Cleveland Clinic Journal of Medicine

More than 2 years have passed since we published the results of the Women’s Health Initiative (WHI), which caused a storm of information—and misinformation—about the effect of long-term dietary intervention on disease outcomes in postmenopausal women. Now that the dust has long settled, what have we learned from this landmark study?

The WHI results led to numerous additional analyses of all aspects of the study.^1–7 What are the implications of all the analyses to clinical practice?

In this article, we summarize key aspects of the clinical trial, including study design, interventions, main results, and future plans. We also discuss potential clinical applications and practical considerations for public health efforts.

WHO WAS ELIGIBLE, WHO WAS NOT

A total of 48,835 postmenopausal women were randomly assigned to either no dietary intervention (n = 29,294) or a dietary intervention (n = 19,541) (see below).⁷ Participants were followed at 40 clinical centers between 1993 and 2005.⁴ Their mean age was 62.3 years; 18.6% were members of minorities.

Women were eligible if they were post-menopausal and had a daily dietary fat intake of at least 32% of total calories, based on assessment via a food-frequency questionnaire. They were excluded from the study if they had any of the following: a history of breast cancer, colorectal cancer, or other cancer except skin cancer during the past 10 years; type 1 diabetes; a medical condition in which the predicted survival was less than 3 years; and a potential barrier to adherence to the study regimen, including alcoholism or a lifestyle that involved often eating meals away from home.

THE WHI DIET: LESS FAT, BUT MORE FRUITS, VEGETABLES, GRAINS

The WHI dietary intervention was designed to prevent breast cancer, based on the evidence available when the study was planned. The targets included a total fat intake of less than 20% of energy (in kilocalories), increasing the intake of fruits and vegetables to at least five servings per day, and increasing the intake of grains to at least six servings per day.

Although reduction in saturated fat intake per se was not part of the WHI protocol, we assumed from previous pilot studies⁸ that the reduction of total fat intake would simultaneously produce a reduction in saturated fat intake to 7% of total calories.

A simpler dietary intervention

Unlike the 2006 American Heart Association guidelines and the US Department of Agriculture’s Dietary Guidelines for Americans 2005, the WHI dietary intervention had no specifications for dietary fiber, specific fatty acids (trans-fatty acids, omega-3 fatty acids, conjugated linoleic acid), complex carbohydrates, whole grains, vegetable protein, or other factors that have emerged as potential risk factors for cardiovascular and other chronic diseases since the study began. The WHI intervention also included no specific recommendation for total calorie intake, nor were patients in the intervention group encouraged to lose weight, as this could have confounded the results of the dietary intervention.

Education and encouragement

Those in the intervention group were each assigned a fat-gram goal, calculated on the basis of height. They were taught how to monitor their intake of total fat, fruits, vegetables, and grains. They attended intensive behavioral modification sessions to encourage them to keep to the dietary program: 18 group sessions in the first year and quarterly maintenance sessions thereafter, touching on a wide variety of nutrition- and behavior-related topics.^7,9 Specially trained and certified nutritionists supervised the dietary intervention and the behavioral modification sessions according to the WHI study protocol.

Control-group participants received a copy of the US Department of Agriculture’s Dietary Guidelines for Americans¹⁰ and other health-related materials. They had no contact with the study nutritionists.

Other arms of the study

The WHI trial design included several arms,^4,11–13 and many participants joined more than one arm: 20,592 postmenopausal women (42.2% of the total enrollment) chose dietary modification only, 8,050 (16.5%) chose diet plus hormone replacement therapy, 25,210 (51.6%) chose diet plus calcium and vitamin D supplementation, and 5,017 (10.3%) enrolled in all three.

Length of follow-up

Participants were followed from enrollment until they died, were lost to follow-up, or requested no further contact, or until the trial’s planned completion date, regardless of adherence to the dietary intervention, according to intention-to-treat analysis. All participants were contacted by clinic staff at 6-month intervals to provide updates on their health outcomes.

Factors assessed

Height, weight, waist circumference, and blood pressure were measured at annual visits using standardized procedures. Fasting blood samples were collected at baseline and at year 1 from all participants and from a subsample of 2,816 women (5.8% of the study population) at years 3 and 6. This subsample was randomly chosen with oversampling of minority women, for whom the odds for selection were six times higher than for white women.

Physical activity was assessed at baseline and at years 1, 3, 6, and 9. Walking and participation in sports and hours of activity per week were calculated for each participant. Physical activity was expressed as metabolic equivalent tasks per week for the analyses.

A food-frequency questionnaire⁶ to assess average dietary intake in the past 3 months was given at baseline and at year 1 for all participants. A third of all participants completed the questionnaire each year in a rotating sample. Completion rates were 100% at baseline and 81% thereafter. Follow-up data were collected from years 5 through 7. Also, 4-day food records were provided by all women before randomization.

HOW OUTCOMES WERE ASSESSED

The primary assessments of clinical outcome^1–3 were mammographic screening, a self-reported medical history documented by a review of medical records, and electrocardiograms digitally obtained every 3 years. Mammograms and electrocardiograms were centrally adjudicated. The diagnosis of acute myocardial infarction was based on an algorithm that included cardiac pain, enzyme levels, and electrocardiographic readings.

OVERALL RESULTS

At 8.1 years, the incidence of breast cancer was 9% lower in the intervention group than in the comparison group (95% confidence interval [CI] = 0.83–1.01; P = .07, P = .09 weighted for length of follow-up).³ Subgroup analysis further showed that women who reported higher intakes of total dietary fat at baseline reduced their risk of breast cancer by 22% (95% CI = 0.64–0.96). Whether extended follow-up will show a significant association has yet to be determined.

Colon cancer rates did not differ between groups, but the number of polyps and adenomas reported was significantly lower in the dietary intervention group.¹ The rate of colon cancer will also be included in the extended follow-up study of the WHI.

Risk factors for coronary heart disease in both groups—including levels of serum total cholesterol and serum low-density lipoprotein cholesterol, body weight, body mass index, diastolic blood pressure, and factor VIIc—improved slightly, but at year 3 of the trial, differences in overall rates of coronary heart disease and stroke in the two groups were not statistically significant.² In addition, the low-fat diet intervention was associated with a reduction in blood estradiol concentrations between baseline and year 1.³ At the end of the study, however, differences in rates of breast cancer, colorectal cancer, and heart disease between the two groups were not statistically significant.

RESULTS OF DIETARY MODIFICATIONS

Fat as a percentage of total calories

At the beginning of the WHI, all participants reported consuming an average of 35% of their caloric intake from fat (Table 1). At 1 year from baseline, the fat intake decreased to 24.3% in the intervention group (short of the study goal of 20%); this level had risen again to 26.7% by year 3 and to 28.8% at the end of the study. Stratified by quartile, women who achieved the greatest reductions in saturated and trans-fatty acids or the largest increases in their intake of fruits and vegetables appeared to have a moderate reduction in the risk of coronary heart disease.² Women in the comparison group also decreased their fat intake initially, but to a lesser degree, and gradually increased it again thereafter. The mean net difference in self-reported total fat intake between the intervention group and the comparison group at 6 years was 8.2% (P < .001) (study goal, 13%).^1–3

Intake of fruits, vegetables, and grains

At baseline, fruit and vegetable intake averaged 3.6 servings per day (Table 1). In the intervention group, this increased to 5.1 servings per day at year 1, and to 5.2 servings at year 3, but at the end of the study it had decreased to 4.9 servings.

Women in the intervention group were eating 4.7 servings of grains per day at baseline. This increased to 5.1 servings at year 1 and then decreased to 4.6 servings at year 3 and to 4.3 servings at the end of the study. It seems that as the women grew older their determination to increase servings of these foods diminished.

Proponents of some currently popular diets blame weight gain on a higher intake of carbohydrates, but the women following the WHI low-fat diet did not gain weight.²

Total fat vs saturated fat

Intake of total fat and saturated fat decreased in the intervention group during the study, but the difference between fat intake in the intervention group and that in the comparison group did not reach the degree expected.

At year 1, total fat as a percentage of total caloric intake was 10.8 percentage points below that of the comparison group, whereas the study expected difference was 13.0. At the end of the trial, the difference was only 8.2 percentage points, whereas the expected difference was 11.0.

Intake of all fatty acids (saturated and unsaturated) decreased at year 1, but then went back up slightly by the end of the trial but did not exceed baseline levels, and saturated fatty acids remained well below baseline levels: 9.5% vs 12.5% of caloric intake at baseline.⁴

INTERPRETING THE RESULTS

It might be tempting to dismiss the results of the WHI dietary intervention trial as not significant and therefore not meaningful. This would be unfortunate. The trial had some remarkable accomplishments and offers important lessons for future investigations.

The initial reductions in total fat intake were impressive, and women who had the highest total fat intake at baseline achieved the greatest reduction of total fat (to less than 22% of total calories).³ Nonetheless, the dietary intervention goal of less than 20% of calories from fat was not achieved despite intensive dietary counseling and a highly motivated study population. Thus, this dietary fat target may not be reasonable in the general population.

Also, despite the absence of targeted intervention on specific fatty acids, the observed blood cholesterol levels were as expected based on the well-known formula of Mensink and Katan,¹⁴ which incorporates information on changes in saturated fat, polyunsaturated fat, and dietary cholesterol intake. The predicted reduction in low-density lipoprotein cholesterol was 2.7 mg/dL; the observed reduction was 2.3 mg/dL.² This illustrates that with greater modifications in specific known dietary risk factors for cardiovascular disease, such as saturated fatty acids, cholesterol, and unsaturated fatty acids, blood cholesterol levels respond in a predictable fashion. This was presumably not observed in WHI precisely because no goals and objectives were provided to participants for intake of saturated or polyunsaturated fatty acids.

Recent findings from the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart)¹⁵ further highlight differences in the total cholesterol response to diets of varying macronutrient (carbohydrate, protein, fat) content compared with the WHI dietary intervention.¹⁵ Participants in OmniHeart had reductions in levels of low-density lipoprotein cholesterol that were predictable from the changes reported in intake of saturated fatty acids. Presumably, the results of the WHI intervention would have been similar if the study had included this level of detail.

QUESTIONS REMAIN

Questions from the WHI that need consideration for future clinical applications include whether the study population may have already been “too old” to achieve a benefit from dietary modification, and whether the best timing for dietary intervention might be earlier adulthood with sustained changes in saturated fat, cholesterol, and unsaturated fat intake throughout life. Future subgroup analyses based on age at baseline will need to address these questions. Likewise, a longer follow-up period may be needed for a definitive evaluation of the impact of a regular low-fat diet on different health outcomes.

As reported by Patterson et al,¹⁶ the major contributors to total dietary fat intake at baseline were “added fats” such as sauces, gravies, butter, and margarines (25.1% of fat intake), followed by meats (20.9% of fat intake), and desserts (12.8% of fat intake). These findings highlight target areas for future interventions in women of this age group.

Another issue is how to standardize the dietary intervention from one clinical center to another—ie, to minimize differences in how each clinical center manages the study patients. Such differences were noted in WHI and other studies.¹⁷ Despite standardized training in delivering the dietary intervention, nutritionists encountered regional and cultural differences that required tailoring the dietary intervention to their patients’ needs. Staff turnover, an unavoidable phenomenon in long-term studies, has previously been reported to negatively influence dietary adherence.¹⁸

LIMITATIONS

A major limitation of diet modification research in general is the self-reporting of dietary intake, primarily by a food-frequency questionnaire. Although the use of a questionnaire is the most practical way to obtain dietary data for large studies, systematic biases may exist that obscure true nutrient-outcome relationships.¹⁹ Biomarker studies of energy balance suggest that people who are overweight or obese may under-report energy intake to a greater degree than people who are not overweight.²⁰ Also, we still do not know how to get people to follow a healthy diet, although theories and models abound, such as social learning and cognitive-behavioral theory, and a lack of data limits our understanding of factors related to dietary adherence.^21,22

FUTURE DIRECTIONS IN WHI

The WHI Extension Study is under way and has been funded through the year 2010. Outcomes ascertainment is the primary focus with no ongoing intervention, although the intervention group participants continue to receive a WHI newsletter that simply reiterates the importance of the study and encourages ongoing participation. As of 2006, an estimated 84% of the cohort, including both observational study and clinical trial participants, are involved. Efforts continue to recruit the remaining 16%, but many of these participants now consider themselves too old or too feeble to respond reliably.

In regard to breast cancer, the results published in 2006 are promising, albeit not statistically significant, and definitive statements cannot yet be made. However, postmenopausal women who are eating the diets highest in fat may have the greatest benefit from reductions in total fat.

Other considerations regarding the lack of statistically significant differences between groups may include the possibility that women in the intervention group may have been at lower risk for breast cancer at baseline. Likewise, although the results of the WHI dietary intervention do not include a statistically significant impact on colorectal cancer outcomes, the significant reduction in polyps and adenomas may later translate into a reduction in invasive cancer risk.

Finally, although no significant reduction was seen in the rate of death due to cardiovascular causes, greater reductions in saturated and trans-fatty acid intake were associated with greater reductions in blood cholesterol and cardiovascular risk.

Numerous subgroup analyses and ongoing assessments of the long-term impact of the diet modification are planned. Further associations are expected to emerge. The current and future results will continue to provide new insights that may lead to new clinical and public health recommendations in the future.

The WHI has raised additional issues that warrant further investigation:

• Will earlier dietary intervention, eg, during premenopausal years or even childhood, alter these results?
• Does the low-fat, high-carbohydrate diet used in WHI facilitate weight maintenance or even weight loss, as proposed by Howard et al²³?
• Do quantitative changes in physical activity and weight control attenuate morbidity and mortality rates beyond changes in diet alone?
• Do vitamin and mineral supplements or hormone therapy alter disease outcomes or quality of life?
• Which behavioral approaches are best suited to the recruitment of patients for dietary intervention trials?

More than 2 years have passed since we published the results of the Women’s Health Initiative (WHI), which caused a storm of information—and misinformation—about the effect of long-term dietary intervention on disease outcomes in postmenopausal women. Now that the dust has long settled, what have we learned from this landmark study?

The WHI results led to numerous additional analyses of all aspects of the study.^1–7 What are the implications of all the analyses to clinical practice?

In this article, we summarize key aspects of the clinical trial, including study design, interventions, main results, and future plans. We also discuss potential clinical applications and practical considerations for public health efforts.

WHO WAS ELIGIBLE, WHO WAS NOT

A total of 48,835 postmenopausal women were randomly assigned to either no dietary intervention (n = 29,294) or a dietary intervention (n = 19,541) (see below).⁷ Participants were followed at 40 clinical centers between 1993 and 2005.⁴ Their mean age was 62.3 years; 18.6% were members of minorities.

Women were eligible if they were post-menopausal and had a daily dietary fat intake of at least 32% of total calories, based on assessment via a food-frequency questionnaire. They were excluded from the study if they had any of the following: a history of breast cancer, colorectal cancer, or other cancer except skin cancer during the past 10 years; type 1 diabetes; a medical condition in which the predicted survival was less than 3 years; and a potential barrier to adherence to the study regimen, including alcoholism or a lifestyle that involved often eating meals away from home.

THE WHI DIET: LESS FAT, BUT MORE FRUITS, VEGETABLES, GRAINS

The WHI dietary intervention was designed to prevent breast cancer, based on the evidence available when the study was planned. The targets included a total fat intake of less than 20% of energy (in kilocalories), increasing the intake of fruits and vegetables to at least five servings per day, and increasing the intake of grains to at least six servings per day.

Although reduction in saturated fat intake per se was not part of the WHI protocol, we assumed from previous pilot studies⁸ that the reduction of total fat intake would simultaneously produce a reduction in saturated fat intake to 7% of total calories.

A simpler dietary intervention

Unlike the 2006 American Heart Association guidelines and the US Department of Agriculture’s Dietary Guidelines for Americans 2005, the WHI dietary intervention had no specifications for dietary fiber, specific fatty acids (trans-fatty acids, omega-3 fatty acids, conjugated linoleic acid), complex carbohydrates, whole grains, vegetable protein, or other factors that have emerged as potential risk factors for cardiovascular and other chronic diseases since the study began. The WHI intervention also included no specific recommendation for total calorie intake, nor were patients in the intervention group encouraged to lose weight, as this could have confounded the results of the dietary intervention.

Education and encouragement

Those in the intervention group were each assigned a fat-gram goal, calculated on the basis of height. They were taught how to monitor their intake of total fat, fruits, vegetables, and grains. They attended intensive behavioral modification sessions to encourage them to keep to the dietary program: 18 group sessions in the first year and quarterly maintenance sessions thereafter, touching on a wide variety of nutrition- and behavior-related topics.^7,9 Specially trained and certified nutritionists supervised the dietary intervention and the behavioral modification sessions according to the WHI study protocol.

