Applied Evidence

CASE Mr. J, a 75-year-old man, presents to your family practice reporting that he feels increasingly unsteady and slow while walking. He fell twice last year, without resulting injury. He now worries about tripping while walking around the house and relies on his spouse to run errands.

Almost 30% of people older than 65 years report 1 or more falls annually.

Clearly, Mr. J is experiencing a problem with balance. What management approach should you undertake to prevent him from falling?

Copyright Scott Bodell

Balance disorders are common in older people and drastically hinder quality of life.^1-4 Patients often describe imbalance as vague symptoms: dizziness, unsteadiness, faintness, spinning sensations.^5,6 Importantly, balance disorders disrupt normal gait and contribute to falls that are a major cause of disability and morbidity in older people. Almost 30% of people older than 65 years report 1 or more falls annually.⁷ Factors that increase the risk of falls include impaired mobility, previously reported falls, reduced psychological functioning, chronic medical conditions, and polypharmacy.^7,8

The cause of any single case of imbalance is often multifactorial, resulting from dysfunction of multiple body systems (TABLE 1^7-56); in our clinical experience, most patients with imbalance and who are at risk of falls do not have a detectable deficit of the vestibular system. These alterations in function arise in 3 key systems—vision, proprioception, and vestibular function—which signal to, and are incorporated by, the cerebellum to mediate balance. Cognitive and neurologic decline are also factors in imbalance.

Considering that 20% of falls result in serious injury in older populations, it is important to identify balance disorders and implement preventive strategies to mitigate harmful consequences of falls on patients’ health and independence.^7,57 In this article, we answer the question that the case presentation raises about the proper management approach to imbalance in family practice, including assessment of risk and rehabilitation strategies to reduce the risk of falls. Our insights and recommendations are based on our clinical experience and a review of the medical literature from the past 40 years.

CASE Mr. J has a history of hypertension, age-­related hearing loss, and osteoarthritis of the knees; he has not had surgery for the arthritis. His medications are antihypertensives and extra-strength acetaminophen for knee pain.

Making the diagnosis of a balance disorder

History

A thorough clinical history, often including a collateral history from caregivers, narrows the differential diagnosis. Information regarding onset, duration, timing, character, and previous episodes of imbalance is essential. Symptoms of imbalance are often challenging for the patient to describe: They might use terms such as vertigo or dizziness, when, in fact, on further questioning, they are describing balance difficulties. Inquiry into (1) their use of assistive walking devices and (2) development or exacerbation of neurologic, musculoskeletal, auditory, visual, and mood symptoms is necessary. Note the current level of their mobility, episodes of pain or fatigue, previous falls and associated injuries, fear of falling, balance confidence, and sensations that precede falls.⁵⁸

Continue to: The medical and surgical histories

The medical and surgical histories are key pieces of information. The history of smoking, alcohol habits, and substance use is relevant.

A robust medication history is essential to evaluate a patient’s risk of falling. Polypharmacy—typically, defined as taking 4 or more medications—has been repeatedly associated with a heightened risk of falls.^53,59-61 Moreover, a dose-dependent association between polypharmacy and hospitalization following falls has been identified, and demonstrates that taking 10 or more medications greatly increases the risk of hospitalization.⁵⁹ Studies of polypharmacy cement the importance of inquiring about medication use when assessing imbalance, particularly in older patients.

Physical examination

A focused and detailed physical examination provides insight into systems that should be investigated:

• Obtain vital signs, including orthostatic vitals to test for orthostatic hypotension⁶²; keep in mind that symptoms of orthostatic dizziness can occur without orthostatic hypotension.
• Examine gait, which can distinguish between causes of imbalance (TABLE 2).^21,40,63-70
• Perform a cardiac examination.
• Assess visual acuity and visual fields; test for nystagmus and identify any optic-nerve and retinal abnormalities.
• Evaluate lower-limb sensation, proprioception, and motor function.
• Evaluate suspected vestibular dysfunction, including dysfunction with positional testing (the Dix-Hallpike maneuver⁷¹). The patient is taken from sitting to supine while the head is rotated 45° to the tested side by the examiner. As the patient moves into a supine position, the neck is extended 30° off the table and held for at least 30 seconds. The maneuver is positive if torsional nystagmus is noted while the head is held rotated during neck extension. The maneuver is negative if the patient reports dizziness, vertigo, unsteadiness, or “pressure in the head.” Torsional nystagmus must be present to confirm a diagnosis of benign paroxysmal positional vertigo.
• If you suspect a central nervous system cause of imbalance, assess the cranial nerves, coordination, strength, and, of course, balance.

CASE

Mr. J’s physical examination showed normal vital signs without significant postural changes in blood pressure. Gait analysis revealed a slowed gait, with reduced range of motion in both knees over the entire gait cycle. Audiometry revealed symmetric moderate sensorineural hearing loss characteristic of presbycusis.

Diagnostic investigations

Consider focused investigations into imbalance based on the history and physical examination. We discourage overly broad testing and imaging; in primary care, cost and limited access to technology can bar robust investigations into causes of imbalance. However, identification of acute pathologies should prompt immediate referral to the emergency department. Furthermore, specific symptoms (TABLE 1^7-56) should prompt referral to specialists for assessment.

Continue to: In the emergency department...

In the emergency department and academic hospitals, key investigations can identify causes of imbalance:

• Electrocardiography and Holter monitoring test for cardiac arrhythmias.
• Echocardiography identifies structural abnormalities.
• Radiography and computed tomography are useful for detecting musculoskeletal abnormalities.
• Bone densitometry can identify osteoporosis.
• Head and spinal cord magnetic resonance imaging can be used to identify lesions of the central nervous system.
• Computed tomographic angiography of the head and neck is useful for identifying stroke, cerebral atrophy, and stenotic lesions of the carotid and vertebral arteries.
• Nerve conduction studies and levels of serum vitamin B₁₂, hemoglobin A1C, thyroid-stimulating hormone, and random cortisol can uncover causes of peripheral neuropathy.
• Bedside cognitive screening tests can be used to measure cognitive decline.⁷²
• Suspicion of vestibular disease requires audiometry and vestibular testing, including videonystagmography, head impulse testing, and vestibular evoked myogenic potentials.

In many cases of imbalance, no specific underlying correctable cause is discovered.

Management of imbalance

Pharmacotherapy

Targeted pharmacotherapy can be utilized in select clinical scenarios:

• Medical treatment of peripheral neuropathy should target the underlying condition.
• Cognitive behavioral therapy and antidepressants are useful for treating anxiety and depressive disorders.⁷³
• Musculoskeletal pain can be managed with acetaminophen and topical nonsteroidal anti-inflammatory drugs (NSAIDs), using a short course of an oral NSAID when needed.⁷⁴
• Cardiovascular disease management might include any of several classes of pharmacotherapy, including antiplatelet and lipid-lowering medications, antiarrhythmic drugs, and antihypertensive agents.
• Acute episodes of vertigo due to vestibular neuritis or labyrinthitis can be managed with an antiemetic.⁴⁶

Surgical treatment

Surgery is infrequently considered for patients with imbalance. Examples of indications include microsurgical resection of vestibular schwannoma, resection of central nervous system tumors, lens replacement surgery for cataract, surgical management of severe spinal fracture, and hip or knee arthroplasty in select patients.

Tools for assessing the risk of falls

Scoring systems called falls risk assessment tools, or FRAT, have been developed to gauge a patient’s risk of falling. The various FRATs differ in specificity and sensitivity for predicting the risk of falls, and are typically designed for specific clinical environments, such as hospital inpatient care or long-term care facilities. Specifically, FRATs attempt to classify risk using sets of risk factors known to be associated with falls.

Continue to: Research abounds into...

In our experience, most patients with imbalance and who are at risk of falls do not have a detectable deficit of the vestibular system.

Research abounds into the validity of commonly used FRATs across institutions, patient populations, and clinical environments:

The Johns Hopkins FRAT^a determines risk using metrics such as age, fall history, incontinence, cognition, mobility, and medications⁷⁵; it is predominantly used for assessment in hospital inpatient units. This tool has been validated repeatedly.^76,77

Peninsula Health FRAT^b stratifies patients in subacute and residential aged-care settings, based on risk factors that include recent falls, medications, psychological status, and cognition.⁷⁸

FRAT-up^c is a web-based tool that generates falls risk using risk factors that users input. This tool has been studied in the context of patients older than 65 years living in the community.⁷⁹

Although FRATs are reasonably useful for predicting falls, their utility varies by patient population and clinical context. Moreover, it has been suggested that FRATs neglect environmental and personal factors when assessing risk by focusing primarily on bodily factors.⁸⁰ Implementing a FRAT requires extensive consideration of the target population and should be accompanied by clinical judgment that is grounded in an individual patient’s circumstances.⁸¹

Continue to: Preventing falls in primary care

An approach to preventing falls includes the development of individualized programs that account for frailty, a syndrome of physiologic decline associated with aging. Because frailty leads to diminished balance and mobility, a patient’s frailty index—determined using the 5 frailty phenotype criteria (exhaustion, weight loss, low physical activity, weakness, slowness)⁸² or the Canadian Study of Health and Aging Clinical Frailty Scale⁸³—is a useful tool for predicting falls risk and readmission for falls following trauma-related injury. Prevention of falls in communities is critical for reducing mortality and allowing older people to maintain their independence and quality of life.

Exercise. In some areas, exercise and falls prevention programs are accessible to seniors.⁸⁴ Community exercise programs that focus on balance retraining and muscle strengthening can reduce the risk of falls.^73,85 The Choosing Wisely initiative of the ABIM [American Board of Internal Medicine] Foundation recommends that exercise programs be designed around an accurate functional baseline of the patient to avoid underdosed strength training.⁵⁴

Multifactorial risk assessment in high-risk patients can reduce the rate of falls. Such an assessment includes examination of orthostatic blood pressure, vision and hearing, bone health, gait, activities of daily living, cognition, and environmental hazards, and enables provision of necessary interventions.^73,86 Hearing amplification, specifically, correlates with enhanced postural control, slowed cognitive decline, and a reduced likelihood of falls.^87-93 The mechanism behind improved balance performance might be reduced cognitive load through supporting a patient’s listening needs.^88-90

Pharmacotherapy. Optimizing medications and performing a complete medication review before prescribing new medications is highly recommended to avoid unnecessary polypharmacy^7,8,18,53-56 (TABLE 1^7-56).

Management of comorbidities associated with a higher risk of falls, including arthritis, cancer, stroke, diabetes, depression, kidney disease, chronic obstructive pulmonary disease, cognitive impairment, hypertension, and atrial fibrillation, is essential.^94-96

Continue to: Home safety interventions

Home safety interventions, through occupational therapy, are important. These include removing unsafe mats and step-overs and installing nonslip strips on stairs, ­double-sided tape under mats, and handrails.^73-97

Screening for risk of falls. The Centers for Disease Control and Prevention recommends that (1) all patients older than 65 years and (2) any patient presenting with an acute fall undergo screening for their risk of falls.⁹⁸ When a patient is identified as at risk of falling, you can, when appropriate, assess modifiable risk factors and facilitate interventions.⁹⁸ This strategy is supported by a 2018 statement from the US Preventive Services Task Force⁹⁹ that recommends identifying high-risk patients who have:

• a history of falling
• a balance disturbance that causes a deficit of mobility or function
• poor performance on clinical tests, such as the 3-meter Timed Up and Go (TUG) assessment (www.cdc.gov/steadi/pdf/TUG_test-print.pdf).

In addition to visual, proprioception, and vestibular dysfunction, cognitive and neurologic decline are also factors in imbalance.

An increased risk of falls should prompt you to refer the patient to community programs and physiotherapy in accordance with the individual’s personal goals⁹⁹; a balance and vestibular physiotherapist is ideally positioned to accurately assess and manage patients at risk of falls. Specifically, the Task Force identified exercise programs and multifactorial interventions as being beneficial in preventing falls in high-risk older people.⁹⁹

Balance assessment and rehabilitation in specialty centers

Polypharmacy— typically, defined as taking 4 or more medications— has been repeatedly associated with a heightened risk of falls.

An individualized rehabilitation program aims to restore safe mobility by testing and addressing specific balance deficits, improving functional balance, and increasing balance confidence. Collaboration with colleagues from physiotherapy and occupational therapy aids in tailoring individualized programs.

Many tests are available to assess balance, determine the risk of falls, and guide rehabilitation:

• The timed 10-meter walk test^d and the TUG test are simple assessments that measure functional mobility; both have normalized values for the risk of falls. A TUG time of ≥ 12 seconds suggests a high risk of falls.
• The 30-second chair stand^e evaluates functional lower-extremity strength in older patients. The test can indicate if lower-extremity strength is contributing to a patient’s imbalance.
• The modified clinical test of sensory interaction in balance^f is a static balance test that measures the integrity of sensory inputs. The test can suggest if 1 or more sensory systems are compromised.
• The mini balance evaluation systems test^g is similar: It can differentiate balance deficits by underlying system and allows individualization of a rehabilitation program.
• The functional gait assessment^h is a modification of the dynamic gait index that assesses postural stability during everyday dynamic activities, including tasks such as walking with head turns and pivots.
• The Berg Balance Scaleⁱ continues to be used extensively to assess balance.

Continue to: The mini balance evaluation systems test...

All patients older than 65 years and any patient presenting with an acute fall should undergo screening for their risk of falls.

The mini balance evaluation systems test, functional gait index, and Berg Balance Scale all have normative age-graded values to predict fall risk.

CASE

Mr. J was referred for balance assessment and to a rehabilitation program. He underwent balance physiotherapy, including multifactorial balance assessment, joined a community exercise program, was fitted with hearing aids, and had his home environment optimized by an occupational therapist. (See examples of “home safety interventions” under “Preventing falls in primary care.”)

Exercise programs should be designed around an accurate functional baseline of the patient to avoid underdosed strength training.

3 months later. Mr. J says he feels stronger on his feet. His knee pain has eased, and he is more confident walking around his home. He continues to engage in exercise programs and is comfortable running errands with his spouse.

CORRESPONDENCE
Jason A. Beyea, MD, PhD, FRCSC, Division of OtolaryngologyHead and Neck Surgery, Queen’s University, 144 Brock Street, Kingston, Ontario, Canada, K7L 5G2; [email protected]

^awww.hopkinsmedicine.org/institute_nursing/models_tools/jhfrat_acute%20care%20original_6_22_17.pdf

^bhttps://content.health.vic.gov.au/sites/default/files/migrated/files/collections/policies-and-guidelines/b/b2b_1a_frat_pdf.pdf

^cwww.ncbi.nlm.nih.gov/pmc/articles/PMC4376110/figure/figure14/?report=objectonly

^dwww.neuropt.org/docs/default-source/cpgs/core-outcome-measures/core-measure-10-meter-walk-test-(10mwt)_final.pdf?sfvrsn=c5585243_2&sfvrsn =c5585243_2

^ewww.cdc.gov/steadi/pdf/STEADI-Assessment-30Sec-508.pdf

^fwww.mdapp.co/mctsib-modified-clinical-test-of-sensory-interaction-in-balance-calculator-404/

^gwww.sralab.org/sites/default/files/2017-07/MiniBEST_revised_final_3_8_13.pdf

^hwww.neuropt.org/docs/default-source/cpgs/core-outcome-measures/function-gait-assessment-pocket-guide-proof9-(2).pdf?sfvrsn=b4f35043_0

ⁱwww.ncbi.nlm.nih.gov/books/NBK574518/

CASE Mr. J, a 75-year-old man, presents to your family practice reporting that he feels increasingly unsteady and slow while walking. He fell twice last year, without resulting injury. He now worries about tripping while walking around the house and relies on his spouse to run errands.

Almost 30% of people older than 65 years report 1 or more falls annually.

Clearly, Mr. J is experiencing a problem with balance. What management approach should you undertake to prevent him from falling?

Copyright Scott Bodell

Balance disorders are common in older people and drastically hinder quality of life.^1-4 Patients often describe imbalance as vague symptoms: dizziness, unsteadiness, faintness, spinning sensations.^5,6 Importantly, balance disorders disrupt normal gait and contribute to falls that are a major cause of disability and morbidity in older people. Almost 30% of people older than 65 years report 1 or more falls annually.⁷ Factors that increase the risk of falls include impaired mobility, previously reported falls, reduced psychological functioning, chronic medical conditions, and polypharmacy.^7,8

The cause of any single case of imbalance is often multifactorial, resulting from dysfunction of multiple body systems (TABLE 1^7-56); in our clinical experience, most patients with imbalance and who are at risk of falls do not have a detectable deficit of the vestibular system. These alterations in function arise in 3 key systems—vision, proprioception, and vestibular function—which signal to, and are incorporated by, the cerebellum to mediate balance. Cognitive and neurologic decline are also factors in imbalance.

Considering that 20% of falls result in serious injury in older populations, it is important to identify balance disorders and implement preventive strategies to mitigate harmful consequences of falls on patients’ health and independence.^7,57 In this article, we answer the question that the case presentation raises about the proper management approach to imbalance in family practice, including assessment of risk and rehabilitation strategies to reduce the risk of falls. Our insights and recommendations are based on our clinical experience and a review of the medical literature from the past 40 years.

CASE Mr. J has a history of hypertension, age-­related hearing loss, and osteoarthritis of the knees; he has not had surgery for the arthritis. His medications are antihypertensives and extra-strength acetaminophen for knee pain.

Making the diagnosis of a balance disorder

History

A thorough clinical history, often including a collateral history from caregivers, narrows the differential diagnosis. Information regarding onset, duration, timing, character, and previous episodes of imbalance is essential. Symptoms of imbalance are often challenging for the patient to describe: They might use terms such as vertigo or dizziness, when, in fact, on further questioning, they are describing balance difficulties. Inquiry into (1) their use of assistive walking devices and (2) development or exacerbation of neurologic, musculoskeletal, auditory, visual, and mood symptoms is necessary. Note the current level of their mobility, episodes of pain or fatigue, previous falls and associated injuries, fear of falling, balance confidence, and sensations that precede falls.⁵⁸

Continue to: The medical and surgical histories

The medical and surgical histories are key pieces of information. The history of smoking, alcohol habits, and substance use is relevant.

A robust medication history is essential to evaluate a patient’s risk of falling. Polypharmacy—typically, defined as taking 4 or more medications—has been repeatedly associated with a heightened risk of falls.^53,59-61 Moreover, a dose-dependent association between polypharmacy and hospitalization following falls has been identified, and demonstrates that taking 10 or more medications greatly increases the risk of hospitalization.⁵⁹ Studies of polypharmacy cement the importance of inquiring about medication use when assessing imbalance, particularly in older patients.

Physical examination

A focused and detailed physical examination provides insight into systems that should be investigated:

• Obtain vital signs, including orthostatic vitals to test for orthostatic hypotension⁶²; keep in mind that symptoms of orthostatic dizziness can occur without orthostatic hypotension.
• Examine gait, which can distinguish between causes of imbalance (TABLE 2).^21,40,63-70
• Perform a cardiac examination.
• Assess visual acuity and visual fields; test for nystagmus and identify any optic-nerve and retinal abnormalities.
• Evaluate lower-limb sensation, proprioception, and motor function.
• Evaluate suspected vestibular dysfunction, including dysfunction with positional testing (the Dix-Hallpike maneuver⁷¹). The patient is taken from sitting to supine while the head is rotated 45° to the tested side by the examiner. As the patient moves into a supine position, the neck is extended 30° off the table and held for at least 30 seconds. The maneuver is positive if torsional nystagmus is noted while the head is held rotated during neck extension. The maneuver is negative if the patient reports dizziness, vertigo, unsteadiness, or “pressure in the head.” Torsional nystagmus must be present to confirm a diagnosis of benign paroxysmal positional vertigo.
• If you suspect a central nervous system cause of imbalance, assess the cranial nerves, coordination, strength, and, of course, balance.

CASE

Mr. J’s physical examination showed normal vital signs without significant postural changes in blood pressure. Gait analysis revealed a slowed gait, with reduced range of motion in both knees over the entire gait cycle. Audiometry revealed symmetric moderate sensorineural hearing loss characteristic of presbycusis.

Diagnostic investigations

Consider focused investigations into imbalance based on the history and physical examination. We discourage overly broad testing and imaging; in primary care, cost and limited access to technology can bar robust investigations into causes of imbalance. However, identification of acute pathologies should prompt immediate referral to the emergency department. Furthermore, specific symptoms (TABLE 1^7-56) should prompt referral to specialists for assessment.

Continue to: In the emergency department...

In the emergency department and academic hospitals, key investigations can identify causes of imbalance:

• Electrocardiography and Holter monitoring test for cardiac arrhythmias.
• Echocardiography identifies structural abnormalities.
• Radiography and computed tomography are useful for detecting musculoskeletal abnormalities.
• Bone densitometry can identify osteoporosis.
• Head and spinal cord magnetic resonance imaging can be used to identify lesions of the central nervous system.
• Computed tomographic angiography of the head and neck is useful for identifying stroke, cerebral atrophy, and stenotic lesions of the carotid and vertebral arteries.
• Nerve conduction studies and levels of serum vitamin B₁₂, hemoglobin A1C, thyroid-stimulating hormone, and random cortisol can uncover causes of peripheral neuropathy.
• Bedside cognitive screening tests can be used to measure cognitive decline.⁷²
• Suspicion of vestibular disease requires audiometry and vestibular testing, including videonystagmography, head impulse testing, and vestibular evoked myogenic potentials.

In many cases of imbalance, no specific underlying correctable cause is discovered.

Management of imbalance

Pharmacotherapy

Targeted pharmacotherapy can be utilized in select clinical scenarios:

• Medical treatment of peripheral neuropathy should target the underlying condition.
• Cognitive behavioral therapy and antidepressants are useful for treating anxiety and depressive disorders.⁷³
• Musculoskeletal pain can be managed with acetaminophen and topical nonsteroidal anti-inflammatory drugs (NSAIDs), using a short course of an oral NSAID when needed.⁷⁴
• Cardiovascular disease management might include any of several classes of pharmacotherapy, including antiplatelet and lipid-lowering medications, antiarrhythmic drugs, and antihypertensive agents.
• Acute episodes of vertigo due to vestibular neuritis or labyrinthitis can be managed with an antiemetic.⁴⁶

Surgical treatment

Surgery is infrequently considered for patients with imbalance. Examples of indications include microsurgical resection of vestibular schwannoma, resection of central nervous system tumors, lens replacement surgery for cataract, surgical management of severe spinal fracture, and hip or knee arthroplasty in select patients.

Tools for assessing the risk of falls

Scoring systems called falls risk assessment tools, or FRAT, have been developed to gauge a patient’s risk of falling. The various FRATs differ in specificity and sensitivity for predicting the risk of falls, and are typically designed for specific clinical environments, such as hospital inpatient care or long-term care facilities. Specifically, FRATs attempt to classify risk using sets of risk factors known to be associated with falls.

Continue to: Research abounds into...

In our experience, most patients with imbalance and who are at risk of falls do not have a detectable deficit of the vestibular system.

Research abounds into the validity of commonly used FRATs across institutions, patient populations, and clinical environments:

The Johns Hopkins FRAT^a determines risk using metrics such as age, fall history, incontinence, cognition, mobility, and medications⁷⁵; it is predominantly used for assessment in hospital inpatient units. This tool has been validated repeatedly.^76,77

Peninsula Health FRAT^b stratifies patients in subacute and residential aged-care settings, based on risk factors that include recent falls, medications, psychological status, and cognition.⁷⁸

FRAT-up^c is a web-based tool that generates falls risk using risk factors that users input. This tool has been studied in the context of patients older than 65 years living in the community.⁷⁹

Although FRATs are reasonably useful for predicting falls, their utility varies by patient population and clinical context. Moreover, it has been suggested that FRATs neglect environmental and personal factors when assessing risk by focusing primarily on bodily factors.⁸⁰ Implementing a FRAT requires extensive consideration of the target population and should be accompanied by clinical judgment that is grounded in an individual patient’s circumstances.⁸¹

Continue to: Preventing falls in primary care

An approach to preventing falls includes the development of individualized programs that account for frailty, a syndrome of physiologic decline associated with aging. Because frailty leads to diminished balance and mobility, a patient’s frailty index—determined using the 5 frailty phenotype criteria (exhaustion, weight loss, low physical activity, weakness, slowness)⁸² or the Canadian Study of Health and Aging Clinical Frailty Scale⁸³—is a useful tool for predicting falls risk and readmission for falls following trauma-related injury. Prevention of falls in communities is critical for reducing mortality and allowing older people to maintain their independence and quality of life.

Exercise. In some areas, exercise and falls prevention programs are accessible to seniors.⁸⁴ Community exercise programs that focus on balance retraining and muscle strengthening can reduce the risk of falls.^73,85 The Choosing Wisely initiative of the ABIM [American Board of Internal Medicine] Foundation recommends that exercise programs be designed around an accurate functional baseline of the patient to avoid underdosed strength training.⁵⁴

Multifactorial risk assessment in high-risk patients can reduce the rate of falls. Such an assessment includes examination of orthostatic blood pressure, vision and hearing, bone health, gait, activities of daily living, cognition, and environmental hazards, and enables provision of necessary interventions.^73,86 Hearing amplification, specifically, correlates with enhanced postural control, slowed cognitive decline, and a reduced likelihood of falls.^87-93 The mechanism behind improved balance performance might be reduced cognitive load through supporting a patient’s listening needs.^88-90

Pharmacotherapy. Optimizing medications and performing a complete medication review before prescribing new medications is highly recommended to avoid unnecessary polypharmacy^7,8,18,53-56 (TABLE 1^7-56).

Management of comorbidities associated with a higher risk of falls, including arthritis, cancer, stroke, diabetes, depression, kidney disease, chronic obstructive pulmonary disease, cognitive impairment, hypertension, and atrial fibrillation, is essential.^94-96

Continue to: Home safety interventions

Home safety interventions, through occupational therapy, are important. These include removing unsafe mats and step-overs and installing nonslip strips on stairs, ­double-sided tape under mats, and handrails.^73-97

Screening for risk of falls. The Centers for Disease Control and Prevention recommends that (1) all patients older than 65 years and (2) any patient presenting with an acute fall undergo screening for their risk of falls.⁹⁸ When a patient is identified as at risk of falling, you can, when appropriate, assess modifiable risk factors and facilitate interventions.⁹⁸ This strategy is supported by a 2018 statement from the US Preventive Services Task Force⁹⁹ that recommends identifying high-risk patients who have:

• a history of falling
• a balance disturbance that causes a deficit of mobility or function
• poor performance on clinical tests, such as the 3-meter Timed Up and Go (TUG) assessment (www.cdc.gov/steadi/pdf/TUG_test-print.pdf).

In addition to visual, proprioception, and vestibular dysfunction, cognitive and neurologic decline are also factors in imbalance.

An increased risk of falls should prompt you to refer the patient to community programs and physiotherapy in accordance with the individual’s personal goals⁹⁹; a balance and vestibular physiotherapist is ideally positioned to accurately assess and manage patients at risk of falls. Specifically, the Task Force identified exercise programs and multifactorial interventions as being beneficial in preventing falls in high-risk older people.⁹⁹

Balance assessment and rehabilitation in specialty centers

Polypharmacy— typically, defined as taking 4 or more medications— has been repeatedly associated with a heightened risk of falls.

An individualized rehabilitation program aims to restore safe mobility by testing and addressing specific balance deficits, improving functional balance, and increasing balance confidence. Collaboration with colleagues from physiotherapy and occupational therapy aids in tailoring individualized programs.

Many tests are available to assess balance, determine the risk of falls, and guide rehabilitation:

• The timed 10-meter walk test^d and the TUG test are simple assessments that measure functional mobility; both have normalized values for the risk of falls. A TUG time of ≥ 12 seconds suggests a high risk of falls.
• The 30-second chair stand^e evaluates functional lower-extremity strength in older patients. The test can indicate if lower-extremity strength is contributing to a patient’s imbalance.
• The modified clinical test of sensory interaction in balance^f is a static balance test that measures the integrity of sensory inputs. The test can suggest if 1 or more sensory systems are compromised.
• The mini balance evaluation systems test^g is similar: It can differentiate balance deficits by underlying system and allows individualization of a rehabilitation program.
• The functional gait assessment^h is a modification of the dynamic gait index that assesses postural stability during everyday dynamic activities, including tasks such as walking with head turns and pivots.
• The Berg Balance Scaleⁱ continues to be used extensively to assess balance.

Continue to: The mini balance evaluation systems test...

All patients older than 65 years and any patient presenting with an acute fall should undergo screening for their risk of falls.

The mini balance evaluation systems test, functional gait index, and Berg Balance Scale all have normative age-graded values to predict fall risk.

CASE

Mr. J was referred for balance assessment and to a rehabilitation program. He underwent balance physiotherapy, including multifactorial balance assessment, joined a community exercise program, was fitted with hearing aids, and had his home environment optimized by an occupational therapist. (See examples of “home safety interventions” under “Preventing falls in primary care.”)

Exercise programs should be designed around an accurate functional baseline of the patient to avoid underdosed strength training.

3 months later. Mr. J says he feels stronger on his feet. His knee pain has eased, and he is more confident walking around his home. He continues to engage in exercise programs and is comfortable running errands with his spouse.

CORRESPONDENCE
Jason A. Beyea, MD, PhD, FRCSC, Division of OtolaryngologyHead and Neck Surgery, Queen’s University, 144 Brock Street, Kingston, Ontario, Canada, K7L 5G2; [email protected]

^awww.hopkinsmedicine.org/institute_nursing/models_tools/jhfrat_acute%20care%20original_6_22_17.pdf

^bhttps://content.health.vic.gov.au/sites/default/files/migrated/files/collections/policies-and-guidelines/b/b2b_1a_frat_pdf.pdf

^cwww.ncbi.nlm.nih.gov/pmc/articles/PMC4376110/figure/figure14/?report=objectonly

^dwww.neuropt.org/docs/default-source/cpgs/core-outcome-measures/core-measure-10-meter-walk-test-(10mwt)_final.pdf?sfvrsn=c5585243_2&sfvrsn =c5585243_2

^ewww.cdc.gov/steadi/pdf/STEADI-Assessment-30Sec-508.pdf

^fwww.mdapp.co/mctsib-modified-clinical-test-of-sensory-interaction-in-balance-calculator-404/

^gwww.sralab.org/sites/default/files/2017-07/MiniBEST_revised_final_3_8_13.pdf

^hwww.neuropt.org/docs/default-source/cpgs/core-outcome-measures/function-gait-assessment-pocket-guide-proof9-(2).pdf?sfvrsn=b4f35043_0

ⁱwww.ncbi.nlm.nih.gov/books/NBK574518/

CASE Mr. J, a 75-year-old man, presents to your family practice reporting that he feels increasingly unsteady and slow while walking. He fell twice last year, without resulting injury. He now worries about tripping while walking around the house and relies on his spouse to run errands.

