ultrasonography.

Muscle

Musculoskeletal ultrasonography is useful for small areas of concern within a muscle (Table 1). It can detect muscle strains and tears, intramuscular collections or lesions, and fascial scarring or fascial injuries such as superficial muscle herniation. Although ultrasonography may yield a definitive diagnosis for a muscle problem, further imaging may be needed.

Nerves

Ultrasonography is useful for peripheral nerve investigation but requires a steep learning curve for sonographers and interpreting physicians.^58,59 It is best suited for directed questions regarding focal abnormal nerve findings on physical examination.

Ultrasonography can help identify areas of nerve entrapment caused by a mass or dynamic compression. It can detect neuritis (Table 1), lesions of peripheral nerves (eg, nerve-sheath tumors), and neuromas (eg, Morton neuroma of the intermetatarsal space). In a large meta-analysis, ultrasonography and MRI were found to be equally accurate for detecting Morton neuroma.⁶⁰ Even for nerve-sheath tumors located deep to the muscular fascia, ultrasonography can confirm the diagnosis because of the characteristic appearance of the nerves. Ultrasonography can also demonstrate a large extent of the course of superficial peripheral nerves while keeping the imaging plane appropriately oriented to the nerves.

Acknowledgment: We would like to sincerely thank Megan Griffiths, MA, for her help in the preparation and submission of this manuscript.

Ultrasonography has been used to evaluate musculoskeletal problems for decades but has only recently become more widely available in the United States. Advances in technology and physician familiarity are increasing its role in orthopedic imaging.

See related editorial

No single imaging method can yield all musculoskeletal diagnoses. Like any imaging technique, ultrasonography has strengths and weaknesses specific to orthopedics. Radiography, computed tomography (CT), and magnetic resonance imaging (MRI) play important roles for investigating musculoskeletal problems and are complementary to each other and to ultrasonography.

To help clinicians make informed decisions about ordering musculoskeletal ultrasonography, this article reviews the basic physics underlying ultrasonography, its advantages and disadvantages compared with other imaging methods, and common clinical applications.

CLASSIC TECHNOLOGY MAKING A RESURGENCE

The first reports of the use of musculoskeletal ultrasonography appeared in the 1970s for investigating the rotator cuff,^1–3 actually preceding reports of its use in obstetrics and gynecology.⁴ In the 1980s, reports emerged for evaluating the Achilles tendon.^5,6 After that, its popularity in the United States plateaued, likely because of the advent of MRI, lower reimbursement and greater variability in interpretation compared with MRI, as well as a lack of physicians and sonographers trained in its use.^7,8

Musculoskeletal ultrasonography is currently experiencing a resurgence. Although it remains a specialized service more commonly available in large hospitals, its use is increasing rapidly, and it will likely become more widely available.

SPECIAL TRAINING REQUIRED

Musculoskeletal ultrasonography is simply an ultrasonographic examination of part of the musculoskeletal system. But because not all ultrasonographic transducers offer sufficient resolution for musculoskeletal evaluation and not all sonographers and imaging physicians are familiar with the specialized techniques, musculoskeletal ultrasonography often has a separate designation (eg, “MSKUS,” “MSUS”). At Cleveland Clinic, it is offered through the department of musculoskeletal imaging by subspecialty-trained musculoskeletal radiologists and specially trained musculoskeletal ultrasonographers with 4 to 5 years of training in the technique.

Musculoskeletal ultrasonography is also performed by physician groups with specialized training, including sports medicine physicians, rheumatologists, physiatrists, neurologists, and orthopedic surgeons. The American Institute of Ultrasound in Medicine offers voluntary accreditation for practice groups using musculoskeletal ultrasonography. Certification in musculoskeletal radiology is offered to sonographers through the American Registry for Diagnostic Medical Sonography.

SONOGRAPHY HAS UNIQUE QUALITIES

Ultrasonography uses high-frequency sound waves to generate images. The transducer (or probe) emits sound from the many piezoelectric elements at its surface, and the sound waves travel through and react with tissues. Sound reflected by tissues is detected by the transducer and converted to an image. Objects that reflect sound appear hyperechoic (brighter), whereas tissues that reflect little or no sound appear hypoechoic.

High-resolution imaging of superficial structures

Ultrasonography involves a fundamental trade-off between image resolution and imaging depth. Higher-frequency sound waves do not penetrate far into tissues but generate a higher-resolution image; lower-frequency sound waves can penetrate much further but yield a lower-resolution image. Although high-resolution imaging of deep structures with ultrasonography is not possible (Figure 1), many musculoskeletal structures are located superficially and are amenable to ultrasonographic evaluation.

Be aware of artifacts

Some materials attenuate sound very little, such as simple fluid. Low attenuation results in artifacts on ultrasonography, making tissues behind the simple fluid appear brighter than neighboring tissues. These artifacts may be reported as “increased through transmission” or “posterior acoustic enhancement.” Conversely, metal and bone reflect all sound waves that reach them, rendering any structures beyond them invisible. This “shadowing” creates a problem for imaging of structures in or near bone. Subcutaneous fat also attenuates sound waves, limiting the use of ultrasonography for patients with obesity (Figure 2).

High-frequency linear transducer sharpens images

High-frequency linear transducers reduce anisotropy because their flat surface keeps sound waves more uniformly perpendicular to the structure of interest.^4,7 Their development has allowed imaging of superficial structures that is superior to that of MRI. A high-frequency linear transducer offers more than twice the spatial resolution of a typical 1.5T MRI examination of superficial tissue.^12,13

Operator experience is critical

Ultrasonography examinations, more than other imaging tests, are dependent on operator experience. A solid understanding of musculoskeletal anatomy is imperative. Because the probe images only a thin section of tissue (about the thickness of a credit card), referencing adjacent structures for orientation is more difficult with ultrasonography than with CT or MRI.

The accuracy of ultrasonography is highly dependent on acquiring and interpreting images, whereas the accuracy of MRI is dependent primarily on image interpretation.⁷ Interpreting physicians must check that sonographers capture relevant targets.

 

 

STRENGTHS OF MUSCULOSKELETAL ULTRASONOGRAPHY

Ultrasonography has multiple advantages:

No ionizing radiation exposure.

Portability. Unlike CT or MRI, ultrasonography equipment is portable.

Increased patient comfort. Patient positioning for an ultrasonography examination is more flexible than for MRI or CT,¹⁴ and the examination does not induce claustrophobia.⁸

High-resolution imaging. Ultrasonography provides very-high-resolution imaging of superficial soft tissues—in some cases, higher than MRI or CT.

Real-time dynamic examinations are possible with ultrasonography, unlike with CT or MRI, and may increase test sensitivity.^4,15–18

Implanted hardware is less of a problem. Although ultrasonography cannot image beyond implanted orthopedic metallic hardware, the hardware does not obscure surrounding soft tissues as it does on CT and MRI.^6,19,20 Also, ultrasonography is safe for patients with a pacemaker.⁸

WEAKNESSES

The main disadvantages of musculoskeletal ultrasonography are inherent to its limited field of view, making it inappropriate for a survey examination (eg, for ankle pain, knee pain,  hip pain).⁴ Unlike CT and MRI, ultrasonography does not provide a “bird’s-eye view,” and important abnormalities can be missed during evaluation of large areas (Figure 4).

Ultrasonography also cannot evaluate bone or intra-articular structures such as cartilage, bone marrow, labrum, and intra-articular ligaments; MRI is the standard for evaluating these structures.²¹

Ultrasonography is time-consuming. To perform a detailed examination of the anterior, posterior, medial, and lateral aspects of the hip, knee, or ankle would require 1.5 to 2 hours of scanning time and an additional 10 to 25 minutes of image checking and interpretation.

CURRENT CLINICAL INDICATIONS

Musculoskeletal ultrasonography is best used for clinical questions regarding limited, superficial musculoskeletal problems.

Fluid collections

Ultrasonography can help evaluate small fluid collections in soft tissue. As is true for a lung opacity on chest radiography, soft-tissue fluid detected on ultrasonography is nonspecific, and results must be correlated with the clinical picture to narrow the differential diagnosis.

Fluid collections can be classified as loculated or nonloculated.

Nonloculated fluid involves more fluid than is simply interposed between tissue planes and has no wall or defined margins. It can be simple or complex in appearance: simple fluid is anechoic, and complex fluid appears more heterogeneous and may contain septations or debris.

Subcutaneous edema, which may occur postoperatively or from trauma, venous insufficiency, or inflammatory or infectious processes, appears on ultrasonography as nonloculated fluid interspersed between subcutaneous fat lobules.

Loculated fluid collections have well-defined margins or a discrete wall that does not follow normal tissue planes. They can also be simple or complex and can be caused by hematoma, abscess, or ganglion. Less commonly, neoplasms can mimic a loculated fluid collection (Figure 4).

A ganglion is a specific type of loculated fluid collection containing synovial fluid arising from a joint or tendon sheath. It tends to occur in specific locations, most commonly around the wrist, most often arising from the dorsal scapholunate ligament and volar wrist between the radial artery and flexor carpi radialis.²² On MRI, it can be difficult to distinguish between small vascular structures and a small ganglion, especially in the hands and feet.²³

Ultrasonography can also help identify a  Baker cyst, a specific fluid collection arising from the semimembranosus bursa between the medial head of the gastrocnemius tendon and the semimembranosus tendon. Ultrasonography can also detect inflammation, rupture, or leaking associated with a Baker cyst.²⁴

Power Doppler is an ultrasonographic examination that can detect increased blood flow surrounding a fluid collection and determine the likelihood of an acute inflammatory or infectious cause.²⁵

Joint effusion and synovitis

Musculoskeletal ultrasonography can help evaluate joints for effusion and synovitis. It is highly sensitive (94%) and specific (95%) for synovitis, making it superior to contrast-enhanced MRI.^26,27 The area of concern should be limited to 1 quadrant of a joint (anterior, posterior, medial, or lateral); for problems beyond that, MRI should be considered.

A joint effusion appears as a distended joint capsule containing hypoechoic (complex) or anechoic (simple) joint fluid.

Complex joint fluid may contain debris and occurs with hemarthrosis, infection, and inflammation.²³ Hypertrophied synovium is hypoechoic and can mimic complex joint fluid.

Power Doppler evaluation can help distinguish synovitis from joint fluid by demonstrating blood flow, a feature of synovitis but not of simple joint fluid. Power Doppler is the most sensitive means of detecting blood flow, although it does not show direction of flow.²⁸

Using ultrasonography can help to improve disease control and minimize disabling changes by monitoring synovitis therapy. In addition, subclinical synovitis and enthesitis (inflammation of insertion sites of tendons or ligaments into bone) detected by ultrasonography may predict future disease and disease flares.^29–31

Ultrasonographic guidance for a wide range of procedures is increasing rapidly.^32–36 Multiple studies have shown the advantage of ultrasonography-guided aspiration and injection compared with techniques without imaging guidance.^37,38

Soft-tissue masses

Accurately diagnosing soft-tissue masses can be difficult. A mass may remain indeterminate even after multiple imaging studies, requiring biopsy or surgical referral. However, for a few specific masses, ultrasonography is highly accurate and can eliminate the need for further imaging.

Ultrasonography can help evaluate soft- tissue masses no larger than 5 cm in diameter and no deeper than superficial muscular fascia. If the mass is larger or deeper than that, ultrasonography is less reliable for showing the margins of the mass and its relationship to adjacent structures (Figure 5). Further imaging by MRI may be recommended in such cases.

Fortunately, many of the most common soft-tissue masses can be accurately diagnosed with ultrasonography, including lipomas, ganglion cysts, foreign bodies, and simple fluid collections.^4,39 Nerve-sheath tumors can also be diagnosed with ultrasonography if the lesion clearly arises from a nerve. Other soft-tissue masses are likely to be indeterminate with ultrasonography, requiring follow-up with MRI with contrast.