Control-group participants received a copy of the US Department of Agriculture’s Dietary Guidelines for Americans¹⁰ and other health-related materials. They had no contact with the study nutritionists.

Other arms of the study

The WHI trial design included several arms,^4,11–13 and many participants joined more than one arm: 20,592 postmenopausal women (42.2% of the total enrollment) chose dietary modification only, 8,050 (16.5%) chose diet plus hormone replacement therapy, 25,210 (51.6%) chose diet plus calcium and vitamin D supplementation, and 5,017 (10.3%) enrolled in all three.

Length of follow-up

Participants were followed from enrollment until they died, were lost to follow-up, or requested no further contact, or until the trial’s planned completion date, regardless of adherence to the dietary intervention, according to intention-to-treat analysis. All participants were contacted by clinic staff at 6-month intervals to provide updates on their health outcomes.

Factors assessed

Height, weight, waist circumference, and blood pressure were measured at annual visits using standardized procedures. Fasting blood samples were collected at baseline and at year 1 from all participants and from a subsample of 2,816 women (5.8% of the study population) at years 3 and 6. This subsample was randomly chosen with oversampling of minority women, for whom the odds for selection were six times higher than for white women.

Physical activity was assessed at baseline and at years 1, 3, 6, and 9. Walking and participation in sports and hours of activity per week were calculated for each participant. Physical activity was expressed as metabolic equivalent tasks per week for the analyses.

A food-frequency questionnaire⁶ to assess average dietary intake in the past 3 months was given at baseline and at year 1 for all participants. A third of all participants completed the questionnaire each year in a rotating sample. Completion rates were 100% at baseline and 81% thereafter. Follow-up data were collected from years 5 through 7. Also, 4-day food records were provided by all women before randomization.

HOW OUTCOMES WERE ASSESSED

The primary assessments of clinical outcome^1–3 were mammographic screening, a self-reported medical history documented by a review of medical records, and electrocardiograms digitally obtained every 3 years. Mammograms and electrocardiograms were centrally adjudicated. The diagnosis of acute myocardial infarction was based on an algorithm that included cardiac pain, enzyme levels, and electrocardiographic readings.

OVERALL RESULTS

At 8.1 years, the incidence of breast cancer was 9% lower in the intervention group than in the comparison group (95% confidence interval [CI] = 0.83–1.01; P = .07, P = .09 weighted for length of follow-up).³ Subgroup analysis further showed that women who reported higher intakes of total dietary fat at baseline reduced their risk of breast cancer by 22% (95% CI = 0.64–0.96). Whether extended follow-up will show a significant association has yet to be determined.

Colon cancer rates did not differ between groups, but the number of polyps and adenomas reported was significantly lower in the dietary intervention group.¹ The rate of colon cancer will also be included in the extended follow-up study of the WHI.

Risk factors for coronary heart disease in both groups—including levels of serum total cholesterol and serum low-density lipoprotein cholesterol, body weight, body mass index, diastolic blood pressure, and factor VIIc—improved slightly, but at year 3 of the trial, differences in overall rates of coronary heart disease and stroke in the two groups were not statistically significant.² In addition, the low-fat diet intervention was associated with a reduction in blood estradiol concentrations between baseline and year 1.³ At the end of the study, however, differences in rates of breast cancer, colorectal cancer, and heart disease between the two groups were not statistically significant.

RESULTS OF DIETARY MODIFICATIONS

Fat as a percentage of total calories

At the beginning of the WHI, all participants reported consuming an average of 35% of their caloric intake from fat (Table 1). At 1 year from baseline, the fat intake decreased to 24.3% in the intervention group (short of the study goal of 20%); this level had risen again to 26.7% by year 3 and to 28.8% at the end of the study. Stratified by quartile, women who achieved the greatest reductions in saturated and trans-fatty acids or the largest increases in their intake of fruits and vegetables appeared to have a moderate reduction in the risk of coronary heart disease.² Women in the comparison group also decreased their fat intake initially, but to a lesser degree, and gradually increased it again thereafter. The mean net difference in self-reported total fat intake between the intervention group and the comparison group at 6 years was 8.2% (P < .001) (study goal, 13%).^1–3

Intake of fruits, vegetables, and grains

At baseline, fruit and vegetable intake averaged 3.6 servings per day (Table 1). In the intervention group, this increased to 5.1 servings per day at year 1, and to 5.2 servings at year 3, but at the end of the study it had decreased to 4.9 servings.

Women in the intervention group were eating 4.7 servings of grains per day at baseline. This increased to 5.1 servings at year 1 and then decreased to 4.6 servings at year 3 and to 4.3 servings at the end of the study. It seems that as the women grew older their determination to increase servings of these foods diminished.

Proponents of some currently popular diets blame weight gain on a higher intake of carbohydrates, but the women following the WHI low-fat diet did not gain weight.²

Total fat vs saturated fat

Intake of total fat and saturated fat decreased in the intervention group during the study, but the difference between fat intake in the intervention group and that in the comparison group did not reach the degree expected.

At year 1, total fat as a percentage of total caloric intake was 10.8 percentage points below that of the comparison group, whereas the study expected difference was 13.0. At the end of the trial, the difference was only 8.2 percentage points, whereas the expected difference was 11.0.

Intake of all fatty acids (saturated and unsaturated) decreased at year 1, but then went back up slightly by the end of the trial but did not exceed baseline levels, and saturated fatty acids remained well below baseline levels: 9.5% vs 12.5% of caloric intake at baseline.⁴

INTERPRETING THE RESULTS

It might be tempting to dismiss the results of the WHI dietary intervention trial as not significant and therefore not meaningful. This would be unfortunate. The trial had some remarkable accomplishments and offers important lessons for future investigations.

The initial reductions in total fat intake were impressive, and women who had the highest total fat intake at baseline achieved the greatest reduction of total fat (to less than 22% of total calories).³ Nonetheless, the dietary intervention goal of less than 20% of calories from fat was not achieved despite intensive dietary counseling and a highly motivated study population. Thus, this dietary fat target may not be reasonable in the general population.

Also, despite the absence of targeted intervention on specific fatty acids, the observed blood cholesterol levels were as expected based on the well-known formula of Mensink and Katan,¹⁴ which incorporates information on changes in saturated fat, polyunsaturated fat, and dietary cholesterol intake. The predicted reduction in low-density lipoprotein cholesterol was 2.7 mg/dL; the observed reduction was 2.3 mg/dL.² This illustrates that with greater modifications in specific known dietary risk factors for cardiovascular disease, such as saturated fatty acids, cholesterol, and unsaturated fatty acids, blood cholesterol levels respond in a predictable fashion. This was presumably not observed in WHI precisely because no goals and objectives were provided to participants for intake of saturated or polyunsaturated fatty acids.

Recent findings from the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart)¹⁵ further highlight differences in the total cholesterol response to diets of varying macronutrient (carbohydrate, protein, fat) content compared with the WHI dietary intervention.¹⁵ Participants in OmniHeart had reductions in levels of low-density lipoprotein cholesterol that were predictable from the changes reported in intake of saturated fatty acids. Presumably, the results of the WHI intervention would have been similar if the study had included this level of detail.

QUESTIONS REMAIN

Questions from the WHI that need consideration for future clinical applications include whether the study population may have already been “too old” to achieve a benefit from dietary modification, and whether the best timing for dietary intervention might be earlier adulthood with sustained changes in saturated fat, cholesterol, and unsaturated fat intake throughout life. Future subgroup analyses based on age at baseline will need to address these questions. Likewise, a longer follow-up period may be needed for a definitive evaluation of the impact of a regular low-fat diet on different health outcomes.

As reported by Patterson et al,¹⁶ the major contributors to total dietary fat intake at baseline were “added fats” such as sauces, gravies, butter, and margarines (25.1% of fat intake), followed by meats (20.9% of fat intake), and desserts (12.8% of fat intake). These findings highlight target areas for future interventions in women of this age group.

Another issue is how to standardize the dietary intervention from one clinical center to another—ie, to minimize differences in how each clinical center manages the study patients. Such differences were noted in WHI and other studies.¹⁷ Despite standardized training in delivering the dietary intervention, nutritionists encountered regional and cultural differences that required tailoring the dietary intervention to their patients’ needs. Staff turnover, an unavoidable phenomenon in long-term studies, has previously been reported to negatively influence dietary adherence.¹⁸

LIMITATIONS

A major limitation of diet modification research in general is the self-reporting of dietary intake, primarily by a food-frequency questionnaire. Although the use of a questionnaire is the most practical way to obtain dietary data for large studies, systematic biases may exist that obscure true nutrient-outcome relationships.¹⁹ Biomarker studies of energy balance suggest that people who are overweight or obese may under-report energy intake to a greater degree than people who are not overweight.²⁰ Also, we still do not know how to get people to follow a healthy diet, although theories and models abound, such as social learning and cognitive-behavioral theory, and a lack of data limits our understanding of factors related to dietary adherence.^21,22

FUTURE DIRECTIONS IN WHI

The WHI Extension Study is under way and has been funded through the year 2010. Outcomes ascertainment is the primary focus with no ongoing intervention, although the intervention group participants continue to receive a WHI newsletter that simply reiterates the importance of the study and encourages ongoing participation. As of 2006, an estimated 84% of the cohort, including both observational study and clinical trial participants, are involved. Efforts continue to recruit the remaining 16%, but many of these participants now consider themselves too old or too feeble to respond reliably.

In regard to breast cancer, the results published in 2006 are promising, albeit not statistically significant, and definitive statements cannot yet be made. However, postmenopausal women who are eating the diets highest in fat may have the greatest benefit from reductions in total fat.

Other considerations regarding the lack of statistically significant differences between groups may include the possibility that women in the intervention group may have been at lower risk for breast cancer at baseline. Likewise, although the results of the WHI dietary intervention do not include a statistically significant impact on colorectal cancer outcomes, the significant reduction in polyps and adenomas may later translate into a reduction in invasive cancer risk.

Finally, although no significant reduction was seen in the rate of death due to cardiovascular causes, greater reductions in saturated and trans-fatty acid intake were associated with greater reductions in blood cholesterol and cardiovascular risk.

Numerous subgroup analyses and ongoing assessments of the long-term impact of the diet modification are planned. Further associations are expected to emerge. The current and future results will continue to provide new insights that may lead to new clinical and public health recommendations in the future.

The WHI has raised additional issues that warrant further investigation:

• Will earlier dietary intervention, eg, during premenopausal years or even childhood, alter these results?
• Does the low-fat, high-carbohydrate diet used in WHI facilitate weight maintenance or even weight loss, as proposed by Howard et al²³?
• Do quantitative changes in physical activity and weight control attenuate morbidity and mortality rates beyond changes in diet alone?
• Do vitamin and mineral supplements or hormone therapy alter disease outcomes or quality of life?
• Which behavioral approaches are best suited to the recruitment of patients for dietary intervention trials?

More than 2 years have passed since we published the results of the Women’s Health Initiative (WHI), which caused a storm of information—and misinformation—about the effect of long-term dietary intervention on disease outcomes in postmenopausal women. Now that the dust has long settled, what have we learned from this landmark study?

The WHI results led to numerous additional analyses of all aspects of the study.^1–7 What are the implications of all the analyses to clinical practice?

In this article, we summarize key aspects of the clinical trial, including study design, interventions, main results, and future plans. We also discuss potential clinical applications and practical considerations for public health efforts.

WHO WAS ELIGIBLE, WHO WAS NOT

A total of 48,835 postmenopausal women were randomly assigned to either no dietary intervention (n = 29,294) or a dietary intervention (n = 19,541) (see below).⁷ Participants were followed at 40 clinical centers between 1993 and 2005.⁴ Their mean age was 62.3 years; 18.6% were members of minorities.

Women were eligible if they were post-menopausal and had a daily dietary fat intake of at least 32% of total calories, based on assessment via a food-frequency questionnaire. They were excluded from the study if they had any of the following: a history of breast cancer, colorectal cancer, or other cancer except skin cancer during the past 10 years; type 1 diabetes; a medical condition in which the predicted survival was less than 3 years; and a potential barrier to adherence to the study regimen, including alcoholism or a lifestyle that involved often eating meals away from home.

THE WHI DIET: LESS FAT, BUT MORE FRUITS, VEGETABLES, GRAINS

The WHI dietary intervention was designed to prevent breast cancer, based on the evidence available when the study was planned. The targets included a total fat intake of less than 20% of energy (in kilocalories), increasing the intake of fruits and vegetables to at least five servings per day, and increasing the intake of grains to at least six servings per day.

Although reduction in saturated fat intake per se was not part of the WHI protocol, we assumed from previous pilot studies⁸ that the reduction of total fat intake would simultaneously produce a reduction in saturated fat intake to 7% of total calories.

A simpler dietary intervention

Unlike the 2006 American Heart Association guidelines and the US Department of Agriculture’s Dietary Guidelines for Americans 2005, the WHI dietary intervention had no specifications for dietary fiber, specific fatty acids (trans-fatty acids, omega-3 fatty acids, conjugated linoleic acid), complex carbohydrates, whole grains, vegetable protein, or other factors that have emerged as potential risk factors for cardiovascular and other chronic diseases since the study began. The WHI intervention also included no specific recommendation for total calorie intake, nor were patients in the intervention group encouraged to lose weight, as this could have confounded the results of the dietary intervention.

Education and encouragement

Those in the intervention group were each assigned a fat-gram goal, calculated on the basis of height. They were taught how to monitor their intake of total fat, fruits, vegetables, and grains. They attended intensive behavioral modification sessions to encourage them to keep to the dietary program: 18 group sessions in the first year and quarterly maintenance sessions thereafter, touching on a wide variety of nutrition- and behavior-related topics.^7,9 Specially trained and certified nutritionists supervised the dietary intervention and the behavioral modification sessions according to the WHI study protocol.

Control-group participants received a copy of the US Department of Agriculture’s Dietary Guidelines for Americans¹⁰ and other health-related materials. They had no contact with the study nutritionists.

Other arms of the study

The WHI trial design included several arms,^4,11–13 and many participants joined more than one arm: 20,592 postmenopausal women (42.2% of the total enrollment) chose dietary modification only, 8,050 (16.5%) chose diet plus hormone replacement therapy, 25,210 (51.6%) chose diet plus calcium and vitamin D supplementation, and 5,017 (10.3%) enrolled in all three.

Length of follow-up

Participants were followed from enrollment until they died, were lost to follow-up, or requested no further contact, or until the trial’s planned completion date, regardless of adherence to the dietary intervention, according to intention-to-treat analysis. All participants were contacted by clinic staff at 6-month intervals to provide updates on their health outcomes.

Factors assessed

Height, weight, waist circumference, and blood pressure were measured at annual visits using standardized procedures. Fasting blood samples were collected at baseline and at year 1 from all participants and from a subsample of 2,816 women (5.8% of the study population) at years 3 and 6. This subsample was randomly chosen with oversampling of minority women, for whom the odds for selection were six times higher than for white women.

Physical activity was assessed at baseline and at years 1, 3, 6, and 9. Walking and participation in sports and hours of activity per week were calculated for each participant. Physical activity was expressed as metabolic equivalent tasks per week for the analyses.

A food-frequency questionnaire⁶ to assess average dietary intake in the past 3 months was given at baseline and at year 1 for all participants. A third of all participants completed the questionnaire each year in a rotating sample. Completion rates were 100% at baseline and 81% thereafter. Follow-up data were collected from years 5 through 7. Also, 4-day food records were provided by all women before randomization.

HOW OUTCOMES WERE ASSESSED

The primary assessments of clinical outcome^1–3 were mammographic screening, a self-reported medical history documented by a review of medical records, and electrocardiograms digitally obtained every 3 years. Mammograms and electrocardiograms were centrally adjudicated. The diagnosis of acute myocardial infarction was based on an algorithm that included cardiac pain, enzyme levels, and electrocardiographic readings.

OVERALL RESULTS

At 8.1 years, the incidence of breast cancer was 9% lower in the intervention group than in the comparison group (95% confidence interval [CI] = 0.83–1.01; P = .07, P = .09 weighted for length of follow-up).³ Subgroup analysis further showed that women who reported higher intakes of total dietary fat at baseline reduced their risk of breast cancer by 22% (95% CI = 0.64–0.96). Whether extended follow-up will show a significant association has yet to be determined.

Colon cancer rates did not differ between groups, but the number of polyps and adenomas reported was significantly lower in the dietary intervention group.¹ The rate of colon cancer will also be included in the extended follow-up study of the WHI.