Almost 30% of people older than 65 years report 1 or more falls annually.

Clearly, Mr. J is experiencing a problem with balance. What management approach should you undertake to prevent him from falling?

Copyright Scott Bodell

Balance disorders are common in older people and drastically hinder quality of life.^1-4 Patients often describe imbalance as vague symptoms: dizziness, unsteadiness, faintness, spinning sensations.^5,6 Importantly, balance disorders disrupt normal gait and contribute to falls that are a major cause of disability and morbidity in older people. Almost 30% of people older than 65 years report 1 or more falls annually.⁷ Factors that increase the risk of falls include impaired mobility, previously reported falls, reduced psychological functioning, chronic medical conditions, and polypharmacy.^7,8

The cause of any single case of imbalance is often multifactorial, resulting from dysfunction of multiple body systems (TABLE 1^7-56); in our clinical experience, most patients with imbalance and who are at risk of falls do not have a detectable deficit of the vestibular system. These alterations in function arise in 3 key systems—vision, proprioception, and vestibular function—which signal to, and are incorporated by, the cerebellum to mediate balance. Cognitive and neurologic decline are also factors in imbalance.

Considering that 20% of falls result in serious injury in older populations, it is important to identify balance disorders and implement preventive strategies to mitigate harmful consequences of falls on patients’ health and independence.^7,57 In this article, we answer the question that the case presentation raises about the proper management approach to imbalance in family practice, including assessment of risk and rehabilitation strategies to reduce the risk of falls. Our insights and recommendations are based on our clinical experience and a review of the medical literature from the past 40 years.

CASE Mr. J has a history of hypertension, age-­related hearing loss, and osteoarthritis of the knees; he has not had surgery for the arthritis. His medications are antihypertensives and extra-strength acetaminophen for knee pain.

Making the diagnosis of a balance disorder

History

A thorough clinical history, often including a collateral history from caregivers, narrows the differential diagnosis. Information regarding onset, duration, timing, character, and previous episodes of imbalance is essential. Symptoms of imbalance are often challenging for the patient to describe: They might use terms such as vertigo or dizziness, when, in fact, on further questioning, they are describing balance difficulties. Inquiry into (1) their use of assistive walking devices and (2) development or exacerbation of neurologic, musculoskeletal, auditory, visual, and mood symptoms is necessary. Note the current level of their mobility, episodes of pain or fatigue, previous falls and associated injuries, fear of falling, balance confidence, and sensations that precede falls.⁵⁸

Continue to: The medical and surgical histories

The medical and surgical histories are key pieces of information. The history of smoking, alcohol habits, and substance use is relevant.

A robust medication history is essential to evaluate a patient’s risk of falling. Polypharmacy—typically, defined as taking 4 or more medications—has been repeatedly associated with a heightened risk of falls.^53,59-61 Moreover, a dose-dependent association between polypharmacy and hospitalization following falls has been identified, and demonstrates that taking 10 or more medications greatly increases the risk of hospitalization.⁵⁹ Studies of polypharmacy cement the importance of inquiring about medication use when assessing imbalance, particularly in older patients.

Physical examination

A focused and detailed physical examination provides insight into systems that should be investigated:

• Obtain vital signs, including orthostatic vitals to test for orthostatic hypotension⁶²; keep in mind that symptoms of orthostatic dizziness can occur without orthostatic hypotension.
• Examine gait, which can distinguish between causes of imbalance (TABLE 2).^21,40,63-70
• Perform a cardiac examination.
• Assess visual acuity and visual fields; test for nystagmus and identify any optic-nerve and retinal abnormalities.
• Evaluate lower-limb sensation, proprioception, and motor function.
• Evaluate suspected vestibular dysfunction, including dysfunction with positional testing (the Dix-Hallpike maneuver⁷¹). The patient is taken from sitting to supine while the head is rotated 45° to the tested side by the examiner. As the patient moves into a supine position, the neck is extended 30° off the table and held for at least 30 seconds. The maneuver is positive if torsional nystagmus is noted while the head is held rotated during neck extension. The maneuver is negative if the patient reports dizziness, vertigo, unsteadiness, or “pressure in the head.” Torsional nystagmus must be present to confirm a diagnosis of benign paroxysmal positional vertigo.
• If you suspect a central nervous system cause of imbalance, assess the cranial nerves, coordination, strength, and, of course, balance.

CASE

Mr. J’s physical examination showed normal vital signs without significant postural changes in blood pressure. Gait analysis revealed a slowed gait, with reduced range of motion in both knees over the entire gait cycle. Audiometry revealed symmetric moderate sensorineural hearing loss characteristic of presbycusis.

Diagnostic investigations

Consider focused investigations into imbalance based on the history and physical examination. We discourage overly broad testing and imaging; in primary care, cost and limited access to technology can bar robust investigations into causes of imbalance. However, identification of acute pathologies should prompt immediate referral to the emergency department. Furthermore, specific symptoms (TABLE 1^7-56) should prompt referral to specialists for assessment.

Continue to: In the emergency department...

In the emergency department and academic hospitals, key investigations can identify causes of imbalance:

• Electrocardiography and Holter monitoring test for cardiac arrhythmias.
• Echocardiography identifies structural abnormalities.
• Radiography and computed tomography are useful for detecting musculoskeletal abnormalities.
• Bone densitometry can identify osteoporosis.
• Head and spinal cord magnetic resonance imaging can be used to identify lesions of the central nervous system.
• Computed tomographic angiography of the head and neck is useful for identifying stroke, cerebral atrophy, and stenotic lesions of the carotid and vertebral arteries.
• Nerve conduction studies and levels of serum vitamin B₁₂, hemoglobin A1C, thyroid-stimulating hormone, and random cortisol can uncover causes of peripheral neuropathy.
• Bedside cognitive screening tests can be used to measure cognitive decline.⁷²
• Suspicion of vestibular disease requires audiometry and vestibular testing, including videonystagmography, head impulse testing, and vestibular evoked myogenic potentials.

In many cases of imbalance, no specific underlying correctable cause is discovered.

Management of imbalance

Pharmacotherapy

Targeted pharmacotherapy can be utilized in select clinical scenarios:

• Medical treatment of peripheral neuropathy should target the underlying condition.
• Cognitive behavioral therapy and antidepressants are useful for treating anxiety and depressive disorders.⁷³
• Musculoskeletal pain can be managed with acetaminophen and topical nonsteroidal anti-inflammatory drugs (NSAIDs), using a short course of an oral NSAID when needed.⁷⁴
• Cardiovascular disease management might include any of several classes of pharmacotherapy, including antiplatelet and lipid-lowering medications, antiarrhythmic drugs, and antihypertensive agents.
• Acute episodes of vertigo due to vestibular neuritis or labyrinthitis can be managed with an antiemetic.⁴⁶

Surgical treatment

Surgery is infrequently considered for patients with imbalance. Examples of indications include microsurgical resection of vestibular schwannoma, resection of central nervous system tumors, lens replacement surgery for cataract, surgical management of severe spinal fracture, and hip or knee arthroplasty in select patients.

Tools for assessing the risk of falls

Scoring systems called falls risk assessment tools, or FRAT, have been developed to gauge a patient’s risk of falling. The various FRATs differ in specificity and sensitivity for predicting the risk of falls, and are typically designed for specific clinical environments, such as hospital inpatient care or long-term care facilities. Specifically, FRATs attempt to classify risk using sets of risk factors known to be associated with falls.

Continue to: Research abounds into...

In our experience, most patients with imbalance and who are at risk of falls do not have a detectable deficit of the vestibular system.

Research abounds into the validity of commonly used FRATs across institutions, patient populations, and clinical environments:

The Johns Hopkins FRAT^a determines risk using metrics such as age, fall history, incontinence, cognition, mobility, and medications⁷⁵; it is predominantly used for assessment in hospital inpatient units. This tool has been validated repeatedly.^76,77

Peninsula Health FRAT^b stratifies patients in subacute and residential aged-care settings, based on risk factors that include recent falls, medications, psychological status, and cognition.⁷⁸

FRAT-up^c is a web-based tool that generates falls risk using risk factors that users input. This tool has been studied in the context of patients older than 65 years living in the community.⁷⁹

Although FRATs are reasonably useful for predicting falls, their utility varies by patient population and clinical context. Moreover, it has been suggested that FRATs neglect environmental and personal factors when assessing risk by focusing primarily on bodily factors.⁸⁰ Implementing a FRAT requires extensive consideration of the target population and should be accompanied by clinical judgment that is grounded in an individual patient’s circumstances.⁸¹

Continue to: Preventing falls in primary care

An approach to preventing falls includes the development of individualized programs that account for frailty, a syndrome of physiologic decline associated with aging. Because frailty leads to diminished balance and mobility, a patient’s frailty index—determined using the 5 frailty phenotype criteria (exhaustion, weight loss, low physical activity, weakness, slowness)⁸² or the Canadian Study of Health and Aging Clinical Frailty Scale⁸³—is a useful tool for predicting falls risk and readmission for falls following trauma-related injury. Prevention of falls in communities is critical for reducing mortality and allowing older people to maintain their independence and quality of life.

Exercise. In some areas, exercise and falls prevention programs are accessible to seniors.⁸⁴ Community exercise programs that focus on balance retraining and muscle strengthening can reduce the risk of falls.^73,85 The Choosing Wisely initiative of the ABIM [American Board of Internal Medicine] Foundation recommends that exercise programs be designed around an accurate functional baseline of the patient to avoid underdosed strength training.⁵⁴

Multifactorial risk assessment in high-risk patients can reduce the rate of falls. Such an assessment includes examination of orthostatic blood pressure, vision and hearing, bone health, gait, activities of daily living, cognition, and environmental hazards, and enables provision of necessary interventions.^73,86 Hearing amplification, specifically, correlates with enhanced postural control, slowed cognitive decline, and a reduced likelihood of falls.^87-93 The mechanism behind improved balance performance might be reduced cognitive load through supporting a patient’s listening needs.^88-90

Pharmacotherapy. Optimizing medications and performing a complete medication review before prescribing new medications is highly recommended to avoid unnecessary polypharmacy^7,8,18,53-56 (TABLE 1^7-56).

Management of comorbidities associated with a higher risk of falls, including arthritis, cancer, stroke, diabetes, depression, kidney disease, chronic obstructive pulmonary disease, cognitive impairment, hypertension, and atrial fibrillation, is essential.^94-96

Continue to: Home safety interventions

Home safety interventions, through occupational therapy, are important. These include removing unsafe mats and step-overs and installing nonslip strips on stairs, ­double-sided tape under mats, and handrails.^73-97

Screening for risk of falls. The Centers for Disease Control and Prevention recommends that (1) all patients older than 65 years and (2) any patient presenting with an acute fall undergo screening for their risk of falls.⁹⁸ When a patient is identified as at risk of falling, you can, when appropriate, assess modifiable risk factors and facilitate interventions.⁹⁸ This strategy is supported by a 2018 statement from the US Preventive Services Task Force⁹⁹ that recommends identifying high-risk patients who have:

• a history of falling
• a balance disturbance that causes a deficit of mobility or function
• poor performance on clinical tests, such as the 3-meter Timed Up and Go (TUG) assessment (www.cdc.gov/steadi/pdf/TUG_test-print.pdf).

In addition to visual, proprioception, and vestibular dysfunction, cognitive and neurologic decline are also factors in imbalance.

An increased risk of falls should prompt you to refer the patient to community programs and physiotherapy in accordance with the individual’s personal goals⁹⁹; a balance and vestibular physiotherapist is ideally positioned to accurately assess and manage patients at risk of falls. Specifically, the Task Force identified exercise programs and multifactorial interventions as being beneficial in preventing falls in high-risk older people.⁹⁹

Balance assessment and rehabilitation in specialty centers

Polypharmacy— typically, defined as taking 4 or more medications— has been repeatedly associated with a heightened risk of falls.

An individualized rehabilitation program aims to restore safe mobility by testing and addressing specific balance deficits, improving functional balance, and increasing balance confidence. Collaboration with colleagues from physiotherapy and occupational therapy aids in tailoring individualized programs.

Many tests are available to assess balance, determine the risk of falls, and guide rehabilitation:

• The timed 10-meter walk test^d and the TUG test are simple assessments that measure functional mobility; both have normalized values for the risk of falls. A TUG time of ≥ 12 seconds suggests a high risk of falls.
• The 30-second chair stand^e evaluates functional lower-extremity strength in older patients. The test can indicate if lower-extremity strength is contributing to a patient’s imbalance.
• The modified clinical test of sensory interaction in balance^f is a static balance test that measures the integrity of sensory inputs. The test can suggest if 1 or more sensory systems are compromised.
• The mini balance evaluation systems test^g is similar: It can differentiate balance deficits by underlying system and allows individualization of a rehabilitation program.
• The functional gait assessment^h is a modification of the dynamic gait index that assesses postural stability during everyday dynamic activities, including tasks such as walking with head turns and pivots.
• The Berg Balance Scaleⁱ continues to be used extensively to assess balance.

Continue to: The mini balance evaluation systems test...

All patients older than 65 years and any patient presenting with an acute fall should undergo screening for their risk of falls.

The mini balance evaluation systems test, functional gait index, and Berg Balance Scale all have normative age-graded values to predict fall risk.

CASE

Mr. J was referred for balance assessment and to a rehabilitation program. He underwent balance physiotherapy, including multifactorial balance assessment, joined a community exercise program, was fitted with hearing aids, and had his home environment optimized by an occupational therapist. (See examples of “home safety interventions” under “Preventing falls in primary care.”)

Exercise programs should be designed around an accurate functional baseline of the patient to avoid underdosed strength training.

3 months later. Mr. J says he feels stronger on his feet. His knee pain has eased, and he is more confident walking around his home. He continues to engage in exercise programs and is comfortable running errands with his spouse.

CORRESPONDENCE
Jason A. Beyea, MD, PhD, FRCSC, Division of OtolaryngologyHead and Neck Surgery, Queen’s University, 144 Brock Street, Kingston, Ontario, Canada, K7L 5G2; [email protected]

^awww.hopkinsmedicine.org/institute_nursing/models_tools/jhfrat_acute%20care%20original_6_22_17.pdf

^bhttps://content.health.vic.gov.au/sites/default/files/migrated/files/collections/policies-and-guidelines/b/b2b_1a_frat_pdf.pdf

^cwww.ncbi.nlm.nih.gov/pmc/articles/PMC4376110/figure/figure14/?report=objectonly

^dwww.neuropt.org/docs/default-source/cpgs/core-outcome-measures/core-measure-10-meter-walk-test-(10mwt)_final.pdf?sfvrsn=c5585243_2&sfvrsn =c5585243_2

^ewww.cdc.gov/steadi/pdf/STEADI-Assessment-30Sec-508.pdf

^fwww.mdapp.co/mctsib-modified-clinical-test-of-sensory-interaction-in-balance-calculator-404/

^gwww.sralab.org/sites/default/files/2017-07/MiniBEST_revised_final_3_8_13.pdf

^hwww.neuropt.org/docs/default-source/cpgs/core-outcome-measures/function-gait-assessment-pocket-guide-proof9-(2).pdf?sfvrsn=b4f35043_0

ⁱwww.ncbi.nlm.nih.gov/books/NBK574518/

The World Health Organization estimates that, in 2020, worldwide, there were 604,000 new cases of uterine cervical cancer and approximately 342,000 deaths, 84% of which occurred in developing countries.¹ In the United States, as of 2018, the lifetime risk of death from cervical cancer was 2.2 for every 100,000, with a mean age of 50 years at diagnosis.²

In this article, we summarize recent updates in the epidemiology, prevention, and treatment of cervical cancer. We emphasize recent information of value to family physicians, including updates in clinical guidelines and other pertinent national recommendations.

Spotlight continues to shine on HPV

It has been known for several decades that cervical cancer is caused by human papillomavirus (HPV). Of more than 100 known HPV types, 14 or 15 are classified as carcinogenic. HPV 16 is the most common oncogenic type, causing more than 60% of cases of cervical cancer^3,4; HPV 18 is second, causing 16.5% of cases—taken together, the 2 types account for more than 75% of cervical cancers.

HPV is the most common sexually transmitted infection, with as many as 80% of sexually active people becoming infected during their lifetime, generally before 50 years of age.⁵ HPV also causes other anogenital and oropharyngeal cancers; however, worldwide, more than 80% of HPV-associated cancers are cervical.⁶ Risk factors for cervical cancer are listed in TABLE 1.⁷ Cervical cancer is less common when partners are circumcised.⁷

Most cases of HPV infection clear in 1 or 2 years. In approximately 1% of untreated cases, cancer develops. Once infection progresses to high-grade dysplasia (ie, cervical intraepithelial neoplasia [CIN] 3), further progression to invasive cervical cancer occurs in approximately 30% of untreated cases.⁸ Patients who develop cervical cancer generally test positive for a high-risk HPV genotype for at least 3 to 5 years before infection progresses to cancer.⁹

At least 70% of cervical cancers are squamous cell carcinoma (SCC); 20% to 25% are adenocarcinoma (ADC); and < 3% to 5% are adenosquamous carcinoma.¹⁰ Almost 100% of cervical SCCs are HPV+, as are 86% of cervical ADCs. The most common reason for HPV-negative status in patients with cervical cancer is false-negative testing because of inadequate methods.

Primary prevention through vaccination

HPV vaccination was introduced in 2006 in the United States for girls,^a and for boys^a in 2011. The primary reason for vaccinating boys is to reduce the rates of HPV-related anal and oropharyngeal cancer. The only available HPV vaccine in the United States is Gardasil 9 (9-valent vaccine, recombinant; Merck), which provides coverage for 7 high-risk HPV types that account for approximately 90% of cervical cancers and 2 types (6 and 11) that are the principal causes of condylomata acuminata (genital warts). Future generations of prophylactic vaccines are expected to cover additional strains.

Continue to: Vaccine studies...

Vaccine studies have been summarized in a Cochrane review,¹¹ showing that vaccination is highly effective for prevention of cervical dysplasia, especially when given to young girls and women^a previously unexposed to the virus. It has not been fully established how long protection lasts, but vaccination appears to be 70% to 90% effective for ≥ 10 years.

Dosing schedule. The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) recommends a 2-dose schedule 6 to 15 months apart, for both girls and boys between 9 and 14 years of age.¹² A third dose is indicated if the first and second doses were given less than 5 months apart, or the person is older than 15 years or is immunocompromised. No recommendation has been made for revaccination after the primary series.

In 2018, the US Food and Drug Administration approved Gardasil 9 for adults 27 to 45 years of age. In June 2019, ACIP recommended vaccination for men^a as old as 26 years, and adopted a recommendation that unvaccinated men and women between 27 and 45 years discuss HPV vaccination with their physician.¹³

The adolescent HPV vaccination rate varies by state; however, all states lag behind the CDC’s Healthy People 2020 goal of 80%.¹⁴ Barriers to vaccination include cost, infrastructure limitations, and social stigma.

Secondary prevention: Screening and Tx of precancerous lesions

Cervical cancer screening identifies patients at increased risk of cervical cancer and reassures the great majority of them that their risk of cervical cancer is very low. There are 3 general approaches to cervical cancer screening:

• cytology-based screening, which has been implemented for decades in many countries
• primary testing for DNA or RNA markers of high-risk HPV types
• co-testing with cytology-based screening plus HPV testing.

Continue to: USPSTF guidance

USPSTF guidance. Recommendations of the US Preventive Services Task Force (USPSTF) for cervical cancer screening were updated in 2018 (TABLE 2¹⁵). The recommendations state that high-risk HPV screening alone is a strategy that is amenable to patient self-sampling and self-mailing for processing—a protocol that has the potential to improve access to testing for patients who are inadequately screened.

ASCCP guidance. The American Society of Colposcopy and Cervical Pathology (ASCCP) makes nearly the same recommendations for cervical cancer screening. An exception is that ASCCP guidelines allow for the possibility of screening using primary high-risk HPV testing for patients starting at 25 years of age.¹⁶

Screening programs that can be initiated at a later age and longer intervals should be possible once the adolescent vaccination rate is optimized and vaccination registries are widely implemented.

Cervical cytology protocol

Cervical cytologic abnormalities are reported using the Bethesda system. Specimen adequacy is the most important component of quality assurance,¹⁷ and is determined primarily by sufficient cellularity. However, any specimen containing abnormal squamous cells of undetermined significance (ASCUS) or atypical glandular cells (AGCs) is considered satisfactory, regardless of the number of cells. Obscuring factors that impair quality include excessive blood; inflammation; air-drying artifact; and an interfering substance, such as lubricant. The presence of reactive changes resulting from inflammation does not require further evaluation unless the patient is immunosuppressed.

Abnormalities are most often of squamous cells, of 2 categories: low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs). HSILs are more likely to be associated with persistent HPV infection and higher risk of progression to cervical cancer.

Continue to: Cytologic findings...

Cytologic findings can be associated with histologic findings that are sometimes more, sometimes less, severe. LSIL cytology specimens that contain a few cells that are suspicious for HSIL, but that do not contain enough cells to be diagnostic, are reported as atypical squamous cells, and do not exclude a high-grade intraepithelial lesion.

Glandular-cell abnormalities usually originate from the glandular epithelium of the endocervix or the endometrium—most often, AGCs. Less frequent are AGCs, favor neoplasia; endocervical adenocarcinoma in situ; and ADC. Rarely, AGCs are associated with adenosquamous carcinoma. Endometrial polyps are a typical benign pathology that can be associated with AGCs.

High-risk HPV screening alone is amenable to patient selfsampling and self-mailing for processing—a protocol that has the potential to improve access to testing.

In about 30% of cases, AGCs are associated with premalignant or malignant disease.¹⁸ The risk of malignancy in patients with AGCs increases with age, from < 2% among patients younger than 40 years to approximately 15% among those > 50 years.¹⁹ Endometrial malignancy is more common than cervical malignancy among patients > 40 years.

AGC cytology requires endocervical curettage, plus endometrial sampling for patients ≥ 35 years. Patients with a history of AGCs are at higher risk of cervical cancer for as long as 15 years.

Cytology-based screening has limitations. Sensitivity is relatively low and dependent on the expertise of the cytologist, although regular repeat testing has been used to overcome this limitation. A substantial subset of results are reported as equivocal—ie, ASCUS.

Continue to: Primary HPV screening

Primary HPV screening

Primary HPV testing was approved by the US Food and Drug Administration in 2015 and recommended as an appropriate screening option by professional societies.

In contrast to cytology-based screening, HPV testing has high sensitivity (≥ 90%); the population-based negative likelihood ratio is near zero.²⁰ This degree of sensitivity allows for extended screening intervals. However, primary HPV testing lacks specificity for persistent infection and high-grade or invasive lesions, which approximately doubles the number of patients who screen positive. The potential for excess patients to be referred for colposcopy led to the need for secondary triage.

Instituting secondary triage. Cytology is, currently, the primary method of secondary triage, reducing the number of referrals for colposcopy by nearly one-half, compared to referrals for all high-risk HPV results, and with better overall accuracy over cytology with high-risk HPV triage.²¹ When cytology shows ASCUS, or worse, refer the patient for colposcopy; alternatively, if so-called reflex testing for HPV types 16 and 18 is available and positive, direct referral to colposcopy without cytology is also appropriate.

In the future, secondary triage for cytology is likely to be replaced with improved technologies, such as immunostaining of the specimen for biomarkers associated with cervical precancer or cancer, or for viral genome methylation testing.²²

Management of abnormal cervical cancer screening results

Routine screening applies to asymptomatic patients who do not require surveillance because they have not had prior abnormal screening results. In 2020, ASCCP published risk-based management consensus guidelines that were developed for abnormal cervical cancer screening tests and for cancer precursors.¹⁶ Guiding principles, and screening situations in which the guidelines can be applied, are summarized in TABLE 3.¹⁶

Continue to: ASCCP guidelines...

ASCCP guidelines provide a framework to incorporate new data and technologies without major revision. The web-based ASCCP resource can be obtained at no cost at http://asccp.org; there is also a smartphone app resource ($9.99).

Some noteworthy scenarios in ASCCP risk-based management are:

• For unsatisfactory cytology with a negative HPV test or no HPV test, repeat age-based screening in 2 to 4 months. (Note: A negative HPV test might reflect an inadequate specimen; do not interpret this result as a true negative.)
• An absent transformation zone (ie, between glandular and squamous cervical cells) with an otherwise adequate specimen should be interpreted as satisfactory for screening in patients 21 to 29 years of age. For those ≥ 30 years and with no HPV testing in this circumstance, HPV testing is preferred; repeating cytology, in 3 years, is also acceptable.
• After a finding of LSIL/CIN1 without evidence of a high-grade abnormality, and after 2 negative annual screenings (including HPV testing), a return to 3-year (not 5-year) screening is ­recommended.
• A cytology result of an HSIL carries a risk of 26% for CIN3+, in which case colposcopy is recommended, regardless of HPV test results.
• For long-term management after treatment for CIN2+, continue surveillance testing every 3 years after 3 consecutive negative HPV tests or cytology findings, for at least 25 years. If the 25-year threshold is reached before 65 years of age, continuing surveillance every 3 years is optional, as long as the patient is in good health (ie, life expectancy ≥ 10 years).
• After hysterectomy for a high-grade abnormality, annual vaginal HPV testing is recommended until 3 negative tests are returned; after that, surveillance shifts to a 3-year interval until the 25-year threshold.

Treatment of cancer precursors

Treatment for cervical dysplasia is excisional or ablative.

Excisional therapy. In most cases, excisional therapy (either a loop electrosurgical excision procedure [LEEP; also known as large loop excision of the transformation zone, cold knife conization, and laser conization] or cone biopsy) is required, or preferred. Excisional treatment has the advantage of providing a diagnostic specimen.

In about 30% of cases, atypical glandular cells (AGCs) found on cytology are associated with premalignant or malignant disease. The risk of malignancy with AGCs increases with age.

The World Health Organization recommends LEEP over ablation in settings in which LEEP is available.²³ ASCCP states that, in the relatively few cases in which treatment is needed and it is for CIN1, either excision or ablation is acceptable. TABLE 4¹⁶ lists situations in which excisional treatment is required because a diagnostic specimen is needed.

Continue to: Ablative treatments

Ablative treatments are cryotherapy, CO₂ laser ablation, and thermal ablation. Ablative therapy has the advantage of presenting less risk of adverse obstetric outcomes (eg, preterm birth); it can be used if the indication for therapy is:

• CIN1 or CIN2 and HPV type 16 or 18 positivity
• concordant cytology and histology
• satisfactory colposcopy
• negative endocervical curettage.

The most common ablative treatment is liquid nitrogen applied to a metal tip under local anesthesia.

Hysterectomy can be considered for patients with recurrent CIN2+ who have completed childbearing or for whom repeat excision is infeasible (eg, scarring or a short cervix), or both.

Cost, availability, and convenience might play a role in decision-making with regard to the treatment choice for cancer precursors.

Is care after treatment called for? Patients who continue to be at increased risk of (and thus mortality from) cervical and vaginal cancer require enhanced surveillance. The risk of cancer is more than triple for patients who were given their diagnosis, and treated, when they were > 60 years, compared to patients treated in their 30s.¹ The excess period of risk covers at least 25 years after treatment, even among patients who have had 3 posttreatment screenings.

Continue to: Persistent HPV positivity...

Persistent HPV positivity is more challenging. Patients infected with HPV type 16 have an increased risk of residual disease.

Cancer management

Invasive cancer. Most cervical cancers (60%) occur among patients who have not been screened during the 5 years before their diagnosis.²⁴ For patients who have a diagnosis of cancer, those detected through screening have a much better prognosis than those identified by symptoms (mean cure rate, 92% and 66%, respectively).²⁵ The median 5-year survival for patients who were not screened during the 5 years before their diagnosis of cervical cancer is 66%.²

In unscreened patients, cervical cancer usually manifests as abnormal vaginal bleeding, especially postcoitally. In approximately 45% of cases, the patient has localized disease at diagnosis; in 36%, regional disease; and in 15%, distant metastases.²⁶

For cancers marked by stromal invasion < 3 mm, appropriate treatment is cone biopsy or simple hysterectomy.²⁷

Most patients with early-stage cervical cancer undergo modified radical hysterectomy. The ovaries are usually conserved, unless the cancer is adenocarcinoma. Sentinel-node dissection has become standard practice. Primary radiation therapy is most often used for patients who are a poor surgical candidate because of medical comorbidity or poor functional status. Antiangiogenic agents (eg, bevacizumab) can be used as adjuvant palliative therapy for advanced and recurrent disease.²⁸

Continue to: After treatment for...

After treatment for invasive cervical cancer, the goal is early detection of recurrence, although there is no consensus on a protocol. Most recurrences are detected within the first 2 years.

After treatment for invasive cervical cancer, the goal is early detection of recurrence. Most recurrences are detected within the first 2 years.

Long-term sequelae after treatment for advanced cancer are considerable. Patients report significantly lower quality of life, comparatively, across multiple dimensions, including mental health, physical health, and sexual function.²⁹

Hormone replacement therapy is generally considered acceptable after treatment of cervical cancer because it does not increase replication of HPV.

Recurrent or metastatic cancer. Recurrence or metastases will develop in 15% to 60% of patients,³⁰ usually within the first 2 years after treatment.

Management depends on location and extent of disease, using mainly radiation therapy or surgical resection. Recurrence or metastasis is usually incurable.

Continue to: Last, there are promising...

Last, there are promising areas of research for more effective treatment for cervical cancer precursors and cancers, including gene editing tools³¹ and therapeutic vaccination,³² which is intended to target and kill infected cells.

Prospects for better cervical cancer care

Prevention. HPV vaccination is likely to have a large impact on population-based risk of both cancer and cancer precursors in the next generation.

Screening in the foreseeable future will gravitate toward reliance on primary HPV screening, with a self-sampling option.

Surveillance after dysplastic disease. The 2019 ASCCP guidelines for surveillance and intervention decisions after abnormal cancer screening results will evolve to incorporate introduction of new technology into computerized algorithms.