 

 

Tendons

Musculoskeletal ultrasonography can be effective for evaluating tendons around joints, especially 1 or a small number of nearby superficial tendons. Tendons particularly well suited for ultrasonographic examination include:

• Upper-extremity tendons located in the rotator cuff or around the elbow, and flexor and extensor tendons of the hands; ultrasonographic evaluation of the rotator cuff is highly accurate, equivalent to that of MRI for partial-thickness and full-thickness tearing^40–43
• Lower-extremity tendons of the extensor mechanism of the knee, distal hamstring tendons, tendons around the ankle,^44–46 and flexor and extensor tendons of the foot.

Ultrasonography can help diagnose a variety of tendon abnormalities (Table 1),^48,49 including tearing, for which a dynamic examination can be performed.

Many tendons have a tendon sheath containing tenosynovium, while others have surrounding peritenon only; either can become thickened and inflamed. Tenosynovitis is a nonspecific finding and may be inflammatory, infectious, or posttraumatic. The presence of tendon sheath fluid alone on ultrasonography can be a normal finding, and some tendon sheaths that communicate with adjacent joints (eg, the long head biceps tendon, the flexor hallucis longus tendon) commonly contain simple fluid.⁶ A dynamic examination with ultrasonography can help diagnose snapping related to abnormal tendon movement, for example, in the case of intra-sheath and extra-sheath subluxation of the peroneal tendons.^45,50,51

Ligaments

Ultrasonography can detect abnormalities in many superficial ligaments (Table 1).

Ankle. Ankle ligaments are superficial and can be clearly visualized. The diagnostic accuracy of ultrasonography for tearing of the anterior talofibular ligament may be as high as 100%.^50,52,53

Elbow and thumb. The larger of the collateral ligaments of the elbow, especially the ulnar collateral ligament, and the ulnar collateral ligament of the thumb can be effectively evaluated with ultrasonography.^54,55

Knee. The collateral ligaments of the knee can be seen with ultrasonography, but injuries of the external ligaments of the knee are often associated with intrinsic derangements that cannot be evaluated with ultrasonography.^56,57 Intra-articular ligaments such as the anterior cruciate ligament are also not amenable to ultrasonography.

Dynamic examination of a ligament with ultrasonography can help determine the grade of the injury.

Deeply located ligaments (eg, around the hip) and ligaments surrounded by bone, such as the Lisfranc ligament, cannot be completely seen on ultrasonography.

Muscle

Musculoskeletal ultrasonography is useful for small areas of concern within a muscle (Table 1). It can detect muscle strains and tears, intramuscular collections or lesions, and fascial scarring or fascial injuries such as superficial muscle herniation. Although ultrasonography may yield a definitive diagnosis for a muscle problem, further imaging may be needed.

Nerves

Ultrasonography is useful for peripheral nerve investigation but requires a steep learning curve for sonographers and interpreting physicians.^58,59 It is best suited for directed questions regarding focal abnormal nerve findings on physical examination.

Ultrasonography can help identify areas of nerve entrapment caused by a mass or dynamic compression. It can detect neuritis (Table 1), lesions of peripheral nerves (eg, nerve-sheath tumors), and neuromas (eg, Morton neuroma of the intermetatarsal space). In a large meta-analysis, ultrasonography and MRI were found to be equally accurate for detecting Morton neuroma.⁶⁰ Even for nerve-sheath tumors located deep to the muscular fascia, ultrasonography can confirm the diagnosis because of the characteristic appearance of the nerves. Ultrasonography can also demonstrate a large extent of the course of superficial peripheral nerves while keeping the imaging plane appropriately oriented to the nerves.

Acknowledgment: We would like to sincerely thank Megan Griffiths, MA, for her help in the preparation and submission of this manuscript.

Striving for athletic excellence, many young women—and some young men—create an energy deficit from increased exercise, decreased intake, or both. In women, the resulting energy deficit can suppress the menstrual cycle and in turn lead to bone demineralization in a syndrome called the female athlete triad.

See related editorial.

Primary care physicians should be aware of this syndrome because it can lead to short-term and long-term health complications, and they are in a good position to screen for, diagnose, and treat it. However, a study of 931 US physicians in 2015 found that only 37% had heard of it.¹

DEFINITION HAS CHANGED: ONLY 1 OF 3 COMPONENTS NEEDED

In 1972, Title IX of the Education Amendment Act was passed, prohibiting sex discrimination in any higher education program or activity receiving federal financial aid. Since then, female athletic participation in the United States has increased more than 10-fold.²

Also increasing has been awareness of the link between athletics, eating disorders, and amenorrhea. The American College of Sports Medicine coined the term female athlete triad in 1992, describing it as the constellation of disordered eating, amenorrhea, and osteoporosis (all 3 needed to be present).³ They broadened the definition in 2007 so that the syndrome can be diagnosed if any of the following is present⁴:

• Low energy availability (with or without an eating disorder)
• Menstrual dysfunction
• Decreased bone mineral density.

Recognizing that low energy availability can affect athletes of either sex and have consequences beyond the female reproductive system and skeleton, in 2014 the International Olympic Committee introduced a broader term called relative energy deficiency in sport.^5,6 Like the triad, this condition occurs when energy intake falls below energy output to the point that it negatively affects an athlete’s physical and mental health.

THE COMPONENTS ARE COMMON

The female athlete triad can be seen in high school, collegiate, and elite athletes⁷ and is especially common in sports with subjective judging (gymnastics, figure skating) or endurance sports that emphasize leanness (eg, running).⁸

In a review of 65 studies, Gibbs et al⁹ found that the prevalence of any one of the triad conditions in exercising women and female athletes ranged from 16.0% to 60.0%, the prevalence of any 2 ranged from 2.7% to 27.0%, and the prevalence of all 3 ranged from 0% to 15.9%.

Low energy availability is categorized as either intentional (ie, due to disordered eating) or unintentional (ie, due to activities not associated with eating). Sustained low energy availability is often associated with eating disorders and subsequent low self-esteem, depression, and anxiety disorders.⁴

The prevalence of eating disorders is high in female athletes—31% and 20% in 2 large studies of elite female athletes, compared with 5.5% and 9%, respectively, in the general population.^10,11 Another study found that the prevalence of disordered eating was 46.7% in sports that emphasize leanness, such as track and gymnastics, compared with 19.8% in sports that did not, such as basketball and soccer.¹²

Calorie restriction is common. In a study of 15 elite ballet dancers and 15 matched controls, the dancers were found to consume only about 3/4 as many calories per day as the controls (1,577 vs 2,075 kcal/day, P ≤ .01).¹³

Menstrual dysfunction. In small studies, the prevalence of secondary amenorrhea was as high as 69% in dancers and 65% in long-distance runners.^4,14–16

Decreased bone mineral density. According to a systematic review, the prevalence of osteopenia in amenorrheic athletes ranged between 22% and 50% and the prevalence of osteoporosis was 0% to 13%, compared with 12% and 2.3%, respectively, in the general population.¹⁷

THE COMPONENTS ARE LINKED

The 3 components of the female athlete triad—low energy availability, menstrual dysfunction, and decreased bone mineral density—are linked, and each exists on a spectrum (Figure 1). The long-term consequences are far-reaching and can affect the cardiovascular, endocrine, reproductive, skeletal, gastrointestinal, renal, and central nervous systems.

Low energy availability is the driving force of the triad, causing menstrual irregularity and subsequent low bone mineral density.

Menstrual dysfunction. Low energy availability can contribute to menstrual disturbances because the body suppresses reproductive function to prevent pregnancy. Functional hypothalamic amenorrhea results from decreased gonadotropin-releasing hormone leading to decreased gonadotropin release from the pituitary gland and, ultimately, to low circulating estrogen levels.¹⁸ Menstrual irregularities related to the triad include:

• Primary amenorrhea (a delay in menarche)
• Oligomenorrhea (menstrual cycles occurring at intervals greater than every 35 days)
• Secondary amenorrhea (cessation of menstruation for 3 consecutive months).

(Primary amenorrhea is defined as no menses by age 15 in the presence of normal secondary sexual development or within 5 years after breast development if that occurs before the age of 10. Secondary amenorrhea is defined as the loss of menses for 90 or more days after menarche.¹⁹)

In animal studies, reducing dietary intake by more than 30% resulted in infertility.⁴ Menstrual abnormalities can present as early as 5 days after a patient enters a state of low energy availability.²⁰ Symptoms of menstrual dysfunction are largely indicative of hypogonadism and include vaginal dryness, infertility, and impaired bone health.

Bone health in women with the female athlete triad can range from optimal to osteoporosis.

Low bone mineral density is a result of low energy availability and menstrual dysfunction leading to estrogen deficiency.^21,22 Specifically, menstrual abnormalities can result in low estrogen and overactivity of osteoclasts, while low energy availability alters the metabolic environment, inducing changes in insulinlike growth factor 1, leptin, and peptide YY, resulting in deficiencies in vitamin D and calcium—nutrients necessary for bone mineralization. In turn, bone health and density are compromised.^21,22

Ninety percent of peak bone mass is attained by age 18. Those who have low bone mineral density as part of the female athlete triad can suffer from long-lasting effects on their bone health.

 

 

SCREENING

Untreated, the triad can lead to fatigue, poor sports performance, and a number of serious comorbid conditions such as osteopenia and osteoporosis (leading to stress fractures) anemia, heart arrhythmias, and amenorrhea. Therefore, it is important for primary care providers to screen female athletes for the triad during routine office visits.

In 2014, the Triad Consensus Panel recommended screening female athletes at the high school and collegiate levels during a preparticipation physical evaluation and then every year by a primary care physician, athletic trainer, team physician, or coach.²³

Risk factors include signs of dietary restriction, low body mass index, delayed menarche, oligomenorrhea or amenorrhea, and bone stress reactions or fractures.²³ Athletes should be questioned about their menstrual history (age of menarche, frequency, and duration of menstrual cycles), history of stress fractures, medication history, family history (osteoporosis, eating disorders, and fractures),^24,25 and dietary habits.

Physical findings include low body mass index, recent weight loss, orthostatic hypotension, lanugo, hypercarotenemia, and signs of eating disorders (restrictive, binging, purging) (Table 1).^25–27

Additionally, it is important to ascertain if the patient receives critical comments regarding performance or body image from coaches, parents, or teammates and if sport-specific training began early in life.

Certain personality factors and behaviors are clues, such as perfectionism, obsessiveness, frequent weight cycling, and overtraining.^4,25 If any of the triad components are apparent, a deeper evaluation can be completed.

Specific screening questions

The Female Athlete Triad Coalition recommends asking 11 screening questions and having prompt discussions regarding the athlete’s nutritional status and body image.²³ If the patient gives a worrisome response to a screening question, further workup for a formal diagnosis should be initiated.

Questions about nutritional status.

• Do you worry about your weight?
• Are you trying to gain or lose weight, or has anyone recommended that you do so?
• Are you on a special diet or do you avoid certain types of foods or food groups?
• Have you ever had an eating disorder?

Questions about menstrual function.

• Have you ever had a menstrual period?
• How old were you when you had your first menstrual period?
• When was your most recent menstrual period?
• How many periods have you had in the last 12 months?
• Are you presently taking any female hormones (estrogen, progesterone, birth control pills)?

Questions about bone health.

• Have you ever had a stress fracture?
• Have you ever been told you have low bone density (osteopenia or osteoporosis)?

Along similar lines, the American Academy of Pediatrics, American Academy of Family Physicians, and American College of Sports Medicine²⁸ have a list of 7 questions:

• Do you worry about your weight?
• Do you limit the foods you eat?
• Do you lose weight to meet image requirements for sports?
• Have you ever suffered from an eating disorder?
• How old were you when you had your first menstrual period?
• How many menstrual cycles have you had in the past 12 months?
• Have you ever had a stress fracture?