Risk factors for coronary heart disease in both groups—including levels of serum total cholesterol and serum low-density lipoprotein cholesterol, body weight, body mass index, diastolic blood pressure, and factor VIIc—improved slightly, but at year 3 of the trial, differences in overall rates of coronary heart disease and stroke in the two groups were not statistically significant.² In addition, the low-fat diet intervention was associated with a reduction in blood estradiol concentrations between baseline and year 1.³ At the end of the study, however, differences in rates of breast cancer, colorectal cancer, and heart disease between the two groups were not statistically significant.

RESULTS OF DIETARY MODIFICATIONS

Fat as a percentage of total calories

At the beginning of the WHI, all participants reported consuming an average of 35% of their caloric intake from fat (Table 1). At 1 year from baseline, the fat intake decreased to 24.3% in the intervention group (short of the study goal of 20%); this level had risen again to 26.7% by year 3 and to 28.8% at the end of the study. Stratified by quartile, women who achieved the greatest reductions in saturated and trans-fatty acids or the largest increases in their intake of fruits and vegetables appeared to have a moderate reduction in the risk of coronary heart disease.² Women in the comparison group also decreased their fat intake initially, but to a lesser degree, and gradually increased it again thereafter. The mean net difference in self-reported total fat intake between the intervention group and the comparison group at 6 years was 8.2% (P < .001) (study goal, 13%).^1–3

Intake of fruits, vegetables, and grains

At baseline, fruit and vegetable intake averaged 3.6 servings per day (Table 1). In the intervention group, this increased to 5.1 servings per day at year 1, and to 5.2 servings at year 3, but at the end of the study it had decreased to 4.9 servings.

Women in the intervention group were eating 4.7 servings of grains per day at baseline. This increased to 5.1 servings at year 1 and then decreased to 4.6 servings at year 3 and to 4.3 servings at the end of the study. It seems that as the women grew older their determination to increase servings of these foods diminished.

Proponents of some currently popular diets blame weight gain on a higher intake of carbohydrates, but the women following the WHI low-fat diet did not gain weight.²

Total fat vs saturated fat

Intake of total fat and saturated fat decreased in the intervention group during the study, but the difference between fat intake in the intervention group and that in the comparison group did not reach the degree expected.

At year 1, total fat as a percentage of total caloric intake was 10.8 percentage points below that of the comparison group, whereas the study expected difference was 13.0. At the end of the trial, the difference was only 8.2 percentage points, whereas the expected difference was 11.0.

Intake of all fatty acids (saturated and unsaturated) decreased at year 1, but then went back up slightly by the end of the trial but did not exceed baseline levels, and saturated fatty acids remained well below baseline levels: 9.5% vs 12.5% of caloric intake at baseline.⁴

INTERPRETING THE RESULTS

It might be tempting to dismiss the results of the WHI dietary intervention trial as not significant and therefore not meaningful. This would be unfortunate. The trial had some remarkable accomplishments and offers important lessons for future investigations.

The initial reductions in total fat intake were impressive, and women who had the highest total fat intake at baseline achieved the greatest reduction of total fat (to less than 22% of total calories).³ Nonetheless, the dietary intervention goal of less than 20% of calories from fat was not achieved despite intensive dietary counseling and a highly motivated study population. Thus, this dietary fat target may not be reasonable in the general population.

Also, despite the absence of targeted intervention on specific fatty acids, the observed blood cholesterol levels were as expected based on the well-known formula of Mensink and Katan,¹⁴ which incorporates information on changes in saturated fat, polyunsaturated fat, and dietary cholesterol intake. The predicted reduction in low-density lipoprotein cholesterol was 2.7 mg/dL; the observed reduction was 2.3 mg/dL.² This illustrates that with greater modifications in specific known dietary risk factors for cardiovascular disease, such as saturated fatty acids, cholesterol, and unsaturated fatty acids, blood cholesterol levels respond in a predictable fashion. This was presumably not observed in WHI precisely because no goals and objectives were provided to participants for intake of saturated or polyunsaturated fatty acids.

Recent findings from the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart)¹⁵ further highlight differences in the total cholesterol response to diets of varying macronutrient (carbohydrate, protein, fat) content compared with the WHI dietary intervention.¹⁵ Participants in OmniHeart had reductions in levels of low-density lipoprotein cholesterol that were predictable from the changes reported in intake of saturated fatty acids. Presumably, the results of the WHI intervention would have been similar if the study had included this level of detail.

QUESTIONS REMAIN

Questions from the WHI that need consideration for future clinical applications include whether the study population may have already been “too old” to achieve a benefit from dietary modification, and whether the best timing for dietary intervention might be earlier adulthood with sustained changes in saturated fat, cholesterol, and unsaturated fat intake throughout life. Future subgroup analyses based on age at baseline will need to address these questions. Likewise, a longer follow-up period may be needed for a definitive evaluation of the impact of a regular low-fat diet on different health outcomes.

As reported by Patterson et al,¹⁶ the major contributors to total dietary fat intake at baseline were “added fats” such as sauces, gravies, butter, and margarines (25.1% of fat intake), followed by meats (20.9% of fat intake), and desserts (12.8% of fat intake). These findings highlight target areas for future interventions in women of this age group.

Another issue is how to standardize the dietary intervention from one clinical center to another—ie, to minimize differences in how each clinical center manages the study patients. Such differences were noted in WHI and other studies.¹⁷ Despite standardized training in delivering the dietary intervention, nutritionists encountered regional and cultural differences that required tailoring the dietary intervention to their patients’ needs. Staff turnover, an unavoidable phenomenon in long-term studies, has previously been reported to negatively influence dietary adherence.¹⁸

LIMITATIONS

A major limitation of diet modification research in general is the self-reporting of dietary intake, primarily by a food-frequency questionnaire. Although the use of a questionnaire is the most practical way to obtain dietary data for large studies, systematic biases may exist that obscure true nutrient-outcome relationships.¹⁹ Biomarker studies of energy balance suggest that people who are overweight or obese may under-report energy intake to a greater degree than people who are not overweight.²⁰ Also, we still do not know how to get people to follow a healthy diet, although theories and models abound, such as social learning and cognitive-behavioral theory, and a lack of data limits our understanding of factors related to dietary adherence.^21,22

FUTURE DIRECTIONS IN WHI

The WHI Extension Study is under way and has been funded through the year 2010. Outcomes ascertainment is the primary focus with no ongoing intervention, although the intervention group participants continue to receive a WHI newsletter that simply reiterates the importance of the study and encourages ongoing participation. As of 2006, an estimated 84% of the cohort, including both observational study and clinical trial participants, are involved. Efforts continue to recruit the remaining 16%, but many of these participants now consider themselves too old or too feeble to respond reliably.

In regard to breast cancer, the results published in 2006 are promising, albeit not statistically significant, and definitive statements cannot yet be made. However, postmenopausal women who are eating the diets highest in fat may have the greatest benefit from reductions in total fat.

Other considerations regarding the lack of statistically significant differences between groups may include the possibility that women in the intervention group may have been at lower risk for breast cancer at baseline. Likewise, although the results of the WHI dietary intervention do not include a statistically significant impact on colorectal cancer outcomes, the significant reduction in polyps and adenomas may later translate into a reduction in invasive cancer risk.

Finally, although no significant reduction was seen in the rate of death due to cardiovascular causes, greater reductions in saturated and trans-fatty acid intake were associated with greater reductions in blood cholesterol and cardiovascular risk.

Numerous subgroup analyses and ongoing assessments of the long-term impact of the diet modification are planned. Further associations are expected to emerge. The current and future results will continue to provide new insights that may lead to new clinical and public health recommendations in the future.

The WHI has raised additional issues that warrant further investigation:

• Will earlier dietary intervention, eg, during premenopausal years or even childhood, alter these results?
• Does the low-fat, high-carbohydrate diet used in WHI facilitate weight maintenance or even weight loss, as proposed by Howard et al²³?
• Do quantitative changes in physical activity and weight control attenuate morbidity and mortality rates beyond changes in diet alone?
• Do vitamin and mineral supplements or hormone therapy alter disease outcomes or quality of life?
• Which behavioral approaches are best suited to the recruitment of patients for dietary intervention trials?

Radiography plays a key role in the initial evaluation of acute knee pain in adults. Yet conflicting studies and the absence of clear guidelines may leave the primary care physician uncertain as to which imaging test to order—ie, whether radiography is sufficient, and when computed tomography (CT) or magnetic resonance imaging (MRI) is needed. This article reviews the indications for radiologic examination of the knee and discusses indications for cross-sectional imaging studies. Imaging in oncology patients is not discussed here.

ACUTE KNEE PAIN: A TYPICAL SCENARIO

A 47-year-old woman presents to the emergency department with left knee pain after a motor vehicle accident that occurred the day before. The car she was driving hit a tree, and she hit her knee on the dashboard. She was wearing a seatbelt at the time of the accident. She says she was unable to walk immediately after the accident because of knee pain.

The initial examination in the emergency room reveals swelling and pain throughout the range of motion. The anterior drawer test and the Lachman test are negative (see below).

The patient is discharged home with a knee immobilizer, pain medication, and crutches, with instructions for a follow-up visit in the orthopedics clinic.

Five days later, she returns to the emergency department complaining of continuing knee pain. She says the knee gives way when she puts weight on it. The physical findings are unchanged, and she is discharged home with a follow-up appointment with orthopedics in 3 days.

At the follow-up visit, she complains of persistent knee pain in the medial aspect of the knee joint. Physical examination is difficult because of pain and swelling, and it reveals mild joint effusion with no gross instability. She has pain on the medial side with valgus stress, but there appears to be a hard end point. There is no posterior sag, and the Lachman test is negative.

Based on the physical examination and the patient’s complaints, she receives a diagnosis of medial collateral ligament strain and injury. She is given a hinged brace and is instructed to undergo a physical rehabilitation program.

Three weeks after the initial evaluation, she returns to the orthopedics clinic with continuing knee problems. Mild knee effusion persists, but she has less pain and swelling, allowing a more complete examination. The examination reveals less limitation of range of motion and a hint of positivity on the Lachman test. The knee is diffusely tender, and the pain seems out of proportion with the maneuvers used during the examination. She requests more pain medication. You suspect internal derangement of the knee. Which imaging test should you order to further evaluate this patient?

A SYSTEMATIC AND COST-EFFECTIVE APPROACH IS NEEDED

The case presented above represents a typical scenario for the presentation of acute knee pain and illustrates the diagnostic challenges.

Knee pain is a common reason for emergency room visits, and it accounts for approximately 1.9 million visits to primary care clinics annually.¹ In the emergency department, most patients undergo plain radiography to assess for fracture, yet approximately 92% of radiographic studies do not show a fracture.² Clearly, the evaluation of knee pain requires a systematic, accurate, and cost-effective approach.

Key elements of the physical examination

In acute knee pain, accurate diagnosis begins with a detailed history and physical examination.

The anterior drawer test is done to evaluate the anterior cruciate ligament. With the relaxed knee flexed to approximately 80° and the foot stabilized in a neutral position, the examiner grasps the proximal tibia in a firm yet gentle grip, and then applies anterior force, noting the degree of anterior displacement compared with the other knee.

The Lachman test, a variation of the anterior drawer test, is more definitive for the anterior cruciate ligament and is carried out with the knee in 15° of flexion and external rotation, in order to relax the iliotibial band. The upper hand grasps the distal thigh, and the lower hand, with the thumb on the tibial tubercle, pulls the tibia forward. The degree of anterior motion in millimeters is noted and compared with that on the other side, and the end point is graded as “soft” or “hard.” An end point is considered hard when a ligament abruptly halts the motion of the bone being tested against the stabilized bone. An end point is considered soft when the ligament is disrupted and the restraints are the more elastic secondary stabilizers.

Debate continues

Some authors contend that in skilled hands a thorough history, physical examination, and radiographic examination are sufficient to diagnose trauma-related intra-articular knee disorders.³ Others contend that MRI plays a key role in the initial evaluation. A number of studies^4–8 have shown that using MRI in the initial evaluation not only identifies key lesions, but also may eliminate the need for an invasive diagnostic procedure (ie, arthroscopy).

For example, MRI can reveal fracture, stress fracture, insufficiency fracture, and transient patellar dislocation—conditions that may satisfactorily explain knee symptoms.

PLAIN RADIOGRAPHY STILL THE FIRST STEP IN KNEE EVALUATION

Radiography is the first step in the evaluation of knee pain. It is quick and inexpensive and can yield many diagnostic clues. It can readily reveal fractures, osteochondral defects, bony lesions, joint effusions, joint space narrowing, and bone misalignment.

In patients with knee trauma, supine anteroposterior and cross-table lateral radiographic images are generally obtained. In patients whose knee pain is not due to trauma, standing projections are done, as well as dedicated projection of the patellofemoral articulation. A standing series is most helpful for evaluating joint space and alignment.

Applying the Ottawa rules

When a patient presents to the emergency room with acute knee pain, the immediate concern is whether he or she has a fracture. The Ottawa knee rules⁹ for when to order radiography in adults with knee pain are highly sensitive for detecting a clinically important fracture. If any one of the five Ottawa criteria applies—ie, the patient is age 55 or older, has tenderness at the head of the fibula, has patellar tenderness, is unable to flex the knee to 90°, or is unable to bear weight—then radiography is indicated.

While studies have validated the ability of the Ottawa rules to detect important fractures in acute knee injury,²,¹⁰ fracture is the cause of only a small percentage of knee complaints in the primary care setting. More common causes include osteoarthritis, meniscal injury, ligamental injury, and crystal arthropathy, and these account for approximately half of all diagnoses. Sprain and strain account for most of the rest of knee injuries.¹

Acute exacerbations of osteoarthritis

Osteoarthritis is a chronic problem, yet it is not unusual for a patient to present to the primary care physician with an acute exacerbation of joint pain. The clinical hallmarks include age over 50, stiffness lasting less than 30 minutes, bony enlargement and tenderness, and crepitus. The radiographic hallmarks, according to the Kellgren-Lawrence grading scale, are joint space narrowing, osteophytes, subchondral cysts, and sclerosis. These radiographic findings correlate well with clinical findings in these patients.¹¹

Situations in which radiography is less helpful

In some cases the radiographic findings may not explain the patient’s clinical signs and symptoms. For example, in suspected crystalline and septic arthritis, the clinical presentation may include warmth, erythema, and effusion. Arthrocentesis would be indicated in such a patient. Indeed, in the case of suspected pseudogout, chondrocalcinosis may be radiographically evident. However, it is also present in many patients without symptoms or with osteoarthritis, so radiographic evidence does not provide a definite diagnosis.

While radiography may not always identify the cause of knee pain, it is useful in excluding serious problems such as fractures, advanced degenerative changes, and neoplasms, and it may help direct further management. Radiography is not useful in the evaluation of the cruciate and collateral ligaments, the menisci, and the hyaline cartilage of the knee and may fail to show an insufficiency or stress fracture. To evaluate these structures and associated soft tissues, MRI is preferable.

COMPUTED TOMOGRAPHY IN ACUTE KNEE PAIN

CURRENT USES OF MRI TO EVALUATE ACUTE KNEE PAIN

As mentioned above, MRI is useful in evaluating suspected meniscal and ligamentous injuries.

Figure 3 shows how T2-weighted MRI was used to evaluate for suspected meniscal injury in our 47-year-old female patient with left knee pain after a motor vehicle accident.

Still a matter of debate

MRI’s role in the diagnosis of knee pain is still a contentious issue.

Advantages of MRI are that it is noninvasive, it does not use ionizing radiation, it gives multiplanar images, and it provides images of soft-tissue structures, which other imaging methods cannot.¹² It is a well-proven and widely accepted test. Its sensitivity for detecting meniscal and cruciate ligament injury ranges from 75% to 88%,¹ and it can help in the evaluation of other injuries for which radiography is not useful, including synovitis, bone bruise, stress or insufficiency fracture, osteochondral defects, and osteonecrosis.

In addition, several studies show that using MRI to establish the diagnosis in acute knee pain can mean that 22% to 42% fewer arthroscopic procedures need to be performed.^4–8 Authors of a prospective double-blind study⁸ recommended that MRI be used in patients with acute knee injury when the findings of the clinical history and examination by orthopedic surgeons prove equivocal.⁸ MRI evaluation is especially desirable for young, active patients who wish to resume activity as soon as possible.

A routine MRI examination consists of T1- and T2-weighted images in three planes, although the number of sequences and planes varies from hospital to hospital. The use of gadolinium contrast is indicated only when osteomyelitis, septic arthritis, or a mass is suspected.