Treatment. New biologic therapies, including monoclonal antibodies and therapeutic vaccines against HPV, will likely be introduced for treating cancer precursors and invasive cancer.

A NOTE FROM THE EDITORS The Editors of The Journal of Family Practice recognize the importance of addressing the reproductive health of gender-diverse individuals. In this article, we use the words “women,” “men,” “girls,” and “boys” in limited circumstances (1) for ease of reading and (2) to reflect the official language of the US Food and Drug Administration and the Advisory Committee on Immunization Practices. The reader should consider the information and guidance offered in this discussion of cervical cancer and other human papillomavirus-related cancers to speak to the care of people with a uterine cervix and people with a penis.

CORRESPONDENCE
Linda Speer, MD, 3000 Arlington Avenue, MS 1179, Toledo, OH 43614; [email protected]

The World Health Organization estimates that, in 2020, worldwide, there were 604,000 new cases of uterine cervical cancer and approximately 342,000 deaths, 84% of which occurred in developing countries.¹ In the United States, as of 2018, the lifetime risk of death from cervical cancer was 2.2 for every 100,000, with a mean age of 50 years at diagnosis.²

In this article, we summarize recent updates in the epidemiology, prevention, and treatment of cervical cancer. We emphasize recent information of value to family physicians, including updates in clinical guidelines and other pertinent national recommendations.

Spotlight continues to shine on HPV

It has been known for several decades that cervical cancer is caused by human papillomavirus (HPV). Of more than 100 known HPV types, 14 or 15 are classified as carcinogenic. HPV 16 is the most common oncogenic type, causing more than 60% of cases of cervical cancer^3,4; HPV 18 is second, causing 16.5% of cases—taken together, the 2 types account for more than 75% of cervical cancers.

HPV is the most common sexually transmitted infection, with as many as 80% of sexually active people becoming infected during their lifetime, generally before 50 years of age.⁵ HPV also causes other anogenital and oropharyngeal cancers; however, worldwide, more than 80% of HPV-associated cancers are cervical.⁶ Risk factors for cervical cancer are listed in TABLE 1.⁷ Cervical cancer is less common when partners are circumcised.⁷

Most cases of HPV infection clear in 1 or 2 years. In approximately 1% of untreated cases, cancer develops. Once infection progresses to high-grade dysplasia (ie, cervical intraepithelial neoplasia [CIN] 3), further progression to invasive cervical cancer occurs in approximately 30% of untreated cases.⁸ Patients who develop cervical cancer generally test positive for a high-risk HPV genotype for at least 3 to 5 years before infection progresses to cancer.⁹

At least 70% of cervical cancers are squamous cell carcinoma (SCC); 20% to 25% are adenocarcinoma (ADC); and < 3% to 5% are adenosquamous carcinoma.¹⁰ Almost 100% of cervical SCCs are HPV+, as are 86% of cervical ADCs. The most common reason for HPV-negative status in patients with cervical cancer is false-negative testing because of inadequate methods.

Primary prevention through vaccination

HPV vaccination was introduced in 2006 in the United States for girls,^a and for boys^a in 2011. The primary reason for vaccinating boys is to reduce the rates of HPV-related anal and oropharyngeal cancer. The only available HPV vaccine in the United States is Gardasil 9 (9-valent vaccine, recombinant; Merck), which provides coverage for 7 high-risk HPV types that account for approximately 90% of cervical cancers and 2 types (6 and 11) that are the principal causes of condylomata acuminata (genital warts). Future generations of prophylactic vaccines are expected to cover additional strains.

Continue to: Vaccine studies...

Vaccine studies have been summarized in a Cochrane review,¹¹ showing that vaccination is highly effective for prevention of cervical dysplasia, especially when given to young girls and women^a previously unexposed to the virus. It has not been fully established how long protection lasts, but vaccination appears to be 70% to 90% effective for ≥ 10 years.

Dosing schedule. The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) recommends a 2-dose schedule 6 to 15 months apart, for both girls and boys between 9 and 14 years of age.¹² A third dose is indicated if the first and second doses were given less than 5 months apart, or the person is older than 15 years or is immunocompromised. No recommendation has been made for revaccination after the primary series.

In 2018, the US Food and Drug Administration approved Gardasil 9 for adults 27 to 45 years of age. In June 2019, ACIP recommended vaccination for men^a as old as 26 years, and adopted a recommendation that unvaccinated men and women between 27 and 45 years discuss HPV vaccination with their physician.¹³

The adolescent HPV vaccination rate varies by state; however, all states lag behind the CDC’s Healthy People 2020 goal of 80%.¹⁴ Barriers to vaccination include cost, infrastructure limitations, and social stigma.

Secondary prevention: Screening and Tx of precancerous lesions

Cervical cancer screening identifies patients at increased risk of cervical cancer and reassures the great majority of them that their risk of cervical cancer is very low. There are 3 general approaches to cervical cancer screening:

• cytology-based screening, which has been implemented for decades in many countries
• primary testing for DNA or RNA markers of high-risk HPV types
• co-testing with cytology-based screening plus HPV testing.

Continue to: USPSTF guidance

USPSTF guidance. Recommendations of the US Preventive Services Task Force (USPSTF) for cervical cancer screening were updated in 2018 (TABLE 2¹⁵). The recommendations state that high-risk HPV screening alone is a strategy that is amenable to patient self-sampling and self-mailing for processing—a protocol that has the potential to improve access to testing for patients who are inadequately screened.

ASCCP guidance. The American Society of Colposcopy and Cervical Pathology (ASCCP) makes nearly the same recommendations for cervical cancer screening. An exception is that ASCCP guidelines allow for the possibility of screening using primary high-risk HPV testing for patients starting at 25 years of age.¹⁶

Screening programs that can be initiated at a later age and longer intervals should be possible once the adolescent vaccination rate is optimized and vaccination registries are widely implemented.

Cervical cytology protocol

Cervical cytologic abnormalities are reported using the Bethesda system. Specimen adequacy is the most important component of quality assurance,¹⁷ and is determined primarily by sufficient cellularity. However, any specimen containing abnormal squamous cells of undetermined significance (ASCUS) or atypical glandular cells (AGCs) is considered satisfactory, regardless of the number of cells. Obscuring factors that impair quality include excessive blood; inflammation; air-drying artifact; and an interfering substance, such as lubricant. The presence of reactive changes resulting from inflammation does not require further evaluation unless the patient is immunosuppressed.

Abnormalities are most often of squamous cells, of 2 categories: low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs). HSILs are more likely to be associated with persistent HPV infection and higher risk of progression to cervical cancer.

Continue to: Cytologic findings...

Cytologic findings can be associated with histologic findings that are sometimes more, sometimes less, severe. LSIL cytology specimens that contain a few cells that are suspicious for HSIL, but that do not contain enough cells to be diagnostic, are reported as atypical squamous cells, and do not exclude a high-grade intraepithelial lesion.

Glandular-cell abnormalities usually originate from the glandular epithelium of the endocervix or the endometrium—most often, AGCs. Less frequent are AGCs, favor neoplasia; endocervical adenocarcinoma in situ; and ADC. Rarely, AGCs are associated with adenosquamous carcinoma. Endometrial polyps are a typical benign pathology that can be associated with AGCs.

High-risk HPV screening alone is amenable to patient selfsampling and self-mailing for processing—a protocol that has the potential to improve access to testing.

In about 30% of cases, AGCs are associated with premalignant or malignant disease.¹⁸ The risk of malignancy in patients with AGCs increases with age, from < 2% among patients younger than 40 years to approximately 15% among those > 50 years.¹⁹ Endometrial malignancy is more common than cervical malignancy among patients > 40 years.

AGC cytology requires endocervical curettage, plus endometrial sampling for patients ≥ 35 years. Patients with a history of AGCs are at higher risk of cervical cancer for as long as 15 years.

Cytology-based screening has limitations. Sensitivity is relatively low and dependent on the expertise of the cytologist, although regular repeat testing has been used to overcome this limitation. A substantial subset of results are reported as equivocal—ie, ASCUS.

Continue to: Primary HPV screening

Primary HPV screening

Primary HPV testing was approved by the US Food and Drug Administration in 2015 and recommended as an appropriate screening option by professional societies.

In contrast to cytology-based screening, HPV testing has high sensitivity (≥ 90%); the population-based negative likelihood ratio is near zero.²⁰ This degree of sensitivity allows for extended screening intervals. However, primary HPV testing lacks specificity for persistent infection and high-grade or invasive lesions, which approximately doubles the number of patients who screen positive. The potential for excess patients to be referred for colposcopy led to the need for secondary triage.

Instituting secondary triage. Cytology is, currently, the primary method of secondary triage, reducing the number of referrals for colposcopy by nearly one-half, compared to referrals for all high-risk HPV results, and with better overall accuracy over cytology with high-risk HPV triage.²¹ When cytology shows ASCUS, or worse, refer the patient for colposcopy; alternatively, if so-called reflex testing for HPV types 16 and 18 is available and positive, direct referral to colposcopy without cytology is also appropriate.

In the future, secondary triage for cytology is likely to be replaced with improved technologies, such as immunostaining of the specimen for biomarkers associated with cervical precancer or cancer, or for viral genome methylation testing.²²

Management of abnormal cervical cancer screening results

Routine screening applies to asymptomatic patients who do not require surveillance because they have not had prior abnormal screening results. In 2020, ASCCP published risk-based management consensus guidelines that were developed for abnormal cervical cancer screening tests and for cancer precursors.¹⁶ Guiding principles, and screening situations in which the guidelines can be applied, are summarized in TABLE 3.¹⁶

Continue to: ASCCP guidelines...

ASCCP guidelines provide a framework to incorporate new data and technologies without major revision. The web-based ASCCP resource can be obtained at no cost at http://asccp.org; there is also a smartphone app resource ($9.99).

Some noteworthy scenarios in ASCCP risk-based management are:

• For unsatisfactory cytology with a negative HPV test or no HPV test, repeat age-based screening in 2 to 4 months. (Note: A negative HPV test might reflect an inadequate specimen; do not interpret this result as a true negative.)
• An absent transformation zone (ie, between glandular and squamous cervical cells) with an otherwise adequate specimen should be interpreted as satisfactory for screening in patients 21 to 29 years of age. For those ≥ 30 years and with no HPV testing in this circumstance, HPV testing is preferred; repeating cytology, in 3 years, is also acceptable.
• After a finding of LSIL/CIN1 without evidence of a high-grade abnormality, and after 2 negative annual screenings (including HPV testing), a return to 3-year (not 5-year) screening is ­recommended.
• A cytology result of an HSIL carries a risk of 26% for CIN3+, in which case colposcopy is recommended, regardless of HPV test results.
• For long-term management after treatment for CIN2+, continue surveillance testing every 3 years after 3 consecutive negative HPV tests or cytology findings, for at least 25 years. If the 25-year threshold is reached before 65 years of age, continuing surveillance every 3 years is optional, as long as the patient is in good health (ie, life expectancy ≥ 10 years).
• After hysterectomy for a high-grade abnormality, annual vaginal HPV testing is recommended until 3 negative tests are returned; after that, surveillance shifts to a 3-year interval until the 25-year threshold.

Treatment of cancer precursors

Treatment for cervical dysplasia is excisional or ablative.

Excisional therapy. In most cases, excisional therapy (either a loop electrosurgical excision procedure [LEEP; also known as large loop excision of the transformation zone, cold knife conization, and laser conization] or cone biopsy) is required, or preferred. Excisional treatment has the advantage of providing a diagnostic specimen.

In about 30% of cases, atypical glandular cells (AGCs) found on cytology are associated with premalignant or malignant disease. The risk of malignancy with AGCs increases with age.

The World Health Organization recommends LEEP over ablation in settings in which LEEP is available.²³ ASCCP states that, in the relatively few cases in which treatment is needed and it is for CIN1, either excision or ablation is acceptable. TABLE 4¹⁶ lists situations in which excisional treatment is required because a diagnostic specimen is needed.

Continue to: Ablative treatments

Ablative treatments are cryotherapy, CO₂ laser ablation, and thermal ablation. Ablative therapy has the advantage of presenting less risk of adverse obstetric outcomes (eg, preterm birth); it can be used if the indication for therapy is:

• CIN1 or CIN2 and HPV type 16 or 18 positivity
• concordant cytology and histology
• satisfactory colposcopy
• negative endocervical curettage.

The most common ablative treatment is liquid nitrogen applied to a metal tip under local anesthesia.

Hysterectomy can be considered for patients with recurrent CIN2+ who have completed childbearing or for whom repeat excision is infeasible (eg, scarring or a short cervix), or both.

Cost, availability, and convenience might play a role in decision-making with regard to the treatment choice for cancer precursors.

Is care after treatment called for? Patients who continue to be at increased risk of (and thus mortality from) cervical and vaginal cancer require enhanced surveillance. The risk of cancer is more than triple for patients who were given their diagnosis, and treated, when they were > 60 years, compared to patients treated in their 30s.¹ The excess period of risk covers at least 25 years after treatment, even among patients who have had 3 posttreatment screenings.

Continue to: Persistent HPV positivity...

Persistent HPV positivity is more challenging. Patients infected with HPV type 16 have an increased risk of residual disease.

Cancer management

Invasive cancer. Most cervical cancers (60%) occur among patients who have not been screened during the 5 years before their diagnosis.²⁴ For patients who have a diagnosis of cancer, those detected through screening have a much better prognosis than those identified by symptoms (mean cure rate, 92% and 66%, respectively).²⁵ The median 5-year survival for patients who were not screened during the 5 years before their diagnosis of cervical cancer is 66%.²

In unscreened patients, cervical cancer usually manifests as abnormal vaginal bleeding, especially postcoitally. In approximately 45% of cases, the patient has localized disease at diagnosis; in 36%, regional disease; and in 15%, distant metastases.²⁶

For cancers marked by stromal invasion < 3 mm, appropriate treatment is cone biopsy or simple hysterectomy.²⁷

Most patients with early-stage cervical cancer undergo modified radical hysterectomy. The ovaries are usually conserved, unless the cancer is adenocarcinoma. Sentinel-node dissection has become standard practice. Primary radiation therapy is most often used for patients who are a poor surgical candidate because of medical comorbidity or poor functional status. Antiangiogenic agents (eg, bevacizumab) can be used as adjuvant palliative therapy for advanced and recurrent disease.²⁸

Continue to: After treatment for...

After treatment for invasive cervical cancer, the goal is early detection of recurrence, although there is no consensus on a protocol. Most recurrences are detected within the first 2 years.

After treatment for invasive cervical cancer, the goal is early detection of recurrence. Most recurrences are detected within the first 2 years.

Long-term sequelae after treatment for advanced cancer are considerable. Patients report significantly lower quality of life, comparatively, across multiple dimensions, including mental health, physical health, and sexual function.²⁹

Hormone replacement therapy is generally considered acceptable after treatment of cervical cancer because it does not increase replication of HPV.

Recurrent or metastatic cancer. Recurrence or metastases will develop in 15% to 60% of patients,³⁰ usually within the first 2 years after treatment.

Management depends on location and extent of disease, using mainly radiation therapy or surgical resection. Recurrence or metastasis is usually incurable.

Continue to: Last, there are promising...

Last, there are promising areas of research for more effective treatment for cervical cancer precursors and cancers, including gene editing tools³¹ and therapeutic vaccination,³² which is intended to target and kill infected cells.

Prospects for better cervical cancer care

Prevention. HPV vaccination is likely to have a large impact on population-based risk of both cancer and cancer precursors in the next generation.

Screening in the foreseeable future will gravitate toward reliance on primary HPV screening, with a self-sampling option.

Surveillance after dysplastic disease. The 2019 ASCCP guidelines for surveillance and intervention decisions after abnormal cancer screening results will evolve to incorporate introduction of new technology into computerized algorithms.

Treatment. New biologic therapies, including monoclonal antibodies and therapeutic vaccines against HPV, will likely be introduced for treating cancer precursors and invasive cancer.

A NOTE FROM THE EDITORS The Editors of The Journal of Family Practice recognize the importance of addressing the reproductive health of gender-diverse individuals. In this article, we use the words “women,” “men,” “girls,” and “boys” in limited circumstances (1) for ease of reading and (2) to reflect the official language of the US Food and Drug Administration and the Advisory Committee on Immunization Practices. The reader should consider the information and guidance offered in this discussion of cervical cancer and other human papillomavirus-related cancers to speak to the care of people with a uterine cervix and people with a penis.

CORRESPONDENCE
Linda Speer, MD, 3000 Arlington Avenue, MS 1179, Toledo, OH 43614; [email protected]

The World Health Organization estimates that, in 2020, worldwide, there were 604,000 new cases of uterine cervical cancer and approximately 342,000 deaths, 84% of which occurred in developing countries.¹ In the United States, as of 2018, the lifetime risk of death from cervical cancer was 2.2 for every 100,000, with a mean age of 50 years at diagnosis.²

In this article, we summarize recent updates in the epidemiology, prevention, and treatment of cervical cancer. We emphasize recent information of value to family physicians, including updates in clinical guidelines and other pertinent national recommendations.

Spotlight continues to shine on HPV

It has been known for several decades that cervical cancer is caused by human papillomavirus (HPV). Of more than 100 known HPV types, 14 or 15 are classified as carcinogenic. HPV 16 is the most common oncogenic type, causing more than 60% of cases of cervical cancer^3,4; HPV 18 is second, causing 16.5% of cases—taken together, the 2 types account for more than 75% of cervical cancers.

HPV is the most common sexually transmitted infection, with as many as 80% of sexually active people becoming infected during their lifetime, generally before 50 years of age.⁵ HPV also causes other anogenital and oropharyngeal cancers; however, worldwide, more than 80% of HPV-associated cancers are cervical.⁶ Risk factors for cervical cancer are listed in TABLE 1.⁷ Cervical cancer is less common when partners are circumcised.⁷

Most cases of HPV infection clear in 1 or 2 years. In approximately 1% of untreated cases, cancer develops. Once infection progresses to high-grade dysplasia (ie, cervical intraepithelial neoplasia [CIN] 3), further progression to invasive cervical cancer occurs in approximately 30% of untreated cases.⁸ Patients who develop cervical cancer generally test positive for a high-risk HPV genotype for at least 3 to 5 years before infection progresses to cancer.⁹

At least 70% of cervical cancers are squamous cell carcinoma (SCC); 20% to 25% are adenocarcinoma (ADC); and < 3% to 5% are adenosquamous carcinoma.¹⁰ Almost 100% of cervical SCCs are HPV+, as are 86% of cervical ADCs. The most common reason for HPV-negative status in patients with cervical cancer is false-negative testing because of inadequate methods.

Primary prevention through vaccination

HPV vaccination was introduced in 2006 in the United States for girls,^a and for boys^a in 2011. The primary reason for vaccinating boys is to reduce the rates of HPV-related anal and oropharyngeal cancer. The only available HPV vaccine in the United States is Gardasil 9 (9-valent vaccine, recombinant; Merck), which provides coverage for 7 high-risk HPV types that account for approximately 90% of cervical cancers and 2 types (6 and 11) that are the principal causes of condylomata acuminata (genital warts). Future generations of prophylactic vaccines are expected to cover additional strains.

Continue to: Vaccine studies...

Vaccine studies have been summarized in a Cochrane review,¹¹ showing that vaccination is highly effective for prevention of cervical dysplasia, especially when given to young girls and women^a previously unexposed to the virus. It has not been fully established how long protection lasts, but vaccination appears to be 70% to 90% effective for ≥ 10 years.

Dosing schedule. The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) recommends a 2-dose schedule 6 to 15 months apart, for both girls and boys between 9 and 14 years of age.¹² A third dose is indicated if the first and second doses were given less than 5 months apart, or the person is older than 15 years or is immunocompromised. No recommendation has been made for revaccination after the primary series.

In 2018, the US Food and Drug Administration approved Gardasil 9 for adults 27 to 45 years of age. In June 2019, ACIP recommended vaccination for men^a as old as 26 years, and adopted a recommendation that unvaccinated men and women between 27 and 45 years discuss HPV vaccination with their physician.¹³

The adolescent HPV vaccination rate varies by state; however, all states lag behind the CDC’s Healthy People 2020 goal of 80%.¹⁴ Barriers to vaccination include cost, infrastructure limitations, and social stigma.

Secondary prevention: Screening and Tx of precancerous lesions

Cervical cancer screening identifies patients at increased risk of cervical cancer and reassures the great majority of them that their risk of cervical cancer is very low. There are 3 general approaches to cervical cancer screening:

• cytology-based screening, which has been implemented for decades in many countries
• primary testing for DNA or RNA markers of high-risk HPV types
• co-testing with cytology-based screening plus HPV testing.

Continue to: USPSTF guidance

USPSTF guidance. Recommendations of the US Preventive Services Task Force (USPSTF) for cervical cancer screening were updated in 2018 (TABLE 2¹⁵). The recommendations state that high-risk HPV screening alone is a strategy that is amenable to patient self-sampling and self-mailing for processing—a protocol that has the potential to improve access to testing for patients who are inadequately screened.

ASCCP guidance. The American Society of Colposcopy and Cervical Pathology (ASCCP) makes nearly the same recommendations for cervical cancer screening. An exception is that ASCCP guidelines allow for the possibility of screening using primary high-risk HPV testing for patients starting at 25 years of age.¹⁶

Screening programs that can be initiated at a later age and longer intervals should be possible once the adolescent vaccination rate is optimized and vaccination registries are widely implemented.

Cervical cytology protocol

Cervical cytologic abnormalities are reported using the Bethesda system. Specimen adequacy is the most important component of quality assurance,¹⁷ and is determined primarily by sufficient cellularity. However, any specimen containing abnormal squamous cells of undetermined significance (ASCUS) or atypical glandular cells (AGCs) is considered satisfactory, regardless of the number of cells. Obscuring factors that impair quality include excessive blood; inflammation; air-drying artifact; and an interfering substance, such as lubricant. The presence of reactive changes resulting from inflammation does not require further evaluation unless the patient is immunosuppressed.

Abnormalities are most often of squamous cells, of 2 categories: low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs). HSILs are more likely to be associated with persistent HPV infection and higher risk of progression to cervical cancer.

Continue to: Cytologic findings...

Cytologic findings can be associated with histologic findings that are sometimes more, sometimes less, severe. LSIL cytology specimens that contain a few cells that are suspicious for HSIL, but that do not contain enough cells to be diagnostic, are reported as atypical squamous cells, and do not exclude a high-grade intraepithelial lesion.

Glandular-cell abnormalities usually originate from the glandular epithelium of the endocervix or the endometrium—most often, AGCs. Less frequent are AGCs, favor neoplasia; endocervical adenocarcinoma in situ; and ADC. Rarely, AGCs are associated with adenosquamous carcinoma. Endometrial polyps are a typical benign pathology that can be associated with AGCs.

High-risk HPV screening alone is amenable to patient selfsampling and self-mailing for processing—a protocol that has the potential to improve access to testing.

In about 30% of cases, AGCs are associated with premalignant or malignant disease.¹⁸ The risk of malignancy in patients with AGCs increases with age, from < 2% among patients younger than 40 years to approximately 15% among those > 50 years.¹⁹ Endometrial malignancy is more common than cervical malignancy among patients > 40 years.

AGC cytology requires endocervical curettage, plus endometrial sampling for patients ≥ 35 years. Patients with a history of AGCs are at higher risk of cervical cancer for as long as 15 years.

Cytology-based screening has limitations. Sensitivity is relatively low and dependent on the expertise of the cytologist, although regular repeat testing has been used to overcome this limitation. A substantial subset of results are reported as equivocal—ie, ASCUS.

Continue to: Primary HPV screening

Primary HPV screening

Primary HPV testing was approved by the US Food and Drug Administration in 2015 and recommended as an appropriate screening option by professional societies.

In contrast to cytology-based screening, HPV testing has high sensitivity (≥ 90%); the population-based negative likelihood ratio is near zero.²⁰ This degree of sensitivity allows for extended screening intervals. However, primary HPV testing lacks specificity for persistent infection and high-grade or invasive lesions, which approximately doubles the number of patients who screen positive. The potential for excess patients to be referred for colposcopy led to the need for secondary triage.

Instituting secondary triage. Cytology is, currently, the primary method of secondary triage, reducing the number of referrals for colposcopy by nearly one-half, compared to referrals for all high-risk HPV results, and with better overall accuracy over cytology with high-risk HPV triage.²¹ When cytology shows ASCUS, or worse, refer the patient for colposcopy; alternatively, if so-called reflex testing for HPV types 16 and 18 is available and positive, direct referral to colposcopy without cytology is also appropriate.

In the future, secondary triage for cytology is likely to be replaced with improved technologies, such as immunostaining of the specimen for biomarkers associated with cervical precancer or cancer, or for viral genome methylation testing.²²

Management of abnormal cervical cancer screening results

Routine screening applies to asymptomatic patients who do not require surveillance because they have not had prior abnormal screening results. In 2020, ASCCP published risk-based management consensus guidelines that were developed for abnormal cervical cancer screening tests and for cancer precursors.¹⁶ Guiding principles, and screening situations in which the guidelines can be applied, are summarized in TABLE 3.¹⁶

Continue to: ASCCP guidelines...

ASCCP guidelines provide a framework to incorporate new data and technologies without major revision. The web-based ASCCP resource can be obtained at no cost at http://asccp.org; there is also a smartphone app resource ($9.99).

Some noteworthy scenarios in ASCCP risk-based management are:

• For unsatisfactory cytology with a negative HPV test or no HPV test, repeat age-based screening in 2 to 4 months. (Note: A negative HPV test might reflect an inadequate specimen; do not interpret this result as a true negative.)
• An absent transformation zone (ie, between glandular and squamous cervical cells) with an otherwise adequate specimen should be interpreted as satisfactory for screening in patients 21 to 29 years of age. For those ≥ 30 years and with no HPV testing in this circumstance, HPV testing is preferred; repeating cytology, in 3 years, is also acceptable.
• After a finding of LSIL/CIN1 without evidence of a high-grade abnormality, and after 2 negative annual screenings (including HPV testing), a return to 3-year (not 5-year) screening is ­recommended.
• A cytology result of an HSIL carries a risk of 26% for CIN3+, in which case colposcopy is recommended, regardless of HPV test results.
• For long-term management after treatment for CIN2+, continue surveillance testing every 3 years after 3 consecutive negative HPV tests or cytology findings, for at least 25 years. If the 25-year threshold is reached before 65 years of age, continuing surveillance every 3 years is optional, as long as the patient is in good health (ie, life expectancy ≥ 10 years).
• After hysterectomy for a high-grade abnormality, annual vaginal HPV testing is recommended until 3 negative tests are returned; after that, surveillance shifts to a 3-year interval until the 25-year threshold.

Treatment of cancer precursors

Treatment for cervical dysplasia is excisional or ablative.

Excisional therapy. In most cases, excisional therapy (either a loop electrosurgical excision procedure [LEEP; also known as large loop excision of the transformation zone, cold knife conization, and laser conization] or cone biopsy) is required, or preferred. Excisional treatment has the advantage of providing a diagnostic specimen.

In about 30% of cases, atypical glandular cells (AGCs) found on cytology are associated with premalignant or malignant disease. The risk of malignancy with AGCs increases with age.

The World Health Organization recommends LEEP over ablation in settings in which LEEP is available.²³ ASCCP states that, in the relatively few cases in which treatment is needed and it is for CIN1, either excision or ablation is acceptable. TABLE 4¹⁶ lists situations in which excisional treatment is required because a diagnostic specimen is needed.

Continue to: Ablative treatments

Ablative treatments are cryotherapy, CO₂ laser ablation, and thermal ablation. Ablative therapy has the advantage of presenting less risk of adverse obstetric outcomes (eg, preterm birth); it can be used if the indication for therapy is:

• CIN1 or CIN2 and HPV type 16 or 18 positivity
• concordant cytology and histology
• satisfactory colposcopy
• negative endocervical curettage.

The most common ablative treatment is liquid nitrogen applied to a metal tip under local anesthesia.

Hysterectomy can be considered for patients with recurrent CIN2+ who have completed childbearing or for whom repeat excision is infeasible (eg, scarring or a short cervix), or both.

Cost, availability, and convenience might play a role in decision-making with regard to the treatment choice for cancer precursors.

Is care after treatment called for? Patients who continue to be at increased risk of (and thus mortality from) cervical and vaginal cancer require enhanced surveillance. The risk of cancer is more than triple for patients who were given their diagnosis, and treated, when they were > 60 years, compared to patients treated in their 30s.¹ The excess period of risk covers at least 25 years after treatment, even among patients who have had 3 posttreatment screenings.

Continue to: Persistent HPV positivity...

Persistent HPV positivity is more challenging. Patients infected with HPV type 16 have an increased risk of residual disease.

Cancer management

Invasive cancer. Most cervical cancers (60%) occur among patients who have not been screened during the 5 years before their diagnosis.²⁴ For patients who have a diagnosis of cancer, those detected through screening have a much better prognosis than those identified by symptoms (mean cure rate, 92% and 66%, respectively).²⁵ The median 5-year survival for patients who were not screened during the 5 years before their diagnosis of cervical cancer is 66%.²

In unscreened patients, cervical cancer usually manifests as abnormal vaginal bleeding, especially postcoitally. In approximately 45% of cases, the patient has localized disease at diagnosis; in 36%, regional disease; and in 15%, distant metastases.²⁶

For cancers marked by stromal invasion < 3 mm, appropriate treatment is cone biopsy or simple hysterectomy.²⁷

Most patients with early-stage cervical cancer undergo modified radical hysterectomy. The ovaries are usually conserved, unless the cancer is adenocarcinoma. Sentinel-node dissection has become standard practice. Primary radiation therapy is most often used for patients who are a poor surgical candidate because of medical comorbidity or poor functional status. Antiangiogenic agents (eg, bevacizumab) can be used as adjuvant palliative therapy for advanced and recurrent disease.²⁸

Continue to: After treatment for...

After treatment for invasive cervical cancer, the goal is early detection of recurrence, although there is no consensus on a protocol. Most recurrences are detected within the first 2 years.

After treatment for invasive cervical cancer, the goal is early detection of recurrence. Most recurrences are detected within the first 2 years.

Long-term sequelae after treatment for advanced cancer are considerable. Patients report significantly lower quality of life, comparatively, across multiple dimensions, including mental health, physical health, and sexual function.²⁹

Hormone replacement therapy is generally considered acceptable after treatment of cervical cancer because it does not increase replication of HPV.

