Commentary

It has been said that “extraordinary claims require extraordinary evidence.”¹ In the pursuit of evidence-based medicine, we are encouraged to follow a similar standard, with an emphasis on waiting for multiple studies with good-quality data and high levels of agreement before changing any aspect of our clinical practice. The ostensible purpose is that studies can be flawed, conclusions can be incorrect, or biases can be overlooked. In such cases, acting on questionable results could imperil patients. It is for this reason that so many review articles sometimes frustratingly seem to conclude that further evidence is needed.²

Based on this standard, recently published addendum guidelines from the National Institute of Allergy and Infectious Diseases for prevention of peanut allergy in the United States³ are somewhat striking in that they make fairly bold recommendations based on results from the 2015 Learning Early about Peanut Allergy (LEAP) study,⁴ a randomized trial evaluating early peanut introduction as a preventive strategy for peanut allergy. Of note, this study was not placebo controlled, was conducted at only 1 site in the United Kingdom, and only included 640 children, though the number of participants was admittedly large for this type of study.⁴ Arguably, the LEAP study alone does not provide enough evidence upon which to base what essentially amounts to an about-face in the official recommendations for prevention of peanut and other food allergies, which emphasized delayed introduction of high-risk foods, especially in high-risk individuals.^5-7 To better understand this shift, we need to briefly explore the context of the addendum guidelines.

As many as one-third of pediatric patients with atopic dermatitis (AD) have food allergies, thus diet often is invoked by patients and providers alike as an underlying cause of the disease.⁸ Many patients in my practice are so focused on potential food allergies that actual treatment of the affected skin is marginalized and often dismissed as a stopgap that does not address the root of the problem. A 2004 study of 100 children with AD found that diet was manipulated by the parents in 75% of patients in an attempt to manage the disease.⁹

Patients are not the only ones who consider food allergies to be a driving force in AD. The medical literature indicates that this theory has existed for centuries; for instance, with regard to the relationship between diet and AD, the author of an article from 1830 quipped, “There is probably no subject in which more deeply rooted convictions have been held . . . than the connection between diet and disease, both as regards the causation and treatment of the latter . . .”¹⁰ More apropos perhaps is a statement from the 2010 National Institute of Allergy and Infectious Diseases guidelines on food allergy management, which noted that while the expert group “does not mean to imply that AD results from [food allergies], the role of [food allergies] in the pathogenesis and severity of this condition remains controversial.”¹¹

Prior to the LEAP study, food allergy recommendations for clinical practice in the United Kingdom in 1998¹² and the United States in 2000¹³ recommended excluding allergenic foods (eg, peanuts, tree nuts, soy, milk, eggs) from the diet in infants with a family history of atopy until 3 years of age. However, those recommendations did not seem to be working, when in fact just the opposite was happening. From 1997 until the LEAP study was conducted in 2015, the prevalence of peanut allergy more than quadrupled and became the leading cause of anaphylaxis and death related to food allergy.¹⁴ Additionally, study after study concluded that elimination diets did not seem to help most patients with AD.¹⁵ As is required in good scientific thinking, when a hypothesis is proven false, other approaches must be considered.

The idea arose that perhaps delaying introduction of allergenic foods was the opposite of the answer.⁴ The LEAP study tested the notion that peanut allergies are rare in countries where peanuts are introduced early and if telling families to delay introduction of peanuts in infants might actually be causing development of a peanut allergy, and the tests bore fruit. It was found that giving infants peanut-containing foods resulted in a more than 80% reduction in peanut allergy at 5 years of age (P<.001).⁴ What was perhaps even more interesting was the connection between AD and peanut allergy. An important idea articulated in the LEAP study is in some ways revolutionary: Rather than foods causing AD, it could be that “early environmental exposure (through the skin) to peanut may account for early sensitization, whereas early oral exposure may lead to immune tolerance.”⁴ This concept—that impaired eczematous skin may actually lead to the development of food allergies—turns the whole thing upside down.

What do these updated guidelines actually suggest? The first guideline focuses on infants with severe AD, egg allergy, or both, who therefore are thought to be at the highest risk for developing peanut allergy.³ Because of the higher baseline risk in this subgroup, measurement of the peanut-specific IgE (peanut sIgE) level, skin prick testing (SPT), or both is strongly recommended before introducing peanut protein into the diet. This testing can be performed by qualified providers as a screening measure, but if positive (≥0.35 kU_A/L for peanut sIgE or >2 mm on the peanut SPT), referral to an allergy specialist is warranted. If these studies are negative, it is thought the likelihood of peanut allergy is low, and it is recommended that caregivers introduce age-appropriate peanut-containing foods (eg, peanut butter snack puffs, diluted peanut butter) as early as 4 to 6 months of age. The second guideline recommends that peanut-containing foods should be introduced into the diets of infants with mild or moderate AD at approximately 6 months of age without the need for prior screening via peanut sIgE or SPT. Lastly, the third guideline recommends that caregivers freely introduce peanut-containing foods together with other solid foods in infants without AD or food allergies in accordance with family preference.³

The results of the LEAP study are certainly exciting, and although the theoretical basis makes good scientific sense and the updated guidelines truly address an important and growing problem, there are several issues with this update that are worth considering. Given the constraints of the LEAP study, it certainly seems possible that the results will not be applicable to all populations or foods. More research is needed to ensure that this robust finding applies to other children and to explore the introduction of other allergenic foods, which the LEAP study investigators also emphasized.⁴

In fairness, the updated guidelines clearly state the quality of evidence of their recommendations and make it clear that expert opinion is playing a large role.³ For the first guideline regarding recommendations for those with severe AD and/or egg allergy, the quality of evidence is deemed moderate, while the contribution of expert opinion is listed as significant. For the second and third guidelines regarding recommendations for mild to moderate AD and those without AD, respectively, the quality of evidence is low and expert opinion is again listed as significant.³

Importantly, delineating severe AD from moderate disease—which is necessary because only severe AD warrants evaluation with peanut sIgE and/or SPT—can be difficult, as the distinction relies on a degree of subjectivity that may vary between specialists. Indeed, 2 publications suggest extending the definition of severe AD to include infants with early-onset AD (<3 months of age) and those with moderate AD not responding to treatment.^16,17

Despite these reservations, the updated guidelines represent a breakthrough in understanding in an area truly in need of advancement. Although the evidence may not be exactly extraordinary, the context for these developments and our deeper understanding suggest that we do indeed live in extraordinary times. 

It has been said that “extraordinary claims require extraordinary evidence.”¹ In the pursuit of evidence-based medicine, we are encouraged to follow a similar standard, with an emphasis on waiting for multiple studies with good-quality data and high levels of agreement before changing any aspect of our clinical practice. The ostensible purpose is that studies can be flawed, conclusions can be incorrect, or biases can be overlooked. In such cases, acting on questionable results could imperil patients. It is for this reason that so many review articles sometimes frustratingly seem to conclude that further evidence is needed.²

Based on this standard, recently published addendum guidelines from the National Institute of Allergy and Infectious Diseases for prevention of peanut allergy in the United States³ are somewhat striking in that they make fairly bold recommendations based on results from the 2015 Learning Early about Peanut Allergy (LEAP) study,⁴ a randomized trial evaluating early peanut introduction as a preventive strategy for peanut allergy. Of note, this study was not placebo controlled, was conducted at only 1 site in the United Kingdom, and only included 640 children, though the number of participants was admittedly large for this type of study.⁴ Arguably, the LEAP study alone does not provide enough evidence upon which to base what essentially amounts to an about-face in the official recommendations for prevention of peanut and other food allergies, which emphasized delayed introduction of high-risk foods, especially in high-risk individuals.^5-7 To better understand this shift, we need to briefly explore the context of the addendum guidelines.

As many as one-third of pediatric patients with atopic dermatitis (AD) have food allergies, thus diet often is invoked by patients and providers alike as an underlying cause of the disease.⁸ Many patients in my practice are so focused on potential food allergies that actual treatment of the affected skin is marginalized and often dismissed as a stopgap that does not address the root of the problem. A 2004 study of 100 children with AD found that diet was manipulated by the parents in 75% of patients in an attempt to manage the disease.⁹

Patients are not the only ones who consider food allergies to be a driving force in AD. The medical literature indicates that this theory has existed for centuries; for instance, with regard to the relationship between diet and AD, the author of an article from 1830 quipped, “There is probably no subject in which more deeply rooted convictions have been held . . . than the connection between diet and disease, both as regards the causation and treatment of the latter . . .”¹⁰ More apropos perhaps is a statement from the 2010 National Institute of Allergy and Infectious Diseases guidelines on food allergy management, which noted that while the expert group “does not mean to imply that AD results from [food allergies], the role of [food allergies] in the pathogenesis and severity of this condition remains controversial.”¹¹

Prior to the LEAP study, food allergy recommendations for clinical practice in the United Kingdom in 1998¹² and the United States in 2000¹³ recommended excluding allergenic foods (eg, peanuts, tree nuts, soy, milk, eggs) from the diet in infants with a family history of atopy until 3 years of age. However, those recommendations did not seem to be working, when in fact just the opposite was happening. From 1997 until the LEAP study was conducted in 2015, the prevalence of peanut allergy more than quadrupled and became the leading cause of anaphylaxis and death related to food allergy.¹⁴ Additionally, study after study concluded that elimination diets did not seem to help most patients with AD.¹⁵ As is required in good scientific thinking, when a hypothesis is proven false, other approaches must be considered.

The idea arose that perhaps delaying introduction of allergenic foods was the opposite of the answer.⁴ The LEAP study tested the notion that peanut allergies are rare in countries where peanuts are introduced early and if telling families to delay introduction of peanuts in infants might actually be causing development of a peanut allergy, and the tests bore fruit. It was found that giving infants peanut-containing foods resulted in a more than 80% reduction in peanut allergy at 5 years of age (P<.001).⁴ What was perhaps even more interesting was the connection between AD and peanut allergy. An important idea articulated in the LEAP study is in some ways revolutionary: Rather than foods causing AD, it could be that “early environmental exposure (through the skin) to peanut may account for early sensitization, whereas early oral exposure may lead to immune tolerance.”⁴ This concept—that impaired eczematous skin may actually lead to the development of food allergies—turns the whole thing upside down.