Disadvantages of MRI include its cost: Medicare reimbursement for knee MRI is around $400, compared with $200 for knee CT and $50 for knee radiography with four views. Also, while studies have shown MRI to have a high sensitivity and specificity in the diagnosis of acute knee injury, some have reported a high false-positive rate for the detection of meniscal tear.¹³,¹⁴ MRI has also been shown to have a lower sensitivity than arthroscopy for lesions of the articular cartilage.¹³ Furthermore, MRI has been shown to reveal cartilage lesions, osteophytes, and meniscal abnormalities in asymptomatic study volunteers with no history of pain, trauma or knee disease.¹⁴ Therefore, findings on MRI must closely correlate with findings on the history and physical examination.

Additional indications for knee MRI

Cartilage can be assessed on routine MRI sequences of the knee. Since closed MRI systems have more powerful magnets than open systems, closed MRI systems provide greater anatomic detail.

MRI can identify other lesions, such as spontaneous osteonecrosis of the knee, usually seen in elderly women who may present with sudden knee pain. In such patients, MRI findings of focal replacement of the bone marrow and surrounding edema are specific for osteonecrosis.

Opinions vary as to whether bone marrow edema is always associated with pain. Sequential MRI studies have shown persistence of bone marrow edema for 2 years in patients with degenerative arthritis whose symptoms have waned. Bone marrow edema may be associated with pain but may be absent or inconsequential in the presence of pain.

Because fluid-sensitive T2-weighted MRI is exquisitely sensitive for mobile water protons (ie, in bone marrow edema), it is important that a cause for the edema-like signal be sought on the MRI scan, since this finding is nonspecific and may be associated with articular disease, trauma, osteonecrosis, infection, or bone tumors. Additionally, clinicians need to be aware that the findings on MRI depend on the quality of the study, and are influenced by technical factors such as magnet strength, imaging planes, and use of surface coils.

MRI should be used in patients in whom surgical treatment, ie, arthroscopy, is being considered. As discussed above, several studies have shown that a significant number of unnecessary arthroscopies may be prevented when preceded by an MRI examination.

Figure 5 shows the use of MRI in the evaluation of a 45-year-old man with left knee pain after a motorcycle accident.

ULTRASONOGRAPHY HAS ONLY A LIMITED ROLE

Ultrasonography does not play a major role in the evaluation of acute knee pain in the United States, in part because the accuracy of the results depend much on the technical skills and experience of the operator.

Ultrasonography can be useful in evaluating for rupture of the quadriceps and patellar tendon, or to assess a repaired tendon after surgery,¹⁵ and it is a quick and reliable way to determine the presence of joint effusion and popliteal cyst. It is also used to guide needle placement for joint aspiration and injection.

Radiography plays a key role in the initial evaluation of acute knee pain in adults. Yet conflicting studies and the absence of clear guidelines may leave the primary care physician uncertain as to which imaging test to order—ie, whether radiography is sufficient, and when computed tomography (CT) or magnetic resonance imaging (MRI) is needed. This article reviews the indications for radiologic examination of the knee and discusses indications for cross-sectional imaging studies. Imaging in oncology patients is not discussed here.

ACUTE KNEE PAIN: A TYPICAL SCENARIO

A 47-year-old woman presents to the emergency department with left knee pain after a motor vehicle accident that occurred the day before. The car she was driving hit a tree, and she hit her knee on the dashboard. She was wearing a seatbelt at the time of the accident. She says she was unable to walk immediately after the accident because of knee pain.

The initial examination in the emergency room reveals swelling and pain throughout the range of motion. The anterior drawer test and the Lachman test are negative (see below).

The patient is discharged home with a knee immobilizer, pain medication, and crutches, with instructions for a follow-up visit in the orthopedics clinic.

Five days later, she returns to the emergency department complaining of continuing knee pain. She says the knee gives way when she puts weight on it. The physical findings are unchanged, and she is discharged home with a follow-up appointment with orthopedics in 3 days.

At the follow-up visit, she complains of persistent knee pain in the medial aspect of the knee joint. Physical examination is difficult because of pain and swelling, and it reveals mild joint effusion with no gross instability. She has pain on the medial side with valgus stress, but there appears to be a hard end point. There is no posterior sag, and the Lachman test is negative.

Based on the physical examination and the patient’s complaints, she receives a diagnosis of medial collateral ligament strain and injury. She is given a hinged brace and is instructed to undergo a physical rehabilitation program.

Three weeks after the initial evaluation, she returns to the orthopedics clinic with continuing knee problems. Mild knee effusion persists, but she has less pain and swelling, allowing a more complete examination. The examination reveals less limitation of range of motion and a hint of positivity on the Lachman test. The knee is diffusely tender, and the pain seems out of proportion with the maneuvers used during the examination. She requests more pain medication. You suspect internal derangement of the knee. Which imaging test should you order to further evaluate this patient?

A SYSTEMATIC AND COST-EFFECTIVE APPROACH IS NEEDED

The case presented above represents a typical scenario for the presentation of acute knee pain and illustrates the diagnostic challenges.

Knee pain is a common reason for emergency room visits, and it accounts for approximately 1.9 million visits to primary care clinics annually.¹ In the emergency department, most patients undergo plain radiography to assess for fracture, yet approximately 92% of radiographic studies do not show a fracture.² Clearly, the evaluation of knee pain requires a systematic, accurate, and cost-effective approach.

Key elements of the physical examination

In acute knee pain, accurate diagnosis begins with a detailed history and physical examination.

The anterior drawer test is done to evaluate the anterior cruciate ligament. With the relaxed knee flexed to approximately 80° and the foot stabilized in a neutral position, the examiner grasps the proximal tibia in a firm yet gentle grip, and then applies anterior force, noting the degree of anterior displacement compared with the other knee.

The Lachman test, a variation of the anterior drawer test, is more definitive for the anterior cruciate ligament and is carried out with the knee in 15° of flexion and external rotation, in order to relax the iliotibial band. The upper hand grasps the distal thigh, and the lower hand, with the thumb on the tibial tubercle, pulls the tibia forward. The degree of anterior motion in millimeters is noted and compared with that on the other side, and the end point is graded as “soft” or “hard.” An end point is considered hard when a ligament abruptly halts the motion of the bone being tested against the stabilized bone. An end point is considered soft when the ligament is disrupted and the restraints are the more elastic secondary stabilizers.

Debate continues

Some authors contend that in skilled hands a thorough history, physical examination, and radiographic examination are sufficient to diagnose trauma-related intra-articular knee disorders.³ Others contend that MRI plays a key role in the initial evaluation. A number of studies^4–8 have shown that using MRI in the initial evaluation not only identifies key lesions, but also may eliminate the need for an invasive diagnostic procedure (ie, arthroscopy).

For example, MRI can reveal fracture, stress fracture, insufficiency fracture, and transient patellar dislocation—conditions that may satisfactorily explain knee symptoms.

PLAIN RADIOGRAPHY STILL THE FIRST STEP IN KNEE EVALUATION

Radiography is the first step in the evaluation of knee pain. It is quick and inexpensive and can yield many diagnostic clues. It can readily reveal fractures, osteochondral defects, bony lesions, joint effusions, joint space narrowing, and bone misalignment.

In patients with knee trauma, supine anteroposterior and cross-table lateral radiographic images are generally obtained. In patients whose knee pain is not due to trauma, standing projections are done, as well as dedicated projection of the patellofemoral articulation. A standing series is most helpful for evaluating joint space and alignment.

Applying the Ottawa rules

When a patient presents to the emergency room with acute knee pain, the immediate concern is whether he or she has a fracture. The Ottawa knee rules⁹ for when to order radiography in adults with knee pain are highly sensitive for detecting a clinically important fracture. If any one of the five Ottawa criteria applies—ie, the patient is age 55 or older, has tenderness at the head of the fibula, has patellar tenderness, is unable to flex the knee to 90°, or is unable to bear weight—then radiography is indicated.

While studies have validated the ability of the Ottawa rules to detect important fractures in acute knee injury,²,¹⁰ fracture is the cause of only a small percentage of knee complaints in the primary care setting. More common causes include osteoarthritis, meniscal injury, ligamental injury, and crystal arthropathy, and these account for approximately half of all diagnoses. Sprain and strain account for most of the rest of knee injuries.¹

Acute exacerbations of osteoarthritis

Osteoarthritis is a chronic problem, yet it is not unusual for a patient to present to the primary care physician with an acute exacerbation of joint pain. The clinical hallmarks include age over 50, stiffness lasting less than 30 minutes, bony enlargement and tenderness, and crepitus. The radiographic hallmarks, according to the Kellgren-Lawrence grading scale, are joint space narrowing, osteophytes, subchondral cysts, and sclerosis. These radiographic findings correlate well with clinical findings in these patients.¹¹

Situations in which radiography is less helpful

In some cases the radiographic findings may not explain the patient’s clinical signs and symptoms. For example, in suspected crystalline and septic arthritis, the clinical presentation may include warmth, erythema, and effusion. Arthrocentesis would be indicated in such a patient. Indeed, in the case of suspected pseudogout, chondrocalcinosis may be radiographically evident. However, it is also present in many patients without symptoms or with osteoarthritis, so radiographic evidence does not provide a definite diagnosis.

While radiography may not always identify the cause of knee pain, it is useful in excluding serious problems such as fractures, advanced degenerative changes, and neoplasms, and it may help direct further management. Radiography is not useful in the evaluation of the cruciate and collateral ligaments, the menisci, and the hyaline cartilage of the knee and may fail to show an insufficiency or stress fracture. To evaluate these structures and associated soft tissues, MRI is preferable.

COMPUTED TOMOGRAPHY IN ACUTE KNEE PAIN

CURRENT USES OF MRI TO EVALUATE ACUTE KNEE PAIN

As mentioned above, MRI is useful in evaluating suspected meniscal and ligamentous injuries.

Figure 3 shows how T2-weighted MRI was used to evaluate for suspected meniscal injury in our 47-year-old female patient with left knee pain after a motor vehicle accident.

Still a matter of debate

MRI’s role in the diagnosis of knee pain is still a contentious issue.

Advantages of MRI are that it is noninvasive, it does not use ionizing radiation, it gives multiplanar images, and it provides images of soft-tissue structures, which other imaging methods cannot.¹² It is a well-proven and widely accepted test. Its sensitivity for detecting meniscal and cruciate ligament injury ranges from 75% to 88%,¹ and it can help in the evaluation of other injuries for which radiography is not useful, including synovitis, bone bruise, stress or insufficiency fracture, osteochondral defects, and osteonecrosis.

In addition, several studies show that using MRI to establish the diagnosis in acute knee pain can mean that 22% to 42% fewer arthroscopic procedures need to be performed.^4–8 Authors of a prospective double-blind study⁸ recommended that MRI be used in patients with acute knee injury when the findings of the clinical history and examination by orthopedic surgeons prove equivocal.⁸ MRI evaluation is especially desirable for young, active patients who wish to resume activity as soon as possible.

A routine MRI examination consists of T1- and T2-weighted images in three planes, although the number of sequences and planes varies from hospital to hospital. The use of gadolinium contrast is indicated only when osteomyelitis, septic arthritis, or a mass is suspected.

Disadvantages of MRI include its cost: Medicare reimbursement for knee MRI is around $400, compared with $200 for knee CT and $50 for knee radiography with four views. Also, while studies have shown MRI to have a high sensitivity and specificity in the diagnosis of acute knee injury, some have reported a high false-positive rate for the detection of meniscal tear.¹³,¹⁴ MRI has also been shown to have a lower sensitivity than arthroscopy for lesions of the articular cartilage.¹³ Furthermore, MRI has been shown to reveal cartilage lesions, osteophytes, and meniscal abnormalities in asymptomatic study volunteers with no history of pain, trauma or knee disease.¹⁴ Therefore, findings on MRI must closely correlate with findings on the history and physical examination.

Additional indications for knee MRI

Cartilage can be assessed on routine MRI sequences of the knee. Since closed MRI systems have more powerful magnets than open systems, closed MRI systems provide greater anatomic detail.

MRI can identify other lesions, such as spontaneous osteonecrosis of the knee, usually seen in elderly women who may present with sudden knee pain. In such patients, MRI findings of focal replacement of the bone marrow and surrounding edema are specific for osteonecrosis.

Opinions vary as to whether bone marrow edema is always associated with pain. Sequential MRI studies have shown persistence of bone marrow edema for 2 years in patients with degenerative arthritis whose symptoms have waned. Bone marrow edema may be associated with pain but may be absent or inconsequential in the presence of pain.

Because fluid-sensitive T2-weighted MRI is exquisitely sensitive for mobile water protons (ie, in bone marrow edema), it is important that a cause for the edema-like signal be sought on the MRI scan, since this finding is nonspecific and may be associated with articular disease, trauma, osteonecrosis, infection, or bone tumors. Additionally, clinicians need to be aware that the findings on MRI depend on the quality of the study, and are influenced by technical factors such as magnet strength, imaging planes, and use of surface coils.

MRI should be used in patients in whom surgical treatment, ie, arthroscopy, is being considered. As discussed above, several studies have shown that a significant number of unnecessary arthroscopies may be prevented when preceded by an MRI examination.

Figure 5 shows the use of MRI in the evaluation of a 45-year-old man with left knee pain after a motorcycle accident.

ULTRASONOGRAPHY HAS ONLY A LIMITED ROLE

Ultrasonography does not play a major role in the evaluation of acute knee pain in the United States, in part because the accuracy of the results depend much on the technical skills and experience of the operator.

Ultrasonography can be useful in evaluating for rupture of the quadriceps and patellar tendon, or to assess a repaired tendon after surgery,¹⁵ and it is a quick and reliable way to determine the presence of joint effusion and popliteal cyst. It is also used to guide needle placement for joint aspiration and injection.

Radiography plays a key role in the initial evaluation of acute knee pain in adults. Yet conflicting studies and the absence of clear guidelines may leave the primary care physician uncertain as to which imaging test to order—ie, whether radiography is sufficient, and when computed tomography (CT) or magnetic resonance imaging (MRI) is needed. This article reviews the indications for radiologic examination of the knee and discusses indications for cross-sectional imaging studies. Imaging in oncology patients is not discussed here.

ACUTE KNEE PAIN: A TYPICAL SCENARIO

A 47-year-old woman presents to the emergency department with left knee pain after a motor vehicle accident that occurred the day before. The car she was driving hit a tree, and she hit her knee on the dashboard. She was wearing a seatbelt at the time of the accident. She says she was unable to walk immediately after the accident because of knee pain.

The initial examination in the emergency room reveals swelling and pain throughout the range of motion. The anterior drawer test and the Lachman test are negative (see below).

The patient is discharged home with a knee immobilizer, pain medication, and crutches, with instructions for a follow-up visit in the orthopedics clinic.

Five days later, she returns to the emergency department complaining of continuing knee pain. She says the knee gives way when she puts weight on it. The physical findings are unchanged, and she is discharged home with a follow-up appointment with orthopedics in 3 days.

At the follow-up visit, she complains of persistent knee pain in the medial aspect of the knee joint. Physical examination is difficult because of pain and swelling, and it reveals mild joint effusion with no gross instability. She has pain on the medial side with valgus stress, but there appears to be a hard end point. There is no posterior sag, and the Lachman test is negative.

Based on the physical examination and the patient’s complaints, she receives a diagnosis of medial collateral ligament strain and injury. She is given a hinged brace and is instructed to undergo a physical rehabilitation program.

Three weeks after the initial evaluation, she returns to the orthopedics clinic with continuing knee problems. Mild knee effusion persists, but she has less pain and swelling, allowing a more complete examination. The examination reveals less limitation of range of motion and a hint of positivity on the Lachman test. The knee is diffusely tender, and the pain seems out of proportion with the maneuvers used during the examination. She requests more pain medication. You suspect internal derangement of the knee. Which imaging test should you order to further evaluate this patient?

A SYSTEMATIC AND COST-EFFECTIVE APPROACH IS NEEDED

The case presented above represents a typical scenario for the presentation of acute knee pain and illustrates the diagnostic challenges.

Knee pain is a common reason for emergency room visits, and it accounts for approximately 1.9 million visits to primary care clinics annually.¹ In the emergency department, most patients undergo plain radiography to assess for fracture, yet approximately 92% of radiographic studies do not show a fracture.² Clearly, the evaluation of knee pain requires a systematic, accurate, and cost-effective approach.

Key elements of the physical examination

In acute knee pain, accurate diagnosis begins with a detailed history and physical examination.

The anterior drawer test is done to evaluate the anterior cruciate ligament. With the relaxed knee flexed to approximately 80° and the foot stabilized in a neutral position, the examiner grasps the proximal tibia in a firm yet gentle grip, and then applies anterior force, noting the degree of anterior displacement compared with the other knee.