Recurrent or metastatic cancer. Recurrence or metastases will develop in 15% to 60% of patients,³⁰ usually within the first 2 years after treatment.

Management depends on location and extent of disease, using mainly radiation therapy or surgical resection. Recurrence or metastasis is usually incurable.

Continue to: Last, there are promising...

Last, there are promising areas of research for more effective treatment for cervical cancer precursors and cancers, including gene editing tools³¹ and therapeutic vaccination,³² which is intended to target and kill infected cells.

Prospects for better cervical cancer care

Prevention. HPV vaccination is likely to have a large impact on population-based risk of both cancer and cancer precursors in the next generation.

Screening in the foreseeable future will gravitate toward reliance on primary HPV screening, with a self-sampling option.

Surveillance after dysplastic disease. The 2019 ASCCP guidelines for surveillance and intervention decisions after abnormal cancer screening results will evolve to incorporate introduction of new technology into computerized algorithms.

Treatment. New biologic therapies, including monoclonal antibodies and therapeutic vaccines against HPV, will likely be introduced for treating cancer precursors and invasive cancer.

A NOTE FROM THE EDITORS The Editors of The Journal of Family Practice recognize the importance of addressing the reproductive health of gender-diverse individuals. In this article, we use the words “women,” “men,” “girls,” and “boys” in limited circumstances (1) for ease of reading and (2) to reflect the official language of the US Food and Drug Administration and the Advisory Committee on Immunization Practices. The reader should consider the information and guidance offered in this discussion of cervical cancer and other human papillomavirus-related cancers to speak to the care of people with a uterine cervix and people with a penis.

CORRESPONDENCE
Linda Speer, MD, 3000 Arlington Avenue, MS 1179, Toledo, OH 43614; [email protected]

It is well-known that per capita health care spending in the United States is more than twice the average in other developed countries¹; nevertheless, the overall health care ranking of the US is near the bottom compared to other countries in this group.² Much of the reason for this poor relative showing lies in the fact that the US has employed a somewhat traditional fee-for-service health care model that does not incentivize efforts to promote health and wellness or prevent chronic disease. The paradigm of promoting physical activity for its disease-preventing and treatment benefits has not been well-integrated in the US health care system.

In this article, we endeavor to provide better understanding of the barriers that keep family physicians from routinely promoting physical activity in clinical practice; define tools and resources that can be used in the clinical setting to promote physical activity; and delineate areas for future work.

Glaring hole in US physical activity education

Many primary care physicians feel underprepared to prescribe or motivate patients to exercise. The reason for that lack of preparedness likely relates to a medical education system that does not spend time preparing physicians to perform this critical task. A study showed that, on average, medical schools require only 8 hours of physical activity education in their curriculum during the 4 years of schooling.³ Likewise, the average primary care residency program offers only 3 hours of didactic training on physical activity, nutrition, and obesity.⁴ The problem extends to sports medicine fellowship training, in which a 2019 survey showed that 63% of fellows were never taught how to write an exercise prescription in their training program.⁵

Medical professionals must be educated on the social determinants of health, including conditions in which people live, work, and play, which can contribute to health inequities.

Without education on physical activity, medical students, residents, and fellows are woefully underprepared to realize the therapeutic value of physical activity in patient care, comprehend current physical activity guidelines, appropriately motivate patients to engage in exercise, and competently discuss exercise prescriptions in different disease states. Throughout their training, it is imperative for medical professionals to be educated on the social determinants of health, which include the conditions in which people live, work, and play. These environmental variables can contribute to health inequities that create additional barriers to improvement in physical fitness.⁶

National guidelines on physical activity

The 2018 National Physical Activity Guidelines detail recommendations for children, adolescents, adults, and special populations.⁷ The guidelines define physical activity as bodily movement produced by skeletal muscles that result in energy expenditure above resting baseline levels, and includes all types, intensities, and domains of activity. Exercise is a subset of physical activity characterized as planned, structured, repetitive, and designed to improve or maintain physical fitness, physical performance, or health.

Highlights from the 2018 guidelines include⁷:

• Preschool-aged children (3 to 5 years of age) should be physically active throughout the day, with as much as 3 hours per day of physical activity of all intensities—light, moderate, and vigorous.
• Older children and adolescents (6 to 17 years) should accumulate 60 minutes per day of moderate-to-vigorous physical activity, including aerobic, muscle-strengthening, and bone-strengthening activities.
• Adults of all ages should achieve approximately 150 to 300 minutes of moderate or 75 to 150 minutes of vigorous physical activity (or an equivalent combination) per week, along with at least 2 days per week of ­muscle-strengthening activities. Other types of physical activity include flexibility, balance, bone-strengthening, and mind–body exercises.

3-step framework for enhancing physical activity counseling

Merely knowing that physical activity is healthy is not enough, during a patient encounter, to increase the level of physical activity. Therefore, it is imperative to learn and adopt a framework that has proved to yield successful outcomes. The Screening, Brief Intervention, and Referral to Treatment (SBIRT) framework, which has predominantly been used to change patient behavior related to alcohol and substance use, is now being utilized by some providers to promote physical activity.⁸ We apply the SBIRT approach in this article, although research is lacking on its clinical utility and outcome measures.

Continue to: SBIRT

An office visit provides an opportunity to understand a patient’s level of physical activity. Often, understanding a patient’s baseline level of activity is only asked during a thorough social history, which might not be performed during patient encounters. As physical activity is the primary determinant of cardiorespiratory fitness (CRF), some health care systems have begun delineating physical activity levels as a vital sign to ensure that the assessment of physical activity is a standard part of every clinical encounter. At a minimum, this serves as a prompt and provides an opportunity to start a conversation around improving physical activity levels when guidelines are not being met.

The exercise vital sign. Assessment and documentation of physical activity in the electronic health record are not yet standardized; however, Kaiser Permanente health plans have implemented the exercise vital sign, or EVS, in its HealthConnect (Epic Systems) electronic health record. The EVS incorporates information about a patient’s:

• days per week of moderate-to-­strenuous exercise (eg, a brisk walk)
• minutes per day, on average, of exercise at this level.

The physical activity vital sign. Intermountain Healthcare implemented the physical activity vital sign, or PAVS, in its iCentra (Cerner Corp.) electronic health record. The 3-question PAVS assessment asks:

• On average, how many days of the week do you perform physical activity or exercise?
• On average, how many total minutes of physical activity or exercise do you perform on those days?
• How would you describe the intensity of your physical activity or exercise: Light (ie, a casual walk)? Moderate (a brisk walk)? Or vigorous (jogging)?

PAVS includes a fourth data point: The physician–user documents whether the patient was counseled to start, increase, maintain, or modify physical activity or exercise.

EVS and the PAVS have demonstrated validity.^9-11

Continue to: Cardiorespiratory fitness as a vital sign

Cardiorespiratory fitness as a vital sign. In 2016, the American Heart Association (AHA) asserted the importance of assessing CRF as a clinical vital sign.¹² CRF is commonly expressed as maximal oxygen consumption (VO₂max = O₂ mL/kg/min) and measured through cardiopulmonary exercise testing (CPET), considered the gold standard by combining conventional graded exercise testing with ventilatory expired gas analysis. CPET is more objective and precise than equations estimating CRF that are derived from peak work rate. AHA recommended that efforts to improve CRF should become standard in clinical encounters, explaining that even a small increase in CRF (eg, 1 or 2 metabolic equivalents^a [METs]) is associated with a considerably (10% to 30%) lower rate of adverse cardiovascular events.¹²

The SBIRT framework, predominantly used to change patient behavior related to alcohol and substance use, is now being utilized by some clinicians to promote physical activity

De Souza de Silva and colleagues revealed an association between each 1-MET increase in CRF and per-person annual health care cost savings (adjusted for age and presence of cardiovascular disease) of $3272 (normal-weight patients), $4252 (overweight), and $6103 (obese).¹³ In its 2016 scientific statement on CRF as a vital sign, AHA listed several methods of estimating CRF and concluded that, although CPET involves a higher level of training, proficiency, equipment, and, therefore, cost, the independent and additive information obtained justifies its use in many patients.¹²

CASE 

Mary Q, 68 years of age, presents for an annual well-woman examination. Body mass index is 32; resting heart rate (HR), 73 bpm; and blood pressure, 126/74 mm Hg. She reports being inactive, except for light walking every day with her dog around the neighborhood, which takes them approximately 15 minutes. She denies any history or signs and symptoms of cardiovascular, metabolic, or renal disease.

You consider 3 questions before taking next steps regarding increasing Ms. Q’s activity level:

• What is her PAVS?
• Does she need medical clearance before starting an exercise program?
• What would an evidence-based cardiovascular exercise prescription for Ms. Q look like?

SBIRT: Brief intervention

When a patient does not meet the recommended level of physical activity, you have an opportunity to deliver a brief intervention. To do this effectively, you must have adequate understanding of the patient’s receptivity for change. The transtheoretical, or Stages of Change, model proposes that a person typically goes through 5 stages of growth—­pre-contemplation, contemplation, preparation, action, and maintenance—in the process of lifestyle modification. This model highlights the different approaches to exercise adoption and maintenance that need to be taken, based on a given patient’s stage at the moment.

Continue to: Using this framework...

Using this framework, you can help patients realize intrinsic motivation that can facilitate progression through each stage, utilizing techniques such as motivational interviewing—so-called change talk—to increase self-efficacy.¹⁴TABLE 1¹⁵ provides examples of motivational interviewing techniques that can be used during a patient encounter to improve health behaviors, such as physical activity.

Writing the exercise prescription

A patient who wants to increase their level of physical activity should be offered a formal exercise prescription, which has been shown to increase the level of physical activity, particularly in older patients. In fact, a study conducted in Spain in the practices of family physicians found that older patients who received a physical activity prescription increased their activity by 131 minutes per week; and compared to control patients, they doubled the minutes per week devoted to moderate or vigorous physical activity.¹⁶

FITT-VP. The basics of a cardiovascular exercise prescription can be found in the FITT-VP (Frequency, Intensity, Time, Type, Volume, and [monitoring of] Progression) framework (TABLE 2^17-19). For most patients, this model includes 3 to 5 days per week of moderate-to-vigorous physical activity for 30 to 60 minutes per session. For patients with established chronic disease, physical activity provides health benefits but might require modification. Disease-specific patient handouts for exercise can be downloaded, at no cost, through the American College of Sports Medicine (ACSM) “Exercise Is Medicine” program, which can be found at: www.exerciseismedicine.org/support_page.php/rx-for-health-series.

Determining intensity level. Although CPET is the gold standard for determining a patient’s target intensity level, such a test might be impracticable for a given patient. Surrogate markers of target intensity level can be obtained by measuring maximum HR (HRmax), using a well-known equation²⁰:

HRmax = 220 – age

which is then multiplied by intensity range:

• light: 30%-39%
• moderate: 40%-59%
• vigorous: 60%-89%

or, more preferably, by calculating the HR training zone while accounting for HR at rest (HRrest). This is accomplished by calculating the HR reserve (HRR) (ie, HRR = HRmax – HRrest) and then calculating the target heart rate (THR)²¹:

THR = [HRR × %intensity] + HRrest

Continue to: The THR calculation...

The THR calculation is performed twice, once with a lower %intensity and again with a higher %intensity to develop a training zone based on HRR.

The HRR equation is more accurate than calculating HRmax from 220 – age, because HRR accounts for resting HR, which is often lower in people who are better conditioned.

Another method of calculating intensity for patients who are beginning a physical activity program is the rating of perceived exertion (RPE), which is graded on a scale of 6 to 20: Moderate exercise correlates with an RPE of 12 to 13 (“somewhat hard”); vigorous exercise correlates with an RPE of 14 to 16 (“hard”). By adding a zero to the rating on the RPE scale, the corresponding HR in a healthy adult can be estimated when they are performing an activity at that perceived intensity.²² Moderate exercise therefore correlates with a HR of 120 and 130 bpm.

The so-called talk test can also guide exercise intensity: Light-intensity activity correlates with an ability to sing; moderate-intensity physical activity likely allows the patient to still hold a conversation; and vigorous-intensity activity correlates with an inability to carry on a conversation while exercising.

An exercise prescription should be accompanied by a patient-derived goal, which can be reassessed during a follow-up visit. So-called SMART goals (Specific, Measurable, Achievable, Relevant, and Time-bound) are tools to help patients set personalized and realistic expectations for physical activity. Meeting the goal of approximately 150 to 300 minutes of moderate or 75 to 150 minutes of vigorous physical activity (or an equivalent combination) per week is ideal, but a patient needs to start where they are, at the moment, and gradually increase activity by setting what for them are realistic and sustainable goals.

Continue to: CASE

CASE

With a PAVS of 105 minutes (ie, 15 minutes per day × 7 days) of weekly light-to-moderate exercise walking her dog, Ms. Q does not satisfy current physical activity guidelines. She needs an exercise prescription to incorporate into her lifestyle (see “Cardiovascular exercise prescription,” at left).

First, based on ACSM pre-participation guidelines, Ms. Q does not need medical clearance before initiating light-to-moderate exercise and gradually progressing to ­vigorous-intensity exercise.

Second, in addition to walking the dog for 105 minutes a week, you:

• advise her to start walking for 10 minutes, 3 times per week, at a pace that keeps her HR at 97-104 bpm.
• encourage her to gradually increase the frequency or duration of her walks by no more than 10% per week.

SBIRT: Referral for treatment

When referring a patient to a fitness program or professional, it is essential to consider their preferences, resources, and environment.²³ Community fitness partners are often an excellent referral option for a patient seeking guidance or structure for their exercise program. Using the ACSM ProFinder service, (www.acsm.org/get-stay-certified/find-a-pro) you can search for exercise professionals who have achieved the College’s Gold Standard credential.

Gym memberships or fitness programs might be part of the extra coverage offered by Medicare Advantage Plans, other Medicare health plans, or Medicare Supplement Insurance (Medigap) plans.²⁴

Continue to: CASE

CASE

After providing Ms. Q with her exercise prescription, you refer her to a local gym that participates in the Silver Sneakers fitness and wellness program (for adults ≥ 65 years of age in eligible Medicare plans) to determine whether she qualifies to begin resistance and flexibility training, for which you will write a second exercise prescription (TABLE 3^17-19).

Pre-participation screening

Updated 2015 ACSM exercise pre-participation health screening recommendations attempt to decrease possible barriers to people who are becoming more physically active, by minimizing unnecessary referral to health care providers before they change their level of physical activity. ACSM recommendations on exercise clearance include this guidance²⁵:

• For a patient who is asymptomatic and already physically active—regardless of whether they have known cardiovascular, metabolic, or renal disease—medical clearance is unnecessary for moderate-intensity exercise.
• Any patient who has been physically active and asymptomatic but who becomes symptomatic during exercise should immediately discontinue such activity and undergo medical evaluation.
• For a patient who is inactive, ­asymptomatic, and who does not have known cardiovascular, metabolic, or renal disease, medical clearance for light- or moderate-intensity exercise is unnecessary.
• For inactive, asymptomatic patients who have known cardiovascular, metabolic, or renal disease, medical clearance is recommended.

Digital health

Smartwatches and health apps (eg, CardioCoach, Fitbit, Garmin Connect, Nike Training Club, Strava, and Training Peaks) can provide workouts and offer patients the ability to collect information and even connect with other users through social media platforms. This information can be synced to Apple Health platforms for iPhones (www.apple.com/ios/health/) or through Google Fit (www.google.com/fit/) on Android devices. Primary care physicians who become familiar with health apps might find them useful for select patients who want to use technology to improve their physical activity level.

However, data on the value of using digital apps for increasing physical activity, in relation to their cost, are limited. Additional research is needed to assess their validity.

Billing and coding

For most patients, the physical activity assessment, prescription, and referral are performed in the context of treating another condition (eg, hypertension, type 2 diabetes, obesity, depression) or during a preventive health examination, and are typically covered without additional charge to the patient. An evaluation and management visit for an established patient could be used to bill if > 50% of the office visit was spent face-to-face with a physician, with patient counseling and coordination of care.

Continue to: Physicians and physical therapists...

Physicians and physical therapists can use the therapeutic exercise code (Current Procedural Terminology code 97110) when teaching patients exercises to develop muscle strength and endurance, joint range of motion, and flexibility²⁶ (TABLE 4²⁶).

Conclusion

Physical activity and CRF are strong predictors of premature mortality, even compared to other risk factors, such as cigarette smoking, hypertension, hypercholesterolemia, and type 2 diabetes.²⁷ Brief physical activity assessment and counseling is an efficient, effective, and cost-effective means to increase physical activity, and presents a unique opportunity for you to encourage lifestyle-based strategies for reducing cardiovascular risk.²⁸

The AHA has asserted the importance of assessing cardiorespiratory fitness as a “vital sign.”

However, it is essential to meet patients where they are before trying to have them progress; it is therefore imperative to assess the individual patient’s level of activity using PAVS. With that information in hand, you can personalize physical activity advice; determine readiness for change and potential barriers for change; assist the patient in setting SMART goals; and arrange follow-up to assess adherence to the exercise prescription. Encourage the patient to call their health insurance plan to determine whether a gym membership or fitness program is covered.

Research is needed to evaluate the value of using digital apps, in light of their cost, to increase physical activity and improve CRF in a clinical setting. Prospective trials should be initiated to determine how routine implementation of CRF assessment in primary care alters the trajectory of clinical care. It is hoped that future research will answer the question: Would such an approach improve clinical outcomes and reduce health care expenditures?¹²

a Defined as O2 consumed while sitting at rest; equivalent to 3.5 mL of O₂ × kg of body weight × min.

CORRESPONDENCE
Matthew Kampert, DO, MS, Sports Medicine, 5555 Transportation Boulevard, Cleveland, OH 44125; [email protected]

It is well-known that per capita health care spending in the United States is more than twice the average in other developed countries¹; nevertheless, the overall health care ranking of the US is near the bottom compared to other countries in this group.² Much of the reason for this poor relative showing lies in the fact that the US has employed a somewhat traditional fee-for-service health care model that does not incentivize efforts to promote health and wellness or prevent chronic disease. The paradigm of promoting physical activity for its disease-preventing and treatment benefits has not been well-integrated in the US health care system.

In this article, we endeavor to provide better understanding of the barriers that keep family physicians from routinely promoting physical activity in clinical practice; define tools and resources that can be used in the clinical setting to promote physical activity; and delineate areas for future work.

Glaring hole in US physical activity education

Many primary care physicians feel underprepared to prescribe or motivate patients to exercise. The reason for that lack of preparedness likely relates to a medical education system that does not spend time preparing physicians to perform this critical task. A study showed that, on average, medical schools require only 8 hours of physical activity education in their curriculum during the 4 years of schooling.³ Likewise, the average primary care residency program offers only 3 hours of didactic training on physical activity, nutrition, and obesity.⁴ The problem extends to sports medicine fellowship training, in which a 2019 survey showed that 63% of fellows were never taught how to write an exercise prescription in their training program.⁵

Medical professionals must be educated on the social determinants of health, including conditions in which people live, work, and play, which can contribute to health inequities.

Without education on physical activity, medical students, residents, and fellows are woefully underprepared to realize the therapeutic value of physical activity in patient care, comprehend current physical activity guidelines, appropriately motivate patients to engage in exercise, and competently discuss exercise prescriptions in different disease states. Throughout their training, it is imperative for medical professionals to be educated on the social determinants of health, which include the conditions in which people live, work, and play. These environmental variables can contribute to health inequities that create additional barriers to improvement in physical fitness.⁶

National guidelines on physical activity

The 2018 National Physical Activity Guidelines detail recommendations for children, adolescents, adults, and special populations.⁷ The guidelines define physical activity as bodily movement produced by skeletal muscles that result in energy expenditure above resting baseline levels, and includes all types, intensities, and domains of activity. Exercise is a subset of physical activity characterized as planned, structured, repetitive, and designed to improve or maintain physical fitness, physical performance, or health.

Highlights from the 2018 guidelines include⁷:

• Preschool-aged children (3 to 5 years of age) should be physically active throughout the day, with as much as 3 hours per day of physical activity of all intensities—light, moderate, and vigorous.
• Older children and adolescents (6 to 17 years) should accumulate 60 minutes per day of moderate-to-vigorous physical activity, including aerobic, muscle-strengthening, and bone-strengthening activities.
• Adults of all ages should achieve approximately 150 to 300 minutes of moderate or 75 to 150 minutes of vigorous physical activity (or an equivalent combination) per week, along with at least 2 days per week of ­muscle-strengthening activities. Other types of physical activity include flexibility, balance, bone-strengthening, and mind–body exercises.

3-step framework for enhancing physical activity counseling

Merely knowing that physical activity is healthy is not enough, during a patient encounter, to increase the level of physical activity. Therefore, it is imperative to learn and adopt a framework that has proved to yield successful outcomes. The Screening, Brief Intervention, and Referral to Treatment (SBIRT) framework, which has predominantly been used to change patient behavior related to alcohol and substance use, is now being utilized by some providers to promote physical activity.⁸ We apply the SBIRT approach in this article, although research is lacking on its clinical utility and outcome measures.

Continue to: SBIRT

An office visit provides an opportunity to understand a patient’s level of physical activity. Often, understanding a patient’s baseline level of activity is only asked during a thorough social history, which might not be performed during patient encounters. As physical activity is the primary determinant of cardiorespiratory fitness (CRF), some health care systems have begun delineating physical activity levels as a vital sign to ensure that the assessment of physical activity is a standard part of every clinical encounter. At a minimum, this serves as a prompt and provides an opportunity to start a conversation around improving physical activity levels when guidelines are not being met.

The exercise vital sign. Assessment and documentation of physical activity in the electronic health record are not yet standardized; however, Kaiser Permanente health plans have implemented the exercise vital sign, or EVS, in its HealthConnect (Epic Systems) electronic health record. The EVS incorporates information about a patient’s:

• days per week of moderate-to-­strenuous exercise (eg, a brisk walk)
• minutes per day, on average, of exercise at this level.

The physical activity vital sign. Intermountain Healthcare implemented the physical activity vital sign, or PAVS, in its iCentra (Cerner Corp.) electronic health record. The 3-question PAVS assessment asks:

• On average, how many days of the week do you perform physical activity or exercise?
• On average, how many total minutes of physical activity or exercise do you perform on those days?
• How would you describe the intensity of your physical activity or exercise: Light (ie, a casual walk)? Moderate (a brisk walk)? Or vigorous (jogging)?

PAVS includes a fourth data point: The physician–user documents whether the patient was counseled to start, increase, maintain, or modify physical activity or exercise.

EVS and the PAVS have demonstrated validity.^9-11

Continue to: Cardiorespiratory fitness as a vital sign

Cardiorespiratory fitness as a vital sign. In 2016, the American Heart Association (AHA) asserted the importance of assessing CRF as a clinical vital sign.¹² CRF is commonly expressed as maximal oxygen consumption (VO₂max = O₂ mL/kg/min) and measured through cardiopulmonary exercise testing (CPET), considered the gold standard by combining conventional graded exercise testing with ventilatory expired gas analysis. CPET is more objective and precise than equations estimating CRF that are derived from peak work rate. AHA recommended that efforts to improve CRF should become standard in clinical encounters, explaining that even a small increase in CRF (eg, 1 or 2 metabolic equivalents^a [METs]) is associated with a considerably (10% to 30%) lower rate of adverse cardiovascular events.¹²

The SBIRT framework, predominantly used to change patient behavior related to alcohol and substance use, is now being utilized by some clinicians to promote physical activity

De Souza de Silva and colleagues revealed an association between each 1-MET increase in CRF and per-person annual health care cost savings (adjusted for age and presence of cardiovascular disease) of $3272 (normal-weight patients), $4252 (overweight), and $6103 (obese).¹³ In its 2016 scientific statement on CRF as a vital sign, AHA listed several methods of estimating CRF and concluded that, although CPET involves a higher level of training, proficiency, equipment, and, therefore, cost, the independent and additive information obtained justifies its use in many patients.¹²

CASE 

Mary Q, 68 years of age, presents for an annual well-woman examination. Body mass index is 32; resting heart rate (HR), 73 bpm; and blood pressure, 126/74 mm Hg. She reports being inactive, except for light walking every day with her dog around the neighborhood, which takes them approximately 15 minutes. She denies any history or signs and symptoms of cardiovascular, metabolic, or renal disease.

You consider 3 questions before taking next steps regarding increasing Ms. Q’s activity level:

• What is her PAVS?
• Does she need medical clearance before starting an exercise program?
• What would an evidence-based cardiovascular exercise prescription for Ms. Q look like?

SBIRT: Brief intervention

When a patient does not meet the recommended level of physical activity, you have an opportunity to deliver a brief intervention. To do this effectively, you must have adequate understanding of the patient’s receptivity for change. The transtheoretical, or Stages of Change, model proposes that a person typically goes through 5 stages of growth—­pre-contemplation, contemplation, preparation, action, and maintenance—in the process of lifestyle modification. This model highlights the different approaches to exercise adoption and maintenance that need to be taken, based on a given patient’s stage at the moment.

Continue to: Using this framework...

Using this framework, you can help patients realize intrinsic motivation that can facilitate progression through each stage, utilizing techniques such as motivational interviewing—so-called change talk—to increase self-efficacy.¹⁴TABLE 1¹⁵ provides examples of motivational interviewing techniques that can be used during a patient encounter to improve health behaviors, such as physical activity.

Writing the exercise prescription

A patient who wants to increase their level of physical activity should be offered a formal exercise prescription, which has been shown to increase the level of physical activity, particularly in older patients. In fact, a study conducted in Spain in the practices of family physicians found that older patients who received a physical activity prescription increased their activity by 131 minutes per week; and compared to control patients, they doubled the minutes per week devoted to moderate or vigorous physical activity.¹⁶

FITT-VP. The basics of a cardiovascular exercise prescription can be found in the FITT-VP (Frequency, Intensity, Time, Type, Volume, and [monitoring of] Progression) framework (TABLE 2^17-19). For most patients, this model includes 3 to 5 days per week of moderate-to-vigorous physical activity for 30 to 60 minutes per session. For patients with established chronic disease, physical activity provides health benefits but might require modification. Disease-specific patient handouts for exercise can be downloaded, at no cost, through the American College of Sports Medicine (ACSM) “Exercise Is Medicine” program, which can be found at: www.exerciseismedicine.org/support_page.php/rx-for-health-series.

Determining intensity level. Although CPET is the gold standard for determining a patient’s target intensity level, such a test might be impracticable for a given patient. Surrogate markers of target intensity level can be obtained by measuring maximum HR (HRmax), using a well-known equation²⁰:

HRmax = 220 – age

which is then multiplied by intensity range:

• light: 30%-39%
• moderate: 40%-59%
• vigorous: 60%-89%

or, more preferably, by calculating the HR training zone while accounting for HR at rest (HRrest). This is accomplished by calculating the HR reserve (HRR) (ie, HRR = HRmax – HRrest) and then calculating the target heart rate (THR)²¹:

THR = [HRR × %intensity] + HRrest

Continue to: The THR calculation...

The THR calculation is performed twice, once with a lower %intensity and again with a higher %intensity to develop a training zone based on HRR.

The HRR equation is more accurate than calculating HRmax from 220 – age, because HRR accounts for resting HR, which is often lower in people who are better conditioned.

Another method of calculating intensity for patients who are beginning a physical activity program is the rating of perceived exertion (RPE), which is graded on a scale of 6 to 20: Moderate exercise correlates with an RPE of 12 to 13 (“somewhat hard”); vigorous exercise correlates with an RPE of 14 to 16 (“hard”). By adding a zero to the rating on the RPE scale, the corresponding HR in a healthy adult can be estimated when they are performing an activity at that perceived intensity.²² Moderate exercise therefore correlates with a HR of 120 and 130 bpm.

The so-called talk test can also guide exercise intensity: Light-intensity activity correlates with an ability to sing; moderate-intensity physical activity likely allows the patient to still hold a conversation; and vigorous-intensity activity correlates with an inability to carry on a conversation while exercising.

An exercise prescription should be accompanied by a patient-derived goal, which can be reassessed during a follow-up visit. So-called SMART goals (Specific, Measurable, Achievable, Relevant, and Time-bound) are tools to help patients set personalized and realistic expectations for physical activity. Meeting the goal of approximately 150 to 300 minutes of moderate or 75 to 150 minutes of vigorous physical activity (or an equivalent combination) per week is ideal, but a patient needs to start where they are, at the moment, and gradually increase activity by setting what for them are realistic and sustainable goals.

Continue to: CASE

CASE

With a PAVS of 105 minutes (ie, 15 minutes per day × 7 days) of weekly light-to-moderate exercise walking her dog, Ms. Q does not satisfy current physical activity guidelines. She needs an exercise prescription to incorporate into her lifestyle (see “Cardiovascular exercise prescription,” at left).

First, based on ACSM pre-participation guidelines, Ms. Q does not need medical clearance before initiating light-to-moderate exercise and gradually progressing to ­vigorous-intensity exercise.

Second, in addition to walking the dog for 105 minutes a week, you:

• advise her to start walking for 10 minutes, 3 times per week, at a pace that keeps her HR at 97-104 bpm.
• encourage her to gradually increase the frequency or duration of her walks by no more than 10% per week.

SBIRT: Referral for treatment

When referring a patient to a fitness program or professional, it is essential to consider their preferences, resources, and environment.²³ Community fitness partners are often an excellent referral option for a patient seeking guidance or structure for their exercise program. Using the ACSM ProFinder service, (www.acsm.org/get-stay-certified/find-a-pro) you can search for exercise professionals who have achieved the College’s Gold Standard credential.

Gym memberships or fitness programs might be part of the extra coverage offered by Medicare Advantage Plans, other Medicare health plans, or Medicare Supplement Insurance (Medigap) plans.²⁴

Continue to: CASE

CASE

After providing Ms. Q with her exercise prescription, you refer her to a local gym that participates in the Silver Sneakers fitness and wellness program (for adults ≥ 65 years of age in eligible Medicare plans) to determine whether she qualifies to begin resistance and flexibility training, for which you will write a second exercise prescription (TABLE 3^17-19).