What do these updated guidelines actually suggest? The first guideline focuses on infants with severe AD, egg allergy, or both, who therefore are thought to be at the highest risk for developing peanut allergy.³ Because of the higher baseline risk in this subgroup, measurement of the peanut-specific IgE (peanut sIgE) level, skin prick testing (SPT), or both is strongly recommended before introducing peanut protein into the diet. This testing can be performed by qualified providers as a screening measure, but if positive (≥0.35 kU_A/L for peanut sIgE or >2 mm on the peanut SPT), referral to an allergy specialist is warranted. If these studies are negative, it is thought the likelihood of peanut allergy is low, and it is recommended that caregivers introduce age-appropriate peanut-containing foods (eg, peanut butter snack puffs, diluted peanut butter) as early as 4 to 6 months of age. The second guideline recommends that peanut-containing foods should be introduced into the diets of infants with mild or moderate AD at approximately 6 months of age without the need for prior screening via peanut sIgE or SPT. Lastly, the third guideline recommends that caregivers freely introduce peanut-containing foods together with other solid foods in infants without AD or food allergies in accordance with family preference.³

The results of the LEAP study are certainly exciting, and although the theoretical basis makes good scientific sense and the updated guidelines truly address an important and growing problem, there are several issues with this update that are worth considering. Given the constraints of the LEAP study, it certainly seems possible that the results will not be applicable to all populations or foods. More research is needed to ensure that this robust finding applies to other children and to explore the introduction of other allergenic foods, which the LEAP study investigators also emphasized.⁴

In fairness, the updated guidelines clearly state the quality of evidence of their recommendations and make it clear that expert opinion is playing a large role.³ For the first guideline regarding recommendations for those with severe AD and/or egg allergy, the quality of evidence is deemed moderate, while the contribution of expert opinion is listed as significant. For the second and third guidelines regarding recommendations for mild to moderate AD and those without AD, respectively, the quality of evidence is low and expert opinion is again listed as significant.³

Importantly, delineating severe AD from moderate disease—which is necessary because only severe AD warrants evaluation with peanut sIgE and/or SPT—can be difficult, as the distinction relies on a degree of subjectivity that may vary between specialists. Indeed, 2 publications suggest extending the definition of severe AD to include infants with early-onset AD (<3 months of age) and those with moderate AD not responding to treatment.^16,17

Despite these reservations, the updated guidelines represent a breakthrough in understanding in an area truly in need of advancement. Although the evidence may not be exactly extraordinary, the context for these developments and our deeper understanding suggest that we do indeed live in extraordinary times. 

It has been said that “extraordinary claims require extraordinary evidence.”¹ In the pursuit of evidence-based medicine, we are encouraged to follow a similar standard, with an emphasis on waiting for multiple studies with good-quality data and high levels of agreement before changing any aspect of our clinical practice. The ostensible purpose is that studies can be flawed, conclusions can be incorrect, or biases can be overlooked. In such cases, acting on questionable results could imperil patients. It is for this reason that so many review articles sometimes frustratingly seem to conclude that further evidence is needed.²

Based on this standard, recently published addendum guidelines from the National Institute of Allergy and Infectious Diseases for prevention of peanut allergy in the United States³ are somewhat striking in that they make fairly bold recommendations based on results from the 2015 Learning Early about Peanut Allergy (LEAP) study,⁴ a randomized trial evaluating early peanut introduction as a preventive strategy for peanut allergy. Of note, this study was not placebo controlled, was conducted at only 1 site in the United Kingdom, and only included 640 children, though the number of participants was admittedly large for this type of study.⁴ Arguably, the LEAP study alone does not provide enough evidence upon which to base what essentially amounts to an about-face in the official recommendations for prevention of peanut and other food allergies, which emphasized delayed introduction of high-risk foods, especially in high-risk individuals.^5-7 To better understand this shift, we need to briefly explore the context of the addendum guidelines.

As many as one-third of pediatric patients with atopic dermatitis (AD) have food allergies, thus diet often is invoked by patients and providers alike as an underlying cause of the disease.⁸ Many patients in my practice are so focused on potential food allergies that actual treatment of the affected skin is marginalized and often dismissed as a stopgap that does not address the root of the problem. A 2004 study of 100 children with AD found that diet was manipulated by the parents in 75% of patients in an attempt to manage the disease.⁹

Patients are not the only ones who consider food allergies to be a driving force in AD. The medical literature indicates that this theory has existed for centuries; for instance, with regard to the relationship between diet and AD, the author of an article from 1830 quipped, “There is probably no subject in which more deeply rooted convictions have been held . . . than the connection between diet and disease, both as regards the causation and treatment of the latter . . .”¹⁰ More apropos perhaps is a statement from the 2010 National Institute of Allergy and Infectious Diseases guidelines on food allergy management, which noted that while the expert group “does not mean to imply that AD results from [food allergies], the role of [food allergies] in the pathogenesis and severity of this condition remains controversial.”¹¹

Prior to the LEAP study, food allergy recommendations for clinical practice in the United Kingdom in 1998¹² and the United States in 2000¹³ recommended excluding allergenic foods (eg, peanuts, tree nuts, soy, milk, eggs) from the diet in infants with a family history of atopy until 3 years of age. However, those recommendations did not seem to be working, when in fact just the opposite was happening. From 1997 until the LEAP study was conducted in 2015, the prevalence of peanut allergy more than quadrupled and became the leading cause of anaphylaxis and death related to food allergy.¹⁴ Additionally, study after study concluded that elimination diets did not seem to help most patients with AD.¹⁵ As is required in good scientific thinking, when a hypothesis is proven false, other approaches must be considered.

The idea arose that perhaps delaying introduction of allergenic foods was the opposite of the answer.⁴ The LEAP study tested the notion that peanut allergies are rare in countries where peanuts are introduced early and if telling families to delay introduction of peanuts in infants might actually be causing development of a peanut allergy, and the tests bore fruit. It was found that giving infants peanut-containing foods resulted in a more than 80% reduction in peanut allergy at 5 years of age (P<.001).⁴ What was perhaps even more interesting was the connection between AD and peanut allergy. An important idea articulated in the LEAP study is in some ways revolutionary: Rather than foods causing AD, it could be that “early environmental exposure (through the skin) to peanut may account for early sensitization, whereas early oral exposure may lead to immune tolerance.”⁴ This concept—that impaired eczematous skin may actually lead to the development of food allergies—turns the whole thing upside down.

What do these updated guidelines actually suggest? The first guideline focuses on infants with severe AD, egg allergy, or both, who therefore are thought to be at the highest risk for developing peanut allergy.³ Because of the higher baseline risk in this subgroup, measurement of the peanut-specific IgE (peanut sIgE) level, skin prick testing (SPT), or both is strongly recommended before introducing peanut protein into the diet. This testing can be performed by qualified providers as a screening measure, but if positive (≥0.35 kU_A/L for peanut sIgE or >2 mm on the peanut SPT), referral to an allergy specialist is warranted. If these studies are negative, it is thought the likelihood of peanut allergy is low, and it is recommended that caregivers introduce age-appropriate peanut-containing foods (eg, peanut butter snack puffs, diluted peanut butter) as early as 4 to 6 months of age. The second guideline recommends that peanut-containing foods should be introduced into the diets of infants with mild or moderate AD at approximately 6 months of age without the need for prior screening via peanut sIgE or SPT. Lastly, the third guideline recommends that caregivers freely introduce peanut-containing foods together with other solid foods in infants without AD or food allergies in accordance with family preference.³

The results of the LEAP study are certainly exciting, and although the theoretical basis makes good scientific sense and the updated guidelines truly address an important and growing problem, there are several issues with this update that are worth considering. Given the constraints of the LEAP study, it certainly seems possible that the results will not be applicable to all populations or foods. More research is needed to ensure that this robust finding applies to other children and to explore the introduction of other allergenic foods, which the LEAP study investigators also emphasized.⁴

In fairness, the updated guidelines clearly state the quality of evidence of their recommendations and make it clear that expert opinion is playing a large role.³ For the first guideline regarding recommendations for those with severe AD and/or egg allergy, the quality of evidence is deemed moderate, while the contribution of expert opinion is listed as significant. For the second and third guidelines regarding recommendations for mild to moderate AD and those without AD, respectively, the quality of evidence is low and expert opinion is again listed as significant.³

Importantly, delineating severe AD from moderate disease—which is necessary because only severe AD warrants evaluation with peanut sIgE and/or SPT—can be difficult, as the distinction relies on a degree of subjectivity that may vary between specialists. Indeed, 2 publications suggest extending the definition of severe AD to include infants with early-onset AD (<3 months of age) and those with moderate AD not responding to treatment.^16,17

Despite these reservations, the updated guidelines represent a breakthrough in understanding in an area truly in need of advancement. Although the evidence may not be exactly extraordinary, the context for these developments and our deeper understanding suggest that we do indeed live in extraordinary times. 

A 56-year-old man presents for his annual physical. He brings in blood work done for all employees in his workplace (he is an aerospace engineer), and wants to talk about the lab that has an asterisk by it. All his labs are normal, except that his mean corpuscular volume (MCV) is 101. His hematocrit (HCT) is 42. He has no symptoms and a normal physical exam.

What test or tests would most likely be abnormal?

A. Thyroid-stimulating hormone.

B. Vitamin B₁₂/folate.

C. Testosterone.

D. Gamma-glutamyl-transferase (GGT).

The finding of macrocytosis is fairly common in primary care, estimated to be found in 3% of complete blood count results.¹ Most students in medical school quickly learn that vitamin B₁₂ and folate deficiency can cause macrocytic anemias. The standard workups for patients with macrocytosis began and ended with checking vitamin B₁₂ and folate levels, which are usually normal in the vast majority of patients with macrocytosis.

For this patient, the correct answer would be an abnormal GGT, because chronic moderate to heavy alcohol use can raise GGT levels, as well as MCVs.

Dr. David Savage and colleagues evaluated the etiology of macrocytosis in 300 consecutive hospitalized patients with macrocytosis.² They found that the most common causes were medications, alcohol, liver disease, and reticulocytosis. The study was done in New York and was published in 2000, so zidovudine (AZT) was a common medication cause of the macrocytosis. This medication is much less commonly used today. Zidovudine causes macrocytosis in more than 80% of patients who take it. They also found in the study that very high MCVs (> 120) were most commonly associated with vitamin B₁₂ deficiency.