These questions are not being widely used. A study of the National Collegiate Athletic Association Division I universities found that only 9% of universities included 9 or more of the recommended 12 questions that the Female Athlete Triad Coalition was recommending at that time, and 22% asked only 1 or 2 of the questions. None of the universities included all 12.²⁹ These findings are not surprising, given that screening for the triad is not state-mandated. Screening discrepancies among providers largely stem from knowledge gaps, nonstandardized questionnaires, lack of time at appointments, and the sensitive nature of the questioning (eg, disordered eating).³⁰

 

 

DIAGNOSING THE TRIAD

Given that the signs of low energy availability and menstrual dysfunction are often subtle, the diagnosis of the triad for those at risk requires input from a multidisciplinary team including a physician, sports dietitian, mental health professional, exercise physiologist, and other medical consultants.

Table 2 lists diagnostic tests the primary care provider should consider.

Diagnosing low energy availability

Energy availability is the dietary energy remaining after exercise energy expenditure; it is normalized to fat-free (lean) mass to account for resting energy expenditure. It is a product of energy intake, energy expenditure, and stored energy, and is calculated as:

An optimal value is at least 45 kcal/kg/day, while physiologic changes start to occur at less than 30 kcal/kg/day.^4,31 Low energy is often seen in adult patients with a body mass index less than 17.5 kg/m² and adolescent patients who are less than 80% of expected body weight.

Energy availability is hard to calculate, but certain assessments can be performed in a primary care setting to approximate it. To assess dietary intake, patients can bring in a 3-, 4-, or 7-day dietary log or complete a 24-hour food recall or food-frequency questionnaire in the office. To objectively document energy expenditure, patients can use heart rate monitors, accelerometers, an exercise diary, and web-based calculators. The fat-free mass can be calculated using a bioelectric impedance scale and skinfold caliper measurements.²⁶

Those with chronic energy deficiency states may have reduced resting metabolic rates, with measured rates less than 90% of predicted and low triiodothyronine (T3) levels.³¹

Diagnosing menstrual dysfunction

When evaluating patients with menstrual dysfunction, it is important to first rule out pregnancy and endocrinopathies. These include thyroid dysfunction, hyperprolactinemia, primary ovarian insufficiency, other hypothalamic and pituitary disorders, and hyperandrogenic conditions such as polycystic ovarian syndrome, ovarian tumor, adrenal tumor, nonclassic congenital adrenal hyperplasia, and Cushing syndrome.

Depending on the patient’s age, laboratory tests can include follicle-stimulating hormone, luteinizing hormone, prolactin, serum estradiol, and a progesterone challenge.³² For hyperandrogenic symptoms, measuring total and free testosterone, dehydroepiandrosterone sulfate, 24-hour urine cortisol, and 17-hydroxyprogesterone levels may be helpful.

An endocrinologist should be consulted to evaluate the underlying cause of amenorrhea and address any associated hormonal imbalances. Attributing menstrual dysfunction to low energy availability is generally a diagnosis of exclusion. Additionally, outflow tract obstruction should be considered and ruled out with transvaginal ultrasonography in patients with primary amenorrhea.

A patient with hypoestrogenemia and amenorrhea may have the same steroid hormone profile as that of a menopausal woman. Lack of estrogen results in impaired endothelial cell function and arterial dilation, with accelerated development of atherosclerosis and subsequent cardiovascular events.^33,34 Further, low energy availability has been linked to negative cardiovascular effects such as decreased vessel dilation leading to decreased tissue perfusion and hastened development of atherosclerosis.³³ Female athletes with hypoestrogenism may show reduced perfusion of working muscle, impaired aerobic metabolism in skeletal muscle, elevated low-density lipoprotein cholesterol, and vaginal dryness.⁴

Diagnosing low bone mineral density

The most common clinical manifestations of low bone mineral density in female athletes are bone stress reactions such as stress fractures. In a study of 311 female high school athletes, 65.6% suffered from musculoskeletal injury from trauma or overuse including stress fractures and the patellofemoral syndrome.³⁵ Many athletes seek medical attention from their primary care physician for stress reactions, providing an opportunity for triad screening.³⁶

In postmenopausal women, osteopenia and osteoporosis are defined using the T score. However, in premenopausal women and adolescents, the International Society for Clinical Densitometry recommends using the Z score. A Z score less than –2.0 is described as “low bone density for chronological age.”¹⁴ For the diagnosis of osteoporosis in children and premenopausal women, the Society recommends using a Z score less than –2.0 along with the presence of a secondary risk factor for fracture such as undernutrition, hypogonadism, or a history of fracture.

Table 2 summarizes the diagnosis of low bone mineral density and osteoporosis in premenopausal women, adolescents, and children as well as when to order dual-energy x-ray absorptiometry (DEXA).^37,38

Adolescents with low bone mineral density should have an annual DEXA scan of the total hip and lumbar spine.²² Amenorrheic athletes typically present with low areal density at the lumbar spine, reduced trabecular volumetric bone mineral density and bone strength index at the distal radius, and deterioration of the distal tibia.³⁹

 

 

EARLY INTERVENTION IS ESSENTIAL

Early intervention is essential in patients with any component of the female athlete triad to prevent long-term adverse health effects. Successful treatment is strongly correlated with a trusting relationship between the athlete and the multidisciplinary team involved in her treatment.⁴⁰

If needed, selective serotonin reuptake inhibitors and other psychotropic medications can be prescribed for comorbid conditions including bulimia nervosa, anxiety, depression, and obsessive-compulsive disorder. Primary providers can identify risk factors that prompt the evaluation and diagnosis of the triad, as well as support the goals of treatment and help manage comorbid conditions.

Eat more, exercise less

The primary goal is to restore body weight, maximizing nutritional and energy status by modifying the diet and adjusting exercise behavior to increase energy availability.⁴¹ Creating an energy-positive state by increasing intake, decreasing energy expenditure, or both increases energy availability, subsequently improves bone mineral density, and normalizes menstrual function.⁴⁰

To sustain normal physiologic function, an energy availability of at least 45 kcal/kg/day is recommended.⁴² Patients should consume a minimum of 2,000 kcal/day, although energy needs may far exceed that, depending on energy expenditure. Olympic athletes participating in women’s crew and other sports have been anecdotally known to require over 12,000 kcal a day to maintain weight and performance. Goals include a body mass index of at least 18.5 kg/m² in adults and a body weight of at least 90% of predicted in adolescents.

Involving a dietitian in the care team can help ensure that the patient consumes an adequate amount of macronutrients and micronutrients necessary for bone growth; these include calcium, vitamin D, iron, zinc, and vitamin K.^4,32 For patients with disordered eating, referral to a mental health professional is important to help them avoid pathologic eating behaviors, reduce dieting attempts, and alter negative emotions associated with food and body image.

Once treatment begins, patients must undergo standardized periodic monitoring of their body weight. Although positive effects such as normalization of metabolic hormones (eg, insulinlike growth factor 1) may be seen in days to weeks by reversing low energy availability, it may take several months for menstrual function to improve and years for measurable improvement in bone mineral density to occur.²³

Menstrual function should improve with weight gain

Normalizing menses in patients with the female athlete triad depends on improving the low energy availability and inducing weight gain.

Pharmacotherapy such as combined oral contraceptives can treat symptoms of hypogonadism.²⁵ However, combined oral contraceptives do not restore spontaneous menses but rather induce withdrawal bleeding, which can lead to a false sense of security.²³ While there are some benefits to prescribing combined oral contraceptives to treat hypogonadism, nonpharmacologic methods should be tried initially to restore menses, including increasing caloric intake and body weight. Golden et al showed that hormone replacement with combined oral contraceptives did not improve bone density in women with low estrogen states (eg, anorexia nervosa, osteopenia).⁴³ Further, combined oral contraceptives may worsen bone health, as oral estrogen suppresses hepatic production of insulinlike growth factor 1, a bone trophic hormone.²³

Treating low bone mineral density

Improving energy availability and menstrual function can help improve bone mineral density. Nutritional enhancement is recommended for mineralization of trabecular bone and growth of cortical bone. Supplemental calcium (1,000–1,500 mg daily) and vitamin D (600–1,000 IU daily) should be incorporated into the treatment of low bone mineral density.^15,19

Additionally, weight gain has a positive effect on bone mineral density independent of its effect on the resumption of menses. However, weight gain alone does not normalize bone mineral density. Resuming normal physiologic production of hormones with estrogen-dependent effects on bone health is integral to normalization as well.²³

Resistance training is encouraged to increase lean mass, although caution must be used to prevent fractures during high-impact activity. Bone mineral density may take up to several years to improve and may not be fully reversible.^4,25,39

Pharmacologic therapy for low bone mineral density has unclear outcomes in women under age 50. The decision to treat should be based on bone mineral density along with fracture history. Given their unknown effects on the human fetal skeleton, bisphosphonates and denosumab should be used with caution in women of childbearing potential.²⁴ No studies have used denosumab or teriparatide in women with the female athlete triad. Despite concerns regarding use of these drugs in premenopausal women, drug therapy should be strongly considered in women with a history of fracture and those with a high risk of subsequent fracture. The decision to treat can be made in conjunction with the athlete’s endocrinologist.

RETURN TO PLAY

If an athlete is noted to be at risk for or diagnosed with the female athlete triad, it is important to formulate a plan for her to return to play once her health improves.

De Souza et al provided a cumulative risk assessment for risk stratification and made recommendations on when an athlete should return to play depending on her level of risk.²³ Using this grading system, primary care physicians can risk-stratify their patients. Those at low risk may be fully cleared to return to play, while those at moderate to high risk must first follow up with a multidisciplinary team to develop treatment strategies for improving their health.

Once a patient reaches her established goals, she may provisionally return to play under the close supervision of a team physician or primary care physician. A written treatment contract, including the goals set by the multidisciplinary team, should be followed closely as the athlete continues to participate in the sport.^23;

Striving for athletic excellence, many young women—and some young men—create an energy deficit from increased exercise, decreased intake, or both. In women, the resulting energy deficit can suppress the menstrual cycle and in turn lead to bone demineralization in a syndrome called the female athlete triad.

See related editorial.

Primary care physicians should be aware of this syndrome because it can lead to short-term and long-term health complications, and they are in a good position to screen for, diagnose, and treat it. However, a study of 931 US physicians in 2015 found that only 37% had heard of it.¹

DEFINITION HAS CHANGED: ONLY 1 OF 3 COMPONENTS NEEDED

In 1972, Title IX of the Education Amendment Act was passed, prohibiting sex discrimination in any higher education program or activity receiving federal financial aid. Since then, female athletic participation in the United States has increased more than 10-fold.²

Also increasing has been awareness of the link between athletics, eating disorders, and amenorrhea. The American College of Sports Medicine coined the term female athlete triad in 1992, describing it as the constellation of disordered eating, amenorrhea, and osteoporosis (all 3 needed to be present).³ They broadened the definition in 2007 so that the syndrome can be diagnosed if any of the following is present⁴:

• Low energy availability (with or without an eating disorder)
• Menstrual dysfunction
• Decreased bone mineral density.

Recognizing that low energy availability can affect athletes of either sex and have consequences beyond the female reproductive system and skeleton, in 2014 the International Olympic Committee introduced a broader term called relative energy deficiency in sport.^5,6 Like the triad, this condition occurs when energy intake falls below energy output to the point that it negatively affects an athlete’s physical and mental health.

THE COMPONENTS ARE COMMON

The female athlete triad can be seen in high school, collegiate, and elite athletes⁷ and is especially common in sports with subjective judging (gymnastics, figure skating) or endurance sports that emphasize leanness (eg, running).⁸

In a review of 65 studies, Gibbs et al⁹ found that the prevalence of any one of the triad conditions in exercising women and female athletes ranged from 16.0% to 60.0%, the prevalence of any 2 ranged from 2.7% to 27.0%, and the prevalence of all 3 ranged from 0% to 15.9%.