Pre-participation screening

Updated 2015 ACSM exercise pre-participation health screening recommendations attempt to decrease possible barriers to people who are becoming more physically active, by minimizing unnecessary referral to health care providers before they change their level of physical activity. ACSM recommendations on exercise clearance include this guidance²⁵:

• For a patient who is asymptomatic and already physically active—regardless of whether they have known cardiovascular, metabolic, or renal disease—medical clearance is unnecessary for moderate-intensity exercise.
• Any patient who has been physically active and asymptomatic but who becomes symptomatic during exercise should immediately discontinue such activity and undergo medical evaluation.
• For a patient who is inactive, ­asymptomatic, and who does not have known cardiovascular, metabolic, or renal disease, medical clearance for light- or moderate-intensity exercise is unnecessary.
• For inactive, asymptomatic patients who have known cardiovascular, metabolic, or renal disease, medical clearance is recommended.

Digital health

Smartwatches and health apps (eg, CardioCoach, Fitbit, Garmin Connect, Nike Training Club, Strava, and Training Peaks) can provide workouts and offer patients the ability to collect information and even connect with other users through social media platforms. This information can be synced to Apple Health platforms for iPhones (www.apple.com/ios/health/) or through Google Fit (www.google.com/fit/) on Android devices. Primary care physicians who become familiar with health apps might find them useful for select patients who want to use technology to improve their physical activity level.

However, data on the value of using digital apps for increasing physical activity, in relation to their cost, are limited. Additional research is needed to assess their validity.

Billing and coding

For most patients, the physical activity assessment, prescription, and referral are performed in the context of treating another condition (eg, hypertension, type 2 diabetes, obesity, depression) or during a preventive health examination, and are typically covered without additional charge to the patient. An evaluation and management visit for an established patient could be used to bill if > 50% of the office visit was spent face-to-face with a physician, with patient counseling and coordination of care.

Continue to: Physicians and physical therapists...

Physicians and physical therapists can use the therapeutic exercise code (Current Procedural Terminology code 97110) when teaching patients exercises to develop muscle strength and endurance, joint range of motion, and flexibility²⁶ (TABLE 4²⁶).

Conclusion

Physical activity and CRF are strong predictors of premature mortality, even compared to other risk factors, such as cigarette smoking, hypertension, hypercholesterolemia, and type 2 diabetes.²⁷ Brief physical activity assessment and counseling is an efficient, effective, and cost-effective means to increase physical activity, and presents a unique opportunity for you to encourage lifestyle-based strategies for reducing cardiovascular risk.²⁸

The AHA has asserted the importance of assessing cardiorespiratory fitness as a “vital sign.”

However, it is essential to meet patients where they are before trying to have them progress; it is therefore imperative to assess the individual patient’s level of activity using PAVS. With that information in hand, you can personalize physical activity advice; determine readiness for change and potential barriers for change; assist the patient in setting SMART goals; and arrange follow-up to assess adherence to the exercise prescription. Encourage the patient to call their health insurance plan to determine whether a gym membership or fitness program is covered.

Research is needed to evaluate the value of using digital apps, in light of their cost, to increase physical activity and improve CRF in a clinical setting. Prospective trials should be initiated to determine how routine implementation of CRF assessment in primary care alters the trajectory of clinical care. It is hoped that future research will answer the question: Would such an approach improve clinical outcomes and reduce health care expenditures?¹²

a Defined as O2 consumed while sitting at rest; equivalent to 3.5 mL of O₂ × kg of body weight × min.

CORRESPONDENCE
Matthew Kampert, DO, MS, Sports Medicine, 5555 Transportation Boulevard, Cleveland, OH 44125; [email protected]

It is well-known that per capita health care spending in the United States is more than twice the average in other developed countries¹; nevertheless, the overall health care ranking of the US is near the bottom compared to other countries in this group.² Much of the reason for this poor relative showing lies in the fact that the US has employed a somewhat traditional fee-for-service health care model that does not incentivize efforts to promote health and wellness or prevent chronic disease. The paradigm of promoting physical activity for its disease-preventing and treatment benefits has not been well-integrated in the US health care system.

In this article, we endeavor to provide better understanding of the barriers that keep family physicians from routinely promoting physical activity in clinical practice; define tools and resources that can be used in the clinical setting to promote physical activity; and delineate areas for future work.

Glaring hole in US physical activity education

Many primary care physicians feel underprepared to prescribe or motivate patients to exercise. The reason for that lack of preparedness likely relates to a medical education system that does not spend time preparing physicians to perform this critical task. A study showed that, on average, medical schools require only 8 hours of physical activity education in their curriculum during the 4 years of schooling.³ Likewise, the average primary care residency program offers only 3 hours of didactic training on physical activity, nutrition, and obesity.⁴ The problem extends to sports medicine fellowship training, in which a 2019 survey showed that 63% of fellows were never taught how to write an exercise prescription in their training program.⁵

Medical professionals must be educated on the social determinants of health, including conditions in which people live, work, and play, which can contribute to health inequities.

Without education on physical activity, medical students, residents, and fellows are woefully underprepared to realize the therapeutic value of physical activity in patient care, comprehend current physical activity guidelines, appropriately motivate patients to engage in exercise, and competently discuss exercise prescriptions in different disease states. Throughout their training, it is imperative for medical professionals to be educated on the social determinants of health, which include the conditions in which people live, work, and play. These environmental variables can contribute to health inequities that create additional barriers to improvement in physical fitness.⁶

National guidelines on physical activity

The 2018 National Physical Activity Guidelines detail recommendations for children, adolescents, adults, and special populations.⁷ The guidelines define physical activity as bodily movement produced by skeletal muscles that result in energy expenditure above resting baseline levels, and includes all types, intensities, and domains of activity. Exercise is a subset of physical activity characterized as planned, structured, repetitive, and designed to improve or maintain physical fitness, physical performance, or health.

Highlights from the 2018 guidelines include⁷:

• Preschool-aged children (3 to 5 years of age) should be physically active throughout the day, with as much as 3 hours per day of physical activity of all intensities—light, moderate, and vigorous.
• Older children and adolescents (6 to 17 years) should accumulate 60 minutes per day of moderate-to-vigorous physical activity, including aerobic, muscle-strengthening, and bone-strengthening activities.
• Adults of all ages should achieve approximately 150 to 300 minutes of moderate or 75 to 150 minutes of vigorous physical activity (or an equivalent combination) per week, along with at least 2 days per week of ­muscle-strengthening activities. Other types of physical activity include flexibility, balance, bone-strengthening, and mind–body exercises.

3-step framework for enhancing physical activity counseling

Merely knowing that physical activity is healthy is not enough, during a patient encounter, to increase the level of physical activity. Therefore, it is imperative to learn and adopt a framework that has proved to yield successful outcomes. The Screening, Brief Intervention, and Referral to Treatment (SBIRT) framework, which has predominantly been used to change patient behavior related to alcohol and substance use, is now being utilized by some providers to promote physical activity.⁸ We apply the SBIRT approach in this article, although research is lacking on its clinical utility and outcome measures.

Continue to: SBIRT

An office visit provides an opportunity to understand a patient’s level of physical activity. Often, understanding a patient’s baseline level of activity is only asked during a thorough social history, which might not be performed during patient encounters. As physical activity is the primary determinant of cardiorespiratory fitness (CRF), some health care systems have begun delineating physical activity levels as a vital sign to ensure that the assessment of physical activity is a standard part of every clinical encounter. At a minimum, this serves as a prompt and provides an opportunity to start a conversation around improving physical activity levels when guidelines are not being met.

The exercise vital sign. Assessment and documentation of physical activity in the electronic health record are not yet standardized; however, Kaiser Permanente health plans have implemented the exercise vital sign, or EVS, in its HealthConnect (Epic Systems) electronic health record. The EVS incorporates information about a patient’s:

• days per week of moderate-to-­strenuous exercise (eg, a brisk walk)
• minutes per day, on average, of exercise at this level.

The physical activity vital sign. Intermountain Healthcare implemented the physical activity vital sign, or PAVS, in its iCentra (Cerner Corp.) electronic health record. The 3-question PAVS assessment asks:

• On average, how many days of the week do you perform physical activity or exercise?
• On average, how many total minutes of physical activity or exercise do you perform on those days?
• How would you describe the intensity of your physical activity or exercise: Light (ie, a casual walk)? Moderate (a brisk walk)? Or vigorous (jogging)?

PAVS includes a fourth data point: The physician–user documents whether the patient was counseled to start, increase, maintain, or modify physical activity or exercise.

EVS and the PAVS have demonstrated validity.^9-11

Continue to: Cardiorespiratory fitness as a vital sign

Cardiorespiratory fitness as a vital sign. In 2016, the American Heart Association (AHA) asserted the importance of assessing CRF as a clinical vital sign.¹² CRF is commonly expressed as maximal oxygen consumption (VO₂max = O₂ mL/kg/min) and measured through cardiopulmonary exercise testing (CPET), considered the gold standard by combining conventional graded exercise testing with ventilatory expired gas analysis. CPET is more objective and precise than equations estimating CRF that are derived from peak work rate. AHA recommended that efforts to improve CRF should become standard in clinical encounters, explaining that even a small increase in CRF (eg, 1 or 2 metabolic equivalents^a [METs]) is associated with a considerably (10% to 30%) lower rate of adverse cardiovascular events.¹²

The SBIRT framework, predominantly used to change patient behavior related to alcohol and substance use, is now being utilized by some clinicians to promote physical activity

De Souza de Silva and colleagues revealed an association between each 1-MET increase in CRF and per-person annual health care cost savings (adjusted for age and presence of cardiovascular disease) of $3272 (normal-weight patients), $4252 (overweight), and $6103 (obese).¹³ In its 2016 scientific statement on CRF as a vital sign, AHA listed several methods of estimating CRF and concluded that, although CPET involves a higher level of training, proficiency, equipment, and, therefore, cost, the independent and additive information obtained justifies its use in many patients.¹²

CASE 

Mary Q, 68 years of age, presents for an annual well-woman examination. Body mass index is 32; resting heart rate (HR), 73 bpm; and blood pressure, 126/74 mm Hg. She reports being inactive, except for light walking every day with her dog around the neighborhood, which takes them approximately 15 minutes. She denies any history or signs and symptoms of cardiovascular, metabolic, or renal disease.

You consider 3 questions before taking next steps regarding increasing Ms. Q’s activity level:

• What is her PAVS?
• Does she need medical clearance before starting an exercise program?
• What would an evidence-based cardiovascular exercise prescription for Ms. Q look like?

SBIRT: Brief intervention

When a patient does not meet the recommended level of physical activity, you have an opportunity to deliver a brief intervention. To do this effectively, you must have adequate understanding of the patient’s receptivity for change. The transtheoretical, or Stages of Change, model proposes that a person typically goes through 5 stages of growth—­pre-contemplation, contemplation, preparation, action, and maintenance—in the process of lifestyle modification. This model highlights the different approaches to exercise adoption and maintenance that need to be taken, based on a given patient’s stage at the moment.

Continue to: Using this framework...

Using this framework, you can help patients realize intrinsic motivation that can facilitate progression through each stage, utilizing techniques such as motivational interviewing—so-called change talk—to increase self-efficacy.¹⁴TABLE 1¹⁵ provides examples of motivational interviewing techniques that can be used during a patient encounter to improve health behaviors, such as physical activity.

Writing the exercise prescription

A patient who wants to increase their level of physical activity should be offered a formal exercise prescription, which has been shown to increase the level of physical activity, particularly in older patients. In fact, a study conducted in Spain in the practices of family physicians found that older patients who received a physical activity prescription increased their activity by 131 minutes per week; and compared to control patients, they doubled the minutes per week devoted to moderate or vigorous physical activity.¹⁶

FITT-VP. The basics of a cardiovascular exercise prescription can be found in the FITT-VP (Frequency, Intensity, Time, Type, Volume, and [monitoring of] Progression) framework (TABLE 2^17-19). For most patients, this model includes 3 to 5 days per week of moderate-to-vigorous physical activity for 30 to 60 minutes per session. For patients with established chronic disease, physical activity provides health benefits but might require modification. Disease-specific patient handouts for exercise can be downloaded, at no cost, through the American College of Sports Medicine (ACSM) “Exercise Is Medicine” program, which can be found at: www.exerciseismedicine.org/support_page.php/rx-for-health-series.

Determining intensity level. Although CPET is the gold standard for determining a patient’s target intensity level, such a test might be impracticable for a given patient. Surrogate markers of target intensity level can be obtained by measuring maximum HR (HRmax), using a well-known equation²⁰:

HRmax = 220 – age

which is then multiplied by intensity range:

• light: 30%-39%
• moderate: 40%-59%
• vigorous: 60%-89%

or, more preferably, by calculating the HR training zone while accounting for HR at rest (HRrest). This is accomplished by calculating the HR reserve (HRR) (ie, HRR = HRmax – HRrest) and then calculating the target heart rate (THR)²¹:

THR = [HRR × %intensity] + HRrest

Continue to: The THR calculation...

The THR calculation is performed twice, once with a lower %intensity and again with a higher %intensity to develop a training zone based on HRR.

The HRR equation is more accurate than calculating HRmax from 220 – age, because HRR accounts for resting HR, which is often lower in people who are better conditioned.

Another method of calculating intensity for patients who are beginning a physical activity program is the rating of perceived exertion (RPE), which is graded on a scale of 6 to 20: Moderate exercise correlates with an RPE of 12 to 13 (“somewhat hard”); vigorous exercise correlates with an RPE of 14 to 16 (“hard”). By adding a zero to the rating on the RPE scale, the corresponding HR in a healthy adult can be estimated when they are performing an activity at that perceived intensity.²² Moderate exercise therefore correlates with a HR of 120 and 130 bpm.

The so-called talk test can also guide exercise intensity: Light-intensity activity correlates with an ability to sing; moderate-intensity physical activity likely allows the patient to still hold a conversation; and vigorous-intensity activity correlates with an inability to carry on a conversation while exercising.

An exercise prescription should be accompanied by a patient-derived goal, which can be reassessed during a follow-up visit. So-called SMART goals (Specific, Measurable, Achievable, Relevant, and Time-bound) are tools to help patients set personalized and realistic expectations for physical activity. Meeting the goal of approximately 150 to 300 minutes of moderate or 75 to 150 minutes of vigorous physical activity (or an equivalent combination) per week is ideal, but a patient needs to start where they are, at the moment, and gradually increase activity by setting what for them are realistic and sustainable goals.

Continue to: CASE

CASE

With a PAVS of 105 minutes (ie, 15 minutes per day × 7 days) of weekly light-to-moderate exercise walking her dog, Ms. Q does not satisfy current physical activity guidelines. She needs an exercise prescription to incorporate into her lifestyle (see “Cardiovascular exercise prescription,” at left).

First, based on ACSM pre-participation guidelines, Ms. Q does not need medical clearance before initiating light-to-moderate exercise and gradually progressing to ­vigorous-intensity exercise.

Second, in addition to walking the dog for 105 minutes a week, you:

• advise her to start walking for 10 minutes, 3 times per week, at a pace that keeps her HR at 97-104 bpm.
• encourage her to gradually increase the frequency or duration of her walks by no more than 10% per week.

SBIRT: Referral for treatment

When referring a patient to a fitness program or professional, it is essential to consider their preferences, resources, and environment.²³ Community fitness partners are often an excellent referral option for a patient seeking guidance or structure for their exercise program. Using the ACSM ProFinder service, (www.acsm.org/get-stay-certified/find-a-pro) you can search for exercise professionals who have achieved the College’s Gold Standard credential.

Gym memberships or fitness programs might be part of the extra coverage offered by Medicare Advantage Plans, other Medicare health plans, or Medicare Supplement Insurance (Medigap) plans.²⁴

Continue to: CASE

CASE

After providing Ms. Q with her exercise prescription, you refer her to a local gym that participates in the Silver Sneakers fitness and wellness program (for adults ≥ 65 years of age in eligible Medicare plans) to determine whether she qualifies to begin resistance and flexibility training, for which you will write a second exercise prescription (TABLE 3^17-19).

Pre-participation screening

Updated 2015 ACSM exercise pre-participation health screening recommendations attempt to decrease possible barriers to people who are becoming more physically active, by minimizing unnecessary referral to health care providers before they change their level of physical activity. ACSM recommendations on exercise clearance include this guidance²⁵:

• For a patient who is asymptomatic and already physically active—regardless of whether they have known cardiovascular, metabolic, or renal disease—medical clearance is unnecessary for moderate-intensity exercise.
• Any patient who has been physically active and asymptomatic but who becomes symptomatic during exercise should immediately discontinue such activity and undergo medical evaluation.
• For a patient who is inactive, ­asymptomatic, and who does not have known cardiovascular, metabolic, or renal disease, medical clearance for light- or moderate-intensity exercise is unnecessary.
• For inactive, asymptomatic patients who have known cardiovascular, metabolic, or renal disease, medical clearance is recommended.

Digital health

Smartwatches and health apps (eg, CardioCoach, Fitbit, Garmin Connect, Nike Training Club, Strava, and Training Peaks) can provide workouts and offer patients the ability to collect information and even connect with other users through social media platforms. This information can be synced to Apple Health platforms for iPhones (www.apple.com/ios/health/) or through Google Fit (www.google.com/fit/) on Android devices. Primary care physicians who become familiar with health apps might find them useful for select patients who want to use technology to improve their physical activity level.

However, data on the value of using digital apps for increasing physical activity, in relation to their cost, are limited. Additional research is needed to assess their validity.

Billing and coding

For most patients, the physical activity assessment, prescription, and referral are performed in the context of treating another condition (eg, hypertension, type 2 diabetes, obesity, depression) or during a preventive health examination, and are typically covered without additional charge to the patient. An evaluation and management visit for an established patient could be used to bill if > 50% of the office visit was spent face-to-face with a physician, with patient counseling and coordination of care.

Continue to: Physicians and physical therapists...

Physicians and physical therapists can use the therapeutic exercise code (Current Procedural Terminology code 97110) when teaching patients exercises to develop muscle strength and endurance, joint range of motion, and flexibility²⁶ (TABLE 4²⁶).

Conclusion

Physical activity and CRF are strong predictors of premature mortality, even compared to other risk factors, such as cigarette smoking, hypertension, hypercholesterolemia, and type 2 diabetes.²⁷ Brief physical activity assessment and counseling is an efficient, effective, and cost-effective means to increase physical activity, and presents a unique opportunity for you to encourage lifestyle-based strategies for reducing cardiovascular risk.²⁸

The AHA has asserted the importance of assessing cardiorespiratory fitness as a “vital sign.”

However, it is essential to meet patients where they are before trying to have them progress; it is therefore imperative to assess the individual patient’s level of activity using PAVS. With that information in hand, you can personalize physical activity advice; determine readiness for change and potential barriers for change; assist the patient in setting SMART goals; and arrange follow-up to assess adherence to the exercise prescription. Encourage the patient to call their health insurance plan to determine whether a gym membership or fitness program is covered.

Research is needed to evaluate the value of using digital apps, in light of their cost, to increase physical activity and improve CRF in a clinical setting. Prospective trials should be initiated to determine how routine implementation of CRF assessment in primary care alters the trajectory of clinical care. It is hoped that future research will answer the question: Would such an approach improve clinical outcomes and reduce health care expenditures?¹²

a Defined as O2 consumed while sitting at rest; equivalent to 3.5 mL of O₂ × kg of body weight × min.

CORRESPONDENCE
Matthew Kampert, DO, MS, Sports Medicine, 5555 Transportation Boulevard, Cleveland, OH 44125; [email protected]

Could screening patients for cytokine markers help direct interventions to prevent quality-of-life deterioration? What evidence is there that a patient’s ­methylenetetrahydrofolate reductase (MTHFR) genotype and baseline folate level can determine whether folate therapy will be needed to prevent stroke?

Favorable findings in these areas and others—eg, that specific probiotics benefit those with various gastrointestinal, respiratory, and lipid disorders—are strengthening support for the clinical approach of functional medicine (FM), which focuses on core functional processes: assimilation, defense and repair, energy, biotransformation and elimination, transport, communication, and structural integrity.

In this article, we describe the paradigm of FM, review its origins, and present the evidence base of selected topics: diagnostic testing, nutrition and supplements, probiotics, and chelation. As FM’s popularity increases, a better understanding of it will help us educate our patients on this approach and implement some of its evidence-backed practices. In preparing this review we used keyword searches of PubMed, Embase, Web of Science, Cochrane Library, University of Florida Health Science Center Library eJournals, the Institute for Functional Medicine website,¹ and Lifestyle Medicine textbook.²

The core of functional medicine

Complementary and alternative medicine (CAM) refers to medical practices diverging from standards of care and not generally taught at US medical schools or available at US hospitals.³ Integrative Medicine encompasses evidence-informed CAM, conventional Western medicine, and whole systems like FM.⁴

FM aims to identify root causes of disease, emphasizing function as a dynamic process that can move back and forth on a continuum between health and disorder.^5,6 There are 7 defining characteristics of FM: (1) patient centered vs disease centered; (2) systems biology approach acknowledging web-like interconnections of physiologic factors; (3) dynamic balance of gene–­environment interactions; (4) personalized care based on biochemical individuality; (5) promotion of organ reserve and sustained health span; (6) health as a positive vitality—not merely the absence of disease; and (7) function vs pathology focused.⁵

The concept of FM is not new. Its origins can be traced to the 19th century. Jeffrey Bland, PhD, credits the term’s first use to Sir Willoughby F. Wade, MD, in an 1871 Lancet editorial, “Clinical lecture on functional medicine.” Bland formulated the FM paradigm and in 1991 founded the Institute for Functional Medicine (the Institute), its main educational and certifying organization.⁷ The Institute certifies masters- or doctorate-prepared health professionals from both conventional and complementary health fields who complete 7 courses (Applying FM in Clinical Practice, Gastrointestinal, Environmental Health, Immune, Hormone, Cardiometabolic, and Bioenergetics), present 1 case report, and pass a written exam. In a retrospective cohort study, researchers found that the FM model was associated with greater improvements in patient-reported, health-related quality of life (QOL) compared with usual care.⁸

Clinical model

FM uses a comprehensive yet practical matrix for obtaining patient histories and for guiding diagnostic testing.⁹ Tools that support ­history-taking include a timeline; weeklong dietary survey; daily activity log; exercise, sleep and self-care questionnaires; and an environmental risk assessment. Instead of a review of symptoms arranged by organ system as is typical with conventional Western medicine, FM assesses the balance of core functional processes: assimilation, defense and repair, energy, biotransformation and elimination, transport, communication, and structural integrity.

Continue to: Within the matrix...

Within the matrix, FM also recognizes 5 modifiable personal lifestyle factors: sleep and relaxation, exercise and movement, nutrition, stress, and relationships. When these lifestyle elements are influenced by specific predisposing factors (antecedents), discrete events precipitating illness (triggers), and ongoing physiologic processes (mediators), fundamental imbalances eventually result in the signs and symptoms characterizing diagnosable diseases.

The essence of the functional medicine therapeutic plan is a discussion of lifestyle changes, personal strengths, and potential adherence challenges.

The essence of the FM therapeutic plan is a discussion of lifestyle changes, personal strengths, and potential adherence challenges so the clinician can better offer assistive resources, which may include multidisciplinary referrals to personalized counselors such as a nutritionist, health coach, mind-body therapist, personal trainer, exercise physiologist, or physical therapist. While these professionals are not unique to FM, they are more frequently used by FM practitioners as part of the health care team.

Diagnostic testing through a different lens

A proposed solution to complex diseases recalcitrant to conventional modern treatments is a systems biology approach to health care.¹⁰ Current laboratory testing such as liver enzymes, C-reactive protein (CRP), and leukocyte count provide some information on organ system homeostasis and molecular pathology, but even high-sensitivity CRP, which measures inflammation across the human system, is not adequate in cardiovascular disease (CVD) risk assessment.¹¹ Genome-wide association studies suggest an association between biological pathways, genes, molecular markers, and QOL domains, and screening patients for cytokine markers may help provide prophylactic interventions to prevent QOL deterioration.¹²

With the purpose of being more systems-biology centric rather than disease centric,¹³ FM practitioners use tests to guide dietary recommendations and supplement selection, the evidence for which is found mostly in symptom-specific case series.^14-16 Commonly used tests include MTHFR genotyping, comprehensive stool profiles, hormone and heavy metal panels, allergy panels, lactulose breath testing, micronutrient and advanced lipid panels, omega 3:6 ratios, and oxidative stress tests.

Some of these tests are performed by standard labs and are covered by insurance. Certain assays are primarily performed by specialized functional laboratories, such as comprehensive stool profiles, provoked heavy metal tests, non-IgE allergy panels, and oxidative stress tests. These laboratories also frequently offer direct-to-consumer orders. The latter situation raises a potential conflict of interest from supplement sales linked to laboratory testing and makes it imperative for health care professionals to understand the reliability and clinical utility of these tests in order to counsel patients accordingly.

Continue to: The remainder of this article...

The remainder of this article focuses on the evidence behind a subset of FM treatments, which typically include various dietary interventions (elimination, cardiometabolic, detox) and multidomain lifestyle modifications. The practitioner’s selection of dietary interventions, nutraceuticals (vitamins, minerals, essential fatty acids, botanicals), and probiotics is informed by results of different diagnostic tests.

Nutrition and supplements

Nearly one-third of older Americans are affected by at least 1 vitamin deficiency or anemia, and even those consuming an adequate diet have a substantial risk of any deficiency (16%), although less so than those with an inadequate diet (57%).¹⁷ The Western diet is known to be nutrient deficient, particularly in vitamin D, thiamine, riboflavin, calcium, magnesium, and selenium.¹⁸ Dietary supplement nonusers have the highest risk of any deficiency (40%) compared with users of “full-spectrum multivitamin-multimineral supplements” (14%) and other dietary supplement users (28%).¹⁷

Common FM tests are MTHFR genotyping, comprehensive stool profiles, hormone and heavy metal panels, allergy panels, lactulose breath testing, and micronutrient and advanced lipid panels.

Nevertheless, the US Preventive Services Task Force (USPSTF) concluded in 2014 that there are not enough data to make a recommendation for or against taking vitamins A, C, or E; multivitamins with folic acid; or combinations of these vitamins for the primary prevention of CVD or cancer.¹⁹ USPSTF also does not recommend daily vitamin D and calcium supplementation in community-dwelling, postmenopausal women for primary prevention of fracture.²⁰ Notwithstanding the lack of supplement recommendations for primary prevention, their benefits in patients with chronic disease is still being investigated. For example, a polyphenol-rich antioxidant may reduce cardiovascular complications in those with diabetes.²¹

Rethinking how nutrition studies are designed. Drawing on studies to determine the benefits of nutrition in chronic disease has been challenging. Factors that must be taken into account include the types of vitamin and mineral supplements patients use, nutrient absorption and utilization, and differing dietary assessment methods and reference values used.¹⁸ For example, vitamin and mineral absorption work best with whole food or fortified diets wherein specific nutrients are consumed together (eg, vitamin D and vitamin E with fat; non-heme iron with vitamin C).^22-24 Foods with competing nutrients or “inhibitors” may even require absorption enhancers at minimum molar ratios.²⁴

Adding to the complexity of vitamin and mineral absorption, botanical dietary supplements have their own modifying effects on micronutrient absorption.²⁵ These are just some of the reasons randomized controlled trials (RCTs) are fundamentally limited when investigating the health outcomes of diet and supplementation, and alternative study methods should be considered for future nutrition clinical trials to better inform clinicians who are prescribing supplements.²⁶ In the meantime, nutrition plans can be individualized to patients’ biological and cultural needs, ideally in conjunction with a multidisplinary team that includes dietitians, behaviorists, and exercise specialists.²⁷

Continue to: Nutrition is one of the most...

Nutrition is one of the most important environmental factors modulating genes and phenotypes (nutrigenomics),^28,29 and recent studies on single nucleotide polymorphisms (SNPs) have reinforced the importance of considering the effect of genetic variation on dietary response (nutrigenetics).^29,30 While nutrigenomics and nutrigenetics have the potential to improve the health of large populations by personalizing dietary advice based on genotype and phenotype, genetic variation occurring within a specific biochemical pathway makes generalizing genotype-based dietary advice to other populations complex.

For instance, Greenlandic Inuit, the indigenous people inhabiting the Arctic regions of Greenland, have a low incidence of CVD, largely due to “non-European” genetic variants that lower their LDL, protecting them from the oxidative stress of their diet high in polyunsaturated fats.^31,32 In a study of European adults, phenotypic and phenotypic-­plus-genotypic information did not enhance the effectiveness of the personalized nutrition advice, demonstrating that more research is needed in larger populations.³³

Another specific, complex example of gene-nutrient interaction is the pathophysiologic outcome of polymorphisms in the MTHFR gene.³⁰ MTHFR is a rate-limiting enzyme involved in folate and homocysteine metabolism, DNA and RNA biosynthesis, and DNA and protein methylation. MTHFR polymorphisms are common in otherwise healthy people, but some have been reported to increase chronic disease susceptibility via MTHFR deficiency. The most common MTHFR variant is the SNP rs1801133 that reduces enzyme activity to ~30% in homozygotes (677TT), which can lead to reduced folate bioavailability and mild-to-moderate hyperhomocysteinemia depending on one’s dietary folate intake and food fortification.

One FM focus at variance with current recommendations. FM’s approach to homocysteine and MTHFR genotyping for nutritional assessment, dietary counseling, and supplement advice contrasts with recommendations from meta-analyses^34-36 and guidelines from the American Heart Association and USPSTF.^37,38 While USPSTF does recommend all women planning or capable of pregnancy take 0.4 to 0.8 mg of folic acid daily to prevent neural tube defects,³⁹MTHFR polymorphism screening to guide supplementation is not recommended during pregnancy given conflicting studies and uncertain clinical significance.⁴⁰ Moreover, while it is generally agreed that the MTHFR C677T polymorphism, and in particular the homozygous MTHFR 677TT genotype, is an independent risk factor for hyperhomocysteinemia, neither variant genotype was an independent coronary artery disease risk factor in several large studies.^41-43

Future research is needed to help optimize probiotic dose, duration, route of administration, and whether microbial communities outperform single-species probiotics.

However, study populations with generally high folate consumption or fortified foods may be a main confounding variable.⁴⁴ For example, in a recent meta-analysis of an elderly population, the T-allele of the MTHFR C677T variant increased pooled stroke risk. While this increased stroke risk is highest in homozygotes, the association was statistically significant only in the Chinese cohort—a group that generally has poor dietary intake of folate and B12.⁴⁵ Therefore, both MTHFR genotype and baseline folate level are important determinants of folate therapy efficacy in stroke prevention, and this may explain why US studies have not clearly identified a patient subset most likely to benefit.⁴⁶ Future high-quality studies should measure baseline folate, target populations with ­moderate-to-severe hyperhomocysteinemia with specific MTHFR polymorphisms, and compare high- and low-dose B vitamins or use 5-­methylfolate (the active form of folate).