Dr. Kaija Seppä and colleagues looked at all outpatients who had a blood count done over an 8-month period. A total of 9,527 blood counts were ordered, and 287 (3%) had macrocytosis.¹ Further workup was done for 113 of the patients. The most common cause found for macrocytosis was alcohol abuse, in 74 (65%) of the patients (80% of the men and 36% of the women). No cause of the macrocytosis was found in 24 (21%) of the patients.

Dr. A. Wymer and colleagues looked at 2,800 adult outpatients who had complete blood counts. A total of 138 (3.7%) had macrocytosis, with 128 of these patients having charts that could be reviewed.³ A total of 73 patients had a workup for their macrocytosis. Alcohol was the diagnostic cause of the macrocytosis in 47 (64%). Only five of the patients had B₁₂ deficiency (7%).

Pearl: Strongly consider alcohol as the cause of the incidental finding of macrocytosis, especially in patients without anemia.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the university. Contact Dr. Paauw at [email protected].

References

1. J Stud Alcohol. 1996 Jan;57(1):97-100.

2. Am J Med Sci. 2000 Jun;319(6):343-52.

3. J Gen Intern Med. 1990 May-Jun;5(3):192-7.

4. Alcohol. 1993 Sep-Oct;10(5):343-7.

5. South Med J. 2013 Feb;106(2):121-5.

A 56-year-old man presents for his annual physical. He brings in blood work done for all employees in his workplace (he is an aerospace engineer), and wants to talk about the lab that has an asterisk by it. All his labs are normal, except that his mean corpuscular volume (MCV) is 101. His hematocrit (HCT) is 42. He has no symptoms and a normal physical exam.

What test or tests would most likely be abnormal?

A. Thyroid-stimulating hormone.

B. Vitamin B₁₂/folate.

C. Testosterone.

D. Gamma-glutamyl-transferase (GGT).

The finding of macrocytosis is fairly common in primary care, estimated to be found in 3% of complete blood count results.¹ Most students in medical school quickly learn that vitamin B₁₂ and folate deficiency can cause macrocytic anemias. The standard workups for patients with macrocytosis began and ended with checking vitamin B₁₂ and folate levels, which are usually normal in the vast majority of patients with macrocytosis.

For this patient, the correct answer would be an abnormal GGT, because chronic moderate to heavy alcohol use can raise GGT levels, as well as MCVs.

Dr. David Savage and colleagues evaluated the etiology of macrocytosis in 300 consecutive hospitalized patients with macrocytosis.² They found that the most common causes were medications, alcohol, liver disease, and reticulocytosis. The study was done in New York and was published in 2000, so zidovudine (AZT) was a common medication cause of the macrocytosis. This medication is much less commonly used today. Zidovudine causes macrocytosis in more than 80% of patients who take it. They also found in the study that very high MCVs (> 120) were most commonly associated with vitamin B₁₂ deficiency.

Dr. Kaija Seppä and colleagues looked at all outpatients who had a blood count done over an 8-month period. A total of 9,527 blood counts were ordered, and 287 (3%) had macrocytosis.¹ Further workup was done for 113 of the patients. The most common cause found for macrocytosis was alcohol abuse, in 74 (65%) of the patients (80% of the men and 36% of the women). No cause of the macrocytosis was found in 24 (21%) of the patients.

Dr. A. Wymer and colleagues looked at 2,800 adult outpatients who had complete blood counts. A total of 138 (3.7%) had macrocytosis, with 128 of these patients having charts that could be reviewed.³ A total of 73 patients had a workup for their macrocytosis. Alcohol was the diagnostic cause of the macrocytosis in 47 (64%). Only five of the patients had B₁₂ deficiency (7%).

Pearl: Strongly consider alcohol as the cause of the incidental finding of macrocytosis, especially in patients without anemia.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the university. Contact Dr. Paauw at [email protected].

References

1. J Stud Alcohol. 1996 Jan;57(1):97-100.

2. Am J Med Sci. 2000 Jun;319(6):343-52.

3. J Gen Intern Med. 1990 May-Jun;5(3):192-7.

4. Alcohol. 1993 Sep-Oct;10(5):343-7.

5. South Med J. 2013 Feb;106(2):121-5.

A 56-year-old man presents for his annual physical. He brings in blood work done for all employees in his workplace (he is an aerospace engineer), and wants to talk about the lab that has an asterisk by it. All his labs are normal, except that his mean corpuscular volume (MCV) is 101. His hematocrit (HCT) is 42. He has no symptoms and a normal physical exam.

What test or tests would most likely be abnormal?

A. Thyroid-stimulating hormone.

B. Vitamin B₁₂/folate.

C. Testosterone.

D. Gamma-glutamyl-transferase (GGT).

The finding of macrocytosis is fairly common in primary care, estimated to be found in 3% of complete blood count results.¹ Most students in medical school quickly learn that vitamin B₁₂ and folate deficiency can cause macrocytic anemias. The standard workups for patients with macrocytosis began and ended with checking vitamin B₁₂ and folate levels, which are usually normal in the vast majority of patients with macrocytosis.

For this patient, the correct answer would be an abnormal GGT, because chronic moderate to heavy alcohol use can raise GGT levels, as well as MCVs.

Dr. David Savage and colleagues evaluated the etiology of macrocytosis in 300 consecutive hospitalized patients with macrocytosis.² They found that the most common causes were medications, alcohol, liver disease, and reticulocytosis. The study was done in New York and was published in 2000, so zidovudine (AZT) was a common medication cause of the macrocytosis. This medication is much less commonly used today. Zidovudine causes macrocytosis in more than 80% of patients who take it. They also found in the study that very high MCVs (> 120) were most commonly associated with vitamin B₁₂ deficiency.

Dr. Kaija Seppä and colleagues looked at all outpatients who had a blood count done over an 8-month period. A total of 9,527 blood counts were ordered, and 287 (3%) had macrocytosis.¹ Further workup was done for 113 of the patients. The most common cause found for macrocytosis was alcohol abuse, in 74 (65%) of the patients (80% of the men and 36% of the women). No cause of the macrocytosis was found in 24 (21%) of the patients.

Dr. A. Wymer and colleagues looked at 2,800 adult outpatients who had complete blood counts. A total of 138 (3.7%) had macrocytosis, with 128 of these patients having charts that could be reviewed.³ A total of 73 patients had a workup for their macrocytosis. Alcohol was the diagnostic cause of the macrocytosis in 47 (64%). Only five of the patients had B₁₂ deficiency (7%).

Pearl: Strongly consider alcohol as the cause of the incidental finding of macrocytosis, especially in patients without anemia.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the university. Contact Dr. Paauw at [email protected].

References

1. J Stud Alcohol. 1996 Jan;57(1):97-100.

2. Am J Med Sci. 2000 Jun;319(6):343-52.

3. J Gen Intern Med. 1990 May-Jun;5(3):192-7.

4. Alcohol. 1993 Sep-Oct;10(5):343-7.

5. South Med J. 2013 Feb;106(2):121-5.

Just over a year ago, I established a solo colorectal surgery clinic within a comprehensive academic medical center hospital system and have since seen a variety of cases: benign anorectal conditions, acute and chronic diseases, complex defecatory dysfunction, and colorectal surgery pre- and postop patients. I also manage a colorectal cancer survivorship clinic. As a PA in this field, I very much appreciated the November 2017 CE/CME, “Anorectal Evaluations: Diagnosing & Treating Benign Conditions” (Clinician Reviews. 2017;27[11]:28-37). The article offered useful highlights and clinical pearls for diagnosing common anorectal conditions. It supplied corresponding images for quick reference, discussed the need for a thorough history, and detailed the finesse of the often-dreaded-yet-so-important physical exam, reassuring providers that the majority of anorectal complaints are, indeed, benign and often treatable on first visit. However, the latter is contingent on one key factor: Are you willing to look?

Primary care is typically a patient’s first stop when experiencing anorectal symptoms. If you see a high volume of these cases and are comfortable and confident in your exam skills, the patient is likely well-served. But because it is not expected of general practitioners to have the experience or knowledge to recognize or discern the more minute features of anorectal atypia, I fully advocate the “when in doubt, refer it out” mentality without hesitation or judgement—and I quickly learned the importance of a quality referral network when I established my own clinic.

What concerns me, though, is how often a referral is made with no mention of an anorectal exam in the office note. I can certainly make a rare exception for the exam that mistakenly did not get recorded, but ultimately, if it wasn’t documented, it didn’t happen, right? And when questioned, most of these patients report that the referring provider didn’t look!

The greater issue therein occurs when a provider who doesn’t perform a physical exam recommends a course of treatment. For example—I see this on a weekly basis—a provider may prescribe a rectal preparation ointment for a patient complaining of “hemorrhoids.” Sometimes, that initial appointment is the only one before the patient is referred to my office; more often, the patient is subject to multiple office visits and excessive trials of prescription and/or homeopathic remedies before a referral is finally made. And all of this occurs without a proper exam!

The patient being treated for a presumed diagnosis of hemorrhoids may have a completely different problem altogether—if only the provider had looked. Optimistically, the patient may have an anal fissure, and the only downfall is a delay in appropriate treatment and symptom resolution. Unfortunately, grimmer outcomes can—and often do—result. I have diagnosed several cases of anal squamous cell cancer from referrals of this nature.

What’s more, recent studies have found that the incidence of anal cancer (all ages) and of colorectal cancer (adults ages 20-54) is on the rise.^1,2 And because both may manifest with mild or seemingly benign symptoms, such as rectal bleeding, anorectal pain, or a change in bowel habits, making an early and accurate diagnosis can be challenging.

These data reinforce my belief that referral to a trusted colorectal specialist with whom you can easily communicate is the best option if any doubt exists. As a provider, I would rather see a patient who is urgently referred for what turns out to be a benign condition than diagnose a serious problem, such as cancer, in a patient who has been lost in the shuffle.

Continue to: Of course, the key in all this is...

Of course, the key in all this is the relationship you establish with your patients. In my case, building relationships with my patients encourages them to more freely discuss anorectal concerns and allows me to regularly perform necessary exams. Since I’ve created my own clinic, I also have the “luxury” (I would call it the responsibility) of maintaining a flexible schedule. Many practice settings accommodate same-day or urgent appointments, but I can assure you that patients with anorectal complaints offer a unique expression of urgency when they call with colorful phrases to describe their pain. My referral coordinator, schedulers, and triage nurses can reach me anytime during the workday; I even see patients during non-clinic time if I’m available and it is appropriate. I know that not everyone can implement this practice the way I can, but putting patients first is part of providing quality care—and it often requires flexibility.