Low energy availability is categorized as either intentional (ie, due to disordered eating) or unintentional (ie, due to activities not associated with eating). Sustained low energy availability is often associated with eating disorders and subsequent low self-esteem, depression, and anxiety disorders.⁴

The prevalence of eating disorders is high in female athletes—31% and 20% in 2 large studies of elite female athletes, compared with 5.5% and 9%, respectively, in the general population.^10,11 Another study found that the prevalence of disordered eating was 46.7% in sports that emphasize leanness, such as track and gymnastics, compared with 19.8% in sports that did not, such as basketball and soccer.¹²

Calorie restriction is common. In a study of 15 elite ballet dancers and 15 matched controls, the dancers were found to consume only about 3/4 as many calories per day as the controls (1,577 vs 2,075 kcal/day, P ≤ .01).¹³

Menstrual dysfunction. In small studies, the prevalence of secondary amenorrhea was as high as 69% in dancers and 65% in long-distance runners.^4,14–16

Decreased bone mineral density. According to a systematic review, the prevalence of osteopenia in amenorrheic athletes ranged between 22% and 50% and the prevalence of osteoporosis was 0% to 13%, compared with 12% and 2.3%, respectively, in the general population.¹⁷

THE COMPONENTS ARE LINKED

The 3 components of the female athlete triad—low energy availability, menstrual dysfunction, and decreased bone mineral density—are linked, and each exists on a spectrum (Figure 1). The long-term consequences are far-reaching and can affect the cardiovascular, endocrine, reproductive, skeletal, gastrointestinal, renal, and central nervous systems.

Low energy availability is the driving force of the triad, causing menstrual irregularity and subsequent low bone mineral density.

Menstrual dysfunction. Low energy availability can contribute to menstrual disturbances because the body suppresses reproductive function to prevent pregnancy. Functional hypothalamic amenorrhea results from decreased gonadotropin-releasing hormone leading to decreased gonadotropin release from the pituitary gland and, ultimately, to low circulating estrogen levels.¹⁸ Menstrual irregularities related to the triad include:

• Primary amenorrhea (a delay in menarche)
• Oligomenorrhea (menstrual cycles occurring at intervals greater than every 35 days)
• Secondary amenorrhea (cessation of menstruation for 3 consecutive months).

(Primary amenorrhea is defined as no menses by age 15 in the presence of normal secondary sexual development or within 5 years after breast development if that occurs before the age of 10. Secondary amenorrhea is defined as the loss of menses for 90 or more days after menarche.¹⁹)

In animal studies, reducing dietary intake by more than 30% resulted in infertility.⁴ Menstrual abnormalities can present as early as 5 days after a patient enters a state of low energy availability.²⁰ Symptoms of menstrual dysfunction are largely indicative of hypogonadism and include vaginal dryness, infertility, and impaired bone health.

Bone health in women with the female athlete triad can range from optimal to osteoporosis.

Low bone mineral density is a result of low energy availability and menstrual dysfunction leading to estrogen deficiency.^21,22 Specifically, menstrual abnormalities can result in low estrogen and overactivity of osteoclasts, while low energy availability alters the metabolic environment, inducing changes in insulinlike growth factor 1, leptin, and peptide YY, resulting in deficiencies in vitamin D and calcium—nutrients necessary for bone mineralization. In turn, bone health and density are compromised.^21,22

Ninety percent of peak bone mass is attained by age 18. Those who have low bone mineral density as part of the female athlete triad can suffer from long-lasting effects on their bone health.

 

 

SCREENING

Untreated, the triad can lead to fatigue, poor sports performance, and a number of serious comorbid conditions such as osteopenia and osteoporosis (leading to stress fractures) anemia, heart arrhythmias, and amenorrhea. Therefore, it is important for primary care providers to screen female athletes for the triad during routine office visits.

In 2014, the Triad Consensus Panel recommended screening female athletes at the high school and collegiate levels during a preparticipation physical evaluation and then every year by a primary care physician, athletic trainer, team physician, or coach.²³

Risk factors include signs of dietary restriction, low body mass index, delayed menarche, oligomenorrhea or amenorrhea, and bone stress reactions or fractures.²³ Athletes should be questioned about their menstrual history (age of menarche, frequency, and duration of menstrual cycles), history of stress fractures, medication history, family history (osteoporosis, eating disorders, and fractures),^24,25 and dietary habits.

Physical findings include low body mass index, recent weight loss, orthostatic hypotension, lanugo, hypercarotenemia, and signs of eating disorders (restrictive, binging, purging) (Table 1).^25–27

Additionally, it is important to ascertain if the patient receives critical comments regarding performance or body image from coaches, parents, or teammates and if sport-specific training began early in life.

Certain personality factors and behaviors are clues, such as perfectionism, obsessiveness, frequent weight cycling, and overtraining.^4,25 If any of the triad components are apparent, a deeper evaluation can be completed.

Specific screening questions

The Female Athlete Triad Coalition recommends asking 11 screening questions and having prompt discussions regarding the athlete’s nutritional status and body image.²³ If the patient gives a worrisome response to a screening question, further workup for a formal diagnosis should be initiated.

Questions about nutritional status.

• Do you worry about your weight?
• Are you trying to gain or lose weight, or has anyone recommended that you do so?
• Are you on a special diet or do you avoid certain types of foods or food groups?
• Have you ever had an eating disorder?

Questions about menstrual function.

• Have you ever had a menstrual period?
• How old were you when you had your first menstrual period?
• When was your most recent menstrual period?
• How many periods have you had in the last 12 months?
• Are you presently taking any female hormones (estrogen, progesterone, birth control pills)?

Questions about bone health.

• Have you ever had a stress fracture?
• Have you ever been told you have low bone density (osteopenia or osteoporosis)?

Along similar lines, the American Academy of Pediatrics, American Academy of Family Physicians, and American College of Sports Medicine²⁸ have a list of 7 questions:

• Do you worry about your weight?
• Do you limit the foods you eat?
• Do you lose weight to meet image requirements for sports?
• Have you ever suffered from an eating disorder?
• How old were you when you had your first menstrual period?
• How many menstrual cycles have you had in the past 12 months?
• Have you ever had a stress fracture?

These questions are not being widely used. A study of the National Collegiate Athletic Association Division I universities found that only 9% of universities included 9 or more of the recommended 12 questions that the Female Athlete Triad Coalition was recommending at that time, and 22% asked only 1 or 2 of the questions. None of the universities included all 12.²⁹ These findings are not surprising, given that screening for the triad is not state-mandated. Screening discrepancies among providers largely stem from knowledge gaps, nonstandardized questionnaires, lack of time at appointments, and the sensitive nature of the questioning (eg, disordered eating).³⁰

 

 

DIAGNOSING THE TRIAD

Given that the signs of low energy availability and menstrual dysfunction are often subtle, the diagnosis of the triad for those at risk requires input from a multidisciplinary team including a physician, sports dietitian, mental health professional, exercise physiologist, and other medical consultants.

Table 2 lists diagnostic tests the primary care provider should consider.

Diagnosing low energy availability

Energy availability is the dietary energy remaining after exercise energy expenditure; it is normalized to fat-free (lean) mass to account for resting energy expenditure. It is a product of energy intake, energy expenditure, and stored energy, and is calculated as:

An optimal value is at least 45 kcal/kg/day, while physiologic changes start to occur at less than 30 kcal/kg/day.^4,31 Low energy is often seen in adult patients with a body mass index less than 17.5 kg/m² and adolescent patients who are less than 80% of expected body weight.

Energy availability is hard to calculate, but certain assessments can be performed in a primary care setting to approximate it. To assess dietary intake, patients can bring in a 3-, 4-, or 7-day dietary log or complete a 24-hour food recall or food-frequency questionnaire in the office. To objectively document energy expenditure, patients can use heart rate monitors, accelerometers, an exercise diary, and web-based calculators. The fat-free mass can be calculated using a bioelectric impedance scale and skinfold caliper measurements.²⁶

Those with chronic energy deficiency states may have reduced resting metabolic rates, with measured rates less than 90% of predicted and low triiodothyronine (T3) levels.³¹

Diagnosing menstrual dysfunction

When evaluating patients with menstrual dysfunction, it is important to first rule out pregnancy and endocrinopathies. These include thyroid dysfunction, hyperprolactinemia, primary ovarian insufficiency, other hypothalamic and pituitary disorders, and hyperandrogenic conditions such as polycystic ovarian syndrome, ovarian tumor, adrenal tumor, nonclassic congenital adrenal hyperplasia, and Cushing syndrome.

Depending on the patient’s age, laboratory tests can include follicle-stimulating hormone, luteinizing hormone, prolactin, serum estradiol, and a progesterone challenge.³² For hyperandrogenic symptoms, measuring total and free testosterone, dehydroepiandrosterone sulfate, 24-hour urine cortisol, and 17-hydroxyprogesterone levels may be helpful.

An endocrinologist should be consulted to evaluate the underlying cause of amenorrhea and address any associated hormonal imbalances. Attributing menstrual dysfunction to low energy availability is generally a diagnosis of exclusion. Additionally, outflow tract obstruction should be considered and ruled out with transvaginal ultrasonography in patients with primary amenorrhea.

A patient with hypoestrogenemia and amenorrhea may have the same steroid hormone profile as that of a menopausal woman. Lack of estrogen results in impaired endothelial cell function and arterial dilation, with accelerated development of atherosclerosis and subsequent cardiovascular events.^33,34 Further, low energy availability has been linked to negative cardiovascular effects such as decreased vessel dilation leading to decreased tissue perfusion and hastened development of atherosclerosis.³³ Female athletes with hypoestrogenism may show reduced perfusion of working muscle, impaired aerobic metabolism in skeletal muscle, elevated low-density lipoprotein cholesterol, and vaginal dryness.⁴

Diagnosing low bone mineral density

The most common clinical manifestations of low bone mineral density in female athletes are bone stress reactions such as stress fractures. In a study of 311 female high school athletes, 65.6% suffered from musculoskeletal injury from trauma or overuse including stress fractures and the patellofemoral syndrome.³⁵ Many athletes seek medical attention from their primary care physician for stress reactions, providing an opportunity for triad screening.³⁶

In postmenopausal women, osteopenia and osteoporosis are defined using the T score. However, in premenopausal women and adolescents, the International Society for Clinical Densitometry recommends using the Z score. A Z score less than –2.0 is described as “low bone density for chronological age.”¹⁴ For the diagnosis of osteoporosis in children and premenopausal women, the Society recommends using a Z score less than –2.0 along with the presence of a secondary risk factor for fracture such as undernutrition, hypogonadism, or a history of fracture.

Table 2 summarizes the diagnosis of low bone mineral density and osteoporosis in premenopausal women, adolescents, and children as well as when to order dual-energy x-ray absorptiometry (DEXA).^37,38

Adolescents with low bone mineral density should have an annual DEXA scan of the total hip and lumbar spine.²² Amenorrheic athletes typically present with low areal density at the lumbar spine, reduced trabecular volumetric bone mineral density and bone strength index at the distal radius, and deterioration of the distal tibia.³⁹

 

 

EARLY INTERVENTION IS ESSENTIAL

Early intervention is essential in patients with any component of the female athlete triad to prevent long-term adverse health effects. Successful treatment is strongly correlated with a trusting relationship between the athlete and the multidisciplinary team involved in her treatment.⁴⁰

If needed, selective serotonin reuptake inhibitors and other psychotropic medications can be prescribed for comorbid conditions including bulimia nervosa, anxiety, depression, and obsessive-compulsive disorder. Primary providers can identify risk factors that prompt the evaluation and diagnosis of the triad, as well as support the goals of treatment and help manage comorbid conditions.

Eat more, exercise less

The primary goal is to restore body weight, maximizing nutritional and energy status by modifying the diet and adjusting exercise behavior to increase energy availability.⁴¹ Creating an energy-positive state by increasing intake, decreasing energy expenditure, or both increases energy availability, subsequently improves bone mineral density, and normalizes menstrual function.⁴⁰

To sustain normal physiologic function, an energy availability of at least 45 kcal/kg/day is recommended.⁴² Patients should consume a minimum of 2,000 kcal/day, although energy needs may far exceed that, depending on energy expenditure. Olympic athletes participating in women’s crew and other sports have been anecdotally known to require over 12,000 kcal a day to maintain weight and performance. Goals include a body mass index of at least 18.5 kg/m² in adults and a body weight of at least 90% of predicted in adolescents.