Continue to: Probiotics

Probiotics

Probiotics are used extensively in FM, and there are very few fields in conventional Western medicine where probiotics have not been researched. Interestingly, gut microbiota (microflora) change rapidly and individually to therapeutic dietary changes, both in composition (community) and function (metabolic plasticity), implicating gut microbiota as a mediator of dietary impact on host metabolism.⁴⁷ This highlights the potential for tailored probiotics to transform dietary nonresponders (eg, those who do not routinely consume a high-fiber diet) into responders whose metabolism becomes enabled to counter such conditions as obesity and type 2 diabetes.⁴⁸

Caveats with probiotic administration. While the strength of recommendation for probiotic therapy is increased by their safe use in pregnancy, infants, and immunocompromised populations,^49-51 various harms (ranging from mild to severe) may be underreported.^52-54 In clinical practice, the effective probiotic strain(s), formulation, and dosage will vary not only by disease, but also from patient to patient, and may be dependent on nutritional factors such as vitamin D,⁵⁵ diet, and even epigenetics.⁵⁶

As we come to more fully recognize commensal microbiota as a major player in overall health with crosstalk in signaling pathways between intestinal bacterial and epithelial immune cells, future research is needed to help optimize probiotic dose, duration, route of administration, and whether microbial communities outperform single-species probiotics.⁵⁰ Furthermore, much of a bacterial community’s effect on the host is through its metabolites, and since certain species can be used interchangeably given similar metabolic activity and function, studies to understand how prebiotics and probiotics affect the host must analyze the metabolome, in addition to the bacterial community composition.⁵¹

Alternative research methods could be informative. Similar to their limited evaluation of health outcomes in nutrition and supplement research, many RCTs examining the health benefits of probiotics often yield ambiguous results or fall short of valid conclusions because the underlying presuppositions are not met.²⁶ For example, assuming the RCT uses a well-defined probiotic formulation, efficacy and generalizability can still be confounded by patient microbiota, diet, mucosa, immune system, and emotional status, which all affect probiotic activity/­potency.⁵⁰ Under these circumstances, other research methods may be more suitable or supplemental—eg, Phase II trials, epidemiologic studies, single-case experiments (n-of-1 trials) and their meta-analyses, using historical controls, preclinical studies for conceptual and theoretical development, and clinical experience.^26,57-59Mechanistic microbiota studies are facilitating early clinical research in numerous diseases,⁶⁰ such as proof-of-concept RCTs in atherosclerosis prevention⁶¹ and brain function.⁶²

Mechanistic microbiota studies are facilitating early clinical research in numerous diseases, such as proof-ofconcept RCTs in atherosclerosis prevention.

It is currently unknown how nonvaginal microbiota affect the health of menopausal women;^63,64 and while a multicenter RCT is underway to examine a novel probiotic’s effect on menopausal symptoms and bone health, the supplemental study methods listed above could be employed as well.

Continue to: Evidence of probiotic effectiveness

Evidence of probiotic effectiveness. Positive evidence in RCTs and meta-analyses suggests that strain-specific probiotics are beneficial for infectious gastroenteritis, persistent antibiotic-associated diarrhea, infant colic,⁵⁰ irritable bowel syndrome (IBS),^50,65Clostridioides difficile prevention,⁶⁶ inflammatory bowel disease (IBD),⁶⁷ ­radiation-induced diarrhea,^68,69 and nongastrointestinal conditions such as multiple sclerosis,⁷⁰ upper respiratory infections,⁵⁰ atopic dermatitis,^50,71,72 surgical site infections,^73,74 hyperlipidemia,^50,75,76 and nonalcoholic steatohepatitis.⁷⁷

However, because of knowledge gaps and low-quality evidence, the American Gastroenterological Association’s (AGA) 2020 Clinical Practice Guidelines recommend “conditional” use of strain-specific probiotics only for necrotizing enterocolitis prevention (in pre-term, low-birth-weight infants), antibiotic-induced C difficile prevention, and pouchitis.^53,54 Additionally, the AGA’s guidelines state that probiotics should only be used for C difficile infection, IBD, or IBS in a clinical trial and not used at all for infectious gastroenteritis.^53,54

Chelation

Chelation therapy is thought to inhibit ­metal-catalyzed oxidation reactions and inflammatory processes in tissues that lead to, and result from, accumulation of oxidative damage. While many FM practitioners recommend some form of chelation therapy, there is much controversy surrounding its use. Well-designed, large-scale clinical trials continue to emerge for what appears to be an old intervention with still uncertain clinical applications.

The first chelation agent, disodium ethylenediaminetetraacetic acid (EDTA), was synthesized in the early 1930s, but it was not until World War II that chelation therapy began with use of dimercaprol, a potent antidote for the arsenical chemical weapon lewisite. Disodium EDTA infusions were first used to treat angina pectoris in the mid-20th century,⁷⁸ and use accelerated in the early 21st century without a clear indication to treat CVD besides decades of anecdotes and case reports.⁷⁹ Strong epidemiologic data support a causal association between heavy metals (arsenic, lead, cadmium, mercury, and copper) and CVD,^80,81 but a distinct mechanism of action is not yet known.

Disodium EDTA was FDA approved in the 1950s for use in patients with hypercalcemia or ventricular arrhythmias from digitalis toxicity, but it was eventually withdrawn from the market in 2008, in part due to safety concerns following 3 deaths from severe hypocalcemia.⁸² These deaths were caused by inappropriate use related to rapid infusions, pediatric use, and in one case inadvertently administering disodium EDTA to a child instead of calcium EDTA (which can safely be bolused to treat pediatric lead toxicity).^82-85

Continue to: The Trial to Assess Chelation Therapy...

The Trial to Assess Chelation Therapy (TACT) was the first large, double-­blinded, placebo-controlled RCT to test post-­myocardial infarction (MI) disodium EDTA infusions (weekly 3-hour infusions for 30 weeks followed by 10 infusions 2 to 8 weeks apart).⁸⁶ Despite the chelation group having a modest reduction in the primary composite endpoint (hazard ratio [HR] = 0.82; 95% CI, 0.69-0.99; P = .035),⁸⁶ especially in those with diabetes (HR = 0.59; 95% CI, 0.44-0.79; P < .001; number needed to treat [NNT] = 6.5),⁸⁷ the authors concluded these results were insufficient to support routine disodium EDTA chelation post MI. Moreover, the 2014 Guidelines for Chronic Ischemic Heart Disease only upgraded chelation therapy from “not recommended” to “uncertain.”⁸⁸

Nevertheless, to put into perspective the magnitude of chelation’s treatment effect post MI in patients with diabetes, it can be compared to standard-of-care statin RCTs for secondary prevention, reported as follows. The absolute risk reduction (ARR) of coronary events with statin therapy in a high genetic risk group (the group with the greatest ARR) was 6.03% in the CARE trial and 6.87% in the PROVE IT-TIMI 22 trial, corresponding to a calculated NNT (1/ARR) of 16.6 and 14.6 respectively.⁸⁹

In order to understand the hesitancy to accept chelation therapy as a reasonable CVD treatment,⁵⁹ one must balance the modest effect demonstrated by TACT with its limitations, the greatest of which was the unusually large proportion of patients who withdrew their consent or were lost to follow-up (~18%).⁸⁶ However, it is important to note that some patients withdrew after experiencing a primary endpoint and that at least 50% more were from the placebo group than the chelation group,⁸⁶ rather than the reverse that was erroneously reported by Fihn et al.⁸⁸ Unblinding was possible, but there were no significant differences in serious adverse events between groups.

Furthermore, since withdrawn subjects had similar CVD risk profiles, more withdrawals in the placebo arm increases the likelihood of more unrecorded primary outcome events in the placebo arm than treatment arm. One possibility is that these could have accentuated the benefit of chelation therapy, and that missing data reduced the reported efficacy. Because of TACT’s profound findings for those with diabetes post MI, the TACT2 Phase 3 clinical trial underway through 2022 will further clarify chelation’s utility for treating stable ischemic heart disease specifically in this group.

Chronic, lowdose chelation therapy may have a role in preventing and treating diabetic CVD and nephropathy.

Interestingly, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldose reductase inhibitors themselves inhibit advanced glycation end products (AGE) formation in diabetes, most likely via chelation. Increased protein glycation and accumulation of AGEs on tissue proteins during hyperglycemia (the Maillard reaction) are hypothesized to be fundamental in the pathogenesis of diabetic vascular complications. Consequently, chronic, low-dose chelation therapy may have a role in preventing and treating diabetic CVD and nephropathy.⁹⁰

ACKNOWLEDGEMENT
The authors thank Ariel Pomputius, MLIS, for contributing to the literature searches during manuscript preparation.

CORRESPONDENCE
Frank A. Orlando, MD, UF Health Family Medicine – Springhill, 4197 NW 86th Terrace; [email protected]

Could screening patients for cytokine markers help direct interventions to prevent quality-of-life deterioration? What evidence is there that a patient’s ­methylenetetrahydrofolate reductase (MTHFR) genotype and baseline folate level can determine whether folate therapy will be needed to prevent stroke?

Favorable findings in these areas and others—eg, that specific probiotics benefit those with various gastrointestinal, respiratory, and lipid disorders—are strengthening support for the clinical approach of functional medicine (FM), which focuses on core functional processes: assimilation, defense and repair, energy, biotransformation and elimination, transport, communication, and structural integrity.

In this article, we describe the paradigm of FM, review its origins, and present the evidence base of selected topics: diagnostic testing, nutrition and supplements, probiotics, and chelation. As FM’s popularity increases, a better understanding of it will help us educate our patients on this approach and implement some of its evidence-backed practices. In preparing this review we used keyword searches of PubMed, Embase, Web of Science, Cochrane Library, University of Florida Health Science Center Library eJournals, the Institute for Functional Medicine website,¹ and Lifestyle Medicine textbook.²

The core of functional medicine

Complementary and alternative medicine (CAM) refers to medical practices diverging from standards of care and not generally taught at US medical schools or available at US hospitals.³ Integrative Medicine encompasses evidence-informed CAM, conventional Western medicine, and whole systems like FM.⁴

FM aims to identify root causes of disease, emphasizing function as a dynamic process that can move back and forth on a continuum between health and disorder.^5,6 There are 7 defining characteristics of FM: (1) patient centered vs disease centered; (2) systems biology approach acknowledging web-like interconnections of physiologic factors; (3) dynamic balance of gene–­environment interactions; (4) personalized care based on biochemical individuality; (5) promotion of organ reserve and sustained health span; (6) health as a positive vitality—not merely the absence of disease; and (7) function vs pathology focused.⁵

The concept of FM is not new. Its origins can be traced to the 19th century. Jeffrey Bland, PhD, credits the term’s first use to Sir Willoughby F. Wade, MD, in an 1871 Lancet editorial, “Clinical lecture on functional medicine.” Bland formulated the FM paradigm and in 1991 founded the Institute for Functional Medicine (the Institute), its main educational and certifying organization.⁷ The Institute certifies masters- or doctorate-prepared health professionals from both conventional and complementary health fields who complete 7 courses (Applying FM in Clinical Practice, Gastrointestinal, Environmental Health, Immune, Hormone, Cardiometabolic, and Bioenergetics), present 1 case report, and pass a written exam. In a retrospective cohort study, researchers found that the FM model was associated with greater improvements in patient-reported, health-related quality of life (QOL) compared with usual care.⁸

Clinical model

FM uses a comprehensive yet practical matrix for obtaining patient histories and for guiding diagnostic testing.⁹ Tools that support ­history-taking include a timeline; weeklong dietary survey; daily activity log; exercise, sleep and self-care questionnaires; and an environmental risk assessment. Instead of a review of symptoms arranged by organ system as is typical with conventional Western medicine, FM assesses the balance of core functional processes: assimilation, defense and repair, energy, biotransformation and elimination, transport, communication, and structural integrity.

Continue to: Within the matrix...

Within the matrix, FM also recognizes 5 modifiable personal lifestyle factors: sleep and relaxation, exercise and movement, nutrition, stress, and relationships. When these lifestyle elements are influenced by specific predisposing factors (antecedents), discrete events precipitating illness (triggers), and ongoing physiologic processes (mediators), fundamental imbalances eventually result in the signs and symptoms characterizing diagnosable diseases.

The essence of the functional medicine therapeutic plan is a discussion of lifestyle changes, personal strengths, and potential adherence challenges.

The essence of the FM therapeutic plan is a discussion of lifestyle changes, personal strengths, and potential adherence challenges so the clinician can better offer assistive resources, which may include multidisciplinary referrals to personalized counselors such as a nutritionist, health coach, mind-body therapist, personal trainer, exercise physiologist, or physical therapist. While these professionals are not unique to FM, they are more frequently used by FM practitioners as part of the health care team.

Diagnostic testing through a different lens

A proposed solution to complex diseases recalcitrant to conventional modern treatments is a systems biology approach to health care.¹⁰ Current laboratory testing such as liver enzymes, C-reactive protein (CRP), and leukocyte count provide some information on organ system homeostasis and molecular pathology, but even high-sensitivity CRP, which measures inflammation across the human system, is not adequate in cardiovascular disease (CVD) risk assessment.¹¹ Genome-wide association studies suggest an association between biological pathways, genes, molecular markers, and QOL domains, and screening patients for cytokine markers may help provide prophylactic interventions to prevent QOL deterioration.¹²

With the purpose of being more systems-biology centric rather than disease centric,¹³ FM practitioners use tests to guide dietary recommendations and supplement selection, the evidence for which is found mostly in symptom-specific case series.^14-16 Commonly used tests include MTHFR genotyping, comprehensive stool profiles, hormone and heavy metal panels, allergy panels, lactulose breath testing, micronutrient and advanced lipid panels, omega 3:6 ratios, and oxidative stress tests.

Some of these tests are performed by standard labs and are covered by insurance. Certain assays are primarily performed by specialized functional laboratories, such as comprehensive stool profiles, provoked heavy metal tests, non-IgE allergy panels, and oxidative stress tests. These laboratories also frequently offer direct-to-consumer orders. The latter situation raises a potential conflict of interest from supplement sales linked to laboratory testing and makes it imperative for health care professionals to understand the reliability and clinical utility of these tests in order to counsel patients accordingly.

Continue to: The remainder of this article...

The remainder of this article focuses on the evidence behind a subset of FM treatments, which typically include various dietary interventions (elimination, cardiometabolic, detox) and multidomain lifestyle modifications. The practitioner’s selection of dietary interventions, nutraceuticals (vitamins, minerals, essential fatty acids, botanicals), and probiotics is informed by results of different diagnostic tests.

Nutrition and supplements

Nearly one-third of older Americans are affected by at least 1 vitamin deficiency or anemia, and even those consuming an adequate diet have a substantial risk of any deficiency (16%), although less so than those with an inadequate diet (57%).¹⁷ The Western diet is known to be nutrient deficient, particularly in vitamin D, thiamine, riboflavin, calcium, magnesium, and selenium.¹⁸ Dietary supplement nonusers have the highest risk of any deficiency (40%) compared with users of “full-spectrum multivitamin-multimineral supplements” (14%) and other dietary supplement users (28%).¹⁷

Common FM tests are MTHFR genotyping, comprehensive stool profiles, hormone and heavy metal panels, allergy panels, lactulose breath testing, and micronutrient and advanced lipid panels.

Nevertheless, the US Preventive Services Task Force (USPSTF) concluded in 2014 that there are not enough data to make a recommendation for or against taking vitamins A, C, or E; multivitamins with folic acid; or combinations of these vitamins for the primary prevention of CVD or cancer.¹⁹ USPSTF also does not recommend daily vitamin D and calcium supplementation in community-dwelling, postmenopausal women for primary prevention of fracture.²⁰ Notwithstanding the lack of supplement recommendations for primary prevention, their benefits in patients with chronic disease is still being investigated. For example, a polyphenol-rich antioxidant may reduce cardiovascular complications in those with diabetes.²¹

Rethinking how nutrition studies are designed. Drawing on studies to determine the benefits of nutrition in chronic disease has been challenging. Factors that must be taken into account include the types of vitamin and mineral supplements patients use, nutrient absorption and utilization, and differing dietary assessment methods and reference values used.¹⁸ For example, vitamin and mineral absorption work best with whole food or fortified diets wherein specific nutrients are consumed together (eg, vitamin D and vitamin E with fat; non-heme iron with vitamin C).^22-24 Foods with competing nutrients or “inhibitors” may even require absorption enhancers at minimum molar ratios.²⁴

Adding to the complexity of vitamin and mineral absorption, botanical dietary supplements have their own modifying effects on micronutrient absorption.²⁵ These are just some of the reasons randomized controlled trials (RCTs) are fundamentally limited when investigating the health outcomes of diet and supplementation, and alternative study methods should be considered for future nutrition clinical trials to better inform clinicians who are prescribing supplements.²⁶ In the meantime, nutrition plans can be individualized to patients’ biological and cultural needs, ideally in conjunction with a multidisplinary team that includes dietitians, behaviorists, and exercise specialists.²⁷

Continue to: Nutrition is one of the most...

Nutrition is one of the most important environmental factors modulating genes and phenotypes (nutrigenomics),^28,29 and recent studies on single nucleotide polymorphisms (SNPs) have reinforced the importance of considering the effect of genetic variation on dietary response (nutrigenetics).^29,30 While nutrigenomics and nutrigenetics have the potential to improve the health of large populations by personalizing dietary advice based on genotype and phenotype, genetic variation occurring within a specific biochemical pathway makes generalizing genotype-based dietary advice to other populations complex.

For instance, Greenlandic Inuit, the indigenous people inhabiting the Arctic regions of Greenland, have a low incidence of CVD, largely due to “non-European” genetic variants that lower their LDL, protecting them from the oxidative stress of their diet high in polyunsaturated fats.^31,32 In a study of European adults, phenotypic and phenotypic-­plus-genotypic information did not enhance the effectiveness of the personalized nutrition advice, demonstrating that more research is needed in larger populations.³³

Another specific, complex example of gene-nutrient interaction is the pathophysiologic outcome of polymorphisms in the MTHFR gene.³⁰ MTHFR is a rate-limiting enzyme involved in folate and homocysteine metabolism, DNA and RNA biosynthesis, and DNA and protein methylation. MTHFR polymorphisms are common in otherwise healthy people, but some have been reported to increase chronic disease susceptibility via MTHFR deficiency. The most common MTHFR variant is the SNP rs1801133 that reduces enzyme activity to ~30% in homozygotes (677TT), which can lead to reduced folate bioavailability and mild-to-moderate hyperhomocysteinemia depending on one’s dietary folate intake and food fortification.

One FM focus at variance with current recommendations. FM’s approach to homocysteine and MTHFR genotyping for nutritional assessment, dietary counseling, and supplement advice contrasts with recommendations from meta-analyses^34-36 and guidelines from the American Heart Association and USPSTF.^37,38 While USPSTF does recommend all women planning or capable of pregnancy take 0.4 to 0.8 mg of folic acid daily to prevent neural tube defects,³⁹MTHFR polymorphism screening to guide supplementation is not recommended during pregnancy given conflicting studies and uncertain clinical significance.⁴⁰ Moreover, while it is generally agreed that the MTHFR C677T polymorphism, and in particular the homozygous MTHFR 677TT genotype, is an independent risk factor for hyperhomocysteinemia, neither variant genotype was an independent coronary artery disease risk factor in several large studies.^41-43

Future research is needed to help optimize probiotic dose, duration, route of administration, and whether microbial communities outperform single-species probiotics.

However, study populations with generally high folate consumption or fortified foods may be a main confounding variable.⁴⁴ For example, in a recent meta-analysis of an elderly population, the T-allele of the MTHFR C677T variant increased pooled stroke risk. While this increased stroke risk is highest in homozygotes, the association was statistically significant only in the Chinese cohort—a group that generally has poor dietary intake of folate and B12.⁴⁵ Therefore, both MTHFR genotype and baseline folate level are important determinants of folate therapy efficacy in stroke prevention, and this may explain why US studies have not clearly identified a patient subset most likely to benefit.⁴⁶ Future high-quality studies should measure baseline folate, target populations with ­moderate-to-severe hyperhomocysteinemia with specific MTHFR polymorphisms, and compare high- and low-dose B vitamins or use 5-­methylfolate (the active form of folate).

Continue to: Probiotics

Probiotics

Probiotics are used extensively in FM, and there are very few fields in conventional Western medicine where probiotics have not been researched. Interestingly, gut microbiota (microflora) change rapidly and individually to therapeutic dietary changes, both in composition (community) and function (metabolic plasticity), implicating gut microbiota as a mediator of dietary impact on host metabolism.⁴⁷ This highlights the potential for tailored probiotics to transform dietary nonresponders (eg, those who do not routinely consume a high-fiber diet) into responders whose metabolism becomes enabled to counter such conditions as obesity and type 2 diabetes.⁴⁸

Caveats with probiotic administration. While the strength of recommendation for probiotic therapy is increased by their safe use in pregnancy, infants, and immunocompromised populations,^49-51 various harms (ranging from mild to severe) may be underreported.^52-54 In clinical practice, the effective probiotic strain(s), formulation, and dosage will vary not only by disease, but also from patient to patient, and may be dependent on nutritional factors such as vitamin D,⁵⁵ diet, and even epigenetics.⁵⁶

As we come to more fully recognize commensal microbiota as a major player in overall health with crosstalk in signaling pathways between intestinal bacterial and epithelial immune cells, future research is needed to help optimize probiotic dose, duration, route of administration, and whether microbial communities outperform single-species probiotics.⁵⁰ Furthermore, much of a bacterial community’s effect on the host is through its metabolites, and since certain species can be used interchangeably given similar metabolic activity and function, studies to understand how prebiotics and probiotics affect the host must analyze the metabolome, in addition to the bacterial community composition.⁵¹

Alternative research methods could be informative. Similar to their limited evaluation of health outcomes in nutrition and supplement research, many RCTs examining the health benefits of probiotics often yield ambiguous results or fall short of valid conclusions because the underlying presuppositions are not met.²⁶ For example, assuming the RCT uses a well-defined probiotic formulation, efficacy and generalizability can still be confounded by patient microbiota, diet, mucosa, immune system, and emotional status, which all affect probiotic activity/­potency.⁵⁰ Under these circumstances, other research methods may be more suitable or supplemental—eg, Phase II trials, epidemiologic studies, single-case experiments (n-of-1 trials) and their meta-analyses, using historical controls, preclinical studies for conceptual and theoretical development, and clinical experience.^26,57-59Mechanistic microbiota studies are facilitating early clinical research in numerous diseases,⁶⁰ such as proof-of-concept RCTs in atherosclerosis prevention⁶¹ and brain function.⁶²

Mechanistic microbiota studies are facilitating early clinical research in numerous diseases, such as proof-ofconcept RCTs in atherosclerosis prevention.

It is currently unknown how nonvaginal microbiota affect the health of menopausal women;^63,64 and while a multicenter RCT is underway to examine a novel probiotic’s effect on menopausal symptoms and bone health, the supplemental study methods listed above could be employed as well.

Continue to: Evidence of probiotic effectiveness

Evidence of probiotic effectiveness. Positive evidence in RCTs and meta-analyses suggests that strain-specific probiotics are beneficial for infectious gastroenteritis, persistent antibiotic-associated diarrhea, infant colic,⁵⁰ irritable bowel syndrome (IBS),^50,65Clostridioides difficile prevention,⁶⁶ inflammatory bowel disease (IBD),⁶⁷ ­radiation-induced diarrhea,^68,69 and nongastrointestinal conditions such as multiple sclerosis,⁷⁰ upper respiratory infections,⁵⁰ atopic dermatitis,^50,71,72 surgical site infections,^73,74 hyperlipidemia,^50,75,76 and nonalcoholic steatohepatitis.⁷⁷

However, because of knowledge gaps and low-quality evidence, the American Gastroenterological Association’s (AGA) 2020 Clinical Practice Guidelines recommend “conditional” use of strain-specific probiotics only for necrotizing enterocolitis prevention (in pre-term, low-birth-weight infants), antibiotic-induced C difficile prevention, and pouchitis.^53,54 Additionally, the AGA’s guidelines state that probiotics should only be used for C difficile infection, IBD, or IBS in a clinical trial and not used at all for infectious gastroenteritis.^53,54

Chelation

Chelation therapy is thought to inhibit ­metal-catalyzed oxidation reactions and inflammatory processes in tissues that lead to, and result from, accumulation of oxidative damage. While many FM practitioners recommend some form of chelation therapy, there is much controversy surrounding its use. Well-designed, large-scale clinical trials continue to emerge for what appears to be an old intervention with still uncertain clinical applications.

The first chelation agent, disodium ethylenediaminetetraacetic acid (EDTA), was synthesized in the early 1930s, but it was not until World War II that chelation therapy began with use of dimercaprol, a potent antidote for the arsenical chemical weapon lewisite. Disodium EDTA infusions were first used to treat angina pectoris in the mid-20th century,⁷⁸ and use accelerated in the early 21st century without a clear indication to treat CVD besides decades of anecdotes and case reports.⁷⁹ Strong epidemiologic data support a causal association between heavy metals (arsenic, lead, cadmium, mercury, and copper) and CVD,^80,81 but a distinct mechanism of action is not yet known.

Disodium EDTA was FDA approved in the 1950s for use in patients with hypercalcemia or ventricular arrhythmias from digitalis toxicity, but it was eventually withdrawn from the market in 2008, in part due to safety concerns following 3 deaths from severe hypocalcemia.⁸² These deaths were caused by inappropriate use related to rapid infusions, pediatric use, and in one case inadvertently administering disodium EDTA to a child instead of calcium EDTA (which can safely be bolused to treat pediatric lead toxicity).^82-85

Continue to: The Trial to Assess Chelation Therapy...

The Trial to Assess Chelation Therapy (TACT) was the first large, double-­blinded, placebo-controlled RCT to test post-­myocardial infarction (MI) disodium EDTA infusions (weekly 3-hour infusions for 30 weeks followed by 10 infusions 2 to 8 weeks apart).⁸⁶ Despite the chelation group having a modest reduction in the primary composite endpoint (hazard ratio [HR] = 0.82; 95% CI, 0.69-0.99; P = .035),⁸⁶ especially in those with diabetes (HR = 0.59; 95% CI, 0.44-0.79; P < .001; number needed to treat [NNT] = 6.5),⁸⁷ the authors concluded these results were insufficient to support routine disodium EDTA chelation post MI. Moreover, the 2014 Guidelines for Chronic Ischemic Heart Disease only upgraded chelation therapy from “not recommended” to “uncertain.”⁸⁸

Nevertheless, to put into perspective the magnitude of chelation’s treatment effect post MI in patients with diabetes, it can be compared to standard-of-care statin RCTs for secondary prevention, reported as follows. The absolute risk reduction (ARR) of coronary events with statin therapy in a high genetic risk group (the group with the greatest ARR) was 6.03% in the CARE trial and 6.87% in the PROVE IT-TIMI 22 trial, corresponding to a calculated NNT (1/ARR) of 16.6 and 14.6 respectively.⁸⁹

In order to understand the hesitancy to accept chelation therapy as a reasonable CVD treatment,⁵⁹ one must balance the modest effect demonstrated by TACT with its limitations, the greatest of which was the unusually large proportion of patients who withdrew their consent or were lost to follow-up (~18%).⁸⁶ However, it is important to note that some patients withdrew after experiencing a primary endpoint and that at least 50% more were from the placebo group than the chelation group,⁸⁶ rather than the reverse that was erroneously reported by Fihn et al.⁸⁸ Unblinding was possible, but there were no significant differences in serious adverse events between groups.

Furthermore, since withdrawn subjects had similar CVD risk profiles, more withdrawals in the placebo arm increases the likelihood of more unrecorded primary outcome events in the placebo arm than treatment arm. One possibility is that these could have accentuated the benefit of chelation therapy, and that missing data reduced the reported efficacy. Because of TACT’s profound findings for those with diabetes post MI, the TACT2 Phase 3 clinical trial underway through 2022 will further clarify chelation’s utility for treating stable ischemic heart disease specifically in this group.

Chronic, lowdose chelation therapy may have a role in preventing and treating diabetic CVD and nephropathy.

Interestingly, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldose reductase inhibitors themselves inhibit advanced glycation end products (AGE) formation in diabetes, most likely via chelation. Increased protein glycation and accumulation of AGEs on tissue proteins during hyperglycemia (the Maillard reaction) are hypothesized to be fundamental in the pathogenesis of diabetic vascular complications. Consequently, chronic, low-dose chelation therapy may have a role in preventing and treating diabetic CVD and nephropathy.⁹⁰

ACKNOWLEDGEMENT
The authors thank Ariel Pomputius, MLIS, for contributing to the literature searches during manuscript preparation.

CORRESPONDENCE
Frank A. Orlando, MD, UF Health Family Medicine – Springhill, 4197 NW 86th Terrace; [email protected]

Could screening patients for cytokine markers help direct interventions to prevent quality-of-life deterioration? What evidence is there that a patient’s ­methylenetetrahydrofolate reductase (MTHFR) genotype and baseline folate level can determine whether folate therapy will be needed to prevent stroke?

Favorable findings in these areas and others—eg, that specific probiotics benefit those with various gastrointestinal, respiratory, and lipid disorders—are strengthening support for the clinical approach of functional medicine (FM), which focuses on core functional processes: assimilation, defense and repair, energy, biotransformation and elimination, transport, communication, and structural integrity.