At the very least, I encourage you to read the CE/CME article that sparked this commentary. Incorporate the techniques into your patient care when someone presents with anorectal discomfort. In short, be willing to look. You never know when you might save a life!

Just over a year ago, I established a solo colorectal surgery clinic within a comprehensive academic medical center hospital system and have since seen a variety of cases: benign anorectal conditions, acute and chronic diseases, complex defecatory dysfunction, and colorectal surgery pre- and postop patients. I also manage a colorectal cancer survivorship clinic. As a PA in this field, I very much appreciated the November 2017 CE/CME, “Anorectal Evaluations: Diagnosing & Treating Benign Conditions” (Clinician Reviews. 2017;27[11]:28-37). The article offered useful highlights and clinical pearls for diagnosing common anorectal conditions. It supplied corresponding images for quick reference, discussed the need for a thorough history, and detailed the finesse of the often-dreaded-yet-so-important physical exam, reassuring providers that the majority of anorectal complaints are, indeed, benign and often treatable on first visit. However, the latter is contingent on one key factor: Are you willing to look?

Primary care is typically a patient’s first stop when experiencing anorectal symptoms. If you see a high volume of these cases and are comfortable and confident in your exam skills, the patient is likely well-served. But because it is not expected of general practitioners to have the experience or knowledge to recognize or discern the more minute features of anorectal atypia, I fully advocate the “when in doubt, refer it out” mentality without hesitation or judgement—and I quickly learned the importance of a quality referral network when I established my own clinic.

What concerns me, though, is how often a referral is made with no mention of an anorectal exam in the office note. I can certainly make a rare exception for the exam that mistakenly did not get recorded, but ultimately, if it wasn’t documented, it didn’t happen, right? And when questioned, most of these patients report that the referring provider didn’t look!

The greater issue therein occurs when a provider who doesn’t perform a physical exam recommends a course of treatment. For example—I see this on a weekly basis—a provider may prescribe a rectal preparation ointment for a patient complaining of “hemorrhoids.” Sometimes, that initial appointment is the only one before the patient is referred to my office; more often, the patient is subject to multiple office visits and excessive trials of prescription and/or homeopathic remedies before a referral is finally made. And all of this occurs without a proper exam!

The patient being treated for a presumed diagnosis of hemorrhoids may have a completely different problem altogether—if only the provider had looked. Optimistically, the patient may have an anal fissure, and the only downfall is a delay in appropriate treatment and symptom resolution. Unfortunately, grimmer outcomes can—and often do—result. I have diagnosed several cases of anal squamous cell cancer from referrals of this nature.

What’s more, recent studies have found that the incidence of anal cancer (all ages) and of colorectal cancer (adults ages 20-54) is on the rise.^1,2 And because both may manifest with mild or seemingly benign symptoms, such as rectal bleeding, anorectal pain, or a change in bowel habits, making an early and accurate diagnosis can be challenging.

These data reinforce my belief that referral to a trusted colorectal specialist with whom you can easily communicate is the best option if any doubt exists. As a provider, I would rather see a patient who is urgently referred for what turns out to be a benign condition than diagnose a serious problem, such as cancer, in a patient who has been lost in the shuffle.

Continue to: Of course, the key in all this is...

Of course, the key in all this is the relationship you establish with your patients. In my case, building relationships with my patients encourages them to more freely discuss anorectal concerns and allows me to regularly perform necessary exams. Since I’ve created my own clinic, I also have the “luxury” (I would call it the responsibility) of maintaining a flexible schedule. Many practice settings accommodate same-day or urgent appointments, but I can assure you that patients with anorectal complaints offer a unique expression of urgency when they call with colorful phrases to describe their pain. My referral coordinator, schedulers, and triage nurses can reach me anytime during the workday; I even see patients during non-clinic time if I’m available and it is appropriate. I know that not everyone can implement this practice the way I can, but putting patients first is part of providing quality care—and it often requires flexibility.

At the very least, I encourage you to read the CE/CME article that sparked this commentary. Incorporate the techniques into your patient care when someone presents with anorectal discomfort. In short, be willing to look. You never know when you might save a life!

Just over a year ago, I established a solo colorectal surgery clinic within a comprehensive academic medical center hospital system and have since seen a variety of cases: benign anorectal conditions, acute and chronic diseases, complex defecatory dysfunction, and colorectal surgery pre- and postop patients. I also manage a colorectal cancer survivorship clinic. As a PA in this field, I very much appreciated the November 2017 CE/CME, “Anorectal Evaluations: Diagnosing & Treating Benign Conditions” (Clinician Reviews. 2017;27[11]:28-37). The article offered useful highlights and clinical pearls for diagnosing common anorectal conditions. It supplied corresponding images for quick reference, discussed the need for a thorough history, and detailed the finesse of the often-dreaded-yet-so-important physical exam, reassuring providers that the majority of anorectal complaints are, indeed, benign and often treatable on first visit. However, the latter is contingent on one key factor: Are you willing to look?

Primary care is typically a patient’s first stop when experiencing anorectal symptoms. If you see a high volume of these cases and are comfortable and confident in your exam skills, the patient is likely well-served. But because it is not expected of general practitioners to have the experience or knowledge to recognize or discern the more minute features of anorectal atypia, I fully advocate the “when in doubt, refer it out” mentality without hesitation or judgement—and I quickly learned the importance of a quality referral network when I established my own clinic.

What concerns me, though, is how often a referral is made with no mention of an anorectal exam in the office note. I can certainly make a rare exception for the exam that mistakenly did not get recorded, but ultimately, if it wasn’t documented, it didn’t happen, right? And when questioned, most of these patients report that the referring provider didn’t look!

The greater issue therein occurs when a provider who doesn’t perform a physical exam recommends a course of treatment. For example—I see this on a weekly basis—a provider may prescribe a rectal preparation ointment for a patient complaining of “hemorrhoids.” Sometimes, that initial appointment is the only one before the patient is referred to my office; more often, the patient is subject to multiple office visits and excessive trials of prescription and/or homeopathic remedies before a referral is finally made. And all of this occurs without a proper exam!

The patient being treated for a presumed diagnosis of hemorrhoids may have a completely different problem altogether—if only the provider had looked. Optimistically, the patient may have an anal fissure, and the only downfall is a delay in appropriate treatment and symptom resolution. Unfortunately, grimmer outcomes can—and often do—result. I have diagnosed several cases of anal squamous cell cancer from referrals of this nature.

What’s more, recent studies have found that the incidence of anal cancer (all ages) and of colorectal cancer (adults ages 20-54) is on the rise.^1,2 And because both may manifest with mild or seemingly benign symptoms, such as rectal bleeding, anorectal pain, or a change in bowel habits, making an early and accurate diagnosis can be challenging.

These data reinforce my belief that referral to a trusted colorectal specialist with whom you can easily communicate is the best option if any doubt exists. As a provider, I would rather see a patient who is urgently referred for what turns out to be a benign condition than diagnose a serious problem, such as cancer, in a patient who has been lost in the shuffle.

Continue to: Of course, the key in all this is...

Of course, the key in all this is the relationship you establish with your patients. In my case, building relationships with my patients encourages them to more freely discuss anorectal concerns and allows me to regularly perform necessary exams. Since I’ve created my own clinic, I also have the “luxury” (I would call it the responsibility) of maintaining a flexible schedule. Many practice settings accommodate same-day or urgent appointments, but I can assure you that patients with anorectal complaints offer a unique expression of urgency when they call with colorful phrases to describe their pain. My referral coordinator, schedulers, and triage nurses can reach me anytime during the workday; I even see patients during non-clinic time if I’m available and it is appropriate. I know that not everyone can implement this practice the way I can, but putting patients first is part of providing quality care—and it often requires flexibility.

At the very least, I encourage you to read the CE/CME article that sparked this commentary. Incorporate the techniques into your patient care when someone presents with anorectal discomfort. In short, be willing to look. You never know when you might save a life!

Where did you learn about nutrition? Was it primarily at home supplemented by a few teachers as you navigated K through 12? Studies have shown that it probably wasn’t during medical school (“How much does your doctor actually know about nutrition?” American Heart Association News, April 30, 2018). A survey of one-third of medicals schools done in 1985 found “inadequate exposure to nutrition,” which prompted the National Academy of Sciences to recommend a minimum of 25 classroom hours. A more recent survey in 2013 discovered that 71% percent of medical schools fail to meet that benchmark.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

Where did you learn about nutrition? Was it primarily at home supplemented by a few teachers as you navigated K through 12? Studies have shown that it probably wasn’t during medical school (“How much does your doctor actually know about nutrition?” American Heart Association News, April 30, 2018). A survey of one-third of medicals schools done in 1985 found “inadequate exposure to nutrition,” which prompted the National Academy of Sciences to recommend a minimum of 25 classroom hours. A more recent survey in 2013 discovered that 71% percent of medical schools fail to meet that benchmark.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

Where did you learn about nutrition? Was it primarily at home supplemented by a few teachers as you navigated K through 12? Studies have shown that it probably wasn’t during medical school (“How much does your doctor actually know about nutrition?” American Heart Association News, April 30, 2018). A survey of one-third of medicals schools done in 1985 found “inadequate exposure to nutrition,” which prompted the National Academy of Sciences to recommend a minimum of 25 classroom hours. A more recent survey in 2013 discovered that 71% percent of medical schools fail to meet that benchmark.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

Like most couples of retirement age, rituals dominate our breakfasts. I eat eggs. Marilyn leans toward baked goods. We each have a bowl of fruit and finish by working the New York Times mini-crossword on our electronic devices. Solving it usually takes somewhere between 40 seconds and 4 minutes. The challenge lies in how fast one can complete the puzzle. And, being who we are, Marilyn and I have ritualized this into a serious competition. She usually takes the first turn and then tries to psyche me out by announcing, “I did it in 2:34, but you should be able to solve it in less than 2 minutes.” This bit of gamesmanship often means that I am going to start the day with thin layer of nervous perspiration.

Antonio_Diaz/thinkstockphotos

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

Like most couples of retirement age, rituals dominate our breakfasts. I eat eggs. Marilyn leans toward baked goods. We each have a bowl of fruit and finish by working the New York Times mini-crossword on our electronic devices. Solving it usually takes somewhere between 40 seconds and 4 minutes. The challenge lies in how fast one can complete the puzzle. And, being who we are, Marilyn and I have ritualized this into a serious competition. She usually takes the first turn and then tries to psyche me out by announcing, “I did it in 2:34, but you should be able to solve it in less than 2 minutes.” This bit of gamesmanship often means that I am going to start the day with thin layer of nervous perspiration.