Involving a dietitian in the care team can help ensure that the patient consumes an adequate amount of macronutrients and micronutrients necessary for bone growth; these include calcium, vitamin D, iron, zinc, and vitamin K.^4,32 For patients with disordered eating, referral to a mental health professional is important to help them avoid pathologic eating behaviors, reduce dieting attempts, and alter negative emotions associated with food and body image.

Once treatment begins, patients must undergo standardized periodic monitoring of their body weight. Although positive effects such as normalization of metabolic hormones (eg, insulinlike growth factor 1) may be seen in days to weeks by reversing low energy availability, it may take several months for menstrual function to improve and years for measurable improvement in bone mineral density to occur.²³

Menstrual function should improve with weight gain

Normalizing menses in patients with the female athlete triad depends on improving the low energy availability and inducing weight gain.

Pharmacotherapy such as combined oral contraceptives can treat symptoms of hypogonadism.²⁵ However, combined oral contraceptives do not restore spontaneous menses but rather induce withdrawal bleeding, which can lead to a false sense of security.²³ While there are some benefits to prescribing combined oral contraceptives to treat hypogonadism, nonpharmacologic methods should be tried initially to restore menses, including increasing caloric intake and body weight. Golden et al showed that hormone replacement with combined oral contraceptives did not improve bone density in women with low estrogen states (eg, anorexia nervosa, osteopenia).⁴³ Further, combined oral contraceptives may worsen bone health, as oral estrogen suppresses hepatic production of insulinlike growth factor 1, a bone trophic hormone.²³

Treating low bone mineral density

Improving energy availability and menstrual function can help improve bone mineral density. Nutritional enhancement is recommended for mineralization of trabecular bone and growth of cortical bone. Supplemental calcium (1,000–1,500 mg daily) and vitamin D (600–1,000 IU daily) should be incorporated into the treatment of low bone mineral density.^15,19

Additionally, weight gain has a positive effect on bone mineral density independent of its effect on the resumption of menses. However, weight gain alone does not normalize bone mineral density. Resuming normal physiologic production of hormones with estrogen-dependent effects on bone health is integral to normalization as well.²³

Resistance training is encouraged to increase lean mass, although caution must be used to prevent fractures during high-impact activity. Bone mineral density may take up to several years to improve and may not be fully reversible.^4,25,39

Pharmacologic therapy for low bone mineral density has unclear outcomes in women under age 50. The decision to treat should be based on bone mineral density along with fracture history. Given their unknown effects on the human fetal skeleton, bisphosphonates and denosumab should be used with caution in women of childbearing potential.²⁴ No studies have used denosumab or teriparatide in women with the female athlete triad. Despite concerns regarding use of these drugs in premenopausal women, drug therapy should be strongly considered in women with a history of fracture and those with a high risk of subsequent fracture. The decision to treat can be made in conjunction with the athlete’s endocrinologist.

RETURN TO PLAY

If an athlete is noted to be at risk for or diagnosed with the female athlete triad, it is important to formulate a plan for her to return to play once her health improves.

De Souza et al provided a cumulative risk assessment for risk stratification and made recommendations on when an athlete should return to play depending on her level of risk.²³ Using this grading system, primary care physicians can risk-stratify their patients. Those at low risk may be fully cleared to return to play, while those at moderate to high risk must first follow up with a multidisciplinary team to develop treatment strategies for improving their health.

Once a patient reaches her established goals, she may provisionally return to play under the close supervision of a team physician or primary care physician. A written treatment contract, including the goals set by the multidisciplinary team, should be followed closely as the athlete continues to participate in the sport.^23;

Striving for athletic excellence, many young women—and some young men—create an energy deficit from increased exercise, decreased intake, or both. In women, the resulting energy deficit can suppress the menstrual cycle and in turn lead to bone demineralization in a syndrome called the female athlete triad.

See related editorial.

Primary care physicians should be aware of this syndrome because it can lead to short-term and long-term health complications, and they are in a good position to screen for, diagnose, and treat it. However, a study of 931 US physicians in 2015 found that only 37% had heard of it.¹

DEFINITION HAS CHANGED: ONLY 1 OF 3 COMPONENTS NEEDED

In 1972, Title IX of the Education Amendment Act was passed, prohibiting sex discrimination in any higher education program or activity receiving federal financial aid. Since then, female athletic participation in the United States has increased more than 10-fold.²

Also increasing has been awareness of the link between athletics, eating disorders, and amenorrhea. The American College of Sports Medicine coined the term female athlete triad in 1992, describing it as the constellation of disordered eating, amenorrhea, and osteoporosis (all 3 needed to be present).³ They broadened the definition in 2007 so that the syndrome can be diagnosed if any of the following is present⁴:

• Low energy availability (with or without an eating disorder)
• Menstrual dysfunction
• Decreased bone mineral density.

Recognizing that low energy availability can affect athletes of either sex and have consequences beyond the female reproductive system and skeleton, in 2014 the International Olympic Committee introduced a broader term called relative energy deficiency in sport.^5,6 Like the triad, this condition occurs when energy intake falls below energy output to the point that it negatively affects an athlete’s physical and mental health.

THE COMPONENTS ARE COMMON

The female athlete triad can be seen in high school, collegiate, and elite athletes⁷ and is especially common in sports with subjective judging (gymnastics, figure skating) or endurance sports that emphasize leanness (eg, running).⁸

In a review of 65 studies, Gibbs et al⁹ found that the prevalence of any one of the triad conditions in exercising women and female athletes ranged from 16.0% to 60.0%, the prevalence of any 2 ranged from 2.7% to 27.0%, and the prevalence of all 3 ranged from 0% to 15.9%.

Low energy availability is categorized as either intentional (ie, due to disordered eating) or unintentional (ie, due to activities not associated with eating). Sustained low energy availability is often associated with eating disorders and subsequent low self-esteem, depression, and anxiety disorders.⁴

The prevalence of eating disorders is high in female athletes—31% and 20% in 2 large studies of elite female athletes, compared with 5.5% and 9%, respectively, in the general population.^10,11 Another study found that the prevalence of disordered eating was 46.7% in sports that emphasize leanness, such as track and gymnastics, compared with 19.8% in sports that did not, such as basketball and soccer.¹²

Calorie restriction is common. In a study of 15 elite ballet dancers and 15 matched controls, the dancers were found to consume only about 3/4 as many calories per day as the controls (1,577 vs 2,075 kcal/day, P ≤ .01).¹³

Menstrual dysfunction. In small studies, the prevalence of secondary amenorrhea was as high as 69% in dancers and 65% in long-distance runners.^4,14–16

Decreased bone mineral density. According to a systematic review, the prevalence of osteopenia in amenorrheic athletes ranged between 22% and 50% and the prevalence of osteoporosis was 0% to 13%, compared with 12% and 2.3%, respectively, in the general population.¹⁷

THE COMPONENTS ARE LINKED

The 3 components of the female athlete triad—low energy availability, menstrual dysfunction, and decreased bone mineral density—are linked, and each exists on a spectrum (Figure 1). The long-term consequences are far-reaching and can affect the cardiovascular, endocrine, reproductive, skeletal, gastrointestinal, renal, and central nervous systems.

Low energy availability is the driving force of the triad, causing menstrual irregularity and subsequent low bone mineral density.

Menstrual dysfunction. Low energy availability can contribute to menstrual disturbances because the body suppresses reproductive function to prevent pregnancy. Functional hypothalamic amenorrhea results from decreased gonadotropin-releasing hormone leading to decreased gonadotropin release from the pituitary gland and, ultimately, to low circulating estrogen levels.¹⁸ Menstrual irregularities related to the triad include:

• Primary amenorrhea (a delay in menarche)
• Oligomenorrhea (menstrual cycles occurring at intervals greater than every 35 days)
• Secondary amenorrhea (cessation of menstruation for 3 consecutive months).

(Primary amenorrhea is defined as no menses by age 15 in the presence of normal secondary sexual development or within 5 years after breast development if that occurs before the age of 10. Secondary amenorrhea is defined as the loss of menses for 90 or more days after menarche.¹⁹)

In animal studies, reducing dietary intake by more than 30% resulted in infertility.⁴ Menstrual abnormalities can present as early as 5 days after a patient enters a state of low energy availability.²⁰ Symptoms of menstrual dysfunction are largely indicative of hypogonadism and include vaginal dryness, infertility, and impaired bone health.

Bone health in women with the female athlete triad can range from optimal to osteoporosis.

Low bone mineral density is a result of low energy availability and menstrual dysfunction leading to estrogen deficiency.^21,22 Specifically, menstrual abnormalities can result in low estrogen and overactivity of osteoclasts, while low energy availability alters the metabolic environment, inducing changes in insulinlike growth factor 1, leptin, and peptide YY, resulting in deficiencies in vitamin D and calcium—nutrients necessary for bone mineralization. In turn, bone health and density are compromised.^21,22

Ninety percent of peak bone mass is attained by age 18. Those who have low bone mineral density as part of the female athlete triad can suffer from long-lasting effects on their bone health.

 

 

SCREENING

Untreated, the triad can lead to fatigue, poor sports performance, and a number of serious comorbid conditions such as osteopenia and osteoporosis (leading to stress fractures) anemia, heart arrhythmias, and amenorrhea. Therefore, it is important for primary care providers to screen female athletes for the triad during routine office visits.

In 2014, the Triad Consensus Panel recommended screening female athletes at the high school and collegiate levels during a preparticipation physical evaluation and then every year by a primary care physician, athletic trainer, team physician, or coach.²³

Risk factors include signs of dietary restriction, low body mass index, delayed menarche, oligomenorrhea or amenorrhea, and bone stress reactions or fractures.²³ Athletes should be questioned about their menstrual history (age of menarche, frequency, and duration of menstrual cycles), history of stress fractures, medication history, family history (osteoporosis, eating disorders, and fractures),^24,25 and dietary habits.

Physical findings include low body mass index, recent weight loss, orthostatic hypotension, lanugo, hypercarotenemia, and signs of eating disorders (restrictive, binging, purging) (Table 1).^25–27

Additionally, it is important to ascertain if the patient receives critical comments regarding performance or body image from coaches, parents, or teammates and if sport-specific training began early in life.

Certain personality factors and behaviors are clues, such as perfectionism, obsessiveness, frequent weight cycling, and overtraining.^4,25 If any of the triad components are apparent, a deeper evaluation can be completed.

Specific screening questions

The Female Athlete Triad Coalition recommends asking 11 screening questions and having prompt discussions regarding the athlete’s nutritional status and body image.²³ If the patient gives a worrisome response to a screening question, further workup for a formal diagnosis should be initiated.

Questions about nutritional status.

• Do you worry about your weight?
• Are you trying to gain or lose weight, or has anyone recommended that you do so?
• Are you on a special diet or do you avoid certain types of foods or food groups?
• Have you ever had an eating disorder?

Questions about menstrual function.

• Have you ever had a menstrual period?
• How old were you when you had your first menstrual period?
• When was your most recent menstrual period?
• How many periods have you had in the last 12 months?
• Are you presently taking any female hormones (estrogen, progesterone, birth control pills)?

Questions about bone health.

• Have you ever had a stress fracture?
• Have you ever been told you have low bone density (osteopenia or osteoporosis)?

Along similar lines, the American Academy of Pediatrics, American Academy of Family Physicians, and American College of Sports Medicine²⁸ have a list of 7 questions:

• Do you worry about your weight?
• Do you limit the foods you eat?
• Do you lose weight to meet image requirements for sports?
• Have you ever suffered from an eating disorder?
• How old were you when you had your first menstrual period?
• How many menstrual cycles have you had in the past 12 months?
• Have you ever had a stress fracture?