In this article, we describe the paradigm of FM, review its origins, and present the evidence base of selected topics: diagnostic testing, nutrition and supplements, probiotics, and chelation. As FM’s popularity increases, a better understanding of it will help us educate our patients on this approach and implement some of its evidence-backed practices. In preparing this review we used keyword searches of PubMed, Embase, Web of Science, Cochrane Library, University of Florida Health Science Center Library eJournals, the Institute for Functional Medicine website,¹ and Lifestyle Medicine textbook.²

The core of functional medicine

Complementary and alternative medicine (CAM) refers to medical practices diverging from standards of care and not generally taught at US medical schools or available at US hospitals.³ Integrative Medicine encompasses evidence-informed CAM, conventional Western medicine, and whole systems like FM.⁴

FM aims to identify root causes of disease, emphasizing function as a dynamic process that can move back and forth on a continuum between health and disorder.^5,6 There are 7 defining characteristics of FM: (1) patient centered vs disease centered; (2) systems biology approach acknowledging web-like interconnections of physiologic factors; (3) dynamic balance of gene–­environment interactions; (4) personalized care based on biochemical individuality; (5) promotion of organ reserve and sustained health span; (6) health as a positive vitality—not merely the absence of disease; and (7) function vs pathology focused.⁵

The concept of FM is not new. Its origins can be traced to the 19th century. Jeffrey Bland, PhD, credits the term’s first use to Sir Willoughby F. Wade, MD, in an 1871 Lancet editorial, “Clinical lecture on functional medicine.” Bland formulated the FM paradigm and in 1991 founded the Institute for Functional Medicine (the Institute), its main educational and certifying organization.⁷ The Institute certifies masters- or doctorate-prepared health professionals from both conventional and complementary health fields who complete 7 courses (Applying FM in Clinical Practice, Gastrointestinal, Environmental Health, Immune, Hormone, Cardiometabolic, and Bioenergetics), present 1 case report, and pass a written exam. In a retrospective cohort study, researchers found that the FM model was associated with greater improvements in patient-reported, health-related quality of life (QOL) compared with usual care.⁸

Clinical model

FM uses a comprehensive yet practical matrix for obtaining patient histories and for guiding diagnostic testing.⁹ Tools that support ­history-taking include a timeline; weeklong dietary survey; daily activity log; exercise, sleep and self-care questionnaires; and an environmental risk assessment. Instead of a review of symptoms arranged by organ system as is typical with conventional Western medicine, FM assesses the balance of core functional processes: assimilation, defense and repair, energy, biotransformation and elimination, transport, communication, and structural integrity.

Continue to: Within the matrix...

Within the matrix, FM also recognizes 5 modifiable personal lifestyle factors: sleep and relaxation, exercise and movement, nutrition, stress, and relationships. When these lifestyle elements are influenced by specific predisposing factors (antecedents), discrete events precipitating illness (triggers), and ongoing physiologic processes (mediators), fundamental imbalances eventually result in the signs and symptoms characterizing diagnosable diseases.

The essence of the functional medicine therapeutic plan is a discussion of lifestyle changes, personal strengths, and potential adherence challenges.

The essence of the FM therapeutic plan is a discussion of lifestyle changes, personal strengths, and potential adherence challenges so the clinician can better offer assistive resources, which may include multidisciplinary referrals to personalized counselors such as a nutritionist, health coach, mind-body therapist, personal trainer, exercise physiologist, or physical therapist. While these professionals are not unique to FM, they are more frequently used by FM practitioners as part of the health care team.

Diagnostic testing through a different lens

A proposed solution to complex diseases recalcitrant to conventional modern treatments is a systems biology approach to health care.¹⁰ Current laboratory testing such as liver enzymes, C-reactive protein (CRP), and leukocyte count provide some information on organ system homeostasis and molecular pathology, but even high-sensitivity CRP, which measures inflammation across the human system, is not adequate in cardiovascular disease (CVD) risk assessment.¹¹ Genome-wide association studies suggest an association between biological pathways, genes, molecular markers, and QOL domains, and screening patients for cytokine markers may help provide prophylactic interventions to prevent QOL deterioration.¹²

With the purpose of being more systems-biology centric rather than disease centric,¹³ FM practitioners use tests to guide dietary recommendations and supplement selection, the evidence for which is found mostly in symptom-specific case series.^14-16 Commonly used tests include MTHFR genotyping, comprehensive stool profiles, hormone and heavy metal panels, allergy panels, lactulose breath testing, micronutrient and advanced lipid panels, omega 3:6 ratios, and oxidative stress tests.

Some of these tests are performed by standard labs and are covered by insurance. Certain assays are primarily performed by specialized functional laboratories, such as comprehensive stool profiles, provoked heavy metal tests, non-IgE allergy panels, and oxidative stress tests. These laboratories also frequently offer direct-to-consumer orders. The latter situation raises a potential conflict of interest from supplement sales linked to laboratory testing and makes it imperative for health care professionals to understand the reliability and clinical utility of these tests in order to counsel patients accordingly.

Continue to: The remainder of this article...

The remainder of this article focuses on the evidence behind a subset of FM treatments, which typically include various dietary interventions (elimination, cardiometabolic, detox) and multidomain lifestyle modifications. The practitioner’s selection of dietary interventions, nutraceuticals (vitamins, minerals, essential fatty acids, botanicals), and probiotics is informed by results of different diagnostic tests.

Nutrition and supplements

Nearly one-third of older Americans are affected by at least 1 vitamin deficiency or anemia, and even those consuming an adequate diet have a substantial risk of any deficiency (16%), although less so than those with an inadequate diet (57%).¹⁷ The Western diet is known to be nutrient deficient, particularly in vitamin D, thiamine, riboflavin, calcium, magnesium, and selenium.¹⁸ Dietary supplement nonusers have the highest risk of any deficiency (40%) compared with users of “full-spectrum multivitamin-multimineral supplements” (14%) and other dietary supplement users (28%).¹⁷

Common FM tests are MTHFR genotyping, comprehensive stool profiles, hormone and heavy metal panels, allergy panels, lactulose breath testing, and micronutrient and advanced lipid panels.

Nevertheless, the US Preventive Services Task Force (USPSTF) concluded in 2014 that there are not enough data to make a recommendation for or against taking vitamins A, C, or E; multivitamins with folic acid; or combinations of these vitamins for the primary prevention of CVD or cancer.¹⁹ USPSTF also does not recommend daily vitamin D and calcium supplementation in community-dwelling, postmenopausal women for primary prevention of fracture.²⁰ Notwithstanding the lack of supplement recommendations for primary prevention, their benefits in patients with chronic disease is still being investigated. For example, a polyphenol-rich antioxidant may reduce cardiovascular complications in those with diabetes.²¹

Rethinking how nutrition studies are designed. Drawing on studies to determine the benefits of nutrition in chronic disease has been challenging. Factors that must be taken into account include the types of vitamin and mineral supplements patients use, nutrient absorption and utilization, and differing dietary assessment methods and reference values used.¹⁸ For example, vitamin and mineral absorption work best with whole food or fortified diets wherein specific nutrients are consumed together (eg, vitamin D and vitamin E with fat; non-heme iron with vitamin C).^22-24 Foods with competing nutrients or “inhibitors” may even require absorption enhancers at minimum molar ratios.²⁴

Adding to the complexity of vitamin and mineral absorption, botanical dietary supplements have their own modifying effects on micronutrient absorption.²⁵ These are just some of the reasons randomized controlled trials (RCTs) are fundamentally limited when investigating the health outcomes of diet and supplementation, and alternative study methods should be considered for future nutrition clinical trials to better inform clinicians who are prescribing supplements.²⁶ In the meantime, nutrition plans can be individualized to patients’ biological and cultural needs, ideally in conjunction with a multidisplinary team that includes dietitians, behaviorists, and exercise specialists.²⁷

Continue to: Nutrition is one of the most...

Nutrition is one of the most important environmental factors modulating genes and phenotypes (nutrigenomics),^28,29 and recent studies on single nucleotide polymorphisms (SNPs) have reinforced the importance of considering the effect of genetic variation on dietary response (nutrigenetics).^29,30 While nutrigenomics and nutrigenetics have the potential to improve the health of large populations by personalizing dietary advice based on genotype and phenotype, genetic variation occurring within a specific biochemical pathway makes generalizing genotype-based dietary advice to other populations complex.

For instance, Greenlandic Inuit, the indigenous people inhabiting the Arctic regions of Greenland, have a low incidence of CVD, largely due to “non-European” genetic variants that lower their LDL, protecting them from the oxidative stress of their diet high in polyunsaturated fats.^31,32 In a study of European adults, phenotypic and phenotypic-­plus-genotypic information did not enhance the effectiveness of the personalized nutrition advice, demonstrating that more research is needed in larger populations.³³

Another specific, complex example of gene-nutrient interaction is the pathophysiologic outcome of polymorphisms in the MTHFR gene.³⁰ MTHFR is a rate-limiting enzyme involved in folate and homocysteine metabolism, DNA and RNA biosynthesis, and DNA and protein methylation. MTHFR polymorphisms are common in otherwise healthy people, but some have been reported to increase chronic disease susceptibility via MTHFR deficiency. The most common MTHFR variant is the SNP rs1801133 that reduces enzyme activity to ~30% in homozygotes (677TT), which can lead to reduced folate bioavailability and mild-to-moderate hyperhomocysteinemia depending on one’s dietary folate intake and food fortification.

One FM focus at variance with current recommendations. FM’s approach to homocysteine and MTHFR genotyping for nutritional assessment, dietary counseling, and supplement advice contrasts with recommendations from meta-analyses^34-36 and guidelines from the American Heart Association and USPSTF.^37,38 While USPSTF does recommend all women planning or capable of pregnancy take 0.4 to 0.8 mg of folic acid daily to prevent neural tube defects,³⁹MTHFR polymorphism screening to guide supplementation is not recommended during pregnancy given conflicting studies and uncertain clinical significance.⁴⁰ Moreover, while it is generally agreed that the MTHFR C677T polymorphism, and in particular the homozygous MTHFR 677TT genotype, is an independent risk factor for hyperhomocysteinemia, neither variant genotype was an independent coronary artery disease risk factor in several large studies.^41-43

Future research is needed to help optimize probiotic dose, duration, route of administration, and whether microbial communities outperform single-species probiotics.

However, study populations with generally high folate consumption or fortified foods may be a main confounding variable.⁴⁴ For example, in a recent meta-analysis of an elderly population, the T-allele of the MTHFR C677T variant increased pooled stroke risk. While this increased stroke risk is highest in homozygotes, the association was statistically significant only in the Chinese cohort—a group that generally has poor dietary intake of folate and B12.⁴⁵ Therefore, both MTHFR genotype and baseline folate level are important determinants of folate therapy efficacy in stroke prevention, and this may explain why US studies have not clearly identified a patient subset most likely to benefit.⁴⁶ Future high-quality studies should measure baseline folate, target populations with ­moderate-to-severe hyperhomocysteinemia with specific MTHFR polymorphisms, and compare high- and low-dose B vitamins or use 5-­methylfolate (the active form of folate).

Continue to: Probiotics

Probiotics

Probiotics are used extensively in FM, and there are very few fields in conventional Western medicine where probiotics have not been researched. Interestingly, gut microbiota (microflora) change rapidly and individually to therapeutic dietary changes, both in composition (community) and function (metabolic plasticity), implicating gut microbiota as a mediator of dietary impact on host metabolism.⁴⁷ This highlights the potential for tailored probiotics to transform dietary nonresponders (eg, those who do not routinely consume a high-fiber diet) into responders whose metabolism becomes enabled to counter such conditions as obesity and type 2 diabetes.⁴⁸

Caveats with probiotic administration. While the strength of recommendation for probiotic therapy is increased by their safe use in pregnancy, infants, and immunocompromised populations,^49-51 various harms (ranging from mild to severe) may be underreported.^52-54 In clinical practice, the effective probiotic strain(s), formulation, and dosage will vary not only by disease, but also from patient to patient, and may be dependent on nutritional factors such as vitamin D,⁵⁵ diet, and even epigenetics.⁵⁶

As we come to more fully recognize commensal microbiota as a major player in overall health with crosstalk in signaling pathways between intestinal bacterial and epithelial immune cells, future research is needed to help optimize probiotic dose, duration, route of administration, and whether microbial communities outperform single-species probiotics.⁵⁰ Furthermore, much of a bacterial community’s effect on the host is through its metabolites, and since certain species can be used interchangeably given similar metabolic activity and function, studies to understand how prebiotics and probiotics affect the host must analyze the metabolome, in addition to the bacterial community composition.⁵¹

Alternative research methods could be informative. Similar to their limited evaluation of health outcomes in nutrition and supplement research, many RCTs examining the health benefits of probiotics often yield ambiguous results or fall short of valid conclusions because the underlying presuppositions are not met.²⁶ For example, assuming the RCT uses a well-defined probiotic formulation, efficacy and generalizability can still be confounded by patient microbiota, diet, mucosa, immune system, and emotional status, which all affect probiotic activity/­potency.⁵⁰ Under these circumstances, other research methods may be more suitable or supplemental—eg, Phase II trials, epidemiologic studies, single-case experiments (n-of-1 trials) and their meta-analyses, using historical controls, preclinical studies for conceptual and theoretical development, and clinical experience.^26,57-59Mechanistic microbiota studies are facilitating early clinical research in numerous diseases,⁶⁰ such as proof-of-concept RCTs in atherosclerosis prevention⁶¹ and brain function.⁶²

Mechanistic microbiota studies are facilitating early clinical research in numerous diseases, such as proof-ofconcept RCTs in atherosclerosis prevention.

It is currently unknown how nonvaginal microbiota affect the health of menopausal women;^63,64 and while a multicenter RCT is underway to examine a novel probiotic’s effect on menopausal symptoms and bone health, the supplemental study methods listed above could be employed as well.

Continue to: Evidence of probiotic effectiveness

Evidence of probiotic effectiveness. Positive evidence in RCTs and meta-analyses suggests that strain-specific probiotics are beneficial for infectious gastroenteritis, persistent antibiotic-associated diarrhea, infant colic,⁵⁰ irritable bowel syndrome (IBS),^50,65Clostridioides difficile prevention,⁶⁶ inflammatory bowel disease (IBD),⁶⁷ ­radiation-induced diarrhea,^68,69 and nongastrointestinal conditions such as multiple sclerosis,⁷⁰ upper respiratory infections,⁵⁰ atopic dermatitis,^50,71,72 surgical site infections,^73,74 hyperlipidemia,^50,75,76 and nonalcoholic steatohepatitis.⁷⁷

However, because of knowledge gaps and low-quality evidence, the American Gastroenterological Association’s (AGA) 2020 Clinical Practice Guidelines recommend “conditional” use of strain-specific probiotics only for necrotizing enterocolitis prevention (in pre-term, low-birth-weight infants), antibiotic-induced C difficile prevention, and pouchitis.^53,54 Additionally, the AGA’s guidelines state that probiotics should only be used for C difficile infection, IBD, or IBS in a clinical trial and not used at all for infectious gastroenteritis.^53,54

Chelation

Chelation therapy is thought to inhibit ­metal-catalyzed oxidation reactions and inflammatory processes in tissues that lead to, and result from, accumulation of oxidative damage. While many FM practitioners recommend some form of chelation therapy, there is much controversy surrounding its use. Well-designed, large-scale clinical trials continue to emerge for what appears to be an old intervention with still uncertain clinical applications.

The first chelation agent, disodium ethylenediaminetetraacetic acid (EDTA), was synthesized in the early 1930s, but it was not until World War II that chelation therapy began with use of dimercaprol, a potent antidote for the arsenical chemical weapon lewisite. Disodium EDTA infusions were first used to treat angina pectoris in the mid-20th century,⁷⁸ and use accelerated in the early 21st century without a clear indication to treat CVD besides decades of anecdotes and case reports.⁷⁹ Strong epidemiologic data support a causal association between heavy metals (arsenic, lead, cadmium, mercury, and copper) and CVD,^80,81 but a distinct mechanism of action is not yet known.

Disodium EDTA was FDA approved in the 1950s for use in patients with hypercalcemia or ventricular arrhythmias from digitalis toxicity, but it was eventually withdrawn from the market in 2008, in part due to safety concerns following 3 deaths from severe hypocalcemia.⁸² These deaths were caused by inappropriate use related to rapid infusions, pediatric use, and in one case inadvertently administering disodium EDTA to a child instead of calcium EDTA (which can safely be bolused to treat pediatric lead toxicity).^82-85

Continue to: The Trial to Assess Chelation Therapy...

The Trial to Assess Chelation Therapy (TACT) was the first large, double-­blinded, placebo-controlled RCT to test post-­myocardial infarction (MI) disodium EDTA infusions (weekly 3-hour infusions for 30 weeks followed by 10 infusions 2 to 8 weeks apart).⁸⁶ Despite the chelation group having a modest reduction in the primary composite endpoint (hazard ratio [HR] = 0.82; 95% CI, 0.69-0.99; P = .035),⁸⁶ especially in those with diabetes (HR = 0.59; 95% CI, 0.44-0.79; P < .001; number needed to treat [NNT] = 6.5),⁸⁷ the authors concluded these results were insufficient to support routine disodium EDTA chelation post MI. Moreover, the 2014 Guidelines for Chronic Ischemic Heart Disease only upgraded chelation therapy from “not recommended” to “uncertain.”⁸⁸

Nevertheless, to put into perspective the magnitude of chelation’s treatment effect post MI in patients with diabetes, it can be compared to standard-of-care statin RCTs for secondary prevention, reported as follows. The absolute risk reduction (ARR) of coronary events with statin therapy in a high genetic risk group (the group with the greatest ARR) was 6.03% in the CARE trial and 6.87% in the PROVE IT-TIMI 22 trial, corresponding to a calculated NNT (1/ARR) of 16.6 and 14.6 respectively.⁸⁹

In order to understand the hesitancy to accept chelation therapy as a reasonable CVD treatment,⁵⁹ one must balance the modest effect demonstrated by TACT with its limitations, the greatest of which was the unusually large proportion of patients who withdrew their consent or were lost to follow-up (~18%).⁸⁶ However, it is important to note that some patients withdrew after experiencing a primary endpoint and that at least 50% more were from the placebo group than the chelation group,⁸⁶ rather than the reverse that was erroneously reported by Fihn et al.⁸⁸ Unblinding was possible, but there were no significant differences in serious adverse events between groups.

Furthermore, since withdrawn subjects had similar CVD risk profiles, more withdrawals in the placebo arm increases the likelihood of more unrecorded primary outcome events in the placebo arm than treatment arm. One possibility is that these could have accentuated the benefit of chelation therapy, and that missing data reduced the reported efficacy. Because of TACT’s profound findings for those with diabetes post MI, the TACT2 Phase 3 clinical trial underway through 2022 will further clarify chelation’s utility for treating stable ischemic heart disease specifically in this group.

Chronic, lowdose chelation therapy may have a role in preventing and treating diabetic CVD and nephropathy.

Interestingly, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldose reductase inhibitors themselves inhibit advanced glycation end products (AGE) formation in diabetes, most likely via chelation. Increased protein glycation and accumulation of AGEs on tissue proteins during hyperglycemia (the Maillard reaction) are hypothesized to be fundamental in the pathogenesis of diabetic vascular complications. Consequently, chronic, low-dose chelation therapy may have a role in preventing and treating diabetic CVD and nephropathy.⁹⁰

ACKNOWLEDGEMENT
The authors thank Ariel Pomputius, MLIS, for contributing to the literature searches during manuscript preparation.

CORRESPONDENCE
Frank A. Orlando, MD, UF Health Family Medicine – Springhill, 4197 NW 86th Terrace; [email protected]

CASE A 34-year-old woman presents with fatigue. She appears defensive when asked about her alcohol use. She answers No to all questions on the CAGE (cut down, annoyed, guilty, eye-opener) screening tool, but acknowledges drinking excessively on rare occasions. Her physician has a high suspicion for alcohol use disorder (AUD) and recommends further testing. The patient agrees but denies having used alcohol over the past several days. Which of the following is most likely to help support the suspicion of a heavy drinking pattern?

1. Routine lab tests (liver panel and complete blood count).
2. Blood or urine alcohol level.
3. Phosphatidylethanol (PEth) level in the blood.
4. Ethyl glucuronide (EtG) in the urine.
5. Carbohydrate-deficient transferrin (CDT) in the blood.

(See "Case answer.").

About 1 in 12 Americans have AUD,¹ and 1 in 10 children live in a home with a parent who has a drinking problem.² While the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) succinctly defines AUD with specific criteria,¹ the term generally refers to an inability to control or stop drinking despite adverse social or health consequences. AUD is regarded as > 4 drinks per day for men and > 3 drinks per day for women.³ A “standard drink” would be a 12-oz bottle of beer, a 5-oz glass of wine, or 1.5 oz of distilled spirits. Effects of chronic alcohol use are vast and include malnutrition, alcohol withdrawal syndrome, alcoholic liver disease, pancreatitis/pancreatic cancer, cardiomyopathy, and stroke.^4-6 Alcohol use by a pregnant woman can lead to fetal alcohol syndrome in her child.⁷

AUD may be more prevalent in the wake of COVID-19. Primary care practitioners tend to miss a large fraction of patients with AUD in their practice, especially younger patients and those without somatic comorbidities.⁸ Systematic screening for AUD can identify many of these people.⁸ Particularly as the COVID-19 pandemic continues to unfold and increases stress for everyone, risk of worsening drinking increases both in individuals with current AUD and for those in remission.⁹ Contrary to common belief, patients visiting primary care favor screening for at-risk drinking.¹⁰ Thus, awareness of the prevalence of AUD and patient acceptance of screening should encourage wider testing.

Screening tools. The 2014 guidelines published by the Centers for Disease Control and Prevention recommend using quick screening tools—ie, single question or ­AUDIT 1-3 (TABLE 1^11-18)—as an objective means of determining whether patients’ drinking creates a risk for themselves or others.¹¹ Excessive drinking identified using alcohol questionnaires can help reduce medical complications and health care costs.¹⁹ The questionnaires we review do not provide a diagnosis but help identify individuals who might benefit from more thorough assessment.²⁰ Following up, as needed, by testing for alcohol biomarkers can provide quantitative insight into problematic alcohol use.²

Primary care practitioners tend to miss a large fraction of patients with alcohol use disorder in their practice. Systematic screening for AUD can identify many of these patients.

But before we discuss the utility of biomarkers, it’s important to quickly review how alcohol is eliminated from the body.

Alcohol elimination

The stomach and small intestine are the primary sites for alcohol absorption. Alcohol elimination from the body occurs through 3 pathways. The first involves oxidative metabolism, which eliminates most ethanol (95%) through the actions of alcohol dehydrogenase, cytochrome P4502E1, or catalase. A lesser amount of alcohol (2%-5%) is eliminated, unchanged, via the second pathway, which includes urine, sweat, and breath. Nonoxidative metabolism makes up the third pathway. Nonoxidative metabolism removes a very small amount (0.1%) of alcohol and involves the direct ethanol biomarkers PEth, EtG, ethyl sulfate (EtS), and fatty acid ethyl esters (FAEEs).²¹ Our emphasis in this article is on assays of direct metabolites of alcohol—particularly PEth.

Continue to: To understand the utility...

To understand the utility of these direct biomarkers, it is helpful to look at the indirect biomarkers first.

Indirect biomarkers have limited sensitivity and specificity

When alcohol is consumed in large enough quantities over time, indirect biomarkers of alcohol can become abnormal.²² The major indirect biomarkers are the liver enzymes aspartate and alanine aminotransferase (AST and ALT), gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV) of red blood cells, and carbohydrate-deficient transferrin (CDT). Indirect biomarkers have limited sensitivity and specificity for AUD. (For specifics on sensitivity and specificity of indirect and direct biomarkers, see TABLE 2.^23-31)

Liver enzymes. AST and ALT are also present in the heart, muscle, and kidneys. Elevated levels usually imply injury to hepatocytes, with ALT being more reflective of liver involvement than AST. Both AST and ALT are elevated in other common liver conditions including hepatitis C virus infection and fatty liver disease. In alcoholic liver disease (ALD), AST is elevated more than ALT; an AST-to-ALT ratio > 3 suggests ALD. An elevated GGT often indicates hepatic injury and is used to confirm that elevated alkaline phosphatase is of hepatic origin.³²

MCV is the average volume of erythrocytes,³³ and an elevated MCV is a potential indicator of excessive alcohol intake. Macrocytosis requires sustained alcohol use, and the test has low sensitivity. Other diseases such as vitamin B12 or folic acid deficiency, hypothyroidism, hematologic diseases (eg, cold agglutinin disease, multiple myeloma, amyloidosis), and certain medications can also increase MCV.³⁴ Moreover, MCV responds slowly to alcohol use, abstinence, and relapse because red cells have a life span of 120 days.³⁵

CDT. Transferrin is a glycoprotein produced in the liver. The level of transferrin with sialic acid chains increases with alcohol consumption as well as in the carbohydrate deficient glycoprotein syndrome, leading to so-called carbohydrate deficient transferrin.³⁶ It is a sensitive marker for detecting alcohol relapse and monitoring sobriety. Moderate-to-heavy alcohol use, averaging ≥ 40 g of alcohol per day for 2 weeks,³⁶ can decrease the amount of carbohydrate attached to transferrin. Two weeks after complete alcohol cessation, CDT levels will return to normal.³⁷

Continue to: CDT is approved...

CDT is approved by the FDA as an assay for alcohol consumption.³⁷ While CDT is felt to be one of the better indirect markers of AUD and can extend the window of detection, there are still issues with its sensitivity and specificity.³⁸ This biomarker can be elevated with other liver diseases and can be affected by the patient’s age, body mass index, gender, and tobacco use.^39,40 Testing for CDT has never achieved widespread clinical use and has been largely supplanted by the more accurate PEth test (described in a bit).

Direct biomarkers offer insight into recent alcohol use

Other than ethanol itself, direct biomarkers of alcohol use are minor ethanol metabolites created through biochemical reactions when ethanol is coupled to endogenous compounds. Hence, the presence of these metabolites is usually directly related to ethanol consumption.⁴¹ Direct alcohol biomarkers are EtG, EtS, FAEEs, and PEth (TABLE 2^23-31). They reflect alcohol consumption over a period of several days, making them useful when paired with questionnaire data, especially for identifying young adults who engage in binge drinking.⁴²

Ethanol can be measured in blood, urine, and breath and is detectable a bit longer in urine than in blood. However, alcohol is detectable in the blood only for 6 to 12 hours after drinking. After alcohol consumption, concentrations peak in the blood within 2 hours. The window for detecting ethanol in the blood depends on the amount of alcohol consumed and the elimination rate of alcohol, which is about 12 mg/dL/h (or 0.012%)—approximately the same amount of alcohol contained in a standard drink (14 g).

EtG can be detected in urine for ≥ 24 hours after just 1 or 2 drinks, and for up to 4 days after heavy consumption.

Checking the blood alcohol level might be helpful in the office if a patient appears intoxicated but denies alcohol use. A blood alcohol level > 300 mg/dL, or > 150 mg/dL without gross evidence of intoxication, or > 100 mg/dL upon routine examination indicates AUD with a high degree of reliability.^33,43 But the short half-life of ethanol in blood limits its use as a biomarker,³³ and it is not a good indicator of chronic drinking.⁴⁴

EtG and EtS. Less than 0.1% of ethanol is secreted as the metabolites EtG and EtS, which are generated, respectively, by the enzymes uridine diphosphate glucuronosyltransferase and sulfotransferase.⁴⁵ They have value in the diagnosis of AUD because of the length of time in which they can be detected. Urinary EtG and EtS have been especially important biomarkers for monitoring relapse in outpatients treated for alcohol-­related problems.⁴⁶ Generally, EtG and EtS can be detected in urine for 13 to 20 hours after a single drink (0.1 g/kg), and for up to 4 to 5 days following ingestion of large amounts of alcohol.⁴⁷

Continue to: EtG has been detectable...

EtG has been detectable in urine for ≥ 24 hours following only 1 or 2 drinks, and for up to 4 days following heavy consumption.⁴⁸ Shortly after alcohol intake, even in small amounts, EtG is detectable. Analysis of EtG in urine is helpful in monitoring alcohol consumption during withdrawal treatment, for workplace testing, and to check for abstinence in legal matters. The EtG urine test is useful in detecting alcohol consumption in a person who claims to be abstinent but who drank 2 or 3 days before the evaluation. Although accurate, EtG’s window for detection is narrower than that of the PEth assay.

EtS is a good marker of acute short-term alcohol use, up to 12 hours in the blood (or longer in heavier drinkers) and up to 5 days in urine.⁴⁹ Its sensitivity is highest in heavy drinkers. Post-sampling formation and degradation of EtS have not been known to occur in urine samples. Testing for this second metabolite of ethanol can slightly improve the sensitivity and specificity of the EtG test. A urine test for EtS has a wider detection window. But it has little practical advantage compared with EtG.⁵⁰

For better clinical specificity, a combination of both EtG and EtS testing has been recommended. However, the EtS assay is more cumbersome and provides little advantage over EtG. EtG values do not correlate precisely with the amount or frequency of ethanol use, but the magnitude of the EtG finding roughly corresponds to the amount of alcohol recently consumed.

False-positive and false-negative results for EtG and EtS are uncommon in practice. However, false-positive results are possible with the EtG test in certain circumstances: presence of Escherichia coli in the specimen, use of ethanol-based hand sanitizers (> 20 times a day) or mouthwashes, and the consumption of substances like pralines, nonalcoholic beer, pharmaceutical products, and fruit juice. Similarly, false-negative results of EtG can occur from degradation if the samples are contaminated with other bacteria, transported without cooling, or stored improperly.⁵¹ In practice, this is uncommon, and the test is believed to be specific with few false-positive results. Commercially available EtG colorimetric test strips permit on-site analysis of urine samples.

FAEEs are a combination of different esters and products of alcohol metabolism through a nonoxidative pathway. They are formed by esterification of endogenous free fatty acids and ethanol in blood and several tissues.²⁹ These are sensitive and specific markers of alcohol ingestion and can differentiate chronic alcohol consumption from binge drinking.²⁹ It is elevated for up to 99 hours in heavy alcohol drinkers.³⁰ It can be detected in hair for a longer period than in blood.⁵² Detection of FAEEs in meconium can help establish fetal alcohol exposure.⁵³

Continue to: PEth

PEth. Use of the PEth assay has increased in recent years and its accuracy has had a transformative effect on the diagnosis of AUD.⁵⁴ PEth is a phospholipid found in erythrocyte membranes, formed by an interaction between ethanol and phosphatidylcholine, catalyzed by phospholipase D.^55,56 Major advantages of PEth include an unusually long half-life and specificity. Red cells lack enzymes to degrade PEth, therefore PEth accumulates in red cells and has a half-life of 4 to 10 days^57,58 allowing for detection of significant ethanol consumption extending back 3 to 4 weeks.⁵⁹ There is no evidence that PEth is formed in the absence of ethanol, making the test essentially 100% specific, particularly at higher cutoff values of ≥ 150 ng/mL.^31,60

PEth is known to be formed only in the presence of ethanol, making the test virtually 100% specific.