Antonio_Diaz/thinkstockphotos

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

Like most couples of retirement age, rituals dominate our breakfasts. I eat eggs. Marilyn leans toward baked goods. We each have a bowl of fruit and finish by working the New York Times mini-crossword on our electronic devices. Solving it usually takes somewhere between 40 seconds and 4 minutes. The challenge lies in how fast one can complete the puzzle. And, being who we are, Marilyn and I have ritualized this into a serious competition. She usually takes the first turn and then tries to psyche me out by announcing, “I did it in 2:34, but you should be able to solve it in less than 2 minutes.” This bit of gamesmanship often means that I am going to start the day with thin layer of nervous perspiration.

Antonio_Diaz/thinkstockphotos

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

The patient was diagnosed with granuloma annulare on the basis of history and clinical exam. A potassium hydroxide prep of skin scrapings was performed to rule out tinea corporis, and did not show evidence of fungal elements. The patient was treated with topical betamethasone with partial improvement.

First described as a “ringed eruption of the fingers” by Thomas Colcott Fox in 1895, granuloma annulare (GA) is a relatively common, benign, and self-limited condition whose precise etiology remains unclear. It is characterized commonly by pink to violaceous aciform or annular plaques on clinical examination. In some cases of GA, annular lesions are not present, or may be formed of grouped papules.

Courtesy Dr. Catalina Matiz

Courtesy Dr. Catalina Matiz

Mr. Kusari is with the division of pediatric and adolescent dermatology, Rady Children’s Hospital, San Diego, and the departments of dermatology and pediatrics, University of California, San Diego. Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. They reported having no conflicts of interest.

References

1. J Am Acad Dermatol. 1980 Sep;3(3):217-30.

2. J Am Acad Dermatol. 2016 Sep;75(3):457-65.

3. Dermatol Online J. 2013 Dec 16;19(12):20719.

4. Acta Derm Venereol. 2008;88(5):519-20.

5. J Cutan Med Surg. 2014 Nov;18(6):413-9.

6. South Med J. 1997 Oct;90(10):1056-9.

7. Am J Dermatopathol. 2003 Apr;25(2):113-6.

8. Am J Clin Dermatol. 2013 Aug;14(4):279-90.

9. Br J Dermatol. 1994 Apr;130(4):494-7.

The patient was diagnosed with granuloma annulare on the basis of history and clinical exam. A potassium hydroxide prep of skin scrapings was performed to rule out tinea corporis, and did not show evidence of fungal elements. The patient was treated with topical betamethasone with partial improvement.

First described as a “ringed eruption of the fingers” by Thomas Colcott Fox in 1895, granuloma annulare (GA) is a relatively common, benign, and self-limited condition whose precise etiology remains unclear. It is characterized commonly by pink to violaceous aciform or annular plaques on clinical examination. In some cases of GA, annular lesions are not present, or may be formed of grouped papules.

Courtesy Dr. Catalina Matiz

Courtesy Dr. Catalina Matiz

Mr. Kusari is with the division of pediatric and adolescent dermatology, Rady Children’s Hospital, San Diego, and the departments of dermatology and pediatrics, University of California, San Diego. Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. They reported having no conflicts of interest.

References

1. J Am Acad Dermatol. 1980 Sep;3(3):217-30.

2. J Am Acad Dermatol. 2016 Sep;75(3):457-65.

3. Dermatol Online J. 2013 Dec 16;19(12):20719.

4. Acta Derm Venereol. 2008;88(5):519-20.

5. J Cutan Med Surg. 2014 Nov;18(6):413-9.

6. South Med J. 1997 Oct;90(10):1056-9.

7. Am J Dermatopathol. 2003 Apr;25(2):113-6.

8. Am J Clin Dermatol. 2013 Aug;14(4):279-90.

9. Br J Dermatol. 1994 Apr;130(4):494-7.

The patient was diagnosed with granuloma annulare on the basis of history and clinical exam. A potassium hydroxide prep of skin scrapings was performed to rule out tinea corporis, and did not show evidence of fungal elements. The patient was treated with topical betamethasone with partial improvement.

First described as a “ringed eruption of the fingers” by Thomas Colcott Fox in 1895, granuloma annulare (GA) is a relatively common, benign, and self-limited condition whose precise etiology remains unclear. It is characterized commonly by pink to violaceous aciform or annular plaques on clinical examination. In some cases of GA, annular lesions are not present, or may be formed of grouped papules.

Courtesy Dr. Catalina Matiz

Courtesy Dr. Catalina Matiz

Mr. Kusari is with the division of pediatric and adolescent dermatology, Rady Children’s Hospital, San Diego, and the departments of dermatology and pediatrics, University of California, San Diego. Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. They reported having no conflicts of interest.

References

1. J Am Acad Dermatol. 1980 Sep;3(3):217-30.

2. J Am Acad Dermatol. 2016 Sep;75(3):457-65.

3. Dermatol Online J. 2013 Dec 16;19(12):20719.

4. Acta Derm Venereol. 2008;88(5):519-20.

5. J Cutan Med Surg. 2014 Nov;18(6):413-9.

6. South Med J. 1997 Oct;90(10):1056-9.

7. Am J Dermatopathol. 2003 Apr;25(2):113-6.

8. Am J Clin Dermatol. 2013 Aug;14(4):279-90.

9. Br J Dermatol. 1994 Apr;130(4):494-7.

Four decades after reverse T₃ (3,3´5´-triiodothyronine) was discovered, its physiologic and clinical relevance remains unclear and is still being studied. But scientific uncertainty has not stopped writers in the consumer press and on the Internet from making unsubstantiated claims about this hormone. Many patients believe their hypothyroid symptoms are due to high levels of reverse T₃ and want to be tested for it, and some even bring in test results from independent laboratories.  

HOW THYROID HORMONES WERE DISCOVERED

In 1970, Braverman et al⁹ showed that T₄ is converted to T₃ in athyreotic humans, and Sterling et al¹⁰ demonstrated the same in healthy humans. During that decade, techniques for measuring T₄ were refined,¹¹ and a specific radioimmunoassay for reverse T₃ allowed a glimpse of its physiologic role.¹² In 1975, Chopra et al¹³ noted reciprocal changes in the levels of T₃ and reverse T₃ in systemic illnesses—ie, when people are sick, their T₃ levels go down and their reverse T₃ levels go up.

The end of the 70s was marked by a surge of interest in T₄ metabolites, including the development of a radioimmunoassay for 3,3´-diiodothyronine (3-3´ T₂).¹⁸

The observed reciprocal changes in serum levels of T₃ and reverse T₃ suggested that T₄ degradation is regulated into activating (T₃) or inactivating (reverse T₃) pathways, and that these changes are a presumed homeostatic process of energy conservation.¹⁹

HOW THYROID HORMONES ARE METABOLIZED

In the thyroid gland, for thyroid hormones to be synthesized, iodide must be oxidized and incorporated into the precursors 3-monoiodotyrosine (MIT) and 3,5-diiodotyrosine (DIT). This process is mediated by the enzyme thyroid peroxidase in the presence of hydrogen peroxide.²⁰

The thyroid can make T₄ and some T₃

T₄ is the main iodothyronine produced by the thyroid gland, at a rate of 80 to 100 µg per day.²¹ It is synthesized from the fusion of 2 DIT molecules.

The thyroid can also make T₃ by fusing 1 DIT and 1 MIT molecule, but this process accounts for no more than 20% of the circulating T₃ in humans. The rest of T₃, and 95% to 98% of all reverse T₃, is derived from peripheral conversion of T₄ through deiodination.

T₄ is converted to T₃ or reverse T₃

The metabolic transformation of thyroid hormones in peripheral tissues determines their biologic potency and regulates their biologic effects.

The number 4 in T₄ means it has 4 iodine atoms. It can lose 1 of them, yielding either T₃ or reverse T₃, depending on which iodine atom it loses (Figure 3). Loss of iodine from the five-prime (5´) position on its outer ring yields T₃, the most potent thyroid hormone, produced at a rate of 30 to 40 µg per day.²¹ On the other hand, when T₄ loses an iodine atom from the five (5) position on its inner ring it yields reverse T₃, produced at a rate slightly less than that of T₃, 28 to 40 µg per day.²¹ Reverse T₃ is inactive.

Both T₃ and reverse T₃ can shed more iodine atoms, forming in turn various isomers of T₂, T₁, and ultimately T₀. Other pathways for thyroid hormone metabolism include glucuronidation, sulfation, oxidative deamination, and ether bond cleavage.^20–22

D1 and D2 catalyze T₃, D3 catalyzes reverse T₃

Three types of enzymes that mediate deiodination have been identified and designated D1, D2, and D3. In humans they are expressed in variable amounts throughout the body:

• D1 mainly in the liver, kidneys, thyroid, and pituitary, but notably absent in the central nervous system
• D2 in the central nervous system, pituitary, brown adipose tissue, thyroid, placenta, skeletal muscle, and heart
• D3 in the central nervous system, skin, hemangiomas, fetal liver, placenta, and fetal tissues.²³

D1 and D2 are responsible for converting T₄ to T₃, and D3 is responsible for converting T₄ to reverse T₃.

Plasma concentrations of free T₄ and free T₃ are relatively constant; however, tissue concentrations of free T₃ vary in different tissues according to the amount of hormone transported and the activity of local deiodinases.²³ Most thyroid hormone actions are initiated after T₃ binds to its nuclear receptor. In this setting, deiodinases play a critical role in maintaining tissue and cellular thyroid hormone levels, so that thyroid hormone signaling can change irrespective of serum hormonal concentrations.^22–24 For example, in the central nervous system, production of T₃ by local D2 is significantly relevant for T₃ homeostasis.^22,23

Deiodinases also modulate the tissue-specific concentrations of T₃ in response to iodine deficiency and to changes in thyroid state.²³ During iodine deficiency and hypothyroidism, tissues that express D2, especially brain tissues, increase the activity of this enzyme in order to increase local conversion of T₄ to T₃. In hyperthyroidism, D1 overexpression contributes to the relative excess of T₃ production, while D3 up-regulation in the brain protects the central nervous system from excessive amounts of thyroid hormone.²³

D3 is the main physiologic inactivator of thyroid hormones. This enzyme plays a central role in protecting tissues from an excess of thyroid hormone.^23,24 This mechanism is crucial for fetal development and explains the high expression of D3 in the human placenta and fetal tissues.