The Lachman test, a variation of the anterior drawer test, is more definitive for the anterior cruciate ligament and is carried out with the knee in 15° of flexion and external rotation, in order to relax the iliotibial band. The upper hand grasps the distal thigh, and the lower hand, with the thumb on the tibial tubercle, pulls the tibia forward. The degree of anterior motion in millimeters is noted and compared with that on the other side, and the end point is graded as “soft” or “hard.” An end point is considered hard when a ligament abruptly halts the motion of the bone being tested against the stabilized bone. An end point is considered soft when the ligament is disrupted and the restraints are the more elastic secondary stabilizers.

Debate continues

Some authors contend that in skilled hands a thorough history, physical examination, and radiographic examination are sufficient to diagnose trauma-related intra-articular knee disorders.³ Others contend that MRI plays a key role in the initial evaluation. A number of studies^4–8 have shown that using MRI in the initial evaluation not only identifies key lesions, but also may eliminate the need for an invasive diagnostic procedure (ie, arthroscopy).

For example, MRI can reveal fracture, stress fracture, insufficiency fracture, and transient patellar dislocation—conditions that may satisfactorily explain knee symptoms.

PLAIN RADIOGRAPHY STILL THE FIRST STEP IN KNEE EVALUATION

Radiography is the first step in the evaluation of knee pain. It is quick and inexpensive and can yield many diagnostic clues. It can readily reveal fractures, osteochondral defects, bony lesions, joint effusions, joint space narrowing, and bone misalignment.

In patients with knee trauma, supine anteroposterior and cross-table lateral radiographic images are generally obtained. In patients whose knee pain is not due to trauma, standing projections are done, as well as dedicated projection of the patellofemoral articulation. A standing series is most helpful for evaluating joint space and alignment.

Applying the Ottawa rules

When a patient presents to the emergency room with acute knee pain, the immediate concern is whether he or she has a fracture. The Ottawa knee rules⁹ for when to order radiography in adults with knee pain are highly sensitive for detecting a clinically important fracture. If any one of the five Ottawa criteria applies—ie, the patient is age 55 or older, has tenderness at the head of the fibula, has patellar tenderness, is unable to flex the knee to 90°, or is unable to bear weight—then radiography is indicated.

While studies have validated the ability of the Ottawa rules to detect important fractures in acute knee injury,²,¹⁰ fracture is the cause of only a small percentage of knee complaints in the primary care setting. More common causes include osteoarthritis, meniscal injury, ligamental injury, and crystal arthropathy, and these account for approximately half of all diagnoses. Sprain and strain account for most of the rest of knee injuries.¹

Acute exacerbations of osteoarthritis

Osteoarthritis is a chronic problem, yet it is not unusual for a patient to present to the primary care physician with an acute exacerbation of joint pain. The clinical hallmarks include age over 50, stiffness lasting less than 30 minutes, bony enlargement and tenderness, and crepitus. The radiographic hallmarks, according to the Kellgren-Lawrence grading scale, are joint space narrowing, osteophytes, subchondral cysts, and sclerosis. These radiographic findings correlate well with clinical findings in these patients.¹¹

Situations in which radiography is less helpful

In some cases the radiographic findings may not explain the patient’s clinical signs and symptoms. For example, in suspected crystalline and septic arthritis, the clinical presentation may include warmth, erythema, and effusion. Arthrocentesis would be indicated in such a patient. Indeed, in the case of suspected pseudogout, chondrocalcinosis may be radiographically evident. However, it is also present in many patients without symptoms or with osteoarthritis, so radiographic evidence does not provide a definite diagnosis.

While radiography may not always identify the cause of knee pain, it is useful in excluding serious problems such as fractures, advanced degenerative changes, and neoplasms, and it may help direct further management. Radiography is not useful in the evaluation of the cruciate and collateral ligaments, the menisci, and the hyaline cartilage of the knee and may fail to show an insufficiency or stress fracture. To evaluate these structures and associated soft tissues, MRI is preferable.

COMPUTED TOMOGRAPHY IN ACUTE KNEE PAIN

CURRENT USES OF MRI TO EVALUATE ACUTE KNEE PAIN

As mentioned above, MRI is useful in evaluating suspected meniscal and ligamentous injuries.

Figure 3 shows how T2-weighted MRI was used to evaluate for suspected meniscal injury in our 47-year-old female patient with left knee pain after a motor vehicle accident.

Still a matter of debate

MRI’s role in the diagnosis of knee pain is still a contentious issue.

Advantages of MRI are that it is noninvasive, it does not use ionizing radiation, it gives multiplanar images, and it provides images of soft-tissue structures, which other imaging methods cannot.¹² It is a well-proven and widely accepted test. Its sensitivity for detecting meniscal and cruciate ligament injury ranges from 75% to 88%,¹ and it can help in the evaluation of other injuries for which radiography is not useful, including synovitis, bone bruise, stress or insufficiency fracture, osteochondral defects, and osteonecrosis.

In addition, several studies show that using MRI to establish the diagnosis in acute knee pain can mean that 22% to 42% fewer arthroscopic procedures need to be performed.^4–8 Authors of a prospective double-blind study⁸ recommended that MRI be used in patients with acute knee injury when the findings of the clinical history and examination by orthopedic surgeons prove equivocal.⁸ MRI evaluation is especially desirable for young, active patients who wish to resume activity as soon as possible.

A routine MRI examination consists of T1- and T2-weighted images in three planes, although the number of sequences and planes varies from hospital to hospital. The use of gadolinium contrast is indicated only when osteomyelitis, septic arthritis, or a mass is suspected.

Disadvantages of MRI include its cost: Medicare reimbursement for knee MRI is around $400, compared with $200 for knee CT and $50 for knee radiography with four views. Also, while studies have shown MRI to have a high sensitivity and specificity in the diagnosis of acute knee injury, some have reported a high false-positive rate for the detection of meniscal tear.¹³,¹⁴ MRI has also been shown to have a lower sensitivity than arthroscopy for lesions of the articular cartilage.¹³ Furthermore, MRI has been shown to reveal cartilage lesions, osteophytes, and meniscal abnormalities in asymptomatic study volunteers with no history of pain, trauma or knee disease.¹⁴ Therefore, findings on MRI must closely correlate with findings on the history and physical examination.

Additional indications for knee MRI

Cartilage can be assessed on routine MRI sequences of the knee. Since closed MRI systems have more powerful magnets than open systems, closed MRI systems provide greater anatomic detail.

MRI can identify other lesions, such as spontaneous osteonecrosis of the knee, usually seen in elderly women who may present with sudden knee pain. In such patients, MRI findings of focal replacement of the bone marrow and surrounding edema are specific for osteonecrosis.

Opinions vary as to whether bone marrow edema is always associated with pain. Sequential MRI studies have shown persistence of bone marrow edema for 2 years in patients with degenerative arthritis whose symptoms have waned. Bone marrow edema may be associated with pain but may be absent or inconsequential in the presence of pain.

Because fluid-sensitive T2-weighted MRI is exquisitely sensitive for mobile water protons (ie, in bone marrow edema), it is important that a cause for the edema-like signal be sought on the MRI scan, since this finding is nonspecific and may be associated with articular disease, trauma, osteonecrosis, infection, or bone tumors. Additionally, clinicians need to be aware that the findings on MRI depend on the quality of the study, and are influenced by technical factors such as magnet strength, imaging planes, and use of surface coils.

MRI should be used in patients in whom surgical treatment, ie, arthroscopy, is being considered. As discussed above, several studies have shown that a significant number of unnecessary arthroscopies may be prevented when preceded by an MRI examination.

Figure 5 shows the use of MRI in the evaluation of a 45-year-old man with left knee pain after a motorcycle accident.

ULTRASONOGRAPHY HAS ONLY A LIMITED ROLE

Ultrasonography does not play a major role in the evaluation of acute knee pain in the United States, in part because the accuracy of the results depend much on the technical skills and experience of the operator.

Ultrasonography can be useful in evaluating for rupture of the quadriceps and patellar tendon, or to assess a repaired tendon after surgery,¹⁵ and it is a quick and reliable way to determine the presence of joint effusion and popliteal cyst. It is also used to guide needle placement for joint aspiration and injection.

Thrombotic thrombocytopenic purpura (TTP) is one of the few hematologic emergencies. Untreated, most patients die, but prompt and appropriate treatment allows most patients not only to survive but to recover, frequently without long-term sequelae.

TTP is rare. The estimated annual incidence of all TTP syndromes is about 11 cases per million in the general population, and the incidence of severe ADAMTS13 deficiency (see discussion below) is about 2 per million. Therefore, even large medical centers typically see only one or two cases each year. The syndromes are much more common in women, and the incidence among blacks is nine times higher than the incidence among non-blacks. Nevertheless, despite the rarity of this disease, good evidence exists to help guide patient care, thanks to national registries and research organizations, such as the Canadian Apheresis Study Group and the Oklahoma TTP-Hemolytic Uremic Syndrome (HUS) Registry.

This article reviews the physiologic basis of TTP, how to recognize it, and how best to treat it. We also discuss other conditions that clinically resemble TTP but probably have different underlying causes.

A YOUNG WOMAN WITH ARM WEAKNESS

A 24-year-old black woman presents to a community hospital with weakness in her left arm, which began about 30 minutes previously. She has had progressive dyspnea over the last several weeks, but has otherwise been completely well and has had no medical problems in the past other than being obese.

Physical examination reveals weakness in her left arm as well as mild dysarthria, which was not previously noted by the patient or her family. Her laboratory findings:

• White blood cell count 16.7 × 10⁹/L (reference range 4.5–11.0)
• Platelet count 32 × 10⁹/L (150–350)
• Hemoglobin concentration 6.5 g/dL (1.4–17.5)
• Peripheral blood smear: normal white cells, rare platelets, red cells normo-chromic with many fragments
• Lactate dehydrogenase (LDH) concentration 2,300 U/L (100–200).

In view of her symptoms and laboratory values, the physician suspects she may have TTP and refers her to McMaster University Medical Center in Hamilton, Ontario, Canada. Plasma exchange is started immediately; one plasma volume is removed and replaced with fresh frozen plasma. Nevertheless, the patient’s condition deteriorates overnight, she becomes more confused and cannot protect her airway, her LDH concentration rises further, and her hemoglobin concentration falls. She is transferred to the intensive care unit. Her plasma exchange prescription is increased to 1.5 volumes twice daily (although little evidence exists that plasma exchange twice daily is more effective than once daily).

On the third day of her stay, she becomes completely paralyzed on the left side. In addition to her twice-daily plasma exchange procedures, a plasma infusion and corticosteroid therapy are initiated. Her platelet count stabilizes at about 20 × 10⁹/L.

The patient next develops renal insufficiency and requires three acute hemodialysis treatments. (Plasma infusion frequently leads to volume overload in critically ill patients. Some intravascular volume can be removed with plasma exchange; however, significant volume overload with significant renal insufficiency can only be treated with renal replacement therapy.)

The patient undergoes 28 consecutive days of twice-daily plasma exchange and gradually improves, as measured by increasing platelet counts, a gradual fall in the LDH concentration, and stabilization of—and ultimately an increase in—the hemoglobin level. She is weaned off plasma infusions, and then plasma exchange is tapered to once a day and then to alternate days.

She is completely well at the time of discharge 4 weeks after her initial admission, with no residual deficits.

Comment. This case shows that even patients with apparently devastating compromise and neurologic deficits can completely recover with aggressive plasma exchange and other therapies. One child treated at the Hospital for Sick Children, affiliated with the University of Toronto, developed TTP and had 120 consecutive days of plasma exchange: she was unconscious and comatose for much of that time, but she ultimately recovered and is now completely well without residual neurologic deficits.

TTP MAY BE DUE TO ADAMTS13 DEFICIENCY

Twenty-five years ago, little was known about TTP except for its clinical manifestations. Now, it is known to be caused in some patients by an acquired deficiency of a circulating metalloproteinase. In very rare cases a hereditary deficiency of ADAMTS13 causes TTP. In addition, a number of conditions share clinical features with TTP but have other underlying causes.

In acquired TTP, an autoantibody forms against ADAMTS13, a zinc-containing metalloproteinase that is also known as von Willebrand factor-cleaving protease. Normally, von Willebrand factor circulates in plasma as multimers that allow platelets to adhere to vascular surfaces. When von Willebrand factor is initially released from endothelial cells, it exists as large multimers, which are more adhesive for platelets than normal. These large multimers are normally cleaved into smaller units by ADAMTS13. If ADAMTS13 is lacking, the very-high-molecular-weight von Willebrand factor multimers accumulate, causing platelet agglutination and the vascular occlusion that results in the manifestations of TTP.

In 1994, ADAMTS13, the gene of which is on the ninth chromosome, was shown to cleave von Willebrand factor under conditions of high shear stress. In 1996, a congenital homozygous deficiency of ADAMTS13 was found to be associated with platelet microthrombi. Afterwards, some patients with TTP were shown to have low or undetectable levels of ADAMTS13, owing to immunoglobulin G antibodies directed against the enzyme.

TTP AND RELATED SYNDROMES

Clinically, TTP encompasses a number of different but related syndromes, some of which have different physiologic bases.

TTP

TTP is characterized by moderate to severe thrombocytopenia, red cell fragmentation, and elevated LDH levels (due to red cell destruction and also muscle and organ ischemia). The pentad of features classically associated with TTP in the era before effective treatment (thrombocytopenia, fever, renal failure, neurologic deficit, and microangiopathic hemolytic anemia) is rarely seen in countries with advanced medical care: renal insufficiency and neurologic events are end-stage manifestations, and the disease should be recognizable well before these manifestations occur. Otherwise unexplained thrombocytopenia, microangiopathic hemolytic anemia, and an elevated LDH should strongly suggest TTP. TTP is the appropriate designation for adults with these clinical features, even in the presence of renal failure. TTP is uncommon in children.

Most patients present with nonspecific constitutional symptoms, such as weakness, abdominal pain, nausea, and vomiting. Typically, the family physician orders a complete blood cell count and finds that the platelet count and hemoglobin are low. Red cell fragments are noted in the peripheral blood smear. Further testing reveals an elevated LDH concentration.

HUS

HUS was initially described 30 years after TTP in children with acute renal failure in addition to thrombocytopenia and microangiopathic hemolytic anemia. The term “HUS” is currently used primarily to describe the condition in children.

In children, two forms of HUS exist:

Diarrhea-associated HUS is associated with diarrhea that is commonly bloody, due to an enterotoxin produced by Escherichia coli O157:H7.

Endemic diarrhea-associated HUS is much more common than HUS associated with epidemics. Endemic cases are caused by E coli O157:H7 present in the environment. Other patients present with clinically apparent HUS but the causal bacterium cannot be detected. The kidney transplant program at our center often sees young patients with this disease who do not have E coli O157:H7 infection, and the pathogenesis is not understood. Epidemic cases are less common but the outbreaks are dramatic. About 10 years ago, E coli O157:H7 entered the water supply in the small city of Walkerton, Ontario, and many people developed the epidemic form of HUS over a period of several weeks. Most such patients spontaneously recovered without plasma exchange, although many were left with impaired renal function.

Atypical HUS. Less often, HUS in children is not associated with a prodrome of diarrhea and is referred to as “atypical” HUS. These children often have a more prolonged and complicated course and resemble adults with TTP.

Familial TTP-HUS

Familial TTP-HUS is very rare. It may present with hemolysis and thrombocytopenia in childhood or early adulthood. Many patients present with renal insufficiency, and only careful evaluation reveals hemolysis and thrombocytopenia. The disease typically manifests acutely: a patient may have an upper respiratory tract infection and subsequently develop an episode of TTP-HUS. Episodes tend to recur, and multiple family members may also be affected.

Plasma infusion is an effective treatment, and plasma exchange is usually not required. Since more patients are now surviving well into adulthood, some are being seen to develop antibodies to the ADAMTS13 in the infused plasma, analogous to patients with severe hemophilia developing inhibitors to factor VIII. The disease may progress despite treatment: we have been treating a young woman who has had a series of catastrophic complications and now has chronic renal failure requiring hemodialysis (see discussion below).

Post-transplant microangiopathy

Post-transplant microangiopathy is most likely to develop after solid-organ or stem-cell allograft transplantation. Manifestations resemble those of TTP, but the mechanism is probably quite different. Multiple causes probably exist, depending on the setting.

Post-transplant microangiopathy does not respond to the usual therapies for TTP, although we treat it, like TTP, with corticosteroids, antiplatelet agents, and plasma exchange. Other centers do not use plasma exchange for these patients. Most patients have a poor prognosis, especially those with a transplant other than a kidney.