These questions are not being widely used. A study of the National Collegiate Athletic Association Division I universities found that only 9% of universities included 9 or more of the recommended 12 questions that the Female Athlete Triad Coalition was recommending at that time, and 22% asked only 1 or 2 of the questions. None of the universities included all 12.²⁹ These findings are not surprising, given that screening for the triad is not state-mandated. Screening discrepancies among providers largely stem from knowledge gaps, nonstandardized questionnaires, lack of time at appointments, and the sensitive nature of the questioning (eg, disordered eating).³⁰

 

 

DIAGNOSING THE TRIAD

Given that the signs of low energy availability and menstrual dysfunction are often subtle, the diagnosis of the triad for those at risk requires input from a multidisciplinary team including a physician, sports dietitian, mental health professional, exercise physiologist, and other medical consultants.

Table 2 lists diagnostic tests the primary care provider should consider.

Diagnosing low energy availability

Energy availability is the dietary energy remaining after exercise energy expenditure; it is normalized to fat-free (lean) mass to account for resting energy expenditure. It is a product of energy intake, energy expenditure, and stored energy, and is calculated as:

An optimal value is at least 45 kcal/kg/day, while physiologic changes start to occur at less than 30 kcal/kg/day.^4,31 Low energy is often seen in adult patients with a body mass index less than 17.5 kg/m² and adolescent patients who are less than 80% of expected body weight.

Energy availability is hard to calculate, but certain assessments can be performed in a primary care setting to approximate it. To assess dietary intake, patients can bring in a 3-, 4-, or 7-day dietary log or complete a 24-hour food recall or food-frequency questionnaire in the office. To objectively document energy expenditure, patients can use heart rate monitors, accelerometers, an exercise diary, and web-based calculators. The fat-free mass can be calculated using a bioelectric impedance scale and skinfold caliper measurements.²⁶

Those with chronic energy deficiency states may have reduced resting metabolic rates, with measured rates less than 90% of predicted and low triiodothyronine (T3) levels.³¹

Diagnosing menstrual dysfunction

When evaluating patients with menstrual dysfunction, it is important to first rule out pregnancy and endocrinopathies. These include thyroid dysfunction, hyperprolactinemia, primary ovarian insufficiency, other hypothalamic and pituitary disorders, and hyperandrogenic conditions such as polycystic ovarian syndrome, ovarian tumor, adrenal tumor, nonclassic congenital adrenal hyperplasia, and Cushing syndrome.

Depending on the patient’s age, laboratory tests can include follicle-stimulating hormone, luteinizing hormone, prolactin, serum estradiol, and a progesterone challenge.³² For hyperandrogenic symptoms, measuring total and free testosterone, dehydroepiandrosterone sulfate, 24-hour urine cortisol, and 17-hydroxyprogesterone levels may be helpful.

An endocrinologist should be consulted to evaluate the underlying cause of amenorrhea and address any associated hormonal imbalances. Attributing menstrual dysfunction to low energy availability is generally a diagnosis of exclusion. Additionally, outflow tract obstruction should be considered and ruled out with transvaginal ultrasonography in patients with primary amenorrhea.

A patient with hypoestrogenemia and amenorrhea may have the same steroid hormone profile as that of a menopausal woman. Lack of estrogen results in impaired endothelial cell function and arterial dilation, with accelerated development of atherosclerosis and subsequent cardiovascular events.^33,34 Further, low energy availability has been linked to negative cardiovascular effects such as decreased vessel dilation leading to decreased tissue perfusion and hastened development of atherosclerosis.³³ Female athletes with hypoestrogenism may show reduced perfusion of working muscle, impaired aerobic metabolism in skeletal muscle, elevated low-density lipoprotein cholesterol, and vaginal dryness.⁴

Diagnosing low bone mineral density

The most common clinical manifestations of low bone mineral density in female athletes are bone stress reactions such as stress fractures. In a study of 311 female high school athletes, 65.6% suffered from musculoskeletal injury from trauma or overuse including stress fractures and the patellofemoral syndrome.³⁵ Many athletes seek medical attention from their primary care physician for stress reactions, providing an opportunity for triad screening.³⁶

In postmenopausal women, osteopenia and osteoporosis are defined using the T score. However, in premenopausal women and adolescents, the International Society for Clinical Densitometry recommends using the Z score. A Z score less than –2.0 is described as “low bone density for chronological age.”¹⁴ For the diagnosis of osteoporosis in children and premenopausal women, the Society recommends using a Z score less than –2.0 along with the presence of a secondary risk factor for fracture such as undernutrition, hypogonadism, or a history of fracture.

Table 2 summarizes the diagnosis of low bone mineral density and osteoporosis in premenopausal women, adolescents, and children as well as when to order dual-energy x-ray absorptiometry (DEXA).^37,38

Adolescents with low bone mineral density should have an annual DEXA scan of the total hip and lumbar spine.²² Amenorrheic athletes typically present with low areal density at the lumbar spine, reduced trabecular volumetric bone mineral density and bone strength index at the distal radius, and deterioration of the distal tibia.³⁹

 

 

EARLY INTERVENTION IS ESSENTIAL

Early intervention is essential in patients with any component of the female athlete triad to prevent long-term adverse health effects. Successful treatment is strongly correlated with a trusting relationship between the athlete and the multidisciplinary team involved in her treatment.⁴⁰

If needed, selective serotonin reuptake inhibitors and other psychotropic medications can be prescribed for comorbid conditions including bulimia nervosa, anxiety, depression, and obsessive-compulsive disorder. Primary providers can identify risk factors that prompt the evaluation and diagnosis of the triad, as well as support the goals of treatment and help manage comorbid conditions.

Eat more, exercise less

The primary goal is to restore body weight, maximizing nutritional and energy status by modifying the diet and adjusting exercise behavior to increase energy availability.⁴¹ Creating an energy-positive state by increasing intake, decreasing energy expenditure, or both increases energy availability, subsequently improves bone mineral density, and normalizes menstrual function.⁴⁰

To sustain normal physiologic function, an energy availability of at least 45 kcal/kg/day is recommended.⁴² Patients should consume a minimum of 2,000 kcal/day, although energy needs may far exceed that, depending on energy expenditure. Olympic athletes participating in women’s crew and other sports have been anecdotally known to require over 12,000 kcal a day to maintain weight and performance. Goals include a body mass index of at least 18.5 kg/m² in adults and a body weight of at least 90% of predicted in adolescents.

Involving a dietitian in the care team can help ensure that the patient consumes an adequate amount of macronutrients and micronutrients necessary for bone growth; these include calcium, vitamin D, iron, zinc, and vitamin K.^4,32 For patients with disordered eating, referral to a mental health professional is important to help them avoid pathologic eating behaviors, reduce dieting attempts, and alter negative emotions associated with food and body image.

Once treatment begins, patients must undergo standardized periodic monitoring of their body weight. Although positive effects such as normalization of metabolic hormones (eg, insulinlike growth factor 1) may be seen in days to weeks by reversing low energy availability, it may take several months for menstrual function to improve and years for measurable improvement in bone mineral density to occur.²³

Menstrual function should improve with weight gain

Normalizing menses in patients with the female athlete triad depends on improving the low energy availability and inducing weight gain.

Pharmacotherapy such as combined oral contraceptives can treat symptoms of hypogonadism.²⁵ However, combined oral contraceptives do not restore spontaneous menses but rather induce withdrawal bleeding, which can lead to a false sense of security.²³ While there are some benefits to prescribing combined oral contraceptives to treat hypogonadism, nonpharmacologic methods should be tried initially to restore menses, including increasing caloric intake and body weight. Golden et al showed that hormone replacement with combined oral contraceptives did not improve bone density in women with low estrogen states (eg, anorexia nervosa, osteopenia).⁴³ Further, combined oral contraceptives may worsen bone health, as oral estrogen suppresses hepatic production of insulinlike growth factor 1, a bone trophic hormone.²³

Treating low bone mineral density

Improving energy availability and menstrual function can help improve bone mineral density. Nutritional enhancement is recommended for mineralization of trabecular bone and growth of cortical bone. Supplemental calcium (1,000–1,500 mg daily) and vitamin D (600–1,000 IU daily) should be incorporated into the treatment of low bone mineral density.^15,19

Additionally, weight gain has a positive effect on bone mineral density independent of its effect on the resumption of menses. However, weight gain alone does not normalize bone mineral density. Resuming normal physiologic production of hormones with estrogen-dependent effects on bone health is integral to normalization as well.²³

Resistance training is encouraged to increase lean mass, although caution must be used to prevent fractures during high-impact activity. Bone mineral density may take up to several years to improve and may not be fully reversible.^4,25,39

Pharmacologic therapy for low bone mineral density has unclear outcomes in women under age 50. The decision to treat should be based on bone mineral density along with fracture history. Given their unknown effects on the human fetal skeleton, bisphosphonates and denosumab should be used with caution in women of childbearing potential.²⁴ No studies have used denosumab or teriparatide in women with the female athlete triad. Despite concerns regarding use of these drugs in premenopausal women, drug therapy should be strongly considered in women with a history of fracture and those with a high risk of subsequent fracture. The decision to treat can be made in conjunction with the athlete’s endocrinologist.

RETURN TO PLAY

If an athlete is noted to be at risk for or diagnosed with the female athlete triad, it is important to formulate a plan for her to return to play once her health improves.

De Souza et al provided a cumulative risk assessment for risk stratification and made recommendations on when an athlete should return to play depending on her level of risk.²³ Using this grading system, primary care physicians can risk-stratify their patients. Those at low risk may be fully cleared to return to play, while those at moderate to high risk must first follow up with a multidisciplinary team to develop treatment strategies for improving their health.

Once a patient reaches her established goals, she may provisionally return to play under the close supervision of a team physician or primary care physician. A written treatment contract, including the goals set by the multidisciplinary team, should be followed closely as the athlete continues to participate in the sport.^23;

Make no bones about it!

We just celebrated 45 years since the passing of Title IX, which opened the floodgates for women’s participation in sports. According to a report by the National Collegiate Athletic Association,¹ in this interval, the participation rate of high school girls increased 1,000 percent, and Division I colleges have the highest female athletic participation rate, with women accounting for 46.7% of athletes.

See related article.

Participating in competitive sports is especially important for women because it increases self-confidence. Indeed, there is a direct relationship between athletics and women in leadership roles. A 2013 Ernst and Young survey of 821 high-level executives demonstrated that 90% of the women and 96% of the women in chief executive positions had played sports.²

Twenty years after Title IX was passed, physicians identified a triad of symptoms commonly seen in female athletes. The original definition of the female athletic triad consisted of eating disorders, irregular menstrual cycles, and reduced bone mineral density (BMD).³ Malnutrition led to abnormalities in the menstrual cycle, which in turn affected bone density. The triad was thought to most commonly affect women participating in weight-dependent or judging sports, such as gymnastics, ice-skating, and endurance running. However, many athletes remained undiagnosed because specific criteria for the triad diagnosis remained elusive.

In 2007, the American College of Sports Medicine updated the diagnostic guidelines, defining the female athlete triad as a constellation of abnormalities in energy availability, menstrual function, and BMD.⁴ Each of these 3 components is part of a spectrum ranging from normal to varying degrees of pathology. Thus, the female athlete no longer needs to demonstrate pathology in all 3 components of the triad to be diagnosed with the syndrome. The presence of 1 or 2 of the components on the pathologic side of the spectrum falls under the umbrella of the triad and may meet the criteria for diagnosis, prompting further assessment.

In 2014, the International Olympic Committee (IOC) coined the term relative energy deficiency in sport (RED-S).⁵ The IOC authors intended for RED-S to be a more comprehensive and broader definition for the triad. As defined in the IOC consensus statement, RED-S is “impaired physiological function including, but not limited to, metabolic rate, menstrual function, bone health, immunity, protein synthesis, [and] cardiovascular health caused by relative energy deficiency.”⁵ The statement indicates that the underlying problem is “energy deficiency relative to the balance between dietary energy intake and energy expenditure required for health and activities of daily living, growth, and sporting activities.”⁵ The IOC consensus statement also expands the vulnerable population, discussing the susceptibility of male athletes, athletes of nonwhite ethnicity, and athletes with a disability.