In adult tissues, the importance of D3 in the regulation of thyroid hormone homeostasis becomes apparent under certain pathophysiologic conditions, such as nonthyroidal illness and malnutrition.

Whenever a reduction in metabolism is homeostatically desirable, such as in critically ill patients or during starvation, conversion to T₃ is reduced and, alternatively, conversion to reverse T₃ is increased. This pathway represents a metabolic adaptation that may protect the tissues from the catabolic effects of thyroid hormone that could otherwise worsen the patient’s basic clinical condition.

Euthyroid sick syndrome or hypothyroid?

In a variety of systemic illnesses, some patients with low T₃, low or normal T₄, and normal thyroid-stimulating hormone (TSH) levels could in fact be “sick euthyroid” rather than hypothyroid. The first reports of the euthyroid sick syndrome or low T₃ syndrome date back to about 1976, and even though assays for reverse T₃ were not widely available, some authors linked the syndrome to high levels of reverse T₃.^15,16 The syndrome is also known as nonthyroidal illness syndrome.

Advances in techniques for measuring T₃, reverse T₃, and other iodothyronines filled a gap in the understanding of the alterations that occur in thyroid hormone economy during severe nonthyroidal diseases. In 1982, Wartofsky and Burman²⁵ reviewed the alterations in thyroid function in patients with systemic illness and discussed other factors that may alter thyroid economy, such as age, stress, and diverse drugs.

More recently, the low-T₃ syndrome was revisited with a generalized concept regarding the role of D3 in the syndrome.²⁶ D3, normally undetectable in mature tissues, is reactivated in diverse cell types in response to injury and is responsible for a fall in serum T₃ levels. Hypoxia induces D3 activity and mRNA in vitro and in vivo.²⁷ Recent studies have focused on the role of cytokines in the low T₃ syndrome. For instance, interleukin 6 reduces D1 and D2 activity and increases D3 activity in vitro.²⁸

In the outpatient setting, diverse conditions may affect thyroid hormone homeostasis, compatible with mild or atypical forms of low-T₃ syndrome, including caloric deprivation, heart failure, and human immunodeficiency virus infection.²⁹

POSSIBLE CLINICAL UTILITY OF MEASURING REVERSE T₃

In inpatients

Unfortunately, measuring serum reverse T₃ levels has not, in general, proven clinically useful for the diagnosis of hypothyroidism in systemically ill patients. Burmeister³⁰ demonstrated, in a retrospective study, that when illness complicates the interpretation of thyroid function tests, serum reverse T₃ measurements do not reliably distinguish the hypothyroid sick patient from the euthyroid sick patient. The best way to make the diagnosis, Burmeister suggested, is by clinical assessment, combined use of free T₄ and TSH measurements, and patient follow-up.

In the outpatient setting, the utility of reverse T3 measurements is controversial. In intensive care units, the differential diagnosis between hypothyroidism and nonthyroidal illness syndrome can sometimes be difficult. Reverse T₃ levels can be low, normal, or high regardless of the thyroidal state of the patient.³⁰ Moreover, endogenous changes in the hypothalamic-pituitary-thyroid axis may be further complicated by medications commonly used in intensive care units, such as dopamine and glucocorticoids. Changes in thyroid function should be evaluated in the context of the patient’s clinical condition (Table 1).²⁰ But regardless of the T₃ level, treatment with T₃ or T₄ should not be started without taking into consideration the patient’s general clinical context; controlled trials have not shown such therapy to be beneficial.²⁰

In outpatients

In noncritical conditions that may be associated with mild forms of low T₃ syndrome, patients generally present with low T₃ concentrations concurrently with low or normal TSH. Not infrequently, however, patients present with a serum reverse T₃ measurement and impute their symptoms of hypothyroidism to “abnormal” reverse T₃ levels, in spite of normal TSH levels.

There is no rationale for measuring reverse T₃ to initiate or to adjust levothyroxine therapy—the single test relevant for these purposes is the TSH measurement. The risks of basing treatment decisions on reverse T₃ levels include the use of excessive doses of levothyroxine that may lead to a state of subclinical or even clinical hyperthyroidism.

TAKE-HOME MESSAGE

The existence of an inactivating pathway of thyroid hormones represents a homeostatic mechanism, and in selected circumstances measuring serum reverse T₃ may be useful, such as in euthyroid sick patients. The discovery of the molecular mechanisms that lead to the reactivation of D3 in illness is an important field of research.

Four decades after reverse T₃ (3,3´5´-triiodothyronine) was discovered, its physiologic and clinical relevance remains unclear and is still being studied. But scientific uncertainty has not stopped writers in the consumer press and on the Internet from making unsubstantiated claims about this hormone. Many patients believe their hypothyroid symptoms are due to high levels of reverse T₃ and want to be tested for it, and some even bring in test results from independent laboratories.  

HOW THYROID HORMONES WERE DISCOVERED

In 1970, Braverman et al⁹ showed that T₄ is converted to T₃ in athyreotic humans, and Sterling et al¹⁰ demonstrated the same in healthy humans. During that decade, techniques for measuring T₄ were refined,¹¹ and a specific radioimmunoassay for reverse T₃ allowed a glimpse of its physiologic role.¹² In 1975, Chopra et al¹³ noted reciprocal changes in the levels of T₃ and reverse T₃ in systemic illnesses—ie, when people are sick, their T₃ levels go down and their reverse T₃ levels go up.

The end of the 70s was marked by a surge of interest in T₄ metabolites, including the development of a radioimmunoassay for 3,3´-diiodothyronine (3-3´ T₂).¹⁸

The observed reciprocal changes in serum levels of T₃ and reverse T₃ suggested that T₄ degradation is regulated into activating (T₃) or inactivating (reverse T₃) pathways, and that these changes are a presumed homeostatic process of energy conservation.¹⁹

HOW THYROID HORMONES ARE METABOLIZED

In the thyroid gland, for thyroid hormones to be synthesized, iodide must be oxidized and incorporated into the precursors 3-monoiodotyrosine (MIT) and 3,5-diiodotyrosine (DIT). This process is mediated by the enzyme thyroid peroxidase in the presence of hydrogen peroxide.²⁰

The thyroid can make T₄ and some T₃

T₄ is the main iodothyronine produced by the thyroid gland, at a rate of 80 to 100 µg per day.²¹ It is synthesized from the fusion of 2 DIT molecules.

The thyroid can also make T₃ by fusing 1 DIT and 1 MIT molecule, but this process accounts for no more than 20% of the circulating T₃ in humans. The rest of T₃, and 95% to 98% of all reverse T₃, is derived from peripheral conversion of T₄ through deiodination.

T₄ is converted to T₃ or reverse T₃

The metabolic transformation of thyroid hormones in peripheral tissues determines their biologic potency and regulates their biologic effects.

The number 4 in T₄ means it has 4 iodine atoms. It can lose 1 of them, yielding either T₃ or reverse T₃, depending on which iodine atom it loses (Figure 3). Loss of iodine from the five-prime (5´) position on its outer ring yields T₃, the most potent thyroid hormone, produced at a rate of 30 to 40 µg per day.²¹ On the other hand, when T₄ loses an iodine atom from the five (5) position on its inner ring it yields reverse T₃, produced at a rate slightly less than that of T₃, 28 to 40 µg per day.²¹ Reverse T₃ is inactive.

Both T₃ and reverse T₃ can shed more iodine atoms, forming in turn various isomers of T₂, T₁, and ultimately T₀. Other pathways for thyroid hormone metabolism include glucuronidation, sulfation, oxidative deamination, and ether bond cleavage.^20–22

D1 and D2 catalyze T₃, D3 catalyzes reverse T₃

Three types of enzymes that mediate deiodination have been identified and designated D1, D2, and D3. In humans they are expressed in variable amounts throughout the body:

• D1 mainly in the liver, kidneys, thyroid, and pituitary, but notably absent in the central nervous system
• D2 in the central nervous system, pituitary, brown adipose tissue, thyroid, placenta, skeletal muscle, and heart
• D3 in the central nervous system, skin, hemangiomas, fetal liver, placenta, and fetal tissues.²³

D1 and D2 are responsible for converting T₄ to T₃, and D3 is responsible for converting T₄ to reverse T₃.

Plasma concentrations of free T₄ and free T₃ are relatively constant; however, tissue concentrations of free T₃ vary in different tissues according to the amount of hormone transported and the activity of local deiodinases.²³ Most thyroid hormone actions are initiated after T₃ binds to its nuclear receptor. In this setting, deiodinases play a critical role in maintaining tissue and cellular thyroid hormone levels, so that thyroid hormone signaling can change irrespective of serum hormonal concentrations.^22–24 For example, in the central nervous system, production of T₃ by local D2 is significantly relevant for T₃ homeostasis.^22,23

Deiodinases also modulate the tissue-specific concentrations of T₃ in response to iodine deficiency and to changes in thyroid state.²³ During iodine deficiency and hypothyroidism, tissues that express D2, especially brain tissues, increase the activity of this enzyme in order to increase local conversion of T₄ to T₃. In hyperthyroidism, D1 overexpression contributes to the relative excess of T₃ production, while D3 up-regulation in the brain protects the central nervous system from excessive amounts of thyroid hormone.²³

D3 is the main physiologic inactivator of thyroid hormones. This enzyme plays a central role in protecting tissues from an excess of thyroid hormone.^23,24 This mechanism is crucial for fetal development and explains the high expression of D3 in the human placenta and fetal tissues.

In adult tissues, the importance of D3 in the regulation of thyroid hormone homeostasis becomes apparent under certain pathophysiologic conditions, such as nonthyroidal illness and malnutrition.

Whenever a reduction in metabolism is homeostatically desirable, such as in critically ill patients or during starvation, conversion to T₃ is reduced and, alternatively, conversion to reverse T₃ is increased. This pathway represents a metabolic adaptation that may protect the tissues from the catabolic effects of thyroid hormone that could otherwise worsen the patient’s basic clinical condition.

Euthyroid sick syndrome or hypothyroid?