A spectrum of related syndromes

A number of diseases clinically resemble TTP. Enhanced diagnostic capacity and better molecular biologic techniques are revealing that they often have very different underlying causes and that in some cases they require different treatment.

TOWARD DIAGNOSTIC CRITERIA

Ruutu et al,¹ in a consensus conference, used rigorous methods to establish diagnostic criteria for microangiopathy associated with stem cell transplantation:

• More than 4% red blood cell fragments in the peripheral blood. A laboratory report that states that “few fragments” are present is not nearly as useful as one that estimates the quantity; eg, 1% fragments would have very different implications than 6% fragments.
• Thrombocytopenia—a platelet count of less than 50 × 10⁹/L or more than a 50% reduction from previous counts
• Increased LDH concentration
• Reduced hemoglobin concentration or increased transfusion requirement
• Decrease in serum haptoglobin, which, like red blood cell fragments, is a marker of hemolysis rather than of reduced synthesis.

The ADAMTS13 level need not be assessed. Metalloproteinase deficiency need not be proved to diagnose TTP. Although our hospital is a TTP referral center, we do not routinely offer the test. Too often the test results cause confusion: a patient can have a normal level of ADAMTS13 and still have TTP that responds to plasma exchange, and levels can be low in conditions other than TTP.

THE CHALLENGES OF TREATMENT

Plasma exchange is the primary treatment for TTP

Rock et al² performed a randomized trial in which 102 patients with TTP received either a 1.5-volume plasma exchange daily for 3 days and then 1-volume plasma exchanges as needed to control the disease or plasma infusion. Patients who received plasma exchange had a better initial response, a higher survival rate, and a lower rate of relapse than patients receiving plasma infusion. These findings established plasma exchange as the treatment of choice for TTP.

However, the trial had some inherent problems: patients who had plasma infusions tended to develop renal insufficiency and as a result did not receive as much plasma because they could not tolerate as much volume as those who had plasma exchange. Plasma exchange probably worked better because it could deliver more plasma over a fixed period of time, enabling patients to obtain more of the ADAMTS13 enzyme, rather than because it was an intrinsically better treatment. This interpretation is the basis for our occasional use of twice-daily plasma exchange in critically ill patients.

TTP is different from other autoimmune diseases such as idiopathic thrombocytopenia purpura, in which the primary treatments are immunosuppressive agents. Some evidence exists for treating TTP with immunosuppressive agents, but the primary treatment should be plasma exchange.

Plasma infusion is useful in some cases

Although small case series and our own experience provide evidence for the benefit of treating TTP with high-dose plasma infusions (25 mL/kg/day, or about 1.5 to 2.0 L/day for an average-sized adult), problems will likely arise with volume overload if the patient has any significant renal insufficiency. Dialysis or ultrafiltration may be used to treat volume overload; however, it is difficult to remove the large volumes of fluid required for high-volume plasma infusion.

Plasma infusion should be reserved for two situations:

• If plasma exchange cannot be promptly started
• For patients with very severe or refractory disease, between plasma exchange sessions.

Benefit of cryoprecipitate-poor plasma is uncertain

Fresh frozen plasma is believed to contain nearly physiologic levels of all of the plasma proteins. When plasma is cooled to around 4°C, a precipitate forms that contains a variety of substances, including the higher molecular weight multimers of von Willebrand factor. Because TTP involves excess large multimers, giving plasma in which the high molecular weight multimers have been removed should in theory be better. In many centers, such cryoprecipitate-poor plasma is routinely used to treat TTP.

However, evidence that cryoprecipitate-poor plasma is better is lacking. A large study in Canada evaluating this question was terminated because of a lack of patient accrual, a common fate of clinical trials of rare diseases. A randomized study in 17 patients failed to show an advantage of cryoprecipitate-poor plasma over regular plasma, but the study was too small to draw firm conclusions given large confidence intervals about the point estimate of the treatment effect.

Cryoprecipitate-poor plasma is more expensive than regular plasma and is not as available. We do not routinely use it in our center to initially manage patients with TTP, but we do use it for patients who are refractory to standard treatment.

Scott et al³ measured the concentration of ADAMTS13 in a variety of plasma products and found that there are significant amounts in cryoprecipitate. Although giving cryoprecipitate-poor plasma provides less of the high molecular weight multimers, which is desirable for patients with TTP, it also provides less ADAMTS13, which is not desirable.

Most algorithms for managing acute TTP include the use of aspirin or dipyridamole (Persantine) or both, and there is some evidence in favor of this approach,⁴ but whether antiplatelet therapy should be used for inpatients with severe thrombocytopenia remains controversial. In our practice, we usually provide antiplatelet therapy even for patients with severe thrombocytopenia because we believe TTP involves platelet-mediated hypercoagulability rather than increased bleeding risk.

Do corticosteroids have a role?

Corticosteroids were widely used to treat TTP even before the disease was discovered to be immune mediated. In our center we routinely use them.

Unfortunately, few data exist on the efficacy of steroid therapy for TTP. As a result, we can only make a weak recommendation for its use: using the American College of Chest Physicians rating system for the strength of clinical evidence, it would receive a 2C recommendation. This is the weakest possible recommendation, being based on widespread use but poor-quality data.

Stopping vs tapering plasma exchange

Whether plasma exchange should be tapered or simply stopped is also controversial and not well studied. Nevertheless, a widespread clinical practice—once the platelet count returns to 200 × 10⁹/L or higher and the patient looks and feels well—is to reduce the plasma exchange sessions to once every 3 days, then to once every 7 days, and then to once every 2 weeks.

In our practice, we taper plasma exchange in this fashion for a minimum of two treatments beyond what we think the patient really needs. As a result, we tend to treat about once every 2 weeks for weeks or even months after the acute illness.

Rituximab may help

Rituximab (Rituxan), a monoclonal antibody against mature B cells, is increasingly being used in treating TTP. Past and present treatments for TTP, including splenectomy, corticosteroids, and plasma exchange are immunomodulatory, so the use of rituximab may be justified. Case reports provided the rationale for a large, multicenter, randomized controlled trial, which is currently under way.⁵

CONDITIONS THAT ARE NOT TTP

Some conditions may be confused with TTP but are clearly something different:

Patients with isolated thrombocytopenia and normal blood smear findings and no coagulopathy most likely have idiopathic thrombocytopenia purpura or, in the correct clinical circumstance, heparin-induced thrombocytopenia.

A patient with an extremely low platelet count but no fragments or very few fragments with microangiopathic hemolytic anemia may have either drug-associated thrombocytopenia or disseminated intravascular coagulopathy, particularly if there is concomitant coagulopathy.

Many pregnancy-associated microangiopathies resemble TTP, and it may be difficult to differentiate them from TTP; if confusion as to the diagnosis exists, the patient should be treated with plasma exchange, as this therapy may be life-saving.

Many rheumatologic conditions are characterized by an acute illness with nonspecific findings, such as low-grade hemolysis and thrombocytopenia. For example, Wegener granulomatosis can present with evidence of hemolysis, thrombocytopenia, and renal impairment.

Systemic lupus erythematosus can also initially present with an “early-TTP”-like picture. Evidence of glomerulonephritis is not consistent with TTP, and urinary red cell casts makes the diagnosis of lupus more likely. Helmet cell fragments in the peripheral blood smear are supposedly more characteristic of TTP, but their presence is not diagnostic.

Scleroderma renal crisis can present like TTP, but because it is unlikely that a patient with known scleroderma would have a second rare disease, it is best to treat it as scleroderma, which does not require plasma exchange or plasma infusion.

In general, if the diagnosis is uncertain, the safest course is to treat the patient with plasma exchange, then try to establish the diagnosis, because TTP is fatal if not promptly treated. Although plasma exchange is probably overused, it is more innocuous than untreated TTP.

Thrombotic thrombocytopenic purpura (TTP) is one of the few hematologic emergencies. Untreated, most patients die, but prompt and appropriate treatment allows most patients not only to survive but to recover, frequently without long-term sequelae.

TTP is rare. The estimated annual incidence of all TTP syndromes is about 11 cases per million in the general population, and the incidence of severe ADAMTS13 deficiency (see discussion below) is about 2 per million. Therefore, even large medical centers typically see only one or two cases each year. The syndromes are much more common in women, and the incidence among blacks is nine times higher than the incidence among non-blacks. Nevertheless, despite the rarity of this disease, good evidence exists to help guide patient care, thanks to national registries and research organizations, such as the Canadian Apheresis Study Group and the Oklahoma TTP-Hemolytic Uremic Syndrome (HUS) Registry.

This article reviews the physiologic basis of TTP, how to recognize it, and how best to treat it. We also discuss other conditions that clinically resemble TTP but probably have different underlying causes.

A YOUNG WOMAN WITH ARM WEAKNESS

A 24-year-old black woman presents to a community hospital with weakness in her left arm, which began about 30 minutes previously. She has had progressive dyspnea over the last several weeks, but has otherwise been completely well and has had no medical problems in the past other than being obese.

Physical examination reveals weakness in her left arm as well as mild dysarthria, which was not previously noted by the patient or her family. Her laboratory findings:

• White blood cell count 16.7 × 10⁹/L (reference range 4.5–11.0)
• Platelet count 32 × 10⁹/L (150–350)
• Hemoglobin concentration 6.5 g/dL (1.4–17.5)
• Peripheral blood smear: normal white cells, rare platelets, red cells normo-chromic with many fragments
• Lactate dehydrogenase (LDH) concentration 2,300 U/L (100–200).

In view of her symptoms and laboratory values, the physician suspects she may have TTP and refers her to McMaster University Medical Center in Hamilton, Ontario, Canada. Plasma exchange is started immediately; one plasma volume is removed and replaced with fresh frozen plasma. Nevertheless, the patient’s condition deteriorates overnight, she becomes more confused and cannot protect her airway, her LDH concentration rises further, and her hemoglobin concentration falls. She is transferred to the intensive care unit. Her plasma exchange prescription is increased to 1.5 volumes twice daily (although little evidence exists that plasma exchange twice daily is more effective than once daily).

On the third day of her stay, she becomes completely paralyzed on the left side. In addition to her twice-daily plasma exchange procedures, a plasma infusion and corticosteroid therapy are initiated. Her platelet count stabilizes at about 20 × 10⁹/L.

The patient next develops renal insufficiency and requires three acute hemodialysis treatments. (Plasma infusion frequently leads to volume overload in critically ill patients. Some intravascular volume can be removed with plasma exchange; however, significant volume overload with significant renal insufficiency can only be treated with renal replacement therapy.)

The patient undergoes 28 consecutive days of twice-daily plasma exchange and gradually improves, as measured by increasing platelet counts, a gradual fall in the LDH concentration, and stabilization of—and ultimately an increase in—the hemoglobin level. She is weaned off plasma infusions, and then plasma exchange is tapered to once a day and then to alternate days.

She is completely well at the time of discharge 4 weeks after her initial admission, with no residual deficits.

Comment. This case shows that even patients with apparently devastating compromise and neurologic deficits can completely recover with aggressive plasma exchange and other therapies. One child treated at the Hospital for Sick Children, affiliated with the University of Toronto, developed TTP and had 120 consecutive days of plasma exchange: she was unconscious and comatose for much of that time, but she ultimately recovered and is now completely well without residual neurologic deficits.

TTP MAY BE DUE TO ADAMTS13 DEFICIENCY

Twenty-five years ago, little was known about TTP except for its clinical manifestations. Now, it is known to be caused in some patients by an acquired deficiency of a circulating metalloproteinase. In very rare cases a hereditary deficiency of ADAMTS13 causes TTP. In addition, a number of conditions share clinical features with TTP but have other underlying causes.

In acquired TTP, an autoantibody forms against ADAMTS13, a zinc-containing metalloproteinase that is also known as von Willebrand factor-cleaving protease. Normally, von Willebrand factor circulates in plasma as multimers that allow platelets to adhere to vascular surfaces. When von Willebrand factor is initially released from endothelial cells, it exists as large multimers, which are more adhesive for platelets than normal. These large multimers are normally cleaved into smaller units by ADAMTS13. If ADAMTS13 is lacking, the very-high-molecular-weight von Willebrand factor multimers accumulate, causing platelet agglutination and the vascular occlusion that results in the manifestations of TTP.

In 1994, ADAMTS13, the gene of which is on the ninth chromosome, was shown to cleave von Willebrand factor under conditions of high shear stress. In 1996, a congenital homozygous deficiency of ADAMTS13 was found to be associated with platelet microthrombi. Afterwards, some patients with TTP were shown to have low or undetectable levels of ADAMTS13, owing to immunoglobulin G antibodies directed against the enzyme.

TTP AND RELATED SYNDROMES

Clinically, TTP encompasses a number of different but related syndromes, some of which have different physiologic bases.

TTP

TTP is characterized by moderate to severe thrombocytopenia, red cell fragmentation, and elevated LDH levels (due to red cell destruction and also muscle and organ ischemia). The pentad of features classically associated with TTP in the era before effective treatment (thrombocytopenia, fever, renal failure, neurologic deficit, and microangiopathic hemolytic anemia) is rarely seen in countries with advanced medical care: renal insufficiency and neurologic events are end-stage manifestations, and the disease should be recognizable well before these manifestations occur. Otherwise unexplained thrombocytopenia, microangiopathic hemolytic anemia, and an elevated LDH should strongly suggest TTP. TTP is the appropriate designation for adults with these clinical features, even in the presence of renal failure. TTP is uncommon in children.

Most patients present with nonspecific constitutional symptoms, such as weakness, abdominal pain, nausea, and vomiting. Typically, the family physician orders a complete blood cell count and finds that the platelet count and hemoglobin are low. Red cell fragments are noted in the peripheral blood smear. Further testing reveals an elevated LDH concentration.

HUS

HUS was initially described 30 years after TTP in children with acute renal failure in addition to thrombocytopenia and microangiopathic hemolytic anemia. The term “HUS” is currently used primarily to describe the condition in children.

In children, two forms of HUS exist:

Diarrhea-associated HUS is associated with diarrhea that is commonly bloody, due to an enterotoxin produced by Escherichia coli O157:H7.

Endemic diarrhea-associated HUS is much more common than HUS associated with epidemics. Endemic cases are caused by E coli O157:H7 present in the environment. Other patients present with clinically apparent HUS but the causal bacterium cannot be detected. The kidney transplant program at our center often sees young patients with this disease who do not have E coli O157:H7 infection, and the pathogenesis is not understood. Epidemic cases are less common but the outbreaks are dramatic. About 10 years ago, E coli O157:H7 entered the water supply in the small city of Walkerton, Ontario, and many people developed the epidemic form of HUS over a period of several weeks. Most such patients spontaneously recovered without plasma exchange, although many were left with impaired renal function.

Atypical HUS. Less often, HUS in children is not associated with a prodrome of diarrhea and is referred to as “atypical” HUS. These children often have a more prolonged and complicated course and resemble adults with TTP.

Familial TTP-HUS

Familial TTP-HUS is very rare. It may present with hemolysis and thrombocytopenia in childhood or early adulthood. Many patients present with renal insufficiency, and only careful evaluation reveals hemolysis and thrombocytopenia. The disease typically manifests acutely: a patient may have an upper respiratory tract infection and subsequently develop an episode of TTP-HUS. Episodes tend to recur, and multiple family members may also be affected.

Plasma infusion is an effective treatment, and plasma exchange is usually not required. Since more patients are now surviving well into adulthood, some are being seen to develop antibodies to the ADAMTS13 in the infused plasma, analogous to patients with severe hemophilia developing inhibitors to factor VIII. The disease may progress despite treatment: we have been treating a young woman who has had a series of catastrophic complications and now has chronic renal failure requiring hemodialysis (see discussion below).

Post-transplant microangiopathy

Post-transplant microangiopathy is most likely to develop after solid-organ or stem-cell allograft transplantation. Manifestations resemble those of TTP, but the mechanism is probably quite different. Multiple causes probably exist, depending on the setting.

Post-transplant microangiopathy does not respond to the usual therapies for TTP, although we treat it, like TTP, with corticosteroids, antiplatelet agents, and plasma exchange. Other centers do not use plasma exchange for these patients. Most patients have a poor prognosis, especially those with a transplant other than a kidney.

A spectrum of related syndromes

A number of diseases clinically resemble TTP. Enhanced diagnostic capacity and better molecular biologic techniques are revealing that they often have very different underlying causes and that in some cases they require different treatment.