Although there is some contention as to how we should refer to this syndrome, the most important facet is that it can be identified in an office setting. Awareness is key to prevention. Unfortunately, in a 2015 survey of 931 physicians, only 37% could identify the 3 components of the triad.⁶ If you do not ask your patients about their nutrition, eating habits, and menstrual cycle, it is not possible to identify any potential problems.

 

 

WHY IS THIS SO IMPORTANT?

Simply stated, it is important to diagnose and treat the triad syndrome to maintain optimal bone health. About 90% of peak bone mass is acquired by age 18. Bone density continues to build until about the age of 25, after which it is only possible to maintain. If young athletes are losing bone density, it cannot be replaced. Athletes who have a relative energy deficiency and are not maximizing bone growth will potentially struggle with lower bone mineral density later in life. Early awareness of bone health is paramount to sustaining it as we age.

Osteoporosis, often called a silent disease, affects more than 75 million men and women in the United States, Europe, and Japan.⁷ According to the International Osteoporosis Foundation, more than 8.9 million fractures are secondary to osteoporosis worldwide each year. Astoundingly, this epidemic equates to an osteoporotic fracture every 3 seconds.⁸

As physicians, we need to do what we can to prevent this, and the easiest prevention is maintaining bone health and adequate nutrition early in life. We know that weight-bearing exercise is important for bone health, but it is counterintuitive to think that active patients who are running and playing sports may be negatively affecting bone health if they have a relative energy deficiency.

Many females (professional athletes, competitive athletes, or just women who want to stay active) exercise excessively and restrict calories to lose or maintain weight. This can be a formula for disaster resulting in a sidelining bone stress injury. A stress fracture occurs when bone experiences more stress or impact than it can handle from overtraining or increasing training too quickly, not providing enough time for the bone to strengthen. Stress fractures can also occur when bone mineral density declines, lowering the impact threshold. This is most often a direct result of a relative energy deficiency or poor nutrition. The incidence of stress fractures in female athletes is 2 to 3 times higher than that in male athletes, and female athletes with missed menstrual cycles have a 2 to 4 times higher risk of stress fractures than females with a normal monthly menstrual cycle.⁹

The triad syndrome is seen not only in women but in all athletes—including men and Paralympic athletes.^10,11 According to Tenforde et al,¹⁰ male athletes, particularly those who participate in sports requiring leanness such as cycling and running, can exhibit nutritional deficits, reduced sex hormone levels, and impaired bone health.¹⁰

If we can educate patients on the importance of maintaining a healthy diet and supplying active bodies with the energy they need, then many of these injuries could be prevented.

Make no bones about it.

Make no bones about it!

We just celebrated 45 years since the passing of Title IX, which opened the floodgates for women’s participation in sports. According to a report by the National Collegiate Athletic Association,¹ in this interval, the participation rate of high school girls increased 1,000 percent, and Division I colleges have the highest female athletic participation rate, with women accounting for 46.7% of athletes.

See related article.

Participating in competitive sports is especially important for women because it increases self-confidence. Indeed, there is a direct relationship between athletics and women in leadership roles. A 2013 Ernst and Young survey of 821 high-level executives demonstrated that 90% of the women and 96% of the women in chief executive positions had played sports.²

Twenty years after Title IX was passed, physicians identified a triad of symptoms commonly seen in female athletes. The original definition of the female athletic triad consisted of eating disorders, irregular menstrual cycles, and reduced bone mineral density (BMD).³ Malnutrition led to abnormalities in the menstrual cycle, which in turn affected bone density. The triad was thought to most commonly affect women participating in weight-dependent or judging sports, such as gymnastics, ice-skating, and endurance running. However, many athletes remained undiagnosed because specific criteria for the triad diagnosis remained elusive.

In 2007, the American College of Sports Medicine updated the diagnostic guidelines, defining the female athlete triad as a constellation of abnormalities in energy availability, menstrual function, and BMD.⁴ Each of these 3 components is part of a spectrum ranging from normal to varying degrees of pathology. Thus, the female athlete no longer needs to demonstrate pathology in all 3 components of the triad to be diagnosed with the syndrome. The presence of 1 or 2 of the components on the pathologic side of the spectrum falls under the umbrella of the triad and may meet the criteria for diagnosis, prompting further assessment.

In 2014, the International Olympic Committee (IOC) coined the term relative energy deficiency in sport (RED-S).⁵ The IOC authors intended for RED-S to be a more comprehensive and broader definition for the triad. As defined in the IOC consensus statement, RED-S is “impaired physiological function including, but not limited to, metabolic rate, menstrual function, bone health, immunity, protein synthesis, [and] cardiovascular health caused by relative energy deficiency.”⁵ The statement indicates that the underlying problem is “energy deficiency relative to the balance between dietary energy intake and energy expenditure required for health and activities of daily living, growth, and sporting activities.”⁵ The IOC consensus statement also expands the vulnerable population, discussing the susceptibility of male athletes, athletes of nonwhite ethnicity, and athletes with a disability.

Although there is some contention as to how we should refer to this syndrome, the most important facet is that it can be identified in an office setting. Awareness is key to prevention. Unfortunately, in a 2015 survey of 931 physicians, only 37% could identify the 3 components of the triad.⁶ If you do not ask your patients about their nutrition, eating habits, and menstrual cycle, it is not possible to identify any potential problems.

 

 

WHY IS THIS SO IMPORTANT?

Simply stated, it is important to diagnose and treat the triad syndrome to maintain optimal bone health. About 90% of peak bone mass is acquired by age 18. Bone density continues to build until about the age of 25, after which it is only possible to maintain. If young athletes are losing bone density, it cannot be replaced. Athletes who have a relative energy deficiency and are not maximizing bone growth will potentially struggle with lower bone mineral density later in life. Early awareness of bone health is paramount to sustaining it as we age.

Osteoporosis, often called a silent disease, affects more than 75 million men and women in the United States, Europe, and Japan.⁷ According to the International Osteoporosis Foundation, more than 8.9 million fractures are secondary to osteoporosis worldwide each year. Astoundingly, this epidemic equates to an osteoporotic fracture every 3 seconds.⁸

As physicians, we need to do what we can to prevent this, and the easiest prevention is maintaining bone health and adequate nutrition early in life. We know that weight-bearing exercise is important for bone health, but it is counterintuitive to think that active patients who are running and playing sports may be negatively affecting bone health if they have a relative energy deficiency.

Many females (professional athletes, competitive athletes, or just women who want to stay active) exercise excessively and restrict calories to lose or maintain weight. This can be a formula for disaster resulting in a sidelining bone stress injury. A stress fracture occurs when bone experiences more stress or impact than it can handle from overtraining or increasing training too quickly, not providing enough time for the bone to strengthen. Stress fractures can also occur when bone mineral density declines, lowering the impact threshold. This is most often a direct result of a relative energy deficiency or poor nutrition. The incidence of stress fractures in female athletes is 2 to 3 times higher than that in male athletes, and female athletes with missed menstrual cycles have a 2 to 4 times higher risk of stress fractures than females with a normal monthly menstrual cycle.⁹

The triad syndrome is seen not only in women but in all athletes—including men and Paralympic athletes.^10,11 According to Tenforde et al,¹⁰ male athletes, particularly those who participate in sports requiring leanness such as cycling and running, can exhibit nutritional deficits, reduced sex hormone levels, and impaired bone health.¹⁰

If we can educate patients on the importance of maintaining a healthy diet and supplying active bodies with the energy they need, then many of these injuries could be prevented.

Make no bones about it.

Make no bones about it!

We just celebrated 45 years since the passing of Title IX, which opened the floodgates for women’s participation in sports. According to a report by the National Collegiate Athletic Association,¹ in this interval, the participation rate of high school girls increased 1,000 percent, and Division I colleges have the highest female athletic participation rate, with women accounting for 46.7% of athletes.

See related article.

Participating in competitive sports is especially important for women because it increases self-confidence. Indeed, there is a direct relationship between athletics and women in leadership roles. A 2013 Ernst and Young survey of 821 high-level executives demonstrated that 90% of the women and 96% of the women in chief executive positions had played sports.²

Twenty years after Title IX was passed, physicians identified a triad of symptoms commonly seen in female athletes. The original definition of the female athletic triad consisted of eating disorders, irregular menstrual cycles, and reduced bone mineral density (BMD).³ Malnutrition led to abnormalities in the menstrual cycle, which in turn affected bone density. The triad was thought to most commonly affect women participating in weight-dependent or judging sports, such as gymnastics, ice-skating, and endurance running. However, many athletes remained undiagnosed because specific criteria for the triad diagnosis remained elusive.

In 2007, the American College of Sports Medicine updated the diagnostic guidelines, defining the female athlete triad as a constellation of abnormalities in energy availability, menstrual function, and BMD.⁴ Each of these 3 components is part of a spectrum ranging from normal to varying degrees of pathology. Thus, the female athlete no longer needs to demonstrate pathology in all 3 components of the triad to be diagnosed with the syndrome. The presence of 1 or 2 of the components on the pathologic side of the spectrum falls under the umbrella of the triad and may meet the criteria for diagnosis, prompting further assessment.

In 2014, the International Olympic Committee (IOC) coined the term relative energy deficiency in sport (RED-S).⁵ The IOC authors intended for RED-S to be a more comprehensive and broader definition for the triad. As defined in the IOC consensus statement, RED-S is “impaired physiological function including, but not limited to, metabolic rate, menstrual function, bone health, immunity, protein synthesis, [and] cardiovascular health caused by relative energy deficiency.”⁵ The statement indicates that the underlying problem is “energy deficiency relative to the balance between dietary energy intake and energy expenditure required for health and activities of daily living, growth, and sporting activities.”⁵ The IOC consensus statement also expands the vulnerable population, discussing the susceptibility of male athletes, athletes of nonwhite ethnicity, and athletes with a disability.

Although there is some contention as to how we should refer to this syndrome, the most important facet is that it can be identified in an office setting. Awareness is key to prevention. Unfortunately, in a 2015 survey of 931 physicians, only 37% could identify the 3 components of the triad.⁶ If you do not ask your patients about their nutrition, eating habits, and menstrual cycle, it is not possible to identify any potential problems.

 

 

WHY IS THIS SO IMPORTANT?

Simply stated, it is important to diagnose and treat the triad syndrome to maintain optimal bone health. About 90% of peak bone mass is acquired by age 18. Bone density continues to build until about the age of 25, after which it is only possible to maintain. If young athletes are losing bone density, it cannot be replaced. Athletes who have a relative energy deficiency and are not maximizing bone growth will potentially struggle with lower bone mineral density later in life. Early awareness of bone health is paramount to sustaining it as we age.

Osteoporosis, often called a silent disease, affects more than 75 million men and women in the United States, Europe, and Japan.⁷ According to the International Osteoporosis Foundation, more than 8.9 million fractures are secondary to osteoporosis worldwide each year. Astoundingly, this epidemic equates to an osteoporotic fracture every 3 seconds.⁸

As physicians, we need to do what we can to prevent this, and the easiest prevention is maintaining bone health and adequate nutrition early in life. We know that weight-bearing exercise is important for bone health, but it is counterintuitive to think that active patients who are running and playing sports may be negatively affecting bone health if they have a relative energy deficiency.

Many females (professional athletes, competitive athletes, or just women who want to stay active) exercise excessively and restrict calories to lose or maintain weight. This can be a formula for disaster resulting in a sidelining bone stress injury. A stress fracture occurs when bone experiences more stress or impact than it can handle from overtraining or increasing training too quickly, not providing enough time for the bone to strengthen. Stress fractures can also occur when bone mineral density declines, lowering the impact threshold. This is most often a direct result of a relative energy deficiency or poor nutrition. The incidence of stress fractures in female athletes is 2 to 3 times higher than that in male athletes, and female athletes with missed menstrual cycles have a 2 to 4 times higher risk of stress fractures than females with a normal monthly menstrual cycle.⁹

The triad syndrome is seen not only in women but in all athletes—including men and Paralympic athletes.^10,11 According to Tenforde et al,¹⁰ male athletes, particularly those who participate in sports requiring leanness such as cycling and running, can exhibit nutritional deficits, reduced sex hormone levels, and impaired bone health.¹⁰

If we can educate patients on the importance of maintaining a healthy diet and supplying active bodies with the energy they need, then many of these injuries could be prevented.