In a variety of systemic illnesses, some patients with low T₃, low or normal T₄, and normal thyroid-stimulating hormone (TSH) levels could in fact be “sick euthyroid” rather than hypothyroid. The first reports of the euthyroid sick syndrome or low T₃ syndrome date back to about 1976, and even though assays for reverse T₃ were not widely available, some authors linked the syndrome to high levels of reverse T₃.^15,16 The syndrome is also known as nonthyroidal illness syndrome.

Advances in techniques for measuring T₃, reverse T₃, and other iodothyronines filled a gap in the understanding of the alterations that occur in thyroid hormone economy during severe nonthyroidal diseases. In 1982, Wartofsky and Burman²⁵ reviewed the alterations in thyroid function in patients with systemic illness and discussed other factors that may alter thyroid economy, such as age, stress, and diverse drugs.

More recently, the low-T₃ syndrome was revisited with a generalized concept regarding the role of D3 in the syndrome.²⁶ D3, normally undetectable in mature tissues, is reactivated in diverse cell types in response to injury and is responsible for a fall in serum T₃ levels. Hypoxia induces D3 activity and mRNA in vitro and in vivo.²⁷ Recent studies have focused on the role of cytokines in the low T₃ syndrome. For instance, interleukin 6 reduces D1 and D2 activity and increases D3 activity in vitro.²⁸

In the outpatient setting, diverse conditions may affect thyroid hormone homeostasis, compatible with mild or atypical forms of low-T₃ syndrome, including caloric deprivation, heart failure, and human immunodeficiency virus infection.²⁹

POSSIBLE CLINICAL UTILITY OF MEASURING REVERSE T₃

In inpatients

Unfortunately, measuring serum reverse T₃ levels has not, in general, proven clinically useful for the diagnosis of hypothyroidism in systemically ill patients. Burmeister³⁰ demonstrated, in a retrospective study, that when illness complicates the interpretation of thyroid function tests, serum reverse T₃ measurements do not reliably distinguish the hypothyroid sick patient from the euthyroid sick patient. The best way to make the diagnosis, Burmeister suggested, is by clinical assessment, combined use of free T₄ and TSH measurements, and patient follow-up.

In the outpatient setting, the utility of reverse T3 measurements is controversial. In intensive care units, the differential diagnosis between hypothyroidism and nonthyroidal illness syndrome can sometimes be difficult. Reverse T₃ levels can be low, normal, or high regardless of the thyroidal state of the patient.³⁰ Moreover, endogenous changes in the hypothalamic-pituitary-thyroid axis may be further complicated by medications commonly used in intensive care units, such as dopamine and glucocorticoids. Changes in thyroid function should be evaluated in the context of the patient’s clinical condition (Table 1).²⁰ But regardless of the T₃ level, treatment with T₃ or T₄ should not be started without taking into consideration the patient’s general clinical context; controlled trials have not shown such therapy to be beneficial.²⁰

In outpatients

In noncritical conditions that may be associated with mild forms of low T₃ syndrome, patients generally present with low T₃ concentrations concurrently with low or normal TSH. Not infrequently, however, patients present with a serum reverse T₃ measurement and impute their symptoms of hypothyroidism to “abnormal” reverse T₃ levels, in spite of normal TSH levels.

There is no rationale for measuring reverse T₃ to initiate or to adjust levothyroxine therapy—the single test relevant for these purposes is the TSH measurement. The risks of basing treatment decisions on reverse T₃ levels include the use of excessive doses of levothyroxine that may lead to a state of subclinical or even clinical hyperthyroidism.

TAKE-HOME MESSAGE

The existence of an inactivating pathway of thyroid hormones represents a homeostatic mechanism, and in selected circumstances measuring serum reverse T₃ may be useful, such as in euthyroid sick patients. The discovery of the molecular mechanisms that lead to the reactivation of D3 in illness is an important field of research.

Four decades after reverse T₃ (3,3´5´-triiodothyronine) was discovered, its physiologic and clinical relevance remains unclear and is still being studied. But scientific uncertainty has not stopped writers in the consumer press and on the Internet from making unsubstantiated claims about this hormone. Many patients believe their hypothyroid symptoms are due to high levels of reverse T₃ and want to be tested for it, and some even bring in test results from independent laboratories.  

HOW THYROID HORMONES WERE DISCOVERED

In 1970, Braverman et al⁹ showed that T₄ is converted to T₃ in athyreotic humans, and Sterling et al¹⁰ demonstrated the same in healthy humans. During that decade, techniques for measuring T₄ were refined,¹¹ and a specific radioimmunoassay for reverse T₃ allowed a glimpse of its physiologic role.¹² In 1975, Chopra et al¹³ noted reciprocal changes in the levels of T₃ and reverse T₃ in systemic illnesses—ie, when people are sick, their T₃ levels go down and their reverse T₃ levels go up.

The end of the 70s was marked by a surge of interest in T₄ metabolites, including the development of a radioimmunoassay for 3,3´-diiodothyronine (3-3´ T₂).¹⁸

The observed reciprocal changes in serum levels of T₃ and reverse T₃ suggested that T₄ degradation is regulated into activating (T₃) or inactivating (reverse T₃) pathways, and that these changes are a presumed homeostatic process of energy conservation.¹⁹

HOW THYROID HORMONES ARE METABOLIZED

In the thyroid gland, for thyroid hormones to be synthesized, iodide must be oxidized and incorporated into the precursors 3-monoiodotyrosine (MIT) and 3,5-diiodotyrosine (DIT). This process is mediated by the enzyme thyroid peroxidase in the presence of hydrogen peroxide.²⁰

The thyroid can make T₄ and some T₃

T₄ is the main iodothyronine produced by the thyroid gland, at a rate of 80 to 100 µg per day.²¹ It is synthesized from the fusion of 2 DIT molecules.

The thyroid can also make T₃ by fusing 1 DIT and 1 MIT molecule, but this process accounts for no more than 20% of the circulating T₃ in humans. The rest of T₃, and 95% to 98% of all reverse T₃, is derived from peripheral conversion of T₄ through deiodination.

T₄ is converted to T₃ or reverse T₃

The metabolic transformation of thyroid hormones in peripheral tissues determines their biologic potency and regulates their biologic effects.

The number 4 in T₄ means it has 4 iodine atoms. It can lose 1 of them, yielding either T₃ or reverse T₃, depending on which iodine atom it loses (Figure 3). Loss of iodine from the five-prime (5´) position on its outer ring yields T₃, the most potent thyroid hormone, produced at a rate of 30 to 40 µg per day.²¹ On the other hand, when T₄ loses an iodine atom from the five (5) position on its inner ring it yields reverse T₃, produced at a rate slightly less than that of T₃, 28 to 40 µg per day.²¹ Reverse T₃ is inactive.

Both T₃ and reverse T₃ can shed more iodine atoms, forming in turn various isomers of T₂, T₁, and ultimately T₀. Other pathways for thyroid hormone metabolism include glucuronidation, sulfation, oxidative deamination, and ether bond cleavage.^20–22

D1 and D2 catalyze T₃, D3 catalyzes reverse T₃

Three types of enzymes that mediate deiodination have been identified and designated D1, D2, and D3. In humans they are expressed in variable amounts throughout the body:

• D1 mainly in the liver, kidneys, thyroid, and pituitary, but notably absent in the central nervous system
• D2 in the central nervous system, pituitary, brown adipose tissue, thyroid, placenta, skeletal muscle, and heart
• D3 in the central nervous system, skin, hemangiomas, fetal liver, placenta, and fetal tissues.²³

D1 and D2 are responsible for converting T₄ to T₃, and D3 is responsible for converting T₄ to reverse T₃.

Plasma concentrations of free T₄ and free T₃ are relatively constant; however, tissue concentrations of free T₃ vary in different tissues according to the amount of hormone transported and the activity of local deiodinases.²³ Most thyroid hormone actions are initiated after T₃ binds to its nuclear receptor. In this setting, deiodinases play a critical role in maintaining tissue and cellular thyroid hormone levels, so that thyroid hormone signaling can change irrespective of serum hormonal concentrations.^22–24 For example, in the central nervous system, production of T₃ by local D2 is significantly relevant for T₃ homeostasis.^22,23

Deiodinases also modulate the tissue-specific concentrations of T₃ in response to iodine deficiency and to changes in thyroid state.²³ During iodine deficiency and hypothyroidism, tissues that express D2, especially brain tissues, increase the activity of this enzyme in order to increase local conversion of T₄ to T₃. In hyperthyroidism, D1 overexpression contributes to the relative excess of T₃ production, while D3 up-regulation in the brain protects the central nervous system from excessive amounts of thyroid hormone.²³

D3 is the main physiologic inactivator of thyroid hormones. This enzyme plays a central role in protecting tissues from an excess of thyroid hormone.^23,24 This mechanism is crucial for fetal development and explains the high expression of D3 in the human placenta and fetal tissues.

In adult tissues, the importance of D3 in the regulation of thyroid hormone homeostasis becomes apparent under certain pathophysiologic conditions, such as nonthyroidal illness and malnutrition.

Whenever a reduction in metabolism is homeostatically desirable, such as in critically ill patients or during starvation, conversion to T₃ is reduced and, alternatively, conversion to reverse T₃ is increased. This pathway represents a metabolic adaptation that may protect the tissues from the catabolic effects of thyroid hormone that could otherwise worsen the patient’s basic clinical condition.

Euthyroid sick syndrome or hypothyroid?

In a variety of systemic illnesses, some patients with low T₃, low or normal T₄, and normal thyroid-stimulating hormone (TSH) levels could in fact be “sick euthyroid” rather than hypothyroid. The first reports of the euthyroid sick syndrome or low T₃ syndrome date back to about 1976, and even though assays for reverse T₃ were not widely available, some authors linked the syndrome to high levels of reverse T₃.^15,16 The syndrome is also known as nonthyroidal illness syndrome.

Advances in techniques for measuring T₃, reverse T₃, and other iodothyronines filled a gap in the understanding of the alterations that occur in thyroid hormone economy during severe nonthyroidal diseases. In 1982, Wartofsky and Burman²⁵ reviewed the alterations in thyroid function in patients with systemic illness and discussed other factors that may alter thyroid economy, such as age, stress, and diverse drugs.