TOWARD DIAGNOSTIC CRITERIA

Ruutu et al,¹ in a consensus conference, used rigorous methods to establish diagnostic criteria for microangiopathy associated with stem cell transplantation:

• More than 4% red blood cell fragments in the peripheral blood. A laboratory report that states that “few fragments” are present is not nearly as useful as one that estimates the quantity; eg, 1% fragments would have very different implications than 6% fragments.
• Thrombocytopenia—a platelet count of less than 50 × 10⁹/L or more than a 50% reduction from previous counts
• Increased LDH concentration
• Reduced hemoglobin concentration or increased transfusion requirement
• Decrease in serum haptoglobin, which, like red blood cell fragments, is a marker of hemolysis rather than of reduced synthesis.

The ADAMTS13 level need not be assessed. Metalloproteinase deficiency need not be proved to diagnose TTP. Although our hospital is a TTP referral center, we do not routinely offer the test. Too often the test results cause confusion: a patient can have a normal level of ADAMTS13 and still have TTP that responds to plasma exchange, and levels can be low in conditions other than TTP.

THE CHALLENGES OF TREATMENT

Plasma exchange is the primary treatment for TTP

Rock et al² performed a randomized trial in which 102 patients with TTP received either a 1.5-volume plasma exchange daily for 3 days and then 1-volume plasma exchanges as needed to control the disease or plasma infusion. Patients who received plasma exchange had a better initial response, a higher survival rate, and a lower rate of relapse than patients receiving plasma infusion. These findings established plasma exchange as the treatment of choice for TTP.

However, the trial had some inherent problems: patients who had plasma infusions tended to develop renal insufficiency and as a result did not receive as much plasma because they could not tolerate as much volume as those who had plasma exchange. Plasma exchange probably worked better because it could deliver more plasma over a fixed period of time, enabling patients to obtain more of the ADAMTS13 enzyme, rather than because it was an intrinsically better treatment. This interpretation is the basis for our occasional use of twice-daily plasma exchange in critically ill patients.

TTP is different from other autoimmune diseases such as idiopathic thrombocytopenia purpura, in which the primary treatments are immunosuppressive agents. Some evidence exists for treating TTP with immunosuppressive agents, but the primary treatment should be plasma exchange.

Plasma infusion is useful in some cases

Although small case series and our own experience provide evidence for the benefit of treating TTP with high-dose plasma infusions (25 mL/kg/day, or about 1.5 to 2.0 L/day for an average-sized adult), problems will likely arise with volume overload if the patient has any significant renal insufficiency. Dialysis or ultrafiltration may be used to treat volume overload; however, it is difficult to remove the large volumes of fluid required for high-volume plasma infusion.

Plasma infusion should be reserved for two situations:

• If plasma exchange cannot be promptly started
• For patients with very severe or refractory disease, between plasma exchange sessions.

Benefit of cryoprecipitate-poor plasma is uncertain

Fresh frozen plasma is believed to contain nearly physiologic levels of all of the plasma proteins. When plasma is cooled to around 4°C, a precipitate forms that contains a variety of substances, including the higher molecular weight multimers of von Willebrand factor. Because TTP involves excess large multimers, giving plasma in which the high molecular weight multimers have been removed should in theory be better. In many centers, such cryoprecipitate-poor plasma is routinely used to treat TTP.

However, evidence that cryoprecipitate-poor plasma is better is lacking. A large study in Canada evaluating this question was terminated because of a lack of patient accrual, a common fate of clinical trials of rare diseases. A randomized study in 17 patients failed to show an advantage of cryoprecipitate-poor plasma over regular plasma, but the study was too small to draw firm conclusions given large confidence intervals about the point estimate of the treatment effect.

Cryoprecipitate-poor plasma is more expensive than regular plasma and is not as available. We do not routinely use it in our center to initially manage patients with TTP, but we do use it for patients who are refractory to standard treatment.

Scott et al³ measured the concentration of ADAMTS13 in a variety of plasma products and found that there are significant amounts in cryoprecipitate. Although giving cryoprecipitate-poor plasma provides less of the high molecular weight multimers, which is desirable for patients with TTP, it also provides less ADAMTS13, which is not desirable.

Most algorithms for managing acute TTP include the use of aspirin or dipyridamole (Persantine) or both, and there is some evidence in favor of this approach,⁴ but whether antiplatelet therapy should be used for inpatients with severe thrombocytopenia remains controversial. In our practice, we usually provide antiplatelet therapy even for patients with severe thrombocytopenia because we believe TTP involves platelet-mediated hypercoagulability rather than increased bleeding risk.

Do corticosteroids have a role?

Corticosteroids were widely used to treat TTP even before the disease was discovered to be immune mediated. In our center we routinely use them.

Unfortunately, few data exist on the efficacy of steroid therapy for TTP. As a result, we can only make a weak recommendation for its use: using the American College of Chest Physicians rating system for the strength of clinical evidence, it would receive a 2C recommendation. This is the weakest possible recommendation, being based on widespread use but poor-quality data.

Stopping vs tapering plasma exchange

Whether plasma exchange should be tapered or simply stopped is also controversial and not well studied. Nevertheless, a widespread clinical practice—once the platelet count returns to 200 × 10⁹/L or higher and the patient looks and feels well—is to reduce the plasma exchange sessions to once every 3 days, then to once every 7 days, and then to once every 2 weeks.

In our practice, we taper plasma exchange in this fashion for a minimum of two treatments beyond what we think the patient really needs. As a result, we tend to treat about once every 2 weeks for weeks or even months after the acute illness.

Rituximab may help

Rituximab (Rituxan), a monoclonal antibody against mature B cells, is increasingly being used in treating TTP. Past and present treatments for TTP, including splenectomy, corticosteroids, and plasma exchange are immunomodulatory, so the use of rituximab may be justified. Case reports provided the rationale for a large, multicenter, randomized controlled trial, which is currently under way.⁵

CONDITIONS THAT ARE NOT TTP

Some conditions may be confused with TTP but are clearly something different:

Patients with isolated thrombocytopenia and normal blood smear findings and no coagulopathy most likely have idiopathic thrombocytopenia purpura or, in the correct clinical circumstance, heparin-induced thrombocytopenia.

A patient with an extremely low platelet count but no fragments or very few fragments with microangiopathic hemolytic anemia may have either drug-associated thrombocytopenia or disseminated intravascular coagulopathy, particularly if there is concomitant coagulopathy.

Many pregnancy-associated microangiopathies resemble TTP, and it may be difficult to differentiate them from TTP; if confusion as to the diagnosis exists, the patient should be treated with plasma exchange, as this therapy may be life-saving.

Many rheumatologic conditions are characterized by an acute illness with nonspecific findings, such as low-grade hemolysis and thrombocytopenia. For example, Wegener granulomatosis can present with evidence of hemolysis, thrombocytopenia, and renal impairment.

Systemic lupus erythematosus can also initially present with an “early-TTP”-like picture. Evidence of glomerulonephritis is not consistent with TTP, and urinary red cell casts makes the diagnosis of lupus more likely. Helmet cell fragments in the peripheral blood smear are supposedly more characteristic of TTP, but their presence is not diagnostic.

Scleroderma renal crisis can present like TTP, but because it is unlikely that a patient with known scleroderma would have a second rare disease, it is best to treat it as scleroderma, which does not require plasma exchange or plasma infusion.

In general, if the diagnosis is uncertain, the safest course is to treat the patient with plasma exchange, then try to establish the diagnosis, because TTP is fatal if not promptly treated. Although plasma exchange is probably overused, it is more innocuous than untreated TTP.

Thrombotic thrombocytopenic purpura (TTP) is one of the few hematologic emergencies. Untreated, most patients die, but prompt and appropriate treatment allows most patients not only to survive but to recover, frequently without long-term sequelae.

TTP is rare. The estimated annual incidence of all TTP syndromes is about 11 cases per million in the general population, and the incidence of severe ADAMTS13 deficiency (see discussion below) is about 2 per million. Therefore, even large medical centers typically see only one or two cases each year. The syndromes are much more common in women, and the incidence among blacks is nine times higher than the incidence among non-blacks. Nevertheless, despite the rarity of this disease, good evidence exists to help guide patient care, thanks to national registries and research organizations, such as the Canadian Apheresis Study Group and the Oklahoma TTP-Hemolytic Uremic Syndrome (HUS) Registry.

This article reviews the physiologic basis of TTP, how to recognize it, and how best to treat it. We also discuss other conditions that clinically resemble TTP but probably have different underlying causes.

A YOUNG WOMAN WITH ARM WEAKNESS

A 24-year-old black woman presents to a community hospital with weakness in her left arm, which began about 30 minutes previously. She has had progressive dyspnea over the last several weeks, but has otherwise been completely well and has had no medical problems in the past other than being obese.

Physical examination reveals weakness in her left arm as well as mild dysarthria, which was not previously noted by the patient or her family. Her laboratory findings:

• White blood cell count 16.7 × 10⁹/L (reference range 4.5–11.0)
• Platelet count 32 × 10⁹/L (150–350)
• Hemoglobin concentration 6.5 g/dL (1.4–17.5)
• Peripheral blood smear: normal white cells, rare platelets, red cells normo-chromic with many fragments
• Lactate dehydrogenase (LDH) concentration 2,300 U/L (100–200).

In view of her symptoms and laboratory values, the physician suspects she may have TTP and refers her to McMaster University Medical Center in Hamilton, Ontario, Canada. Plasma exchange is started immediately; one plasma volume is removed and replaced with fresh frozen plasma. Nevertheless, the patient’s condition deteriorates overnight, she becomes more confused and cannot protect her airway, her LDH concentration rises further, and her hemoglobin concentration falls. She is transferred to the intensive care unit. Her plasma exchange prescription is increased to 1.5 volumes twice daily (although little evidence exists that plasma exchange twice daily is more effective than once daily).

On the third day of her stay, she becomes completely paralyzed on the left side. In addition to her twice-daily plasma exchange procedures, a plasma infusion and corticosteroid therapy are initiated. Her platelet count stabilizes at about 20 × 10⁹/L.

The patient next develops renal insufficiency and requires three acute hemodialysis treatments. (Plasma infusion frequently leads to volume overload in critically ill patients. Some intravascular volume can be removed with plasma exchange; however, significant volume overload with significant renal insufficiency can only be treated with renal replacement therapy.)

The patient undergoes 28 consecutive days of twice-daily plasma exchange and gradually improves, as measured by increasing platelet counts, a gradual fall in the LDH concentration, and stabilization of—and ultimately an increase in—the hemoglobin level. She is weaned off plasma infusions, and then plasma exchange is tapered to once a day and then to alternate days.

She is completely well at the time of discharge 4 weeks after her initial admission, with no residual deficits.

Comment. This case shows that even patients with apparently devastating compromise and neurologic deficits can completely recover with aggressive plasma exchange and other therapies. One child treated at the Hospital for Sick Children, affiliated with the University of Toronto, developed TTP and had 120 consecutive days of plasma exchange: she was unconscious and comatose for much of that time, but she ultimately recovered and is now completely well without residual neurologic deficits.

TTP MAY BE DUE TO ADAMTS13 DEFICIENCY

Twenty-five years ago, little was known about TTP except for its clinical manifestations. Now, it is known to be caused in some patients by an acquired deficiency of a circulating metalloproteinase. In very rare cases a hereditary deficiency of ADAMTS13 causes TTP. In addition, a number of conditions share clinical features with TTP but have other underlying causes.

In acquired TTP, an autoantibody forms against ADAMTS13, a zinc-containing metalloproteinase that is also known as von Willebrand factor-cleaving protease. Normally, von Willebrand factor circulates in plasma as multimers that allow platelets to adhere to vascular surfaces. When von Willebrand factor is initially released from endothelial cells, it exists as large multimers, which are more adhesive for platelets than normal. These large multimers are normally cleaved into smaller units by ADAMTS13. If ADAMTS13 is lacking, the very-high-molecular-weight von Willebrand factor multimers accumulate, causing platelet agglutination and the vascular occlusion that results in the manifestations of TTP.

In 1994, ADAMTS13, the gene of which is on the ninth chromosome, was shown to cleave von Willebrand factor under conditions of high shear stress. In 1996, a congenital homozygous deficiency of ADAMTS13 was found to be associated with platelet microthrombi. Afterwards, some patients with TTP were shown to have low or undetectable levels of ADAMTS13, owing to immunoglobulin G antibodies directed against the enzyme.

TTP AND RELATED SYNDROMES

Clinically, TTP encompasses a number of different but related syndromes, some of which have different physiologic bases.

TTP

TTP is characterized by moderate to severe thrombocytopenia, red cell fragmentation, and elevated LDH levels (due to red cell destruction and also muscle and organ ischemia). The pentad of features classically associated with TTP in the era before effective treatment (thrombocytopenia, fever, renal failure, neurologic deficit, and microangiopathic hemolytic anemia) is rarely seen in countries with advanced medical care: renal insufficiency and neurologic events are end-stage manifestations, and the disease should be recognizable well before these manifestations occur. Otherwise unexplained thrombocytopenia, microangiopathic hemolytic anemia, and an elevated LDH should strongly suggest TTP. TTP is the appropriate designation for adults with these clinical features, even in the presence of renal failure. TTP is uncommon in children.

Most patients present with nonspecific constitutional symptoms, such as weakness, abdominal pain, nausea, and vomiting. Typically, the family physician orders a complete blood cell count and finds that the platelet count and hemoglobin are low. Red cell fragments are noted in the peripheral blood smear. Further testing reveals an elevated LDH concentration.

HUS

HUS was initially described 30 years after TTP in children with acute renal failure in addition to thrombocytopenia and microangiopathic hemolytic anemia. The term “HUS” is currently used primarily to describe the condition in children.

In children, two forms of HUS exist:

Diarrhea-associated HUS is associated with diarrhea that is commonly bloody, due to an enterotoxin produced by Escherichia coli O157:H7.

Endemic diarrhea-associated HUS is much more common than HUS associated with epidemics. Endemic cases are caused by E coli O157:H7 present in the environment. Other patients present with clinically apparent HUS but the causal bacterium cannot be detected. The kidney transplant program at our center often sees young patients with this disease who do not have E coli O157:H7 infection, and the pathogenesis is not understood. Epidemic cases are less common but the outbreaks are dramatic. About 10 years ago, E coli O157:H7 entered the water supply in the small city of Walkerton, Ontario, and many people developed the epidemic form of HUS over a period of several weeks. Most such patients spontaneously recovered without plasma exchange, although many were left with impaired renal function.

Atypical HUS. Less often, HUS in children is not associated with a prodrome of diarrhea and is referred to as “atypical” HUS. These children often have a more prolonged and complicated course and resemble adults with TTP.

Familial TTP-HUS

Familial TTP-HUS is very rare. It may present with hemolysis and thrombocytopenia in childhood or early adulthood. Many patients present with renal insufficiency, and only careful evaluation reveals hemolysis and thrombocytopenia. The disease typically manifests acutely: a patient may have an upper respiratory tract infection and subsequently develop an episode of TTP-HUS. Episodes tend to recur, and multiple family members may also be affected.

Plasma infusion is an effective treatment, and plasma exchange is usually not required. Since more patients are now surviving well into adulthood, some are being seen to develop antibodies to the ADAMTS13 in the infused plasma, analogous to patients with severe hemophilia developing inhibitors to factor VIII. The disease may progress despite treatment: we have been treating a young woman who has had a series of catastrophic complications and now has chronic renal failure requiring hemodialysis (see discussion below).

Post-transplant microangiopathy

Post-transplant microangiopathy is most likely to develop after solid-organ or stem-cell allograft transplantation. Manifestations resemble those of TTP, but the mechanism is probably quite different. Multiple causes probably exist, depending on the setting.

Post-transplant microangiopathy does not respond to the usual therapies for TTP, although we treat it, like TTP, with corticosteroids, antiplatelet agents, and plasma exchange. Other centers do not use plasma exchange for these patients. Most patients have a poor prognosis, especially those with a transplant other than a kidney.

A spectrum of related syndromes

A number of diseases clinically resemble TTP. Enhanced diagnostic capacity and better molecular biologic techniques are revealing that they often have very different underlying causes and that in some cases they require different treatment.

TOWARD DIAGNOSTIC CRITERIA

Ruutu et al,¹ in a consensus conference, used rigorous methods to establish diagnostic criteria for microangiopathy associated with stem cell transplantation:

• More than 4% red blood cell fragments in the peripheral blood. A laboratory report that states that “few fragments” are present is not nearly as useful as one that estimates the quantity; eg, 1% fragments would have very different implications than 6% fragments.
• Thrombocytopenia—a platelet count of less than 50 × 10⁹/L or more than a 50% reduction from previous counts
• Increased LDH concentration
• Reduced hemoglobin concentration or increased transfusion requirement
• Decrease in serum haptoglobin, which, like red blood cell fragments, is a marker of hemolysis rather than of reduced synthesis.