PEth levels are not affected by age, gender, or underlying liver or renal disease.⁶¹ PEth can differentiate between heavy alcohol use and social drinking and can therefore identify chronic excessive use.⁶² With chronic excessive alcohol consumption, PEth is detectable in blood up to 28 days after sobriety.⁶³ A correlation exists between PEth concentrations in blood and the amount of consumed ethanol. PEth has increased specificity and sensitivity for the detection of latent ethanol use compared with other direct biomarkers.²¹ It can identify recent heavy drinking earlier than indirect biomarkers, as it does not rely on hepatic injury.

Using a cutoff level of 20 ng/mL, PEth assays have a sensitivity of 73% for any alcohol use in the past month; at 80 ng/mL, the sensitivity is 91% for > 4 drinks/d.⁶¹ PEth is considered semi-quantitative. The World Health Organization defines acceptable social alcohol use at a PEth value < 40 ng/dL for men and < 20 ng/dL for women. Chronic excessive use is defined by a level > 60 ng/dL.⁵⁵ The cutoff levels tend to be arbitrary and vary with different guidelines.

PEth may be a useful marker in difficult-toassess settings, or in confirming or invalidating self-reported alcohol consumption.

Although false-positive PEth test results may be possible, most experts believe that dishonesty in self-reporting by test subjects is more likely. That said, the true specificity of PEth remains unknown; a lower value detected should not be regarded as absolute proof of relapse or chronic alcoholism.

Studies have shown a positive correlation between the AUDIT-C score and PEth values combined with self-reported alcohol consumption, indicating that PEth may be a useful marker in difficult-to-assess settings, or in confirming or invalidating self-reported alcohol consumption.^61,64,65 The PEth test is now widely available and, in the authors’ experience, usually costs $100 to $200. Analysis typically costs $40 to $100,⁶⁶ and costs could decrease as the test becomes more widely used. Turnaround time for PEth is 5 to 10 days. It is now the recommended assay by transplant hepatologists for detecting alcohol use.⁶⁷TABLE 3^22,68 explains the currently accepted ranges for various PEth results.

Continue to: CASE ANSWER

CASE ANSWER While every test mentioned can aid in detecting alcohol consumption, the PEth assay in this scenario would be the most clinically useful.

CORRESPONDENCE
Frederick Nunes, MD, Pennsylvania Hospital of University of Pennsylvania, 230 West Washington Square, 4th Floor, Philadelphia, PA 19104; [email protected]

CASE A 34-year-old woman presents with fatigue. She appears defensive when asked about her alcohol use. She answers No to all questions on the CAGE (cut down, annoyed, guilty, eye-opener) screening tool, but acknowledges drinking excessively on rare occasions. Her physician has a high suspicion for alcohol use disorder (AUD) and recommends further testing. The patient agrees but denies having used alcohol over the past several days. Which of the following is most likely to help support the suspicion of a heavy drinking pattern?

1. Routine lab tests (liver panel and complete blood count).
2. Blood or urine alcohol level.
3. Phosphatidylethanol (PEth) level in the blood.
4. Ethyl glucuronide (EtG) in the urine.
5. Carbohydrate-deficient transferrin (CDT) in the blood.

(See "Case answer.").

About 1 in 12 Americans have AUD,¹ and 1 in 10 children live in a home with a parent who has a drinking problem.² While the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) succinctly defines AUD with specific criteria,¹ the term generally refers to an inability to control or stop drinking despite adverse social or health consequences. AUD is regarded as > 4 drinks per day for men and > 3 drinks per day for women.³ A “standard drink” would be a 12-oz bottle of beer, a 5-oz glass of wine, or 1.5 oz of distilled spirits. Effects of chronic alcohol use are vast and include malnutrition, alcohol withdrawal syndrome, alcoholic liver disease, pancreatitis/pancreatic cancer, cardiomyopathy, and stroke.^4-6 Alcohol use by a pregnant woman can lead to fetal alcohol syndrome in her child.⁷

AUD may be more prevalent in the wake of COVID-19. Primary care practitioners tend to miss a large fraction of patients with AUD in their practice, especially younger patients and those without somatic comorbidities.⁸ Systematic screening for AUD can identify many of these people.⁸ Particularly as the COVID-19 pandemic continues to unfold and increases stress for everyone, risk of worsening drinking increases both in individuals with current AUD and for those in remission.⁹ Contrary to common belief, patients visiting primary care favor screening for at-risk drinking.¹⁰ Thus, awareness of the prevalence of AUD and patient acceptance of screening should encourage wider testing.

Screening tools. The 2014 guidelines published by the Centers for Disease Control and Prevention recommend using quick screening tools—ie, single question or ­AUDIT 1-3 (TABLE 1^11-18)—as an objective means of determining whether patients’ drinking creates a risk for themselves or others.¹¹ Excessive drinking identified using alcohol questionnaires can help reduce medical complications and health care costs.¹⁹ The questionnaires we review do not provide a diagnosis but help identify individuals who might benefit from more thorough assessment.²⁰ Following up, as needed, by testing for alcohol biomarkers can provide quantitative insight into problematic alcohol use.²

Primary care practitioners tend to miss a large fraction of patients with alcohol use disorder in their practice. Systematic screening for AUD can identify many of these patients.

But before we discuss the utility of biomarkers, it’s important to quickly review how alcohol is eliminated from the body.

Alcohol elimination

The stomach and small intestine are the primary sites for alcohol absorption. Alcohol elimination from the body occurs through 3 pathways. The first involves oxidative metabolism, which eliminates most ethanol (95%) through the actions of alcohol dehydrogenase, cytochrome P4502E1, or catalase. A lesser amount of alcohol (2%-5%) is eliminated, unchanged, via the second pathway, which includes urine, sweat, and breath. Nonoxidative metabolism makes up the third pathway. Nonoxidative metabolism removes a very small amount (0.1%) of alcohol and involves the direct ethanol biomarkers PEth, EtG, ethyl sulfate (EtS), and fatty acid ethyl esters (FAEEs).²¹ Our emphasis in this article is on assays of direct metabolites of alcohol—particularly PEth.

Continue to: To understand the utility...

To understand the utility of these direct biomarkers, it is helpful to look at the indirect biomarkers first.

Indirect biomarkers have limited sensitivity and specificity

When alcohol is consumed in large enough quantities over time, indirect biomarkers of alcohol can become abnormal.²² The major indirect biomarkers are the liver enzymes aspartate and alanine aminotransferase (AST and ALT), gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV) of red blood cells, and carbohydrate-deficient transferrin (CDT). Indirect biomarkers have limited sensitivity and specificity for AUD. (For specifics on sensitivity and specificity of indirect and direct biomarkers, see TABLE 2.^23-31)

Liver enzymes. AST and ALT are also present in the heart, muscle, and kidneys. Elevated levels usually imply injury to hepatocytes, with ALT being more reflective of liver involvement than AST. Both AST and ALT are elevated in other common liver conditions including hepatitis C virus infection and fatty liver disease. In alcoholic liver disease (ALD), AST is elevated more than ALT; an AST-to-ALT ratio > 3 suggests ALD. An elevated GGT often indicates hepatic injury and is used to confirm that elevated alkaline phosphatase is of hepatic origin.³²

MCV is the average volume of erythrocytes,³³ and an elevated MCV is a potential indicator of excessive alcohol intake. Macrocytosis requires sustained alcohol use, and the test has low sensitivity. Other diseases such as vitamin B12 or folic acid deficiency, hypothyroidism, hematologic diseases (eg, cold agglutinin disease, multiple myeloma, amyloidosis), and certain medications can also increase MCV.³⁴ Moreover, MCV responds slowly to alcohol use, abstinence, and relapse because red cells have a life span of 120 days.³⁵

CDT. Transferrin is a glycoprotein produced in the liver. The level of transferrin with sialic acid chains increases with alcohol consumption as well as in the carbohydrate deficient glycoprotein syndrome, leading to so-called carbohydrate deficient transferrin.³⁶ It is a sensitive marker for detecting alcohol relapse and monitoring sobriety. Moderate-to-heavy alcohol use, averaging ≥ 40 g of alcohol per day for 2 weeks,³⁶ can decrease the amount of carbohydrate attached to transferrin. Two weeks after complete alcohol cessation, CDT levels will return to normal.³⁷

Continue to: CDT is approved...

CDT is approved by the FDA as an assay for alcohol consumption.³⁷ While CDT is felt to be one of the better indirect markers of AUD and can extend the window of detection, there are still issues with its sensitivity and specificity.³⁸ This biomarker can be elevated with other liver diseases and can be affected by the patient’s age, body mass index, gender, and tobacco use.^39,40 Testing for CDT has never achieved widespread clinical use and has been largely supplanted by the more accurate PEth test (described in a bit).

Direct biomarkers offer insight into recent alcohol use

Other than ethanol itself, direct biomarkers of alcohol use are minor ethanol metabolites created through biochemical reactions when ethanol is coupled to endogenous compounds. Hence, the presence of these metabolites is usually directly related to ethanol consumption.⁴¹ Direct alcohol biomarkers are EtG, EtS, FAEEs, and PEth (TABLE 2^23-31). They reflect alcohol consumption over a period of several days, making them useful when paired with questionnaire data, especially for identifying young adults who engage in binge drinking.⁴²

Ethanol can be measured in blood, urine, and breath and is detectable a bit longer in urine than in blood. However, alcohol is detectable in the blood only for 6 to 12 hours after drinking. After alcohol consumption, concentrations peak in the blood within 2 hours. The window for detecting ethanol in the blood depends on the amount of alcohol consumed and the elimination rate of alcohol, which is about 12 mg/dL/h (or 0.012%)—approximately the same amount of alcohol contained in a standard drink (14 g).

EtG can be detected in urine for ≥ 24 hours after just 1 or 2 drinks, and for up to 4 days after heavy consumption.

Checking the blood alcohol level might be helpful in the office if a patient appears intoxicated but denies alcohol use. A blood alcohol level > 300 mg/dL, or > 150 mg/dL without gross evidence of intoxication, or > 100 mg/dL upon routine examination indicates AUD with a high degree of reliability.^33,43 But the short half-life of ethanol in blood limits its use as a biomarker,³³ and it is not a good indicator of chronic drinking.⁴⁴

EtG and EtS. Less than 0.1% of ethanol is secreted as the metabolites EtG and EtS, which are generated, respectively, by the enzymes uridine diphosphate glucuronosyltransferase and sulfotransferase.⁴⁵ They have value in the diagnosis of AUD because of the length of time in which they can be detected. Urinary EtG and EtS have been especially important biomarkers for monitoring relapse in outpatients treated for alcohol-­related problems.⁴⁶ Generally, EtG and EtS can be detected in urine for 13 to 20 hours after a single drink (0.1 g/kg), and for up to 4 to 5 days following ingestion of large amounts of alcohol.⁴⁷

Continue to: EtG has been detectable...

EtG has been detectable in urine for ≥ 24 hours following only 1 or 2 drinks, and for up to 4 days following heavy consumption.⁴⁸ Shortly after alcohol intake, even in small amounts, EtG is detectable. Analysis of EtG in urine is helpful in monitoring alcohol consumption during withdrawal treatment, for workplace testing, and to check for abstinence in legal matters. The EtG urine test is useful in detecting alcohol consumption in a person who claims to be abstinent but who drank 2 or 3 days before the evaluation. Although accurate, EtG’s window for detection is narrower than that of the PEth assay.

EtS is a good marker of acute short-term alcohol use, up to 12 hours in the blood (or longer in heavier drinkers) and up to 5 days in urine.⁴⁹ Its sensitivity is highest in heavy drinkers. Post-sampling formation and degradation of EtS have not been known to occur in urine samples. Testing for this second metabolite of ethanol can slightly improve the sensitivity and specificity of the EtG test. A urine test for EtS has a wider detection window. But it has little practical advantage compared with EtG.⁵⁰

For better clinical specificity, a combination of both EtG and EtS testing has been recommended. However, the EtS assay is more cumbersome and provides little advantage over EtG. EtG values do not correlate precisely with the amount or frequency of ethanol use, but the magnitude of the EtG finding roughly corresponds to the amount of alcohol recently consumed.

False-positive and false-negative results for EtG and EtS are uncommon in practice. However, false-positive results are possible with the EtG test in certain circumstances: presence of Escherichia coli in the specimen, use of ethanol-based hand sanitizers (> 20 times a day) or mouthwashes, and the consumption of substances like pralines, nonalcoholic beer, pharmaceutical products, and fruit juice. Similarly, false-negative results of EtG can occur from degradation if the samples are contaminated with other bacteria, transported without cooling, or stored improperly.⁵¹ In practice, this is uncommon, and the test is believed to be specific with few false-positive results. Commercially available EtG colorimetric test strips permit on-site analysis of urine samples.

FAEEs are a combination of different esters and products of alcohol metabolism through a nonoxidative pathway. They are formed by esterification of endogenous free fatty acids and ethanol in blood and several tissues.²⁹ These are sensitive and specific markers of alcohol ingestion and can differentiate chronic alcohol consumption from binge drinking.²⁹ It is elevated for up to 99 hours in heavy alcohol drinkers.³⁰ It can be detected in hair for a longer period than in blood.⁵² Detection of FAEEs in meconium can help establish fetal alcohol exposure.⁵³

Continue to: PEth

PEth. Use of the PEth assay has increased in recent years and its accuracy has had a transformative effect on the diagnosis of AUD.⁵⁴ PEth is a phospholipid found in erythrocyte membranes, formed by an interaction between ethanol and phosphatidylcholine, catalyzed by phospholipase D.^55,56 Major advantages of PEth include an unusually long half-life and specificity. Red cells lack enzymes to degrade PEth, therefore PEth accumulates in red cells and has a half-life of 4 to 10 days^57,58 allowing for detection of significant ethanol consumption extending back 3 to 4 weeks.⁵⁹ There is no evidence that PEth is formed in the absence of ethanol, making the test essentially 100% specific, particularly at higher cutoff values of ≥ 150 ng/mL.^31,60

PEth is known to be formed only in the presence of ethanol, making the test virtually 100% specific.

PEth levels are not affected by age, gender, or underlying liver or renal disease.⁶¹ PEth can differentiate between heavy alcohol use and social drinking and can therefore identify chronic excessive use.⁶² With chronic excessive alcohol consumption, PEth is detectable in blood up to 28 days after sobriety.⁶³ A correlation exists between PEth concentrations in blood and the amount of consumed ethanol. PEth has increased specificity and sensitivity for the detection of latent ethanol use compared with other direct biomarkers.²¹ It can identify recent heavy drinking earlier than indirect biomarkers, as it does not rely on hepatic injury.

Using a cutoff level of 20 ng/mL, PEth assays have a sensitivity of 73% for any alcohol use in the past month; at 80 ng/mL, the sensitivity is 91% for > 4 drinks/d.⁶¹ PEth is considered semi-quantitative. The World Health Organization defines acceptable social alcohol use at a PEth value < 40 ng/dL for men and < 20 ng/dL for women. Chronic excessive use is defined by a level > 60 ng/dL.⁵⁵ The cutoff levels tend to be arbitrary and vary with different guidelines.

PEth may be a useful marker in difficult-toassess settings, or in confirming or invalidating self-reported alcohol consumption.

Although false-positive PEth test results may be possible, most experts believe that dishonesty in self-reporting by test subjects is more likely. That said, the true specificity of PEth remains unknown; a lower value detected should not be regarded as absolute proof of relapse or chronic alcoholism.

Studies have shown a positive correlation between the AUDIT-C score and PEth values combined with self-reported alcohol consumption, indicating that PEth may be a useful marker in difficult-to-assess settings, or in confirming or invalidating self-reported alcohol consumption.^61,64,65 The PEth test is now widely available and, in the authors’ experience, usually costs $100 to $200. Analysis typically costs $40 to $100,⁶⁶ and costs could decrease as the test becomes more widely used. Turnaround time for PEth is 5 to 10 days. It is now the recommended assay by transplant hepatologists for detecting alcohol use.⁶⁷TABLE 3^22,68 explains the currently accepted ranges for various PEth results.

Continue to: CASE ANSWER

CASE ANSWER While every test mentioned can aid in detecting alcohol consumption, the PEth assay in this scenario would be the most clinically useful.

CORRESPONDENCE
Frederick Nunes, MD, Pennsylvania Hospital of University of Pennsylvania, 230 West Washington Square, 4th Floor, Philadelphia, PA 19104; [email protected]

CASE A 34-year-old woman presents with fatigue. She appears defensive when asked about her alcohol use. She answers No to all questions on the CAGE (cut down, annoyed, guilty, eye-opener) screening tool, but acknowledges drinking excessively on rare occasions. Her physician has a high suspicion for alcohol use disorder (AUD) and recommends further testing. The patient agrees but denies having used alcohol over the past several days. Which of the following is most likely to help support the suspicion of a heavy drinking pattern?

1. Routine lab tests (liver panel and complete blood count).
2. Blood or urine alcohol level.
3. Phosphatidylethanol (PEth) level in the blood.
4. Ethyl glucuronide (EtG) in the urine.
5. Carbohydrate-deficient transferrin (CDT) in the blood.

(See "Case answer.").

About 1 in 12 Americans have AUD,¹ and 1 in 10 children live in a home with a parent who has a drinking problem.² While the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) succinctly defines AUD with specific criteria,¹ the term generally refers to an inability to control or stop drinking despite adverse social or health consequences. AUD is regarded as > 4 drinks per day for men and > 3 drinks per day for women.³ A “standard drink” would be a 12-oz bottle of beer, a 5-oz glass of wine, or 1.5 oz of distilled spirits. Effects of chronic alcohol use are vast and include malnutrition, alcohol withdrawal syndrome, alcoholic liver disease, pancreatitis/pancreatic cancer, cardiomyopathy, and stroke.^4-6 Alcohol use by a pregnant woman can lead to fetal alcohol syndrome in her child.⁷

AUD may be more prevalent in the wake of COVID-19. Primary care practitioners tend to miss a large fraction of patients with AUD in their practice, especially younger patients and those without somatic comorbidities.⁸ Systematic screening for AUD can identify many of these people.⁸ Particularly as the COVID-19 pandemic continues to unfold and increases stress for everyone, risk of worsening drinking increases both in individuals with current AUD and for those in remission.⁹ Contrary to common belief, patients visiting primary care favor screening for at-risk drinking.¹⁰ Thus, awareness of the prevalence of AUD and patient acceptance of screening should encourage wider testing.

Screening tools. The 2014 guidelines published by the Centers for Disease Control and Prevention recommend using quick screening tools—ie, single question or ­AUDIT 1-3 (TABLE 1^11-18)—as an objective means of determining whether patients’ drinking creates a risk for themselves or others.¹¹ Excessive drinking identified using alcohol questionnaires can help reduce medical complications and health care costs.¹⁹ The questionnaires we review do not provide a diagnosis but help identify individuals who might benefit from more thorough assessment.²⁰ Following up, as needed, by testing for alcohol biomarkers can provide quantitative insight into problematic alcohol use.²

Primary care practitioners tend to miss a large fraction of patients with alcohol use disorder in their practice. Systematic screening for AUD can identify many of these patients.

But before we discuss the utility of biomarkers, it’s important to quickly review how alcohol is eliminated from the body.

Alcohol elimination

The stomach and small intestine are the primary sites for alcohol absorption. Alcohol elimination from the body occurs through 3 pathways. The first involves oxidative metabolism, which eliminates most ethanol (95%) through the actions of alcohol dehydrogenase, cytochrome P4502E1, or catalase. A lesser amount of alcohol (2%-5%) is eliminated, unchanged, via the second pathway, which includes urine, sweat, and breath. Nonoxidative metabolism makes up the third pathway. Nonoxidative metabolism removes a very small amount (0.1%) of alcohol and involves the direct ethanol biomarkers PEth, EtG, ethyl sulfate (EtS), and fatty acid ethyl esters (FAEEs).²¹ Our emphasis in this article is on assays of direct metabolites of alcohol—particularly PEth.

Continue to: To understand the utility...

To understand the utility of these direct biomarkers, it is helpful to look at the indirect biomarkers first.

Indirect biomarkers have limited sensitivity and specificity

When alcohol is consumed in large enough quantities over time, indirect biomarkers of alcohol can become abnormal.²² The major indirect biomarkers are the liver enzymes aspartate and alanine aminotransferase (AST and ALT), gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV) of red blood cells, and carbohydrate-deficient transferrin (CDT). Indirect biomarkers have limited sensitivity and specificity for AUD. (For specifics on sensitivity and specificity of indirect and direct biomarkers, see TABLE 2.^23-31)

Liver enzymes. AST and ALT are also present in the heart, muscle, and kidneys. Elevated levels usually imply injury to hepatocytes, with ALT being more reflective of liver involvement than AST. Both AST and ALT are elevated in other common liver conditions including hepatitis C virus infection and fatty liver disease. In alcoholic liver disease (ALD), AST is elevated more than ALT; an AST-to-ALT ratio > 3 suggests ALD. An elevated GGT often indicates hepatic injury and is used to confirm that elevated alkaline phosphatase is of hepatic origin.³²

MCV is the average volume of erythrocytes,³³ and an elevated MCV is a potential indicator of excessive alcohol intake. Macrocytosis requires sustained alcohol use, and the test has low sensitivity. Other diseases such as vitamin B12 or folic acid deficiency, hypothyroidism, hematologic diseases (eg, cold agglutinin disease, multiple myeloma, amyloidosis), and certain medications can also increase MCV.³⁴ Moreover, MCV responds slowly to alcohol use, abstinence, and relapse because red cells have a life span of 120 days.³⁵

CDT. Transferrin is a glycoprotein produced in the liver. The level of transferrin with sialic acid chains increases with alcohol consumption as well as in the carbohydrate deficient glycoprotein syndrome, leading to so-called carbohydrate deficient transferrin.³⁶ It is a sensitive marker for detecting alcohol relapse and monitoring sobriety. Moderate-to-heavy alcohol use, averaging ≥ 40 g of alcohol per day for 2 weeks,³⁶ can decrease the amount of carbohydrate attached to transferrin. Two weeks after complete alcohol cessation, CDT levels will return to normal.³⁷

Continue to: CDT is approved...

CDT is approved by the FDA as an assay for alcohol consumption.³⁷ While CDT is felt to be one of the better indirect markers of AUD and can extend the window of detection, there are still issues with its sensitivity and specificity.³⁸ This biomarker can be elevated with other liver diseases and can be affected by the patient’s age, body mass index, gender, and tobacco use.^39,40 Testing for CDT has never achieved widespread clinical use and has been largely supplanted by the more accurate PEth test (described in a bit).

Direct biomarkers offer insight into recent alcohol use

Other than ethanol itself, direct biomarkers of alcohol use are minor ethanol metabolites created through biochemical reactions when ethanol is coupled to endogenous compounds. Hence, the presence of these metabolites is usually directly related to ethanol consumption.⁴¹ Direct alcohol biomarkers are EtG, EtS, FAEEs, and PEth (TABLE 2^23-31). They reflect alcohol consumption over a period of several days, making them useful when paired with questionnaire data, especially for identifying young adults who engage in binge drinking.⁴²

Ethanol can be measured in blood, urine, and breath and is detectable a bit longer in urine than in blood. However, alcohol is detectable in the blood only for 6 to 12 hours after drinking. After alcohol consumption, concentrations peak in the blood within 2 hours. The window for detecting ethanol in the blood depends on the amount of alcohol consumed and the elimination rate of alcohol, which is about 12 mg/dL/h (or 0.012%)—approximately the same amount of alcohol contained in a standard drink (14 g).

EtG can be detected in urine for ≥ 24 hours after just 1 or 2 drinks, and for up to 4 days after heavy consumption.

Checking the blood alcohol level might be helpful in the office if a patient appears intoxicated but denies alcohol use. A blood alcohol level > 300 mg/dL, or > 150 mg/dL without gross evidence of intoxication, or > 100 mg/dL upon routine examination indicates AUD with a high degree of reliability.^33,43 But the short half-life of ethanol in blood limits its use as a biomarker,³³ and it is not a good indicator of chronic drinking.⁴⁴

EtG and EtS. Less than 0.1% of ethanol is secreted as the metabolites EtG and EtS, which are generated, respectively, by the enzymes uridine diphosphate glucuronosyltransferase and sulfotransferase.⁴⁵ They have value in the diagnosis of AUD because of the length of time in which they can be detected. Urinary EtG and EtS have been especially important biomarkers for monitoring relapse in outpatients treated for alcohol-­related problems.⁴⁶ Generally, EtG and EtS can be detected in urine for 13 to 20 hours after a single drink (0.1 g/kg), and for up to 4 to 5 days following ingestion of large amounts of alcohol.⁴⁷

Continue to: EtG has been detectable...

EtG has been detectable in urine for ≥ 24 hours following only 1 or 2 drinks, and for up to 4 days following heavy consumption.⁴⁸ Shortly after alcohol intake, even in small amounts, EtG is detectable. Analysis of EtG in urine is helpful in monitoring alcohol consumption during withdrawal treatment, for workplace testing, and to check for abstinence in legal matters. The EtG urine test is useful in detecting alcohol consumption in a person who claims to be abstinent but who drank 2 or 3 days before the evaluation. Although accurate, EtG’s window for detection is narrower than that of the PEth assay.

EtS is a good marker of acute short-term alcohol use, up to 12 hours in the blood (or longer in heavier drinkers) and up to 5 days in urine.⁴⁹ Its sensitivity is highest in heavy drinkers. Post-sampling formation and degradation of EtS have not been known to occur in urine samples. Testing for this second metabolite of ethanol can slightly improve the sensitivity and specificity of the EtG test. A urine test for EtS has a wider detection window. But it has little practical advantage compared with EtG.⁵⁰

For better clinical specificity, a combination of both EtG and EtS testing has been recommended. However, the EtS assay is more cumbersome and provides little advantage over EtG. EtG values do not correlate precisely with the amount or frequency of ethanol use, but the magnitude of the EtG finding roughly corresponds to the amount of alcohol recently consumed.

False-positive and false-negative results for EtG and EtS are uncommon in practice. However, false-positive results are possible with the EtG test in certain circumstances: presence of Escherichia coli in the specimen, use of ethanol-based hand sanitizers (> 20 times a day) or mouthwashes, and the consumption of substances like pralines, nonalcoholic beer, pharmaceutical products, and fruit juice. Similarly, false-negative results of EtG can occur from degradation if the samples are contaminated with other bacteria, transported without cooling, or stored improperly.⁵¹ In practice, this is uncommon, and the test is believed to be specific with few false-positive results. Commercially available EtG colorimetric test strips permit on-site analysis of urine samples.

FAEEs are a combination of different esters and products of alcohol metabolism through a nonoxidative pathway. They are formed by esterification of endogenous free fatty acids and ethanol in blood and several tissues.²⁹ These are sensitive and specific markers of alcohol ingestion and can differentiate chronic alcohol consumption from binge drinking.²⁹ It is elevated for up to 99 hours in heavy alcohol drinkers.³⁰ It can be detected in hair for a longer period than in blood.⁵² Detection of FAEEs in meconium can help establish fetal alcohol exposure.⁵³

Continue to: PEth

PEth. Use of the PEth assay has increased in recent years and its accuracy has had a transformative effect on the diagnosis of AUD.⁵⁴ PEth is a phospholipid found in erythrocyte membranes, formed by an interaction between ethanol and phosphatidylcholine, catalyzed by phospholipase D.^55,56 Major advantages of PEth include an unusually long half-life and specificity. Red cells lack enzymes to degrade PEth, therefore PEth accumulates in red cells and has a half-life of 4 to 10 days^57,58 allowing for detection of significant ethanol consumption extending back 3 to 4 weeks.⁵⁹ There is no evidence that PEth is formed in the absence of ethanol, making the test essentially 100% specific, particularly at higher cutoff values of ≥ 150 ng/mL.^31,60

PEth is known to be formed only in the presence of ethanol, making the test virtually 100% specific.

PEth levels are not affected by age, gender, or underlying liver or renal disease.⁶¹ PEth can differentiate between heavy alcohol use and social drinking and can therefore identify chronic excessive use.⁶² With chronic excessive alcohol consumption, PEth is detectable in blood up to 28 days after sobriety.⁶³ A correlation exists between PEth concentrations in blood and the amount of consumed ethanol. PEth has increased specificity and sensitivity for the detection of latent ethanol use compared with other direct biomarkers.²¹ It can identify recent heavy drinking earlier than indirect biomarkers, as it does not rely on hepatic injury.

Using a cutoff level of 20 ng/mL, PEth assays have a sensitivity of 73% for any alcohol use in the past month; at 80 ng/mL, the sensitivity is 91% for > 4 drinks/d.⁶¹ PEth is considered semi-quantitative. The World Health Organization defines acceptable social alcohol use at a PEth value < 40 ng/dL for men and < 20 ng/dL for women. Chronic excessive use is defined by a level > 60 ng/dL.⁵⁵ The cutoff levels tend to be arbitrary and vary with different guidelines.

PEth may be a useful marker in difficult-toassess settings, or in confirming or invalidating self-reported alcohol consumption.

Although false-positive PEth test results may be possible, most experts believe that dishonesty in self-reporting by test subjects is more likely. That said, the true specificity of PEth remains unknown; a lower value detected should not be regarded as absolute proof of relapse or chronic alcoholism.

Studies have shown a positive correlation between the AUDIT-C score and PEth values combined with self-reported alcohol consumption, indicating that PEth may be a useful marker in difficult-to-assess settings, or in confirming or invalidating self-reported alcohol consumption.^61,64,65 The PEth test is now widely available and, in the authors’ experience, usually costs $100 to $200. Analysis typically costs $40 to $100,⁶⁶ and costs could decrease as the test becomes more widely used. Turnaround time for PEth is 5 to 10 days. It is now the recommended assay by transplant hepatologists for detecting alcohol use.⁶⁷TABLE 3^22,68 explains the currently accepted ranges for various PEth results.

Continue to: CASE ANSWER

CASE ANSWER While every test mentioned can aid in detecting alcohol consumption, the PEth assay in this scenario would be the most clinically useful.

CORRESPONDENCE
Frederick Nunes, MD, Pennsylvania Hospital of University of Pennsylvania, 230 West Washington Square, 4th Floor, Philadelphia, PA 19104; [email protected]