More recently, the low-T₃ syndrome was revisited with a generalized concept regarding the role of D3 in the syndrome.²⁶ D3, normally undetectable in mature tissues, is reactivated in diverse cell types in response to injury and is responsible for a fall in serum T₃ levels. Hypoxia induces D3 activity and mRNA in vitro and in vivo.²⁷ Recent studies have focused on the role of cytokines in the low T₃ syndrome. For instance, interleukin 6 reduces D1 and D2 activity and increases D3 activity in vitro.²⁸

In the outpatient setting, diverse conditions may affect thyroid hormone homeostasis, compatible with mild or atypical forms of low-T₃ syndrome, including caloric deprivation, heart failure, and human immunodeficiency virus infection.²⁹

POSSIBLE CLINICAL UTILITY OF MEASURING REVERSE T₃

In inpatients

Unfortunately, measuring serum reverse T₃ levels has not, in general, proven clinically useful for the diagnosis of hypothyroidism in systemically ill patients. Burmeister³⁰ demonstrated, in a retrospective study, that when illness complicates the interpretation of thyroid function tests, serum reverse T₃ measurements do not reliably distinguish the hypothyroid sick patient from the euthyroid sick patient. The best way to make the diagnosis, Burmeister suggested, is by clinical assessment, combined use of free T₄ and TSH measurements, and patient follow-up.

In the outpatient setting, the utility of reverse T3 measurements is controversial. In intensive care units, the differential diagnosis between hypothyroidism and nonthyroidal illness syndrome can sometimes be difficult. Reverse T₃ levels can be low, normal, or high regardless of the thyroidal state of the patient.³⁰ Moreover, endogenous changes in the hypothalamic-pituitary-thyroid axis may be further complicated by medications commonly used in intensive care units, such as dopamine and glucocorticoids. Changes in thyroid function should be evaluated in the context of the patient’s clinical condition (Table 1).²⁰ But regardless of the T₃ level, treatment with T₃ or T₄ should not be started without taking into consideration the patient’s general clinical context; controlled trials have not shown such therapy to be beneficial.²⁰

In outpatients

In noncritical conditions that may be associated with mild forms of low T₃ syndrome, patients generally present with low T₃ concentrations concurrently with low or normal TSH. Not infrequently, however, patients present with a serum reverse T₃ measurement and impute their symptoms of hypothyroidism to “abnormal” reverse T₃ levels, in spite of normal TSH levels.

There is no rationale for measuring reverse T₃ to initiate or to adjust levothyroxine therapy—the single test relevant for these purposes is the TSH measurement. The risks of basing treatment decisions on reverse T₃ levels include the use of excessive doses of levothyroxine that may lead to a state of subclinical or even clinical hyperthyroidism.

TAKE-HOME MESSAGE

The existence of an inactivating pathway of thyroid hormones represents a homeostatic mechanism, and in selected circumstances measuring serum reverse T₃ may be useful, such as in euthyroid sick patients. The discovery of the molecular mechanisms that lead to the reactivation of D3 in illness is an important field of research.

In the article, “Point-of-care ultrasound: Coming soon to primary care?” (J Fam Pract. 2018;67:70-79), Bornemann et al outline potential uses for point-of-care ultrasound (POCUS), describing in detail its role in cardiovascular and pulmonary exams, screening for abdominal aortic aneurysms, and diagnosing deep vein thrombosis. The American Academy of Family Physicians, in the Recommended Curriculum Guidelines for Family Medicine Residents (available at: https://www.aafp.org/medical-school-residency/program-directors/curriculum.html), also discusses obstetric and gynecologic uses for POCUS, such as determining fetal presentation and distinguishing viable pregnancy from miscarriage.

In my practice, I most often use POCUS for gynecologic and pregnancy-related issues, such as to ensure proper placement of an intrauterine device (IUD) when the strings are not visible, to determine gestational age in patients with uncertain last menstrual periods, and to confirm pregnancy location when patients have risk factors for, or symptoms suggestive of, ectopic pregnancy.

The breadth of care provided in family medicine is what makes it special. We must make sure that as we expand our care with new technologies, we do not trade tried and true uses of those technologies for newer ones.

Zoey Thill, MD, MPP
Bronx, NY

In the article, “Point-of-care ultrasound: Coming soon to primary care?” (J Fam Pract. 2018;67:70-79), Bornemann et al outline potential uses for point-of-care ultrasound (POCUS), describing in detail its role in cardiovascular and pulmonary exams, screening for abdominal aortic aneurysms, and diagnosing deep vein thrombosis. The American Academy of Family Physicians, in the Recommended Curriculum Guidelines for Family Medicine Residents (available at: https://www.aafp.org/medical-school-residency/program-directors/curriculum.html), also discusses obstetric and gynecologic uses for POCUS, such as determining fetal presentation and distinguishing viable pregnancy from miscarriage.

In my practice, I most often use POCUS for gynecologic and pregnancy-related issues, such as to ensure proper placement of an intrauterine device (IUD) when the strings are not visible, to determine gestational age in patients with uncertain last menstrual periods, and to confirm pregnancy location when patients have risk factors for, or symptoms suggestive of, ectopic pregnancy.

The breadth of care provided in family medicine is what makes it special. We must make sure that as we expand our care with new technologies, we do not trade tried and true uses of those technologies for newer ones.

Zoey Thill, MD, MPP
Bronx, NY

In the article, “Point-of-care ultrasound: Coming soon to primary care?” (J Fam Pract. 2018;67:70-79), Bornemann et al outline potential uses for point-of-care ultrasound (POCUS), describing in detail its role in cardiovascular and pulmonary exams, screening for abdominal aortic aneurysms, and diagnosing deep vein thrombosis. The American Academy of Family Physicians, in the Recommended Curriculum Guidelines for Family Medicine Residents (available at: https://www.aafp.org/medical-school-residency/program-directors/curriculum.html), also discusses obstetric and gynecologic uses for POCUS, such as determining fetal presentation and distinguishing viable pregnancy from miscarriage.

In my practice, I most often use POCUS for gynecologic and pregnancy-related issues, such as to ensure proper placement of an intrauterine device (IUD) when the strings are not visible, to determine gestational age in patients with uncertain last menstrual periods, and to confirm pregnancy location when patients have risk factors for, or symptoms suggestive of, ectopic pregnancy.

The breadth of care provided in family medicine is what makes it special. We must make sure that as we expand our care with new technologies, we do not trade tried and true uses of those technologies for newer ones.

Zoey Thill, MD, MPP
Bronx, NY

This country continues to struggle with the issue of how to pay for health care. But regardless of the source of payment, primary care usually gets caught in the middle. Squeezed between volume and value, family physicians know all too well the gap that exists between what our patients need and what our training and health care system allow us to provide.

This knowledge prompted me to change how I conduct my day-to-day office visits. To routinely restore healing to the patient-provider conversation, I developed a tool called the HOPE (Healing Oriented Practices and Environments) Note. It consists of a set of questions to ask during a routine office visit that are specifically geared toward uncovering and addressing patients’ personal determinants of health and healing.

During a HOPE consultation, I seek to reframe the orientation from one that focuses only on disease treatment to one that emphasizes self-healing. Example questions include: What matters to you? What brings you joy? How is your social support? What do you eat? How is your sleep? What is your home like? Do you feel safe? How do you manage stress?

From there, I develop a personalized health promotion plan adjusted to the patient’s needs, personality, readiness, resources, and circumstances. Usually, patients benefit from additional assistance, such as health coaching and ways to measure and track progress. I have created a HOPE Note Checklist to teach students and residents about this approach, and a patient guide to help prepare patients for the visit ahead of time. (To access the guide and other free HOPE Note tools, see www.drwaynejonas.com/hope.)

Of course, these tools won’t single-handedly solve the issue of health care costs. But by practicing in a way that prioritizes what really matters to patients, we begin to take health care reform into our own hands.

Wayne B. Jonas, MD
Alexandria, Va

This country continues to struggle with the issue of how to pay for health care. But regardless of the source of payment, primary care usually gets caught in the middle. Squeezed between volume and value, family physicians know all too well the gap that exists between what our patients need and what our training and health care system allow us to provide.

This knowledge prompted me to change how I conduct my day-to-day office visits. To routinely restore healing to the patient-provider conversation, I developed a tool called the HOPE (Healing Oriented Practices and Environments) Note. It consists of a set of questions to ask during a routine office visit that are specifically geared toward uncovering and addressing patients’ personal determinants of health and healing.

During a HOPE consultation, I seek to reframe the orientation from one that focuses only on disease treatment to one that emphasizes self-healing. Example questions include: What matters to you? What brings you joy? How is your social support? What do you eat? How is your sleep? What is your home like? Do you feel safe? How do you manage stress?

From there, I develop a personalized health promotion plan adjusted to the patient’s needs, personality, readiness, resources, and circumstances. Usually, patients benefit from additional assistance, such as health coaching and ways to measure and track progress. I have created a HOPE Note Checklist to teach students and residents about this approach, and a patient guide to help prepare patients for the visit ahead of time. (To access the guide and other free HOPE Note tools, see www.drwaynejonas.com/hope.)

Of course, these tools won’t single-handedly solve the issue of health care costs. But by practicing in a way that prioritizes what really matters to patients, we begin to take health care reform into our own hands.

Wayne B. Jonas, MD
Alexandria, Va

This country continues to struggle with the issue of how to pay for health care. But regardless of the source of payment, primary care usually gets caught in the middle. Squeezed between volume and value, family physicians know all too well the gap that exists between what our patients need and what our training and health care system allow us to provide.

This knowledge prompted me to change how I conduct my day-to-day office visits. To routinely restore healing to the patient-provider conversation, I developed a tool called the HOPE (Healing Oriented Practices and Environments) Note. It consists of a set of questions to ask during a routine office visit that are specifically geared toward uncovering and addressing patients’ personal determinants of health and healing.

During a HOPE consultation, I seek to reframe the orientation from one that focuses only on disease treatment to one that emphasizes self-healing. Example questions include: What matters to you? What brings you joy? How is your social support? What do you eat? How is your sleep? What is your home like? Do you feel safe? How do you manage stress?

From there, I develop a personalized health promotion plan adjusted to the patient’s needs, personality, readiness, resources, and circumstances. Usually, patients benefit from additional assistance, such as health coaching and ways to measure and track progress. I have created a HOPE Note Checklist to teach students and residents about this approach, and a patient guide to help prepare patients for the visit ahead of time. (To access the guide and other free HOPE Note tools, see www.drwaynejonas.com/hope.)

Of course, these tools won’t single-handedly solve the issue of health care costs. But by practicing in a way that prioritizes what really matters to patients, we begin to take health care reform into our own hands.

Wayne B. Jonas, MD
Alexandria, Va