The ADAMTS13 level need not be assessed. Metalloproteinase deficiency need not be proved to diagnose TTP. Although our hospital is a TTP referral center, we do not routinely offer the test. Too often the test results cause confusion: a patient can have a normal level of ADAMTS13 and still have TTP that responds to plasma exchange, and levels can be low in conditions other than TTP.

THE CHALLENGES OF TREATMENT

Plasma exchange is the primary treatment for TTP

Rock et al² performed a randomized trial in which 102 patients with TTP received either a 1.5-volume plasma exchange daily for 3 days and then 1-volume plasma exchanges as needed to control the disease or plasma infusion. Patients who received plasma exchange had a better initial response, a higher survival rate, and a lower rate of relapse than patients receiving plasma infusion. These findings established plasma exchange as the treatment of choice for TTP.

However, the trial had some inherent problems: patients who had plasma infusions tended to develop renal insufficiency and as a result did not receive as much plasma because they could not tolerate as much volume as those who had plasma exchange. Plasma exchange probably worked better because it could deliver more plasma over a fixed period of time, enabling patients to obtain more of the ADAMTS13 enzyme, rather than because it was an intrinsically better treatment. This interpretation is the basis for our occasional use of twice-daily plasma exchange in critically ill patients.

TTP is different from other autoimmune diseases such as idiopathic thrombocytopenia purpura, in which the primary treatments are immunosuppressive agents. Some evidence exists for treating TTP with immunosuppressive agents, but the primary treatment should be plasma exchange.

Plasma infusion is useful in some cases

Although small case series and our own experience provide evidence for the benefit of treating TTP with high-dose plasma infusions (25 mL/kg/day, or about 1.5 to 2.0 L/day for an average-sized adult), problems will likely arise with volume overload if the patient has any significant renal insufficiency. Dialysis or ultrafiltration may be used to treat volume overload; however, it is difficult to remove the large volumes of fluid required for high-volume plasma infusion.

Plasma infusion should be reserved for two situations:

• If plasma exchange cannot be promptly started
• For patients with very severe or refractory disease, between plasma exchange sessions.

Benefit of cryoprecipitate-poor plasma is uncertain

Fresh frozen plasma is believed to contain nearly physiologic levels of all of the plasma proteins. When plasma is cooled to around 4°C, a precipitate forms that contains a variety of substances, including the higher molecular weight multimers of von Willebrand factor. Because TTP involves excess large multimers, giving plasma in which the high molecular weight multimers have been removed should in theory be better. In many centers, such cryoprecipitate-poor plasma is routinely used to treat TTP.

However, evidence that cryoprecipitate-poor plasma is better is lacking. A large study in Canada evaluating this question was terminated because of a lack of patient accrual, a common fate of clinical trials of rare diseases. A randomized study in 17 patients failed to show an advantage of cryoprecipitate-poor plasma over regular plasma, but the study was too small to draw firm conclusions given large confidence intervals about the point estimate of the treatment effect.

Cryoprecipitate-poor plasma is more expensive than regular plasma and is not as available. We do not routinely use it in our center to initially manage patients with TTP, but we do use it for patients who are refractory to standard treatment.

Scott et al³ measured the concentration of ADAMTS13 in a variety of plasma products and found that there are significant amounts in cryoprecipitate. Although giving cryoprecipitate-poor plasma provides less of the high molecular weight multimers, which is desirable for patients with TTP, it also provides less ADAMTS13, which is not desirable.

Most algorithms for managing acute TTP include the use of aspirin or dipyridamole (Persantine) or both, and there is some evidence in favor of this approach,⁴ but whether antiplatelet therapy should be used for inpatients with severe thrombocytopenia remains controversial. In our practice, we usually provide antiplatelet therapy even for patients with severe thrombocytopenia because we believe TTP involves platelet-mediated hypercoagulability rather than increased bleeding risk.

Do corticosteroids have a role?

Corticosteroids were widely used to treat TTP even before the disease was discovered to be immune mediated. In our center we routinely use them.

Unfortunately, few data exist on the efficacy of steroid therapy for TTP. As a result, we can only make a weak recommendation for its use: using the American College of Chest Physicians rating system for the strength of clinical evidence, it would receive a 2C recommendation. This is the weakest possible recommendation, being based on widespread use but poor-quality data.

Stopping vs tapering plasma exchange

Whether plasma exchange should be tapered or simply stopped is also controversial and not well studied. Nevertheless, a widespread clinical practice—once the platelet count returns to 200 × 10⁹/L or higher and the patient looks and feels well—is to reduce the plasma exchange sessions to once every 3 days, then to once every 7 days, and then to once every 2 weeks.

In our practice, we taper plasma exchange in this fashion for a minimum of two treatments beyond what we think the patient really needs. As a result, we tend to treat about once every 2 weeks for weeks or even months after the acute illness.

Rituximab may help

Rituximab (Rituxan), a monoclonal antibody against mature B cells, is increasingly being used in treating TTP. Past and present treatments for TTP, including splenectomy, corticosteroids, and plasma exchange are immunomodulatory, so the use of rituximab may be justified. Case reports provided the rationale for a large, multicenter, randomized controlled trial, which is currently under way.⁵

CONDITIONS THAT ARE NOT TTP

Some conditions may be confused with TTP but are clearly something different:

Patients with isolated thrombocytopenia and normal blood smear findings and no coagulopathy most likely have idiopathic thrombocytopenia purpura or, in the correct clinical circumstance, heparin-induced thrombocytopenia.

A patient with an extremely low platelet count but no fragments or very few fragments with microangiopathic hemolytic anemia may have either drug-associated thrombocytopenia or disseminated intravascular coagulopathy, particularly if there is concomitant coagulopathy.

Many pregnancy-associated microangiopathies resemble TTP, and it may be difficult to differentiate them from TTP; if confusion as to the diagnosis exists, the patient should be treated with plasma exchange, as this therapy may be life-saving.

Many rheumatologic conditions are characterized by an acute illness with nonspecific findings, such as low-grade hemolysis and thrombocytopenia. For example, Wegener granulomatosis can present with evidence of hemolysis, thrombocytopenia, and renal impairment.

Systemic lupus erythematosus can also initially present with an “early-TTP”-like picture. Evidence of glomerulonephritis is not consistent with TTP, and urinary red cell casts makes the diagnosis of lupus more likely. Helmet cell fragments in the peripheral blood smear are supposedly more characteristic of TTP, but their presence is not diagnostic.

Scleroderma renal crisis can present like TTP, but because it is unlikely that a patient with known scleroderma would have a second rare disease, it is best to treat it as scleroderma, which does not require plasma exchange or plasma infusion.

In general, if the diagnosis is uncertain, the safest course is to treat the patient with plasma exchange, then try to establish the diagnosis, because TTP is fatal if not promptly treated. Although plasma exchange is probably overused, it is more innocuous than untreated TTP.

A frail 75-year-old woman with diabetes, hyperlipidemia, and a history of rheumatic fever in childhood presents to the emergency department of a community hospital with complaints of chest pressure, shortness of breath on exertion, and easy fatigability. Her shortness of breath started 6 months ago but has become much worse over the past few days.

On examination, her pulse is 110 and irregular, and she has markedly distended neck veins and evidence of pulmonary edema. She has a systolic murmur, but it is difficult to characterize due to tachycardia. Electrocardiography shows atrial fibrillation with rapid ventricular response and right axis deviation. Chest radiography shows bilateral pleural effusions.

The patient is given a diuretic, anticoagulation is started to prevent thromboembolism, and she undergoes cardioversion for the atrial fibrillation.

Transthoracic echocardiography is performed and reveals biatrial enlargement, anterior mitral valve leaflet thickening, mitral valve calcification, and moderate mitral regurgitation. Her ejection fraction is normal, but she has mild right ventricular systolic dysfunction with moderate tricuspid regurgitation and an estimated right ventricular systolic pressure of 90 mm Hg (normal range 15–30 mm Hg).

After an uneventful hospital course, she is discharged on a stable dose of a diuretic and oral anticoagulation. Despite adequate diuresis and maintenance of normal sinus rhythm, however, she continues to experience severe dyspnea, which limits her ability to perform simple tasks, such as dusting the furniture in her home. She is referred to Cleveland Clinic for further evaluation.

WHAT IS THE CAUSE OF HER SYMPTOMS?

1. What was the most likely cause of this patient’s initial acute presentation to the emergency department?

• An acute decrease in mitral valve area
• Rheumatic mitral valve stenosis
• Acute coronary syndrome
• Atrial fibrillation

Although an acute decrease in mitral valve area caused by an atrial myxoma, thrombus, or vegetation is a possibility, this patient’s symptoms gradually increased over a period of months. She also did not have signs of infection, nor did she have any signs of embolic phenomena to suggest myxoma, thrombus, or vegetation, all of which frequently present with emboli.

Given her history of rheumatic fever and her echocardiographic findings, rheumatic mitral valve stenosis is high on the list of differential diagnoses. Rheumatic mitral valve stenosis is a chronic process in which the valve area decreases at a rate of about 0.1 cm²/year.^1,2

Acute coronary syndrome is a possibility in this elderly woman with multiple risk factors for coronary artery disease. An evaluation for coronary insufficiency should be considered, but the most striking finding on her initial electrocardiogram is atrial fibrillation with a rapid ventricular response.

The onset of atrial fibrillation in the setting of valvular heart disease is the most likely cause of her acute decompensation with signs and symptoms of congestive heart failure. In severe mitral stenosis, because the mitral valve orifice is narrowed, a higher left atrial pressure and longer ventricular filling time are required to maintain forward flow. Now add atrial fibrillation to this situation: the left atrium no longer contracts properly, so less blood is forced through the narrowed valve, and with the rapid heart rate the left ventricle has less time to fill. These two conditions result in elevated left atrial and pulmonary venous pressures, which in turn result in pulmonary edema and congestive heart failure. Thus, patients with mitral stenosis tolerate atrial fibrillation poorly.

WHAT IS THE NEXT STEP?

2. What would be the most appropriate next step for our patient?

• Transesophageal echocardiography
• Right heart catheterization
• An exercise treadmill stress test0

Transesophageal echocardiography is a reasonable option, as mitral stenosis is strongly suspected but transthoracic echocardiography did not reveal severe mitral valve disease. The use of transesophageal echocardiography for the diagnosis of mitral stenosis in this situation is a class IC recommendation (ie, the procedure is recommended, although very few trials have been done) in the American College of Cardiology and American Heart Association Valvular Disease guidelines.³

Right heart catheterization is the diagnostic test of choice in this situation, as the patient has evidence of biventricular heart failure and her right ventricular systolic pressure of 90 mm Hg is consistent with severe pulmonary hypertension. Right heart catheterization would help differentiate primary pulmonary hypertension causing dyspnea from pulmonary hypertension secondary to elevated left-sided pressures. It would also provide a direct hemodynamic estimate of her cardiac function.

Exercise treadmill testing. Evaluation for myocardial ischemia is a reasonable option, as our patient is elderly and has hypertension and diabetes, both of which are risk factors for coronary artery disease. Moreover, in a patient with diabetes, myocardial ischemia can present as dyspnea without typical anginal chest pain. Because of her age and severely limiting dyspnea, however, she would be unlikely to achieve an adequate heart rate during exercise treadmill testing, so this may not be the optimal type of stress test.

Although asymptomatic patients with moderate or severe mitral stenosis should undergo evaluation of exercise capacity and change in pulmonary artery pressures with exercise to determine the need for percutaneous balloon mitral valvuloplasty (see below),³ our patient is symptomatic and already has evidence of severe pulmonary hypertension on transthoracic echocardiography.

Other options for evaluating for myocardial ischemia include pharmacologic stress testing with imaging (eg, dobutamine echocardiography or adenosine nuclear imaging) or proceeding directly to coronary angiography.

CASE CONTINUED: RIGHT HEART CATHETERIZATION, CORONARY ANGIOGRAPHY

• Mean right atrial pressure 6 mm Hg (normal 2–7 mm Hg)
• Right ventricular pressure 102/6 mm Hg (consistent with severe pulmonary hypertension) (normal 15–30/1–7 mm Hg)
• Pulmonary artery pressure 102/40 mm Hg (normal 15–30/4–12 mm Hg)
• Mean pulmonary capillary wedge pressure 25 mm Hg (normal 4–12 mm Hg)
• Cardiac output 3.16 L/min (normal 4–8 L/min)
• Cardiac index 2.10 L/min/m² (normal 2.5–4.2 L/min/m²)
• v waves are not prominent.

Because her symptoms raise concern for ischemia, coronary angiography is also performed and shows minimal, nonobstructive coronary artery disease. Her left ventricular end-diastolic pressure is 8 mm Hg (normal 5–12 mm Hg).

WHAT IS THE DIAGNOSIS?

3. What is the most likely diagnosis?

• Tricuspid stenosis
• Pulmonic stenosis
• Mitral stenosis
• Mitral regurgitation

Tricuspid stenosis would result in a higher pressure in the right atrium than in the right ventricle. In our patient, the right atrial pressure and the right ventricular diastolic pressure are both 6 mm Hg, eliminating this possibility.

Similarly, pulmonic stenosis would result in a higher pressure in the right ventricle than in the pulmonary artery. In our patient both the right ventricular systolic pressure and the pulmonary artery systolic pressures are 102 mm Hg.

Acute mitral regurgitation may result in increased wedge pressure and tall v waves (reflecting left atrial filling during ventricular systole). In chronic mitral regurgitation, however, the wedge pressure may be normal and the patient may have relatively normal-appearing v waves.⁴

Mitral stenosis results in a marked gradient between the pulmonary capillary wedge pressure and the left ventricular diastolic pressure in the absence of pulmonary veno-occlusive disease. This gradient can be measured by simultaneous catheterization of the right heart (to measure the wedge pressure, which is an indirect measure of left atrial pressure) and the left heart (to measure the left ventricular diastolic pressure). If the patient does not have significant mitral stenosis, the wedge pressure should be approximately equal to the left ventricular diastolic pressure. In our patient, the wedge pressure (and therefore the left atrial pressure) is 25 mm Hg, and the left ventricular end-diastolic pressure is 8 mm Hg—a difference of 17 mm Hg, consistent with significant mitral stenosis.

CASE CONTINUED: TRANSESOPHAGEAL ECHOCARDIOGRAPHY

WHAT IS THE TREATMENT?

4. Which of the following is the preferred technique for correcting mitral stenosis in this patient?

• Percutaneous balloon mitral valvuloplasty
• Mitral valve surgery
• Percutaneous mitral valve replacement

Although there are several options for mechanical treatment of mitral stenosis, percutaneous balloon mitral valvuloplasty by experienced operators is the procedure of choice for patients who have symptomatic moderate-to-severe mitral stenosis with favorable valve morphology but do not have significant mitral regurgitation or left atrial thrombus.³ The hemodynamic and symptomatic improvement that can be expected after this procedure can be predicted using several echocardiographic criteria, including valve mobility, subvalvular thickening, valve leaflet thickening, and valve leaflet calcification,⁵ as well as the degree of commissural calcification or commissural fusion.⁶ Success rates are better if the valve is relatively more mobile and has lesser degrees of valvular and subvalvular thickening, calcification, and commissural fusion.

Mitral valve surgery (repair if possible) is indicated in patients with acceptable operative risk who have symptomatic (New York Heart Association class III or IV) moderate-to-severe mitral stenosis if percutaneous balloon mitral valvuloplasty is unavailable, in cases in which an atrial thrombus or moderate-to-severe mitral regurgitation precludes balloon valvuloplasty, or when the valve morphology is not favorable for balloon valvulo-plasty.³

Although she has moderate mitral regurgitation and poor valve morphology, our patient is a poor surgical candidate because of her advanced age, severe pulmonary hypertension, and poor functional status. Patients with moderate-to-severe mitral stenosis and class III or IV symptoms who have nonpliable, calcified valves but are not candidates for open heart surgery have a class IIb indication for percutaneous balloon mitral valvuloplasty—ie, the procedure may be considered.³

In addition, the procedure also carries a class IIb recommendation in patients with moderate-to-severe mitral stenosis and new-onset atrial fibrillation (provided that they do not have a thrombus in the left atrium or moderate-to-severe mitral regurgitation), even without symptoms.³

Percutaneous mitral valve replacement is not available in clinical practice, although this is an active area of clinical research and may be available in the future.

CASE CONTINUED: THE PATIENT UNDERGOES BALLOON VALVULOPLASTY