Make no bones about it.

Nail fold capillaroscopy did not reveal telangiectasia or ragged cuticles. Further examination of the skin showed confluent macular violaceous erythema on the eyelids (suggestive of the heliotrope sign), V area of the neck, upper arms, and back.

She also had a low-grade intermittent fever for the past 2 months, as well as difficulty in getting up from a squatting position and combing her hair, dyspnea on exertion, blue discoloration of the fingers on exposure to cold, and intermittent pain, stiffness, and swelling in the small joints of both hands that was worse in the morning and seemed to be relieved by activity. She had no history of dysphagia or nasal regurgitation of food. Strength against resistance was reduced in both arms and knee extensors. A diagnosis of dermatomyositis with “mechanic’s hands” was considered.

Laboratory testing was negative for antinuclear antibodies and showed elevated creatine kinase and positive anti-Jo-1 antibodies. High-resolution computed tomography of the chest showed evidence of interstitial lung disease. Features were consistent with antisynthetase syndrome and dermatomyositis. An age-appropriate malignancy screen was normal.

The patient was started on oral prednisolone 60 mg, hydroxychloroquine 300 mg, and azathioprine 100 mg. For her hands, topical clobetasol propionate 0.05% with 3% salicyclic acid and emollients were advised. Her muscle weakness improved considerably after 2 months, but the photosensitivity and mechanic’s hands improved only minimally.

ANTISYNTHETASE SYNDROME

Antisynthetase syndrome is a subset of idiopathic inflammatory myopathies characterized by fever, Raynaud phenomenon, arthritis, myositis, interstitial lung disease, and mechanic’s hands. It is associated with myositis-specific antibodies directed against aminoacyl-tRNA synthetases, of which anti-Jo-1 is the most common. Other antibodies including anti-PL-7 and anti-PL-12 may be present, whereas antinuclear antibodies may be negative.

Mechanic’s hands is seen in about 30% of patients with antisynthetase syndrome and is an important physical sign, as its presence in a patient with myositis and arthritis prompts an evaluation to exclude interstitial lung disease. Its onset later in the disease course may herald the flare-up of interstitial lung disease.¹ A similar hyperkeratosis may also affect the feet, and the importance of a careful cutaneous examination of the hands and feet should be stressed in patients presenting with polymyositis and dermatomyositis.

In contrast, hyperkeratotic eczema of the hand is usually pruritic, and involvement of the tips and palmar aspects of the fingers and palms is characteristic.^2,3 Vesicles (pompholyx) and coarse pitting of the nails may also be seen in eczema. Other features that help rule out eczema are the development of these features over a short period of time, asymptomatic nature, presence of systemic symptoms, and involvement of only the lateral margins of the index fingers, with no involvement of the palmar aspects and other fingers.

Degenerative collagenous plaque, closely resembling mechanic’s hands, is common in elderly people with photodamaged skin. It is asymptomatic, is not associated with systemic illness, and features clumping and thickening of elastic fibers on histopathology.

Association with cancer risk

Though antisynthetase syndrome was not previously considered to be associated with an increased risk of malignancy, a retrospective review of 124 patients with antisynthetase syndrome recently showed a malignancy risk of 6.5%.⁴ Overall, the data regarding the association of malignancy and antisynthetase syndrome are conflicting, and this needs further study. Therefore, an age-appropriate malignancy screen is recommended.^4–6 Also, the presence of malignancy and interstitial lung disease is associated with a poor prognosis in these patients.

Treatment

Glucocorticoids are the mainstay of treatment, and azathioprine and methotrexate are important steroid-sparing agents.^5,7 Use of methotrexate warrants caution in patients with interstitial lung disease, since methotrexate itself can cause pulmonary fibrosis.

In our patient, prednisolone was slowly tapered to 20 mg/day, and hydroxychloroquine and azathioprine were continued at 300 mg/day and 100 mg/day, respectively. Topical treatment for mechanic’s hands was continued, with only minimal improvement.             

Nail fold capillaroscopy did not reveal telangiectasia or ragged cuticles. Further examination of the skin showed confluent macular violaceous erythema on the eyelids (suggestive of the heliotrope sign), V area of the neck, upper arms, and back.

She also had a low-grade intermittent fever for the past 2 months, as well as difficulty in getting up from a squatting position and combing her hair, dyspnea on exertion, blue discoloration of the fingers on exposure to cold, and intermittent pain, stiffness, and swelling in the small joints of both hands that was worse in the morning and seemed to be relieved by activity. She had no history of dysphagia or nasal regurgitation of food. Strength against resistance was reduced in both arms and knee extensors. A diagnosis of dermatomyositis with “mechanic’s hands” was considered.

Laboratory testing was negative for antinuclear antibodies and showed elevated creatine kinase and positive anti-Jo-1 antibodies. High-resolution computed tomography of the chest showed evidence of interstitial lung disease. Features were consistent with antisynthetase syndrome and dermatomyositis. An age-appropriate malignancy screen was normal.

The patient was started on oral prednisolone 60 mg, hydroxychloroquine 300 mg, and azathioprine 100 mg. For her hands, topical clobetasol propionate 0.05% with 3% salicyclic acid and emollients were advised. Her muscle weakness improved considerably after 2 months, but the photosensitivity and mechanic’s hands improved only minimally.

ANTISYNTHETASE SYNDROME

Antisynthetase syndrome is a subset of idiopathic inflammatory myopathies characterized by fever, Raynaud phenomenon, arthritis, myositis, interstitial lung disease, and mechanic’s hands. It is associated with myositis-specific antibodies directed against aminoacyl-tRNA synthetases, of which anti-Jo-1 is the most common. Other antibodies including anti-PL-7 and anti-PL-12 may be present, whereas antinuclear antibodies may be negative.

Mechanic’s hands is seen in about 30% of patients with antisynthetase syndrome and is an important physical sign, as its presence in a patient with myositis and arthritis prompts an evaluation to exclude interstitial lung disease. Its onset later in the disease course may herald the flare-up of interstitial lung disease.¹ A similar hyperkeratosis may also affect the feet, and the importance of a careful cutaneous examination of the hands and feet should be stressed in patients presenting with polymyositis and dermatomyositis.

In contrast, hyperkeratotic eczema of the hand is usually pruritic, and involvement of the tips and palmar aspects of the fingers and palms is characteristic.^2,3 Vesicles (pompholyx) and coarse pitting of the nails may also be seen in eczema. Other features that help rule out eczema are the development of these features over a short period of time, asymptomatic nature, presence of systemic symptoms, and involvement of only the lateral margins of the index fingers, with no involvement of the palmar aspects and other fingers.

Degenerative collagenous plaque, closely resembling mechanic’s hands, is common in elderly people with photodamaged skin. It is asymptomatic, is not associated with systemic illness, and features clumping and thickening of elastic fibers on histopathology.

Association with cancer risk

Though antisynthetase syndrome was not previously considered to be associated with an increased risk of malignancy, a retrospective review of 124 patients with antisynthetase syndrome recently showed a malignancy risk of 6.5%.⁴ Overall, the data regarding the association of malignancy and antisynthetase syndrome are conflicting, and this needs further study. Therefore, an age-appropriate malignancy screen is recommended.^4–6 Also, the presence of malignancy and interstitial lung disease is associated with a poor prognosis in these patients.

Treatment

Glucocorticoids are the mainstay of treatment, and azathioprine and methotrexate are important steroid-sparing agents.^5,7 Use of methotrexate warrants caution in patients with interstitial lung disease, since methotrexate itself can cause pulmonary fibrosis.

In our patient, prednisolone was slowly tapered to 20 mg/day, and hydroxychloroquine and azathioprine were continued at 300 mg/day and 100 mg/day, respectively. Topical treatment for mechanic’s hands was continued, with only minimal improvement.             

Nail fold capillaroscopy did not reveal telangiectasia or ragged cuticles. Further examination of the skin showed confluent macular violaceous erythema on the eyelids (suggestive of the heliotrope sign), V area of the neck, upper arms, and back.

She also had a low-grade intermittent fever for the past 2 months, as well as difficulty in getting up from a squatting position and combing her hair, dyspnea on exertion, blue discoloration of the fingers on exposure to cold, and intermittent pain, stiffness, and swelling in the small joints of both hands that was worse in the morning and seemed to be relieved by activity. She had no history of dysphagia or nasal regurgitation of food. Strength against resistance was reduced in both arms and knee extensors. A diagnosis of dermatomyositis with “mechanic’s hands” was considered.

Laboratory testing was negative for antinuclear antibodies and showed elevated creatine kinase and positive anti-Jo-1 antibodies. High-resolution computed tomography of the chest showed evidence of interstitial lung disease. Features were consistent with antisynthetase syndrome and dermatomyositis. An age-appropriate malignancy screen was normal.

The patient was started on oral prednisolone 60 mg, hydroxychloroquine 300 mg, and azathioprine 100 mg. For her hands, topical clobetasol propionate 0.05% with 3% salicyclic acid and emollients were advised. Her muscle weakness improved considerably after 2 months, but the photosensitivity and mechanic’s hands improved only minimally.

ANTISYNTHETASE SYNDROME

Antisynthetase syndrome is a subset of idiopathic inflammatory myopathies characterized by fever, Raynaud phenomenon, arthritis, myositis, interstitial lung disease, and mechanic’s hands. It is associated with myositis-specific antibodies directed against aminoacyl-tRNA synthetases, of which anti-Jo-1 is the most common. Other antibodies including anti-PL-7 and anti-PL-12 may be present, whereas antinuclear antibodies may be negative.

Mechanic’s hands is seen in about 30% of patients with antisynthetase syndrome and is an important physical sign, as its presence in a patient with myositis and arthritis prompts an evaluation to exclude interstitial lung disease. Its onset later in the disease course may herald the flare-up of interstitial lung disease.¹ A similar hyperkeratosis may also affect the feet, and the importance of a careful cutaneous examination of the hands and feet should be stressed in patients presenting with polymyositis and dermatomyositis.

In contrast, hyperkeratotic eczema of the hand is usually pruritic, and involvement of the tips and palmar aspects of the fingers and palms is characteristic.^2,3 Vesicles (pompholyx) and coarse pitting of the nails may also be seen in eczema. Other features that help rule out eczema are the development of these features over a short period of time, asymptomatic nature, presence of systemic symptoms, and involvement of only the lateral margins of the index fingers, with no involvement of the palmar aspects and other fingers.

Degenerative collagenous plaque, closely resembling mechanic’s hands, is common in elderly people with photodamaged skin. It is asymptomatic, is not associated with systemic illness, and features clumping and thickening of elastic fibers on histopathology.

Association with cancer risk

Though antisynthetase syndrome was not previously considered to be associated with an increased risk of malignancy, a retrospective review of 124 patients with antisynthetase syndrome recently showed a malignancy risk of 6.5%.⁴ Overall, the data regarding the association of malignancy and antisynthetase syndrome are conflicting, and this needs further study. Therefore, an age-appropriate malignancy screen is recommended.^4–6 Also, the presence of malignancy and interstitial lung disease is associated with a poor prognosis in these patients.

Treatment

Glucocorticoids are the mainstay of treatment, and azathioprine and methotrexate are important steroid-sparing agents.^5,7 Use of methotrexate warrants caution in patients with interstitial lung disease, since methotrexate itself can cause pulmonary fibrosis.

In our patient, prednisolone was slowly tapered to 20 mg/day, and hydroxychloroquine and azathioprine were continued at 300 mg/day and 100 mg/day, respectively. Topical treatment for mechanic’s hands was continued, with only minimal improvement.